Clinical Approach to Infection in the Compromised Host

Clinical Approach to Infection in the Compromised Host Fourth Edition

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Clinical Approach to Infection in the Compromised Host Fourth Edition Edited by

ROBERT H. RUBIN, M.D. Associate Director, Division of Infectious Disease Brigham & Women’s Hospital Boston, Massachusetts and Director of the Center for Experimental Pharmacology and Therapeutics Harvard University–Massachusetts Institute of Technology Division of Health Sciences and Technology Cambridge, Massachusetts

and

LOWELL S. YOUNG, M.D. Director of Kuzell Institute for Arthritis and Infectious Diseases Chief of the Division on Infectious Diseases Pacific California Medical Center San Francisco, California

With a Foreword by

RALPH VAN FURTH, M.D.

KLUWER ACADEMIC PUBLISHERS NEW YORK, BOSTON, DORDRECHT, LONDON, MOSCOW

eBook ISBN: Print ISBN:

0-306-47527-8 0-306-46693-7

©2002 Kluwer Academic Publishers New York, Boston, Dordrecht, London, Moscow Print ©2002 Kluwer Academic/Plenum Publishers New York All rights reserved No part of this eBook may be reproduced or transmitted in any form or by any means, electronic, mechanical, recording, or otherwise, without written consent from the Publisher Created in the United States of America Visit Kluwer Online at: and Kluwer's eBookstore at:

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Contributors Sarah W. Alexander Division of Hematology and Oncology, Rainbow Babies and Children’s Hospital, University Hospital of Cleveland, Cleveland, Ohio 44106 Constance A. Benson Division of Infectious Diseases, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262 Michael Boeckh Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, and Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98109 John C. Christenson Department of Pediatrics, Division of Infectious Diseases and Geographic Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84132 A. Benedict Cosimi Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114 Jules L. Dienstag Gastrointestinal Unit, Medical Services, Massachusetts General Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114

Harry R. Hill Departments of Pediatrics, Internal Medicine, and Pathology, Division of Clinical Immunology and Allergy, University of Utah School of Medicine, Salt Lake City, Utah 84132 Richard Allen Johnson Harvard Medical School, Infectious Disease Unit, Massachusetts General Hospital, and Department of Dermatology, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02114 Bart Jan Kullberg Department of Medicine, Nijmegen University Medical Center St. Radboud, 6500 HB Nijmegen, Netherlands Kieren A. Marr Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, and Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98109 Brigitta U. Mueller Deparment of Medicine, Children’s Hospital, Boston, Massachusetts, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115

Jay Alan Fishman Infectious Disease Division and Transplantation Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

Philip A. Pizzo Deparment of Medicine, Children’s Hospital, Boston, Massachusetts, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115

Mitchell Goldman Indiana University School of Medicine Division of Infectious Diseases, Indianapolis, Indiana 46202

Peter M. Rosenberg St. John’s Health Center, Santa Monica, California 90404

Reginald Greene Chest Division, Radiology Service, Massachusetts General Hospital, and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114 Paul D. Griffiths Department of Virology, Royal Free and University College School of Medicine, London, NW3 2PF, United Kingdom

Robert H. Rubin Division of Infectious Disease, Brigham and Women’s Hospital; Center for Experimental Pharmacology and Therapeutics, Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology; and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114 George A. Sarosi Roudebush VA Medical Center, Indianapolis, Indiana 46202 V

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CONTRIBUTORS

W. Michael Scheld Departments of Internal Medicine (Infectious Diseases) and Neurosurgery, University of Virginia School of Medicine, Charlottesville, Virginia, 22908 Robert T. Schooley Division of Infectious Diseases, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262 Arthur Sober Harvard Medical School, Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts 02115 Allan R. Tunkel Department of Internal Medicine, MCP Hahnemann University, Philadelphia, Pennsylvania 19129

Jos W. M. van der Meer Department of Medicine, Nijmegen University Medical Center, St. Radboud, 6500 HB Nijmegen, Netherlands Ralph van Furth University of Leiden Medical School, 2341 NL Oegstgees, Netherlands L. Joseph Wheat Department of Medicine, Indiana University School of Medicine, and Department of Veterans Affairs Hospital, Indianapolis, Indiana 46202 Lowell S. Young Kuzell Institute for Arthritis and Infectious Diseases, Division of Infectious Diseases, California Pacific Medical Center, University of California at San Francisco, San Francisco, California 94115

Foreword At the beginning of the new millennium, it is opportune to review what has been accomplished in the field of infectious diseases during the last decades of the previous century. The paradigm of the immunocompromised host has taught much about the pathophysiology of infectious diseases, particularly with regard to immunological aspects of host defense. In the beginning, Robert Good called immunodeficiency syndromes “experiments of nature.” In the 1960s and subsequent decades, the clinical and immunological aspects of immune deficiencies were studied and adequate treatment attempted. A reflection of these developments were the three successful meetings on these topics in Veldhoven, The Netherlands (1980), Stirling, Scotland (1982) and Toronto, Canada (1984) and the foundation of the International Immunocompromised Host Society in 1985. Since then, the IIHS has organized meetings every two years. The main concern of clinicians is to understand the ways in which the courses of infectious processes differ in individuals with impaired host defense from that of healthy individuals. Scientists attracted to this field want to unravel the pathophysiology of immune deficiencies. These aspects of this field—particularly the clinical pictures of inborn and acquired immune deficiency, the therapeutic interventions, and the modes of prevention of infections in immunocompromised patients—are all covered in the fourth edition of Clinical Approach to Infection in the Compromised Host. This volume includes the knowledge accumulated during the last 50 years and it is timely that this new edition appeared. An infection can be defined as a defense reaction of the host upon the invasion and multiplication of microorganisms. A compromised host can have damaged integument, i.e., skin or mucosa, allowing easy penetration of bacteria, or a defective humoral and/or cellular immune function, as a result of which microorganisms cannot be eliminated optimally. During the last decade, research on immune deficiency was directed mainly toward the un-

raveling of the molecular pathways of impaired host defense mechanisms and the characterization of the genetic mutations involved, with the prospect of novel strategies for therapeutic interventions and possible corrective gene therapy. In this foreword, I will take a helicopter view of the various aspects of host defense mechanisms with special emphasis on genetic factors, because of their relevance for the course and outcome of infections. During life, there exist phases of age-related compromised immune functions. After birth there is a physiological immune deficiency because the production of antibodies commences slowly upon contact of the neonate with microorganisms and upon vaccination. The production of IgM commences at the fifth month of gestation and reaches mature levels between the second and fourth years of life. The production of IgG antibodies starts immediately after birth and is at a mature level between the ages of 6 and 10 years. The production of serum IgA and secretory IgA commences during the first trimester of life, and reaches mature levels at 12–16 years and 2–4 years of age. Thus, during the first years of life the humoral immune system is deficient, which might help explain the frequent occurrence of respiratory and gastrointestinal infections in children under 12 years of age. At the other end of life, in the elderly, the immune functions wane gradually. In individuals older than 65 years antibody production—for example, after influenza or pneumococcal vaccination—is less than in younger adults. Attenuation of neutrophil functions and T lymphocyte-mediated immune responses also occurs with age. This decrease of host defense mechanisms explains in part why the elderly suffer a higher morbidity and mortality from infections. Another explanation for the frequent occurrence of (viral) respiratory and other infections in the elderly is their contact with children who suffer from such infections, which they have acquired in day care centers, kindergarten, or primary school. Most microorganisms enter the body via mucosal vii

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membranes, which implies a sequence of events from adherence of microorganisms to epithelial cells, their penetration of epithelial cells or passage between these cells, multiplication of microorganisms within host cells or connective tissues, and their subsequent dissemination via lymphatics or blood vessels to other sites of the body. The knowledge of the structures at the surface of microorganisms by which they adhere to binding sites of epithelial host cells, such as protein or carbohydrate structures, is rather limited. It is of interest that several classes of host-cell receptors, which are involved in immunological processes, also serve as receptors for some viruses; for example, ICAM-1 for rhinoviruses, epidermal growth factor receptor for reovirus and vaccinia virus, CD46 (membrane cofactor receptor) for measles virus, CD2 receptor for Epstein–Barr virus, VLA2 receptor for echovirus, and integrin receptors for adenovirus, epidermal growth factor receptor for vaccinia, IgG superfamily receptor for poliovirus, CD4, and the chemokine receptors CXCR4 and CCR5 for the human immunodeficiency virus (HIV). Since the expression of these receptors can be modulated by, for example, cytokines and chemokines such changes can also affect the host cell– virus interaction. Virus–receptor interactions will lead to signal transduction within the host cells and subsequent biochemical and functional changes. It is often not well appreciated that viruses can alter the immune responses by infecting immunocompetent cells, such as lymphocytes, NK cells, monocytes/macrophages, and dendritic cells. The most ardent immunosuppressive virus is HIV, but other viruses like HTLV I, measles, rubella, cytomegalovirus, Epstein–Barr virus, rubella, and hepatitis B can cause immunosuppression as well. Viruses can also evade the immune system by suppressing the expression of MHC class I and II molecules or cell-adhesion molecules, or form defense molecules that interfere with cytokine or chemokine functions. Whether there is a relation between the genetic makeup of the infected patient and the occurrence of immunosuppression by the virus is not yet known. Individuals suffering from primary immune deficiency disorders, which are due to mutations in genes involved in the formation of components involved in the immune response, have an impaired host defense against infections. At the present time a large number of mutations involved in primary immune deficiency have been identified. In the case of agammaglobulinemia, the absence of antibodies will preclude bactericidal serum activity and the elimination of microorganisms by phagocytes. Subtler

are the subclass deficiencies with the consequent increased susceptibility for infections with encapsulated bacteria and defective response to polysaccharide antigens upon vaccination, which occur among Caucasians, particularly in several ethnic groups. IgA deficiency is the most common form of subclass deficiency in Caucasians and is less frequent in other ethnic groups. Although individuals with IgA deficiency are at risk for mucosal infections, they are usually healthy, probably because of a compensatory increased synthesis of IgM, including secretory IgM. How can we respond adequately to prevent infections in individuals with inborn errors of antibody formation? Substitution therapy with gammaglobulin is probably the best option for patients with severe hypo- and agammaglobulinemia, as well as for those with serious infection in the setting of IgG subclass deficiency. In some cases bone-marrow transplantation might be indicated, but this is infrequently applied. Immune globulins specific for varicella–zoster or cytomegalovirus can be given as prophylaxis or treatment in immunocompromised patients. Parenteral vaccination of individuals with defective antibody formation will often not lead to an adequate antibody response. However, in the case of IgG deficiency, stimulation of the synthesis of secretory antibodies is of utmost importance since they can prevent invasion of microorganisms. Therefore, the development of new vaccines—for example, DNA vaccines—and of new formulations which can be used for mucosal immunization is warranted. Vaccine delivery by transgenic plants or fruits is an attractive option. Individuals genetically deficient in components of the classic or alternative complement pathways are particularly susceptible to infections with Neisseria species. When such infection cannot be controlled with antimicrobial therapy, plasma transfusion can be considered. Phagocytes are the most important cells for the elimination of microorganisms from the body. These cells, formed in the bone marrow, are transported via the circulation to areas of infection, where they adhere to endothelial cells. Transendothelial migration occurs in the postcapillary venules by squeezing between endothelial cells. Local accumulation of phagocytes is determined by adhesion molecules on the luminal surface of endothelial cells (ICAM-1, ICAM-2, or VCAM-1) which serve as receptors for complementary adhesion molecules (the integrins LFA-1, CR3, p150,95, and the integrin VLA-4) on circulating cells. During infection upregulation of expression and activation of adhesion molecules on endothelial cells and leukocytes occurs by stimulation with

FOREWORD

cytokines and other inflammatory mediators and by intact bacteria or their products, such as endotoxin, thus enhancing the adhesion of leukocytes to endothelial cells and their subsequent migration. In children with leukocyte adhesion deficiency (LAD I)—a congenital defect of integrins—neutrophils do not adhere to endothelial cells, and as a consequence are unable to migrate to tissues with a resulting lack of pus formation at sites of infection. A similar gene mutation encoding for integrins occurs in Holstein cattle and dogs. Phagocytosis of microorganisms is facilitated by opsonins, i.e., immunoglobulins and components of the complement system, that are recognized by respective immunoglobulin receptors and and also and complement receptors (CR1, CR3, and CR4). Recently, allotypic polymorphism of receptors, which affect the affinity for IgG2, has been discovered. Consequently, IgG2-opsonized bacteria and IgG2-immune complexes, which can determine the course and outcome of infections, are less efficiently phagocytosed by individuals who are homozygous for the lowaffinity receptors. On the other hand, during infection cytokines can up- or downregulate the expression and function of Fc and complement receptors of neutrophils and monocytes/macrophages, which will also affect the elimination of opsonized microorganisms. Cytokines and chemokines are humoral mediators that act in a network and determine the outcome of infections as favorable, chronic, or fatal. These factors stimulate or inhibit the recruitment, movement, and function of cells involved in inflammation, thus being essential in the containment or removal of microorganisms. In contrast to extracellular bacteria that are eliminated mainly by neutrophils, intracellular bacteria (e.g., mycobacteria, Listeria, salmonellae, and brucellae) are eliminated optimally only by cytokine-activated macrophages, a condition called cell-mediated immunity. Recently, a number of individual patients and families suffering from recurrent or chronic infections with mycobacteria and/or salmonellae were described, who did not recover despite adequate antimicrobial therapy. In these patients, mutations in genes coding for interleukin-12 (IL-12) receptors or interferon gamma receptors have been identified. These receptors are functionally defective and the production of and IL-12 is usually reduced in these patients. Patients with inherited IL-12 deficiency are described as well, but inherited deficiencies of other cytokines are not reported as yet. Possibly, such deficiencies are not compatible with normal embryonic development.

ix

The chronic course or fatal outcome of infections in all these kinds of patients can be explained by their inability to develop adequate cell-mediated immunity. The total absence of neutrophils is in essence not compatible with life, but cyclic granulocytopenia is a condition accompanied with recurrent infections. There is a multitude of congenital disorders of neutrophils and other leukocytes that are caused by mutation in genes coding for enzymes involved in the functions of these cells. Patients with such disorders, which are relatively rare, suffer frequently from severe infections. Possibilities for preventive measures are limited, with the exception of treatment of chronic granulomatous disease patients; other options are bone marrow transplantation and, in the future, gene therapy. To my knowledge, individuals without monocytes/ macrophages do not exist. It is probable that these cells play a pivotal role in embryonic development, and in the absence of these cells no viable fetus will develop. During the last decade, we have learned more about genetic factors that determine the predisposition for certain infections. It has been known for some time that individuals heterozygous for sickle cell anemia are less susceptible to malaria. Recently, it has been reported that homozygous mutation of the cystic fibrosis gene increases the susceptibility for typhoid fever. Polymorphism of HLA class II immune response genes determines differences in immune responsiveness between individuals. For example, the susceptibility and/or course of mycobacterial infections, such as leprosy and tuberculosis, typhoid fever and other salmonellosis, paralytic poliomyelitis, and dengue fever, are linked with HLA class II alleles. More recently a correlation between the susceptibility or outcome of meningococcal disease and genes for mannose-binding, lectin, and factors influencing the production of TNF or IL-10 has been reported. Pharmacogenomics is a new discipline that is also relevant for the treatment of the immunocompromised host. It concerns the interindividual variability in drug response based on the genetic polymorphism of multiple genes involved in metabolic and physiologic pathways. For example, the genetic polymorphism of the cytochrome P-450 system determines the pharmacodynamics of some antimicrobial drugs. The poor or extensive enzyme activity of cytochrome P-450 affects the acetylation of isoniazid and, thus, the therapeutic levels of this drug; antimicrobials like rifampicin, erythromycin, antimycotic drugs, and antiretroviral protease inhibitors increase or decrease cytochrome P-450 isoenzymes which results in a decrease or increase of their pharmacodynamic effects. In

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the future, the detection of genetic polymorphism of individuals may have great potential for the development of new drugs and avoidance of drug toxicity. In this foreword, I had the intention of triggering the attention of clinicians for some immunological and genetic aspects which have an impact on the clinical ap-

proach to infections in the immunocompromised host. I trust this will be an adjunct during the reading of this excellent volume. Ralph van Furth Oegstgeest, The Netherlands

Preface As we open the freshly minted pages of the fourth edition of Clinical Approach to Infection in the Compromised Host, we look back in amazement at the more than two decades that have passed since this project was initiated. Who would have thought? It all began in the spring of 1977, at the annual Epidemic Intelligence Service (EIS) Conference of the Centers for Disease Control when two friends from medical school days (both ex-EISers), one now in California and one still in Boston, met and began to discuss their current clinical and research interests. By happy coincidence, we had both become enthralled in a very specialized aspect of infectious disease—the infectious disease problems of the immunocompromised host. Even the term “compromised host” was a relatively novel one. We belonged to a small community of clinical investigators who were part infectious disease clinicians, part microbiologists, part hematologists, oncologists, and organ transplanters, as well as clinical immunologists and white cell biologists. As a community we were convinced that these compromised hosts provided an ideal opportunity for deciphering the nuances of host–pathogen interaction. In addition, even in the 1970s, it was already clear that for a number of diseases previously untreatable, disease modifying therapy was on the immediate horizon provided we could learn to prevent and treat the invasive infections made possible by this diseasemodifying therapy. In the more than two decades that have passed, the number of immunocompromised patients has increased exponentially due to two factors, one predictable and positive while the other was unexpected and has had catastrophic consequences. The first of these has been the remarkable transformation that has occurred in the prognosis of patients who formerly succumbed rapidly to their malignancy, their end-stage renal, cardiac, hepatic, and pulmonary disease, and to such autoimmune processes as vasculitis, inflammatory bowel disease, and other conditions. Today, these individuals have reasonable hopes of

years, if not decades, of productive life because of advances in the use of cancer chemotherapeutic agents and immunosuppressive therapy, in immunology and transplantation, and in the linkage of effective antimicrobial therapy to prevent and treat the infectious complications of the disease-modifying therapy. For example, the prophylactic use of trimethoprim–sulfamethoxazole in a variety of immunocompromised patients has essentially eradicated Pneumocystis carinii pneumonia, nocardiosis, listeriosis, and, perhaps, toxoplasmosis from many compromised patient populations; and the preemptive use of intravenous, followed by oral, ganciclovir has decreased the incidence of symptomatic cytomegalovirus disease in the transplant patient receiving antilymphocyte antibody therapy from ~65% to near zero. Thus, the appropriate deployment of antimicrobial programs can make safe immunosuppressing therapies that can control the underlying disease. Our task is to delineate other prophylactic and preemptive strategies to prevent the infections that are still occurring in these patients. The second factor, the unexpected and catastrophic, is obviously the advent of the epidemic of human immunodeficiency virus (HIV) infection that results in the acquired immunodeficiency syndrome (AIDS). From a cluster of cases of opportunistic infection in gay males, this has been transformed into an epidemic of worldwide proportions, threatening the existence of whole societies in Africa and Asia, and causing great morbidity and mortality throughout the world. Today, although the greatest burden of this disease is borne by the poor, all segments of society are at risk. Despite the catastrophe, remarkable progress has been made in dealing with this plague in the past two decades. This program has included: the identification of the causative virus, the dynamics of its replication, and the modulation of this by cytokines and chemokines elaborated by the host in response to other processes; a whole array of diagnostic tests, the most important being reliable anti-HIV antibody testing and viral load measurexi

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ments by molecular diagnostic techniques (these not only allow early diagnosis but guide therapy, as well as provide protection of the blood and allograft supply); a clear understanding of the epidemiology of the AIDS epidemic and what public health measures can help alleviate the spread of HIV; an increased understanding of virus–host interactions; the definition of the clinical manifestations of AIDS and the correlation of these with viral load and CD4 lymphocyte measurements; and last, but far from least, the development of an armamentarium of anti-HIV drugs and the knowledge of how to use them. The advent of highly active antiretroviral therapy (HAART) has transformed AIDS from a progressive illness with an early death sentence into a manageable chronic disease, with issues now being quality of life and therapeutic side effects rather than the immediacy of death itself. The biggest problem now is the cost of these drugs and how to get them to the impoverished, particularly in the developing areas of the world. The net result of these two factors—successful immunosuppressing therapy and HAART therapy for AIDS— has meant that many of these patients are being returned to relatively normal lives in the general community. No longer are their infectious disease problems the sole province of ivory tower academicians who communicated chiefly with each other. It is fair to say that the infectious disease problems of the immunocompromised host are now the concern of all practitioners of medicine, of as much concern to the primary care physician as to the tertiary care specialist. Gratifyingly, there has been an accompanying explosion of information on the science and practice of caring for the infectious disease problems of these patients. Despite the medical conferences, new journals, newsletters, cassettes, videotapes, and other

multimedia attempts to convey the necessary information to the expanding group of physicians who need such knowledge, we continue to believe that there is a compelling need for the clinician to have access in the dead of night or the heat of day to well-written, sage advice from veterans of battles similar to those they are now undertaking. We have previously stated that the best way to learn is to sit at the feet of a master—such as Mark Hopkins and the Log—for several years. It is our hope that we have been able to bring together a group of Mark Hopkinses, all veterans of these battles and distinguished contributors to the field, with this book serving as a Log for all those with a need to know. All credit for achieving these objectives is owed to our contributors. We accept responsibility for any inadequacies. As we peruse this edition, we are also reminded that, as in any dynamic field of medicine and science, we stand on the shoulders of those who have gone before. These include our teachers, our patients, and our colleagues. Unfortunately, much of what we have learned has come from the study of patients who, despite the best efforts that could be made at the time, have succumbed to their infections. Memories of them and their courage in the face of extreme adversity continue to inspire us, and this book is in part dedicated to them and honors them. It is also dedicated to the memory of two of our teachers: Dr. Louis Weinstein and Dr. Alex Langmuir, who taught us the joys, challenges, science, and art that illuminate the practice of infectious disease care, epidemiology, and research. Giants surely did once walk the Earth ... Robert H. Rubin Lowell S. Young Boston and San Francisco

Preface to the First Edition The science and practice of infectious disease cut across all medical disciplines, from medicine to surgery, and from cardiology to neurology. Because of the diverse nature of infection and the clinical settings in which it occurs, the acquisition of the skills needed to become expert in clinical infectious diseases has usually required a lengthy apprenticeship. As one of us has noted, “The practice of infectious disease is akin to many primitive arts, being handed down by oral traditions from generation to generation. The best way to learn is to sit at the feet of a master for several years, asking, observing, and studying—the medical equivalent of Mark Hopkins and the Log.” However, increasingly it has become apparent that a more efficient means of communicating the art and science of clinical infectious disease to the general medical community is necessary. The infections themselves, the potential therapeutic modalities, the clinical settings in which they occur, and the occurrence of such infections far away from the academic medical center—all these have put a new emphasis on disseminating the most upto-date information available to diagnose and treat clinical infection. This is particularly true when one considers the gamut of infections that afflict the patient with a defect in host defense. Those of us with a particular interest in this area of medicine and infectious diseases are painfully aware of the special nature of these patients and their problems and the rather extended apprenticeship we have served in learning to deal with these problems. We have been impressed that although great strides have been taken in general infectious disease in moving beyond the Log and the oral tradition, in this area of infectious disease such efforts are just beginning. Thus, the idea for this book was conceived to attempt to meld the scientific advances in this area with the experience we had in dealing with such patients to construct a useful, practical

guide to the problem of infection in the compromised host. We wanted to share the fruits of our apprenticeship with the rest of the medical community who increasingly are being called on to deal with these clinical problems. The next step was to find out whether a publisher would be interested. Ms. Hilary Evans of Plenum was quickly recruited to the effort. She has been a bulwark of strength and encouragement during the lengthy gestation period. Finally, there comes the recruitment of the other contributors. Perhaps the most pleasant surprise in this whole experience was the enthusiasm with which our contributors brought their expertise to the endeavor—all of us agreeing that a need existed for a practical guide to patient management in the immunosuppressed host that was based on firm scientific data whenever this was available and on the art and judgment of medicine when such data was unavailable. With admiration and gratitude we thank our contributors, who have taught us so much in the preparation of this book. Finally, it is fitting that we express our gratitude to three different groups of individuals who have made this book possible—our teachers, Mort Swartz, Louis Weinstein, Alex Langmuir, Don Armstrong, and Don Louria, who have served as our models in their ability to blend the sciences of microbiology, immunology, and epidemiology with the art of clinical medicine; our families, who have supported us in this effort and whose time has been stolen to prepare this work; and perhaps most of all, our patients, the immunocompromised patients with lifethreatening infections who continue to teach us and inspire us with their courage and faith as we painfully learn how best to deal with infection in the compromised host. Robert H. Rubin Lowell S. Young Boston and Los Angeles

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Contents 1 Introduction

1

ROBERT H. RUBIN and LOWELL S. YOUNG

2 Defects in Host Defense Mechanisms

5

JOS W. M. VAN DER MEER and BART JAN KULLBERG 1. Colonization 2. First Line of Defense 2.1. Skin 2.2. Mucosa 3. Second Line of Defense 3.1. Humoral Defense Mechanisms 3.2. Cellular Defense Mechanisms 4. Factors that Influence the Quality of Host Defense 4.1. Genetic Control of Host Defense against Infection 4.2. Nutritional Status 4.3. Age and Host Defense 4.4. Body Temperature and Host Defense 4.5. Stress and Host Defense 5. Diseases that Affect Host Defense 5.1. Leukemia and Lymphoma 5.2. Splenectomy 5.3. Sickle Cell Anemia 5.4. Diabetes Mellitus 5.5. Chronic Renal Failure 5.6. Alcoholism and Hepatic Cirrhosis 5.7. Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Felty’s Syndrome 5.8. Infections 6. Immunosuppressive Drugs 6.1. Glucocorticosteroids 6.2. Other Immunosuppressive Agents 6.3. Blood Products 7. Plasmapheresis 8. Radiation 9. Attempts to Strengthen Host Defense References

5 5 5 5 6 6 13 20 20 20 21 22 22 22 22 23 23 24 24 25 25 26 27 27 28 29 29 29 30 32

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3 Mucocutaneous Infections in the Immunocompromised Host

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RICHARD ALLEN JOHNSON and ARTHUR SOBER 1. Introduction 2. Skin as a Barrier to Infection 3. Types of Skin Infection 3.1. Primary Skin Infections with Common Pathogens 3.2. Unusually Widespread Cutaneous Infection 3.3. Opportunistic Primary Cutaneous Infection 3.4. Systemic Infection Metastatic to Cutaneous and Subcutaneous Sites 4. Diagnostic Aspects of Skin Infections in the Compromised Patient 5. Opportunistic Infections by Pathogen 5.1. Bacterial Infections 5.2. Fungal Infections 5.3. Viral Infections 5.4. Sexually Transmitted Diseases 5.5. Parasitic Infestations 5.6. Arthropod Infestations 6. Diagnostic Aspects of Skin Infections in the Compromised Patient 7. Inflammatory Disorders that Simulate Infection in the Compromised Host 7.1. HIV-Associated Eosinophilic Folliculitis 7.2. Neutrophilic Dermatoses 8. Conclusion Bibliography References

4 Clinical Approach to the Compromised Host with Fever and Pulmonary Infiltrates

49 49 50 51 51 54 55 55 55 55 65 75 95 97 99 99 100 100 100 100 101 101

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ROBERT H. RUBIN and REGINALD GREENE 1. The Febrile Pneumonitis Syndrome and Its Importance 2. Overview of the Infectious Causes of the Febrile Pneumonitis Syndrome in the Immunocompromised Host 2.1. Factors that Determine the Risk of Pulmonary Infection 2.2. Pathology of Pulmonary Infections in the Immunocompromised Host 2.3. Clinical Clues to the Diagnosis of Pulmonary Infection 3. Overview of Noninfectious Causes of the Febrile Pneumonitis Syndrome 3.1. Radiation Pneumonitis 3.2. Drug-Induced Pneumonitis 3.3. Neoplastic Pulmonary Invasion 3.4. Other Noninfectious Causes of the Febrile Pneumonitis Syndrome 4. Radiologic Clues to the Diagnosis of the Febrile Pneumonitis Syndrome 4.1. Correlation of Radiologic Findings, Rate of Progression, and Clinical Signs 4.2. Radiologic Aspects of Thoracic Disease in AIDS Patients 5. Specific Diagnosis 5.1. Immunologic Techniques for Specific Diagnosis 5.2. Sputum Examination 5.3. Invasive Diagnostic Techniques 6. Superinfection References

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5 Central Nervous System Infection in the Immunocompromised Host

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ALLAN R. TUNKEL and W. MICHAEL SCHELD 1. Introduction 2. Viral Infections 2.1. Human Immunodeficiency Virus Type 1 2.2. Herpesviruses 2.3. Progressive Multifocal Leukoencephalopathy 3. Bacterial Infections 3.1. Meningitis 3.2. Brain Abscess 3.3. Tuberculosis 4. Fungal Infections 4.1. Meningitis 4.2. Brain Abscess 5. Protozoal Infections 5.1. Toxoplasmosis 5.2. Strongyloidiasis References

6 Fungal Infections in the Immunocompromised Host

163 163 163 166 170 172 172 180 183 188 188 193 196 196 200 201

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L. JOSEPH WHEAT, MITCHELL GOLDMAN, and GEORGE A. SAROSI 1. Introduction 1.1. Fungal Infections in Granulocytopenia 1.2. Fungal Infections in Organ Transplantation 1.3. Fungal Infections in Acquired Immunodeficiency Syndrome 2. Antifungal Prophylaxis in the Immunocompromised Host 2.1. Prophylaxis in Hematology 2.2. Antifungal Prophylaxis in Liver Transplant Recipients 2.3. Antifungal Prophylaxis in Lung Transplant Recipients 2.4. Ongoing Investigations in Antifungal Prophylaxis 2.5. Recommendations for Prophylaxis 3. Empiric Antifungal Therapy in Neutropenic Patients with Persistent Fever 3.1. Amphotericin B Deoxycholate 3.2. Lipid Preparation of Amphotericin B as Empiric Antifungal Therapy 3.3. Triazole Agents as Empiric Antifungal Therapy 3.4. Ongoing Investigations in Empiric Therapy 3.5. Recommendations for Empiric Therapy 4. Candidiasis 4.1. Epidemiology 4.2. Clinical Findings 4.3. Diagnosis 4.4. Treatment 5. Aspergillosis 5.1. Epidemiology 5.2. Pathogenesis 5.3. Clinical Manifestations 5.4. Diagnosis

215 215 216 216 216 216 218 218 219 219 219 220 220 220 221 221 221 221 222 222 222 224 224 225 225 225

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6.

7.

8.

9.

10.

11.

12. 13.

5.5. Treatment 5.6. Prevention Zygomycosis 6.1. Epidemiology 6.2. Clinical Manifestations 6.3. Diagnosis 6.4. Treatment Fusariosis 7.1. Epidemiology and Pathogenesis 7.2. Clinical Manifestations 7.3. Diagnosis 7.4. Treatment Cryptococcosis 8.1. Epidemiology and Pathogenesis 8.2. Clinical Manifestations 8.3. Diagnosis 8.4. Treatment Histoplasmosis 9.1. Epidemiology and Pathogenesis 9.2. Clinical Findings 9.3. Diagnosis 9.4. Treatment Coccidioidomycosis 10.1. Epidemiology and Pathogenesis 10.2. Clinical Manifestations 10.3. Diagnosis 10.4. Treatment Blastomycosis 11.1. Epidemiology 11.2. Clinical Manifestations 11.3. Diagnosis 11.4. Treatment Unusual Fungal Pathogens Antifungal Agents 13.1. Amphotericin B 13.2. Lipid Formulations of Amphotericin B 13.3. 5-Flucytosine 13.4. Fluconazole 13.5. Itraconazole 13.6. Voriconazole 13.7. Posaconazole (SCH 56592) 13.8. Echinocandins 13.9. Nikkomycin Z References

7 Mycobacterial and Nocardial Diseases in the Compromised Host

226 227 227 227 227 227 228 228 228 228 228 228 228 228 228 229 229 231 231 231 231 231 232 232 232 233 233 234 234 234 234 235 235 236 236 236 237 237 238 238 238 239 239 239

249

LOWELL S. YOUNG and ROBERT H. RUBIN 1. Introduction 2. Microbiologic Classification and Clinical Syndromes 3. Pathogenesis and Epidemiology 3.1. Association of Tuberculosis with HIV Disease

249 250 250 252

CONTENTS

3.2. Revised Guidelines for Tuberculin Reactivity and Preventative Chemotherapy 4. Treatment of Tuberculosis, Drug-Resistant Tuberculosis, and Alternative Antituberculosis Chemotherapy 4.1. Chemotherapy of MAC Disease 4.2. Role of in Vitro Susceptibility Testing 5. Nocardiosis 5.1. Microbiology and Epidemiology 5.2. Pathogenesis and Pathology 5.3. Clinical Manifestations 5.4. Diagnosis 5.5. Clinical Management References

8 Pneumocystis carinii and Parasitic Infections in the Immunocompromised Host

253 254 254 256 257 257 258 258 260 260 261

265

JAY ALAN FISHMAN 1. Introduction 1.1. Parasite-Specific Factors: Development and Distribution 1.2. Host–Parasite Interactions and Mechanisms of Immune Evasion 1.3. Missing Infections in Compromised Hosts 2. Pneumocystis carinii 2.1. The Organism: Taxonomy and Life Cycle 2.2. Epidemiology 2.3. Changing Patterns of Pneumocystis 2.4. Clinical Manifestations of Pneumocystis Infection 2.5. Radiology of Pneumocystis carinii Pneumonia 2.6. Laboratory Evaluation 2.7. Histopathologic Diagnosis 2.8. Therapy of Pneumocystis carinii Infections 2.9. Prevention of Pneumocystis carinii Pneumonia in the Susceptible Host 3. Toxoplasma gondii 3.1. The Organism 3.2. Clinical Presentations of Toxoplasmosis 3.3. Diagnosis 3.4. Therapy of Toxoplasma gondii Infection 4. Cryptosporidium Species 4.1. The Organism 4.2. Epidemiology 4.3. Diagnosis 4.4. The Patient 4.5. Therapy of Cryptosporidiosis 5. Isospora belli 5.1. The Organism: Life Cycle and Epidemiology 5.2. The Patient 5.3. Histopathology and Diagnosis 5.4. Therapy 6. Microsporidia 6.1. The Organism 6.2. The Patient 6.3. Diagnosis 6.4. Therapy

265 265 267 268 268 268 271 272 273 275 279 279 282 287 290 290 292 295 298 301 301 302 303 304 304 305 306 306 306 306 306 307 307 307 308

xix

xx

CONTENTS

7. Strongyloides stercoralis 7.1. The Organism 7.2. Epidemiology 7.3. Pathogenesis 7.4. The Patient 7.5. “Hyperinfection Syndrome” and Disseminated Strongyloidiasis 7.6. Diagnosis 7.7. Therapy 8. Entamoeba histolytica and Amebiasis 8.1. The Organism 8.2. Life Cycle 8.3. Epidemiology 8.4. Immunology 8.5. Pathogenesis 8.6. The Patient 8.7. Diagnosis 8.8. Therapy 9. Primary Amebic Meningoencephalitis 9.1. The Organism 9.2. Epidemiology 9.3. Pathogenesis 9.4. The Patient and Diagnosis 9.5. Therapy 10. Leishmaniasis 10.1. The Organism 10.2. Epidemiology 10.3. Pathogenesis and Immunology 10.4. The Patient 10.5. Diagnosis 10.6. Therapy 11. Other Parasitic Diseases of the Immunocompromised Host 11.1. Giardia lamblia 11.2. Malaria 11.3. Babesiosis 11.4. American Trypanosomiasis (Chagas’ Disease) 11.5. African Trypanosomiasis 11.6. Cyclospora References

9 Viral Hepatitis in the Compromised Host

309 309 309 310 310 311 312 312 313 314 314 314 315 315 315 316 317 317 317 318 318 318 319 319 319 319 320 320 321 321 321 322 322 323 323 324 325 325

335

PETER M. ROSENBERG and JULES L. DIENSTAG 1. Introduction 2. Role of Immunologic Mechanisms in the Pathogenesis of Viral Hepatitis 2.1. Hepatitis B 2.2. Hepatitis C 3. Viral Hepatitis in the Immunocompromised Host 3.1. Hemodialyzed Patients with Chronic Renal Failure 3.2. Hepatitis in Recipients of Organ Transplants 3.3. Hepatitis in Oncology Patients 3.4. Hepatitis in Patients with AIDS 4. Prevention 5. Summary References

335 336 336 337 337 338 340 348 350 351 353 354

CONTENTS

10 The Herpesviruses

361

PAUL D. GRIFFITHS 1. General Characteristics of Herpesviruses 1.1. Herpesviruses Have Coevolved with Humans 1.2. Herpesviruses Have Large Complex Genomes 1.3. Herpesviruses Avoid Immune Responses 1.4. Herpesviruses Are Important in the Immunocompromised 2. Characteristics of Particular Herpesviruses 2.1. Herpes Simplex 1 and 2 2.2. Varicella–Zoster Virus 2.3. Cytomegalovirus 2.4. Human Herpesvirus 6 and 7 2.5. Epstein–Barr Virus 2.6. Human Herpesvirus 8 References

361 361 362 370 372 374 374 377 380 389 392 395 397

11 Morbidity in Compromised Patients Related to Viruses Other than Herpes Group and Hepatitis Viruses

405

ROBERT T. SCHOOLEY 1 . Introduction 2. DNA Viruses 2.1. Adenoviruses 2.2. Papovaviruses 2.3. Vaccinia 3. RNA Viruses 3.1. Picornaviruses 3.2. Paramyxoviruses 3.3. Rotaviruses References

12 Pathogenesis and Clinical Manifestations of HIV-1 Infection

405 405 405 407 410 411 411 412 413 414

421

ROBERT T. SCHOOLEY and CONSTANCE A. BENSON 1. 2. 3. 4. 5.

6. 7. 8.

Epidemiology of HIV-1 Infection Primary HIV-1 Infection Pathogenesis of HIV-1 Infection Neurologic Manifestations of HIV-1 Infection 4.1. Pathogenesis of the Neurologic Complications of HIV-1 Clinical Manifestations of AIDS Dementia Complex 5.1. Aseptic Meningitis 5.2. Subacute Encephalitis 5.3. Peripheral Neuropathy 5.4. Vacuolar Myelopathy Cachexia and Wasting in HIV-1 Infection Metabolic Disturbances Principles of Antiretroviral Chemotherapy 8.1. Classes of Agents 8.2. Clinical Use of Antiretroviral Agents

421 422 422 424 424 425 425 425 426 427 427 427 427 428 429

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xxii

CONTENTS

9. Primary and Secondary Prophylaxis of Opportunistic Infections in HIV-l-Infected Individuals 9.1. Pneumocystis carinii Pneumonia and Toxoplasma gondii 9.2. Tuberculosis 9.3. Mycobacterium avium Complex 9.4. Cytomegalovirus Disease 9.5. Invasive Fungal Infections 9.6. Bacterial Respiratory Infections 9.7. Human Herpesvirus 8 9.8. Hepatitis C Virus References

13 Infectious Complications in Children with Cancer and Children with Human Immunodeficiency Virus Infection

431 431 431 432 432 432 432 433 433 433

441 1

SARAH W. ALEXANDER, BRIGITTA U. MUELLER, and PHILIP A. PIZZO 1. Introduction 2. Background 2.1. Malignancies in Childhood 2.2. HIV Infection in Childhood 3. Interface between Cancer and Infections 4. Perturbations of Host Defense that Contribute to Infection 5. Fever 5.1. Fever and Neutropenia in Children 5.2. Fever and Neutropenia: Differences between Adults and Children 5.3. Risk Stratification 5.4. Prolonged Fever and Neutropenia: Antifungal Therapy 5.5. Viral Infections 5.6. Protozoa, Pneumocystis carinii 5.7. Fever in Pediatric HIV Infection 6. Immunizations 6.1. Live Vaccines 6.2. Live Bacteria 6.3. Inactivated Bacteria, Inactivated Viruses, Polysaccharide–Protein Conjugates, and Toxoids 6.4. Passive Immunization 7. Infection Prophylaxis 7.1. Prophylaxis during Episodes of Fever and Neutropenia 7.2. Mycobacterial Prophylaxis 7.3. Antifungal and Antiparasitic Prophylaxis 7.4. Antiviral Prophylaxis 8. Use of Growth Factors 9. Conclusions References

14 Infections Complicating Congenital Immunodeficiency Syndromes

441 442 442 443 446 446 447 447 449 449 449 450 451 452 452 453 453 453 454 454 455 455 455 457 457 458 458

465

JOHN C. CHRISTENSON and HARRY R. HILL 1. Introduction 2. Aim of Therapy in Congenital Immunodeficiency Diseases

465 467

CONTENTS

2.1. Treatment of Life-Threatening Infections 2.2. Minimizing the Effects of Less Severe Acute Infections 2.3. Prevention of Chronic Infections and Their Sequelae 3. Specific Infections in Immunodeficiency Syndromes 3.1. Combined B- and T-Cell Defects 3.2. Congenital Pure T-Cell Immunodeficiencies 3.3. B-Cell Immunodeficiency 3.4. Complement Component Deficiencies 3.5. Phagocyte Abnormalities References

15 Management of Infections in Leukemia and Lymphoma

467 470 473 475 476 480 481 483 485 490

497

LOWELL S. YOUNG 1. 2. 3. 4. 5. 6. 7. 8.

9. 10. 11.

Introduction Host Defenses against Infection in Leukemias and Lymphomas The Role of Infection in Mortality from Leukemia and Lymphomas Problems with the Interpretation of Fever and Infection Incidence Data in Neutropenic States Causes of Fever in Leukemia and Lymphoma Site of Involvement and the Nature of the Microbial Pathogen(s) Synthesis Summary of Recommended Therapeutic Strategies 8.1. Different Approaches to Leukemia and Lymphoma 8.2. Environmental Considerations 8.3. Prophylactic Antibiotics 8.4. Systemic Antimicrobial Agents 8.5. Risk Assessment and Conversion to Outpatient Treatment Approach to the Splenectomized Patient Neutrophil Transfusions in the Treatment and Prophylaxis of Infection Immunoprophylaxis and Immunotherapy of Infection 11.1. Childhood and Adult Immunizations 11.2. Passive Antibody 11.3. Influenza Immunization 11.4. Pneumococcal Immunization References

16 Infection in Hematopoietic Stem Cell Transplantation

497 498 501 502 503 506 511 514 514 514 515 516 517 517 518 520 520 520 520 521 522

527

MICHAEL BOECKH and KIEREN A. MARR 1. 2. 3. 4. 5.

Introduction Transplantation Techniques Recovery of Host Defenses Phases of Infection after HSCT Phase I: Infections between Conditioning and Engraftment 5.1. Bacteremia and Candidemia 5.2. Early Pneumonia 5.3. Intravascular Catheter-Related Infection 5.4. Fungal Infections 5.5. Antibiotic and Antifungal Treatment 6. Phase II: Infections between Engraftment and Day 100 6.1. Interstitial Pneumonia

527 527 528 529 530 530 530 532 532 537 541 541

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CONTENTS

CMV Infection and Disease Infections with Community Respiratory Viruses Mold Infections Hepatosplenic Candidiasis Idiopathic Pneumonia Syndrome Herpes Simplex Virus Infection III: After 100 Days Varicella–Zoster Virus Infection CMV Disease Invasive Fungal Infections Pneumocystis carinii Pneumonia Infections with Encapsulated Bacteria in Patients with Chronic GVHD 7.6 Late Poor Graft Function Associated with Infections Other Infections 8.1. Parasitic Infections 8.2. Legionellosis 8.3. Epstein–Barr Virus 8.4. HHV-6, -7, and -8 8.5. Adenovirus 8.6. Hepatitis Viruses 8.7. BK and JC Viruses 8.8. Parvovirus B 19 8.9. Other Viral Infections 8.10. Mycobacterial Infections 8.11. Nocardiosis Pretransplant Infectious Disease Considerations 9.1. Pretransplant Infections 9.2. Donor Issues Infection Control Programs and Surveillance 10.1. Isolation Practices 10.2. Use of Surveillance Culture 10.3. Prevention of Exposure by Personnel, Family Members, and Visitors 10.4. Postexposure Prophylaxis 10.5. Immunization Conclusions and Future Considerations References

561 562 562 562 562

17 Infection in the Organ Transplant Recipient

573

6.2. 6.3. 6.4. 6.5. 6.6. 6.7. 7. Phase 7.1. 7.2. 7.3. 7.4. 7.5.

8.

9.

10.

11.

542 548 550 551 551 552 552 552 553 554 554 555 556 556 556 556 556 557 557 557 557 557 558 558 559 559 559 560 560 560 561

ROBERT H. RUBIN 1. Introduction 1.1. The Therapeutic Prescription 2. Risk of Infection in the Organ Transplant Recipient 2.1. Epidemiologic Exposures of Importance 2.2. The Net State of Immunosuppression 3. Timetable of Infection in the Organ Transplant Recipient 4. Infection Occurring in the First Month Posttransplant 4.1. Preexisting Infection in the Allograft Recipient 4.2. Infection from the Donor 4.3. Wound Infection 4.4. Other Causes of Infection in the First Month

573 574 579 580 582 583 585 586 589 593 596

CONTENTS

4.5. Noninfectious Causes of Fever in the First Month Posttransplant 5. Infection 1 to 6 Months Posttransplant 5.1. Herpes Group Virus Infections in the Organ Transplant Recipient 5.2. Hepatitis in the Organ Transplant Recipient 5.3. HIV Infection in the Organ Transplant Recipient 5.4. The Clinical Impact of Papovaviruses in the Organ Transplant Recipient 5.5. Urinary Tract Infection in the Renal Transplant Patient 6. Infection in Organ Transplant Patients More than 6 Months Posttransplant 7. Infectious Disease Problems of Particular Importance in the Organ Transplant Patient 7.1. CNS Infection in the Organ Transplant Patient 7.2. Bacteremia in the Organ Transplant Patient 7.3. Fungal Infections in the Organ Transplant Patient 7.4. Mycobacterial Infections in the Organ Transplant Patient 8. Vaccine Use in Organ Transplant Recipients 9. Summary and Prospects for the Future References

18 Surgical Aspects of Infection in the Compromised Host

598 598 599 629 635 637 638 639 640 640 645 646 647 648 649 650

681

A. BENEDICT COSIMI 1. Introduction 2. Diagnostic Approach 2.1. Diffuse Pulmonary Infiltrates in the Immunocompromised Host 2.2. Focal Pulmonary Infiltrates or Nodule(s) in the Immunocompromised Host 2.3. Gastrointestinal Complications of the Immunosuppressed State 2.4. Occult Intra-abdominal Sources of Fever and Infection 3. Preoperative Preparation 3.1. Infection and Adrenal Insufficiency 3.2. Infection and Ketoacidosis 3.3. Infection and Malnutrition 3.4. Preoperative Antibiotics 4. Intraoperative Considerations 4.1. Choice of Anesthesia and Patient-Monitoring Techniques 4.2. Surgical Technique 4.3. The Effect of AIDS on Surgical Practice 5. Postoperative Management 5.1. Respiratory Management in the Immunocompromised Patient 5.2. General Postoperative Care in the Immunocompromised Patient 5.3. Management of the Burn or Trauma Patient 5.4. Postoperative GI Bleeding in the Immunocompromised Patient 5.5. Sepsis following Splenectomy 6. Conclusions References

681 681 681 683 683 687 688 689 689 690 691 692 692 692 695 697 697 697 698 700 701 702 703

Color Plates

707

Index

709

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Clinical Approach to Infection in the Compromised Host Fourth Edition

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1

Introduction ROBERT H. RUBIN and LOWELL S. YOUNG

Two terms that have become common in the contemporary literature of internal medicine, surgery, and pediatrics are the immunocompromised host and opportunistic infection. The first of these terms, immunocompromised host (or such variants as the compromised host), describes a group of individuals with impairment of either or both natural and specific immunity to infection (impaired host defenses) such that they are at increased risk for infection by a variety of microorganisms. The microorganisms that invade these individuals may be grouped into three major categories:

1. True pathogens are the classic plagues of mankind (e.g., influenza, typhoid fever, bubonic plague, diphtheria), invading normal and abnormal host alike. The organisms causing these infections possess virulence factors that are capable of overcoming the natural resistance mechanisms of the nonimmune host, with survival being dependent on either the rapid development of a specific immune response or the institution of effective antimicrobial therapy or both. The virulence factors involved include the production of toxins and/or the ability to traverse mucocutaRobert H. Rubin Division of Infectious Disease, Brigham and Women’s Hospital; Center for Experimental Pharmacology and Therapeutics, Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology; and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114. Lowell S. Young Kuzell Institute for Arthritis and Infectious Diseases, Division of Infectious Diseases, California Pacific Medical Center, University of California at San Francisco, San Francisco, California 94115. Clinical Approach to Infection in the Compromised Host (Fourth Edition), edited by Robert H. Rubin and Lowell S. Young. Kluwer Academic/Plenum Publishers, New York, 2002.

neous barriers, evade phagocytosis, and resist extra- and intracellular microbicidal systems. 2. Sometime pathogens are commonly present as colonizers of the mucocutaneous surfaces of the body, causing clinical disease only when they are introduced into normally sterile tissues following a break in the integrity of a mucocutaneous surface. When such a break occurs, these organisms then possess sufficient virulence characteristics to cause lethal infection, again unless either specific immunity develops or effective antimicrobial therapy is introduced. Examples of this form of infection include staphylococcal and Group A streptococcal sepsis following breaks in skin integrity and gram-negative and Bacteroides fragilis sepsis following bowel perforation. 3. Nonpathogens are generally susceptible to nonspecific (natural) resistance supplemented by specific immunity. They usually have no impact on the normal host, being capable of invading and causing disease only in individuals with impairment of either nonspecific or specific host defenses or both. Examples of this form of infection include Pneumocystis carinii pneumonia and invasive aspergillosis. The term opportunistic infection is used to denote invasive infection due to nonpathogens or to infections with sometime or even true pathogens of a type and/or severity rarely encountered in the normal host [e.g., disseminated zoster in the lymphoma patient, hepatosplenic candidiasis in the leukemic patient, and recurrent Salmonella bacteremia in the acquired immunodeficiency syndrome (AIDS) patient]. Although opportunistic infection appropriately has been the focus of attention in the compromised host, it 1

2

CHAPTER 1

is important to emphasize the impact of both true and sometime pathogens in this patient population. As the number of immunocompromised patients has exploded in recent years, responsibility for their care has spread from the academic medical center to practitioners at every level—the primary care physician, the general internist and surgeon, as well as the subspecialist. It is incumbent on all of us to become familiar both with the unusual infectious disease problems that occur in these patients—the prevention, diagnosis, and treatment of these problems—and with the ways in which underlying disease and/or its therapy can modify the clinical presentation and management of common conditions. For example, too often we have seen the diagnosis of a perforated abdominal viscus in a patient on immunosuppressive therapy missed and the patient succumb because of the absence of the classic signs of an acute abdomen, a not uncommon event in such patients. This volume was conceived as an attempt to deal with this issue; to summarize directly and succinctly the major issues and controversies involving the medical and surgical management of immunocompromised patients. We hope that the dominant characteristics of this assembly of views are candor and the presentation of a particular approach to the clinical management of infection in the compromised host. The contributors have been asked to meet the important issues “head-on” and to identify those areas in which useful knowledge does or does not exist. After giving a fair summary of the published literature, they elaborate on their views about the most expeditious, economically sound, logical approach to the challenging manifestations of infection in what are likely to be very ill patients. Where data are insufficient to enable one to choose among several clinical alternatives, the contributors have said so, thereby distinguishing established principle from opinion. This effort is not intended as an encyclopedic compendium of the recent medical knowledge on this complicated subject, but rather as a practical guide to clinical decision making. The guiding theme of this volume is to identify the epidemiologic, pathophysiologic, and clinical clues that will lead to early diagnosis and effective therapy or, better yet, prevention, rather than to discuss the way a disease looks at the autopsy table. This volume has been purposely organized with this perspective in mind. On the one hand, there are detailed chapters on host defenses, as well as particularly important infections (e.g., herpesviruses, fungi, parasites). On the other hand, since the patient does not present with a label stating the name of the infection, other chapters are devoted to particular organ system infections (e.g., of the skin, lungs, and

central nervous system) and infection in particular patient groups (e.g., pediatric and adult cancer, bone marrow and organ transplant, and AIDS patients). The clinician needs both kinds of information; e.g., an approach to the patient with pneumonia as well as a detailed analysis of what to do and what to anticipate once the cause of the pneumonia in this particular patient population has been determined. Although such a multifaceted approach results in some repetition of material, we believe that such repetition is both warranted and useful (“creative redundancy”). Throughout the volume, great reliance has been placed on actual case examples to illustrate important clinical points. There clearly has been a great deal of ferment and progress in this field since the last edition of this volume. The challenges, however, remain:

1. A myriad of infectious agents can cause potentially lethal infection in these patient groups. Although treatment of established disease has improved, prevention should be the first goal of the clinician: we need to develop better epidemiologic protection, as well as additional preemptive and prophylactic strategies against such important pathogens as Epstein–Barr virus, fungi, antimicrobial-resistant bacteria, and the communityacquired respiratory viruses. 2. The impaired inflammatory response of immunosuppressed patients, particularly those with profound neutropenia and those receiving corticosteroids, can greatly attenuate the signs and symptoms of microbial invasion until the disease is relatively far advanced. Since the chance of recovery from most infections in this population is directly related to how early the diagnosis is made and effective therapy instituted, subtle signs and symptoms require constant attention, expert radiological evaluation [particularly computed tomographic (CT) scanning for indications not acceptable in the normal host], and invasive biopsies. 3. Diagnostic techniques adequate for the care of the nonimmunosuppressed population are not optimal for these patients, at least in part since the nature of the infections can be so different. For example, conventional blood culturing techniques are not adequate for the diagnosis of invasive fungal and nocardial infection. Even when an isolate is made, usually after an invasive procedure, standardized antimicrobial techniques are not widely available. 4. The nature of many of the infections observed is

INTRODUCTION

such that prolonged therapy is often necessary, increasing the risk of toxicity due to such drugs as amphotericin, high-dose trimethoprim–sulfamethoxazole, ganciclovir, and others. 5. In addition to the risk of infection, the differential diagnosis in many of these patients includes such noninfectious etiologies as recurrent neoplastic disease, allograft rejection, graft-versus-host disease, and relapsing collagen vascular disease, thus complicating the clinician’s task. As we face these and other challenges, controversy is inevitable. Table 1 delineates some of the most important questions facing the clinician today in dealing with the compromised host. Gratifyingly, these are distinctly different than those outlined in the previous edition, indicating progress. Answering these questions will clearly advance the field significantly in the next decade.

1. What is the best strategy for preventing bacterial and fungal infection in the neutropenic cancer or bone marrow transplant patient? 2. What is the optimal empiric antimicrobial therapy for suspected bacterial sepsis in the neutropenic patient? Monotherapy versus potentially synergistic combination therapy? Vancomycin as primary therapy with the gram-negative regimen or only after the diagnosis of gram-positive infection is made? 3. What is the relative efficacy of the different antifungal drugs for the different fungi at different sites? Conventional amphotericin versus the different lipid-associated amphotericin preparations, and these versus the new drugs such as voriconazole and the echinocandins? Do combinations offer any advantage? 4. What are the indications for initiating and stopping empiric antifungal therapy? Which of the drugs is best for what patient populations? 5. What are the indications for continued empiric antimicrobial therapy in the culture-negative but persistently febrile neutropenic patient? 6. What is the most cost-effective program for preventing the infectious disease consequences of cytomegalovirus and Epstein–Barr virus infection in transplant patients? 7. Will antiviral strategies decrease the incidence of allograft injury and/or graft-versus-host disease in transplant patients? 8. What is the best strategy for managing hepatitis B and C virus infection in patients already or about to be immunosuppressed (e.g., organ transplant candidates and recipients)? 9. What is optimal anti-HIV therapy for the different stages of this infection such that the measurable antiviral load is undetectable and resistance is avoided? 10. Other than Pneumocystis carinii infection, are there opportunistic infections that can be effectively prevented with prophylactic or preemptive strategies in the AIDS patient and other immunocompromised patient populations?

3

There are two competing major developments that will affect our ability as well as Europe’s ability to meet these challenges and settle the controversies that characterize this field. One development is the governmental and societal pressures for the implementation of costeffective measures in clinical practice. How we define cost-effectiveness per se is controversial. Anyone who treats patients is aware, however, of the increased consciousness relating to reducing unnecessary tests, the use of less expensive antimicrobial agents, and the desire to discharge patients early following chemotherapy or pharmacological therapy with the potential for persisting side effects. One would hope that many of these cost-cutting measures have been of benefit. In certain situations, however, they may limit our ability to understand fully the complexities of the biological phenomena that are occurring in our more complicated immunosuppressed patients. Clinically, early discharge may spell early readmission. By their very nature, immunocompromised patients tend to require expensive care; one example of this being the frequent need for CT scanning when conventional radiography is adequate for the normal host. It is likely that the trend emphasizing economics will persist, and many of the changes in this text are aimed at providing the clinician with useful guidelines that will enable the practice of first-rate medicine that is responsive to the demands of cost control. If economics is an issue in the United States and Europe, it is a reality in the developing world where the care of AIDS patients is nonexistent. How the economic issues are solved will determine greatly what progress will be made in the care of the immunocompromised host. A happier development is that we are beginning to enjoy the fruits of the revolution in science that has occurred in the pharmaceutical and biotechnology industries. Never before have we had such a richness of approved drugs and drugs in development as we have now. The molecular biology revolution, monoclonal antibody technology, combinatorial chemistry, and rapid throughput screening have brought us effective AIDS drugs, new immunosuppressive and chemotherapeutic agents, and some new antibacterial, antifungal, and antiviral agents. It is paradoxical that a traditional area of pharmaceutical strength—the development of new antibiotics—has been lagging behind such areas as recombinant proteins, hematopoietic growth factors, and therapeutic monoclonal antibodies at a time when antimicrobial resistance is burgeoning. Clearly, particularly for the immunocompromised host new antimicrobial agents in all categories are needed if we are not to be overwhelmed with drug-resistant

4

CHAPTER 1

tuberculosis, azole-resistant fungi, ganciclovir-resistant herpesviruses, lamivudine-resistant hepatitis B, vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, penicillin-resistant pneumococci, and highly resistant gram-negative bacilli, virtually all of which have a higher attack rate in the immunocompromised patient than in the general population. Finally, there is a compelling need both for new paradigms for developing and deploying these new agents (in a costeffective way) and for trained clinical investigators for facilitating this process. It is hoped that the material in this volume will both lead to the optimal management of immunocompromised patients today and help to show the way to new approaches

for tomorrow. This volume is primarily an attempt to summarize the many developments that have occurred in a rapidly evolving field and to direct the thoughts of investigators to where major opportunities lie. The volume should be regarded as serving three purposes: (1) a status report as to where we are in the understanding and management of an increasingly important group of patients, (2) a practical guide to the clinician for the everyday management of these patients, and (3) a charge to the future to investigators who constantly seek to improve what we can for a courageous and deserving group of human beings: the increasing population of individuals who are immunocompromised by disease and/or its therapy.

2

Defects in Host Defense Mechanisms JOS W. M. VAN DER MEER and BART JAN KULLBERG

1. Colonization Under normal conditions, large areas of the human body surface are colonized with microorganisms. The skin and the mucous membranes of the oropharynx, nasopharynx, intestinal tract, and parts of the genital tract each have their own microflora.1 These patterns of colonization are determined by microbial factors, exogenous factors, and host factors. An important microbial factor is adhesion to epithelial cells, often with distinct specificity for a certain type of epithelial cell.2 Microorganisms also can influence the patterns of colonization by producing bacteriocins and other products that inhibit the growth of other microorganisms3 or by competing for essential nutrients.4 By means of such mechanisms, colonizing microorganisms form a barrier against microorganisms from the outside world. This type of barrier has been designated colonization resistance.5 In the nose,6 diphtheroids hamper the local growth of Staphylococcus aureus, whereas in the gastrointestinal tract, anaerobic microorganisms inhibit the colonization and outgrowth of aerobic gramnegative rods.4,5 By contrast, certain pathogenic microorganisms (e.g., respiratory viruses) facilitate bacterial colonization.7,8 Of the exogenous factors that influence the normal flora, diet1,9 and, more significantly, disinfectants and antimicrobial drugs10 should be mentioned. The host factors that play a role in colonization are complex. The adherence of bacteria to epithelial cells is

dependent on specific receptors on somatic cells.2,11 Host factors like fibrinogen and fibronectin (see Section 3.1.3) may play a role. Interindividual differences in bacterial adherence to epithelial cells may be based on certain blood group glycoproteins12 or human leukocyte antigen (HLA) types" that are expressed on epithelial cells and serve as receptors. The precise mechanisms by which race,14 hormonal status,15 pregnancy,16 alcoholism,17 intravenous drug abuse,18 hemodialysis,19 and underlying diseases such as cancer20-22 and diabetes17 alter colonization are unknown. Several other factors, considered part of the host defense in a stricter sense (Table 1), also influence colonization of the body surface. 2. First Line of Defense 2.1. Skin Normal skin is not very hospitable to most microorganisms.23 By desquamation of the horny layer, bacteria are constantly eliminated from the skin. Dependent on their chemical structure, skin surface lipids produced by the sebaceous glands as well as keratinocytes either inhibit the growth of bacteria, such as streptococci, or promote the growth of diphtheroids.23 The lactic acid in sweat can be used as a source of energy by staphylococci, although inhibition of growth occurs at higher concentrations.24 When the skin is humid and the pH increases, higher bacterial counts are found. 25

Jos W. M. van der Meer and Bart Jan Kullberg Department of Medicine, Nijmegen University Medical Center St Radboud, 6500 HB Nijmegen, The Netherlands.

2.2. Mucosa

Clinical Approach to Infection in the Compromised Host (Fourth Edition), edited by Robert H. Rubin and Lowell S. Young. Kluwer Academic/Plenum Publishers, New York, 2002.

At the mucosal level, a number of effective mechanisms are encountered. Ciliary motion, ventilation, and coughing maintain sterile airways below the vocal cords 5

6

CHAPTER 2

moral and cellular defense mechanisms (Table 1), is needed for elimination of the invaders.

3. Second Line of Defense The second line of defense is made up of humoral and cellular defense mechanisms (Table 1) that act in close cooperation. Thus, discussing humoral and cellular defense mechanisms separately is a somewhat artificial approach. However, for reasons of clarity and because quite a number of pathological states involve either the humoral or the cellular defense mechanisms, these mechanisms are dealt with in separate sections. 3.1. Humoral Defense Mechanisms

in the healthy human being.26 Gastric acid is an effective barrier against bacteria from outside; thus, hypochlorhydria (e.g., as induced by receptor antagonists) is associated with colonization of the stomach and even intestinal infections.27 Unconjugated bile has antibacterial properties and probably helps restrict the number of bacteria in the small intestine.28 Intestinal motility also inhibits bacterial outgrowth. Colonization of the urinary tract is largely prevented by regular voiding.29 In the female genital tract, production of antimicrobial factors by the commensal Lactobacillus species creates an environment that is hostile to many pathogens.30 Lysozyme and lactoferrin in tears and saliva display antibacterial activity: lysozyme through inhibition of the cell wall synthesis of gram-positive bacteria and lactoferrin through interference with bacterial iron metabolism31,32 (see Section 3.1.1). More important are the immunoglobulins, especially secretory IgA, on these surfaces; by coating microorganisms, secretory IgA prevents adherence to mucosal cells (see Section 3.1.6). Symbiosis of the host with colonizing microflora depends in the first instance on the integrity of the mechanical barrier of skin and mucous membranes. Damage to this first line of defense, even by trivial injuries such as a puncture, can turn colonizing microorganisms into pathogens that impose great demands on the other defense mechanisms. Moreover, pathogens from the outside world then may gain entrance and cause infection. At this point, it should be stressed that a number of microorganisms are capable of penetrating intact epithelia. If the microorganisms succeed in passing the first line of defense, then the second line of defense, consisting of hu-

The humoral defense system consists of a number of nonspecific and specific factors that interact with microorganisms (Table 1). 3.1.1. Lysozyme and Lactoferrin Lysozyme, one of the nonspecific factors (see also Section 2.2), is an enzyme found in many body fluids. It is present in high concentrations in the azurophilic and specific granules of polymorphonuclear phagocytes and is constitutively secreted by mononuclear phagocytes.33 By cleaving the linkage between N-acetyl-muramic acid, lysozyme interferes with cell wall synthesis, especially . that of gram-positive bacteria31; it also markedly amplifies the effector mechanism of the complement cascade34 (see Section 3.1.2). Lactoferrin is an iron-binding protein that, when not fully saturated with iron, inhibits the growth of microorganisms, such as gram-negative and gram-positive bacteria and various Candida species.32 It then acts as an iron-chelating agent, thereby depriving the microorganisms of the iron necessary for their growth. It is an important enzyme of neutrophil-specific granules (see Section 3.2.1h). 3.1.2. Complement More important in the humoral host defense is the complement system, which consists of at least 19 plasma proteins that are able to react in a cascade.33,34 This cascade has four essential elements: (1) classic activation, (2) alternative activation, (3) amplification, and (4) the effector mechanism (Fig. 1). Antigen–antibody complexes can bind the first component of the complement system (C1) at the exposed Fc portion of the antibody; in this way,

DEFECTS IN HOST DEFENSE MECHANISMS

classic activation is initiated. The classic route also can be started by the acute-phase reactant mannan-binding protein (MBP) to microorganisms or by activated factor XII. Once activated, C1 activates C4 and C2; the next step is activation of C3, which is converted into C3a and C3b. Bacterial products, especially molecules with repeating chemical structures (lipopolysaccharides, teichoic acid, and endogenous molecules like CRP and fibrillar can activate the alternative route via factors B, P, and D. When C3b, formed by either the classic or the alternative route, reacts with factors B, P, and D, complement activation may be amplified. The effector mechanism is then initiated by the conversion of C5 into C5b and C5a and subsequent formation of the multimolecular complex C5b6789. A variety of inhibitors, also part of the complement system, regulate the system. For a more detailed account of these factors, the reader is referred to the reviews by Joiner et al.34 and Figueroa and Densen.36 The biological effects of complement are essentially as follows: Factors C3a and C5a are able to liberate histamine and serotonin from mast cells and basophils, thereby increasing vascular permeability. Factors C5a, Ba, and C5b67, and to a much lesser extent, C3a, have a chemotactic effect on leukocytes; in addition, C5a induces adhesiveness, oxidative burst, and degranulation of neutrophils (see Section 3.2.1). Since C3b-bound complexes can bind to C3b receptors on granulocytes and monocytes–macrophages, C3b acts as an opsonin (see Section 3.2.1e) and promotes phagocytosis. The effector complex C5b6789 is able to penetrate cell membranes, leading to lysis of the microorganisms as well as of erythrocytes and tumor cells. Thus, the complement system provides protection with a potent host defense system against microorganisms that operates even before a specific immune response has developed via the alternative pathway and via the classic

7

route once there is an acute phase response or a specific antibody response. Moreover, it appears that certain antibodies also amplify the alternative route. From the deficiencies of individual complement components in humans, the relative role and importance of these factors in host defense can be assessed. Infections are relatively rare in patients with a deficiency of C1, C4, and C2, probably because the alternative pathway is intact. Recurrent infections, especially those caused by encapsulated bacteria, have been reported in patients lacking C3.37,38 Deficiency of C5 is associated with an impaired capacity to generate chemotactic activity in serum and with recurrent pyogenic infections.39 Leiner’s syndrome (eczema, diarrhea, and recurrent gram-negative bacteremia) has been qualified as a C5-dysfunction syndrome; generation of chemotactic factors is defective and there is a concomitant, as yet unexplained, opsonic defect.40 Among those with a deficiency of one of the terminal components (C5–C8), a high incidence of chronic or recurrent Neisseria infections has been found.36,41 The mortality rate of the latter infections in these patients is remarkably low, suggesting that an intact terminal pathway contributes to a poor outcome. Deficiencies in alternative pathway proteins are rare. A combined deficiency of factors B and C2 predisposes to serious infections with encapsulated bacteria.42 Similar infectious conditions occur in the event of factor D deficiency43 and also in C3b-inactivator deficiency.44 In sickle cell anemia (see Section 5.3), reduced activation of alternative pathway factors leads to impaired opsonization of pneumococci and salmonellae.45,46 A more detailed discussion of the primary complement deficiencies is given in Chapter 14. During various disease states, such as gram-negative or gram-positive bacteremia, massive complement activation may occur in association with hypotension, respiratory distress syndrome, and disseminated intravascular coagulation (DIG).47 Under these circumstances, acquired complement deficiency can develop, leading to an inability to cope with infectious agents.48,49 Acquired complement deficiency, as in systemic lupus erythematosus (SLE), has been reported to be associated with meningococcal infection.41,50,51 In Felty’s syndrome, acquired hypocomplementemia appears to predispose to serious infectious conditions52 (see Section 5.7). Nonenzymatic glycosylation of C3 may occur in diabetes mellitus and may lead to impaired opsonization53 (see Section 5.4). That virus infections are not an overt problem in complement-deficiency states does not imply that the complement system does not play a role in the defense against viruses. In fact, there is considerable evidence

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indicating that the complement system has a central role in host defense mechanisms, as reviewed by Lachmann.54 3.1.3. Fibronectin Fibronectin originally has been described as coldinsoluble globulin in fibrinogen-rich plasma. It has a molecular weight of 440,000 and is detectable in normal plasma at a concentration of approximately 0.35 g/liter.55 Most of the soluble, circulating fibronectin is produced by hepatocytes.56 This soluble form is secreted on mucosal surfaces. When the molecule binds to cellular receptors and is incorporated into extracellular and basement membrane matrix, it forms an insoluble protein.55 Fibronectin has an important function in adherence of cells to other cells, to basement membranes, and to microorganisms. Although mononuclear phagocytes have receptors for fibronectin,57 it is questionable whether fibronectin should be regarded as an opsonin,58 i.e., a ligand between a particle and a phagocyte that mediates ingestion (see Section 3.2.1). It is more likely that fibronectin acts by inducing more receptors for endocytosis on phagocytic cells.57,58 It also enhances bactericidal activity of mononuclear phagocytes,58 In experimental animal studies, plasma fibronectin has been shown to promote clearance of injected particles.58 Deficiency of plasma fibronectin has been reported in DIG, septicemia, trauma, and shock.59 Fibronectin-rich cryoprecipitate infusions are not beneficial in patients with sepsis.60 Congenital fibronectin deficiency does not seem to be associated with impaired host defense.61 3.1.4. Interferons The interferons (IFNs) are a group of speciesspecific glycoproteins that exert a wide array of biological effects. Three main classes of IFN are distinguished on the basis of their antigenic specificities: inand formerly called “leukocyte interferon,” is highly heterogeneous: There are more than a dozen genes that code for human formerly called “fibroblast interferon,” exists as two subtypes, whereas only one type of (formerly called “immune interferon” or “acid-labile interferon”) is known. Generally speaking, and act mainly as antiviral agents, whereas is more active as an immunomodulator. The overall effects of the IFNs are shown schematically in Fig. 2. The antiviral effects are not virus specific; they are mediated partly by intracellular changes leading to inhibition of viral replication in a

number of ways.63 In vivo, the antiviral effects also seem to be mediated by stimulation of host defense mechanisms, especially natural killer (NK) cells (see Section 3.2.2) and macrophages (see Section 3.2.3c).62,64 is a major cytokine, and as such it is an important activator of macrophages65 (see Section 3.2.3c). After exposure to macrophages are more sensitive to bacterial endotoxin, and these cells will produce more of the proinflammatory cytokines66 (see Section 3.1.5). It is very likely that the IFNs are designed to work at short range, mainly at the site of infection. Nevertheless, serum IFN activity can be measured during viral infections such as influenza.67 An important question with therapeutic implications is whether deficiency of IFNs occurs, e.g., at the cellular level. Such deficiencies indeed have been reported for in newborns68 and in patients with primary immunodeficiencies69–71 or the acquired immunodeficiency syndrome (AIDS).72–74 For allograft recipients, deficient production of both and has been reported.75,76 Congenital defects in the receptor77,78 will be discussed under Section 3.2.3d. IFNs recently have become available on a large scale, and their clinical use to treat the compromised host is discussed in Section 9. 3.1.5. Cytokines 3.1.5a. Interleukins and Tumor Necrosis Factor. “Interleukins” is the collective name for a series of humoral factors that are produced mainly (but not exclusively) by leukocytes, especially mononuclear phagocytes and lymphocytes, and transfer signals between cells of the immune system and usually also between other

DEFECTS IN HOST DEFENSE MECHANISMS

cells. As such, they act as local and systemic mediators of the host response to infection. Formerly, they were designated as “lymphokines” if they were primarily produced by lymphocytes and as “monokines” if mononuclear phagocytes were the major source of production. At present, the term “interleukin” (IL) or the more general term “cytokine” is preferred. According to an international convention, these cytokines are now numbered (IL-1, IL-2, ...).79 The nomenclature is not consequent, in a sense; e.g., tumor necrosis factor synonym: “cachectin”) and lymphotoxin should have been assigned an interleukin number. The same holds for the interferons, especially (see Section 3.1.4). Although not all these factors have been shown to have a sizable impact on host defense, this rapidly expanding field is briefly reviewed. “Interleukin-1” is the collective name for two 17kDa proteins that are produced and released mainly by mononuclear phagocytes (see Section 3.2.1c) when these cells encounter bacterial lipopolysaccharide, microbial cell wall substances (peptidoglycan, muramyl peptides), and bacterial exotoxins (e.g., toxic shock syndrome toxin 1)80; other cells (e.g., endothelial cells, keratinocytes, astrocytes) also are able to produce largely is released extracellularly and acts as an autocrine, a paracrine, and an endocrine substance,

9

whereas stays mainly cell associated and is believed to exert its function in cell–cell interaction. IL-1 has a large number of important biological effects: It acts as an endogenous pyrogen and stimulates endothelial cells, neutrophils, T and B lymphocytes, hematopoietic cells, and mesenchymal cells (Fig. 3).80 These biological effects are produced either directly by interaction of IL-1 with specific receptors on the membrane of the target cell or indirectly by the induction of intermediary cytokines like IL-6 and IL-8. Inside the effector cells, the effects of IL-1 are largely mediated via the liberation of arachidonic acid, via the cyclooxygenase pathway or the lipoxygenase pathway.80 also is a 17-kDa protein that shares many of its effects with IL-1,81 although it binds to different receptors. Like IL-1, this cytokine is produced and secreted by stimulated mononuclear phagocytes and by other cells. Many of the effects of these cytokines are definitely beneficial in host defense against infection. This beneficence is underscored by experiments showing that a low dosage of exogenous IL-1 protects against lethal bacterial infection even in granulocytopenic animals82 and by the observations in experimental animals that the absence of TNF has a negative impact on granuloma formation in mycobacterial infection, formation of abscesses in intra-abdominal infection, and fungal infection.83,84

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Under certain circumstances, however, these cytokines may be deleterious for the host. During serious bacterial infection, TNF, and IL-6 have been detected in the circulation; high concentrations of these cytokines, particularly of TNF, in the circulation appear to indicate a poor prognosis.85,86 In a rabbit model, IL-1 and TNF produce a state with the clinical characteristics of septic shock and respiratory distress syndrome.87 In other serious infections, such as cerebral malaria, and in inflammatory states (e.g., the capillary leak syndrome induced by IL-2 treatment), the aforementioned cytokines play an important pathophysiologic role.88,89 Interference with deleterious cytokinemia, e.g., by administration of antibodies against TNF, so far has failed as a therapeutic option in septic shock and in severe malaria in humans (see also Chapter 4). IL-2, a 15-kDa glycoprotein originally described as a T-cell growth factor, is produced and secreted by a subset of T lymphocytes; it is the major mediator of the proliferation of T lymphocytes and stimulates production of other cytokines by T cells.90 In addition, IL-2 activates B lymphocytes and NK cells (see Section 3.2.2). The activation of blood lymphocytes by IL-2 and the induction of other cytokines are the bases for the anticancer therapy with this cytokine (IL-2 with or without ex vivo activated killer cells).91 Probably due to liberation of cytokines such as TNF and IL-1,89 serious side effects (capillary leak syndrome) occur with high-dose IL-2 therapy. IL-3 is a multilineage hematopoietic growth factor produced mainly by T lymphocytes.92 It synergizes with other hematopoietic growth factors (see Section 3.1.5b). IL-4, a product of T-helper lymphocytes, acts on many types of cells and has a role in the activation, proliferation, and differentiation of B lymphocytes. The molecule plays a crucial stimulatory role in immunoglobulin E (IgE) production,93 an effect that can be blocked by IFNs, and also plays a role in the activation of T lymphocytes and NK cells. On mononuclear phagocytes, IL-4 induces the expression of class II antigens of the major histocompatibility complex, and it downregulates the expression of various Fc receptors; in addition, IL-4 blocks the production of IL-1, IL-6, IL-8, and TNF by these cells.93 Because of the latter effects, IL-4 can be considered an anti-inflammatory cytokine. In experimental leishmaniasis, IL-4 plays a beneficial role.94 IL-5, produced by T lymphocytes, is the major growth and differentiation factor for eosinophils; it also activates eosinophils and is chemotactic for these cells.95 IL-5 plays a key role in states of eosinophilia (see Section 3.2.1f). IL-6 is a 22-kDa cytokine produced by many types of cells (macrophages, fibroblasts, endothelial cells, and smooth muscle cells), especially if these cells are stimu-

lated by IL-1 and TNF.96 IL-6 is a growth factor for B lymphocytes (see Section 3.1.6), stimulates T cells together with IL-1, and is a major stimulant for the synthesis of acute phase proteins by the hepatocytes.97 The molecule also stimulates hematopoiesis and is a relatively weak but probably crucial endogenous pyrogen; its action should probably be considered more anti-inflammatory that proinflammatory.98 IL-7, a cytokine produced by bone marrow stroma, seems to be an important cytokine in the control of lymphocytopoiesis (for both T and B lymphocytes).99 IL-8 is produced by many types of cells after stimulation with a variety of exogenous inducers (e.g., endotoxin) and physiological inducers (IL-1 and TNF).100 In fact, this molecule is responsible for neutrophil-activating effects originally ascribed to IL-1. These neutrophilactivating effects are induction of directed migration, degranulation of specific granules, and superoxide production.100 IL-9, a 30- to 40-kDa glycoprotein produced by stimulated T-helper lymphocytes, stimulates proliferation of a restricted number of T-helper lymphocytes and of hematopoietic progenitor cells, especially those of the erythroid lineage.101–103 IL-10 is a 17- to 20-kDa cytokine produced by a number of cell types.104 It is a major anti-inflammatory cytokine, since it inhibits the macrophage-induced production of other cytokines, especially and TNF, and enhances the proliferative response of thymocytes and mast cells to IL-2 and IL-4.104 IL-10 also is involved in B-lymphocyte proliferation and function. IL-11 is a 20-kDa cytokine that resembles IL-6: it stimulates hematopoiesis and induces hepatic acute phase proteins. It has less of an effect on T and B lymphocytes. An interesting function is the protection of intestinal epithelium.105 IL-12 is a heterodimer composed of a 35-kDa and a 40-kDa subunit. It is one of the major cytokines. Thereby it plays a crucial role in host defense against intracellular pathogens such as mycobacteria and Salmonella spp.106 Its role in these infections has become apparent from recent reports of patients with a defective IL-12 receptor, who suffer from recalcitrant infections caused by these pathogens.107,108 IL-13 is a cytokine that resembles IL-4, in that it plays a role in IgE production by B lymphocytes. It stimulates differentiation of macrophages from precursors, but at the same time inhibits proinflammatory cytokine production.109 IL-14 is a 55-kDa molecule that stimulates the proliferation of B lymphocytes; it also has a role in the maintenance of B-cell memory.110 IL-15 induces proliferation

DEFECTS IN HOST DEFENSE MECHANISMS

and differentiation of B cells, T cells, NK cells, and mast cells.111,112 IL-16 is a product of CD8+ lymphocytes and attracts CD4+ lymphocytes. It seems to play a role in viral infection.113,114 IL-17 is a product of CD4+ cells and induces production of IL-6, IL-8, G-CSF, as well as prostaglandin E2 by a variety of cells. IL-17 also plays a role in neutrophil differentiation.115 IL-18 is related to the IL-1 family in terms of both structure and function. Similar to IL-1, IL-18 participates in both innate and acquired immunity. Formerly called factor, IL-18 plays an important role in the TH1 response, primarily by its ability to induce production in T cells and natural killer cells.116 Similar to IL-18 is synthesized as a biologically inactive precursor molecule, and the IL-18 precursor requires cleavage into an active, mature molecule by the protease called IL-1 beta-converting enzyme (ICE), which is also known as caspase-1.117 Mature IL-18 induces a variety of other proinflammatory cytokines and chemokines, e.g., IL-8, macrophage inflammatory and monocyte chemotactic protein-1 in mononuclear cells.118 There are accumulating data that IL-18 plays an important role in the innate host response to infection. 3.1.5b. Colony-Stimulating Factors. Colonystimulating factors (CSFs) are hematopoietic growth factors that are capable of stimulating the clonal growth of hematopoietic precursor cells in vitro.119,120 One of the CSFs, IL-3, has been discussed in the preceding section. Also available in recombinant form and for clinical use are three other growth factors: granulocyte–macrophage CSF (GM-CSF), granulocyte CSF (G-CSF) (see Section 9), and macrophage CSF (M-CSF). These CSFs stimulate proliferation and differentiation of cells from bone marrow and blood. GM-CSF is a 22-kDa glycoprotein produced by many types of cells, especially macrophages, endothelial cells, and T lymphocytes. With increasing concentrations of GM-CSF in vitro, growth of the precursor cells of mononuclear phagocytes, neutrophils, eosinophils, and megakaryocytes is stimulated.119,120 In addition, GM-CSF induces differentiation of granulocytes and mononuclear phagocytes and at high concentrations potentiates the microbicidal function of these cells.121 In vivo, GM-CSF is used to combat the neutropenia in AIDS and in hematologic disorders and to ameliorate the neutropenia induced during cancer chemotherapy and after bone marrow transplantation.119,120 Although enhanced neutrophil function has been found in humans after administration of GM-CSF,121,122 the clinical relevance of this finding has not been established. G-CSF, a 19-kDa protein produced by mononuclear phagocytes, fibroblasts, and endothelial cells, acts primar-

11

ily as a terminal differentiation and activation factor for neutrophils.119 G-CSF can induce oxygen metabolism in neutrophils123 (see Section 3.2.1f) and enhances survival of these cells. In humans, it has been used for the same indications as GM-CSF. By virtue of its selective effect on neutrophils, rG-CSF is an important therapeutic agent for patients with congenital or acquired neutropenia.120,124 In addition, rG-CSF is used to elicit white blood cells from donors, raising renewed interest in white blood cell transfusions in patients with neutropenia-related infections (see Section 9).125 Because of its capacity to activate neutrophils, rG-CSF is under investigation as a therapeutic agent in severe pneumonia and in disseminated candidiasis in patients without neutropenia.126,127 In addition to the proinflammatory effects on granulocytes, G-CSF has anti-inflammatory effects, since it inhibits proinflammatory cytokine production.128 M-CSF is a 70- to 90-kDa glycoprotein, which is a product of mononuclear phagocytes, fibroblasts, and endothelial cells. It promotes the growth of mononuclear phagocytes and stimulates macrophage function.119 The clinical experience with this molecule has been limited. 3.1.5c. Cytokine Network. The cytokines and growth factors discussed above interact with each other and with the interferons (see Section 3.1.4) in a complicated network. Many of these cytokines are able to induce each other in vivo. For example, IL-1 readily induces IL-6 and IL-8 (see Section 3.1.5a) and also induces itself in an autocrine and paracrine fashion (Fig. 3); in addition, it induces TNF.129 Apart from these positive-feedback loops, inhibitory loops also are activated. The most important inhibitors recognized so far for the cytokine network are the IL-1 receptor antagonist (IL-lra), the soluble receptors for TNF, and the induction of cytokines with anti-inflammatory properties, such as IL-4, IL-10, and 130–132 transforming growth The potential of these inhibitors of the cytokine network to interfere with deleterious cytokinemia and local cytokine responses (see Section 3.1.5) has been demonstrated by a large number of preclinical studies.133–136 In experimental infections in mice (especially leishmaniasis) two major cytokine patterns have been recognized and linked to production by certain types of T lymphocytes (see Section 3.2.3b): the so-called T-helper-1 (TH1 or type 1) response is characterized by production of IL-2, IL-12, and whereas the T-helper-2 (TH2 or type 2) response produces IL-4, IL-5, and IL-10.137,138 The TH1 response enhances host defense and immunity and the TH2 response dampens the immune response. In humans, immune responses to several chronic infections appear to polarize along TH1/TH2 lines as well.139 Although the TH1/TH2 concept is useful to give a simple

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description of the prevalent cytokine pattern, it is not very useful in infectious diseases in which a neutrophil response is crucial. Also a strict dichotomy, as originally proposed, is an oversimplification.140,141 In many clinical situations both patterns are found and thereby the concept loses its significance. It also does not take into account that many types of cells other than T-helper lymphocytes produce cytokines: macrophages, granulocytes, NK cells, endothelial cells, mast cells, and epithelial cells. Finally, the concept does not deal much with sequential production of pro- and anti-inflammatory cytokines. 3.1.6. Immunoglobulins The immunoglobulins, which make up the specific humoral response, are products of the B-lymphocyte system. During the development of the pre-B cells, clonal diversity is generated as a consequence of a series of gene rearrangements.142 In this way, the potential to generate millions of B-cell clones is created. On encounter with an antigen, certain B-cell clones expand to produce specific antibodies. Early in this response, IgG is secreted; during differentiation to the plasma cell stage, recombination or deletion of DNA may occur so that the other Ig classes (IgG, IgA, IgE, IgD) are produced and finally secreted. The functioning of B lymphocytes is controlled by regulatory T cells (see Section 3.2.3b) and various humoral B-cell growth and differentiation factors such as IL-1, IL-2, IL-6, IL-11, and IL-14 (see Section 3.2.3a). Some B cells do not differentiate into plasma cells but become long-lived memory B cells, which enable the body to produce an immediate antibody response to secondary exposure to the antigen. Immunoglobulins carry out their functions by means of antigen binding at the Fab sites on the Ig molecule. These functions include neutralization and agglutination of the antigen, complement activation and binding (see Section 3.1.2), prevention of epithelial attachment of the antigen, and mediation of endocytosis, i.e., opsonization (see Section 3.2.1e). Not all the different classes and subclasses of immunoglobulins carry out all these functions to the same extent. IgM is not in itself an opsonin; only when combined with complement factor C3b is this complex opsonic. Because of its pentameric structure, IgM is very efficient as an agglutinin. There are four IgG subclasses in humans; of these, IgGl and IgG3 bind C3b and are especially important as opsonins (see Section 3.2.1e). IgG2 and possibly IgG4 are thought to play a role as antibodies against microbial polysaccharides, e.g., those of the capsules of type B Haemophilus influenzae and Streptococcus pneumoniae.143,144

The IgA found on mucosal surfaces consists of equal amounts of the two subclasses IgAl and IgA2, produced locally by plasma cells in the mucosa; this secretory IgA is a dimer of two IgA molecules coupled by a small polypeptide, the J chain, with a secretory component that is a polypeptide produced by epithelial cells.145 Secretory IgA is not very opsonic; it prevents adherence of bacteria to the mucosal surface, inhibits the motility of bacteria, may agglutinate bacteria, and neutralizes enterotoxins and viruses.145 Of the two subclasses of IgA on the mucosa, only IgAl is cleaved by the IgA proteases produced by such bacteria as Neisseria gonorrhoeae, N. meningitidis, H. influenzae, S. pneumoniae, and S. sanguis.145 About 90% of the IgA in serum, which is produced by plasma cells in bone marrow, is of the IgAl subclass.146 The few IgA-bearing B lymphocytes in peripheral blood are probably on their way to the mucosal surfaces. The role of circulating IgA in host defense is unclear. IgE is normally present in the circulation in very low concentrations.147 This immunoglobulin plays a role in acute allergic reactions and helminthic infestation. Its production is under the control of IL-493 (see Section 3.1.5a). When antigen combines with IgE on mast cells and basophils, these degranulate and subsequently release a variety of amines (e.g., histamine). These products are responsible for increased vascular permeability and the influx of eosinophils. IgE also acts as a ligand for the killing of schistosomes by macrophages148; the ligand for killing of these organisms by eosinophils is not IgE, but IgG and complement.149 The role of circulating IgD is unclear. As an immunoglobulin on the surface of B cells (like membrane-bound IgM), it serves as a receptor for antigens.150 Clearly, the various immunoglobulin classes and subclasses play different roles in the handling of antigens. Therefore, a deficiency of all immunoglobulins, i.e., hypogammaglobulinemia, is associated with undue susceptibility not only to encapsulated bacteria, such as S. pneumoniae and H. influenzae (both of which exhibit tropism in the respiratory tract), but also to enteric pathogens such as species of Salmonella and Campylobacter.l51–153 In addition, there is susceptibility to the protozoa Giardia lamblia.154 These patients also find it difficult to cope with viruses such as poliovirus, echovirus, and rotavirus.155–157 Severe Mycoplasma and Ureaplasma infections have also been reported.158,159 Patients with selective IgA deficiency may suffer from recurrent respiratory infections and protracted giardiasis.160 Those with IgG subclass deficiencies, which may be associated with an IgA deficiency, exhibit a relatively high incidence of H. influenzae infections.144,161 Patients with IgM deficiency are especially at risk for

DEFECTS IN HOST DEFENSE MECHANISMS

meningococcal infections.162 Remarkably, not all cases of selective immunoglobulin isotype deficiencies are associated with repeated infections; many IgA-deficient persons are asymptomatic.160 For instance, an asymptomatic familial complete deficiency of IgAl, IgGl, IgG2, and IgG4 has also been reported.163 Primary immunoglobulin deficiency states are due to (1) B-cell defects (as in X-linked hypogammaglobulinemia, in which functional Bruton tyrosin kinase is lacking164), (2) abnormalities of T-cell subpopulations or macrophages (as in some cases of late-onset hypogammaglobulinemia) and their soluble products,165,166 (3) deficiency of molecules that are responsible for intercellular signaling between T and B lymphocytes (e.g., the crucial signaling molecule CD40 ligand),167,168 or (4) mechanisms that have not yet been elucidated. A more detailed account of the primary immunoglobulin-deficiency states and their treatment is given in Chapter 20. Secondary immunoglobulin deficiencies are defined as (1) disorders in which immunoglobulin synthesis is decreased, as occurs in chronic lymphocytic leukemia, multiple myeloma, and other lymphoproliferative diseases and to some extent after splenectomy (see Section 5.2), or (2) disorders with increased immunoglobulin catabolism associated with severe burns, proteinlosing enteropathies, and nephrotic syndrome. Administration of immunoglobulin to treat disorders with immunoglobulin losses is not beneficial in most cases. Tuftsin is a tetrapeptide (Thr-Lys-Pro-Arg) that binds covalently to the Fc portion of IgG.169 Its principal function is thought to be activation of phagocytes. To do this, tuftsin first must be freed from the immunoglobulin by the action of a splenic enzyme (tuftsin endocarboxypeptidase) and by the enzyme leukokinase, which is bound to the membrane of a neutrophil or mononuclear phagocyte. Its biological relevance is suggested by the occurrence of a congenital deficiency state associated with recurrent infections of the respiratory tract, skin, and lymph nodes.169 The infectious conditions associated with splenectomy can be explained in part by a failure to free tuftsin from its carrier, the immunoglobulin (see Section 5.2). Deficiency of tuftsin has been reported in AIDS; this finding could partially explain the human immunodeficiency virus (HlV)-infected patient’s susceptibility to encapsulated bacteria.170 3.2. Cellular Defense Mechanisms 3.2.1. Phagocytic Cells Phagocytic cells are the cells of the granulocytic series (neutrophilic granulocytes and eosinophilic granu-

13

locytes) and the mononuclear phagocytes. The development of these cells is shown in Fig. 4. 3.2.1a. Kinetics of Neutrophilic Granulocytes. The proliferation of neutrophil precursors is under the control of hematopoietic growth factors such as IL-3, GM-CSF, and G-CSF (see Section 3.1.5).171 In the neutrophilic granulocyte series, it takes approximately 6 days for metamyelocytes to form by sequential division and another 6 days for the metamyelocytes to mature into polymorphonuclear granulocytes.172 A large number of neutrophils (approximately 10 times the circulating population) remain in the bone marrow as a reserve that can be released into the circulation when there is an inflammatory stimulus. The neutrophils that enter the circulation are distributed over two compartments: one consisting of free circulating neutrophils (circulating pool) and the other of neutrophils that adhere loosely to the vascular endothelium (marginating pool).171 Under normal circumstances, the two pools are of approximately equal size and in dynamic equilibrium. Several factors can influence the pool sizes by disturbing adherence to the endothelium. Epinephrine and the glucocorticosteroids are potent inhibitors of margination.173 C5a (the chemotactically active cleavage product of complement factor C5) plays a key role in the margination of neutrophils.174 The process of neutrophil extravasation requires a cascade of sequential events between neutrophils and endothelial cells, that usually are divided into four steps (Fig. 5).175,176 After an inflammatory stimulus, the first step of the neutrophil adhesion cascade is principally mediated by the selectins. L-selectin, expressed on neutrophils, E-selectin and P-selectin, both expressed by activated endothelial cells, interact with their mucinlike ligands and circulating neutrophils begin to roll over the endothelial cell surface.177 In step 2, neutrophils become activated by locally produced tissue-derived factors (e.g., chemokines). This process leads to both shedding of L-selectin and activation of specific leukocyte integrins, such as very late activation antigen 4 (VLA-4), Mac-1, and leukocyte function-associated molecule 1 (LFA-1). In the third step, the interaction of these activated integrins on neutrophils with their ligands on endothelial cells— vascular cell adhesion molecule 1 (VCAM-1) with VLA-4 and intercellular adhesion molecule 1 (ICAM-1) with Mac-1 and LFA-1—causes the firm adhesion of neutrophils to the endothelium. Finally, leukocytes migrate between the endothelial cells and invade the tissues.175,176 The magnitude of the marginating pool is also principally regulated by the selectins.171 The transient neutropenia that occurs during hemodialysis is the result of complement activation by the dialyzer membrane and subsequent neutrophil margination and sequestration in the pulmo-

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nary circulation.178 Neutrophils disappear randomly from the circulation into the tissues with a half-life of approximately 6 hr; in the tissues, they are estimated to survive approximately 1–3 days.172 3.2.1b. Kinetics of Eosinophils. The eosinophilic granulocytes most probably develop from their own com-

mitted stem cells (Fig. 4).179 The proliferation and maturation of eosinophilic precursors is under the control of IL-3, GM-CSF, and IL-5.180 The time needed for proliferation, maturation, and circulation seems to be similar to that described for neutrophils.180 Eosinophils become activated by exposure to IL-5 and activated eosinophils

DEFECTS IN HOST DEFENSE MECHANISMS

themselves are capable of producing a variety of cytokines, such as IL-3, IL-5, GM-CSF, IL-6, IL-8, as well as mediators such as leukotriene C4 and platelet-activating factor.181 Autocrine cytokines inhibit apoptosis of eosinophils, leading to a prolonged survival in the tissues of 12– 14 days, as opposed to a normal cell survival of 48 hr.182 The cause of persistent eosinophilia and the hypereosinophilic syndrome is unknown. Recent studies suggest that in patients with the hypereosinophilic syndrome, a clone of abnormal T cells produces large amounts of IL-5, which may cause the eosinophilia.183 3.2.1c. Kinetics of Mononuclear Phagocytes. Mononuclear phagocytes also derive from the bone marrow.184 Monoblasts185,186 divide to form promonocytes, which divide and form monocytes. Without further maturation, the monocytes enter the circulation, which they leave again with a half-life of approximately 70 hr.187 In the tissues where these cells differentiate into one of the various types of macrophages, they survive for several weeks.184 The macrophages, together with their precursor cells, form the mononuclear phagocyte system (MPS)188 depicted in Fig. 6. The reticuloendothelial system, a

15

grouping of macrophages, reticulum cells, fibroblasts, endothelial cells, and other cells of divergent origin proposed by Aschoff, is considered an outdated concept. It is uncertain whether the Langerhans cell in the skin, the veiled cell in the afferent lymph, and the interdigitating cell in the lymph nodes and spleen are mononuclear phagocytes.188 3.2.1d. Kinetics of Phagocytes during Inflammation. During an acute inflammation, an increase in phagocytes is observed at the site of inflammation. Neutrophils and sometimes eosinophils first appear in the inflammatory field, followed by an increasing number of macrophages. The formation of this inflammatory exudate is the result of various mechanisms. Activation of several inflammatory humoral factors (e.g., kinins, cytokines, prostaglandins, complement factors) leads to increased local blood flow and increased vascular permeability. Humoral factors (especially C5a, leukotriene B, IL-8 and related cytokines, and bacterial products) attract neutrophils and mononuclear phagocytes (chemotaxis).190 In the blood, neutrophilia develops as a result of the release of the marrow reserve as well as increased

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granulocytopoiesis. Several humoral factors (e.g., IL-1) seem to play a role in the induction of this granulocytosis.80 Monocytopoiesis also is stimulated; humoral factors produced by tissue macrophages seem to be responsible.191 In humans IL-10 injection is followed by monocytosis.192 Generally, eosinopenia is observed initially during the inflammatory response.179 Under certain conditions (e.g., metazoal infection), eosinophilia and eosinophil accumulation in the tissues occur; IL-5 appears to be a major factor in this process.95 3.2.1e. Endocytosis. Endocytosis is the cellular uptake of materials, such as microorganisms, debris, immune complexes, effete red blood cells, and tumor cells by engulfment via the cell membrane. It can be subdivided into (1) pinocytosis (drinking by cells) and (2) phagocytosis (eating by cells). Pinocytosis is the uptake of small particles in small vacuoles. For the uptake of many kinds of molecules, pinocytosis is a receptormediated process. Monocytes and macrophages, fibroblasts, endothelial cells, hepatocytes, and various other cells are able to perform pinocytosis; granulocytes are believed incapable of pinocytosis. Phagocytosis is the uptake of particles larger than It is a receptor-mediated process, which means that the particles that are taken up bind to receptors on the cell membrane either directly or by means of ligands. The most efficient uptake occurs via the receptor and the C3b receptor with IgGl, IgG3, and C3b as ligands or opsonins (Fig. 7). Thus, the first step is the binding of the opsonins to the particle. IgM is not in itself an opsonin,

since there are no receptors for the Fc portion of IgM on phagocytic cells (see Section 3.1.6). However, C3b can bind to IgM and then to the C3b receptors on the phagocyte, thereby mediating endocytosis. Fibronectin may be an opsonin as well (see Section 3.1.3). Binding of the opsonins to a series of receptors in a zipperlike fashion193 leads to engulfment of the particle (Fig. 7). The pseudopods of the cell close around the particle until it is enclosed in a vacuole, the phagosome. The rate of ingestion by neutrophils is greater than that by monocytes and macrophages.194 Eosinophils also are slower phagocytes than are neutrophils.179 3.2.1f. Intracellular Killing. As soon as the particle (or the opsonins) makes contact with the cell membrane, oxidases in the membrane are triggered to activate oxygen-dependent microbicidal mechanisms.195 Substances such as superoxide hydrogen peroxide and hydroxyl radical are formed. During and after ingestion, the lysosomes (granules) fuse with the phagosome and pour their enzymes into the vacuole (degranulation) (Fig. 7). The lysosomal enzymes196 react with the ingested particle. One lysosomal enzyme, myeloperoxidase, triggers the reaction of with chloride, which yields the potent microbicidal product hypochlorite. A number of antimicrobial polypeptides in the lysosomes (e.g., cathepsin G, elastase, lysozyme, and defensins) contribute to microbial killing in an oxygen-independent way.197 The formation of reactive nitrogen products, especially nitric oxide (NO), from L-arginine represents another potent microbicidal mechanism. The production of these products is under the control of inducible nitric oxide synthase (iNOS); iNOS is stimulated by cytokines such as TNF. The evidence regarding the role of NO in intracellular killing, especially of mycobacteria, comes from studies in rodents; its status in humans is less clear.198 Peroxynitrite is a combined product of and has microbicidal activity, e.g., against Candida species.199,200 Inhibition of the pathways for either or NO production inhibits microbial killing by Production of by macrophages is under the influence of During the process of phagocytosis and intracellular killing of microorganisms, neutrophils usually die and are taken up by macrophages, which have a greater ability to survive and which digest much of the endocytosed material enzymatically. Certain microorganisms are not readily killed by normal macrophages, but can be digested when the latter are activated by products of stimulated T lymphocytes. These mechanisms are discussed in Section 3.2.3c. Eosinophils are able to kill several species of meta-

DEFECTS IN HOST DEFENSE MECHANISMS

zoa, this killing being largely an extracellular event. After attachment of the eosinophil to the parasite, a process mediated by IgE and probably also by complement, the parasite is damaged by exocytosed products of the eosinophil; in particular, major basic protein, eosinophil cationic protein, eosinophil peroxidase, and oxidative products.180 IL-5 (see Section 3.1.5a) activates the effector function of eosinophils.95 3.2.1g. Clearance of Particles from the Bloodstream. The preceding sections described phagocyte function in the inflammatory field. However, there remains an important question: What happens to foreign particles (e.g., bacteria) that have gained access to the bloodstream? Circulating neutrophils and monocytes do not seem to play an important role in the elimination of such substances; macrophages in the liver (Kupffer cells) and spleen are especially important, however, for the uptake of this material.201 The rate of clearance by these macrophages is dependent on the nature of the material, i.e., their charge and chemical composition, which determine binding to macrophage receptors or ligands (opsonins). In addition, the availability of opsonins and the functional state of the macrophages are important for the rate of clearance.202,203 Opsonins not only increase the rate of clearance but also determine the site of uptake; particles opsonized by IgG are taken up mainly in the spleen, whereas C3b causes binding by Kupffer cells.201,204 3.2.1h. Other Functions of Phagocytes. Neutrophils contain two types of lysosomes, i.e., primary (azurophilic) granules and secondary (specific) granules, both of which contain different enzymes.196 The primary granules tend to fuse with phagosomes (see Section 3.2.1f). Degranulation of specific granules, however, occurs earlier, at the time of nonspecific surface contact (e.g., during diapedesis), and the enzymes (e.g., lysozyme, lactoferrin, and vitamin protein) are released extracellularly by exocytosis.196 In addition, cytokines like IL-1 and IL-1ra are produced and secreted by neutrophils. The secretory capacity of macrophages, however, is much greater. IL-1, TNF, IL-6, IL-8, IL-10, and other cytokines (see Section 3.1.5a), procoagulant factor, various complement factors, prostaglandins and other arachidonate metabolites, growth factors, and many other substances, in addition to the lysosomal enzymes, are secretory products of macrophages.205 Apart from this secretory function, macrophages play a role in the processing and presentation of antigen to T cells206,207 (see Section 3.2.3a). 3.2.1i. Deficient Phagocyte Function. The phagocytic cells constitute such a major defense system against infections that when there is a numeric or functional deficiency of these cells, bacterial or fungal infec-

17

tions are almost inevitable. A shortage of circulating neutrophils, as in idiopathic neutropenia, aplastic anemia, drug-induced agranulocytosis, and leukemia, predisposes to bacterial and fungal infections. There is a quantitative relationship between the number of circulating neutrophils and the incidence of infection208,209: at concentrations below and even more so below there is a high risk for these infections among patients with leukemia and aplastic anemia and to a lesser extent idiopathic granulocytopenia.210 This difference in susceptibility to infection can probably be explained by the presence of damaged mucosa resulting from cytotoxic therapy for leukemia, such damaged mucosa providing an easy route of entry for microorganisms. In idiopathic granulocytopenic patients, the normal or even elevated monocyte counts also may compensate for the defect. In neutropenia, infectious complications usually arise insidiously, with little or no inflammatory signs and without formation of pus. Such infections usually run a fulminant course (see Chapter 15). Qualitative defects can affect the various steps of the phagocytic process (see Fig. 6), each of which can be assessed in the laboratory. Congenital defects of adhesion molecules exist, e.g., LAD type 1 syndrome, which is 211 caused by a defect in the and LAD type 2, which is caused by a defect in the fucosylation of the ligands for the selectins.212 As in the case of deficiency of chemotactic factors (e.g., C3 or C5) and defective chemotaxis (either congenital or acquired), these syndromes also are associated with recurrent bacterial and fungal infections. The congenital defects are more extensively reviewed in Chapter 14; the acquired defects are discussed in Sections 4–9. During the late 1950s, it was shown that a delay in the migration of neutrophils of no more than 2 hr has a devastating effect on experimental infections.213 In patients with defective chemotaxis, purulent infections of the skin, subcutaneous tissues, lymph nodes, and lungs are commonly encountered, whereas septicemia is a rare event. Staphylococcus, Streptococcus, Candida species, and Escherichia coli are the major pathogens. Opsonization of S. pneumoniae and H. influenzae in particular is impaired in hypogammaglobulinemia (see Section 3.1.6). C3 deficiency also leads to impaired opsonization and clinically to purulent infections caused by gram-positive and gram-negative bacteria as well as fungi. Similar opsonic defects may develop during massive complement consumption (see Section 3.1.2). Low plasma concentrations of fibronectin, as observed in shock, septicemia, and trauma, probably should not be considered indicative of a hypo-opsonic state60 (see Section 3.1.3).

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Primary defects of endocytosis by granulocytes and mononuclear phagocytes are rare, but a number of disease states and drugs have been reported to affect endocytosis (see Sections 4–7). Moreover, it has been well established in in vivo experiments that the uptake of particles from the circulation by macrophages can easily become saturated.203 Patients with systemic lupus erythematosus (SLE) and other diseases in which circulating immune complexes are present214–218 exhibit impaired clearance, probably due to saturation of receptors by the circulating complexes. Decreased Fc-mediated clearance has been found in end-stage renal disease219 and also in AIDS.220 Certain histocompatibility antigens (especially HLAB8/ DR3 and DR2 haplotypes) have been associated with an Fc-receptor defect.221,222 In primary biliary cirrhosis, defective C3b-mediated clearance has been demonstrated.223 Impaired clearance of injected material (e.g., labeled aggregated albumin) has been described in alcoholic liver cirrhosis.224–226 Fat emulsions administered intravenously (Intralipid) have been shown to produce mononuclear phagocyte blockade227; this blockade could contribute to greater susceptibility to generalized infection and possibly to a poor outcome of infection as well. High doses of intravenous gammaglobulin preparations may block Fc receptors in idiopathic thrombocytopenic purpura.228 Such a mechanism could have a negative impact in compromised hosts receiving such preparations (e.g., hypogammaglobulinemic patients and bone marrow transplant recipients). Clinically, these gammaglobulin preparations seem to cause no such problems. Moreover, no evidence of Fc-receptor blockade was found in hypogammaglobulinemic patients treated with intravenous immunoglobulin.229 Defects of intracellular killing may be congenital or acquired; the congenital abnormalities such as chronic granulomatous disease are discussed in Chapter 14. Some of the acquired abnormalities of intracellular killing are discussed in Sections 4–8. 3.2.2. Natural Killer Cells NK cells, which originate in bone marrow and probably belong to the lymphocyte series, are able to kill certain virus-infected cells as well as tumor cells.230 These cells are not phagocytic and can carry out their cytotoxic function without previous sensitization, without involvement of the major histocompatibility system, and in the absence of antibody and complement. Phenotypically, they are described as large granular lymphocytes.230 Killing of target cells is mediated by so-called perforins, originating from the granules. These substances are similar to the membrane attack complex of the terminal path-

way of the complement cascade (see Section 3.1.2), in that they penetrate cell membranes and produce cell lysis.231 The relative role of NK cells in host defense in vivo is not precisely known, but susceptibility to certain viruses [e.g., herpes simplex virus, cytomegalovirus (CMV)] can be correlated with NK-cell activity.232,233 Deficient NK cell function is found in AIDS234 (see Section 5.8). An important interaction is that between the IFNs, IL-2, and NK cells, in which the activity of the latter is enhanced.62,230 NK cells produce cytokines like IL-1 and Since these killer cells have receptors for IgG, they also may function as killer cells in the presence of antibody, i.e., antibody-dependent cellular cytotoxic ity.230 3.2.3. Cellular Immunity Cellular immunity consists of a number of effector mechanisms in which T lymphocytes and macrophages interact. 3.2.3a. Initiation of Cellular Immune Response. To initiate an immune response in T lymphocytes (and B lymphocytes) (see Section 3.1.5), most antigens have to be processed and presented by accessory cells.206 Mononuclear phagocytes act as accessory cells; in addition, dendritic cells235 and Langerhans cells in the skin236 (see Fig. 6) also present antigen efficiently. Whether the latter two cell types belong to the mononuclear phagocyte system is uncertain.188 T cells of the helper–inducer type recognize antigen only when it is presented on the membrane of the antigen-presenting cell together with an HLA-class II molecule: HLA-D(R), HLA-DP, HLA-DQ (Fig. 8). For the activation and proliferation of T cells that respond specifically to a certain antigen, a number of cytokines, adhesion molecules (LFA-1, ICAM), and other accessory molecules (CD40, Fas) are required. For instance, antigen-stimulated macrophages release IL-1, IL-6, IL-12, and IL-18, which trigger the activation and proliferation of T lymphocytes.80,96,116,237 Once triggered by antigen, IL-1, and IL-6, T lymphocytes produce IL-2 90,237 and which induces clonal expansion of activated T lymphocytes that respond to that specific antigen (Fig. 8). 3.2.3b. T Lymphocytes. T lymphocytes can be divided into effector T cells and regulatory cells238 (see Fig. 8). Of the effector T cells, the cytotoxic T cells have been well characterized. These cells are able to kill virusinfected cells and tumor cells in the absence of antibody. For recognition of the target by cytotoxic T cells, class I (HLA-A, HLA-B, HLA-C) molecules must appear together with the antigen.239 Since HLA class I molecules are expressed on every nucleated cell, this effector mech-

DEFECTS IN HOST DEFENSE MECHANISMS

anism could be operational against all kinds of virusinfected cells. Another effector T cell is the T cell that plays a role in delayed-type hypersensitivity (DTH) reactions and produces lymphokines that activate macrophages. Regulatory T cells can be subdivided into T-helper– inducer cells (synonym: T-helper cells) and suppressor T cells.238 The helper–inducer cells regulate the proliferation and differentiation of not only effector T cells but also B cells (Fig. 8). During differentiation, T lymphocytes express phenotypically stable antigens that are easily recognizable with commercially available monoclonal

19

antibodies. However, it should be kept in mind that these phenotypes cannot be directly associated with function. For example, the CD4-positive population contains not only helper cells but also effector cells as well as suppressor–inducer cells.240 T lymphocytes are important producers of cytokines and this property has been the basis for the TH1/TH2 concept, discussed in Section 3.1.5c. 3.2.3c. Activated Macrophages. With the microbicidal systems (see Section 3.2.1f), normal macrophages will not be able to kill a number of microorganisms. These microorganisms, which include protozoa (Toxoplasma gondii, Leishmania spp., Trypanosoma spp.), fungi (Histoplasma capsulatum, Cryptococcus neoformans, Pneumocystis carinii), bacteria (Mycobacteria, Listeria monocytogenes, Salmonella spp., Brucella spp., Legionella spp.), Chlamydia, and viruses, survive and even replicate inside the macrophages of a nonimmune individual.241,242 When T-cell immunity arises, activated T-helper cells will produce cytokines, such as IL-12,237 65 and TNF243 (see Sections 3.1.4 and 3.1.5a), that activate the macrophages65,244 (Fig. 8). On activation, several events take place in the macrophages; the oxygendependent and oxygen-independent (e.g., nitrogen products) microbicidal mechanisms (see Section 3.2.If) become fully activated, leading to killing of the intracellular pathogens. 3.2.3d. Defective Cellular Immunity. All components of the cellular immune system are crucial to optimal functioning. Thus, abnormalities of, or even an imbalance among, regulatory T cells, effector T-cell deficiencies, deficient signaling between cells, and macrophage dysfunction may lead to decreased cellular immunity. Quite a number of molecular defects leading to cellular immunodeficiency have been discovered in recent years.245 Examples are defects of the intracellular signaling pathways in T cells,246 or intercellular signaling molecules, such as CD40/CD40 ligand167 and Fas–Fas ligand,247,248 or receptor defects, such as defects of the IL-12 and receptor.77,78,107,108,249 (see also Section 3.1.5a). It should be stressed that not all disturbances of this delicate network necessarily lead to a state of cellular immunodeficiency. The most impressive acquired deficiency of helper T cells is AIDS, in which the retrovirus HIV infects and destroys these T lymphocytes (see Section 5.8 and Chapter 16). In severe, chronic, inflammatory disease states (e.g., sarcoidosis250), an imbalance among regulatory T cells has been demonstrated. In some immunodeficiency states (congenital as well as acquired disorders), both the cellular and humoral immunities are defective. The quality of cellular immunity in patients can be measured to

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CHAPTER 2

some extent with both in vitro and in vivo tests. An important in vitro test is still the lymphocyte transformation study using T-cell mitogens such as anti-CD3, phytohemagglutinin, and concanavalin A as well as anamnestic antigens. To sort out the nature of a defect, more sophisticated tests can be performed. Assessment of the intra- and intercellular signaling pathways is becoming increasingly important in the workup of presumed cellular immune defects.251 Measurement of macrophage activation in patient material is difficult. In vivo tests include measurement of DTH skin reactions to recall antigens such as tuberculin, varidase, trichophyton antigen, Candida antigen, and mumps antigen, as well as a primary antigen such as Helix pomata hemocyanin,252 after sensitization. A person who does not respond to the antigens is called “anergic.” In the face of true cellular immunodeficiency, infections caused by viruses and the intracellular pathogens (see Section 3.2.3c) may ensue. The relative importance of these pathogens is reflected by the fact that many are discussed in separate chapters of this volume. The congenital immunodeficiency diseases with major deficiencies of cell-mediated immunity (CMI) are discussed in detail in Chapter 14. Acquired disturbances of cellular immunity occur as a result of (1) malignant diseases involving the lymphoid system or the mononuclear phagocyte system, e.g., Hodgkin’s disease and non-Hodgkin’s lymphoma (see Section 5.1); (2) treatment with immunosuppressive drugs, e.g., glucocorticosteroids, azathioprine, cyclophosphamide, and cyclosporin A (see Section 6.2.2); (3) viral infections, such as cytomegalovirus (CMV) infection, Epstein–Barr virus (EBV) infection, probably hepatitis C, and especially HIV infection (see Section 5.8); (4) pregnancy253; (5) high estrogen status254; (6) protein energy malnutrition (see Section 4.2); and (7) aging (see Section 4.3). The mechanisms behind these states of cellular immunodeficiency are rather complex and differ in the various conditions mentioned, since they may involve either regulatory T cells, effector T cells, macrophages, soluble factors such as cytokines (production as well as response), or combinations thereof.

4. Factors that Influence the Quality of Host Defense

4.1. Genetic Control of Host Defense against Infection The quality of the defense against a variety of microorganisms appears to be under genetic control. Animal experiments have demonstrated that genetic susceptibility and resistance involves various aspects of the humoral

and cellular immune responses.255 Also in humans, it is likely that susceptibility to most microorganisms is determined by a large number of polymorphic genes.256 The degree of the antibody response to a series of antigens is associated with HLA and also with certain immunoglobulin allotypes (i.e., genetically variable markers within immunoglobulin molecules257). There is circumstantial evidence that survival during epidemics is under control of the HLA system.258 In this context the association between certain common West African HLA antigens and protection from severe malaria may be relevant.259 The HLA-DR background may directly control the quality of antigen presentation; however, since the genes for cytokines like and lymphotoxin are located closely to those of HLA-DR, some of the effects of HLA on disease susceptibility may be due to genetic polymorphism of these cytokines.260 For susceptibility to severe malaria and fulminant meningococcal infection, genetic polymorphism of cytokines such as and IL-10 has been investigated directly.261 From the published data no clear picture has emerged so far and more studies are awaited. The genetic polymorphisms of Fc receptors and the control of the Fc-receptor function of phagocytic cells by HLA haplotypes are discussed in Section 3.2.1i. Another example of genetic surveillance of immune reactivity is encountered in mycobacterial diseases, notably tuberculosis and leprosy. Already many years ago it was found that the HLA type seems to determine the type of disease that develops.262 More recently a number of exciting discoveries have addressed the role of the NRAMP1 gene in host defense to infections. In mice, natural resistance to infection with some mycobacteria is influenced by the gene for naturalresistance-associated macrophage protein 1 (Nramp1), but the exact role of the human homologue of this gene, NRAMP1, in tuberculosis is unknown. Four NRAMP1 polymorphisms were each significantly associated with susceptibility to tuberculosis in West Africa.263 Genetic polymorphisms of molecules such as the vitamin D receptor,264 as well as the receptor and the IL-12 receptor determine severity and outcome of mycobacterial infection.77,78,107,108,249 Despite these developments, our knowledge of the genetic control of host defense is still too limited to be taken into account clinically,265 with the exception of administering recombinant cytokines such as in case of clear deficiency of or its inducers.107

4.2. Nutritional Status Quantitatively inadequate protein-energy nutrition is an important problem in the world, not only for inhabi-

DEFECTS IN HOST DEFENSE MECHANISMS

tants of developing countries but also in many patients with a severe underlying illness requiring intensive treatment. In these patients, host defense mechanisms may deteriorate further, because malnutrition has an important impact on host defense and may lead to infectious complications. Chandra266 has provided an impressive list of infections that are influenced by nutritional status. Of these, tuberculosis, bacterial diarrhea, bacterial and viral respiratory infections, Pneumocystis carinii infection, candidiasis, and aspergillosis should be mentioned. Host defense defects that are produced by protein-energy malnutrition are dependent on the degree of malnutrition and can be summarized from the vast amount of literature as follows266,267: 1. The skin and mucous membrane barriers may become somewhat impaired by thinning of the mucosa with a low lysozyme concentration and decreased secretory IgA levels. 2. Both pathways of the complement system are invariably impaired, which affects chemotaxis and especially opsonization. 3. Apart from the previously mentioned decrease in secretory IgA, the immunoglobulin levels and the antibody response to most protein antigens are normal. 4. Although the microbicidal function of neutrophils has been reported to be reduced, it is doubtful whether this reduction contributes to the increased susceptibility to infection. 5. Depressed NK cell activity has been found in malnourished children.268 6. Distorted thymic morphology, deficiency of some thymic factors, and an insufficiency of regulatory T cells (especially helper T cells) are probably responsible for the observed disorder of CMI. 266

A shortage of some vitamins may affect CMI. There is now good evidence that vitamin A supplementation to children with mild vitamin A deficiency has an important impact on mortality from infection.269–272 Deficiencies of trace elements also may further impair host defense in already compromised patients. Zinc deficiency produces disturbed T-cell function, at least in experimental animals, and increases their susceptibility to Listeria and Salmonella species.273 It is important to remember that zinc deficiency—believed to be responsible, at least in part, for the immunosuppression in proteinenergy malnutrition—has been reported during total parenteral nutrition274 and in sickle cell anemia (see Section 5.3). Supplements of zinc have been shown to affect the functions of phagocytic cells as well as those of T cells.274

21

Whether iron deficiency leads to a significantly increased susceptibility to infection in humans is uncertain.275 However, killing of microorganisms by neutrophils and abnormal function of T lymphocytes have been found in patients with iron deficiency.275,276 In contrast, iron repletion and iron overload predispose to infection, probably by making iron available to microorganisms as a nutrient.277 This phenomenon had been observed already by Trousseau in the 19th century (cited by Murray et al.277). Iron is an essential growth factor for most bacteria. The organisms obtain iron by producing chelators called “siderophores,” which bind iron for uptake into the bacteria. Several microorganisms, such as Yersinia enterocolitica, are thought to be of low virulence because they lack siderophores. During iron overload, listeriosis and severe yersiniosis have been reported, as well as the rare but severe infection with the fungi of the class of Zygomycetes, zygomycosis or mucormycosis 278,279 These infections are seen particularly in patients treated with deferoxamine, since this agent can be utilized by the microorganisms as an exogenous siderophore, leading to increased iron uptake and enhanced outgrowth. A phosphate deficit, which may occur during intravenous hyperalimentation, is associated with a decrease in the chemotactic, phagocytic, and microbicidal functions of granulocytes and clinically with fungal and bacterial infections.280 Intravenous fat emulsions, which are associated with coagulase-negative staphylococcal bacteremia and Malassezia furfur fungemia,281,282 are able to suppress the oxidative metabolism in neutrophils283; their effects on the mononuclear phagocyte system are discussed in Section 3.2.1i. In addition, lipoproteins enhance the growth of Candida albicans both directly and by interfering with plasma candidastatic factors.284 4.3. Age and Host Defense Human beings are most susceptible to infection at the two extremes of life. Neonates can be considered compromised hosts, since they have an important route of entry for microorganisms (i.e., the umbilicus), a blood– cerebrospinal fluid barrier that allows bacteria easy access to the meninges, and immature host defense mechanisms. Of the latter, the initial absence of IgM and IgA, the weak antibody response to polysaccharide antigens,285 the lower levels of complement factors (especially factors of the alternative pathways286,287), and the inadequate functioning of the phagocytic cells288–291 are crucial. The chemotactic activity of both polymorphs and monocytes is low.292,293 Cord blood serum does not provide optimal opsonization of microorganisms that require activation of the alternate complement pathway (e.g., E. coli).287 Pha-

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gocytosis is generally normal, with the exception of the phagocytosis of group B streptococci by neonatal monocytes.291 The microbicidal function of granulocytes and monocytes in newborns is a controversial subject. Marodi et al.291 showed normal killing of E. coli, S. aureus, and group B streptococcus by neonatal granulocytes; for monocytes, they found defective killing of S. aureus and group B streptococcus and normal killing of E. coli. The relative importance of abnormal antigen presentation by monocytes, defective production, and NK cell function in neonates is difficult to assess.68,294–296 In the elderly, the decline in the quality of the first line of defense (i.e., atrophy and dryness of skin and mucous membranes), reduced vitality, and increased risk for trauma, together with retardation of the repair process, should probably be regarded as the major causes of increased susceptibility to infections. In addition, the primary and secondary humoral responses297,298 have been reported to be reduced. Also, there is evidence for reduced oxidative metabolism of the neutrophils, which interestingly can be improved by the addition of recombinant growth hormone.299 In aged individuals, CMI is suboptimal, probably due to impaired T-cell function.300,301 The extent to which these changes in the second line of defense play a role in susceptibility to infection and outcome is unclear.

4.5. Stress and Host Defense It is a common belief that psychological stress suppresses host defense against infection. Indeed, there is evidence that psychological stress has an influence on the function of T cells and NK cells.307,308 The effects are most likely mediated by endogenous opioids, the hypothalamic–pituitary–adrenal axis, catecholamines, heat-shock proteins, and cytokines like IL-1.308–311 The question whether psychological stress leads to an increased susceptibility to infection has been the subject of several studies (reviewed by Swartz309). It was demonstrated that psychological stress was associated with an increased risk of acute viral respiratory illness, a risk that was related to the amount of stress.312 The effects of stress were consistent but small. There is no information on nonviral infections and on susceptibility in the already compromised host.

5. Diseases that Affect Host Defense Throughout this chapter, diseases that affect the particular host defense mechanisms have been mentioned. In this section, a number of disease states associated with suppressed host defense mechanisms are discussed. 5.1. Leukemia and Lymphoma

4.4. Body Temperature and Host Defense Elevated body temperature directly affects the susceptibility to infection. First, the replication of certain viruses and bacteria is inhibited at higher temperatures.302 Microorganisms may require more iron for growth at elevated temperatures.275 Antibody synthesis as well as T-cell proliferation and function increase at higher temperatures.303,304 These effects are explained by the greater efficacy of pyrogenic cytokines like IL-1 (see Section 3.1.5a) at higher temperatures. By contrast, NK cell activity seems to be impaired at higher temperatures.305 Both production and activity of IFNs appear to be enhanced at higher temperatures.306 The effects of elevated temperatures on the function of phagocytic cells are less straightforward, but in general, phagocytosis and intracellular killing are more efficient at higher temperatures.306 Thus, whether fever is beneficial in humans is clearly a difficult judgment; the answer most likely depends to a great extent on the type of infection. Appropriate management of body temperature could be important for compromised hosts, but our knowledge in this respect is still too limited to make this statement with certainty.

