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PATHOLOGY AND PATHOGENESIS OF H U M A N VIRAL DISEASE

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PATHOLOGY AND PATHOGENESIS OF HUMAN VIRAL DISEASE

John E. Craighead, MD Department of Pathology University of Vermont Burlington

Academic Press San Diego New York Boston London Sydney Tokyo Toronto

This book is printed on acid-free paper. © Copyright © 2000 by ACADEMIC PRESS All Rights Reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the Publisher. Academic Press a Harcourt Science and Technology Company 525 B Street, Suite 1900, San Diego, California 92101-4495 http:/ / www.academicpress.com Academic Press Limited 24-28 Oval Road, London NWl 7DX, UK http: / / www.hbuk.co.uk / ap / Library of Congress Catalog Card Number: 99-63992 PRINTED IN CHINA 99 00 01 02 03 04 EV 9 8 7 6 5 4 3 2 1

This book is dedicated to Christina, who, without complaint, provided loving support and patience while helping me with the tedium of editing.


In Memory of Ernest William Goodpasture, MD (1886-1960) Professor of Pathology and Chair of the Department, Vanderbilt Medical School (1924-55) Scientific Director, Armed Forces Institute of Pathology (1955-59)

Generally acknowledged to be the father of viral pathology in the United States, Dr. Ernest William Goodpasture was also recognized worldwide for his contributions to our understanding of the pathogenesis of viral diseases. An expert microscopist and microbiologist. Dr. Goodpasture made important discoveries by studying human tissue in influenza, respiratory syncytial pneumonia, measles, giant cell pneumonia, and cytomegalic inclusion disease. He was also a dedicated, insightful, and painstaking investigator in the research laboratory, where his work significantly contributed to elucidating the pathogenesis of herpetic encephalitis, mumps, and fowl pox. His most important research contribution was the development of the chicken embryo as a model for the study of viral diseases as well as a medium for vaccine development. His guiding hand can be detected in many chapters in this book.

Dr. Robert D. Collins, Professor of Pathology at Vanderbilt University, and Dr. Goodpasture's historian, assisted in the preparation of these comments.


Contents

CHAPTER

Preface xv Acknowledgments xvii

Rhinoviruses CHAPTER

Enteroviruses

CHAPTER

Introduction 1 Virology and Epidemiology 2 Neurological Disease 3 Aseptic Meningitis 3 Encephalitis 4 Poliomyelitis 4 Post-Poliomyelitis Syndrome (PPS) 6 Chronic CNS Infection in the Immunocompromised Patient 8 Heart Disease 10 Clinical Diagnostic Criteria 10 Pathological Diagnostic Criteria: The "Dallas" Criteria 11 Enterovirus Etiology 13 Natural History of Group B Coxsackievirus Myocarditis 13 Pathogenic Mechanisms 14 Striated Muscle Disease 16 Epidemic Myalgia: Pleurodynia, Bornholm Disease 17 Lung Disease 18 Testicular Disease 18 Liver Disease 19 Kidney Disease 19 Placental Lesions of Neonatally Infected Infants 20 Skin and Mucus Membrane Disease 20 Type I Diabetes Mellitus 21

Influenza Viruses Influenza Viruses 35 Risk Factors 39 Lung Disease 40 Heart Disease 41 Muscle Disease 43 Salivary Gland Disease 43 Central Nervous System Disease 43 Reye-Johnson Syndrome 43

CHAPTER

Parainfluenza Viruses

CHAPTER

Respiratory Syncytial Virus (RSV) IX

Contents CHAPTER

Herpesviruses: General Principles Introduction 61 Cellular Virus Replication 61 Herpesvirus Latency 62 Herpesvirus Cytopathology (Alpha and Beta) 63

CHAPTER

7 Herpes Simplex Virus (HSV) Types 1 and 2 Introduction 65 Primary and Recurrent Oral and Skin Infections 65 Urogenital Tract Disease 66 Generalized Systemic Disease 69 Central Nervous System Disease 71 Respiratory Tract Disease 75 Digestive Tract Disease 76 Liver Disease 11 Lymph Node Disease 78 Eye Disease 78