The number of granulocytes is not the only factor that determines the susceptibility to infection in acute leukemia (see Section 3.2.1i); other factors include mucosal damage due to cytotoxic therapy, concomitant monocytopenia and lymphopenia, tissue infiltration leukemic cells, leukostasis in the vasculature, and use of intravascular catheters. Bone marrow transplantation (BMT), an important therapeutic approach to acute leukemia, aplastic anemia, severe combined immunodeficiencies, and a number of inborn errors of metabolism, is accompanied by a series of infectious complications, depending on the phase of the BMT procedure.313 Soon after BMT, there are infections associated with granulocytopenia and indwelling intravascular catheters; herpes simplex infections may also occur. If graft-versus-host disease of the intestinal tract develops, bacteremia and fungemia may arise in the gut. After BMT, there is a state of severe T-cell dysfunction,314 during which CMV and varicella–zoster virus (VZV) infections are frequently encountered. Since the B-cell function is suboptimal314 and there is little humoral immunity left after BMT, severe pneumococcal infections

DEFECTS IN HOST DEFENSE MECHANISMS

may develop after the patient is released from the hospital. A more detailed account of these infectious conditions and the management of such patients is given in Chapter 15. In chronic lymphocytic leukemia, hypogammaglobulinemia may become so severe that recurrent infections caused by Pneumococcus and Haemophilus influenzae develop (see Section 3.1.6). Despite these infectious complications, immunoglobulin substitution in these cases does not seem to be cost-effective.315 Similar problems may be encountered in other B-cell malignancies, such as myeloma. In hairy cell leukemia, infections caused by intracellular microorganisms, especially mycobacteria, are prominent and point to T-cell dysfunction.316 In Hodgkin’s disease, T-cell function is disturbed because of an excess of T-suppressor cells, particularly in the advanced stages and in certain histologic types of the disease.317 T-cell dysfunction decreases CMI, which can be measured both in vitro and in vivo. Infections with intracellular microorganisms, especially VZV, thus can be explained. In Hodgkin’s disease, the significance of a circulating inhibitor of chemotaxis318 for the susceptibility to infection is unclear. Chemotherapy and radiotherapy cause not only impairment of T-cell function (see Sections 6 and 8) but also a decrease in the ability to mount specific antibodies against H. influenzae B.319 In addition, splenectomy may enhance the risk of fulminant pneumococcal and H. influenzae infections (see Section 5.2). Although not yet studied as extensively, the host defense defects in other lymphoproliferative disorders are very likely to be quite similar to those found in Hodgkin’s disease. 5.2. Splenectomy

For patients undergoing splenectomy during a staging procedure for hematologic malignancy or for treatment of acquired hemolytic anemia or thalassemia, the risk that they will develop overwhelming septicemia some time during their life is approximately 5%.320–322 This risk is much lower after splenectomy due to traumatic rupture of the spleen. The septicemia is caused mainly by S. pneumoniae and H. influenzae, but the presence of such microorganisms as Meningococcus, Staphylococcus, and Capnocytophaga canimorsus (formerly DF2 bacillus) also has been reported.320–323 The reasons for this increased susceptibility seem to be manifold. First, the architecture of the spleen is such that it can be considered as a sieve, in which macrophages are present at strategic positions. It is the most important organ for the removal of particles that are not opsonized by comple-

23

ment (see Section 3.2.1g). In fact, an increased amount of antibody has been found to be necessary for efficient clearance of opsonized particles after splenectomy.324 The spleen also plays an important role in the humoral response: The primary immunoglobulin response takes place in the spleen,325 and low levels of IgM have been observed after splenectomy in children.326 Impaired antibody production against pneumococcal and other thymusindependent antigens has been reported in splenectomized adults.327,328 A reduced level of the complement factor properdin, which could lead to suboptimal opsonization, has been demonstrated after splenectomy.329 Furthermore, postsplenectomy there is a decrease in functional tuftsin (see Section 3.1.6), which also may be important.330 Because of the risk of pneumococcal infection after splenectomy, immunization with polyvalent pneumococcal vaccine is recommended. For patients undergoing elective splenectomy, it is good practice to administer the vaccine in the weeks before the splenectomy to obtain a better immune response. The polysaccharide vaccine is T-cell-independent and therefore does not induce immunologic memory. The protection provided, especially in the compromised host, is probably not longer than a couple of years. Revaccination is presumably necessary after 3–5 years. Although vaccination has been shown to be effective, infection may still occur, especially in patients with underlying disease and in small children.330 Thus, antibiotic prophylaxis is still recommended for small children. For adults splenectomized for Hodgkin’s disease, we advocate patient-initiated treatment with oral amoxicillin at the onset of a febrile illness. Now that a vaccine against Haemophilus influenzae type B (HIB) has become available, HIB vaccination in patients with splenectomy may be considered. However, protective antibodies against HIB are usually acquired naturally during childhood. Indeed, in a recent study, 100% of 561 patients splenectomized before 1993 (i.e., before HIB vaccine was introduced) had natural protective antibodies, which was in sharp contrast to their immunity to pneumococci.331 Nevertheless, while studies assessing the value of HIB vaccination in this patient group are pending, it seems prudent to vaccinate splenectomized patients against HIB.332 5.3. Sickle Cell Anemia

Infections, especially pneumococcal septicemia, meningitis, and Salmonella osteomyelitis, are a major cause of morbidity and mortality in patients with sickle cell anemia.333 The risk of infectious complications is

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highest for children with a palpable spleen before 6 months of age. Functional splenectomy, the result of repeated splenic infarctions, appears to be an important host defense defect. Johnston et al.45 demonstrated deficient opsonization due to a defect in the alternate pathway of complement. These defective host defense mechanisms enhance the risk of pneumococcal complications. Susceptibility to Salmonella infections can be explained at least in part by a similar mechanism.46 Suppressed CMI with zinc deficiency and decreased nucleoside phosphorylase activity was described in sickle cell disease.334 The efficacy of the pneumococcal vaccine in patients with sickle cell disease has been demonstrated, but pneumococcal infections still occur330,335 (see also Section 5.2). 5.4. Diabetes Mellitus Because of the assumption that diabetes is associated with an increased susceptibility to infection, many investigators have studied host defense in this disease. A major question is whether diabetics should be regarded as truly compromised hosts.336 Breaches in the first line of defense due to injections, diabetic vascular disease, and neuropathy are important determinants of infections. High concentrations of glucose in urine and secretions may promote colonization by Candida species and other microorganisms. Still, it is difficult to explain in this manner the association of diabetes mellitus with, for instance, malignant external otitis (caused by Pseudomonas aeruginosa).337 Rare but rather specific for the diabetic patient is rhinocerebral zygomycosis, which is especially manifested during diabetic ketoacidosis.338 Zygomycosis (also called mucormycosis) is caused by fungi that are strongly dependent on iron supply and compete with serum apotransferrin for the uptake of iron.339 It has been demonstrated that the change of pH during diabetic ketoacidosis reduces the affinity of serum apotransferrin to bind iron. Thus, during acidosis, increased amounts of iron may be available to the microorganism, leading to enhanced outgrowth.340 Abnormalities in the second line of defense in diabetics can be summarized as follows: 1. Immunoglobulin response appears to be normal in diabetic patients. Nonenzymatic glycosylation of complement factor 3 has been reported in diabetics; this may lead to impaired opsonization of, for example, Candida albicans.53 2. In a series of studies, the chemotactic activity of granulocytes was shown to be impaired341–343; these abnormalities are not associated with keto-

acidosis. The chemotactic responsiveness of monocytes has been found to be depressed, possibly as a consequence of autooxidative cell damage.344 The delayed inflammatory response already noted in experimental diabetic animals many years ago345 thus can be explained. 3. Phagocytic adherence and phagocytosis have been shown to be reduced at high glucose concentrations, high osmolarity, and low pH.346,347 Abnormalities of the bactericidal function of granulocytes have also been described348,349; the impaired glucose metabolism of the phagocytes could well be the basis of the observed abnormalities. 4. Clearance studies with aggregated albumin demonstrate no abnormalities in patients with diabetes.350 5. The T-cell function can be considered normal in diabetic patients, with the possible exception of patients with poorly controlled diabetes.351,352 Animal experiments have provided some evidence for altered CMI,353 but the consequences for host defense in diabetic patients are unclear. An interesting observation is the high frequency of diabetes among patients with myeloperoxidase deficiency and fungal infections.354,355 Although the clinical importance of myeloperoxidase for the host defense against invasive candidiasis is not clear, the myeloperoxidase activity in leukocytes of diabetic patients with severe infections should be determined. 5.5. Chronic Renal Failure Patients with chronic renal failure are said to be at increased risk for bacterial infection,356 but it is questionable whether the chronic renal failure itself is an important factor.357 Chronic renal failure per se does not seem to impair humoral defense mechanisms. However, discrete abnormalities of the cellular defense mechanisms have been reported. A decreased bone marrow pool reserve of granulocytes has been found in uremic patients.358 Reduced neutrophil accumulation in vivo359 and impaired neutrophil chemotaxis in vitro360 have been observed. These defects can be attributed largely to impaired generation of chemotactic factors in uremic serum and are partially corrected by peritoneal dialysis, but not by hemodialysis.360 Both granulocytic function, as measured by surface adherence, phagocytosis, and intracellular killing, and opsonization were shown to be normal in patients with chronic renal failure.361 Phagocytosis by mononuclear phagocytes appears to be abnormal both in

DEFECTS IN HOST DEFENSE MECHANISMS 362

219,363

vitro and in vivo. CMI, as measured by the DTH skin reaction, is diminished in chronic renal failure and does not improve with hemodialysis.364 Lymphocytopenia, which occurs in uremia, and suppression of the proliferative response by uremic serum are in agreement with this observation.365 In vitro, the mitogenic and antigenie responses of lymphocytes from uremic patients were found to be normal by some investigators and abnormal by others.366,367 The situation becomes different when a treatment such as hemodialysis is taken into account. The first line of defense is damaged by multiple punctures, which may lead to intravascular infection, especially when prosthetic material is present. The effects of hemodialysis on complement activation and neutrophil kinetics are discussed in Section 3.2.1a. The fact that antibody response is abnormal in hemodialysis patients was suggested by hepatitis B vaccine trials.368–371 This response can be enhanced by coadministration of IL-2.372 In addition, abnormal CMI has also been observed in patients on hemodialysis.373–375 Iron overload in hemodialysis patients increases the risk of bacteremia376 (see Section 4.2). On the other hand, dialysis patients who are treated with deferoxamine to chelate aluminum or iron have been shown to be at risk for zygomycosis. The fungus requires iron as a growth factor and is able to utilize the exogenous deferoxamine as an exogenous siderophore in place of its endogenous siderophore rhizoferrin to facilitate iron uptake, leading to enhanced outgrowth.338,377,378 In patients on chronic ambulatory peritoneal dialysis (CAPD), peritonitis is the most frequently encountered infectious complication,379 and gram-positive microorganisms (especially Staphylococcus epidermidis) are the most common microorganisms. Exogenous contamination, the catheter, and intestinal disease (such as diverticulitis) play an important role in the pathogenesis. The phagocytic and microbicidal functions of peritoneal macrophages from CAPD patients appear to be adequate, whereas a serious deficiency of opsonins (IgG as well as C3) has been found in the peritoneal dialysis effluent.380,381 In a prospective study, low heat-stable opsonic activity correlated with a high incidence of S. epidermidis peritonitis.381 Interestingly, diabetic CAPD patients are not at increased risk for peritonitis,382 and their peritoneal effluent exhibits high opsonic activity.381 5.6. Alcoholism and Hepatic Cirrhosis Alcoholism is associated with a number of infectious complications, such as pneumonia and tuberculosis. In alcoholism, the first line of defense easily may become severely compromised. Repeated aspiration of stomach

25

contents, a depressed cough reflex, reduced glottal closure, trauma, and lifestyle play a role in the pathogenesis of infections. Many disorders also are present in the second line of defense. The antibody response to new antigens is impaired, whereas the secondary response is normal.383 Depressed complement activity sometimes found in alcoholics may be responsible for decreased chemotactic responsiveness.341 Inhibition of granulocyte adherence can be attributed to alcohol,384,385 and this may explain the leukopenia and a blunted granulocyte response to bacterial infection that have often been noted.385 Phagocytosis and the microbicidal function of granulocytes are generally considered normal, whereas macrophage function (including clearance of particles from the bloodstream) and response to cytokines are abnormal385,386; also, CMI has been found to be depressed in severe alcoholism.385,387 Fewer T cells and a reduced mitogenic responsiveness also have been described.385 Alcoholism has an inhibitory effect on NK cell function.388 In alcoholism, other factors usually contribute to the increased susceptibility to infection; often, there will be a concomitant protein-energy malnutrition and vitamin deficiency (see Section 4.2) as well as liver cirrhosis. In liver cirrhosis, septicemia and spontaneous bacterial peritonitis are the major infectious complications.389 In patients with cirrhosis, serum has been shown to be less chemotactic for neutrophils than normal serum, probably due to the presence of a specific inhibitor.390,391 Although usually normal, reduced complement activity and abnormal opsonization have been observed in some patients with alcoholic cirrhosis.391,392 The concentration of complement factor C3 in ascitic fluid appears to be related to the risk of developing spontaneous bacterial peritonitis.393 Phagocytosis and intracellular killing by granulocytes and monocytes are normal.394 Clearance of particles from the bloodstream is impaired, partly as the result of a diminished hepatic blood flow.223,224 Furthermore, the T-cell responses in cirrhosis may be depressed.394 The relative roles of the reported abnormalities as well as their relevance for clinical practice are unclear. 5.7. Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Felty’s Syndrome It is uncertain whether SLE per se predisposes to infection.395,396 Such factors as immunosuppressive therapy may well account for the clinical impression of increased susceptibility to infection.397 Herpes zoster, fungal, and CMV infections are not rare in SLE patients on immunosuppressive therapy.398 A number of host defense defects have been found in SLE. Acquired complement deficiencies with defective generation of chemotactic fac-

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tors and poor opsonization as well as a C5a inhibitor have been reported in SLE.399–401 A serum inhibitor of both phagocytosis and degranulation could explain the decreased particle uptake in vitro,402 while immune complexes are probably responsible for impaired particle clearance in vivo214,215 (see Section 3.2.1g). Furthermore, granulocytopenia and possibly a decreased granulocyte reserve403 could further contribute to defective host defense. The same holds for the frequently occurring lymphopenia (both T and B cells) and depressed CMI, which lead to anergy.404 Whether there is increased susceptibility to infection in rheumatoid arthritis is even more questionable, although a case can be made for infectious arthritis,396 which may develop as a hematogenous infection or as a complication of intra-articular injections. Hypocomplementemia, the presence of immune complexes and rheumatoid factor, an impaired chemotactic response,405 and depression of the bactericidal function of monocytes406 have been suggested as explanations for increased susceptibility to infection. Local defense in joints may be impaired; a factor that impedes phagocytosis has been found in synovial fluid.407 The frequent infections encountered in Felty’s syndrome (rheumatoid arthritis with splenomegaly and granulocytopenia) cannot be related solely to the degree of granulocytopenia.408 The cause of the granulocytopenia is still controversial; impaired granulocytopoiesis, decreased granulocyte reserve, excessive margination, and increased neutrophil destruction have all been suggested.396 The defects in the host defense mechanisms are similar to those seen in rheumatoid arthritis.396 Severe hypocomplementemia may be a major factor in the susceptibility to infection in Felty patients.52,408 There is no consensus regarding the therapeutic value of splenectomy in Felty’s syndrome, but the risk of postsplenectomy septicemia should be taken into account (see Section 5.2). 5.8. Infections Many microorganisms are able to diminish the resistance of the host, thus opening a route for infection with secondary pathogens. Via numerous mechanisms, microorganisms are able to compromise the first line of defense as well as humoral and cellular defense mechanisms (extensively reviewed by Mackowiak409 and O’Grady and Smith410). Hypocomplementemia and blockading of the mononuclear phagocyte system are dealt with in Sections 3.1.2 and 3.2.1i. Whether the function of neutrophils and monocytes is impaired by viral or bacterial infection is a controversial subject.411,412 An interesting pathogen in this

respect is Capnocytophaga species. Capnocytophaga gingivalis, C. ochracea, and C. sputigena are dental microorganisms that may cause invasive infection in the compromised host.413 Reportedly, these Capnocytophaga species are able to induce a disorder of neutrophil migration in vivo.414 Impairment of CMI during the infectious disease (by affecting either the macrophages or T-cell function) also is important Viruses that are able to weaken cellular immunity include CMV, EBV, hepatitis C virus, and last but not least HIV. It is well known that CMV infection (which is more extensively discussed in Chapter 13) is accompanied by secondary infections with bacteria, fungi, and protozoa.415–417 A low level of helper T cells and an increased number of suppressor T cells, as seen in CMV mononucleosis, may be an explanation.418 However, olhers have found that such T-cell abnormalities are not produced by CMV in recipients of renal transplants treated with low-dose immunosuppressives.419 The association of non-A, non-B hepatitis with prolonged kidney graft survival and increased susceptibility to infection, suggesting impairment of CMI, has been reported.420 This notion is sustained by the observation that liver transplant recipients with HCV hepatitis have significantly more episodes of major infections than all other types of patients. The incidence of major bacterial infections is not higher in HCV patients, but the risk of fungal infections and CMV disease is significantly increased.421 During infection with HIV, the T lymphocytes that express the CD4 molecule (the receptor for the virus) disappear by formation of syncytia of these cells and by other cytotoxic mechanisms that have not been fully elucidated.422 Macrophages, which bear the CD4 molecule, are less susceptible to killing by HIV. The macrophages may become functionally impaired to some extent (decreased chemotaxis and impaired killing)423; it is unclear whether this effect is directly due to the infection of these cells. In symptomatic HIV-infected patients, the number of CD4-positive T lymphocytes decreases over time. When CD4-positive cell counts fall below 200/mm, opportunistic infections indicative of AIDS tend to occur (see Chapter 12). These are, first of all, the types of infections related to severely impaired CMI: Pneumocystis carinii pneumonia (and extrapulmonary pneumocystosis), CMV infection, VZV infection, herpes simplex infection, mycobacterial infection, toxoplasmosis, cryptococcosis, histoplasmosis, papovavirus infection, and salmonellosis (see Chapter 12). When patients respond to highly active antiretroviral therapy (HAART) with a clinically significant rise in CD4 cells, host defense against these opportunistic pathogens is restored.424 The HAARTinduced restoration of cell-mediated immunity may lead

DEFECTS IN HOST DEFENSE MECHANISMS

to paradoxical worsening of inflammation through increasing numbers and reactivity of CD4 cells, e.g., in mycobacterial infection.425 Interestingly, some opportunistic infections regularly seen in patients with impaired CMI, e.g., listeriosis, are relatively rare in AIDS patients.426 A variety of infections occur in symptomatic HIV infection that cannot be easily explained by the impaired CMI. First, the exact defense defect underlying the severe and persistent mucosal candidiasis is not very well understood.427 Even though neutropenia (due to the HIV infection itself or to drugs like zidovudine) and impaired neutrophil function428,429 occur in AIDS, candidemia and disseminated candidiasis are remarkably rare in AIDS. The host defense defects that permit infections with a number of intestinal pathogens, such as Isospora belli, Cryptosporidium, and Microsporidium, also are not elucidated, but probably the T-cell defect is responsible here. The increased incidence of infections caused by encapsulated bacteria, such as pneumococci and H. influenzae,430,431 points to defective humoral immunity. Indeed, antigen-specific B-lymphocyte responses are impaired, despite polyclonal B-cell activation.234 This result also becomes clear from the impaired antibody response to protein and polysaccharide vaccines.432–434 The reported deficiency of tuftsin (see Section 3.1.6) may contribute to the development of these infections.170 An additional explanation for the occurrence of these bacterial infections and possibly also those caused by S. aureus435 is the impaired Fc-receptor-mediated clearance in AIDS220 (see Section 3.2.1i). The defense against Aspergillus species also may be impaired, although it is unclear to what extent the deficient T-cell function contributes to this impairment436,437; factors that may contribute to the relatively rare Aspergillus infections in AIDS patients are neutropenia, corticosteroid therapy, marijuana use, previous Pneumocystis pneumonia and CMV disease, the development of cystic lung lesions, and antibiotics.438 The impact of the impaired NK cell function that has been noted in AIDS is not clear.234

6. Immunosuppressive Drugs 6.1. Glucocorticosteroids Although there is consensus that both excessive endogenous production439 and therapeutically administered440 glucocorticosteroids lead to increased susceptibility to infection, the magnitude of this problem for the

27

individual patient is difficult to predict. A thorough metaanalysis revealed that the rate of infectious complications was not increased in patients given prednisone at a daily dose of less than 10 mg or a cumulative dose of less than 700 mg.441 The glucocorticosteroids are able to affect many aspects of the host defense. The skin and mucous membrane barriers suffer relatively little damage, although atrophy and delayed healing after injury may play a role in the pathogenesis of infections. Of the humoral defense mechanisms, the complement system does not seem to be affected, whereas some changes in immunoglobulin levels have been observed.442,443 The major problems involve the cellular defense mechanisms. Although granulocytopoiesis seems to be enhanced by glucocorticosteroids444 and the marrow pool reserve is mobilized by these drugs,445 the negative effects on neutrophilic granulocytes seem to outweigh these advantages. At the site of inflammation, there is reduced accumulation of neutrophils as a result of impaired margination, probably due to reduced stickiness of the granulocytes and diminished chemotactic activity.384,446,447 Glucocorticosteroids affect phagocytosis and intracellular killing by neutrophils only at very high concentrations; most investigators therefore agree that these effects are not of clinical importance. A fall in the number of eosinophils in the blood is seen after glucocorticosteroid administration.179 The mononuclear phagocyte system (MPS) also is affected by glucocorticosteroids. First, profound monocytopenia occurs after administration of these drugs.446,448 Monocyte chemotaxis may become impaired,449 but the effects on intracellular killing by mononuclear phagocytes are controversial.449–451 The clearance of particles from the bloodstream has been shown to be reduced.452 The production of a number of macrophage products (e.g., IL-1, TNF) is inhibited by glucocorticosteroids.453,454 Preexposure of macrophages to or granulocyte colony-stimulating factor prevents such inhibition.455,456 The reduced production of cytokines such as IL-1 may have important consequences for T-cell function, febrile response, and other aspects of the acute-phase response. Also, macrophage activation is impaired, probably mainly by inhibition of the response to cytokines.457 Glucocorticosteroids also have effects on T lymphocytes (reviewed by Cupps and Fauci458). Within hours after administration of glucocorticosteroids, a profound lymphocytopenia (also involving B cells to some extent) occurs due to redistribution of these cells.440 In contrast to the situation in mice, rats, and rabbits, lymphocytolysis is not an important mechanism in humans.440 The redistribution of lymphocytes as well as the effects on the MPS are thought to be the major reasons for

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altered functioning of lymphocytes during corticosteroid therapy.458 From the foregoing, the anti-inflammatory and immunosuppressive effects of glucocorticosteroids are clear and the consequences for susceptibility to infection can be understood. These effects may even become enhanced by their influence on vascular permeability, wound healing, and a number of metabolic processes. The infections that occur are those associated with impaired phagocyte function, such as infections caused by staphylococci, gram-negative bacteria, Candida, and Aspergillus species,459 as well as with suppressed CMI (see Sections 3.2.3c and 3.2.3d). To avoid infectious complications, patients who need chronic glucocorticosteroid treatment should be converted to a single, alternate-day dose whenever possible.440,446 6.2. Other Immunosuppressive Agents 6.2.1. Cytotoxic Drugs Cytotoxic drugs such as cyclophosphamide, azathioprine, and methotrexate (MTX) interfere with host defense mainly through their effects on cell proliferation. Thus, by inducing neutropenia, monocytopenia, and lymphocytopenia (the degree depending on the drug given), such immunosuppressive drugs may give rise to infectious complications. Cyclophosphamide is a potent lymphocytotoxic drug; by interference with the B-cell system, it is able to suppress especially the primary but also the secondary antibody responses,460 and by inhibition of the T-cell response, the drug impairs CMI.461,462 The thiopurines azathioprine and 6-mercaptopurine produce moderate suppression of both the humoral and the cellular immune responses. The views on the effects of thiopurines on immunoglobulin synthesis are conflicting.463 Granulocyte function does not seem to be affected, whereas monocyte exudation is impaired,464,465 NK-cell function is somewhat suppressed, and the effect of T-cell function is not pronounced.466,467 MTX decreases immunoglobulin synthesis468,469 and inhibits phagocytosis and intracellular killing by granulocytes.470 In addition, MTX affects monocyte production and macrophage activation.471,472 The production of IL-1 is decreased both in vitro and in patients with rheumatoid arthritis receiving their first dose of MTX, but not after prolonged treatment.472,473 There is little effect on T-lymphocyte function.468 The combination of immunosuppressive cytotoxic agents and glucocorticosteroids greatly affects the susceptibility to infections as well as the outcome of these infections.

6.2.2. Cyclosporin and Tacrolimus Cyclosporin is a potent immunosuppressive drug that is widely used in transplantation medicine and for treatment of immunologic disorders. Its main site of action is the T-helper-inducer lymphocyte subpopulation; cyclosporin has no direct effect on the functions of B cells, macrophages, neutrophils, or NK cells.474 Tacrolimus (FK506) has a similar mechanism of action.475 Both drugs bind to cytoplasmatic T-cell receptors, leading to inactivation of calcineurin.476 Calcineurin is a crucial enzyme in the signaling pathway inducing IL-2 gene transcription, and treatment with either of these calcineurin inhibitors blocks production of IL-2 (see Section 3.1.5) and lymphokines such as (see Section 3.1.4).476,477 Controlled clinical studies have shown that in transplant recipients, cyclosporin therapy leads to increased graft survival and is associated with equal or lower incidence of bacterial or viral infections than conventional immunosuppressive agents (reviewed by Kim and Perfect474). Important side effects of cyclosporin include acute and chronic nephrotoxicity, which contributes not only to renal vasoconstriction and ischemia, but also to induction 478 of transforming growth A discussion of the numerous interactions of cyclosporin with other drugs is beyond the scope of this chapter. Tacrolimus appears to be more potent than cyclosporin, leading to a lower incidence of acute and long-term rejection of both kidney and liver transplants than with cyclosporinbased immunosuppression.479,480 6.2.3. Mycophenolate Mofetil, Sirolimus, and IL-2 Receptor Antibodies Mycophenolate mofetil (MMF) is an antiproliferative agent, which interrupts the DNA replication of T cells that proliferate after stimulation of the IL-2 receptor, analogous to the mechanism of action of azathioprine.481 MMF now has largely replaced azathioprine in renal transplant patients, due to its potency to reduce the incidence of acute rejection.482,483 However, MMF reportedly increases the risk of invasive cytomegalovirus infection.482–484 Since the IL-2 receptor is expressed only on activated T cells, blocking the IL-2 receptor may provide highly specific immunosuppression. Two IL-2 receptorblocking monoclonal antibodies, daclizumab and basiliximab, have been developed. Initial clinical trials have suggested that these agents are effective in preventing transplant rejection, without occurrence of opportunistic infections.485–487 Sirolimus is a pharmacologic inhibitor of the intracellular signaling pathway of the IL-2 receptor.

DEFECTS IN HOST DEFENSE MECHANISMS

Preliminary data suggest that sirolimus may lead to further reduction of allograft rejection when added to a cyclosporin-based regimen.488 Other strategies currently under investigation include blocking of ligand–receptor interactions between antigen-presenting cells and T cells, e.g., aimed at blockade of CD28/B7, CD40/154, ICAM-1/ LFA1, and LFA3/CD2.489 The impact of these modalities on host defense to infection is still unclear. 6.2.4. Antimicrobials In vitro studies have shown that numerous pharmacologic agents, e.g., antimicrobial drugs (reviewed by Hauser and Remington490), negatively affect the function of cells involved in the defense against microorganisms. The clinical significance of these findings is doubtful. The same holds for claims that certain antimicrobials are immunostimulating. Such claims have been published for macrolides,491 certain cephalosporins (e.g., cefodizime),492 ciprofloxacin,493 fusidin,494 and amphotericin B.495,496 So far, these immunostimulating effects do not have practical implications. 6.2.5. Antilymphocyte Antibodies Polyclonal antithymocyte globulin (ATG) and monoclonal antilymphocyte antibodies (such as OKT3, WT32) are potent immunosuppressive agents used mainly for prevention and treatment of transplant rejection.497–500 Through the destruction of T lymphocytes, these agents lead to lymphocytopenia and suppression of CMI, and thus to increased susceptibility to infections (especially CMV infections).497,501 The polyclonal ATG products also act on non-T cells (depending on brand and batch), which may further depress host defenses.497 Using OKT3, Thistlethwaite et al.498 reported a 22% incidence of infections after single exposure to the monoclonal antibodies and more than a 50% incidence after multiple exposures, and others have also reported that the incidence of infection is higher with the use of these polyclonal or monoclonal antibodies than with immunosuppressive drugs, such as glucocorticosteroids, azathioprine, and cyclosporin.500–506 6.3. Blood Products The immunosuppressive effects of blood products have received much attention for two reasons: (1) survival of organ transplants can be improved by pretransplantation blood transfusion when the transfusion is matched for HLA-DR antigen,507,508 and (2) immunologic abnor-

29

malities occur in hemophiliacs receiving repeated doses of plasma protein concentrates.218,509 A detailed discussion of these observations goes beyond the scope of this chapter. Suffice it to say that depressed cellular immunity has been observed in HIV-negative hemophiliacs (abnormal T-cell subsets, defective NK cell activity) and in patients who have received multiple blood transfusions (reduced NK cell activity).510 The significance for susceptibility to infection is unknown. Transmission by transfusion of infectious agents that modulate the immune response (e.g., CMV, hepatitis C) also should be taken into account (see Section 5.8).

7. Plasmapheresis Plasma exchange is a treatment modality used in a variety of disorders; plasmapheresis is especially applied in diseases that seem to be immunologically mediated, and this treatment therefore often is instituted in patients who already are receiving immunosuppressive therapy. On the basis of a small retrospective study in rapidly progressive glomerulonephritis, it has been suggested that this procedure increases the incidence of lifethreatening opportunistic infection.511 However, this suggestion was not confirmed in a relatively large, randomized, controlled trial in severe lupus nephritis.512 It is a common assumption that one of the modes of action of plasmapheresis is through the removal of circulating cytokines. However, in view of the short half-life of these molecules, this concept is not tenable.513,514 The removal of mediators that have a lower endogenous clearance, such as soluble receptors for and IL-6 as well as C-reactive protein, is well established.515 Also, it has been suggested that anti-inflammatory mediators may be supplemented by plasmapheresis, such as Cl-inhibitor, antithrombin III, and the anticoagulant factors protein S and protein C.515

8. Radiation Radiation damages both proliferating and nonproliferating cells in a dose-dependent fashion. Thus, host defense mechanisms may be affected in a number of ways. The effects are dependent not only on the dose, but also on the time course and the radiosensitivity of the cells in the area of the body that is receiving radiation. At the level of the first line of defense, the epithelial barrier may be damaged; the rapidly proliferating epithelium of the gastrointestinal tract in particular is highly sensitive to

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radiation injury, and invasion by intestinal bacteria may ensue. When B cells are irradiated, the primary antibody response is depressed for several weeks.516 Secondary antibody response is much less sensitive to radiation damage, while plasma cells that produce antibody are relatively radioresistant. Cellular defense may be affected because of the radiosensitivity of the hematopoietic tissues. Granulocytopenia, which occurs after destruction of the mitotic pool and after depletion of the marrow pool reserve (i.e., not until 48–72 hr after total-body irradiation), is the major factor leading to infectious complications. After meningeal irradiation for acute lymphocytic leukemia, neutrophils acquire a transient microbicidal defect that probably reflects damage to the granulocyte precursors.517 Mononuclear phagocyte precursors in bone marrow also are radiosensitive, whereas monocytes and macrophages are not. Since the latter cells are relatively long-lived, a deficiency of mononuclear phagocytes (e.g., in CMI) may not be immediately apparent. Of the counterpart in cellular immunity—the T cells—it is known that thymocytes are radiosensitive, whereas mature T cells are radioresistant.516 CMI may become suppressed when radiation precedes exposure to the antigen, whereas existing cellular immunity reactions are not hampered until large dosages are given.518 Relapses of infections caused by dormant intracellular pathogens (e.g., Mycobacterium tuberculosis, VZV) may occur, especially when the focus of infection is within the area that received radiation. Total lymphoid irradiation,519 which has been a part of the treatment of Hodgkin’s disease and non-Hodgkin’s lymphoma for more than two decades, is not accompanied by significant infectious complications. Nevertheless, there is profound and sustained immunosuppression,519 which has also been exploited for the treatment of nonhematologic diseases.

9. Attempts to Strengthen Host Defense When a patient exhibits a defective host defense, the prevention of infection is the main concern, followed by optimal treatment once infection has developed. Prevention of both damage to the first line of defense and colonization that could lead to infection with (multiresistant) microorganisms is important, as are the prevention and control of the adverse effects of treatment. Thanks to modern biotechnology (recombinant DNA technology and monoclonal antibody techniques), a number of modalities are now emerging for the substitution of host defense defects, for the strengthening of certain defense

mechanisms, and for the treatment of a number of specific infections. Before we briefly review these strategies, it should be stressed that such measures as physiotherapy, improvement of nutritional status, and immunization with relevant vaccines remain crucial. The most important vaccines that are used in the compromised host are hepatitis B vaccine (see Section 5.5), pneumococcal polysaccharide vaccine (see Section 5.2), and Haemophilus influenzae type B conjugate vaccine.520 Still, very little can be done to improve the first line of defense, although we can find some pointers in the treatment of burns, which involves not only creams such as silver sulfadiazine to strengthen the barriers, but also skin grafting and even covering the injury with in vitro cultured epithelium.509 Acceleration of wound healing using epidermal growth factor and maybe other cytokines are potentially important treatment modalities.521,522 An elegant way of strengthening the first line of defense against urinary tract infections in postmenopausal women is through the local administration of estrogens. In this way, the glycogen in the vaginal epithelium is restored, allowing recolonization with lactobacilli.523,524 Various options are available to improve the second line of defense. Administration of fresh plasma or supplementation of individual complement components is worthwhile in primary complement-deficiency states.36 Whether such supplementation is beneficial in secondary complement deficiencies is not known. Substitution with fibronectin-rich cryoprecipitates during sepsis and trauma does not seem to be effective60 (see Section 3.1.3). has an important role as antiviral agent in the therapy of chronic viral diseases, such as for genital warts525 and for chronic hepatitis B and C. In patients with active hepatitis B, treatment leads to viral eradication and seroconversion in 25–40%.526,527 Long-term follow-up now has established a significant improval of survival in treated patients with chronic hepatitis B and cirrhosis.528 In patients with hepatitis C, of whom 70 to 85% will go on to develop chronic hepatitis, treatment with alone leads to a sustained response in 15 to 20%.529 With the addition of ribavirin to monotherapy, the response rate increases to approximately 50%.530 increases the resistance to a number of infections, probably by enhancing cellular defense (see Section 3.2.3c). Treatment with had a beneficial effect when administered to patients with lepromatous leprosy in some,531 but not all studies.532,533 In combination with pentavalent antimony, is effective in visceral leishmaniasis.534,535 Impressive results have been obtained with this cytokine used prophylactically and therapeutically in chronic granulomatous disease.536,537 The

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incidence of invasive aspergillosis in the group of CGD patients who received prophylaxis was significantly reduced from 24 to 4% in 2 years536 (see Chapter 14). Although the mode of action of at the molecular level in this disorder is not understood, neutrophils from patients on were found to produce significantly more damage to Aspergillus hyphae in vitro.538 also has been used successfully in refractory tuberculosis and atypical mycobacterial infection.539,540 It is likely that more indications for as a therapeutically useful immunostimulator for infections in the compromised host will emerge during the next decade. Animal models have demonstrated that early treatment with IL-1 protects against death from bacterial and candidal infection, even in neutropenic animals.82,541 Recombinant TNF seems to be somewhat less active in such infections,542 but may be therapeutically useful in mycobacterial infections.83,244 These cytokines have not yet been used for the treatment of infections in humans because of toxicity. The proinflammatory cytokines may become useful as vaccine adjuvants. IL-2 already has been used as such for low responders to hepatitis B vaccine.372 IL-2 also has been applied therapeutically in a few patients with severe immunodeficiency whose T lymphocytes did not produce IL-2.543,544 Furthermore, intradermal injections of this cytokine in lepromatous leprosy have led to a reduction in the number of bacilli in the skin.545 It should be kept in mind that a high incidence of bacteremia due to Staphylococcus aureus and S. epidermidis has been encountered in patients treated with high dosages of IL-2; this result may be explained by an acquired chemotactic defect in the neutrophils of these patients.546 Promising results have been obtained with the colonystimulating factors GM-CSF and G-CSF (see Section 3.1.5b). In cancer patients, colony-stimulating factors have been used both to shorten the duration of chemotherapy-induced granulocytopenia547 and as adjunctive therapy in patients with febrile neutropenia.548 The potential beneficial role of rGM-CSF in the prevention of fungal infections has been suggested in a placebo-controlled study of patients with acute myelogenous leukemia.549 rGM-CSF was associated with a higher rate of complete response, longer overall survival, and lower fungal infection-related mortality.549 In spite of the concept that neutropenia is a strong risk factor for infections, all other studies have failed to demonstrate a benefit of CSFinduced accelerated bone marrow recovery on either the incidence of invasive infections or mortality in cancer patients. This is in sharp contrast with the beneficial results of prolonged rG-CSF treatment in patients with

31

congenital neutropenia, leading to a significant reduction in infections.124,550 Several studies have addressed the beneficial role of rG-CSF on neutrophil function in nonneutropenic patients. Treatment with rG-CSF accelerates radiological improvement of severe community-acquired pneumonia and reduces the rate of serious complications (e.g., empyema, adult respiratory distress syndrome, and disseminated intravascular coagulation).126 Preclinical studies have demonstrated the benefit of G-CSF in the treatment of disseminated candidiasis in nonneutropenic animals.551 Subsequently, a randomized clinical study has suggested that the combination of rG-CSF with fluconazole is beneficial in nonneutropenic patients with invasive or disseminated candidiasis.127 Substitution with IgG, given either intravenously552 or subcutaneously,553 is indicated in severe hypogammaglobulinemia (see Chapter 14). The latter method is particularly useful in patients who experience serious side effects with intravenous or intramuscular immunoglobulins or who have circulating anti-IgA.553,554 High-titered specific antibody preparations played an important role in the treatment of varicella infections in immunocompromised children before acyclovir became available.555 At present, anti-CMV IgG is given prophylactically to prevent CMV pneumonitis after bone marrow transplantation and therapeutically in conjunction with the antiviral drug ganciclovir556–558 (see Chapter 17). In bone marrow transplant recipients, intravenous immunoglobulins appear to be beneficial for other infections as well.559 In neutropenic patients, it is important to also consider plasma supplementation, since a deficiency of opsonins has been noted in such patients.555,560 Administration of immunoglobulin can block T-cell activation by staphylococcal and streptococcal superantigens in vitro.561 High doses of intravenous immunoglobulin have been suggested to be beneficial in patients with streptococcal toxic shock syndrome caused by group A streptococcus.562 Randomized studies are under way to further explore this modality. In infants with prematurity or bronchiopulmonary dysplasia, who are at high risk for acquiring respiratory syncytial virus (RSV) infection, prophylaxis with RSV-IgG leads to a reduction in incidence and severity of RSV infection.563,564 This modality is now replaced by monthly injections of palivizumab, a monoclonal IgG antibody that binds to RSV, resulting in a significant reduction of RSV infections in high-risk patient groups.565 Treatment of life-threatening gram-negative infection with passive immunization with monoclonal antibodies against endotoxin core so far has failed566,567 (see

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Chapter 4). Even in patients with fulminant meningococcal septicemia, which is considered the prototype of severe endotoxinemia, monoclonal antibodies against endotoxin did not alter the course of the disease.568 On the basis of experimental animals,130,569 clinical trials have attempted to modulate the proinflammatory cytokine response in patients with severe sepsis, using monoclonal antibodies against recombinant soluble receptor, or recombinant IL-1 receptor antagonist. In contrast to the favorable results in animal models of endotoxin challenge or serious infection, the clinical studies so far have been disappointing.570–572 The reasons for these failures are multifactorial: the clinical syndrome of sepsis is very heterogeneous with a vast number of confounders; the intervention is started relatively late in the course of the illness; the optimal dose and duration of treatment are unknown; a single intervention may not be sufficient; and the 28-day mortality is an unrealistic endpoint.573,574 In sharp contrast with these negative results are those obtained in rheumatoid arthritis575 and in Crohn’s disease, in which the anticytokine strategies (especially anti-TNF treatments) have met with spectacular results.576 The possible downside of anti-TNF treatment is that such strategies have a negative effect on infections that are to be contained in granulomas, such as those caused by mycobacteria and fungi, and in abscesses.577 There are uncontrolled data in the literature to support plasma exchange in fulminant meningococcal septicemia (see Section 7).513,578,579 In severely neutropenic patients with bacterial infection, granulocyte transfusions have been given as an adjunct to antimicrobial therapy for a number of years. The enthusiasm for this approach has vanished for cost-benefit as well as risk-benefit reasons580 and also because expectations were that treatment of neutropenic patients with rCSF would have a great impact on the incidence and severity of infections. For some patients with phagocyte dysfunction (as in chronic granulomatous disease), granulocyte transfusions have been beneficial,581 but in these patients, treatment with is the primary therapy of choice.536 In refractory infection in patients with phagocyte disorders, as well as in neutropenic patients with refractory infection, many centers now have begun to administer granulocyte transfusions derived from donors pretreated with rG-CSF.125 This pretreatment of donors with daily injections of rG-CSF leads to a four- to tenfold increase of their absolute neutrophil count, greatly enhances the yield of neutrophils, and by preserving the granulocytes by inhibition of apoptosis, the 1- and 24-hr posttransfusion neutrophil counts in the recipients are substantially higher.582

There also is some experience with the local instillation of donor granulocytes, e.g., in abscesses. Transfusions of monocytes, which have a longer life span, have not yet been given. For treatment of phagocyte disorders, quite a number of drugs (e.g., ascorbic acid, levamisole, cimetidine) have been tried, mostly without success.581 Bone marrow transplantation cannot be considered firstline treatment for these disorders.581 To restore T-cell function, thymus transplantation or the administration of either thymic hormones or (antigenspecific) transfer factor has been undertaken in selected patients.583 Lymphocyte transfusions, which are not a common form of treatment, have not been successful in AIDS patients. Adenosine deaminase (ADA) deficiency results in severe combined immune deficiency disease, which is fatal without treatment. The cause for this is believed to be the accumulation of one of the substrates for ADA, 2´-deoxyadenosine to which especially T cells are hypersensitive. For ADA deficiency and other disorders like Wiskott–Aldrich syndrome, bone marrow transplantation has been shown to be a solution (see Chapter 14). Weekly injections of ADA coupled to polyethylene glycol (to prolong the half-life of the enzyme) have corrected the immune defect in ADA deficiency.584 Efficient transfer of a recombinant ADA gene into hematopoietic stem cells is a therapeutic option if it results in the outgrowth of a “genetically repaired” lymphoid system. Several patients have now been treated with ADA gene therapy, although persistence of the gene has been limited until now.585,586 In animal experiments, resistance to infection has been enhanced by immunomodulators such as endotoxin, detoxified endotoxin, Corynebacterium parvum, BCG and muramyl peptides, and glucan.542 It is likely that these therapies work by induction of cytokines. It is our expectation that treatment with cytokines will have a greater future than is currently realized.

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544. Pahwa R, Chatila T, Pahwa S, et al: Recombinant interleukin 2 therapy in severe combined immunodeficiency disease. Proc Natl Acad Sci USA 86:5069–5073, 1989. 545. Cohn ZA, Kaplan G: Hansen’s disease, cell-mediated immunity, and recombinant lymphokines. J Infect Dis 163:1195–1200, 1991. 546. Klempner MS, Noring R, Mier JW, Atkins MB: An acquired chemotactic defect in neutrophils from patients receiving interleukin-2 immunotherapy. N Engl J Med 322:959–965, 1990. 547. Crawford J, Ozer H, Stoller R, et al: Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 325:164–170, 1991. 548. Maher DW, Lieschke GJ, Green M, et al: Filgrastim in patients with chemotherapy-induced febrile neutropenia. A double-blind, placebo-controlled trial. Ann Intern Med 121:492–501, 1994. 549. Rowe JM, Andersen JW, Mazza JJ, et al: A randomized placebocontrolled phase III study of granulocyte-macrophage colonystimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: A study of the Eastern Cooperative Oncology Group (E1490). Blood 86:457–462, 1995. 550. Boxer LA, Hutchinson R, Emerson S: Recombinant human granulocyte-colony-stimulating factor in the treatment of patients with neutropenia. Clin Immunol Immunopathol 62:S39–S46, 1992. 551. Kullberg BJ, Netea MG, Curfs JHAJ, Keuter M, Meis JFGM, Van der Meer JWM: Recombinant murine granulocyte colonystimulating factor protects against acute disseminated Candida albicans infection in non-neutropenic mice. J Infect Dis 177:175– 181, 1998. 552. Buckley RH, Schiff RI: The use of intravenous immune globulin in immunodeficiency diseases. N Engl J Med 325:110–117, 1991. 553. Van der Meer JWM, De Windt GE, Van den Broek PJ: Subcutaneous immunoglobulin substitution in hypogammaglobulinemia. In Krijnen HW, Strengers PFW, Van Aken WG (eds): Immunoglobulins. CLB, Amsterdam, 1988, pp. 71–76. 554. Gardulf A, Hammarstrom L, Smith CI: Home treatment of hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion. Lancet 338:162–166, 1991. 555. Winston DJ, Young LS: Immunization of the compromised host against infectious complications. In Allen JC (ed): Infection in the Compromised Host: Clinical Correlations and Therapeutic Approaches. Williams & Wilkins, Baltimore, 1981, pp. 37–89. 556. Winston DJ, Ho WG, Lin CH, et al: Intravenous immune globulin for prevention of cytomegalovirus infection and interstitial pneumonia after bone marrow transplantation. Ann Intern Med 106:12– 18, 1987. 557. Reed EC, Bowden RA, Dandliker PS, Lilleby KE, Meyers JD: Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med 109:783–788, 1988. 558. Emanuel D, Cunningham I, Jules-Elysee K, et al: Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. Ann Intern Med 109:777–782, 1988. 559. Sullivan KM, Kopecky KJ, Jocom J, et al: Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation. N Engl J Med 323:705–712, 1990. 560. Keusch GT, Ambinder EP, Kovacs I, Goldberg JD, Phillips DM, Holland JF: Role of opsonins in clinical response to granulocyte transfusion in granulocytopenic patients. Am J Med 73:552–563, 1982.

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561. Norrby-Teglund A, Kaul R, Low DE, et al: Plasma from patients with severe invasive group A streptococcal infections treated with normal polyspecific IgG inhibits streptococcal superantigeninduced T cell proliferation and cytokine production. J Immunol 156:3057–3064, 1996. 562. Kaul R, McGeer A, Norrby-Teglund A, et al: Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome—A comparative observational study. Clin Infect Dis 28:800–807, 1999. 563. Groothuis JR, Simoes EA, Levin MJ, et al: Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. The Respiratory Syncytial Virus Immune Globulin Study Group. N Engl J Med 329:1524–1530, 1993. 564. The PREVENT Study Group: Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics 99:93–99, 1997. 565. The IMpact-RSV Study Group: Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 102:531–537, 1998. 566. Ziegler EJ, Fisher CJ Jr, Sprung CL, et al: Treatment of gramnegative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. N Engl J Med 324:429–436, 1991. 567. Greenberg RN, Wilson KM, Kunz AY, Wedel NI, Gorelick KJ: Randomized, double-blind phase II study of anti-endotoxin antibody (E5) as adjuvant therapy in humans with serious gramnegative infections. Prog Clin Biol Res 367:179–186, 1991. 568. Derkx B, Wittes J, McCloskey R, and the Euroean Pediatric Meningococcal Septic Shock Trial Study Group: Randomized, placebo-controlled trial of HA-!A, a human monoclonal antibody to endotoxin, in children with meningococcal septic shock. Clin Infect Dis 28:770–777, 1999. 569. Tracey KJ, Fong Y, Hesse DG, et al: Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330:662–664, 1987. 570. Fisher CJ Jr, Agosti JM, Opal SM, et al: Treatment of septic shock with the tumor necrosis factor recepton:Fc fusion protein. N Engl J Med 334:1697–1702, 1996. 571. Abraham E, Wunderink R, Silverman H, et al: Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, doubleblind, multicenter clinical trial. JAMA 273:934–941, 1995. 572. Opal SM, Fisher CJ Jr, Dhainaut JF, et al: Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: A phase III, randomized, double-blind, placebo-controlled, multicenter trial.

573. 574.

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The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med 25:1115–1124, 1997. Bone RC: Why sepsis trials fail. JAMA 276:565–566, 1996. Zeni F, Freeman B, Natanson C: Anti-inflammatory therapies to treat sepsis and septic shock: A reassessment. Crit Care Med 25:1095–1100, 1997. Elliott MJ, Maini RN, Feldmann M, et al: Randomised doubleblind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 344:1105–1110, 1994. Targan SR, Hanauer SB, Van Deventer SHJ, et al: A short-term study of chimeric monoclonal antibody Ca2 to tumor necrosis factor-α for Crohn’s disease. N Engl J Med 337:1029–1035, 1997. Echtenacher B, Falk W, Mannel DN, Krammer PH: Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J Immunol 145:3762–3766, 1990. Scharfman WB, Tillotson JR, Taft EG, Wright E: Plasmapheresis for meningococcemia with disseminated intravascular coagulation. N Engl J Med 300:1277–1278, 1979. Bjorvatn B, Bjertnaes L, Fadnes HO, et al: Meningococcal septicaemia treated with combined plasmapheresis and leucapheresis or with blood exchange. Br Med J (Clin Res Ed) 288:439–441, 1984. Winston DJ, Ho WG, Gale RP: Therapeutic granulocyte transfusions for documented infections. A controlled trial in ninety-five infectious granulocytopenic episodes. Ann Intern Med 97:509– 515, 1982. van der Meer JW, van den Broek PJ: Present status of the management of patients with defective phagocyte function. Rev Infect Dis 6:107–121, 1984. Feldman E, Hester JP, Vartivarian SE. The use of granulocyte colony-stimulating factor-enhanced granulocyte transfusions from normal donors in patients with neutropenia-related fungal infections. 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC, 1993, Abstract 711. Hassner A, Adelman DC: Biologic response modifiers in primary immunodeficiency disorders. Ann Intern Med 115:294–307, 1991. Hershfield MS, Buckley RH, Greenberg ML, et al: Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase. N Engl J Med 316:589–596, 1987. Hoogerbrugge PM, van Beusechem VW, Fischer A, et al: Bone marrow gene transfer in three patients with adenosine deaminase deficiency. Gene Ther 3:179–183, 1996. Onodera M, Ariga T, Kawamura N, et al: Successful peripheral T-lymphocyte-directed gene transfer for a patient with severe combined immune deficiency caused by adenosine deaminase deficiency. Blood 91:30–36, 1998.

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Mucocutaneous Infections in the Immunocompromised Host RICHARD ALLEN JOHNSON and ARTHUR SOBER 1. Introduction Among the most formidable challenges to the clinician is the care of the patient with an impaired immune system— the compromised host. Two characteristics in particular contribute to the complexity of management of infection in these patients: (1) the exceptionally broad variety of potential microbial pathogens and (2) the wide spectrum of clinical manifestations of disease resulting from the abnormal immune response. In the compromised patient, cutaneous and subcutaneous tissues may be expected to be an important aspect of infection, for three reasons.1,2 First, the skin together with the mucosal surfaces represents the first line of defense of the body against the external environment. These barriers assume an even greater importance when secondary defenses, such as phagocytosis, cell–mediated immunity, and antibody production, are impaired. Second, the rich blood supply of the skin provides a route of spread of infection both from the skin to other bodily locations and to the skin from infected sites. In the latter case, a skin lesion may serve as an early warning system to alert the patient and the clinician to the existence of a systemic infection. These cutaneous lesions may be benign in ap– Richard Allen Johnson Harvard Medical School, Infectious Disease Unit, Massachusetts General Hospital, and Department of Dermatology, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115. Arthur Sober Harvard Medical School Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts 02115. Clinical Approach to Infection in the Compromised Host (Fourth Edition), edited by Robert H. Rubin and Lowell S. Young. Kluwer Academic/Plenum Publishers, New York, 2002.

pearance, presumably because of the impaired host immune response, and therefore may be easily missed or dismissed as insignificant. Third, skin infections are common, occurring in up to one–third of significantly compromised hosts. This chapter will give an overview of infection of the cutaneous and subcutaneous tissues in compromised hosts. Topics of discussion are the skin as a barrier to infection, a four-part classification of skin infection in compromised patients, dermatologic lesions associated with human immune deficiency virus (HIV) disease, and diagnostic considerations. In that opportunistic neoplasms and various paraneoplastic inflammatory disorders can enter into the differential diagnosis of opportunistic infection, these also will be discussed.

2. Skin as a Barrier to Infection The skin is usually quite resistant to infection. The mechanisms by which the resistance occurs are not well understood. Three important components that contribute to microbial resistance are nonspecific: (1) intact keratinized layers of the skin, which prevent penetration of microorganisms; (2) dryness of the skin, which retards the growth of certain organisms such as aerobic gramnegative bacilli and Candida species; and (3) the suppressant effect of the normal skin flora, which appears to reduce colonization of pathogens, a phenomenon known as “bacterial interference.” Within this framework, then, one might expect potentially serious skin infections to develop under the following circumstances: (1) destruction by trauma or bypass by introduction of intravascular 49

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catheters of the previously intact keratinized layer of skin; (2) moistening of the skin, such as under occlusive dressings; and (3) alteration of the normal colonizing flora, such as after administration of antimicrobial agents. These types of events would represent some risk to the normal patient, but are considerably more threatening to the compromised patient with impaired immunologic defenses that are likely to be more readily overwhelmed when the primary cutaneous barrier breaks down. An example of these phenomena is the development of invasive fungal infection in compromised patients whose skin has been traumatized by tape holding intra– vascular lines in place. Infection with Rhizopus species has been associated with use of Elastoplast tape to secure intravascular catheters.3 Skin infection with Aspergillus species has occurred at the site of boards to stabilize arms to protect intravenous lines.4 Because of the occurrence of these types of infections, the following approach would seem warranted: Occlusive dressings in immunocompro– mised patients should be avoided when possible, and skin covered by such dressings should be routinely inspected. Paper tape should be used in preference to cloth tape, and surgical dressings might be secured with girdles of elas– ticized netting rather than tape whenever possible. The effect of chronic administration of cortico–

steroids on the skin is another factor that may contribute to increased susceptibility of compromised patients to infection. Steroid therapy appears to inhibit proliferation of fibroblasts, synthesis of mucopolysaccharides, and deposition of collagen. The net effect is thin and atrophic skin that heals poorly. Minor trauma generates lesions that tend to persist, providing potential portals of entry for pathogens. An example of the phenomenon that has been observed is recurrent staphylococcal cellulitis about the elbow in patients receiving chronic immunosuppressive therapy after renal transplantation. These patients exhibited two adverse effects of chronic corticosteroid administration: (1) thinning of the skin leading to enhanced susceptibility of the tissue to trauma and (2) steroid-induced proximal myopathy. Because of the myopathy, the patients tended to rise from the sitting position by pushing off with their elbows, and thus traumatizing them. Cellulitis about the elbows recurs in these patients until protection is provided to their elbows and the steroid dose is decreased.

3. Types of Skin Infection

Infection of the cutaneous and subcutaneous tissues in compromised patients can be classified in a variety of

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ways: by pathogen, by underlying immunologic defect, or by pace of illness. An additional categorization considers pathophysiologic events and consists of four groups (Fig. 1): (1) infection originating in skin and being typical of that which occurs in immunocompetent persons, albeit with the potential for more serious illness; (2) extensive cutaneous involvement with pathogens that normally produce trivial or well-localized disease in immunocompetent patients; (3) infection originating from a cutaneous source and caused by opportunistic pathogens that rarely cause disease in immunocompetent patients but may cause either localized or widespread disease in compromised persons; and (4) cutaneous or subcutaneous infection that represents metastatic spread from a noncutaneous site. Cutaneous and subcutaneous infections in compromised patients are discussed in this section within the framework of these four groups.

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compromised host. Gram-positive organisms, such as Staphylococcus aureus and group A streptococci, most commonly cause these infections. Patients with granulocytopenia are more susceptible to cellulitis caused by less virulent (for the skin) bacterial pathogens, such as Enterobacteriaceae and Pseudomonas species, and by anaerobic bacteria. Patients with leukemia or diminished cellmediated immunity may have erysipelas-like infection, caused by such organisms as Cryptococcus neoformans or Candida species, mimicking cellulitis caused by common gram-positive bacteria. When evaluating cellulitis in a compromised patient, common as well as uncommon/rare pathogens must be considered as potential pathogens. If a patient does not respond to conventional antimicrobial therapy, an aggressive approach to diagnosis is warranted, with biopsy of lesions for Gram and other stains, cultures, and dermatopathology, to correctly identify the pathogen.

3.1. Primary Skin Infections with Common Pathogens

3.2. Unusually Widespread Cutaneous Infection

The incidence and severity of conventional forms of infections originating in the skin often are increased in the

Nonvirulent skin fungi and viruses constitute the two major causes of infection in this category. These patho-

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gens typically cause minor infections in immunocompetent persons, but in compromised patients they tend to cause more extensive disease that may lead to more serious systemic illness. Viruses that cause exanthems (e.g., those caused by rubella, measles, or enterovirus) do occur in immunocompromised patients, but the more problematic pathogens include the family of herpesviruses and human papillomaviruses (HPV).

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Nonvirulent fungi include the dermatophytes (Trichophyton species, Microsporum species, and Epidermophyton), Candida species, Pityrosporum species, Fusarium solani, and Alternaria alternata. These fungi frequently colonize human skin and cause localized, superficial skin infection in immunocompetent persons, particularly when the skin has been traumatized. The incidence and severity of infection may be increased in

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compromised patients. Topical corticosteroid preparations prescribed mistakenly for epidermal dermatophytoses compromise local immunity, facilitating growth of the fungus causing extensive local epidermal infection (so-called tinea incognito in that the diagnosis of dermatophytosis is missed); dermatophytic folliculitis (Majocchi’s granuloma) commonly is seen as an associated finding. Systemic corticosteroid therapy also can cause widespread epidermal dermatophytosis. These dermatomycoses are best treated with oral agents such as terbinafine, itraconazole, or fluconazole; secondary prophylaxis is often necessary. In chronically immunosuppressed patients, HPVinduced lesions, i.e., verrucae and condylomata, either may be extremely numerous or may form large confluent lesions. Up to 40% of renal transplant recipients develop warts following transplantation, half of these have more than ten warts, and up to 1% have extensive disease. The incidence and severity of warts seem to be related to immunosuppression, with previously acquired latent virus reactivating with institution of immunosuppressive therapy. In compromised patients, HPV-induced lesions have the potential for malignant transformation, particularly in sun-exposed areas of the body. Squamous cell carcinoma (SCC) arising in sites of chronic sun exposure occur 36 times more frequently in renal transplant recipients than in the general population, some clearly arising within warts; HPV DNA is demonstrable within the tumors. Management of patients with extensive warts should include avoidance of sun exposure, use of strong sunscreens, reduction in immunosuppressive therapy when possible, and careful observation for the development of malignant lesions. HPV-induced anogenital in situ and invasive SCC also is more common in transplant recipients and HIV-infected individuals; these persons also should be screened for in situ and invasive SCC with Papanicolaou test of the anus and cervix and lesional biopsy when indicated. Skin infections with members of the herpesvirus family, particularly herpes simplex virus (HSV) and varicella–zoster virus (VZV), are very common in compromised patients. Nasolabial or anogenital infections due to HSV occur in as many as half of renal transplant recipients, patients with malignancy, those receiving chemotherapy, and HIV-infected individuals. Immunocompromised patients may have more serious forms of HSV infection including chronic herpetic ulcers, esophageal or respiratory tract infection, or disseminated infection [patients with lymphoma, transplant recipients (bone marrow, renal, cardiac, or liver), and neonates]. In compromised patients, reactivation of VZV is com-

mon, occurring in 14% of persons with Hodgkin’s disease, 8% of non-Hodgkin’s lymphoma and renal transplant recipients, and 2% with solid tumors. Visceral dissemination occurs in 15 to 30% of patients with Hodgkin’s disease with zoster; systemic dissemination, however, is uncommon in renal transplant recipients. Reactivated VZV infection is particularly problematic for bone marrow transplant recipients, of whom one-half will develop herpes zoster. In one-third of these, VZV will disseminate, and in one-fourth a generalized atypical recurrent varicellalike illness will develop. Reactivated cytomegalovirus (CMV) causes hepatitis, pneumonitis, chorioretinitis, encephalitis, and gastroenteritis in transplant recipients and HIV-infected individuals; cutaneous CMV infections are rare. Cutaneous CMV infections are reported to present as nodules, ulcers, indurated plaques, vesicles, petechiae, or a maculopapular exanthem. Reactivation of Epstein–Barr virus (EBV) results in oral hairy leukoplakia on the lateral aspects of the tongue, a lesion nearly pathognomonic for HIV disease. 3.3. Opportunistic Primary Cutaneous Infection

Following inoculation into the skin, organisms of low virulence can cause local or disseminated infections in some persons with impaired immune defenses. Localized disease can be caused by Paecilomyces, atypical mycobacteria, and Prototheca. Localized disease with life-threatening systemic spread may be caused by Pseudomonas aeruginosa, Aspergillus species, Candida species, and Rhizopus species. P. aeruginosa causes a necrotizing soft-tissue infection, i.e., ecthyma gangrenosum, which occurs at the portal of entry (most commonly in naturally occluded sites such as the anogenital region or axillae), especially in granulocytopenia patients. Histologically, the organism causes a necrotizing vasculitis that results in tissue infarction and hematogenous dissemination. Paecilomyces is a saprophytic fungus that may cause an ulcerating soft-tissue infection following laceration of the pretibial region in renal transplant recipients. Environmental mycobacteria such as M. marinum, M. chelonae, M. kansasii, and M. haemophilum may cause cutaneous infection following inoculation. In the normal host, the infection is localized and may resolve without therapeutic intervention; however, in the compromised host, more extensive local infection may occur as well as lymphatic or hematogenous dissemination. Prototheca wickerhamii is an algalike organism ubiquitous in nature that may cause localized infection following trauma or surgery. Primary infection caused by Aspergillus, Rhizopus,

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or Candida species arises at localized cutaneous sites, but has the potential for disseminated disease in the compromised host. Primary cutaneous infection with these fungi has been associated with use of adhesive or Elastoplast tape, cardiac electrode leads, or extravasation of intravenous fluids. Aspergillus and Rhizopus species can invade blood vessels, resulting in infarction, hemorrhage, and hematogenous dissemination. 3.4. Systemic Infection Metastatic to Cutaneous and Subcutaneous Sites In a report of dermatologic manifestations of infection in compromised patients, 8 of 31 patients (26%) had apparent spread of systemic infection to cutaneous and subcutaneous tissues.2 In 6 of these 8 patients, cutaneous or subcutaneous lesions were the first clinical sign of disseminated infection. In compromised hosts, cutaneous lesions resulting from hematogenous spread of infection are caused in general by three classes of pathogens: (1) Pseudomonas aeruginosa and other bacteria; (2) the endemic systemic mycoses (Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, and Penicillium marneffei (Southeast Asia); and (3) the ubiquitous opportunistic organisms Aspergillus species, Cryptococcus neoformas, Candida species, Rhizopus species, and Nocardia species. Hematogenous dissemination of P. aeruginosa to the skin of a compromised patient can result in subcutaneous nodules, cellulitis, or necrotizing soft-tissue infection (pyoderma gangrenosum). The usual setting is profound granulocytopenia, often with acute leukemia. Fungi endemic to geographical regions often cause asymptomatic primary pulmonary infection, followed by prolonged latency. In the setting of deficiency of cellmediated immunity, latent fungi can cause local pulmonary infection with subsequent hematogenous dissemination, commonly to mucocutaneous sites. Ubiquitous opportunistic fungi and Nocardia species can cause asymptomatic pulmonary infections that disseminate hematogenously in the compromised host. Candida usually disseminates from the gastrointestinal tract or an infected intravascular line. Disseminated cryptococcosis often presents with cutaneous lesions (molluscum contagiosumlike facial lesions), subcutaneous nodules, or cellulitis prior to the clinical presentation of meningitis. Disseminated histoplasmosis also presents on the skin with molluscum contagiosumlike facial lesions, guttate psoriasislike lesions, as well as other morphologies. Nocardia disseminates from pulmonary infection, resulting in subcutaneous nodules.

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4. Diagnostic Aspects of Skin Infections in the Compromised Patient In the immunocompetent patient, the gross appearance of a skin lesion is an important aspect of diagnosis. By contrast, the clinical value of the gross appearance of a cutaneous lesion in a compromised host is likely to be limited, for two reasons: First, in compromised patients, the variety of organisms that may cause infection is substantially greater than in immunocompetent persons. Second, in compromised patients, the inflammatory response to infection may be altered. A cutaneous lesion results not only from the invading pathogen itself but also from the inflammatory response of the body to the microbe. Thus, with an impaired inflammatory response, the prediction is that the diagnostic usefulness of gross appearance would be suboptimal. For these two reasons, it is key to realize that the differential diagnosis of a particular skin lesion in a compromised patient is extensive. The approach to biopsy of a cutaneous lesion suspected to be infectious should include two considerations: (1) The most rapid and most sensitive methods for detecting microbes both histologically and immunologically should be used and (2) appropriate cultures and stains should be obtained to optimize the chance of identifying the pathogen. A 6- or 8-mm punch biopsy is usually adequate. Half the tissue is sent for histopathologic evaluation by routine methods and also by special stains for fungi, mycobacteria, and bacteria. The other half is sent to the microbiology laboratory for culture for aerobic and anaerobic bacteria, mycobacteria, and fungi (at 25°C and 37°C) and also for Gram’s stain, acid-fast, modified acidfast, and direct fungal stains of touch preparations or ground tissue.

5. Opportunistic Infections by Pathogen 5.1. Bacterial Infections 5.1.1. Staphylococcus aureus Staphylococcus aureus causes the greater majority of all pyodermas and soft-tissue infections. Although not one of the cutaneous resident flora, it colonizes the anterior nares in up to 25% of healthy individuals at any one time and more than 50% of chronically ill individuals. The incidence of S. aureus nasal carriage is higher in chronically ill individuals, especially those with HIV disease, diabetes mellitus, cancer (especially hematologic malignancies), neutropenia, abnormal leukocyte func-

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tion, chronic granulomatous disease, hyperimmunoglobulinemia E syndrome, and interleukin-2 therapy. Ensconced in the nares, S. aureus is able to colonize and infect superficial skin lesions by entering hair follicles or small breaks in the epidermis, by secondary infection (Fig. 2) of dermatologic disorders (scabies, eczematous dermatitis, herpetic ulcer, Kaposi’s sarcoma, molluscum contagiosum), drug injection sites (Fig. 3), or via vascular access line and drainage tubes, resulting in pyodermas (folliculitis, furuncles, carbuncles, abscess, impetigo, bullous impetigo, and ecthyma). Once established in the skin, S. aureus is able to invade more deeply into the soft tissue with resultant erysipelas (horizontal

spread in lymphatics) and cellulitis (vertical spread into subcutaneous fat) (Fig. 4). S. aureus is the most common cause of wound infections. Risk factors for surgical wound infection are dependent on the following: host factors (immune status, diabetes mellitus); surgical factors (disruption of tissue perfusion that accompanies the surgical procedure, foreign body use); staphylococcal factors (substances that mediate tissue adherence and invasion or that enable staphylococci to survive host defenses and antibiotics in tissues, and antimicrobial prophylaxis). Bacteremia can result in deposition of S. aureus in the skin, resulting in petechiae, hemorrhages, subcutaneous nodules, soft-tissue infections, and pyomyositis.

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Various strains of S. aureus are capable of producing a variety of toxins, which cause the clinical syndromes of staphylococcal scalded skin syndrome (rare in infants greater than 2 years of age), staphylococcal scarlet fever, and toxic shock syndrome (TSS). TSS is a febrile, multiorgan disease caused by the elaboration of staphylococcal toxins, characterized by a generalized scarlatiniform eruption, hypotension, functional abnormalities of three or more organ systems, and desquamation in the evolution of the exanthem. Cellulitis caused by S. aureus that produce TSS toxins can be accompanied by the cutaneous and systemic findings of staphylococcal scarlet fever or TSS.5

5.1.2.

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Streptococcus

Group A streptococci (Streptococcus pyogenes) (GAS) commonly colonize the upper respiratory tract and secondarily infect (impetiginize) minor skin lesions from which invasive infection can arise.6–8 Certain strains of group A streptococci have a higher affinity for the skin than the respiratory tract and can colonize the skin, subsequently causing superficial pyodermas or softtissue infections. Lymphatic obstruction/lymphedema predisposes to erysipelas or cellulitis. Individuals at higher risk are those who have had radical mastectomy with axillary node dissection or saphenous vein harvest. Absence

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of antibodies against pyrogenic exotoxins A and/or B has been reported as a risk factor for developing invasive streptococcal disease; toxic shock and mortality were associated with a lack of antipyrogenic exotoxin A antibodies.9 Antibodies against pyrogenic exotoxin A were vital for mediating the outcome of invasive GAS disease. Group B streptococci commonly colonize the perineum and may cause soft-tissue infections at this site. Advanced age, cirrhosis, diabetes, stroke, breast cancer, surgical wounds, decubitus ulcer, neurogenic bladder, and foreign bodies (breast or penile implants) have all been associated with a significantly increased risk of acquiring group B streptococcus infection. An unusual form of

recurrent cellulitis of the lower extremities in women results from impaired lymphatic drainage due to neoplasia, radical vulvectomy or pelvic surgery, or radiation therapy. Morbidity and mortality are relatively high for group B streptococcus infections, with a high incidence of bacteremia. Other streptococci such as the enterococcus can cause invasive infections with septicemia, endocarditis (Fig. 5), and soft-tissue infections. 5.1.3. Streptococcus pneumoniae (Pneumococcus) Streptococcus pneumoniae is a rare cause of cellulitis, occurring in individuals predisposed by connective

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take either of two forms: (1) primary infections [cellulitis at bone marrow biopsy sites, infection at insertion sites of intravascular catheters, skin fissures (perianal)]12–14 and (2) secondary infections (erythematous or hemorrhagic papular rash, soft–tissue abscess, or necrotic lesions) following bacteremia from primary infection sites.15 5.1.6. Escherichia coli and Other Gram-Negative Bacilli Escherichia coli and other gram-negative bacilli rarely cause soft-tissue infection (Fig. 6) or hemorrhagic plaques associated with hematogenous dissemination, in individuals with cirrhosis, neutropenia, or leukocyte dysfunction.16–22 In a report of seven patients with gramnegative bacillary cellulitis and cirrhosis, soft-tissue infections were characterized by bullous lesions, ulcers, abscesses, or extensive cutaneous necrosis. Bacteremia occurred in six patients and patients eventually died. Isolates from the skin included Klebsiella pneumoniae, E. coli, P. aeruginosa, Proteus mirabilis, and A. hydrophila. 5.1.7. Pseudomonas aeruginosa

tissue disease, alcoholism, drug abuse, HIV disease, or corticosteroid therapy.10,11 Clinically, infected areas are characterized by bullae, brawny erythema, and a violaceous hue. Approximately 50% of cases are the result of pneumococcal bacteremia, often from a pulmonary source. Because of underlying medical conditions and often pneumonia, the morbidity is high. 5.1.4. Bacillus cereus Primary cutaneous Bacillus cereus infection presents as a single bulla with necrosis on the extremity of an immunocompromised patient.12–14 The large gram–positive rods of B. cereus may be mistaken for Clostridium species in lesional biopsy specimens and smears. 5.1.5. Corynebacterium jeikeium Skin and soft-tissue infections due to Corynebacterium jeikeium occur in granulocytopenic patients and

Pseudomonas aeruginosa causes the necrotizing soft-tissue infection ecthyma gangrenosum (EG), which occurs as a primary skin infection (Fig. 7)23–25 or as a complication of pseudomonal bacteremia.26 EG occurs commonly as a nosocomial infection, especially in immunocompromised patients with diabetes, neutropenia, or poor neutrophil function. P. aeruginosa is the most common pathogen causing gangrenous cellulitis in childhood. P. aeruginosa gains entry into the dermis and subcutaneous tissues via adnexal epidermal structures or areas of loss of epidermal integrity (pressure ulcers, thermal burns, and trauma). EG occurs most frequently in the axillae or anogenital regions but can arise at any cutaneous site. Clinically, EG presents initially as an erythematous, painful plaque that quickly undergoes necrosis. Established lesions show bulla formation, hemorrhage, necrosis, and surrounding erythema. If effective antibiotic therapy is not initiated promptly, the necrosis often may extend rapidly. Bacteremia occurs soon after the onset of EG and may result in metastatic spread of P. aeruginosa with subcutaneous nodules and abscesses. Histologically, EG is characterized by a distinctive septic vasculitis. Hematogenous dissemination of P. aeruginosa to the skin can result in multiple subcutaneous nodules, hemorrhagic bullae, multiple small hemorrhagic papules, and/ or EG.27

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5.1.8. Stenotrophomonas (Xanthomonas) maltophilia

5.1.10. Vibrio Species

Stenotrophomonas [formerly classified as Xanthomonas (formerly classified as Pseudomonas)] maltophilia is a significant cause of morbidity and mortality in hospitalized patients with neutropenia, cancer, and undergoing chemotherapy. Primary cellulitis (often necrotizing), disseminated cutaneous nodules, and mucocutaneous ulcers caused by Xanthomonas are often associated with underlying malignancies.28

Vibrio vulnificus is a free-living gram-negative rod, occurring naturally in the marine environment, occasionally contaminating oysters and other shellfish. Marine Vibrio species can cause sepsis and soft-tissue infections (Fig. 8), particularly in patients with cirrhosis and/or diabetes mellitus.31 V. damselae may cause fulminant necrotizing soft-tissue infections in immunocompetent patients. Either ingestion of raw seafood or exposure of open wounds to seawater can result in Vibrio bacteremia and soft-tissue infections. Individuals with cirrhosis, hemochromatosis, and diabetes mellitus and other patients with chronic disease are advised to avoid eating raw seafood. Marine Vibrio soft-tissue infections occur by direct inoculation into a superficial wound or by bacteremic spread to the skin (metastatic infection). Following ingestion of V. vulnificus in contaminated seafood, the organism is capable of crossing the gut mucosa rapidly, invading the bloodstream without causing gastrointestinal symptoms. The clinical picture is one of abrupt onset of chills and fever, often followed by hypotension, usually complicated by development of metastatic cutaneous lesions within 36 hr after onset. The cutaneous lesions

5.1.9. Aeromonas Species Aeromonas hydrophila, a gram-negative facultative rod that is found naturally in aqueous environments, causes soft-tissue infections in healthy individuals and more serious infections in the compromised host.29,30 A. hydrophila soft-tissue infections occur following injuries sustained in a contaminated aquatic environment or the “outdoors.” A. hydrophila (a normal inhabitant of the foregut of leeches) cellulitis has also followed the therapeutic use of leeches (in 7–20% of patients) following reimplantation or flap surgery. In the compromised host, Aeromonas causes severe cellulitis and necrotizing softtissue infections.

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cinaedi bacteremia (11 were HIV-infected; the others had underlying alcoholism, diabetes, or malignancy), 9 had cellulitis (some with a distinctive red brown or copper discoloration with minimal warmth). In a series of 7 patients (6 HIV-infected, 1 with a history of alcoholism) with H. cinaedi soft-tissue infections, cellulitis with adjacent arthritis occurred in 2 patients. The organism is carried as bowel flora in 10% of homosexual men (no carriage in other groups). Diagnosis is made by considering it in immunocompromised individuals, demonstrating cellulitis on lesional biopsy (excluding panniculitis), and failure to isolate other pathogens. Bacteremia is intermittent; the organism is difficult to isolate, requiring hydrogen in the culture vial. Ciprofloxacin 500 mg bid or clarithromycin 500 mg bid is effective, given for 6 to 8 weeks to prevent relapse. 5.1.12. Mycobacteria Infections

begin as erythematous plaques, rapidly evolving to hemorrhagic bullae and then to necrotic ulcers. The lesions arise commonly on the extremities, occasionally bilaterally. Soft-tissue infections also can arise following inoculation of V. vulnificus or V. alginolyticus directly into a site of soft-tissue injury. Infection by either of these Vibrio species can be life threatening in compromised hosts. 5.1.11. Helicobacter cinaedi

Helicobacter cinaedi causes a syndrome characterized by fever, bacteremia, and recurrent and/or chronic cellulitis (resembling erythema nodosum) in compromised patients. In a series of 23 febrile patients with H.

5.1.12a. Mycobacterium tuberculosis. In developing countries, tuberculosis is the most common opportunistic infection in HIV disease; however, cutaneous tuberculosis is relatively uncommon. As has been true in the past, most cases of symptomatic tuberculosis represent reactivation of latent infection. In non-HIV-infected persons who have tuberculosis in some form, the incidence of extrapulmonary tuberculosis is 15%; in HIV disease, 20 to 40%. In advanced HIV disease, the incidence of extrapulmonary disease increases to 70%. The etiologic agents of human tuberculosis include M. tuberculosis, M. bovis, and occasionally bacillus Calmette–Guérin (BCG). Cutaneous tuberculosis is highly variable in its clinical presentation. Cutaneous tuberculosis occurs following M. tuberculosis exposure to an exogenous source or by autoinoculation or endogenous spread from another site. Modes of endogenous spread to skin include: direct extension from underlying tuberculous infection, i.e., lymphadenitis or tuberculosis of bones and joints results in scrofuloderma; lymphatic spread to skin results in lupus vulgaris; hematogenous dissemination results in either acute miliary tuberculosis,32–34 lupus vulgaris, or metastatic tuberculosis abscess. Tuberculosis cutis miliaris disseminata is the lesion of miliary tuberculosis, presenting as 1- to 4-mm red–brown papules–papulovesicles–papulopustules.35,36 On acidfast stain of lesional skin biopsy specimens, numerous acid-fast bacilli are seen; however, giant cells and granulomas are absent. In HIV-infected individuals, prior BCG immunization can be followed by reactivation of and infection by BCG at the site of immunization, dissemination of BCG, or lymphadenitis.

MUCOCUTANEOUS INFECTIONS

5.1.12b. Environmental Mycobacteria. Mycobacteria other than tuberculosis (MOTT) (also known as nontuberculous mycobacteria, environmental mycobacteria, potentially pathogenic environmental mycobacteria, atypical mycobacteria, nonleprous mycobacteria) are widely distributed in soil, dust, and water. They are classified by Runyon groups: group I (photochromogens), M. marinum, M. kansasii; group II (scotochromogens), M. szulgai, M. gordonae, M. malmoense; group III (nonphotochromogens), M. avium-intracellulare complex (MAC); group IV (rapid growers), M. fortuitum complex [M. fortuitum, M. chelonae, M. abscessus (MFC)]. In the immunocompetent host, injury (trauma or surgery) is followed by the development of localized cellulitis or abscess formation in four to six weeks. In the compromised host, the usual presentation is of multiple erythematous or violaceous subcutaneous nodules without history of trauma; lesions may progress to abscesses that drain and ulcerate.37 M. kansasii,,38,39 M. marinum,40–42 M. gordonae,43 M. malmoense,44 M. fortuitum,45,46 and M. chelonae47,48 (Fig. 9) can cause infection in the healthy as well as the compromised host. Inoculation has occurred via puncture wounds (injection or traumatic) or surgical procedures (augmentation mammoplasty, median sternotomy,47,48 percutaneous catheterization), or rarely primary cellulitis occurs without recognizable skin trauma. Contaminated gentian violet used for skin marking has been the source in some outbreaks. MFC soft-tissue infections characteristically occur several weeks after the injury and appear as indolent wound infections (nodules, ulcers, granulomatous papules, or verrucous plaques). In immunocompromised individuals, MFC can disseminate hematogenously to skin (multiple recurring abscesses on the extremities) and joints.49 In advanced HIV disease, MAC commonly causes systemic infection; however, it rarely causes cutaneous infection.50–52 Cutaneous MAC infections usually are complications of disseminated disease; lesions vary from papules, nodules, pustules, and soft-tissue abscesses to ulcerations; localized infection without apparent disseminated infection has been reported.51 Cutaneous ulcerations have occurred at the sites of underlying MACassociated lymphadenitis. Subcutaneous abscesses and ulcers due to localized MAC infection also have been described. Interpretation of isolation of MAC and/or demonstration of acid-fast bacilli in skin biopsy specimens from patients with advanced HIV disease is difficult in that approximately 40% of these individuals have MAC bacteremia (if not on prophylaxis for MAC). In most cases in whom MAC is demonstrated on lesional biopsy speci-

63

men, the presence of MAC is incidental, having no part in the pathogenesis of the cutaneous lesion. MAC infection has been reported in three patients who presented with either submandibular, axillary, or inguinal lymphadenitis.53 Following incision and drainage or spontaneous rupture, scrofuloderma occurred with the formation of deep ulcerative lesions; resolution occurred after a short course of routine antituberculous therapy. Subcutaneous masses also can represent underlying osteomyelitis. Cutaneous M. haemophilum infection has been reported to induce erythema, swelling, painful nodules, and abscess formation and disseminated cutaneous lesions with systemic involvement of bones, joints, lymphatics, and lungs.54–58 Recovery of M. haemophilum requires a

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high level of clinical suspicion and special handling of mycobacterial cultures by the microbiology laboratory, including cultivation on enriched chocolate agar or heme– supplemented media and incubation at 30°C for up to 8 weeks. Response to antimycobacterial therapy has been poor; disease tends to recur and progress. 5.1.12c. Mycobacterium leprae. The interrelationship of M. leprae and HIV in dually infected persons has not been adequately studied to date.59–62 Tropical areas such as Africa and India that have a high prevalence of leprosy are expected to bear the brunt of the HIV epidemic during the next decade. It is probable that leprosy will accelerate the course of HIV disease and that HIV infection will result in a higher ratio of cases of lepromatous versus tuberculoid leprosy and resistance to antilepromatous therapy.63,64 The natural history of leprosy in HIV disease has been reported in 275 patients from Haiti; 6.5% of the entire cohort was HFV-seropositive. No difference in HIV seropositivity was detected in patients with either lepromatous or tuberculoid types of leprosy. Of the HIV-seropositive patients, 22% developed new skin lesions and lepromin anergy during the course of dapsone–rifampin leprosy therapy, as compared to 0.8% of HIV-seronegative patients. 5.1.13. Bacillary Angiomatosis Bacillary angiomatosis (BA) and bacillary peliosis (BAP) occur most commonly in the setting of HIV-induced immunodeficiency, characterized by angioproliferative lesions resembling pyogenic granulomas or Kaposi’s sarcoma.65 BAP is caused by infection with fastidious gramnegative bacilli of the genus Bartonella, B. henselae, and B. quintana. The vascular lesions are referred to as BA and those occurring in the liver or spleen as peliosis (BAP). In immunocompetent individuals, B. henselae also causes cat scratch disease. HIV-infected individuals with BAP usually have moderate to advanced disease; rarely, BA occurs in immunocompetent, non-HIV-infected individuals. The varied tissue response to Bartonella infection in the immunocompetent individual is analogous to the clinical patterns occurring in leprosy. Individuals with intact cellular immunity develop cat scratch disease or tuberculous leprosy; those with impaired cellular immunity develop BAP or lepromatous leprosy. Currently, the prevalence of BA is very low due to prophylaxis given for infections such as Mycobacterium avium complex (MAC) and improved immune function with highly active antiretroviral therapy (HAART). In a study of 49 individuals with BAP, 53% were infected with B. henselae and 47% were infected with B.

quintana.66 B. henselae and B. quintana were equally likely to cause cutaneous BA; only B. henselae was associated with hepatosplenic peliosis. Patients with B. henselae infection were epidemiologically linked to cat and flea exposure. Those with B. quintana infections were linked to low income, homelessness, and exposure to head or body lice. Prior treatment with macrolide (erythromycin, clarithromycin, azithromycin) antibiotics appeared to be protective against infection with either species. The domestic cat serves as a major persistent reservoir for B. henselae. Cats experience prolonged, asymptomatic bacteremia, and can transmit the infection to humans.67 The cat flea is the vector of B. henselae among cats. The domestic cat, however, appears to be a major vector (by scratch or bite) from cat to humans. Antibiotic treatment of infected cats and control of flea infestation are potential strategies for decreasing exposure to Bartonella. Whether asymptomatic or latent infection occurs in humans is not known. The incubation period is unknown, but is probably days to weeks. Patients with localized infection may be free of systemic symptoms. Cutaneous BA may be painful; in contrast, similar-appearing lesions of Kaposi’s sarcoma usually are not painful unless ulcerated or secondarily infected. Individuals with more widespread disseminated Bartonella infection often experience fever, malaise, and weight loss. Clinically, the cutaneous lesions of BA are red-toviolaceous, dome-shaped papules, nodules, or plaques, ranging in size from a few millimeters up to 2 to 3 cm in diameter (dermal vascular lesions with thinned or eroded epidermis). Less commonly, domed subcutaneous masses occur without the characteristic red color of more superficial vascular lesions.68 Lesions are soft to firm and may be tender to palpation. The number of lesions ranges from solitary lesions to hundreds. Nearly any cutaneous site may be involved, but the palms, soles, and oral cavity are usually spared. Following hematogenous or lymphatic dissemination, the spectrum of internal disease caused by B. henselae and B. quintana includes soft-tissue masses, bone marrow, lymphadenopathy, splenomegaly, and hepatomegaly; internal involvement can occur with or without cutaneous lesions. The differential diagnosis of the cutaneous papulonodular lesions includes Kaposi’s sarcoma, pyogenic granuloma, epithelioid (histiocytoid) angioma, cherry angioma, sclerosing hemangioma, angiokeratomas, and disseminated deep fungal infections. Subcutaneous BA nodules and tumor must be differentiated from enlarged lymph nodes and subcutaneous masses. The histopathology of lesional skin biopsy specimens of BA is characterized by two patterns of lobular prolif-

MUCOCUTANEOUS INFECTIONS

erations of capillaries and venules. Pyogenic granulomalike lesions are characterized by proliferation of small round blood vessels with plump endothelial cells. The stroma is edematous and loose. The inflammatory infiltrate is composed of lymphocytes, histiocytes, and neutrophils. The overlying epidermis may show collarette formation, thinning, or ulceration. Few if any bacteria are visualized by silver stain. The second type of lesion arising deeper in the dermis or subcutis appears more cellular, made up of myriad small, round blood vessels lined by plump endothelial cells. The interstitium shows a granular amphophilic material. Abundant clusters of bacilli, corresponding to sites of granular material, are visualized by silver stain. Percutaneous liver biopsy in patients with peliosis hepatis may be contraindicated because of the vascular nature of the lesions and the risk for uncontrolled bleeding. Histology of liver lesions shows blood–filled cysts with clusters of bacilli in the connective tissue rims of the cysts.69 The infecting Bartonella species can be identified by molecular techniques on tissue samples. Isolation of Bartonella is possible from lesional tissue biopsy specimens and/or blood. The diagnosis also can be confirmed by detection of anti-Bartonella antibodies. The diagnosis of BAP usually is made by the demonstration of pleomorphic bacilli on a Warthin–Starry or similar silver stain, or by electron microscopy. The course of BA is variable. In some patients, lesions regress spontaneously. BA infection may spread hematogenously or via lymphatics to involve bone marrow, bone, spleen, and liver. Death may occur secondary to laryngeal obstruction, liver failure, or pulmonary infection. As with other opportunistic infections in HIV disease, BAP can recur. During the past decade, the incidence of BA has decreased due to the use of antibiotics for MAC prophylaxis and improved immune function following HAART. BAP is preventable. B. henselae is contracted from cats; avoidance should prevent infection. B. quintana occurs among homeless people; infection can be prevented by improved hygiene.70 The antibiotics of choice are erythromycin 250–500 mg PO qid or doxycycline 100 mg bid, continued until the lesions resolve, usually in 3 to 4 weeks. Secondary prophylaxis is indicated in patients with recurrent BAP, especially if immune restoration is not possible. 5.1.14. Nocardiosis Cutaneous nocardiosis can occur as a primary cutaneous infection [abscesses, ulcers, granulomas, softtissue infection, mycetoma, sporotrichoid (lymphocuta-

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neous) infection] or secondary cutaneous infection (pustules, abscesses, nodules) complicating hematogenous dissemination from the lungs.73–76 Nocardiosis in HIV disease is rare; prophylaxis for Pneumocystis carinii pneumonia (PCP) with sulfonamides also may provide primary prophylaxis for nocardiosis.77 Primary cutaneous nocardiosis in HIV disease has been reported to occur at the site of heroin injection; abscesses appeared initially that evolved into large ulcerations. Primary cutaneous nocardiosis may result in lymphangitic proximal extension (sporotrichoid pattern).78,79 5.2. Fungal Infections 5.2.1. Superficial Fungal Infections (Dermatomycoses) 5.2.1a. Dermatophytoses. Dermatophytes, i.e., Trichophyton, Microsporum, and Epidermophyton, may occur on any keratinized epidermal structure, i.e., epidermis (stratum corneum), nails, and hair. This group of fungi infect nonviable tissue in otherwise healthy individuals; however, in the compromised host, direct invasion of the dermis may occur. Dermatophytoses are of importance for three reasons: the morbidity and disfigurement caused by the dermatophyte infection itself, which can be quite extensive; the breakdown in the integrity of the skin that can occur, providing a portal of entry for other pathogens, particularly S. aureus; and such infections can cause clinical manifestations that mimic other dermatologic conditions.80 Dermatophyte infections in the compromised host are more frequent, often widespread, atypical in appearance, or invasive.81 Epidermal dermatophytosis often is widespread in HIV-infected individuals (Fig. 10) and in transplant recipients. Local immunity to dermatophytic infection is commonly suppressed in patients who have been misdiagnosed as having an inflammatory dermatosis such as eczema or psoriasis and treated with topical corticosteroid preparations, so-called tinea incognito. Clinically this presents as one or many plaques, in some cases with sharply marginated borders, in some cases without scaling, and variable degrees of erythema. Papules or nodules within tinea incognito represent a dermatophytic folliculitis (Majocchi’s granuloma). Majocchi’s granuloma does occur in the absence of topical corticosteroid use.82 Inflammatory plaques, ± abscess formation, ± hemorrhage associated with dermal invasion also have been reported to occur in hairy and glabrous sites.83–85 Epidermal dermatophytosis also can occur in sites of irradiation in which local immunosuppression has occurred.86

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In immunocompromised individuals, Trichophyton rubrum causes proximal subungual onychomycosis (PSO), and infection of the undersurface of the proximal nail plate (Fig. 11). PSO occurs most often in HIV-infected individuals, and its diagnosis is an indication for HIV testing. PSO also can be seen in transplant recipients and Waldenström’s macroglobulinemia. Clinically, PSO initially appears as a chalky white discoloration of the proximal nail plate. KOH preparation of the dorsal nail plate is negative for fungal elements; the undersurface of the nail plate obtained from a core of nail with a skin punch reveals fungal elements on the undersurface of the involved nail plate. Unless immunocompromise is restored, dermatophyte infections are chronic and recurrent.87 In that many patients are taking oral imidazoles such as fluconazole or itraconazole for candidiasis or cryptococcosis, dermatophytoses are inadvertently treated and kept under control. Terbinafine, which is highly efficacious for dermatophytic infection, is not predictably effective for nondermatophytic fungal infections. 5.2.1b. Pityrosporiasis. Malassezia furfur (P. orbiculare, Pityrosporum ovale) can cause extensive pityriasis (tinea) versicolor, especially in diabetics and individuals treated with topical or systemic corticosteroids. Pityrosporum folliculitis, which occurs more commonly

in HIV disease, transplant recipients, pregnancy, malignancy, and chronic renal failure, presents as multiple small folliculocentric papules and pustules (acneform) on the upper trunk.88,89 Diagnosis is made by demonstration of yeast in the follicular infundibulum. Pityrosporum folliculitis must be differentiated from both cutaneous candidiasis and hematogenously disseminated candidiasis to skin in the compromised host.90 Pityrosporum may have some role in the pathogenesis of seborrheic dermatitis, which is common in HIV disease. 5.2.1c. Candidiasis. Oropharyngeal candidiasis (OPC) associated with Pneumocystis carinii pneumonia in young homosexual men marked the advent of the HIV epidemic.91 OPC occurs in the majority of HIV-infected individuals during the natural course of HIV disease as a result of impaired cell-mediated immunity. The oropharynx is the most common site of mucosal candidiasis, which may extend into the esophagus and/or tracheobron– chial tree in advanced HIV disease. Recurrent candidal vulvovaginitis is common in HIV-infected women, and may be the first clinical expression of immunodeficiency.92 In contrast, Candida intertrigo, which is more common than mucosal candidiasis in the normal host, is uncommon in adults with HIV disease. Candidiasis of moist, keratinized cutaneous sites such as the anogenital

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region occurs with some frequency. Systemic infection originating in the bowel occurs in individuals with prolonged neutropenia. OPC in the absence of predisposing local or systemic causes always should raise the issue of HIV serotesting. Candida colonization of the oropharynx is common in HIV-infected individuals.93 In a study of HIV-infected outpatients (median CD4 cell count Candida species were isolated from the oral swabs in 60% of individuals, in the absence of any clinical findings of thrush.94 C. albicans was the most prevalent colonizing species isolated from each individual. Five other species were also isolated; 22% of patients were colonized with two different Candida species. Isolation of non–albicans species alone correlated with advanced HIV diseases with very low CD4 cell counts. OPC is a marker of HIV disease progression.95 In a study of the onset of oropharyngeal candidiasis following documented dates of HIV seroconversion, candidiasis was noted in 4% at 1 year after seroconversion, 8% at 2 years, 15% at 3 years, 18% at 4 years, 26% at 5 years; the median CD4 cell count was when OPC was first detected. OPC and esophageal candidiasis have been reported to occur as manifestations of primary HIV infection.96 Esoph-

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ageal candidiasis, an AIDS-defining condition, occurs only with advanced CD4 count reduction Although OPC often is asymptomatic, the presence of white curdlike colonies of Candida within the mouth is a constant reminder of HIV disease to the patient. When symptomatic, common complaints associated with OPC include a soreness or burning sensation in the mouth, sensitivity eating spicy foods, and/or reduced or altered sense of taste. Symptomatic esophageal candidiasis is less common than oropharyngeal infection, and is usually, but not invariably, associated with oropharyngeal disease. The most common symptoms associated with esophageal candidiasis include retrosternal burning and odynophagia. Female patients with HIV infection are increasingly subject to vulvovaginal candidiasis associated with vulvar pruritus, dysuria, dyspareunia, and vaginal discharge. On physical examination and esophagoscopy, oropharyngeal and esophageal candidiasis present most commonly with a pseudomembranous (thrush) pattern (Fig. 12) and less often with a chronic hyperplastic and/or atrophic pattern. Pseudomembranous candidiasis is characterized by white to creamy curdlike plaques on any surface of the oral mucosa, with these white areas being colonies of Candida. The “curds” are easily removed

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with a dry gauze (in contrast to the lesions of oral hairy leukoplakia, which are relatively fixed to the underlying mucosa), with some bleeding of the mucosa sometimes occurring. Atrophic candidiasis often is overlooked on examination of the mouth and often is the initial presentation of oropharyngeal candidiasis; it appears as patches of erythema, most commonly occurring in the vault of the mouth on the hard and/or soft palate. On the dorsal surface of the tongue, atrophic candidiasis causes areas of depapillation resulting in a smooth red mucosa. There may be areas of pseudomembranous involvement at some sites, while others manifest the atrophic pattern. Chronic hyperplastic candidiasis presents as both red and white patches at any site in the oropharynx. In edentulous patients with dentures, pseudomembranous and/or atrophic candidiasis typically is seen under the mucosa occluded by dentures. Candidal angular cheilitis occurs at the corners of the mouth as an intertrigo, unilaterally or bilaterally, and is more common in edentulous patients; it may occur in conjunction with oropharyngeal or esophageal disease or as the only manifestation of candidal infection. Chronic and/or recurrent candidal vulvovaginitis is a common opportunistic infection in HIV-infected women with moderate to advanced immunodeficiency. Children

with HIV infection commonly experience candidiasis in the diaper area and intertrigo in the axillae and neck fold. The incidence of cutaneous candidiasis, i.e., Candida intertrigo, may be somewhat increased in immunocompromised adults. Fingernail chronic Candida paronychia with secondary nail dystrophy (onychia) is common in HIV-infected children.97 Candidemia occurs in HIV-infected individuals undergoing total parenteral nutrition, intravenous antibiotic therapy through a central venous catheter, or cancer chemotherapy, having a central venous catheter for >90 days. In a study of HIV-infected children with fungemia, non–Candida albicans species and Candida (Torulopsis) glabrata were isolated relatively commonly.98 Clinically, cutaneous dissemination of candidiasis presents as multiple erythematous papules on ears, extremities, and the trunk; lesions may be ecchymotic in the setting of thrombocytopenia. The diagnosis of mucocutaneous candidal infection requires the presence of clinical manifestations of infection plus the demonstration of the organism on microscopic examination of a potassium hydroxide preparation of material taken from the lesion. Since Candida is a commensal organism in the oral cavity, isolation of the organism on culture in the absence of a clinically overt

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abnormality is not very meaningful. At times, lesional biopsy is required for the diagnosis of hyperplastic candidiasis. The differential diagnosis of oropharyngeal candidiasis includes oral hairy leukoplakia, migratory glossitis (geographic tongue), lichen planus, bite line irritation, and smoker’s leukoplakia. Management of mucosal candidiasis should be directed at control of symptomatic candidiasis, which may be followed by secondary prophylaxis (Table 3). Prolonged prophylaxis with topical or systemic agents increases the risk of azole-resislant infection. Topical treatments rely on high patient compliance in that they require administration 4 to 5 times daily, but they usually are preferred over systemic drugs for initial treatment. Agents for topical therapy of OPC include nystatin (suspension, tablets, pastilles),99 clotrimazole (troche), itraconazole solution, fluconazole solution, and amphotericin B solution. The imidazoles, fluconazole (oral solution, tablets, IV solution), itraconazole (capsules, oral solution100), and ketoconazole (tablets) are available for systemic therapy. Terbinafine is an excellent agent for dermatophytoses, but not for candidal infections.101 OPC relapses in approximately 40% of cases within 4 weeks of discontinuing therapy. Secondary prophylaxis of OPC and esophageal can-

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didiasis often is indicated unless the immunocompromise is restored. Fluconazole-resistant oropharyngeal and/or esophageal candidiasis occurs relatively frequently in chronically treated patients.102,103 HIV-infected individuals taking fluconazole 200 mg/day prophylactically experienced reduction in the frequency of cryptococcal infection, esophageal candidiasis, and superficial fungal infection, especially those with CD4 cell counts of but they did not experience reduction in overall mortality rate.104 Despite fluconazole efficacy in preventing fungal infections, daily routine prophylaxis is not recommended for all individuals with advanced HIV disease because of cost, possible emergence of drug-resistant candidiasis, and potential drug interactions.105 5.2.2. Invasive Fungal Infections Involving the Skin The major importance of the cutaneous manifestations of systemic mycotic infection is that these manifestations may be the first clue to the presence of such disseminated infection. The most important examples of this phenomenon are disseminated cryptococcal infection, which occurs in approximately 10% of patients with untreated advanced HIV disease and infection due to Histoplasma capsulatium or Coccidioides immitis. These

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last are seen much less frequently, since exposures to these organisms occur only in geographically restricted areas (H. capsulatum being found in the east central portion of the United States, Ohio and Mississippi River valleys, Virginia and Maryland, as well as parts of Central America and, in the case of H. capsulatum var. duboisii, Africa; C. immitis being found in the desert soil of the southwestern United States, Mexico, and parts of Central and South America). In Southeast Asia, systemic infection with Penicillium marneffei in HIV disease has been reported.106 The pathogenesis of these infections resembles that of tuberculosis: primary infection occurs in the lungs following the inhalation of air contaminated with these organisms. The initial response to this event is a polymorphonuclear leukocyte one, which serves to limit the extent of primary infection. However, the definitive host response is a cell-mediated immune response, which both limits the impact of postprimary systemic dissemination of the organisms and prevents the subsequent breakdown of sites of dormant infection. Thus, patients with advanced HIV disease are at risk for three patterns of infection: (1) progressive, primary infection with systemic spread due to a failure of the normal cell-mediated immune response; (2) reactivation of dormant sites of infection, with secondary systemic dissemination of the organisms; and (3) reinfection in a patient who has lost the protective immunity engendered years previously on exposure to this same organism, with such reinfection resulting in a pattern of disease akin to that seen in patients with progressive primary infection. Whenever systemic dissemination of these organisms occurs, there is an approximately 10% incidence of mucocutaneous disease, often as the first recognizable manifestation of systemic infection.107 Skin lesions occurring in disseminated mycotic infections for the most part are asymptomatic apart from their cosmetic appearance. Thus, the symptom complex that the patient presents with is determined primarily by the other sites of involvement: symptoms referable to the respiratory tract in patients with active lung infection; symptoms referable to the central nervous system in patients with seeding of the central nervous system; systemic complaints of fever, chills, sweats, weight loss, and so forth dependent on the organism load and the intensity of the host inflammatory response.108 Oral and/or esophageal ulcerations due to Histoplasma capsulatum may, however, be painful. The most common appearence of skin lesions due to systemic fungal infection in the HIV-infected individual is that of multiple molluscum contagiosumlike lesions,

papules, or nodules occurring on the face.109,110 On occasion these lesions may become ulcerated, taking on a herpetiform appearance. Other reported cutaneous findings include erythematous macules; necrotic or keratinplugged papules and nodules; pustules, folliculitis, or acneform lesions; vegetative plaques; or a panniculits.111 Facial lesions are most common, but lesions also are seen on the trunk and extremities. Oral mucosal lesions occurring in HIV-infected patients with disseminated mycotic infections include nodules and vegetations; ulcerations may occur on the soft palate, oropharynx, epiglottis, and nasal vestibule. These occur most commonly with histoplasmosis, occasionally in cryptococcosis, but not in coccidioidomycosis. Hepatosplenomegaly and/or lymphadenopathy occur commonly in patients with disseminated histoplasmosis. The cornerstone of diagnosis in this clinical situation is skin biopsy for culture and pathologic examination. It is important to recognize that such biopsies have two purposes: diagnosis of a particular skin lesion and early recognition of disseminated infection in a compromised host. Because of these dual objectives, any unexplained skin lesion in these patients should be considered for biopsy. Histologically, diagnosis is made by demonstration of fungal forms with hematoxylin–eosin, periodic acid–Schiff (PAS), or methenamine silver stain of the lesional biopsy specimens or of a touch preparation. Tzanck smears obtained by scraping the top of a lesion, placing the material on a glass slide, fixing with methyl alcohol, and staining with rapid Giemsa technique show multiple encapsulated and budding yeast. India ink preparation of lesional skin scraping also can be used to demonstrate encapsulated and budding cryptococcal yeast forms. Fungi also can be isolated on culture of the skin biopsy specimen. The differential diagnosis of patients with skin lesions possibly due to systemic fungal infection includes molluscum contagiosum, verruca vulgaris, verruca plana, disseminated herpetic or varicella infection, bacillary angiomatosis, and furunculosis. The diagnosis of cutaneous infection with Cryptococcus neoformans, Coccidioides immitis, or Histoplasma capsulatum is prima facie evidence of disseminated infection and must be treated as such. 5.2.2a. Ubiquitous Fungi. 1. Candidiasis, invasive. Invasive candidiasis is the most common invasive fungal infection. Candida albicans causes 75% of cases of disseminated candidal infections; C. tropicalis, 20% of cases. C. tropicalis, however, causes 60% of cases of dissemiated candidal infections with cutaneous involvement and C. albicans causes

MUCOCUTANEOUS INFECTIONS l12

only 20%. The gastrointestinal tract is the site of primary invasion; Candida enters blood vessels and disseminates widely. Diagnosis often is delayed because of the nonspecific clinical manifestations and difficulty in identifying Candida isolated on culture as a pathogen. The usual clinical scenario is of a patient with fever, neutropenia, clinical deterioration, and failure of response to multiple antimicrobial agents. The cutaneous findings usually are subtle, with erythematous papules (single, multiple, localized, or diffuse) (Fig.

71 113,114

13) arising on the trunk and proximal extremities, and in some cases, papulonodules, purpura, central necrosis, ecthyma gangrenosum-like lesions, and nodular folliculitis in hair-bearing areas (heroin users).115–118 Other clinical findings include endophthalmitis seen on fundoscopic examination, arthritis, and muscle abscess.119,120 A touch preparation of a punch biopsy specimen examined with KOH or Gram’s stain may show Candida, allowing rapid diagnosis.121 Lesional skin biopsy specimens show a range of inflammatory changes ranging from a sparse perivascular mononuclear infiltrate to a leukocytoclastic vasculitis; Candida may be sparse or present in large numbers, in and around dermal blood vessels. 2. Cryptococcosis. Cryptococcus neoformans is the second most common fungal opportunist (C. albicans being the most common, usually causing mucocutaneous infection as well as invasive disease) in the compromised host.122,123 Disseminated cryptococcosis is by far the most common life-threatening fungal infection in HIV disease. Cutaneous cryptococcosis occurs in 5–10% of individuals with disseminated infection124 and essentially is always associated with systemic infection in advanced HIV disease (CD4 cell count Cutaneous manifestations can present 2 to 6 weeks before signs of systemic infection. Hematogenous dissemination of C. neoformans to the skin results in lesions of various morphologies that generally are asymptomatic. The most common morphology of cutaneous cryptococcosis is of molluscum contagiosumlike lesions (Fig. 14), i.e., umbilicated skin-colored or pink papules or nodules (54%); other types of cutaneous lesions include pustules, cellulitis,125 ulceration, panniculitis, palpable purpura, subcutaneous abscesses, and vegetating plaques.126,127 Lesions commonly occur on the face, but may be widespread. Oral nodules and ulcers also occur alone or with cutaneous lesions. The papules and nodules of cryptococcosis, ranging from solitary to greater than 100 in number, are usually skin-colored, with little if any inflammatory erythema, lacking the central umbilication or keratotic plug characteristic of mollusca. Occasionally, crusting or ulceration occurs resembling chronic herpetic ulcers. In more darkly pigmented individuals, lesions may be hypo- or hyperpigmented. Cutaneous cryptococcosis in some cases occurs in the absence of demonstrable fungal infection in the lung or meninges. Hematogenous dissemination of Histoplasma capsulatum or Coccidioides immitis can produce identical skin lesions on the face. Cryptococcal cellulitis occurs following fungemia and most often occurs in the compromised host (corticosteroid therapy, systemic lupus, chronic lymphocytic leukemia, myeloma, chronic active hepatitis, cervical

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medullary tumor, congenital lymphedema, congenital lymphedema with lymphopenia, liver transplantation, inflammatory bowel disease, and kidney transplantation). This fungal cellulitis presents with a single or multiple red, hot, tender plaques.128,129 Primary cutaneous cryptococcosis has been reported, presenting as a nodule, plaque, or ulcer, or in some cases with sporotrichoid spread.130–132 3. Aspergillosis. Aspergillus species are ubiquitous in the environment in food, water, soil, plants, and decaying vegetation. Aspergillosis can involve the skin either as a primary cutaneous infection or secondarily via invasion into the skin from an underlying infected site (nose, sinuses, and orbit) or hematogenous dissemination to the skin (usually from a primary lung infection). Aspergillosis occurs in the setting of severe or prolonged granulocytopenia due to cytotoxic therapy for leukemia or lym-

phoma, high-dose or prolonged systemic corticosteroid therapy in transplant recipients or those with collagen vascular disease. Primary cutaneous aspergillosis occurs at sites of intravascular catheters and drainage tubes, use of arm boards, and extensive trauma or burns.4,133–136 Primary cutaneous aspergillosis has been reported more commonly in children with acute lymphocytic leukemia. Lesions arise most commonly on the palm, initially with erythematous or purpuric papules that progress to violaceous plaques with hemorrhagic bullae, which in turn ulcerate and form necrotic eschars. Secondary cutaneous or disseminated aspergillosis presents as erythematous macules or papules that evolve to purpuric or necrotic lesions, hemorrhagic bullae, and subcutaneous nodules or abscesses. Potassium hydroxide preparation of scraping from the inner aspect of the bulla roof shows large hyphae. Lesional skin biopsy shows regularly septate, dichotomously branching hyphal elements that may be angioinvasive, which must be differentiated from Scopulariopsis, Pseudoallescheria, Fusarium, and Penicillium. The majority of patients with invasive disseminated aspergillosis die, despite treatment with amphotericin B.137 4. Sporotrichosis. Sporotrix schenkii is ubiquitous in the environment in rotting organic matter. Percutaneous inoculation results in limited forms of cutaneous sporotrichosis in immunocompetent individuals. In the compromised host, dissemination of local infection to other organs occurs from lung or skin foci. Dissemination of sporotrichosis is associated with severe malnutrition, sarcoidosis, malignancy, diabetes mellitus, alcoholism, organ transplantation, and HIV disease. A range of cutaneous lesions includes papules to nodules, which may become eroded, ulcerated, crusted, or hyperkeratotic (Fig. 15).138,139 Individual lesions may remain discrete or become confluent. Lesions are often disseminated, but sparing the palms, soles, and oral mucosa. Ocular involvement results in hypopeon, scleral perforation, and prolapse of the uvea.140 Joint infection with frank arthritis also is common in the disseminated form of sporotrichosis occurring in HIV disease. Other organs involved in disseminated sporotrichosis in HIV disease include joints, lung, liver, spleen, intestine, and meninges. 5. Mucormycosis. Mucormycosis is a group of infectious syndromes caused by Mucor, Rhizopus, Absidia, and Cunninghamella species, which have identical presentations and appear morphologically identical in tissue. Conditions predisposing to cutaneous mucormycosis include diabetes, severe thermal burns, trauma, leukemia, organ transplantation, and use of Elastoplast dressing. Superficial cutaneous mucormycosis presents as erythe-

MUCOCUTANEOUS INFECTIONS

matous plaque with subsequent vesicles, pustules, and ulceration at sites dressed with contaminated elasticized adhesive tape. The fungus also can enter the skin via breaks caused by intravascular lines, injections, macerated skin, burns, or insect bites (Fig. 16). The fungus causes a necrotizing infection with subsequent vascular invasion, soft-tissue infection, necrosis, and ulceration. Rhinocerebral mucormycosis occurs in the setting of poorly controlled diabetes (especially with ketoacidosis) and systemic corticosteroid therapy, especially in patients with leukemia, lymphoma, or organ transplant recipients. Infection begins on the palate or in the nose and paranasal sinuses, spreading rapidly to the central nervous system via the orbit and cribriform plate. Infected mucosal sites are black and necrotic. With extension of infection through the nasal turbinates, orbital cellulitis occurs associated with extraocular muscle paresis, proptosis, chemosis, and eyelid edema. Histologically, broad, irregularly shaped

73

nonseptate hyphae with right-angle branching are seen in the infected tissue. 6. Phaeohyphomycosis. The phaeohyphomycoses present as a clinically varied group of fungal infections caused by dematiaceous (pigmented or black) fungi that in tissue appear as yeastlike cells, branched or unbranched septate hyphae, or a combination of these forms. Chromomycosis appears clinically as verrucous, nodular, or tumorous plaques with pseudoepitheliomatous hyperplasia, showing large, pigmented, round, thickwalled cells with septation (sclerotic or Medlar bodies). Mycetoma appears clinically as a tumor with draining sinuses and granules in the abscesses. The clinical presentation varies with the host’s immune response. The causative fungi include Exophiala, Phialophora, Fonsecaea, Cladosporium, Alternaria, Bipolaris, Curvularia, and Exserohilum species. In the compromised host, infection with dematiaceous

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fungi can present as primary subcutaneous phaeohyphomycosis, localized inoculation cutaneous phaeohyphomycosis, and systemic or invasive phaeohyphomycosis with secondary or metastatic cutaneous lesions. Primary inoculation phaeohyphomycosis may present with a spectrum of clinical lesions: ulcer with necrosis, subcutaneous cyst, boggy verrucous plaque, crusted nodule with pustules, subcutaneous abscesses with sinus tracts, dermatomal vesicles and crusts, fluctuant abscess with surrounding cellulitis, and a necrotic ulcerated plaque resembling ecthyma gangrenosum. Disseminated phaeohyphomycosis involving the skin presents as tender erythematous nodules, ulcerated papules, hemorrhagic pustules, and scaling hyperpigmented plaques. 7. Hyalohyphomycosis. The hyalohyphomycoses are a variety of opportunistic fungal infections caused by nondematiaceous molds or yeasts, having a nonseptated tissue form. The fungi in this group include Fusarium, Penicillium, Paecilomyces, Acremonium, and Scopulariopsis species. Fusarium species are ubiquitous soil saprophytes. Risk factors for infection are granulocytopenia and systemic corticosteroid therapy. Localized cutaneous infection is associated with thermal burns, punctures, and intravascular lines and can be the source of hematogenous dissemination. Fusarium onychomycosis can be the source of disseminated Fusarium infection in the compromised host.141,142 Disseminated fusariosis is characterized by evolution of widespread cutaneous lesions from erythematous to necrotic lesions, propensity for vascular invasion and thrombosis with tissue infarction, and acute branching broad septate hyphae.143 Tissue infarction also is seen in the lesions of Aspergillus and Mucor infections. The dimorphic fungus Penicillium marneffei is the third most common opportunistic infection in HIV-infected residents of countries of Southeast Asia and the southern part of China.144,145 In a report of 92 patients,146 the clinical presentation included fever, weight loss, cough, anemia, and disseminated papular skin lesions (71%). The most common skin lesions were umbilicated papules, occurring most frequently on the face, ears, upper trunk, and arms. Genital ulcers also were reported, ranging in size from 20 lesions scattered outside the initial dermatome, or systemic infection (hepatitis, pneumonitis, encephalitis). Disseminated

79

VZV infection in an individual harboring latent VZV can present with clinical pattern of scattered vesicles in the absence of dermatomal HZ. The compromised host previously infected with VZV is subject to exogenous reinfection with VZV.183 Underlying conditions of immunocompromise that are associated with an increased incidence of HZ include Hodgkin’s disease, non-Hodgkin’s lymphoma, solid tumors (e.g., small cell carcinoma of the lung), solid organ and bone marrow transplantation, and HIV disease. Local immunosuppression related to irradiation, nodal involvement by tumor, or surgical sites also is associated with an increased incidence of HZ.184 Rarely, the reactivation of VZV can produce pain without any cutaneous lesions (zoster sine zoster). In immunocompetent individuals, the main complication of zoster is postherpetic neuralgia (defined as pain persisting more than 6 weeks after the development of cutaneous lesions). Rare complications are myelitis or large–vessel granulomatous arteritis. In the compromised host, central nervous system complications are more serious in the form of progressive small-vessel encephalitis or myelitis. Primary VZV infection is nearly always symptomatic (i.e., varicella or chickenpox)185; reactivated infection presents as HZ. Children with HIV disease represent the largest reservoir of VZV-susceptible immunodeficient children in the world, numbering several million in Africa. Varicella occurring in HIV-infected children and adults can be severe, prolonged,186 and complicated by VZV dissemination (pneumonia, hepatitis, encephalitis, and pancreatitis), disseminated intravascular coagulation, bacterial superinfection, and death. Primary, recurrent, and persistent VZV infections are a frequent cause of morbidity and hospitalization for HIV–infected children. Rather than resolving, persistent crusted lesions can occur at sites of initial vesicle formation, lasting for weeks or months. In a report of HIV-infected children with varicella, the most common complication was recurrence of VZV infection in 53% of cases.187–189 Sixty-one percent of children experienced herpes zoster during the first episode of reactivated VZV infection; 32% had dissemination of herpes zoster, associated with a low CD4 cell count. A second episode of varicella can occur, presumably following exposure to a different VZV strain than that which caused varicella initially. In a study of 30 cases of varicella in HIV-infected children, 27% developed HZ an average of 1.9 years after varicella (range, 0.8– 3.7).187–189 children with 90% of the adult population in the United States is seropositive for VZV. Acute varicella does not appear to worsen the course of HIV infection with regard to CD4 or CD8 cell levels. The more common problem in the compromised host is reactivated infection, where latent virus present in the dorsal nerve root ganglia becomes reactivated.190 Typically zoster occurs for the first time relatively early in the course of HIV disease, even before oral hairy leukoplakia and oropharyngeal candidiasis.191,192 Thus, among a group of 112 HIV-infected homosexual men with zoster, 23% had developed AIDS 2 years later, 46% 4 years later, and 73% 6 years later.193 The more extensive the dermatomal

involvement, the greater the pain, and the more extensive the involvement of cranial and cervical dermatomes, the more advanced the HIV infection is found to be. HZ is also common in other compromised hosts as well.194,195 The first manifestation of zoster is often pain in the dermatome that subsequently manifests the classical grouped vesicles on an erythematous base. At times, multidermatomal involvement, either contiguous (Fig. 21) or noncontiguous, may occur. Zoster also may recur within the same dermatome or persist chronically for many months.196 Occasionally, in these patients, the dermatomal eruption may be bullous, hemorrhagic, or necrotic and be accompanied by severe pain. Not infrequently, patients with zoster experience hematogenously borne cutaneous dissemination, without visceral involvement or inordinate morbidity. Persistent disseminated VZV lesions are often very painful and appear as crusted to

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hyperkeratotic plaques, 1–2 cm in diameter, occasionally with marginal vesicles.197 These ecthymatous or chronic VZV infections are sparse, typically 5 to 15 in number, on the trunk or proximal extremities.198,199 The majority of HIV-infected patients with zoster have an uneventful recovery. Herpes zoster can be the initial clinical presentation of HIV disease. Those who acquire HIV infection sexually are reported to experience HZ more commonly than do those who acquire it by injecting drug use.200 In a report from Kenya, 85% of patients (16–50 years old) presenting with HZ were HIV-infected.201 The duration of illness was longer in HIV-infected patients compared with non-HIV-infected cases of HZ (32 vs. 22 days). Seventy–four percent of HIV–infected individuals with HZ had generalized lymphadenopathy compared with only 3% in the noninfected group. Severe pain (69% vs. 39%), bacterial superinfection (15% vs. 6%), more than one affected dermatome (38% vs. 18%), and cranial nerve involvement were all more common in HIV-infected individuals with HZ. The mean CD4 cell count at presentation was in the HIV-infected group and in the HIV-negative group. Recovery was generally com-

81

plete and uncomplicated. In Ethiopia, 95% of patients (mean age 35 years) with HZ ophthalmicus were reported to be HIV–infected. 202 Severe eyelid involvement occurred in 25%, ocular involvement in 78%, visual loss in 56%, and postherpetic neuralgia in 55%. Severity of HZ ophthalmicus was associated with delay in presentation, lack of antiviral therapy, and advanced HIV disease. In a report of homosexual men followed after HIV-1 seroconversion, 20% had an episode of HZ after a mean follow-up of 54 months; 10% of those experienced one recurrence.203 In a report of patients with advanced HIV disease (CD4 cell count treated with zidovudine, 16% had a history of HZ on enrollment and 13% of these had a recurrence during the 2-year follow-up.204 HZ was not associated with a more rapid progression to AIDS. Major complications of HZ occur in one-quarter of cases and include blindness (HZ ophthalmicus), neurological complications, chronic cutaneous infection, postherpetic neuralgia, and bacterial superinfection, all of which occur more commonly if the CD4 cell count is HZ is a clinical indicator of faltering immunity, and its occurrence always should raise the issue of HIV sero-

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testing. The incidence of HZ in HIV disease is approximately 25%. In a cohort study of 287 homosexual men with well-defined dates of HIV seroconversion and 419 HIV-seronegative homosexual men, the incidence of HZ was 15 times greater in HIV-seropositive men [29.4 cases/1000 person-years (PY)] than in HIV-seronegative men (2.0 cases/1000 PY).205 The overall age-adjusted relative risk was 16.9. Herpes zoster often occurs early in the course of HIV disease and can occur soon after varicella in children. In several studies, HZ was not predictive of faster progression to advanced HIV disease. Extent of dermatomal involvement, severity of pain, and involvement of cranial or cervical dermatomes have been correlated with a poor outcome of HIV disease. In a study of men with HZ, the incidence of first episode was 52 per 1000 PY in HIV-infected men and 3.3 per 1000 PY in non-HIV-infected men.206 HZ recurred in 26% of HIV-infected men. The incidence of HZ increased by 31.2 per 1000 PY at 47.2 per 1000 PY at CD4 cells and 97.5 per 1000 PY at CD4 cells The incidence of HZ increases with the decrease in CD4 cell counts and T-cell reactivity, but HZ is not an independent predictor of disease progression. Clinically, HZ is typical in most cases. In advanced HIV disease, the spectrum of lesions is much wider. Solitary or few ulcerations can occur. Epidermal proliferative lesions, either solitary or few, resemble basal cell or squamous cell carcinomas.207 Scattered or zosteriform verrucous lesions also occur.208 In advanced HIV disease, VZV can also infect the neural tissue of the central nervous system (encephalitis), retina (acute retinal necrosis), or the spinal cord, with or without cutaneous lesions.209–212 HZ precedes the onset of acute retinal necrosis by several days in 60–90% of cases. In that zoster often occurs early in HIV disease, the course is fairly uneventful for the majority of patients. It is most often unidermatomal, but may be multidermatomal (Fig. 21), recurrent within the same dermatome, or disseminated. The eruption may be bullous, hemorrhagic, and/or necrotic and may be accompanied by severe pain. The majority of HIV-infected patients with HZ experience an uneventful recovery, but atypical clinical courses are not uncommon. Limited cutaneous dissemination of zoster secondary to viremia is common in some patients with zoster, but uneventful recovery is the rule. Ophthalmic zoster has the highest incidence of serious complications, which include corneal ulceration, variable decrease of visual acuity,213,214 and retinal necrosis.215 Viral encephalitis can occur via entry into the brain by VZV infection of the optic nerve,216 or follow hematogenous dissemina-

tion.217 Cutaneous dissemination of VZV in patients with HZ is relatively common (Figs. 22, 23)218; however, significant visceral involvement is rare. Viscerally disseminated HZ in a compromised host can be life-threatening. In HIV–diseased individuals, cutaneous VZV lesions can persist199 for months following either primary198 or reactivated VZV infection with a pattern of zoster196,219 or disseminated infection,197,220 referred to as chronic verrucous or ecthymatous VZV infection. Lesions may persist for months, either in the localized or disseminated form, appearing as hyperkeratotic, ulcerated, painful lesions (Fig. 24) often with central crusting and/or ulceration with a border of vesicles.190 A rare complication of zoster is the occurrence of a granulomatous vasculitis in the involved dermatome, without persistence of the VZV genome, possibly as a reaction to minute amounts of viral

MUCOCUTANEOUS INFECTIONS

proteins.221 Small-vessel encephalitis caused by VZV is more common in the compromised host.182 The diagnosis of varicella and HZ can be confirmed by detection of viral antigen on a smear of the base of a vesicle or erosion or in a section of a lesional biopsy specimen. A positive Tzanck test confirms the diagnosis of either VZV or HSV. Isolation of VZV on culture is more difficult than isolation of HSV. Lesional biopsy also is helpful to establish a diagnosis, especially in unusual manifestations of VZV infection such as ecthymatous or chronic verrucous lesions; the diagnosis is confirmed by detection of VZV antigen. Administration of varicella vaccine in early HIV disease in children appears safe and beneficial. HIVinfected children exposed to VZV, whether varicella or zoster, may benefit by treatment with varicella–zoster immune globulin prophylactically, as well as acyclovir.