CHAPTER

Epstein-Barr Virus (EBV) Introduction and Historical Overview 117 Cellular and Molecular Biology of EBV 118 Infectious Mononucleosis (IM) 120 Neuromuscular Disease 122 Myocarditis and Pericarditis 123 Kidney Disease 123 Lower Female Genital Tract 123 X-Linked Lymphoproliferative Disease (XLP) (Duncan's Disease) 123 Burkitt's Lymphoma (BL) 124 Lymphoproliferative Disorders (LPDs) Associated with Immunosuppression 127 Non-Hodgkin's Lymphoma 129 Hodgkin's Disease (HD) 130 Nasopharyngeal Carcinoma (NPC) 131 Lymphoepitheliomatous Gastric Carcinoma 133 Sinonasal Tumors 133 Pulmonary Disease 134 Lymphomatoid Granulomatosis 135 Inflammatory Pseudotumors 135 Sjogren's Syndrome and Salivary Gland Tumors 135 Hairy Leukoplakia (HCL) 136 Virus-Associated Hematophagocytic Syndrome 138

CHAPTER

8 Cytomegalovirus Historical Overview 87 Cytomegalic Inclusion Body Cells 88 Epidemiology and Natural History 89 Congenital CMV Infection and Disease 90 Placental Infection and Diseases 92 Infections of Immunologically Intact Children and Adults 92 Mononucleosis and the Posttransfusion Syndrome 93 Nervous System Infection and Disease 93 Pulmonary Infection and Disease 96 Digestive Tract Infection and Disease 100 Liver Infection and Disease 101 Pancreas Infection and Disease 102 Genitourinary Tract Infection and Disease 102 Myocardial Infection and Disease 105 Eye Disease 106 Ear Disease 107 Possible Role of CMV in Atherosclerosis 107

CHAPTER

10 Varicella-Zoster Virus (VZV) Introduction and Historical Overview 147 Disseminated Childhood VZV Infection of the Skin: Chickenpox 147 Hemorrhagic VZV Infections of the Skin 149 Chronic VZV Infections of the Skin 150 Nervous System Disease 151 Herpes Zoster 151 Encephalopathies 154 Eye Disease 156 Ear Disease 158 Pulmonary Disease 158 Digestive Tract Disease 159 Liver Disease 159 Renal Disease 160 Testicular Disease 162 Heart Disease 162 Joint, Synovial, and Muscle Diseases 162 Congenital VZV Infection 162

Contents

CHAPTER

XI

CHAPTER

11

16

Herpesvirus Type 6 (HHV-6)

Human Immunodeficiency Viruses

CHAPTER

12 Kaposi Sarcoma-Associated Herpesvirus (KSHV, HHV-8) Introduction 171 Epidemiology 173 Pathogenesis and Pathology 174 Angiosarcomas and Other Vascular Lesions 178 Body Cavity-Based Non-Hodgkin's Lymphoma (BCBL) 178 Angiof oUicular Lymph Node Hyperplasia 180

CHAPTER

13 Herpesvirus Simiae Virus (Herpes B)

CHAPTER

14 Adenoviruses Introduction 189 Epidemiology 189 Respiratory Tract Disease 191 Disease in Immunosuppressed Patients 195 Genitourinary Tract Disease 196 Digestive Tract Disease 197 Myocardial Disease 197 Central Nervous System Disease 197 Eye Disease 198

CHAPTER

15 Retroviruses: General Principles

Human Immunodeficiency Viruses 1 and 2 (HIV-1 and HIV-2) 205 HIV-1 Clinical Course in Adults 207 HIV-1 Clinical Course in Infants and Children 210 Persistent Generalized Lymphadenopathy (PGL) (syn. Progressive Generalized Lymphadenopathy) 212 Diseases of the Hematopoietic System 215 Diseases of the Central Nervous System 216 Acute Meningitis 216 HIV-1 Encephalopathy 216 Cognitive/Motor Complex (Syn. Dementia Complex) 217 Myelopathy and Myelitis 219 Neuropathy 219 Myositis 220 Opportunistic CMV Infections of the Central and Peripheral Nervous Systems 221 Diseases of the Respiratory Tract 222 Diffuse Alveolar Damage (DAD) 222 Lymphoid Interstitial Pneumonia (LIP), Nonspecific Interstitial Pneumonia (NIP), Follicular Bronchitis/Bronchiolitis (FBB) 222 Pulmonary Hypertension and VascularOcclusive Disease 223 Opportunistic Infections of the Lung 225 Diseases of the Heart 226 Diseases of the Vasculature 227 Diseases of the Kidney 228 Diseases of the Testis 229 Diseases of the Digestive Tract 230 Tubuloreticular Structures (TRSs) and Cylindrical Confronting Cisternae (CCC) 231 Lymphomas 231 Kaposi's Sarcoma 232 Cervical Cancer 234 CHAPTER

17 Human T Cell Leukemia/Lymphoma Viruses (HTLV-1 and -2) Introduction 243 T Cell Leukemia/Lymphoma (TLL) Syndrome 244 Tropical Spastic Paraparesis (TSP) 247 Inflammatory Conditions Associated with HTLV-1 Infection 248 HTLV-2 249

Contents

XII

CHAPTER

CHAPTER

18

20

Hepatitis Viruses

Hantavirus Pulmonary Syndrome (HPS)

Introduction 253 Orally Acquired Short-Incubation-Period Acute Hepatitis 254 Hepatitis A Virus (HAV) 254 Hepatitis E Virus (HEV) 255 Parentally Acquired Long-Incubation-Period Acute and Chronic Hepatitis 257 Hepatitis B Virus (HBV) 257 Hepatitis D Virus (HDV) (Delta Agent) 260 Hepatitis C Virus (HCV) 260 Chronic Hepatitis (CH) 262 Hepatocellular Carcinoma (HCC) 264 Autoimmune Hepatitis (AH) 270 Papillary Acrodermatitis (Gianotti-Crosti Syndrome; GCS) 271 Glomerulonephritis 272

CHAPTER

19

CHAPTER

21 Papillomaviruses Introduction 303 Disease of the Skin 305 Disease of the Female Genital Tract 308 Vulva and Vagina 309 Cervix Uteri 311 Endometrium 314 Disease of the Glans Penis 314 Disease of the Digestive Tract 315 Oropharynx 315 Esophagus 315 Anus 317 Disease of the Larynx and Tracheobronchial Tree 317 Disease of the Eye 321 Disease of the Middle Ear 322

Hemorrhagic Fever Viruses Introduction 277 Arenaviruses 277 Argentinian and Bolivian Hemorrhagic Fevers 278 Venezuelan and Sao Paulo Hemorrhagic Fever 280 West African Hemorrhagic Fever (Lassa Virus) 280 Bunyaviruses 282 Hemorrhagic Fever with Renal Disease 282 Rift Valley Fever (RVF) 285 Crimean-Congo Hemorrhagic Fever (CCHF) 286 Filoviruses 287 Marburg Virus Disease 287 Ebola Virus 287 Flaviviruses 289 Yellow Fever 290 Dengue 292 Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) 293

CHAPTER

22 Papovaviruses Introduction 327 Progressive Multifocal Leukoencephalopathy (PML) 329 Urinary Tract Infection and Disease 331

CHAPTER

23 Parvoviruses Introduction 335 Joint Disease 337 Erythropoietic Systemic Disease 337 Infections in Pregnancy 339 Inflammatory Lesions 340 Tissue Diagnosis 340

Contents

XIII

CHAPTER

CHAPTER

24

27

Neurotropic ArthropodTransmitted Viruses

Mumps

Introduction 343 Togaviruses (Alphaviruses) 344 Eastern Equine Encephalitis (EEE) 346 Western Equine Encephalitis (WEE) 347 Venezuelan Equine Encephalitis (VEE) 348 Flaviviruses 349 St. Louis Encephalitis (SLE) 351 Japanese B Encephalitis (JBE) 352 Other Flavivirus Encephalitides 353 Bunyaviruses 354 LaCrosse (California Encephalitis Group) 354 Reoviruses 354

Introduction 381 Salivary Gland Disease 382 Central Nervous System Disease 382 Testicular Disease 383 Pancreatic Disease 384 Mumps-Associated Diabetes Mellitus 385 Ear Disease 386 Joint Disease 386