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Most persons with zoster occurring in early HIV disease do well without antiviral therapy. The same drugs approved for treatment of HSV are approved for treatment of VZV infection: famciclovir, valaciclovir, and acyclovir. Intravenous acyclovir (10 mg/kg every 8 hr) is given for severe infections. Because of the risk of visual impairment following ophthalmic zoster, intravenous acyclovir is usually given. As with HSV infections, acyclovirresistant strains emerge following prolonged acyclovir treatment; most of these resistant strains respond to foscarnet therapy. Secondary prophylaxis usually is not indicated after VZV infection resolves. The diagnosis of VZV infection usually is made on a clinical basis, supported by the finding of giant and/or multinucleated acanthocytes on cytologic study of vesicle fluid. Alternatively, the lesions can be biopsied or cultured. The differential diagnosis of varicella includes dis-

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seminated HSV infection, cutaneous dissemination of zoster, eczema herpeticum, disseminated vaccinia, bullous impetigo, and various vesicular viral exanthems such as enterovirus infection. The prodromal pain of herpes zoster can mimic cardiac or pleural disease, an acute abdomen, or vertebral disk disease. The rash must be distinguished from zosteriform HSV infection. Ecthymatous VZV lesions must be differentiated from impetigo, ecthyma, or deep mycotic infections. The management of VZV infections in patients with mild to moderate immunocompromise is identical to that in the immunocompetent host (Table 5). The cornerstone of treatment for severe VZV infection and/or VZV infection in the severely immunocompromised host is intravenous acyclovir. As with HSV infection, acyclovirresistant VZV has been reported following chronic acyclovir therapy for persistent or recurrent VZV infec-

tion.222,223

5.3.2c. Epstein–Barr Virus Infections. EpsteinBarr virus (EBV) selectively infects cells of the B-lymphocyte lineage and certain types of squamous epithelium. The majority of adults have been infected with EBV and harbor the latent virus. EBV infection plays an important role in the pathogenesis of three important clinical conditions in the HIV-infected patient population: oral hairy leukoplakia (OHL), classic Burkitt’s lymphoma, and EBV–positive large–cell lymphoma. Of these, OHL is the one with primary effects on the mucocutaneous tissues and correlates with moderate to advanced HIVinduced immunodeficiency.224,225 EBV DNA can be detected in the oral epithelium in HIV-infected patients without clinical signs of OHL, and its detection may be a marker for symptomatic HIV disease.226 Whether OHL develops after reactivation of latent EBV or superinfection is uncertain.227 OHL is a lesion specific to HIV disease. OHL has

MUCOCUTANEOUS INFECTIONS

been reported in up to 28% of HIV-infected patients, and is more common in males.228,229 In a study of OHL as a clinical marker of HIV disease progression, OHL was detected in 9% of individuals 1 year after seroconversion, 16% at 2 years, 15% at 3 years, 35% at 4 years, and 42% at 5 years.95 The median CD4 cell count when OHL was first detected was In individuals without an AIDSdefining illness when OHL is first detected, the probability of developing AIDS (without HAART) has been reported to be 48% by 16 months after detection and 83% by 31 months.224 Persons with OHL and a history of hepatitis B virus infection have a fourfold risk for early progression to AIDS; those with syphilis have a nearly threefold risk for early AIDS diagnosis.230 In a study of HIV–associated mucocutaneous disorders in 456 patients (1982–1992),231 OHL was diagnosed in 16% of cases, when the median CD4 cell count was Median survival time after OHL diagnosis was 20 months. In patients with a CD4 cell count of the detection of OHL was associated with shorter median survival time of 25 months compared with 52 months in those without OHL. Oral hairy leukoplakia typically presents as hyperplastic, verrucous, whitish, epithelial plaques on the lateral aspects of the tongue (Fig. 25), frequently extending

85

onto the contiguous dorsal or ventral surfaces.232 Usually, a single lesion or three to six discrete plaques separated by normal-appearing mucosa are observed. Much less commonly, OHL occurs on the buccal mucosa opposing the tongue and on the soft palate. Although described as hairy, the most frequently noted appearance of the lesion occurring on the tongue is a corrugated appearance, with parallel white rows arranged nearly vertically. Useful diagnostic criteria for OHL are a white lesion, involvement of the lateral aspect of the tongue, lack of change in appearence with rubbing, and the lesion does not respond to antifungal therapy. Differential diagnostic considerations include hyperplastic oral candidiasis, condyloma acuminatum, geographic (migratory) glossitis, lichen planus, tobacco-associated leukoplakia, mucous patch of secondary syphilis, squamous cell carcinoma, and occlusal trauma. The differential diagnosis includes hyperplastic oral candidiasis, HPV-induced neoplasia [condyloma acuminatum, squamous intraepithelial lesion (SIL) (also known as dysplasia or intraepithelial neoplasia), squamous cell carcinoma (SCC) in situ, or invasive SCC], geographic tongue, lichen planus, tobacco-associated leukoplakia, mucous patch of secondary syphilis, and bite trauma. The histologic findings of OHL are acanthosis,

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marked parakeratosis with the formation of ridges and keratin projections, areas of ballooning cells resembling HPV-induced koilocytosis, and little or no dermal inflammatory reaction. Electron microscopy demonstrates 100nm intranuclear virions and 240-nm encapsulated virus particles. Using in situ hybridization, EBV DNA can be demonstrated within nuclei in the upper portions of the epithelium. Keratinocytes are widely infected with EBV; however, expression of viral antigens and replication appears dependent on some process in the epithelial cell maturation–differentiation phase. The diagnosis of OHL is usually made on clinical findings; however, if the diagnosis is uncertain, confirmatory lesional biopsy is advised. For the most part, OHL is asymptomatic, but its presence may be associated with some degree of anxiety. Patients should be reassured and advised that OHL is not thrush. With HAART, OHL usually resolves without additional interventions. In concerned patients with persistent lesions, topically applied podophyllin in benzoin is effective; recurrence within weeks to months is common. Acyclovir, valaciclovir, famciclovir, ganciclovir, or foscarnet, given for other indications, are often effective therapies for OHL. Posttransplant cutaneous B-cell lymphoma, associated with EBV infection, is an uncommon complication of solid organ transplantation.233 Findings are usually confined to the limited regions of the skin; systemic involvement is not common. Treatment is usually directed at the lesions, with surgery or radiotherapy. 5.3.2d. Cytomegalovirus. Seroprevalence studies of cytomegalovirus (CMV) infection indicate that 50% of the general population is infected by age 50 years. The seroprevalence is much higher in lower socioeconomic groups and among injecting drug users. Most cases of primary CMV infection are asymptomatic; following primary infection, CMV enters a latent phase of infection, during which asymptomatic viral shedding in saliva, semen, and/or urine is extremely common. In the compromised host, CMV disease occurs via primary CMV infection, reactivation of latent CMV infection, or reinfection with a new CMV subtype. In most cases, CMV disease represents reactivation of latent virus. CMV infection often occurs soon after immunosuppression associated with cancer chemotherapy, organ transplantation, and systemic corticosteroid therapy. CMV is the most common viral pathogen in patients with advanced HIV-induced immunodeficiency. In a study of 82 HIV-1-seropositive persons, 51.7% of those with either AIDS-related complex (ARC) or AIDS had evidence of CMV infection of circulating polymorphonuclear cells, whereas no infec-

tion was detected among the 50 asymptomatic HIVinfected persons. Manifestations of CMV infection include retinitis, esophagitis, colitis, gastritis, hepatitis, and encephalitis. In a multicenter study of 1002 persons with AIDS or ARC, median survival after diagnosis of CMV disease was 173 days, and CMV was an independent predictor of death.234 Disseminated CMV has been demonstrated in 93% of patients with AIDS; at autopsy, however, association with skin lesions was not reported. CMV reactivation and dissemination are common events as immunodeficiency worsens. As an opportunistic organism CMV commonly infects the retina, causing a sight-threatening retinitis,235 and the large intestine, causing colitis manifested by intractable diarrhea. Widespread infection is associated with a generalized wasting syndrome, pneumonitis, and encephalitis. CMV infection, although present within various organs as documented by viral culture, is not necessarily the cause of the tissue dysfunction.160 Specific CMV-induced skin lesions have not been identified in compromised individuals. Cutaneous ulcers and a morbilliform eruption are the most common presentation of cutaneous CMV involvement.31,236–238 Evidence for CMV infection in a variety of mucous membrane lesions, implied by specific cytopathic changes in biopsy specimens by light and electron microscopy, immunofluorescence, immunoperoxidase, and in situ hybridization techniques, has been reported239,240; however, the role of CMV in pathogenesis of the lesions is not certain. Perianal ulceration caused by CMV occurs as the infection spreads from contiguous gastrointestinal sites. CMV was considered to be the cause of perianal and oral ulceration in five patients with advanced disease studied, based on typical histologic changes and positive fluorescent monoclonal anti-CMV antibody studies. Empirical treatment with acyclovir failed, but all ulcers healed with either foscarnet or ganciclovir treatment. Other reported presentations of CMV infection in skin of HIV-infected individuals include macular purpura of the extremities associated with leukocytoclastic vasculitis and small, keratotic, verrucous lesions, 1 to 3 cm in diameter, scattered on the trunk, limbs, and face. 5.3.2e. Human Herpesvirus-8 (Kaposi’s SarcomaAssociated Herpesvirus). Kaposi’s sarcoma (KS) is a hemangiomalike proliferation of endothelial-derived cells, first reported by Moritz Kaposi in 1872 as “idiopathic pigmented sarcoma of the skin.” Classic KS occurs in men of Mediterranean or Eastern European ancestry and clinically presents as slowly growing tan to violaceous papules, nodules, and tumors on the lower extremities. In the 1950s, African KS was described in young persons

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from equatorial Africa. In the 1960s, a third variant of KS was described in patients on long-term immunosuppressive therapy (i.e., recipients of organ transplants). Most recently, in 1981, epidemic or HIV–associated KS was one of the first disorders to be identified in patients with AIDS. Most cases of HIV-associated KS occurred in homosexual or bisexual males. Early in the HIV epidemic, approximately 40% of homosexual or bisexual men with AIDS had KS; more recently the prevalence of KS appears to have declined. In all other groups at risk for HIV infection, the prevalence of KS has been and remains at the 1 to 3% level. HHV–8 is a lymphotropic, oncogenic that was first detected in KS in 1994.241,242 HHV–8 also has been detected in other neoplasms such as body cavitybased lymphoma and Castleman’s tumor. HHV–8 has been identified in every variant of KS, with its DNA being confined to the nuclei of proliferating spindle cells. The HHV–8 genome also was detected in peripheral blood mononuclear cells of approximately 50% of HIV-KS patients, occasionally months before the occurrence of lesions.243,244 The role of HHV-8 as a true infectious agent was confirmed in several serological studies that provided evidence for a humoral immune response to HHV-8; seroconversion has been detected months before the clinical appearance of KS.245,246 After infection with HHV-8, en-

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dothelial cells change their biological behavior, resulting in the production of and susceptibility to various inflammatory and angiogenic cytokines. Once morphologic transformation into spindle cells has occurred, these cells start to produce autocrine and paracrine growth factors such as basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), platelet–derived growth factor (PDGF), and interleukin-6 (IL-6), which stimulate KS cell proliferation and regular angiogenesis. Although the clinical course of HIV-associated KS may be quite variable, it is far more aggressive than other variants of KS, with the frequent occurrence of widespread cutaneous and visceral lesions.247 Early lesions of HIV-associated KS present as slight discolorations of the skin, usually barely palpable papules, and if very early, macules. These lesions arise within the dermis, lacking any epidermal change, and are pinkish in color, with faint hues of tan, yellow, and green (biliverdin), giving the appearance of a bruise. Over a period of weeks to months to years, these early lesions enlarge into nodules (Fig. 26) or frank tumors, and the color darkens to a violaceous, Concord grape color, often with a yellow–green halo. As lesions enlarge, epidermal changes may occur, showing a shiny, atrophic appearance if stretched, or at times hyperkeratosis with scale formation. In late lesions, tumor necrosis may occur with erosion or ulceration of the surface.

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Oral lesions are common and may be the first site of involvement, occurring typically on the hard palate as a violaceous stain of the mucosa. Although HIV-associated KS can occur at any site on the skin, certain sites are much more common than others. On the head and neck, lesions commonly develop on the tip of the nose, the cheeks (Fig. 27), eyelids, and ears. In time, discrete lesions may coalesce, forming large plaques (Fig. 28). Occasionally, KS lesions may form on the bulbar conjunctiva, appearing as a subconjunctival hemorrhage. Facial edema is common, due to lymphatic obstruction by the KS lesions, and is sometimes extreme, causing gross distortion of the patient’s appearance. In some patients, visible lesions are scanty or absent and the presentation of the KS is predominantly that of edema isolated to the face and/or one or more of the extremities.

In a study of 173 patients with epidemic KS the distribution of mucocutaneous lesions was trunk, 52%; legs, 45%; arms, 38%; face, 33%: and oral cavity (Figs. 29, 30), 40%. Koebnerization of KS lesions has been reported at sites of venipuncture, BCG injection, abscess formation, and contusions. Although the diagnosis of KS usually can be suspected clinically, in most instances histologic diagnosis on a lesional punch biopsy specimen should be accomplished. The differential diagnosis of possible KS lesions depends on the stage of disease encountered. An early, nearly macular (patch stage) lesion can be mistaken for a bruise, hemangioma, dermatofibroma, insect bite, or benign nevus. More advanced, nodular, or plaque KS lesions must be differentiated from psoriasis, lichen planus, secondary syphilis, insect bites, benign nevi, nonmelanoma cancer, melanoma, and metastatic visceral malig

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nancies. Once the individual KS plaque or tumorous lesions have coalesced to form tuberous lesions, the major alternative diagnosis is lymphoma. The course of KS depends on restitution of immune function. Few patients die of complications directly related to KS. Currently, individuals with untreated HIV disease still present with KS. With effective response to HAART, KS is relatively uncommon, and if present usually regresses or resolves without specific therapy for KS. Without immune restitution by HAART, however, established KS lesions tend to enlarge in size and deepen in color, at times coalescing, while more and more lesions appear. An occasional patient will develop KS lesions involving internal organs in the absence of any visible mucocutaneous involvement. At postmortem examination, most patients with KS will be found to have lesions in the gastrointestinal tract, lymph nodes, liver, lung, spleen, and/or kidneys. In addition, there appears to be

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an increased incidence of second malignancies in patients with AIDS-associated KS. In the management of KS, the initial therapeutic focus is reduction in immune compromise by changing immunosuppressive drug therapies or by effective treatment of HIV disease with HAART. In many cases, KS will regress or resolve. For persistent KS, a spectrum of increasingly aggressive therapies are available. Localized cutaneous disease is best treated with application of a panretin gel, intralesional injection of vinblastine,248 cryotherapy,249 surgical excision, or radiation. Indolent, disseminated cutaneous KS is best treated with systemic immunotherapy or chemotherapy. Systemic alpha–interferon is effective in indolent or slowly growing KS in patients with CD4– lymphocyte counts who have few systemic symptoms and no opportunistic infections (40 to 50% response rate, although this rate may be higher when zidovudine also is administered). Because of its slow onset of action, usually requiring 6 to 8 weeks for an initial response, systemic alpha-interferon is inappropriate therapy for rapidly growing KS. In such patients and those who fail to respond to interferon therapy, chemotherapy akin to that utilized for the more aggressive forms of the disease may then be employed. Systemic chemotherapy is indicated for aggressive disseminated and/or visceral KS. The chemotherapeutic agents of choice are vincristine and bleomycin, both of which are marrow-sparing agents, usually in combination with adriamycin. Such regimens yield a significant response in 79% of cases. Liposome-encapsulated doxorubicin has enhanced tumor uptake and lesser systemic side effects. Paclitaxel may be effective as a single agent. Antiviral agents, effective in treatment of HHV-8 infection, may be effective in treatment of KS.250,251 5.3.3. Molluscum Contagiosum Molluscum contagiosum virus (MCV) commonly infects keratinized skin subclinically and can cause lesions at sites of minor trauma and in the infundibular portion of the hair follicle.252 Transmission is usually via skin-to-skin contact, occurring commonly in children and sexual partners. The clinical course of MCV infection in HIV disease differs significantly from that in the normal host and is an excellent clinical marker of the degree of immunodeficiency.253 In adults with multiple mollusca occurring outside of the genital area, especially head and neck lesions, HIV infection should be considered. Large and confluent lesions cause significant morbidity and disfigurement. Extensive MCV infection is uncommon in other compromised adults such as those with atopic der-

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matitis,254 sarcoidosis,255 cutaneous T-cell lymphoma,256 lymphatic leukemia, lymphoma,257 and thymoma.258 Prior to HAART, MCV infections were detected in 10% of individuals with HIV disease, and in 30% of those with CD4 cell counts of the number of lesions was inversely related to the CD4 cell count.259 In a study of 27 HIV–infected patients with MCV infection,253 mean CD4 cell count was 85.7 within 60 days of mollusca diagnosis; 52% of patients had facial and neck lesions alone, and 26% had lesions in areas associated with sexual transmission. Pneumocystis carinii pneumonia previously had occurred in 30% of individuals and KS had been diagnosed in 56%. Clinically, MCV infection presents as skin–colored papules or nodules, often with a characteristic central umbilicated keratotic plug. Lesions are usually 2 to 6 mm in diameter, but may be >1 cm in diameter (giant molluscum). Large lesions may mimic epidermal inclusion cysts, arising on or about the ear or on the trunk. Shortly after their appearance, lesions may be solitary; in time, multiple lesions are more typical (50+ lesions). With persistent and progressive immunodeficiency, mollusca may continue to enlarge and proliferate, resulting in confluent masses of lesions, e.g., involving the entire beard area. Large and/or multiple confluent facial lesions cause significant cosmetic disfigurement. The most characteris-

tic sites of occurrence in HIV-infected adults are on the face (Fig. 31), beard area, neck, and scalp; anogenital and intertriginous [axillae, groin (Fig. 32)] involvement also is common. In males, lesions are often confined to the beard area, the skin having been inoculated during the process of shaving. Occasionally, lesions become secondarily infected with S. aureus, resulting in abscess formation, or with P. aeruginosa with resultant necrotizing cellulitis. Significant postinflammatory hyper- or hypopigmentation (Fig. 31), more pronounced in more heavily melanized skin, may occur following cryosurgery of lesions, adding to the cosmetic disfigurement of the mollusca. The diagnosis of MCV infection in the HIV–infected patient is usually made on clinical grounds, but histologic confirmation is required in some patients. The differential diagnosis of solitary molluscum contagiosum includes verruca vulgaris, condyloma acuminatum, basal cell carcinoma, keratoacanthoma, and squamous cell carcinoma. The differential diagnosis of multiple facial mollusca contagiosa includes hematogenous dissemination to the skin of invasive fungal infections (cryptococcosis, histoplasmosis, coccidioidomycosis, and penicilliosis). Lesional skin biopsy is indicated in patients with sudden appearance of molluscalike facial papules associated with fever, headache, confusion, or pulmonary infiltrate to rule

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out deep mycosis with hematogenous dissemination to the skin. In HIV-infected individuals, MCV infection tends to be progressive and recurrent after the usual therapies. In HIV-infected individuals, MCV has been demonstrated within clinically normal epidermis surrounding lesions, suggesting the mechanism by which new lesions recur at treatment sites.260,261 With response to HAART, MCV infections regress or resolve completely, associated with increased CD4 cell counts and reduced viral load level.262 Therapeutically, the most efficacious approach toward MCV infection is correction of the underlying immunodeficiency; if this can be accomplished, lesions regress. If correction of immunodeficiency is not possible, treatment is directed at controlling the numbers and bulk of cosmetically disturbing lesions rather than at eradica-

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tion of all lesions. Liquid nitrogen cryospray is the most convenient therapy and usually must be repeated every 2 to 4 weeks. Electrosurgery is more effective than cryosurgery; local anesthesia is required by most subjects with either injected lidocaine or EMLA cream. or pulsedye laser ablation also is effective but relatively costly. Five percent imiquimod cream applied three times a week is an effective patient-administered therapy in children and adults. Cidofovir, a nucleotide analogue with activity against several DNA viruses, given either intravenously or topically as a cream, may be an effective therapy.263 5.3.4. Human Papillomavirus Infections Subclinical infection with human papillomavirus (HPV) is nearly universal in humans. With immuno-

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compromise, cutaneous and/or mucosal HPV infection (re)emerges from latency, presenting clinically as verruca, condyloma acuminatum, squamous intraepithelial lesion (SIL), squamous cell carcinoma in situ (SCCIS), or invasive squamous cell carcinoma (SCC).264 Human papillomavirus colonizes keratinized skin of all humans, producing common warts (verruca vulgaris, verruca plantaris, verruca plana) in many healthy individuals during the course of a lifetime. The greater majority of sexually active individuals are subclinically infected with one or multiple HPV types. HPV-6 and -11 infect mucosal sites (genitalia, anus, perineum, oropharynx) and cause genital warts (condyloma acuminatum); HPV-16 and -18 cause precancerous lesions SIL, SCCIS, and invasive SCC. In organ transplant recipients, HIV–infected individuals, and other compromised hosts, verrucae are not unusual in morphology, number, or response to treatment; however, with advancing disease, verrucae can enlarge (Fig. 33), become confluent, and become unresponsive to therapy.265 HPV-5 can cause an unusual pattern of extensive verruca plana and pityriasis (tinea) versicolorlike warts, similar to the pattern seen in epidermodysplasia verruciformis. With moderate or advanced immunodeficiency, warts and condyloma (Fig. 34) may become much more numerous, confluent, and refractory to usual treat-

ment modalities. Precancerous lesions identical to mucosal lesions, namely, SIL and SCCIS, can occur periungually on the fingers (Fig. 35). In some cases, invasive SCC can arise at one or multiple sites on the fingers and/ or nail bed. These tumors are aggressive and invade to the underlying periosteum and bone relatively early due to the proximity of the underlying bony structures. HPV–induced SIL, SCCIS, and invasive SCC of mucosal sites, especially the transitional epithelium of the cervix and anus, are increasingly more common in HIV disease. SIL and SCCIS occur in spite of maintained or improved immune function as a result of HAART. Invasive cervical SCC has been added to the list of AIDSdefining conditions. HPV–induced neoplasms may well be diagnosed more frequently as the life span of persons with HIV diseases is increased with treatment. HPV DNA is 2 to 3 times as frequent in cervicovaginal lavage specimens and almost 15 times as common in anal swab specimens from HIV–infected women than in those from HIV-seronegative women.266,267 HIVseropositive women are 5 times as likely as HIVseronegative women to have vulvovaginal condyloma and oral or anal SIL.268,269 The increased prevalence of HPV-induced lesions in HIV disease probably is related to deficient cell–mediated immunity rather than impaired

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specific antibody formation.270 Increased HPV replication of the more oncogenic HPV types occurs with more advanced immunosuppression.271 In a study of the association between anal SIL, HPV infection, and immunosuppression among HlV-seropositive and HIV-seronegative homosexual men, anal HPV DNA was detected in 55% of HIV-seropositive and 23% of HIV-seronegative men by Southern transfer hybridization and in 92 and 78% by polymerase chain reaction (PCR).272 Anal SIL was noted in 26% of HIV-seropositive and in 8% of HIV-seronegative men; high-grade SIL was noted in 4% of HIV-seropositive and in 0.5% of HIVseronegative men. Among HIV-infected men, anal SIL, detection of specific anal HPV types, and detection of high levels of anal HPV DNA were all associated with advanced HIV disease. The risk of anal SIL among HIV-

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seropositive men with CD4 cell counts was increased 2.9-fold over that of HIV-seropositive men with CD4 counts In a study of HPV infection in HIV-seronegative and seropositive women, HPV DNA was detected in 83% of the seropositive and 62% of the seronegative women.266 Twenty percent of seropositive women and 3% of seronegative women had persistent infections with HPV-16-associated viral types (16, 31, 33, 35, 58) or HPV-18-associated types (18 or 45), which are most strongly associated with cervical cancer. HIV-infected women were noted to have a high rate of persistent HPV infections with the types of HPV that are strongly associated with the development of high-grade SIL and invasive SCC. The degree of immunosuppression correlates with the presence of HPV DNA, extent of HPV infection, and potential for malignant transformation, with individuals with CD4 cell counts being at greatest risk.273 The potential for malignant transformation varies considerably according to the type and site of HPV-infected epithelium, being greatest for the transitional epithelium of the cervix and anus, lesser for vulvar epithelium, and least for the epithelium of the male genitalia, perineum, inguinal folds, and perianal regions. The immune mechanisms underlying the increased rates of anogenital neoplasia in HIV-infected individuals274–277 are not well understood but are thought to be related to high prevalence of HPV infection, impairment of cellular immunity, activation of latent HPV replication, and local suppression of cytokine production. With advanced immunodeficiency, low- or highgrade SIL caused most frequently by HPV-16 and -18 can arise on epithelium of the cervix, external genitalia, perineum, anus, oropharynx, or keratinized skin, especially the nail beds. Although differentiation from condyloma cannot be made on clinical grounds alone, SIL and SCCIS often present as multiple smooth, pink to skin color to tan/ brown macules or papules, which may form confluent cobblestoned, well-demarcated plaques. Lesions are usually multifocal but may be unifocal. In some cases, multiple foci of epithelial erosion occur and concomitant herpetic infection must be ruled out. Massive HPV– induced lesions (older terminology “giant condyloma of Buschke–Löwenstein”) have a much greater chance of showing foci of SIL, SCCIS, or invasive SCC histologically. Extragenital HPV-induced SIL, SCCIS, and invasive SCC also occur in keratinized skin such as the nail beds.278,279 Oropharyngeal HPV-induced lesions resemble anogenital condyloma, and are pink or white in color but

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never the tan to brown color of some genital lesions. Extensive intraoral condyloma acuminatum (oral florid papillomatosis) presents as multiple large plaques, analogous to anogenital giant condylomata acuminata of Buschke–Löwenstein, and can also transform to verrucous carcinoma. The diagnosis of verrucae and condylomata usually is made on clinical findings. In individuals with advanced HIV disease, biopsy of suspected HPV infections of the anogenital region is recommended because of the high prevalence of SIL and SCCIS. Exfoliative cytology is very effective at detecting SIL or SCC of the cervix and also may be helpful with anal involvement.280 External anogenital SIL and SCCIS, unlike cervical and anal lesions, cannot be screened for by the Papanicolaou test using exfoliative cytology. Lesional biopsy specimens should be obtained from several sites, especially in individuals at higher risk for malignant transformation. In most patients, histologic findings are relatively uniform at multiple biopsy sites, ranging from low- or high-grade SIL to SCCIS. At one point, however, invasive SCC usually is unifocal within a field of SCCIS. A larger nodule within a field of SIL or SCCIS should be excised to rule out invasive SCC. Over the course of HPV-

induced neoplasia, multiple invasive SCCs may arise at various anogenital epithelial sites. The natural history of external anogenital HPVinduced neoplasia is probably similar to that of condyloma acuminatum. Prolonged, severe immunodeficiency provides the necessary milieu for the emergence of HPVinduced anogenital neoplasia. The incidence of transformation of SCCIS to invasive SCC appears to be low. The relative risk for HPV–related anal SCC is much higher in HIV–infected than in non-HIV-infected homosexual men and is more likely in advanced HIV disease. Invasive cervical SCC is an AIDS-defining condition; however, a documented increase in incidence has not yet been reported. Cervical and anal neoplasias are likely to become more common manifestations of HIV disease as patients with profound immunodeficiency, who previously would have succumbed to opportunistic infections, are now surviving for extended periods because of increasingly effective antiretroviral prophylaxis of opportunistic infections and newer antimicrobial therapies. External anogenital SIL and SCCIS also may become more common in long-term survivors of HIV disease. Low- or high-grade SIL of the external anogenital

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epithelium can be treated by several methods: topical chemotherapy (5% 5-fluorouracil or 5% imiquimod cream, especially for extensive multifocal lesions); surgical excision of single or several lesions; or focal destruction of lesions by cryosurgery, electrosurgery, or laser surgery. Unlike topical 5-fluorouracil or imiquimod, surgical modalities treat only clinically detectable lesions and not subclinical infection. For minimally invasive SCC arising in an area of external anogenital SCCIS, surgical excision is recommended with adequate borders around the lesion. The role for adjunctive radiotherapy has not yet been defined, nor has the use of combined modality therapy with external beam radiotherapy plus chemotherapy. Individuals with documented external anogenital high-grade SIL or SCCIS should be followed by periodic follow-up examinations (every 3 to 4 months), noting the appearance of new lesions at these sites or an enlarging nodule or ulcerated site; biopsy of these sites is recommended. In that HPV-induced neoplasia may extend to the cervix and/or anus, direct examination by speculum and anoscope also should be performed; samples for cytology should be obtained using a cervical brush and cytofix solution. The number of individuals with SIL/SCCIS of the external anogenital region is expected to grow with the increasing numbers of long-term survivors of HIV disease. The prevalence of HPV infection of nonkeratinized and mucous epithelium in HIV-infected homosexual men is high, up to 20% having clinically detectable anogenital condylomata and up to 50% having infection detectable by cytologic smears of anal canal mucosa.281 HPV types 6 and 11, which in the normal host infect the anogenital epithelium and are of low oncogenic risk, can be demonstrated in extensive verrucae on the hands and feet and in invasive anogenital SCC of HIV-infected men. Similarly, HIV-infected women have rates of cervical dysplasia five to ten times higher than non-HIV-infected women. Thus, in one group of HIV-infected women, three–fourths had vulvar HPV infection, two-thirds of these having condylomata and one-third vulvar intraepithelial neoplasia.282,283 Verrucae occurring in HIV-infected individuals usually are asymptomatic, the most common complaint being a cosmetic one. Warts on the plantar aspect of the foot can become large and painful. Verruca vulgaris and verruca plantaris appear as well-demarcated keratotic papules or nodules, usually with multiple tiny red–brown dots representing thrombosed capillaries; palmar and plantar warts characteristically interrupt the normal dermatoglyphics. They may be very numerous and confluent, giving the appearance of a mosaic. Verruca plana appears as a well-

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demarcated, flat-topped papule, which lacks the dots seen in other types of verrucae.284,285 When present in the beard area, hundreds of flat warts may be present. All types of verrucae may have a linear arrangement due to koebnerization or autoinoculation. Condylomata acuminata are usually asymptomatic, although voluminous lesions may be painful and bleed.286 Pain associated with HPV infection most commonly is due to therapy, but also is sensed in voluminous verrucous masses. Condylomata appear as well-demarcated papular or nodular lesions arising anywhere on the anogenital, vaginal, cervical, rectal, or oropharyngeal epithelium. Lesions may be very numerous and become confluent. The prevalence of cervical intraepithelial neoplasia is increased in HIV disease; however, prevalence of invasive SCC of the cervix is not certain at this time.283 Intraepithelial neoplasia involving the anogenital skin also is increased; there may be an increase in the incidence of invasive SCC as well.287,288 The diagnosis of verrucae and condylomata usually is made on a clinical basis. Acetowhitening, the appearence of white micropapules or macules after the application of 5% acetic acid (white vinegar) to the anogenital epithelium, can be helpful in defining the extent of HPV infection. The diagnosis of intraepithelial neoplasia and invasive SCC can be made only histologically and atypical lesions should be biopsied. The differential diagnoses of verrucae include molluscum contagiosum, various benign and malignant epidermal neoplasms, KS deep mycotic lesions hematogenously disseminated to the skin, and bacillary angiomatosis. The differential diagnoses of condylomata acuminata include various benign and malignant mucocutaneous neoplasms, condylomata lata of secondary syphilis, and molluscum contagiosum. Efficacy of treatment of verruca vulgaris and condyloma acuminatum in HIV disease varies with the degree of immunocompromise. In patients with early disease, these lesions should be managed as in the normal host. In patients with advanced HIV-induced immunodeficiency, complete eradication of benign HPV-induced lesions is unlikely, and aggressive treatment such as laser surgery is contraindicated.289 Cytologic smears and/or lesional biospies should be obtained to monitor the evolution from cytologic atypia to intraepithelial neoplasia or invasive SCC. 5.4. Sexually Transmitted Diseases Genital ulcer disease caused by syphilis, genital herpes, and chancroid has been associated with increased transmission of HIV.

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Syphilis Coinfection with Treponema pallidum and HIV interacts at several levels.290,291 Both are sexually transmitted diseases and may be acquired from a dually infected sex partner. Primary syphilis (characterized by chancres or ulcers on the vulva, cervix, penis, anus, rectum, or oropharynx) facilitates acquisition of HIV because of the break in the integrity of the epithelium. Syphilis occurring in more advanced HIV disease can present with highly atypical findings (Table 6): the immunologic defects associated with HIV infection may block the appearance of the usual antibody response to T. pallidum infection, so that false-negative serologic tests for syphilis can be observed in the face of active and even progressive infection; the clinical manifestations of the disease may be altered, the response to therapy decreased; the duration of the stages of syphilis may be greatly telescoped, all due to the immunocompromised state of the host. Shortly after T. pallidum penetrates the intact mucous membrane or abraded skin, it spreads via lymphatics and the systemic circulation. Healing of the primary chancre, control of the infection in draining lymph nodes, the development of lesions at metastatic sites, the rapidity with which normally late manifestations of syphilis develop, the clinical manifestations of the infection, and the response to antimicrobial therapy are all influenced by the

degree of immunocompromise present. Thus, the greater the immunocompromise, the slower the healing, the greater the organism burden, the more common systemic spread, the more rapid the development of “late-stage” disease, and the more likely the failure of conventional antimicrobial therapy, particularly if bacteriostatic drugs such as doxycycline or erythromycin are utilized. The majority of HIV-infected persons who acquire syphilis have the expected clinical course of disease and the expected serologic findings in serum and cerebrospinal fluid, and they respond to the recommended therapeutic regimens. In a small percentage, however, the clinical manifestations, clinical course, serologic response, and response to antibiotic treatment are unusual, especially with moderate to advanced HIV-induced immunodeficiency. In that unusual clinical presentations or failures of treatment are reported as single or a few cases, the percentage of cases of syphilis in HIV-infected patients with an unusual clinical course of disease is unknown. An inadequate immune response to T.pallidum is considered to cause the various abnormalities in the course of syphilis in the HIV-infected patient.292,293 Not uncommonly, however, the extent of ulceration is far greater than normally seen, and multiple chancres may be observed.294 Instead of healing within 3–6 weeks, persistent ulceration may occur. Any of the clinical manifestations of secondary syphilis that occur in the normal host may occur in the HIV patients, with the most important mucocutaneous abnormalities outlined in Table 6.295 In addition, lues maligna, a rare form of secondary syphilis characterized by pleomorphic skin lesions including pustules, nodules, ulcers, and a necrotizing vasculitis, may be seen.296 However, the most notable aspect of syphilis in the HIVinfected individual is the rapid progression of disease, such that normally late sequelae of T. pallidum infection may be observed less than 6 months after primary infection, even in the face of normally adequate therapy.297,298 In general, HIV-infected individuals with syphilis have a higher incidence of systemic symptoms, simultaneous multiorgan involvement, and atypical rashes and are particularly prone to the development of neurosyphilis and uveitis. Because of the malignant course of the disease and the unreliability of traditional diagnostic and therapeutic approaches, both an aggressive biopsy and treatment program are essential. The cornerstone of the diagnostic approach to syphilis in non-HIV-infected individuals is serologic testing.299,300 However, since both false-positive and falsenegative results occur in HIV-infected persons,301,302 such testing must be supplemented by biopsies of suspicious

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lesions. Fluid from such lesions should be examined immediately by dark-field microscopy. In addition, specific immunofluorescent or immunoperoxidase staining of the pathologic specimens can lead to the definitive diagnosis. The differential diagnosis of syphilitic cutaneous lesions is quite broad, depending on the particular lesion being considered. Thus, the differential diagnosis of primary lesions of syphilis includes mainly herpes simplex infection, chancroid, and bacterially infected genital lesions of any cause, although under appropriate epidemiologic conditions such entities as donovanosis, lymphogranuloma venereum, mycobacterial infection, and tularemia must be considered. The differential diagnosis of secondary syphilis includes drug eruption (e.g., captopril), pityriasis rosea, infectious exanthems, infectious mononucleosis, tinea corporis, tinea versicolor, scabies, “id” reaction, condylomata acuminata, acute guttate psoriasis, and lichen planus. The differential diagnosis of tertiary syphilis includes lymphoma, tuberculosis, sarcoidosis, and deep fungal infections. In HIV-infected patients with syphilis, two rules of clinical management apply: (1) disseminated infection, particularly with central nervous system involvement, should be assumed, and therapy appropriate for neuro– syphilis prescribed in any patient coinfected with syphilis and HIV who has evidence of compromised immune function, regardless of the apparent clinical stage of syphilis observed; and (2) close follow-up, with repeated clinical, serologic, and cerebrospinal fluid examinations, is necessary, as even the best of regimens will sometimes fail in HIV-infected patients with significant immunocompromise.304,305 In a report of syphilis and HIV infection, 23% of individuals who presented with syphilis were concurrently HIV-infected.306 The clinical presentation of syphilis in patients with HIV infection differs from that of patients without HIV infection in that patients with HIV infection present more often in the secondary stage (53% vs. 33%) and those with secondary syphilis are more likely to have chancres (43% vs. 15%). HIV testing is advised for all sexually active patients with syphilis. Although uncommon, seronegative primary and secondary syphilis have been reported in HIV-infected individuals.301 Nearly all HIV-infected individuals with symptomatic neurosyphilis have positive syphilis serologies.302 Normally, treponemal tests remain positive throughout life. However, 7% of asymptomatic HIVinfected patients with a history of syphilis and 38% of those with symptomatic HIV infection with a history of syphilis have been reported to lose reactivity of treponemal tests.307

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Neurosyphilis should be considered in the differential diagnosis of neurologic disease in HIV-infected persons. When clinical findings suggest syphilis but serologic tests are negative or confusing, alternative tests such as biopsy of lesions, dark-field examination, and direct fluorescent antibody staining of lesion material should be used. In comparison with HIV-seronegative individuals, HIV-infected patients who have early syphilis may be at increased risk for neurologic complications and may have higher rates of treatment failure with currently recommended regimens. The magnitude of these risks, although not defined precisely, is probably minimal. No treatment regimens for syphilis are demonstrably more effective in preventing neurosyphilis in HIV-infected patients than the syphilis regimens recommended for HIV-seronegative individuals. Careful follow–up after therapy is essential. The current Centers for Disease Control recommendations for treating early syphilis appear adequate for most patients, whether or not HIV infection is present.308,309 Penicillin regimens should be used whenever possible for all stages of syphilis in HIV: benzathine penicillin G, 2.4 million units IM, as for HIV–seronegative individuals. Some authorities advise cerebrospinal fluid examination and/or treatment with a regimen appropriate for neurosyphilis for all patients coinfected with syphilis and HIV, regardless of the clinical stage of syphilis. Patients should be followed clinically and with quantitative nontreponemal serologic tests (VDRL, RPR) at 1, 2, 3, 6, 9, and 12 months after treatment. Patients with early syphilis whose titers increase or fail to decrease fourfold within 6 months should undergo cerebrospinal fluid examination and be re-treated. In such patients, cerebrospinal fluid abnormalities could be due to HIV-related infection, neurosyphilis, or both.290 In that T. pallidum may persist in the central nervous system of the HIV-infected patient in spite of adequate antibiotic treatment, the possibility of chronic maintenance treatment, analogous to secondary prophylaxis of cryptococcal meningitis, has been raised. 5.5. Parasitic Infestations

Protozoan infections are among the most common opportunistic infections in HIV disease; mucocutaneous involvement, however, is uncommon.310 5.5.1. Extrapulmonary Pneumocystosis

Pneumocystis carinii is a common opportunistic pathogen in untreated HIV disease with CD4 counts most commonly causing pneumonia. Ex-

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trapulmonary pneumocystosis can be rare in the initial presentation of HIV infection, manifested by unilateral or bilateral polyploid masses, and may be accompanied by loss of hearing. Similar lesions may occur at the tympanic membrane, middle ear, and mastoid air cells, associated with retrograde spread via the eustachian tube. Gangrene of the foot has been reported in a patient with widespread pneumocystosis; microemboli containing P.carinii were present in smaller arterioles and capillaries within necrotic skin of the toes. Widespread violaceous papules and nodules arising on the torso, arms, and legs, resembling KS have been reported.311 5.5.2. Strongyloidiasis

Once infected with Strongyloides stercoralis, the organism persists in the host via autoinoculation. In the compromised host with underlying conditions such as chronic infection (HIV disease, tuberculosis, lepromatous leprosy), neoplasms (lymphoma, leukemia), or organ transplantation, the number of filariform larvae can increase tremendously resulting in disseminated strongyloidiasis or hyperinfection syndrome. Disseminated strongyloidiasis should be considered in the following circumstances312: (1) eosinophilia may be modest or absent; systemic corticosteroids and host debilitation may suppress this characteristic finding; the presence of eosinophilia should initiate a vigorous search for parasites; (2) unexplained and/or persistent bacteremia with enteric organisms despite administration of appropriate antibiotics; (3) serious infection (pneumonia, meningitis, bacteremia) from a suspected intra–abdominal source; (4) nonspecific gastrointestinal symptoms (abdominal pain and distention, diarrhea, nausea, and vomiting); (5) nonspecific pulmonary symptoms and signs (cough, wheezing, hemoptysis, transient interstitial infiltrates); (6) concurrent infection or prior therapy for other intestinal parasites; and (7) history of residence or travel to an endemic area even many years previously. Clinically, periumbilical purpura is suggestive of disseminated strongyloidiasis. The ecchymoses are said to resemble multiple thumbprints on the abdominal wall, radiating from the umbilicus to the flanks and lower extremities.313 Fine petechiae are also seen having a reticulated pattern of linear and serpiginous purpuric streaks.314

endothelial system. Subclinical Leishmania infection is common in Mediterranean countries; 5–15% of adults in parts of Italy have a positive leishmanin skin test.315 In previously infected individuals, antigen-specific T cells and NK cells interact with parasitized phagocytes in an equilibrium such that only a very low level of replication of Leishmania occurs. In HIV–infected persons, the equilibrium is lost.316 As immunodeficiency progresses, the protozoans may escape confinement by immune surveillance and cause visceral leishmaniasis (VL) (kala-azar). Reactivated leishmaniasis also occurs in organ transplant recipients. Coinfection with HIV and Leishmania has been reported in >700 patients living in the Mediterranean basin, with the greatest number in Spain. In southern Europe, 50% of adult VL cases have occurred in HIV–infected individuals; 1.5 to 9% of HIV-infected individuals have either newly acquired or reactivated VL. More than 400 cases of coinfection with HIV and Leishmania have been reported from Spain, 85% in injecting drug users (IDU). Person-to-person transmission of Leishmania as well as HIV has been suggested in IDUs. VL may be the presenting manifestation of HIV disease. The course of persons who harbor Leishmania as well as HIV remains poorly defined. Coinfection of HIV and Leishmania in other sites of endemic leishmaniasis such as Kenya, Sudan, India, and Brazil is not well defined. No characteristic skin lesions have been described in HIV disease. Normal skin also may be parasitized. Cutaneous leishmaniasis (CL) usually represents primary infection presenting in multiple crusted papulonodules in sites exposed to insect vectors, disseminated nodules,317 as well as an erythrodermic and dermatomyositislike eruption.318 A generalized psoriasiform eruption has been reported in a patient with VL.319 Leishmaniasis also can present at sites of HSV or VZV infection or of KS in HIVinfected individuals with CL or VL.320 Digital necrosis has been reported associated with leishmanial vasculitis.321 Diagnosis may be confirmed by demonstration of Leishmania on lesional skin biopsy and/or bone marrow aspiration. Leishmanial serology is often negative. The incidence of relapse of visceral leishmaniasis is high in HIV–infected individuals. 5.5.4. American Trypanosomiasis (Chagas’ Disease)

5.5.3. Leishmaniasis

Following asymptomatic or symptomatic primary infection, Leishmania often remains latent in the reticulo–

American trypanosomiasis can reactivate in patients with cardiomyopathy treated with cardiac transplantation, and present with lesions resembling soft–tissue infec–

MUCOCUTANEOUS INFECTIONS 322–326

tion. In patients who have received transplants, try– panosomiasis reactivates with clinical presentation of fever, heart failure, and soft-tissue infection on the trunk and/or lower extremities. Trypanosoma cruzi can be detected on lesional skin biopsy. 5.5.5. Acanthamoebiasis

Acanthamoebae are free-living amoebae, which can enter the upper respiratory tract, disseminate hematogenously, and cause encephalitis and disseminated cutaneous lesions in advanced HIV disease. Cutaneous lesions appear as initially erythematous dermal to subcutaneous papules and/or nodules that suppurate, forming abscesses and ulcerations.327–330 Acanthamoebic cysts and trophozoites, which resemble macrophages, can be visualized in lesional biopsy specimens with PAS or Gomori’s methenamine silver stain and immunofluorescence techniques.331 A leukocytoclastic vasculitis can also occur. The organism can be isolated on culture of a biopsy specimen. 5.5.6. Protothecosis

Prototheca species are algae, found in water, sewage, soil, and trees; Prototheca wickerhamii is the only one capable of infecting humans. Human infection occurs at sites of traumatic inoculation, producing localized infection in the olecranon bursa in the normal host. In the compromised host, lesions occur at site of inoculation and have a widely varied clinical appearance, ranging from papules, vesicles, ulcers, or verrucous plaques.332,333 Disseminated infection can occur following localized cutaneous lesions such as insect bite in the compromised host.334 Prototheca can be identified by PAS and silver stains of lesional biopsy specimens and isolated on Sabouraud’s dextrose agar. 5.6. Arthropod Infestations Crusted (Norwegian) Scabies

Crusted or hyperkeratotic or Norwegian scabies occurs in compromised hosts. Currently in the United States, HIV disease is the most common associated immunocompromised state; crusted scabies also occurs in leprosy (the original report of crusted or Norwegian scabies was in lepers from Norway), Down’s syndrome, transplant recipients,335 chronic lymphocytic leukemia,336 adult T–cell leukemia,337 solid tumors, and vasculitis. In obtunded or compromised individuals, pruritus

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may be diminished or absent in crusted scabies. Scabetic infestation can be severe, with millions of mites infesting the skin, presenting as a hyperkeratotic dermatitis but resembling atopic erythroderma, psoriasis vulgaris, keratoderma blennorrhagicum, keratosis follicularis (Darier’s disease), or seborrheic dermatitis (in infants).338 Thickly crusted plaques occur on the ears, buttocks, and extensor surfaces of the extremities, palms, and soles. Heavy infestation occurs around the nails with nail dystrophy and subungual and periungual scale–crust.339,340 Scabetic infestation, which usually spares the head and neck in adults, can be generalized. Staphylococcus aureus and gram-negative superinfection can occur, which has been complicated by septicemia and death.295,341,342 Because of the number of organisms in crusted scabies, recurrences are common and hospital epidemics may occur. Use of potent topical corticosteroids for such previously diagnosed pruritic conditions may mask the presence of scabetic infestation. Eradication of the infestation is difficult because of the number of organisms. Topical treatment with gamma benzene hexachloride, permethrin lotion, or 10% sulfur ointment is effective; total-body application is required. Keratolytic agents are needed to debride hyperkeratotic areas in conjunction with debridement of involved nails. Orally administered ivermectin has been reported to be effective in scabies.343,344

6. Diagnostic Aspects of Skin Infections in the Compromised Patient

In the immunocompetent patient, the gross appearance of a skin lesion is an important aspect of diagnosis. By contrast, the clinical value of the gross appearance of a cutaneous lesion in a compromised person is likely to be limited, for two reasons: First, in compromised patients, the variety of organisms that may cause infection is substantially greater than in immunocompetent persons. Second, in compromised patients, the inflammatory response to infection may be altered. It is noteworthy that a cutaneous lesion results not only from the invading pathogen itself but also from the inflammatory response of the body to the microbe. Thus, with an impaired inflammatory response, the prediction is that the diagnostic usefulness of gross appearance would be suboptimal. For these two reasons, it is key to realize that the differential diagnosis of a particular skin lesion in a compromised patient is extensive. This point is emphasized in Table 1, which indicates that no gross morphology of a skin lesion in a compromised person is pathognomonic for a single etio-

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logic agent. All these considerations stress the value of skin biopsy in establishing a diagnosis. The approach to biopsy of a cutaneous lesion suspected to be infectious should include two considerations: (1) the most rapid and sensitive methods for detecting microbes both histologically and immunologically should be used and (2) appropriate cultures and stains should be obtained to optimize the chance of identifying the pathogen. Biopsy, if possible, should be a generous wedge excision. Half the tissue is then sent for histopathologic evaluation by routine methods and also by special stains for fungi, mycobacteria, and bacteria. The other half is sent to the microbiology laboratory for culture for aerobic and anaerobic bacteria, mycobacteria (at 25°C and 37°C), and fungi, as well as for Gram’s, acid-fast, modified acidfast, and direct fungal stains of touch preparations or ground material. In conclusion, to take advantage of the skin as an early warning system of serious infection in compromised patients, both physician and patient should search for cutaneous and subcutaneous lesions. Unexplained skin lesions then should be evaluated by biopsy for culture and histologic examination.

7. Inflammatory Disorders that Simulate Infection in the Compromised Host

Several inflammatory cutaneous disorders occur in the compromised host that can be mistaken for infections. These disorders are treated with anti-inflammatory agents such as corticosteroids. Antibiotics are ineffective and surgical debridement contraindicated. 7.1. HIV-Associated Eosinophilic Folliculitis

Eosinophilic folliculitis is a relatively common pruritic eruption of sterile, pruritic papules and pustules on the face, trunk, and extremities.345 The eruption occurs nearly exclusively in HIV disease, presenting in either advanced HIV disease or during immune reconstitution following initiation of HAART.346 Histologically, neutrophilic and eosinophilic infiltration of the hair follicles is observed. A clinical entity (Ofuji’s disease) with identical histology occurs in non-HIV-infected individuals. Clinically, however, nonfollicular pustules, coalescing plaques, and urticarial lesions are seen. A 1- to 2-week course of oral corticosteroids is highly effective in providing symptomatic relief of eosinophilic folliculitis. Agents used for long-term suppression of eosinophilic folliculitis

included topical corticosteroid preparations, ultraviolet B phototherapy, and oral agents such as isotretinoin and itraconazole. 7.2. Neutrophilic Dermatoses 7.3.1. Acute Febrile Neutrophilic Dermatosis (Sweet’s Syndrome)

Acute febrile neutrophilic dermatosis presents as painful inflammatory plaques often accompanied by fever, arthralgia, and peripheral leukocytosis (neutrophilia). Multiple lesions arise acutely, are tender and/or painful, and occur most commonly on the face, neck, arms, and legs. Systemic symptoms of fever, headache, arthralgia, and malaise often accompany the cutaneous manifestations. Sweet’s syndrome occurs as a paraneoplastic reaction pattern as well as associated with various infections and inflammatory disorders (parainflammatory). Approximately 10% of cases of Sweet’s syndrome are associated with malignancies, i.e., preleukemias (myelodysplastic syndrome), leukemias, and solid tumors. When associated with an underlying malignancy, Sweet’s syndrome persists for months or years. The treatment of choice for Sweet’s syndrome is prednisone 70 mg tapered over 1 to 2 weeks. Lesions recur unless the underlying malignancy is effectively treated. 7.3.2. Pyoderma Gangrenosum

Pyoderma gangrenosum is a rapidly evolving, idiopathic, chronic, and severely disabling skin disease, characterized by sudden occurrence of single or multiple inflammatory plaques. Approximately half of cases are idiopathic, while others are associated with paraproteinemia, myeloma, and leukemia. Surgical debridement is contraindicated, for any trauma to the skin of these individuals can cause the lesions to flare at that site. The most effective agents for management are oral corticosteroids and cyclosporin A.

8. Conclusion

To take advantage of the skin as an early warning system of serious infection in compromised patients, both the physician and the patient should routinely search for cutaneous and subcutaneous lesions. Unexplained skin lesions should be evaluated by biopsy for culture and histologic examination.

MUCOCUTANEOUS INFECTIONS

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from associated sepsis [letter]. J Am Acad Dermatol 16:396–399, 1987. Meinking TL, Taplin D, Hermida JL, Pardo R, Kerdel FA: The treatment of scabies with ivermectin. N Engl J Med 333:26–30, 1995. Taplin D, Meinking TL: Treatment of HIV-related scabies with emphasis on the efficacy of ivermectin. Semin Cutan Med Surg 16:235–240, 1997. Rosenthal D, LeBoit PE, Klumpp L, Berger TG: Human immunodeficiency virus-associated eosinophilic folliculitis. A unique dermatosis associated with advanced human immunodeficiency virus infection. Arch Dermatol 127:206–209, 1991. Bachmeyer C, Cordier F, Cazier A, Blum L, Mougeot-Martin M: [Eosinophilic folliculitis associated with AIDS after antiretroviral tri-therapy (letter)]. Presse Med 28:2226, 1999.

4

Clinical Approach to the Compromised Host with Fever and Pulmonary Infiltrates ROBERT H. RUBIN and REGINALD GREENE 1. The Febrile Pneumonitis Syndrome and Its Importance The immunocompromised patient in whom fever and pneumonitis develop presents a formidable challenge to the clinician for several reasons: 1. First and foremost, a legion of microbial invaders, ranging from common viral and bacterial pathogens to exotic fungal and protozoan agents, can cause pulmonary infection in these patients.1–9 2. Dual or sequential infection is common; hence, the clinician must be alert to the possibility that a single diagnosis may not adequately characterize a patient or lead to optimal therapy.2,3 3. The differential diagnosis of the febrile pneumonitis syndrome includes not only infection but also a multitude of noninfectious causes of pulmonary inflammation; e.g., radiation lung injury, drug reactions, the underlying neoplasm, pulmonary embolic disease, leukoagglutinin transfusion reactions, pulmonary hemorrhage, atypical pulmonary edema, and alveolar proteinosis.2,3,5,9–11 Robert H. Rubin Division of Infectious Disease, Brigham and Women’s Hospital; Center for Experimental Pharmacology and Therapeutics, Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology; and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114. Reginald Greene Chest Division, Radiology Service, Massachusetts General Hospital, and Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114. Clinical Approach to Infection in the Compromised Host (Fourth Edition), edited by Robert H. Rubin and Lowell S. Young. Kluwer Academic/Plenum Publishers, New York, 2002.

In addition to the broad differential diagnosis that must be considered, the clinician’s task is further complicated in many patients by the subtlety of the clinical presentation. The impaired inflammatory response that is characteristic of so many immunocompromised states may greatly alter the clinical presentation of the pulmonary process. Since physical findings, presenting symptoms, radiologic patterns, and even tissue pathology are largely determined by the inflammatory response to the inciting agent, it is axiomatic that all these phenomena can be greatly modified in the compromised host. In particular, the manifestations of microbial invasion can be greatly attenuated until late in the disease process in these patients. As a consequence, the microbial load present at the time of diagnosis is usually significantly greater than in the normal host, thus providing a greater challenge to the clinician prescribing antimicrobial therapy.3,6,12,13 It is not surprising, then, that the survival of the immunocompromised host with pulmonary infection is determined in large part by the speed with which diagnosis is made and effective therapy instituted. Accordingly, even subtle clinical and radiologic findings must be carefully evaluated. Thus, an unexplained cough in an individual with the acquired immunodeficiency syndrome (AIDS), even in the absence of physical findings or abnormalities on the chest roentgenogram, can represent significant Pneumocystis carinii pneumonia, demonstrable by nuclear medicine or computerized tomographic (CT) scan and diagnosable by examination of respiratory secretions. Similarly, an unexplained fever in a leukemic patient with prolonged chemotherapy-induced neutropenia can be due to invasive pulmonary aspergillosis that may be delineated on a CT scan of the chest, in the face of negative 111

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conventional chest radiography, and diagnosed by percutaneous needle aspiration biopsy. Of all the host defense defects, severe granulocytopenia will have the most profound effect in this regard (although high-dose corticosteroids and advanced AIDS can have a similar impact). The incidence of cough and purulent sputum production, rate of development and progression of radiologic findings, occurrence of cavitation, and pleural space involvement are all markedly diminished in patients with profound granulocytopenia. At the same time, the unopposed microbial invasion is proceeding at a far more rapid rate than is normally observed. As a consequence, the effects of the pulmonary process in granulocytopenic patients may be modified.3,6,12,13 For example, in children with acute leukemia and pneumonia who have absolute granulocyte counts of less than the incidence of positive blood cultures has been reported to be 64%, with the incidence of positive blood cultures falling to 0% in children with leukemia, pneumonia, and absolute granulocyte counts greater than Similarly, although septic shock is a rare occurrence in an immunologically normal patient with pneumonia, it is not unusual in a severely granulocytopenic patient.3 The clinical importance of the febrile pneumonitis syndrome is illustrated by the following observations: The lungs are involved in more than 50% of immunocompromised patients who develop febrile complications, with autopsy evidence of pulmonary infection in more than 90% of patients who succumb.5 As many as 58% of patients with cancer and profound granulocytopenia who die have been shown at autopsy to have clinically unrecognized, and hence inadequately treated, pneumonia.9,14 Patients with significant lung injury from noninfectious processes, particularly pulmonary infarction, have a high rate of secondary infection, which is often the immediate cause of death. This result is particularly likely if the primary lung injury required prolonged intubation and HEPA filtered air was not being provided.2 Mortality rates of 35–90% have been reported in immunocompromised patients with pneumonia, with the exact incidence depending on the underlying disease, the severity of the pneumonia at the time of diagnosis, and the degree of host defense impairment.10,15 For example, Poe et al.16 have reported mortality rates that approached 100% in immunocompromised patients with pneumonia who demonstrated the following characteristics: a within 72 hr of admission, corticosteroid administration at the time of presentation, and the need for mechanical ventilation. The foundation of the approach to the febrile pneu-

monitis syndrome in this patient population is the recognition of the clinical importance of this syndrome, an awareness of the subtlety of its clinical presentation, and the need for more intensive and invasive diagnostic procedures than in the normal host. Despite the obvious difficulties, a variety of clues are available to the clinician in approaching this clinical problem: (1) the clinical and epidemiologic setting in which the pulmonary process is occurring; (2) an understanding of the host defense defects present; (3) the rate of progression of the illness; (4) the pattern of radiologic abnormality produced on chest radiography; and (5) the proper deployment and application of information gained from a series of increasingly invasive diagnostic techniques. A logical approach based on these elements will enable the clinician to arrive rapidly at the appropriate diagnosis. Such rapid diagnosis and appropriate institution of therapy can result, even in this population, in a gratifying rate of clinical response and meaningful patient survival.2,3

2. Overview of the Infectious Causes of the Febrile Pneumonitis Syndrome in the Immunocompromised Host The first concern of the clinician confronted with an immunocompromised patient with fever and pulmonary infiltrates is infection. Overall, 75–90% of episodes are due to infection, with particularly high rates of noninfectious causes of the febrile pneumonitis syndrome occurring in cancer patients and transplant recipients, especially the former (Table l).2,3,5,8–11 Most published series devoted to pulmonary infections in immunocompromised patients have emphasized the importance of opportunistic gram-negative, fungal, nocardial, and herpes group viral infections. Such series have been primarily concerned with infections in patients with acute leukemia or other illnesses being treated with intensive immunosuppressive therapy within the hospital environment.17,18 This emphasis on opportunistic infection is also appropriate in patients with AIDS.19 However, in all immunocompromised patients, even the AIDS patient, common infectious and noninfectious causes of pneumonitis must be considered as well (Table l).1,7–9,20,21 It also should be emphasized that in some patients who are less intensively immunosuppressed, opportunistic infections are uncommon. The number one cause of respiratory infections in these patients, when they are not undergoing acute, immunosuppressive therapy, are the community-acquired respiratory viruses, most commonly influenza but also including parainfluenza, respiratory

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chill, pleuritic chest pain, an increased cough now productive of purulent blood-tinged sputum, and shortness of breath. Physical examination revealed a toxic, tachypneic gentleman with a temperature of 103.4°F (39.7°C) and a respiratory rate of 35. Herpes labialis was evident and signs of consolidation were present at the left lung base. Laboratory data revealed Hct of 43%, WBC of with 80% polys, 14% bands, 3% lymphs, and 3% monos. Sputum examination revealed sheets of polymorphonuclear leukocytes and gram-positive diplococci. Sputum and two blood cultures grew Streptococcus pneumoniae. Chest radiography (Fig. 1) demonstrated a focal air space consolidation of the lung. Comment: This is the classic presentation of community-acquired pneumococcal pneumonia following a viral upper respiratory infection. Indeed, a communitywide influenza outbreak was taking place, with immunosuppressed individuals such as this bearing a particularly heavy burden from this infection. In this case, bacterial superinfection with Streptococcus pneumoniae further complicated the clinical course. In this stable heart transplant patient receiving maintenance immunosuppressive therapy, the pathogenesis, clinical presentation, physical findings, chest radiography, and response to therapy are virtually identical to those observed in the general population.

2.1. Factors that Determine the Risk of Pulmonary Infection

syncytial virus, adenoviruses, and even rhinoviruses. In the setting of communitywide respiratory virus activity, immunosuppressed patients are at particular risk, with higher rates of viral pneumonia and bacterial (and even fungal) superinfection than what is observed in the general population.22–28 Similarly, Streptococcus pneumoniae is the single most common bacterial infection in the cancer, organ transplant, and AIDS populations, especially those that acquire their infections in the community. 2–4,20,21 Illustrative Case 1 A 42-year-old male cardiac transplant patient was admitted with a 4-hr history of fever, rigors, pleurisy, purulent sputum production, and shortness of breath. He had received a heart transplant for a congestive cardiomyopathy 3 years previously. Since then, he had had no episodes of rejection and was currently maintained on cyclosporine 250 mg, azathioprine 100 mg, and prednisone 10 mg/day. One week prior to admission, he developed an upper respiratory infection characterized by low-grade fever, malaise, anorexia, myalgias, and nonproductive cough. A number of individuals at work, his wife, and one of his children had similar illnesses. He had appeared to be getting somewhat better, when he was awakened early on the morning of admission with a shaking

The risk in the compromised host of invasive infection in general and of pulmonary infection in particular is determined largely by the interaction of two factors: the patient’s net state of immunosuppression and the epidemiologic exposures he or she encounters. Thus, if the infecting inoculum is great enough, even a normal individual can develop life-threatening infection; conversely, if the degree of immunosuppression is great enough, even the most innocuous of commensal organisms can pose a severe threat.29 Certain defects in host defense render the individual particularly susceptible to infection with particular classes of microorganisms (Table 2). These correlations are especially useful in pediatric patients with congenital defects that are relatively “pure,” such as isolated defects in antibody formation, complement function, or granulocyte function (see Chapters 2 and 14). In most individuals, however, the situation is far more complicated, with a variety of defects present in the same individual due to the effects of acquired disease and its therapy. For example, following a combination of splenectomy, radiation, and chemotherapy, patients with Hodgkin’s disease, which itself is associated with profound defects in T-lymphocyte function and cell-mediated immunity, will develop marked B-lymphocyte dysfunction as manifested by low levels of serum immunoglobulin M and specific antibody against Haemophilus influenzae type B, poor response to pneumococcal vaccine, and an increased risk of life-threatening systemic and pulmonary infection with these two organ-

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isms.30–32 Thus, in the majority of immunocompromised patients, the concern is the “net state of immunosuppression,” rather than a single defect. 2.1.1. Net State of Immunosuppression

The net state of immunosuppression is a complex function determined by the interaction of a number of factors29: 1. Host defense defects caused by the disease process itself. 2. Dose, duration, and temporal sequence of immunosuppressive therapy employed. 3. Presence or absence of neutropenia. 4. Anatomic integrity of the tracheobronchial tree (including the presence or absence of such “foreign bodies” as endotracheal tubes and obstructing tumor masses). 5. “Functional” integrity of the oropharyngeal and gastric mucosae in terms of their ability to resist

the adherence of potential pathogens to these mucosal surfaces. 6. Such metabolic factors as protein–calorie malnutrition, uremia, and, perhaps, hyperglycemia. 7. Presence of infection with one or more of the immunomodulating viruses: human immunodeficiency virus (HIV), the hepatitis viruses B and C (HBV and HCV), cytomegalovirus (CMV), Epstein–Barr virus (EBV), and probably human herpes virus 6 (HHV-6). The most important determinant of the net state of immunosuppression is the nature of the immunosuppressive therapy that has been and continues to be administered. A few general points regarding immunosuppressive therapy bear special emphasis. The first and perhaps most important is that the particular dose of immunosuppression being administered on a given day is less important than the dosages employed over a sustained period of time (the area under the curve). For example, although the highest daily doses of immunosuppressive therapy that

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are employed in organ transplantation are administered in the first 2–3 weeks posttransplant, the risk of opportunistic infection is extremely low until more than 4 weeks posttransplant, at which time the daily doses of immunosuppressive drugs have fallen significantly. We have suggested that immunosuppressive therapy is like buying something by credit card: if you increase immunosuppression, you have the immediate gratification of improved allograft function; the bill (in terms of infection) comes due 3–4 weeks later.29,33 The second general point is that the effects of the entire immunosuppressive regimen must be considered; the net state of immunosuppression is determined not just by the summation of the effects of the individual agents,

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but also by the interactions of these different effects. For example, whereas such antilymphocyte antibody therapies as antithymocyte globulin (polyclonal, of either equine or rabbit origin) or OKT3 (monoclonal, of murine origin) are capable of reactivating such viruses as CMV and EBV from latency, cyclosporine, tacrolimus, and rapamycin are not. However, once virus is reactivated, cyclosporine, tacrolimus, and rapamycin will greatly amplify the effects of these viruses by specifically blocking the virus-specific cytotoxic T-cell response, the key host defense. Thus, from the point of view of the host, the worst possible scenario is to reactivate virus with antilymphocyte antibody therapy and then accentuate the effects of the virus that has been reactivated with the other

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immunosuppressive drugs. Indeed, in this instance specific preemptive antiviral therapy needs to be administered concomitantly (see Chapter 17).34–36 Finally, it is now apparent that cytokines, chemokines, and other factors elaborated by the host in response to a variety of insults (e.g., infection, allograft rejection, graft vs. host disease, and antilymphocyte antibody therapy) will modulate the course of different infections and interact with the effects of exogenous immunosuppressive therapy on the host. For example, it is clear that there are at least three signaling pathways that can result in the reactivation of CMV from latency: tumor necrosis factor (TNF) interacting with the TNF receptor on latently infected cells; catecholamines through cyclic AMP; and certain proinflammatory cytokines. The TNF pathway appears to be the most important of these. Thus, replicating CMV can appear in any circumstance where TNF is released (e.g., sepsis, rejection, antilymphocyte antibody therapy). The CMV will then be modulated by the immunosuppression being administered and in turn the level of CMV will help determine the susceptibility to a variety of opportunistic pulmonary pathogens, ranging from Pneumocystis carinii to Aspergillus species.29,37 More than 95% of the pneumonias that occur in the

immunocompromised patient follow the delivery of sufficient numbers of virulent microorganisms to the lower respiratory tract via the tracheobronchial tree. In most cases, this infection occurs following the aspiration of gastric or oropharyngeal flora, thus emphasizing the importance of microbial colonization patterns in the pathogenesis of pneumonia,38,39 particularly bacterial pneumonia. Even in the case of invasive pulmonary aspergillosis, however, there is evidence that preceding nasopharyngeal colonization may play a role in the pathogenesis of this form of infection as well.40–43 In addition, inhalation of aerosolized pathogens that are present in unusually high amounts in the patient’s environment can be responsible for the microbial challenge to the lungs (see Section 2.1.2). The normal bacterial flora of the oropharynx is predominantly gram positive and sensitive to a broad range of antibiotics. In particular, the prevalence of gramnegative oropharyngeal colonization in a normal population is on the order of 2–6%, and even challenging normal individuals with gram-negative organisms will rarely induce sustained colonization with these antibiotic-resistant, virulent bacterial species. This remains true for “physically healthy” hospitalized patients (e.g., psychiatric patients), but the rate of Staphylococcus aureus and/or gram-negative carriage rises to 35% in the moderately ill hospitalized patients and to 73% in critically ill patients.38,39,44–46 Sustained colonization with one or any combination of Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, or Candida species is the rule in many immunocompromised patient populations, particularly cancer patients being treated with cytoreductive chemotherapy. Although environmental exposures, the use of antimicrobial therapies, the deployment of respiratory therapy equipment, and other factors will contribute to the rate of nasopharyngeal colonization, the crucial factor is the alteration in the surface characteristics of the mucosal epithelium. In the face of chemotherapyinduced mucositis, steroid therapy, an advanced state of illness, and other factors, the adherence of the more virulent flora, the first step in the pathogenesis of pneumonia in many immunocompromised individuals, is promoted.4,44,47,48 Adherence of bacteria to epithelial cells is mediated through specific interactions between adhesins on the surfaces of bacteria (particularly specialized appendages termed “pili” or “fimbriae”) and receptors on the surfaces of the epithelial cells. Oropharyngeal epithelial cells from individuals colonized with gram-negative organisms have been shown to support an increased rate of gram-negative adherence when compared to epithelial cells from uncolonized individuals.44–48 The mechanisms

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involved in this change in adherence patterns are still being delineated, although the ubiquitous glycoprotein fibronectin appears to be a critical determinant of the microbial flora of the oropharynx. Normally, fibronectin coats this epithelial surface, promoting the attachment of gram-positive organisms and enhancing the bactericidal function of phagocytic cells directed against other microbial species. This causes a selective disadvantage for gram-negative bacteria, impeding colonization with these organisms. Destruction of this fibronectin coat or inadequate production, as occurs in a variety of disease states, malnutrition, dehydration, and in response to chemotherapy, will have at least two adverse effects: (1) It will impede the attachment of the desirable normal flora and (2) it will expose epithelial cell surface receptors for a variety of gram-negative bacterial surface adhesins. The net result is gram-negative overgrowth of the oropharynx.4,44–54 Once gram-negative oropharyngeal colonization is established, it tends to persist. The next step is aspiration of these organisms into the lower respiratory tract. Pharyngeal secretions are aspirated in the majority of normal individuals during sleep and in 70% of individuals with a decreased level of consciousness. The impact of the aspiration episode(s) is increased by depressed gag and cough reflexes, with further amplification in the presence of endotracheal and nasogastric tubes. Two statistics emphasize the importance of these observations: (1) Approximately 90% of patients with gram-negative pneumonia have had prior oropharyngeal colonization with the same organism and (2) pneumonia develops five to eight times more frequently in individuals colonized with these virulent gram-negative organisms. Hence, the ability of the host’s epithelial surfaces to resist colonization with virulent microbial species is an important determinant of the net state of immunosuppression.4,44–54 An additional source of gram-negative bacillary pneumonia is the stomach in the compromised host. The normal production of acid by the stomach maintains a low bacterial count. However, as gastric pH rises, the level of microbial contamination (particularly with gram-negative organisms) rises, serving as a reservoir for both the oropharynx and the respiratory tract.4,55–57 The use of drugs such as proton pump inhibitors, histamine-2 blockers, and antacids, which can raise gastric pH, have been linked in some, but not all, studies to an increased risk of gramnegative pneumonia (with sucralfate for gastric mucosal protection in some, but not all, studies being free of this added risk). The use of enteral feedings, many of which have a pH between 6.4 and 7,0, also will favor gramnegative colonization. It also has been suggested that impaired gastric and small intestinal motility result in

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bacterial overgrowth in the duodenum. This overgrowth is followed by duodenal-gastric reflux, with further amplification of bacterial growth caused by elevated gastric pH. Once these events have occurred, oropharyngeal and tracheal colonization can occur quite readily, thus facilitating the development of pneumonia.55–61 2.1.2. Epidemiologic Aspects The epidemiologic aspects of pulmonary infection in the immunocompromised host can be divided into two general categories: pulmonary infections related to exposures occurring within the community and pulmonary infections related to exposures within the hospital environment. 2.1.2a. Community-Acquired Infection. There are four major considerations when considering the possibility of community-acquired pulmonary infection in the compromised host 1–4,22–29 : 1. The geographically restricted, systemic mycoses (e.g., blastomycosis, coccidioidomycosis, and histoplasmosis). 2. Tuberculosis. 3. Strongyloides stercoralis infection. 4. Community-acquired respiratory viruses (e.g., influenza, respiratory syncytial virus, parainfluenza, adenoviruses, and rhinoviruses). The systemic mycoses and tuberculosis share a similar pathogenesis. The portal of entry is the lung, with primary infection following inhalation of a sufficient inoculum that escapes an initial nonspecific inflammatory response and postprimary dissemination to other bodily sites being a not infrequent event. Limitation of the extent of both the pulmonary and sites of metastatic infection is dependent on the development of a specific cell-mediated immune response. At a later date, reactivation of latent infection can occur, with the possibility of secondary dissemination, due to the waning of immunity and/or local anatomic factors (e.g., erosion of an infected node into the lung). Because of the central role of specific cell-mediated immunity in the control of these infections, it is not surprising that immunocompromised individuals with deficits in this aspect of host defense are susceptible to these infections, with three patterns of disease being observed: progressive primary infection of the lungs; reactivation infection, usually of the lungs, with the potential for secondary dissemination; and reinfection following a new exposure, with a high probability of dissemination, in individuals whose immunity has been ablated due to disease or its therapy. The end result in many immuno-

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compromised patients (especially AIDS patients, but also transplant patients, those with lymphoma, and those receiving intensive immunosuppressive therapy) is disseminated infection, with either or both extensive pulmonary disease and evidence of metastatic infection to such sites as the skin, central nervous system, and skeletal system. In particular, the coexistence of tuberculosis, especially drug-resistant tuberculosis, in populations with a high incidence of HIV infection is now recognized as a particular threat not only to these patients and other immunocompromised patients but also to the community at large.29,33,62–67 Illustrative Case 2 A 37-year-old Hispanic male, who worked at a municipal hospital as an emergency ward attendant, presented with fevers, a nonproductive cough, and increasing shortness of breath of several weeks’ duration. Although several friends and lovers had previously been diagnosed with AIDS, he had refused HIV testing for himself. Over the past year, he had sought treatment outside his place of employment for recurrent anogenital herpes and oral thrush. On physical examination, his temperature was

102.2°F (39°C), his respiratory rate was 24, and his blood pressure was 110/70. He appeared thin and chronically ill, with oral thrush, a painful 2 × 3 cm ulceration adjacent to his anus, and a slightly enlarged liver and spleen. Laboratory studies revealed the following: Hct 29%, WBC with 65% polys, 14% bands, 12% monocytes, and 9% lymphs; SGOT 110; alkaline phosphatase three times the upper limits of normal; bilirubin 2.4/3.0. Chest X-ray, which was initially interpreted as negative, revealed a faint, diffuse miliary infiltrate (Fig. 2). Subsequently, his HIV antibody test was shown to be positive, and he was found to have a CD4 count of 61. Mycobacterium tuberculosis, subsequently found to be resistant to isoniazid and rifampin, was isolated from an induced sputum and from Dupont isolator blood cultures. On admission, he was placed in isolation and following evaluation begun on therapy with isoniazid, pyrazinamide, rifampin, ethambutol, and streptomycin, as well as anti-HIV therapy. Unfortunately, he continued to decline and expired 2 weeks after admission, even before the suspected diagnosis of miliary tuberculosis could be confirmed. Comment. This case was part of a cluster of cases of drug-resistant tuberculosis involving immunocompromised individuals at this municipal hospital and dramatically delineates a current public health dilemma. This Hispanic man with undiagnosed AIDS could have contracted his drug-resistant tuberculosis within his community or occupationally. The extent and pace of his illness were greatly amplified by the level of immunocompromise engendered by his HIV infection, and both within

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the community and within the hospital he posed a significant risk to other individuals, particularly other immunocompromised individuals, with whom he came into contact. The extent of his illness was underestimated by the initial evaluation of his chest radiograph (presumably due to the limited inflammatory response he was able to mount), thereby increasing the hazard to both himself and others.

Illustrative Case 3 A 46-year-old man with non-Hodgkin’s lymphoma previously treated with radiotherapy and chemotherapy, but for the past 6 months with prednisone and weekly vincristine, entered with a 2-week history of a “cold.” He had been relatively well until the gradual onset of fever, night sweats, anorexia, a 10-pound weight loss, increased fatiguability, and headaches. He did not complain of chest pain but had noted some dyspnea on exertion. There was no history of past tuberculosis or tuberculous exposure. Although he had been a resident of New England for the last 10 years, he had lived and worked for more than 30 years of his life on a farm in the San Joaquin valley of California. Physical examination revealed a chronically ill man with a respiratory rate of 18, temperature of 101°F (38.3°C), coarse rhonchi over the right upper chest posteriorly, and an enlarged spleen. Laboratory data revealed Hct of 32% and WBC count of with 85% polys, 3% bands, and 12% lymphs. Skin testing revealed anergy (including testing with coccidioidin). Sputum examination revealed abundant polymorphonuclear leukocytes and normal throat flora. Cerebrospinal fluid examination revealed 89% lymphs and 11% polys, a sugar of 31 mg/dl (simultaneous blood sugar of 110 mg/dl), and a protein of 96 mg/ dl. Chest radiograph revealed a cavitary lesion in the right upper lobe. Complement-fixing antibody to Coccidioides immitis was positive in both the serum and the cerebrospinal fluid. Comment. This is an example of disseminated coccidioidomycosis years after the patient had been primarily infected, with reactivation of an old pulmonary focus and secondary dissemination. The impaired cell-mediated immunity of this patient, induced primarily by the treat-

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ment of his lymphoma, made these events possible. The important clue to the diagnosis lay in the patient’s remote epidemiologic history, with the diagnosis established by serologic testing. A negative coccidioidin skin test and a positive serologic test constitute the characteristic pattern observed in this circumstance.

Strongyloides stercoralis is of particular concern, because of its unique life cycle. Alone among the intestinal nematodes that affect humans, S. stercoralis possesses an autoinfection cycle that can take place entirely within a person’s gastrointestinal (GI) tract. As a result, chronic asymptomatic GI infestation can be maintained for decades after the person has been exposed in an endemic area. With the onset of depressed cell-mediated immune function, due either to disease or its therapy, overwhelming systemic invasion by this organism can occur. Hemorrhagic pulmonary consolidation or diffuse, bilateral alveolar opacities, often with accompanying GI complaints (including hemorrhagic enterocolitis), may develop. Alternatively, systemic strongyloidiasis may be accompanied by the adult respiratory distress syndrome (see Chapter 8).68,69 Perhaps the most important community exposure for immunocompromised patients is that related to respiratory viruses in the household, workplace, and general community (alternatively, these same viruses can be brought into the hospital setting from the community, with rapid spread among patients and staff). The community-acquired respiratory viruses causing disease in the immunocompromised patient population are diverse, including the

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Orthomyxoviridae (influenza viruses), the Paramyxoviridae (respiratory syncytial virus and the parainfluenza viruses), the Picornaviridae (rhinoviruses and enteroviruses), the Coronaviridiae (coronaviruses), and the Adenoviridae (adenoviruses). Transmission of the virus is through contact with virus-laden respiratory secretions: person to person in aerosols or on the hands, or through contact with fomites. Infection in immunocompromised individuals generally reflects the level of virus transmission in the general community. The importance of these infections is underlined by the following statistics: At the MD Anderson Cancer Center, during two 6-month surveillance periods in the early 1990s, 67 (31%) of 217 hematopoietic stem cell patients admitted with an acute respiratory illness had infection with one or more of these respiratory viruses (49% respiratory syncytial virus, 18% influenza, 18% picornavirus, 9% parainfluenza viruses, and 6% adenoviruses); 58% of these infections were complicated by pneumonia and 51% of the pneumonias were fatal.70 Similar data are available from the Huddinge University Hospital in Sweden, where a prospective surveillance study among a comparable population of patients was carried out between 1989 and 1996 and involved 545 patients. This study revealed an incidence of communityacquired respiratory virus disease of 9.3% in allogeneic and 1.8% in autologous hematopoietic stem cell transplant patients (38% influenza viruses, 21% respiratory syncytial virus, 21% parainfluenza viruses, and 21% adenoviruses).71 Less complete information is available in other populations, but what information is available is consistent with that cited for the hematopoietic stem cell transplant population.72–75 For example, during a recent communitywide epidemic of influenza A infection, 28 kidney and liver transplant recipients were admitted to the Massachusetts General Hospital over a 6-week period, with more than half of these having pneumonia. As a general rule then, immunosuppressed patients with these infections have a higher attack rate for viral pneumonia, superinfecting bacterial pneumonia, rate of transmitting the infection to others, and prolonged illness than the general population. At present, prevention and treatment of communityacquired respiratory virus infection in immunocompromised patients is in its infancy. Although yearly influenza immunization is recommended for these patients, efficacy is significantly attenuated when compared with the general population.72,76–79 There is inadequate information available to comment regarding amantadine, rimantadine, or the new neuraminidase inhibitors in the prevention or treatment of influenza in immunosuppressed patients. There are anecdotal reports of success with ribavirin in the management of both respiratory syncytial virus and

adenovirus infection, but its true efficacy (with or without immunoglobulin) remains to be defined.72 In sum, avoidance of exposure and traditional infection control procedures are the cornerstones of our present efforts to control this important class of infection. 2.1.2b. Hospital-Acquired Infection. As important as community exposures are in the evaluation of immunocompromised hosts with the febrile pneumonitis syndrome, exposures within the hospital are even more important. Nosocomial exposures to air contaminated with Pseudomonas aeruginosa, Klebsiella pneumoniae and other Enterobacteriaceae, and Aspergillus species, as well as to potable water laden with Legionella species, have resulted in epidemic pulmonary infection in immunocompromised patients. 1–3,40,41,80–88 As far as Legionella infection is concerned, L. pneumophila, as in the general population, accounts for the majority of cases in the immunocompromised patients, but in addition the burden of disease from unusual Legionella species (e.g., L. micdadei, L. longbeachae, L. bozemanii) is borne most heavily in these patients.89–91 The source of nosocomial legionellosis is a contaminated potable water system, with patients aspirating the organisms thus presented.84 The extent of the problem is underlined by a recent survey undertaken in the United Kingdom, in which Legionella species were isolated from 55% of the water supplies of 69 transplant units, with L. pneumophila being isolated from 45%.85 Prevention of nosocomial legionellosis requires surveillance and then disinfection of infected water supplies. Although hyperchlorination was recommended in the past for this purpose, superheat and flush or copper– silver ionization are currently the preferred methods.84 Nosocomial outbreaks of pulmonary infection have been observed among immunocompromised patients, with two epidemiologic patterns having been identified: domiciliary and nondomiciliary. The term “domiciliary” is used to describe outbreaks in which the patient is infected on the ward or in his or her hospital room. Such epidemics of Pseudomonas, Aspergillus, and Klebsiella (among others) infection have been not uncommon and are relatively easily identified because of temporal and spatial clustering of cases of opportunistic infection. The exposures have been due to construction, aerosolization of standing water laden with gram-negative bacilli or Legionella, or contamination of the air-handling system for the ward or the patient’s room. Such outbreaks are effectively prevented by the provision of high-efficiency particulate air (HEPA) filtering in hospital locations where immunocompromised patients are housed. As one measure of the effectiveness of this approach, our experience with intubated transplant patients is very striking. In the absence of HEPA-filtered air, the incidence of gram-

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negative or Aspergillus superinfection in transplant patients requiring more than 3 days of tracheal intubation and ventilatory support approached 100%; at present, when care is administered in HEPA-filtered rooms, the incidence of secondary infection of the lungs does not become significant for at least a week, and we have successfully cared for immunosuppressed patients who required intubation for more than a month. Thus, an adequately filtered air supply is directly translated into a lower incidence of pulmonary infection and a decreased mortality due to opportunistic pulmonary infection.2,23,29,92 Although reports of domiciliary outbreaks of nosocomial pulmonary infection among immunocompromised patients are not uncommon, nondomiciliary exposures and outbreaks are actually a greater problem. These infections occur when patients are taken from their rooms through the hospital to the radiology, endoscopy, or operating suites for essential procedures, with exposures occurring along the way or at the site of the procedure. Construction within the hospital environment has been the major cause of air contamination leading to nondomiciliary outbreaks. Thus, we have observed an outbreak of invasive pulmonary aspergillosis among transplant patients, leukemic patients, and patients receiving immunosuppressive therapy for collagen vascular disease due to construction in the central radiology suite.92 Similarly, cardiac transplant patients have acquired this infection while waiting outside the cardiac catheterization laboratory for a routine endomyocardial biopsy procedure. The use of routine surgical masks to protect these patients has not been effective. Although the ideal equipment has yet to be designed for protecting patients being transported in the hospital environment, efforts to develop prototype portable HEPA-filtered transport equipment to protect patients when they must travel out of the protected environment of the transplant or oncology units are to be commended.93 In the meantime attention to transport routes in the hospital, with the avoidance of areas of construction, must receive a high priority for these patients. Illustrative Case 4 An 11-year-old girl in remission after induction chemotherapy for acute myelogenous leukemia entered the hospital for a scheduled round of chemotherapy. Five days postadmission, she spiked a fever and an infiltrate was noted on chest CT scan. Needle aspiration biopsy yielded a pure growth of Aspergillus fumigatiis. Amphotericin therapy was instituted, with a good response after a prolonged hospitalization. That month, five other immunocompromised patients (three renal transplant patients, an adult oncology patient, and one patient being treated with high-dose corticosteroids for systemic lupus erythematosus) from different locations within the hospital developed invasive pulmonary aspergillosis. The epidemic was traced to construction in the central

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radiology suite. With cessation of the construction, the epidemic came to an end. Comment. This is a well-documented nondomiciliary outbreak of invasive pulmonary aspergillosis. Such nondomiciliary exposures are probably quantitatively more important than domiciliary exposures, but are more difficult to identify because of the lack of temporal and spatial clustering. Constant surveillance of immunocompromised patients for such excessive environmental hazards is essential. Suspicion regarding such a nondomiciliary, nosocomial exposure should be aroused whenever opportunistic pulmonary infection is identified in a patient whose net state of immunosuppression should not be great enough for such an infection to occur unless the patient had experienced an unusually intense exposure. For example, the occurrence of invasive aspergillosis in the first 3 weeks postorgan transplantation or in the first week of cancer chemotherapy should be cause for an epidemiologic investigation.

Immunocompromised patients, then, can be compared to “sentinel chickens” placed in the swamps surrounding major population centers to monitor the level of mosquito-borne arbovirus infection. In this context, it is our contention that immunocompromised patients are sentinel chickens placed in the swamps of our hospital (and community) environment. Any excess traffic in microbes will be seen first and most severely in these individuals and constant vigilance is necessary to protect these patients. The lesson for the clinician is twofold: Constant surveillance to effect early identification and correction of hazards is important to prevent infection; in addition, while correcting circumstances that have epidemic potential, the clinician must be aware of the prevalent endemic microbial flora at any point in time to facilitate the care of the individual patient.94

2.2. Pathology of Pulmonary Infections in the Immunocompromised Host The evaluation of pulmonary biopsy material for possibly treatable infection is an important part of the assessment of many immunocompromised patients with the febrile pneumonitis syndrome. The histologic patterns of pulmonary injury observed following microbial invasion in this patient population have been classified by Nash into six general patterns, each with its own differential diagnostic considerations: acute nonnecrotizing pneumonia, acute necrotizing pneumonia, diffuse alveolar damage, diffuse alveolar damage with foamy alveolar exudate, granulomatous pneumonitis, and bronchiolitis obliterans-organizing pneumonia (BOOP).95 2.2.1. Acute Nonnecrotizing Pneumonia Acute nonnecrotizing pneumonia is caused by a variety of bacterial agents, most commonly Streptococcus pneumoniae. It is characterized by a fibrinopurulent exu-

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date filling airways and air spaces, without destruction of the alveoli. In most instances, the causative agent can be isolated from the respiratory secretions and lung tissue and effective antimicrobial therapy can result in complete healing of the process. Indeed, lung biopsy is usually not necessary to make this diagnosis.95 2.2.2. Acute Necrotizing Pneumonia Acute necrotizing pneumonia adds the element of pulmonary tissue destruction to the previous pattern of acute inflammation. The distribution of the lesions depends on the route by which the organisms invade the lung: Organisms that reach the lung via the tracheobronchial tree and invade at the level of the bronchi and adjacent airspaces produce a pattern of bronchopneumonia (e.g., Staphylococcus aureus), whereas those that invade the lung at the level of the distal airspaces produce an airspace consolidation that can progress to a fullblown lobar pneumonia (e.g., Klebsiella pneumoniae). Hematogenous spread of organisms to the lung typically produces a nodular focus of necrotizing pneumonia that is located in the periphery of the lung and has no relationship to the segmental anatomy of the tracheobronchial tree. Such lesions are caused by a variety of virulent organisms once they enter the bloodstream, including S. aureus, Pseudomonas aeruginosa, Candida albicans and tropicalis, and Aspergillus jumigatus.95 The most common bacterial infections that produce acute necrotizing pneumonia in the immunocompromised host are S. aureus, K. pneumoniae, P. aeruginosa, and Legionella species. In the case of P. aeruginosa infection, in addition to the nonspecific necrotizing features, so-called Pseudomonas vasculitis characterized by masses of bacteria surrounding and invading blood vessels is a common finding. In the case of Legionella infection, the inflammatory exudate usually contains numerous macrophages in addition to the neutrophils seen with the other bacterial processes, and extensive leukocytoclasis of alveolar inflammatory cells may be observed.95,96 Candida, Aspergillus, and Zygomycetes are the fungal species most commonly associated with pulmonary necrosis, both because of direct effects of these organisms and because of their propensity for invading pulmonary arteries, causing infarction and hemorrhage (as well as a propensity for hematogenous dissemination). The opportunistic bacterial pathogen, Nocardia asteroides, the clinical effects of which resemble those of Aspergillus, can likewise produce necrotizing changes in the lung.95,97 Finally, the herpes group viruses and adenoviruses can cause necrotizing pneumonias associated with a neutrophilic exudate. Cytomegalovirus

(CMV) and adenovirus infection may be associated with two pathologic patterns: a necrotizing pneumonia (in the case of adenoviruses, bronchiolitis and bronchitis as well) and diffuse alveolar damage. In the case of CMV, enlarged cells exhibiting the characteristic cytopathic CMV changes may be present, although the absence of these cells does not rule out this diagnosis. Viral culture, immunofluorescent staining, and in situ polymerase chain reaction (PCR) are more sensitive in diagnosing CMV pulmonary infection than the demonstration of the cytomegaly cells with their intranuclear inclusions.95,97 2.2.3. Diffuse Alveolar Damage Diffuse alveolar damage is a nonspecific response to a variety of insults and is the pathologic finding seen in the adult respiratory distress syndrome (ARDS) and its less severe variant, acute lung injury (ALI), such as that occurring in sepsis and septic shock. The term “diffuse alveolar damage” is given to a pathologic pattern of damaged alveolar capillary endothelium and alveolar epithelium, interstitial edema, and hyaline membranes. Over a few weeks, this acute exudative picture evolves into an organizing (proliferative) phase characterized by interstitial fibrosis, chronic inflammation, and regenerating alveolar epithelium. This lesion is the characteristic one caused by a variety of viruses, most notably influenza, but also including CMV and adenoviruses.95,97 2.2.4. Diffuse Alveolar Damage with Foamy Alveolar Exudate Diffuse alveolar damage with eosinophilic alveolar foam is the classic pathologic finding with Pneumocystis carinii pneumonia.98 Typically, at the time of biopsy evidence of the organizing phase of alveolar damage is already present, with the organisms being demonstrable within the alveolar foam with such special stains as the methenamine–silver stain or by immunohistochemical methods. It also should be emphasized, however, that the absence of the alveolar foam does not rule out pneumocystosis, with organisms still being demonstrable in association with nonspecific diffuse alveolar damage with the special stains. As with other infections that occur in the AIDS patient, the burden of Pneumocystis organisms is far higher in this group of immunosuppressed individuals and the consequences of the P. carinii infection are often greater in AIDS patients than in other immunocompromised patients with this infection: a higher likelihood of developing changes of ARDS, a higher incidence of severe interstitial fibrosis, the occurrence of metastatic in-

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fection to other bodily sites, and the not uncommon occurrence of pneumatoceles or bullae as a consequence of the Pneumocystis infection—unusual events in the nonAIDS patient.95,97 2.2.5. Granulomatous Pneumonitis Granulomatous pneumonitis is characterized by a nodular infiltrate composed of epithelioid histiocytes, multinucleated giant cells, and surrounding areas of fibrosis and chronic inflammation. Varying degrees of central necrosis may be observed. This is the classic pathologic lesion observed with Mycobacterium tuberculosis, Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis. In saying this, however, two points must be particularly emphasized: First, prior to the development of the established granuloma, an acute neutrophilic response is the first line of defense against invasion with these microbes. Therefore, the exact mix of acute and granulomatous inflammation seen will depend on the age of the lesion biopsied. Second, the most important factor in determining the exact pathologic picture observed with the organisms is the ability of the particular host to generate an inflammatory response. For example, depending on the level of cell-mediated immune response possible, the pathologic pattern may range from a fully developed granulomatous response to the presence of organisms in the lung without any inflammatory response. Hence, when an etiologic diagnosis is not immediately apparent after careful examination of the biopsy material, a broad range of special stains and probes aimed at delineating specific organisms should be employed, recognizing that the more immunocompromised the individual, the greater the likelihood of an atypical pathologic response.95,97 2.2.6. Bronchiolitis Obliterans-Organizing Pneumonia The term “bronchiolitis obliterans-organizing pneumonia” (BOOP) encompasses a pathologic entity consisting of fibrous organization of an inflammatory exudate. As such, it is the end result of a variety of infectious and noninfectious inflammatory processes that affect the lung and is a not uncommon finding on biopsy, particularly if the biopsy is carried out relatively late in the disease process. Cultures are usually negative from tissue with this pathologic pattern. Since this pattern is a “final common pathway” for a variety of processes, this finding is of little use in terms of etiologic diagnosis and therapy, although the extent of the fibrotic reaction may have

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important prognostic implications as to the reversibility of the pulmonary injury.95,97,99

2.3. Clinical Clues to the Diagnosis of Pulmonary Infection An important component in constructing a differential diagnosis for an immunosuppressed patient with possible pneumonia is an understanding of the “temporal” aspects of the underlying disease. That is, whether the patient’s immunocompromised state is due to antileukemia chemotherapy or HIV infection or cyclosporinebased immunosuppression postorgan transplantation, the duration of the immunosuppressed state is an important determinant of what microorganisms are likely to be present; there is a timetable for each type of patient that defines when in the postimmunosuppressed state different microbes are likely to invade the lung (exceptions to the timetable usually are due to unusual environmental exposures within the hospital).29 Thus, patients with acute leukemia who have pneumonia on first presentation almost assuredly have either bacterial infection or leukemic infiltrates rather than opportunistic infection and almost never require a lung biopsy before initiating effective antimicrobial therapy. In contrast, this same patient with fever and pneumonitis after 3 weeks of chemotherapyinduced neutropenia and broad-spectrum antibacterial therapy is at high risk for invasive fungal infection. Thus, the understanding of the expected timetable of infection for each of the immunocompromising illnesses (see Chapters 13–17) can play an extremely useful role in constructing the differential diagnosis. Perhaps the most useful clue to the correct diagnosis in patients with the febrile pneumonitis syndrome comes from an assessment of the mode of onset and rate of progression of the pulmonary process. Thus, an acute onset over less than 24 hr of symptoms severe enough to bring the patient to medical attention would suggest conventional bacterial infection (and, of the noninfectious causes, pulmonary embolic disease, pulmonary edema, a leukoagglutinin reaction, or pulmonary hemorrhage). A subacute onset over a few days to a week would suggest viral or Mycoplasma infection, Pneumocystis, or in some instances Aspergillus, Nocardia, or Rhodococcus. A more chronic course over one or more weeks would suggest fungal, nocardial, rhodococcal, or tuberculous infection (as well as tumor or radiation or drug-induced pneumonitis). When the mode of clinical presentation is combined with the radiologic finding, the range of etiologic possibilities becomes considerably smaller and much more manageable for the clinician (Table 3).2,3

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25 organ transplant recipients with primary fungal or nocardial pulmonary infections, all but 2 had a value of >70 mm Hg. Both exceptions had concomitant congestive heart failure and chronic obstructive pulmonary disease to explain their low values.2,3 The hypoxemia in patients with acute bacterial and viral infection and the noninfectious causes of the febrile pneumonitis syndrome results from a large shunt combined with regions of low ventilation–perfusion (V/Q) ratios in the involved lung tissues. Maintenance of the in the fungal, nocardial, tuberculous, rhodococcal, and presumably tumor patients appears to be due to diversion of obstructed blood flow to the involved lung, thus minimizing V/Q mismatch. The pathogenetic mechanism for this obstruction may be thrombosis, vascular obstruction, direct invasion of the blood vessels, or a strong, unopposed reflex arteriolar vasoconstriction in response to regional alveolar hypoxia.2,3

3. Overview of Noninfectious Causes of the Febrile Pneumonitis Syndrome

Additional useful information may also be obtained by measuring the arterial partial pressure of oxygen while the patient is breathing room air. Most of the disease processes that cause the febrile pneumonitis syndrome in the compromised host are associated with significant impairment in oxygenation early in the clinical course (room air By contrast, most patients with pulmonary disease caused by fungi, tuberculosis, Nocardia, Rhodococcus, and tumor will have relatively well-maintained oxygenation (room air until very late in the course, despite extensive consolidation on chest radiography. Although a rare patient with these forms of infection will have an acute overwhelming pneumonia resembling conventional acute bacterial infection in both clinical presentation and arterial blood gas findings, the great majority will have subacute or chronic presentations associated with wellpreserved oxygenation. For example, among more than

The occurrence of noninfectious forms of the febrile pneumonitis syndrome in the compromised host is determined by the underlying disease and how it is treated. Thus, in the patient with malignant disease, the major causes of this syndrome are radiation pneumonitis, druginduced pulmonary injury, parenchymal tumor invasion, and rarely an unusual form of alveolar proteinosis. In the organ transplant patient, in the patient receiving corticosteroids, and in other groups of patients immunocompromised by nonmalignant disease, the major considerations are pulmonary emboli and pulmonary edema. In the patient with HIV infection, noninfectious causes of pulmonary infiltrates of particular importance include Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and two unusual forms of interstitial lung disease of unclear etiology: lymphoid interstitial pneumonitis (particularly in children with AIDS) and nonspecific interstitial pneumonitis. AIDS patients also can develop drug-induced pulmonary disease as a consequence of the use of such drugs as bleomycin in the treatment of the secondary malignancies that can complicate the course of the AIDS patient (Table 4). In addition, critically ill patients with all forms of immunocompromise can develop ARDS as a result of systemic sepsis. Less commonly, any patient with a major clotting or platelet disorder can develop pulmonary hemorrhage and any transfused patient is at risk for the development of a leukoagglutinin reaction (Table l).3,5,8,10,11

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3.1. Radiation Pneumonitis Radiation lung injury is of two types: an acute form, radiation pneumonitis, which begins at the end of a course of radiation therapy or up to 6 months later, and a chronic form, radiation fibrosis, which may follow acute disease or begin without premonitory symptoms 6 or more months following the completion of therapy. Pathologically, radiation pneumonitis is characterized by the desquamation of bronchiolar and alveolar cells and by the formation of protein-rich hyaline membranes as a result of the exudation of plasma into the alveolar spaces through injured pulmonary capillaries. Engorgement and thrombosis of capillaries and arterioles are evident and the alveolar septa are thickened by lymphocytic infiltrates and immature collagen deposition. Changes in surfactant production and metabolism may be particularly striking during this phase of radiation injury. This exudative phase is manifested on CT scan by findings of a homogeneously increased attenuation that progresses over time to patchy and then more dense consolidation. Particularly in the early exudative phase, high-dose corticosteroid administration is associated with rapid resolution of these CT scan findings (although moderate doses of prednisone, 10–15 mm) include lobular nodular opacities and are often space-occupying, nonanatomic lesions with well-defined, more or less rounded edges surrounded by aerated lung. These are often seen in fungal infection. Occasionally, small, well-defined, peripheral consolidations may take on the appearance of macronodules. The nodules of Kaposi’s sarcoma are variable, ranging from sublobular to lobular and to macronodular size (Fig. 8). The peribronchial location of nodules in Kaposi’s sarcoma is a clue to their identity and interstitial location. 4. Other characteristics that should be looked for include pleural fluid, atelectasis, cavitation, lymphadenopathy, cardiac enlargement, and pericardial abnormality. Pleural fluid is a clue to congestive heart failure and fluid overload when bilateral and to necrotizing or granulomatous infection (or subdiaphragmatic inflammation), especially when associated with lymphadenopathy or cavitation, when unilateral. 5. In the case of pulmonary nodules seen on CT in the severely neutropenic transplant patient, a surrounding halo of ground-glass opacification is an important characteristic early CT lesion of invasive aspergillosis attributed to hemorrhage associated with local infarction2–5 (Figs. 9, 10), and an air crescent cavitation is an important characteristic CT lesion of late invasive aspergillosis attributed to ischemic necrosis6–8 (Fig. 11). The ground-glass halo is identified as a substantial surround of ground-glass opacity and should be differentiated from the faint indistinct margination that might be caused by technical volume averaging (Figs. 9, 10). An air crescent is identified by a distinct crescent of gas capping a ball of necrotic debris in a healing focus of invasive aspergillosis and needs to be differentiated from a thick-walled cavity lacking a distinct crescent (Fig. 11). 4.1. Correlation of Radiologic Findings, Rate of Progression, and Clinical Signs

By combining this classification of radiologic findings with information concerning the rate of progression of the illness (acute vs. subacute–chronic), as outlined in Table 3 (Section 2.3), a useful differential diagnosis is

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then generated. Thus, focal or multifocal consolidation of acute onset will quite likely be caused by bacterial infection; similar lesions with subacute-chronic histories are most likely secondary to fungal, tuberculous, or nocardial infections. Macronodules are usually a sign of fungal or nocardial disease, particularly if they are subacute in onset. Subacute disease with diffuse abnormalities, either of the peribronchovascular type or miliary micronodules,

are often caused by viruses or Pneumocystis (although in the AIDS patient, disseminated tuberculosis and systemic fungal infection are also considerations). As noted in Table 3, noninfectious causes are added to the differential diagnosis when the history is appropriate, the radiologic findings are consistent, and ancillary radiographic signs (such as hilar adenopathy in patients with Hodgkin’s disease) are present.2,3

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Additional clues can be found by examining the pulmonary lesion for the development of cysts or cavitation or by carefully delineating the location of the opacity or opacities. Cavitation suggests necrotizing infection such as that caused by fungi, Nocardia, Rhodococcus,

certain gram-negative bacilli (most commonly Klebsiella and Pseudomonas), and Staphylococcus aureus, or necrotic tumor.2,3,95,245,246 Atypical upper lobe cysts may be found in AIDS patients treated with inhaled pentamidine who develop Pneumocystis carinii pneumonia (Fig. 12).

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In an appropriate setting, air crescent cavitation may suggest late invasive aspergillosis. The best clues to the radiologic diagnosis of radiation pneumonitis are the timing of onset with respect to radiation treatment and the location and configuration of

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the pulmonary infiltrate, which is almost always confined to the outlines of the radiation portals. Thus, the diagnosis of radiation pneumonitis should be suspected when imaging demonstrates an infiltrate (particularly a peribronchovascular one) with relatively sharp margins that do not

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correspond to the bronchopulmonary anatomy but adjoin the edges of the radiation field (Fig. 3). Changes that occur outside this area should be minor. Since many cases of radiation pneumonitis follow mediastinal irradiation, the infiltrates are often central in location, in contrast to the usual peripheral location of most other processes that affect this population.100–104,108,124 The depressed inflammatory response of the immunocompromised host may greatly modify or delay the

appearance of a pulmonary lesion on images. This depression is most frequently seen in patients with severe neutropenia (particularly those with an absolute granulocyte 247–249 but is also seen with steroid count 250 treatment. When such severe neutropenia is present, atelectasis may be the only radiologic clue to the presence of clinically important pulmonary infection. In particular, radiologic evidence of fungal invasion, which normally excites a less exuberant inflammatory response than does

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bacterial invasion, will often be very slow to appear. By contrast, in patients recovering from neutropenia there may be a paradoxical increase in the radiologic findings (and sputum production) as the granulocyte count recovers, despite a good clinical response to antimicrobial therapy.247–249 CT of the chest has revolutionized the evaluation of the immunocompromised host with the febrile pneumonitis syndrome. This has become even more true as technical advances have resulted in more rapid acquisition of higher-quality CT images, thus reducing breathing artifacts associated with tachypnea. Although conventional chest radiography remains the first procedure for evaluating immunocompromised patients for possible pulmonary disease, the high sensitivity and precise anatomic localization possible with CT scanning can result in earlier localization, diagnosis, and treatment. Thus, CT provides a greater chance of survival from opportunistic infection.251,252 CT is more sensitive and effective than chest radiography in diagnosing disease in the immunocompromised patient.253 It is especially useful when the chest radiograph is negative and when the radiographic findings are subtle or nonspecific. Since localizing pulmonary symptoms are often absent, CT is a great aid in localizing disease for biopsy. CT can be more specific than radiography in the diagnosis of opportunistic infection. For example, under appropriate clinical circumstances, the CT halo sign often can differentiate nodules caused by Aspergillus species from infections caused by conventional bacterial or viral species9,254 (Fig. 10). Similarly, high-resolution CT can be extremely useful in the

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evaluation of patients with possible Pneumocystis infection.255 Thus, CT is now of primary importance in the evaluation of the immunosuppressed patient in the following situations: 1. In the evaluation of febrile, severely neutropenic patients with negative or subtle chest radiographic findings, CT is far more sensitive in the detection of potentially treatable opportunistic infection, particularly that due to fungal pathogens such as Aspergillus. Intrathoracic complications of bone marrow transplantation, for instance, are found with CT in 57% of patients with clinical symptoms and negative radiographs.256 Thus, CT has become the established imaging method of choice for the diagnosis of occult or subtle disease because of the limited sensitivity of conventional radiography, especially when the inflammatory response is impaired by severe neutropenia. 2. Similarly, equivocal chest radiographs of patients receiving exogenous immunosuppressive therapy (e.g., organ transplant patients) are best reevaluated with chest CT. For example, we have seen a number of patients with pulmonary nodules due to such organisms as Cryptococcus neoformans that were clearly seen on chest CT evaluation after no abnormality or very minimal findings were detected on chest radiography (Fig. 13). Cure of such individuals is far more easily accomplished by the earlier diagnosis afforded by CT than after systemic dissemination and CNS seeding has occurred by which time radiography may have become positive. Nodules detected with CT are suggestive of fungal, nocardial, rhodococcal,

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or tuberculous infection in the transplant patient. By the time conventional radiography becomes definitely abnormal, the disease process is often far advanced. 3. In the AIDS patient, with a negative chest radiograph and a clinically compatible syndrome (e.g., nonproductive cough, fever, and hypoxemia), CT is of value

in detecting Pneumocystis carinii pneumonia. Since 10– 20% of Pneumocystis patients have normal chest radiographs, CT may be useful both in detecting subtle disease and in ruling out the possibility of this infection (Fig. 14) 255,257

4. Although an abnormal chest radiograph may lead

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to the diagnosis of infection, it greatly underestimates the extent of the disease process compared with CT. Particularly with opportunistic fungal and nocardial infection, precise knowledge of the extent of the infection at diagnosis and the response of all sites of disease to therapy will lead to the best therapeutic outcome. A general rule of thumb in the treatment of opportunistic infection in the immunocompromised host is that the best clinical results will be obtained if the clinician continues therapy at least

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until all evidence of clinical disease has resolved. This goal can best be achieved with CT guidance. 5. Since dual or sequential pulmonary infections are not uncommon in the immunocompromised host, more than one etiologic agent may be responsible for a given clinical episode.2,3,258,259 In patients who have responded slowly or poorly to what should be appropriate therapy, CT may provide clues that additional diagnostic possibilities should be considered. For example, in AIDS pa-

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tients with Pneumocystis pneumonia, characteristic CT and radiographic findings usually reflect the diffuse interstitial and alveolar abnormalities (Fig. 14). Since acinar and macronodular opacities are relatively unusual manifestations of P. carinii pneumonia,255,260 their identification in a patient not responding to appropriate therapy should raise the possibility of concomitant Kaposi’s sarcoma (Fig. 8) or infection with other agents (Fig. 15). In

particular, the identification of a thick-walled cavitary nodule is highly suggestive of a new or coexisting fungal or bacterial infection in the patient with microbiologically or pathologically confirmed P. carinii infection.7 6. CT also can help in defining which invasive diagnostic procedure is most likely to yield a diagnosis and where the disease is most likely to be found for successful biopsy.7 CT can provide precise guidance for percutane-

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ous needle biopsy, thoracoscopic, or open lung excision in the case of peripheral lung nodules.261 CT also is the best means of predicting whether bronchoscopy is likely to be the most appropriate diagnostic modality for a particular patient. Thus, in patients with pulmonary nodules, CT demonstration of the feeding bronchus correlates with a 60% diagnostic yield with bronchoscopy, as opposed to a 30% yield if this finding is not present.262 If CT demonstrates centrally located diffuse opacifications, a bronchoscopic approach is the modality of choice for diagnosis.263 7. CT also can narrow the differential diagnosis in the patient with suspected opportunistic infection. Cavitary CT lesions are suggestive of infections with Nocardia, Rhodococcus, Cryptococcus, and Aspergillus. Opacified secondary pulmonary lobules in the lung periphery are suggestive of bland pulmonary infarcts and of cavitated septic or hemorrhagic Aspergillus infarcts. Diffuse peribronchial opacities are suggestive of fluid overload and graft-versus-host disease (Fig. 16). Dense regional or lobar consolidation on CT is most suggestive of bacterial pneumonia or fungal infection (Fig. 1). Apical cystic CT lesions are suggestive of P. carinii pneumonia, especially in AIDS patients treated with prophylactic aerosolized pentamidine.264 High-resolution CT can aid in differentiating between apical lung opacities that are due to M tuberculosis scars and benign apical “cap.”265

4.2. Radiologic Aspects of Thoracic Disease in AIDS Patients

Since the early days of the HIV epidemic, pulmonary disease has been recognized as a major cause of morbidity and mortality. Prior to the advent of Pneumocystis prophylaxis, 70% of patients had Pneumocystis pneumonia as their AIDS defining illness, with Pneumocystis also being the most common cause of death. Two major advances in the care of AIDS patients have markedly changed the nature of the intrathoracic complications observed: The first of these was the widespread deployment of anti-Pneumocystis prophylaxis, resulting in a significant decrease in the incidence of this infection. The second advance was the development of highly active antiretroviral therapy (HAART), which has greatly improved the prognosis for HIV-infected individuals, with a corresponding fall in all forms of pulmonary infection in these patients. The three most common causes of respiratory infection in patients with HIV infection are acute bronchitis (~13 episodes/100 patient years), bacterial pneumonia (~5 episodes/100 patient years), and P. carinii (~5 episodes/100 patient years). When one follows HIV patients over a 5-year period, there is a gradual increase in the incidence of both bacterial pneumonia and Pneumocystis (from 3–4 in the first year to 7–10 episodes/100 patient years in the fifth year), as well as other opportunis-

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tic infections and tuberculosis. Not surprisingly, the nature of the pulmonary infection occurring can be correlated with the CD4 count of the patient: acute bronchitis being the predominant lower respiratory infection of a cohort of patients who enter with a CD4 in members of the cohort with CD4 acute bronchitis, bacterial pneumonia, and Pneumocystis all occurred at high rates.267 Once either bacterial pneumonia or Pneumocystis pneumonia occur, the mean survival rate is approximately 2 years.268 Other causes of pulmonary disease in AIDS patients include mycobacterial infection, Kaposi’s sarcoma, fungus infection, lymphoma, and lymphocytic interstitial pneumonitis. Other less common AIDS-related conditions include septic and nonseptic pulmonary emboli and viral infection, particularly that due to CMV and herpes simplex virus.7,269 Typical radiologic findings in AIDS patients with these conditions are presented in Table 5. 4.2.1. Pneumocystis carinii Pneumonia

The two factors that determine risk of Pneumocystis infection in HIV-infected individuals are CD4 count and whether or not effective anti-Pneumocystis prophylaxis is being administered. This infection is quite uncommon with a CD4 With patients not receiving prophylaxis, the median CD4 count of those developing while for those receiving pro266,270,271 phylaxis the median The disease most often presents as diffuse, perihilar, bronchovascular lung opacities, but focal and multifocal opacities also occur. The radiographic findings are often quite subtle in the early stages of the disease and may be

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overlooked if the AIDS history is unknown or if no prior chest radiographs are available for comparison. Approximately 10–20% of Pneumocystis infections are totally occult by conventional radiography.272 CT is not generally required or employed to make the diagnosis in typical cases. However, when radiographic findings are absent, CT may demonstrate more typical or extensive diffuse ground-glass lung opacities characteristic of P. carinii pneumonia. In more chronic Pneumocystis infection, or at the conclusion of therapy, CT may show evidence of pulmonary fibrosis and septal lines.273 Atypical findings of Pneumocystis in AIDS patients include focal lung opacities, cavities, miliary nodules, and very rarely intrathoracic lymphadenopathy and pleural effusions.260,274 Radiographic detection of pleural effusion and intrathoracic lymphadenopathy, however, are not characteristic of Pneumocystis,275 but massive pleural effusion and massive lymphadenopathy have been rarely reported.276,277 Small pleural effusions and small intrathoracic lymph nodes are more likely to be detected with CT.278 Pneumocystis pneumonia often presents as apical lung opacities with cysts or cavities in those previously treated with aerosolized pentamidine (Fig. 8).279 The cavities and subpleural cysts tend to have thicker walls than true subpleural areas of emphysema.279–281 Some Pneumocystis patients may first present with pneumothorax.282–284 Rarely, Pneumocystis pulmonary lesions have been described to increase off steroids and to decrease if steroids are reapplied.250 Gallium-67 lung uptake in AIDS-related Pneumocystis pneumonia is usually diffuse and intense, while thallium lung uptake is negative. Calcifications in affected abdominal viscera may be seen with CT after treatment for Pneumocystis pneumonia.277 Although

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magnetic resonance imaging (MRI) has not yet established itself as an important diagnostic modality in Pneumocystis, higher total T1 and T2 signal has been found in patients with Pneumocystis when compared with normals.285 In order of frequency, CT images of Pneumocystis pneumonia can show diffuse opacification, patchy opacities with spared regions, and focal peripheral opacities. Pneumocystis pneumonia often heals with pulmonary fibrosis, cystic spaces, and zones of emphysema, especially in the upper lung zones.252 Radiographic and CT images of CMV pneumonia are indistinguishable from those of Pneumocystis. 4.2.2. Mycobacterial Infection Tuberculosis is an infection of great importance in the AIDS patient. In these individuals, tuberculosis is most often the result of reactivation of a dormant focus, but the radiologic appearance more closely resembles that of primary tuberculosis. Thus, tuberculosis in AIDS patients more often presents with intrathoracic lymphadenopathy, miliary lung nodules, pleural fluid, and extrapulmonary disease, rather than the apical consolidation and cavitary disease characteristic of reactivation disease.286–288 Once again, CD4 count can be used to stratify the appearance of tuberculosis, with being associated with the miliary form of the disease and higher counts with more typical reactivation disease.266 Approximately 85% of AIDS patients with tuberculosis have abnormal chest radiographs.289 Tuberculosis and infection with atypical mycobacteria are by far the most common infectious causes of intrathoracic lymph node enlargement in the AIDS patient (Fig. 10). Hilar and mediastinal lymphadenopathy may be evident on conventional radiographs, but CT is significantly more sensitive. Enlarged intrathoracic lymph nodes with low CT attenuation centers and enhancing rims are characteristic of tuberculosis,290 but are occasionally observed in patients with disseminated fungal infection. The low CT attenuation of tuberculous lymph nodes is different from the higher attenuation of enlarged nodes in Kaposi’s sarcoma and lymphoma. Gallium-67 uptake in the lung tends to be more patchy and less intense than in Pneumocystis. Atypical mycobacterial infection of the lungs, especially with Mycobacterium avium-intracellulare (MAI), occurs in the AIDS patient but is much less common than pulmonary infection with M. tuberculosis and tends to occur late in the course of AIDS, tending to occur in the AIDS patient with a CD4 MAI infection, unlike M. tuberculosis, usually has a gastrointestinal portal of entry and is disseminated by the time it is first

detected in the chest. Radiologic findings are not distinguishable from disseminated M. tuberculosis infection and include intrathoracic adenopathy and miliary nodules or tree-in-bud opacities (Fig. 2).10,291 Other atypical mycobacterial infections of the lungs, including the newly described M. celatum292 occasionally can be seen in patients with advanced AIDS. 4.2.3. Pyogenic Bacterial Pneumonia As previously stated, community-acquired bacterial pneumonia is common in AIDS and is most commonly due to Streptococcus pneumoniae, Haemophilus influenzae, and in the late stages of disease a variety of gramnegative organisms, including Pseudomonas aeruginosa.266 Of importance, prophylaxis for Pneumocystis with trimethoprim–sulfamethoxazole and for MAI with azithromycin or clarithromycin is associated with a lower risk of bacterial pneumonia.293 The radiologic manifestations of bacterial pneumonia are similar in AIDS and nonAIDS patients, with pulmonary lesions that are likely to be focal, consolidative, cavitary, and associated with pleural fluid. However, bacterial pneumonia can present with regional or even diffuse interstitial-appearing opacities that can mimic Pneumocystis.294 Under appropriate therapy, bacterial infections are much more likely to clear within 3 weeks than is Pneumocystis. Gallium-67 uptake in the lung is less likely to be positive in bacterial pneumonia. 4.2.4. Kaposi’s Sarcoma of the Lung Kaposi’s sarcoma involves the lung in about one fifth of AIDS patients with skin lesions. The lesions tend to be diffuse interstitial or airspace opacities and associated with small peribronchial nodular opacities.295 The peribronchovascular lung lesions are often associated with subpleural nodules that are particularly well seen on CT (Fig. 8).296 The lesions can simulate lymphatic spread of tumor. Asymptomatic lung lesions of Kaposi’s sarcoma are often found at postmortem examination in AIDS patients with normal chest radiographs.297 Hilar lymph node enlargement and pleural effusions are common accompaniments of lung lesions. When the mucosa of the tracheobronchial tree is involved, atelectasis may develop.298 The lymph nodes harboring Kaposi’s sarcoma tend to take up thallium.299 When AIDS patients with Kaposi’s sarcoma of the skin develop diffuse lung opacities, gallium scanning can be helpful in differentiating between Pneumocystis and Kaposi’s sarcoma of the lung. The lung lesions of Kaposi’s sarcoma do not take up

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gallium, while the lungs of patients with Pneumocystis pneumonia avidly take up the gallium.257 4.2.5. Fungus Infection of the Lung

The most common fungal agent invading the lungs of the AIDS patient (other than Pneumocystis, which is now classified as a fungus) is Cryptococcus neoformans (Fig. 9). Other fungi that commonly affect the lungs of AIDS patients include Aspergillus species, Histoplasma capsulation, and Coccidioides immitis (these last two being relatively common in the geographic regions where this fungus grows in the soil, e.g., the midwestern section of the United States for Histoplasma and the southwestern section of the United States for Coccidioides). In a substantial minority of patients ~25%) disseminated fungal infection is first discovered in the lungs, especially when CT scanning is employed.300 In cryptococcal disease, chest radiographs usually are negative or reveal focal disease, with or without cavitation.301 Diffuse lung disease is often found in patients with H. capsulatum infection. Aspergillus species tend to cause lung infection late in the course of AIDS and are not as common in AIDS as in other immunocompromised patients (e.g., transplant patients, patients with neutropenia, patients receiving prolonged courses of corticosteroids). Radiographs of pulmonary fungal infection can reveal consolidations, nodules, nodules with halos, cavities, cavities with air crescents, and pleural effusions. In AIDS patients, Aspergillus infections produce varied imaging findings, including upper lobe cavities similar to tuberculosis, pleural-based lung nodules and infarcts, and diffuse infiltrates.302 4.2.6. Lymphoma of the Lung

A small but important group of AIDS patients develop B-cell or other forms of non-Hodgkin’s lymphoma in the central nervous system and/or abdominal viscera. The lesions tend to occur as macronodules in the lung parenchyma, often in association with pleural fluid.303 Lymphoma in AIDS patients causes enlargement of mediastinal and hilar lymph nodes only rarely.272,304,305 Lung involvement and pleural effusions are more common in AIDS-related lymphomas than in non-AIDS lymphomas. CT is extremely useful in detecting the focal or multifocal solid lung masses of AIDS-related lymphomas of the lung.306 Nuclear scanning is said to differentiate among pulmonary infection, lymphoma, and Kaposi’s sarcoma.299 In infection the 3-hr delayed thallium scan is negative, while the gallium scan is positive in the lungs. In lym-

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phoma of the lung, both thallium and gallium scans are positive. In Kaposi’s sarcoma, the thallium scan is positive, while the gallium scan is negative. Lymph node uptake of gallium is avid in mycobacterial infection and lymphoma.306 Potential causes of lymphadenopathy in the AIDS patient include follicular hyperplasia, nonHodgkin’s lymphoma, mycobacterial infection, metastatic cancer, Kaposi’s sarcoma, multiple infectious agents, and drug-induced disease (e.g., that due to trimethoprim– sulfamethoxazole).307 By far the most common cause of radiologically identifiable lymph node enlargement in the AIDS patient is tuberculosis. High CT attenuation of enlarged lymph nodes in AIDS is suggestive of Kaposi’s sarcoma. Low CT attenuation of enlarged lymph nodes is more often associated with mycobacterial infection.308 4.2.7. Lymphocytic Interstitial Pneumonitis

Lymphocytic interstitial pneumonitis is not uncommonly found in pediatric patients with AIDS. The lung lesions tend to be nonspecific linear interstitial opacities admixed with patchy areas of airspace consolidation. In contradistinction to Pneumocystis, gallium uptake in the lung is mild or negative in AIDS-related lymphocytic interstitial pneumonia.257,306

5. Specific Diagnosis

The effective therapy of the febrile pneumonitis syndrome in immunocompromised patients requires rapid and precise diagnosis. Although the diagnostic clues discussed thus far may greatly limit the differential diagnostic possibilities, the specific diagnosis should be sought whenever possible. An aggressive approach to diagnosis will limit drug toxicity and the risk of potentially lethal superinfection without exposing the patient to potentially inadequate therapy. Not surprisingly, several studies have shown that the rapidity with which the diagnosis is made has a major impact in determining the outcome of therapy, whether one is dealing with a noninfectious disease, a conventional bacterial infection, or invasive fungal, nocardial, or rhodococcal disease. 1–3,140,177,309 Therefore, great emphasis must now be placed on the techniques available for making a precise diagnosis: immunologic studies, conventional examination of expectorated or induced sputum specimens, and a variety of invasive procedures designed to sample either lower respiratory tract secretions or lung tissue or both. Indeed, it is largely the skill of the clinician in utilizing the specific diagnostic techniques available that will determine the rate of sur-

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vival in immunocompromised patients with the febrile pneumonitis syndrome. As we discuss this aggressive approach to diagnosis, we also must emphasize that the clinician must constantly keep in mind both the risks and the benefits that are involved. The critical question that must be asked before undertaking any invasive procedure in this patient population is what is the likelihood that this procedure will result in a major change in therapy and prolongation of patient survival. Thus, invasive procedures are rarely indicated in patients with advanced leukemia, AIDS, or metastatic cancer. On the other hand, an aggressive approach for precise diagnosis is clearly indicated in organ transplant recipients, patients with treatable Hodgkin’s disease or other forms of cancer with a reasonable expectation of a meaningful response to therapy, and patients with such conditions as collagen vascular disease or inflammatory bowel disease being treated with immunosuppressive therapy. In addition to the ethical considerations involved in this distinction between these two groups of individuals, the practical matter is that the diagnostic yield of invasive procedures is much higher in the second group of patients. In the poor-prognosis patient, even open lung biopsy may not lead to any diagnosis in as many as 20% of patients and in others the findings may include diagnoses such as hemorrhage, tumor, and bronchiolitis obliterans that do not lead to effective therapy. Therefore, risk–benefit analysis must be a careful part of the clinician’s diagnostic approach to the febrile pneumonitis syndrome in the immunocompromised patient.1–3,5,10

develop a positive HIV antibody test until more than 2½ years later, at which time he already had overt AIDS.306 In contrast to the lack of sensitivity of the antibody response in diagnosing clinical disease, a variety of antibody measurements are helpful in predicting the risk of disease if exposed: Thus, a negative test for circulating antibody to Toxoplasma gondii is very useful in ruling out the possibility of encephalitis due to this organism in AIDS patients, as well as in predicting susceptibility to systemic toxoplasmosis and the need for prophylaxis in a recipient of a cardiac allograft from a seropositive donor. Similarly, a negative antibody test for varicella zoster virus in an immunocompromised individual delineates an individual very susceptible to disseminated visceral infection on exposure to this virus. Finally, the attack rate for clinical disease due to CMV in transplant patients can be predicted by knowing the antibody status of the donor and recipient (see Chapters 17 and 18). 2. Since many of the opportunistic infections that cause life-threatening disease in the compromised host cause asymptomatic subclinical infection in the normal population, the presence of a positive result may have little meaning. The classic examples of this phenomenon are the many attempts to make the diagnosis of invasive candidiasis or aspergillosis on the basis of the presence of precipitating or agglutinating antibodies directed against these organisms. It is now clear that because of the failure of development of such antibodies in many compromised patients and because of their presence in many normals, these tests are of limited diagnostic value.307–309 3. Appropriate serologic or skin tests are not available for many of the disease processes under consideration.

5.1. Immunologic Techniques for Specific Diagnosis Measurement of antibody and delayed hypersensitivity skin test responsiveness to microbial antigens are time-honored techniques for diagnosing invasive infection. However, such methods have limited applicability when caring for immunosuppressed patients with the febrile pneumonitis syndrome, for several reasons: 1. Even under the best of circumstances in the normal host, there is a delay between the onset of infection and the development of a measurable immune response. In the immunocompromised patient, such responses may be further delayed or totally abrogated. To wait for the development of such a response can interfere greatly with the need and desire to arrive at a rapid diagnosis. For example, we have cared for a liver transplant patient who contracted HIV infection at the time of transplantation (prior to the availability of HIV testing) but who did not

Therefore, the effectiveness of such traditional immunologic techniques for diagnosis has been disappointing. Antibody testing has been useful in patients with histories of possible exposure to Coccidioides immitis or Histoplasma capsulatum, in whom the demonstration of elevated or rising titers of complement-fixing antibody is an excellent clue to the presence of active infection with these agents (see Illustrative Case 3 and Chapter 6). 5.2. Sputum Examination The usual clinical approach to the diagnosis of pneumonia is based on the Gram’s stain and cultural examination of expectorated sputum specimens. It should be emphasized that strict criteria should be employed when viewing the Gram’s stain of an expectorated sputum specimen before trusting the validity of the specimen: few

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squamous epithelial cells (25 per lowpower field). If such criteria are not met, the validity of the specimen is in question. For a variety of reasons, such an approach is often of little diagnostic value in the compromised patient. First, many of these patients, particularly those with significant leukopenia, fail to produce sputum.12,13,310–313 Second, the upper respiratory tract of many of these patients is frequently colonized with a large number of potential pathogens, particularly gram-negative bacilli and fungi. Expectorated sputum specimens therefore will be contaminated by these potential pathogens and differentiation between organisms truly invading the lung and those that colonize the pharynx may be quite difficult. Third, certain organisms that commonly cause pneumonia in this population, particularly the fungi, rarely shed sufficient organisms into the sputum to permit diagnosis by cultural or microscopic examination. Finally, the noninfectious causes of pulmonary infiltrates will not be diagnosed by examination of expectorated sputum specimens. Therefore, although the clinician should always initiate the diagnostic evaluation of the patient with possible pneumonia by an examination of an expectorated sputum specimen, more invasive diagnostic procedures are usually necessary. Because of the large number of AIDS patients presenting with possible P. carinii pneumonia and the need for noninvasive tests for diagnosis, attention has been focused on the examination of induced sputum. Provided skilled respiratory therapists are carrying out the sputuminduction procedure and equally skilled microbiologists are evaluating the material obtained, the diagnostic yield can be high. Thus, in AIDS patients, approximately two thirds of Pneumocystis pneumonias can be diagnosed following staining with Giemsa and other conventional stains. When immunofluorescent staining utilizing a monoclonal antibody specific for P. carinii is used, sensitivity and specificity of greater than 90% can be obtained. One caution must be noted, however. Because the organism burden is far greater in AIDS patients with Pneumocystis pneumonia than in other immunocompromised patients such as transplant or lymphoma patients with this infection, the sensitivity of this procedure is considerably less (at least 25% less in our experience) in these other patient groups.314–317 With the increased ability to carry out inducedsputum examinations, many centers are looking to utilize this procedure in the diagnosis of other forms of pneumonia, particularly those due to bacteria and fungi. Although precise data regarding sensitivity and specificity for other infections in different patient populations are not

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currently available, there is general agreement that examination of an induced-sputum specimen is an improvement over conventional expectorated-sputum examination. Indeed, it has largely replaced transtracheal aspiration in the initial evaluation of patients with pneumonia of unclear cause. Problems with the transtracheal approach have included hemorrhage, cervical cellulitis, and oropharyngeal contamination (particularly in nonexpert hands).5,318 This having been said, however, it is fair to say that in the hands of an experienced operator, transtracheal aspiration can be particularly useful in the evaluation of the occasional patient with possible bacterial infection, particularly anaerobic bacterial infection, provided the following guidelines are followed2,3,319,320: 1. There are three absolute contraindications to transtracheal aspiration: (a) an uncooperative patient, (b) a patient with unsuitable anatomic characteristics (such as an obese person, a child, or one who has undergone surgery or radiation therapy of the neck) that make the procedure technically difficult, and (c) those with uncorrectable bleeding diatheses. 2. In the process of anesthetizing the area over the cricothyroid membrane where the lavage needle and catheter will be inserted, a small 25-gauge needle is employed both to deliver the local anesthesia and to delineate the track that the larger needle will follow. 3. In neutropenic patients, broad-spectrum antibacterial therapy is initiated immediately after the procedure and continued for a minimum of 48 hr postprocedure. 5.3. Invasive Diagnostic Techniques

If the diagnosis has not been made by sputum examination, a more invasive procedure in which direct sampling of lower respiratory secretions, pulmonary tissue, or both may be accomplished is then required. The choice of procedure is dependent on several factors: the patient’s degree of illness, the rate of progression of the disease, the type of imaging rinding, and the relative expertise and experience of personnel at the institution. If the presumed pneumonitis and the degree of hypoxia are progressing rapidly, the definitive diagnostic procedure—the open lung biopsy—should be carried out immediately. This urgency is particularly true when the imaging pattern is nonspecific and diffuse or multifocal. Despite the need for general anesthesia, thoracotomy, and a postoperative chest tube, it is remarkable how well this procedure is

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tolerated, especially if the treatable process is identified. Increasingly, video-assisted transthoracoscopic biopsy in skilled hands is proving to be a satisfactory alternative to the traditional open lung biopsy, with considerably less morbidity for the patient. If the pulmonary process is progressing at a more desultory pace, progressive hypoxia is not an immediate problem, and the clinical problem is more of a diagnostic dilemma than a therapeutic emergency, then less invasive techniques can be attempted, with the open or transthoracoscopic lung biopsy held in reserve if these techniques fail.3,5,318 5.3.1. Bronchoscopic Diagnostic Techniques

Fiberoptic bronchoscopy has become a cornerstone of invasive diagnostic studies in the immunocompromised host because it provides opportunities for bronchoalveolar lavage, transbronchial biopsy, bronchial brushing, and inspection of the anatomy of the tracheobronchial tree. Two cautions should be emphasized, however, regarding bronchoscopy in this susceptible patient population. First, even uncomplicated bronchoalveolar lavage will cause a fall in oxygen saturation of 5–10% during and immediately after the procedure, a decline that can be clinically significant in terms of the subsequent need for assisted ventilation.321 Second, particularly in the elderly debilitated patient, too much local anesthesia from the procedure will leave the patient with an impaired gag reflex that is inadequate to protect the airway from aspiration pneumonia. In addition, contamination of the diagnostic material obtained by the bactericidal anesthetic agents can lower the diagnostic yield.322–324 Fiberoptic bronchoscopy and the ancillary procedures it makes possible is the diagnostic procedure of choice in the immunocompromised patient with diffuse lung disease. Bronchoalveolar lavage by itself, which has the lowest rate of complications of any of the bronchoscopic procedures, is particularly useful in diagnosing P. carinii infection and pulmonary hemorrhage (>95% sensitivity in experienced hands) and is moderately effective in diagnosing cryptococcal pneumonia in the AIDS patient. In the transplant patient, the diagnostic yield of lavage for isolated cryptococcal nodules is far less (70% mortality with no or ineffective therapy).54 In the United States, herpes simplex encephalitis is thought to account for about 10– 20% of encephalitic viral infections of the CNS55; the majority of cases (94–96%) are caused by HSV-1. Herpes simplex encephalitis occurs throughout the year and in patients of all age groups53; Caucasians account for 95% of patients with biopsy-proven disease. HSV encephalitis does not appear to be more common in immunosuppressed patients, although its incidence may be increased among persons infected with HIV-1 (6% in one series).56 VZV causes two clinically distinct diseases: (1) varicella, characterized by a generalized vesicular rash that occurs in epidemics, and (2) zoster, a common reactivation infection usually seen in the elderly.57 Humans are the only known reservoir for VZV. Varicella is presumed to be transmitted via the respiratory route, with initial viral replication in the nasopharynx or upper respiratory tract.58 Varicella is endemic in the population, but becomes epidemic among susceptible individuals during the late winter and early spring; 90% of cases occur in children less than 10 years of age. The actual incidence of CNS complications during active varicella infection is unknown, although the observed incidence ranges from 0.1 to 0.75% in some series.59 Herpes zoster is a consequence of reactivation of latent VZV. Persons at greatest

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risk for developing herpes zoster, as well as those at increased risk for complications, are individuals with deficiencies in cell-mediated immunity.57 A direct correlation exists between cutaneous dissemination and the appearance of visceral complications, including meningoencephalitis.60,61 A variety of VZV-induced neurologic disorders have been described in AIDS patients, including multifocal leukoencephalitis, ventriculitis, myelitis, myeloradiculitis, and focal brain stem lesions.57 A multifocal VZV leukoencephalitis grossly resembling progressive multifocal leukoencephalopathy also has been described in patients with underlying malignancies.57,62 In general, the CNS complications of herpes zoster are associated with a higher morbidity and mortality than are those of acute varicella, possibly due in part to the patient’s advanced age and underlying disease status.59 CMV infections also are ubiquitous, although these viruses are highly species-specific, linked only to infection in humans. Most individuals experience CMV infection at some point during their lifetime; the prevalence of antibodies indicating infection increases with advancing age.63,64 Routes of transmission include sexual, salivary, close contact with an infected person excreting virus, parenteral via blood transfusion or organ transplantation, and transplacental leading to intrauterine infection.65,66 The most common form of CNS disease occurs early in life as a consequence of intrauterine infection; only 1% of newborns excrete CMV at birth, 10% of whom develop clinical evidence of disease. Immunocompromised patients (e.g., patients with AIDS or following bone marrow or organ transplantation) represent a common group that can present with life- and sight-threatening disease due to CMV67–69; CNS complications, however, are uncommon. In patients with AIDS, CNS infection with CMV results in two distinct neuropathologic patterns: microglial nodular encephalitis and ventriculoencephalitis.70 2.2.2. Clinical Presentation The majority of patients with biopsy-proven herpes simplex encephalitis present with a focal encephalopathic process characterized by altered mentation and decreasing levels of consciousness with focal neurologic findings (e.g., dysphasia, weakness, paresthesias) (Table 2).53,71 These patients nearly always present with fever and personality changes. Seizures, either focal or generalized, occur in approximately two thirds of patients with proven disease. The clinical course may evolve slowly or with alarming rapidity; progressive loss of consciousness leading to coma, unfortunately, is common. Although clinical evidence of a localized temporal lobe lesion often is

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thought to be herpes simplex encephalitis, a variety of other diseases can be shown to mimic this condition.72 Immunocompromised patients with herpes simplex encephalitis may develop a more diffuse nonnecrotizing encephalitis involving the cerebral hemispheres and brain stem.73 Several categories of CNS infection are caused by varicella virus. Cerebellar ataxia is the most common neurologic abnormality associated with varicella; the frequency of cerebellar dysfunction is approximately 1 in 4000 cases.57 Symptoms include nausea, vomiting, headache, nuchal rigidity, and ataxia; seizures are rare. The cerebellar manifestations of varicella are usually selflimited, resolving within several weeks. Meningoencephalitis or cerebritis is a less common but frequently more severe CNS complication of varicella.57 Neurologic symptoms may occur from 11 days before to several weeks after the onset of the varicella rash. Headache, fever, and vomiting often are accompanied by an altered sensorium; seizures occur in 29–52% of cases. Focal neurologic abnormalities include cranial nerve dysfunction, aphasia, and hemiplegia.60 Encephalitis is the most common CNS abnormality associated with herpes zoster. It is seen most commonly in patients of advanced age, in patients following immunosuppression, and in patients

with disseminated cutaneous zoster.57,74 Altered mentation without other explanation in patients with either localized or disseminated herpes zoster may be the sole manifestation; fever may not be present. Other symptoms and signs include hallucinations, meningismus, ataxia, seizures, and motor paralysis. A distinctive CNS process that sometimes is seen in cases of ophthalmic zoster is contralateral hemiplegia57; it accounts for up to one third of cases of CNS abnormalities in herpes zoster. In typical cases, zoster ophthalmicus precedes the appearance of hemiplegia by several weeks or more,75 although the onset of hemiplegia may be as late as 6 months after the rash has resolved.76 CNS complications due solely to CMV infection are uncommon and usually manifest as meningitis, encephalitis, or meningoencephalitis. A form of CNS disease also occurs in the immunocompromised host following organ transplantation (usually documented on postmortem examination of brain tissue)77,78 and in patients with AIDS.79,80 CMV encephalitis in AIDS usually presents in a subacute or chronic course, with cortical dysfunction leading to confusion, disorientation, and perhaps seizures81; if present, brain stem lesions may produce focal signs. In patients with necrotizing ventriculoencephalitis, a rapidly fatal form of CMV encephalitis, cranial nerve defects, nystagmus, and cognitive disturbances (mental slowness and memory deficit) often are observed.70,82 2.2.3. Diagnosis

The diagnosis of herpes simplex encephalitis is established by brain biopsy, which currently remains the most specific means of diagnosis. However, proper localization of the major disease focus by clinical, electrical, and radiographic techniques is mandatory before a biopsy is attempted. In the early stages of herpes simplex encephalitis, congestion of capillaries and other small vessels in the cortex and subcortical white matter is evident, as are petechiae.83,84 Perivascular cuffing becomes prominent in the second and third weeks of infection. The microscopic appearance then becomes dominated by evidence of necrosis and inflammation, with widespread areas of hemorrhagic necrosis. The presence of intranuclear inclusions (Cowdry type A) supports the diagnosis of viral infection, but is found in only about 50% of patients. Immunofluorescence studies of brain tissue provide a rapid, sensitive, and reliable method for detecting herpes antigen, provided that sufficient antigen is present in the specimen and nonspecific immunofluorescence can be minimized.85 Virus also can be isolated from brain biopsy specimens.86 The decision to perform a brain bi-

CENTRAL NERVOUS SYSTEM INFECTION

opsy in patients with presumed herpes simplex encephalitis is discussed in Section 2.2.4. CSF examination with routine studies in patients with herpes simplex encephalitis is nondiagnostic.53,87 The white cell count is invariably elevated (mean of in 97% of patients with brain-biopsy-proven disease, with a predominance of lymphocytes. The CSF protein is similarly elevated, averaging approximately 1.0 g/liter (100 mg/dl). The presence of red blood cells in CSF is not diagnostic for herpes simplex encephalitis, but suggests this diagnosis in the appropriate clinical setting. About 5–10% of patients with herpes simplex encephalitis have completely normal CSF on first evaluation. Routine attempts to isolate the virus from CSF are rarely successful (about 4% positive). An assay technique for the detection of HSV antigen in the CSF of patients with herpes simplex encephalitis has been developed and is 80% sensitive and 90% specific if performed within 3 days of the onset of illness.88 Recent studies suggest that detection of HSV DNA within CSF cells by the polymerase chain reaction (PCR) is highly sensitive and specific for the diagnosis of herpes simplex encephalitis.89 In one study, the sensitivity and specificity of PCR were 91% and 92%, respectively, in patients with biopsyproven disease90; the specificity would have been higher except that some tissue specimens were fixed in formalin, which killed infectious virus. PCR detection of HSV DNA in CSF has become the diagnostic procedure of choice in patients with herpes simplex encephalitis.53 Noninvasive neurodiagnostic studies may support a diagnosis of herpes simplex encephalitis. Electroencephalography (EEG) appears to be the most sensitive (about 84%) for diagnosis, exhibiting characteristic spike-andslow-wave activity and periodic lateralized epileptiform discharges (PLEDs), which arise predominantly over the temporal and frontotemporal regions91,92; the specificity of this test is only 32.5%, however. CT scans initially show low-density areas with mass effect localized to the temporal lobe, which can progress to either or both radiolucent and hemorrhagic areas93,94; these areas are seen in 50–75% of patients at some time during the illness. Magnetic resonance imaging (MRI) (with enhancement) demonstrates lesions earlier and is superior to CT in localizing these lesions to the orbital–frontal and temporal lobes.95,96 In varicella-associated cerebritis, the CSF is often abnormal, with a mild to moderate lymphocytic pleocytosis and elevated protein.57 The EEG usually is diffusely abnormal, although focal abnormalities may occur even without clinical seizure activity. Postmortem studies of the brain in fatal varicella cerebritis reveal a lack of distinctive histopathologic findings. There usually is dif-

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fuse cerebral edema; intranuclear inclusions rarely have been observed. In herpes-zoster-associated encephalitis, lumbar puncture frequently yields an abnormal CSF formula, with a lymphocytic pleocytosis, elevated protein, and normal glucose. It should be noted, however, that as many as 40–50% of patients with uncomplicated herpes zoster without CNS symptoms have a mild CSF pleocytosis or elevated CSF protein concentration.57 A diffuse slowing may be evident on EEG without detection of a specific abnormal focus.57,60 VZV has been cultured from brain and CSF in a number of cases of herpes-zosterassociated encephalitis,97–99 and viral inclusions in glial cells, neurons, and arteries of the brain are well described in fatal cases100; VZV antibodies and lymphocyte-associated VZV antigens also have been demonstrated in the CSF of these patients.98,101,102 In zoster ophthalmicus with contralateral hemiplegia, cerebral angiography often demonstrates unilateral arteritis or thrombosis of individual vessels75.76; CT may show evidence of cerebral infarction in some cases.103 The gold standard for the diagnosis of CMV disease in any site is isolation of the organism; however, it may take as long as 2–4 weeks before evidence of cytopathic effect is observed in cell culture systems. Even if brain biopsy specimens are obtained, they may not reveal typical CMV histopathology or a positive culture. Diagnosis of CNS infection caused by CMV is best made by PCR of CSF, which has a high sensitivity and specificity for CNS involvement.104–107 Focal abnormalities on CT also have been described in CNS infections caused by CMV,108 including one patient with a ring-enhancing lesion that proved to be a CMV abscess.109 2.2.4. Treatment The therapy of herpes simplex encephalitis has undergone a major evolution in recent years. The first antiviral drug available (in the late 1960s and early 1970s) was idoxuridine110–112; unfortunately, severe toxicity (bone marrow suppression and secondary bacterial infections) limited its usefulness.54 Later studies documented the efficacy of vidarabine in biopsy-proven herpes simplex encephalitis. Initial double-blind, placebo-controlled studies revealed that vidarabine decreased mortality in herpes simplex encephalitis from 70 to 28% 1 month after disease onset and from 70 to 44% 6 months later.113 A subsequent open, uncontrolled trial of nearly 100 patients with proven disease defined a long-term mortality rate of 40%.114 Younger patients (10 million population),176 the incidence of bacterial meningitis decreased dramatically as a result of a vaccine-related decline in meningitis caused by H. influenzae type B such that, in the United States, bacterial meningitis is now a disease predominantly of adults rather than infants and children. In the subgroup of patients 16 years of age and older, most cases of bacterial meningitis are caused by S. pneumoniae, N. meningitidis, and L. monocytogenes.177 The isolation of particular bacterial species varies depending on the patient’s age, underlying disease status, and other predisposing conditions. Haemophilus influenzae is a gram-negative bacillus

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that was previously isolated in 45–48% of all cases of bacterial meningitis in the United States175,178; this organism is now isolated in only 7% of cases.176 The overall mortality rate is 3–6%.175,176,178 The vast majority of cases previously occurred in children less than 6 years of age, with 90% of cases caused by capsular type B strains. The use of H. influenzae type B conjugate vaccines has reduced the incidence of H. influenzae type B meningitis more than 90% among infants and children.179,180 Haemophilus influenzae represents only about 5% of total CSF isolates after 6 years of age; isolation of the organism in this age group should suggest the presence of certain predisposing conditions such as sinusitis, otitis media, epiglottitis, pneumonia, head trauma with CSF leak, diabetes mellitus, alcoholism, splenectomy or asplenic states, and immune deficiency (e.g., hypogammaglobulinemia).181,182 Neisseria meningitidis is a non-spore-forming, oxidase-positive, gram-negative coccus that may appear as biscuit-shaped diplococci in clinical specimens. It most often causes meningitis in children and young adults in the United States, with an overall mortality rate of 3– 13%.175,176,178 Infection with the meningococcus may occur in epidemics (usually due to serogroups A and C), although in sporadic cases, serogroup B strains account for many isolates in this country. Serogroup Y strains may be associated with pneumonia. Several outbreaks of disease caused by serogroup C meningococci have been reported in the United States and Canada, with most caused by one strain of electrophoretic type 37 (ET-37) complex termed ET-15.183,184 Neisseria meningitidis infections are more likely in patients who have deficiencies of the terminal complement components (C5, C6, C7, C8, and perhaps C9),185 the so-called membrane attack complex, in which there is a greater than 8000-fold increased incidence of neisserial infection, although mortality rates from neisserial infections are lower than in patients with an intact complement system. Streptococcus pneumoniae is a non-spore-forming, nonmotile, gram-positive coccus that typically appears lancet-shaped in clinical specimens. Pneumococcal meningitis is now the most common etiologic agent of bacterial meningitis in the United States, accounting for 47% of total cases, with a mortality rate of 19–26%.175,176,178 Infection often is associated with distant or contiguous foci of infection (e.g., pneumonia, otitis media, mastoiditis, sinusitis, endocarditis). Serious infections with S. pneumoniae may be observed in patients with predisposing conditions such as splenectomy or asplenic states, multiple myeloma, hypogammaglobulinemia, and alcoholism.186,187 The pneumococcus is the most common

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CSF isolate in head trauma patients who have suffered basilar skull fracture with subsequent CSF leak.188 Other bacterial species are less common causes of bacterial meningitis, but may be more frequently observed in immunocornpromised patients. Meningitis due to Listeria monocytogenes, a gram-positive, catalasepositive bacillus, represents only about 8% of cases of bacterial meningitis in the United States, but carries a high mortality rate (15–29%).175,176,178 Infection with Listeria is more common in neonates, the elderly, alcoholics, cancer patients, and immunosuppressed adults (e.g., renal transplant patients). 189–193 Despite the increased incidence of Listeria infection in patients with deficiencies in cellmediated immunity, however, Listeria meningitis is infrequently found in patients with HIV-1 infection.194,195 In addition, up to 30% of adults and 54% of children and young adults who have listeriosis have no apparent underlying disease. Outbreaks of listerial infection, including meningitis, have been associated with the consumption of contaminated cole slaw, milk, and cheese, with sporadic cases traced to contaminated cheese, turkey franks, and alfalfa sprouts, pointing to the intestinal tract as the usual portal of entry.189,192,193 Aerobic gram-negative bacilli have become increasingly important as etiologic agents of meningitis.196,197 Klebsiella species, Escherichia coli, and Pseudomonas aeruginosa may be isolated from CSF of patients after head trauma, neurosurgical procedures, the elderly, immunosuppressed patients, and patients with gram-negative septicemia. Staphylococcus epidermidis is the most common cause of meningitis in patients with CSF shunts.198 Meningitis due to Staphylococcus aureus usually is found in the early postneurosurgical period as well as in patients with CSF shunts.199 Underlying diseases in patients with S. aureus meningitis also include diabetes mellitus, alcoholism, chronic renal failure requiring dialysis, and malignancies. The group B streptococcus (S. agalactiae) is a common cause of meningitis in neonates,200 but also occasionally is observed to cause meningitis in adults, especially in those more than 60 years of age; additional risk factors for group B streptococcal meningitis include diabetes mellitus, malignancy, alcoholism, hepatic failure, renal failure, and corticosteroid therapy.201,202 Rarely, meningitis due to Nocardia species has been reported. Nocardia are non-spore-forming, filamentous, gram-positive branching rods that are partially acid-fast. In a recent review of 28 patients who met the criteria for nocardial meningitis,203 predisposing conditions (immunosuppressive drug therapy, malignancy, head trauma, prior CNS procedures, chronic granulomatous disease, sarcoidosis) were noted in approximately 75% of cases.

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CNS disease is thought to occur via hematogenous dissemination from a primary site, usually the lungs. 3.1.2. Clinical Presentation The classic clinical presentation in patients with bacterial meningitis includes fever, headache, meningismus, and signs of cerebral dysfunction204–206; these are found in more than 85% of patients. The meningismus may be subtle or marked, or accompanied by either or both Kernig’s and Brudzinski’s signs207; however, these signs are elicited in only about 50% of adults with bacterial meningitis, and their absence does not rule out this diagnosis. Cerebral dysfunction is manifested by confusion, delirium, or a declining level of consciousness ranging from lethargy to coma. Cranial nerve palsies and focal cerebral signs are uncommon (10–20% of cases), while seizures occur in about 30% of cases. Cranial nerve palsies (especially involving cranial nerves III, IV, VI, and VII), when they occur, likely develop as the nerve becomes enveloped by exudate in the arachnoid sheath surrounding the nerve. Alternatively, cranial nerve palsies may be a sign of increased intracranial pressure. Focal neurologic deficits and seizure activity arise from cortical and subcortical ischemia and infarction, which is the result of inflammation and thrombosis of blood vessels, often within the subarachnoid space. Hemiparesis also may be a sign of a large subdural effusion, which arises when infection in the adjacent subarachnoid space leads to an increase in permeability of the thin-walled capillaries and veins of the inner layer of the dura. This effusion is usually a selflimited process in which the fluid in the subdural space is resorbed, although an enlarging effusion can lead to mass effect with resultant hemiparesis. Papilledema is rare (50%) in

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CSF; this finding is more common in neonatal gramnegative meningitis and in meningitis due to L. monocytogenes. Occasionally, patients may have very low CSF white cell counts despite high bacterial concentrations in CSF, a finding associated with a poor prognosis. Therefore, a Gram stain and culture always should be performed on CSF specimens even if the white cell count is normal. A CSF glucose concentration of less than 2.2 mmoles/liter (40 mg/dl) is found in about 60% of patients with bacterial meningitis and a CSF/serum glucose ratio of less than 0.31 in about 70% of patients.211 The CSF protein is elevated in virtually all cases of bacterial meningitis, presumably due to disruption of the blood–brain barrier. A recent analysis found that a CSF glucose of less than 1.9 mmoles/liter (34 mg/dl), a CSF/ blood glucose ratio of less than 0.23, a CSF protein of more than 2.2 g/liter (220 mg/dl), a CSF leukocyte count of more than or a CSF neutrophil count of more than was an individual predictor of bacterial meningitis, as compared to viral meningitis, with a certainty of 99% or better.212 A normal CSF white cell count and protein may be seen in specimens obtained at the onset of meningitis, in some cases of neonatal meningitis, and in severely immunocompromised patients. CSF examination by Gram stain may permit a rapid, accurate identification of the causative microorganism in 60–90% of cases of bacterial meningitis.211 The probability of detecting the organism correlates with bacterial concentrations in CSF; concentrations less than or equal to colony-forming units (CFU)/ml are associated with poor microscopic results (organisms seen 25% of the time), whereas microscopy is positive in 97% of cases in

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which CSF bacterial concentrations are equal to or greater than CFU/ml.213 The probability of identifying an organism may decrease in patients who have received prior antimicrobial therapy.214,215 The CSF Gram stain is positive in less than half of cases of meningitis due to L. monocytogenes.190 Several rapid diagnostic tests also have been developed to aid in the diagnosis of bacterial meningitis.216 Counterimmunoelectrophoresis (CIE) may detect specific antigens in CSF due to meningococci (serogroups A and C), H. influenzae type B, pneumococci (83 serotypes), type III group B streptococci, and E. coli K1. The sensitivity of CIE ranges from 62 to 95%, although the test is highly specific. Newer tests employing staphylococcal coagglutination or latex agglutination are more rapid and sensitive than CIE, with the ability to detect much lower concentrations (~1 ng/ml) of bacterial antigen. However, none of the tests currently available detects group B meningococcal antigens. One of these rapid diagnostic tests (preferably latex agglutination) should be performed on all CSF specimens from patients in whom bacterial meningitis is suspected if the CSF indices are consistent with the diagnosis and the CSF Gram stain is negative. However, it must be emphasized that a negative test does not rule out infection due to a particular meningeal pathogen. Lysate prepared from amoebocytes of the horseshoe crab, Limulus polyphemus, is useful in suspected cases of gram-negative meningitis in which a positive test is due to the presence of endotoxin,217 although the test does not distinguish among gram-negative organisms that may be present in CSF. Recently, procalcitonin has been evaluated as a marker to differentiate bacterial from viral meningitis. In one study, a serum procalcitonin concentration >0.2 ng/ml had a sensitivity and specificity of up to 100% in the diagnosis of bacterial meningitis218; further studies are needed, however, to determine the utility of this test in distinguishing bacterial from viral meningitis. CSF studies in nocardial meningitis usually reveal a neutrophilic pleocytosis that tends to persist in the presence of empiric antimicrobial therapy.203 Nocardia species typically grow on routine laboratory media, but growth may require several weeks of incubation. Although culture of large CSF volumes and use of enhanced concentration techniques before staining may improve the yield, the utility of these maneuvers for nocardial meningitis has not been well defined. 3.1.4. Treatment 3.1.4a. Specific Antimicrobial Agents. The initial management of patients with presumed bacterial men-

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ingitis includes performance of an emergent lumbar puncture.206,219 If the CSF formula is consistent with that diagnosis, empiric antimicrobial therapy should be initiated rapidly, often before results of Gram stain or CSF bacterial antigen tests are available. If no etiologic agent can be identified by results of Gram stain or rapid diagnostic tests, empiric therapy should be initiated on the basis of the patient’s age and underlying disease status. In patients who present with a focal neurologic examination, a CT scan should be performed immediately to exclude the presence of an intracranial mass lesion. However, if there is any delay in obtaining the CT scan, empiric antimicrobial therapy should be started immediately and before the lumbar puncture because of the high mortality rate in patients with bacterial meningitis in whom antimicrobial therapy is delayed. Choices for empiric antibiotic therapy in patients with presumed bacterial meningitis based on age and underlying disease are shown in Table 4. Once the infecting microorganism is isolated, antimicrobial therapy can be modified for optimal treatment (Table 5); choices of specific agents are reviewed in greater detail below. Recommended doses of antimicrobial agents for CNS infections in adults with normal renal function are shown in Table 6. For meningitis caused by S. pneumoniae, penicillin

G and ampicillin are equally efficacious for susceptible strains. However, on the basis of recent studies of pneumococcal susceptibility patterns, these agents are not recommended for empiric therapy when the pneumococcus is considered a likely infecting pathogen. In the past, pneumococci were uniformly susceptible to penicillin with minimal inhibitory concentrations (MICs) of 0.06 or less. Several reports have now documented pneumococcal strains that are relatively resistant (MIC range: or highly resistant to penicillin.206,219–222 Pneumococcal strains resistant to the third-generation cephalosporins also have been reported; these agents have been associated with treatment failure in patients with pneumococcal meningitis.206,219 Because sufficient CSF concentrations of penicillin are difficult to achieve with standard parenteral dosages (initial CSF concentrations of ~1 penicillin never should be used as empiric therapy for suspected or proven pneumococcal meningitis. Empiric therapy should consist of the combination of vancomycin plus a third-generation cephalosporin (either cefotaxime or ceftriaxone), pending susceptibility testing of the pneumococcal isolate. Once susceptibility testing of the isolate is performed, antimicrobial therapy can be modified for optimal treatment (Table 5). Of concern is the report of 11 consecutive patients with CSF-cultureproven pneumococcal meningitis who were treated with intravenous vancomycin.223 All patients initially improved and 10 were ultimately cured of their infection, although 4 patients experienced a therapeutic failure, leading to a change in vancomycin therapy. These data indicate the need for careful monitoring of adult patients receiving vancomycin therapy for pneumococcal meningitis. In patients not responding, use of intrathecal or intraventricular vancomycin is a reasonable option.224 The addition of rifampin to vancomycin, with or without the third-generation cephalosporin, also has been recommended by some authorities, although clinical data are not available; rifampin should only be added if the organism is susceptible and the expected clinical or bacteriologic response is delayed.225 Penicillin G and ampicillin also are efficacious for meningitis due to N. meningitidis. However, these recommendations may change in the future as meningococcal strains that are relatively resistant to penicillin (MIC range: have been described in several areas, particularly Spain226; 20% of meningococcal isolates were relatively resistant to penicillin in 1989.227 This resistance appears to be mediated by a reduced affinity of the antibiotic for penicillin-binding proteins 2 and 3. In the United States, meningococcal strains relatively resis-

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tant to penicillin also have been described, accounting for 3% of isolates in one population-based surveillance study.228 In addition, chloramphenicol resistance among meningococci has recently been reported.229 The clinical significance of these resistant isolates is unclear because patients with meningococcal meningitis have recovered with standard penicillin therapy, although some authorities would treat patients with meningococcal meningitis

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with a third-generation cephalosporin pending results of susceptibility testing. Therapy of meningitis due to H. influenzae type B has been markedly altered due to the emergence of strains, accounting for approximately 24% and 32% of CSF isolates overall in the United States in 1981175 and 1986,178 respectively. Resistance to chloramphenicol also has been described, al-

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though it occurs more commonly in Spain (>50% of isolates)230,231 than in the United States (11 hr, retransplantation and early fungal colonization.12 The spectrum of fungal diseases varies during the early versus late time period after organ transplantation. For example, Candida and Aspergillus account for most of the early fungal infections following liver transplantation (Candida, 70%, and Aspergillus, 25%). Impaired phagocytic cell function caused by use of high-dose corticosteroid therapy predisposes to these early infections. Later, chronic low-dose corticosteroids, cyclosporin A, or tacrolimus and mycophenolate mofetil impair cellular immunity, predisposing to mucocutaneous candidiasis and systemic mycoses. 1.3. Fungal Infections in Acquired Immunodeficiency Syndrome

Fungal infections are common in patients with acquired immunodeficiency syndrome (AIDS). Mucocutaneous candidiasis occurs in up to 90% of patients but systemic candidiasis is rare. Cryptococcal meningitis occurs in 5 to 12% of patients, histoplasmosis in 2 to 5%, and coccidioidomycosis in 5% in the southwestern United States. Aspergillosis and infections with Mucoraceae, Pseudallescheria, Alternaria, Blastomyces dermatitidis, Paracoccidioides brasiliensis, and Sporothrix schenckii have been reported. The incidence and severity of systemic fungal infections increase with progression of HIV infection and reduction in CD4 counts. While mucocutaneous candidiasis may develop in patients with CD4 counts between 200 and most patients have lower counts. Esophagitis occurs after CD4 counts fall below 100 Systemic mycoses usually occur in patients with CD4 counts below 100 (median below and aspergillosis in those with counts below

often in conjunction with granulocytopenia or corticosteroid therapy.14 Although the incidence of mucosal and systemic mycoses has fallen since introduction of highly active antiretroviral therapies,15 they persist as problems in persons who have not accessed health care, who are nonadherent to therapy, or who have failed antiretroviral therapy.

2. Antifungal Prophylaxis in the Immunocompromised Host 2.1. Prophylaxis in Hematology

A recent meta-analysis evaluating nearly 6000 subjects enrolled in randomized clinical trials has concluded that antifungal prophylaxis with fluconazole, itraconazole, or low-dose amphotericin B has reduced the morbidity and mortality related to fungal infections in neutropenic cancer patients, particularly among those receiving hematopoietic stem cell or bone marrow transplants.16 While a number of different regimens of antifungal prophylaxis have resulted in reductions in fungal colonization and superficial fungal infections, a more important goal is the prevention of serious life-threatening systemic fungal infections. To date, the greatest benefits of antifungal prophylaxis in reducing systemic fungal infections have been realized in patients following allogeneic or high-risk autologous bone marrow transplantation where significant decreases in Candida albicans infections have been realized.17,18 As not all patients receiving chemotherapy for acute leukemia are at high risk for invasive fungal infections, it has been more difficult to demonstrate benefit in this population using antifungal prophylaxis.19,20 Most presently available antifungals when used in prophylaxis regimens have significant limitations, including low efficacy, toxicity, drug interactions, and cost.21–23 Acknowledging these limitations, antifungal prophylaxis appears to be appropriate at institutions where there is a high incidence of invasive fungal infections in patients expected to be profoundly granulocytopenic for >7 days and for those requiring significant doses of immunosuppressant medications following bone marrow or stem cell transplantation. 2.1.1. Fluconazole

Fluconazole has several advantages over other presently available antifungal agents including its overall safety profile, excellent bioavailability in both oral and intravenous preparations, and minor drug interaction potential. Large placebo-controlled studies have demon-

FUNGAL INFECTIONS

strated a useful role for fluconazole prophylaxis in bone marrow transplant recipients. In addition to reductions in superficial fungal infections, fluconazole prophylaxis at a dose of 400 mg daily was associated with a reduction in systemic candidiasis from 18% to 7% in one study and from 15.8% to 2.8% in another study of patients undergoing allogeneic or autologous bone marrow transplantation.17,18 A more recent study has shown reductions in proven and probable invasive fungal infections in patients receiving autologous bone marrow transplants not supported with hematopoietic growth factors, while reductions in fungal infections were not seen for those treated with hematopoietic growth factors.20 Fluconazole prophylaxis was associated with a reduction in overall mortality in one large study in bone marrow transplant recipients,18 presumably because of the continuation of fluconazole during the 2 months of high risk following transplantation. As expected, fluconazole prophylaxis has had no effect on the incidence of aspergillosis. Fluconazole 100–200 mg daily also may be effective.24 Fluconazole prophylaxis during therapy for acute leukemia reduced fungal colonization and superficial infections but did not prevent invasive fungal infections.19,23 The lack of consistent efficacy of fluconazole prophylaxis in leukemic populations may be attributed to inclusion of heterogeneous populations with differing risks for serious mycoses. Fluconazole prophylaxis is most efficacious in patients with acute myelogenous leukemia undergoing induction therapy with cytarabine plus anthracyclinebased regimens.20 Fluconazole is less active against non-albicans Candida species25 and is inactive against filamentous fungi. In particular, C. krusei is resistant to fluconazole and C. glabrata isolates are frequently less susceptible or resistant. Retrospective review of fungal infections after bone marrow transplantation showed a sevenfold increase in C. krusei infection in patients receiving fluconazole and an increase in colonization with C. glabrata,26 as recently confirmed by others.27 Also, fluconazole-resistant C. albicans has been noted in patients receiving prophylaxis. While the emergence of colonization and infection with fluconazole-resistant organisms is concerning, the reduction in serious Candida infection and its attributable mortality justifies its use for prophylaxis.27 Illustrative Case 1 A 34-year-old female underwent a T-cell-depleted allogeneic bone marrow transplantation for chronic myelocytic leukemia. Antifungal prophylaxis with fluconazole, 200 mg daily, was started concurrently with chemotherapy. On the 8th posttransplant day C. krusei was isolated from blood, showing a minimum inhibitory concentration (MIC) to fluconazole of Amphotericin B was initiated, the central

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venous catheters were removed, and the patient defervesced on the following day.

2.1.2. Itraconazole Itraconazole is attractive as prophylaxis because of its activity against Aspergillus. Most studies have used the capsule formulation, which exhibits variable absorption and drug interactions with agents that reduce gastric acidity. An uncontrolled study of patients with hematologic malignancies reported reduction in proven fatal fungal infections, mostly aspergillosis, in patients who had received itraconazole 400 mg daily compared to those who received ketoconazole in a prior study.28 Other uncontrolled studies also showed reductions in systemic yeast infections29 or fungal mortality,30 compared to historical controls. In a small placebo-controlled study in patients with hematologic malignancies, however, itraconazole prophylaxis when added to oral amphotericin B prophylaxis did not prevent systemic fungal infections or mortality.31 A study comparing itraconazole 100 mg and fluconazole 50 mg, each given twice daily, in patients undergoing chemotherapy or autologous stem cell transplantation observed no differences in the rate of fungal infections or mortality, 32 but dosages of both agents were too low to assess their efficacies. Blood concentrations of itraconazole of at least 1000 ng/ml are needed to prevent aspergillosis,33 requiring doses of up to 600 mg daily. The oral solution formulation of itraconazole in cyclodextrin is better absorbed and yields higher blood concentrations than does the capsule. In a controlled study in patients with hematologic malignancies, itraconazole solution at a dose of 2.5 mg/kg twice daily was associated with a reduction in fungemias due to Candida species (0.5% vs. 4% in placebo recipients) and in proven and suspected deep fungal infections from 33% to 24%.34 No differences in the rate of aspergillosis or mortality were observed. Experience with itraconazole solution 2.5 mg/ kg twice daily compared to fluconazole 100 mg orally in a nonblinded randomized trial of 581 patients with hematologic malignancies showed no significant difference in proven invasive fungal infections.35 There were six (2%) proven fungal infections in the fluconazole group and one (0.3%) in the itraconazole group. Post hoc analysis of subjects who developed fungal infections beyond the specified period of study observation did reveal a lower rate of proven fungal infections and aspergillosis in the itraconazole group. A trial is in progress in bone marrow transplant patients comparing fluconazole to itraconazole given intravenously and then orally in the solution formulation.

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2.1.3. Intravenous Amphotericin B

The use of amphotericin B as primary antifungal prophylaxis has been less well studied than fluconazole prophylaxis. Uncontrolled trials have reported significant reductions in systemic fungal infections including aspergillosis in allogeneic marrow transplant recipients after instituting low-dose amphotericin B.36 Low-dose amphotericin B 0.1 mg/kg per day resulted in reduction in fungal colonization and empiric use of high-dose amphotericin B, compared to placebo in autologous transplant recipients, but was not associated with reductions in proven fungal infections.37 Amphotericin B prophylaxis 0.5 mg/ kg per day three times weekly was more toxic but no more effective than fluconazole in patients undergoing chemotherapy for leukemia.38 In a separate study comparing low-dose amphotericin B at a dose of 2 mg/kg daily to fluconazole 400 mg daily in bone marrow transplant patients, low-dose amphotericin B was as effective as fluconazole but was associated with greater toxicity.39 Overall, the efficacy of low-dose amphotericin B as prophylaxis is unproven and the potential for toxicity is considerable. 2.1.4. Lipid Preparations of Amphotericin B

The lipid preparations of amphotericin B are less nephrotoxic than the deoxycholate formulation.40 Liposomal amphotericin B (AmBisome) also has been shown to have less infusion-related side effects than standard amphotericin B.41 In a placebo-controlled study in allogeneic bone marrow transplant recipients, liposomal amphotericin B 1 mg/kg per day reduced fungal colonization but did not prevent invasive fungal infections.42 A more recent study comparing liposomal amphotericin B at 2 mg/kg three times weekly to placebo also failed to prevent fungal infections.43 Finally, a trial comparing amphotericin B colloidal dispersion (ABCD, Amphocil) with fluconazole for antifungal prophylaxis was stopped early due to the severe side effects caused by this lipid preparation.44 2.2. Antifungal Prophylaxis in Liver Transplant Recipients

Recent studies have indicated that liver transplant recipients at highest risk for serious invasive fungal infections include those with a number of risk factors as indicated in Section 1.2. To date, published studies of antifungal prophylaxis in this patient group have included those patients at variable risk for fungal infections.45–48 In a multicenter comparison of fluconazole 100 mg

daily compared to oral–nasogastric administration of nystatin suspension 1,000,000 units every 6 hr for 28 days after transplantation, fluconazole was associated with a 50% reduction in superficial fungal infections and colonization attributed to Candida.45 Invasive Candida infections occurred in 9% of the nystatin group and 2.6% of the fluconazole group, but the difference did not reach statistical significance. Finally, there was no difference in mortality comparing nystatin to fluconazole. More recently, fluconazole 400 mg daily for 10 weeks after transplantation was compared to placebo in patients undergoing liver transplantation.46 Fluconazole significantly reduced superficial (28% with placebo vs. 4% with fluconazole) and invasive fungal infections (23% with placebo vs. 6% with fluconazole). Fluconazole was well tolerated without apparent hepatotoxicity, but cyclosporine levels were higher and adverse neurologic events were more common in the fluconazole group. While there were fewer deaths attributed to fungal infections in the fluconazole group, overall mortality was not affected. Fluconazole prevented infections by most Candida species except C. glabrata. Itraconazole oral solution 2.5 mg/kg twice daily also has been used in one small placebo-controlled trial in liver transplant recipients and was associated with significant reductions in the combined end point of superficial, proven deep, and suspected deep fungal infections.49 All infections in this study were attributed to Candida species. In a retrospective study in high-risk liver transplant recipients, low-dose amphotericin B (10–20 mg daily) prevented Candida infections and reduced empiric amphotericin B use, when compared to historical controls.47 Liposomal amphotericin B (AmBisome) has been evaluated in a randomized placebo-controlled trial.48 At a dose of 1 mg/kg per day for 5 days, started during transplant operation, invasive fungal infections occurred in none of 40 (0%) patients receiving prophylaxis and 6 of 37 (16%) placebo recipients (P 16 years of age. 3.2. Lipid Preparation of Amphotericin B as Empiric Antifungal Therapy A report combining two prospective randomized clinical trials showed that liposomal amphotericin B at 1 or 3 mg/kg daily was significantly better tolerated than conventional amphotericin B at a dose of 1 mg/kg daily.63 Success of therapy, defined by resolution of fever, lack of need to add antifungal therapy, and lack of development of a systemic fungal infection, was more common in subjects receiving liposomal amphotericin B 3 mg/kg per day (64%) than in those receiving conventional amphotericin B (49%) (P = .03). The efficacy of liposomal amphotericin B 1 mg/kg daily was no different than conventional amphotericin B, however. Another study showed liposomal amphotericin B 3 mg/kg daily and conventional amphotericin B 0.6 mg/kg daily to be equally effective with respect to resolution of fever and mortality, but there were significantly fewer break-

through fungal infections with the lipid preparation (3.2%) than conventional amphotericin B (7.8%).41 Nephrotoxicity and infusion-related side effects also were reduced with liposomal amphotericin B. Liposomal amphotericin B (AmBisome) at 3 or 5 mg/kg daily has been compared to amphotericin B lipid complex (ABLC, Abelcet) 5 mg/kg.64 No differences in breakthrough fungal infections or mortality were reported. Nephrotoxicity and treatment discontinuations due to intolerance were less common with liposomal amphotericin B, however. Amphotericin B colloidal dispersion 4 mg/kg daily has been compared to conventional amphotericin B 0.8 mg/kg daily.65 The efficacy of this lipid formulation was comparable to that of conventional amphotericin B, while renal dysfunction was significantly less common for those receiving the colloidial dispersion. Infusion-related events were significantly more common in those treated with the colloidial dispersion than with the deoxycholate preparation, however. 3.3. Triazole Agents as Empiric Antifungal Therapy 3.3.1. Fluconazole as Empiric Antifungal Therapy Fluconazole has been studied as an alternative to amphotericin B as empiric antifungal for febrile neutropenia.66–68 As fluconazole lacks activity against Aspergillus, its empiric use in patients at risk for aspergillosis has remained a significant concern, however. Due to the potential for infection with fluconazole-resistant Candida, studies of fluconazole in this setting have excluded patients who had received prior systemic azole prophylaxis. In one small study comparing empiric fluconazole therapy to amphotericin B in patients with hematologic malignancies, enrollment was limited to those with normal chest radiographs, no previous aspergillosis, and negative surveillance cultures for Aspergillus.66 In this patient population, fluconazole at a dose of 400 mg daily was as effective as amphotericin B 0.8 mg/kg when given after at least 96 hr of prior antibacterial therapy. The largest randomized study comparing fluconazole to amphotericin B to date enrolled 317 patients, including 120 who had undergone bone marrow or stem cell transplantation.67 Nearly 60% had abnormal chest radiographs at randomization and surveillance studies for Aspergillus were not performed. Empiric antifungal therapy was initiated after at least 96 hr of fever unresponsive to antibacterial therapy. Fluconazole was given at a loading dose of

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800 mg followed by 400 mg daily and compared to amphotericin B 0.5 mg/kg daily. Fluconazole was as effective as amphotericin B with responses to therapy seen in 68% of fluconazole recipients and 67% of amphotericin B recipients. No differences in overall mortality or mortality due to fungal infections were found. Persistent or new fungal infections were documented in 8% of fluconazoletreated patients and 6% of those receiving amphotericin B. As expected, fluconazole was better tolerated than amphotericin B. While this study demonstrated equal efficacy of fluconazole and amphotericin B in the setting of neutropenic fever, the study was characterized by a low incidence of invasive aspergillosis and relatively short duration of neutropenia, mostly attributed to support with hematopoietic growth factors. The authors of this study indicated that careful assessment including chest computerized tomography (CT) for patients at risk for aspergillosis be performed before considering fluconazole as empiric therapy. 3.3.2. Itraconazole as Empiric Antifungal Therapy As itraconazole has antifungal activity against both Candida and Aspergillus, following the development of both intravenous and a more reliably absorbed oral cyclodextrin formulation, there has been increased interest in the use of itraconazole as empiric antifungal therapy for persistently febrile neutropenic patients. While itraconazole has not been extensively studied in this setting, preliminary results from a recently completed randomized trial comparing itraconazole to amphotericin B in patients with underlying hematological malignancies have been reported.69 In this investigation, amphotericin B at a dose of 0.7–1.0 mg/kg daily was compared with intravenous itraconazole 200 mg twice daily for 2 days followed by 200 mg daily for a maximum of 12 days before converting to itraconazole oral solution at a dose of 200 mg twice daily. This study excluded those with evidence of a fungal infection at baseline. Five patients in each study arm developed a deep fungal infection; overall itraconazole was at least as effective as amphotericin B and less toxic. 3.4. Ongoing Investigations in Empiric Therapy Ongoing evaluations of investigational agents as empiric antifungal therapy for persistent fever and neutropenia include study of voriconazole,70 a new triazole agent with activity against Aspergillus and Candida, including fluconazole-resistant species, and study of cas-

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pofungin acetate (MK-0991), an echinocandin agent with activity against Candida and Aspergillus.71 3.5. Recommendations for Empiric Therapy Amphotericin B 0.7 mg/kg per day is recommended as empiric antifungal therapy for neutropenic patients with granulocyte counts below for more than 7 days who have persistent fever of undefined etiology after at least 96 hr of antibiotic therapy or recurrent fever despite antibacterial therapy (Table 2). A higher dose of 1.0 mg/kg per day may be preferred for patients who have received prior antifungal prophylaxis, because of the increased risk for infection with non-albicans Candida or Aspergillus. Liposomal amphotericin B is at least as effective and better tolerated, but its higher cost limits its use except in special situations, such as renal insufficiency or treatment with medications that increase the risk for renal insufficiency. Fluconazole 400 to 800 mg daily could be considered if the likelihood of aspergillosis was low and the patient had not received a systemic azole for prophylaxis or treatment of a presumed or proven fungal infection. While less well studied, itraconazole is an alternative in subjects who have not received prior systemic azole therapy for prophylaxis or treatment.

4. Candidiasis 4.1. Epidemiology Candidiasis occurs in 9 to 25% of patients following bone marrow transplantation, 1 to 13% with granulocytopenia caused by chemotherapy for hematologic malignancy, 1 to 2% following chemotherapy for lymphoma, and 0.5% following chemotherapy for solid tumors. Sys-

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temic candidiasis occurs following liver transplantation in up to 18% of patients and less commonly following other types of organ transplantation. C. albicans is the most common species isolated from immunocompromised host, causing 40 to 50% of cases of systemic candidiasis. C. glabrata is responsible for 5 to 35%, and C. tropicalis for 8 to 43% of cases. Less common Candida species, including guilliermondi, lusitaniae, krusei, and parapsilosis, have accounted for 4 to 12% of cases. Non-albicans species may be more common in patients who have received antifungal prophylaxis.26 Risk factors for systemic candidiasis following bone marrow transplantation included older age, impaired donor match, use of total-body irradiation, presence of underlying disease, occurrence of acute GVHD, and presence of Candida colonization. Prolonged antibiotic treatment and long duration of granulocytopenia also are important predisposing factors.

60% of patients. Of note, hepatic lesions may disappear during granulocytopenia and recur after granulocyte recovery, complicating assessment of response to therapy.76 4.3. Diagnosis 4.3.1. Mycologic Methods Despite widespread dissemination, fungemia can be documented in only a third to half of patients. If skin lesions are present, organisms can be seen by fungal stain and isolated in cultures. Isolation of Candida species from surveillance cultures may provide a clue to the diagnosis of candidiasis. Surveillance cultures were positive in 91% of cases of systemic candidiasis in one study.77 While Candida species often can be isolated from routine culture media, use of special fungal media for blood cultures and mycotic media for isolation of fungi from other specimens may improve the diagnostic yield. 4.3.2. Serologic Methods

4.2. Clinical Findings Fever unresponsive to antibiotic therapy is the usual mode of presentation of systemic candidiasis in the neutropenic patient, usually occurring during the second week of antibiotic therapy or at the time of bone marrow recovery. Dissemination is common, more so with C. tropicalis than with C. albicans.72 Common sites of dissemination, in descending order, include the liver, kidney, spleen, heart, gastrointestinal tract, skin, lungs, brain, eye, pancreas, and thyroid. Pulmonary manifestations include local, diffuse, or miliary infiltrates. Skin manifestations include nodules, papules, ecthyma gangrenosum, verrucous plaques, and a picture of purpura fulminans associated with coagulopathy and shock.73 Candidiasis may cause intra-abdominal abscesses and peritonitis following organ transplantation.74 Hepatic involvement is common in disseminated candidiasis in neutropenic subjects, but lesions may not be seen until resolution of granulocytopenia.75 Alkaline phosphatase elevation may be a clue to the presence of hepatic candidiasis. Abdominal CT scan shows focal lesions in the liver and the spleen. The kidneys, muscle, and other organs also may be involved. White nodules, 1–2 mm in size, stud the liver at laparoscopy, and larger lesions measuring several centimeters in diameter may be seen on CT scans. Biopsy shows microabscesses or granulomas, but organisms may be missed unless multiple sections are examined. Despite demonstration of organisms in fungal stains, cultures are positive in only 30 to

Diagnosis by detection of antigenic materials or metabolic products of Candida has been reviewed.78 Measurement by gas chromatography of ratios of D-arabinitol/ L-arabinitol in the urine of neutropenic patients yielded positive results in all ten patients with proven candidiasis and negative results in 94% of controls.79 Detection of antigen in sera by latex agglutination was not accurate, however.80 Enzyme immunoassay (EIA) methods show promise,81 but have not been proven to be useful in patient management. Diagnosis by detection of and polymerase chain reaction (PCR) amplification of gene products83 requires confirmation. Antibody tests are not useful for several reasons. First, several weeks are required to mount an antibody response.84 Second, colonization leads to development of antibodies in individuals without significant Candida infection, detracting from the significance of a positive test. Third, immunocompromised individuals may not mount an antibody response. Tests for Candida antibodies have been falsely negative in half of all patients with serious candidiasis.85 4.4. Treatment Challenges in treatment of candidiasis result from the difficulty with recognition and diagnosis and increasing problems with resistance to antifungal therapy. The widespread usage of fluconazole for prophylaxis or empiric therapy has resulted in more infections with non-albicans

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species and fluconazole-resistant C. albicans.8 Polyene resistance has been reported.86 Catheter management is an important aspect of treatment of candidemia.87,88 Most experts recommend changing all nonsurgically placed catheters, but would attempt to sterilize the bloodstream without removal of tunneled catheters unless the tunnel appeared infected88 or the fungemia persisted despite treatment. 4.4.1. Amphotericin B Amphotericin B dosage should be at least 0.7 mg/kg per day,88 but higher doses of 1 mg/kg per day may be needed for non-albicans species, including C. glabrata and C. krusei. Mortality is higher in patients infected by strains with MICs above Therapy should be continued until at least 2 weeks after the last positive blood culture and resolution of the clinical manifestation of candidiasis,88 but amphotericin B may be replaced by fluconazole. 4.4.2. Lipid Formulations of Amphotericin B Response rates of 50 to 80% in neutropenic patients were observed with AmBisome,90 Amphotec,91 or Abelcet.92 Similar findings were reported in bone marrow and liver transplant recipients.93,94 A single, unpublished randomized study comparing Abelcet with amphotericin B noted comparable efficacy but improved tolerability with the lipid formulation.95 In the absence of evidence for improvement in outcome, the main reason to choose a lipid preparation is concern for nephrotoxicity. 4.4.3. 5-Flucytosine One study reporting a higher mortality in patients receiving amphotericin B alone (84%) compared to amphotericin B and 5-flucytosine (34%) acknowledged that the patients receiving amphotericin B alone were sicker and that the outcomes were similar if the groups were matched for baseline severity of illness,96 Some experts recommend combined therapy in patients with candidemia who are clinically unstable or have evidence for disseminated infection, but at reduced 5-flucytosine doses of 100 mg/kg per day.88 Flucytosine blood concentrations should be measured and maintained between 75 and 100 and dosage should be adjusted for renal function. However, the poor tolerability and lack of an intravenous preparation reduce the feasibility of this regimen and its utility has not been established.

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4.4.4. Fluconazole Fluconazole has been used for treatment of disseminated candidiasis in those who failed amphotericin B treatment.97,98 Expert opinion supports fluconazole use in patients who are stable clinically, without evidence for disseminated involvement, infected with C. albicans, and who have not received prophylaxis with a triazole antifungal agent.88 Fluconazole also may play a role for continued therapy in patients who were initially treated with amphotericin B and subsequently experienced clinical improvement and resolution of granulocytopenia.88 A loading dosage of 12 mg/kg followed by 6 mg/kg daily in patients with normal renal function is recommended. A dosage of 12 mg/kg per day is advised if fluconazole is used for treatment of C. glabrata infection and measurement of blood concentrations is suggested in patients receiving this high dosage. Fluconazole should not be combined with amphotericin B because of absence of data showing that combined therapy improves outcome, but a study evaluating combination therapy of candidemia in the nongranulocytopenic host is under analysis (Dr. John Rex for the Mycoses Study Group). There is potential for antagonism when these agents are combined.

4.4.5. Adjunctive Cytokine Therapy Cases of hepatosplenic candidiasis have been described that benefited from and granulocyte–monocyte colony-stimulating factor (GM-CSF).99 GM-CSF also has shown benefit in treating esophageal candidiasis.100,101 Some experts recommend administration of GM-CSF or granulocyte colony-stimulating factor (G-CSF) in persistently granulocytopenic patients with candidiasis.88

4.4.6. Prevention of Recurrence during Subsequent Granulocytopenia Patients who have recovered from candidiasis are at risk for recurrence during future granulocytopenia.97,102 Prophylactic use of amphotericin B or fluconazole during subsequent chemotherapy is advised.102 In one report, none of 15 consecutive patients with prior hepatosplenic candidiasis experienced relapse following bone marrow transplantation under the protection of intravenous amphotericin B begun before transplantation and continued until engraftment.102 Lesions may not clear despite good clinical responses to therapy, however.102

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4.4.7. Treatment Recommendations Recommendations for treatment of candidiasis have been reviewed.88,103 Amphotericin B 0.7 to 1 mg/kg per day, or one of the lipid formulations (3–5 mg/kg per day) in patients at increased risk for renal impairment is indicated for treatment of patients with more severe manifestations and for those who have recently received a triazole for antifungal prophylaxis (Table 3). Fluconazole, 6 mg/kg daily, adjusted for renal function, is appropriate for those with milder manifestations and for continuation of treatment after response to amphotericin B. Fluconazole should not be used as initial therapy if the patient has received it frequently in the past, because of the risk for infection with azole-resistant strains. If fluconazole is used for C. glabrata infection, the dose should be increased to 12 mg/ kg daily and blood concentrations should be determined to avoid levels above A minimum duration of 2 weeks is recommended in patients with fungemia who lack evidence for deep tissue involvement or dissemination. For others, treatment should continue until the lesions have disappeared or calcified as determined by CT scan.

5. Aspergillosis 5.1. Epidemiology Most infections are acquired in the hospital104 but patients may become colonized before admission. Geno-

typing may be used to show the relationship of the patient’s strain to that of environmental isolates, assisting in the evaluation of possible nosocomial acquisition.105 Air sampling is not useful for predicting exposure, however.106 Exposure also has been attributed to smoking marijuana.107 Reactivation following a prior episode of aspergillosis also occurs.108 Use of protective environments reduces the risk for aspergillosis.109 Invasive aspergillosis has been reported in 5 to 24% of patients during chemotherapy-induced granulocytopenia. Duration of granulocytopenia during chemotherapy for leukemia, receipt of an allogeneic marrow, positive cytomegalovirus serostatus, delayed marrow engraftment, and age greater than 18 years are important risk factors for aspergillosis following bone marrow transplantation.110,111 Most cases occur following engraftment during treatment for GVHD.7,104 The incidence following solid organ transplantation is lower than following bone marrow transplantation.112 In a recent study, invasive aspergillosis occurred in only 1% of liver transplant recipients, suggesting that advances in transplant immunology and the use of immunosuppressive drugs have lowered the risk for aspergillosis.113 The median time to onset was 17 days following transplantation and 75% of cases occurred within 90 days. A. fumigatus and A. flavus cause the majority of cases, 73% and 15%, respectively. Risk factors include use of high-dose corticosteroids, OKT3 monoclonal antibodies, renal dysfunction, and cytomegalovirus infection.113

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5.2. Pathogenesis

Inhalation is the source for invasive rhinosinusitis and tracheopulmonary aspergillosis, while cutaneous inoculation may cause skin disease. Aspergillus invades blood vessels causing infarction and hematogenous dissemination, but fungemia is rare. However, necrosis may not develop until granulocytopenia resolves. 5.3. Clinical Manifestations

Aspergillosis is progressive and usually fatal in the severely neutropenic patient, but may be more indolent in those with less severe immunosuppression.114 Invasive pulmonary aspergillosis is the most common clinical manifestation, occurring in about 75% of cases. Necrotizing tracheobronchitis may precede pulmonary involvement.115 Rhinosinusitis116 or cutaneous disease from direct inoculation occurs in 5 to 10% of cases. Dissemination to extrapulmonary sites is common. 5.3.1. Invasive Pulmonary Aspergillosis

Pulmonary complaints or hypoxia should raise suspicion of invasive pulmonary aspergillosis. Pleuritic chest pain, pleural friction rub, and nodular or wedge-shaped infiltrates occur in 30% of cases. Chest radiograms show focal or diffuse infiltrates but may be normal.117 Chest CT scans are more sensitive that radiograms and may reveal nodular lesions surrounded by a zone of attenuation producing a halo effect.118 Frequently a vague infiltrate first noted during granulocytopenia progresses to a classic wedge-shaped infarct or nodular lesion with cavitation following bone marrow recovery.118

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gillosis. Patients also may experience embolic skin lesions,118 which evolve from a macule or papule to a pustule with ulceration and eschar formation. 5.3.4. Disseminated Aspergillosis

Dissemination occurs in up to half of patients. Sites of involvement include the brain in 50 to 60%, gastrointestinal tract in 40 to 50%, kidney in 30%, liver in 30%, thyroid in 25%, heart in 15%, and spleen in 15%. Endocardium and myocardium may be involved, causing emboli to large blood vessels. Rapidly progressive multiorgan failure may occur. Aspergillus is a common cause of central nervous system infection, manifested by meningitis, encephalitis, abscesses, and granulomas.120 Other less common manifestations have been reviewed.114 Illustrative Case 2 A 41-year-old male who underwent liver transplantation received 2 g of methylprednisolone for rejection on posttransplant days 3 and 8. Obtundation and multiorgan failure developed on posttransplant day 7. Chest roentgenogram showed diffuse infiltrates and head CT scan showed multiple masses. Hyphal elements were seen in a fungal smear from the nasopharynx and A. flavus was isolated. Amphotericin B was initiated but he died later that day. Autopsy revealed aspergillosis of the tracheobronchial tree, lungs, myocardium, endocardium, and brain.

5.4. Diagnosis

Diagnosis of aspergillosis before death may be difficult. Chest CT may assist in early diagnosis, improving the outcome of treatment.121 Bronchoalveolar lavage is useful in patients with CT abnormalities.122 Similarly, CT of the sinuses and endoscopic examination of the nares may facilitate early diagnosis of rhinosinusitis.

5.3.2. Rhinosinusitis and Otitis

Patients may experience nasal congestion, epistaxis, nasal discharge, and sinus and eye pain116 and examination shows facial tenderness, crusting at the inferior turbinate or cartilaginous septum, nasal or palatal ulcers, and necrotic lesions. Infection may extend to the soft tissues of the face, orbit, or mastoid bone. Invasive external otitis has been observed.119 This diagnosis should be suspected in immunocompromised patients with ear pain, hearing loss, and otorrhea. 5.3.3. Cutaneous Aspergillosis

Redness and induration that progresses to necrosis with eschar formation characterize inoculation asper-

5.4.1. Mycologic Methods

Aspergillus can be isolated from sputum in fewer than half of cases of invasive pulmonary aspergillosis,118,123 but a higher yield (60–75%) may be achieved by bronchoscopy.104,117 Several other fungi resemble Aspergillus histopathologically, including Fusarium, Pseudallescheria, Penicillium, and other less common molds. Isolation of Aspergillus should be regarded as presumptive evidence for aspergillosis.124 In one study, 55% of patients with invasive aspergillosis but 4 weeks), antiviral resistance should also be considered. Both short- and long-term courses of ganciclovir have been used for preemptive therapy. Short courses are usually given until the virologic marker is negative. Repeated courses are required in up to 30-40% of patients.35,104 Occasional cases of CMV disease shortly after discontinuation of short-term ganciclovir based on antigenemia have been reported in patients on high-dose steroids,35,155 although such early rebound has not been seen in PCR-based strategies.150 Advantages of shortterm treatment include lower cost, a lower risk for side effects, and an improved CMV-specific immune reconstitution, which may be associated with a lower risk of late CMV disease.35 A recent randomized trial demonstrated that foscarnet is as effective as ganciclovir for preemptive treatment of pp65 antigenemia and PCR positivity with less marrow toxicity, with a trend towards increased nephrotoxicity.156 Cidofovir shows acceptable toxicity,157 but comparative efficacy data are lacking. Prophylaxis with Intravenous Immunoglobulin (IVIG), Hyperimmune Globulin (CMV-Ig), or CMV-Specific Monoclonal Antibodies. The use of IVIG or CMV-Ig for the prophylaxis of CMV infection and disease after allogeneic transplants remains controversial. Although the prophylactic use of IVIG is associated with virtually no toxicity, the regimens proposed are costly and most controlled studies do not show a reduction of CMV disease.158–165 Some studies showed a reduction of bacteremia, interstitial pneumonia, and/or acute GVHD, while

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other studies did not report such a difference. An improvement of survival has not been reported in any of the studies. Only one small randomized trial of CMV-Ig has been reported in patients who received antigenemiabased preemptive treatment.166 In this study, there was no reduction of CMV antigenemia compared to pooled IVIG and the incidence of acute GVHD was similar.166 A randomized study of MSL-109, a human glycoprotein H-specific monoclonal antibody, did not show a reduction of CMV infection or disease in CMV seropositive allogeneic recipients or seronegative recipients with a seropositive donor.167 There was a transiently reduced mortality in D+/R– patients that was not due to a reduction of CMV disease but the numbers were small and additional studies are needed to confirm this finding. Whether there are indirect effects of CMV-Ig on other opportunistic infections similar to those observed after liver transplantation has not been studied in allogeneic marrow transplant recipients who receive antigenemia- or PCR-guided ganciclovir or ganciclovir prophylaxis. Prevention of Primary CMV Infection. The risk for CMV transmission in CMV seronegative patients with seronegative stem cell donors is mainly through blood products.162 Two options exist for reducing this risk of CMV transmission: the use of blood products from CMV seronegative donors or the use of leukocyte-reduced blood products. A recent randomized trial suggests that these two strategies result in similar rates of CMV infection.168 However, there remains a small risk of CMV disease (up to 2.3% with leukocyte-reduced blood products).168 Therefore, some centers perform virologic monitoring for antigenemia or CMV DNA with preemptive therapy. There is also a risk of late acquisition of CMV in patients with chronic GVHD. Thus, seronegative or leukocyte-depleted blood should be used beyond day 100 in these patients. The risk of transmission of CMV via the marrow or stem cell product from a seropositive donor to the recipient is approximately 15–20%.169 Thus, these patients should be considered at risk for CMV disease and antigenemia- or PCR-guided antiviral therapy should be given. IVIG prophylaxis is not effective in preventing CMV disease in this setting,163,165 although CMV viremia is reduced. Patients who are CMV seronegative before transplant should receive a transplant from a CMV negative donor whenever possible. Prevention in Autologous Transplantation. Highdose acyclovir given from day –5 until day 30 does not appear to be effective in prevention of CMV disease in seropositive autograft recipients.117 The low disease incidence would favor a preemptive therapy strategy and CMV quantitation may be useful in identifying patients at risk for disease who might benefit from preemptive treat-

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ment. A retrospective analysis suggests that a strategy of ganciclovir based on an antigenemia level of five positive cells per slide reduced the incidence of CMV disease by approximately 60%.28,119 For CD34-selected seropositive autograft recipients a similar strategy as for allograft recipients has been advocated, e.g., treatment of any level of antigenemia.28 6.2.4. Treatment

Treatment of CMV pneumonia with ganciclovir and CMV-Ig or IVIG remains unsatisfactory since fatality rates are still more than 50%.100,170 Analysis of various antiviral dosing regimens suggests that induction dosing should be continued for 2-3 weeks.34 Outcome is particularly grim in the presence of copathogens and in mechanically ventilated patients.170 Whether antiviral combination therapy consisting of ganciclovir and foscarnet or cidofovir results in better outcomes has not been studied. CMV gastrointestinal disease and retinitis usually respond to ganciclovir alone.171 For CMV gastrointestinal disease prolonged courses of induction doses are required, especially when ulcers are deep on endoscopic examination. Treatment of CMV-related marrow failure consists of foscarnet and G-CSF.172 Alternatively, ganciclovir, CMV-Ig, or G-CSF can be used.173 Illustrative Case 3 A 49-year-old man on day 120 after matched-related donor, nonmyeloablative peripheral blood stem cell transplant for AML was admitted with confusion and somnolence. The patient’s pretransplant serologies were positive for HSV and VZV. The CMV status was negative with a positive donor. The patient developed gut GVHD after transplant which was treated with corticosteroids. On admission, he indicated one episode of diarrhea, otherwise no nausea, vomiting, fever, or chills. Medication on admission included cyclosporine, ranitidine, omeprazole, fluconazole, and TMP-SMX. The physical exam was unremarkable. Laboratory values were within normal limits (neutrophil count, creatinine, and electrolytes). A head MRI was negative. CSF evaluation showed a normal protein, no RBC or WBC, bacterial and fungal cultures negative, a negative acid-fast stain, a negative cryptococcal antigen, and no detectable HHV-6 DNA. By day 2 postadmission, mental changes were nearly resolved without specific therapy, but the patient’s gastrointestinal symptoms were more pronounced. A flexible sigmoidoscopy was performed. A colon biopsy showed cytomegalic inclusions. Comment. This case illustrates several points. First, CMV gastrointestinal disease may occur without preceding CMV antigenemia and sometimes even without DNAemia (Table 6). The reasons for this are poorly understood but strain differences have been implicated.174 Thus, gastrointestinal symptoms in patients at risk for CMV disease should be evaluated by biopsy to initiate appropriate treatment. The major differential diagnosis is GVHD, which requires treatment with corticosteroids. The negative predictive value of the CMV antigenemia assay for gastrointestinal disease is only 85%.34,175 For gastrointestinal disease, extended ganciclovir treatment is often required. Induction dosing for 2–3 weeks and subsequent maintenance until day 100 is recommended.

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The addition of IVIG does not appear to improve the outcome of CMV gastrointestinal disease.171 Second, this case occurred after nonmyeloablative transplantation. The median day of onset is usually later but by 1 year, the incidence is similar to that observed in myeloablative transplant recipients.112 Third, the patient was a D+/R– patient. D+/R– patients have only a 15% risk of CMV infection after transplantation when seronegative or leukocyte-reduced blood products are given.32,169 Importantly, late CMV disease seems to occur predominantly in patients who had signs of CMV infection during the first 100 days after transplant. However, rarely, late CMV disease is seen without CMV infection during the first 100 days. In these cases, patients usually have chronic GVHD and are exposed to CMV via unscreened blood products or through other means of primary acquisition (e.g., toddlers who shed CMV or sexual transmission).

6.3. Infections with Community Respiratory Viruses Community-acquired respiratory virus infections are an important cause of morbidity and mortality after HSCT. These viruses include RSV, parainfluenza viruses, influenza viruses, and rhinoviruses. The infection epidemiology in HSCT recipients usually parallels that observed in the community, as these viruses circulate in immunocompetent individuals (including healthcare personnel and family members). RSV, influenza viruses, and rhinovirus have a seasonal distribution, while parainfluenza virus infections often occur year-round. The biggest impact on morbidity and mortality after HSCT has been from RSV followed by parainfluenza viruses and influenza viruses.94,95,176–178 Whether rhinovirus can cause lower tract disease remains controversial.179,180 Several methods exist for the diagnosis of respiratory viruses.181 Since viral load in immunocompromised adults may be very low, appropriate specimen handling is important for recovery of the virus. Nasal wash specimens should be placed on ice or in the refrigerator immediately and transported to the laboratory without delay.181 Specimen setup in the laboratory should occur within 2–4

hr. Methods available for testing include standard viral cultures (results available in several days), shell vial centrifugation cultures using RSV-specific monoclonal antibodies (results after 1-3 days), direct fluorescent antibody tests (2 hr), enzyme immunoassays (2 hr), and, more recently, RT PCR. A problem with the rapid test methods is a relatively low sensitivity.181 This can be overcome by combining two rapid tests. On tissue sections from lung biopsy or autopsy specimens, virus-specific monoclonal antibody staining can be used. RSV. RSV is an RNA virus (paramyxovirus) that causes a wide spectrum of respiratory diseases ranging from life-threatening bronchiolitis in infants and potentially fatal pneumonia in transplant recipients to a mild upper respiratory infection (URI) in immunocompetent adults and older children. The virus is increasingly implicated in a number of respiratory illnesses in immunocompetent or mildly immunosuppressed individuals, such as otitis media, exacerbation of chronic obstructive lung disease, and community-acquired pneumonia. After HSCT and also in severely immunosuppressed nontransplant patients with hematologic malignancies,182 RSV causes URI, which may progress to fatal pneumonia.183 During the respiratory virus season (Fig. 11), the incidence is approximately 10% and both allogeneic and autologous transplant recipients may be infected (Table 5). In a large study, no risk factor other than the winter season and male gender could be identified for the acquisition of RSV in HSCT recipients.95 URI precedes pneumonia in 80% of patients and approximately 40–50% of patients with RSV URI progress to pneumonia after a median of 7 days; however, in 20% of patients with RSV pneumonia, URI is not present or very mild or occurs only concurrently with the onset of pneumonia. Risk factors for progression to pneumonia are older age and transplantation from an HLA mismatched or unrelated donor.95 Without treatment, RSV pneumonia is almost uniformly fatal.183 Pulmonary copathogens are detected in one-third of the patients with RSV pneumonia and require aggressive treatment. No controlled trials exist for the treatment of RSV infection and pneumonia in the HSCT setting. Available evidence comes from small uncontrolled cohort studies. The data suggest that treatment of early pneumonia (i.e., prior to mechanical ventilation) is associated with improved outcome. Intermittent short-duration aerosolized ribavirin (2 g over 2 hours three times per day) is considered the treatment of choice for RSV pneumonia. With this regimen, the 30-day all-cause mortality is approximately 45% at our center (Table 5). Systemic ribavirin alone does not seem to be effective, and can cause dermatologic toxicity.184,185 Whether combined oral and

HEMATOPOIETIC STEM CELL TRANSPLANTATION

aerosolized ribavirin is more effective than aerosolized ribavirin alone has not been studied. The role of concomitant IVIG or RSV-specific immunoglobulin remains unclear. Uncontrolled data suggest that high-titer antibody preparations may be required if such adjunctive therapy is given,186,187 although this issue has not been studied in a controlled fashion. Whether palivizumab,188 an RSVspecific monoclonal antibody directed at the F protein of

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RSV, is effective as adjunctive therapy for RSV pneumonia has not been studied. Due to the high mortality of RSV pneumonia, much interest has focused on prevention. Possible strategies are similar to those employed for prevention of CMV. While it is well established that RSV URI precedes pneumonia in the majority of cases,95 limited information is available on the extent of asymptomatic shedding of respiratory

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viruses in HSCT recipients.189,190 Currently, controlled studies are under way to evaluate the efficacy and toxicity of preemptive antiviral therapy based on RSV shedding190 or based on RSV URL95 Prophylactic measures recommended throughout the respiratory virus season included isolation of infected patients, hand washing prior to, and after, every patient contact, educational efforts targeted at health care personnel and family members, avoiding patient contact of health care personnel and family members with uncontrolled secretions, as well as influenza vaccination of health care personnel and family members.191,192 Whether pharmacologic prophylaxis (e.g., palivizumab, RSV-Ig) throughout the respiratory virus season is effective in preventing infection and disease in HSCT recipients has not been studied. Parainfluenza Viruses. Of the four types of parainfluenza viruses, parainfluenza virus 3 is most common (approximately 90%). Parainfluenza virus infection usually does not follow a seasonal pattern (Fig. 11). Overall, the incidence was 7% in two studies.94,193 Similar to RSV, URI is the predominant presentation, although progression to pneumonia seems to be less common (Table 5).94 The most important risk factor for the progression from URI to pneumonia is the use of systemic corticosteroids.94 Although the overall progression rate to pneumonia is only 18%, in allograft recipients receiving >1 mg/kg of prednisone, the risk is 40%, and is 65% with 2 mg/kg.94 Parainfluenza 3 pneumonia may also occur after autologous transplantation, although mainly in the setting of CD34 selection or use of high-dose steroids.94 Parainfluenza 3 pneumonia is often associated with serious pulmonary copathogens (53%) such as Aspergillus fumigatus. Factors associated with poor outcome after pneumonia include presence of copathogens and mechanical ventilation.94 Thus, aggressive diagnostic intervention (i.e., BAL) and therapy are indicated in patients with suspected parainfluenza pneumonia. In a large retrospective analysis both URI and pneumonia due to parainfluenza virus 3 were associated with overall mortality in multivariable models.94 Mortality of pneumonia ranges from 35 to 50%.94,176 In a retrospective analysis, neither aerosolized ribavirin nor IVIG led to improved outcome of pneumonia or a reduction in viral shedding following pneumonia.94 Randomized treatment studies have not been performed. Whether earlier treatment is effective in the prevention of pneumonia is unknown.194 Influenza Viruses. Influenza virus infections seem to be less common than RSV and parainfluenza virus infections. Both subtypes can cause infection, although

type A appears to be more common.177,178,195 Progression to severe pneumonia can occur similar to RSV and parainfluenza virus.195 Interestingly, the clinical presentation in HSCT often lacks myalgia, which is commonly seen in immunocompetent individuals. Fortunately, effective prevention is available for influenza, possibly explaining the somewhat lower incidence. As such, healthcare personnel, family members, and visitors are advised to get vaccinated against influenza early in the season. Antiviral therapy is available for influenza virus infection, but these agents have not been studied in HSCT recipients. Amantadine and rimantadine (with a more favorable side effect profile) are effective against influenza A in prevention and treatment of immunocompetent adults. During treatment, rapid emergence of resistance has been described. More recently, neuraminidase inhibitors (i.e., zanamivir, oseltamivir) became available.196,197 Both agents are active against influenza A and B and are potentially useful alone or in combination with rimantadine. Illustrative Case 4 A 27-year-old woman presents 24 days after matched-unrelated marrow transplant for AML in remission with bilateral interstitial pneumonia. The patient had a runny nose for 5 days and a cough for 3 days, no shortness of breath, but was otherwise without symptoms. Pretransplant serologies were negative for CMV (donor positive), positive for VZV, HSV, and Toxoplasma. The conditioning regimen consisted of cyclophosphamide and TBI, and she received cyclosporin A and methotrexate for GVHD prophylaxis. Engraftment occurred on day 18 after transplant. The patient developed skin GVHD on day 20 and treatment with steroids was initiated (2 mg/kg prednisone). CMV surveillance by the pp65 antigenemia assay has been negative. The patient is currently receiving prednisone (2 mg/kg), cyclosporin A, and daily dapsone for PCP prophylaxis. A BAL was performed and revealed RSV by direct fluorescent antibody staining and shell vial centrifugation cultures. Treatment with aerosolized ribavirin (2 g three times daily) was initiated and continued for 10 days. Comment. Pneumonia caused by community-acquired respiratory virus should be considered in an HSCT recipient, especially during the winter season. However, parainfluenza virus infection may occur yearround. The patient had upper respiratory symptoms for several days, which offered the first clue to the diagnosis. Since respiratory virus pneumonia is often associated with copathogens, a BAL is always recommended, even if the virus is recovered from the upper respiratory spaces. Institution of treatment before respiratory failure is important.

6.4. Mold Infections Although mold infections were discussed in the section describing preengraftment infections, it is important to note that the majority of Aspergillus pneumonias in allograft recipients actually occur after engraftment, corresponding to the period of acute GVHD (Fig. 6). One

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survey of Aspergillus infections in allograft recipients actually noted a median date of diagnosis of 136 days posttransplantation.50 Thus, the appearance of nodular pulmonary lesions in an allograft recipient postengraftment should be treated with antifungals and an aggressive approach to securing a diagnosis should be attempted. Although infections with Aspergillus spp. and Candida spp. are most common, a variety of fungi cause disease in HSCT recipients. Many are recognized as “emerging” pathogens and will likely continue to attract attention in these immunosuppressed hosts.198 Most infections are acquired by respiratory inhalation and are dependent on ongoing suppression (i.e., corticosteroids) to cause clinically recognized disease. It is noteworthy that endemic mycoses such as blastomycosis, histoplasmosis, and coccidioidomycosis occur infrequently in this setting.199 The explanations for this remain unexplained but it is possible that donor-derived cellular immunity is the reason such infections do not occur at a higher frequency. Other respiratory-acquired molds of importance include those caused by Zygomycetes. A series of HSCT patients revealed an incidence of 0.9% during the period of 1974 to 1989.37 Of 9 patients with disseminated infection, 6 had invasion into deep tissues and 10 of 13 patients died due to the infection. In this series, most (6 patients) were diagnosed at autopsy. Our recent experience suggests that this infection is currently being diagnosed more frequently antemortem in patients undergoing HSCT.200 From 1980 to 1999, 29 cases of invasive infection were diagnosed in our institution primarily in patients with severe GVHD. As non-Aspergillus mold infections appear to be increasing in frequency (Fig. 12), it has become important to seek microbial diagnoses to direct therapy. 6.5. Hepatosplenic Candidiasis Hepatosplenic candidiasis is a distinct clinical syndrome of invasive candidiasis, characterized by fever and hypodense liver and/or splenic lesions, usually appearing after engraftment. Histology of biopsied liver shows primarily chronic inflammation, with or without yeast forms.201 Cultures of blood and biopsy are frequently negative, and thus this diagnosis is primarily made radiographically, sometimes with histologic confirmation. A recent retrospective autopsy study of HSCT patients revealed a low incidence of hepatosplenic candidiasis (3%) in patients treated with prophylactic fluconazole compared to those who did not receive fluconazole (16%).49

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This emphasizes the importance of Candida albicans as an etiologic agent in this syndrome. Although rare in the azole prophylaxis era, hepatosplenic candidiasis carries a poor prognosis and aggressive treatment is critical. We favor a short treatment course with an amphotericin formulation (e.g., 2-4 weeks), with consideration of alternative oral agents for “maintenance therapy” while the patient has ongoing immunosuppression. Although this infection can be treated successfully with fluconazole in non-HSCT recipients, initial treatment should include amphotericin formulations.64 Patients who develop infection while on prophylaxis should be treated with antifungals having activity against azole-resistant Candida species in molds (i.e., amphotericin B). In refractory cases, combination with 5-flucytosine or fluconazole may be considered. Initial CT or MRI findings clear in the majority of patients but may get worse during therapy and persist as granulomas after successful treatment.202 6.6. Idiopathic Pneumonia Syndrome The most perplexing aspect of the syndrome of interstitial pneumonia has been the inability to identify an infectious agent in one third of patients with histologically demonstrated pneumonia.98 Idiopathic pneumonia is otherwise indistinguishable clinically and radiologically from CMV or Pneumocystis pneumonia. Time of onset is similar to that of other pneumonias, and the mortality rate is about 60%. Etiologies investigated for idiopathic pneumonia have included chlamydial pneumonia, Mycoplasma, BK virus, and Legionella pneumophilia.98,203 None of these studies has been revealing. Recently, human herpesvirus type 6 (HHV-6) has been implicated but controversy persists on the pathogenic role of HHV-6 in pneumonia after HSCT.203,204 Although it remains possible that a heretofore unknown infectious agent is responsible for idiopathic pneumonia, the present data suggest instead that it is the result of radiation and chemotherapy toxicity. These data reveal a lower risk among aplastic anemia patients who do not receive TBI, receipt of fractionated versus single-exposure TBI, and much lower dose rates of radiation. There are no specific recommendations about treatment. Steroids continue to be used without adequate controlled data.98 Empirical broadspectrum antimicrobial treatment is often given until final results of BAL and biopsies are available. AntiCMV therapy may be started until results of BAL are available in patients who are at high risk for CMV disease (i.e., seropositive recipients) who did not have adequate

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surveillance tests performed. Similarly, anti-Pneumocystis treatment may be started empirically in patients who did not receive PCP prophylaxis until results of BAL or biopsy are available. 6.7. Herpes Simplex Virus Infection There was a major shift in the epidemiology of HSV infection in the mid-1980s with the introduction of acyclovir. Without acyclovir prophylaxis, HSV infection usually begins during the granulocytopenic period when it is most difficult to differentiate oral mucosal breakdown (mucositis) from virus infection. Many progress to more typical herpetic lesions involving the lips and nose, although others have HSV recovered from oropharyngeal cultures without such lesions. Without antiviral prophylaxis, 80% of seropositive patients excrete HSV, mostly from the oropharynx, at some time during the first 50 days after transplant (peak excretion during weeks 2–3 after HSCT). By contrast, fewer than 1% of seronegative patients excrete HSV after transplant, and for most purposes (e.g., use of acyclovir prophylaxis), it can be assumed that seronegative patients are not at risk for HSV reactivation. Reactivation of HSV clearly increases the severity of oral mucositis. Untreated patients heal slowly, beginning with recovery of the granulocyte count, and lesions (and excretion) may recur later after HSCT. HSV was a common cause of esophagitis before the availability of acyclovir and has also been recovered from gastric and intestinal ulcers. Patients may develop distant cutaneous lesions, as well as herpes keratitis, through autoinoculation. Cutaneously disseminated HSV infection or encephalitis has been rare, however. One syndrome of note is HSV pneumonia which occurs with either preceding or coincident oral or genital HSV infection, or both.205 Herpetic whitlow has occurred among patient care personnel, and glove isolation should be used for patients with known oral herpes. Systemic acyclovir (intravenous or oral) has been highly effective in the treatment of established HSV infection after HSCT.206 Recommended treatment courses in patients with normal renal function are every 8 hr IV, 800 mg acyclovir PO three times daily, or 500 mg valaciclovir PO three times daily. In each case, the course should be a minimum of 7 days. Acyclovir treatment has been associated with delay in the specific immune response to HSV after HSCT,22 as well as with the recovery of HSV strains with reduced sensitivity to acyclovir.207 Neither of these observations should prevent the use of acyclovir for the treatment of active HSV infection after HSCT when warranted by the clinical situation.

Because of the predictable timing and high frequency of HSV reactivation among seropositive patients, acyclovir is recommended. Intravenous acyclovir given two or three times daily per dose), oral acyclovir (800 mg twice daily), or valaciclovir (500 mg twice daily) have been shown to be effective, although compliance with oral drugs may be a problem early after transplant due to myositis.71 Acyclovir prophylaxis is started 1 week before HSCT and continued for 4 weeks after transplant (unless the patient is discharged earlier and has no mucositis) to prevent HSV reactivation among seropositive patients. During the period of severe mucositis, (val)acyclovir is replaced with intravenous acyclovir twice daily). If prophylaxis is stopped 4 weeks after transplant, subsequent HSV reactivation will occur in approximately 30-40% of seropositive patients, but clinical manifestions are usually mild and treatable with acyclovir.35 Some patients have repeated reactivations of HSV which often are associated with a development of acyclovir resistance.207,208 The mechanism of acyclovir resistance is a deficient activity of the viral thymidine kinase (TK) and rarely an altered substrate affinity of the viral TK gene or an altered DNA polymerase. Foscarnet is the drug of choice for acyclovirresistant HSV infection (40 mg/kg three times per day).209 It should be noted that subsequent reactivations following acyclovir resistance are usually caused by wild-type HSV strains. Thus, acyclovir may be used in subsequent episodes of reactivation. Long-term suppression with acyclovir or valaciclovir is recommended if a patient has more than two episodes of HSV reactivation after transplant.

7. Phase III: After 100 Days Infections occurring after 100 days are determined in part by the residual immune deficiency shared by all patients and in part by the additional immunosuppression associated with chronic GVHD and its treatment. The most prominent example of infection determined by the former is VZV infection. A minority of patients with GVHD have an increased incidence of recurrent bacterial infections. The epidemiology of some infections (e.g., CMV) has changed over the last decade due to prevention strategies now routinely administered during the first 100 days after transplant (Fig. 1). 7.1. Varicella-Zoster Virus Infection Up to 40% of all HSCT patients develop VZV infection.30,210–213 Median time of onset is 5 months after trans-

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plant, and most cases occur within the first year. In a study of 92 patients with VZV infection transplanted during the pre-acyclovir era, 77 had herpes zoster, and 15 had varicellalike infection.30 In some patients, this was undoubtedly true primary infection, whereas others probably had atypical generalized zoster. One-third of patients with untreated herpes zoster had subsequent cutaneous dissemination. The case-fatality rate for untreated varicella is 35%, and is 30% for treated herpes zoster with dissemination. All deaths have occurred during the first 9 months after HSCT. Other syndromes of importance have included trigeminal zoster with keratitis, postherpetic neuralgia, and local scarring or bacterial superinfection. The incidence of VZV infection is increased among patients with allogeneic (versus autologous and syngeneic) transplants and among those with acute or chronic GVHD. However, if CD34 selection is used in autologous transplantation, the incidence and severity of VZV infection may be similar to those observed after allogeneic transplantation.214 In the subgroup of patients with chronic GVHD, patients with demonstrable nonspecific suppressor cells have the highest incidence.215 One study identified VZV seropositive allogeneic transplant recipients of age >10 years who received TBI as a subgroup at particular high risk for VZV infection (cumulative incidence at 3 years after transplant: 44%).210 Because of the high mortality rate from VZV infection after HSCT, treatment of all patients with VZV infection with acyclovir every 8 hr) is recommended. Treatment is continued for 7 days in uncomplicated cases but may be prolonged if patients have persistent new lesions or disseminated disease. In patients with localized zoster, treatment may be continued with valaciclovir (1000 mg three times per day) after 24 hours of IV treatment with acyclovir. VZV infection may recur after the initial episode. Oral acyclovir at a dose of 800 mg twice daily for 1 year prevents VZV infection after HSCT without rebound disease after discontinuation of prophylaxis, and may be particularly useful in patients with ongoing immunosuppression for GVHD after day 100.216 Strategies that use lower doses and shorter doses of acyclovir were ineffective in preventing VZV infection late after transplant.217

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and methotrexate were administered for GVHD prophylaxis. The early posttransplant course was complicated by neutropenic fever which resolved after administration of broad-spectrum antibiotics, acute GVHD of the skin (for which systemic corticosteroids were given), and the development of chronic GVHD. On physical exam, the patient had diffuse abdominal pain, maximum in the right upper quadrant, and positive bowel sounds. The rest of the exam was unremarkable. Laboratory findings included an AST level of 540 U/liter (1250 U/liter 4 hr later), and normal values for total bilirubin, serum amylase, absolute neutrophil count, and serum creatinine. Bacterial and fungal blood cultures as well as CMV pp65 antigenemia were all negative. An abdominal radiograph and CT were both normal. Within the first day after admission the patient’s status deteriorated rapidly and she died 48 hours after admission. In the hours before death, a few vesicular skin lesions were noted. Comment. A manifestation of VZV that is particularly difficult to diagnose is the VZV hepatitis that presents without skin lesions. Patients typically are VZV seropositive and present with moderate to severe abdominal pain, often in the right upper quadrant and sometimes only controllable by morphine derivatives, and no apparent skin lesions. Imaging studies are usually negative but transaminases rise rapidly (ALT >500 U/liter). Skin lesions usually occur 48-72 hr after the start of pain, may be low in frequency, and are always disseminated. The recognition of this manifestation of VZV requires a high level of suspicion by the transplant physician or Infectious Diseases consultant because the outcome is invariably fatal without prompt institution of empirical treatment with high-dose intravenous acyclovir every 8 hr).

7.2. CMV Disease Late CMV disease is now the major manifestation of CMV disease at many transplant centers.35,105,218 The majority of late disease occurs during the first year after transplant (median day of onset: 170), but there may be cases up until 3 years after transplant if immunosuppression continues. The clinical manifestation of late CMV disease is similar to that observed early after transplant (Table 6) with the exception of retinitis, which only occurred late after transplant in our experience.219 Outcome of late CMV disease is poor with pneumonia having the highest mortality. About one third of patients who survive the first episode of late disease will suffer a relapse after a median of 3 months.220 At 3 months after transplant, late CMV disease can be predicted by the presence of early CMV infection (e.g., pp65 antigenemia), and presence of GVHD.220 Continued monitoring (pp65 antigenemia, PCR for CMV DNA) of high-risk patients is useful in identifying patients at risk for late CMV disease.220

Illustrative Case 5 A 32-year-old female patient who underwent an HLA-matchedunrelated marrow transplant for AML presents on day 189 with severe abdominal pain, localizing to the right upper quadrant. The patient has no fever and no diarrhea. Pretransplant serologies were positive for CMV (donor negative), HSV, VZV, and Toxoplasma. The conditioning regimen consisted of cyclophosphamide and TBI, and cyclosporin A

Illustrative Case 6 A 27-year-old woman presented 145 days after matched-unrelated marrow transplant for AML in remission with cough and mild shortness of breath. A chest radiograph shows bilateral interstitial pneumonia. Pretransplant serologies were positive for CMV (donor negative), VZV, HSV, and Toxoplasma. The conditioning regimen consisted of cyclo-

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in patients with GVHD. The outcome of both mold and candidal infections in this setting remains poor. 7.4. Pneumocystis carinii Pneumonia

phosphamide and fractionated TBI, and the patient received cyclosporin A and methotrexate for GVHD prophylaxis. Engraftment occurred on day 20 after transplant. Subsequently, the patient developed skin and gut GVHD (day 28) and treatment with steroids was initiated (2 mg/kg prednisone). She was treated for CMV pp65 antigenemia from day 51 to 99 after transplant. Chronic GVHD was diagnosed on day 86. Current medication consists of prednisone (2 mg/kg), cyclosporin A, and daily TMP-SMX. A BAL showed CMV by shell vial centrifugation cultures, and no other copathogens. The patient died despite immediate start of treatment with ganciclovir and CMV-Ig. Comment. This is a typical case of late CMV pneumonia. Late CMV disease is an independent cause of late mortality in seropositive recipients. Prevention strategies for late CMV disease are needed. Since virologic markers are highly predictive for late CMV disease, patients who are at high risk for late CMV disease should have continued CMV surveillance by pp65 antigenemia or PCR and preemptive therapy. Since long-term monitoring may not be feasible in many cases, long-term prophylaxis with an oral agent (e.g., valganciclovir or valaciclovir) is currently being studied with regard to efficacy, feasibility, toxicity, and development of resistance.

7.3. Invasive Fungal Infections Late invasive aspergillosis appears to be an increasingly frequent event in allograft recipients with chronic GVHD and preceding viral infections.200 In contrast, candidiasis occurs infrequently after day 100. The long-term follow-up of a randomized study comparing fluconazole and placebo revealed that invasive candidiasis (blood or tissue infection) occurred in 8 of 96 patients who received placebo and 1 of 121 patients who received fluconazole for 75 days (p = 0.0068).80 Importantly, clinically extensive chronic GVHD was present in 66% of patients who developed disseminated infection. Thus, although invasive fungal infections are less common “late” after HSCT, invasive aspergillosis and candidiasis do occur, especially

With the availability of effective prophylaxis (Table 2) early cases are rarely seen and the majority of cases now occur late after transplant (Fig. 8).40 Most cases occur in patients who do not take the prescribed prophylaxis, are unable to tolerate TMP-SMX due to side effects or allergy, or receive ineffective alternative prophylaxis regimens. The optimal duration of prophylaxis after autologous transplant is currently unknown but recent data from our institution suggest that there is late PCP in autograft recipients as well.221 Thus, prolonged prophylaxis in some autograft recipients may be required. Approximately 15% of HSCT recipients require alternative prophylaxis regimens at some time after transplantation.222 Reasons for the need of alternative prophylaxis include allergy to TMP-SMX, gastrointestinal intolerance, increased transaminases, and neutropenia. In our experience, the use of intravenous pentamidine (4 mg/kg monthly or twice monthly up to 3 g total dose) as an alternative form of prophylaxis in TMP-SMX-allergic patients has not prevented PCP.222 Monthly aerosolized pentamidine has been advocated71 but there are only small reports on its efficacy in HSCT recipients. Dapsone given twice weekly was not effective in preventing PCP after HSCT.40 However, dapsone given daily at a dose of 50 mg twice daily provides a more effective alternative.34 Before starting dapsone, glucose-6-phosphate dehydrogenase deficiency should be ruled out. However, due to the superior results with TMP-SMX in both transplant and HIVinfected patients, it should be given whenever possible. Desensitization is therefore recommended in all patients with allergy to TMP-SMX40,222 and administration of alternative drugs should only be given until the underlying condition that required the discontinuation of TMPSMX has improved. There are no data on atovaquone in HSCT recipients. Although now infrequent, the outcome of PCP remains poor. In a recent review of 10 cases, the fatality rate was 70%.40 Without prophylaxis, the median time of onset of PCP is 9 weeks after HSCT, similar to that of other nonbacterial pneumonias. The clinical syndrome is indistinguishable both clinically and radiologically from other nonbacterial pneumonias. The diagnosis of P. carinii infection is established by either BAL, induced sputum, or thoracoscopic or open lung biopsy. Commonly used staining techniques include methenamine silver or immunofluorescence among others. The treatment of

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choice is intravenous TMP-SMX, at a dose of 15–20 mg/kg per day (TMP component) given as divided doses either every 6 or 8 hr among patients with normal renal function. Corticosteriods (40 mg prednisone twice a day for 5 days followed by 40 mg/day for 5 days and 20 mg/day for 11 days) are usually given in the beginning based on results in HIV-infected patients.223 Intravenous TMP-SMX is preferred for treatment because of uncertainties about absorption. Treatment with TMP-SMX is given for 14 days. Alternative agents used in the HIV setting include intravenous pentamidine, atovaquone, clindamycin/primaquine, dapsone/trimethoprim, and trimetrexate, but no data on treatment outcome are available for HSCT recipients. 7.5. Infections with Encapsulated Bacteria in Patients with Chronic GVHD Among 89 patients followed 6 months or longer after HSCT, only 30 (34%) remained free of infection.224 Twenty-five (28%) had three or more infections. Upper respiratory or pulmonary infections were most common. Ten patients had bacterial septicemia. In contrast to the early granulocytopenic period, when gram-negative bacteria were predominant, Streptococcus pneumoniae was the most common isolate in proven bacterial infection, followed by Staphylococcus aureus. Significant risk factors in the development of late infection were the occurrence of chronic GVHD, inability to respond to dinitrochlorobenzene skin sensitization, and male gender.31 The occurrence of pneumococcal bacteremia is especially intriguing. In some patients recurrent bacteremias may occur.34

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The presumed explanation for bacteremic pneumococcal infections is that HSCT patients lose and do not subsequently make opsonizing antibody to encapsulated gram-positive organisms, even after recovery from infection.31 Patients also respond poorly to immunization with prototype pneumococcal vaccines for the first 1–2 years after transplant, although the response again improves with time.225 It would seem unlikely that immunization with the available pneumococcal vaccine would provide significant protection for those most in need, patients with chronic GVHD.226 Antibacterial prophylaxis is recommended in patients with chronic GVHD to prevent both bacteremic pneumococcal and other infection (Table 2).71,226 While penicillin appears to work for this indication, the recent emergence of penicillin-resistant pneumococci makes it a less preferable choice.227 Rather, TMP-SMX given once daily (80 mg TMP component) provides protection against both PCP and encapsulated bacteria. Controlled data are not available to evaluate the efficacy of such prophylaxis, but a retrospective study of nonrandomized treatment groups indicates that patients with chronic GVHD who receive TMP-SMX prophylaxis have a significantly lower incidence of infection. Oral penicillins should be reserved for patients who are unable to tolerate TMP-SMX because of rash, GI side effects, or apparent marrow suppression. There is no reported experience with new quinolones or macrolides for this indication. Because infection with other organisms including both Staphylococcus species and gram-negative aerobic bacteria also occurs, empirical antibiotic treatment of

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HSCT patients admitted with clinical sepsis should include broad-spectrum coverage until the identity of the infecting organisms is known. 7.6. Late Poor Graft Function Associated with Infections Late graft failure may be due to infection. However, the diagnosis is often difficult to establish. Infections that have been associated with impaired graft function are CMV, HHV-6, and human parvovirus B 19. Noninfectious causes such as drug toxicity (e.g., TMP-SMX, mycophenolate, ganciclovir) and hematologic causes such as relapse and rejection must be ruled out. Generally, a bone marrow biopsy is required to make the diagnosis. Techniques used to diagnose organisms in the marrow aspirate include PCR, culture, and immunohistochemistry. Longterm marrow cultures can be used to detect infection of stromal cells.136 One potential problem in the interpretation of PCR results from marrow samples is the concomitant detection of DNA in the peripheral blood, which might contaminate the marrow sample. However, it should be pointed out that CMV-related graft failure can occur in the absence of a detectable systemic viral load.136 An operational definition for infection-related graft dysfunction is poor graft function in the absence of other possible causes (i.e., drugs, hematologic causes) and detection of the organism in the marrow aspirate. Since definitive proof of a causative role of the infectious organism is often not possible in a timely fashion, an empiric course of antimicrobial therapy seems reasonable. 8. Other Infections 8.1. Parasitic Infections Toxoplasmosis appears to be rare after transplantation.228–230 Disease has occurred exclusively among patients seropositive before HSCT, and thus appears to be caused by reactivation of latent infection. Involvement of heart, lung, and brain has been identified at postmortem examination. As in other immunocompromised hosts, serologic studies are usually unrevealing, and biopsy of implicated organs may be needed for diagnosis. However, cultures or PCR may be used to detect Toxoplasma in blood.231 A review in European centers showed that no clinical cases of posttransplant toxoplasmosis occurred in autologous HSCT recipients, while the incidence was 0.93% in the allogeneic population. Almost one-third of patients had received T-cell-depleted allografts. The brain was the most commonly affected organ (89% of cases)

with lung (49%), liver, heart, and spleen also involved. Dissemination frequently occurs prior to the development of CNS symptoms, which may be associated with fever, pneumonia, or hepatitis.229 Prophylaxis is warranted for high-risk patient populations such as Toxoplasma seropositive HSCT recipients, particularly those receiving manipulated allografts (i.e., T cell depleted or CD34 selected). Primary prophylaxis usually consists of TMPSMX (at least four double-strength tablets/week), which also provides protection against PCP. Alternatives include pyrimethamine (25 mg/day), though additional measures must be considered for PCP prophylaxis. Prospective screening with PCR may be effective for directing preemptive therapy, but the data are insufficient at this time. Treatment is with pyrimethamine and sulfadiazine. Alternative treatment options include pyrimethamine and clindamycin, or more recently, atovaquone.230 Treatment for several months may be required. Cryptosporidiosis also appears to be very rare after HSCT. Clinical manifestations include diarrheal illnesses and sometimes also pneumonia.232,233 No controlled treatment data exist. Antimicrobials that have been used include spiramycin and paromomycin alone or in combination with azithromycin.234,235 8.2. Legionellosis Legionellosis is a rare but potentially fatal infection after HSCT.236,237 Non-pneumophila species account for about half of the cases. Pneumonia is the principal clinical manifestation but unusual presentations such as pericarditis have been described. Risk factors have not been identified. The hospital water system is a potential source of the infection and should be tested if the incidence changes suddenly.238 Diagnostic tests include culture, direct fluorescent antibody test, urine antigen tests (L. pneumophila only), and the modified Hiemenez stain, which detects acid-fast bacteria on tissue sections.236 PCR will probably replace some of these techniques in the future.239 No controlled treatment studies have been published but most patients respond to antimicrobial chemotherapy consisting of quinolones or erythromycin and rifampicin for at least 3 weeks. Longer treatment may be required.236,237 8.3. Epstein-Barr Virus Epstein-Barr virus (EBV) is a DNA virus of the herpesvirus group. It can cause lymphoproliferative disease in transplant recipients (see also Chapter 10). This occurs mainly in T-cell-depleted allograft recipients.240–243

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However, therapies directed at T cells such as ATG are also associated with a higher risk. Cases have also been described in CD34-selected autograft recipients who received rabbit ATG.244 Monitoring of EBV by quantitative PCR may prove useful for predicting the disease.245,246 Initial results with rituximab, an anti-CD20 monoclonal antibody, are encouraging.247 Donor lymphocyte or EBVspecific T cell therapy appears useful when given prophylactically.248 However, T cell therapy for established disease may be associated with toxicity.248,249 8.4. HHV-6, -7, and -8

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studies. Intravenous ribavirin has been used, but without success in recent studies.34,266,267 Recently, cidofovir has been shown to have in vitro activity and initial small case series show promising results.268 8.6. Hepatitis Viruses

The impact of hepatitis viruses on transplantation outcome has been reviewed extensively.269 Hepatitis B virus is more likely than hepatitis C virus to cause severe clinical hepatitis and death from posttransplant liver disease.270 However, these events are still relatively rare. Hepatitis C is a risk factor for venoocclusive disease of the liver and may cause late cirrhosis and liver failure.271 Screening of donor and recipient is important for appropriate counseling and potential therapy.269 While antiviral therapy exists for both hepatis B and C virus, these therapies have not been evaluated in the HSCT setting.

HHV-6 and -7 are herpesviruses (similar to CMV), while HHV-8 is a herpesvirus (similar to EBV). HHV-6 and -7 are reviewed in detail in Chapter 10. Several longitudinal studies have examined the role of HHV-6 after HSCT.250–253 HHV-6 reactivates early after transplant and can be detected in the blood at a median of day 20 after transplant, usually before CMV. Type B is far more common than type A. The search for a clinical syndrome associated with HHV-6 revealed rash, a CNS syndrome consisting of encephalitis and impaired memory,254 a possible association with interstitial lung disease,204,255 and an association with delayed platelet engraftment.253 Secondary graft failure has been documented in case reports.256 PCR has been used to diagnose HHV-6-associated encephalitis.254 Whether monitoring for HHV-6 viremia is useful in predicting these clinical syndromes is not known. In solid organ transplant recipients, there seems to be an interaction between HHV-6 and CMV.257,258 Whether such interaction exists after HSCT has not been studied. Both foscarnet and ganciclovir have in vitro activity against HHV-6 and have been used in patients. No controlled treatment data exist. The impact of HHV-7 after HSCT has been examined in two longitudinal studies but no correlation with clinical disease was found. There was, however, a possible association with CMV infection.250 HHV-8 is associated with Kaposi’s sarcoma in HIV-infected individuals. Two recent reports suggest that it can cause a febrile syndrome and marrow failure in HSCT recipients.259,260

Polyomaviruses are DNA viruses that can cause disease in HSCT recipients. BK virus is a cause of posttransplant hemorrhagic cystitis.272 Although BK virus is often detected in urine by PCR, an association with clinical symptoms may be difficult to prove.273 Detection in blood was not associated with hemorrhagic cystitis in one study.274 In a study of pediatric HSCT recipients BK virusassociated hemorrhagic cystitis occurred between day 24 and 50 after transplant in 9 of 117 patients. Infection was characterized by a long duration, correlated with use of busulfan, and resulted in bladder tamponade in 2 of 9 patients.275 One case of BK virus-associated pneumonia has been reported.276 There is no established treatment. Cidofovir has activity in vitro but there are only anecdotal treatment results to date.277 JC virus is the cause of progressive multifocal leukoencephalopathy in immunosuppressed patients. Several cases have been reported after HSCT.278,279 PCR detection of JC virus in the cerebrospinal fluid is used for diagnosis.280 Cidofovir has activity in vitro but little is known about its in vivo efficacy.281

8.5. Adenovirus

8.8. Parvovirus B 19 261–263

Adenovirus infections are common after HSCT, and some recent reports suggest that they may be increasing, possibly related to transplantation practices (e.g., T cell depletion).264 Clinical manifestations include pneumonia, hepatitis, diarrhea, nephritis, cystitis, and eye infections.261,263,265 There are no controlled treatment

8.7. BK and JC Viruses

Parvovirus B 19 can infect erythroid progenitor cells. In addition to transient marrow failure, parvovirus B 19 can cause chronic anemia and rarely pancytopenia in HSCT recipients.282,283 PCR is useful as a diagnostic tool.283 IVIG is effective in treating parvovirus B 19 symptomatic infection.284 Prophylactic IVIG seems to

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have a protective effect against parvovirus B 19, although this has not been established in a randomized study.285 8.9. Other Viral Infections

Infections with human papillomavirus (HPV) rarely occur after transplant.286 In one series, 3 of 238 allogeneic HSCT recipients developed anogenital condylomata associated with HPV.286 8.10. Mycobacterial Infections

General aspects of mycobacterial infections are reviewed in Chapter 7. In nonendemic regions for Mycobacterium tuberculosis (TB), atypical mycobacteria are significantly more common.45,287 Atypical mycobacteria occur in both allogeneic and autologous transplant recipients. However, unrelated and HLA mismatched related transplant recipients seem to have the highest incidence.45 The overall incidence in two large studies was 0.26– 0.76% in autologous patients, and 0.37–0.6% in allograft recipients, with a predominance in unrelated transplant recipients (1 versus 0.22% in matched-related allograft recipients). Clinical manifestations of infections with rapid-growing atypical mycobacteria include bacteremia and central line infections with or without fever (Fig. 13). Pulmonary infections are rare but invasive pulmonary disease does occur. For the diagnosis of pulmonary disease, tissue biopsy is required, as colonization is common.45 Infection responds to combination antibiotic treatment, although removal of the catheter is mandatory. If tunnel infection is present, surgical debridement may be

necessary.45 The duration of treatment of infection caused by atypical mycobacteria is 4 weeks for line-associated infections with rapid-growing organisms, 2–3 weeks for exit site infection without bacteremia, 6–8 weeks for tunnel infections or bacteremia, and 6 months for biopsyproven pulmonary disease.45 M. tuberculosis only rarely causes disease in nonendemic regions but is a common problem in endemic areas. The incidence of TB after transplantation varies from 0.05% in nonendemic areas to 1.4–5.5% in endemic areas such as Turkey or Hong Kong.45,287–289 Clinically, pulmonary TB is the most common manifestation, followed by extrapulmonary and disseminated forms. Risk factors include allogeneic transplant, GVHD, and conditioning with TBI. Limited data are available on the management of clinical TB in HSCT recipients. The use of rifampin often causes problems due to drug interactions and liver toxicity. Alternatives to rifampin include quinolones, beta-lactam antibiotics with beta-lactamase inhibitors (not preferred for long-term use), and streptomycin. However, longer duration of treatment is required with these alternative regimens (especially with regimens without streptomycin) due to slow bacterial responses. Prevention strategies recommended in endemic and nonendemic areas consist of tuberculin skin testing of the recipient and donor and administration of prophylaxis with isoniazid for 6–12 months given to positive reactors.288 Alternative options for prophylaxis include rifampin plus pyrazinamide, rifampin alone, or a combination of quinolones and ethambutol. Healthcare workers in contact with transplant recipients should be regularly tested for tuberculosis.

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8.11. Nocardiosis General aspects of nocardial infections are reviewed in Chapter 7. Nocardiosis is a rare late complication after HSCT (median day of onset 226 days).290,291 Nocardia asteroides complex accounted for 96% of the isolates in one study. Infection occurs predominantly in allograft recipients.291 Nocardiosis has been observed in patients who received intermittent prophylaxis with TMP-SMX for prevention of PCP. The clinical manifestation consists of pulmonary and disseminated disease.292 Response to treatment with TMP-SMX alone or in combination with synergistic agents is usually good.291

9. Pretransplant Infectious Disease Considerations 9.1. Pretransplant Infections As a general principle, patients with active infections should not be transplanted. However, little specific information has been published regarding the optimal duration of pretransplant treatment and subsequent risk. Often one has to balance the need to treat pretransplant infections with the urgent requirement of transplantation due to the progression of the underlying disease. 9.1.1. Invasive Fungal Infections before Transplantation Many patients undergoing HSCT have experienced previous episodes of acute candidiasis (i.e., candidemia) and suffer no apparent consequences during the HSCT course. The impact of other, more chronic fungal infections such as hepatosplenic candidiasis and invasive aspergillosis is of more concern. One study has documented that patients with a history of hepatosplenic candidiasis can undergo HSCT while maintained on a low dose (0.5 mg/kg per day) of amphotericin B while neutropenic.293 In this study, 11 of 15 (73%) patients followed prospectively had persistently abnormal CT scans during HSCT, although only 3 of 15 died with evidence of progressive fungal infection. Currently we administer amphotericin B during neutropenia, followed by fluconazole postengraftment in patients undergoing HSCT. Although invasive aspergillosis carries a grim prognosis in patients with hematologic malignancies, it is not uncommon to successfully treat this infection in a patient receiving induction or consolidation chemotherapy.52 One recent retrospective analysis of 48 patients with documented or probable invasive aspergillosis and subsequent HSCT with amphotericin coverage revealed that

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the overall incidence of relapsed fungal infection was low (33%); however, the study included mainly good-risk patients.294 Once aspergillosis relapsed after transplant, the success of treatment was poor (12%).294 In this series of patients, conditioning with busulfan and cyclophosphamide was associated with a beneficial outcome compared to those patients who received combined TBI. Although the role of surgical resection and the optimal prophylaxis regimen have yet to be denned, previous fungal infection is not an absolute contraindication for subsequent HSCT.53,294 Secondary treatment and prophylactic regimens should be developed on an individual patient basis, with consideration for previous fungal, viral, and bacterial infections experienced prior to HSCT. Additional use of prophylactic granulocyte infusions from G-CSF-stimulated donors is given on an experimental basis in patients with pretransplant aspergillosis. 9.1.2. Bacterial Infections Bloodstream infections, sinusitis, pneumonia, and other invasive infections should be treated with appropriate antibiotics for 2 weeks or until recovery. For specific infections (e.g., mycobacterial infections), extended pretransplant treatment courses are required.45 Whether specific prophylaxis should be given throughout the preengraftment period has not been studied for most bacterial infections. It is our policy to choose antibacterials for empirical treatment of fever that are active against the pathogens documented before transplant. For severe pretransplant infections (e.g., mycobacterial infections), we continue treatment throughout the posttransplant period (i.e., 3–6 months) with no detectable relapse.45 9.1.3. Viral Infections For pretransplant RSV or parainfluenza virus infections, most transplant centers postpone the transplant until resolution and cessation of viral shedding, especially when an allogeneic transplant is planned. However, the issue has not been studied systematically and there is some evidence that low-risk autologous transplant patients may be transplanted without adverse outcome.295 More studies are needed to define which patients require postponing the transplantation procedure. Use of prophylaxis (e.g., RSV-Ig, palivizumab) during transplant in patients with pretransplant respiratory virus infections has not been studied. CMV disease has been reported in patients with hematologic malignancies who have received intense chemotherapy and in patients with T cell immunodefi-

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ciencies.34 There is a wide spectrum of severity ranging from mild pneumonia which resolves without treatment, to fatal disease. Although the disease seems to respond to antiviral agents alone in most cases, relapse after transplantation is common and associated with a high fatality rate if the patient is transplanted within 6 months of the disease.34 Thus, we recommend prophylaxis throughout the posttransplant course (at least 3 months), starting with foscarnet until engraftment followed by ganciclovir or foscarnet.

prior travel to malaria-endemic areas, (2) suitable donors can be scheduled for hematopoietic stem cell donation any time after they have completed the 4-week prescribed antimalaria prophylaxis following return from travel, and (3) suitable donors who have traveled to malaria-endemic areas in the preceding 6 months, and have not received antimalaria prophylaxis, should be evaluated for malaria at the time of donor workup. For additional donor issues see the CDC guidelines for preventing opportunistic infections among HSCT recipients.71

9.2. Donor Issues

All donors should be in good health at the time of marrow or stem cell donation. However, since stem cell donors are limited, risks and benefits of using a donor who might transmit an infection may have to be weighed in individual cases. Donations following exposure to infectious diseases that have a viremic phase should be avoided within the incubation time of the infection. Serologic testing should be done within 1–2 months before transplant.71 For a CMV seronegative recipient, a CMV seronegative donor is the preferred choice, if possible, due to an increased mortality with CMV seropositive donors even with CMV antigenemia-guided ganciclovir treatment.34 Stem cell donations from donors with current or previous hepatitis have been reviewed comprehensively.269 There is a risk of transmission if the donor has active hepatitis B (HBsAg positive) or C (HCV RNA positive) and alternative donors should be considered. Donors infected with HIV are usually not used. Also, people with active TB should not donate.71 The stem cell products are screened by culture at the time of harvest but results are often not available at the time of infusion. Antimicrobial therapy of the recipients may be required in rare cases when culture results become positive subsequently. Transplantation during incubation time after proven or potential exposure of the donor should be avoided. Also, stem cell donations directly following vaccination with live-virus vaccine (e.g., polio) should be avoided, although no adverse outcome results have been reported. With regard to travel into malaria-endemic areas, blood bank guidelines for blood donations apply (i.e., donors are deferred for 1 year after travel to malariaendemic areas and for 3 years donors who have resided in malaria-endemic areas or who have a history of malaria).71 However, if the only suitable donor does not fit these criteria and immediate transplantation is required, stem cell donation may be considered. In these cases, we use the following guidelines: (1) the team caring for the recipient should be alerted about the stem cell donor’s

10. Infection Control Programs and Surveillance 10.1. Isolation Practices

The use of a protective environment (i.e., laminar airflow isolation) is increasingly controversial among transplanters. Our center abandoned the practice several years ago for all patients. General infection control procedures consist of a private room and careful handwashing.71 Increased isolation methods are used in specific situations, i.e., contact isolation consisting of gowns and gloves for infection or colonization with enteric pathogens (e.g., VRE, C. difficile) or highly resistant organisms (e.g., MRSA, multiresistant gram-negative organisms). Respiratory isolation is used for respiratory viruses and VZV (masks, gowns, gloves, and eye protection).71 For disseminated VZV infection, the patient is placed in a negative pressure room with double doors. The use of the protective environment remains a controversial issue in 2000, nearly 30 years after inception of the concept. The protective environment is defined as an infection control program consisting of skin cleansing, topical and oral nonabsorbable or absorbable antibiotics, sterile food, and a laminar airflow room.296 A protective environment has theoretical benefits in addition to infection control for HSCT patients.296 Both graft rejection and GVHD may be influenced by reduction in endogenous bacterial flora and infection.297 However, only a few randomized trials have been performed. Among patients transplanted for aplastic anemia, those treated in the protective environment had significantly less acute GVHD compared with patients not transplanted in the protective environment.298 This effect was also associated with significantly better survival after transplant. Patients with leukemia have not shown such statistically significant benefits, although the incidence of acute GVHD has been lower and survival somewhat better among those transplanted in the protective environment. A recent study by Beelen et al. has renewed interest

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in the question of whether reduction in endogenous bacterial flora and infection can reduce acute GVHD.69 In a nonblinded, randomized study, patients transplanted under laminar airflow conditions who received ciprofloxacin and metronidazole prophylactically had a lower incidence of acute grade 2–4 GVHD than patients who received ciprofloxacin alone. The effect was only seen in matched-related transplant recipients and was associated with a decrease in the anaerobic flora. Overall survival and the incidence of chronic GVHD were not affected but there was also a trend toward improved survival in matched-related patients.69 There are several unresolved questions regarding the use of the protective environment. Although the recent study by Beelen et al.69 is intriguing and there may be a reduced incidence of early invasive Aspergillus infections in patients transplanted in laminar airflow rooms,39 several recent developments in transplantation practices put the concept into question. These changes include improved methods of prevention of GVHD, availability of HEPA filtration, shorter time to engraftment, and finally cost effectiveness. Indeed, many transplant centers in North America have abandoned the concept entirely (including for patients with aplastic anemia) and use HEPA filtration instead. Perhaps the most important question is whether a laminar airflow room is actually required when HEPA filtration is used and whether effective reduction in endogenous bacterial flora can be accomplished without using laminar airflow room isolation practices. Since oral antibiotics and antifungal agents with good tolerability such as fluoroquinolones, metronidazole, and azoles are now available, this issue should be addressed in a randomized study. Another important issue is the trend to shorten the inpatient stay dramatically. A shorter inpatient stay would thereby further reduce the potential benefit of the laminar airflow room. 10.2. Use of Surveillance Culture The use of “surveillance” cultures has been debated for some time, and many procedures differ between institutions. It is accepted that granulocytopenic patients usually become infected by resident organisms, either those “endogenous” organisms brought into the hospital with the patient, which include normal flora, or those acquired “exogenously” from the hospital environment and which have become part of the patient’s flora after admission (e.g., resistant Staphylococcus, Enterococcus, Pseudomonas, Candida, or molds). Thus, with the exception of patients monitored serially for study of specific infectioncontrol programs, we obtain bacterial and fungal cultures

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(oropharynx, rectum, vagina) only at admission. Others continue to monitor for resistant organisms. During febrile granulocytopenic periods, blood cultures are often obtained daily, although a recent study suggests that the continued culturing only rarely provides useful information.299 We perform blood culture surveillance three times a week in patients who receive systemic corticosteroids regardless of neutrophil counts (due to the fever-masking effect of corticosteroids). Additional cultures from clinically relevant sites are obtained any time infection is suspected. We perform weekly mouth washes for the detection of mold, and administer preemptive therapy with amphotericin drugs if these cultures turn positive. Viral surveillance testing is performed for CMV in all patients and is the basis for preemptive treatment strategies.71 The frequency is generally weekly; however, some high-risk patients (e.g., patients after T cell depletion, CD34 selection, during high-dose corticosteroid therapy) may benefit from twice-a-week monitoring during high-risk periods. For respiratory viruses, nasal washes are performed everytime the patient has upper respiratory symptoms (targeted surveillance). Results can be used for preemptive therapy as well as for infection control purposes (duration of isolation). Whether weekly surveillance during the respiratory virus season is useful has not been established. 10.3. Prevention of Exposure by Personnel, Family Members, and Visitors Personnel, family members, and visitors with communicable diseases should be restricted from contact with HSCT recipients. This includes patients with symptoms of URI and those exposed to or with clinical VZV infection.71 In addition to the widely recommended handwashing procedures before and after each patient contact, we have recently instituted a “sign-in” procedure during the respiratory virus season in which all members of the personnel (including the medical staff), family members, and visitors are asked daily to confirm with their signature that they are free of URI symptoms (i.e., uncontrolled secretions). All individuals with uncontrolled secretions are restricted from patient contact until symptoms have disappeared. For VZV, vaccination of all family members and visitors with a negative history for chickenpox is advised prior to arrival at the transplant center.71 This advice should be given during the first contact with the transplant center, thereby allowing necessary time to get the vaccination completed before arrival. Once a contact person has been exposed or infected with VZV, this per-

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son will be restricted from contact with the transplant recipient, usually from 8 to 22 days after exposure or until all lesions are crusted, whichever occurs later. 10.4. Postexposure Prophylaxis Postexposure prophylaxis is recommended in VZV seronegative transplant recipients. VZV-specific immunoglobulin is the standard of care (400 mg/kg). Postexposure use of acyclovir has been reported to ameliorate the disease in immunocompetent patients.300 Because of the potentially fatal outcome of primary varicella infections, we use postexposure valaciclovir (3 g three times per day) from day 3 to 22 following exposure, in addition to VZVspecific immunoglobulin. After an exposure of seronegative family members or caretakers, we recommend isolation as outlined above. If it is not feasible to isolate the patient during this time period, postexposure valaciclovir or postexposure immunization301 may be considered. This strategy is aimed at reducing infectivity of the index case and thereby potentially also reducing the risk of transmission to the patient. 10.5. Immunization Immunization guidelines for HSCT recipients are summarized in the Guidelines for Preventing Opportunistic Infections Among HSCT Recipients, a consensus statement issued by the Centers for Disease Control and Prevention, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation.71

11. Conclusions and Future Considerations Major progress has been made in the diagnosis and prevention of infections in HSCT over the last decade. Perhaps the most impressive examples are the prevention of CMV disease by ganciclovir and of early Candida albicans infections by fluconazole. However, many issues in the care of the HSCT recipient remain unresolved. Invasive mold infections are now the leading infectious cause of death at many centers. Thus, there is a great need for improved diagnosis of fungal infections, as well as for prevention and treatment. Although early CMV disease has been reduced significantly with preemptive treatment or prophylactic strategies, CMV continues to have a significant impact on morbidity and mortality. Late CMV disease remains a clinical problem in patients with continued immunosup-

pression. Prevention strategies are urgently needed to address this question. Options include long-term antiviral prophylaxis or preemptive treatment strategies based on virologic monitoring as well as immunotherapy strategies such as adoptive transfer of donor-derived T cells. Improved treatment strategies for CMV pneumonia are required due to the persistently poor outcome with ganciclovir and CMV-Ig or IVIG. Thus, antiviral combination strategies, including agents with different mechanisms of action, should be studied. Respiratory viruses have been recognized as cause of fatal pneumonia after HSCT. RSV and parainfluenza viruses can cause severe pneumonias after HSCT. Infection control strategies including vaccination against influenza of susceptible family members and patient care personnel are critical for prevention. The impact of new transplantation techniques such as CD34 selection and non-myeloablative conditioning regimens on risk for infection requires careful evaluation and possibly adjustment of prevention strategies. Infections occurring in long-term survivors of HSCT are related both to the persistence of immunologic defects and to the additional effects of chronic GVHD and its treatment. Current prevention strategies using chemoprophylaxis are far from perfect, and novel means of augmentation of late immune reconstitution (e.g., vaccination, adoptive transfer of antigen-specific T cells, IL-2) as well as better prevention and treatment for GVHD are needed. ACKNOWLEDGMENTS. Earlier editions of this chapter were written by Raleigh Bowden, M.D., and the late Joel D. Meyers, M.D. We thank T. Chauncey, M.D., for providing the figure on the incidence of Pneumocystis carinii pneumonia and Julio Gonzales, M.D., for providing Case 3. Michael Boeckh and Kieren Marr were supported in part by grants awarded by the National Institute of Health Cancer Institute (CA 18029 and KO-8 AI1571).