CHAPTER

28 Rubellavirus

CHAPTER

25

Introduction 389 Naturally Acquired Postnatal Infections 390 Congenitally Acquired Infections 391

Rabiesviruses Introduction 357 Epidemiology 357 Clinical Disease 358 Pathogenesis 359 Central Nervous System Disease 360

CHAPTER

29 Rubeola (Measles)

CHAPTER

26 Poxviruses Introduction 365 Orthopoxviruses 366 Variola (Major and Minor) 367 Vacciniavirus 371 Monkeypox 373 Parapoxviruses 375 Milker's Nodules 377 Bovine Papular Stomatitis (BPS) 377 Ecthyma Contagiosum (orf) 377 MoUuscipoxviruses 377

Introduction 397 Respiratory Tract Disease 399 Atypical Measles Syndrome 402 Central Nervous System Disease 403 Meningoencephalitis After Natural Infection 403 Meningoencephalitis in the Immunosuppressed Patient 403 Meningoencephalitis After Measles Vaccine 404 Subacute Sclerosing Panencephalitis (SSPE) 404 Middle Ear Disease 407 Eye Disease 407 Pregnancy 407

Contents

XIV

CHAPTER

CHAPTER

30

31

Transmissible Spongiform Encephalopathy

Lymphocytic Choriomeningitis Virus (LCMV)

Introduction 411 Scrapie 412 Human Spongiform Encephalopathies: Clinical Features 412 Creutzfeldt-Jakob Disease (CJD) 413 Gerstmann-Straussler-Scheinker Disease (GSS) 414 Kuru 414 Fatal Familial Insomnia (FFI) 415 Human Spongiform Encephalopathies: Pathological Features 415 Prions (Protein Infectious Organisms) 417 New Variant CJD (vCJD) 421 Iatrogenic CJD 422 Precautions for Pathologists 422 Ancillary Nonhistopathological Diagnostic Approaches of the Prion Diseases 424

CHAPTER

32 Enteric Viral Disease Introduction 431 Norwalk-Like Viruses (NLVs) 432 Rotaviruses (RVs) 433 Additional Enteric Viruses 438 Pathophysiology of Viral Enteritis 439

Index 441

Preface

bring to the attention of the reader the general as well as the unique pathological features of individual diseases and their clinical ramifications. Often, I have given reference to some of the rarer clinical conditions attributable to viruses. This is not an overview text of medical virological pathology, but one that deals with the common and uncommon lesions observed in specific organ systems. The illustrations are selective, inasmuch as some of the fundamental disease processes have a well-established morphology appreciated by most pathologists and clinicians. I have selected illustrations to demonstrate important and unique features of a disease. Thus, this is not a pathology "picture book" that one can turn to in order to accomplish a diagnosis. This is a single-authored book, and I take responsibility for the accuracy and interpretation of the material. In this manner, I have attempted to minimize redundancy and provide balance and consistency to the presentation.

This book can be useful to experimental and diagnostic pathologists who deal with issues of infection regularly in the course of their work. It will be of value to virologists who have an interest in the medical aspects of their field, and infectious disease physicians who wish to garner a better appreciation of the pathology of the illnesses they deal with on a daily basis. My emphasis is on disease from the clinical perspective and the associated structural alterations in cells, tissues, and organs in the context of the biology and epidemiology of the responsible viruses, and the pathogenesis of the diseases they cause. This is not traditional diagnostic virology, but rather a book that the diagnostic morphologist can use in evaluating tissues for evidence of viral infection. The organizational framework is an amalgam of classical virology interwoven with considerations of pathologic syndromes to which a number of different viruses contribute. For example, I have included specific chapters on the hemorrhagic diseases and hepatitis from the perspective of the pathologic process inasmuch as the clinical disease is the common outcome of infection with a number of different agents. I have attempted to

John E. Craighead, MD Burlington, VT

XV


Acknowledgments

Ms. Laurie Sabens has served loyally as my assistant by spending countless hours in the library as well as long sessions typing and retyping drafts of chapters. Her dedicated, uncomplaining, and cheerful help is gratefully acknowledged. I could ask for little more. Gary Nelson's accomplished skills in medical illustration are reflected in figures throughout the text. Tim Oliver focused his experienced eye on my material and brought drafts and illustrations into published form. Numerous colleagues contributed invaluable illustrations; I trust I have satisfactorily acknowledged their contribution in the text. More specifically, Drs. Sally Huber, John Lunde, Bruce MacPherson, Brenda

Waters, and Washington Winn have read selected chapters and provided guidance. Many years ago, Drs. Robert Chanock, Robert Hubner, and Wallace Rowe taught me the basics of virology and epidemiology. My friend and mentor. Dr. Alexis Shelokov, counseled me in the design and conduct of experiments, and patiently helped edit countless drafts of my early papers. His editorial guidance during the formative years of my career as a virologist is reflected in this text. In addition, numerous pathologists over the years have shared their insights into the relevant morphological changes in organs and tissues that serve as the basis for this work. John E. Craighead, MD Burlington, VT

XVII


C H A P T E R

1 Enteroviruses INTRODUCTION 1 VIROLOGY AND EPIDEMIOLOGY 2 NEUROLOGICAL DISEASE 3

Aseptic Meningitis 3 Encephalitis 4 Poliomyelitis 4 Post-Poliomyelitis Syndrome (PPS) 6 Chronic CNS Infection in the Immunocompromised Patient 8 HEART DISEASE 10

Clinical Diagnostic Criteria 10 Pathological Diagnostic Criteria: The "Dallas'' Criteria 11 Enterovirus Etiology 13 Natural History of Group B Coxsackievirus Myocarditis 13 Pathogenic Mechanisms 14 STRIATED MUSCLE DISEASE 16 EPIDEMIC MYALGIA: PLEURODYNIA, BORNHOLM DISEASE

17

LUNG DISEASE 18 TESTICULAR DISEASE 18 LIVER DISEASE 19 KIDNEY DISEASE 19 PLACENTAL LESIONS OF NEONATALLY INFECTED INFANTS 19 SKIN AND MUCUS MEMBRANE DISEASE 20 TYPE I DIABETES MELLITUS 21 REFERENCES 23

INTRODUCTION Enteroviruses are human pathogens known to be responsible for over 20 different cHnical disease syndromes. They are members of the picornavirus (pico = small; rna = ribonucleic acid) family, which includes the enteroviruses, the rhinoviruses (see Chapter 2), and two genera of viruses causing disease in domestic and wild animals (aphthoviruses and cardioviruses). Hepatitis A virus (see Chapter 18) was initially classified as an enterovirus; however, its biological features are sufficiently unique to assign it to a separate taxonomic category The enterovirus genus contains almost 70 antigenically distinct species that infect humans. Traditionally categorized there are three distinct groups.


based on their biological and pathogenetic characteristics. The polioviruses, of which there are three serotypes, and the coxsackieviruses, which are divided into two groups: A, with 23 serotypes, and B, comprised of 6 serotypes. In addition, there are more than 31 enteric cytopathic human orphan (ECHO) viruses and four agents that remain unclassified. Contemporary classification is largely based on the antigenic makeup of the VPl capsid protein. Molecular analysis of enteroviruses now indicates that the traditional classification schema is somewhat artifactual, despite its established practical usefulness (Hyypia ei al., 1997). The contemporary nomenclature for the human enteroviruses reflects the historical growth of our understanding of this large genus. Thus, poliovirus refers to the dominant clinical manifestation of the three viruses in this group. The designation Coxsackievirus is based on the geographic site of the initial discovery of the first member of the group (Coxsackie, NY), whereas the echoviruses were designated "orphans" because their role as a potential cause of disease was unknown at the time they were first identified almost 50 years ago. Although these terms are firmly established in the literature, current understanding of the biology of the enteroviruses argues against a rigid categorization of these agents into groups because their virological and clinical features overlap. Moreover, because of the high degree of mutability of the various viruses, individual serotypes are comprised of a heterogeneous collection of agents having differing degrees of tissue tropism and virulence, although retaining a basic antigenic identity. New variants arise during the multiple replicative cycles that occur in the individual human host and during transmission in the population. Thus, the pathogenic properties of a specific virus are under continuous evolutionary pressure to change. The hypothetical selection process in vivo is, no doubt, intense. Given these features, and the inevitable intrinsic variability in the susceptibility of individual infected human hosts, it is not surprising that the disease manifestations of a specific virus serotype differs so greatly among individual patients, and from outbreak to outbreak.