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230. Roemer E, Blau W, Basara N, et al: Toxoplasmosis, a severe complication in allogeneic hematopoietic stem cell transplantation: Successful treatment strategies during a 5-year single-center experience. Clin Infect Dis 32:1–8, 2001. 231. Held TK, Kruger D, Switala AR, et al: Diagnosis of toxoplasmosis in bone marrow transplant recipients: Comparison of PCR-based results and immunohistochemistry. Bone Marrow Transplant 25:1257–1262, 2000. 232. Kibbler CC, Smith A, Hamilton-Dutoit SJ, et al: Pulmonary cryptosporidiosis occurring in a bone marrow transplant patient. Scand J Infect Dis 19:581–584, 1987. 233. Manivel C, Filipovich A, Snover DC: Cryptosporidiosis as a cause of diarrhea following bone marrow transplantation. Dis Colon Rectum 28:741–742, 1985. 234. Smith NH, Cron S, Valdez LM, Chappell CL, White AC Jr: Combination drug therapy for Cryptosporidiosis in AIDS [see comments]. J Infect Dis 178:900–903, 1998. 235. Nachbaur D, Kropshofer G, Feichtinger H, Allerberger F, Niederwieser D: Cryptosporidiosis after CD34-selected autologous peripheral blood stem cell transplantation (PBSCT). Treatment with paromomycin, azithromycin and recombinant human interleukin-2. Bone Marrow Transplant 19:1261–1263, 1997. 236. Harrington RD, Woolfrey AE, Bowden R, McDowell MG, Hackman RC: Legionellosis in a bone marrow transplant center. Bone Marrow Transplant 18:361–368, 1996. 237. Meletis J, Ariet G, Dournon E, et al: Legionnaires’ disease after bone marrow transplantation. Bone Marrow Transplant 2:307– 313, 1987.

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238. Kool JL, Fiore AE, Kioski CM, et al: More than 10 years of unrecognized nosocomial transmission of Legionnaires’ disease among transplant patients [see comments]. Infect Control Hosp Epidemiol 19:898–904, 1998. 239. Cloud JL, Carroll KC, Pixton P, Erali M, Hillyard DR: Detection of Legionella species in respiratory specimens using PCR with sequencing confirmation. J Clin Microbiol 38:1709–1712, 2000. 240. Zutter MM, Martin PJ, Sale GE, et al: Epstein–Barr virus lymphoproliferation after bone marrow transplantation. Blood 72:520– 529, 1988. 241. Shapiro RS, McClain K, Frizzera G, et al: Epstein–Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood 71:1234–1243, 1988. 242. Hale G, Waldmann H: Risks of developing Epstein–Barr virusrelated lymphoproliferative disorders after T-cell-depleted marrow transplants. CAMPATH users. Blood 91:3079–3083, 1998. 243. Papadopoulos EB, Carabasi MH, Castro-Malaspina H, et al: T-cell-depleted allogeneic bone marrow transplantation as postremission therapy for acute myelogenous leukemia: Freedom from relapse in the absence of graft-versus-host disease. Blood 91:1083–1090, 1998. 244. Nash RA, Dansey R, Storek J, et al: EBV-associated PTLD after high-dose immunosuppressive therapy and autologous CD34– selected stem cell transplantation for severe autoimmune diseases. Blood 96(Suppl):406a (abstract 1747), 2000. 245. Lucas KG, Filo F, Heilman DK, et al: Semiquantitative Epstein– Barr virus polymerase chain reaction analysis of peripheral blood from organ transplant patients and risk for the development of lymphoproliferative disease. Blood 92:3977–3978, 1998. 246. Gustafsson A, Levitsky V, Zou JZ, et al: Epstein–Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: Prophylactic infusion of EBV-specific cytotoxic T cells. Blood 95:807–814, 2000. 247. Kuehnle I, Huls MH, Liu Z, et al: CD20 monoclonal antibody (rituximab) for therapy of Epstein–Barr virus lymphoma after hemopoietic stem-cell transplantation. Blood 95:1502–1505, 2000. 248. Bollard CM, Rooney CM, Huls MH, et al: Long term follow-up of patients who received EBV specific CTLs for the prevention or treatment of EBV lymphoma. Blood 96(Suppl):478a, 2000 (abstract 2057). 249. Papadopoulos EB, Ladanyi M, Emanuel D, et al: Infusions of donor leukocytes to treat Epstein–Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation [see comments]. N Engl J Med 330:1185–1191, 1994. 250. Wang FZ, Dahl H, Linde A, et al: Lymphotropic herpesviruses in allogeneic bone marrow transplantation. Blood 88:3615–3620, 1996. 251. Cone RW, Huang ML, Corey L, et al: Human herpesvirus 6 infections after bone marrow transplantation: Clinical and virologic manifestations. J Infect Dis 179:311–318, 1999. 252. Kadakia MP, Rybka WB, Stewart JA, et al: Human herpesvirus 6: Infection and disease following autologous and allogeneic bone marrow transplantation. Blood 87:5341–5354, 1996. 253. Ljungman P, Wang FZ, Clark DA, et al: High levels of human herpesvirus 6 DNA in peripheral blood leucocytes are correlated to platelet engraftment and disease in allogeneic stem cell transplant patients. Br J Haematol 111:774–781, 2000. 254. Wang FZ, Linde A, Hagglund H, et al: Human herpesvirus 6 DNA in cerebrospinal fluid specimens from allogeneic bone marrow transplant patients: Does it have clinical significance? Clin Infect Dis 28:562–568, 1999.

255. Buchbinder S, Elmaagacli AH, Schaefer UW, Roggendorf M: Human herpesvirus 6 is an important pathogen in infectious lung disease after allogeneic bone marrow transplantation [In Process Citation]. Bone Marrow Transplant 26:639–644, 2000. 256. Carrigan DR, Knox KK: Bone marrow suppression by human herpesvirus-6: Comparison of the A and B variants of the virus [letter; comment]. Blood 86:835–836, 1995. 257. Mendez JC, Dockrell DH, Espy MJ, et al: Human beta-herpesvirus interactions in solid organ transplant recipients. J Infect Dis 183:179–184, 2001. 258. Griffiths PD, Ait-Khaled M, Bearcroft CP, et al: Human herpesviruses 6 and 7 as potential pathogens after liver transplant: Prospective comparison with the effect of cytomegalovirus. J Med Virol 59:496–501, 1999. 259. Luppi M, Barozzi P, Schulz TF, et al: Nonmalignant disease associated with human herpesvirus 8 reactivation in patients who have undergone autologous peripheral blood stem cell transplantation [In Process Citation]. Blood 96:2355–2357, 2000. 260. Luppi M, Barozzi P, Schulz TF, et al: Bone marrow failure associated with human herpesvirus 8 infection after transplantation. N Engl J Med 343:1378–1385, 2000. 261. Shields AF, Hackman RC, Fife KH, Corey L, Meyers JD: Adenovirus infections in patients undergoing bone-marrow transplantation. N Engl J Med 312:529–533, 1985. 262. Hale GA, Heslop HE, Krance RA, et al: Adenovirus infection after pediatric bone marrow transplantation. Bone Marrow Transplant 23:277–282, 1999. 263. van Kraaij MG, Dekker AW, Verdonck LF, et al: Infectious gastroenteritis: An uncommon cause of diarrhoea in adult allogeneic and autologous stem cell transplant recipients [In Process Citation]. Bone Marrow Transplant 26:299–303, 2000. 264. Flomenberg P, Babbitt J, Drobyski WR, et al: Increasing incidence of adenovirus disease in bone marrow transplant recipients. J Infect Dis 169:775–781, 1994. 265. Cox GJ, Matsui SM, Lo RS, et al: Etiology and outcome of diarrhea after marrow transplantation: A prospective study. Gastmenterology 107:1398–1407, 1994. 266. Liles WC, Cushing H, Holt S, et al: Severe adenoviral nephritis following bone marrow transplantation: Successful treatment with intravenous ribavirin [see comments]. Bone Marrow Transplant 12:409–412, 1993. 267. Chakrabarti S, Collingham KE, Fegan CD, Milligan DW: Fulminant adenovirus hepatitis following unrelated bone marrow transplantation: Failure of intravenous ribavirin therapy. Bone Marrow Transplant 23:1209–1211, 1999. 268. Hayashi M, Lee C, de Magalhaes-Silverman M, et al: Adenovirus infections in BMT patients successfully treated with cidofovir. Blood 96(Suppl):189a (abstract 810), 2000. 269. Strasser SI, McDonald GB: Hepatitis viruses and hematopoietic cell transplantation: A guide to patient and donor management. Blood 93:1127–1136, 1999. 270. Lau GK, Lie AK, Kwong YL, et al: A case-controlled study on the use of HBsAg-positive donors for allogeneic hematopoietic cell transplantation. Blood 96:452–458, 2000. 271. Strasser SI, Sullivan KM, Myerson D, et al: Cirrhosis of the liver in long-term marrow transplant survivors. Blood 93:3259–3266, 1999. 272. Bedi A, Miller CB, Hanson JL, et al: Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol 13:1103–1109, 1995. 273. Azzi A, Cesaro S, Laszlo D, et al: Human polyomavirus BK

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17

Infection in the Organ Transplant Recipient ROBERT H. RUBIN

1. Introduction

Over the past 30 years, organ transplantation has been transformed from an interesting experiment in human immunobiology to the most practical means of rehabilitating patients with end-stage disease of the kidney, heart, liver, lungs, and, perhaps, the pancreas and small bowel. As we enter the twenty-first century, the diseases that can be corrected by transplantation continue to increase, the success continues to grow, and the only limitation appears to be the availability of suitable organs for transplantation—a situation hopefully to be corrected in the not too distant future by xenotransplantation. In the United States at the present time, the statistics are as follows: From 1988 to 1996, the 1-year survival rate for renal allografts from living donors increased from 88.8 to 93.9%, and the rate for cadaveric renal allografts from 75.7 to 87.7%. Of equal importance, the long-term survival of functioning allografts has shown similar improvement: the half-life for grafts from living donors increased from 12.7 to 21.6 years, and for grafts from cadaveric donors 7.9 to 13.8 years. If the data are censored to remove patients who died with functioning allografts, the results are even more impressive: from 16.9 to 35.9

Robert H. Rubin Division of Infectious Disease, Brigham and Women’s Hospital; Center for Experimental Pharmacology and Therapeutics, Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology; and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114. Clinical Approach to Infection in the Compromised Host (Fourth Edition), edited by Robert H. Rubin and Lowell S. Young. Kluwer Academic/Plenum Publishers, New York, 2002.

years for recipients of allografts from living donors, and from 11.0 to 19.5 years for recipients of allografts from cadaveric donors.1 For the other organs, the following 1and 5-year allograft survival statistics are being achieved according to the most recent statistics from the United Network for Organ Sharing (UNOS): liver—80 and 63%, respectively; heart—85 and 68%; and lung—74 and 42%. UNOS patient survival statistics for the same periods at 1 and 5 years are as follows: cadaveric kidney— 94 and 82%; living donor kidney—98 and 91%; liver— 88 and 74%; heart—86 and 70%; and lung—75 and 44%.2 In some centers, even better results are being achieved. For example, the 1-year graft survival rate at Massachusetts General Hospital for cadaveric donor kidneys, livers, hearts, lungs, and pancreases is > 90%, and the 1-year patient survival rate after both cadaveric and living related donor kidney transplantation is > 95%. The remarkable clinical success being achieved at organ transplant centers throughout the world has been accomplished because of progress in the five major areas that contribute to successful transplantation3:

1. Optimal tissue typing and matching of donor organ to potential recipient, with a particular emphasis on presensitization testing, thus minimizing the incidence and extent of the rejection process.4 2. Careful donor evaluation, meticulous procurement and preservation of the donor organ, and proper preparation of the recipient (in particular, eradicating all treatable infection prior to transplant). 3. Impeccable surgical technique, resulting in a 573

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minimum of tissue injury, secure vascular, bladder, ureteral, biliary, and bronchial anastomoses, and the prevention and/or aggressive drainage of fluid collections, be they blood, urine, lymphatic, or biliary in origin. 4. Precise, individualized management of the immunosuppressive regimen; on the one hand, effectively preventing or treating allograft rejection, and, on the other, minimizing the severe depression of a broad range of host defenses against infection that can be the consequence of overly aggressive immunosuppressive therapy. 5. Prevention of infection whenever possible with prophylactic or preemptive antimicrobial therapy, and prompt diagnosis and aggressive treatment of microbial invasion when prevention fails. The net result has been better control of rejection and better prevention and treatment of infection—the two major barriers to successful organ transplantation. These two are closely related, being essentially mirror images of one another, linked by the requirement for immunosuppressive therapy: any intervention that decreases the incidence of infection will permit the safer deployment of more intensive immunosuppressive therapy and thus better management of rejection; and any intervention that decreases the intensity and extent of rejection, thus permitting lesser amounts of immunosuppressive therapy, will be associated with a lower rate of infection. Rejection and infection may be regarded as the two sides of the same problem. Indeed, cytokines, chemokines, and growth factors elaborated in response to either process modulate the occurrence and severity of the other process. Thus, the therapeutic prescription for the organ transplant recipient should be regarded as having two components: an immunosuppressive program to prevent and treat rejection, and an antimicrobial strategy to make this safe. Until specific tolerance becomes a reality in human transplantation, exogenous immunosuppressive therapy will be required. Every immunosuppressive program that has been devised or is presently in development increases the risk of infection. The responsibility of the clinician is to understand this risk and to develop the necessary strategy to reduce the risk, whether the strategy involves active or passive immunization or the targeted deployment of specific antimicrobial agents. In general, the intensity of the immunosuppression, particularly if effective antimicrobial strategies cannot be developed, will determine both the risk of infection and the risk of certain malignancies, particularly lymphoma.3,5,6

1.1. The Therapeutic Prescription 1.1.1. Immunosuppressive Agents Employed in Transplantation

The immunosuppressive drugs currently in use for the prevention and treatment of rejection of organ transplants include the following agents: corticosteroids, azathioprine, mycophenolate mofetil, the calcineurin inhibitors (cyclosporine and tacrolimus), rapamycin (sirolimus), and polyclonal and monoclonal antilymphocyte antibodies. Corticosteroids, particularly prednisone and methylprednisolone, have been key components of the antirejection program since the earliest days of clinical transplantation. One of the major lessons, however, and a cornerstone of modern immunosuppressive therapy is the recognition that there is a limit to the amount of steroids an individual can receive without an undue risk of infection. This has led to the concept of “steroid sparing” therapy, the addition of other drugs that work by other mechanisms in order to achieve the desired net state of immunosuppression while permitting the lowering of the corticosteroid dose. The effects of corticosteroids on the transplant patient can be divided into two general categories: anti-inflammatory and immunosuppressive. The anti-inflammatory effects are particularly striking5,7:

1. Effects on cytokine production. The most important anti-inflammatory effects of steroids are secondary to the inhibition of proinflammatory cytokine production (Table 1). 2. Effects on circulating leukocytes. Steroids have a complex effect on leukocytes. Although they raise the circulating levels of polymorphonuclear leukocytes (PMNs)—due to both increased production by the bone marrow and demargination of mature PMNs normally adherent to vascular endothelial cells—steroids also decrease PMN accumulation at sites of infection and inflammation. Steroids not only decrease the numbers of circulating lymphocytes, but also change the relationship among the various lymphocyte subpopulations—increasing the ratio of B to T cells, and CD8 to CD4 cells. In addition, steroids cause a decrease in circulating monocytes, eosinophils, and basophils. Many of these effects are due to the impact of steroids on the production of cytokines. 3. Effects on arachidonic acid pathways. Steroids inhibit essentially all arachidonic acid metabolites (prostaglandins, thromboxane, and leuko-

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munizations, whenever possible, prior to the initiation of corticosteroid therapy.5–8 From an infectious disease point of view, the most important adverse effects of corticosteroids have to do with their inhibition of the inflammatory response to microbial invasion, particularly in the early stages of the infectious process. The consequences of the impaired inflammatory response are twofold: the signs and symptoms of infection, as well as the X-ray findings, will be greatly blunted until late in the clinical course; and the microbial burden at the site of infection is likely to be far higher than that observed in normal hosts. Illustrative Case 1

trienes), as well as platelet-activating factor— potent mediators of inflammation. 4. Effects on vascular permeability. Steroids inhibit the production of mediators of vasodilatation and the response to these mediators. Steroids also inhibit the inducible form of nitric oxide synthase, thus decreasing macrophage nitric oxide production, endothelial relaxation, and microvascular leak. The net result is inhibition of microvascular permeability, an important component of the inflammatory response. The key immunosuppressive effect of corticosteroids is the inhibition of T-cell activation and proliferation (thus blocking clonal expansion in response to antigenic stimulation), which is mediated by its suppression of interleukin-2 (IL-2) and other cytokines required for this to occur. Hence, there is a striking inhibition of cell-mediated immunity. This renders the organ transplant patient particularly susceptible to herpes group viral infections, hepatitis viruses, fungal, nocardial, and mycobacterial processes, Strongyloides stercoralis, and infection with such intracellular organisms as Listeria monocytogenes and Salmonella species. In contrast, although steroids can inhibit the activation of immature B cells (as would be necessary for a primary response to a vaccine), established B-cell responses (or anamnestic responses) are quite resistant to the effects of steroids. Hence, the clinician would be well advised to complete appropriate im-

A 57-year-old man underwent single lung transplantation for chronic obstructive pulmonary disease. He was immunosuppressed with antilymphocyte antibody induction therapy, cyclosporine, prednisone, and azathioprine. He was maintained on low-dose trimethoprimsulfamethoxazole prophylaxis. In the first 4 months posttransplant, he required multiple pulse doses of methylprednisolone (500 mg intravenously) and a maintenance prednisone dose of 25 mg/day (usual maintenance dose of because of severe rejection. He presented 4 months posttransplant with complaints of two or three loose bowel movements and mild left lower quadrant discomfort. On physical examination, his temperature was 99.6°F, respiratory rate 18, pulse 85 and regular, and blood pressure 140/90. The patient was obese and somewhat cushingoid in appearance. Positive physical findings were restricted to the abdomen where bowel sounds were slightly hyperactive and there was mild tenderness to deep palpation in the left lower quadrant. There was no guarding, rebound tenderness, or other signs of peritonitis. Pertinent laboratory data included a WBC of Hct 34, normal urinalysis, BUN 36, creatinine 1.4 mg/dl. A CT scan following the administration of rectal contrast revealed a perforation of the sigmoid colon and evidence of inflammation in the surrounding soft tissues. He was taken to the operating room where active diverticulitis with a 2-cm perforation and free peritonitis were noted. A sigmoid colectomy, colostomy, and Hartmann’s pouch were performed, and the patient was treated with intravenous ampicillin–sulbactam. He made an uneventful recovery. Comment: A potentially lethal intra-abdominal catastrophe presented with minimal symptoms because of the anti-inflammatory effects of the immunosuppressive program, particularly the corticosteroids. Despite a free perforation of colonic contents into the peritoneal cavity, the patient did not manifest signs of peritoneal inflammation. If a prompt CT scan with rectal contrast had not been carried out, it is likely the patient would have died of sepsis. The teaching point is that the clinical presentation of life-threatening infection can be very occult, and the clinician must be quick to pursue an aggressive diagnostic workup in the face of subtle signs and symptoms.

Azathioprine has been a cornerstone of steroid sparing therapy for organ transplant recipients for more than 35 years. It is converted into 6-mercaptopurine following administration, with subsequent transformation to a series of intracellularly active metabolites, most notably thiosinic acid and 6-thioguanine nucleotides. These inhibit

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both an early step in de novo purine synthesis and several steps in the purine salvage pathway, thus depleting cellular purine stores and inhibiting DNA and RNA synthesis. The impact of azathioprine is greatest on actively dividing lymphocytes responding to antigenic stimulation, with minimal effects on mature elements of antigenic memory or end-stage lymphocyte function. Azathioprine’s major toxicity is on the bone marrow. Its major adverse effects on the course of infection are of two types: it inhibits microbial specific T-cell responses, thus increasing the risk of infection with herpes group viruses, papillomaviruses, fungi, mycobacteria, S. stercoralis, and other intracellular organisms; and neutropenia, which can predispose to bacterial sepsis.5,9 A key step in the metabolism of azathioprine is catalyzed by the enzyme thiopurine methyltransferase. There is considerable genetic heterogeneity in this enzyme in humans, and it is likely that both bone marrow toxicity and the degree of immunosuppression induced by the drug are significantly influenced by whether an individual is a rapid or slow metabolizer of the drug. In general, optimal results are obtained with azathioprine when dosages of are employed. However, with the recent pharmacogenetic information on the key role of thiopurine methyltransferase, it is reasonable to believe that phenotyping the patient in terms of the activity of this enzyme should greatly improve the therapeutic index of this very useful drug.9–12 Mycophenolate mofetil (MMF) is a prodrug, which is administered orally and then cleaved by plasma esterases quite rapidly into the active agent, mycophenolic acid. MMF is a highly selective, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase, a crucial enzyme in the de novo biosynthesis of guanosine. Proliferating lymphocytes require this pathway, whereas resting lymphocytes and other cell types can make use of the purine salvage pathway if this synthetic option is blocked. MMF is a potent inhibitor of the proliferative response of both B and T lymphocytes to allospecific stimulation. In addition, because guanine nucleotides are necessary for the glycosylation of adhesion molecules, inhibition of lymphocyte migration to sites of rejection or inflammation and decreased adherence to endothelial cells or extracellular protein matrix can be shown. Practically, mycophenolate is often substituted for azathioprine in immunosuppressive regimens, with there seeming to be a more potent antirejection effect without a major increase in either infection or lymphoma (vide infra). In terms of the infections that are promoted by this drug, they are essentially identical to those seen with azathioprine, with the notable exception of a lower incidence of neutropenia-related infection. Doses of 1 g

two or three times per day are usually employed, with the dose-limiting toxicity usually being gastrointestinal (cramps and diarrhea) rather than bone marrow dysfunction.5,9,13,14 Cyclosporine is the immunosuppressive agent that revolutionized organ transplantation. Prior to the advent of cyclosporine-based immunosuppressive regimens in the early 1980s, the 1-year survival rate for cadaveric allografts was barely 50%. Since the deployment of cyclosporine (or its fellow calcineurin inhibitor, tacrolimus— vide infra) as the cornerstone of currently used immunosuppression, 1-year cadaveric allograft survival rates of are being achieved throughout the world. Cyclosporine exerts its effects through a complex signaling pathway that results in the inhibition of the transcriptional activation of lymphokine and other genes required for T-cell proliferation, activation, and function. The first step in mediating cyclosporine effects is binding to the cyclophilins, a particular family of immunophilins. The resulting complex has as a target the calcium-dependent serinethreonine phosphatase, calcineurin. Calcineurin, in turn, is involved in the activation of the transcription factor NFAT, which is required for the transcription of the genes for the cytokines IL-2, IL-3, IL-4, IL-5, tumor necrosis granulocyte–monocyte colony-stimulating factor (GM-CSF), and the receptors for IL-2 and IL-7. Of these, the IL-2 effects are particularly crucial, resulting in a potent suppression of T-cell function and effect, making cyclosporine a potent inhibitor of allograft rejection. The infectious disease effects of cyclosporine are a direct result of its therapeutic action— a dose-related inhibition of microbial specific T-cell cytotoxic activity being the most important. Thus, cyclosporine will amplify the extent and the effects of any replicating herpes group virus, most notably cytomegalovirus (CMV) and Epstein–Barr virus (EBV) (vide infra). 5,15 Tacrolimus (FK506) has a mechanism of action similar to that of cyclosporine. Thus, the first step occurs with the binding of cyclosporine to a family of immunophilins similar but distinct from those to which cyclosporine binds. These, termed FK506 binding proteins (FKBPs), form a complex with tacrolimus, which inhibits the activity of calcineurin. Once again, the effects of T-cell activation are blocked through the inhibition of IL-2 promoter induction. Calcineurin is required for calcium-dependent signal transduction and the activation of the transcription factor NF-AT required for cytokine gene activation. Tacrolimus affects the same array of cytokine genes as cyclosporine, but is 10–100 times more potent. Other immunosuppressive effects of these drugs include the inhibition of

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T-cell proliferation and the inhibition of primary or secondary cytotoxic cell proliferation in vitro, although direct cytotoxicity and calcium-independent T-cell stimulation are not affected. Both induced immunoglobulin production by B cells and the proliferation of stimulated B cells are inhibited, thus limiting the ability to respond to vaccine administration. Secondary antibody responses, natural killer or antibody-dependent cytotoxic cell function are not inhibited. The effects of tacrolimus on infection are comparable to those seen with cyclosporine, with a particular impact on CMV- and EBV-associated events (vide infra).5,16,17 Rapamycin (Sirolimus) is structurally quite similar to tacrolimus, but does not exert its immunosuppressive effects by inhibiting calcineurin or the transcription of lymphokine genes. Rather, its targets include RAFT1/FRAP proteins in mammalian cells, which are associated with cell cycle phase In addition, rapamycin selectively inhibits the synthesis of ribosomal proteins and the induction of mRNA for new ribosomal proteins, which likewise prolongs the cell cycle at the interface. Finally, rapamycin inhibits the progression to DNA synthesis and S phase. The net effect is that rapamycin is a less potent inhibitor of cytokine synthesis than cyclosporine or tacrolimus, but is able to inhibit such cyclosporine-resistant immune functions as B-cell immunoglobulin synthesis, antibody-dependent cellular cytotoxicity, lymphocyteactivated killer cells, and natural killer cells. Of perhaps greater importance is rapamycin’s ability to inhibit growth factor signaling for both immune and nonimmune cells. This antiproliferative effect may be useful in the prevention and treatment of chronic allograft injury. At present, the primary use of rapamycin is in synergistic combination with cyclosporine, thus permitting lower doses of cyclosporine and, presumably, lesser amounts of nephro2toxicity. In addition, such a combination may permit more steroid sparing therapy. The infectious disease effects of rapamycin, then, are similar to those of cyclosporine, although a particularly high incidence of transient aphthous ulcers and Pneumocystis carinii pneumonia have been noted with rapamycin. Because of the latter effect, anti-Pneumocystis prophylaxis (e.g., trimethoprim– sulfamethoxazole) should be mandatory whenever significant doses of rapamycin are used.5,18–21 Polyclonal antilymphocyte antibodies (antithymocyte globulin, ATG; antilymphocyte serum, ALS). In the United States there are two currently marketed antithymocyte globulins, one of equine and one of rabbit origin. These are potent pan-T-lymphocyte depleting agents that can be employed in two different modes: as induction therapy immediately following transplantation

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to prevent rejection; and as a powerful tool to reverse acute rejection that has not responded to pulse doses of methylprednisone (so-called “steroid fast rejection”). The major advantage of induction therapy is that it permits the avoidance of cyclosporine and tacrolimus for 5– 14 days (depending on the duration of the ATG therapy), thus avoiding a nephrotoxic insult for kidneys that may be in the throes of ischemia-reperfusion injury and acute tubular necrosis. ATG preparations are not without their problems, however: first is lack of specificity of this polyclonal preparation—antibodies in the preparation can induce neutropenia, thrombocytopenia, and hemolysis; allergic reactions to the foreign protein are common, with these ranging from fevers to anaphylaxis and serum sickness; finally, particularly with the first two or three doses, ATG administration causes the release of IL-1 and TNF in large amounts, resulting in fever, chills, hypotension, and malaise. In addition, these proinflammatory cytokines play an important role in the pathogenesis of CMV and EBV infection (vide infra). 5,22 Monoclonal antilymphocyte antibodies. OKT3, a murine monoclonal antibody to the CD3 T-cell receptor complex, was developed to provide a more specific alternative to polyclonal ATG. Indeed, it has essentially eliminated the nonspecific antibody-induced problems of ATG, while still providing potent induction and antirejection therapy (OKT3 is, at present, the most potent therapy for steroid fast rejection). The adverse effects of OKT3 of infectious disease importance can be grouped into three general categories: (1) elaboration of proinflammatory cytokines, with consequences similar to those observed with the ATG preparations; (2) inhibition of microbialspecific T-cell responses, thus rendering the patient more susceptible to the effects of the herpes group viruses, fungal invasion, and mycobacterial infection; and (3) immune responses to the murine antibody, which will produce fever and allergic manifestations, as well as interfere with its ability to deplete T cells and effect immunosuppression. The use of both OKT3 and ATG, particularly as antirejection therapy, adds significantly to the net state of immunosuppression, requiring an increase in the antimicrobial program needed to prevent infection (vide infra).5,8,23,24

In an effort to develop more specific immunosuppressive therapies, and in view of the central role of IL-2 and the IL-2 receptor in lymphocyte proliferation and the rejection response, monoclonal antibodies to the IL-2 receptor have been developed. Daclizumab which is a humanized IgG, and basilixmab which is a human and mouse chimeric antibody, have been approved for the prevention of allograft rejection.

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Clinical trials with both of these antibodies have shown that these nondepleting, noncytokine-releasing monoclonal antibodies decrease the incidence of acute rejection episodes. Whether or not this will also decrease the incidence of chronic rejection remains to be determined. It is believed that these antibodies have a less marked effect on the course of viral, fungal, and mycobacterial infection than either ATG or OKT3, at least in part due to the absence of the proinflammatory cytokine response with these newer agents but regularly seen with ATG and OKT3.5,25 At the present time, standard immunosuppression consists of three-drug therapy: a calcineurin inhibitor (cyclosporine or tacrolimus), azathioprine or mycophenolate, and low-dose prednisone. In patients with acute renal dysfunction, induction ATG or OKT3 is not uncommonly prescribed, in order to avoid nephrotoxic insults from the calcineurin antagonists. Acute rejection is initially treated with two or three daily doses of intravenous methylprednisolone, with OKT3 or ATG utilized if these do not reverse the process. There is at present considerable interest in preventing chronic allograft injury and being able to safely wean patients off prednisone. Newer agents such as rapamycin and the anti-IL-2 receptor antibodies are getting close scrutiny in this regard. 1.1.2. Principles of Antimicrobial Use in Transplantation Antimicrobial drugs play a major role in the therapeutic prescription for the organ transplant recipient. There are three modes in which antimicrobial agents can be prescribed5,8,26: 1. Therapeutic mode, in which antimicrobial agents are administered as curative treatment of a patient with clinical infection. 2. Prophylactic mode, in which antimicrobial agents are administered to an entire population before an event to prevent infection. For such a strategy to be worthwhile, three criteria must be met: (a) the infection to be prevented must be common enough and important enough to justify the intervention; (b) the antimicrobial regimen is nontoxic enough to make the intervention safe; and (c) the intervention can be shown to be cost effective. 3. Preemptive mode, in which antimicrobial agents are administered before clinical infection occurs to a subgroup of individuals shown to be at high risk for life-threatening infection on the basis of a clinical/epidemiologic or a laboratory marker.

The therapeutic use of antimicrobial agents in transplant patients is greatly influenced by the possibility of drug interactions with the immunosuppressive agents, particularly cyclosporine and tacrolimus. There are three general ways in which antimicrobial agents can interact with the calcineurin inhibitors, two of them due to effects on the metabolism of these drugs by hepatic cytochrome P450 enzymes and the third due to enhanced nephrotoxicity5,8,26: 1. Antimicrobial agents (most notably rifampin, nafcillin, and isoniazid) can upregulate the metabolism of the calcineurin inhibitors, resulting in lower blood levels for a given dose of drug, and a high risk for insufficient immunosuppression and resulting allograft rejection. 2. Antimicrobial agents (most notably the macrolides—erythromycin > clarithromycin > azithromycin; and azoles—ketoconazole > itraconazole, voriconazole > fluconazole) can downregulate the metabolism of the calcineurin inhibitors, resulting in higher blood levels for a given dose of drug, and a high risk for overimmunosuppression, infection, and nephrotoxicity. 3. Antimicrobial agents given in appropriate doses to patients with therapeutic (not toxic) blood levels of the calcineurin inhibitors can develop nephrotoxicity on the initiation of certain antimicrobial drugs, despite the fact that there is no change in the blood level of the calcineurin inhibitor. There are three variants of this form of interaction: (a) dose related—thus, low doses of fluoroquinolones and trimethoprim–sulfamethoxazole are well tolerated, but higher doses are not (e.g., 250 mg of ciprofioxacin or a single-strength trimethoprim–sulfamethoxazole tablet twice daily are well tolerated, higher doses have a dose-related increased risk of renal dysfunction); (b) “accelerated nephrotoxicity”—thus, drugs such as amphotericin or aminoglycosides, which commonly produce nephrotoxicity with sustained exposure (and drugs such as vancomycin, which rarely do), will now manifest nephrotoxicity when added to a calcineurin inhibitor at a much lower cumulative dose (e.g., 100–200 mg of amphotericin in a transplant patient, as opposed to > 500 mg for someone not receiving immunosuppression); (c) “idiopathic nephrotoxicity”—single doses of gentamicin, amphotericin, and intravenous trimethoprim–sulfamethoxazole in the face of therapeutic levels of cyclosporine or tacrolimus have been documented to produce oliguric renal failure in some patients. Practically, the risk of these interactions leads to the avoidance of aminoglycosides and amphotericin (when possible) in these patients, with the preferential use of advanced-spectrum beta-lactams and azoles in the treat-

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ment of bacterial and fungal infections in transplant recipients. When any drug is utilized that affects the hepatic metabolism of the calcineurin antagonists, it is essential that cyclosporine and tacrolimus levels be closely monitored and dosage adjustments made on both the initiation and 5,8,26 completion of the course of antimicrobial therapy The most successful antimicrobial prophylactic strategy in transplant patients is the use of low-dose trimethoprim–sulfamethoxazole posttransplant for a minimum of 6–12 months posttransplant (or even longer). This regimen markedly decreases the incidence of urinary tract infection, and essentially eliminates the risk of Pneumocystis carinii pneumonia (~15% risk in the first 6 months posttransplant at most transplant centers if antiPneumocystis prophylaxis is not administered), listeriosis, nocardiosis, and, perhaps, toxoplasmosis. The other prophylactic strategy that has been clearly shown to be cost effective in transplant patients is perioperative (12– 72 hr) wound prophylaxis. In addition, many transplant programs utilize antiviral prophylaxis in the prevention of CMV disease (vide infra).5,8,26 Two forms of preemptive therapy have been defined and are alternative approaches to the prevention of clinical CMV disease: The first is based on clinical/epidemiologic observations: the administration of OKT3 or ATG to patients seropositive for CMV markedly increases the risk of CMV disease; initiating ganciclovir therapy at the time of antilymphocyte antibody therapy preempts this increased risk. Alternatively, a different approach can be taken: 2–7 days prior to the onset of clinical disease, viremia can be demonstrated by polymerase chain reaction (PCR) or antigenemia assay. A preemptive strategy triggered by such a laboratory result can also be successful. Other preemptive strategies to be considered in the transplant patient include the following: candidiuria in a renal transplant patient carries a risk for the development of obstructing fungal balls and ascending candidal pyelonephritis; accordingly, preemptive therapy of asymptomatic candidiuria in renal transplant patients is recommended. Colonization of the respiratory tract of transplant patients with Aspergillus species carries an increased risk of subsequent invasive disease. Accordingly, preemptive anti-Aspergillus therapy is advocated in such circumstances.5,8,24,26 A final point regarding antibacterial and antifungal therapy is the proper deployment of these drugs in patients with infection complicating a surgical misadventure (or other situation in which tissue is devitalized, fluid collections occur, or visceral leaks, e.g., urine or bile, are present). The optimal use of antimicrobial drugs is in

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conjunction with corrective surgery. The use of antimicrobial therapy without such surgical correction has a high probability of not only failing but of failing with the induction of antimicrobial-resistant infection.5,8

2. Risk of Infection in the Organ Transplant Recipient Table 2 delineates the broad range of infections that occur in organ transplant recipients, classified by the primary factor by which they invade. The risk of these infections, particularly opportunistic infection, in the organ transplant recipient is largely determined by the interaction among three factors: the occurrence of technical mishaps that lead to devitalized tissue, fluid collections, the ongoing need for invasive devices for vascular access, drainage catheters, and other foreign bodies that abridge or otherwise attenuate the primary mucocutaneous barriers to microbial invasion; the epidemiologic exposures the patient encounters; and the patient’s net state of immunosuppression. The first of these, the technical/anatomical abnormalities that develop as a consequence of the surgical procedure and the perioperative care, is the most important cause of infection in the first month posttransplant (although the development of such abnormalities at any time in the posttransplant course can increase the risk of infection). Indeed, the incidence of such events is determined by the complexity of the surgery involved—being most common following liver and lung transplantation, somewhat less common following heart transplantation, and least common following kidney transplantation.3,5,8,26,27 In those patients free of technical/anatomic abnormalities—the majority of transplant recipients at the most skilled transplant centers—the risk of infection, particularly opportunistic infection, is largely determined by the interaction between the epidemiologic exposures and the net state of immunosuppression. The relationship between these two factors is semi quantitative: if the epidemiologic exposure to a microbial agent is intense enough, even nonimmunosuppressed individuals will become ill; conversely, if the net state of immunosuppression is great enough, then minimal exposure to normally noninvasive, commensal organisms can result in life-threatening infection. This concept is of great practical importance, as the occurrence of invasive infection related to such organisms as Aspergillus species, Legionella species, and a variety of gram-negative bacilli, at a time when the net state of immunosuppression should not be great enough to permit such an event to occur, can be an important clue

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to an excessive environmental hazard that requires immediate attention.3,5,8,26,27 2.1. Epidemiologic Exposures of Importance The epidemiologic exposures of importance for the transplant recipient can be divided into two general categories: those occurring in the community and those occurring within the hospital environment. Community exposures

of potential concern include the following: Mycobacterium tuberculosis, the geographically restricted systemic mycoses (Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum), Strongyloides stercoralis, hepatitis B and C, the human immunodeficiency virus (HIV), the enteric bacterial pathogens (particularly Salmonella species), and respiratory viruses that can circulate rapidly within households, the workplace, and the community (e.g., influenza, parainfluenza, adenovirus, and respiratory syncytial virus).3,5,8,26,27 In the case of M. tuberculosis and the mycoses, similar epidemiologic, pathogenetic, and clinical mechanisms are at work. Primary infection occurs via the lungs, after inhalation of an aerosol containing a large inoculum of infectious particles. Primary infection produces a flulike syndrome, with progressive pulmonary disease and postprimary dissemination being limited by the development of an intense cell-mediated immune response. Late reactivation occurs when such immunity wanes. With posttransplant immunosuppressive therapy particularly aimed at inhibiting cell-mediated immune function, three patterns of clinical disease are observed following infection with these agents in the transplant patient: progressive primary disease with widespread dissemination; reactivation of a long-dormant infection, with progressive local disease (either in the lungs or at sites of previous metastatic spread such as the skeletal system) and/or secondary dissemination; and superinfection, again with dissemination, as immunosuppression causes a waning of previously acquired immunity, with new exposure causing disease. Thus, when evaluating transplant patients with an infectious disease syndrome, careful attention must be paid to the possibility of both recent and remote exposures to these organisms.3,5,8,26,27 Strongyloides stercoralis is the one helminth with an autoinoculation cycle in humans; chronic, albeit asymptomatic, infection can be maintained for decades after an individual was initially infected (long after the patient has left endemic areas such as Southeast Asia or South and Central America), and intense and/or disseminated infection can develop after the initiation of immunosuppressive therapy (vide infra). 8,27 Transplant candidates, by the nature of their underlying diseases, are more likely to have received blood products prior to presentation for transplantation, and thus have been at increased risk for acquisition of both hepatitis viruses (hepatitis B, HBV; hepatitis C, HCV) and HIV. Clearly, they are at the same kind of risk for acquiring these infections following such activities as intravenous drug abuse or high-risk sexual practices as the rest of the population. Since these infections can have

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a major impact on the posttransplant course, with immunosuppression amplifying the extent and effects of these infections (vide infra), patients must be screened for their presence prior to transplant, and they should be counseled and protected from acquiring these infections pre- and posttransplant. The most common form of community-acquired infection occurring in the transplant recipient is that caused by the acute respiratory viruses. Now that successful transplantation and patient rehabilitation is the rule and not the exception, increasing attention is being paid to the occurrence of such common infections as those caused by influenza, parainfluenza, adenoviruses, respiratory syncytial virus, and, probably, even rhinoviruses. Communitywide outbreaks of these infections will have a particular impact on these patients, with more prolonged courses, a higher rate of pneumonia, and an increased rate of bacterial and fungal superinfection compared with the general population. Lung transplant patients appear to be particularly susceptible to these agents, with long-term and progressive lung injury being a too frequent consequence of such infection in lung transplant recipients. 8,28–34 Postinfluenza myocarditis has even been observed in transplant recipients.35 A variation on this theme is the increasing concern that community-acquired Chlamydia pneumoniae infection could be playing a role in the pathogenesis of chronic vasculopathy, particularly in cardiac allograft recipients.36 Increased attention must be turned to the evaluation and deployment of such preventive and early intervention strategies as vaccination, antiviral strategies (e.g., rimantadine, amantadine, and the neuraminidase inhibitors for influenza), and, most important at this point in time, the isolation of transplant patients from individuals with respiratory infections in the community.8 Other exposures of importance to the transplant patient in the community include the enteric pathogens, particularly Salmonella species and Listeria monocytogenes, in inadequately prepared food, and such recreational pursuits as gardening, in which aerosols of organic material can be created, resulting in exposure to such organisms as Aspergillus and Nocardia species.8 As important as community exposures are to the occurrence of infection in transplant patients, exposures within the hospital are even more important. Nosocomial epidemics of opportunistic infection in transplant patients caused by Aspergillus species, Legionella species, and gram-negative organisms such as Pseudomonas aeruginosa are well recognized. Two epidemiologic patterns of nosocomial exposure have been defined: domiciliary and nondomiciliary. Domiciliary exposures occur in the room

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or on the ward where the patient is housed, and are usually caused by contamination of the air supply or potable water by these opportunistic pathogens. Such contamination can occur because of construction; because of the presence of plants contaminated with gram-negative organisms within the patients’ rooms; because of showers and toilet facilities that create aerosols of gram negatives or Legionella species when used; and because of contaminated water systems and air conditioning or air handling systems. The net result is that these immunosuppressed individuals inhale aerosols contaminated with excessive numbers of these pathogens, producing life-threatening disease. Outbreaks of this type are characterized by clustering of cases in time and space. By prohibiting the entry of plants and flowers into the rooms of these patients, close monitoring of the functioning of showers and toilets, monitoring the hospital water system for Legionella contamination, and by the provision of HEPA-filtered air handling systems (particularly in institutions where air supply has been shown to be a problem), this form of excessive epidemiologic exposure can be essentially eliminated.8,37,38 Far more problematic are nondomiciliary exposures. These occur when patients are taken from their rooms to such central facilities for essential procedures as the operating room, the radiology suite, the cardiac catheterization laboratory, and others. It is now apparent that excessive exposures of this type are both more common than domiciliary exposures, and more difficult to identify (because of the lack of clustering of cases in time and space). The common denominator in these two forms of nosocomial exposure is usually hospital construction or refurbishing, with the resultant creation of aerosols of potential pathogens. For example, we have observed life-threatening Aspergillus infection in renal transplant patients exposed to construction in a radiology suite, in a heart transplant patient exposed while awaiting endomyocardial biopsy outside a cardiac catheterization laboratory, and liver and lung transplant patients exposed in the operating room or intensive care unit. Others have had similar experiences. As a result, increasing emphasis is being placed on protecting patients with special masks and transport devices when they travel within the hospital, and closely monitoring travel routes within the hospital, thus avoiding areas of construction and refurbishment. The operative principle is that the transplant recipient, like other immunosuppressed hosts, is a “sentinel chicken” within the hospital environment—any excess traffic in microbes will be seen first in this patient population, and constant surveillance is essential to prevent catastrophic outbreaks of lifethreatening infection.3,4,8,24,37–40

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2.2. The Net State of Immunosuppression

The net state of immunosuppression is a complex function determined by the interaction of a number of factors. The prime determinant of the net state of immunosuppression is the immunosuppressive regimen prescribed—the dose, the duration, and the temporal sequence in which the drugs that constitute the regimen are deployed. Also to be considered are host defense defects produced by comorbid conditions or the underlying disease that led to the end organ failure that resulted in the need for transplantation. The second group of factors include neutropenia and the presence or absence of such acquired abnormalities as damage to the mucocutaneous surfaces of the body: foreign bodies that bypass or otherwise compromise the normal functioning of the mucocutaneous barriers, such as bladder, biliary, chest, and drainage catheters, endotracheal tubes, and vascular access devices. As far as neutropenia is concerned, granulocyte colony-stimulating factor (G-CSF) has been shown to be safe and effective in promptly raising the white cell count when it is low, whether this is due to immunosuppressive drugs (e.g., azathioprine or mycophenolate), interferon therapy, or viral infection (e.g., CMV infection). What is less clear is whether or not this translates into less infectious disease morbidity and mortality. In the case of CMV-induced neutropenia, the likely answer is yes, as G-CSF therapy permits the safe use of intravenous ganciclovir therapy of the virus. In the other instances, the evidence is currently lacking. What is apparent is that the administration of G-CSF as an “immune response modifier” to patients with normal white blood cell counts, while safe, is without benefit.41,42 Recently, the group at the Cleveland Clinic have reported several cases of hypogammaglobulinemia following heart transplantation, with an increased incidence of such infections as nocardiosis and CMV in this setting. The occurrence of hypogammaglobulinemia was related to intensive immunosuppressive therapy with mycophenolate and tacrolimus. The suggestion is that this phenomenon may be more common than is currently recognized, and can be an important contributor to the net state of immunosuppression.43 The mucocutaneous surfaces of the body should be regarded as the primary barriers to microbial invasion in transplant patients, particularly important since the secondary defenses are compromised by immunosuppressive therapy. Because the consequences of invasive infection can be so significant in these patients, great emphasis is placed on protection of the skin and mucosal surfaces, the removal of foreign bodies as quickly as possible, and,

perhaps, the employment of new technology such as silver, chlorhexidine, and/or antimicrobial-impregnated devices, particularly vascular access catheters.44,45 Transplant patients are a “leveraged” population in terms of an increased incidence and severity of device-related infections, and are therefore an obvious group for the trial of such new technology. The third group of factors that help determine the net state of immunosuppression are incompletely understood at present, and these are metabolic abnormalities such as protein-calorie malnutrition, uremia (the effects of uremia on host defenses are delineated in Table 3), and, perhaps, hyperglycemia. Although these by themselves are not sufficiently potent to measurably increase the rate of infection, when such other factors as immunosuppressive therapy are present, they do have an effect. For example, organ transplant patients with a serum albumin level have a 10-fold greater risk of developing life-threatening infection.8,26 Consistent with this observation is a report that a low serum albumin level has been correlated with an increased risk of death in dialysis patients as well.46 Geriatric (over the age of 60) transplant recipients have an increased risk of infectious disease complications, compared with younger patients, particularly when mycophenolate rather than azathioprine is part of the immunosuppressive regimen.47 The mechanism for this observation is unclear, with plausible explanations including the following: specific metabolic abnormalities associated with the aging process; decreased metabolism of a particular component of the immunosuppressive regimen associated with age; and an aging immune system that is particularly susceptible to standard doses of immu-

INFECTION IN THE ORGAN TRANSPLANT RECIPIENT

nosuppressive drugs. Whatever the mechanism involved, it is clear that age (presumably including the infant as well as the geriatric patient) should be added to the list of factors that contribute to the net state of immunosuppression. An interesting observation is that race may play a role in the susceptibility to infection posttransplant. It has long been known that African-Americans have an increased incidence of allograft rejection and allograft loss. Recently, Meier-Kriesche et al.48 reported a decreased incidence of infection posttransplant in AfricanAmericans. This observation, if confirmed, has important implications. First, it suggests that these patients would tolerate more intense immunosuppressive therapy without an undue increase in infectious complications; that is, standard immunosuppressive regimens, primarily defined in Caucasian populations, could be significantly augmented in African-Americans, with clinical benefit. Second, this could be an important clue to the identity of human immune response genes, the definition of which could allow more precise prescription of immunosuppression to each individual. A major factor in determining the net state of immunosuppression is the presence or absence of infection with one of the immunomodulating viruses—CMV, EBV, HBV, HCV, HIV, and perhaps such viruses as human herpesvirus-6 (HHV-6). It is now clear that, other than the actual immunosuppressive regimen being employed, these are the most important determinants of the net state of immunosuppression. Indeed, an important aspect of the adverse effects of immunosuppressive therapy are their effects in amplifying the impact of these agents (vide infra). One statistic underlines the importance of these viruses in this regard: Over the past two decades, more than 90% of transplant patients at our institution developing opportunistic infection with such organisms as Aspergillus species, Pneumocystis carinii, Nocardia astemides, and Cryptococcus neoformans did so in the setting of immunomodulating viral infection. Indeed, the few exceptions were patients who acquired their infection as a result of an unusually intense environmental exposure, usually within the hospital environment.3,5,8,27 It is also likely that other factors may contribute to the net state of immunosuppression. Among these factors are the immunogenetic makeup of the individual and such previously unconsidered factors as thrombocytopenia. For example, there is evidence that genetic polymorphisms in the genes that control tumor necrosis factor (TNF) production may be important in this regard, with genetically mediated low production of TNF being associated with an increased risk of infection.49,50 There is also increasing evidence that platelets are specialized in-

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flammatory cells that play a particularly important role in controlling possible fungal infection. Because of the frequency of thrombocytopenia in liver transplant recipients, this is a particular issue in this patient population.51

3. Timetable of Infection in the Organ Transplant Recipient

As immunosuppressive regimens have become standardized, it has become apparent that different pathogens affect the transplant recipient at different time points in the posttransplant course. Thus, although infectious disease syndromes can occur at any point in time, the etiology of these syndromes is very different in the first month than at later times. For example, although CMV infection is the most important single cause of clinical infectious disease syndromes in the period 1–4 months posttransplant, it rarely has clinical effects in the first 20 days. Similarly, cryptococcal disease is unusual earlier than 6 months posttransplant, and clinically significant liver disease from newly acquired hepatitis virus infection is usually not observed for several years posttransplant. In addition, although the impact and some of the details are different for the different organs transplanted, the overall pattern is the same for all forms of organ transplantation (Fig. 1). It is useful to divide the posttransplant period into three phases when evaluating the patient for possible infection3,5,8,27: 1. Infection in the first month posttransplant. The infectious disease problems in this time period are of three types: (a) Infection that was present in the allograft recipient prior to transplant and that continues posttransplant, perhaps exacerbated by posttransplant immunosuppression. The prime concerns here are pneumonia (particularly in the liver, heart, lung, and heart–lung recipient who may have been intubated or whose airway would not be protected because of encephalopathy or severe debility) and bloodstream infection caused by vascular access infection. Because of a shortage of donors, patients coming to extrarenal transplantation often are severely ill, requiring intensive monitoring and support for maintenance care prior to transplant. This results in an increased incidence of aspiration pneumonia and bloodstream infection prior to transplant. In addition, the advanced debility induced by their severe organ failure increases the risk of such processes as tuberculosis, systemic mycoses (both the geographically restricted mycoses and the opportunistic pathogens such as Cryptococcus neoformans), and opportunistic pulmonary infection

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(including Pneumocystis carinii and Aspergillus species), particularly if corticosteroids have been used in the management of their primary disease. In general, this is less of an issue for those coming to renal transplantation, since these patients can be maintained usually in a better state of health because of the availability of hemo- and peritoneal dialysis. (b) Infection transmitted via a contaminated allograft, with allograft infection being acquired either from the donor (usually) or in the procurement and preservation process prior to the transplant operation. (c) The same bacterial and candidal infections of the surgical wound, lungs, vascular access, bladder, biliary, chest, and drainage catheters that occur in nonimmunosuppressed patients undergoing comparable amounts of surgery, although the consequences of such infections are much greater in transplant recipients. These last account for greater than 90% of the infections that occur in the first month posttransplant. It is important to emphasize that infection with such opportunistic pathogens as Aspergillus species, Pneumocystis carinii, Legionella species, and Nocardia asteroides is not normally observed in the first month posttransplant. The lack of such infections under normal post-

transplant circumstances at a time when the daily dosage of immunosuppressive therapy is at its highest underlines two important points: (1) The duration of immunosuppression (“the area under the curve”) is a more important determinant of the net state of immunosuppression than the particular dose of drug being administered on a given day or over a few days. Indeed, we have likened immunosuppressive therapy to buying a luxury item by credit card—if one raises the dose of immunosuppressive drugs, there is the immediate gratification of improved allograft function, with the bill coming due in 2–4 weeks in terms of infectious disease consequences. (2) The occurrence of opportunistic infection during this first month “golden period” is prima facie evidence of an excessive epidemiologic exposure, since the net state of immunosuppression should not be great enough as yet to permit such an event to occur. 2. Infection 1–6 months posttransplant. Although residual effects of infection acquired earlier may still be noted in this time period, the major infectious disease problems in this time period are predominantly of two different types, with one type contributing to the occurrence of the second: (a) the immunomodulating viruses (partic-

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ularly CMV, but also including HHV-6, EBV, HBV, HCV, and HIV) which, unless the temporal course is altered by preventive strategies (vide infra), exert their primary direct clinical effects in this time period; and (b) such opportunistic pathogens as Pneumocystis carinii, Listeria monocytogenes, Aspergillus species, and Nocardia asteroides. The net state of immunosuppression, resulting from the combined effects of sustained immunosuppressive therapy and immunomodulating viral infection, is now great enough for such opportunistic infection to occur, even in the absence of an excessive epidemiologic exposure.3,5,8,27 3. Infection in the late period, more than 6 months posttransplant. Organ transplant recipients with functioning allografts (and who are thus continuing to receive immunosuppressive therapy) can be divided into three categories in terms of their infectious disease problems: (a) Approximately 75% of transplant recipients will have good graft function, be on maintenance immunosuppression, and be free of chronic viral infection—their infectious disease problems resemble those of the general community (e.g., community-acquired respiratory virus infection, pneumococcal pneumonia, and urinary tract infection); (b) 10–15% of patients have chronic viral infection with CMV, the hepatitis viruses, EBV, papillomavirus, or even HIV, which leads inexorably (unless an effective antiviral program can be prescribed) to destruction of the organ involved (e.g., cirrhosis in the case of HBV and HCV infection), malignancy (hepatocellular carcinoma from the hepatitis viruses, posttransplant lymphoproliferative disease due to the effects of EBV, squamous cell carcinoma from papillomavirus, and, probably, Kaposi’s sarcoma from HHV-8), or overt AIDS (from HIV infection); (c) 10–15% of patients with relatively poor allograft function due to both acute and chronic rejection, who have received excessive amounts of immunosuppressive therapy, and who are often infected with one or more of the immunomodulating viruses—these patients, whom we have termed “chronic ne’er-do-wells,” are at the highest risk for life-threatening opportunistic infection caused by such agents as Cryptococcus neoformans, Pneumocystis carinii, Listeria monocytogenes, and Nocardia asteroides. Ideally, this last group would be better served by decreasing immunosuppression (in the case of renal allograft recipients, returning them to dialysis) and retransplanting. Unfortunately, in part because of the shortage of donors and in part because of the patients’ debility at this point, this is often not possible. In that event, prophylactic antimicrobial therapy with trimethoprim–sulfamethoxazole and, possibly, fluconazole should be prescribed for these particularly vulnerable individuals (vide infra). 3,5,8,27

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The utility of this timetable as the clinician approaches the issue of infection in the organ transplant recipient is threefold: (1) In the individual patient with a possible infectious disease syndrome the timetable can be quite useful in constructing a differential diagnosis of the possible etiologies. (2) It is a useful infection control device for hospital epidemiologists, as the occurrence of infections not predicted by the timetable is usually a clue to the presence of a previously unidentified environmental exposure of consequence, usually connoting a hazard within the hospital environment. (3) The timetable is the cornerstone on which cost-effective, focused, antimicrobial preventative strategies are based.3,5,8,27 Illustrative Case 2 A 56-year-old woman underwent an uncomplicated renal transplant from a cadaveric donor for end-stage renal disease caused by chronic glomerulonephritis. Immunosuppression was accomplished with cyclosporine, mycophenolate, and prednisone, with immediate excellent function. By the third posttransplant day, the serum creatinine level had fallen to 1 mg/dl, where it remained. Ten days posttransplant, fever, chills, and a nonproductive cough developed. Chest radiography revealed a left lower lobe infiltrate. Bronchoscopy with bronchoalveolar lavage was nondiagnostic. Therapy was instituted with piperacillin and tobramycin, but over the next 36 hr increasing dyspnea and fever developed, as well as left-sided pleuritic chest pain. Chest CT scan revealed a pleural-based cavitary lesion in the left lower lobe as well as additional small nodules in both lungs (a total of four, ranging in size from 0.5 to 2.0 cm). Needle aspiration of the cavitary lesion yielded a pure culture of Aspergillus fumigatus. Therapy with amphotericin B at a dose of 1.25 mg/kg per day was instituted, and immunosuppression was markedly decreased and then stopped. Unfortunately, progressive disease involving the brain and heart developed, and the patient succumbed. Epidemiologic investigation revealed that this patient and three other immunocompromised patients acquired their invasive aspergillosis through exposure to a radiology suite undergoing reconstruction. Comment: This is a classic case of a nondomiciliary outbreak of invasive aspergillosis, with a tragic outcome in this woman with a high probability of success from her renal transplant. The lessons here are twofold: rapid, specific diagnosis in transplant patients with progressive pulmonary infection is of critical importance; and opportunistic infection occurring at a point in time when the net state of immunosuppression was relatively low (scarcely 2 weeks posttransplant) is a tip-off to the presence of a significant environmental hazard. This is an example that when the timetable is “wrong,” an epidemiologic investigation is in order, even if it is only a single case exception to the timetable.

4. Infection Occurring in the First Month Posttransplant

In the first month posttransplant, the dominant factors determining the risk of infection are technical ones. Because of the technical complexity associated with liver, lung, and heart–lung transplantation, this first month is the critical time period in terms of life-threatening infection for these forms of organ transplantation. Reflecting

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the technical issues involved, the most important forms of infection are deep wound infection, infection related to vascular insufficiency of the allograft (infarcted tissue being highly prone to microbial invasion), and complications of critical care (pneumonia, if prolonged intubation is required, as well as vascular access and drainage catheter-related sepsis). In the case of renal allograft recipients, the same kinds of technically related infections are of concern, but their incidence is far lower. Cardiac transplant patients have an intermediate risk in terms of the technically related problems of the first month, significantly greater than kidney transplant patients but less than liver and lung recipients. After this first month, the general pattern of infections in terms of incidence, etiology, and clinical significance becomes very similar for all forms of organ transplantation.3,5,8,27 When attributing the occurrence of infection to technical issues, this clearly is meant to apply to the surgery itself, as well as the management of the endotracheal tube, vascular access devices, and drainage catheters. One further technical issue that must be stressed is the condition of the organ being transplanted. The result of transplanting damaged, even if uninfected, kidneys, livers, hearts, and lungs is often disastrous. Prolonged allograft nonfunction, usually caused by prolonged ischemia prior to transplantation, has systemic consequences that lead to metabolic derangement, bleeding, encephalopathy, and cardiopulmonary failure—all resulting in increased infection and excessive mortality. Thus, careful attention to the condition of the donor organ is obligatory as part of the technical aspects of transplantation that impact on the incidence of life-threatening infection.3,5,8 4.1. Preexisting Infection in the Allograft Recipient It is axiomatic that a potential organ transplant recipient must be rendered free of active, treatable infection prior to operation and the initiation of immunosuppressive therapy. In particular, ongoing bloodstream infection with Candida and bacterial organisms is an absolute contraindication to transplant, as such infection threatens the vascular anastomosis required at the time of transplant. Even in the absence of clear-cut tissue invasion, bloodstream infection should be considered in the following groups of patients: any patient with indwelling vascular access devices, particularly central venous catheters and Swan–Ganz lines; patients with end-stage liver disease and severe portosystemic shunting; and patients with chronic skin disease or compromised bowel mucosal barrier function of any cause. Although chronic infection with such viruses as HBV, HCV, and HIV may be upregu-

lated by immunosuppressive therapy, eradication of the infection prior to transplant is not feasible, and the decision regarding the transplant candidacy of individuals infected with these viruses must be individualized (vide infra). In contrast, active bacterial, fungal, and protozoan infections are absolute contraindications to transplantation until they have been eliminated. Among renal transplant recipients, we have observed the following catastrophic forms of infection in the early posttransplant period when active, although asymptomatic, infection was not identified and effectively treated prior to transplant: systemic sepsis and deep wound infection with loss of the allograft caused by smoldering infection of the native kidneys at the time of transplant; miliary tuberculosis in a patient with unsuspected, active tuberculosis at the time of transplant; staphylococcal sepsis from a deep abscess that had been present for months at the site of previous surgery; and progressive lung infection related to a succession of organisms from gram-negative bacilli to fungi, when pneumonia had not been adequately treated prior to transplantation. The problem is even greater with the extrarenal organs, where the pressure for transplantation in the absence of an artificial life support system akin to dialysis may make the decision-making particularly difficult. A particular concern is the lungs—peritransplant lung injury, whether such injury be due to thromboembolic disease and resulting infarction, chemical injury following aspiration, or microbial invasion, is associated with a high incidence of superinfection posttransplant, with prohibitively high mortality rates resulting. Lung injury must be allowed to heal prior to transplant. An alternative approach can include surgical excision of focal disease, particularly if pulmonary infarction has occurred. This is a particularly important issue in liver transplantation. First, cirrhotic patients are at increased risk for both bacterial and fungal pneumonia.8 In addition, as failure of the native liver progresses, hepatic encephalopathy ensues, with its associated impairment in the ability to protect the airway against aspiration. We have seen a number of patients with end-stage liver disease lapse into coma, aspirate, and develop diffuse lung injury with infection. Liver transplantation following this event is uniformly unsuccessful, and the ability to clear the lungs of inflammation and infection following this event is very limited; most of these individuals will die before transplantation can safely be performed. Thus, we strongly advocate close monitoring of liver transplant candidates for their ability to protect their airways, and, if this is compromised, intubate prior to aspiration. The patient is then placed on the highest priority emergency transplant list

INFECTION IN THE ORGAN TRANSPLANT RECIPIENT

(aiming to transplant within 72 hr of intubation) unless aggressive therapy of the hepatic encephalopathy permits safe extubation and a more leisurely approach to transplantation.52 A second issue in liver transplant candidates is intraabdominal infection. The most common untoward event is unrecognized or inadequately treated spontaneous bacterial peritonitis; in addition, a diverticular abscess, appendiceal abscess, or other break in bowel integrity suffered pretransplant can be a significant problem posttransplant. A rare cause of problems is portal vein thrombosis, with retrograde spread into the mesenteric venous system, venous infarction of the bowel, and abscess formation. Again, it is the obligation of the responsible clinician to certify that the patient is free of treatable infection prior to transplantation. As part of this effort, and with the increasing success of liver transplantation, patients with progressive liver disease should be considered, whenever possible, for transplantation weeks to months before the final downhill spiral occurs. Two statements summarize this point of view: If at all possible, the patient should be able to walk to the operating room for the transplant rather than require life support systems. Better to transplant 6 months too early than 1 week too late.52–54 In the case of heart, heart–lung, and lung transplant candidates, two particular sites of concern are the respiratory tract and vascular access line-related infection. Active pulmonary infection in these forms of transplantation is likewise associated with a high probability of lethal infection posttransplant; and bacteremia from any source, usually related to venous lines, intra-aortic balloon pumps, or left ventricular assist devices (LVADs) in this situation, threatens the integrity of the vascular anastomoses performed during the transplant procedure. With the increasing use of LVADs as a “bridge” to heart transplantation, there has been particular interest in the infectious complications of these devices and their impact on the subsequent posttransplant course. Currently available information suggests the following55: infection complicating the use of the LVAD is common (approximately half of these individuals), including bloodstream, LVAD drivelines, and central venous catheter infection; however, with close surveillance and aggressive bactericidal antimicrobial therapy, these patients can be successfully transplanted, with there being no difference in survival posttransplant in those free of LVAD-associated infection and those with such infection (~60% success rate). In the case of lung transplant candidates, cystic fibrosis patients are a particular problem, as resistant Pseudomonas aeruginosa strains are usually present in the respiratory tract pretransplant, and will usually be present

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in the transplanted lungs, despite replacement of both native lungs. Presumably the nasal sinuses are the source of the Pseudomonas posttransplant. Two organisms of additional concern are Aspergillus species and Burkholderia cepacia. Persistent respiratory tract colonization with Aspergillus increases the risk of subsequent invasive pulmonary aspergillosis, and attempts to eradicate such carriage with antifungal drugs are recommended by many transplant groups. B. cepacia colonization has traditionally been associated with a high rate of lung allograft failure at some, but not all, centers. It is now apparent that B. cepacia is not a single species, but rather is a group of closely related bacterial species, all of which are capable of colonizing the respiratory tracts of cystic fibrosis patients. These different species share the characteristic of broad-spectrum antimicrobial resistance, but appear to differ in terms of epidemiology, virulence, and impact on lung transplantation. It is likely that one or more of the B. cepacia complex is responsible for a bad outcome following lung transplantation, but that others of the complex have a more benign prognosis. Our view is that until the specifics of these relationships are better delineated, B. cepacia colonization should be regarded as a relative, not absolute, contraindication to transplantation.56–61 In patients with respiratory failure receiving single lung transplants, leaving one native lung in place (e.g., patients with emphysema), the native lung can be a source of posttransplant infection of potentially dire consequence. Hence, careful attention to and eradication of infection in the native lung are essential.62 A particular problem of special importance in whole pancreas transplantation is that of candidal infection. Because of the abundance of glucose and glycogen in the body fluids of diabetics, the candidal organism burden is significantly higher in the gut, in the vagina, and on the skin of diabetics. This increases the rate of deep wound infection posttransplant with Candida species. Because of this, we advocate fluconazole prophylaxis peritransplant in recipients of pancreatic allografts.63 Underlying anatomical or structural weaknesses of important tissues may leave the recipient vulnerable to significant infection posttransplant. Three examples of this phenomenon are especially important: patients with a history of symptomatic diverticulitis pretransplant are at high risk of recurrent diverticulitis with perforation posttransplant; similarly, patients with biliary tract disease pretransplant are at high risk of infectious complications posttransplant; and, finally, patients with significant skin disease (e.g., psoriasis or eczema) are at high risk of staphylococcal bacteremia posttransplant. Recognizing these risks, we advocate sigmoid colectomy for the pa-

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tients with a history of symptomatic diverticulitis, cholecystectomy for those with cholelithiasis, and aggressive therapy, up to and including pretransplant cyclosporine, to eradicate the skin disease—all to be completed prior to transplant.8,64 The 1990s have witnessed an exponential growth in the incidence of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium infection. Transplant recipients, particularly liver transplant recipients, have been particularly affected by these infections, with prolonged in-hospital stays (especially in intensive care units), technical mishaps from the surgery and perioperative care, and exposure to broad-spectrum antibiotics (especially cephalosporins and vancomycin) all playing a role in the epidemiology of these infections. Although the licensure of quinupristin/dalfopristin and linezolid has added significantly to our ability to treat infections due to these organisms, considerable morbidity and mortality, as well as spread to other patients, are still occurring. Surveillance for colonization in the immediate pretransplant period can be helpful in the management of patients posttransplant (e.g., need for infection control precautions, choice of antimicrobial therapy in the initial treatment of infectious disease syndromes, and need for prompt drainage of any fluid collections).65–69 The most important parasitic infection that could appear posttransplant, after being asymptomatic pretransplant, is that due to Strongyloides stercoralis. S. stercoralis is an intestinal nematode that is endemic in many areas of the world. For example, in the United States, it has been found in 36 states.70,71 The organism has a complex life cycle, the most important aspect of which is an autoinfection component that allows the organism to be maintained in the gastrointestinal (GI) tract of a human host for decades after initial infection had been acquired—long after the host might have moved from an endemic area. Such individuals may be asymptomatic or have only minor GI complaints. Apparently, tissue invasion is prevented by an intact cell-mediated immune response.72 Following transplantation and the initiation of immunosuppressive therapy, a disastrous hyperinfection syndrome and/or disseminated strongyloidiasis can develop, because of the inhibition of normal cell-mediated immune function. The hyperinfection syndrome represents an exaggeration of the normal life cycle of the parasite, with major impact on the GI tract (a severe, ulcerating, hemorrhagic enterocolitis) and/or lungs (hemorrhagic pneumonia). Disseminated strongyloidiasis consists of extension of the infection outside its normal domain, with the filariform larvae invading all portions of the body. Both of the severe forms of strongy-

loidiasis in the compromised host are associated with recurrent or persistent gram-negative bacteremia and/or meningitis, despite apparently appropriate antibacterial therapy. This appears to be caused by the adherence of gut bacteria to the external surface of the migrating larvae.70–81 Morgan et al.71 have emphasized that although early diagnosis is the key to effective therapy of these potentially devastating infections in the transplant patient, there are a number of barriers to achieving this: The organism persists long after the individual has left endemic areas; eosinophilia, a cardinal sign of parasitic infection, is commonly absent because of exogenous immunosuppression and concomitant systemic bacterial infection; routine stool examinations for ova and parasites are negative in the overwhelming majority of cases, and more useful diagnostic tests (such as sampling of proximal small bowel contents and sputum cytology) are usually not thought of or performed; and signs and symptoms are nonspecific—complicating bacterial infection will frequently obscure the picture. Therapy of established systemic strongyloidiasis with thiabendazole or ivermectin plus systemic antibacterial therapy aimed at the complicating bacteremia or meningitis is possible (see Chapter 8 for details of management), but mortality remains greater than 50%.71,73 It is of potential interest that cyclosporine appears to have antiparasitic properties against S. stercoralis.82 However, it is still strongly recommended that the asymptomatic carrier be identified prior to the transplant, and such infection be preemptively eradicated prior to the initiation of immunosuppressive therapy.83,84 Since routine stool examinations for ova and parasites will diagnose only 27% of asymptomatic carriers,85 we advocate screening of residents or former residents of Strongyloides endemic areas by one of the following approaches pretransplant: examination of Papanicolaou stained smears of sputum and duodenal aspirates and of purged stool specimens; or screen serologically for the presence of antibody to the organism and then making the assumption that a seropositive individual who has not been appropriately treated for this organism harbors it asymptomatically and merits preemptive therapy. Illustrative Case 3 A 14-year-old boy who had immigrated from Cambodia 2 years previously developed end-stage renal disease caused by reflux nephropathy. While being maintained on chronic hemodialysis, he underwent bilateral nephrectomies in preparation for transplantation. Pretransplant evaluation revealed a negative tuberculin test, no eosinophilia on peripheral blood smear, and three negative stool examinations for ova and parasites. Three weeks after receiving an HLA-identical kidney from his brother, he presented with fever, rigors, cough productive of bloody sputum, abdominal pain, and bloody diarrhea. Chest radiography re-

INFECTION IN THE ORGAN TRANSPLANT RECIPIENT vealed bilateral patchy densities consistent with bronchopneumonia. Colonoscopy revealed hemorrhagic colitis. Peripheral white blood cell count was with 85% polymorphonuclear leukocytes and 15% band forms. Two blood cultures grew E. coli sensitive to all antibiotics, with persistent bacteremia documented despite therapy with imipenem and gentamicin. He began complaining of a headache 24 hr after admission, and a lumbar puncture revealed an opening pressure of 300 mm 400 leukocytes cerebrospinal fluid (CSF) glucose < 20 mg/dl, and protein 110 mg/ dl. CSF cultures grew the same antibiotic-sensitive E. coli. Despite continued broad-spectrum antibiotics, the patient died 3 days after admission. Postmortem examination revealed systemic strongyloidiasis involving the GI tract, brain, heart, lung, liver, and renal allograft. There was evidence of an extensive hemorrhagic bronchopneumonia and enterocolitis. Serologic testing on a saved serum specimen drawn pretransplant but tested postmortem was positive for S. stercoralis antibody. Comment. This tragic case of disseminated strongyloidiasis emphasizes several important points. As more transplants are being performed on patients from Southeast Asia and Latin America, the incidence of this entity will continue to increase unless appropriate screening is carried out. Clinical disease usually presents in the first few months posttransplant. Negative routine stool examinations for ova and parasites do not rule out the possibility of this infection, nor does the lack of eosinophilia. The diagnosis of the underlying S. stercoralis infection is often obscured by the protean clinical manifestations and the pace of this disseminated syndrome. Treatment of the accompanying bacteremia and bacterial meningitis alone is inadequate if the patient is to be salvaged. This patient would have been best served by preemptive therapy based on a positive serology pretransplant.

4.2. Infection from the Donor Careful evaluation of the potential organ donor, both living related and cadaveric, is essential in preventing the transmission of life-threatening infection with the allograft. The infections to be considered can be divided into the following categories: (1) active viral infection, particularly with HIV and the hepatitis viruses HBV and HCV; (2) latent infection with such microbial agents as CMV and Toxoplasma gondii, which are capable of being reactivated posttransplant, with the possibility of systemic dissemination and clinical disease if appropriate preventive strategies are not utilized; and (3) active infection of the allograft, particularly with bacteria and fungi, but also including certain viruses, that is present as a result of the terminal illness or its care, or as a result of metastatic spread of infection during a preceding illness.8,27 Organ transplantation is an extremely efficient means of transmitting HBV, HCV, and HIV. Preventing acute HBV transmission in the peritransplant period by screening of potential donors of both organs and blood is extremely important since acquisition of HBV in this time period is associated with a markedly increased risk of fulminant hepatitis. Presently available methods of screen-

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ing for hepatitis B surface antigen (HBsAg), the most important marker for the presence of infectious, transmissible virus, are extremely sensitive. It is currently estimated that the risk of transmitting HBV, when adequate testing standards are employed, with blood transfusions is now on the order of 0.002%.27,86 Transplanting an organ from an HBsAg-positive donor into an anti-HBsAgnegative recipient carries a risk that approaches 100% for infecting the recipient with HBV. Rarely, renal allografts have been transplanted from HBsAg-positive donors into anti-HBsAg-positive recipients without transmitting HBV to the recipient. These successes may have been due to protective effects of previous immunization, despite the absence of a serologic response to the vaccine.87 Donors who are anti-HBsAg positive may harbor PCR-detectable HBV DNA in their sera and their livers, although the risk of transmitting the virus via the allograft is < 1%.88,89 In recent years, there has been considerable interest in the outcome of transplanting organs from donors who are HBsAg negative, but anti-HBc positive. It is now apparent that for renal, and presumably the other extrahepatic organs, the risk of transmitting HBV infection in this fashion is negligible.90 However, liver allografts procured from HBsAg-negative, anti-HBc-positive donors carry a significant risk of transmitting HBV. Indeed, PCRdetectable virus can be detected in these livers. There is some evidence that the posttransplant HBV infection in these recipients is milder than HBV acquired in other circumstances, and preliminary evidence suggests that posttransplant administration of hepatitis B immune globulin (HBIG) and/or lamivudine is particularly effective in this circumstance. Until more data are available on this point, we would reserve livers from anti-HBc-positive donors for critically ill individuals, and utilize the combination of HBIG and lamivudine posttransplant.91–97 It is likely that a second group of individuals who would benefit from livers from anti-HBc donors are those who are already anti-HBsAg positive.97 The approach to HCV infection remains more controversial. Approximately 5% of potential organ donors are anti-HCV positive, with approximately 50% of these having demonstrable viremia by PCR assay. Organs from donors who are HCV viremic will transmit the virus to a recipient with an efficiency that approaches 100%. Unfortunately, currently available PCR assays do not provide information in a timely enough fashion to impact on the evaluation of a potential cadaveric donor (although, clearly, all possible living donors who are anti-HCV positive should be evaluated for viremia). Hence, the decisionmaking regarding the suitability of an anti-HCV-positive cadaveric donor cannot be based on knowledge of the true

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risk of transmission; rather, it has to be made by considering the risks and benefits of providing an organ to a particular individual. Presently available evidence suggests that recipients of organs from an anti-HCV-positive donor have a 50% incidence of becoming anti-HCV positive themselves, ~25% become viremic, and 35% develop liver disease. One suggestion has been to restrict the use of organs from anti-HCV-positive donors to anti-HCVpositive recipients. However, anti-HCV does not prevent reinfection even with the same strain of virus, so this idea has been controversial, although presently available information suggests that liver transplantation from an antiHCV-positive donor into an anti-HCV-positive recipient does not appear to carry a statistically significant increase in morbidity and mortality. Also, it is clear that adverse effects of HCV infection do not usually become manifest for a number of years after infection acquisition, although chronic liver disease (even requiring liver transplantation) will develop in a significant number of individuals after 5–10 years. Therefore, we have advocated the following approach to organs from anti-HCV-positive donors: We would not use such organs in children and young adults who have the potential for decades of posttransplant life. We would (with informed consent from the recipient) utilize such organs in patients at immediate risk of death without a transplant, the elderly, highly sensitized individuals unlikely to have access to other renal allografts, diabetics, and other individuals with potential life spans of < 10 years. Whether a particular effort in this regard should be devoted to matching anti-HCV-positive donors to anti-HCV-positive recipients remains, in our opinion, unclear at the present time.86,97–109 The report that certain polyclonal immunoglobulin preparations provide significant protection against HCV infection offers another strategy for safely capturing organs from antiHCV-positive donors for transplantation.110 Although the risks of HBV and HCV infection for transplant patients have been well described, it is clear that as yet undescribed hepatitis viruses are causing chronic hepatitis in transplant recipients; that is, non-A, non-B, non-C, non-D, and non-E hepatitis is present in ~25% of patients with chronic hepatitis. So-called hepatitis G virus, found commonly in both dialysis and transplant recipients, is an “orphan virus,” not being linked to any known clinical condition.111 HIV infection is also efficiently transmitted by transplantation, with near 100% transmission of the virus from anti-HIV-positive donors. In addition, since there is a window of time in which the virus is present in the blood before the individual seroconverts, there have been a few instances in which HIV has been transmitted from a

viremia-positive, antibody-negative donor. There are two safeguards to prevent this uncommon event: First, a careful history should be taken on every potential donor to rule out high-risk behavior that carries a risk for HIV acquisition; i.e., parenteral illegal drug use, male homosexual behavior, promiscuous sexual behavior that could have included contact with HIV-infected individuals, incarceration in a correctional facility, and a history of a clotting disorder (e.g., hemophilia) requiring humanderived clotting factor concentrates. Second, in the near future, it is likely that a rapid test for the HIV p24 antigen will be available, allowing for the routine screening of donors for viremia, especially those in the high-risk group.97,112,113 Far more important than concerns regarding falsenegative HIV antibody testing is ensuring that the potential donor’s own blood and not transfused blood is the specimen being analyzed. In one tragic example, a motor vehicle accident victim who received more than 50 units of blood products prior to being evaluated as a potential donor transmitted HIV infection to the organ recipients. The blood sample that had been judged as HIV antibody negative had been drawn after the administration of the blood products and effective exchange transfusion. In this case, false negativity and a tragic outcome ensued.113 Serologic tests for several latent infections that can be carried by the allograft to the recipient, with reactivation and clinical disease posttransplant are well recognized. Important examples of this are CMV, EBV, and, in the case of heart transplant recipients, Toxoplasma gondii. Seropositivity for each of these agents connotes latent infection, with this information, plus similar information on the recipient, determining the nature of the posttransplant preventive strategies that will be employed (vide infra). Rarely, dormant fungal or mycobacterial infection that had asymptomatically metastasized to the organ (most commonly the kidney) of the donor during recognized or unrecognized primary infection can be passed to the recipient with potentially catastrophic results. Examples of histoplasmosis114 and cryptococcosis115 transmitted in this fashion have been reported. It is thus important in the evaluation of a potential donor that a complete clinical and epidemiologic history be obtained. Although we would not rule out a potential donor on the basis of a positive tuberculin test or a history of residence in a geographic area endemic for histoplasmosis, blastomycosis, or coccidioidomycosis, such information is useful in caring for the recipient posttransplant in terms of the index of suspicion and type of evaluation to which the recipient is subjected for otherwise unexplained febrile illnesses.

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The most critical issue in evaluating potential donors, particularly cadaveric donors, is the possibility of transmitting infection related to the terminal illness. There are two considerations here: systemic or isolated organ infection that was the cause of the patient’s demise; and bacterial or fungal infection that was acquired in the terminal stage of the individual’s illness as part of the care of the patient in the intensive care unit (e.g., vascular access sepsis, pneumonia caused by aspiration, catheterrelated urinary tract infection). The latter are usually the most important considerations in evaluating the donor, although the consequences of transplanting an organ from a patient with ongoing bacteremia or fungemia of either type are the same: anastomotic suture lines are threatened, with the vascular suture line being at particular risk for the development of mycotic aneurysms and of catastrophic rupture.97,116,117 Clearly, all potential donors with inadequately treated systemic infection are eliminated from consideration. The consequences of failing to do so are illustrated by the report of the cross-Canada spread of the same methicillin-resistant Staphylococcus aureus from a cadaveric donor to recipients of the kidneys and liver, with a corneal ring also being positive for the same organism.118 Similarly, focal infection of the kidneys, lungs, biliary tree, or heart will forestall the use of these organs for transplantation. The key point is not to transplant an already infected organ, or an organ obtained from a patient with ongoing bacteremia or fungemia.116,117,119–122 The first group of issues in this area that need to be addressed has to do with the possibility of utilizing organs from donors with systemic infection. Although the individual may have developed irreversible brain injury as a consequence of the infectious process, effective antibiotic therapy may have sterilized the infection such that the organs can be safely used for transplantation. For example, organs from a patient dying of enterococcal endocarditis treated with several days of antibiotics prior to organ procurement have been successfully utilized for transplantation.123 Because there is considerable interest in increasing the number of organs that might be safely transplanted, we have suggested that the following issues be considered when confronted with this question117: 1. The organism(s). Not all microbes are of equal virulence in terms of adherence to cardiovascular endothelial surfaces or the ability to metastasize to organs of interest for transplantation. Thus, enterococci, Staphylococcus aureus, viridans streptococci, and Pseudomonas aeruginosa are noted for their ability to adhere to endothelial

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surfaces, and Staphylococcus aureus, Salmonella species, Aspergillus species, and P. aeruginosa are notable for their ability to establish metastatic infection in organs of interest. In contrast, E. coli, Enterobacter species, and Klebsiella species generally exhibit neither characteristic. 2. Antimicrobial efficacy. Not all antimicrobial strategies are of equal efficacy in terms of eliminating bloodstream infection. For the purposes of cleansing the bloodstream and organs of interest of infection, it would seem logical to require bactericidal (as opposed to bacteriostatic) therapy. Because of the far slower response of fungal infection to antimicrobial therapy, patients with candidemia should require far more extensive therapy than those with acute bacteremia or else be eliminated from consideration. 3. Time course of infection. The duration and level of bacteremia, and the clinical and microbiologic response to appropriate therapy are important variables to be considered as well. For example, a potential donor with sustained S. aureus bacteremia over several days would be an undesirable candidate for this approach. In contrast, acute pneumococcal or meningococcal meningitis, for which appropriate therapy clears the bloodstream in 4–5 days quite reliably, and where metastatic infection to organs such as the kidneys and liver is unusual, might be entities that would lend themselves to an expanded donor pool consideration. With these considerations in mind, we would propose the following approach, which is aimed at safely expanding the donor pool. It should be emphasized that informed consent on the part of the potential recipient is an integral part of this process. 1. The potential donor has had a bacteremia with a relatively bland organism (e.g., the Enterobacteriaceae with the exception of Salmonella species, or viridans streptococci) or with an organism that is rapidly cleared from the bloodstream with effective bactericidal therapy (e.g., penicillin-sensitive pneumococci and meningococci) that has been treated with bactericidal therapy for at least 5 days, and where blood cultures have been shown to become negative. Ideally, some evidence of clinical response to such therapy should be present. Patients with undrained, infected fluid collections (“pus under pressure”) require more prolonged treatment regardless of the causative organism.

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2. Potential donors with bloodstream infection due to the following organisms would require a minimum of 2 weeks of bactericidal therapy and then “proof of cure” (i.e., negative blood cultures over a week’s period off antibiotics): Staphylococcus aureus, Pseudomonas aeruginosa, and infections due to streptococci that have decreased susceptibility to penicillin. 3. Potential donors with bloodstream or invasive tissue infection due to the following more difficult to treat organisms should be eliminated from consideration for the present: Group A streptococcal infection, vancomycin-resistant enterococcal infection, Streptococcus milleri infection, Salmonella infection, and fungal, nocardial, or active mycobacterial infection. 4. All recipients receiving organs from this category of expanded donors should receive bactericidal antibiotic therapy directed against the donor’s organism for a minimum of 10–14 days posttransplant. 5. An international registry should be established in which all situations in which infected donors were utilized, both successes and failures, are collected, collated, and summarized for the transplant community. The second group of issues has to do with infection acquired in the terminal care of the donor and/or through contamination during the organ procurement and transport process. In recent years, in an attempt to salvage more organs, several steps have been taken to more closely evaluate these infections in the potential donor and to take steps to limit their consequences: 1. In patients with bladder catheter-associated bacteriuria, as the organs are procured, urine samples are obtained directly from the ureters for urinalysis, Gram stain, and culture. In the absence of evidence of upper urinary tract infection or inflammation, we have successfully utilized such kidneys. 2. In patients with atelectasis and forms of pneumonia unlikely to be associated with bacteremia (e.g., Haemophilus species in an adult, Acinetobacter and other forms of nosocomial gramnegative pneumonia), if systemic antibiotic therapy effective against the patient’s respiratory flora has been administered prior to organ procurement, it may be possible to utilize at least some of the organs for transplantation.

3. In this era of multiorgan procurement from the same donor, great care must be taken to protect each organ from contamination from the other organs. Thus, we have observed contamination of the great vessels of the heart, with subsequent rupture of a mycotic aneurysm at a vascular suture line, caused by spillage of bacteria from the respiratory tract during the procurement procedure. 4. When organs from patients with nosocomial infection distant from the organ utilized are transplanted, after the above precautions are taken, peritransplant prophylaxis is usually extended for 10–14 days to provide an extra level of safety to the recipient. Other techniques that are employed to protect allograft recipients from contaminated organs include the culturing of organ perfusate and transport media. Indeed, a 4–40% rate of positive cultures has been documented.119,120,124–127 Most such positive cultures are with nonvirulent skin flora, and these results have correlated poorly with the occurrence of posttransplant allograft infection. Conversely, the occasional instance in which such surveillance cultures have yielded gram-negative bacilli, particularly P. aeruginosa, and Candida species, have been highly correlated with infection involving the vascular anastomoses of the transplant, with the development of mycotic aneurysms and/or vascular disruption with lifethreatening hemorrhage.119,128–130 The importance of gram-negative infection of the perfusate has been emphasized in a dog transplant model. In these studies, the perfusate was purposely contaminated with E. coli, and the kidney was then transplanted. All of the recipients died in approximately 4 days of either vascular anastomotic disruption or generalized sepsis.130 Unfortunately, negative perfusate cultures and careful clinical evaluation of the donor prior to organ procurement do not preclude the possibility of serious allograft infection. We have reported a case of unsuspected donor Pseudomonas sepsis (donor afebrile prior to transplant, but with premortem donor blood cultures becoming positive several days later for the identical P. aeruginosa strain subsequently isolated from the recipient) causing life-threatening infection in both recipients of kidneys from this single donor. In the second posttransplant week, both kidney allograft recipients required emergency graft nephrectomies because of a massive retroperitoneal bleed. At operation, the arterial anastomosis was completely necrotic and disrupted, and grew the same Pseudomonas.119

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We are aware of similar scenarios involving the vascular anastomoses of the other organs as well. Freeman et al.131 have published a reassuring paper in which the outcomes of transplanting organs from donors with positive blood cultures were reviewed retrospectively in the New England region. Of 95 cases of bacteremia in the donor, none of the 212 transplant recipients became infected. However, before we become complacent about this issue, several points bear emphasis: the great majority of the organisms were relatively bland (~15% gram negatives); the duration and level of bacteremia were not well defined; and virtually all of the recipients received appropriate antibiotics posttransplant. We remain particularly concerned about unsuspected donor bacterial or candidal sepsis acquired in the intensive care unit while the donor receives care for the terminal illness, and employ the following approach119:

1. Careful culturing of the donor (including preterminal blood cultures) and of the perfusates or organ transplant medium should be continued, with systemic antimicrobial therapy initiated for positive cultures, utilizing shorter durations of therapy (< 7 days) for the nonvirulent organisms and longer durations (> 14 days) if the cultures yield gram-negative bacilli, Staphylococcus aureus, or Candida species. 2. Certain potential donors at a particularly high risk for occult sepsis should not be used. These include victims of drowning (who may be infected with microorganisms found in water), burn victims, and patients who have been maintained on a respirator with indwelling lines and catheters for a period of more than 7 days.132,133 Even these steps will not completely solve the problem of occult sepsis contaminating allografts. The ultimate answer will depend on the development of rapid noncultural diagnostic techniques for detecting microbial DNA or microbial products so that potential donors can be rapidly screened for occult sepsis that could impact on the allograft. 4.3. Wound Infection The most important form of treatable infection in this time period, in terms of both frequency and clinical impact, is wound-related sepsis. Most of the data in this area have come from studies of renal transplantation, and we will consider this first, with later comments on the special issues that apply to the other forms of organ transplantation.

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4.3.1. Wound Infection in Renal Transplant Recipients The reported incidence of wound infection following renal transplantation has varied from 1.8 to 56%.134–138 The impact of such infections, particularly when deep in the perinephric space, can be great, with 75% of deep perinephric infections resulting in the need for transplant nephrectomy, and with many lives lost because of systemic sepsis originating from this site or from the development of a mycotic aneurysm in the area of the vascular anastomoses.139,140 That such infections should be common in these patients is no surprise in view of the effects of chronic uremia, possible protein malnutrition, immunosuppressive therapy, and so forth, on wound healing and resistance to infection. Even more important in the pathogenesis of wound infection is the occurrence of technical complications of the surgery. For example, in one series from the University of Minnesota, the incidence of wound infection was 6.1% among 439 consecutive renal transplant operations. If, however, those occurring in conjunction with the presence of a hematoma or urinary fistula are excluded, the incidence of wound infection in the uncomplicated wounds was only 1.6%, with all being superficial infections. If diabetics and retransplanted patients are excluded, the incidence of wound infection was only 0.7%, again, all superficial.140 By way of comparison, the rate of wound infection for clean general surgical procedures in nonimmunosuppressed patients is reported as 1.8%.141 Other transplant groups have noted similarly low rates of wound infection.142–145 The unavoidable conclusion is that the most important factor in the prevention of wound sepsis in the transplant patient is the technical quality of the surgery performed. There is probably no other area of general surgery comparable to transplant surgery in which anything less than impeccable surgical technique can have such disastrous consequences. The incidence of wound infection is determined by the ability of the surgeon to prevent urine leaks, wound hematomas, and the development of lymphoceles—all of which markedly increase the risk of infection. One additional factor is the avoidance of unnecessary “dirty” surgery at the time of transplant. For example, a high rate of Bacteroides fragilis bacteremia has been observed when elective appendectomy was performed at the time of renal transplantation.146 This observation is an extension of two general principles: all active infections must be eradicated prior to transplant, and ill-advised surgery has consequences as grave as technically flawed surgery.

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Prevention of urinary leaks begins at the time of organ procurement. The primary concern here is to preserve the blood supply of the donor ureter, as ureteral vascular insufficiency resulting in distal ureteral necrosis or fibrosis is a major cause of both urinary extravasation and ureteral obstruction. Damage to this blood supply as a result of stripping of the periureteral adventitial tissue in which the blood vessels run, too extensive dissection of the hilum of the kidney, or the failure to recognize the presence of multiple renal arteries are the major technical problems that must be avoided by the organ procurement surgeon.147,148 If this is accomplished, attention is then turned to the urinary anastomosis, be it a ureteroneocystostomy or ureteropyelostomy, in which watertight, nonobstructing anastomoses are essential. Although a discussion of the surgical details of the urinary anastomosis and the choice between the types is beyond the scope of this chapter, their importance cannot be minimized. In the best hands, urologic complication rates of less than 2% should be obtained.149–151 When such complications occur, they must be promptly corrected, with drainage, and provision made for unobstructed urine flow. If unattended, there is a high risk of life-threatening sepsis. The second major preventable factor in the development of wound sepsis is the formation of a wound hematoma. Any technical problems resulting in bleeding will be exacerbated by the uremic state and by the heparin commonly employed when posttransplant hemodialysis is required. Wound hemostasis at the time of transplantation must be meticulous. When bleeding or other complications require reexploration or transplant nephrectomy, the incidence of wound infection increases 10-fold.138–140,152 The final technical consideration here is the prevention of lymphoceles. Such collections of lymph in the retroperitoneal wound of the renal transplant patient occur at reported rates of 2–18% and may result in mechanical obstruction and/or become secondarily infected.153–155 Lymphoceles result when, at the time of transplantation, lymphatic vessels, especially those crossing the iliac arteries, are cut without ligation or lymph nodes are removed for tissue typing purposes, again without adequate ligation of the lymphatic channels. Lymph collecting in the retroperitoneal space will not be absorbed and must be drained surgically, either externally or into the peritoneal cavity. A clinical clue to the presence of such a lymphocele is the development of unilateral leg edema on the side of the transplant.139,153–156 Thus far, the factors leading to the development of wound infection in the renal transplant recipient have been explored. Next to be considered are the questions of how best to prevent (other than with expert surgery), diagnose, and treat wound infections. In the area of pre-

vention, there is general agreement among most transplant surgeons that local irrigation of the transplant wound with antibacterial solutions is beneficial, although such practice has never been subjected to a careful randomized study in the transplant setting. Similarly, the use of open drains, such as Penrose drains, is thought to be associated with the risk of introducing microorganisms from the skin surface.138,139,157 Many groups, including our own, employ closed suction drainage (as with a Jackson–Pratt drain) in an effort to obliterate dead space and prevent fluid collections, removing the drain when less than 40 ml/day is being delivered into the system. Usually the drain can be removed in less than 5 days, after an ultrasound study is negative for a drainable fluid collection. If copious, nonbloody drainage continues for a longer period, either a lymph leak or a urine leak is present. The latter can be ruled out by administering intravenously the dye indigo carmine, which imparts a blue color to the urine, and checking the color of the drainage. Perioperative antibiotic prophylaxis has been reported to decrease the incidence of wound infection. A regimen aimed at uropathogens and staphylococci, such as ampicillin–sulbactam or cefazolin, should be used. Such therapy should be initiated on call to the operating room, and continued for no more than 24 hr posttransplant. The exact choice of antibiotics should be guided by knowledge of the prevalent bacterial flora causing wound infection at a particular institution and the antibiotic susceptibility patterns of these organisms. Two points should be emphasized regarding such a prophylactic program: (1) no antibiotic prophylaxis program can take the place of technically expert surgery and (2) such a program is aimed at protecting against wound infection, not later urinary tract infection or other problems. There are better methods for preventing urinary tract infection (vide infra), and prolonging broad-spectrum parenteral antibiotic prophylaxis adds little to the care of transplant patients.5,8,27,143–145,152,157 The diagnosis of wound infection requires a high index of suspicion. As detailed in Chapter 18, the immunosuppressive therapy being administered will frequently obscure the usual presenting signs of wound infection. Therefore, any transplant patient with an unexplained fever should be subjected to either ultrasonographic or computed tomographic (CT) scanning of the deeper operative sites. In selected patients, sterile needle aspiration of the wound can be helpful in diagnosing more superficial wound collections. Any collection identified should be promptly drained under broad-spectrum antibiotic coverage. If infection is identified, then appropriate antibiotics are usually contin-

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ued for 10–14 days or until the patient has been afebrile for 5–7 days. Whenever perinephric infection is identified, the possible need for graft nephrectomy to facilitate drainage and to prevent catastrophic anastomotic leaks should always be kept in mind. If deep sterile collections are found, we once again prefer closed suction drainage to the placement of Penrose drains. 4.3.2. Wound Infection in Liver Transplant Recipients As with wound infection in renal transplant patients, the major determinants of wound infection (as well as other forms of infection in the first month posttransplant) in the liver transplant recipient are technical aspects of the operation itself. The complexity of the surgery—hepatectomy, and then four vascular anastomoses (the suprahepatic vena caval anastomosis, the infrahepatic vena caval anastomosis, the portal vein anastomosis, and the reconstruction of the hepatic artery), as well as a biliary anastomosis—in a patient with a bleeding diathesis is a daunting challenge, to say the least. Intra-abdominal bleeding and contamination with upper GI microbial flora are not uncommon, leading to a relatively high rate of deep wound infection—probably on the order of 5–15%, which is increased further if reexploration for bleeding or retransplantation are required, or a biliary leak occurs. Intra-abdominal fluid collections, particularly hematomas, must be drained or the risk of secondary infection is prohibitive. This is especially true of hematomas, in which the benefits of removing these nidi for future infection outweigh the risks of reexploration. Typically, such reexploration is best carried out 2–4 days posttransplant, at a time when the coagulopathy that contributed to the intra-abdominal bleeding has been corrected. The nature of the biliary anastomosis also plays a role in determining the frequency of posttransplant wound infection, with choledochojejunostomies carrying an increased risk because of the bowel manipulations necessary to effect the anastomosis.158–165 Although peritransplant antimicrobial prophylaxis for the renal transplant patient is more or less optional, most transplant groups regard it as being obligatory for liver transplantation. The controversy concerns the constituents of this prophylactic program. Most groups use perioperative systemic prophylaxis consisting of a cephalosporin (usually cefazolin or cefotaxime) ± ampicillin or gentamicin, beginning on call to the operating room, and continuing for 3–7 days posttransplant. In addition, the transplant groups at Groningen and the Mayo Clinic have championed the concept of selective bowel decontamination, beginning at least 1 week before likely

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transplantation, and continuing for the first 21 days posttransplant. A common program of selective bowel decontamination that is employed consists of the administration four times per day of the following: a suspension of gentamicin, 80 mg/10 ml; polymyxin E, 100 mg/10 ml; nystatin, 2 × 106 U/10 ml; plus mucosal paste (Orabase) containing the same antibiotics at 2% concentrations. This program, when combined with perioperative systemic antibiotics, has been associated with a very low rate of infection.166–170 This stands in direct contrast to reports from other centers of a 16–42% incidence of fungal infections in their liver transplant patients,170–174 including a 16% incidence of fungemia in one of these studies.174 Recent studies by Arnow and colleagues175,176 have shown that beginning the program of selective bowel decontamination in the perioperative period adds little to the effects of systemic antibiotics, thus emphasizing the need to begin this program a week or more prior to transplantation to reap its optimal benefits. In many patients, this may be logistically difficult to accomplish. Because of the lack of controlled trials in this area, however, it is not clear what the optimal prophylactic regimen should be. For example, at Massachusetts General Hospital, we have a similarly low rate of wound infection and postoperative candidal infection (< 3%), utilizing the following program: oral nystatin or clotrimazole three to four times a day, beginning as soon as it appears likely that the patient is within 3 weeks of transplantation (“high on the waiting list”), continuing this through the transplant period and whenever antibacterial therapy is being administered; cefazolin, 1 g every 8 hr, is administered for 3 days, followed by oral trimethoprim–sulfamethoxazole (or ciprofloxacin, in the trimethoprim–sulfamethoxazoleintolerant patient) for 6–12 months. Despite the difficulties in comparing results of different regimens from different programs, we would suggest that the following principles for preventing deep wound infection in the liver transplant recipient appear reasonable at the present time: 1. The first rule of wound infection prevention is technically perfect surgery. 2. Because of the relatively large numbers of candidal species present in the upper GI tract, the fungal promoting effects of the immunosuppressive therapy (particularly the corticosteroids), and the exposure of the patient to the selective pressures of broad-spectrum antibacterial therapy, it is not surprising that invasive candidal infection is a particular problem in the first month after liver transplantation. Therefore, it is reasonable to believe that an antifungal prophylaxis

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program should be undertaken. Our approach at present is to utilize mucosal prophylaxis with oral nystatin or clotrimazole, reserving fluconazole for use in patients likely to have high candidal burdens in their GI tracts and/or to be at significant risk of candidal contamination of the surgical site. Hence, we employ fluconazole in the following instances: in diabetics, in patients who have received broad-spectrum antibacterial therapy in the weeks just prior to transplantation, in patients undergoing choledochojejunostomy biliary anastomoses, and in patients undergoing reexploration.177,178 Both oral and parenteral fluconazole are well tolerated in the liver transplant patient when it is clinically indicated, although it is important to remember that fluconazole will downregulate cyclosporine and tacrolimus metabolism. Hence, lower doses of these drugs must be administered in the face of fluconazole therapy or toxic blood levels of the calcineurin inhibitors will be achieved.179 3. The best regimen for antibacterial prophylaxis also remains to be defined. One cannot argue against selective bowel decontamination, although there is a need for controlled trials to prove its efficacy. Quinolones, which have shown efficacy in other immunosuppressed patient populations when compared with nonabsorbable antibiotics, merit a trial here as well, probably in combination with an antifungal regimen.173 Perioperative systemic therapy with such drugs as cefazolin and cefotaxime (with or without other drugs) appears to be well established, although there is a need to establish the best regimen. Although there are conflicting data on this subject, we believe that systemic antimicrobial agents should be redosed during the liver transplant procedure, commensurate with the level of blood replacement that is needed.175 In other operative situations, the efficacy of prophylactic cephalosporin therapy has been shown to be significantly attenuated when intraoperative blood levels are allowed to fall below therapeutic levels.180–182 4.3.3. Wound Infection in Heart, Lung, and Heart– Lung Transplant Recipients The incidence of wound infection following cardiac transplantation has been reported to vary from 3.6 to 62.5%, but most of these cases are usually related to various catheter sites or vascular cutdown sites and are

rarely fatal.183–185 Lower-dose steroid therapy appears to be associated with a decreased risk of wound infection in these patients.186 The big concern is infection of the median sternotomy wound, with its potential for mediastinitis and infection spreading directly to the allograft. Sternal wound osteomyelitis and infectious pericarditis are other consequences of wound infection in these patients.187,188 Fortunately, with careful surgical technique and antimicrobial prophylaxis, this is uncommon. Most cardiac surgical groups utilize a cephalosporin either alone or with vancomycin for perioperative prophylaxis, continuing it until the chest tubes and all catheters have been removed (usually 5–7 days posttransplant). An uncommon, but usually disastrous, complication is infection at the aortic suture line, resulting in a mycotic aneurysm.189–193 Whether such complications will increase in patients having left ventricular assist devices placed as a “bridge” to transplantation remains to be determined.194 In the case of single, double lung, or heart–lung transplantation, the biggest additional concern is the integrity of the bronchial anastomosis. Otherwise, the incidence of wound infection is related to the technical management of the surgery, and the drainage catheters. We find it useful to monitor chest tube drainage approximately every 3 days prior to removal, aggressively treating organisms that are present in the pleural space or mediastinum. A variety of antimicrobial prophylaxis programs have been utilized in the various forms of lung transplantation. Our own approach is based on two observations: the sputum of many patients coming to lung or heart–lung transplantation is usually colonized with a variety of pathogenic gram-negative bacilli, Staphylococcus aureus, and/or fungal species; and the microbial flora of the native respiratory tract is an important source of wound infection (as well as postoperative pneumonia) in lung transplant recipients. Rather than utilizing the same prophylactic regimen for all lung transplant recipients, we prefer to monitor these patients, as they approach transplantation, with weekly sputum cultures, and then design individualized antimicrobial prophylaxis programs based on the results of these cultures. 4.4. Other Causes of Infection in the First Month The major remaining causes of infection in the renal transplant patient during the first month following transplantation are pneumonia, urinary tract infection, and intravenous line-related sepsis. One general principle underlines the occurrence of each of these—the immunosuppressed patient tolerates poorly the presence of foreign bodies that bypass normal local host defenses; i.e.,

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endotracheal tubes, urinary catheters, and plastic intravenous catheters. These should be used sparingly, removed promptly, and managed with impeccable aseptic technique. In the case of pneumonia, the first concern is prevention with the use of appropriate anesthetic and analgesic management so that the endotracheal tube can be removed as quickly as possible posttransplant, aspiration is prevented, and chest physical therapy and early patient mobilization are employed to prevent atelectasis. An additional factor in preventing pneumonia is the aggressive management of nausea to prevent vomiting, even if a nasogastric tube is required because of gastric dysfunction (particularly in diabetics). Aspiration pneumonia is a frequent consequence of vomiting in the immunosuppressed patient. Plastic catheters for intravenous use are to be discouraged, particularly central venous pressure catheters or Swan–Ganz pulmonary artery catheters for hemodynamic monitoring. Unless a major complication occurs in the perioperative period, virtually no suitable candidate for a renal transplant should require this type of monitoring. Although the problem of intravenous line-related sepsis is a general one throughout the hospital, its consequences can be particularly disastrous in these patients. For example, although a transient intravenous line-related Candida septicemia is associated with metastatic infection in less than 5% of normal individuals, among immunosuppressed patients more than 50% will develop metastatic infections if left untreated.195 The same general considerations apply to the other forms of organ transplantation, except even more intensely. In the case of liver transplantation, patency of the vascular anastomoses and the intactness of the biliary anastomosis are more frequently an issue than patency of the renal vascular anastomoses and stability of the ureteral anastomosis. Portal vein thrombosis, hepatic artery thrombosis, and hepatic vein occlusion developing in the first few days posttransplant are well-recognized complications of liver transplantation, particularly in young children whose tiny vessels can pose a major technical problem and in patients who become hypotensive. Manifestations of these complications include ascites, variceal bleeding, and deterioration in liver function tests and clinical status. Not uncommonly, fever and bacteremia may be the major clues. Sepsis is particularly common following interruption in the hepatic arterial circulation, with secondary infection of hepatic infarcts leading to areas of hepatic gangrene, abscess formation, and fulminant sepsis related to bowel flora or candidal organisms. A more insidious consequence of vascular insufficiency can result when the vascular supply to the liver parenchyma remains intact, but the biliary anastomosis is

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rendered ischemic. This results in a breakdown of the biliary anastomosis, a bile leak (or late stenosis), and secondary infection. Such secondary infection may take the form of deep wound infection, cholangitis, liver abscess, and/or bacteremia, with the microorganisms causing this derived from the normal flora of the small bowel—streptococci, Enterobacteriaceae, anaerobes, and Candida species. Polymicrobial infection is the rule in these circumstances. This more occult result of vascular insufficiency is totally analogous to the ureteral leaks and stenoses developing after renal transplantation following vascular insufficiency of the ureter.158–162,170–174,196–203 As experience has been gained with liver transplantation, problems with the vascular anastomoses have become less common. The biliary anastomosis, however, remains the Achilles heel of liver transplantation. Whenever possible, the anastomosis of choice is a choledochocholedochostomy, which maintains the native sphincter of Oddi intact. When this is not possible for anatomic reasons, as in children with biliary atresia or ducts too small to safely carry out this anastomosis, or in adults with sclerosing cholangitis or other abnormalities of the extrahepatic biliary system, a choledochojejunostomy constructed with a Roux-en-Y technique that offers protection against microbial contamination from the GI tract can be employed. Although biliary leaks can develop with either anastomosis, obstruction is the major concern with the choledochocholedochostomy procedure, whereas reflux of organisms is the weakness of the choledochojejunostomy anastomosis. In either case, secondary infection is the consequence.203,204 The cardinal rule in the first few weeks following liver transplantation is that any episode of unexplained fever or bacteremia should be regarded as a manifestation of a technical problem involving the vascular tree, the biliary anastomosis, or deep wound infection until proven otherwise. Accordingly, such diagnostic procedures as abdominal CT scanning and/or ultrasound with Doppler to look for collections as well as vascular patency, cholangiography, and, when appropriate, hepatic angiography must be carried out expeditiously as well. Prompt surgical attack of technical problems under antimicrobial coverage can salvage these patients.204 Colonization of the bile of liver transplant patients with bacteria is the rule rather than the exception, and this can be easily documented by bile cultures in patients with T-tubes left in place to protect the biliary anastomosis. The colonizing flora usually consists of bowel streptococci, Staphylococcus species, and, intermittently, a variety of gram-negative bacilli. Such colonization by itself requires no therapy under normal circumstances. Indeed, patients developing symptomatic infection re-

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lated to biliary colonization in the absence of biliary manipulation should be regarded as having an anatomic abnormality—obstruction or a leak—of the biliary tree, and should be investigated immediately. Occasionally, Candida species will colonize the biliary tree. Asymptomatic candidal colonization of the biliary tree can result in obstruction related to the formation of fungal balls, analogous to what can be observed in the urinary tract (vide infra). Accordingly, we treat such colonization preemptively, usually with fluconazole. The asymptomatic colonization of the biliary tree becomes of importance under three circumstances: (1) biliary manipulations such as cholangiography can result in cholangitis and systemic sepsis; (2) liver biopsies can result in intraparenchymal collections of bile and blood, culminating in liver abscess formation; and (3) when the T-tube is removed, usually more than 2 months posttransplant, a bile leak with chemical and/or bacterial peritonitis can occur. We have found that administering single doses of broad-spectrum antibiotics prior to these procedures is quite helpful in preventing complications. Such prophylaxis is particularly important if the biliary anastomosis is a choledochojejunostomy. In the first month following lung transplantation, the biggest concerns relate to the integrity of the bronchial anastomosis and postoperative pneumonia. Indeed, the great advances in lung transplantation have occurred as the surgical management of this anastomosis has improved (analogous to the ureteral and biliary anastomoses with renal and hepatic transplantation), including the provision of an omental wrap of the anastomosis. Avoidance of high-dose steroids to promote wound healing, care to preserve the vascular supply, and antimicrobial therapy to protect the anastomosis have all contributed to the success now being achieved.205,206 Pneumonia, however, remains a significant problem for several reasons: Colonization of the native respiratory tract, particularly with gram-negative bacilli and Aspergillus species, provides an important source of infection for the new lung.206,207 This is a particular problem in patients with cystic fibrosis. 4.5. Noninfectious Causes of Fever in the First Month Posttransplant

The most common noninfectious cause of fever in the first month posttransplant is allograft rejection. Approximately two-thirds of transplant recipients will have acute rejection in the first month posttransplant, with a little less than half of these having steroid-resistant rejection that requires antilymphocyte antibody therapy. Although less striking than in the precyclosporine era, fever

may still be the first manifestation of rejection, particularly in this early posttransplant period. This is especially true in children, who tend to have more exaggerated temperature responses than adults. An important clinical point is that small children who receive an adult kidney may have significant rejection before changes in the serum creatinine level can be detected. Thus, an unexplained fever in the first few weeks posttransplant in a small child who has undergone renal transplantation should prompt either a renal biopsy or consideration of a steroid pulse. We have observed that in children who were febrile for 5–7 days prior to a rise in serum creatinine, if acute antirejection therapy was delayed until then, it was too late and the allograft was lost.208 The second most common noninfectious cause of fever in this time period is antilymphocyte antibody therapy. The first two or three doses of OKT3 (a monoclonal pan-T-cell antibody preparation) or antithymocyte globulin (a polyclonal pan-T-cell antibody preparation) are invariably associated with the release of a variety of cytokines, most notably tumor necrosis factor. In addition to fever and chills, some patients can develop hypotension, a febrile pulmonary edema syndrome, aseptic meningitis, encephalopathy, and other manifestations of a massive cytokine release. Some of this can be avoided with extra corticosteroids, diphenhydramine, and acetaminophen. As new anticytokine strategies become available, these inflammatory events should become more easily managed. In the great majority of patients, fever, chills, and malaise that disappear by the third dose are the only acute manifestations of antilymphocyte antibody therapy. The reappearance of fevers in the latter part of a 10- to 14-day course of therapy suggests an immunologic response to these animal proteins (murine in the case of OKT3 and equine or rabbit in the case of antithymocyte globulin) that may be limiting the antirejection effects of this treatment.209,210 Other noninfectious causes of fever to be considered include pulmonary emboli and drug reactions. Probably because of the anti-inflammatory effects of the immunosuppressive program, drug fevers and rashes are less common in transplant patients than in the normal population, although such adverse effects as bone marrow toxicity, hepatic toxicity, and renal injury are at least as common.