Copyright © 2000 by Academic Press. All rights of reproduction m. ariy form reserved.

Pathology and Pathogenesis of Human Viral Disease

VIROLOGY A N D EPIDEMIOLOGY The enterovirus virion is ca. 30 nm in diameter and non-enveloped. It has a symmetrical icosahedral capsid comprised of 60 subunit capsomeres that are made up of four polypeptides. The virion has within its core an RNA of approximately 7400 nucleotides that codes a polypeptide responsible for the various structural and functional proteins required for virus replication. This RNA is intrinsically infectious once introduced into the cell; the amino acid composition of the structural proteins dictates the three-dimensional configuration of the capsid. To a large extent, the spatial configuration of the capsid determines tissue tropism of the virions largely as a result of its "fit" with receptors on the plasma membrane of the susceptible cell. Tropism of the enteroviruses for specific cells relies on the presence of transmembrane immunoglobulin superfamily moieties on the cell surface that serve as receptors binding virus to the cell. These receptors also assist in internalizing the virion by endocytosis and the subsequent uncoating of the capsid in the cytoplasm. The receptor for the polioviruses seems to be ICAM-1 (Norkin, 1995) but a second poliovirus receptor, CD44 (a lymphocyte homing receptor) has been described (Shepley and Racaniello, 1994). This receptor seems to influence the cell tropism of the virus. Cell surface integrins bind some members of the echovirus group, and the decay accelerating factor (DAF) is the receptor for others (Bergelson et al, 1994). The receptor for the encephalomyocarditis virus (mengo), a nonhuman cardiovirus, is VCAM-1 (Huber et al, 1994). The identity of the coxsackievirus receptor is unknown. While considerable information on specific cell receptors remains to be accumulated, the evidence thus far suggests that the picornaviruses have adapted to their host by parasitizing preexisting cell surface glycoproteins having intrinsic biologic importance to the host. After uncoating of the virion in the endosome, the RNA is released into the cytoplasm, where it serves as an mRNA to mobilize the protein synthetic machinery of the cell for its replicative purposes. Within about 2 hours, normal cellular function is aborted and the virus enters a noninfectious eclipse phase during which its intrinsic components are manufactured by the cell. As viral proteins accumulate in the cytoplasm during subsequent hours, cytolysis begins. The nucleus gradually changes in structure and assumes the form of a crescent with the DNA marginated adjacent to the nuclear membrane. Morphological changes also become evident in the cytoplasm. The cell plasma membranes begin to leak and intermediate filaments become prominent and rearrange. It is believed that these filaments

serve as the locus for viral RNA replication. Membranous vesicles form during the replicative cycle of the virus and gradually fill the cytoplasm. The virions are assembled during this stage. The mode of egress of the virus from the cell may differ among various cell types. Although cell lysis most probably is the mechanism involved in the release of virus into the environment, cultured differentiated intestinal mucosal cells seem to spin off virions from their intact apical surfaces (Tucker et al, 1993). The enteroviruses are usually transmitted in a clinically inapparent fashion by direct or indirect human contact. The established routes of spread are (1) fecaloral, (2) respiratory droplet, and (3) water, food, and fomites. After a primary infection, viruses are shed from the upper respiratory tract for as long as 3 weeks and from the gut for periods of as long as 2 months (Modlin, 1997). On rare occasions, transplacental spread from a mother, with a newly acquired infection, to the fetus occurs, but in these cases fecal contamination of the offspring at the time of parturition may be the mode of transmission. Neonates infected in this fashion occasionally develop a devastating multisystem disease with encephalitis, myocarditis, and necrosis of the liver and adrenal glands. On the other hand, under natural circumstances of transmission, a high proportion of infants and children are subclinically infected by one or another of the many enteroviruses, and widespread epidemics of a particular virus strain occur commonly in the absence of clinical disease caused by the virus. Infection under these circumstances is documented by the recovery of virus from the oropharynx or stool. Age appears to be the most consequential factor influencing susceptibility, with the prevalence of infections decreasing as mucosal and systemic immunity to the various serotypes of virus accumulate. Season is a second consideration: transmission of enteroviruses occurs year-round in the subtropics and tropics, but predominantly in the summer and autumn months in temperate climates. The prevalence of enterovirus infections is also influenced by environmental conditions, with attack rates often being several times higher among children of lower socioeconomic groups, in comparison to those living in better circumstances. While these factors influence the subclinical spread of the viruses, they also are reflected in the prevalence of clinical disease. Systemic illnesses due to enteroviruses appear to be largely a reflection of "spill-over" of virus from the aerodigestive system into the blood stream in an individual who lacks systemic humoral immunity. In general, the acquisition of immunity occurs earlier in life among residents of the tropics and among members of lower socioeconomic groups. This, in large part, seems to reduce the fre-