5. Infection 1 to 6 Months Posttransplant Unless technical complications that can lead to lifethreatening infection have occurred during the first month, the time period 1–6 months posttransplant is the critical

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period for the transplant patient in terms of the greatest risk of the infections that are unique to these immunocompromised individuals:

1. Immunosuppressive therapy is still at a relatively high level, particularly if significant amounts of antirejection therapy have been required. Even more important, the duration of immunosuppression is now sufficient that opportunistic forms of infection can occur. 2. Infections occurring during this period are usually quite challenging to treat with antimicrobial therapy, since most are caused by viruses, antibiotic-resistant bacterial species, and a variety of fungi. 3. Any technical errors lingering from the perioperative period (e.g., persistent anastomotic leaks, vascular compromise with tissue infarction) will, by definition, be serious. These require the presence of drains, catheters, and drainage tubes, for prolonged periods of time. The longer such foreign bodies are required, the greater the incidence of superinfection, and the more difficult to treat the infection becomes, usually evolving from an antibiotic-sensitive bacterial species to increasingly resistant gram-negative and fungal species. 4. The key factor, other than the technical issues that determine graft viability, in determining the patient’s fate in this time period is the presence or absence of infection with the immunomodulating viruses (the herpes group viruses, hepatitis viruses, and, uncommonly, HIV). 5.1. Herpes Group Virus Infections in the Organ Transplant Recipient The human herpes group viruses [CMV, EBV, varicella–zoster virus (VZV), herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), and HHV-6, -7, and -8] share several characteristics that make them the most important group of microbial pathogens that affect organ transplant recipients8,27: 1. Latency. The term latency is used to designate the fact that once infected with these viruses, an individual is infected for life, even after evidence of active viral replication is no longer demonstrable. The viral genome is present in latently infected cells, but gene expression is limited, infectious virus is not produced, and the virus is hidden from attack by the host’s immune system. Latent virus can be reactivated at a later date, either sponta-

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neously or in response to exogenous influences. The laboratory marker for the presence of latent infection is the presence of circulating antibody (“seropositivity”) in the absence of active viral replication. The different herpes group viruses differ in the stability of their latency, although all will be reactivated by immunosuppressive programs that include antilymphocyte antibodies, as well as other components (vide infra). CMV is latent in a more stable fashion, only being reactivated when the individual is exposed to certain forms of immunosuppression, as a result of an allogeneic reaction, during pregnancy, and on exposure to certain proinflammatory factors (vide infra). In contrast, EBV’s latency is very unstable, with spontaneous reactivation occurring repetitively for variable periods of time in seropositive individuals. VZV and HHV-6, -7, and -8 seem to resemble CMV, requiring a specific event for reactivation to occur. In contrast, HSV-1 and -2 are more like EBV, being reactivated by a variety of “stresses” but also in conjunction with no apparent stimuli. Once viral reactivation occurs, then the extent of the viral replication, and the subsequent clinical effects, is amplified by the level of immunosuppression present. 2. Cell association. The term cell association means that these viruses are spread between individuals by intimate cell-to-cell contact, transfusion, or transplantation. Similarly, spread within tissues and systemically is accomplished by the direct contact of infected cells with other susceptible cells. This renders humoral immunity inefficient, and places particular emphasis on cell-mediated immunity for elimination of the infected cells. In particular, major histocompatibility complex (MHC)-restricted, virus-specific, cytotoxic T cells are the most important host defense against these viruses. The impact of different immunosuppressive agents and programs on the course of infection with these viruses is in large part related to the immunosuppressive program’s effects on the functioning of the critical cytotoxic T-cell response. The MHC restriction of these T cells suggests that the transplant patient would have particular difficulty in eliminating virusinfected cells within allografts that are MHC disparate with the host. As will be discussed, this possibility may indeed be clinically important. 3. Oncogenicity. All herpes group viruses should be considered potentially oncogenic. Two types of oncogenic effects can be seen. First, and most important, is direct oncogenicity, as exemplified by the causation of posttransplant lymphoproliferative disorder (PTLD) by EBV and Kaposi’s sarcoma by HHV-8. In addition, there can be more indirect effects. Thus, preceding CMV disease has been shown to increase the risk of subsequent EBV-associated PTLD 7- to 10-fold.211,212

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4. Clinical effects. With regard to the clinical effects of the herpes group viruses, both direct and indirect effects must be considered. Direct effects include the various infectious disease clinical syndromes (e.g., pneumonia, hepatitis, tissue ulceration, gastroenteritis) that are a consequence of lytic viral infection, tissue invasion, and the host response to these events. Indirect effects refer to those events produced by cytokines, chemokines, and growth factors elaborated in response to viral replication. These indirect effects can be grouped into three categories: (a) immunomodulatory, such that the net state of immunosuppression is increased and opportunistic superinfection is promoted; (b) pathogenesis of allograft injury; and (c) oncogenesis. In many patients the indirect effects are at least as important as the direct. 5.1.1. CMV Infection in Organ Transplant Recipients CMV has been, and continues to be, the single most important microbial pathogen affecting organ transplant recipients, contributing directly and indirectly to both morbidity and mortality in these patients. Evidence of CMV replication can be found in more than half of transplant recipients, although the rate of clinical illness is a fraction of this figure. There is a complex relationship between the effects of CMV replication and the two phenomena that are inherent in the transplant experience: allograft rejection and chronic immunosuppressive therapy. The end result is twofold: CMV, which latently infects more than half of the general population (the CMV seropositive population), will be reactivated from sites within the recipient, from the allograft itself, or from viable leukocyte-containing blood products; and the ability of the host to eradicate virus from any of these sources can be greatly impaired, leading to the possibility of prolonged or relapsing viral infection and a multitude of consequences. These consequences, the direct and indirect effects of CMV on the transplant recipient, can be grouped into four distinct categories3,8,27,213: 1. The direct causation of a variety of clinical infectious disease syndromes by the virus itself, ranging from prolonged fevers and a mononucleosis-like syndrome, pneumonia, hepatitis, and GI ulcerations and inflammation acutely, to a chronically progressive chorioretinitis. 2. The production of an immunosuppressed state that is over and above that caused by the immunosuppressive drugs being administered. This contributes significantly to the net immunosuppressed

state of the transplant patient and plays an important role in the pathogenesis of opportunistic superinfection caused by such organisms as Pneumocystis carinii, a variety of other fungi, Nocardia asteroides, and Listeria monocytogenes. 3. A probable role in the production of acute and chronic allograft injury, such that anti-CMV therapy may have a role in improving allograft function and longevity. 4. A possible role in the production of certain forms of malignancy. 5.1.1a. Epidemiology of CMV Infection in the Organ Transplant Recipient. There are three major sources, and one uncommon one, by which transplant patients may acquire active CMV infection3,8,27,213–220: from latently infected allografts from seropositive donors; from viable leukocyte-containing blood products that similarly harbor latent virus from seropositive donors; from reactivation of endogenous virus in seropositive transplant recipients; and, finally, by acquisition of the virus in the general community, as a result of intimate contact with an actively infected individual (this usually involves CMV-naive transplant recipients having sexual intercourse with such an individual, and acquiring primary infection via this route). Although this last is uncommon, it is important to emphasize that the manifestations can be every bit as devastating as primary infection acquired via the allograft, even though this communityacquired infection usually occurs many months posttransplant. There are three major epidemiologic patterns of CMV infection in transplant recipients, each with its own rate of clinical illness3,5,8,27,213–223: 1. Primary. CMV disease occurs when the transplant patient has had no pretransplant experience with this virus (and is seronegative for CMV before the transplant), and is infected with virus carried latently in cells from a seropositive, latently infected donor. More than 90% of the time, the allograft is the source of such infections. In the remainder, viable leukocyte-containing blood products from seropositive donors are the source of primary infection. This is a particular problem in liver transplantation, when prodigious quantities of blood products may be required. Without anti-CMV therapy or the use of CMV-free blood products, ~15% of seronegative liver allograft recipients who receive allografts from CMVseronegative donors develop symptomatic disease.224 Similarly, in a large seroepidemiologic study of CMV infection involving 50 renal transplant centers around the United States, ~20% of seronegative recipients of kidneys

INFECTION IN THE ORGAN TRANSPLANT RECIPIENT

from seronegative donors who received blood transfusions seroconverted (and it would be expected that approximately two-thirds of these would develop symptomatic disease).225 In contrast, among 79 seronegative individuals who received kidneys from seronegative donors and who were not transfused, not a single instance of seroconversion could be demonstrated.225 Clinical disease following acquisition of primary CMV infection from blood products tends to be milder than when the allograft is the source, possibly because the burden of latently infected cells is significantly greater in the allograft.226 Transmission of CMV via blood products can be prevented by the use of blood from CMV-seronegative donors or by the use of leukocyte filters.8,27 Approximately 90% of seronegative recipients who receive kidneys from seropositive cadaveric donors, as opposed to approximately 70% of seronegative recipients of kidneys from seropositive living related donors, seroconvert posttransplant. Presumably, this difference in attack rate is related to the increased level of rejection and the accompanying proinflammatory cytokines and other mediators elaborated in the process (vide infra), as well as the more intensive immunosuppressive therapy required with the transplantation of cadaveric as opposed to living related donors.225 When the two kidneys from a seropositive donor are transplanted into two seronegative recipients, either both recipients develop symptomatic infection or neither does.227 At present, there are no laboratory markers that delineate whether or not the organs of a particular seropositive donor are capable of transmitting the virus. Overall, approximately 50–60% of patients at risk for primary CMV infection, as defined by the donor being seropositive and the recipient seronegative, become clinically ill.8,27,213,215–223 2. Reactivation. CMV disease occurs when the transplant recipient is seropositive for CMV pretransplant, and reactivates endogenous latent virus posttransplant. It would appear that the great majority of patients who are seropositive pretransplant will show some evidence (serologic and/or virologic) of active CMV infection. Traditionally, it has been stated that 10– 20% of individuals at risk for reactivation infection become clinically ill, although this can be greatly modified by the type of immunosuppression administered (vide infra) and whether or not the allograft donor is seropositive 8,27,213,215–223,228,229 3. Superinfection. CMV disease occurs when an allograft from a seropositive donor is transplanted into a seropositive recipient, and the virus that is reactivated is of donor rather than endogenous origin. The possible occurrence of this phenomenon had been a cause of much

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speculation for some time, as it had long been recognized that human CMV isolates in nature exhibit considerable genomic and antigenic heterogeneity.27,213 Studies in other forms of CMV infection—in congenital CMV infection,230 and in the AIDS patient231—have demonstrated that superinfection could occur. In two large studies in renal transplant populations, Fryd,232 Smiley,233 and their colleagues suggested that CMV superinfection was clinically important, since seropositive recipients of kidneys from seropositive donors had an outcome that was worse than if the kidneys came from seronegative donors. Utilizing DNA restriction enzyme analysis, several groups have now proven that CMV superinfection does occur commonly among allograft recipients. In at least 50% of cases, the virus that is reactivated following the transplantation of kidneys (and presumably other organs) from a seropositive donor into a seropositive recipient is of donor origin.220–222 What is less clear is whether superinfected individuals are at increased risk of clinical disease from CMV than are those with reactivation of their own endogenous virus. Grundy et al.222 reported that 40% of individuals with evidence of superinfection became symptomatic, whereas none of those with endogenous reactivation became symptomatic. Others have failed to find a difference between these two groups of patients in terms of the incidence of clinical disease.234 Our own view is somewhere in between: superinfection has a somewhat greater impact than reactivation, but this difference is attenuated when intensive immunosuppression is administered and the incidence of clinical disease rises significantly in all seropositive individuals (vide infra). The demonstration that superinfection occurs commonly has important clinical as well as scientific implications. Clearly, it increases the desirability of a CMVseronegative donor for all recipients, not just seronegative ones. Similarly, the use of CMV-negative blood products or leukocyte filters when such products are administered would seem to be indicated for even seropositive individuals in order to prevent superinfection from blood administration. Finally, if natural infection cannot prevent symptomatic superinfection posttransplant, the challenge in developing an effective CMV vaccine appears to be quite daunting. The level of CMV infection in the general community has important effects on the occurrence of CMV among transplant patients. In western Europe and North America, the level of seropositivity is 15% by age 2, 30% in young adults, and 50–60% in those over the age of 50, with higher rates among lower socioeconomic groups,

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male homosexuals, recipients of blood transfusions, and the sexually promiscuous. Thus, the incidence of CMV infection and the percentage of cases related to primary infection, superinfection, or endogenous reactivation will vary from center to center depending on the population being served.213,235 Person-to-person spread of CMV among dialysis and transplant unit patients and personnel does not appear to occur under normal circumstances.236 If no antiviral therapy is administered to the transplant recipient, CMV infection will occur almost exclusively in the time period 1–4 months posttransplant, with a peak incidence ~5 weeks posttransplant.237 Presently available antiviral preventive strategies offer incomplete protection, but, even when they fail, the incubation period is usually prolonged. For example, in a recent study comparing oral ganciclovir to oral acyclovir prophylaxis for 12 weeks after an initial 10-day course of intravenous ganciclovir in organ transplant recipients at risk for primary infection (donor seropositive, recipient seronegative), the mean time to disease when prophylaxis failed was 291 days for the ganciclovir patients and 212 days for the acyclovir patients.238 5.1.1b. Pathogenesis of CMV Infection. The critical first step in the pathogenesis of CMV infection is the reactivation of the virus from latency, whether the latent virus is present in the allograft or in the recipient’s tissues. The CMV replication cycle has three distinct phases: (1) an immediate early phase, which lasts 3–4 hr, and results in the synthesis of proteins that regulate the subsequent expression of the remaining viral genes; (2) an early phase, which lasts 4–12 hr, and results in the synthesis of viral DNA polymerase (and other viral proteins); and (3) a late phase, which lasts 6–12 hr, during which structural viral proteins are produced, whole virions are assembled, and new infectious virus is released. The total replication cycle, then, takes an average of 18– 24 hr, with the expression of the immediate early proteins being the key step in the initiation of this process.239–242 The key mediator in beginning this process is tumor necrosis (TNF), which combines with the TNF receptor of latently infected cells, resulting in a downstream signaling process that involves activation of protein kinase C and NFkB. The resulting activated p65/p50 NFkB heterodimer translocates into the nucleus and binds to the CMV immediate early enhancer region to initiate the process of viral replication.242–246 The importance of this observation cannot be overestimated, as it explains why CMV infection and disease are linked to such widely disparate factors as sepsis, fulminant hepatic failure, allograft rejection, and the administration of such antilymphocyte antibodies as ATG and OKT3—all of these

are associated with the release of large amounts of TNF (and other proinflammatory factors) and hence will cause activation of latent virus.8,242,247–251 It is likely that the observation that hypothermia in liver transplantation is associated with an increased risk of CMV infection is also mediated through TNF.252 There are two other signaling pathways that can be utilized to reactivate CMV from latency, although the TNF pathway appears to be the most important of the three: The first of these pathways is activated by the stress catecholamines, epinephrine and norepinephrine. Their effects on increasing concentrations of cyclic AMP result in immediate early enhancer/promoter stimulation and resultant viral reactivation. Similarly, proinflammatory prostaglandins, elaborated in the course of a variety of inflammatory processes, will also promote viral reactivation through the cyclic AMP pathway. In sum, inflammation, infection, and stress are the stimuli responsible for reactivating CMV from latency.242 Once actively replicating virus is present, the most important exogenous factor influencing the course of CMV infection posttransplant is the type and intensity of immunosuppression administered. Steroids, by themselves, appear to have minimal effects in terms of reactivating latent CMV. Thus, CMV infection in transplant patients was essentially unknown prior to the addition of such cytotoxic drugs as cyclophosphamide and azathioprine to the antirejection regimen.8,27,213,253 Clinical observations over the past two decades have shown that, when antilymphocyte antibody therapy was added to conventional immunosuppression (whether azathioprine and prednisone in the 1970s, or cyclosporine- or tacrolimusbased immunosuppression in the 1980s and 1990s), the incidence of CMV disease increased strikingly. In this regard, it does not seem to matter whether the antilymphocyte antibody preparation employed is polyclonal (antithymocyte globulin, antilymphocyte serum, or antilymphocyte globulin) or monoclonal (OKT3). The incidence of viremia, and the incidence and severity of clinical disease, are increased in patients receiving antilymphocyte antibody therapy. In addition, the prophylactic benefits of such antiviral prophylactic programs as human leukocyte interferon, high-dose acyclovir, and hyperimmune antiCMV immunoglobulin are attenuated by the use of antilymphocyte antibody therapies.3,27,213,253–257 Recent studies in the murine CMV model and in human transplant recipients provide a plausible explanation for these observations and reemphasize the importance of immunosuppression in modulating the effects of this virus. The two key steps in the pathogenesis of CMV infection are reactivation from latency and amplification

INFECTION IN THE ORGAN TRANSPLANT RECIPIENT

and dissemination of actively replicating virus—the critical host defense against this last step being the previously mentioned MHC-restricted, CMV-specific, cytotoxic T cells. When equivalent antirejection regimens of cyclosporine, tacrolimus, antithymocyte globulin, anti-CD3 monoclonal antibody, rapamycin, or other immunosuppressive agents are administered to mice with either latent or active infection, very different effects are observed. Whereas cyclosporine, rapamycin, tacrolimus, and corticosteroids cannot reactivate latent virus, the antilymphocyte antibodies readily can; cytotoxic drugs such as cyclophosphamide and azathioprine are moderately potent in reactivating latent virus. In contrast, after active, replicating virus is present, cyclosporine, rapamycin, and tacrolimus are more potent in promoting viral replication and dissemination than are the antilymphocyte antibodies. Not surprisingly, then, the sequence in which immunosuppressive therapy is administered has an important effect on the course of CMV infection. The most dangerous scenario, unless an effective antiviral strategy is employed, is the reactivation of virus by antilymphocyte antibody therapy, followed by a cyclosporine- or tacrolimus-based immunosuppressive regimen that blocks the host’s response to the now active virus.5,8 Observations in CMV-seropositive organ transplant recipients are consistent with these experimental results. When these patients receive only cyclosporine-based immunosuppression after transplantation, the incidence of clinical disease ranges between 10 and 20%. When OKT3 or polyclonal antilymphocyte antibody therapy is added to the program, the incidence of overt disease rises to as high as 60%. Thus, it appears that the host’s ability to limit the replication of even small amounts of virus is blunted by current cyclosporine-based immunosuppressive regimens.5,8,256 The importance of cyclosporine- and tacrolimusbased immunosuppressive regimens in amplifying the extent of CMV (and other herpes group virus infections once reactivation from latency has occurred) is further emphasized by another clinical observation: In the precyclosporine era, relapsing CMV infection was, with rare exceptions, essentially unknown; that is, patients became ill with CMV and either succumbed or recovered. In the present cyclosporine/tacrolimus era, patients almost universally require ganciclovir therapy to recover from symptomatic disease, and there is a 15–25% relapse rate of clinical disease following a course of treatment; that is, patients who become asymptomatic during therapy develop recrudescent symptoms 1–4 weeks after the completion of a 2- to 3-week course of ganciclovir. Presumably, small amounts of replicating CMV are amplified by

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the calcineurin inhibitors until the virus reaches a level great enough to cause recrudescent clinical disease. We refer to the effects of cyclosporine and tacrolimus on replicating herpes group virus infection as “an in vivo PCR effect.”5,8 It is likely that viral load, both at the initiation of therapy (one measure of this being the presence of multiorgan disease) and at the completion of therapy, is a predictor of the risk of later relapse.258 The effects of the immunosuppressive program in amplifying the extent and effects of CMV replication are mediated largely through its effects on specific T-cell immunity directed against the virus. In particular, CMVspecific cytotoxic T lymphocytes (CTLs) act to limit the systemic viral load, the key determinant of the clinical effects of CMV replication (vide infra). In generating this response, helper T cells directed against CMV are essential both for recovery from viral invasion and to provide protection against such invasion (memory function). Recently, the complexity of this essential helper and cytotoxic T-cell response has been delineated. There is an expansion of gammadelta T cells in this process, and CTLs with varying specificities have been shown to be present. Particularly prominent in this array of T-cell responses are CTLs directed against the immediate early-1 (IE1) antigen and the late structural protein (pp65) that is the basis for the CMV antigenemia assay (vide infra). 259–264 Granzyme B (GrB) is produced by CTLs to induce apoptosis in target cells. Not surprisingly, then, the primary immune response to CMV infection is marked by the expansion of the numbers of cells and the appearance of soluble granzyme B in the peripheral blood.265 Secondary immune responses to CMV appear to involve a recall response involving memory cells with the phenotype.266 As previously stated, the CTL response is MHC restricted. One can then ask the question as to how the transplant patient eliminates virus from an allograft that has a significant MHC discrepancy from that of the recipient. Two observations suggest that MHC restriction of the CTL response may be important: studies in renal allograft recipients have shown that persistent viruria can be present for years after transplantation (that is, persistent infection of the allograft is present)267; more recently, Fishman et al.268 reported a high rate of relapsing CMV disease among patients with six antigen MHC donor– recipient mismatches. Traditionally, antibody responses to CMV have been utilized for diagnostic purposes, and have not been viewed as playing a major role in the patient’s defense against the virus or recovery from clinical disease. A recent report documenting that the delayed acquisition of high-avidity anti-CMV antibody is corre-

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lated with prolonged bloodstream infection with the virus suggests that the contribution of humoral immunity to the host defense against CMV merits reexamination.269 What is needed is a series of studies in which a careful assessment of both humoral and cellular immunity is carried out, with correlation of virologic parameters and clinical disease. The cytokine response to CMV replication is an important determinant of the clinical effects of the virus and also its impact on such other processes as allograft rejection. For example, patients with symptomatic CMV disease have significantly greater evidence of a TNF response than those patients without symptoms from their CMV infection. Conversely, the major anti-inflammatory cytokine produced by monocytes, IL-10, is significantly increased in the asymptomatic patients compared to those with symptomatic disease. Thus, the balance between the proinflammatory TNF response and the anti-inflammatory IL-10 response is a significant determinant of the clinical effects of the virus.270 5.1.1c. Direct Clinical Effects of CMV in the Organ Transplant Recipient. Whatever the category of CMV infection—primary, reactivation, or superinfection—its clinical and virologic manifestations are primarily seen in the time period 1–4 months posttransplant (unless the patient is receiving antiviral prophylaxis, in which case CMV disease can be observed more than 6 months posttransplant), with one delayed manifestation, chorioretinitis, occurring after that period. The effects of CMV in the different organ transplant populations are quite similar, with one major exception: CMV has far greater effects on the organ transplanted than on native organs. Thus, CMV hepatitis is a major problem in liver transplant patients, but is a relatively trivial issue in the other transplant populations; the attack rate for CMV pneumonia is far greater in lung and heart–lung recipients than in the other organ transplant populations; and CMV myocarditis is essentially only recognized in heart transplant patients.258,271 The explanation for these observations is unclear, but several possibilities that are not mutually exclusive exist: There is a direct interaction or synergy between the effects of the virus and the effects of rejection on the allograft; the greatest viral burden, at least initially, is in the allograft where reactivation first occurs; and, finally, as previously discussed, the allograft is a privileged site for virus replication since the MHCrestricted, virus-specific, cytotoxic T cells will be unable to eliminate virally infected cells in the face of MHC mismatch. As with most viral infections, CMV usually begins insidiously with constitutional symptoms of anorexia,

malaise, and fever, often accompanied by myalgias and arthralgias. In many patients, unexplained fever and constitutional symptoms are all that the virus produces; in fact, prolonged fever is the most common recognizable clinical syndrome produced by CMV (approximately one-third of patients with clinically overt disease). These patients resemble normal hosts with CMV mononucleosis, even to the presence of 5–10% atypical lymphocytes on peripheral blood smear. The major difference lies in the usual absence of splenomegaly and lymphadenopathy in the organ transplant patient. In about one-third of patients who develop fever, a dry, nonproductive cough develops within a few days of the onset of the constitutional symptoms. Initially, dyspnea and tachypnea are not noted, but over several days progressive respiratory distress can ensue, although most patients with CMV pneumonia experience little respiratory distress at rest. On physical examination in patients with respiratory symptoms secondary to CMV infection, auscultation of the lungs is usually unrevealing. The best correlate on physical examination with the degree of respiratory embarrassment— hypoxemia on arterial blood gas determination and pneumonia on chest radiography—is the respiratory rate. Plugging of the lung by cytomegalic endothelial cells as well as the local inflammatory response to the virus appear to play an important role in the pathogenesis of CMV pneumonia.213,217–219,255,272–277 The radiographic manifestations of CMV pneumonia in the transplant patient may take a variety of forms. By far the most common form is a bilateral, symmetrical, peribronchovascular (interstitial), and alveolar process predominantly affecting the lower lobes.219,278 Although a few renal, liver, and heart transplant patients with CMV pneumonia progress to total lung whiteout and respiratory failure,279 in most individuals the lung involvement is relatively minor and would go unappreciated if a chest radiograph had not been obtained. The severe form of pneumonia is far more common in lung and heart–lung transplant patients. Less commonly, a focal consolidation more suggestive of bacterial or fungal disease,219 or even a solitary pulmonary nodule may be caused by CMV.280 Positive gallium281 or indium-111-leukocyte282 scans of the lungs have been reported in patients with CMV pneumonitis, although such information usually adds little to the diagnostic decision-making process in most patients. An important point that cannot be overemphasized when considering the rate of progression of pneumonia in the nonpulmonary organ transplant patient is that CMV causes a subacute process that evolves over several days (in the lung transplant patient, this process can be greatly telescoped). The major differential consideration is to

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rule out Pneumocystis carinii infection, which presents in similar fashion and which is frequently present in addition to CMV. If acute respiratory deterioration over less than 12 hr occurs, superinfection with bacterial or invasive fungal agents should be considered rather than attributing such a deterioration to an exacerbation of the CMV infection. A relapsing form of CMV pneumonia has been reported, occurring when immunosuppression is reinstituted after recovery from serious CMV infection.283 In addition to actual invasive disease of the lung caused by CMV, careful studies by van Son and colleagues in The Netherlands have documented the presence of subtle abnormalities in pulmonary function in the majority of patients with CMV infection.284,285 Concomitantly, evidence of complement activation, probably through the alternative pathway, can be found; it is appealing to speculate that these two events are related, just as subtle changes in oxygenation in the first few minutes of hemodialysis with a Cuprophane membrane are related to complement activation and resulting pulmonary leukosequestration.286 The second major organ system to be invaded with CMV in a fashion that can be life-threatening is the GI tract. Serious CMV hepatitis requiring intensive therapy is not uncommon in liver transplant patients (Fig. 2)213,287–289; similarly, pancreatitis severe enough to form “abscesses” may be produced by CMV in the pancreatic allograft.290,291 In the other forms of organ transplantation, CMV infection of these organs is not a major clinical problem, although chemical abnormalities connoting infection at these sites are not uncommon.8,213,219,292 Far more important clinically is the occurrence of infection of the gut itself. The consequences of GI CMV infection include diffuse inflammation with functional disturbances, hemorrhage, frank ulceration, perforation, and, possibly, the development of pneumatosis intestinalis. The stomach appears to be the most frequent site of symptomatic CMV infection, and appears to be associated with subjective complaints of nausea, a sense of abdominal fullness, and, occasionally, emesis and/or dysphagia. These symptoms have been correlated with the presence of CMV gastritis and inadequate gastric emptying, presumably the result of the infection. The Pittsburgh group has reported an incidence of upper GI CMV infection of 28% in liver transplant patients receiving cyclosporinebased immunosuppression, and a somewhat lower incidence (20%) in those treated with tacrolimus.275,293–303 Unexplained abdominal pain, particularly midepigastric pain, in renal (and presumably other forms of solid organ) transplant recipients has been linked to the presence of active CMV infection in the upper GI tract.303

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CMV infection at other sites in the upper GI tract is not uncommon, as well, with both esophagitis and duodenitis (including ulceration) being well documented.300–304 A CMV-induced “pseudolymphoma” of the duodenum that responded to antiviral therapy has been reported in a renal transplant patient.305 Colonic ulceration, often involving the right colon, presenting as GI hemorrhage or perforation, is a common manifestation of CMV infection.292–297,299 Unusual forms of colonic CMV disease include pseudomembranous colitis,306 and localized disease mimicking a neoplasm (including an apple core lesion on X-ray) or ischemic colitis.307,308 Acute colonic pseudoobstruction (Ogilvie’s syndrome) following liver transplantation has been linked to CMV, with resolution of the pseudoobstruction on treatment with ganciclovir.309 Thus, it is clear that CMV can have significant effects on the function of both the upper and lower GI tract. Uncommon effects of CMV on the GI tract in transplant patients include hemorrhoiditis310 and cholecystitis.311 Although CMV infection of the gut and of hepatic and pancreatic allografts can occur as part of a systemic febrile process, it is important to recognize that hematochezia, nausea and vomiting, hepatic enzyme abnormalities, and so on, in the absence of fever, leukopenia, or other manifestations of clinical CMV disease, can be the result of invasion of these viscera by this virus. Similarly, evidence of viremia (vide infra) may be absent in patients with CMV disease of the GI tract, requiring biopsy for diagnosis. Recognition of these clinical entities without some of the more common manifestations of CMV disease can lead to effective therapy with ganciclovir.293–314 Hematologic abnormalities are common during the course of CMV infection. For example, small numbers of atypical lymphocytes may be detected on examination of the peripheral blood smear. The most important effects, however, are on the white blood cell (WBC) and platelet counts. Leukopenia, not infrequently to counts less than and/or thrombocytopenia, usually in the range of but sometimes even lower, occur in 20–30% of patients with CMV infection. Again, these hematologic findings may be the first manifestation of systemic CMV infection or be part of a multiorgan systemic process.27,213–219 Idiopathic thrombocytopenic purpura has been reported as a consequence of CMV infection.312 Simmons et al.275 have described what they have termed “the lethal CMV syndrome,” which begins with fever and leukopenia (as does the more benign form of the illness), but progresses rapidly to include severe pulmonary and hepatic dysfunction, central nervous system (CNS) abnormalities, GI hemorrhage, and death. Death is

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usually caused by superinfection or bowel hemorrhage. Fortunately, the availability of ganciclovir therapy and the recognition of the possibility of this syndrome have resulted in early diagnosis and therapy, with few patients today developing the full-blown lethal syndrome. It is important to continue to emphasize, however, the poten-

tial for this constellation of events and the need for the clinician to be alert for early manifestations of severe disease. The addition of leukopenia to fever as a manifestation of CMV infection is often the first indication that serious clinical disease is developing, and prompt and aggressive therapy is mandatory.8,27,213

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In renal transplant recipients, CMV infection has been associated with a number of processes that adversely affect the kidney: tubulointerstitial nephritis with cytomegalic inclusions within renal cells, particularly the tubular epithelium223,313; ureteral inflammation and/or necrosis311,314; hemolytic uremic syndrome315; thrombotic microangiopathy responsive to ganciclovir therapy316; and necrotizing and crescentic glomerulonephritis.317 In addition, in renal transplant recipients, CMV infection has been associated with renal artery thrombosis318; whereas in liver transplant recipients, CMV infection has been associated with hepatic artery thrombosis.319 Uncommon infectious disease syndromes occurring in the organ transplant patient as a result of CMV infection include the following: endometritis320; epididymitis321; encephalitis322; transverse myelitis323; and skin ulcerations associated with an apparent cutaneous vasculitis.294 Chorioretinitis is the major late manifestation of CMV infection, usually being noted for the first time more than 6 months posttransplant. Although the retinitis may be asymptomatic at the time of discovery, most patients present with complaints of blurred vision, scotoma, and decreased visual acuity. Although symptoms

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are frequently restricted to one eye initially, progression to bilateral involvement is common. The initial retinal lesion on fundoscopic examination appears as scattered white dots or white granular patches without any characteristic distribution pattern. Irregular sheathing of the adjacent retinal vessels is common. This appearance of a gradually expanding, whitish, necrotic retinitis is thought to be distinctive for CMV. This fundoscopic picture of hypopigmented (white) areas surrounding atrophic retina corresponds to pathological findings in which the retinal pigment epithelium in the involved areas becomes so extensively necrotic that its capacity to proliferate is lost. The white, cordlike appearance of the involved retinal arterioles is thought to be secondary to the sloughing of infected endothelial cells from the retinal vessels, which leads to subendothelial hemorrhage and the collection of serofibrinous material in the same area (Figs. 3 and 4). Occasionally, retinal detachment or an anterior uveitis with secondary glaucoma may develop as the retinitis progresses, causing further loss of vision.324–334 In one report from a heart transplant center, ~7% of patients had healed scars consistent with CMV retinitis or active CMV retinitis.335 In our experience, the incidence of active retinitis is Rarely, CMV can cause acute retinal necrosis.336

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One other consequence of CMV infection in the transplant patient that bears mention is the possible impact on pregnancy. Congenital CMV infection has been documented in a child born to a woman who had suffered systemic CMV infection 3 years previously following her renal transplant. The mother had had an unspecified febrile illness during her first trimester of pregnancy, due either to a relapse in her infection or to superinfection. In any case, the child was severely affected, a tragic outcome that underlines the need for careful monitoring of successful transplant recipients for CMV replication before pregnancy is contemplated and during the course of the pregnancy, with prompt intervention if viremia is documented.337 5.1.1d. Indirect Clinical Effects of CMV Infection on the Organ Transplant Recipient. CMV is an important contributor to the transplant recipient’s net state of immunosuppression. Indeed, with the advent of effective antiviral chemotherapy against CMV (vide infra), it can be argued that the most important infectious disease effect of CMV on the transplant patient is its potentiation of superinfection. The clinical marker that appears to delineate those organ transplant patients most at risk for superinfection appears to be CMV-induced leukopenia. Severe leukopenia in conjunction with symptomatic CMV disease of greater than 5 days’ duration, without ganciclovir and/or G-CSF therapy, has been associated with a greater than 50% mortality caused by superinfection, both of the lung and of the bloodstream. In the lung, Pneumocystis carinii, Aspergillus species, and a variety of gram-negative pathogens are the primary culprits. As far as the first two of these are concerned, alveolar macrophage dysfunction induced by CMV (in addition to the leukopenia in the case of Aspergillus) appears to be an important factor in the pathogene-

sis of superinfection with these organisms.8,27,219,338–342 In addition, CMV appears to facilitate the colonization of the upper respiratory tract with gram-negative bacilli, with these serving as the reservoir from which gramnegative pulmonary infection is then derived.343 Septicemia with a variety of agents, but most particularly with Listeria monocytogenes, Candida species, and gram-negative organisms, is common in these patients with severe CMV-induced leukopenia. It is of interest that reports of infection from transplant centers not actively studying CMV disease have noticed a preponderance of both pneumonia and CNS infection in the period 1–4 months posttransplant, suggesting again a major role for this virus in the pathogenesis of serious infection. As with other clinical manifestations of CMV, such events appear to be more common in patients with primary as opposed to reactivation disease (in this context, all patients who are seropositive for CMV prior to transplant are regarded as having reactivation disease, with inadequate information currently available to distinguish between the clinical spectra caused by true reactivation as opposed to superinfection with a new strain of the virus). Again, viremia is a useful virologic marker to delineate those patients most at risk for this phenomenon.213,344–349 In addition to the abnormalities in leukocyte number and, possibly, function induced by the virus, a variety of other defects in host defense play a role as well. Humoral immunity, as measured by antibody response to the virus, appears to remain relatively intact in the majority of transplant patients with clinical CMV disease.350 One possible detrimental effect of the humoral response to CMV has been suggested by Baldwin et al.351–353 who demonstrated that IgM immune complexes appear in transplant patients in association with CMV infection, and that these have lymphocytotoxic properties. In addi-

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tion, some CMV-induced rheumatoid factors may modify the immune response through anti-idiotypic activity. Cellmediated immunity, whether measured by skin testing with Candida, SKSD, mumps, or intermediate-strength tuberculin recall antigens or by in vitro lymphocyte responsiveness to CMV antigens, other viral antigens, or a variety of mitogens, is markedly impaired.350,354 It is noteworthy that patients with demonstrable cell-mediated immunity to CMV prior to transplantation, whether naturally induced or vaccine induced, lose this response in the first month posttransplant and may still be unresponsive more than 6 months posttransplant.354,355 Clinical recovery from CMV in the absence of specific antiviral therapy is largely dependent on the previously discussed activity of CMV-specific, MHC-restricted (class I MHC antigen), cytotoxic T cells and NK cells, particularly the former. During CMV infection, expansion and activation of these lymphocyte populations occurs.259–265,356–365 Van den Berg et al.366 have demonstrated the importance of the dynamic relationship between viral burden (as quantitated by the antigenemia assay) and these lymphocyte responses. Whereas NK cells, as nonspecific effector cells, appear to be important in limiting viral replication and dissemination during the early phase of primary CMV infection, clinical recovery is determined by the ability to mount an activated, cytotoxic T-cell response commensurate with the level of virus present. In addition, development of this activated, cytotoxic T-cell response in the course of antiviral therapy appears to be a useful predictor that relapse will not occur following the cessation of antiviral therapy. This kind of analysis, which monitors both the replicating viral burden and the host’s ability to defend against this burden, should permit a more precise approach to antiviral therapy. These findings also explain the occasional discrepancies that occur when clinical predictors are based solely on virologic measurements or lymphocyte measurements; what is really needed is an assessment of both.366 The mechanism by which CMV causes depressed cell-mediated immunity has received extensive investigation. At present, it would appear that CMV infection is associated with suppression of both monocyte and NK cell function, and that monocyte-induced suppression of lymphocyte function is the end result.367–376 CMV infection of cells results in a downregulation of class I MHC antigens on these cells.377–379 Since presentation of viral antigen by MHC class I antigens is of critical importance in mediating the key cytotoxic T-cell response to the virus, this may be an important mechanism by which the virus evades host defenses.380 In addition, exhaustion of antiviral cytotoxic T cells may also play a role here.381

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An accessible marker of disordered cell-mediated immunity induced by CMV involves the use of flow cytometry (and fluorescein-labeled monoclonal antibodies to lymphocyte cell surface markers) to characterize circulating T-lymphocyte subsets. In the normal individual, the ratio of (helper/inducer) cells to (cytotoxic/ suppressor) cells is normally approximately 1.5–2; in patients with CMV and EBV infection, there is a marked reversal in this relationship, with the ratio now falling to 0.1–0.5, with clinical recovery being associated with normalization. The great majority of opportunistic infections occur in the subset of transplant patients with these changes in circulating T cells. Indeed, the occurrence of opportunistic infection in patients with normal circulating T cells and hence a reasonable net state of immunosuppression is an important clue to an excessive epidemiologic hazard in the environment (vide supra).364,382 Studies in the murine CMV model have supplemented these observations. If animals are given sublethal challenges with CMV, Candida albicans, P. aeruginosa, or other organisms, not much happens. If CMV is combined with each of the other organisms, then lethality approaches 100%.383 In the murine model, CMV has been shown to reactivate latent Toxoplasma gondii infection in the lungs, producing an active pneumonia. Pathogenetically, it was suggested that a CMV-induced fall in the number of lymphocytes played a role in the reactivation of the protozoan, while the subsequent influx of cells was responsible for the active pneumonia that developed.384 Of interest, evidence that HHV-6 activation is promoted by CMV infection (vide infra), particularly primary infection, in the transplant patient, suggests that this CMV-induced traffic in lymphocytes, and the elaboration of a variety of cytokines in conjunction with it, can play a role in the pathogenesis of a variety of secondary infections in the transplant recipient.385 In 1970, Simmons et al.386 first suggested that CMV infection could in some fashion lead to allograft dysfunction. Proof of this relationship has been difficult to obtain, in part because of the ubiquity of CMV infection, and in part because of the lack of an adequate laboratory marker for distinguishing clinically important CMV infection from the asymptomatic or trivial. In addition, there has been a problem in most studies with an insufficient number of patients to permit adequate stratification that would control for such variables as type of donor, histocompatibility match, donor and recipient CMV status, and form of immunosuppression administered.364,386–396 Despite these difficulties there is now a compelling body of information suggesting that CMV can be involved in the pathogenesis of certain forms of allograft injury.

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First, there are occasional cases in which renal dysfunction occurs with a biopsy picture that reveals cells laden with cytomegalic inclusions—typically in the tubular epithelium and interstitium, occasionally within the glomerulus. In these cases, treatment with ganciclovir can result in restoration of renal function.223,313,397,398 However, such cases are few and far between, and clearly do not account for the increased incidence of renal dysfunction linked to CMV infection in several studies of renal transplant populations.223,225,232,233,393,398–400 Particularly intriguing are studies in which “late rejection” was diagnosed in patients with asymptomatic CMV antigenemia—treatment with ganciclovir, but not immunosuppression, was effective in reversing the episode of renal dysfunction.242,401,402 If, then, under intensive immunosuppression, CMV can adversely affect renal allograft function, what is the mechanism? In vitro studies have shown that essentially all types of renal cells—glomerular, tubular, interstitial, and so on—can support the growth of this virus.403 However, it is clear that if CMV is involved in the pathogenesis of allograft injury in more than a rare instance of disseminated infection, then direct infection, the deposition of immune complexes, and complement activation are not involved (although both circulating immune complexes and complement activation may occur not uncommonly in transplant patients with CMV infection).27,223,404 The renal lesion that has been the subject of the most discussion regarding possible linkage with CMV infection was studied by Richardson et al.405 Patients were stratified on the basis of the presence or absence of CMV viremia, with renal biopsies obtained at the time of acute functional deterioration of the kidney being interpreted without knowledge of their CMV status. The results were striking. Those patients with nonviremic CMV disease and no CMV disease had renal biopsies that revealed the classic tubulointerstitial findings of acute cellular rejection; in contrast, those patients with viremic CMV disease were free of such changes and, instead, had a distinctive glomerular lesion on biopsy characterized by endothelial cell hypertrophy, necrosis, and loss with narrowing or obliteration of capillary lumina and the formation of finely fibrillary material between cells, and mild segmental hypercellularity. Immunofluorescent staining revealed deposits of immunoglobulin and the third component of complement within these glomeruli. Vascular injury was not uncommon in these biopsies, and no evidence of the virus could be found. Since that original study, the following observations have been made by our group regarding this glomerulopa223,364,405,406 thy : In the original study, CMV viremia was the stratification marker that permitted us to separate out

this lesion. Overall, CMV-infected recipients who are viremic have about twice the frequency of glomerulopathy as those who are nonviremic (58 versus 32%). Of 36 biopsies taken for renal allograft dysfunction, the glomerulopathy was observed in 12 of 25 (48%) with CMV and 0 of 11 with no virologic or serologic evidence of CMV (p < 0.005). Not unexpectedly, the glomerulopathy was highly associated with the previously described changes in circulating T-cell subsets that viral infection causes. When the infiltrating cells were characterized in patients with the glomerular lesion, there was a striking increase in the number of cells (compared with biopsies from patients with typical tubulointerstitial rejection); there was an increase in activated mononuclear phagocytes present; and the glomeruli from the glomerulopathy cases stained more intensely for MHC class I antigens than the tubules, in contrast to the typical rejection cases. Renal dysfunction associated with the glomerular lesion is far less likely to respond to antirejection therapy than classical rejection (> 90% in classical rejection versus < 20% for the glomerular cases). Finally, early intervention with ganciclovir therapy appears to have made this lesion far less common. Since our description of this glomerular lesion, its existence has been confirmed by several groups. What has been controversial is the issue of whether this lesion is related to CMV infection. What all observers do agree on is the fact that this glomerular lesion only occurs in renal allografts. Studies in bone marrow transplant patients and recipients of other organ allografts, AIDS patients, and nonimmunosuppressed individuals with CMV infection who had renal tissue examined failed to yield evidence of this lesion. In sum, a histologic finding distinct from classical rejection has been described in renal allograft recipients that may be linked in some instances to CMV infection, but clearly has occurred in patients without evidence of CMV infection. As we look at the experience with the other allografts, it is clear that we must come up with a unifying hypothesis to link these two kinds of observation. In addition, the possibility that CMV infection could be involved in the pathogenesis of allograft injury that has a histologic picture more typical of classical rejection must also be kept in mind.27,394–396,404 In liver transplantation, this issue is even more complicated, since the direct and possibly indirect effects of CMV infection on the liver may be obscured by the impact of both classical allograft rejection and hepatitis C infection. However, Paya et al.288 have observed among liver transplant recipients a group of individuals with pathological findings of focal necrosis and clustering neutrophils within the liver lobules, a picture distinct from

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that of typical hepatic allograft rejection. This pathological picture occurred in the setting of CMV viremia, but in individuals without histological or cultural evidence of CMV infection of the liver itself, a phenomenon similar to the glomerulopathy described in renal transplant patients. In addition, it has been postulated that CMV infection, when there is a one- to two-antigen match between donor and recipient, is associated with the disappearing bile duct syndrome in liver transplant recipients.407 In patients with chronic rejection of the liver allograft, CMV infection of bile ducts and endothelial cells can be demonstrated.408,409 Interestingly, CMV infection is associated with increased inflammation and severe bile duct damage in a rat liver allograft model as well.410 Even more important in terms of assessing the role of CMV in the pathogenesis of hepatic allograft injury are studies reporting an increased incidence of acute and chronic rejection, as well as mortality, in patients with CMV infection.411–414 A particularly close relationship between rejection and CMV infection has been observed in those with a partial HLA class I match between donor and recipient.415 An intriguing report from the University of Oregon has suggested that all CMV isolates do not carry the same risk for inducing rejection. In this analysis, CMV is divided into four genotypes on the basis of the envelope glycoprotein gB. In this study, CMV infection in general was associated with significantly reduced patient and graft survival rates at 1 and 5 years following orthotopic liver transplantation. Infection with CMV genotype gBl was associated with a higher mean number of acute rejection episodes.416 Perhaps the most convincing clinical data linking CMV infection with allograft injury come from the cardiac transplant experience, where a number of studies have linked both acute rejection and accelerated coronary atherosclerosis in the allograft to both symptomatic and asymptomatic infection with the virus. In particular, CMV has been associated with what has been called cardiac allograft vasculopathy.417–426 That vascular injury could be a consequence of systemic CMV infection should be no surprise: In the general population, CMV has long been hypothesized as playing a role in the pathogenesis of atherosclerosis, with evidence of herpesvirus infection at sites of atheromatous lesions in major arteries, as demonstrated by both DNA hybridization and immunoperoxidase staining for specific viral antigens. Epidemiologically, patients who required vascular surgery for atherosclerotic disease had a higher rate of CMV seropositivity than in matched control subjects.426–429 Finally, a number of studies have compellingly demonstrated that CMV infection of both vascular smooth mus-

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cle and endothelium is a regular occurrence during CMV infection, thus providing a mechanism for vascular injury—felt to be the foundation of chronic allograft injury.426,430–436 Indeed, CMV-infected endothelial cells can be found in the circulation, presumably providing a means of viral dissemination as well as a possible measure of vascular injury at the capillary level.435,436 As in liver transplantation (vide supra), different CMV strains appear to have differing abilities to affect vascular endothelial cells.437 In a similar fashion, CMV has been linked to the development of bronchiolitis obliterans in lung and heart– lung transplant recipients. This entity, the limiting factor in the long-term success of lung transplantation, as is the case with cardiac allograft vasculopathy, can occur without CMV on a pure “immunologic” basis. However, the incidence is increased with CMV, with at least some evidence suggesting synergy between virus and rejection in the pathogenesis of bronchiolitis obliterans. Relapsing CMV infection of the lung allograft, particularly in the presence of rejection, carries a particularly high risk for bronchiolitis obliterans.426,438–445 The suggestion that CMV infection in general and relapsing or chronic infection in particular synergize with acute rejection in the pathogenesis of chronic allograft injury, has also been made in renal and liver transplant patients.446,447 One potential link between rejection and CMV infection is the observation that both processes result in the release of endothelial cells, both infected and uninfected, potentially amplifying the extent of the infection and the immunologic stimulation from the allograft endothelium.448 Extensive effort has been devoted to determining the mechanisms by which CMV infection could result in acute and chronic allograft injury. In this effort, animal models that combine transplantation of tissues and organs across MHC barriers and CMV infection have provided important information that has greatly supplemented the information obtained from clinical studies. The essential challenge is to delineate how CMV could exert its effect when a pathologically identical process can occur in the absence of this virus. Careful studies in a rat aortic allograft model demonstrated that early rat CMV infection (each species has its own specific virus, so human CMV cannot be utilized in rodent studies) was associated with inflammation of the endothelium, smooth muscle cell proliferation, and intimal arteriosclerotic alterations.426,449,450 Similarly, rat CMV infection introduced into a rat heterotopic cardiac allograft model that included triple-drug immunosuppression (cyclosporine, methylprednisolone, and azathioprine) accelerated the development of cardiac allograft

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vasculopathy.451 Utilizing a heterotopic, allogeneic, tracheal transplant model in rats, CMV was shown to cause enhanced MHC class II expression on the respiratory epithelium, airway wall infiltration with T cells and macrophages, and a 5-fold increase in luminal occlusion of the trachea—changes identical to “immunologically” caused rejection; that is, in this model bronchiolitis obliterans could be caused by either classical rejection or CMV.452,453 In this model, platelet-derived growth factor appeared to play an important pathogenetic role in the evolution of these changes.452 Of interest, increased immunosuppression decreased the changes induced by both processes (although increased immunosuppression could be expected to increase the level of viral replication), suggesting the possibility that CMV was acting through a signaling pathway similar to that involved with rejection.426,449–452 Conversely, CMV-enhanced cardiac allograft vasculopathy is abolished by ganciclovir prophylaxis in the rat model.451,454 Recently, a series of studies exploring the mechanisms involved in the pathogenesis of CMV-induced allograft injury have extended our understanding of these processes considerably. First, it is clear that not only are key cells (e.g., vascular and bronchial smooth muscle cells, respiratory epithelium) infected, but there are consequences other than the generation of “cytomegaly” cells with inclusions or cytolysis. Thus, there is an increased display of MHC antigens, as well as activation of a variety of cell types involved in tissue injury— leukocytes, endothelial cells, and so on.455–457 Particularly striking is the upregulation in the expression of proinflammatory adhesion molecules induced by CMV infection: CMV infection of human vascular endothelial cells results in the de novo expression of VCAM-1 and E-selectin, and a 200-fold increase of ICAM-1; in contrast, infection of vascular smooth muscle cells results in the de novo induction of ICAM-1, but has no effect on the expression of VCAM-1 or E-selectin. Of most importance, however, was the observation that uninfected cells in the same tissue culture system manifested the same findings as the infected cells, and these changes could be induced by a virus-free supernate from infected cells. Subsequent work demonstrated that the mediator of these effects was released by CMV-infected cells, and the upregulation of the proinflammatory adhesion molecules on uninfected cells is due to the paracrine effects of this mediator produced in response to CMV infection.458,459 The immediate early-1 antigen of CMV has been shown to upregulate gene expression as well as that of another proinflammatory cytokine, IL-6.460,461 Other adhesion molecules upregulated or induced de novo in re-

sponse to CMV infection are sialyl and antigens on human endothelial cells.462 Perhaps of greatest interest are studies of a rat kidney transplant model in which chronic allograft rejection occurred. The introduction of systemic CMV infection resulted in an increase in the level of inflammation within the kidney and accelerated and amplified the extent of the chronic rejection process. In this kidney model, as in the in vitro experiments, there was a significant and prolonged increase in VCAM-1 and ICAM-1 expression on the vascular endothelium of the renal allografts. In addition, the inflammatory cells infiltrating the allograft had a marked increase in their ligand adhesion molecules LFA-1 and VLA-4. These effects were secondary to the release of proinflammatory cytokines in response to CMV replication.463,464 Interestingly, CMV infection and ischemic injury appeared to have similar and additive effects in contributing to the occurrence of “chronic rejection.”465 Other mechanisms are possible as well. A variety of autoantibodies are produced as a consequence of CMV infection, including anti-endothelial cell antibodies.466,467 Endothelial cells infected with CMV on the one hand manifest increased neutrophil and mononuclear cell adherence, and, on the other hand, provide a potent stimulus for a cytotoxic T-cell response that destroys uninfected bystander endothelial cells.468–470 CMV also increases the production of the C-X-C chemokine and IL-8, thus causing neutrophil recruitment and enhanced neutrophil transendothelial migration.471,472 A more direct form of immune injury precipitated by CMV infection also is possible. Sequence homology and immunologic cross-reactivity between an immediate early antigen of human CMV and the HLA-DR beta chain have been demonstrated.473 In addition, CMV-infected cells produce a glycoprotein homologous to MHC class I antigens.474 Thus, it is not unreasonable to speculate that immune injury triggered by the virus could be directed at cells that bear either the appropriate HLA-DR antigen or the particular class I antigen in a form of molecular mimicry.404 The interaction between CMV infection, MHC antigens, and allograft injury may be even more complex. First, studies in the murine model have clearly shown that susceptibility to the virus is closely linked to the MHC locus (the H-2 complex in mice), with non-MHC genes also playing a role.475,476 Several studies have suggested that DRmatched transplants may result in an increased incidence of CMV disease, and, possibly, chronic allograft injury. Thus, in evaluating the potential contribution of CMV infection to acute and chronic allograft injury, the MHC typing and the degree of match between donor and recipient may be important.477,478

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CMV infection in transplant patients is associated with profound evidence of systemic immunologic/inflammatory activation: increased blood levels of IL-6, soluble forms of VCAM-1, and IL-2R, as well as a marked increase in the numbers of circulating cells.479–482 As previously noted, activation of humoral inflammatory pathways can be demonstrated as well in transplant patients with CMV infection: the presence of circulating immune complexes, rheumatoid factor, and circulating products of complement activation C3d and C3a des-arg are easily demonstrated.284,351–353 In addition, murine CMV infection has been shown in some mouse strains to cause an increase in alloreactivity.483 Perhaps the most compelling information to emerge linking CMV infection to allograft injury comes from reports that antiviral preventive programs aimed at CMV resulted in a decrease in the incidence of both acute and chronic rejection. Thus, oral valaciclovir and oral ganciclovir prophylaxis for the first 3–4 months posttransplant not only decreased the incidence of CMV infectious disease events, but also decreased the incidence of acute rejection episodes in both renal and liver transplant recipients.238,484 In addition, there is preliminary evidence that in human cardiac transplant recipients, the administration of intravenous ganciclovir for a month decreased the incidence and severity of coronary artery atherosclerosis.485,486 In sum, an ever-expanding body of evidence has linked CMV infection to acute and chronic allograft injury. It would appear that a similar array of cytokines, chemokines, and growth factors are elaborated in the course of both CMV infection and classical rejection processes. Indeed, there is a bidirectional relationship between these two processes, with the one being influenced by the other, and both being influenced by the nature of the immunosuppressive therapy being administered. The fact that both of these can result in similar histologic pictures is not surprising—the mediators of allograft injury in both processes are similar; that is, although the initial stimuli may be different, the ultimate signaling pathway that effects injury is the same. A question that has long been debated has finally been answered: Which comes first, CMV or rejection? The answer is clearly either. What also becomes a reasonable hypothesis according to this view is that other infections (e.g., HHV-6) could have similar effects, and that ultimately the extent of allograft injury is the integration of a number of different processes that include ischemia, infection, and classical rejection, with room in this model for other as yet to be defined processes. The final possible indirect effect of CMV to be con-

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sidered is its possible role in the pathogenesis of malignancy in the transplant patient. Like other herpes group viruses, CMV must be thought of as a potentially oncogenic agent. Portions of the CMV genome have been shown to be homologous to the myc oncogene.487,488 Not only is the intact virus a transforming agent in certain cell lines (the in vitro correlate of oncogenesis), but also specific cloned CMV DNA fragments are able to transform the NIH 3T3 cell line.489 In other species, under special conditions, administration of the virus has been associated with the production of malignancy.235 What about humans? Rather weak associations between CMV and human colonic carcinoma and prostatic carcinoma have been made, chiefly on the basis of finding CMV DNA in the tumors of some patients with the former and a higher rate of serologic positivity for CMV in the sera of patients with the latter.235 An association of testicular carcinoma with high antibody levels against VZV, herpes simplex virus, and CMV, with the strongest association being with the CMV titers, has been reported.490 The clearest relationship between CMV and malignancy is with EBV-associated posttransplant lymphoproliferative disease (PTLD) (vide infra). The incidence of PTLD is increased 7- to 10-fold in individuals with symptomatic CMV disease. Conversely, PTLD occurring in a transplant patient harboring latent CMV infection is almost uniformly associated with CMV reactivation. We would suggest that there is once again a bidirectional relationship between these two processes, with the link being cytokines, chemokines, and growth factors produced by the host in response to these processes. This hypothesis suggests that one could positively influence PTLD by antiviral strategies aimed at CMV (and possibly EBV).211,491

5.1.1e. The Diagnosis of CMV Infection in the Organ Transplant Patient. The diagnostic techniques utilized in evaluating the transplant patient for CMV infection can be divided into two general categories: serologic and virologic. Serologic techniques are most useful for assessing the past experience of donor and recipient with the virus, and thus for predicting risk of subsequent clinical disease (vide supra). Such techniques can also be utilized serially to delineate rises in titer or seroconversion as an indirect measure of the presence of active viral infection that is stimulating an immune response, although antibody response lags significantly behind the time when virologic diagnosis can be made. In this era of effective anti-CMV therapy, such a time lag is unacceptable, and thus the emphasis should be placed on virologic diagnosis of clinical disease, rather than waiting for sero-

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logic evidence of infection.8,27,492 (As a general rule in immunocompromised patients, whose antibody response to microbial invasion may be attenuated, delayed, or totally abrogated, demonstration of replicating microbes in some fashion is far to be preferred to serial measurements of antibody levels.) A variety of serologic techniques are currently available that measure the level of antibody to CMV in the serum. Essentially all of them utilize antigen extracted from fibroblasts infected with a laboratory strain of CMV (usually AD169). Although in theory the antigenic variation among different CMV strains in nature could affect the performance of a serologic assay, in practice this does not appear to be a major problem. Far more important in terms of the performance of a serologic assay is the method employed in extracting the antigen; for example, the development of the glycine-extracted complement fixing (CF) assay represented a major improvement in the sensitivity and reliability of the CF test.492 Although the CF assay has traditionally been considered the gold standard for testing for anti-CMV antibodies, today because of cost, speed, and sensitivity, most diagnostic laboratories have converted to immunofluorescence, ELISA, and latex agglutination systems for detecting anti-CMV antibodies. The advantages and pitfalls of these newer assays have been reviewed,492 but one particular issue bears special emphasis here: Whereas there is a large clinical experience documenting the biologic meaning of a CF liter of (a “true positive,” meaning that the patient harbors latent or replicating virus), the meaning of similar titers with the newer, “more sensitive” assays is less clear. Thus, in a seroepidemiologic study of more than 1200 transplant patients in which multiple techniques were utilized in the analysis of each serum specimen, a small group of patients was identified that was negative by CF assay but positive in one or more of the newer assays at relatively low levels. Analysis of the clinical courses of these patients suggested that they were a heterogeneous group—a few with true-positive assays, and the remainder with false-positive assays. Therefore, the clinician needs to be aware of the performance characteristics of the assay being employed, as well as what the reliable cutoff level is that distinguishes true positives from more equivocal results.225 Most of the assays utilized to measure anti-CMV antibodies assess total antibody, both IgG and IgM. Commercially available CMV-specific IgM assays have added little to our diagnostic abilities: In primary infection, demonstration of replicating virus in blood and/or urine will usually precede the IgM response; some immunocompromised patients may not mount an antibody re-

sponse even in the face of fatal infection; and IgM antibody can be present in asymptomatic reactivation infection. For all of these reasons, there is little to recommend the measurement of CMV-specific IgM for routine clinical use.492 Two other serologic techniques that bear mention here are the measurement of anti-CMV neutralizing antibody and the measurement of antibodies to specific viral proteins. Measurement of neutralizing antibody levels is a time- and resource-consuming research test that is impractical for routine clinical use, as the presence of measurable titers of neutralizing antibody activity does not guarantee either protection or recovery from clinical disease.493 Studies with the murine CMV model have shown that monoclonal antibodies that were neutralizing in vitro were not necessarily protective in vivo, while other antibodies that were not neutralizing in vitro still could be protective in vivo.494 Thus, the routine measurement of the titer of neutralizing antibody has no clear-cut clinical use at the present lime. Considerable work has been carried out to define the antibody response to specific CMV proteins. Thus, antibodies to various epitopes that mediate neutralizing activily, as well as antibodies to a variety of structural and regulatory proteins have been defined. Studies of a large number of patients have shown that there is considerable heterogeneity of response, and there is hope that one or more patterns of antibody response will correlate with the occurrence of clinical events. Such information would be of key importance both in defining protective immunity, and for the formulation of both an anti-CMV vaccine and an anti-CMV IgG product for the prevention and/or treatmenl of clinical disease.492,495–501 The cornerstone of CMV diagnosis, however, remains the direct demonstration of the presence of the virus in blood, respiratory secretions, urine, or tissues. Classical CMV virology involves the inoculation of specimens on fibroblast monolayers, with the endpoint for positivity being a cytopathic effect related to full replication of the virus, and the induction of visible changes in the monolayers. On average, this takes 1–2 weeks (and, thus, many replicative cycles are necessary before a cytopathic effect can be visualized), and may lake upwards of 6 weeks if the viral burden is low.492 A major advance in CMV diagnosis came with the development of the shell vial technique. In this technique, the clinical specimen is centrifuged onto the fibroblast monolayer, which assists adsorption of any virus present, resulting in a fourfold increase in the infectivity of the viral inoculum. Twentyfour to forty-eight hours later, at a time when there is no visible evidence of viral replication, the fibroblast mono-

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layer is stained with a monoclonal antibody to the 72-kDa major immediate early protein of CMV, which can be demonstrated by immunofluorescence hours after inoculation. Urine and respiratory tract secretions are particularly well served by the shell vial technique. Unfortunately, cultures of buffy coat for evidence of viremia are less sensitive, because of leukocyte toxicity for the monolayer and problems with the centrifugation procedure; false-negative cultures of the buffy coat occur in as many as 50% of individuals. In addition, a single monoclonal antibody may yield falsely negative results because of antigenic variation among different isolates.492,502–506 Because of the importance of viremia in CMV diagnosis, particularly to facilitate early antiviral therapy, two other techniques have become the standard for the care of transplant patients: an antigenemia assay and PCR assays.492,507 The and colleagues in The Netherlands have developed a direct immunoperoxidase assay on buffy coat preparations for the same-day diagnosis of viremia, utilizing monoclonal antibodies to a specific CMV antigen. Their assay utilizes monoclonal antibodies directed against a 65-kDa lower matrix phosphoprotein, a late structural antigen. At a time when granulocytes and monocytes positive for this antigen are easily demonstrated, only a fraction of these will show evidence of the immediate early antigen. It is now believed that the 65kDa late antigen that is identified in the antigenemia assay represents antigen exogenously derived, probably from infected endothelial cells, which has been taken up by receptor-mediated endocytosis.508 Although these findings have importance in terms of understanding the pathogenesis of CMV infection in transplant patients, they also have practical diagnostic importance: Whereas studies with The’s reagents have been uniformly successful, with a diagnostic sensitivity and specificity of > 95% in patients with clinical syndromes compatible with CMV,508 other antigenemia assays, based on other monoclonal antibodies directed against other antigens, particularly the immediate early antigen, have been less useful.509–511 Therefore, great care must be utilized in the choice of reagents used for the performance of this diagnostic test. The antigenemia assay has three advantages over previous diagnostic approaches: it is semiquantitative, giving a measure of the level of infection, viral load, as it occurs and as therapy is instituted; when performed prospectively, it, like the PCR assay for CMV, turns positive 4–7 days prior to the onset of clinical disease, opening up the possibility of preemptive therapy for those patients at major risk for clinical disease (not all patients with antigenemia become symptomatic, but sustained antigenemia, particularly a rising

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titer, appears to be quite predictive); and, finally, it can serve as a means for monitoring the effects of antiviral chemotherapy.508,512–519 At the present time, the CMV antigenemia assay is the most accessible test for detecting viremia, determining viral load, and evaluating the need for and success of therapy. The availability of results in 1 day and the “low tech” nature of the test make it a useful assay for serial measurements. However, certain limits to the assay must be recognized. Although the assay has an excellent positive and negative predictive value when assessing patients with a mononucleosis-like syndrome and CMV pneumonia in non-lung transplant patients, there are situations in which the antigenemia assay has its limitations. Patients with significant CMV enterocolitis, proven on biopsy and responsive to ganciclovir therapy, will commonly have negative antigenemia assays. Lung transplant patients may have replicating CMV in their respiratory tracts, not infrequently with evidence of parenchymal invasion, in the face of a negative antigenemia assay. Finally, the blood specimen drawn for the assay needs to be processed within a few hours of attainment. A lapse of > 12 hr between blood draw and processing can greatly compromise the reliability of the results, a serious disadvantage when patients are being monitored at a distance from the transplant center—the assay does not “travel well.” Clearly, the future lies with PCR assays for CMV. The selective amplification of specific nucleic acid sequences, first introduced by Saiki et al. in 1985,520 represents a major breakthrough in the application of molecular biology to diagnostics, including the diagnosis of CMV viremia. Although PCR assays require great technical skill, they have now been shown to be useful in the diagnosis of CMV viremia. Early concerns that active, replicating virus could not be differentiated from latent virus have not been borne out, provided the appropriate primers, number of amplification cycles, and specified stringency conditions are employed. In skilled laboratories, PCR and the antigenemia assay provide very similar information, although PCR may detect viremia a day or so earlier. In general, most laboratories that rely on PCR assays employ a qualitative PCR for screening, and then utilize a quantitative technique to determine the viral load, with serial measurements of viral load providing a dynamic picture of the interaction among virus, host defenses, and the antiviral strategy being employed. What is less clear at the moment is the precise format of the assay that is ideal and whether a whole blood, leukocyte-based, or serum assay provides optimal information. It is likely that these details will be worked out in the next few years,

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and that a “user-friendly” PCR assay will become the cornerstone of CMV diagnosis.521–528 Whether it is determined by antigenemia assay or by PCR, the key determination with CMV, as it is for HIV infection, is the viral load. Viral load determinations, preferably on blood but also on urine, provide critically important information for a number of purposes: viral load measurements have an important predictive value in determining subsequent risk of clinical disease; serial viral load measurements can form the basis for a preemptive antiviral strategy (vide infra); serial viral load measurements can be utilized to monitor the response to therapy; and viral load determinations at the conclusion of therapy can be utilized to predict the chance of relapsing clinical disease.529–541 5.1.1f. Clinical Management of CMV Infection in the Organ Transplant Patient. Given the protean manifestations of CMV infection in the organ transplant recipient, it is not surprising that an extensive effort has been made to control this infection. This effort can be divided into two categories: the prevention of infection and disease, and the treatment of disease. Within the prevention category, there are three strategies that merit attention: those aimed at decreasing the risk of virus acquisition and reactivation; the induction, either actively or passively, of immunologic protection; and the utilization of antiviral drugs to prevent the clinical effects of viral replication. In fact, these strategies are not mutually exclusive, and are probably best used in combination. As one approaches the task of preventing the consequences of CMV replication, the key issue is what aspects of CMV infection is it desirable to prevent—the direct or the indirect effects of the virus? Although virtually all of the data that have been published in this regard have to do with the prevention of the infectious disease syndromes caused by the virus, the recent reports of antiviral therapy protecting against acute and chronic allograft injury suggest that the endpoints of anti-CMV intervention should be changed.238,484–486 There are two major sources of exogenous CMV infection for the transplant patient: viable leukocytecontaining blood products and the allograft itself. The first of these, transfusion-related infection, should be totally preventable, whereas the issues regarding allografttransmitted infection are more complex. With the clear-cut evidence that CMV superinfection occurs in seropositive transplant patients (vide supra), and that this may have a greater clinical impact than endogenous reactivation, it is our belief that all transplant patients, not just seronegative ones, should receive only blood products that are free of CMV risk. This can be accomplished in two ways: (1)

screening all units of blood for the presence of CMV antibody (positive ones potentially harboring latently infected leukocytes), and utilizing only blood from seronegative donors for transplant patients, or (2) utilizing high-efficiency leukocyte filters to remove the viable leukocytes that harbor the virus. Both of these strategies work, in terms of preventing transfusion-related CMV infection; they differ in terms of cost and the possible prevention of other infections.542–544 Screening units of blood for CMV antibody can be accomplished at a cost of approximately $3 per unit; in contrast, a leukocyte filter costs approximately $21 per unit of red blood cells and a leukocyte filter for platelets costs approximately $40, and must be changed after the administration of six units of platelets through it. Therefore, costwise, the utilization of CMV-seronegative blood products is to be preferred, provided they are available. Theoretically, the removal of viable leukocytes might also be beneficial in decreasing the transmission of other infectious agents, such as EBV and HHV-6, through transfusions. Whatever strategy is employed, it is clear that the time has come when all blood products administered to transplant patients should be free of risk of transmitting CMV. This is particularly important in liver transplantation where a 16% incidence of primary infection resulting from transfusions has been documented.192 The issue of protective matching of donor and recipient so that an organ from a seropositive donor is not placed in a seronegative recipient is less clear-cut. Although eminently reasonable, such a policy would seriously curtail the potential donor pool. Data currently available suggest that the advantages of a living related transplant far outweigh any possible disadvantages from primary CMV,224 so the only population to which protective matching could be applied would be patients awaiting cadaveric donor allografts. Even in these patients, both because of ethical issues related to the possible penalty for seropositive recipients who would then receive all of the organs from seropositive donors, and because of the desire not to further limit the already inadequate donor pool, our preference is not to carry out such protective matching. Instead, we would prefer to deploy an effective antiviral preventive program. Two possible immunologic interventions against CMV have been evaluated in organ transplant patients: active immunization with a CMV vaccine and passive immunization with a variety of intravenous immunoglobulin preparations. Pioneering efforts by Plotkin and his colleagues have suggested that a CMV vaccine could have utility in organ transplant patients.355,545–549 Their work with the live, attenuated Towne strain CMV vaccine

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demonstrated the following: administration of the vaccine to seronegative dialysis patients resulted in seroconversion, and if they received kidneys from seropositive donors, there appeared to be a decrease in the severity of the clinical disease that occurred, although there was no difference in the rate of viral infection. Of interest, graft survival at 36 months was improved in vaccinated recipients of cadaver kidneys compared with unvaccinated recipients. Pretransplant, a cell-mediated immune response to CMV could be demonstrated (although neither the humoral nor the cell-mediated immune response was as great in the uremic patient as in seronegative normal volunteers); however, this disappeared posttransplant in the face of immunosuppressive therapy. Reassuringly, reactivation of vaccine strain virus was not detected. Vaccination of seropositive patients prior to transplant had no discernible clinical benefit. Finally, efforts to develop a subunit vaccine have begun: In preliminary studies, normal human volunteers, administered purified glycoprotein B, the major envelope glycoprotein of CMV, developed both neutralizing antibodies and CMV-specific lymphocyte proliferation. The concern, here, is whether or not the antigenic variation among CMV strains that exists will prevent the development of an effective monovalent vaccine. Clearly, this effort needs to be continued, although as a practical strategy today, the vaccine option is not yet available.355,545–549 The administration of intravenous immunoglobulin preparations (IV-Ig) prophylactically to organ transplant patients is moderately effective in preventing CMV disease in organ transplant recipients (Table 4).22 In saying this, one must recognize that the database is incomplete for a number of reasons: Since it is not clear what the

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critical viral antigen(s) is in terms of protective antibody, the definition of protective titers has not been possible. Studies in the murine model have underlined the difficulties involved: When various lots of an anti-murine CMV immunoglobulin preparation were studied, utilizing different techniques for titering the level of murine CMV antibody present, there was a discordance among the results obtained with the different assay systems, and none of them were reliably predictive of the level of antibody needed to protect against lethal challenge with the virus. Although titers of antibody that are protective in vivo cannot be measured in humans, it is very clear that there is a very poor correlation between antibody titers as measured by ELISA assay and in vitro neutralizing titers.550 This is true both in individual patients, and when evaluating a variety of IgG preparations. Further complicating the issue is the antigenic heterogeneity of CMV strains in nature. Finally, it is very clear that different immunoglobulin preparations, both standard IV-Ig and hyperimmune anti-CMV, are very different from one another in terms of their anti-CMV content, and, in addition, there can be significant lot-to-lot variation.551 Given the challenges of defining and standardizing IgG preparations, and defining a dosage schedule for administering the preparation, what is remarkable is that they do have efficacy. Landmark studies by Snydman et al. 552–555 have demonstrated the following: Their hyperimmune anti-CMV IgG preparation significantly decreased the incidence of symptomatic disease in renal transplant recipients at risk for primary infection, although this benefit is modulated by the immunosuppressive therapy administered—prophylaxis with this agent decreased the incidence of primary disease by two-thirds

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when patients were being treated with azathioprine and prednisone, by one-half when immunosuppression was with cyclosporine-based programs, and is particularly attenuated when antilymphocyte antibody therapy is needed to treat rejection. In liver transplant patients, all treated with triple-drug immunosuppressive therapy (cyclosporine, azathioprine, and prednisone) ± antilymphocyte antibodies, this same group has noted significant protection against symptomatic disease in seropositive patients, in seronegative patients at risk for primary transfusionrelated disease, but not in patients at risk for primary infection when the allograft is the source of the virus (donor seropositive, recipient seronegative).192 Utilizing a different anti-CMV hyperimmune globulin preparation, the Rotterdam group has reported prophylactic benefit in both renal and heart transplant recipients at risk for primary disease, but not for seropositive individuals.556,557 In contrast, a Finnish group could not demonstrate protection in renal transplant patients at risk for primary disease, when they used a different globulin preparation and a different dosage schedule.558 In a different study, CMV hyperimmune globulin appeared to attenuate the severity of clinical disease, but not its incidence, when administered in conjunction with antirejection therapy.557 In a recent report, CMV immune globulin prophylaxis was reported to increase survival after orthotopic liver transplantation.559 Finally, Steinmuller et al.560 have reported that unselected lots of IV-Ig decreased the number of febrile days and the number of hospital days relating to CMV, as well as the number of CMV-related complications, when administered prophylactically to seropositive renal transplant recipients. Similarly, in a study restricted to pediatric renal transplant recipients, IV-Ig appeared to decrease both the incidence of CMV disease and the severity of that disease that broke through, although anti-CMV immune globulin was even more effective.561,562 In sum, then, the prophylactic administration of antiCMV antibody is moderately effective, particularly in renal transplant patients. In addition to the issues previously raised, there are three other problems related to its use: cost (approximately $4800/patient in the Snydman study), the logistical difficulties involved in having to administer repeated intravenous doses of the globulin over a 4-month period, and, finally, the need to provide protection against other viruses, particularly EBV, and not just CMV22 Although Tsevat et al.555 have delineated the cost-effectiveness of anti-CMV IgG ($29,800/life saved for those patients at risk for primary disease), our own feeling is that anti-CMV IgG is most useful when combined with an antiviral drug, when the dosage schedule

and cost can be made more “user-friendly,” while the efficacy is increased.22 However, with the advent of newer antiviral approaches to CMV prevention (vide infra), the routine use of intravenous IgG preparations in organ transplant patients without hypogammaglobulinemia or who are not undergoing plasmapheresis still remains to be defined. High-dose oral acyclovir (approximately 3200 mg/ day, with such high doses required because of the poor bioavailability of administered for 4–6 months posttransplant has also been shown to be moderately effective in preventing CMV disease (Table 4), again with attenuation of benefit in the face of antilymphocyte antibody antirejection therapy. As with immunoglobulin prophylaxis, acyclovir is more effective in seropositive individuals as opposed to those at risk for primary disease. What is perhaps most interesting here is that prophylactic efficacy occurs when peak levels of acyclovir in the blood are approximately and the average 50% inhibitory concentration in vitro is approximately twice that. This suggests that inhibition of the virus is most easily accomplished as it emerges from latency, when only small amounts of replicating virus are present. If so, then other antiviral strategies concentrating on this time point may also be effective.22,563–568 Studies in which intravenous ganciclovir followed by oral acyclovir is compared to acyclovir alone have demonstrated that the combined regimen is more effective than acyclovir alone,569,570 and the combination of immune globulin (particularly anti-CMV immune globulin) with acyclovir may be more effective than acyclovir alone.571,572 With the immunosuppressive regimens now in use, it is fair to say that either high-dose acyclovir alone or immunoglobulin alone is less effective than regimens in which the acyclovir is combined with another modality, or a ganciclovir preparation or valaciclovir is administered alone.573–575 Valaciclovir, the valine ester of acyclovir, has a bioavailability of 50–60% (in terms of the amount of acyclovir that enters the circulation). Not surprisingly, it far surpasses oral acyclovir in terms of its prophylactic efficacy, being the most effective anti-CMV prophylactic agent other than ganciclovir currently available.434 In a pharmacoeconomic analysis, prophylactic valaciclovir was shown to be particularly cost effective in patients at risk for primary infection, decreasing by 5.5 days the number of inhospital patient days required; for seropositive individuals, there was little cost saving compared with placebo.576 Ganciclovir is the most potent anti-CMV drug currently available. When administered intravenously for 1 month to heart transplant recipients, it provided signifi-

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cant protection to seropositive recipients but none to those at risk for primary infection In those patients whom the ganciclovir failed to protect (as is also true for oral ganciclovir, acyclovir, and valaciclovir), the incubation period is prolonged. Thus, in patients receiving prophylaxis with any of these agents, instead of the peak incidence being 1–4 months posttransplant (peak approximately 5 weeks), the CMV disease may occur 4–9 months posttransplant (6 weeks to 6 months after the completion of a prophylactic regiment). The exact timing will depend on the immunosuppressive program as well as whether or not systemic TNF release has occurred (as with infection, antilymphocyte antibody therapy, or rejection—vide supra). These events are more common the shorter the course of antiviral therapy administered.577,578 In contrast, when intravenous ganciclovir is administered for 100 days or longer posttransplant, effective prophylaxis is achieved (although, at least in a liver transplant population, there was no overall effect on mortality).579,580 The key question has been whether or not oral ganciclovir, administered for 3–4 months, with its poor bioavailability of could provide effective prophylaxis without the need for prolonged vascular access required for intravenous prophylaxis. Currently available data show that at a dose of 1000 mg two or three times daily, significant protection is achieved.581–584 Pharmacokinetic studies performed in patients with renal dysfunction and on dialysis have provided the following dosing guidelines: creatinine clearance > 50 ml/min, 1000 mg tid; creatinine clearance of 25–50 ml/min, 1000 mg every 24 hr; creatinine clearance of 10–24 ml/min, 500 mg each day; creatinine clearance < 10 ml/min or on dialysis, 500 mg every other day (after dialysis).585 It should also be noted that although in animal studies ganciclovir has been noted to be teratogenic, thus far, at the doses cited, it appears to be free of these effects.586 A particular problem has been the prevention of CMV disease, especially CMV-pneumonitis, in lung transplant recipients. Sequential therapy with ganciclovir and nonselected IV-Ig for approximately 3 weeks, followed by a variety of doses of oral acyclovir was ineffective in preventing primary CMV disease.587 More recently, prolonged courses of intravenous and/or oral ganciclovir or intravenous ganciclovir plus IV-IGg have been shown to have significant benefit in the protection of the lung transplant patient against CMV disease.580,588–590 An alternative approach to CMV prevention is a preemptive one. As described previously, there are two forms of preemptive therapy (vide supra): The first is based on the observation that CMV-seropositive individuals treated without antilymphocyte antibodies have a 10–

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15% incidence of CMV disease, while the 15% with steroid-fast rejection who receive antilymphocyte antibody therapy have a 65% incidence of CMV disease. Rather than administer the same prophylaxis to all seropositive transplant recipients, we have chosen to develop a program in which antiviral therapy is triggered by the need for antilymphocyte therapy. A daily dose of intravenous ganciclovir (5 mg/kg per day, with dosage correction for renal dysfunction) will decrease the incidence of CMV disease to ~20%; when this is followed by oral ganciclovir at a dose of 1 g two or three times per day, the incidence falls to zero.581,591 Thus, an effective preventive strategy has been triggered by a clinical–epidemiologic observation, namely, the cytokine storm produced by antirejection antilymphocyte antibody therapy induces CMV disease at such a high rate that antiviral intervention, particularly one as effective as this one, is justified both clinically and pharmacoeconomically. The second form of preemptive therapy is derived directly from the bone marrow transplant experience, in which monitoring patients for asymptomatic viral replication led directly to intravenous ganciclovir therapy, thus markedly decreasing the incidence of severe CMV disease.592,593 The advent of quantitative virologic assays for viremia (antigenemia and quantitative PCR, vide supra) has made possible the monitoring of patients for early evidence of viremia and then developing algorithms for effecting preemptive therapy on the basis of this laboratory information. The appeal of this approach, once again, is to restrict the use of antiviral therapy to those who would most benefit from it. The disadvantages of this preemptive approach are logistic (getting blood specimens on a timely basis during the period of 2 weeks to 4 months posttransplant) and economic—although the cost of drug is decreased, the cost of the laboratory assays can be quite high. Despite these disadvantages this approach can work and is worthy of further attention.446,530–541,594–597 These prophylactic and preemptive regimens are likely to undergo further revision in the near future. The valine ester of ganciclovir has a bioavailability of ~50%, making possible the achievement via the oral route of blood levels of ganciclovir only possible up to now with intravenous therapy (much as was shown with the valine ester of acyclovir, valaciclovir).598 This will permit the development of more efficacious regimens, although it is likely that the incidence of bone marrow toxicity will also be increased. Even more important, valganciclovir should be an ideal agent for testing whether or not eliminating CMV replication will protect the allograft from acute and chronic injury (vide supra). In sum, major strides have been made in the preven-

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tion of CMV disease. It is likely that the regimen of the future will consist of some form of prophylaxis for patients at risk for primary disease, accompanied by preemptive therapy in association with antirejection therapy, and monitored by assays for presymptomatic viremia (which would also trigger preemptive therapy). Seropositive individuals would likely not require prophylaxis, but would receive the last two parts of the program (unless such prophylaxis can be shown to provide significant protection against the indirect effects of the virus, particularly allograft injury).599 The treatment of established clinical disease due to CMV is more straightforward. Ganciclovir at a dose of 5 mg/kg twice per day (with appropriate revision in the face of renal dysfunction) is quite effective in the treatment of CMV disease, even permitting the simultaneous treatment of rejection with increased immunosuppression.600–604 However, the report of Duncan and Cook on the outcome of treating CMV pneumonia in heart transplant patients with ganciclovir issues an important caution.605 Although therapy interrupted viral replication and resulted in initial clinical improvement, at 6 months follow-up, 70% of the patients had died because of late sequelae, predominantly cardiac allograft dysfunction. This report reemphasizes two lessons: Prevention is still far better than treatment of established disease; and, although ganciclovir therapy is quite effective for treating the direct infectious disease consequences of CMV infection, the indirect effects of the virus may not be managed quite as well. Another important issue is the appropriate duration of the intravenous ganciclovir treatment. Many groups routinely utilize a fixed regimen of 2–3 weeks. However, in patients with a high viral load, such a duration of therapy may not be adequate to totally eradicate virus from the blood (and, presumably important tissue sites), with the continuing requirement for cyclosporine or tacrolimus then amplifying the residual virus, allowing for relapse to occur. Such relapse is particularly common in patients with a high viral load, an inadequate course of intravenous ganciclovir, high-dose immunosuppression, and a six-antigen mismatch between donor and recipient. Whereas primary ganciclovir resistance is essentially unheard of, relapsing infection is often associated with the development of ganciclovir resistance, requiring the use of the far more toxic foscarnet in management. One particular error in management that can lead to ganciclovir resistance is the initiation of oral ganciclovir while the patient still has evidence of a high viral load. Although oral ganciclovir is useful prophylactically, because of its poor oral bioavailability it is likely to induce resistance when used in a treatment mode. Quantitative assessment

of viral load (vide supra) before the end of intravenous ganciclovir therapy is of great use in this regard. Oral ganciclovir added after clearance of viremia is useful prophylactically then in preventing relapse. Relapsing infection with the risk of ganciclovir resistance is a particular issue in lung transplant patients, but can occur in any transplant patient with a high viral load and an inadequate course of intravenous ganciclovir. Thus, rather than a fixed regimen of intravenous ganciclovir for every patient with CMV disease, the course needs to be guided by viral load measurements and the recognition that unless immunosuppression can be decreased, more prolonged parenteral therapy is needed.268,606–608 Illustrative Case 4 A 47-year-old woman with end-stage liver disease caused by chronic biliary cirrhosis had undergone orthotopic hepatic transplantation 4 weeks previously. The donor had been CMV seronegative and the recipient CMV seronegative. Twenty-six units of red blood cells and 12 units of platelets were administered without leukocyte filters in the perioperative period; information was not available concerning the CMV serologic status of the donors of the blood products. The patient had a smooth peritransplant course, receiving standard triple-drug immunosuppression (cyclosporine, azathioprine, and prednisone) until the 11th posttransplant day when a low-grade fever and an elevation in the SGOT (from 25 to 65) and total bilirubin (from 1.7 to 2.5 mg/dl) were noted. Two pulse doses of methylprednisolone, 500 mg each, were administered intravenously over the next 48 hr. When the liver function tests failed to improve, a biopsy was performed, which revealed acute cellular rejection. OKT3, 5 mg/kg per day, was administered intravenously for 10 days, with prompt normalization of the liver function tests. No antiviral prophylaxis was prescribed. The patient remained well until 1 week later when, at a routine outpatient visit, her SGOT was again noted to be abnormal (three times the upper limits of normal), her alkaline phosphatase was twice the normal, and her bilirubin had doubled. Evaluation of the patient consisted of the following: a negative physical examination, including no fever; a normal T-tube cholangiogram; a positive CMV antigen assay (with 650 positive cells noted on a buffy coat smear); and a liver biopsy which revealed CMV hepatitis (Fig. 2). The patient was treated for 3 weeks with ganciclovir at a dose of 5 mg/kg twice daily, with improvement in her liver function tests first observed after 5 days of therapy. The patient then remained well for 26 days, when she returned with similar abnormalities in her liver function, fever, and malaise. Once again, a positive CMV antigenemia assay was noted (425 positive cells), and ganciclovir was reinstituted at the same dose for 6 weeks, with a drop in the antigenemia assay to 310 positive cells 7 days after the reinitiation of therapy. The antigenemia assay was documented to be negative prior to discontinuing the intravenous ganciclovir therapy. This was followed by 3 months of oral ganciclovir at a dose of 1000 mg twice daily for 3 months. In addition, there was a 50% decrease in the dose of her immunosuppressive drugs. The patient has remained well since then. Comment. This is a case of primary, transfusion-acquired CMV infection that presented initially with hepatocellular dysfunction, in the absence of other symptoms, as the sole manifestation of disease. Biopsy

INFECTION IN THE ORGAN TRANSPLANT RECIPIENT was necessary to distinguish between rejection and infection, although the positive antigenemia assay argued strongly for infection. Indeed, the reason for the biopsy was to rule out the presence of dual processes. In this case, as in 15–20% of patients treated with ganciclovir, relapsing disease occurred. Fortunately, drug-resistant infection did not occur in this instance. By monitoring the viral load 1 week after reinstitution of the intravenous ganciclovir, a drug response could be documented, and foscarnet, with its attendant renal toxicities (renal failure, as well as excessive magnesium and calcium losses in the urine), could be avoided. Alternatively, if the patient had been more ill, it would have been appropriate to initiate therapy with foscarnet until testing of the virus isolate for ganciclovir resistance could be carried out. Because of the concerns regarding an increased risk of superinfection during the CMV infection, the patient was also maintained on anti-Pneumocystis prophylaxis, and protected while in the hospital from an ongoing nosocomial problem with Aspergillus infection by housing her in a HEPAfiltered room.

5.1.2. EBV Infection in Organ Transplant Recipients The epithelial cells of the upper respiratory tract, particularly those of the oropharynx and the parotid duct, are the natural reservoir for EBV, with transmission of the virus occurring by means of intimate contact and the exchange of virus-laden saliva. Such infection is lytic in nature, resulting in the release of replicating virus, causing pharyngitis during infectious mononucleosis. Following acquisition of EBV, and the replication of the virus in the upper respiratory tract epithelium, long-lived B lymphocytes become infected as they travel through the lymphoid tissues of the oral cavity. Although the virus can be demonstrated in the cervical epithelium and semen, sexual transmission has yet to be proven. EBV can occasionally be transmitted through blood transfusion or bone marrow transplantation. The receptor for the virus on both epithelial cells and B lymphocytes is the CD21 molecule, which is also the receptor for the C3d component of complement.609–611 Whereas infection of epithelial cells results in viral replication, with release of infectious virions, infection of B lymphocytes usually results in latent infection without replication or release of virus. The consequences of such B-cell infection with EBV are transformation and immortalization. The nature of the EBV infection in these B lymphocytes is very different from that in the oropharynx: The virus exists in its circular episomal form (which is not susceptible to antiviral chemotherapy), and expresses only a few of the genes that EBV expresses during lytic infection—these genes are essential for the transformation of the B lymphocytes. Latent infection of the B lymphocytes by EBV is characterized by the differential expression of six EBV nuclear antigens (EBNAs), two

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EBV-encoded RNAs (EBERs), and three latent membrane proteins (LMPs). Although a detailed examination of the role of these in the pathogenesis of PTLD is beyond the scope of this chapter, a few general comments can be made: EBNA-1 is important in maintaining the episomal form of EBV DNA within the dividing B cell and in the initiation of the expression of the other EBNAs. It also blocks HLA class I antigen expression, which may allow EBV-infected B cells to escape immune surveillance by cytotoxic T cells. EBNA-2 is essential for B cell immortalization, as are other EBNAs, EBERs appear to block the effects of thus promoting the immortalization process. LMP1 may be considered an oncogene, with its ability to transform cells being due at least in part to its antiapoptotic effects.612–618 In the normal host, clinical disease is initiated by the infection of epithelial cells and B lymphocytes, which in turn incites an intense, CTL response to the B lymphocytes that have been latently infected, and become widely dispersed throughout the body, especially the liver, bone marrow, spleen, lymph nodes, and CNS. This immune response is responsible for most of the clinical manifestations of infectious mononucleosis, and is also the explanation for the lack of efficacy of antiviral chemotherapy in affecting this clinical syndrome.615 Strains of EBV found in nature have been divided into two types, EBV-1 and EBV-2, on the basis of the gene that encodes EBV nuclear antigen (EBNA) 2A, a gene product involved in the immortalization of B lymphocytes. There is in vitro evidence that EBV-1 is a more efficient transformer of B lymphocytes than is EBV-2, and, at least in one series, infection with EBV-1 was particularly associated with the development of lymphoproliferative disease.611,619,620 Although most adults who are EBV seropositive harbor B lymphocytes latently infected with EBV that have the potential for unlimited growth, lymphoproliferation does not occur because of an active immunologic surveillance mechanism based primarily on MHC-restricted, EBV-specific, cytotoxic T cells. Suppression of this mechanism in vitro, or in such in vivo situations as EBV infection in mice with severe combined immunodeficiency, AIDS patients, and transplant patients results in outgrowth of these immortalized B cells and evident lymphoproliferation.610,611,613,618,621 Primary EBV infection carries a significantly greater risk for PTLD than does reactivation infection (vide infra), presumably because of the lack of a preexisting immunologic surveillance mechanism in patients whose immunosuppressive therapy will attenuate their ability to develop such a response.611,618 Of probable importance, EBV-immortalized B cells produce growth factors, including lactic acid, IL-6, and

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IL-10, that stimulate their own proliferation in an autocrine loop. IL-10, a pleiotropic cytokine produced mainly by activated Th2 cells, is of particular interest for several reasons: it has suppressive effects on macrophage, natural killer cell, and Thl functions, including cytokine production, T-cell proliferation, and cytotoxicity; it increases the proliferation of activated B cells, their differentiation, and the secretion by these cells of immunoglobulin; in addition to T-cell production of IL-10, the protein product of the BCRF-1 region of the EBV genome exhibits extensive homology with the T-cell-derived IL-10, exhibiting similar ability to inhibit secretion, and suppress T-cell proliferation in response to antigenic and mitogenic stimuli. Thus, it has been hypothesized that these two forms of IL-10 play an important role in amplifying the extent of transformed B cells, a key step in the pathogenesis of PTLD.610,618,622,623 The question that may be asked is whether the elaboration of cytokines and growth factors in the course of other processes common in transplant patients (e.g., allograft rejection, the first few doses of antilymphocyte antibodies, or other infections) could also enhance the lymphoproliferative response. Consistent with this hypothesis is the observation that symptomatic CMV infection is a risk factor for the subsequent development of EBV-associated lymphoproliferative disease, increasing the risk of PTLD 7- to 10-fold.212,624–628 In addition, there is a report that HCV infection is associated with a > 5-fold increased risk of PTLD among liver transplant recipients.629 Since many of these effects are thought to be mediated by cytokines elaborated in response to these infections, it is not surprising that synergy among different processes can be observed in the promotion of PTLD. For example, the combination of pretransplant seronegativity for EBV, status (thus, risk of primary infection with both of these viruses), and anti-CD3 monoclonal antibody treatment increases the risk of PTLD more than 500fold.212,624,628 Since more than 90% of adults are seropositive for EBV, and far more transplants are performed in adults than children, the great majority of EBV infections in transplant patients represent reactivation infections, although EBV superinfection analogous to what is observed with CMV is quite possible. Such viral reactivation and excretion may occur without changes in antibody titer. In particular, heterophile antibodies do not appear with any regularity in transplant patients with either viral excretion or rises in specific antibody titer.27 Primary EBV infection in transplant patients may occur in the community, or be acquired from the allograft or viable leukocyte-containing blood products. This is most com-

mon in pediatric transplant patients, the majority of whom are seronegative, with consequences ranging from asymptomatic infection to a mononucleosis syndrome to a rapidly fatal multiorgan lymphoproliferative disease similar to that seen in boys with the X-linked lymphoproliferative disorder that follows EBV infection. The infectious disease consequences of EBV reactivation closely resemble those observed with CMV, although, because of the ubiquity of CMV, the contributions of EBV to individual morbidity may be difficult to discern.591,610,628,630–642 However, liver transplant patients with chronic hepatic allograft dysfunction resulting from primary EBV infection possibly acquired from the allograft have been described.643 This entity appears to be more common than previously recognized, with a histologic picture of activated mononuclear infiltrates in the portal tracts associated with lobular disarray and sinusoidal lymphocytes arranged in linear beads and small aggregates. Demonstration of EBER-1 RNA in these mononuclear cells confirms the diagnosis.642 The analogy to CMV hepatitis in the liver transplant recipient is obvious, and it is likely that other infectious disease syndromes currently attributed to CMV are actually related to EBV. It is also clear that EBV has immunosuppressive effects similar to those produced by CMV. Whether EBV infection has any influence on graft function is totally unknown. Another important unanswered question is whether dual infection with the two viruses has a greater impact than infection with either. The identification of symptomatic CMV infection as a risk factor for EBV lymphoproliferative disease suggests that such dual infection may be clinically important. Far more important than EBV-induced hepatitis or mononucleosis in the transplant patient is the role this virus plays in the pathogenesis of the PTLD. The incidence of PTLD varies from 1–3% among kidney, heart, and liver transplant recipients to 7–33% among lung, intestine, and multivisceral transplants.610,628,638,644,645 Approximately 90% of PTLD in organ transplant patients is of recipient origin; and a similar percentage shows evidence of EBV infection.644 PTLD encompasses a range of pathologic entities, with the most useful classification system currently available being that put forth by the Society of Hematopathology, in which four distinct categories of PTLD are defined645–647: 1. Lymphoid hyperplasia (“early lesions”). Included in this category are plasma cell hyperplasia, lesions resembling infectious mononucleosis, and other forms of atypical lymphoid hyperplasia with preservation of the underlying architecture. These lesions are usually polyclonal

INFECTION IN THE ORGAN TRANSPLANT RECIPIENT

and often regress with reduction of immunosuppression. 2. Polymorphic PTLD. These are destructive lesions that infiltrate and destroy underlying tissue, with a wide range of B-cell maturation being present. Molecular studies suggest that virtually all of these tumors are monoclonal. Oncogene or tumor suppressor gene abnormalities are not a feature of these tumors. A lower percentage of these tumors respond to reduction of immunosuppression. 3. Lymphomatous or monomorphic PTLD. Most such tumors are of the diffuse large B-cell lymphoma subtype, although Burkitt-like lymphomas and mucosa-associated lymphomas (MALT lymphomas) may also occur as variants of B-cell disease. Abnormalities in the ras or p53 genes of the diffuse B-cell lymphomas are not uncommon. These tumors are monoclonal, with only a minority responding to decreased immunosuppressive therapy. In addition, such uncommon forms of PTLD as T cell, null cell, and NK cell lymphoma are placed in this category. A minority of these non-B-cell tumors are EBV positive, and response to decreased immunosuppression is uncommon. 4. Other forms of PTLD. Included in this category are such uncommon tumors as plasmacytoma, myeloma, and T-cell-rich/Hodgkin’s disease-like large B-cell lymphoma. These tumors may or may not be EBV positive, and tend to be clinically aggressive. In general, EBV-positive tumors occur in the first 6 months posttransplant; in contrast, although the EBVnegative PTLDs can occur as early as 6 months posttransplant, they occur at a mean time of >4 years posttransplant, accounting for the majority of the late PTLDs.645–647 A growing body of evidence suggests that there are two interacting factors that determine the incidence of PTLD in the transplant patient: the number of B lymphocytes infected and transformed by EBV, which is a manifestation of viral load; and the ability of the EBV-specific cytotoxic T-cell surveillance mechanism to eliminate these transformed cells, which is determined by the nature of the immunosuppressive therapy being administered and the cytokine, chemokine, and growth factor milieu that is present. These last are determined by such other factors as concomitant infections and the severity of rejection and the intensity of its therapy.611,618,627,628 In prospective, quantitative studies of oropharyngeal

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EBV shedding among renal and cardiac transplant patients, Preiskaitis et al.611 reported that significantly higher levels of EBV shedding are observed in patients with primary, as opposed to reactivation infection, and in association with intensive immunosuppressive therapy with antilymphocyte antibodies or > 4 g of pulse methylprednisolone therapy. Similarly, the percentage of patients shedding is likewise modulated by the immunosuppressive regimen: in the general population, the incidence is approximately 20%; among transplant patients on maintenance immunosuppression, the figure rises to 30%; in association with a course of antilymphocyte antibody therapy, the incidence rises to approximately 80%.611,630 Patients with the highest level of EBV shedding had the poorest serologic response to the virus, and the greatest risk for the development of PTLD. Finally, both acyclovir and ganciclovir were shown to totally suppress oropharyngeal shedding of EBV. It appears likely that the increased EBV replication noted in the oropharynx in these patients results in increased infection of circulating B lymphocytes. This may result directly in the polyclonal type of lymphomas or provide a larger pool of activated, replicating B lymphocytes for the cellular events that result in monoclonal tumors. Immunosuppressive therapy may thus promote the development of PTLD at two levels: increasing the incidence and level of oropharyngeal EBV replication (particularly by antilymphocyte antibody therapy), and blocking the surveillance mechanism (particularly by cyclosporine, but also by the rest of the immunosuppressive program). Since this relationship between viral shedding and risk of PTLD was demonstrated, emphasis has shifted to correlations between levels of EBV DNA, as determined by PCR assay, in the blood and subsequent risk of PTLD. Although there is still lingering controversy about the optimum assay technique (lymphocytes, whole blood, or plasma), it is clear that serial measurements of EBV viral load in the blood can be utilized in a number of ways: a negative assay essentially rules out the possibility of PTLD in a patient with a clinically compatible syndrome; high levels of viral DNA have a high predictive value for either the presence of PTLD or the future development of it; and, perhaps most exciting, serial monitoring of EBV DNA levels may permit the adjustment of immunosuppressive therapy and/or the prescription of antiviral therapy so as to preempt the development of PTLD.648–651 Thus, the possibility exists that if one could interrupt EBV replication at a critical point in the posttransplant course (e.g., the replication induced by antirejection therapy), one could interrupt the oncogenic process by limiting the number of B lymphocytes that are transformed at a

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time when the surveillance mechanism has been particularly suppressed by high-dose immunosuppressive therapy.654–661 Thus, a strategy akin to the preemptive program for CMV that was previously described, could have dual efficacy in also providing protection against the development of PTLD. A high priority must be given to determining if this strategy does indeed provide significant protection. The clinical presentation of EBV-associated PTLD can be quite variable, and includes one or more of the following: unexplained fever (an FUO); a mononucleosistype syndrome with fever, malaise, and lymphadenopathy, with or without pharyngitis/tonsillitis; a GI presentation, which can include GI bleeding, abdominal pain, gut perforation or obstruction; hepatocellular dysfunction; gallbladder disease presenting as acute cholecystitis; and CNS dysfunction such as seizures, change in state of consciousness, and focal neurologic disease. Not uncommonly, the allograft itself is frequently involved with the process, not particularly surprising given the MHC restriction of the EBV-specific cytotoxic T-cell surveillance mechanism—the MHC-disparate allograft representing a privileged immunologic site for the EBV-driven process to occur. Alternatively, PTLD can present as a hilar mass in renal transplant recipients resulting in hydronephrosis or renal vessel invasion (or a portal mass in liver transplant patients causing biliary obstruction). Finally, involvement of the bone marrow, lung, and virtually every other organ has been described. An important clinical point is that absence of adenopathy on CT scanning does not rule out PTLD, as this disease can be totally extranodal in nature.638,662–664 At present, optimal therapy for PTLD is unclear. An estimated 20–30% of patients improve with the cessation of immunosuppression, with a greater percentage of children (with PTLD as a consequence of primary EBV) responding to this maneuver than adults (virtually all of whom have PTLD as a consequence of reactivation of EBV). Although the evidence in favor of antiviral therapy with acyclovir, ganciclovir, or foscarnet is purely anecdotal,627,665,666 most transplant centers do utilize one of these while decreasing immunosuppression. The concept justifying this approach is that although the EBV-transformed B cells present in the tumor are not exhibiting lytic infection, lytic infection is going on systemically “feeding the fire.” Eliminating this element of the process, either directly or through modification of the resulting cytokine milieu, could add to the therapeutic program.618,642,666 One subgroup of patients that does particularly well with PTLD is the group that presents with GI bleeding, obstruction, or perforation, and has a single tumor site resected. For the majority of patients,

however, in whom PTLD is discovered, further therapy is needed. Traditional therapies with antilymphoma chemotherapy, radiotherapy, and surgery have not yielded satisfactory results, and attention has turned to alternative approaches. In solid organ transplant patients with PTLD, these experimental therapies have included plus nonspecific IgG, or the possible use of adoptive transfer therapy with the infusion of donor T lymphocytes or EBV-specific CTLs (although this last has had considerable success in bone marrow transplant patients with PTLD where donor cells are available, it is more problematic to utilize this approach in organ transplant patients where donor cells may not be available). What has been particularly exciting in recent years has been the experience with anti-B-cell monoclonal antibodies (directed against the CD20, CD21, or the CD24 antigens). More than 60% of patients, many of whom had failed earlier interventions, responded to such therapy, which was well tolerated. Other anti-B-cell antibodies (antiCD19, anti-CD37, and anti-CD38) are also in development for this purpose. An interesting alternative approach is the use of a monoclonal antibody directed against IL-6. This was chosen because of IL-6’s important role as a growth factor for EBV-induced B-cell proliferation. Complete remission was achieved in 5 of 12 patients so treated, with partial remission in another 3 patients, and stability in 1 patient; 3 patients showed no response to the therapy. These observations are important not only for defining a possible therapeutic option, but also for confirming the importance of the cytokine milieu in the evolution of PTLD.627,665–673 Our own practice at present is to decrease immunosuppression significantly (halting it completely and returning the patient to dialysis in the case of renal transplant patients) and to initiate systemic antiviral chemotherapy, while monitoring EBV DNA levels in the blood. Approximately 4–6 weeks is devoted to this effort. Progressive disease or failure to improve during this period indicates the need for further therapy. Our current preference is anti-B-cell antibody therapy, reserving more standard lymphoma chemotherapy for patients who fail this form of therapy. Clearly, prevention is much to be preferred, hence the emphasis on determining whether prophylactic or preemptive antiviral strategies, particularly at times of intensive immunosuppression, can prevent the evolution of this process. Illustrative Case 5 A 47-year-old man underwent cardiac transplantation in treatment of an ischemic cardiomyopathy. The donor and recipient were seropositive for both CMV and EBV. His immediate posttransplant course was marked by severe acute renal failure, resulting in the cessation of

INFECTION IN THE ORGAN TRANSPLANT RECIPIENT cyclosporine on the third posttransplant day and the initiation of a 14day course of antithymocyte globulin. At the end of this time, he was doing well, with recovery of renal function and a well-functioning graft, with immunosuppression being maintained with cyclosporine, azathioprine, and prednisone. He was receiving no antiviral prophylaxis. Four weeks posttransplant, significant cellular rejection was diagnosed on routine endomyocardial biopsy, and, following two pulse doses of 500 mg of intravenous methylprednisolone, a 10-day course of OKT3 was initiated. Follow-up endomyocardial biopsy was negative, but 6 weeks posttransplant fever, leukopenia, hepatocellular dysfunction, and an interstitial pneumonia were noted, and CMV was isolated from the blood and on bronchoalveolar lavage. Ganciclovir and anti-CMV hyperimmune IgG therapy were instituted, with gradual clinical improvement. The patient received 4 weeks of therapy, and had returned home for the last week of this. He remained well until 6 months posttransplant, when he presented with fever, encephalopathy, hepatocellular dysfunction, and GI bleeding. PTLD was diagnosed on liver biopsy and on colonoscopic biopsy of a colonic mass. Therapy was instituted by a 50% decrease in immunosuppressive therapy, followed by CHOP chemotherapy. In addition, full-dose ganciclovir therapy was administered. Unfortunately, the patient rapidly deteriorated, developing progressive encephalopathy, pancytopenia, and hepatic failure. At postmortem examination, PTLD involving the brain, liver, colon, small bowel, and infiltrating the cardiac allograft were found. Episomal EBV could be demonstrated quite easily in the tumorbearing tissues. Samples of the tumor were demonstrated to manifest oligoclonality. Comment. This cardiac transplant patient was heavily immunosuppressed, receiving two courses of antilymphocyte antibody therapy, without any concomitant antiviral preventive strategy. His sequence of clinical CMV disease followed by EBV-related PTLD was both expected and probably interrelated. Although management of the immunosuppression was expertly handled, the lack of an effective antiviral program in conjunction with the augmented immunosuppression virtually guaranteed the tragic course of events that occurred. Ideally, he would have received intravenous ganciclovir during the courses of antilymphocyte antibody, followed by 4 months of oral ganciclovir. It is likely that the CMV disease would have been prevented by this regimen. Such an approach would have decreased the risk of PTLD. However, because of the intensive immunosuppression required in this patient, monitoring of EBV blood DNA levels would have been of great interest prior to overt presentation of PTLD. Finally, given the gravity of the illness—rate of progression and disseminated tumor burden—early deployment of anti-B-cell antibody ± anti-IL-6 therapy would have been desirable.

5.1.3. Herpes Simplex Virus Infection in Organ Transplant Recipients In the absence of antiviral prophylaxis, HSV is probably second only to CMV among viral agents causing clinical disease in the organ transplant patient. Virtually all of the infections caused by HSV are the result of reactivation of latent virus. Information currently available would suggest that approximately three fourths of patients with antibody to HSV pretransplant will excrete the virus in their throat washings, and approximately two thirds will demonstrate a fourfold or greater increase in their antibody titers. About one-half of the seropositive

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patients and two-thirds of those who excrete the virus will develop visible mucocutaneous lesions. There appears to be no relationship among the presence, severity, or extent of such lesions, and the subsequent development of allograft dysfunction.631,674 By far the most common clinical manifestation of HSV infection in the organ transplant patient is herpes labialis, usually beginning by the second week posttransplant, peaking in severity by the end of the first month, healing over the next 2–6 weeks, and exacerbated and prolonged by acute antirejection therapy. Not only are such infections more prolonged than in the normal host, but they are considerably more severe: large, painful, crusted ulcerations that bleed or interfere with normal nutrition and require at least local analgesia. In some individuals, these lesions can interfere sufficiently with the handling of oral secretions to predispose to aspiration. Intraoral and esophageal infection may occur in association with the herpes labialis, particularly if the mucosa has been traumatized by endotracheal or nasogastric tubes. These should be avoided if possible in transplant patients who have active labial or intraoral infection. Both clinically and radiologically, herpetic esophagitis mimics the effects seen with candidal esophagitis. As in normal hosts, virtually all isolates from patients with oral HSV infection are type 1 (HSV-1). Although herpetic orolabial infection in the transplant patient can cause heaped-up, verrucous lesions of the lips, care must be taken in those individuals who fail to respond to conventional acyclovir therapy that a squamous cell carcinoma is not either simultaneously or solely present.214,675,676 In renal, cardiac, and liver transplant patients, HSV pneumonia is an uncommon event, usually occurring as a secondary bronchopneumonia in patients requiring prolonged intubation because of some other form of primary lung injury. The pathogenesis in these cases is related to the presence of replicating HSV that has been reactivated in the oropharynx, trauma to the mucosa by the endotracheal tube, and spread via the endotracheal tube to the lower respiratory tract. Recipients of lung and heart–lung transplants, however, if not receiving some form of acyclovir or ganciclovir prophylaxis, have a relatively high incidence of HSV pneumonia. Presumably the same pathogenetic mechanisms are involved here as previously stated, with the more prolonged intubation of these patients adding to the risk. In addition, by analogy to CMV infection, where the transplanted organ is more intensively affected than the native organ, it is not unreasonable to speculate that the lung allograft is more susceptible to inoculation with HSV than the native lungs of the other transplant groups. Because of this risk, our practice is to place all of our lung transplant patients on either

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ganciclovir or acyclovir prophylaxis in the first 4 months posttransplant (vide infra).677 Less commonly, anogenital infection may occur, caused predominantly by HSV-2. Unusually severe anogenital infection characterized by the presence of large coalescing, ulcerated lesions, without clear-cut vesicles, may be caused by HSV-2 in transplant patients who have been treated with particularly aggressive immunosuppressive therapy. In the evaluation of these lesions, routine bacteriologic cultures, Tzanck preparations, and morphologic evaluation will not yield the appropriate diagnosis. Viral culture or direct immunofluorescence studies with specific monoclonal antibodies directed against HSV—both performed on swabs of the lesion—will result in rapid diagnosis. Such lesions may become secondarily infected and act as a portal of entry for a variety of stool flora, resulting in local cellulitis and/or bacteremias, particularly if the patient is leukopenic.678 We have also cared for a number of transplant patients with recurrent zosteriform lesions on the buttocks caused by HSV-2, and chronic chancrelike genital lesions caused by this virus have been reported.679 More severe HSV infections in the organ transplant patient are uncommon. In particular, although HSV may act as a secondary pathogen in an intubated patient with severe pneumonia caused by other agents, it is rarely a primary cause of pneumonia. The clinician evaluating an organ transplant patient with pneumonia who isolates HSV from respiratory secretions should be very circumspect in terms of accepting this as an adequate explanation for the pneumonitic process that is present.680 Although several transplant patients have been reported with an illness characterized by severe oral lesions followed by high fever, fulminant hepatitis, GI bleeding, and disseminated intravascular coagulation because of HSV, this syndrome is exceedingly uncommon in the organ transplant setting.681–685 Uncommonly, disseminated cutaneous infection with HSV, occurring at sites of previous skin injury such as burns or eczema (termed eczema herpeticum or Kaposi varicelliform eruption), may develop. In these cases, recovery without visceral dissemination is the rule, even without specific antiviral therapy. Anora et al.686 reported an interesting case of a 34-yearold man in whom fever and then multiple vesicles around the sutures of his transplant incision developed about 2 weeks after receiving a kidney from his brother. HSV-2 was cultured from these vesicles, and an antibody response was documented. It is now apparent that on rare occasions the allograft may convey active HSV infection, which has resulted in disseminated disease in seronegative graft recipients.687

Similarly, CNS infection with HSV in the transplant patient is uncommon. Rarely, HSV-2 meningoencephalitis following anogenital infection may be noted, but more typical HSV-1 encephalitis as seen in the normal host is essentially unknown.675 Dunn et al.688 have suggested that the combination of HSV and CMV infections in the same individual was associated with a worse clinical outcome than either infection alone. In their experience at the University of Minnesota, concurrent HSV and CMV infection was associated with both increased patient mortality and increased allograft loss. The advent of antiviral prophylaxis and therapy has had a remarkable effect on the occurrence and impact of HSV disease in organ transplant patients. Both acyclovir and ganciclovir are quite effective anti-HSV drugs, and essentially any preventive strategy utilizing these drugs that is effective against CMV and EBV will have a similar salutary effect on HSV infection. Symptomatic infection is easily treated with oral acyclovir, 200 mg five times per day for 7–10 days (prolonging the course of therapy, as needed, if intensive immunosuppressive therapy is being prescribed at the same time). Of importance, unlike in the AIDS patient, acyclovir-resistant HSV has not been a clinical issue in organ transplant recipients, even if the patient has received antiviral prophylaxis. An alternative to treatment of overt infection is the use of acyclovir prophylaxis in HSV-seropositive patients (in doses of 200 mg four times per day for the first month posttransplant), which is quite successful in preventing HSV disease. Since symptomatic HSV is relatively easy to treat, we prefer not to prophylax for this infection by itself, and tend to choose strategies primarily aimed at the other herpes group viruses (which, in most cases, will also provide significant benefit for HSV). Finally, the occasional patient with recurrent, symptomatic HSV infection may benefit from prophylaxis with acyclovir, 200 mg three or four times per day for periods of 6 months or longer.22,679,689,690 5.1.4. VZV in Organ Transplant Recipients Three clinical syndromes are commonly recognized in organ transplant patients as being caused by VZV. First is typical localized dermatomal zoster resulting from viral reactivation which may involve two or three adjoining dermatomes, and even manifest a few sites of cutaneous dissemination at distant sites, but which is without evidence of visceral involvement. VZV can be isolated quite easily from these skin lesions, and rises in antibody to VZV can be demonstrated in the majority of such individuals. Traditionally, approximately 10% of organ trans-

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plant patients who remained on immunosuppression developed clinical zoster posttransplantation as a result of reactivation of VZV long dormant in dorsal root ganglia. Such infections were uncommon earlier than 2 months and later than 3 years posttransplant. With the widespread deployment of antiviral agents like acyclovir and ganciclovir, both of which have activity against VZV, the incidence of zoster has decreased, and those cases that do occur usually are later in the posttransplant course. Antiviral therapy with ganciclovir or valaciclovir will hasten the healing of the skin lesions. Such therapy is particularly indicated for zoster involving the face, the sacral dermatomes (as bladder and/or bowel function could be compromised), if significant underlying skin disease is present, or if high-dose immunosuppressive therapy is required to control rejection. Unlike the situation in individuals immunosuppressed by Hodgkin’s disease and its therapy, visceral dissemination is uncommon in the organ transplant recipient.22,675,691,692 Second, disseminated VZV infection characterized by hemorrhagic pneumonia and skin lesions, encephalitis, pancreatitis, hepatitis, and disseminated intravascular coagulation may be observed as a consequence of primary VZV infection in organ transplant patients. In addition, there is some preliminary evidence suggesting that primary VZV infection in the organ transplant recipient may be associated with allograft injury in a fashion similar to that postulated for CMV (vide supra). If primary VZV infection is recognized sufficiently early, it can be effectively treated with high-dose intravenous acyclovir (10 mg/kg three times per day, with revisions of the dose for renal dysfunction). Rarely, VZV has been conveyed with the allograft to a seronegative recipient. More than 90% of adults are seropositive for VZV, and thus not at risk for primary VZV. Therefore, children are the prime concern. Our practice is to screen all transplant candidates serologically for VZV. Seronegative individuals should receive the varicella vaccine, with repeat serologic testing carried out to document seroconversion and protection. Seronegative transplant recipients, whether or not there has been a history of varicella vaccine administration prior to transplant, are instructed to promptly report all VZV exposures so that zoster immune globulin (ZIG) can be administered in a timely fashion. Oral valaciclovir prophylaxis is another option, although careful study of this approach in the transplant population has not been carried out. Although ZIG prophylaxis offers significant protection, in some individuals it will only attenuate the skin lesions while visceral infection spreads, thus delaying recognition and effective therapy.693–697 Recently, VZV-seropositive pediatric renal trans-

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plant recipients receiving an immunosuppressive program of cyclosporine, prednisone, and mycophenolate mofetil developed disseminated cutaneous varicella infection, with a generalized vesicular eruption without a dermatomal distribution. All of these episodes occurred in the first year posttransplant. None of the patients developed fever, respiratory, CNS, or other visceral disease, and had responded to acyclovir therapy. This syndrome was presumably due to reinfection in children whose immunity, despite seropositivity, was partially abrogated by the mycophenolate-containing regimen.698 Finally, a syndrome of unilateral pain without skin eruption associated with rises in specific antibody to VZV has been described in transplant patients and is presumably also caused by this virus. In addition, serial studies in transplant patients have demonstrated that asymptomatic rises in antibody titer to VZV may occur. This finding has been ascribed to an unstable relationship between virus and host, and is cited in support of the argument by HopeSimpson that subclinical release of virus with resulting antigenic stimulation may maintain immunity to VZV.692,697 5.1.5. HHV-6 Infection in Organ Transplant Recipients HHV-6 is a closely related to both CMV and HHV-7. Indeed, there is 66% DNA sequence homology between CMV and HHV-6.699 HHV-6 infects and replicates within a variety of leukocytes: most prominently T lymphocytes, but also including lymphocytes, NK cells, macrophages, megakaryocytes, glial cells, and epithelial cells.700,701 In addition, HHV-6 replication is a powerful stimulus for the elaboration of a broad array of proinflammatory cytokines, including TNF, IL-1, and From this brief description of HHV-6’s properties, one would predict that HHV-6 could cause febrile illnesses akin to those produced by CMV in transplant patients, that bone marrow dysfunction and encephalitis would also be within the range of illnesses produced by this virus, and that a variety of indirect effects would be produced by HHV-6 (e.g., promotion of CMV disease, contribution to the net state of immunosuppression and thus increasing the risk of opportunistic superinfection, and the potential for causing acute and chronic allograft injury).700,702–704 Primary infection with HHV-6 usually occurs in the first year of life; 90% of adults are seropositive for this virus and harbor latent virus. In the general population, HHV-6 has been shown to be the cause of roseola (exanthem subitum), a febrile exanthem of young children. In addition, HHV-6 has been linked to a mononucleosis

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syndrome, autoimmune disorders, lymphomas, necrotizing lymphadenitis, encephalitis, as well as multiple sclerosis and other demyelinating conditions.700,701,705,706 HHV-6 infection has been documented, primarily in the period 1–6 months posttransplant, in 30–50% of organ transplant recipients. Although the transplantation of an allograft from a seropositive donor into a seronegative recipient carries a > 50% risk of virus transmission (primary infection), the great majority of infections are thought to be due to reactivation of latent virus.700,707 Despite this information, several factors have rendered difficult the delineation of the clinical role of HHV-6 in transplantation: the fact that the clinical effects of this virus are probably very similar to those of such other viruses as CMV and EBV, whose peak level of replication is occurring during the same time period as HHV-6; the ubiquity of the other herpes group viruses in this patient population; and the fact that there can be serologic crossreactivity between anti-CMV antibody and anti-HHV-6 antibody.700,708–714 At present, it is possible to say that the direct clinical effects of HHV-6 in transplant patients include fever with or without mononucleosis, interstitial pneumonitis, and hepatitis. Far more important are bone marrow suppression and CNS dysfunction (encephalitis). The CNS effects include mental status changes, seizures, and headache, with focal neurologic findings being rare. Evaluation of patients with HHV-6 CNS disease reveals less than dramatic results: minimal if any pleocytosis in the CSF; HHV-6 DNA demonstrable in the CSF of a distinct minority of patients; and usually negative neuroimmaging studies. Rarely, low-attenuation white matter changes virtually identical to those seen with immunosuppressionassociated leukoencephalopathy may be seen.596,700,708–716 As previously mentioned, simultaneous infection with multiple herpesviruses, particularly HHV-6, CMV, and/or EBV, is a common event. It is likely, although not yet proven, that the patient with multiple infections will suffer greater direct and indirect consequences than if a single virus is replicating. Of interest is a study from the Royal Free Hospital in London in which HHV-6 infection was the leading factor correlating with both length of hospital stay and need for readmission.717 Although HHV-6 can be isolated by culture, and serologic assays are available, it is fair to say that reliable diagnosis of HHV-6 requires either antigenemia or PCR assay. The analogy to CMV is clear—serologic studies are primarily useful pretransplant to stratify risk; cultures require 5–21 days for results (and a shell vial assay is relatively insensitive); with antigenemia or quantitative PCR on blood being both timely and useful.700

The optimal management of HHV-6 infection remains to be defined. In vitro assays demonstrate susceptibility to ganciclovir and foscarnet analogous to that of CMV. Indeed, clinical benefit has been demonstrated with both of these drugs in patients with encephalitis.715 It is likely that antiviral strategies aimed at CMV and employing ganciclovir are having a beneficial effect on the course of HHV-6 infection. However, optimal management, prophylaxis, and/or preemptive therapy remain to be defined. It might be predicted that in the future antiviral programs will not be aimed at a single virus like CMV; rather, programs will be directed at multiple agents simultaneously. For the present, a ganciclovir preparation appears to be the best means for accomplishing this. 5.1.6. HHV-7 Infection in Organ Transplant Recipients HHV-7 resembles HHV-6 in its epidemiology, with primary infection being acquired commonly by the age of 5. It has a similar tropism for T lymphocytes, but unlike HHV-6, utilizes the CD4 molecule itself as its receptor.700 The clinical effects of this “orphan virus” are currently unclear. Preliminary data from some,718,719 but not all,720 studies suggest that HHV-7 replication is a significant risk factor for clinical CMV disease. If one were to speculate on other possible clinical effects of this virus, it would be in the realm of indirect effects—that is, cytokines, chemokines, and growth factors produced in response to HHV-7 replication could influence the net state of immunosuppression (and the risk of other infections), the processes of allograft injury, and even the pathogenesis of certain forms of malignancy. Currently available evidence suggests that HHV-7 is ganciclovir resistant, and it is not clear what, if any, antiviral strategy should be employed for this virus.721 5.1.7. HHV-8 Infection in Organ Transplant Recipients HHV-8 is a which is the causative agent of Kaposi’s sarcoma (KS). Most cases of KS in transplant patients represent instances in which viral reactivation from latency has occurred posttransplant. However, instances of primary HHV-8 infection in which an organ from a seropositive individual was transplanted into a seronegative individual are well documented, with subsequent development of KS in these individuals. Both corticosteroids and OKT3 administration appear to amplify the extent of HHV-8 replication. The incidence of KS in transplant recipients mirrors the seroprevalence of HHV-8

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in a given population (with seropositivity equaling the presence of latent infection capable of being reactivated posttransplant). Thus, the incidence of KS in the United States is 0.5%, in Italy 1.6%, in Israel 2.4%, in South Africa 4%, and in Saudi Arabia 5.3%. The incidence of KS among HHV-8-seropositive transplant recipients approaches 25–30% in the first 3 years after transplantation. Genetic polymorphism in HHV-8 isolates has been demonstrated, but those causing KS are thought to belong to a single, or limited number of genotypes.700,722–726 Clinical manifestations of KS in transplant patients resemble those seen in other populations. Skin involvement with violaceous/blackish nodules is the most common presenting finding. However, visceral lesions involving the lungs, GI tract, bladder, and other sites can be found in of transplant recipients with KS. GI manifestations include bleeding, abdominal discomfort, perforation, obstruction, and protein-losing enteropathy. Diagnosis of KS is made on biopsy; the diagnosis of HHV-8 infection is made by PCR assay of peripheral blood leukocytes, with viral load being an excellent predictor of the risk of developing KS. Optimal management is still being determined. The first step is to significantly reduce immunosuppression. There is suggestive evidence that such drugs as ganciclovir, foscarnet, adefovir, cidofovir, and HPMA [(S)-l-(3-hydroxy-2-phosphonylmethoxypropyadenine] may be useful in the management of high viral loads, and, possibly, overt KS. Clearly, an analogy can be made with EBV-associated PTLD and the concept of monitoring viral load, and then manipulating immunosuppression and/or preemptive antiviral therapy on the basis of these measurements. In patients not responding to the above interventions, more classical cancer chemotherapy is an option.700,727–729 5.2. Hepatitis in the Organ Transplant Recipient The incidence of chronic liver disease in organ transplant patients has not changed significantly in 20 years, with 10–15% of successful transplant recipients being subject to the morbidity and mortality associated with what is usually progressive disease. In considering liver disease in this patient population, two types of etiologies must be considered: drug-induced hepatotoxicity; and virus-induced disease, particularly with a group of viruses that are subject to modulation by the immunosuppressive therapy being administered.5 Two of the drugs that are a standard part of the immunosuppressive regimen, azathioprine and cyclosporine, can be injurious to the liver under certain circumstances. Of these drugs, azathioprine has received the most attention. At a dose of 2–4 mg/kg

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per day, this drug is clearly hepatotoxic, with a histologic pattern consistent with chronic active hepatitis. However, at the doses of azathioprine utilized today (1–1.5 mg/kg per day), azathioprine is unlikely to be responsible for the development of chronic, progressive liver disease and cirrhosis. The substitution of cyclophosphamide for azathioprine in transplant patients with unexplained hepatocellular dysfunction is rarely associated with improvement. Similarly, although high-dose cyclosporine, particularly when administered intravenously, can cause hepatic injury, there is no convincing evidence that it is the cause of chronic, progressive liver disease in transplant recipients. Of importance, there is also little evidence that discontinuing azathioprine in transplant patients with proven viral hepatitis caused by hepatitis B will have a beneficial effect on the course of such infections.5,730–735 There are, however, unusual forms of liver injury that are caused by azathioprine administration that will respond to cessation of the drug: hepatic veno-occlusive disease (usually in men), peliosis hepatitis, perisinusoidal (Disse’s space) fibrosis, and nodular regenerative hyperplasia. It has been postulated that azathioprine, even in the doses currently employed, can damage the endothelial cells lining the hepatic sinusoids and the terminal hepatic venules, producing this range of clinical disease.736–738 In addition to immunosuppressive agents, the transplant patient is subjected to a wide array of other pharmaceutical agents, most commonly antimicrobial drugs, antihypertensive agents, and diuretics. Although they are unusual causes of chronic liver disease, these should always be considered in the transplant patient. Perhaps the most common causes of hepatotoxicity have been the antituberculous medications isoniazid and rifampin, trimethoprim–sulfamethoxazole (particularly the sulfonamide component), alpha-methyl-dopa, and the azole group of antifungal drugs. As far as these last agents are concerned, it is reassuring that the initial experience with fluconazole has been so positive in organ transplant patients in terms of adverse interactions with the liver. It has been safely used, even in liver transplant patients, in the face of significant hepatic dysfunction, and its use has not been associated with significant hepatic injury in our experience of over 200 organ transplant patients treated with the drug.5,179 As previously noted, the herpes group viruses not uncommonly affect the liver. In particular, the rare instances of disseminated primary infection with HSV and VZV can have a major effect on the liver. In addition, the important effects of CMV and EBV, particularly on the transplanted liver, have already been reviewed. It is important to point out, however, that there is no evidence

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linking these viruses, or such other agents as adenoviruses (an unusual cause of fulminant hepatitis in the transplant patient),739,740 to the pathogenesis of chronic liver disease that leads to end-stage liver failure—the entity under discussion here. Thus, the predominant causes of chronic hepatitis in transplant recipients are the classical hepatitis viruses. At present, five different viruses have been defined, each with a differing potential for injuring transplant patients (see Chapter 12)86: 1. Hepatitis A virus (HAV). HAV is a small RNA virus that is spread via the fecal–oral route. Although HAV can cause fulminant hepatitis that can require emergency liver transplantation and relapsing hepatitis can occur, chronic disease has never been shown to result from this virus.86,741 Because viremia during the course of HAV infection is both transient and at a very low level, and because of the lack of chronic infection, HAV is rarely transmitted by blood transfusion, has not been documented to be transmitted by organ transplantation, and is not a significant problem among dialysis patients (unlike hepatitis B and C).86,742–744 A number of patients with fulminant HAV infection have now successfully undergone emergency liver transplantation, although recurrent HAV infection of the allograft has been reported.745 2. Hepatitis B virus (HBV). HBV is caused by a DNA virus of the hepadna virus group. Unlike the situation with hepatitis A, HBV is present in a fully infectious form in the blood for prolonged periods (as long as 20 weeks in normal individuals with acute, self-limited infection; and as long as 20 years in patients with chronic infection). HBV infection is efficiently transmitted by transfusion or through the transplantation of organs from HBV carriers, as well as by such other routes as intimate mucosal contact between virus carriers and susceptible individuals. Just as the demonstration of HBsAg in the blood is a marker for infectious virus, antibody to HBsAg (anti-HBs) is a reliable marker for immunity to the virus. There have, however, been documented instances of antiHBs-positive individuals reverting to HBsAg positivity with the initiation of immunosuppressive therapy.746 HBV has an important impact on transplant patients in terms of the production of chronic active hepatitis and cirrhosis both before and after transplant, as well as in the pathogenesis of hepatocellular carcinoma in these patients. Although the liver is the major site of HBV replication, it is now clear that such extrahepatic reservoirs of HBV infection as mononuclear cells and bone marrow cells exist, and can account for the reinfection of liver allografts following transplantation (vide infra).86,747–749

3. Hepatitis C virus (HCV). HCV is an RNA virus that is the cause of the majority of parenterally transmitted and bloodborne cases of non-A, non-B hepatitis (NANBH). It is also likely to play the same role in transplant recipients. HCV is the hepatitis virus most likely to produce chronic, progressive liver disease. For example, in the normal population, 50% of individuals with posttransfusion HCV infection will have biochemical evidence of chronic liver disease at 12 months, with at least 40% of these having evidence of chronic active hepatitis and 10–20% having cirrhosis 5 years posttransfusion.750,751 Thus, HCV is a not uncommon cause of end-stage liver disease necessitating liver transplantation, may cause progressive liver disease following transplantation, and is an important contributor to the net state of immunosuppression posttransplant (vide infra). 86 4. Hepatitis D virus (HDV). HDV, sometimes called the delta virus, is a defective RNA virus whose replication requires the presence of HBV. When such coinfection occurs, there seems to be a higher rate of acute (including fulminant) and chronic hepatitis, as opposed to asymptomatic disease, than with HBV alone. Patients with chronic HBV infection who acquire HDV will frequently develop acute exacerbations, including fulminant hepatic failure. These events have been documented in transplant patients, particularly in countries such as Italy where HDV infection is common.86,746,752 5. Hepatitis E virus (HEV). HEV is the cause of enterically transmitted NANBH, a frequent cause of epidemic hepatitis in developing countries, and a major cause of sporadic hepatitis on the Indian subcontinent. HEV resembles HAV in terms of its fecal–oral mode of spread, its lack of ability to produce chronic liver disease, and its failure to have an impact on transplant patients.86,753 Thus, the two agents responsible for virtually all of the chronic liver disease in transplant patients are HBV and HCV, both viruses that are transmitted by blood products and by allografts from infected donors and whose effects are modulated by the immunosuppressive therapy being administered. It is estimated that ~20% of hepatitis occurring after transplantation remains unexplained, and that there are likely additional viruses causing hepatitis in these patients remaining to be described (so-called nonA, non-B, non-C virus or viruses).111 5.2.1. The Clinical Impact of HBV Infection on the Organ Transplant Recipient

The techniques currently employed in testing for HBsAg (and hence the presence of infectious virus) are so

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sensitive and specific that the current incidence of posttransfusion HBV infection is estimated to be approximately 0.002% per transfusion, with a comparable figure for organ transplantation. Because of this, the acute acquisition of HBV at the time of transplantation from either infected blood or a contaminated allograft is now extremely rare. This is fortunate for two reasons: The acquisition of HBV infection in the peritransplant period is associated with a markedly increased incidence of fulminant hepatitis; and HBV vaccine has a low rate of efficacy in dialysis patients, in those with end-stage liver disease and other debilitating illnesses, as well as posttransplant.747,751,754–758 The major problem with HBV infection in transplantation is the optimal management of the patient who is already infected with the virus prior to transplant, as virtually all such individuals will remain persistently infected posttransplant. Corticosteroid therapy seems to have a direct stimulatory effect on the level of virus replication, with a rapid increase in HBV DNA polymerase activity, HBeAg levels, HBV DNA, and HBsAg levels being observed. This stands in contrast to the gradual decrease in HBV production that is often observed in carriers of the virus not receiving immunosuppressive therapy.746,759,760 The effects of the other immunosuppressive agents on HBV replication are currently unclear: In a short-term human hepatocyte tissue culture system, the amplifying effects of corticosteroids on HBV replication could be clearly demonstrated, with neither cyclosporine nor azathioprine having any effect761; in the woodchuck hepatitis virus model (which is felt to mimic many of the host–virus interactions of HBV in humans), the administration of cyclosporine during the incubation period increased significantly the incidence of chronic infection.762 Thus, the in vivo effects may be greater than the tissue culture effects of these other agents. Paradoxically, liver function test abnormalities and even histologic evidence of disease activity may be blunted by the immunosuppressive therapy, despite the upregulation in viral replication. Unfortunately, despite this, liver injury is accelerated, and progressive liver disease can occur, even in the face of relatively normal biopsies until late in the course. Despite immunosuppression, a significant HBVspecific, MHC class II-restricted T-cell response is present. This is associated with both the local production and systemic release of and TNF, which is proportional to the degree of neuroinflammatory activity in the allograft.86,763 The effects of HBV on kidney and, presumably, other forms of nonhepatic transplantation should be considered in two time frames: the first 2 years posttrans-

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plant, and the late period after that. In the early period, HBV infection appears to have little clinical impact on the posttransplant course, with the possible exception of contributing to the net state of immunosuppression. However, beginning approximately 2 years posttransplant, patients with chronic HBV infection receiving chronic immunosuppression begin to develop serious illness resulting from progressive liver disease and/or the development of hepatocellular carcinoma.748,764–772 As far as this last fact is concerned, the HBx gene of HBV, which codes for a viral transactivator, can induce the production of liver cancer in transgenic mice.773 HBx appears to function through a complex signal transduction mechanism that activates a tumor promoter signaling pathway.774 Presumably, the increased level of viral proliferation that is made possible by transplant patients’ immunosuppressive therapy promotes this process, explaining in part the excessive incidence of hepatocellular carcinoma in this patient population. The long-term effects of chronic HBV infection have been well chronicled in renal transplant patients. There is little reason to believe that these effects should be any different in the other forms of nonhepatic organ transplantation. By 8–10 years posttransplant, patients with HBV-associated chronic liver disease had an increased death rate from hepatic failure, hepatocellular cancer, and sepsis, with HBV-infected patients doing significantly worse than transplant patients with other forms of liver disease.746,764–772 For example, Rao and Andersen reported that 38% of long-term renal transplant patients with HBV infection had chronic progressive hepatitis, 38% had chronic active hepatitis, 42% had evidence of cirrhosis, and 54% died of liver failure.770 In contrast, only 17% of the HBsAg-negative patients had chronic progressive hepatitis, 14% had chronic active hepatitis, 19% had cirrhosis, and 12% died of liver failure. Thus, although NANBH in transplant patients is not a benign illness, HBV infection, in the absence of therapy, has carried a significantly worse prognosis. More recent reports, perhaps reflecting the use of cyclosporine-based immunosuppressive regimens that employ much lower steroid doses, have suggested that the 10-year prognosis for renal transplant patients with HBV is more optimistic.87,775 In the case of renal transplantation, because of this profound impact of chronic HBV infection on longterm well-being and survival, arguments have been presented that such individuals would be better served by dialysis therapy rather than transplantation.765–769 This has been controversial, to say the least, particularly in view of the more recent experience cited above and the dawn of a new era in which meaningful therapy of HBV

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infection is starting to become available (vide infra). One important point that bears further study is that preliminary evidence is available suggesting that the presence of HBeAg in the blood prior to renal transplant and/or histological findings of chronic progressive or active hepatitis delineate a group of patients at particularly high risk of progressive liver disease and excessive mortality after transplantation.746,776 Our approach to this issue is to regard HBsAg positivity as a relative, rather than absolute, contraindication to transplantation in patients with endstage renal, heart, and lung disease. Such other factors as evidence of liver disease and HBeAg positivity (or, ideally, more specific markers of viral proliferation, such as HBV DNA levels), level of nutrition, other comorbid illnesses, quality of life, and, perhaps most important, the patient’s own wishes should then enter into the decisionmaking. The often dismal results of transplanting individuals with HBV infection have taken a significant turn for the better in recent years because of the emergence of new antiviral approaches. The first of these, has been shown to induce remission in approximately 40% of nonimmunosuppressed individuals with chronic HBV infection. However, in transplant patients, the rate of response is less than half of that. In addition, although appears to be well tolerated in liver transplant recipients, experience in renal allograft recipients has indicated a significant risk of severe rejection in these patients. Hence, interferon therapy, at least with this agent alone, does not appear to be a promising avenue to follow.777–780 Famciclovir, but not ganciclovir, has some activity against HBV, but clearly is not the answer to the problem.781–785 The advent of lamivudine represents the first major advance in this field. Lamivudine is a nucleoside analogue that is the most powerful inhibitor of HBV replication currently available, due to its effects on the viral polymerase/reverse transcriptase. The drug has been well tolerated and extremely effective not only in lowering HBV levels but also in improving hepatic function and histology, including patients with the devastating, fibrosing cholestatic hepatitis form of HBV disease. The major disadvantage of lamivudine is the emergence of drugresistant mutants (usually in a highly conserved region of the reverse transcriptase known as the YMDD motif). These mutants begin to emerge approximately 1 year after the drug is initiated, with an increasing incidence over time. The higher the viral load, the more likely and more quickly resistance mutants will emerge. After 1 year of therapy, the incidence of resistance is 14–31%; after 2 years, it is 38%. It is clear that multidrug programs will

be necessary to prevent this occurrence, analogous to what is required for the control of HIV infection. Such drugs in development as adefovir and entecavir offer great promise in this regard (see Chapter 12). Because lamivudine efficacy has a limited time span before the mutants appear and liver disease reemerges, there is currently great controversy about how best to use lamivudine— pretransplant, early posttransplant, or only treatment of symptomatic disease. Hopefully, the ability to use drug combinations in the near future will make this debate irrelevant.785–802 Liver transplantation in patients with HBV infection remains a particular challenge. Without antiviral intervention, there is almost universal recurrence of infection in the allograft despite perioperative hyperimmune globulin or and there have been a number of reports of excessive mortality in the first 6 months posttransplant, and even the occurrence of de novo hepatocellular carcinoma in the transplanted liver within 4 years of successful transplantation. Evidence of active viral replication at the time of transplantation has been particularly associated with poor results in some series.749,803–809 Although fulminant HBV may occur posttransplant in these patients, the major cause of early death is sepsis, suggesting that the immunomodulating effects of this virus play an important role in the excessive early mortality.805 The Boston Center for Liver Transplantation reported a 57% 1-year and 54% 3-year survival following liver transplantation for HBV infection without anti-HBV therapy, with most of the mortality resulting from infection in the first 6 months. A particularly poor result was obtained in patients with hepatocellular carcinoma and HBV infection (their mortality in the first year was > 80%).810 The first major advance in this area came from the use of prolonged immunoprophylaxis with anti-HBs hyperimmune globulin. Whereas high doses of this therapy restricted to the anhepatic phase of the operation and immediate perioperative period were ineffective, longterm immunoprophylaxis has had a major impact.811–815 For example, Samuel et al.811 have reported on an immunoprophylaxis program in which hyperimmune globulin was administered during the anhepatic phase of the liver transplant operation, daily for 6 days thereafter, and then as needed to maintain a circulating level > 100 IU/liter of anti-HBs. During an average follow-up of 20 months, all 110 HBsAg-positive patients became seronegative posttransplant, with circulating HBsAg reappearing in 22.7%— usually, approximately 9 months posttransplant. Overall 1-year survival was 83.6%. This prophylactic program was least effective in preventing HBV reinfection in patients with postnecrotic cirrhosis caused by HBV (59%

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recurrence rate), more effective in those with combined HBV and HDV infection (13% recurrence), and was totally effective in those with fulminant hepatitis B, a population that has had fewer problems with HBV infection posttransplant in general. As in renal transplant patients, evidence of active viral replication (HBV DNA being a better marker than HBeAg) at the time of transplantation was highly predictive of HBV recurrence, a 96% rate of recurrence at 2 years. In general, HBsAg-positive patients surviving liver transplantation for more than 6 months have usually done quite well for the next 12–24 months. Although the hyperimmune globulin approach is a significant advance, there are two remaining problems with it in addition to the lack of complete efficacy: cost—$25,000/year, although newer lower dose intramuscular regimens appear to offer comparable protection against reinfection at a significantly lower cost.816 Of even greater concern is the selection of mutants with the globulin that are still pathogenetic but have changes in the surface antigen, thus obviating the effectiveness of the hyperimmune globulin approach.817–821 Underlining the difficulties of single-modality therapy, there are now reports of patients for whom sequential therapy with immune globulin and then famciclovir and lamivudine, was associated with the development of mutants resistant to each of these in turn.822,823 At present the combination of lamivudine and immune globulin appears to be the best available program for preventing reinfection of the transplanted liver with HBV.824–828 A variation on this theme is the substitution of adefovir plus immune globulin when the patient has lamivudine-resistant infection prior to liver transplantation.800 5.2.2. The Clinical Impact of HCV Infection on the Organ Transplant Recipient HCV is the major cause of NANBH in nontransplant patients, and appears to be the source of more than 80% of the progressive liver disease that occurs posttransplant.86 End-stage liver disease caused by HCV is the leading indication for liver transplantation in Europe and the United States, accounting for more than one-third of all transplants.829 In addition, chronic HCV infection, like chronic HBV infection, can result in the development of hepatocellular carcinoma.830,831 HCV is spread via parenteral contact with blood with a high degree of efficiency. Thus, HCV infection posttransfusion (accounting for approximately 90% of cases of posttransfusion hepatitis) in intravenous drug users, in healthcare workers with occupational exposure to blood, and in hemodialysis patients is well recognized. In addition, as already discussed,

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transplantation of an organ from an HCV-viremic individual is a highly efficient means of transmitting this virus. These epidemiologic risk factors account for only 50– 60% of cases of acute hepatitis C, with sporadic cases occurring in the community. It is likely that sexual transmission, albeit with a low efficiency, accounts for many of these sporadic cases.527,530,832–835 HCV appears to be the etiology only rarely of fulminant hepatitis, either sporadic or epidemic.836,837 The critical scientific step in unraveling the HCV story came when Choo et al.838 successfully cloned a portion of the genome of this virus. The expression product of this clone has been used to devise a series of increasingly refined assays for detecting antibodies to this virus, as well as establishing the basis for the development of a PCR test for HCV RNA, which is now central to patient management. Currently available information on the antibody test may be summarized as follows: The antibody response to HCV takes a relatively long time to develop, even in individuals with normal immune responsiveness. Thus, although in one study, 80% of patients with posttransfusion NANBH developed anti-HCV by ELISA assay, the mean interval between the date of transfusion and anti-HCV seroconversion was 18 weeks; 61% of patients seroconverted within 15 weeks of transfusion, about 90% by 26 weeks, and one patient not until 12 months posttransfusion. In transplant patients, the development of the anti-HCV response is even more attenuated, with the degree of attenuation being proportional to the intensity of the immunosuppressive therapy being administered. Thus, anti-HCV testing would underestimate the presence of HCV infection among transplant patients. Consistent with the relatively weak immunizing effect of HCV are studies in chimpanzees suggesting that rechallenge with infectious virus, with either homologous or heterologous strains, had a high rate of reinfection—an observation of great potential importance for transplantation. 86,839–846 In the general population, more than 50% of individuals with acute HCV infection develop chronic infection, with the course of the illness being extremely protracted in the majority (20–40 years). Approximately 20% develop serious end-stage liver disease and/or hepatocellular carcinoma as a consequence of the chronic HCV replication, with hepatocellular carcinoma being uncommon.847 As with many infections in transplant patients, clinical consequences of HCV posttransplant are more common and occur over a shorter time span. LaQuaglia et al.848 reported on the basis of studies in a renal transplant population from the precyclosporine era that more than 80% of individuals who develop liver function

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test abnormalities suggestive of NANBH maintain such abnormalities indefinitely. In the first 1–2 years posttransplant, acute clinical hepatitis caused by NANBH is quite unusual, and the major impact of such a process has been as an important contributor to the net state of immunosuppression as manifested by both an increased incidence of infection and an increased allograft survival. Beginning 3–5 years after renal transplantation, progressive liver disease begins to present in these patients, often culminating in all of the manifestations of end-stage liver disease. In renal transplant recipients, patients with chronic HCV infection have a similar mortality to those who are not infected for the first decade, but with a significantly increased mortality over the second decade (20-year survival for the HCV group, 63.9% versus 87.9% for the uninfected). As previously noted, both the incidence and the rate of progression of HBV-induced liver disease are greater than those for NANBH. However, because the incidence of NANBH is so very much higher, the net result is that more cases of serious liver disease are caused by NANBH in transplant patients than by HBV.86,747,849–853 On the other hand, it would appear that patients with chronic HCV infection and end-stage renal disease fare better with renal transplantation than with dialysis. However, biopsy is recommended pretransplant to rule out significant cirrhosis and to determine the need for antiviral therapy (vide infra). It is of interest that the combination of HBV and HCV appears to have a greater clinical impact than either of the viruses by themselves. On the other hand, the so-called hepatitis G virus has no impact on the course of patients with HCV infection (see Chapter l2).850,854–858 In liver transplant recipients who come to liver transplantation with HCV infection, reinfection of the allograft is the rule, with the source of the infection being HCVinfected peripheral blood mononuclear cells.86,859,860 The consequences of HCV reinfection are controversial, with the incidence of adverse events being in part determined by the presence or absence of a variety of risk factors (vide infra) and, even more importantly, the duration of time over which these consequences are being assessed. In general, even up to 10 years, there is no effect of HCV reinfection on mortality following liver transplantation.861 However, the following data from different series do suggest the potential for considerable morbidity: 42% of patients with recurrent HCV infection developed chronic hepatitis, with 25% of these going on to cirrhosis862; the King’s College group reported that at 5 years, 20% of those transplanted for end-stage liver disease due to HCV had cirrhosis.863

A number of risk factors have been defined that are correlated with an increased morbidity and mortality from HCV reinfection, as well as with a shorter time course to end-stage liver disease. These include the following: viral load—the higher the viral load the greater the risk and the more accelerated the course; intensity of immunosuppression—in particular, higher doses (as pulse doses for acute rejection) and more sustained courses of corticosteroids, OKT3 therapy, and, perhaps, mycophenolate mofetil use have been correlated with marked increases in HCV viral load; allograft rejection—probably by two mechanisms: cytokines, chemokines, and growth factors produced in the rejection process will increase the level of circulating virus; and the increased immunosuppression required to treat the rejection will likely amplify the virus (a common error is to pare back immunosuppression so intensively that rejection is produced, thus leading to higher viral loads and an acceleration of the HCV infection far greater than if adequate immunosuppression had been provided); HCV genotype—genotype 1b infection has been associated with higher viral loads, a more accelerated course, and a poorer response to interferon-based treatment regimens; the presence of quasispecies—the greater the heterogeneity in the HCV population present, the greater difficulty the host has in containing the infection; CMV viremia—a risk factor for allograft cirrhosis after liver transplantation for hepatitis C (conversely, active HCV can trigger CMV disease; a bidirectional relationship between these two viruses mediated by cytokines and chemokines elaborated by the host in response to these infections); iron overload—iron overload decreases the host’s cytotoxic T cell response against the virus, thus amplifying the level of virus; donor and recipient class II HLA matching—appears to promote reinfection and allograft injury; and donor tumor necrosis factor gene—the donor promoter genotype may influence the inflammatory response to HCV infection of the graft and the extent of subsequent allograft injury.864–879 In addition to chronic active hepatitis and allograft cirrhosis, there are two relatively uncommon complications of HCV infection that can have devastating consequences for the transplant patient. The first of these is fibrosing cholestatic hepatitis. First described in patients with HBV infection and immunodeficiency (vide supra), this is a syndrome in which there are high levels of circulating HCV, rapidly progressive hepatic failure, mildly elevated serum aminotransferase level, an extensive periportal fibrosis, intense cholestasis, minimal inflammatory infiltrate, and no cirrhosis. The hepatocytes themselves are literally choked with exceedingly high

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levels of HCV which results in direct hepatocyte injury. This diagnosis requires immediate decrease in immunosuppression and the initiation of the best available antiviral therapy (vide infra).880–882 The second of these complications is glomerulonephritis, which can occur in both the general population with HCV infection, as well as the transplant recipient. Indeed, patients have been reported with severe nephrotic syndrome due to HCV, who improved with liver transplantation, and then relapsed when significant reinfection developed in the allograft. The most common form of this is membranoproliferative glomerulonephritis with or without mixed cryoglobulinemia. This is an immune complex-mediated condition, and, not surprisingly, other laboratory abnormalities commonly demonstrated include rheumatoid factor and hypocomplementemia. Of interest, a patient has been reported who developed fibrosing cholestatic hepatitis with cryoglobulinemia and a severe systemic vasculitis. A second form of glomerular disease reported in association with HCV is membranous glomerulonephritis. Other less common conditions linked to HCV are acute and chronic transplant glomerulopathy and thrombotic microangiopathy with anticardiolipin antibody. Management of these complications of HCV replication is difficult, and is focused on antiviral therapy directed against the HCV infection and supportive care of the renal disease.883–889 HCV infection has a considerable effect on the wellbeing and quality of life of patients following transplantation, particularly liver transplantation. At present, because of the availability of lamivudine and anti-HBs immune globulin, patients with HBV infection have less depression and an improved quality of life compared with those with HCV infection.890–893 The first principle of managing HCV infection is to attempt to decrease immunosuppressive therapy and to treat such other conditions as CMV infection. and ribavirin individually have some activity against the virus. However, when combined, there is synergistic benefit, with ~50% of patients developing a meaningful response to such therapy. It must be emphasized, however, that these drugs have considerable side effects (interferon—fever, malaise, bone marrow dysfunction, and risk of rejection; ribavirin—hemolytic anemia), and new drugs are badly needed. The first of the new drugs will be pegolated versions of which permit weekly (as opposed to thrice weekly or more frequent injections) administration, have increased efficacy over the standard formulations, and have a similar adverse effect profile. In general, patients are more likely to respond, the lower the viral load.800,894–900

Illustrative Case 6 A 52-year-old woman with end-stage renal disease resulting from polycystic kidney disease underwent bilateral nephrectomy and cadaveric renal transplantation. Posttransplant, she had no clinical episodes of rejection, and by 1 year posttransplant, she had a serum creatinine of 0.7 mg/dl while being immunosuppressed with azathioprine 100 mg/day and prednisone 30 mg every other day. During the first year posttransplant, despite minimal immunosuppression and the absence of CMV infection, she had had bouts of Listeria sepsis, invasive pulmonary aspergillosis, and gram-negative sepsis caused by a perforated sigmoid diverticulum. The latter condition was treated surgically. Her liver function tests, which had been normal prior to transplant, began to show an SGOT level more than twice normal (without other abnormalities) by the third month posttransplant. Over the next 5 years, her renal function remained excellent on the same immunosuppressive program. Her SGOT remained elevated at this same level (two to four times normal) as well. Percutaneous liver biopsy performed 2 years posttransplant revealed minimal changes of chronic persistent hepatitis. Substitution of cyclophosphamide for azathioprine had no effect on her SGOT level, and the azathioprine was restarted. Six years posttransplant, after a 2-month history of progressively increasing abdominal girth and edema, she presented with fever, rigors, and increasing abdominal pain. A diagnosis of E. coli peritonitis, with positive ascites and blood cultures, was made. Despite therapy with high-dose intravenous ampicillin and gentamicin (to which the organism was sensitive), as well as stress doses of steroids, the patient died on the second hospital day. At autopsy, far-advanced cirrhosis with esophageal varices and evidence of spontaneous bacterial peritonitis were noted. All tests for HBV were negative. The transplanted kidney appeared totally normal grossly and microscopically. Retrospective studies of stored sera revealed the following: the patient was anti-HCV negative pretransplant and throughout her posttransplant course; the patient was HCV RNA negative prior to transplant, and became positive, remaining so for the rest of her life, approximately 3 months posttransplant; the donor was anti-HCV and HCV RNA positive. Comment. A tragic instance of chronic HCV infection, acquired from the donor at the time of transplantation, marred the course of an otherwise successful renal transplant. In the first year posttransplant, there were three notable events: several episodes of life-threatening extrahepatic infection, no rejection on minimal immunosuppression, and the development of mild elevations of the serum transaminase level. The first two of these presumably represent the contribution of HCV infection to the net state of immunosuppression. The “transaminitis” remained constant over the next 6 years and appeared to be of little consequence, particularly in view of the “benign” liver biopsy 2 years posttransplant. She then presented 6 years posttransplant with faradvanced cirrhosis and portal hypertension, and acute, spontaneous bacterial peritonitis that caused her death. This form of disease must be prevented.