Enteroviruses

quency of enterovirus diseases in older children, adolescents, and adults. For unknown reasons, infection often results in a more severe illness among older persons. The factors contributing to viral virulence and the capacity of an agent to cause disease are not well understood. It seems likely that pathogenicity is influenced by the natural selection of strains exhibiting invasive characteristics and by the capacity of a virus to replicate more efficiently in the host cell. Whatever the properties may be, they most probably are multifactorial rather than a reflection of a single biological function. From a practical perspective, it is clear that epidemic strains of virus differ with regard to the frequency and type of disease they cause in a population. Host factors other than those related to acquired immunity are also important influences determining whether illness will develop. Observations made in the past on the epidemiology of poliomyelitis provide vivid examples, since only a small number of the many who were infected developed paralytic disease. In addition, the extent of the paralysis differed greatly among those exposed to the same epidemic strain. Often, the occurrence of paralysis appeared to be influenced by fatigue and exercise, and paralytic complications in specific muscle groups often related to the site of an operative procedure or trauma. Older children and adolescents as well as adults prove to be more severely affected than infants and young children. Pregnancy is a significant risk factor. Finally, among the various enterovirus diseases, males are invariably more often affected than females, with the male:female ratio customarily being 2:1 or greater. The explanation for this sex predominance is unknown, but it is charac-

teristic of a number of virus infections other than due to enteroviruses. The density of viral sackievirus receptors on cells increases under the ence of testosterone, an effect that could affect infectivity.

NEUROLOGICAL DISEASE Aseptic Meningitis Aseptic meningitis is the most common clinically important syndrome attributable to systemic enterovirus infections. Non-polio enteroviruses are the most frequent cause of nonbacterial meningitis in developed countries (see Table 1.1). The actual prevalence is difficult to assess because of the seasonal and geographic epidemiology of the disease and the year-toyear variability in the occurrence of cases. In a recent study carried out in Finland, the incidence of aseptic meningitis among children less than 1 year of age was 219 per 1 x 10^ per year, but only 19 per 1 x 10^ in those aged 1-4. Abundant laboratory evidence now indicates that the prevalence of enterovirus meningitis based on virus isolation using tissue culture is seriously underestimated. At least two-thirds of all cases that fail to yield virus from the oropharynx, rectum, or cerebrospinal fluid by traditional isolation techniques prove to be caused by an enterovirus infection when the cerebrospinal fluid is evaluated by PCR. Thus, this laboratory approach is now obligatory if the physician wishes to establish the specific cause in an individual case (Rotbart, 1995).