5.3. HIV Infection in the Organ Transplant Recipient Transplantation of an organ from an HIV-infected donor into an uninfected recipient is an extremely effective mechanism for transmitting the virus, with a trans-

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mission efficiency that approaches 100%. Indeed, the transplantation literature of the 1980s was replete with the whole gamut of clinical effects caused by HIV in this patient population: asymptomatic infection, mononucleosis, AIDS-related complex, recurrent opportunistic infection, Kaposi’s sarcoma, and transmission of the virus to a spouse. With currently available techniques for screening prospective donors, virtually all transmission of the virus at the time of transplantation should be blocked.901–904 Having emphasized that appropriate screening of blood and organ donors for HIV positivity will significantly block the development of primary HIV infection posttransplant, it is only fair to state that HIV has been transmitted by an allograft from a donor who was seronegative for HIV by conventional testing (for antibody to HIV) but still harbored the virus. Presumably, such a donor is in the so-called “window period” when replicating virus is present but an antibody response has not yet appeared.112 Studies in which PCR techniques have been used have shown that, in certain high-risk individuals, antibody-negative HIV infection that is transmissible can be present for several months.112,113,903,904 Therefore, in addition to antibody screening, we would not, under normal circumstances, accept a donor with epidemiologic risk factors for HIV infection such as history of homosexual or bisexual behavior, history of intravenous drug abuse, hemophilia, promiscuous sexual history, incarceration in prisons with a high incidence of HIV, and so on. In such exceptional circumstances as a living related donor with one of these risk factors, PCR or viral culture techniques should be carried out in addition to routine antibody testing.113 When primary HIV infection is acquired posttransplant, it not uncommonly produces a mononucleosis syndrome, akin to that produced by CMV or EBV, approximately 6 weeks posttransplant. Most transplant patients seroconvert within weeks of this event, although we have reported a patient who remained HIV antibody negative for approximately 3 years posttransplant, until he developed rapidly progressive AIDS. The mean time to the development of overt AIDS in patients who acquire primary HIV infection at the time of transplant has been approximately 3 years.113,901–904 A far bigger issue than primary HIV infection posttransplant is the optimal management of patients with asymptomatic HIV infection who present with end-stage renal, hepatic, cardiac, or lung disease, and who otherwise would be deemed satisfactory transplant candidates. Currently available information suggests that HIV-positive individuals undergoing organ transplantation without highly active antiretroviral therapy (HAART) can be di-

vided into three approximately equal groups in terms of clinical outcome: one third do very poorly, dying within 6 months of transplantation, primarily of infection; one third do very well, and are alive with a functioning allograft 5–7 years later; and one third have an intermediate result, developing clinical AIDS with a rapid downhill course 2–4 years posttransplant.113,904–906 Over the past two decades, it has been the general practice of virtually all transplant centers to exclude HIVpositive individuals from receiving an organ transplant. With the great success of HAART therapy, the prognosis for HIV-infected individuals has been changed markedly (see Chapter 12), and cautious efforts are being initiated to reopen this question. There are a number of hurdles to be overcome before this can become a routine step: drug interactions between anti-HIV drugs and the calcineurin inhibitors require careful attention; optimal dosimetry of both the immunosuppressive drugs and the AIDS drugs will need to be defined; and the ethical issues of the appropriate allocation of allografts will need to be carefully examined. Having said that, it would appear that cautious efforts for proceeding in this area are reasonable.905–910 We have established the following criteria for proceeding in this area at the present time:

1. In general, we would restrict our transplant efforts in HIV-infected individuals to instances in which the organ is required to maintain life— hearts, livers, lungs, and kidneys only when dialysis is no longer an option. All such efforts should be regarded as clinical research requiring Human Studies Committee approval and Informed Consent. 2. Transplantation of HIV-infected individuals should only be carried out at centers with great expertise in both transplantation and HIV infection, and where these skills can be brought to bear in the day-to-day care of the patient. 3. HIV-infected patients accepted for transplantation should be on a stable HAART regimen, known to be compliant, and to have undetectable HIV viral loads. 4. HIV-infected patients accepted for transplantation should have no other contraindications for transplant, be well nourished, have a CD4 count and have been free of infection for The report of the rapid development of a myelopathy after the transmission of HTLV-1 infection via a transfusion during heart transplantation emphasizes the care that must be taken to prevent the transmission of infection

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with the allograft or with blood.911 In the present context, this case reminds us that in addition to screening for HIV-1, such other retroviruses as HIV-2, HTLV-1, and, probably, HTLV-2 should be part of the screening of potential donors.911–913 5.4. The Clinical Impact of Papovaviruses in the Organ Transplant Recipient The papovaviruses are DNA viruses comprising two genera, the polyomaviruses and the papillomaviruses. The human polyomaviruses BK virus (BKV) and JC virus (JCV) infect most normal individuals during childhood, apparently without demonstrable clinical illness.914–916 These agents are of interest for several reasons: immunosuppression results in the excretion of these agents and/or a specific antibody rise in the majority of transplant patients; BKV, JCV, and simian virus 40 (SV40) are closely related both antigenically and structurally; JCV is the cause of progressive multifocal leukoencephalopathy, a subacute, progressive demyelinating disease of the CNS; BKV is an increasingly important cause of interstitial nephritis in renal transplant patients; and all three agents are at least potentially oncogenic.917–932 BKV was first isolated by Gardner and colleagues in 1971 from the urine of a renal transplant patient 3 months posttransplant who presented with a ureteral stricture during an apparent rejection episode.917 Since then, additional cases linking ureteral strictures and urinary papovavirus have been reported in renal transplant recipients.915,917–919,921–924 Far more important has been the recognition of BKV as a not uncommon cause of progressive interstitial nephritis (an incidence as high as 5%, although evidence of asymptomatic BKV replication can be found in some 40% of renal transplant recipients). Renal biopsies from patients with kidney infection reveal the following: viral cytopathic changes (nuclear atypia, smudging, and inclusions), with necrosis and particular involvement of the tubular epithelium, and a dense, inflammatory infiltrate that can contain numerous plasma cells. Differential diagnosis considerations include calcineurin inhibitor toxicity and severe rejection. Definitive diagnosis can be made with immunoperoxidase staining with a monoclonal antibody specific for BKV, or electron microscopy of ultrathin sections from the biopsy. Patients’ urine can be screened for BKV by cytologic examination (cytological evidence of BKV replication is made by the identification of so-called decoy cells, which contain intranuclear inclusions typical for polyomavirus) or by electron microscopic examination of negatively stained urine specimens. Negative results of a urine screen essen-

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tially rule out BKV interstitial nephritis. Positive results, in the face of renal dysfunction, necessitate a biopsy for definitive diagnosis, as asymptomatic urinary shedding of BKV in the face of rejection is not uncommon.929–932 BKV interstitial nephritis is being recognized with increasing frequency. It has been associated with intense immunosuppression (particularly regimens that include tacrolimus ± mycophenolate) and significant rejection episodes. It has been suggested that damage to the tubular epithelium by rejection plays a role in the severe tubulointerstitial nephritis that develops. BKV nephritis has a poor prognosis, with progressive renal dysfunction being the rule. There is currently no antiviral drug effective for this entity. Increased immunosuppression will accelerate the process; decreased immunosuppression has been reported, in some patients, to be associated with an amelioration of the process. Practically, there is often difficulty in ruling out concomitant rejection as the immunosuppression is being tapered, with serial biopsies being necessary in the management of these patients.929–932 JCV was first isolated from the brain of a 38-yearold man with progressive multifocal leukoencephalopathy (PML),933 and since then has been shown to be the cause of this illness (a demyelinating disease of the white matter of the brain, characterized by the development of progressive motor and sensory deficits, dementia, and death within 3-6 months). As with BKV, there is no known treatment, although decreased immunosuppression is strongly recommended. Polyomavirus infection has also been linked to pancreatic disease in the transplant recipient.917–933 Papillomavirus infection in transplant patients is of significance for several reasons: The most common manifestation in this population, as it is in the general population, is the production of warts. In the transplant patient warts may be so numerous as to be disfiguring, with the incidence and severity of warts in these patients being directly proportional to the intensity of the immunosuppressive therapy being prescribed. Such therapy appears to reactivate latent virus posttransplant. The significance of the warts goes beyond the cosmetic, however, as malignant transformation, particularly in sun-exposed areas, has been well documented. Human papillomavirus DNA has been demonstrated in the skin cancers of these patients, and it is likely that such cancers arise as a result of the combined effects of the virus, immunosuppression, and ultraviolet irradiation.934–940 A particular subgroup of papillomaviruses, the epidermodysplasia verruciformis associated types, has been linked to the pathogenesis of cutaneous and anogenital squamous cell carcinomas in these patients, as well as to the presence of certain kera-

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totic skin lesions that presumably represent premalignant lesions.941–944 Cervical papillomavirus, likewise, is more extensive in transplant recipients, is similarly modulated by the intensity of immunosuppressive therapy, and has been linked to the pathogenesis of cervical cancer in both the general population and among transplant patients. Such cancers are significantly increased in this patient population, commensurate with the increase in papillomavirus infection that is present at this site.945,946 5.5. Urinary Tract Infection in the Renal Transplant Patient The most common form of bacterial infection affecting renal transplant recipients is urinary tract infection (UTI). The incidence of UTI in patients not receiving antimicrobial prophylaxis has been reported to vary from 35 to 79% in different series.947–952 In addition, approximately 60% of the bacteremias observed in transplant patients have traditionally originated from this site.953,954 The pathogenesis of such infections is only partially understood. In the earlier days of transplantation, UTI was particularly associated with two factors: technical complications associated with the ureteral anastomosis and UTI present prior to transplantation. Despite improvements in surgical techniques and the removal of native kidneys that were thought to be possibly harboring infection, the attack rate remained in the 35–45% range.952,955 The three major factors leading to this high incidence of posttransplant UTI appear to be the postoperative urinary catheter, the physical and immunologic trauma that the kidney suffers, and the immunosuppressive therapy that is administered. Now that bladder catheters are routinely removed 1–4 days posttransplant, it is unusual for overt infection to be documented while the catheter is still in place. However, the catheter tips not infrequently become contaminated, and provide a reservoir from which infection is derived. In animal models, the combination of bacteria inoculated into the bladder and trauma to the kidney will result in pyelonephritis, whereas bladder infection without renal trauma results only in a transient cystitis. It is logical that the kidney harvesting, transport, and then transplantation cause significant trauma to this organ, making it more susceptible to bacterial invasion—a susceptibility that is presumably exacerbated by the exogenous immunosuppressive therapy.27,956–960

UTI occurring in the first 3 months posttransplant is frequently associated with overt pyelonephritis, bacteremia (with even transient urosepsis having the potential

for metastatic seeding in this patient population), and a high rate of relapse when treated with a conventional course of antibiotics. In contrast, UTI occurring at a later time is usually benign, can be managed with a conventional 10- to 14-day course of antibiotics, uncommonly is associated with a bacteremia or requires hospitalization, and has an excellent prognosis. Exceptions to this general pattern should be evaluated for such functional or anatomical abnormalities of the urinary tract as a stone, obstructive uropathy, or a poorly functioning bladder.952,960 The potential consequences of UTI and urosepsis in the renal transplant patient go beyond the direct infectious disease effects of the infection. It is now apparent that proinflammatory cytokines such as TNF, IL-1, IL-6, and others are released locally and systemically in response to bacterial invasion of the urinary tract.762,763 As earlier discussed, this same array of cytokines is involved in two other processes of great importance in the transplant patient: allograft rejection and the reactivation from latency of CMV and other herpesviruses. Thus, clinically, it is not uncommon to see two events in the setting of transplant pyelonephritis, namely, measurable renal dysfunction and clinical CMV disease. The latter we refer to as “a second wave phenomenon,” that is, 10–21 days after a febrile illness caused by UTI (and after a clinical response to effective antimicrobial therapy) fever reappears with demonstrable CMV viremia. Not surprisingly, then, a great deal of effort has been expended in the prevention of UTI, with such significant progress that UTI and urosepsis have been largely eliminated in the transplant patient with the use of antibacterial prophylaxis. Trimethoprim–sulfamethoxazole (we use a dose of one single-strength tablet at bedtime, others use higher doses), trimethoprim, and ciprofloxacin (and presumably other fluoroquinolones) will all decrease the incidence of UTI to less than 10%, with the eradication of urosepsis unless obstruction to urine flow is present.961–964 At this low dose of trimethoprim–sulfamethoxazole, nephrotoxicity caused by interactions with cyclosporine does not occur, although such other toxicities of trimethoprim–sulfamethoxazole as rash, Stevens–Johnson syndrome, bone marrow toxicity, and, rarely, interstitial nephritis can occur in these patients as well as the general population.963,964 An additional benefit of trimethoprim– sulfamethoxazole prophylaxis is that it also provides significant protection against P. carinii pneumonia, Nocardia asteroides infection, sepsis caused by L. monocytogenes, and, probably, toxoplasmosis.27,963,964 It is for this “extra protection” that we routinely utilize low-dose trimethoprim–sulfamethoxazole prophylaxis in the extrarenal transplant recipients as well. In a study comparing

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ciprofloxacin with trimethoprim–sulfamethoxazole for UTI prophylaxis in renal transplant recipients, ciprofloxacin was equal or superior to the standard regimen in terms of preventing UTI and in its side effect profile. However, 10% of the patients receiving ciprofloxacin developed P. carinii pneumonia, versus none of the patients receiving trimethoprim–sulfamethoxazole.964 Therefore, our current practice is to utilize trimethoprim–sulfamethoxazole as our standard prophylaxis if the patient tolerates it; if some other regimen is necessary, we will combine ciprofloxacin with an alternative anli-Pneumocystis regimen, such as atavoquone. One additional form of UTI that bears mention here is that relating to Candida species. Although asymptomatic candiduria is frequently also observed in the general population, in the renal transplant patient it can be particularly dangerous because of the potential for developing obstructing candidal fungal balls. This occurs most commonly in diabetic patients with poorly functioning bladders. Once such candidal fungal balls develop, ascending candidal pyelonephritis and candidal sepsis will ensue. For this reason, we preemptively treat even asymptomatic candiduria, preferably with fluconazole, or with low-dose amphotericin plus flucytosine if this fails.27

6. Infection in Organ Transplant Patients More Than 6 Months Posttransplant One of the measures of the increasing success of organ transplantation in recent years is the fact that investigators are now looking at long-term survival and complications, rather than the 1-year statistics that have been standard for so long. As previously described, the patients who have had a good result from their transplant are primarily at risk for the usual community-acquired infections, particularly the respiratory viruses; in contrast, the “chronic n’er-do-wells” (patients who have received too much acute and chronic immunosuppression in an effort to salvage the allograft) are at special risk for the opportunistic bacteria (Listeria monocytogenes and Nocardia asteroides) and fungi (Cryptococcus neoformans and Aspergillus fumigatus in particular).3,8,27 6.1. Community-Acquired Respiratory Virus Infection in Organ Transplant Recipients Respiratory virus infection circulating in the community can have a special impact on transplant recipients. Thus, during influenza epidemics, we have noted patients admitted with complications of influenza ranging from

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malaise, fever, and dehydration, to respiratory failure relating to influenza pneumonia, or complicating bacterial pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and gramnegative bacilli. Although precise information on this subject is not available, we have the impression that complications of influenza are more common in this patient population. Trials of influenza vaccine in renal transplant patients have shown a lack of toxicity or adverse effects, but a disappointing level of efficacy. At present, there is no available information on the efficacy, side effects, or potential for cyclosporine interaction with amantadine prophylaxis in transplant patients. A high priority should be given to garnering this information.8,965 Respiratory syncytial virus (RSV) infection of a particularly virulent nature, causing an increased rate of pneumonia and mortality, has been reported in children following organ transplantation, particularly liver transplantation. In addition, we have documented RSV infection on lung biopsy of adult transplant patients with acute respiratory failure. Others have diagnosed RSV on bronchoalveolar lavage specimens from similar patients. Since aerosolized ribavirin therapy may have therapeutic efficacy for this infection, the possibility of RSV infection should be considered even in adult transplant patients with otherwise unexplained pneumonia.5,23–25,966–968 Adenoviruses not uncommonly infect the general population, producing asymptomatic disease or clinical illnesses such as upper and lower respiratory tract infection, conjunctivitis, and hemorrhagic cystitis. These viruses appear to have a particular propensity for causing disease in transplant patients: Diffuse interstitial pneumonia has been documented to occur by means of adenoviruses (types 34 and 35) previously not recognized; epidemic disease in a particular transplant population has been well documented; infection of the liver, lung, and GI tract by adenoviruses has been reported among pediatric liver transplant patients, with a mortality rate of 45%; and, finally, both tubulointerstitial nephritis and hemorrhagic cystitis have been documented to occur. The possibility that one or more of these adenoviruses could be oncogenic in this patient population is also worthy of investigation.5,26–28,969–978 Other community-acquired respiratory viruses reported to cause serious respiratory disease in the transplant patient include rhinoviruses and parainfluenza virus.23,24,29 There are two general messages here: Transplant patients have a greater rate of complications from respiratory virus infection than do immunologically normal individuals, and it is worth a special effort to isolate them from such exposures, even in the late posttransplant period.

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7. Infectious Disease Problems of Particular Importance in the Organ Transplant Patient 7.1. CNS Infection in the Organ Transplant Patient Infection of the CNS is a significant cause of morbidity and mortality in the organ transplant patient, with an incidence of approximately 5%. Although the subject of CNS infection in the immunosuppressed patient is reviewed in more detail in Chapter 5, several points of particular emphasis in the transplant patient bear emphasis here. Four distinct patterns of infection may be observed in this population: (1) acute to subacute meningitis, almost invariably caused by Listeria monocytogenes, by far the most frequent cause of bacterial CNS infection in the organ transplant recipient; (2) subacute to chronic meningitis, usually caused by Cryptococcus neoformans, although such organisms as Mycobacterium tuberculosis and Coccidioides immitis can cause an identical clinical syndrome (subacute onset of fever and headache, sometimes associated with a decreased state of consciousness, with a lymphocytic pleocytosis and hypoglycorrhachia on CSF examination), and should be seriously considered if the appropriate epidemiologic history is obtained; (3) focal brain infection causing focal neurologic disturbances, which is occasionally caused by Listeria, Toxoplasma, Cryptococcus, Nocardia, or HHV-6, but is most commonly related to Aspergillus infection metastatic from a site of active pulmonary infection; and (4) progressive dementia resulting from progressive multifocal leukoencephalopathy, caused by the polyomavirus JCV. Together, Listeria, Cryptococcus, and Aspergillus account for more than three-fourths of the CNS infections occurring in the organ transplant patient.348,349,979,980 Each of these infections tends to occur at a particular time period posttransplant. The first month posttransplant is relatively free of CNS infection, unless an unusual epidemiologic exposure has occurred. Indeed, the major causes of CNS symptomatology in this time period are seizures secondary to cyclosporine, particularly the intravenous formulation, a severe OKT3 reaction (which can, not uncommonly, produce an aseptic meningitis picture), metabolic encephalopathy (especially in liver transplant patients with a poorly functioning allograft), cyclosporineor tacrolimus-induced leukoencephalopathy, and a stroke (particularly in diabetics or in heart transplant patients with a poorly functioning allograft).27,348,349,966,979–983 If one then divides the time intervals into an early period 1–4 months posttransplant (corresponding to the period of maximal net immunosuppression relating to the combination of viral infection and sustained immunosup-

pression) and a later period, the following observations can be made: Listeria, Nocardia, Toxoplasma, and Aspergillus infection occur both in the early period and in the late period among the patients with failing allografts who have been intensively immunosuppressed (“the chronic ne’er-do-wells”). In contrast, cryptococcal infection is virtually always a late infection, again particularly in the chronic ne’er-do-wells.3,27,348,349,979–981 In the face of trimethoprim–sulfamethoxazole prophylaxis, Listeria and nocardial infection, and possibly Toxoplasma infection, are effectively prevented. The issue of Toxoplasma infection is not completely settled, as there is conflicting information available on the efficacy of trimethoprim–sulfamethoxazole against this infection.980 In the setting of noncardiac organ transplantation, toxoplasmosis has not been a significant problem, and it is likely that trimethoprim–sulfamethoxazole provides adequate protection. In the special case of cardiac transplantation when the donor is seropositive and the recipient is seronegative, disseminated toxoplasmosis, with particular impact on the heart and the CNS, is a major problem (occurring in 10–20% of cardiac transplant patients, and an estimated 50% at risk of primary infection); current practice is to actively prophylax with pyrimethamine and sulfonamide, and not rely on trimethoprim–sulfamethoxazole. This regimen also supplies anti-Pneumocystis and antinocardial prophylaxis.984–993 It is important to emphasize that the presentation of CNS infection in the organ transplant patient may be very different from that in the normal host. In particular, the anti-inflammatory effects of the immunosuppressive therapy being administered may obscure the signs of meningeal irritation usually associated with meningitis in the normal patient. For example, in the Massachusetts General Hospital experience, only 60% of patients with Listeria meningitis had any evidence of meningeal irritation on physical examination, and, in many of these, the findings were subtle. Mild alterations in the state of consciousness were observed in 70% of patients; however, the most reliable combination of clinical findings for suggesting the possibility of significant CNS infection is the presence of fever and headache.348,349,980,994 Any transplant patient with an unexplained headache, especially if febrile, should undergo careful neurologic examination. If there is no evidence of papilledema or focal neurologic deficit, an immediate lumbar puncture should be carried out. If papilledema, focal neurologic deficit, or decreased state of consciousness is present, an immediate CT scan should be performed prior to the lumbar puncture. Magnetic resonance imaging (MRI) should be considered in the patient with spinal cord findings, the

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patient with focal neurologic findings or unexplained decreased mental status, and the patient with an abnormal CSF formula without an etiologic explanation—even in the face of a negative CT scan. The MRI scan is more sensitive than the CT, although more nonspecific findings may be observed. The CSF obtained at lumbar puncture should undergo the following evaluation: cell count, protein and sugar determinations, Gram’s stain, acid-fast and fungal stains, fungal, mycobacterial, and bacterial cultures, and cryptococcal antigen testing. In addition, it is wise to save 2 ml of CSF for any later special studies (e.g., Histoplasma capsulatum or Coccidioides immitis antibody titers).348,349,980,994 7.1.1. Listeria monocytogenes Infection in the Organ Transplant Recipient

L. monocytogenes is a gram-positive bacillus that can produce a variety of clinical syndromes, the most important of which in the immunocompromised patient are bacteremia alone, meningitis, meningoencephalitis, and cerebritis without concomitant meningitis.347,980,981,994–998 When parenchymal seeding of the brain occurs, Listeria has a particular propensity for involving the brain stem, causing a clinical syndrome akin to bulbar polio.980,994,999 In addition, it has been reported to cause myocarditis in the cardiac transplant patient.1000 In nonimmunosuppressed patients, Listeria is a well-recognized cause of bacterial endocarditis, and transplant patients should be assumed to be at comparable risk (i.e., transient Listeria bacteremia can seed abnormal heart valves). The portal of entry for Listeria is the GI tract, and, indeed, it is not uncommon for transplant patients with Listeria sepsis to report cramps and diarrhea as the initial manifestations of their infection.348,980,994,1001 The Listeria gene that mediates penetration of the gut epithelial cells has been identified (it encodes internalin, a leucine-rich protein). Whether it or another protein is responsible for the remarkable CNS tropism of this organism remains to be determined.1002 Traditionally, listeriosis has been classified as a zoonosis, and, indeed, contact with animals and animal manure can result in human infection. However, for most patients, listeriosis is transmitted via contaminated food, particularly milk and cheeses, undercooked chicken and other meats, and uncooked vegetables (particularly ones grown in a manure fertilizer, as in a large epidemic in Canada in 1981, traceable to cole slaw from a farm that used sheep manure as fertilizer, with listeriosis having been documented in these sheep).1003 In recent years, outbreaks of listeriosis have been particularly associated with mass-produced and distributed hot dogs and sau-

sages. In these instances, it is apparent that contamination of the machinery used to produce these foods greatly amplifies the epidemic risk. It is important for the clinician caring for transplant patients to be aware that the bacteriology laboratory may mistakenly identify this organism initially as a diphtheroid, as a Bacillus species, or even as Streptococcus pneumoniae, when it is first isolated from a blood or CSF culture. In the context of a transplant patient, all such initial readings should be followed by further evaluation to rule out Listeria, with appropriate therapy instituted while this further evaluation is being carried out.348,349,980 All patients with documented Listeria bacteremia should undergo lumbar puncture to assess the possibility of CNS seeding. Even if the lumbar puncture is negative, the assumption should be made that subclinical CNS seeding has occurred. Watson et al.l004 reported relapse of listerial infection with cerebritis in patients treated previously with a 10- to 14-day course of intravenous penicillin for documented bacteremia without, initially, evidence of CNS seeding. Both Watson’s group and our own have observed a similar phenomenon in patients treated for 2 weeks for meningitis. Because of this pattern of relapse, we prefer to treat for at least 3 weeks with meningeal doses of antibiotics for documented listerial infection whether or not CNS involvement is initially documented. In addition, reinfection with separate episodes of listerial sepsis has been reported in transplant patients, presumably because of the effects of immunosuppressive therapy.1005,1006 Optimal antimicrobial therapy remains somewhat unclear. In nonallergic patients, penicillin or ampicillin in meningeal doses is the mainstay of therapy. In the transplant patient with varying degrees of renal dysfunction, we prefer to use ampicillin, because the alternate hepatobiliary route of excretion will prevent toxic accumulation of the drug while allowing full dosages to be used, ensuring that adequate therapeutic levels are reached.348,349,980 In the laboratory, the combination of penicillin or ampicillin and an aminoglycoside leads to synergistic killing of the organism analogous to what is observed with enterococci.1007 Whether this is clinically important is as yet unknown. Our practice is to combine ampicillin at a dose of 1.5–2.0 g intravenously every 4 hr with gentamicin at full therapeutic doses for the level of renal function present for the first 7 days of treatment and then finish the course of therapy with ampicillin alone. In penicillinallergic patients, alternative therapy is usually employed. Although tetracycline, erythromycin, and chloramphenicol have all been suggested as possible alternatives in the penicillin-allergic patient, use of these bacteriostatic anti-

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biotics in the treatment of systemic listeriosis has failed in a number of instances. In the past, we have preferred to desensitize penicillin-allergic patients with Listeria sepsis and/or meningitis and have used this approach successfully in a total of five patients with meningitis. With the clear-cut demonstration that trimethoprim–sulfamethoxazole can be successfully used in the treatment of lifethreatening Listeria infection, we now would regard this as the preferred regimen in penicillin-allergic patients, reserving penicillin desensitization for the patient who cannot tolerate this drug as well.1008,1009

Illustrative Case 7 A 47-year-old man had undergone cardiac transplantation 8 months previously for congestive cardiomyopathy. His posttransplant course had been marked by recurrent rejection requiring repetitive pulse doses of steroids, as well as courses of antithymocyte globulin and OKT3. He received preemptive ganciclovir therapy to prevent viral infection during these antirejection treatments, as well as prophylactic trimethoprim– sulfamethoxazole for 6 months posttransplant. Because of continuing rejection activity, he had received high-dose steroids 1 month before, and he was placed on a tacrolimus, mycophenolate, and prednisone regimen instead of cyclosporine, azathioprine, and prednisone. The patient lived in rural Vermont on a working farm, although he himself had not been strong enough to work for some time. The patient entered now with a 3-day illness characterized by abdominal cramps and diarrhea, fever and chills, and increasing headache. On physical examination, his temperature was 103.2°F, pulse 110, respiratory rate 22. He was a moderately ill-appearing man without nuchal rigidity or photophobia. Both the general physical examination and neurologic examination were within normal limits. CT scan was negative, but lumbar puncture revealed an opening pressure of 240 mm 140 leukocytes (98% polys), protein 78 mg/dl, and sugar of 34 (peripheral blood sugar 69). Blood and CSF cryptococcal antigen were negative. Both blood and CSF grew Listeria monocytogenes. The patient was treated for 3 weeks with intravenous antibiotics: 2 g of ampicillin IV every 4 hr plus gentamicin, 80 mg IV every 8 hr for 1 week, and then with the ampicillin alone for an additional 2 weeks. He was markedly improved within 48 hr of initiating therapy, and was afebrile by the fifth hospital day. The patient made a complete recovery. Comment. This is a classical case of systemic listeriosis, with CNS seeding, occurring 8 months posttransplant in a cardiac transplant patient who could be characterized as a “ne’er-do-well.” His clinical presentation of a GI prodrome, and then the subacute onset of a febrile headache syndrome is characteristic of this infection. The epidemiologic history is probably relevant. The patient’s response to intensive antimicrobial therapy was indeed gratifying. However, in the best of all possible worlds, this infection should have been prevented. As a “chronic ne’er-do-well,” the patient should have been maintained on low-dose trimethoprim–sulfamethoxazole indefinitely. It is highly likely that this approach would have prevented this serious infection (vide supra).

7.1.2. Cryptococcus neoformans Infection in the Organ Transplant Recipient C. neoformans is the single most common cause of CNS infection in the organ transplant patient, occurring

almost exclusively in the late posttransplant period. It is the classic cause of subacute to chronic meningitis, often presenting after days to weeks of waxing and waning headaches and fever. Approximately one-third of patients will also note coughs related to the primary pulmonary portal of entry of such infection. Indeed, some of these patients will have simultaneous pulmonary and meningeal infection. The pathogenesis of cryptococcal disease consists of primary pulmonary infection following inhalation of aerosolized organisms, postprimary dissemination with seeding of skin, CNS (as well as the eye), the urinary tract, and the skeletal system, and the possibility of dormancy and later reactivation, again with the possibility of systemic dissemination. At least 20% of patients will have skin lesions early in the course of systemic cryptococcal infection, with this always connoting systemic infection with a high probability of simultaneous or subsequent CNS disease. As delineated in Chapter 3, skin lesions can be the first indication of systemic opportunistic infection, and careful search and biopsy of unexplained papules, nodules, and areas of atypical cellulitis can lead to the early diagnosis of systemic cryptococcal infection. 177,348,349,934,980,994,1010–1015 Alternatively, cryptococcal infection can present as an asymptomatic pulmonary nodule discovered on chest X-ray or as sterile pyuria, with the organism identified on urine culture. This is particularly important in males, since the prostate is a not uncommon site of metastatic infection. Surgical manipulation of these sites carries a significant risk of bloodstream invasion and CNS seeding, even if it had not yet occurred. To prevent such events, a short course of antifungal therapy (usually with fluconazole; vide infra) should be considered.177,934,1011–1016 There have been two major advances in the management of cryptococcal disease in transplant patients: the development of the cryptococcal antigen test on blood and CSF, facilitating diagnosis; and the availability of fluconazole. The cryptococcal antigen test on blood is almost invariably positive in patients with systemic spread, and is particularly helpful in the evaluation of patients with undiagnosed skin lesions. The quantitative antigen test on CSF not only is useful in diagnosing meningitis, but also is of great help when measured serially in assessing the response to therapy.177,934,1011–1016 Standard therapy for cryptococcal infection has long been amphotericin with or without flucytosine. However, because of nephrotoxicity related to the interaction of amphotericin and cyclosporine, we (and others) have turned to fluconazole therapy, which can be administered both orally and intravenously. Based on the experience in both transplant patients and AIDS patients with cryptococcal infection, the following statements can be made: In

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the acutely, desperately ill patient, amphotericin remains the treatment of choice, despite toxicity issues, as amphotericin will gain microbiologic and clinical control more quickly than fluconazole; once such control has been achieved, the patient can be switched to fluconazole to eradicate the infection. In the more subacutely ill patient, we have used fluconazole as primary therapy successfully in a number of transplant patients, even in the face of preexisting renal or liver dysfunction. Toxicity from fluconazole has included a penicillinlike drug rash and the usual antimicrobial-associated upper GI distress, with only the drug rash leading to a change in therapy. To some extent (but not nearly as much as ketoconazole), fluconazole does block the metabolism of cyclosporine, requiring close monitoring of both cyclosporine and creatinine levels. One of the most difficult questions to answer is duration of therapy. Our approach to this, and essentially all fungal disease, is to treat until there is no evidence of the fungus (e.g., cultures are negative and the cryptococcal antigen has cleared), and then treat for an extra 2–4 weeks for added safety. Since, at that point, the drug is being administered orally, the extra therapy is no great hardship for most individuals.177,1013,1016 Note has already been made that cryptococcosis in the transplant patient usually occurs more than 6 months posttransplant, particularly in the “chronic ne’er-dowell” population. However, in recent years, we have observed an increasing number of patients coming to transplantation severely malnourished, a history of pretransplant immunosuppression, and an altered state of consciousness. The most common examples are patients with end-stage liver disease, in whom the altered mental status is attributed to hepatic encephalopathy. Posttransplant, when their neurologic status is still impaired, it is discovered that they have cryptococcosis. Retrospective testing of serum specimens drawn prior to transplant reveals that the cryptococcosis was present pretransplant. Unfortunately, the combination of pretransplant untreated cryptococcosis combined with a liver transplant operation, anesthesia, and exogenous immunosuppression carries a terrible prognosis, even with aggressive therapy. Therefore, evaluation of individuals with altered mental status for cryptococcosis (e.g., blood and CSF cryptococcal antigen testing) prior to transplant is strongly advocated. Illustrative Case 8 A 55-year-old man had undergone cadaveric renal transplantation 14 months previously for chronic renal failure secondary to polycystic disease. Posttransplant immunosuppression was with azathioprine and prednisone. Despite mild chronic rejection that had been treated with multiple pulse doses of methylprednisolone, he had maintained a stable

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serum creatinine of 2.5 mg/dl. Four weeks prior to admission, several small papular lesions on an indurated base were noted on both arms but were not further evaluated. Over the last 10 days prior to admission, he had noted a bifrontal headache, first intermittently and then constantly, with increasing severity. Over the last 2 days, nausea and vomiting as well as fever developed, and he sought medical attention. On physical examination, the temperature was 100.6°F and the blood pressure was 150/100. Skin examination revealed four to five nontender papular lesions on the dorsal surfaces of both wrists, with a small area of subcutaneous induration at the base of each papule. Fundoscopic examination revealed papilledema. There were no meningeal signs. Neurologic examination was otherwise unremarkable. A CT scan of the brain was nondiagnostic, and a lumbar puncture was performed that revealed an opening pressure of 300 mm CSF protein 70 mg/ dl, sugar 47 mg/dl, (80% lymphocytes), a positive India ink preparation, and a cryptococcal antigen titer of 1:128 in the CSF. A skin biopsy of one of the papular lesions revealed cryptococci (Fig. 5). Both the CSF and skin specimens grew C. neoformans. The patient was first treated with amphotericin B and flucytosine, and then with amphotericin B alone because of flucytosine-induced bone marrow toxicity in association with a serum creatinine climbing to 5.2 mg/dl. After a total dose of 2.5 g amphotericin, and with a negative cryptococcal antigen titer in the CSF, therapy was discontinued. Three months later, he presented again with relapsing cryptococcal infection. This time therapy was complicated by progressive renal failure and, despite combined amphotericin and flucytosine therapy, he succumbed to his infection. Comment. This tragic result might have been avoided if the skin lesions had been biopsied 1 month before the onset of CNS symptoms, the diagnosis made, and appropriate therapy instituted earlier. We have made the diagnosis of systemic cryptococcosis on the basis of skin biopsy in more than a dozen patients now, and have cured virtually all of them before the development of CNS infection. This case example occurred before the availability of fluconazole. If this case presented today, a prolonged course of oral fluconazole would have been utilized, either by itself or following an initial course of amphotericin (< 500 mg), to gain control. Such an approach allows one to avoid premature termination of therapy because of toxicity, and, indeed, we have salvaged both patient and allograft in a number of instances with this approach.

7.1.3. Aspergillus Infection in the Organ Transplant Patient Other than cryptococcal infection, the most common fungal agent affecting the CNS in the organ transplant patient is Aspergillus, particularly A. fumigatus (A. flavus is the second most common Aspergillus species causing invasive infection, with A. niger, A. terreus, and A. nidulans being quite uncommon). In this setting, Aspergillus appears to occur exclusively as a result of metastatic infection from a pulmonary (or, uncommonly, a nasal sinus) portal of entry. The usual sequence of events begins with a primary viral or bacterial pulmonary infection in a debilitated patient who has responded poorly to therapy, and this is followed by Aspergillus superinfection, which metastasizes to the brain via the hematogenous route within days of its invasion of the lung. This

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sequence of events is particularly common if the patient’s primary pulmonary process has required prolonged intubation. Alternatively, the normal lung is invaded because of an unusually intense exposure to the organism by means of contaminated air, but again with dissemination via the bloodstream to the brain. This sequence of events

is a result of this organism’s propensity for invading blood vessels, which accounts for the three cardinal manifestations of Aspergillus infection—infarction, hemorrhage, and metastasis. The best way to deal with Aspergillus CNS infection is to prevent it either by preventing the pulmonary infection entirely or by recognizing it early

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and beginning high-dose antifungal therapy before hematogenous dissemination has occurred.348,349,980,990,1016–1019 The optimal therapy of invasive aspergillosis is currently in a state of flux, as data regarding a number of new agents are currently not available. Conventional amphotericin remains the gold standard of therapy, despite its toxicity. When dealing with CNS infection due to Aspergillus species, we, and others, commonly add a second drug such as rifampin, which has been shown to be synergistic with amphotericin in vitro, although translation of this into increased clinical efficacy has not been accomplished. Lipid-associated amphotericin preparations have come into increased use, and clearly are associated with less toxicity (both the acute fever, rigors, and hypotension that is mediated by cytokine release in response to amphotericin infusion; and nephrotoxicity). However, their expense is considerable, and it is not yet clear which amphotericin preparation is superior in terms of efficacy, particularly for CNS infection. Itraconazole is now available in an intravenous formulation as well as in a new oral formulation, which should make the pharmacokinetics and bioavailability more tractable, but once again efficacy data are incomplete, particularly in comparison with amphotericin preparations. The imminent availability of voriconazole and the new echinocandins will complicate decision-making further, until the database is more complete. At present, our practice is to initiate therapy with conventional amphotericin ± rifampin, switching to a lipid amphotericin formulation or voriconazole when toxicity issues become important. The echinocandins may play an important role in combination with regimens such as this.980 Nocardia asteroides as well as other fungal agents may follow a similar pattern (pulmonary portal of entry, with subsequent metastasis to the brain and elsewhere), although usually in less lethal fashion and with a greater chance that a single cerebral lesion may be identified and treated. As with all serious infections in the transplant patient, early diagnosis and aggressive therapy are the only hope for recovery.348,349,980,994 7.2. Bacteremia in the Organ Transplant Recipient

The organ transplanted has traditionally been the major source of posttransplant bacteremia. Thus, in the renal transplant patient, the urinary tract has been the portal of entry for 60–70% of bacteremias, and in the liver transplant patient, the biliary tree and infarcted liver following vascular anastomotic problems has been a major source of invasive infection. In the lung and heart patients, intravenous lines and pneumonia have been the major causes

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of difficulties. In general, technical issues are the foundation of bacteremias occurring in the first 2 or 3 weeks posttransplant, as emphasized in Table 2. With better control of technical issues, and as the time posttransplant increases, listerial sepsis has been the most common cause of bacteremia in many transplant populations. However, with the widespread use of trimethoprim– sulfamethoxazole prophylaxis, this problem has become quite uncommon.27 At present, bacteremias in the organ transplant patient can be divided into three general categories: (1) those related to technical problems involving the allograft, intravenous lines, or, particularly in the liver transplant patient, collections of blood, lymph, bile, or urine that become secondarily infected causing soft tissue infection, peritonitis, and so on; (2) those related to breaks in the integrity of the GI tract, leading to inflammation of the gut wall and/or abscess or frank peritonitis; the most common example of this is sigmoid diverticulitis, which commonly leads to abscess formation and perforation; and (3) acute bacterial gastroenteritis, particularly that caused by Salmonella species. Nontyphoidal salmonella infection, acquired, usually, by the ingestion of a contaminated foodstuff (particularly inadequately cooked chicken or other fowl), poses a particular hazard to the transplant patient. Whereas in the normal host, salmonella gastroenteritis is associated with a risk of bacteremia of less than 5%, in the transplant patient, more than 50% of individuals will have bloodstream invasion with this organism. In addition, metastatic infection as a consequence of such bloodstream invasion is the rule rather than the exception in the transplant patient. Seeding of the urinary tract, with positive urine cultures, is common. The cardiovascular tree, at sites of preexisting atherosclerotic lesions, aneurysms, fistulas, and so forth, is commonly involved. With involvement of the heart and/or vasculature, eradication of infection with antibiotics alone is often not possible. For this reason, prolonged antibiotic therapy is indicated in any transplant patient with documented salmonella bacteremia or evidence of metastatic seeding.1020–1024 Enterococcal infection, including vancomycin-resistant enterococci (VRE), is a particular problem in liver transplant recipients. Approximately 10–15% of liver transplant recipients will experience enterococcal bacteremia as a consequence of intravenous line-related sepsis, deep wound infection, or technical/anatomic problems with the liver transplant itself. In all types of organ transplant patients, enterococcal bacteremia occurs predominantly in the first month posttransplant, emphasizing the role of technical problems in the pathogenesis.1025–1027

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7.3. Fungal Infections in the Organ Transplant Patient Fungal infection in the organ transplant patient can be divided into two categories: pulmonary and/or disseminated infection with one of the geographically restricted systemic mycoses (histoplasmosis, coccidioidomycosis, or blastomycosis); and opportunistic infection with fungal species that rarely cause invasive infection in the normal host (Candida species, Pneumocystis carinii, Aspergillus species, Cryptococcus neoformans, the Mucoraceae, and others). In the case of the systemic mycoses, two different patterns of disease are commonly observed: primary infection in the immunosuppressed patient with progressive disease and postprimary dissemination; and reactivation infection with secondary dissemination. In addition, in an occasional individual, reinfection, again with the potential for dissemination, may occur if immunosuppression has caused previous immunity to wane. The similarity to the pathogenesis of tuberculosis is obvious.1028–1040 With the emphasis on pulmonary and disseminated infection with each of these entities, a variety of clinical presentations should lead to the consideration of these infections in the differential diagnosis: a subacute respiratory illness, with either focal or disseminated interstitial or miliary infiltrates on chest radiograph; a nonspecific febrile illness; or an illness in which metastatic aspects of the infection predominate (e.g., mucocutaneous manifestations in histoplasmosis and blastomycosis, or CNS manifestations in coccidioidomycosis). Amphotericin therapy remains the standard of care for these entities, although increasing experience with the azole antifungal agents, fluconazole and itraconazole, suggests that they are valuable for completing a course of treatment after clinical control has been achieved (see Chapter 6).1028–1040 A more common problem is the acquisition of opportunistic fungal infection posttransplant. Three patterns are observed: primary infection, usually of the lungs, occasionally of the nasal sinuses, most commonly by P. carinii, C. neoformans, or A. fumigatus; sequential and concurrent secondary infection, either of the lungs or via infected intravenous lines, by Candida species or Aspergillus species; and primary cutaneous infection following a break in the skin by Aspergillus species, Paecelomyces, Penicillium, Pseudallescheria boydii, and a variety of newly emerging fungal species. Two points bear reemphasis here. First, metastatic infection is the rule rather than the exception with these agents and the clinically similar N. asteroides. Therefore, a search for metastases should be carried out whenever a primary focus of infection is docu-

mented. Second, careful surveillance should be maintained for possible clustering of cases of opportunistic fungal infection, particularly Aspergillus. Such clustering suggests a major environmental hazard.3,348,1039,1041–1044 7.3.1. Candidiasis in the Organ Transplant Patient Candidal species are commonly found on diseased skin, throughout the GI tract, and in the vagina. Overgrowth of these mucocutaneous surfaces occurs when the nutrient supply is increased because of elimination of the normal bacterial flora with antibiotics or because of metabolic factors (e.g., diabetes, corticosteroids, pregnancy). The most common manifestation of candidal infection in the transplant patient, then, is mucocutaneous overgrowth, which can cause one or more of the following clinical entities: oropharyngeal thrush, candidal esophagitis, vaginitis, intertrigo, and/or paronychia or onychomycosis. Topical therapy with nonabsorbable fungal agents such as clotrimazole or nystatin, when given together with antibacterial drugs in the transplant patient, will prevent the development of mucocutaneous infection and is usually effective in treating it when it occurs. If these agents do not produce a prompt therapeutic response, then fluconazole and, probably, the other azoles are quite effective.177 Once candidal overgrowth has occurred, the next step in the pathogenesis of invasive infection is penetration beyond the mucocutaneous barrier. In transplant patients, this often results from technical factors, e.g., contaminated intravenous lines or complicated liver transplantation with spillage of candidal organisms from the upper GI tract into devitalized tissue, hematomas, or ascites. If bloodstream invasion occurs, dissemination with the potential for visceral seeding will occur in 50% or more of transplant patients because of their immunosuppressed state (in contrast, transient candidemia in a normal host will disseminate in only 5% of instances). Therefore, every documented episode of invasive candidal infection in the transplant patient requires therapy. The clinical manifestations of disseminated candidal infection in the transplant patient are diverse, ranging from an acute septic picture to situations in which the metastatic site of infection is the predominant cause of symptoms—skin lesions, endophthalmitis, osteomyelitis, splenic abscess, meningitis, and so forth. The therapeutic approach to invasive candidal infection in the transplant patient is similar to that for cryptococcal infection: initiating therapy with amphotericin if the patient is a therapeutic emergency, and then switching to fluconazole to complete the course of therapy while

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minimizing toxicity; primary therapy with fluconazole when the patient is more subacutely ill (a “diagnostic dilemma” as opposed to a “therapeutic emergency”). It should be emphasized that not all candidal species are equally susceptible to fluconazole, however. Fortunately, the most common species, C. albicans and C. tropicalis, are susceptible. In contrast, C. krusei and C. glabrata should always be considered fluconazole resistant, and amphotericin therapy is obligatory. There are currently insufficient data to evaluate the role of itraconazole, voriconazole, and the echinocandins in this situation. 27 7.4. Mycobacterial Infections in the Organ Transplant Patient One of the more controversial issues in the management of transplant patients is the approach to tuberculosis. The incidence of active tuberculosis in this patient population has been approximately 1%, compared with an overall rate in the United States at the same time of approximately 15 per 100,000.1045–1053 The advent of the tuberculosis epidemic, including drug-resistant tuberculosis, in conjunction with AIDS, is in the process of increasing these figures further. One can predict that it is only a matter of time until the incidence of tuberculosis in transplant patients begins to rise as well, particularly in those urban areas where tuberculosis is having a major effect on the general community. Although the advent of drug-resistant infection will clearly complicate the process, it is important to emphasize that tuberculosis in a transplant patient can be effectively treated. A variety of forms of tuberculosis have been observed in transplant patients, from cavitary disease of the lungs to miliary disease, from bowel disease to skeletal disease, and from skin to CNS disease. Particularly noteworthy have been instances in which the graft carried the infection from donor to recipient or when the graft was infected in the recipient as part of hematogenous dissemination of the organisms. An unusually high rate of bone and joint involvement has been noted in transplant patients with tuberculosis.1045–1057 It is also worth emphasizing that epidemic disease can occur within a transplant program if prompt isolation of infected individuals is not carried out.1058 What has been surprising is not that tuberculosis has occurred in these immunocompromised patients, but rather that it has not occurred more frequently. For example, at the Massachusetts General Hospital, we have carried out organ transplantation in more than 1000 patients whose pretransplant tuberculin status was known. Of these, 127 were tuberculin positive and did not receive

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isoniazid prophylaxis either pre- or posttransplant. In only one of these was the tuberculosis reactivated, and this was promptly identified and treated successfully. Why not use isoniazid prophylaxis routinely? The issue of isoniazid prophylaxis in transplant patients is a controversial one. On the one hand, the guidelines of the American Thoracic Society have traditionally recommended 1 year of isoniazid prophylaxis for individuals with positive tuberculin tests who are subjected to a prolonged course of immunosuppressive therapy. Recently, the Tuberculosis Committee of the Infectious Disease Society of America has advocated 9 months of isoniazid or 2 months of rifampin plus pyrazinamide for all individuals with positive tuberculin tests, although noting that because of toxicity issues judgment needs to be utilized in each individual.1059 We and others have concluded that the risk of isoniazid hepatotoxicity is greater than the benefits of isoniazid prophylaxis in transplant patients with postive tuberculin tests and no other risk factors for tuberculosis. This is particularly true for liver transplant recipients.1060–1062 The additional risk factors that would lead us to institute isoniazid prophylaxis in transplant patients include the following: recent tuberculin conversion; non-Caucasian racial background; the presence of other immunosuppressing conditions such as protein malnutrition; a history of active tuberculosis, particularly if it had been inadequately treated; and the presence of significant abnormalities on chest radiograph. Current recommendations for the treatment of active tuberculosis include 6 months of therapy with isoniazid, rifampin, and pyrazinamide, with ethambutol added if antimicrobial resistance is deemed likely.1059 Our own preference in transplant patients is to continue such therapy for a minimum of 6–9 months after all evidence of disease activity is no longer present. Particularly in liver transplant patients, such a regimen is often poorly tolerated. In those cases, innovative regimens such as the combination of ethambutol and ofloxacin are effective, but the duration of therapy with such less effective (but less toxic) regimens should be expanded to 2 years.1062 One other aspect of antituberculosis therapy in the transplant patient that bears comment is that antituberculous drugs can have an adverse effect on allograft survival through their effects on steroid metabolism. Isoniazid and rifampin cause the induction of hepatic microsomal enzymes that increase the catabolism of steroids. Similarly, rifampin, and possibly isoniazid, increase the metabolism of cyclosporine and tacrolimus by the hepatic cytochrome P450 enzyme system. Thus, patients will be underimmunosuppressed if only standard dosages are utilized. Fortunately, in the case of cyclosporine and tacrolimus,

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blood levels can be followed and dosages adjusted appropriately. In addition to typical mycobacterial infection, atypical mycobacterial infection has been observed in transplant patients.1063 This can be divided into two general categories: pulmonary, skin, skeletal, and disseminated infection related primarily to M. kansasii,1048,1051,1053,1064,1065 but occasionally also to such other species as M. chelonae1066 and M. xenopi1067; and skin infection alone with a variety of relatively less virulent mycobacterial species, including M. marinum,1068 M. haemophilum,1069 M. thermoresistibile,1070 and M. chelonae.1071,1072 In both categories, the atypical mycobacterial infection is often superimposed on previous tissue injury. In addition, rare instances of intestinal infection due to M. avium/intracellulare invasion analogous to that seen in AIDS patients have been reported in transplant recipients.1073–1075 Treatment of atypical mycobacterial infection is guided by antimicrobial susceptibility testing, with therapy usually initiated with a multidrug regimen that includes a macrolide (azithromycin or clarithromycin), ethambutol, and a third drug (clofazimine, rifabutin, or ciprofloxacin or another quinolone). Treatment should be for 2 years, preferably with a decrease in immunosuppression.1075,1076

8. Vaccine Use in Organ Transplant Recipients Since prevention of infection is a primary goal in the management of transplant patients, an important consideration is the appropriate use of vaccines in this population of patients. There are two issues: safety and efficacy. When considering safety, two considerations come into play, namely, if a live virus vaccine is being considered, then the possibility of vaccine strain-induced disease is of primary concern; a general concern, whether the vaccine is a live virus vaccine or an inactivated or subunit vaccine, is the possibility of inducing rejection by the immunization process. In terms of efficacy, it can be generalized that the response posttransplant is attenuated, both in terms of the rate of seroconversion and in terms of the level of protective antibody produced if seroconversion indeed occurred (with the peak level of antibody obtained being a useful marker for predicting the duration of protection). Thus, from both a safety and an efficacy point of view, an important truism of transplant infectious disease is that all immunizations should be carried out before transplant (ideally, > 1 month pretransplant), and assessment of a transplant candidate’s vaccine status, with cor-

rection of any deficits, is an important aspect of the pretransplant evaluation. An important question is whether or not immunization with an indicated vaccine could induce rejection. In general, randomized controlled trials of such vaccines as influenza, hepatitis B, and tetanus toxoid have not revealed any statistically significant increased incidence of allograft rejection.1077–1080 However, occasional reports have suggested that vaccine administration could have such an effect.1079,1081 We have observed two renal transplant recipients who were > 12 months posttransplant, without previous history of allograft rejection, who proceeded to develop severe rejection (culminating in allograft loss) following tetanus toxoid administration. That these severe rejection episodes occurred in individuals with normal renal function (serum creatinine levels ~0.8 mg/dl) at a time when they should have been free from such a risk raises the question as to whether or not in an occasional patient vaccine administration could precipitate a rejection crisis. If so, then, what would be the mechanism and a rational way for the clinician to proceed? The following hypothesis would be consistent with what has previously been presented in this chapter; that is, that cytokines, chemokines, and growth factors elaborated in response to a variety of stimuli could impact on the processes leading to allograft injury (vide supra). In this situation, it is well known that certain individuals, in response to the administration of particular vaccines, develop a flulike syndrome characterized by fever, inflammation at the administration site, and malaise that is mediated by the local and systemic release of proinflammatory cytokines in response to the vaccine. It is possible that individuals with particularly severe vaccine reactions would be the ones likely to develop allograft dysfunction due to the cytokine milieu that has resulted in response to the vaccine. This chain of events is analogous to what has been postulated to result from such infections as CMV, HHV-6, and, perhaps, others (vide supra). With these considerations in mind, appropriate vaccine use would include the following: use of vaccines when needed (vide infra), but careful screening for a history of previous vaccine reactions; all transplant patients receiving vaccines should be monitored postvaccination for allograft function, particularly those who have evidence of an inflammatory response to the vaccine. As far as specific recommendations regarding the different vaccines, the reader is directed to the excellent review of Burroughs and Moscone.1077 The following comments, however, bear particular emphasis:

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1. Live virus vaccines have, in general, been shunned posttransplant. This is particularly important with the oral polio vaccine, where the administration of this vaccine to a transplant recipient or a family member (with subsequent person-to-person spread within the family) can result in vaccine-induced progressive meningoencephalitis. Accordingly, when polio vaccine is indicated for either a transplant patient or a family member, the inactivated polio vaccine is strongly advocated.1077,1082–1084 2. As far as other live virus vaccines are concerned, there is less of a consensus. In the case of the varicella vaccine, it has been safely used in other immunosuppressed patient populations, particularly seronegative leukemics and AIDS patients, although seroconversion rates have been lower than in the normal population. In one study of 17 pediatric renal transplant recipients, 65% developed protective antibody titers, with one child developing mild varicella postimmunization. As far as efficacy is concerned, 3 of these patients developed attenuated varicella 2–4 years later, suggesting some degree of protection.1085 Our own experience has suggested a lower rate of seroconversion, often requiring multiple doses of the vaccine to achieve this, an ~10% incidence of mild varicella postimmunization, easily managed with acyclovir (vide supra). 3. Measles and mumps are clearly of increased severity in immunocompromised individuals, so immunization against these is clearly to be desired (there is less evidence of this for rubella, but most groups would use the combined measles–mumps–rubella vaccine when vaccinating against the other two viruses). Admittedly scanty data, particularly in other immunocompromised patients, suggest safety and possible efficacy.1077 If possible, immunization should be followed up by serologic testing to demonstrate protection. This is particularly important for measles, where pediatric transplant recipients who are unvaccinated or whose immunity is not documented, should receive intramuscular immunoglobulin within 6 days of exposure to measles.1077 4. The use of inactivated or subunit vaccines needs to be individualized for the needs of the particular patient—use when clearly indicated, with close follow-up following vaccination. Pharmacoeconomic issues enter into consideration here as well. Thus, we routinely employ yearly influenza vaccination for heart and lung transplant recipients (after administering influenza and pneumococcal vaccines pretransplant), but regard it as more optional for kidney and liver transplant recipients, because of concerns about efficacy. More information in this area is badly needed.

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9. Summary and Prospects for the Future The advances in transplantation that have occurred over the past decade can be appreciated by comparing the discussion on the infectious complications in the four editions of this book. In the first edition, published in 1981, only bone marrow and kidney transplantation were discussed. In the second edition, published in 1988, liver and heart transplantation were extensively explored as well. In the third edition, published in 1994, issues peculiar to lung, heart–lung, and pancreatic transplantation were added to our consideration. Small bowel transplantation is now on the radar screen as well—the technical problems have been largely overcome, the immunosuppressive issues are being settled, and the major problems remaining to be overcome are infectious, particularly the translocation of aerobic gut flora (especially gram-negative) and candidal species across a mucosa whose barrier function is at least temporarily impaired; and the high incidence of EBVrelated lymphoproliferative disease in these patients. The lessons learned with the other allografts should aid us here as well, and as we look to expand the horizons of transplantation by protecting patients from lifethreatening infection, the following principles should be followed: 1. The infections that occur in transplant patients may be divided into three general categories: those related to technical complications, those related to epidemiologic exposures, and those related to viruses lurking in the graft recipient or his donor and that are rendered clinically manifest posttransplant. The modulation of these infections is accomplished by the dose, duration, and type of immunosuppressive therapy being administered. 2. The risk of infection in the transplant patient is determined by the interaction among three factors: the presence of technical/anatomical abnormalities, the epidemiologic exposures the patient encounters, and the net state of immunosuppression. 3. There is an expected timetable according to which particular infections occur at particular times in the posttransplant course. Exceptions to this timetable are usually the result of exposure to excessive environmental hazards. As one approaches new forms of transplantation or radically different immunosuppressive regimens, the obligation of the transplant infectious disease clinician is to define the timetable that fits this new situation. 4. The biggest challenge in approaching the infectious disease problems of the transplant patient is the

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prevention and treatment of those viral diseases that contribute so broadly to the morbidity and mortality still associated with clinical human transplantation. The viruses of greatest importance are the herpes group viruses and the hepatitis viruses, with each of them modulated by immunosuppressive therapy. The advent of preemptive and prophylactic regimens for at least some of these infections holds promise that we can gain control and bring the promise of transplantation to reality for more patients. 5. Because of the impaired inflammatory response of this patient population, signs and symptoms of infection may be greatly muted. Physicians caring for such patients must be alert and aggressive in their approach to “minor” skin lesions or radiographic findings. 6. The therapeutic prescription for the transplant patient consists of an immunosuppressive regimen to prevent and treat rejection, and an antimicrobial strategy to make it safe. Just as we have learned to individualize the immunosuppressive program to fit the needs of the particular patient, we must be prepared to individualize the antimicrobial strategy in a similar fashion. 7. When considering the effects of a given infectious process on the transplant patient, both direct and indirect manifestations must be considered. The indirect effects are mediated by cytokines, chemokines, and growth factors elaborated by the patient in response to microbial invasion and replication. Among the indirect effects that have been defined are allograft injury, modulation of other infectious processes, and oncogenesis. In the next edition of this book, it is likely that we will be defining antimicrobial regimens in terms of their effects on the indirect as well as direct processes. As we follow these precepts, it is important not to lose sight of the most important guideline of all: Although the challenge of caring for these patients is great, the rewards are even greater. We have come a long way in the care of these patients. Continued progress is on the horizon.

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793. Perrillo R, Rakela J, Dienstag J, et al: Multicenter study of lamivudine therapy for hepatitis B after liver transplantation. Lamivudine Transplant Group. Hepatology 29:1581–1586, 1999. 794. Mutimer D, Pillay D, Dragon E, et al: High pre-treatment serum hepatitis B virus titre predicts failure of lamivudine prophylaxis and graft re-infection after liver transplantation. J Hepatol 30:715–721, 1999. 795. Bartholomew MM, Jansen RW, Jeffers LJ, et al: HepatitisB-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation [see comments]. Lancet 349:20–22, 1997. 796. Gauthier J, Bourne EJ, Lutz MW, et al: Quantitation of hepatitis B viremia and emergence of YMDD variants in patients with chronic hepatitis B treated with lamivudine. J Infect Dis 180: 1757–1762, 1999. 797. Seehofer D, Rayes N, Berg T, et al: Lamivudine as first- and second-line treatment of hepatitis B infection after liver transplantation [In Process Citation]. Transplant Int 13:290–296, 2000. 798. Puchhammer-Stockl E, Mandl CW, Kletzmayr J, et al: Monitoring the virus load can predict the emergence of drug-resistant hepatitis B virus strains in renal transplantation patients during lamivudine therapy. J Infect Dis 181:2063–2066, 2000. 799. Fontaine H, Thiers V, Chretien Y, et al: HBV genotypic resistance to lamivudine in kidney recipients and hemodialyzed patients. Transplantation 69:2090–2094, 2000. 800. Peters MG, Singer G, Howard T, et al: Fulminant hepatic failure resulting from lamivudine-resistant hepatitis B virus in a renal transplant recipient: Durable response after orthotopic liver transplantation on adefovir dipivoxil and hepatitis B immune globulin. Transplantation 68:1912–1914, 1999. 801. Malkan G, Cattral MS, Humar A, et al: Lamivudine for hepatitis B in liver transplantation: A single-center experience. Transplantation 69:1403–1407, 2000. 802. Mutimer D, Dusheiko G, Barrett C, et al: Lamivudine without HBIg for prevention of graft reinfection by hepatitis B: Longterm follow-up. Transplantation 70:809–815, 2000. 803. Demetris AJ, Jaffe R, Sheahan DG, et al: Recurrent hepatitis B in liver allograft recipients. Differentiation between viral hepatitis B and rejection. Am J Pathol 125:161–172, 1986. 804. Portmann B, O’Grady J, Williams R: Disease recurrence following orthotopic liver transplantation. Transplant Proc 18(Suppl), 1986. 805. Freeman RB, Sanchez H, Lewis WD, et al: Serologic and DNA follow-up data from HBsAg-positive patients treated with orthotopic liver transplantation. Transplantation 51:793–797, 1991. 806. Levy GA, Sherker A, Fung LS, et al: Relevance of hepatitis B viral DNA in assessment of potential liver allograft recipients. Transplant Proc 21:3333–3334, 1989. 807. Demetris AJ, Todo S, Van Thiel DH, et al: Evolution of hepatitis B virus liver disease after hepatic replacement. Practical and theoretical considerations. Am J Pathol 137:667–676, 1990. 808. O’Grady JG, Smith HM, Davies SE, et al: Hepatitis B virus reinfection after orthotopic liver transplantation. Serological and clinical implications. J Hepatol 14:104–111, 1992. 809. Lavine JE, Lake JR, Ascher NL, et al: Persistent hepatitis B virus following interferon alfa therapy and liver transplantation. Gastroenterology 100:263–267, 1991. 810. Eason J, Freeman RJ, Rohrer R, et al: Should liver allograft transplantation be performed for patients with hepatitis B? Transplantation 70:397–401, 1994.

811. Samuel D, Bismuth A, Mathieu D, et al: Passive immunoprophylaxis after liver transplantation in HBsAg-positive patients. Lancet 337:813–815, 1991. 812. Lauchart W, Muller R, Pichlmayr R: Long-term immunoprophylaxis of hepatitis B virus reinfection in recipients of human liver allografts. Transplant Proc 19:4051–4053, 1987. 813. Grazi GL, Mazziotti A, Sama C, et al: Liver transplantation in HBsAg-positive HBV-DNA—Negative cirrhotics: Immunoprophylaxis and long-term outcome. Liver Transplant Surg 2:418– 425, 1996. 814. Tchervenkov JI, Tector AJ, Barkun JS, et al: Recurrence-free long-term survival after liver transplantation for hepatitis B using interferon-alpha pretransplant and hepatitis B immune globulin posttransplant. Ann Surg 226:356–365; discussion 365–368, 1997. 815. Sawyer RG, McGory RW, Gaffey MJ, et al: Improved clinical outcomes with liver transplantation for hepatitis B-induced chronic liver failure using passive immunization. Ann Surg 227: 841–850, 1998. 816. Burbach GJ, Bienzle U, Neuhaus R, et al: Intravenous or intramuscular anti-HBs immunoglobulin for the prevention of hepatitis B reinfection after orthotopic liver transplantation. Transplantation 63:478–480, 1997. 817. Terrault NA, Zhou S, McCory RW, et al: Incidence and clinical consequences of surface and polymerase gene mutations in liver transplant recipients on hepatitis B immunoglobulin. Hepatology 28:555–561, 1998. 818. Ghany MG, Ayola B, Villamil FG, et al: Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis [see comments]. Hepatology 27:213–222, 1998. 819. Carman WF, Owsianka A, Wallace LA, Dow BC, Mutimer DJ: Antigenic characterization of pre- and post-liver transplant hepatitis B surface antigen sequences from patients treated with hepatitis B immune globulin. J Hepatol 31:195–201, 1999. 820. Shields PL, Owsianka A, Carman WF, et al: Selection of hepatitis B surface “escape” mutants during passive immune prophylaxis following liver transplantation: Potential impact of genetic changes on polymerase protein function. Gut 45:306–309, 1999. 821. Santantonio T, Gunther S, Sterneck M, et al: Liver graft infection by HBV S-gene mutants in transplant patients receiving long-term HBIg prophylaxis. Hepatogastroenterology 46:1848–1854, 1999. 822. Tillmann HL, Trautwein C, Bock T, et al: Mutational pattern of hepatitis B virus on sequential therapy with famciclovir and lamivudine in patients with hepatitis B virus reinfection occurring under HBIg immunoglobulin after liver transplantation. Hepatology 30:244–256, 1999. 823. de Man RA, Bartholomeusz AI, Niesters HG, Zondervan PE, Locarnini SA: The sequential occurrence of viral mutations in a liver transplant recipient re-infected with hepatitis B: Hepatitis B immune globulin escape, famciclovir non-response, followed by lamivudine resistance resulting in graft loss. J Hepatol 29:669– 675, 1998. 824. Markowitz JS, Martin P, Conrad AJ, et al: Prophylaxis against hepatitis B recurrence following liver transplantation using combination lamivudine and hepatitis B immune globulin. Hepatology 28:585–589, 1998. 825. Yoshida EM, Erb SR, Partovi N, et al: Liver transplantation for chronic hepatitis B infection with the use of combination lamivudine and low-dose hepatitis B immune globulin. Liver Transplant Surg 5:520–525, 1998.

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826. Bain V: Hepatitis B in transplantation. Transplant Infect Dis 2: 153–165, 2000. 827. Yao FY, Osorio RW, Roberts JP, et al: Intramuscular hepatitis B immune globulin combined with lamivudine for prophylaxis against hepatitis B recurrence after liver transplantation. Liver Transplant Surg 5:491–496, 1999. 828. Angus PW, McCaughan GW, Gane EJ, Crawford DH, Harley H: Combination low-dose hepatitis B immune globulin and lamivudine therapy provides effective prophylaxis against posttransplantation hepatitis B [In Process Citation]. Liver Transplant 6:429–433, 2000. 829. McCaughan G, Zekry A: Effects of immunosuppression and organ transplantation on the natural history and immunopathogenesis of hepatitis C virus infection. Transplant Infect Dis 2:166–185, 2000. 830. Bruix J, Barrera JM, Calvet X, et al: Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis [see comments]. Lancet 2:1004– 1006, 1989. 831. Yu MC, Tong MJ, Coursaget P, et al: Prevalence of hepatitis B and C viral markers in black and white patients with hepatocellular carcinoma in the United States [see comments]. J Natl Cancer Inst 82:1038–1041, 1990. 832. Esteban JI, Lopez-Talavera JC, Genesca J, et al: High rate of infectivity and liver disease in blood donors with antibodies to hepatitis C virus [see comments]. Ann Intern Med 115:443–449, 1991. 833. Kao JH, Chen PJ, Yang PM, el al: Intrafamilial transmission of hepatitis C virus: The important role of infections between spouses. J Infect Dis 166:900–903, 1992. 834. Prince AM, Brotman B, Inchauspe G, et al: Patterns and prevalence of hepatitis C virus infection in posttransfusion non-A, nonB hepatitis. J Infect Dis 167:1296–1301, 1993. 835. McCashland TM, Wright TL, Donovan JP, et al: Low incidence of intraspousal transmission of hepatitis C virus after liver transplantation. Liver Transplant Surg 1:358–361, 1995. 836. Wright TL, Hsu H, Donegan E, et al: Hepatitis C virus not found in fulminant non-A, non-B hepatitis [see comments]. Ann Intern Med 115:111–112, 1991. 837. Woodfield DG: Acute post-transfusion fulminant hepatitis C virus infection: A case report. Gastroenterol Jpn 26(Suppl 3):221– 223, 1991. 838. Choo QL, Kuo G, Weiner AJ, Overby LR, et al: Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362, 1989. 839. Kuo G, Choo QL, Alter HJ, et al: An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 244:362–364, 1989. 840. Alter HJ, Purcell RH, Shih JW, et al: Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med 321:1494–1500, 1989. 841. Alter MJ, Hadler SC, Judson FN, et al: Risk factors for acute nonA, non-B hepatitis in the United States and association with hepatitis C virus infection. JAMA 264:2231–2235, 1990. 842. Roth D, Fernandez JA, Burke GW, Esquenazi V, Miller J: Detection of antibody to hepatitis C virus in renal transplant recipients. Transplantation 51:396–400, 1991. 843. Read AE, Donegan E, Lake J, et al: Hepatitis C in patients undergoing liver transplantation. Ann Intern Med 114:282–284, 1991. 844. Prince AM, Brotman B, Huima T, et al: Immunity in hepatitis C infection. J Infect Dis 165:438–443, 1992.

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940. Barr BB, Benton EC, McLaren K, et al: Human papilloma virus infection and skin cancer in renal allograft recipients. Lancet 1:124–129, 1989. 941. Hopfl R, Bens G, Wieland U, et al: Human papillomavirus DNA in non-melanoma skin cancers of a renal transplant recipient: Detection of a new sequence related to epidermodysplasia verruciformis associated types. J Invest Dermatol 108:53–56, 1997. 942. Arends MJ, Benton EC, McLaren KM, et al: Renal allograft recipients with high susceptibility to cutaneous malignancy have an increased prevalence of human papillomavirus DNA in skin tumours and a greater risk of anogenital malignancy. Br J Cancer 75:722–728, 1997. 943. Bens G, Wieland U, Hofmann A, Hopfl R, Pfister H: Detection of new human papillomavirus sequences in skin lesions of a renal transplant recipient and characterization of one complete genome related to epidermodysplasia verruciformis-associated types. J Gen Virol 79:779–787, 1998. 944. de Jong-Tieben LM, Berkhout RJ, ter Schegget J, et al: The prevalence of human papillomavirus DNA in benign keratotic skin lesions of renal transplant recipients with and without a history of skin cancer is equally high: A clinical study to assess risk factors for keratotic skin lesions and skin cancer. Transplantation 69:44–49, 2000. 945. Alloub MI, Barr BB, McLaren KM, et al: Human papillomavirus infection and cervical intraepithelial neoplasia in women with renal allografts. Br Med J 298:153–156, 1989. 946. Leptak C, Ramon y Cajal S, Kulke R, et al: Tumorigenic transformation of murine keratinocytes by the E5 genes of bovine papillomavirus type 1 and human papillomavirus type 16 [published erratum appears in J Virol 66(3):1833, 1992]. J Virol 65:7078– 7083, 1991. 947. Hinman F Jr, Schmaelzle JF, Belzer FO: Urinary tract infection and renal homotransplantation. II. Post-transplantation bacterial invasion. J Urol 101:673–679, 1969. 948. Leigh DA: The outcome of urinary tract infections in patients after human cadaveric renal transplantation. Br J Urol 41:406– 413, 1969. 949. Martin DC: Urinary tract infection in clinical renal transplantation. Arch Surg 99:474–476, 1969. 950. Prout GR Jr, Hume DM, Williams GM, Lee HM: Some urological aspects of 93 consecutive renal homotransplants in modified recipients. J Urol 97:409–425, 1967. 951. Ramsey DE, Finch WT, Birtch AG: Urinary tract infections in kidney transplant recipients. Arch Surg 114:1022–1025, 1979. 952. Rubin RH, Fang LS, Cosimi AB, et al: Usefulness of the antibody-coated bacteria assay in the management of urinary tract infection in the renal transplant patient. Transplantation 27:18–20, 1979. 953. Myerowitz RL, Medeiros AA, O’Brien TF: Bacterial infection in renal homotransplant recipients. A study of fifty-three bacteremic episodes. Am J Med 53:308–314, 1972. 954. Nielsen HE, Korsager B: Bacteremia after renal transplantation. Scand J Infect Dis 9:111–117, 1977. 955. Pearson JC, Amend WJ Jr, Vincenti FG, Feduska NJ, Salvatierra O Jr: Post-transplantation pyelonephritis: Factors producing low patient and transplant morbidity. J Urol 123:153–156, 1980. 956. Burleson RL, Brennan AM, Scruggs BF: Foley catheter tip cultures: A valuable diagnostic aid in the immunosuppressed patient. Am J Surg 133:723–725, 1977. 957. Schaeffer AJ: Catheter-associated bacteriuria in patients in reverse isolation. J Urol 128:752–754, 1982.

958. Schaeffer AJ, Chmiel J: Urethral meatal colonization in the pathogenesis of catheter-associated bacteriuria. J Urol 130:1096– 1099, 1983. 959. Hepinstall R: Experimental pyelonephritis: A comparison of blood-borne and ascending patterns of infection. J Pathol 89:71– 80, 1965. 960. Tolkoff-Rubin NE, Rubin RH: Urinary tract infection in the immunocompromised host. Lessons from kidney transplantation and the AIDS epidemic. Infect Dis Clin North Am 11:707–717, 1997. 961. Tolkoff-Rubin N, Cosimi A, Russell P, et al: A controlled study of trimethoprim–sulfamethoxazole prophylaxis of urinary tract infections in renal transplant recipients. Rev Infect Dis 4:614– 618, 1982. 962. Fox BC, Sollinger HW, Belzer FO, Maki DG: A prospective, randomized, double-blind study of trimethoprim–sulfamethoxazole for prophylaxis of infection in renal transplantation: Clinical efficacy, absorption of trimethoprim–sulfamethoxazole, effects on the microflora, and the cost-benefit of prophylaxis. Am J Med 89:255–274, 1990. 963. Maki DG, Fox BC, Kuntz J, Sollinger HW, Belzer FO: A prospective, randomized, double-blind study of trimethoprim– sulfamethoxazole for prophylaxis of infection in renal transplantation. Side effects of trimethoprim–sulfamethoxazole, interaction with cyclosporine. J Lab Clin Med 119:11–24, 1992. 964. Hibberd P, Tolkoff-Rubin N, Doran M, et al: Trimethoprim– sulfamethoxazole compared with ciprofloxacin for the prevention of urinary tract infection in renal transplant recipients. Online: J Curr Clin Trials Doc. #15, 1992. 965. Hibberd PL, Rubin RH: Approach to immunization in the immunosuppressed host. Infect Dis Clin North Am 4:123–142, 1990. 966. Cosimi AB, Colvin RB, Burton RC, et al: Use of monoclonal antibodies to T-cell subsets for immunologic monitoring and treatment in recipients of renal allografts. N Engl J Med 305: 308–314, 1981. 967. Peigue-Lafeuille H, Gazuy N, Mignot P, et al: Severe respiratory syncytial virus pneumonia in an adult renal transplant recipient: Successful treatment with ribavirin. Scand J Infect Dis 22:87–89, 1990. 968. Doud JR, Hinkamp T, Garrity ER Jr: Respiratory syncytial virus pneumonia in a lung transplant recipient: Case report. J Heart Lung Transplant 11:77–79, 1992. 969. Hierholzer JC, Atuk NO, Gwaltney JM Jr: New human adenovirus isolated from a renal transplant recipient: Description and characterization of candidate adenovirus type 34. J Clin Microbiol 1:366–376, 1975. 970. Myerowitz RL, Stalder H, Oxman MN, et al: Fatal disseminated adenovirus infection in a renal transplant recipient. Am J Med 59:591–598, 1975. 971. Keller EW, Rubin RH, Black PH, Hirsch MS, Hierholzer JC: Isolation of adenovirus type 34 from a renal transplant recipient with interstitial pneumonia. Transplantation 23:188–191, 1977. 972. Stalder H, Hierholzer JC, Oxman MN: New human adenovirus (candidate adenovirus type 35) causing fatal disseminated infection in a renal transplant recipient. J Clin Microbiol 6:257–265, 1977. 973. Lecatsas G, Prozesky OW, van Wyk J: Letter: Adenovirus type II associated with haemorrhagic cystitis after renal transplantation. S Afr Med J 48:1932, 1974. 974. Harnett GB, Bucens MR, Clay SJ, Saker BM: Acute haemorrhagic cystitis caused by adenovirus type 11 in a recipient of a transplanted kidney. Med J Aust 1:565–567, 1982.

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975. Huebner R, Rowe W, Lane WT: Oncogenic effects in hamsters of human adenoviruses types 12 and 18. Proc Natl Acad Sci USA 48:2051–2058, 1962. 976. Koneru B, Jaffe R, Esquivel CO, et al: Adenoviral infections in pediatric liver transplant recipients. JAMA 258:489–492, 1987. 977. Yagisawa T, Takahashi K, Yamaguchi Y, et al: Adenovirus induced nephropathy in kidney transplant recipients. Transplant Proc 21:2097–2099, 1989. 978. Wreghitt TG, Gray JJ, Ward KN, et al: Disseminated adenovirus infection after liver transplantation and its possible treatment with ganciclovir [letter]. J Infect 19:88–89, 1989. 979. Hall WA, Martinez AJ, Dummer JS, et al: Central nervous system infections in heart and heart–lung transplant recipients. Arch Neurol 46:173–177, 1989. 980. Tolkoff-Rubin N, Hovingh G, Rubin R: Central nervous system infections. In Wijdicks E (ed): Neurologic Complications in Organ Transplant Recipients. Boston, Butterworth Heinemann, 1999, pp. 141–168. 981. Singh N, Husain S: Infections of the central nervous system in transplant recipients. Transplant Infect Dis 2:101–111, 2000. 982. de Groen PC, Aksamit AJ, Rakela J, Forbes GS, Krom RA: Central nervous system toxicity after liver transplantation. The role of cyclosporine and cholesterol. N Engl J Med 317:861–866, 1987. 983. Wijdicks E: Neurologic manifestations of immunosuppressive agents. In Wijdicks E (ed): Neurologic Complications in Organ Transplant Recipients. Boston, Butterworth Heinemann, 1999, pp. 127–140. 984. Ryning FW, McLeod R, Maddox JC, Hunt S, Remington JS: Probable transmission of Toxoplasma gondii by organ transplantation. Ann Intern Med 90:47–49, 1979. 985. Luft BJ, Naot Y, Araujo FG, Stinson EB, Remington JS: Primary and reactivated toxoplasma infection in patients with cardiac transplants. Clinical spectrum and problems in diagnosis in a defined population. Ann Intern Med 99:27–31, 1983. 986. Rose AG, Uys CJ, Novitsky D, Cooper DK, Barnard CN: Toxoplasmosis of donor and recipient hearts after heterotopic cardiac transplantation. Arch Pathol Lab Med 107:368–373, 1983. 987. McGregor CG, Fleck DG, Nagington J, et al: Disseminated toxoplasmosis in cardiac transplantation. J Clin Pathol 37:74– 77, 1984. 988. Nagington J, Martin AL: Toxoplasmosis and heart transplantation [letter]. Lancet 2:679, 1983. 989. Hakim M, Esmore D, Wallwork J, English TA, Wreghitt T: Toxoplasmosis in cardiac transplantation. Br Med J (Clin Res Ed) 292:1108, 1986. 990. Britt RH, Enzmann DR, Remington JS: Intracranial infection in cardiac transplant recipients. Ann Neurol 9:107–119, 1981. 991. Luft BJ, Billingham M, Remington JS: Endomyocardial biopsy in the diagnosis of toxoplasmic myocarditis. Transplant Proc 18:1871–1873, 1986. 992. Michaels MG, Wald ER, Fricker FJ, del Nido PJ, Armitage J: Toxoplasmosis in pediatric recipients of heart transplants. Clin Infect Dis 14:847–851, 1992. 993. Wreghitt TG, Gray JJ, Pavel P, et al: Efficacy of pyrimethamine for the prevention of donor-acquired Toxoplasma gondii infection in heart and heart–lung transplant patients. Transplant Int 5:197–200, 1992. 994. Conti DJ, Rubin RH: Infection of the central nervous system in organ transplant recipients. Neurol Clin 6:241–260, 1988. 995. Ascher NL, Simmons RL, Marker S, Najarian JS: Listeria infec-

996. 997.

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tion in transplant patients. Five cases and a review of the literature. Arch Surg 113:90–94, 1978. Schroter GP, Weil RD: Listeria monocytogenes infection after renal transplantation. Arch Intern Med 137:1395–1399, 1977. Niklasson PM, Hambraeus A, Lundgren G,et al: Listeria encephalitis in five renal transplant recipients. Acta Med Scand 203:181– 185, 1978. Tilney NL, Kohler TR, Strom TB: Cerebromeningitis in immunosuppressed recipients of renal allografts. Ann Surg 195:104– 109, 1982. Armstrong RW, Fung PC: Brainstem encephalitis (rhombencephalitis) due to Listeria monocytogenes: Case report and review. Clin Infect Dis 16:689–702, 1993. Stamm AM, Smith SH, Kirklin JK, McGiffin DC: Listerial myocarditis in cardiac transplantation. Rev Infect Dis 12:820–823, 1990. MacGowan AP, Marshall RJ, MacKay IM, Reeves DS: Listeria faecal carriage by renal transplant recipients, haemodialysis patients and patients in general practice: Its relation to season, drug therapy, foreign travel, animal exposure and diet. Epidemiol Infect 106:157–166, 1991. Gaillard JL, Berche P, Frehel C, Gouin E, Cossart P: Entry of L. monocytogenes into cells is mediated by internalin, a repeat protein reminiscent of surface antigens from gram-positive cocci. Cell 65:1127–1141, 1991. Schlech WFd, Lavigne PM, Bortolussi RA, et al: Epidemic listeriosis—Evidence for transmission by food. N Engl J Med 308:203–206, 1983. Watson GW, Fuller TJ, Elms J, Kluge RM: Listeria cerebritis: Relapse of infection in renal transplant patients. Arch Intern Med 138:83–87, 1978. Larner AJ, Conway MA, Mitchell RG, Forfar JC: Recurrent Listeria monocytogenes meningitis in a heart transplant recipient. J Infect 19:263–266, 1989. Peetermans WE, Endtz HP, Janssens AR, van den Broek PJ: Recurrent Listeria monocytogenes bacteraemia in a liver transplant patient. Infection 18:107–108, 1990. Moellering RC Jr, Medoff G, Leech I, Wennersten C, Kunz LJ: Antibiotic synergism against Listeria monocytogenes. Antimicrob Agents Chemother 1:30–34, 1972. Scheer MS, Hirschman SZ: Oral and ambulatory therapy of Listeria bacteremia and meningitis with trimethoprim–sulfamethoxazole. Mt Sinai J Med 49:411–414, 1982. Spitzer PG, Hammer SM, Karchmer AW: Treatment of Listeria monocytogenes infection with trimethoprim–sulfamethoxazole: Case report and review of the literature. Rev Infect Dis 8:427– 430, 1986. Agarwal A, Gupta A, Sakhuja V, et al: Retinitis following disseminated cryptococcosis in a renal allograft recipient. Efficacy of oral fluconazole. Acta Ophthalmol 69:402–405, 1991. Schroter GP, Temple DR, Husberg BS, Weid RD, Starzl TE: Cryptococcosis after renal transplantation: Report of ten cases. Surgery 79:268–277, 1976. Ellner JJ, Bennett JE: Chronic meningitis. Medicine 55:341–369, 1976. Bennett JE, Dismukes WE, Duma RJ, et al: A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 301:126–131, 1979. Hellman RN, Hinrichs J, Sicard G, et al: Cryptococcal pyelonephritis and disseminated cryptococcosis in a renal transplant recipient. Arch Intern Med 141:128–130, 1981.

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1015. Plunkett JM, Turner BI, Tallent MB, Johnson HK: Cryptococcal septicemia associated with urologic instrumentation in a renal allograft recipient. J Urol 125:241–242, 1981. 1016. Conti DJ, Tolkoff-Rubin NE, Baker GP Jr, et al: Successful treatment of invasive fungal infection with fluconazole in organ transplant recipients. Transplantation 48:692–695, 1989. 1017. Weiland D, Ferguson RM, Peterson PK, et al: Aspergillosis in 25 renal transplant patients. Epidemiology, clinical presentation, diagnosis, and management. Ann Surg 198:622–629, 1983. 1018. Montero CG, Martinez AJ: Neuropathology of heart transplantation: 23 cases. Neurology 36:1149–1154, 1986. 1019. Green M, Wald ER, Tzakis A, Todo S, Starzl TE: Aspergillosis of the CNS in a pediatric liver transplant recipient: Case report and review. Rev Infect Dis 13:653–657, 1991. 1020. Rubin R, Weinstein L: Salmonellosis: Microbiologic, Pathologic and Clinical Features. New York, Stratton Intercontinental, 1977. 1021. Smith EJ, Milligan SL, Filo RS: Salmonella mycotic aneurysm after renal transplantation. South Med J 74:1399–1401, 1981. 1022. Berk MR, Meyers AM, Cassal W, Botha JR, Myburgh JA: Nontyphoid salmonella infections after renal transplantation. A serious clinical problem. Nephron 37:186–189, 1984. 1023. Samra Y, Snaked Y, Maier MK: Nontyphoid salmonellosis in renal transplant recipients: Report of five cases and review of the literature. Rev Infect Dis 8:431–440, 1986. 1024. Dhar JM, al-Khader AA, al-Sulaiman M, al-Hasani MK: Nontyphoid salmonella in renal transplant recipients: A report of twenty cases and review of the literature. Q J Med 78:235–250, 1991. 1025. Wade JJ, Rolando N, Hayllar K, et al: Bacterial and fungal infections after liver transplantation: An analysis of 284 patients. Hepatology 21:1328–1336, 1995. 1026. Patel R, Badley AD, Larson-Keller J, et al: Relevance and risk factors of enterococcal bacteremia following liver transplantation. Transplantation 61:1192–1197, 1996. 1027. George DL, Arnow PM, Fox A, et al: Patterns of infection after pediatric liver transplantation. Am J Dis Child 146:924–929, 1992. 1028. King RW Jr, Kraikitpanitch S, Lindeman RD: Subcutaneous nodules caused by Histoplasma capsulatum [letter]. Ann Intern Med 86:586–587, 1977. 1029. Kauffman CA, Israel KS, Smith JW, et al: Histoplasmosis in immunosuppressed patients. Am J Med 64:923–932, 1978. 1030. Davies SF, Khan M, Sarosi GA: Disseminated histoplasmosis in immunologically suppressed patients. Occurrence in a nonendemic area. Am J Med 64:94–100, 1978. 1031. Davies SF, Sarosi GA, Peterson PK, et al: Disseminated histoplasmosis in renal transplant recipients. Am J Surg 137:686–691, 1979. 1032. Peterson PK, Dahl MV, Howard RJ, Simmons RL, Najarian JS: Mucormycosis and cutaneous histoplasmosis in a renal transplant recipient. Arch Dermatol 118:275–277, 1982. 1033. Deresinski SC, Stevens DA: Coccidioidomycosis in compromised hosts. Experience at Stanford University Hospital. Medicine 54:377–395, 1975. 1034. Bayer AS, Yoshikawa TT, Galpin JE, Guze LB: Unusual syndromes of Coccidioidomycosis: Diagnostic and therapeutic considerations: A report of 10 cases and review of the English literature. Medicine 55:131–152, 1976. 1035. Schroter GP, Bakshandeh K, Husberg BS, Well RD: Coccidioidomycosis and renal transplantation. Transplantation 23:485–489, 1977.

1036. Cohen IM, Galgiani JN, Potter D, Ogden DA: Coccidioidomycosis in renal replacement therapy. Arch Intern Med 142:489– 494, 1982. 1037. Gallis HA, Berman RA, Cate TR, et al: Fungal infection following renal transplantation. Arch Intern Med 135:1163–1172, 1975. 1038. Serody JS, Mill MR, Detterbeck FC, Harris DT, Cohen MS: Blastomycosis in transplant recipients: Report of a case and review. Clin Infect Dis 16:54–58, 1993. 1039. Mayer JM, Nimer L, Carroll K: Isolated pulmonary aspergillar infection in cardiac transplant recipients: Case report and review. Clin Infect Dis 15:698–700, 1992. 1040. Sridhar NR, Tchervenkov JI, Weiss MA, Hijazi YM, First MR: Disseminated histoplasmosis in a renal transplant patient: A cause of renal failure several years following transplantation. Am J Kidney Dis 17:719–721, 1991. 1041. Benedict LM, Kusne S, Torre-Cisneros J, Hunt SJ: Primary cutaneous fungal infection after solid-organ transplantation: Report of five cases and review [see comments]. Clin Infect Dis 15:17– 21, 1992. 1042. Durand F, Bernuau J, Dupont B, et al: Aspergillus intraabdominal abscess after liver transplantation successfully treated with itraconazole. Transplantation 54:734–735, 1992. 1043. Kusne S, Torre-Cisneros J, Manez R, et al: Factors associated with invasive lung aspergillosis and the significance of positive Aspergillus culture after liver transplantation. J Infect Dis 166: 1379–1383, 1992. 1044. Le Conte P, Blanloeil Y, Michel P, Francois T, Paineau J: Cutaneous aspergillosis in a patient with orthotopic hepatic transplantation. Transplantation 53:1153–1154, 1992. 1045. Rattazzi LC, Simmons RL, Spanos PK, Bradford DS, Najarian JS: Successful management of miliary tuberculosis after renal transplantation. Am J Surg 130:359–361, 1975. 1046. Oliver WA: Tuberculosis in renal transplant patients. Med J Aust 1:828–829, 1976. 1047. Bell TJ, Williams GB: Successful treatment of tuberculosis in renal transplant recipients. J R Soc Med 71:265–268, 1978. 1048. Ascher NL, Simmons RL, Marker S, Klugman J, Najarian JS: Tuberculous joint disease in transplant patients. Am J Surg 135:853–856, 1978. 1049. Riska H, Kuhlback B: Tuberculosis and kidney transplantation. Acta Med Scand 205:637–640, 1979. 1050. Vaz AJ: Miliary tuberculosis and the adult respiratory distress syndrome in a renal transplant recipient [letter]. Chest 75:412, 1979. 1051. Lloveras J, Peterson PK, Simmons RL, Najarian JS: Mycobacterial infections in renal transplant recipients. Seven cases and a review of the literature. Arch Intern Med 142:888–892, 1982. 1052. Coutts, II, Jegarajah S, Stark JE: Tuberculosis in renal transplant recipients. Br J Dis Chest 73:141–148, 1979. 1053. Spence RK, Dafoe DC, Rabin G, et al: Mycobacterial infections in renal allograft recipients. Arch Surg 118:356–359, 1983. 1054. Qunibi WY, al-Sibai MB, Taher S, et al: Mycobacterial infection after renal transplantation—Report of 14 cases and review of the literature. Q J Med 77:1039–1060, 1990. 1055. al-Sulaiman MH, Dhar JM, al-Hasani MK, Haleem A, AlKhader A: Tuberculous interstitial nephritis after kidney transplantation. Transplantation 50:162–164, 1990. 1056. Higgins RM, Cahn AP, Porter D, et al: Mycobacterial infections after renal transplantation. Q J Med 78:145–153, 1991. 1057. Sterneck M, Ferrell L, Ascher N, et al: Mycobacterial infection after liver transplantation: A report of three cases and review of the literature. Clin Transplant 6:55–61, 1992.

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1058. Sundberg R, Shapiro R, Darras F, et al: A tuberculosis outbreak in a renal transplant program. Transplant Proc 23:3091–3092, 1991. 1059. Horsburgh CR Jr, Feldman S, Ridzon R: Practice guidelines for the treatment of tuberculosis [In Process Citation]. Clin Infect Dis 31:633–639, 2000. 1060. Thomas PA Jr, Mozes MF, Jonasson O: Hepatic dysfunction during isoniazid chemoprophylaxis in renal allograft recipients. Arch Surg 114:597–599, 1979. 1061. Higgins R, Kusne S, Reyes J, et al: Mycobacterium tuberculosis after liver transplantation: Management and guidelines for prevention. Clin Transplant 6:81–90, 1992. 1062. Meyers BR, Papanicolaou GA, Sheiner P, Emre S, Miller C: Tuberculosis in orthotopic liver transplant patients: Increased toxicity of recommended agents; cure of disseminated infection with nonconventional regimens. Transplantation 69:64–69, 2000. 1063. Novick RJ, Moreno-Cabral CE, Stinson EB, et al: Nontuberculous mycobacterial infections in heart transplant recipients: A seventeen-year experience. J Heart Transplant 9:357–363, 1990. 1064. Cruz N, Ramirez-Muxo O, Bermudez RH, Santiago-Delpin EA: Pulmonary infection with M. kansasii in a renal transplant patient. Nephron 26:187–188, 1980. 1065. Bolivar R, Satterwhite TK, Floyd M: Cutaneous lesions due to Mycobacterium kansasii. Arch Dermatol 116:207–208, 1980. 1066. Trulock EP, Bolman RM, Genton R: Pulmonary disease caused by Mycobacterium chelonae in a heart–lung transplant recipient with obliterative bronchiolitis. Am Rev Respir Dis 140:802–805, 1989. 1067. Weber J, Mettang T, Staerz E, Machleidt C, Kuhlman U: Pulmonary disease due to Mycobacterium xenopi in a renal allograft recipient: Report of a case and review. Rev Infect Dis 11:964– 969, 1989. 1068. Gombert ME, Goldstein EJ, Corrado ML, Stein AJ, Butt KM: Disseminated Mycobacterium marinum infection after renal transplantation. Ann Intern Med 94:486–487, 1981. 1069. Davis BR, Brumbach J, Sanders WJ, Wolinsky E: Skin lesions caused by Mycobacterium haemophilum. Ann Intern Med 97: 723–724, 1982. 1070. Neeley SP, Denning DW: Cutaneous Mycobacterium thermoresistibile infection in a heart transplant recipient. Rev Infect Dis 11:608–611, 1989. 1071. Heironimus JD, Winn RE, Collins CB: Cutaneous nonpulmonary Mycobacterium chelonei infection. Successful treatment with sulfonamides in an immunosuppressed patient. Arch Dermatol 120:1061–1063, 1984.

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1072. Cooper JF, Lichtenstein MJ, Graham BS, Schaffner W: Mycobacterium chelonae: A cause of nodular skin lesions with a proclivity for renal transplant recipients. Am J Med 86:173–177, 1989. 1073. Kochhar R, Indudhara R, Nagi B, Yadav RV, Mehta SK: Colonic tuberculosis due to atypical mycobacteria in a renal transplant recipient [letter]. Am J Gastroenterol 83:1435–1436, 1988. 1074. Patel R, Roberts GD, Keating MR, Paya CV: Infections due to nontuberculous mycobacteria in kidney, heart, and liver transplant recipients. Clin Infect Dis 19:263–273, 1994. 1075. Munoz RM, Alonso-Pulpon L, Yebra M, et al: Intestinal involvement by nontuberculous mycobacteria after heart transplantation. Clin Infect Dis 30:603–605, 2000. 1076. Diagnosis and treatment of disease caused by nontuberculous mycobacteria [published erratum appears in Am Rev Respir Dis 143(1):204, 1991] [see comments]. Am Rev Respir Dis 142:940– 953, 1990. 1077. Burroughs M, Moscone A: Immunization of pediatric solid organ transplant candidates and recipients. Clin Infect Dis 30:857–869, 2000. 1078. Loinaz C, de Juanes JR, Gonzalez EM, et al: Hepatitis B vaccination results in 140 liver transplant recipients. Hepatogastroenterology 44:235–238, 1997. 1079. Blumberg EA, Albano C, Pruett T, et al: The immunogenicity of influenza virus vaccine in solid organ transplant recipients. Clin Infect Dis 22:295–302, 1996. 1080. Admon D, Engelhard D, Strauss N, Goldman N, Zakay-Rones Z: Antibody response to influenza immunization in patients after heart transplantation. Vaccine 15:1518–1522, 1997. 1081. Blumberg EA, Fitzpatrick J, Stutman PC, Hayden F, Brozena SC: Safety of influenza vaccine in heart transplant recipients. J Heart Lung Transplant 17:1075–1080, 1998. 1082. Gershon AA: Immunizations for pediatric transplant patients. Kidney Int Suppl 43:S87–S90, 1993. 1083. Pediatrics AAo: Poliovirus infections. In Georges M (ed): Red Book: Report of the Committee on Infectious Disease. Elk Grove Village, IL, American Academy of Pediatrics, 1997, pp. 424–433. 1084. Nkowane BM, Wassilak SG, Orenstein WA, et al: Vaccineassociated paralytic poliomyelitis. United States: 1973 through 1984. JAMA 257:1335–1340, 1987. 1085. Zamora I, Simon JM, Da Silva ME, Piqueras AI: Attenuated varicella virus vaccine in children with renal transplants. Pediatr Nephrol 8:190–192, 1994.

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Surgical Aspects of Infection in the Compromised Host A. BENEDICT COSIMI 1. Introduction

Steadily increasing numbers of patients with compromised immune responsiveness are being encountered in current surgical practice. The spectrum of these patients (Table 1) ranges from those with severely impaired host resistance, such as victims of acquired immunodeficiency syndrome (AIDS) or immunosuppressed transplant recipients, to those with more subtle defects, as occur in diabetics and those at the extremes of age. These patients should be expected to respond to inflammation and surgical stress quite differently than do normal individuals. Thus, it is not unusual to encounter as great as a 12-fold increase in postoperative sepsis and mortality1 in patients whose acute condition is complicated by factors that diminish host defenses. The surgeon called on to evaluate a problem requiring possible surgical intervention in such patients must be aware of the special considerations that have been found to adversely influence their prognosis. Successful operative intervention is usually not possible following the solo approach employed for acute focal or traumatic conditions in the otherwise healthy individual. For compromised hosts, close collaboration and planning with the internist, infectious disease consultant, and anesthetist are essential. This chapter presents a number of guidelines found helpful in the diagnostic approach, preoperative preparation, intraoperative techniques, and A. Benedict Cosimi Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114. Clinical Approach to Infection in the Compromised Host (Fourth Edition), edited by Robert H. Rubin and Lowell S. Young. Kluwer Academic/Plenum Publishers, New York, 2002.

postoperative management of infectious conditions in these patients, illustrated by a review of typically encountered cases.

2. Diagnostic Approach

Since impaired immune responsiveness not only provides the soil for atypical infectious conditions but also masks the commonly expected signs and symptoms of the inflammatory process (Table 2), an unusually aggressive diagnostic approach must often be pursued in these patients. Their outcome is almost entirely dependent on the rapidity with which the correct diagnosis is established and specific therapy is instituted. In our experience with pulmonary infections in renal transplant recipients, for example, the overall mortality of patients diagnosed in the first 5 days of illness was 21%, as opposed to 65% for those whose diagnosis was not clarified until after 5 days of illness.2 Others have emphasized that therapeutic delay for pulmonary infection in immunocompromised patients is, in fact, almost universally fatal and that the specific diagnosis is too often made only at postmortem examination.3,4 2.1. Diffuse Pulmonary Infiltrates in the Immunocompromised Host Illustrative Cases 1 and 2 A 54-year-old renal allograft recipient (Case 1) was admitted with a history of low-grade fevers and dyspnea of 2 months’ duration. His past history was complicated, including kidney transplantation 10 years earlier and then retransplantation 2 years earlier for recurrent membranous 681

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glomerulonephritis. He had been maintained on cyclosporine (CyA), azathioprine, and prednisone and had good allograft function. Prophylactic trimethoprim–sulfamethoxazole (TMP-SMX) therapy had been discontinued, according to protocol, at 6 months after the second renal transplant. Two months prior to admission, cough, low-grade fever, and malaise were first noted. Chest radiography showed only linear scarring at the bases. In view of negative sputum cultures, a presumptive diagnosis of viral upper respiratory infection was made and his prednisone and azathioprine dosages were reduced. Nevertheless, the respiratory symptoms persisted. Subsequently, a 5-day empirical course of azithromycin was administered, but his dyspnea continued to worsen. He was then referred to our institution for further evaluation. At the time of admission, he appeared acutely ill with fever and severe hypoxemia while breathing room air. Chest radiography showed bilateral hilar infiltrates consistent with infection or fluid overload. Intensive diuresis only marginally improved the respiratory function. Induced sputum smears and cultures remained nondiagnostic. By 48 hr after admission, tracheal intubation for ventilator-assisted respiration became necessary. On the second hospital day, a thoracoscopically obtained lung biopsy confirmed the presumptive diagnosis of Pneumocystis carinii pneumonia, which ultimately responded to high dosage TMP-SMX therapy. A 60-year-old woman (Case 2) had been treated for 5 months with cyclophosphamide, methotrexate, and 5-fluorouracil for stage II breast cancer. She was now admitted with fever and respiratory distress of several days’ duration. Chest radiography showed a focal consolidation in the right lung. When the transtracheal sputum aspirate yielded Streptococcus pneumoniae, ampicillin and gentamicin therapy were begun.

Sequential radiographs showed progressive involvement of both lung fields. Further sputum cultures were not helpful. Despite the addition of erythromycin and TMP-SMX, her symptoms worsened, requiring tracheal intubation for assisted ventilation. An open lung biopsy revealed drug-induced pneumonitis with no evidence of significant infection. Following the addition of steroid therapy, the patient’s condition rapidly improved, and she was discharged on a different adjuvant chemotherapy regimen for her breast cancer. Comment. These cases emphasize the nature of the challenge the physician faces when assessing diffuse pulmonary infiltrates in an immunosuppressed patient. The differential diagnosis must include not only the usual bacterial or viral pathogens but also noninfectious causes, such as drug-induced pneumonitis,5 pulmonary emboli or edema, and, most importantly, invasion by opportunistic agents such as Pneumocystis or Legionella.6 The role of the surgeon in this assessment is to provide, as efficiently and safely as possible, appropriate secretions or tissues for study. Although empirical therapy is often begun immediately in these critically ill patients, one must expeditiously pursue clarification of the definitive diagnosis before, as in Case 1, the potentially treatable process has become life-threatening.

Spontaneously expectorated sputum specimens from immunocompromised patients are often nondiagnostic. We, therefore, favor obtaining an induced sputum as the initial approach to isolation of the infective agent. In our experience, this simple noninvasive procedure provides the specific diagnosis in approximately 50% of individuals with diffuse infiltrates, being most useful in patients with P. carinii pneumonia. If the induced sputum is nondiagnostic, early use of more invasive diagnostic approaches is essential. These include bronchoscopic lavage or transbronchial biopsy, percutaneous lung aspiration biopsy, and video-assisted thoracoscopic or even open lung biopsy. We favor early thoracoscopic biopsy, since the ample tissue obtained almost always provides the diagnosis, whereas the “less invasive” procedures not infrequently provide inadequate specimens and result in disappointing delays. Although some investigators continue to question the impact of lung biopsy in the management of these patients, many have concluded it is essential for early specific treatment. An unexpected diagnosis or change in therapy following lung biopsy has been reported in 45– 50% of immunocompromised patients.7,8 We have found that even open lung biopsy can be accomplished with relatively few complications using a limited intercostal incision through which the most obviously abnormal area is isolated using noncrushing clamps. After the wedge biopsy is obtained, the incised lung can be oversewn while the clamps maintain complete control of bleeding and air leakage. Similar results can be achieved using the automatic stapler for lung repair. Despite postoperative mechanical ventilation, bronchopleural fistula formation is seldom a problem. Nevertheless, even this limited procedure can lead to

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further complications in these fragile patients, so that most surgeons now favor thoracoscopic transpleural lung biopsy even for children.9 This video-assisted procedure allows for an aggressive approach in obtaining tissue for diagnostic purposes without fear of the possible complications associated with standard thoracotomy. There is not much more morbidity than with transbronchial biopsy, but the tissue obtained is far superior, with an 85% successful diagnostic rate being achieved in patients with diffuse infiltrates.

2.2. Focal Pulmonary Infiltrates or Nodule(s) in the Immunocompromised Host Illustrative Case 3 The patient was a 4-year-old male who underwent liver transplantation for biliary atresia. Induction immunosuppression included tacrolimus (FK506), azathioprine, and steroids. Primary nonfunction of the allograft necessitated emergency retransplantation on day 6. Excellent hepatic function was achieved by the second allograft, but methylprednisolone pulses and then a 10-day course of OKT3 monoclonal antibody were required for persistent rejection beginning on day 14. On day 21, a single colony of Aspergillus fumigatus was noted on routine surveillance sputum culture but the patient’s chest X-ray revealed only minimal atelectasis in the right upper lobe. At that point, the patient’s prophylactic antifungal therapy was changed from fluconazole to itraconazole. Over the following 10 days, several further sputum cultures became positive for Aspergillus and the right upper lobe pulmonary infiltrate progressed. Thoracic computerized tomography (CT) on day 31 revealed several nodular lesions in the right upper lung field. Liposomal amphotericin B therapy was begun and over the next 14 days the patient received a total of 60 mg/kg of this agent. Nevertheless, there was progression of the pulmonary process and head CT then revealed several lesions consistent with aspergillosis infection. Amphotericin B was therefore substituted for the liposomal preparation. Over the next 38 days, the patient received a total of more than 40 mg/kg of this agent. At that point, he developed seizures followed rapidly by brain death, presumably from hemorrhage into a cerebral lesion. Comment. Invasive pulmonary aspergillosis has been reported to occur in 1–4% of liver transplant recipients.10,11 At greatest risk are retransplant recipients, patients on high-dosage steroids, patients who have suffered vascular or biliary complications resulting in prolonged courses of antibiotics, and recipients whose transplant was required on an urgent basis or was accomplished with large-volume blood loss. Initial presentation may be only with unimpressive pulmonary infiltrates on chest X ray accompanied by low-grade fever. Bronchoscopy or even needle biopsy at this point are seldom diagnostic. Chest CT, however, may be useful in demonstrating pulmonary nodules at an early stage of the disease. Unfortunately, as in Case 3, there is often a delay in instituting appropriate medical therapy for invasive pulmonary aspergillosis and standard treatment in neutropenic patients or liver transplant recipients then fails in over 90% of the patients.10,12 In view of these dismal mortality rates, some groups have turned to aggressive early surgical resection of suspected localized disease.10 Survival rates of as high as 60% have been reported in patients undergoing resection of pulmonary masses within 7–10 days of the time that the diagnosis of aspergillosis was suggested clinically and confirmed by chest CT.

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2.3. Gastrointestinal Complications of the Immunosuppressed State Illustrative Case 4 A 61-year-old man was treated with azathioprine and prednisone after receiving a renal allograft from his daughter. With the onset of acute rejection 9 days after transplantation, the steroid dosage was sharply increased, and local graft irradiation was instituted. Renal function gradually improved, and tapering of the steroid dosage was begun. Six weeks after the transplant, the patient returned to his home in a neighboring state with normal allograft function while receiving azathioprine 125 mg/day and prednisone 20 mg/day. One week later, he complained of lower abdominal discomfort. He was evaluated at his community hospital, where a temperature of 101°F (38°C) was noted and the abdomen was described as slightly distended with moderate direct and rebound tenderness. Laboratory evaluation revealed a white blood cell (WBC) count of hematocrit (Hct) of 33%, and no abnormalities of hepatic or renal function. Surgical consultation recommended routine abdominal radiographs. Since these were normal and the patient had remained reasonably stable, admission and simple observation were advised. During the succeeding hours, the patient complained of increasing abdominal distention and discomfort. By 12 hr after admission, he had developed oliguria, hypotension, and restlessness consistent with gram-negative septicemia. When transfer to a transplant center and emergency laparotomy were finally accomplished, diffuse fecal peritonitis secondary to perforated sigmoid diverticulitis was found. Despite resection of the involved bowel with construction of an end-colostomy, extensive irrigation and drainage of the abdomen, and intensive postoperative supportive measures, the patient subsequently expired.

Illustrative Case 5 A 48-year-old man with a history of antitrypsin deficiency had undergone bilateral lung transplantation 2 months earlier. Maintenance immunosuppression with CyA, steroids, and azathioprine had resulted in good pulmonary rehabilitation. He presented with a 2-day history of diarrhea followed by lower abdominal discomfort. Evaluation revealed him to be afebrile, in moderate distress from the abdominal pain, but otherwise stable except for definite lower abdominal direct and rebound tenderness. Hematologic and serum chemistry studies revealed mild leukocytosis. Plain radiographs and ultrasound examination of the abdomen were not remarkable. Paracentesis produced several milliliters of thin, yellow fluid containing multiple neutrophils on microscopic examination. Abdominal CT with rectal contrast revealed colonic diverticulae and a small pelvic air-fluid level interposed between the bladder and the rectum. Emergency laparotomy performed within 4 hr of admission confirmed the preoperative diagnosis of perforated sigmoid colon which was treated by resection and end-sigmoid colostomy. Postoperatively, the patient recovered without incident. The colostomy was successfully closed as a subsequent procedure. Comment. Since the possible occult sites of acute inflammatory processes in the abdomen or retroperitoneum are numerous, accurate evaluation in this situation is perplexing. Furthermore, because of the host’s impaired response, typical findings of an acute abdominal catastrophe may be deceptively mild. In these compromised patients, active bowel sounds with continuing bowel movements and even diarrhea are not unusual, despite extensive peritoneal soilage. The impairment of the inflammatory response, unfortunately, also results in an inability to wall

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off the pathologic process so that irreversible disseminated sepsis may develop during even brief periods of hopeful observation. Most reports of colonic perforation in steroid-treated or uremic patients emphasize the paucity of symptoms, signs, and laboratory evidence of visceral perforation, leading to fatal delays in treatment or to an incorrect preoperative diagnosis in the majority of cases.13,14 This complication has been reported so frequently that some authorities suggest that there is a direct adverse effect of steroids on normal colon. Certainly, inhibition of the normal inflammatory response, antifibroblastic activity, and atrophy of lymphoid elements of the bowel wall could interfere with normal barriers to invasive infection by intraluminal bacteria. Thus, perforation may occur whether the colon was previously diseased or not and, indeed, has been observed in apparently normal areas of the bowel.15 This, plus the host’s inability to adequately localize the process, results in extensive contamination. Early clinical recognition of this problem, therefore, is essential, and perforation of the colon should always be a prime suspect in any steroid-treated patient with fever and abdominal symptoms. Paracentesis has been particularly helpful in this diagnosis, often yielding purulent fluid despite absence of free air on plain radiographs. If the diagnosis remains in doubt or to better localize the process, contrast radiographic studies of the lower gastrointestinal (GI) tract should not be delayed. In general, a water-soluble contrast agent is preferred, but establishment of the diagnosis of perforated colon with barium studies has been reported without the serious complication of barium peritonitis. Because of the often devastating consequences of perforated diverticulitis occurring posttransplantation, some centers have recommended that pretransplant diagnostic screening be performed on all potential candidates over 50 years of age.16 Prophylactic colonic resection is then advised for individuals found to have significant diverticular disease. A more recent review of this issue has concluded that such an aggressive approach does not accurately predict posttransplant complications and should probably be abandoned.17

As more potent immunosuppressive drugs have been introduced into clinical protocols, other infectious agents such as cytomegalovirus (CMV) and Epstein–Barr virus (EBV) have been added as either primary or comorbid factors in the pathophysiology of GI complications.18 CMV can present in a variety of forms ranging from asymptomatic infection, diagnosed by serologic or viral shedding studies, to symptomatic syndromes including a constellation of manifestations. These may include fever, myalgias, malaise, dyspnea, and leukopenia, and evidence of isolated organ involvement such as pneumonitis, retinitis, pancreatitis, hepatitis, GI hemorrhage or perforation, and even multiple organ system failure. Recently, several groups have emphasized that the pattern of CMV disease appears to be changing as it more frequently affects the GI tract in severely immunocompromised hosts.19,20 CMV infection can affect the GI tract from the esophagus to the rectum. The most common manifestations are abdominal pain, GI bleeding, and diarrhea. GI perforation is not infrequent. Some of the more interesting presentations of CMV GI disease are related to the

development of pneumatosis intestinalis21 or ischemic vasculitis.22 The pathogenesis of these conditions is not well understood, but their early diagnosis, usually by endoscopy, so that specific treatment can be instituted is essential. Illustrative Case 6 This patient was a 60-year-old man with severe encephalopathy and recurrent variceal bleeding resulting from chronic non-A, non-B hepatitis. He underwent semiemergent hepatectomy and orthotopic liver replacement following the most recent episode of variceal bleeding. Both donor and recipient were serologically positive for CMV. The operative procedure was complicated by significant blood loss requiring transfusion of 30 liters of blood products. Intraoperative anuria persisted into the early recovery period prompting the administration of OKT3 monoclonal antibody rather than cyclosporine as initial induction immunosuppression.23 Following a 10-day course of OKT3 therapy, the patient’s renal function recovered and he was subsequently maintained on CyA, azathioprine, and prednisone. The patient’s recovery, however, was further delayed by an episode of aspiration pneumonitis requiring reintubation and intensive antibiotic therapy. By 3 weeks posttransplantation, the patient was extubated and normal hepatic and renal function had returned. He began to complain of moderate abdominal pain and intermittent diarrhea but seemed to be slowly recovering. Abdominal CT revealed no significant abnormalities. Despite symptomatic and antacid therapy, there was no improvement; 10 days later, intermittent upper GI bleeding developed. Endoscopic examination revealed diffuse mucosal ulcerations which on biopsy confirmed tissue-invasive CMV. Despite institution of ganciclovir therapy at that point, the patient developed multiple organ failure and eventually expired. Comment. CMV infection is perhaps the single most important infection affecting transplant recipients.24 Typically CMV syndromes become manifest 1–4 months posttransplantation, but, as in this patient, these infections may occur earlier in hepatic allograft recipients. The important lesson of this case is that the surgeon evaluating vague abdominal symptoms must consider CMV infection as early as 3 weeks posttransplantation, even in the previously seropositive recipient. This epidemiologic form of the disease apparently results from reactivation of the patient’s latent virus and results in symptomatic infection in approximately 20% of previously seropositive recipients.24 A more aggressive diagnostic approach including early endoscopy in this patient with vague abdominal symptoms probably would have revealed the tissue-invasive CMV and led to more timely institution of potentially lifesaving therapy.25

Immunosuppressed allograft recipients are also at significantly increased risk for the development of virusrelated malignant lymphoma and other lymphoproliferative disorders. The risk is increased when the patient is treated for rejection with repeated courses of high-dosage immunosuppression or with multiple agents. The interval between organ transplantation and the development of lymphoma is frequently short, often only a few months, when CyA or FK506 is part of the immunosuppressive regimen. In contrast, the average time to the development of lymphoma is usually over a year in allograft recipients

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treated with immunosuppressive regimens that do not include these calcineurin inhibitors. There is strong evidence for the association of EBV infection with posttransplantation lymphoproliferative disorders of B-cell lineage. Nearly all patients have serologic evidence of primary or reactivation infection with EBV.26 Patients receiving immunosuppression without CyA or FK506 are at greatest risk for extranodal disease, with a striking predilection for the development of lymphoma of the central nervous system.27 In contrast, in patients receiving calcineurin inhibitors, the disease more often involves lymph nodes and CNS lymphoma develops much less frequently. The single most common extranodal site for the development of lymphoproliferative disease in patients treated with CyA or FK506 is the GI tract.26,28 Both the small intestine and the large intestine can be involved, and the patients can present with bleeding, perforation, or even intussusception. Illustrative Case 7 A 56-year-old woman underwent cadaver donor kidney transplantation 5 months prior to the present admission. She received immunosuppression with CyA, azathioprine, and prednisone. Her early postoperative course was complicated by several acute rejection episodes which were successfully reversed with high-dosage steroids and a 12day course of OKT3 monoclonal antibody. One month after the most recent episode, she was readmitted with fever and pulmonary infiltrates.

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CMV was cultured from urine and buffy coat blood. Treatment with ganciclovir was instituted and the patient’s pulmonary status gradually resolved. She then began to note mild, diffuse abdominal pain and diarrhea without localizing peritoneal signs. Five days after the onset of these abdominal symptoms, a routine X-ray film of the chest revealed pneumoperitoneum. Emergency laparotomy disclosed a perforation of the transverse colon associated with an ulcerated mucosal mass. Right colectomy with terminal ileostomy and suture closure of the distal transverse colon were performed. The resected specimen revealed multiple mucosal lesions (Fig. 1), which on microscopic examination were consistent with B-cell lymphoma (Fig. 2). Despite withdrawal of immunosuppressive therapy, recurrent bleeding necessitated several subsequent bowel resections, all of which revealed evidence of lymphoma. The patient ultimately expired. Comment. The features of this case are consistent with either CMVmediated enteritis or the posttransplant lymphoproliferative disorder (PTLD) typically associated with EBV. The incidence of PTLD varies29 according to the organ transplant and the type and degree of immunosuppression (Table 3). As in the case presented above, patients who develop these complications in the early posttransplant period have typically received an immunosuppressive regimen that included CyA or FK506, often in combination with one of the antilymphocyte serum preparations such as ATG or OKT3, during the previous several months. Methods proposed for treating these lymphoproliferative disorders vary widely. They include surgical excision (especially of tumors localized to the GI tract), decreased immunosuppression, acyclovir therapy, immunoglobulin infusions, radiation therapy, and chemotherapy. Although favorable survival results have been reported,30 most centers continue to observe a significant mortality rate in these patients often because of the insidious progression of the disease before it is finally diagnosed by catastrophic complications as occurred in our patient.

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Another bowel complication being encountered with increasing frequency in the elderly or otherwise immunocompromised patient is intestinal infarction unrelated to major vascular occlusion. Although some investigators dispute the vascular etiology of the condition, it continues to be termed nonocclusive mesenteric ischemia. Illustrative Case 8 A 46-year-old man received a cadaver donor renal allograft in the right iliac fossa, after which he was treated with cyclosporine and prednisone. He was continued on hemodialysis during a period of resolving acute tubular necrosis. During this interval, he received sodium poly-

SURGICAL ASPECTS OF INFECTION styrene (Kayexalate) in sorbitol enemas on several occasions for treatment of hyperkalemia. Left-sided abdominal pain and tenderness and passage of grossly bloody stool occurred on the fifth posttransplant day. This was accompanied by worsening hyperkalemia despite hemodialysis. Plain radiographs of the abdomen were unremarkable. Sigmoidoscopy revealed pale rectal mucosa up to 18 cm, where the mucosa appeared dusky, edematous, and ulcerated. Biopsy revealed only severe inflammation. Barium enema revealed an area of narrowing in the distal sigmoid colon with irregularity and shallow ulcerations without perforation. At exploratory laparotomy, the left colon was severely ischemic with multiple areas of infarction despite pulsatile mesenteric vessels along the entire segment of involved bowel. A left colectomy with endtransverse colostomy and a distal mucous fistula were performed. Pathology of the resected specimen revealed prominent edema of all layers of the bowel with a diffuse, inflammatory infiltrate, extensive mucosal loss, and several areas of full-thickness infarction. Postoperatively, the patient’s immunosuppressive therapy was markedly reduced. He recovered rapidly and was discharged home with adequate allograft function 2 weeks later. He has subsequently had reestablishment of GI continuity and continues to do well with good renal allograft function. Comment. Various etiologic mechanisms for this condition have been suggested, including steroid-induced vasculitis, connective tissue alterations which reduce mucosal resistance to bacteria, and the toxic effects of Kayexalate enemas.31 Similar lesions have also been described in trauma victims who have suffered periods of hypotension. Undoubtedly, numerous other factors, including host immunoincompetence, postoperative blood volume changes, hypotension, marginally adequate blood supply secondary to atherosclerotic disease, uremia, and postoperative coagulopathies, are operative with differing degrees of importance in these individuals. The common denominator in all reports, however, is that delay in establishing the diagnosis in the compromised host almost invariably leads to a fatal outcome. In some patients, the acute symptomatology is preceded by reasonably prolonged periods of vague abdominal distress, malaise, and low-grade fevers. As in this patient, the development of difficult-to-control hyperkalemia or metabolic acidosis should serve as a diagnostic clue that intra-abdominal ischemic injury may be present. The surgeon should proceed with diagnostic evaluation on the premise that bowel pathology is likely unless proved otherwise. Confirmatory signs, such as guaiacpositive or bloody stool, demand immediate sigmoidoscopic examination which may reveal pale or cyanotic mucosa or areas of edema and ulceration. Barium enema in the early, less severe stages may show only “thumbprinting” secondary to hemorrhage into the bowel wall. This may progress to narrowing of the lumen and pseudopolyploid filling defects, indicating mucosal necrosis, and finally to perforation as total bowel wall infarction ensues. Obviously, hope of salvaging these patients is dependent on definitive surgical therapy during the early, more difficult to diagnose stages.

A GI complication that appears to be closely related to, if not a variant of, non-occlusive mesenteric ischemia is that of neutropenic colitis. Other common names for this condition are typhilitis or the ileocolic syndrome. Although most cases are associated with chemotherapy, the disease has also been described in transplant recipients and patients with aplastic anemia. The syndrome consists of fever, diarrhea, and abdominal pain—always in the setting of severe neutropenia. The pathogenesis is

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believed to be that of chemotherapy-induced damage to the intestinal mucosa which, when coupled with neutropenia, allows bacterial invasion of the bowel wall. This then leads to variable degrees of necrosis with a predilection for the wall of the terminal ileum, cecum, and right colon. Several reviews have documented that this condition is the most common intra-abdominal disease discovered in neutropenic patients undergoing emergency laparotomy.32,33 Of greatest importance to the surgical consultant has been the finding that many patients with this condition respond to bowel rest and antibiotics without the need for bowel resection.34 Thus, careful sequential examinations are essential to distinguish the patients with resolving signs from those with a surgical condition. An excellent algorithm for such evaluation has been developed.35

2.4. Occult Intra-abdominal Sources of Fever and Infection In patients with occult fever but no indication of an acute intra-abdominal catastrophe, the search for a surgically drainable collection often requires more sophisticated studies. Illustrative Case 9 An 18-year-old patient with end-stage renal disease was being supported with hemodialysis while awaiting renal transplantation when he began having intermittent fevers in the range of 100.4–101.2°F (38– 39°C). Five years earlier, he had undergone a right nephrectomy after several unsuccessful attempts to reconstruct a congenitally deformed drainage system. Renal function of the successfully reconstructed left kidney provided a marginal creatinine clearance, adequate to delay the need for dialysis during the succeeding 4½ years. With the onset of the febrile course, there was occasional right-sided abdominal distress but no significant GI symptoms. CBT suggested a fluid collection in the right lower quadrant. The patient was taken to surgery with a preoperative diagnosis of periappendiceal abscess. An isolated, encapsulated 200-ml collection of white, purulent fluid that subsequently cultured Staphylococcus aureus was drained from the retroperitoneal site of the previous nephrectomy. A normal intraperitoneal appendix was removed as well. The postoperative and subsequent posttransplant course were benign. Comment. Ultrasonography, CBT, or magnetic resonance imaging (MRI) have proved to be invaluable in the assessment of immunocompromised hosts with occult fevers. Most current reports favor ultrasound or CT-guided percutaneous aspiration of identified collections as the initial therapeutic approach.36 Ultimately, however, exploratory laparotomy may be required as the definitive diagnostic and therapeutic maneuver. Previous, apparently healed surgical sites should always be regarded with an index of suspicion in an immunocompromised patient. Hidden infections may be demonstrated months or even years after apparent uncomplicated healing. Needle aspiration or ultrasonography of areas of even minimal tenderness, erythema, or questionable fluctuance are often successful in revealing incredibly extensive underlying collections.

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Obviously, an awareness of the likelihood of specific infectious complications aids the surgical evaluation. As noted, wound infections and colonic complications are seen commonly in the immunocompromised host. Another common but frequently overlooked condition is the occult perianal abscess which should always be carefully excluded, particularly in neutropenic patients. Appendicitis is less common in immunosuppressed patients and can be difficult to diagnose even following perforation.37 In neutropenic children receiving chemotherapy, abdominal pain and fever have been considered sufficient findings to justify immediate laparotomy with appendectomy being anticipated. For adults, we have found newer diagnostic tools, such as helical computed tomography (Fig. 3), to be very useful, providing rapid diagnosis with greater than 90% accuracy.38,39 Acute pancreatitis, although its etiology remains obscure, unfortunately, is not unusual in immunosuppressed patients. Illustrative Case 10 This patient had received a cadaver donor renal allograft 4 months earlier. Excellent allograft function had been maintained with an immunosuppressive regimen including CyA and prednisone. The patient was admitted with complaints of abdominal pain, “bloating,” and fever. He was found to have a serum amylase level of 515 units/liter (N < 100). With intravenous alimentation and conservative therapy, the symptoms resolved but the amylase level fell only to the 200 range. Ultrasound and CT studies identified no abscess cavities but suggested persistent edema of the tail of the pancreas. With each attempt to resume oral alimentation, recurrent pain and low-grade fever developed. Exploratory laparotomy revealed an edematous pancreas with multiple abscesses in the tail. Distal pancreatectomy provided complete relief of symptoms. Four months later, the patient returned with similar findings while

being maintained on cyclosporine and prednisone. Ultimately, subtotal pancreatectomy was required, again revealing multiple small abscesses in the gland. Following this, he has remained asymptomatic. Comment. The incidence of acute focal pancreatitis in steroidtreated patients has been reported to be as great as 28.5% versus only 3.7% of matched but non-steroid-treated controls.40 In allograft recipients, the incidence of clinically significant pancreatitis has been reported to range between 2 and 20%.41,42 The mechanism whereby steroids could produce pancreatitis may be ductal ectasia and epithelial metaplasia, which favor obstruction. Perhaps of more significance is the fact that many of these patients have coincident severe infection, often of viral etiology. This may be the important underlying factor, with even direct viral infection of the pancreas being a possibility. Azathioprine has also been implicated as an etiologic agent for pancreatitis, emphasizing the probable multifactorial origin.43 The mortality in these patients can be as high as 70%. The major factors responsible for this high mortality are the considerable delay in establishing the diagnosis and the unusually high incidence of later complications such as pseudocyst and abscess formation. In Case 10, the multiple pancreatic abscesses remained undetected for some time despite numerous radiographic studies. Fortunately, the process remained localized (presumably a benefit of the much lower dosages of steroids currently being used for allograft recipients) and could be managed by sequential surgical procedures. As in colonic perforation, the surgeon is presented with the demanding role of providing early clinical recognition of the condition followed by direction of the necessarily aggressive management, which includes nasogastric suction; fluid, electrolyte, and caloric replacement; and further steroid reduction. Most importantly, prompt detection and appropriate, possibly repeated, drainage of developing collections is essential.

3. Preoperative Preparation

Once the need for surgery in an immunoincompetent patient has been established, the degree to which preoperative preparation can be extended is determined primarily by the nature and urgency of the surgical indica-

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tion. Usual preoperative resuscitative measures including volume replacement, institution of antibiotic therapy, and correction of electrolyte imbalances follow the same guidelines employed for any acute surgical state. If the surgical indication is less urgent, a preoperative attempt to begin restoration of immunocompetence toward normal may be possible. Withdrawal of cytotoxic chemotherapy or high-dosage steroids will permit some recovery of depressed bone marrow and host-defense function and should reduce the risks of superinfection in the postoperative period. In addition, certain comorbid conditions unique to these patients must be considered. 3.1. Infection and Adrenal Insufficiency Illustrative Case 11 A 27-year-old woman had been treated for several years with various immunosuppressive regimens, including steroids, cyclophosphamide, and azathioprine for an ill-defined vasculitis characterized by diabetes, blindness, and impaired renal function. Because of the need for frequent venipunctures and hemodialysis, a saphenous vein-to-femoral artery A-V fistula had been constructed for vascular access 6 months previously. The current admission followed the development of fever, chills, and pain in the area of the A-V fistula. On examination, she was found to be obtunded but arousable; temperature was 104.9°F (40.5°C); and blood pressure, which had been chronically elevated, was found to be 95/60. The soft tissues around the A-V fistula were erythematous and edematous, with a 3 × 5-cm tender fluctuant mass beneath the site of a recent venipuncture. The patient was begun on antibiotics and intravenous volume replacement. Under local anesthesia, the fluctuant mass was drained of 75 ml of purulent fluid containing numerous neutrophils and gram-negative bacteria. She nevertheless remained obtunded, febrile, and hypotensive, requiring vasopressor and massive fluid support. The diagnosis of relative adrenal insufficiency was eventually suggested. Increased doses of steroids were administered, resulting in satisfactory stabilization of the vital signs, defervescence, and improved mental function. The patient was continued on intravenous antibiotics and local wound care. Over the succeeding 2 weeks, there was complete resolution of the local infection, and the patient was discharged for continuing outpatient hemodialysis.

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Comment. Of the many side effects suffered by patients receiving chronic steroid therapy (Table 4). one of the unique, admittedly unusual, conditions to keep in mind is occult adrenal insufficiency which may develop during periods of acute stress.44 A hypotensive febrile crisis, abdominal findings, including severe ileus, and a variety of central nervous system (CNS) symptoms ranging from obtundation to mania may be rapidly reversed by administration of a single intravenous hydrocortisone bolus. However, the surgeon should avoid this crisis by advising perioperative steroid (hydrocortisone, 50–100 mg) supplementation, with maintenance doses continuing into the postoperative period. A typical schedule might be hydrocortisone, 50–100 mg q8h the day of surgery and 25 mg q8h the following day. By this time, resumption of the preoperative maintenance dosage should be adequate, provided continuing severe stress is not present.

Some investigators have reported that functional adrenal suppression is uncommon in allograft recipients receiving low-dosage baseline immunosuppression.45 This group has concluded that continued administration of only the previously established maintenance steroid dosage through periods of physiologic stress is usually a safe approach, at least for this subset of patients. Nevertheless, they acknowledge that the steroid requirement may be qualitatively different for patients on higherdosage steroids or with other diseases. We, therefore, continue to recommend the administration of “stress steroids” to all of these patients, recognizing that this brief period of modest-dosage glucocorticoid supplementation will have minimal detrimental effects on wound healing or infection control while completely preventing the possibility of clinical symptoms resulting from adrenal insufficiency.

3.2. Infection and Ketoacidosis In addition to the acute infection, the immunocompromised patient’s underlying condition must be considered and appropriately managed.

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Illustrative Case 12 A 59-year-old diabetic patient had undergone successful renal transplantation for end-stage diabetic nephropathy, 3 years previously. He was admitted at the present time with fever and shaking chills of 2 days’ duration and abdominal pain and vomiting for 1 day. Prior to these symptoms, he had been in good health with normal renal function while receiving maintenance dosages of CyA and prednisone. On examination, he was found to be severely ill with a temperature of 103°F (39.5°C), pulse rate of 133/min, respiratory rate of 30/min, and blood pressure of 85/60. The renal allograft was not obviously enlarged but was slightly tender and the abdomen was moderately distended with direct and rebound tenderness, particularly in the epigastrium. Bowel sounds were hypoactive. The hematocrit was 43%, and the WBC Urinalysis revealed many white and red cells and gramnegative bacteria. Significant chemical abnormalities included a blood sugar of 595 mg/dl and content of 14 mEq/liter. Abdominal and chest radiographs revealed only a distended stomach without evidence of free air. The admitting diagnosis was gram-negative septicemia with consequent diabetic ketoacidosis. Although the ultrasound showed no stones, the source of infection was presumed to be acute, possibly gangrenous, cholecystitis. Urinary tract infection was also diagnosed. In preparation for proposed emergency laparotomy, intravenous antibiotics, rehydration, and insulin therapy were instituted. As the dehydration and ketoacidosis were corrected, the abdominal symptoms and signs rapidly resolved, and the patient’s vital signs stabilized. Surgery was therefore deferred. Subsequent workup of the biliary tree revealed a normally functioning gallbladder without stones. Comment. Diabetics may present with ketoacidosis in conjunction with a condition requiring surgery, in which case surgery must be delayed while vigorous treatment with insulin and intravenous fluids is initiated. It is important to recognize, however, that diabetic ketoacidosis itself may mimic an acute abdominal emergency. In this situation, treatment of the ketoacidosis may result in resolution of the symptoms and signs originally thought to require urgent surgical intervention. In the case reported above, the urinary tract infection apparently precipitated the ketoacidosis and the abdominal symptoms. On the other hand, the surgeon must not fall into the trap of ascribing all acute abdominal symptoms in diabetics to the pseudoperitonitis of ketoacidosis. During the few hours required to begin correcting the ketoacidosis with vigorous insulin and fluid therapy, the significance of the abdominal symptoms will usually become clarified.

The initial diagnosis of cholecystitis in Case 12 raises the issue of the most appropriate management of asymptomatic or mildly symptomatic cholelithiasis in immunocompromised patients. Some groups, for example, have recommended mandatory screening and prophylactic cholecystectomy, if cholelithiasis is demonstrated in patients awaiting transplantation.46 More recent experience, however, has indicated that only a minority of patients with asymptomatic gallstones will become symptomatic after transplantation.47 Thus, we do not routinely screen these patients or recommend cholecystectomy for incidentally discovered cholelithiasis. In those patients

who do become symptomatic, laparoscopic cholecystectomy can typically be performed, without incident, even in the early posttransplant period.48 3.3. Infection and Malnutrition

Another factor, the importance of which has only recently received significant appreciation, is the role that malnutrition plays in the increased morbidity and mortality of surgical patients. A number of studies have evaluated the ability of various clinical measurements to identify surgical patients at risk for nutritionally related postoperative complications. Such measures as serum albumin levels 20% have been suggested as specific determinants of significant malnutrition and increased likelihood of postoperative sepsis. Pre- and postoperative hyperalimentation (enteral or parenteral) has been recommended by some groups for surgical candidates meeting these criteria (e.g., cancer patients) if the proposed procedure can be safely delayed. Although improvement in various immune parameters after nutritional repletion can be demonstrated,49 considerable controversy persists as to whether this regularly translates into decreased postoperative morbidity or which patients are truly appropriate candidates for hyperalimentation. A recent meta-analysis of randomized clinical trials in critically ill or surgical patients concluded that postoperative infectious complications may be reduced by hyperalimentation, but mortality rates are not influenced.50 These observations emphasize that there is little evidence for the routine use of hyperalimentation for marginally nourished surgical candidates. Nevertheless, the well-documented evidence of poor anastomotic healing in severely proteindepleted experimental and clinical subjects does suggest the applicability of pre- and postoperative hyperalimentation for specific conditions, including enterocutaneous fistulas, burns, and upper GI malignancies.49 One must, of course, recognize the hazards associated with administration of parenteral alimentation, particularly in immunocompromised hosts. The most serious and prevalent complication is catheter-related sepsis. A suggested solution to this problem has been routine replacement of the catheter over a guide wire every 3–4 days. A controlled study, however, has demonstrated that this approach does not prevent infection.51 In contrast, the use of central venous catheters impregnated with antimicrobial agents is associated with reduced rates of catheter-related bloodstream infection.52 Thus, the use of

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single-lumen, antimicrobial-impregnated catheters that are restricted solely to parenteral nutrition administration and are placed and maintained by meticulous aseptic technique remains the most effective approach to limiting line-related infections. Illustrative Case 13 A 27-year-old man was evaluated for complaints of crampy abdominal pain and bloody diarrhea. Barium enema was consistent with the diagnosis of regional enteritis of the distal ileum. Despite intensive medical therapy, intermittent fever, anorexia, and chronic diarrhea persisted over the succeeding 4-month period. The patient’s weight fell from 165 to 130 lb (75 to 59 kg). Hospital admission was eventually required when increasing colicky pain, abdominal distention, and vomiting suggested partial bowel obstruction. Examination revealed a chronically ill young man who had a normal temperature and blood pressure. The abdomen was modestly distended with hyperactive, highpitched bowel sounds in rushes, resulting in frequent watery stools. Significant laboratory studies revealed Hct 32%, WBC count and serum albumin 2.6 g/dl. Barium enema with reflux into the terminal ileum revealed marked thickening and irregularity of the bowel wall and a narrowed lumen with several enteroenteric fistulas, but no obstruction. Following resolution of the vomiting with nasogastric suction and intravenous fluids over the first 4 days, the patient was taken to surgery, for resection of all grossly diseased bowel, including the distal ileum and right colon. Over the subsequent 3 months, the patient was reexplored three times for subphrenic and pelvic abscesses and attempted closure of multiple enterocutaneous fistulas. Despite the eventual initiation of intravenous hyperalimentation, his weight continued to fall, to 105 lb (47.7 kg). Renal failure developed, prompting his transfer here for hemodialysis. At the time of admission, he was obtunded and wasted with a temperature of 102.5°F (39°C) and persistent anemia, hypoalbuminemia, and uremia. The partially disrupted abdominal incision was grossly purulent with evident tracking of the purulence into the perineum. Several persistent enterocutaneous fistulas were present. During the subsequent 3-week hospitalization, the patient was treated with blood products, total parenteral nutrition, various antibiotics, multiple drainage procedures of abdominal and subcutaneous abscesses, suction drainage of the fistulas, and hemodialysis. Despite these measures, he had repeated positive blood cultures for gramnegative organisms, showed little evidence of wound healing, and finally expired 4 months after the initial surgical procedure. Comment. Inflammatory bowel disease of the transmural type is frequently associated with partial bowel obstruction, fistulas, intraabdominal abscess, and malabsorption. These patients are markedly malnourished, protein and electrolyte depleted, and severely catabolic. In this setting, preoperative hyperalimentation may be a valuable tool. Improvement in various immune parameters and remission of acute symptoms may be achieved. Even if only partial resolution occurs, the patient has become an improved operative candidate as nutritional deficiencies are partially corrected. One may assume that significant malnutrition exists in any patient who presents with weight loss of greater than 0.2% per day or 20% of normal, serum albumin of less than 3.0 g/dl, serum transferrin level of less than 200 mg/dl, or inability to respond to common delayed hypersensitivity skin tests. Such patients should be considered appropriate candidates for pre- and postoperative

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hyperalimentation. With selective use of such therapy, many of the disastrous complications illustrated by this case should be avoided.

3.4. Preoperative Antibiotics Preoperative administration of antibiotics to the compromised host may have therapeutic and prophylactic goals. Certainly, when a specific infectious process is suspected or has already been identified, or when a contaminated procedure such as bowel resection is planned, appropriate antibiotic coverage should be recommended. The importance of prophylactic antibiotics for “clean” surgical procedures in the compromised host remains more controversial. There is considerable evidence that antibiotic prophylaxis, even in the noncompromised host, reduces the risk of infections following extensive clean procedures, such as hip arthroplasty and cardiothoracic surgery.53 The efficacy of this approach has been extended to even lesser procedures.54 Not surprisingly, therefore, some transplant groups strongly recommend pre- and intraoperative broad-spectrum antibiotic coverage, particularly for diabetic patients. This therapy has been suggested to be a major reason for declining mortality risks for these patients. Our own experience without routine antibiotic coverage in renal allograft recipients, however, has indicated an extremely low rate of infection (less than 2%) of the primary transplant wound or following other uncontaminated procedures in these patients. Thus, prophylactic antibiotics have not been recommended for fear of selecting out resistant, more highly virulent, bacterial flora. For potentially contaminated procedures, the status of the natural bacterial flora may suggest appropriate prophylactic antibiotics. For example, early studies of infection in cancer patients undergoing major surgical procedures suggested that pre- and postoperative antibiotic therapy for potential enteric pathogens greatly decreases the incidence of serious infection.55 Based on such results, many surgeons advise the use of prophylactic antibiotics in all patients undergoing major surgical resections for malignancy. Specific recommendations obviously vary, but the antibiotic chosen is usually one with broad-spectrum coverage with particular consideration of the potential pathogens (e.g., oral, respiratory, enteric) expected to be encountered. The type of procedure to be undertaken is also an important determinant. For example, the indications for antibiotic coverage are greater if a major orthopedic or vascular procedure is to be performed versus a simple excision or node dissection.

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It has been repeatedly demonstrated that there is a limited time period during which it is possible to augment the host’s antibacterial mechanisms using antibiotics and that this period lasts only a few hours beginning at the time of bacterial contamination.56 Thus, if they are to be used, it is essential that prophylactic antibiotics be administered before the incision is made. Following surgery, the course of antibiotic administration should be brief unless the host is colonized with resistant organisms. Another approach, the precise value of which remains to be established, is that of selective decontamination of the GI tract. Studies have clearly demonstrated that intestinal flora can translocate to the peritoneal cavity, lymph nodes, liver, and spleen in patients with severe trauma or burns.57 These observations have prompted evaluation of the efficacy of gut decontamination for preventing septic complications in variably compromised patients or experimental models.58 Although a decreased incidence of nosocomial infections can be achieved, a decreased mortality rate has been more difficult to demonstrate. Continuing controlled trials will help to define the specific role of this approach to the antibacterial management of immunocompromised patients.59

4. Intraoperative Considerations

4.1. Choice of Anesthesia and Patient-Monitoring Techniques Selection of anesthetic techniques in these patients is influenced primarily by any limitations resulting from the underlying disease. For example, in uremic individuals, agents eliminated via renal excretion should be avoided or dosages appropriately decreased. The use of average doses of galamine triethiodide, for example, in renal transplant recipients results in prolonged paralysis in 20% of patients. We have observed a similar problem following administration of pancuronium bromide, and therefore favor the use of agents such as atracurium to avoid protracted neuromuscular blockade.60 This complication can be particularly serious because of the increased risk of pulmonary infection in immunosuppressed patients if prolonged endotracheal intubation is required. One important goal of anesthesia management, therefore, is to provide for return of adequate spontaneous respiratory activity and early postoperative extubation whenever possible. Some patients, such as those with hepatic failure, are predisposed to developing hypoxia from atelectasis, due to ascites, and from intrapulmonary arteriovenous shunts.

In these individuals, careful preoxygenation and rapid sequence induction anesthesia are commonly used. An appropriately sized, low pressure cuff endotracheal tube is placed in anticipation of a possibly prolonged period of intubation. Adequate padding of the heels, sacrum, elbows, and head is provided to prevent pressure ulceration during the operation which not infrequently extends beyond 8 hr. Effective warming appliances are also essential and may even help to reduce the incidence of postoperative infection.61 The selection of anesthetic agents for liver transplantation is governed by the high-cardiac-output, lowperipheral-vascular-resistance state typically associated with end-stage liver disease. The preferred maintenance agent for hemodynamic stability is a narcotic anesthetic employing fentanyl and/or morphine. Because some patients may not tolerate administration of routine anesthesia, they are often given a benzodiazepine as well, to block memory. Lorazepam is frequently chosen, since this agent requires only glucuronidation for excretion. The complexity of the procedure requires a number of extra lines. In adult recipients, access for infusion and monitoring is typically accomplished via a right radial arterial line, a large-bore intravenous site in the right arm, and introducer catheters in each internal jugular vein, one for placement of the pulmonary artery catheter and one for connection to the rapid infusion pump. Access sites in the legs are avoided since infusions would be unreliable during the period of vena cava occlusion. Recognition that any indwelling line in these patients can be the source of serious bacteremia should emphasize that their use should never be allowed for only marginal indications, and that they should be removed as soon as clinical conditions permit. With the observation of such possibly obvious precautions, the administration of general or conduction anesthesia to immunocompromised patients can be provided without an unacceptably high incidence of complications. 4.2. Surgical Technique The surgeon managing these patients must be prepared to constantly reevaluate and modify his usual techniques in order to deal with tissues (Fig. 4) that are weak, hold sutures poorly, and can be expected to require unusually prolonged healing periods. Illustrative Case 14 A 71-year-old woman with leukemia received 6-thioguanine and cytosine arabinoside treatment for 5 months prior to the present hospital admission which was prompted by the sudden onset of crampy abdomi-

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nal pain. On admission, her temperature was 104°F (40°C) and blood pressure 90/70. The abdomen was distended and tympanitic, and both direct and rebound tenderness were present. Following institution of antibiotics and rapid rehydration, the patient underwent emergency laparotomy. A volvulus of the distal ileum with dilation of the proximal bowel was found. A localized abscess surrounding a perforation of the antimesenteric border of the ileum was present as well. The volvulus was reduced, and no evidence of nonviable bowel was noted. The edges of the perforation were excised, and the defect was closed in two layers with chromic catgut and silk sutures. Postoperatively, the patient remained febrile with a quiet, distended abdomen until the fifth day, when a fecal fistula was noted at the inferior margin of the abdominal incision. Emergency reoperation revealed dehiscence of the bowel closure with local peritonitis. The involved small bowel segment was resected, and an end-to-end anastomosis constructed. The patient remained stable for several days but then developed fever, hypotension, and blood cultures positive for Escherichia coli. Her condition rapidly deteriorated, and she expired shortly thereafter. Postmortem examination revealed dehiscence of the bowel anastomosis and diffuse peritonitis. Comment. In urgent GI tract operations in the compromised host, stomas should be considered in preference to anastomoses more frequently than in the usual surgical subject. The patient’s chances of survival are enhanced if ileostomy or colostomy are constructed rather than a primary anastomosis which may result in fatal leakage when replaced in the abdomen.62 Several months after construction of the stoma, when the patient has recovered from the acute event and host defenses have been at least partially restored, reestablishment of bowel continuity becomes a relatively minor surgical procedure. If sutured bowel must be left in the abdomen, nonabsorbable sutures must be used, and the surgeon should attempt to isolate and reinforce the closure, for

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example, with omentum, and provide proximal decompression via colostomy, gastrostomy, and so on. Similarly, tragic experience has emphasized that local drainage and proximal colonic diversion, which is adequate therapy for perforated diverticulitis in the usual patient, is totally inadequate following sigmoid perforation in the compromised host. In these patients, sepsis continues to spread, despite apparently complete local drainage, because the depressed inflammatory response is unable to provide satisfactory containment. Thus, exteriorization or primary resection of the involved bowel and construction of a descending colostomy and distal mucous fistula or turn in is the treatment of choice. With such an approach, one should expect at least an 80–85% salvage rate in these patients for a condition previously found to be almost universally fatal. Copious intraperitoneal lavage should be used to reduce the residual contamination and limit the possibility of subsequent abscess formation. Some authors recommend antibiotic or antibacterial irrigations with continuing lavage into the postoperative period; however, saline alone is probably as efficacious and does not expose the patient to any side effects of the irrigation itself. Liberal drainage of all four quadrants and of the subphrenic spaces and pelvic pouch should be considered. Following abdominal surgery in the immunocompromised host, the surgeon should anticipate the possibility of prolonged periods of gastric dysfunction. Drainage via gastrostomy tube is often employed to avoid the pulmonary and esophageal complications associated with nasogastric tubes. At the same time, consideration should be given to using the small bowel for early resumption of nutritional support. In fact, motility and absorption by the small intestine usually returns within hours of successful control of the septic process. Most patients with a reasonable length of normal small intestine can be given full nutrition via jejunostomy administration of elemental diet beginning in the early

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postoperative period. The elemental diet is absorbed in the proximal intestine without the need for digestion, thus providing an early return to anabolism without the risks of prolonged hyperalimentation via central venous lines. Because of the poor healing in these patients, special precautions must be taken during placement of cutaneous-enteric tubes. Unless the bowel around the enterostomy is carefully and completely sutured to the anterior abdominal wall, a satisfactory seal of the tract will not develop. Subsequent leakage of enteric contents around the tube and into the peritoneal cavity can be regularly anticipated. Similarly, poor tissue healing should be expected in all incised tissues.

Illustrative Case 15 A 10-year-old girl with end-stage liver failure and massive ascites was admitted because of fever and abdominal pain. Following the initial diagnostic impression of acute appendicitis, exploratory laparotomy was performed. Slightly cloudy ascites revealed white blood cells but no organisms on Gram’s stain. Cultures subsequently yielded E. coli. The remainder of the examination, including the appendix, revealed no acute inflammatory process. A diagnosis of primarily infected ascites was presumed and continued antibiotic therapy was advised. The wound closure included all layer retention sutures because of the fear of poor healing. Postoperatively, continued ascites leakage around the sutures led to wound disruption, purulent peritonitis, and eventual death. Comment. This patient’s history emphasizes two points at which

different surgical approaches could have changed her course. The correct diagnosis might have been made if a preoperative paracentesis had been performed. This would have avoided completely the surgical procedure. Once the laparotomy was performed, the possibility of wound complications was correctly recognized, but the inadequate nature of the approach taken for this problem is emphasized by the patient’s postoperative course. Because of the expected delayed healing, closure with interrupted nonabsorbable suture material is advisable. We have found fine stainlesssteel sutures or synthetic monofilament products particularly appealing. Silk or cotton sutures are, of course, inadvisable in wounds at high risk of infection. Subcuticular skin closure (Fig. 5) also seems to decrease the incidence of complications since microabscesses, which frequently develop around transcutaneous sutures left in place for more than a few days, are avoided. Similarly, we rigorously avoid the use of all-layer sutures, especially in patients with ascites where direct communication between skin flora and peritoneum can occur along the suture tract because of the host’s inability to effectively seal off the site. The value of topical application of antibacterial solutions into surgical wounds remains controversial. Some reports63 seem to provide evidence that such irrigations lower the frequency of subcutaneous infections, especially in highly contaminated cases. Others suggest that normal saline is an equally effective irrigant.64 In our renal transplantation practice, in which we do not use systemic prophylactic antibiotics but irrigate the incision with local antibiotics, a wound infection rate of less than 2% has

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65

been achieved, an observation similar to that reported by others. If the surgical procedure was one of marked contamination, delayed or secondary closure of the skin is in some instances safer than attempted primary closure.

Surgical management of certain conditions, usually unrelated to the patient’s underlying immunologic defect, sometimes demands innovative intraoperative modifications. For example, more renal allograft recipients are surviving into their seventh and eighth decades, abdominal aortic aneurysms and aortoiliac occlusive disease are being encountered with increasing frequency. These vascular lesions typically develop in the aortoiliac segment proximal to the site of prior anastomosis of the donor renal artery. The standard technique of repair in this situation involves temporary interruption of blood flow to the allograft. Expeditious completion of this part of the procedure limits the period of warm ischemia and hopefully the degree of postoperative renal dysfunction.66 However, the difficulty to be encountered during aneurysmectomy, the time required to complete the anastomoses, and the quality of collateral blood flow to the allograft cannot always be judged accurately prior to this procedure. Thus, some groups advise allograft protection, using temporary vascular bypass, to maintain partial perfusion to the pelvic vessels especially if the aortoiliac disease approaches or involves the area of the allograft vessel anastomosis.67 Illustrative Case 16 A 66-year-old man was admitted to the emergency ward with a 4-hr history of back and left lower quadrant pain. Two years earlier, he had received a cadaver donor renal allograft, placed into the left iliac fossa with end-to-side anastomosis of the donor renal artery to recipient external iliac artery. At the current admission, the Hct was 31% and serum creatinine was modestly elevated to 2.0 mg/dl from his typical baseline of 1.6 mg/dl. CBT scan demonstrated a 6.5-cm distal aortic aneurysm with probable retroperitoneal bleeding. At emergency surgical exploration, proximal control of the ruptured but contained aneurysm was quickly achieved. The common iliac arteries were divided and cold heparinized Ringer’s lactate solution was infused into the distal left iliac artery. Replacement of the aneurysm with a bifurcated prosthesis was completed in the usual fashion. The total cross-clamp time of the left iliac artery was 35 min. The patient recovered well following this procedure, but allograft dysfunction persisted with the serum creatinine peaking at 4.5 mg/dl during the first postoperative week. Subsequently, his renal function gradually improved with a new stable baseline of 2.1–2.3 mg/dl. Comment. The emergent procedure in this patient did not permit ready placement of a temporary arterial bypass system. Rapid completion of the operation and partial hypothermic perfusion were therefore relied on to protect the allograft. The subsequent renal dysfunction, although not life-threatening, undoubtedly worsens the prognosis for long-term function of this allograft. Such experience has led some groups to conclude that a temporary shunting technique should be used in these patients if it is feasible. 67 The proximal end of the shunt can be

placed in the aorta above the aneurysm (Fig. 6). In some situations, the axillary or brachial artery can be used as the source of inflow. If the aneurysm is confined to the aorta, the distal shunt is placed into the common iliac artery on the side of the renal allograft. If there is aneurysmal involvement distally, however, the shunt is placed into the femoral or external iliac artery for retrograde perfusion of the allograft as depicted in Fig. 6.

4.3. The Effect of AIDS on Surgical Practice Of increasing importance to the surgeon is the issue of transmission of the human immunodeficiency virus (HIV) within the medical setting. There are two aspects of this problem that are of special importance to the surgeon: the possibility that a surgeon will acquire HIV infection from percutaneous or mucosal inoculation with infected blood; and the possibility that an HIV-positive surgeon might transmit the virus to a patient during the course of an invasive procedure. Currently available data suggest that the risk of HIV acquisition through percutaneous or mucous membrane exposure is less than 0.5%.68 This has resulted in the report to the United States Centers for Disease Control and Prevention of over 150 documented or possible cases of occupationally acquired HIV infection in healthcare workers.69 These observations and reports of a slowly

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rising incidence of undiagnosed HIV infection among patients presenting to urban hospitals for emergency care70 underline the need for great care on the part of healthcare workers. In the operating room, increased attention to effective barrier precautions such as face shields and fluid-resistant gowns, the development of puncture-resistant glove materials, and improved surgical techniques to minimize percutaneous needle sticks will decrease the risk of HIV transmission.71 Even with presently available gloves, data suggest that there is significant reduction in the volume of blood (and presumably the amount of virus) transmitted via needle stick when the needles pass through glove material before entering the skin. As noted above, needle stick and other sharp injuries are of greatest concern. They account for greater than 80% of occupationally acquired cases of HIV infection among healthcare workers.71,72 Whereas outside the operating room the majority of needle stick injuries involve nursing personnel, in the operating room more than 90% of such injuries involve surgeons or residents.73 Percutaneous sharp injury occurs in approximately 7% of operative procedures. Most injuries to the surgeon involve solid suture needle sticks, usually occurring on the palmar surface of the fingers of the nondominant hand. These occur predominantly during the unsafe practice of manipulating the needle tip by blind palpation rather than by instrument control, as, for example, during vaginal hysterectomy or other gynecologic procedures deep within the pelvis. If a recognized exposure to blood has occurred, a series of steps is recommended.74 Although no data are currently available to document the efficacy of such procedures, it is not unreasonable to copiously rinse and decontaminate the local wound. The exposure should be reported to the responsible office within the hospital. The patient and the exposed healthcare worker should be evaluated clinically, epidemiologically, and by laboratory testing for HIV antibody and viral load (as well as for hepatitis B and C). In the case of HIV, this presently requires informed consent of the individuals involved. The Centers for Disease Control currently recommends follow-up HIV testing over the next 6 months, if the exposure indeed involved HIV-infected material. If unexplained fever, lymphadenopathy, rash, pharyngitis, aseptic meningitis, or lymphopenia (features of acute retroviral illness) develop, the healthcare worker should return immediately for further clinical and laboratory evaluation. The question of whether or not early postexposure antiretroviral chemoprophylaxis should be initiated is generally answered affirmatively.75 There are anecdotal

reports of zidovudine prophylaxis failure when given as a single agent, but these typically represented relatively massive exposures and/or significant delay in initiating therapy.76 Unfortunately, significant bone marrow and GI toxicity can be observed in individuals receiving antiviral prophylaxis, especially if combination therapy is utilized. Most centers, therefore, take the position that the final decision to initiate antiretroviral prophylaxis should still be made by the healthcare worker after complete disclosure of the available information. One group of individuals for whom chemoprophylaxis is currently not recommended are women who are pregnant or who might become pregnant in the near future. The second issue regarding HIV infection and surgical practice is the possibility that the virus could be transmitted from an infected surgeon to a patient undergoing an invasive procedure. This theoretical possibility was brought to the public’s attention when a well-publicized group of six individuals receiving dental care from the same dentist acquired HIV infection.77 Subsequent extensive evaluation of over 23,000 individuals who had received surgical, medical, or dental care from HIV-infected individuals has identified only a single instance of probable transmission of HIV to a patient when other risk factors for HIV acquisition were not also present.78,79 Therefore, the risk of transmission of HIV from a healthcare worker to a patient appears to be vanishingly small. As a result, routine screening of healthcare workers for HIV positivity is not currently recommended. Rather, the following recommendations have been made by the Centers for Disease Control80:

1. All healthcare workers should adhere to universal precautions, including the appropriate use of hand washing, protective barriers, and care in the use and disposal of needles and other sharp instruments. Healthcare workers who have exudative lesions or weeping dermatitis should refrain from all direct patient care and from handling patient-care equipment and devices used in performing invasive procedures. 2. Currently available data provide no basis for recommendations to restrict the practice of healthcare workers infected with HIV or hepatitis B virus who perform invasive procedures not identified as exposure-prone. 3. Exposure-prone procedures should be identified by medical/surgical/dental organizations and institutions at which the procedures are performed. 4. Healthcare workers who perform exposure-prone procedures should know their HIV antibody status.

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5. Healthcare workers who are infected with HIV should not perform exposure-prone procedures unless they have sought counsel from an expert review panel and been advised under what circumstances, if any, they may continue to perform these procedures. Such circumstances would include notifying prospective patients of the healthcare worker’s seropositivity. 5. Postoperative Management

5.1. Respiratory Management in the Immunocompromised Patient As emphasized above, an important goal following postanesthesia stabilization of the compromised host is early extubation. We have observed superinfection pneumonitis in over 50% of immunosuppressed allograft recipients who require endotracheal intubation for longer than 96 hr. Such experience indicates that the importance of respiratory therapy in the early postoperative period cannot be overemphasized. Moderate areas of atelectasis or pooling of tracheobronchial secretions, which may be inconsequential in lower-risk surgical candidates, can provide the appropriate environment for sepsis in the compromised host. This is all too often followed by pulmonary failure, which is typically the initial event in a cumulative sequence of multiorgan failure leading to death. Thus, increased attention to positioning, early ambulation, oxygenation and humidification of inspired air, and aggressive respiratory therapy which includes judicious endotracheal suction or bronchoscopy to clear bronchial plugs is mandatory following extubation. An important consideration related to the endotracheal intubation in immunocompromised patients has been the observation that the nasotracheal route may favor the development of sinus infection leading to serious complications. Thus, orotracheal intubation should usually be employed even when it is anticipated the tube will be in place for a number of days.

5.2. General Postoperative Care in the Immunocompromised Patient Other postoperative considerations include careful monitoring of wounds for collections that may be deceptively asymptomatic. We recommend immediate needle aspiration of any suspicious area of even minimal induration or tenderness. Prompt ultrasound or CBT examination of the operative site is also indicated in any patient with signs of occult sepsis. Attempts to accelerate wound

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healing in these patients with any of the widely studied adjuvant agents (e.g., cartilage, zinc) are clearly not warranted. However, provision of adequate caloric and protein intake to achieve a positive nitrogen balance as early as possible is obviously appropriate. Similarly, addition of vitamins, particularly A and C, to the chronically malnourished patient cannot be severely criticized. Guidelines for the administration of perioperative transfusions for all surgical patients have become increasingly conservative, as the risks of viral disease transmission, particularly CMV, hepatitis, and HIV, have become evident. In the immunocompromised patient, there is the additional concern that allogeneic blood transfusions themselves may produce a detrimental effect on the immune system.81 This could be clinically advantageous to transplant recipients, and this effect had been incorporated into earlier immunosuppressive protocols to improve allograft survival.82 The efficacy of currently used immunosuppressive agents has essentially eliminated any additional benefit of blood products so that deliberate transfusion is now seldom practiced. The importance of these observations, which were initially made in transplant recipients, raised the possibility that blood transfusions may be undesirable in other surgical patients because they could increase the risk of infectious complications or the more rapid growth or metastasis of residual tumor in patients undergoing resection for cancer.83 In fact, retrospective clinical reviews have shown a significantly worse prognosis for patients who received perioperative transfusions during cancer surgery when compared with those who did not receive blood products.84 Despite the obvious limitations of such retrospective analyses, these observations have significant implications, particularly for the surgeon caring for any immunocompromised patient. Increased efforts to use alternative methods of vascular volume support should be made. The arbitrary hematocrit level of 28–30% at which transfusion was previously thought necessary is no longer applicable. Where the threshold is reset obviously must be individualized on the basis of comorbidity risks. Many surgeons, however, accept a stable hematocrit in the 21– 26% range unless there is evidence of inadequate tissue oxygen delivery or of the potential for localized ischemia, such as a history of coronary artery disease. There is little evidence that moderate anemia adversely affects the postoperative recovery, and iron supplementation, together with administration of recombinant erythropoietin, rapidly increases autologous erythrocytosis to restore the patient’s hematocrit within a period of weeks. If transfusion is necessary, some groups recommend use of leukofiltered blood, since the immunomodulatory effects ap-

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pear to be mediated by transfused allogeneic passenger leukocytes.85 The previous practice of administering granulocyte transfusions to prevent gram-negative sepsis in patients with severe neutropenia has been essentially replaced by widespread use of hematopoietic growth factors.86 It is now evident that myeloid recovery can be significantly accelerated by both granulocyte-macrophage colonystimulating factor (GM-CSF) and granulocyte colonystimulating factor (G-CSF) and that such agents play an important role in the care of immunocompromised patients whose course is complicated by periods of neutropenia.87 In fact, some groups have suggested that routine use of G-CSF, targeting a blood granulocyte count of in the perioperative period, can decrease the incidence of sepsis in immunocompromised patients.88 Other postoperative measures, such as vigorous patient isolation, are generally not required for immunosuppressed patients—except for those with severe neutropenia (granulocyte count less than or with major burns (see Section 5.3). Nevertheless, it is clear that significant environmental contamination in the hospital will be manifested first in these patients. Thus, any unusual incidence in the number of infections by organisms such as Aspergillus or Legionella must be immediately investigated and the contaminating source controlled.

limited oral intake. On day 45, the patient developed respiratory insufficiency requiring mechanical ventilation after which he continued to deteriorate metabolically. He eventually died on day 54, at which time more than 90% of the burns had been successfully covered with autografts. Comment. Despite major advances in the immediate resuscitation and surgical management of severe trauma victims, an unacceptably large fraction of these previously healthy, often young patients succumb in the later postoperative period, usually with multiple organ failure. Intensive evaluation of this syndrome has begun to clarify that the late onset of sepsis in these patients is enhanced by limitation of protein synthesis, possibly secondary to growth hormone resistance,90 and excessive cytokine production. In Case 17, the Pseudomonas sepsis was already established at the time of admission. Despite institution of intensive efforts to eradicate the infection, it was never possible to regain.control. The typical downhill course, inevitably leading to death, ensued even though the burns were nearly covered. In patients with burns, as with all trauma, the goal must be to convert the open, contaminated wound to a closed, clean wound in the shortest time possible. This is especially important for major burns where continuing immune depression is produced by the wound itself.91 In most cases, repeated skin grafting from uninjured donor areas is an adequate solution to the problem. However, if the area of normal skin available for donor sites is insufficient to provide reasonably prompt skin graft closure, we have again found that a much more aggressive approach is required. Following the serial evaluation of a number of techniques, we initially recommended immediate wound closure with skin allografts, whose survival was prolonged by immunosuppressive agents, as the most useful method of reducing fluid, protein, heat, and energy loss, controlling infection, and protecting underlying structures.92 More recently, the addition of synthetic “skin” has revised this approach making it possible to remove allografts earlier and, thus, immunosuppressive agents are no longer required.93

5.3. Management of the Burn or Trauma Patient

In patients with massive burns, prompt excision and wound closure by a number of successive surgical procedures is begun usually on the first or second day after the burn injury when all available donor sites are harvested to cover a comparable area of excised eschar with autografts. Subsequent procedures consist of excision of eschar and closure with allograft skin or artificial skin (Fig. 7). Eventually, the allografts are excised stepwise and replaced with autografts as donor sites regenerate. Patients with massive burns are usually nursed in some form of protective environment. We favor the bacteria-controlled nursing unit pictured in Fig. 8. The patient is protected against contact cross-infection by clear plastic access walls, and by a system of medical care delivery whereby the nursing and medical personnel do not directly enter the protected environment of the units. Autoinfection of the burn wound from the patient’s respiratory or GI tract is reduced by meticulous aseptic precautions and the use of 0.5% aqueous silver nitrate dressings to the burn eschar until excised, to donor sites, and to newly grafted areas of the extremities. The metabolic balance of these patients is carefully maintained with the goal of daily parenteral and enteric

The syndrome of sepsis and sequential postoperative organ failure may develop in a previously healthy immunocompetent host, particularly in the setting of major trauma such as burns or multiple injuries that produce chronic stress.89 Illustrative Case 17 A 9-year-old boy was admitted to the burn unit 9 days after suffering a flaming gasoline injury producing full-thickness burns over 80% of the body surface area. During the period between injury and transfer, the burns had been treated with dressing; but, at the time of admission, early Pseudomonas sepsis of the thighs and buttocks was noted. These areas were debrided; the chest and abdomen were primarily excised and covered with autografts from the scalp. The patient was continued on dressing and both enteric and parenteral hyperalimentation while being housed in the protective environment of a bacteria-controlled nursing unit. Initially, the take of the skin grafts was excellent, but by postgraft day 10, there was evidence of spread of Pseudomonas sepsis and partial graft loss. Multiple procedures of burn excision followed by coverage with allografts and autografts were successful in closing most of the trunk and proximal extremity wounds, but the patient’s course was continually complicated by spiking fevers, positive blood cultures, and recurrent pulmonary infiltrates. By hospital day 35, GI dysfunction with ileus, distention, and vomiting severely

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intake of at least and 3 g/kg of protein. Malfunction of the GI tract taking the form of gastric retention with ileus or diarrhea is an ominous sign. Its onset usually heralds severe malnutrition and sepsis.94 Patients who expire usually develop diarrhea followed by persistent ileus and gastric retention that prevents oral alimentation. Surviving patients have occasional limited episodes of ileus, usually following an operative procedure, but GI tract dysfunction is not severe enough to interfere with nutrition and body weight is maintained throughout the course of the illness. A large part of the effective control of bacterial infection demonstrated by these patients must be laid to the beneficial effect of prompt and almost complete wound closure and the maintenance of normal nutrition during periods of maximal stress. The contribution of the protective environment provided by the bacteria-controlled nursing unit is difficult to assess. Cross-infection is rarely seen in this group of highly susceptible patients, however, and late development of bacterial pneumonitis is seen only as a terminal episode in patients who fail to survive. Thus, although a dogmatic statement concerning the exact contribution of a protective environment to the immunosuppressed burn patient cannot be made, the evidence available indicates the contribution is probably significant. Prior to the addition of immunosuppression to the routine treatment plan, which included prompt excision of dead tissue and immediate wound closure with autografts and allografts, the controlled environment of the bacteria-controlled nursing unit, intensive metabolic alimentation, and topical patients with full-thickness burns of greater than 80% of the body surface suffered 100% mortality. With the addition of immunosuppression, which allowed continued wound closure by the allografts until they were electively replaced with autografts, we found it possible to salvage over half of this group of patients. Further advances, including the increasing use of synthetic “skin” without immunosuppression, have improved the care of these massively burned patients to the point that current mortality is around 33%. Intensive postoperative support including nutritional management is also essential for preventing delayed sepsis and multiple organ failure in other postsurgical patients, in whom it is anticipated that oral alimentation will not be possible within 5–7 days. As noted in Section 3, many malnourished patients can be identified prior to surgery and will have already been started on a nutritional repletion program that is continued through the postoperative period. In previously healthy patients such as victims of major trauma, however, the extent of the postoperative catabolic response and increasingly nega-

tive nitrogen balance may not be appreciated until delayed wound healing, occult fevers, and early hepatic dysfunction become manifest. Unfortunately, at this point, institution of hyperalimentation is often ineffective. Thus, even in these acutely injured patients, it should be anticipated that although the body can initially employ its carbohydrate and fat reserves to meet the increased metabolism and negative caloric balance, these reserves are depleted within a few days of the injury or surgery. Thereafter, protein must be mobilized to provide these needs. Since there are no protein reserves as such, this immediate assault on the functional and structural capacity of the body must be prevented by early enteric or parenteral administration of adequate calories and amino acids. 5.4. Postoperative GI Bleeding in the Immunocompromised Patient

A particularly difficult postoperative problem is acute upper GI bleeding. Despite the use of antacids and antagonists, this life-threatening complication continues to occur. In transplant recipients, the incidence of bleeding gastroduodenal lesions has been reported to range from 1 to 10% with a mortality rate as high as 40%.95,96 In the attempt to limit these complications, some groups have recommended prophylactic gastric surgery for patients with a history of ulcer disease or demonstrable hyperacidity. More recent reviews suggest that prophylactic surgery is not an effective approach to reducing the incidence of posttransplant gastroduodenal complications except for patients whose peptic ulcer disease has already proved to be recalcitrant to medical therapy.97 Thus, immunocompromised patients who develop postoperative or posttraumatic gastroduodenal bleeding must often be managed surgically during their acute illness. Illustrative Case 18 A 55-year-old woman with severe arthritis requiring chronic steroid therapy was admitted to the hospital with fever and lower abdominal pain. Bowel sounds were present, and the abdomen was nondistended, but lower abdominal direct and rebound tenderness was demonstrable. Urgent laparotomy revealed peritonitis secondary to perforated sigmoid diverticulitis which was managed with resection and end-sigmoid colostomy. A gastrostomy was performed, and extensive peritoneal lavage and drainage were instituted. The wound was managed with delayed primary closure. The patient initially did well, but on postoperative day 7, black, guaiac-positive gastrostomy drainage was noted. This cleared with iced saline lavage. Endoscopy revealed diffuse superficial ulcerations of the distal stomach. Bright red bleeding developed 24 hr later. Selective angiography showed marked hypervascularity of the gastric mucosa. With somatostatin infusion, the bleeding was controlled for approxi-

SURGICAL ASPECTS OF INFECTION mately 48 hr. However, active bleeding (hen recurred. Surgery was recommended but the patient and her family adamantly refused. Over the subsequent 7 days, repeated intra-arterial vasopressin infusions and embolic occlusion of the left gastric artery only intermittently controlled the slow but persistent bleeding. During this time, multiple blood cultures became positive for Cryptococcus. Culture of the removed angiography catheter similarly was positive for this organism. Despite amphotericin therapy and broad-spectrum antibiotic coverage, the patient remained febrile and lethargic, eventually developing pneumonia and respiratory failure leading to death.

Illustrative Case 19 An 18-year-old man suffered a severe crushing injury to the abdomen, pelvis, and legs in a motor-vehicle accident and required splenectomy, resection of devitalized bowel, and reduction and fixation of multiple fractures. Postoperatively, acute renal failure developed. He remained relatively stable, but intermittent fever occurred usually in association with hemodialysis treatments. On postinjury day 10, massive upper GI bleeding occurred. This was only partially controlled with iced saline lavage. Endoscopy revealed several prepyloric bleeding ulcerations. Cimetidine therapy was added, and the bleeding appeared to stop, only to recur 48 hr later. At exploration, a 300-ml foul-smelling hematoma was evacuated from the left subphrenic space. Vagotomy and distal gastrectomy were performed. The patient subsequently recovered without further bleeding or other significant complications. Comment. Stress ulceration continues to provide a significant surgical challenge. Such ulcers characteristically bleed or perforate during the early postinjury or postoperative period. The incidence is markedly increased when significant complications, particularly sepsis, follow the initial procedure. In fact, the association of systemic or localized infection with acute gastroduodenal ulceration is so constant that a surgical axiom has been coined for these patients. It cautions that in the face of upper GI bleeding laparotomy is more urgently indicated for detection of the underlying sepsis than for control of the bleeding site. The occult subphrenic abscess in Case 19 emphasizes this point. Interestingly, this patient also exhibits another diagnostic clue occasionally observed, namely, the febrile episodes associated with hemodialysis. It has been suggested that these may be the result of expansion of the infected collection or release of cytokines during the rapid osmotic shifts associated with dialysis.

The pathologic condition of stress ulceration varies from diffuse erosive changes to a single punched-out ulcer with virtually no surrounding reaction. The progression of mucosal damage is closely related to the duration of sepsis. In patients studied serially, gastroduodenal disease becomes worse as sepsis is prolonged. On the other hand, mucosal lesions show a dramatic improvement when focal infection and septicemia are eradicated.98 The mechanism of sepsis-induced gastroduodenal lesion formation is unclear, but it may be favored by ischemia of the mucosa as it is with acute ulcers of other origins. It is possible that a vasoconstrictive process of the gastroduodenal mucosa is associated with the septic focus and is independent of systemic shock. In support of this, endoscopies have shown a pale, ischemic, marbled mucosa that strongly suggests an ischemic etiology.

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Medical therapy of stress ulcers is often disappointing. The addition of antagonists has improved these results, but again, ultimate patient survival can only be achieved if the accompanying sepsis is controlled as well. The development of bipolar and laser coagulation devices has provided another approach to control for the patient who continues to bleed despite intensive medical therapy.99 Emergency mesenteric angiography is usually undertaken only after endoscopy has been unsuccessful in identifying or controlling the bleeding site. If a bleeding site is defined by angiography, selective intra-arterial or peripheral intravenous infusion of aqueous vasopressin or somatostatin is sometimes successful. This is particularly true in patients with diffuse superficial gastric mucosal lesions in whom bleeding can often be controlled following infusion via the left gastric artery.100 In heavily immunosuppressed patients, especially in the presence of leukopenia, we have had little success with long-term angiographic control of GI bleeding. An obvious hazard is the development of sepsis from the indwelling catheter as occurred in Case 18. Thus, most groups advise surgical intervention if bleeding is not controlled within 24–48 hr following institution of treatment by selective angiography or somatostatin infusion.101 Surgical therapy in these patients also leaves much to be desired. The choice of operation is largely a matter of unsupported preference. Most authorities agree that vagotomy should be performed.102 Gastric resection has been advised as well, since the incidence of rebleeding after vagotomy with only gastric drainage is usually higher. Of course, the greater morbidity and mortality following resection must also be taken into consideration.

5.5. Sepsis following Splenectomy Illustrative Case 20 A 35-year-old man on chronic hemodialysis because of end-stage polycystic kidney disease was admitted to the hospital with fever and hypotension. Two years earlier, he had required left nephrectomy for infection. At that time, splenectomy was also performed because of intraoperative trauma to the spleen. He had been well until 1 week before the present admission when he noted the onset of occasional headaches and malaise. On the day of admission, he had been hiking on the beach, where he felt unusually hot. Swimming precipitated chills and he subsequently noted fever to 103°F (39°C). He was admitted to a local hospital with the possible diagnosis of heatstroke. He was observed there to be intermittently alert with a systolic blood pressure of 70 mm Hg and an oral temperature of 105°F (41°C). Ice packs were applied after which the temperature fell to 103°F (39°C), but the patient became increasingly obtunded and hypotensive. When transferred here, he was found to have generalized petechiae and ecchymoses. Despite intravenous pressors,

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antibiotics, and fluid resuscitation, he died 5 hr after admission. Blood cultures subsequently grew Streptococcus pneumoniae. Comment. The occurrence of fulminant bacterial sepsis in splenectomized patients was first clearly demonstrated by King and Shumacker.103 For many years, the risk was believed to be limited to infants or young children but subsequent studies have emphasized that splenectomy done at any age and for any reason increases the risks of death resulting from infection.104

Although well-opsonized bacteria are removed primarily by the liver, the spleen is responsible for removing nonopsonized blood-borne bacteria. The spleen also plays an important role in the humoral response, as the primary immunoglobulin response takes place in the spleen. Low levels of IgM have been observed after splenectomy in children. In addition, a reduced level of the complement factor, properdin, has been demonstrated after splenectomy. The spleen also serves as a major site of synthesis of tufsin, a basic tetrapeptide that coats polymorphonuclear leukocytes to promote phagocytosis. Children are clearly more susceptible to postsplenectomy sepsis than adults, especially during the first 6 to 12 months after splenectomy. In patients who underwent splenectomy for trauma, the risk of serious infection is approximately 1.5%, whereas asplenic patients with thalassemia have a risk of serious infection approaching 25%.105 The mortality rate for overwhelming postsplenectomy infection is approximately 45%.104 The surgeon’s role in the management of this condition should be on several fronts. First, it is clear that splenectomy is usually not required to achieve hemostasis following splenic disruption. Numerous reports have now documented the feasibility of splenic salvage procedures.106 Second, if splenectomy is unavoidable because of exsanguinating hemorrhage or for definitive control of a specific disease process, the patient should be protected as much as possible by polyvalent pneumococcal vaccine and should be appropriately informed of the need for aggressive treatment of all infections.104 Finally, the surgeon, who may be the first to evaluate these patients in an emergency ward, must keep this possibility in mind lest valuable time be lost, as in the case above, while nonspecific treatment for the fever is being administered. Another concern of particular importance for surgeons results from the recent dramatically increased incidence of vancomycin-resistant enterococcus (VRE) colonization in hospitalized patients.107

treatment of recurrent otitis media, spontaneous bacterial peritonitis, and complications of chronic nutritional deficiency. At the time of admission for transplantation, there were no localizing signs of infection. Surveillance cultures proved to be unremarkable except for VRE in the patient’s stool. The transplant procedure using a reduced-size adult liver allograft was uncomplicated. The biliary tree was reconstructed with a Roux-enY choledochojejunostomy. Postoperatively, good allograft function was achieved, but fever and abdominal pain developed during the second postoperative week. Cholangiography demonstrated a bile leak and a small subhepatic fluid collection. At the time of exploration, a subhepatic hematoma, which subsequently proved to be colonized with VRE, was evacuated. The choledochojejunostomy was successfully revised. The patient subsequently developed a clinical picture consistent with intra-abdominal sepsis including renal failure requiring dialysis, hectic fevers, and persistent ileus. Despite treatment with chloramphenicol and synercid, cultures of the abdominal drainage fluid, bile, and stool were persistently positive for VRE. A therapeutic approach that included weekly laparotomy for drainage of loculated collections and debridement of any devitalized tissues was undertaken. Over the next 4 weeks, the patient’s course gradually stabilized as the sepsis was controlled. He was gradually weaned from hemodialysis and he remains well with normal renal and hepatic function 2 years later. Comment. This patient’s postoperative course was initially complicated by biliary tract leakage, a continuing cause of significant morbidity and mortality following OLT.108,109 Although many of these leaks can be managed nonoperatively, immediate surgery was recommended in this instance because of the known likelihood of VRE contamination. In fact, the finding at that point of a VRE-infected subhepatic hematoma presaged the patient’s complicated subsequent hospital course.

In our experience, colonization of the biliary tree by VRE is almost universal following OLT in recipients whose baseline GI tract flora includes this organism. As a result, enterococcal infectious episodes are now being reported in as many as 20% of OLT recipients, even if no biliary leakage develops in the postoperative period.110,111 We and others have found that aggressive open surgical debridement of devitalized or loculated collections is often required, since there is a much higher rate of unresolved infection following percutaneous drainage of intraabdominal abscesses in patients with VRE.112 In Case 21, the sites requiring this unusual (almost preantibiotic era) surgical approach included the subhepatic space around the biliary reconstruction as well as the resection margins of the reduced-sized liver allograft. As in this patient, pursuit of such aggressive surgical management will probably remain the only approach to salvaging patients with extensive intra-abdominal sepsis until an effective antimicrobial agent for VRE becomes available.

Illustrative Case 21

6. Conclusions

A 5-year-old African-American child underwent orthotopic liver transplantation (OLT) for treatment of end-stage liver failure secondary to Alagille’s syndrome. His previous history was significant for surgical repair of tetralogy of Fallot and multiple hospitalizations for antibiotic

Surgical management of infection in the compromised host requires special considerations related to the diagnosis, preoperative preparation, intraoperative tech-

SURGICAL ASPECTS OF INFECTION

niques, and postoperative care (Table 5) of these fragile patients. With observation of certain guidelines as outlined here, it is possible to perform even highly complicated procedures with acceptable morbidity and mortality. The surgeon should consider appropriately aggressive evaluation and surgical intervention in these patients from the viewpoint that delay in performance of an indicated procedure, far from being the conservative approach, will more likely be the determining factor that prevents the patient’s rehabilitation or even precludes survival. ACKNOWLEDGMENTS. I am grateful for the excellent secretarial and editorial assistance provided by Cathy Padyk in the preparation of this manuscript.

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colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 325:164-169, 1991. Foster PF, Mital D, Sankary HN, et al: The use of granulocyte colony-stimulating factor after liver transplantation. Transplantation 59:1557–1563, 1995. Tran DD, Cuesta MA, vanLeeuwen PAM, et al: Risk factors for multiple organ system failure and death in critically injured patients. Surgery 114:21–30, 1993. Singh KP, Prasad R, Chari PS, et al: Effect of growth hormone therapy in burn patients on conservative treatment. Burns 24:733– 738, 1998. Nguyen TT, Gilpin DA, Meyer NA, et al: Current treatment of severely burned patients. Ann Surg 223:14–25, 1996. Cosimi AB, Burke JF, Russell PS: Transplantation of skin. Surg Clin North Am 24:435–451, 1978. Staley M, Richard R: Management of the acute burn wound: An overview. Adv Wound Care 10:39–44, 1997. Wolf SE, Rose JK, Desai MH, et al: Mortality determinants in massive pediatric burns. An analysis of 103 children with >80% TBSA burns. Ann Surg 225:554–569, 1997. Feduska NJ, Amend WJC, Vincenti F, et al: Peptic ulcer disease in kidney transplant recipients. Ann J Surg 148:51–55, 1984. Barsdaxoglou E, Maddern G, Ruso L, et al: Gastrointestinal surgical emergencies following kidney transplantation. Transplant Int 6:148–152, 1993. Bansky G, Do UH, Largiader F, et al: Gastroduodenal complications after renal transplantation: The role of prophylactic gastric surgery in hyperacid kidney allograft recipients. Clin Transplant 1:209–213, 1987. LeGall JR, Mignon FC, Rapin M, et al: Acute gastroduodenal lesions related to severe sepsis. Surg Gynecol Obstet 142:377– 380, 1976. Donahue PE, Mobarhan S, Layden TJ, et al: Endoscopic control of upper gastrointestinal hemorrhage with a bipolar coagulation device. Surg Gynecol Obstet 159:113–118, 1984. Nusbaum M, Deren J, Chait A: Angiographic control of bleeding. Contemp Surg 23:79–123, 1983. Jenkins SA, Poulianos G, Coraggio F, et al: Somatostatin in the treatment of non-variceal upper GI bleeding. Dig Dis 16:214–224, 1998. Moody FG, Miller TA: Answers to questions on stress ulcer. Hosp Med 11:33–56, 1983. King H, Shumacker HB: Splenic studies: Susceptibility to infection after splenectomy performed in infancy. Ann Surg 136:239– 242, 1952. Waghorn DJ, Mayon-White RT: A study of 42 episodes of overwhelming post-splenectomy infection: Is current guidance for asplenic individuals being followed? J Infect 35:289–294, 1997. Wilson SA, Johnson WD: Infections complicating surgical or functional splenectomy. In Grieco MH (ed): Infections in the Abnormal Host. Yorke, New York, 1980, pp. 848–865. Clancy TV, Ramshaw DG, Maxwell JG, et al: Management outcomes in splenic injury: A statewide trauma center reviewed. Ann Surg 226:17–24, 1997. Fleenor-Ford A, Hayden MK, Weinstein RA: Vancomycin-resistant enterococci: Implications for surgeons. Surgery 125:121–125, 1999. Vicente E, Perkins JD, Sterioff S, et al: Biliary tract complications following orthotopic liver transplantation. Clin Transplant 1:138– 142, 1987.

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109. Greif F, Bronsther OL, VanThiel DH, et al: The incidence, timing, and management of biliary tract complications after orthotopic liver transplantation. Ann Surg 219:40–45, 1994. 110. Patel R, Badley AD, Larson-Keller J, et al: Relevance and risk factors of enterococcal bacteremia following liver transplantation. Transplantation 61:1192–1197, 1996. 111. Papanicolaou GA, Meyers BR, Meyers J, et al: Nosocomial infec-

tions with vancomycin-resistant Enterococcus faecium in liver transplant recipients: Risk factors for acquisition and mortality. Clin Infect Dis 23:760–766, 1996. 112. Linden PK, Pasculle AW, Manez R, et al: Differences in outcome for patients with bacteremia due to vancomycin-resistant E. faecium or vancomycin-susceptible E. faecium. Clin Infect Dis 22:663–670, 1996.

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Index

Acanthamoebiasis/Acanthamoeba, 99, 317–319 Actin dysfunction, 487 Acute lymphoblastic leukemia (ALL), 442, 453 Acyclovir (ACV) for herpesviruses, 76, 78–79, 365–366, 374, 377, 552 CMV, 387, 389, 545, 618 VZV, 380, 553 and nucleosides, 365–366, 369 prophylactic use of, 377, 387, 545, 553, 618 for transplant patients, 545, 552, 618 Acyclovir-resistant herpesvirus infections, 76, 78, 368–370, 377 Adenosine deaminase (ADA), 32, 479 Adenoviruses, 405–407, 557, 639 Adrenal insufficiency, 689 Aeromonas spp., 60 A. hydrophilia, 60 Age and host defense, 21–22 Agranulocytosis, infantile lethal, 485 AIDS dementia complex, 164–165 clinical manifestations, 425–427 AIDS patients: see also HIV CMV in, 383 CNS infections in, 171, 189, 198–200 fungal infections in, 216, 230–233 hepatitis in, 350–351 infections regularly seen in, 27 Kaposi’s sarcoma in, 136 mycobacterial diseases, 249–250 parasitic infections, 265, 266, 268, 272–273, 275–289, 314 PML, JC virus, and, 409 prophylaxis to prevent fungal infections, 230 pulmonary infections in, 118, 122, 134, 135, 383 surgical practice with, 695–697 Alcoholism, 25 ALL (acute lymphoblastic leukemia), 442, 453 Allograft recipients, 372 Allograft rejection, 634 Alveolar damage, diffuse, 122 with foamy alveolar exudate, 122–123 Alveolar proteinosis, pulmonary, 131 Amebiasis, 313–314

Amphotericin B, 236, 450, 472, 517 for aspergillosis, 226, 645 for blastomycosis, 235 for candidiasis, 223 for coccidioidomycosis, 233, 234 for histoplasmosis, 231–232 intrathecal, 233 intravenous, 218 lipid preparations/formulations of, 218, 220, 223, 226, 236–237 indications for, 237 toxicity and pharmacokinetics of, 236 for meningitis, 191–193 for mucormycosis, 196 for neutropenic patients with persistent fever, 219–220 Amphotericin B colloidal dispersion (ABCD), 236–237 Ampicillin, 176–177, 641 Anemia, aplastic, 498 Anesthesia, choice of and patient monitoring techniques, 692 Antibiotics: see also specific drugs preoperative, 691–692 Antibodies antilymphocyte, 29, 598 monoclonal, 577–578 CMV-specific, 546–547 IL-2 receptor, 28 polyclonal antilymphocyte, 577 prophylactic, 515–516 Antifungal agents, 517; see also specific drugs newer, 232 Antifungal therapy; see also under Fungal infections in neutropenic patients with persistent fever, 219–221 Antimicrobials, 29; see also specific drugs Antisense compounds, 367 Antithymocyte globulin (ATG), 29, 577, 578 Antiviral drugs: see also specific drugs chemical structures of, 368 Arachidonic acid pathways, 574–575 Arthropod infestations, 99 Aspergillosis, 72, 147, 153, 559 clinical manifestations, 225

709

710

INDEX

Aspergillosis (cont.) cutaneous, 225 diagnosis, 225 mycologic methods, 225 serologic methods, 226 disseminated, 225 epidemiology and risk factors, 224, 537 invasive pulmonary, 133, 137–139, 218–219, 225 pathogenesis, 225 prevention/prophylaxis, 227, 455–456 use of protective environments, 227 in transplant patients, 539, 540, 579, 587 treatment, 220, 221, 226–227 surgery, 227 Aspergillosis spp., 72, 193–194, 196, 224, 534–536 Ataxia telangiectasia, 480 Atovaquone, 285 Azathioprine, 575–576, 629 Azoles, 233–234, 238; see also Fluconazole; Itraconazole AZT (zidovudine), 287 B lymphocytes (B cells), 528 B-cell defects, 476–480 B-cell immunodeficiency, 481–484 Babesiae/Babesia spp., 323 B. divergens, 323 B. microti, 323 Bacillary angiomatosis (BA), 64–65 Bacillary peliosis (BAP), 64, 65 Bacilli, gram-negative, 59 Bacillus Calmette-Guérin (BCG), 62 Bacillus Calmette-Guérin (BCG) vaccine, 453 Bacillus cereus, 59 Bacteremia, 507–508, 530 fatal P. aeruginosa, 507, 508 in organ transplant recipients, 641, 645 Balamuthia mandrillaris, 317–319 Barrier containment, 227 Bartonella spp., 64, 65 B. henselae, 64, 65 B. quintana, 64, 65 Benzimidivir, 367–368 Biopsy: see also Lung biopsy transbronchial, 150 BK virus (BKV), 407, 410, 557, 637 Blastomycosis, 74 clinical manifestations, 234 diagnosis, 234–235 epidemiology, 234 treatment, 235 Bleomycin pulmonary injury, 128 Blood products, immunosuppressive effects of, 29 Body temperature and host defense, 22 Bone marrow, cytokine therapy for stimulation of, 519–520 Bone marrow transplantation (BMT), 22, 544 detection of HHV-6 and HHV-7 after, 390 Brain abscess clinical presentation, 180–181, 194 diagnosis, 181–182, 194–196 epidemiology and etiology, 180, 193–194 treatment, 196

Brain abscess (cont.) treatment (cont.) antimicrobial therapy, 182–183 surgical, 183 Bronchial brushing, 151 Bronchiolitis obliterans-organizing pneumonia (BOOP), 123, 129 Bronchoalveolar lavage (BAL), 530–532, 534, 544, 552 Bronchoscopic diagnostic techniques, 150–151 Bronchoscopy, fiberoptic, 150, 282 Burkholderia cepacia, 587 Burn patients, 698, 699 postoperative management of, 698, 700 Busulfan pulmonary injury, 127–128 Cachexia, 427 Cancer patients, 509; see also Chemotherapy neutropenic, 219–220 Cancer(s): see also Leukemia(s); Lymphoma(s) in childhood, 442–443, 446 interface between infections and, 446 pulmonary invasion, 130 relative frequency of opportunistic pathogens in various, 508 Candidemia, 71, 530 Candidiasis/Candida spp., 55, 478 C. albicans, 222, 223, 532 C. glabrata, 217, 223 C. krusei, 217 chronic mucocutaneous, 481 clinical findings, 67–68, 222 diagnosis, 68–69, 190, 222 epidemiology, 66–67, 188, 221–222 hepatosplenic, 551 invasive, 70–71 meningitis, 188, 190, 193 prophylaxis, 69 in transplant patients, 530, 534–536, 646–647 treatment, 69, 193, 221–224, 534–536 Cardiac allograft vasculopathy, 611 Catheter-related infection, intravascular, 532 Cell association, 599 Cell-mediated immunity (CMI), 20, 21, 24–26, 28, 371–372; see also Cellular immunity Cellular defense mechanisms, 13–20 Cellular immune response, initiation of, 18 Cellular immunity, 18–19, 297–298; see also Cell-mediated immunity defective, 19–20 Cellulitis, 57, 58, 60, 62, 63 cryptococcal, 71–72 Central nervous system (CNS) infections, 163; see also Toxoplasmosis; specific infections antimicrobial therapy, 177 recommended doses, 178 bacterial, 164, 172–187 fungal, 164, 187–196 in organ transplant patients, 640–641 protozoal, 164, 196–201 viral, 163–172, 385 Chagas’ disease, 98–99, 267–268, 323–324 Chemotaxis, defective, 486–487, 489 Chemotherapeutic agents that induce pulmonary disease, 124, 125

INDEX Chemotherapy, 499 hepatitis B in oncology patients receiving, 348–350 Chickenpox, immunization of children to prevent, 377 Children, 441–442, 458; see also specific topics Chorioretinitis, 607 Chronic ambulatory peritoneal dialysis (CAPD), 25 Chronic granulomatous disease (CGD), 468, 487–488 Chronic myelogenous leukemia (CML), 293 Clindamycin, 285 Coccidioidal meningitis, 192 Coccidioidomycosis, 74 clinical manifestations, 232–233 diagnosis, 233 epidemiology and pathogenesis, 232 treatment, 233–234 Colony-stimulating factors (CSFs), 11, 32 granulate, 11, 31, 223, 286, 457, 485, 582 granulate-macrophage, 11, 31, 32, 223, 286, 458 macrophage, 11, 519–520 Complement component deficiencies, 483 C6, C7, and C8 deficiency, 484–485 C3 and C5 deficiency, 484 early classic pathway component deficiencies, 483–484 Complement system, 6–7 Congenital B-cell immunodeficiency, 481–484 Congenital ichthyosis, 486 Congenital immunodeficiency diseases: see also Phagocyte abnormalities aim of therapy in minimizing the effects of less severe acute infections, 470–473 prevention of chronic infections and their sequelae, 473–475 treatment of life-threatening infections, 467–470 early diagnosis of infection, 468–469 suggested initial empiric therapy for specific infections, 477 Congenital immunodeficiency syndromes, infections in, 475–476 combined B- and T-cell defects, 476–480 Congenital neutropenias, 485–486 Congenital pure T-cell immunodeficiencies, 480–481 Congenital toxoplasmosis, 292 Corticosteroids, 50, 574 Corynebacterium jeikeium, 59 Cotrimoxazole: see Trimethoprim Coxsackievirus, 411–412 Cryptococcal meningitis, 189, 192 Cryptococcosis, 456 clinical manifestations, 228–229 diagnosis antigen detection, 229 mycologic methods, 229 epidemiology and pathogenesis, 228 treatment, 230 antifungal medications, 229–230 management of immunosuppressive medications, 230 transplantation following, 230–231 Cryptococcosis spp., 71, 72, 189 C. neoformans, 71, 139, 141, 188 Cryptosporidium spp., 301, 471–472 diagnosis, 303–304 epidemiology, 302–303 organism, 301–302 patient, 304

711

Cryptosporidium spp. (cont.) prophylaxis, 456–457 therapy, 304–305 Cutaneous and subcutaneous sites, systemic infection metastatic to, 55 Cutaneous infections, 472–473 opportunistic primary, 54–55 unusually widespread, 51, 53–54 Cutaneous leishmaniasis (CL), 98 Cyclic 3',5'-adenosine monophosphate (cAMP), 475 Cyclic 3',5'-guanosine monophosphate (cGMP), 475 Cyclospora spp., 325 Cyclosporin, 28, 576 Cytokine network, 11–12 Cytokine therapy, 223, 519–520 Cytokines, 8–11, 230, 574, 575 Cytolytic T lymphocytes (CTLs), 337, 609 Cytomegalovirus (CMV), 26, 431, 432, 474, 582 and cell-mediated immunity, 371–372 in children, 451 clinical manifestations and effects, 86, 384–385, 542–544, 604–613 CNS complications due to, 167–169 cutaneous, 54, 86 diagnosis, 169, 385, 544, 613–616 epidemiology, 86, 167, 380–381, 542–544, 600–602 herpesviruses and, 367, 371–372, 390–391 immunization, 520, 616–617 “lethal CMV syndrome,” 605 necrotizing pneumonia, alveolar damage, and, 122 pathogenesis, 602–604 disease processes within infected organs, 382–384 viremia and viral load, 381–382 Pneumocystis and, 272, 275 prevention, 544, 545, 579 in autologous transplantation, 547 preemptive antiviral therapy, 546 prophylaxis, 387, 545–547, 579 prevention of primary CMV infection, 547 reactivated/reactivatation of, 54, 75, 116, 275, 601 risk factors, 542–544 in transplant recipients, 579, 600–622 hematopoietic stem cell transplant, 541–548, 553–554, 562 primary, 600–601 renal transplant patients, 342 superinfection, 601–602 treatment/management, 367, 385, 547–548, 616–621 double-blind, placebo-controlled RCTs, 386–387 strategies for chemotherapy, 385–389 Cytomegalovirus (CMV) diseases in the immunocompromised, 384 Cytomegalovirus (CMV) pneumonia, “nodular,” 533 Cytomegalovirus (CMV)-specific antibodies, 546–547 Cytotoxic T lymphocytes (CTL), 372, 528, 603 Dapsone, 285 Decontamination, 227 Defense (mechanisms), host, 6 attempts to strengthen, 30–32 diseases that affect, 22–27 factors that influence quality of, 20–22 first line of, 5–6 second line of, 6–20

712

INDEX

Dementia: see AIDS dementia complex Dermatomycoses: see Fungal infections, superficial Dermatophytoses, 65–66 Dexamethasone, 179–180 DFMO 286 Diabetes mellitus, 24 Diagnostic approach, and surgery, 681–688 Diagnostic techniques, 2; see also specific topics immunologic, 148 DiGeorge’s syndrome, 480–481 Diptheria-pertussis-tetanus (DPT), 453–454 DNA viruses, 405–411 Donor and recipient class II HLA matching, 634 Donor issues (transplantation), 560 Donor tumor necrosis factor gene, 634 Down’s syndrome, 338, 489 Drug-induced pneumonitis, 126–130 Echinocandins, 239 Echoviruses, 411–412 Ecthyma gangrenosum (EG), 59, 61 Edema, hydrostatic “batwing” pulmonary, 144, 394 Encephalitis CMV, 385 herpes simplex: see Herpesviruses, CNS pathology subacute, 425–426 Endocytosis, 16 Endoplasmic reticulum (ER), 371 Endothelial cells, 13, 14 Entamoeba histolytica, 313–314 diagnosis, 316–317 epidemiology, 314–315 immunology, 315 life cycle, 314 pathogenesis, 315 patients with, 315–316 therapy, 317 Enterococcus, 59 Environmental conditions, 514–515 Enzyme deficiencies, purine pathway, 479 Eosinophils, kinetics of, 14–15 Epstein-Barr virus (EBV), 75, 84–86, 362 cancer and, 446 clinical manifestations, 393–394 diagnosis, 394–395 EBV-encoded proteins expressed during latency, 392 epidemiology, 392 management, 395 in organ transplant patients, 556–557, 599, 621–625 pathogenesis, 392–393 Epstein-Barr virus (EBV)-encoded RNAs (EBERs), 621 Epstein-Barr virus (EBV) nuclear antigens (EBNAs), 621 Escherichia coli (E. coli), 59, 60 Esophageal candidiasis, treatment of, 69 Famciclovir (FCV), 78 Fansidar, 289 Felty’s syndrome, 26 Fever, 384 causes of, 598 in leukemia and lymphoma, 503–506

Fever (cont.) in children, 447–452, 455 vs. adults, 449 management of, 219–221 IDSA guidelines, 514 modifications of therapy, 450 prophylaxis during episodes of fever, 455 occult intra-abdominal sources of, 687–688 problems with interpretation of, 502–503 prolonged, 449–450 Fibronectin, 8 Fibrosing cholestatic hepatitis (FCH), 345, 347, 634 FK506 (tacrolimus), 28, 576–577 Fluconazole, 191–193, 237–238, 450, 455, 472, 516 for candidiasis, 223 for coccidioidomycosis, 233–234 for histoplasmosis, 232 for neutropenic patients with persistent fever, 220–221 prophylactic use of, 216–217, 219 5-flucytosine, 223, 226, 237 Fluoroquinolones, 455 Foscarnet, 367, 377 Fungal infections, 50, 65, 215; see also Antifungal agents; specific infections in AIDS, 216, 230–233 antifungal prophylaxis, 216–219, 230, 232, 455–457 indications for, 219 diagnosis, 533–534 in granulocytopenia, 215 invasive, 432, 554, 559 involving the skin, 69–75 of the lung, 147 superficial, 65–69 in transplant patients, 216, 532–537, 559, 646 treatment, 224, 235, 534–537 underlying diseases in opportunistic, 509, 510 Fungal pathogens, unusual, 235–236 Fungi endemic, 55, 74–75 ubiquitous, 70–74 Fusariosis, 74, 228 clinical manifestations, 74 diagnosis, 74 epidemiology and pathogenesis, 74 treatment, 74 Ganciclovir (GCV) for herpesviruses, 365–366 CMV, 387–388, 545–546, 618–620 nucleosides and, 365–366 prophylactic use, 545–546, 618–620 Gangrenosum ecthyma, 59, 61 pyoderma, 100 Gastroenteritis, 406–407 Gastrointestinal (GI) bleeding, postoperative, 700–701 Gastrointestinal (GI) complications of immunosuppressed state, 683– 687 Gastrointestinal (GI) disease, 384 Gastrointestinal (GI) infections, 471–472, 605 Genetic control of host defense, 20

INDEX Giardia lamblia, 322, 471 Globulins antithymocyte, 29, 577, 578 HBIG, 345, 346, 353, 589 hyperimmune, 546–547 zoster immune, 380, 627 Glomerulonephritis, 635 Glucocorticosteroids, 574 Graft function, poor associated with infections, 556 Graft-versus-host disease (GVHD), 478, 527, 530, 546–547, 553, 554, 560–561 infections with encapsulated bacteria in patients with chronic, 555 Granulate CSF (G-CSF), 11, 31, 223, 286, 457, 485, 582 Granulate-macrophage CSF (GM-CSF), 11, 31, 32, 223, 286, 458 Granulocyte transfusions, 541 Granulocytes, neutrophilic, 13–14 Granulocytopenia, 223, 227 Granulomatous disease, chronic, 468, 487–488 Granulomatous febrile pneumonitis, 123 Group A $-hemolytic streptococci (Streptococcus pyogenes) (GAS), 57–58 Group B streptococci, 58 Growth factors, 457–458, 541 Haemophilus influenzae, 12, 172–173, 470, 471, 479 Haemophilus influenzae type B (HIB), 23, 172, 454 Heart transplant recipients preexisting infection, 587 wound infection, 596 Helicobacter cinaedi, 62 Hematology, prophylaxis in, 216 Hematoma, wound, 594 Hematopoietic growth factors, 226–227 Hematopoietic stem cell transplantation (HSCT), 527, 562 antibiotic administration, duration of, 539 antibiotic coverage, prophylactic and empirical, 537–539 antifungal use, prophylactic, 539–541 future considerations, 562 infection control programs and surveillance isolation practices, 560–561 postexposure prophylaxis, 562 prevention of exposure by personnel, family, and visitors, 561– 562 use of surveillance culture, 561 phases of infections after, 529–530 between conditioning and engraftment, 530, 532–541 between engraftment and day 100, 541–552 after 100 days, 552–556 pretransplant infectious disease considerations, 559–560 recovery of host defenses, 528–529 transplantation techniques, 527–528 Hematopoietic stem cell transplantation (HSCT) recipients, antimicrobial prophylaxis regimens in, 538 Hepatic cirrhosis. 25 Hepatitis, 335–338, 353–354, 557 adenovirus, 406 CMV and, 384 fibrosing cholestatic, 345, 347, 634 in hemodialyzed patients with chronic renal failure, 338–340 hepatitis A virus (HAV), 335, 630

713

Hepatitis (cont.) hepatitis B core antigen (HBcAg), 336 hepatitis B e antigen (HBeAg), 336, 338, 631–633 hepatitis B immune globulins (HBIG), 345, 346, 353, 589 hepatitis B surface antigen (HBsAg), 336–341, 345, 348–352, 589, 630–633 hepatitis B virus (HBV), 336–342, 344–348, 350–353, 589, 630, 634 hepatitis C virus (HCV), 337, 340, 346–348, 351, 433, 589–590, 630 clinical impact on organ transplant recipients, 630, 633–635 hepatitis C virus (HCV) genotype, 634 hepatitis D virus (HDV), 346, 630 hepatitis E virus (HEV), 630 hepatitis G virus (HGV/GB virus C), 335, 340 in organ transplant recipients, 340–348, 629–630 clinical impact, 630–633 prevention, 351–353 role of immunologic mechanisms in pathogenesis of, 336–337 Hepatosplenic candidiasis, 551 Herpes simplex virus (HSV) diseases/infections acyclovir-resistant, 76, 78, 377 in the immunocompromised, 376, 552 in organ transplant recipients, 625–626 Herpes simplex virus (HSV) virion, structural proteins of, 364–365, 367 Herpes simplex virus-1 and -2 (HSV-1 and -2), 75–79, 375, 376, 626 in children, 451 treatment, 78–80 Herpes simplex virus-1 (HSV-1) capsid, structure of, 366 Herpes simplex virus-8 (HSV-8) clinical features, 396–397 diagnosis, 397 epidemiology, 395–396 management, 397 pathogenesis, 396 Herpes zoster (HZ), 79–83 Herpesviruses (HHV), 75–86 and avoiding immune reactions, 370 establishing immunity, 370 interfering with immune responses, 370–372 clinical manifestations, 376 CNS pathology clinical presentation and findings, 167–168 diagnosis, 168–169 treatment, 169–170 co-evolvution with humans, 361 cofactor, stimulating HIV replication, 373–374 diagnosis, 376 discovery of human, 361–362 epidemiology and etiology, 166–167 genomes, 362 cascade sequence of gene expression, 363–364 core set of replicative genes, 364, 367 genes mutated in resistant strains, 368–370 genes targeted for antiviral chemotherapy, 365–368 genome structures/nomenclature, 362–363 “nonessential” genes, 370 structural genes, 364–365 human herpesviruses 6 and 7 (HHV-6 and HHV-7), 372–373, 551, 557, 627–628

714

INDEX

Herpesviruses (HHV) (com.) human herpesviruses 6 and 7 (HHV-6 and HHV-7) (cont.) clinical manifestations, 391 detection of, after BMT, 390 diagnosis, 391 epidemiology, 389 management, 391 pathogenesis, 389–391 human herpesvirus 8 (HHV-8), 86–89, 433, 557, 628–629 and immunopathologic disease, 373 and increased incidence and severity of disease, 373 interacting with HIV, 373–374; see also HIV infection/disease, herpesviruses and as opportunistic agents, 372 and organ transplant recipients, 599–629 pathogenesis, 375 direct effects, 375–376 indirect effects, 376 temporal appearance, 372–373 treatment/management, 365–368, 377 triggering other pathologic phenomena, 373 High-efficiency particulate air (HEPA), 120–121, 561 Histoplasma spp., 189 H. capsulatum, 74, 188 Histoplasmosis, 74–75 clinical findings, 231 diagnosis, 231 epidemiology and pathogenesis, 231 treatment, 231–232 HIV-associated eosinophilic folliculitis, 100 HIV-associated KS, 87–88 HIV classification, pediatric, 444 immunologic and clinical categories, 444–445 HIV infection/disease antiretroviral chemotherapy, 429 bacterial infections and, 64 in childhood, 443–446 fungal infections and, 66, 69–70, 72 hepatitis and, 350–351 herpesviruses and, 75–89, 372–375 HPV and, 92–95 MCV and, 90–91 in organ transplant recipients, 590, 635–637 parasitic infections, 268, 272–273 PML, JC virus, and, 409 syphilis occurring in, 96–97 T cells and, 26–27 HIV-1, 410, 421 antiretroviral chemotherapy, 427–428, 430 classes of agents, 428–429 clinical use of antiretroviral agents, 429–431 cachexia and wasting, 427 CNS pathology clinical presentation, 164–165 diagnosis, 165–166 treatment, 166 dynamics of, in vivo, 423 epidemiology and etiology, 163–164, 421–422 metabolic disturbances, 427 neurologic manifestations, 424 pathogenesis of neurologic complications, 424–425

HIV-1 (cont.) pathogenesis, 422–424 primary, 422 primary and secondary prophylaxis of opportunistic infections, 431–433 Hodgkin’s disease, 130; see also Lymphoma(s) Hodgkin’s disease patients, immunologic abnormalities of, 499–500 Hospital-acquired pulmonary infection, 120–121 Host resistance, impaired causes of, 681, 682 consequences affecting surgical management, 681, 682 Human lymphocyte antigen (HLA), 18, 20, 371, 475, 479 Human papillomavirus (HPV), 54, 91–95, 558 Humoral defense mechanisms, 6 Humoral immunity, 370–371 Hyalohyphomycosis spp., 74 Hyper-IgE syndrome, 486–487 Hyperimmune globulin (MVC-Ig), 546–547 Hyperimmunoglobulinemia A, 487 Hyperimmunoglobulinemia E, 486–487 Hyperinfection syndrome, 311–312 Hypertension, management of intracranial, 230 Hypogammaglobulinemia associated with hyperimmunoglobulinemia M, 482 common variable, 483 with increased IgM, neutropenia with, 486 of infancy, transient, 481 sex-linked, 481–482 Ichthyosis, congenital, 486 Idiopathic pneumonia syndrome (IPS), 529, 551–552 Immunocompromised host, defined, 1 Immunoglobulin (Ig) therapy, 407 Immunoglobulin(s): see also Intravenous immunoglobulin (IVIG) cellular immunodeficiency with, 480 intramuscular, 474 VZV-specific, 562 Immunoglobulin A (IgA), 12–13 Immunoglobulin A (IgA) deficiency, selective, 482–483 Immunoglobulin E (IgE), 12 Immunoglobulin G (IgG), 12–13, 31, 198, 199, 297, 298, 394, 482, 617, 618 Immunoglobulin M (IgM), 12, 16, 198, 297, 298, 394, 614 Immunoglobulin M (IgM) deficiency, selective, 482 Immunosuppression, 634 net state of, 114–117 Immunosuppressive drugs, 27–29 cytotoxic, 28 Inactivated polio vaccine (IPV), 453 Infections: see also specific topics in compromised host areas of controversy in management of, 3 future challenges regarding, 2–3 impact on host defense, 26–27 perturbations of host defense that contribute to, 446–447 Inflammatory disorders that simulate infection in compromised host, 100 Inflammatory response, 575 impaired, 2 Influenza immunization, 520–521 Influenza viruses, 550

INDEX

271, 286, 475, 487 Interferons (IFNs), 8, 20, 30–31 Interleukin (IL), 8–11, 576 Interleukin-1 (IL-1) biological activities, 9 Interleukin-2 (IL-2), 31, 576 receptor antibodies, 28 Intracellular killing, 16–17 Intramuscular (IM) immunoglobulin (IMIG), 474 Intravenous immunoglobulin (IVIG), 454, 457, 469–470, 473–474, 478–480, 546–547 Iron deficiency, 21 Iron overload, 634 Isolation practices, 560–561 Isospora belli, 305–306 Itraconazole, 238, 516 for aspergillosis, 226, 645 for histoplasmosis, 232 for neutropenic patients with persistent fever, 221 prophylactic use of, 217 Ivermectin, 313 JC virus (JCV), 170, 171, 407–410, 557, 637 Kaposi’s sarcoma (KS), 64, 90, 395–396 of the lung, 136, 146–147 Kaposi’s sarcoma-associated herpes virus: see Herpesviruses, human herpesvirus 8 Ketoacidosis, 689–690 Ketoconazole, 233 Lactoferrin, 6 Lamivudine, 632 Latency, 75, 599 Latent membrane proteins (LMPs), 621 “Lazy-leukocyte” syndrome, 486 Left ventricular assist devices (LVAD), 587 Legionellosis/Legionella spp., 556, 581 Leishmania spp., 98, 267, 319 diagnosis, 321 epidemiology, 319–320 organism characteristics, 319 pathogenesis and immunology, 320 patient characteristics, 320–321 therapy, 321 Leprosy, 250 Leukemia(s), 22–23, 130, 511–512 acute lymphoblastic, 442, 453 causes of fever in, 503–506 chronic myelogenous, 293 infection in host defenses against, 498–501 immunoprophylaxis and immunotherapy of, 520–522 interpretation of fever and infection incidence data, 502–503 recommended therapeutic strategies, 514–517 role in mortality, 501–502 primary causes of death in acute, 501 site of involvement and nature of microbial pathogen(s), 506–511 Leukoagglutinin reaction, 131, 132 Leukocyte adhesion deficiency (LAD), 489–490 Leukocytes, 574

715

Leukocytes (cont.) polymorphonuclear, 257, 475, 485–489, 574 Leukoencephalopathy: see Progressive multifocal leukoencephalopathy Leukopenia, 384 Listeria spp., 173, 640 L. monocytogenes, 173–174, 179, 500, 641–645 Liver transplant recipients, 597–598; see also Transplant recipients antifungal prophylaxis in, 218 hepatitis in, 344–348 preexisting infection, 586–587 wound infection, 595–596 Lung biopsy, 150 open, 152–153, 282 percutaneous needle, 151–152 Lung transplant recipients, 598; see also Transplant recipients antifungal prophylaxis in, 218–219 preexisting infection, 586, 587 wound infection, 596 Lymphoceles, 594 Lymphocytes: see B lymphocytes; T lymphocytes Lymphocytic interstitial pneumonitis, 147 Lymphoid hyperplasia, 622–623 Lymphoma(s), 22–23, 30, 511–514 body cavity, 396–397 infection in host defenses against, 498–501 immunoprophylaxis and immunotherapy of, 520–522 interpretation of fever and infection incidence data, 502–503 recommended therapeutic strategies, 514–517 role in mortality, 501–502 site of involvement and nature of microbial pathogen(s), 506– 511 of the lung, 130, 147 Lymphoproliferation of EBV, 393 X-linked, 393 Lymphoproliferative syndrome, 393–395 X-linked, 393–395 Lysozyme, 6 Macrophage CSF (M-CSF), 11, 519–520 Macrophage-T lymphocyte interaction, 19 Macrophages, activated, 19 Major histocompatibility complex (MHC), 599, 603, 609, 612 Malaria, 322–324 Malnutrition, 21, 690–691 Measles, 75, 412–413 Measles-mumps-rubella (MMR) vaccine, 453, 649 Meningitis: see also Tuberculosis (TB) infections of the CNS aseptic, 425 clinical presentation and findings, 174, 175, 188–189 diagnosis, 174–175, 189–190, 229 epidemiology and etiology, 172–174, 188 treatment, 175–179 adjunctive, 179–180, 193 antifungal, 190–193, 229–230 empiric therapy of purulent meningitis, 176 Meningoencephalitis: see Primary amebic meningoencephalitis Methotrexate (MTX), 28 Methotrexate (MTX) pulmonary injury, 128, 130 Microorganisms, categories of, 1

716

INDEX

Microsporidia, 306–307 diagnosis, 307–308 organism, 307 patient, 307 therapy, 308–309 Mold infections, 550–551; see also Aspergillosis Molluscum contagiosum (MCV), 75, 89–91 Monoclonal antilymphocyte antibodies, 577–578 Monocyte chemotactic deficiency, 487 Mononuclear phagocyte system (MPS), 15, 27 Mononucleosis, infectious, 393–395 Mucormycosis, 72–73, 194, 196; see also Zygomycosis Mucosa, as first line of defense, 5–6 Mucosal candidiasis, 67–68 MVC-Ig (hyperimmune globulin), 546–547 Mycobacteria/Mycobacterium spp. environmental, 62–64 M. avium-intracellulare complex (MAC), 63, 135, 146, 249–250, 431, 432, 455 chemotherapy of, 254–256, 431, 432 M. chelonae, 63 M. leprae, 64 M. tuberculosis (TB), 62, 183, 187, 250–252, 558, 580; see also Tuberculosis in vitro susceptibility testing, 256–257 microbiologic classification and clinical syndromes, 250 pathogenesis and epidemiology, 250–254 Mycobacterial infections, 143, 146, 558 in organ transplant patients, 647–648 Mycobacterial prophylaxis, in children, 455 Mycophenolate mofetil (MMF), 28, 576 Myelopathy, vacuolar, 427 Myeloperoxidase deficiency, 488–489 Naegleria fowleri, 317, 318 Natural killer (NK) cells, 18, 609 Neisseria meningitidis, 173 Nephrotoxicity, 578 Neuropathy, peripheral, 426–427 Neurosyphilis, 97 Neutropenia(s), 487 in children, 447–450, 455 vs. adults, 449 chronic benign, 485–486 congenital, 485–486 guidelines for empiric antifungal therapy during, 221 modifications of therapy in patients with, 450 Neutropenic patients, 219–221 Neutropenic states, 502–503 Neutrophil transfusions, 518–519 Neutrophilic dermatosis(es), 100 acute febrile, 100 Neutrophilic granulocytes, 13–14 Neutrophils, 498–499 Nikkomycin Z, 239 Nitric oxide (NO), 16 Nocardia spp., 173, 175 N. asteroides, 257, 259, 645 N. farcinica, 257 Nocardial infection, 137 Nocardiosis, 65, 257, 559

Nocardiosis (cont.) clinical management, 260–261 clinical manifestations, 258–260 diagnosis, 260 microbiology and epidemiology, 257–258 pathogenesis and pathology, 258 Non-A, non-B hepatitis (NANBH), 634 Nonpathogens, 1 NRAMP1 gene, 20 Nucleosides, 365–366 Nucleotides, 366–367 Nutritional status, 20–21, 690–691 Ocular toxoplasmosis, 292–293 OKT3, 577, 578, 598 Oncogenicity, 75, 599 Oncology patients, hepatitis C in, 350 Onychomycosis, proximal subungual, 66–67 Opportunistic infection (OI), 1–2; see also specific topics defined, 1 Oral hairy leukoplakia (OHL), 84–86 Oral polio vaccine (OPV), 453 Oropharyngeal candidiasis (OPC), 66–67 treatment, 69 Otitis, 225 Paecilomyces, 54 Papillomavirus, 54, 91–95, 558, 637–638 Papovaviruses, 407–410 clinical impact of, in organ transplant recipients, 637–638 Parainfluenza viruses, 549, 550 Paramyxoviruses, 412–413 Parasites, therapy for common intestinal, 305 Parasitic infections, 267, 321–322, 556 in AIDS patients, 265, 266, 314 antiparasitic prophylaxis, 455–457 host-parasite interactions and mechanisms of immune evasion, 267–268 missing infections in compromised hosts, 267 parasite-specific factors, 265–267 Parasitic infestations, 97–99 Parvovirus B 19, 557–558 Pathogens, 1 Penciclovir (PCV), 365, 366 Penicillin G, 182 Penicillin therapy, 97, 176–177, 641 Penicillium marneffei, 74 Pentamidine, 284–285, 287 Percutaneous needle aspiration, 282 Peripheral blood stem cell (PBSC), 528, 543 Peritoneal dialysis, chronic ambulatory, 25 Phaeohyphomycosis spp., 73–74 Phagocyte abnormalities, 472, 485 chemotactic defects, 486–487 microbicidal defects, 472, 487–489 Phagocyte function, 17 deficient, 17–18 Phagocytes kinetics of, during inflammation, 15–16 kinetics of mononuclear, 15 Phagocytic cells, 13

INDEX Phagocytic cells (cont.) development of, 14 Phagocytosis, neonates with combined defects in chemotaxis and, 489 Phosphate deficiency, 21 Picornaviruses, 411–412 Pityrosporiasis, 66 Pityrosporum folliculitis, 66 Plasmapheresis, 29 Plasmodium spp., 323 P. falciparum, 322–323 P. malariae, 323 P. vivax, 323 Pneumococcal immunization, 521–522 Pneumococcus: see Streptococcus spp., S. pneumoniae Pneumocystis spp., 144, 145 diagnostic techniques, 150 P. carinii pneumonia (PCP), 268; see also Pneumonia antimicrobial prophylaxis, 145, 288–290, 456 changing patterns of, 272–273 in childhood, 451–452 clinical manifestations, 273–275 conditions associated with, 271–272 diagnosis and radiology, 136, 140, 142, 145–146, 275–282, 382 diffuse alveolar damage with foamy alveolar exudate, 122 epidemiology and risk factors, 145, 271–272 hematopoietic stem cell transplant and, 554–555 in HIV and AIDS patients, 97–98, 140, 142 laboratory evaluation, 279 prophylaxis, 287–288, 431, 554 taxonomy and life cycle, 268–271 treatment, 282–287, 478, 554–555 Pneumonia, 478, 530, 532; see also Pneumocystis spp.; Streptococcus spp., S. pneumoniae adenovirus, 406 BOOP, 123, 129 interstitial clinical presentation and diagnosis, 542 etiology and risk factors, 541–542 pyogenic bacterial, 146 Pneumonitis (syndrome), febrile, 112–113, 385; see also Pulmonary infection acute necrotizing, 122 acute nonnecrotizing, 121–122 diagnosis of, 147–153 radiologic clues to, 133 radiologic findings, progression, and clinical signs, 133–134, 136–142, 144 thoracic disease in AIDS patients and, 144–147 etiology, 112, 113 infectious causes, 112–113 noninfectious causes, 124–131 granulomatous, 123 interstitial, lymphocytic, 147 interstitial plasma cell, children with epidemic, 275–276 pathology, 121–124 Polio vaccines, 453 Poliomyelitis, 411 Polyclonal antithymocyte antibodies, 577 Polyclonal antithymocyte globulin (ATG), 29, 577 Polymorphonuclear leukocytes (PMNs), 257, 475, 485–489, 574

717

Polyradiculopathy, 385 Polysaccharide-protein conjugates, 453–454 Posaconazole (SCH 56592), 238–239 Postoperative management, 697–702 Posttransplant lymphoproliferative disease (PTLD), 613, 622–624 lymphomatous/monomorphic, 623 polymorphic, 623 Primaquine, 285 Primary amebic meningoencephalitis (PAM), 317 epidemiology, 318 organism, 317–318 pathogenesis, 318 patient and diagnosis, 318–319 therapy, 319 Progressive multifocal leukoencephalopathy (PML), 408–410, 637 clinical presentation, 171 diagnosis, 171 epidemiology and etiology, 170–171 treatment, 171–172 Prophylaxis: see also specific topics in children, 454–457 in hematology, 216 Protease inhibitors, HIV-1, 428–429 Prototheca spp., 99 Protothecosis, 99 Protozoa: see Parasites; Pneumocystis Proximal subungual onychomycosis (PSO), 66, 67 Pseudallescheria boydii, 194–196 Pseudomembranous candidiasis, 67–68 Pseudomonas aeruginosa, 54, 55, 59, 61, 499, 507, 508, 539, 592 Pulmonary edema, hydrostatic “batwing,” 144, 394 Pulmonary infarct, 134 Pulmonary infection: see also specific infections clinical clues to diagnosis, 123–124 risk factors, 113–117 epidemiologic aspects, 117–121 Pulmonary infiltrates in the immunocompromised host diffuse, 681–683 focal, 683 Pulmonary injury, busulfan, 127–128 Pulmonary invasion, neoplastic, 130 Purine pathway enzyme deficiencies, 479 Pyoderma gangrenosum, 100 Pyrimethamine, 200, 285–286 Quasispecies, 634 Radiation, 29–30 Radiation pneumonitis, 125–126 Rapamycin, 577 Renal failure, chronic, 24–25 Renal parenchymal involvement by adenovirus, 407 Renal transplant recipients, 341–344, 601, 607; see also Transplant recipients urinary tract infection in, 638–639 wound infection in, 593–595 Respiratory infections, 470–471, 483; see also Pulmonary infection bacterial, 432 Respiratory management, postoperative, 697 Respiratory syncytial virus (RSV), 31, 413, 457, 474, 548–549, 639 Respiratory viruses, community-acquired, 548–550, 639

718

INDEX

Retinitis, 384–385, 607 Reverse transcriptase inhibitors, 428 Rheumatoid arthritis, 26 Rhinosinusitis, 225 RNA viruses, 411–414 Rotaviruses, 413–414 Salmonella, 645 Scabies, crusted (Norwegian), 99 SCH 56592 (posaconazole), 238–239 Screening tests, immunologic, 468 Sepsis, following splenectomy, 701–702 Septicemia, 608 Septicemic infections, organisms implicated in, 507 Severe combined immunodeficiency disease (SCID), 476–479 Sexually transmitted diseases (STDs), 95–97 Sickle cell anemia, 23–24 Sirolimus, 28–29 Skin as barrier to infection, 49–50 as first line of defense, 5 Skin infection diagnostic aspects, 55, 99–100 pathogens and types of, 50–55 primary, with common pathogens, 51 Somatostatin, 305 Sometime pathogens, 1 Sorivudine (BVaraU), 366 Spiramycin, 304 Splenectomized patient, approach to, 517–518 Splenectomy, 23, 701–702 Sporotrichosis spp., 72, 73 Sporotrix schenkii, 72 Sputum examination, 148–149 Squamous cell carcinoma (SCC), 54, 92 Squamous cell carcinoma in situ (SCCIS), 92 Squamous intraepithelial lesions (SIL), 92–95 Staphylococcus aureus, 55–58 Stem cell transplantation: see Hematopoietic stem cell transplantation Stenotrophomonas (Xanthomonas) maltophilia, 60 Steroid therapy, side effects and complications of, 689 Steroids, 50, 574 Streptococcus spp., 58 S. pneumoniae, 12, 58–59, 113, 114, 173, 469–471, 479 immunization, 521–522 S. pyogenes, 57–58 Stress and host defense, 22 Strongyloidiasis/Strongydiasis spp., 98, 311–312, 588 clinical presentation, 201 diagnosis, 201, 312 epidemiology and etiology, 200–201 S. stercoralis, 119, 200, 201, 266, 309, 580 epidemiology, 309–310 “hyperinfection syndrome” and disseminated strongyloidiasis, 311–312 organism characteristics, 309 pathogenesis, 310 patient characteristics, 310–311 treatment, 201, 312–313 Sulfadiazine, 200 Sulfamethoxazole, 260–261; see also Trimethoprim-sulfamethoxazole

Sulfonamides, 260–261 Superinfection, 153–154 Surgery, 681, 702–703 for aspergillosis, 227 impaired host resistance and, 681, 682 postoperative management, 697–702 preoperative preparation, 688–692 for tuberculosis infections of CNS, 187 Surgical practice, AIDS and, 695–697 Surgical techniques, 692–695 Syncytial virus: see Respiratory syncytial virus Syphilis, 95–97 variations in, occurring in HIV disease, 96–97 Systemic lupus erythematosus (SLE), 25–26 T lymphocytes (T cells), 18–19, 271, 528, 609 Tacrolimus (FK506), 28, 576–577 Thiabendazole, 312–313 Thoracoscopy, video-assisted, 282 Thrush (candidiasis), 67–68 Thymidine kinase (Tk), 365, 369–370, 552 Thymosin, 474, 480 Toxic shock syndrome (TSS), 57 Toxoids, 453–454 Toxoplasmosis/Toxoplasma gondii, 290 acquired, in immunocompetent individuals, 292 clinical presentation, 197–198, 292 congenital, 292 diagnosis, 198–200 histopathology and culture, 296–297 laboratory evaluation, 295 radiology, 295–296 skin testing and cellular immunity, 297–298 epidemiology and etiology, 196–197, 291–292 in immunocompromised hosts, 293–295 life cycle, 290–291 ocular, 292–293 prophylaxis, 300–301, 431, 456 in transplant patients, 556, 640 treatment, 200, 298–300 Transfusions granulocyte, 541 neutrophil, 518–519 Transplant recipients classification of infections in, 579, 580 infection from donor, 589–593 infectious disease problems of particular importance in, 640–648 noninfectious causes of fever in, 598 preexisting infections in, 586–589 risk of infection, 579–580 epidemiologic exposures, 580–581 net state of immunosuppression, 582–583 timetable of infection in, 583, 584 first month posttransplant, 583–598 1–6 months posttransplant, 584–595, 598–639 more than 6 months posttransplant, 639 wound infection in, 593–596 Transplantation, 573–574; see also Hematopoietic stem cell transplantation future prospects regarding, 649–650 immunosuppressive agents employed in, 574–578

INDEX

Transplantation (com.) principles of antimicrobial use in, 578–579 timing of, 234 toxoplasmosis, 293–294 Transtracheal aspiration, 282 Treponema pallidum, 96 Triazole agents: see Fluconazole; Itraconazole Trimethoprim, 260–261 Trimethoprim-sulfamethoxazole (TMP-SMZ) for cancer patients, 455, 515 for HIV patients, 456 for nocardiosis, 559 for parasitic infections, 306 for pneumonia, 283–285, 288–289, 452, 456, 476, 478, 538, 554– 555 prophylactic use, 283, 284, 455, 456, 515, 538, 554, 559, 638–639 for transplant patients, 538, 638–640 Trimetrexate, 285 True pathogens, 1 Trypanosoma spp., 323 T. cruzi, 323, 324 Trypanosomiasis African, 324 American, 98–99, 323–324 Tuberculin reactivity and preventative chemotherapy, 253–254 Tuberculomas, 183–185 Tuberculosis (TB), 146, 647; see also under Mycobacteria associated with HIV disease, 252–253, 431–432 miliary, 118 multiple drug-resistant (MDR), 254 prevalence of, in neoplastic diseases, 509 treatment, 254, 647–648 Tuberculosis (TB) infections of the CNS clinical presentation, 183–184 diagnosis, 184–185 epidemiology and etiology, 183 treatment adjunctive, 187 antimicrobial, 186–187 surgery, 187 Tumor necrosis factor (TNF), 8–11, 32, 116, 583, 602, 604 Tumor necrosis 424–425, 602, 634

Vaccines (com.) live, 453 passive immunization, 454 pneumococcal, 521–522 use in organ transplant recipients, 648–649 Vaccinia, 410–411 Vacuolar myelopathy, 427 Valaciclovir, 78 Vancomycin, 517 Vancomycin resistant enterococci (VRE), 645 Varicella-zoster virus (VZV), 54, 75, 78–84, 167 chickenpox vaccine and severity of, 378 in children, 451 clinical manifestations, 378–379 diagnosis, 379 epidemiology, 377 in the immunocompromised, 379 in organ transplant recipients, 626–627 pathogenesis, 377–378 direct effects, 378 prevention, 379–380, 561–562 treatment/management, 84, 380 Varicella-zoster virus (VZV)-specific immunoglobulin, 562 Varicella-zoster virus (VZV) vaccine, 377–380 Vascular permeability, 575 Vibrio spp., 60, 62 V. vulnificus, 60, 62 Viral infections, 75 in childhood, 450–451 pretransplant, 559–560 Viral load, 634 Viremia, 381–382, 385, 634 Virus capsid antigen (VCA), 394 Visceral leishmaniasis (VL), 98 Vitamin A deficiency, 21 Voriconazole, 226, 238 Wiskott-Aldrich syndrome, 479–480 Wound infection, 593–596 Xanthomonas maltophilia, 60 YMDD, 346

Upper respiratory infection (URI), 548, 550 Uremic patients, 582 Urinary leaks, 594 Urinary tract infection (UTI), 638–639 Vaccines, 377, 395, 411, 452–453, 520 CMV, 520, 616–617 for hematopoietic stem cell transplant recipients, 562 inactivated, 453–454 influenza, 520–521

Zidovudine (AZT), 287 Zinc deficiency, 21 Zoster-associated pain (ZAP), 379, 380 Zoster immune globulin (ZIG), 380, 627 Zygomycosis: see also Mucormycosis clinical manifestations, 227 diagnosis, 227–228 epidemiology, 227 treatment, 228

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