TABLE 1.1 M o s t C o m m o n N o n - P o l i o Enterovirus Serotypes Isolated i n the U n i t e d States, 1970-1983 Serotype Echovirus 11 Echovirus 9 Coxsackievirus Echovirus 4 Echovirus 6 Coxsackievirus Coxsackievirus Coxsackievirus Coxsackievirus Echovirus 3 Echovirus 7 All others

Percentage

B5

B2 B4 A9 B3

Data from Strikas et al, 1986.

those coxinfluviral

12.2 11.3 8.7 6.3 5.5 4.8 4.6 4.5 4.5 3.2 3.0 31.4


At one time or another, all members of the poliovirus and coxsackievirus group B (Gard, 1955), and most, but not all, of the echoviruses have been shown to cause the disease. The syndrome is wellknown to clinicians, being characterized by the sudden onset of fever with nonspecific, generalized complaints accompanied by headache and evidence of meningeal irritation. Very young infants experience the most severe illness and the majority of deaths occur in this age group. Few pathologists have had an opportunity to examine central nervous system tissue from patients with aseptic meningitis since virtually all patients over the age of 1 who are infected recover without significant morbidity. Neurodevelopmental sequelae of enterovirus aseptic meningitis are generally not found after recovery from the acute illness (Rantakallio et al, 1970). In a recently reported carefully controlled clinical study (Rorabaugh et al, 1993), residual neurological and mental abnormalities were not found during the long-term follow-up of infants under 2 years of age who had serious acute enterovirus illness associated with meningitis. To a large extent, therefore, our understanding of the pathologic features of aseptic meningitis arise from postmortem studies of patients succumbing with poliomyelitis, although rare, fatal cases of coxsackievirus meningitis accompanied by myocarditis are reported (Kibrick and Benirschke, 1956; Sutinen et al, 1971; Price et al, 1970). In these cases, a variety of mononuclear cells are seen in spotty infiltrates of the leptomeninges, ependyma, and choroid plexus. As of yet, these cells have not been further characterized. In fatal cases, pathological evidence of encephalitis is often found.

Lesions of the brain associated with non-poliovirus enteroviruses are customarily focal and of more limited severity, without an apparent predilection for specific centers (Kibrick and Benirschke, 1956). Customarily, encephalitis due to non-polioviruses occurs in neonates and is rarely reported in older children and adults. Involvement of the brain by these viruses is often accompanied by evidence of a global encephalitis and a depressed sensorium, although focal neurological signs are occasionally seen. Because of the frequent concomitant presence of aseptic meningitis, the attribution of signs and symptoms to one or the other of these processes is somewhat arbitrary. In one systematic study, enteroviruses were isolated from 13% of brain biopsies carried out to establish the virological diagnosis of encephalitis clinically attributed herpesviruses (Whitley et al, 1989) (see Chapter 7). Systematic pathological studies to define the distribution of lesions in the nervous system of patients with non-poliovirus enterovirus infections have not been reported. Poliomyelitis Less than 2% of poliovirus infections result in clinically significant paralytic disease, and about 10% of motor cortex

Encephalitis Prior to implementation of poliovirus immunization, encephalitis due to poliovirus infections among children and adults was common during outbreaks of paralytic disease. The distribution of pathological changes in the poliovirus-infected patient with brain involvement generally coincides with the distribution of infectious virus as shown by Sabin and Ward (1941) long ago. Lesions in the central nervous system are largely confined to the precentral motor cortex and the globus pallidus. The cerebellar hemispheres and pontine system remains uninvolved, whereas the vermis and deeper cerebellar nuclei often exhibit severe lesions. In the brainstem, the hypothalamus and the thalamus usually show prominent changes. The distribution of lesions in paralytic and nonparalytic cases appears to be roughly comparable (Figure 1.1) (Bodian, 1959).

reticular formation

anterior horn

F I G U R E 1.1 Lateral view of human brain and spinal cord showing diagrammatically the general distribution of lesions in acute bulbar spinal poliomyelitis (dots). In the cerebral cortex, lesions are largely confined to the precentral gyrus. The cerebellar roof nuclei are commonly involved. Lesions are widespread in the brainstem. Adapted with permission from a diagram by David Bodian (Bodian, 1959).

Enteroviruses

these cases are fatal. Age is an important factor influencing the development of paralysis, with the prevalence in adults being as much as tenfold greater than in children. Oropharyngeal and intestinal infections often precede the onset of paresis by 2 to 3 weeks and can persist for weeks or even a month thereafter. Clinically and pathologically, the paralytic disease can be characterized as bulbar or spinal, or a combination of both. Bulbar poliomyelitis involves any one or a combination of cranial nerve centers, including the respiratory center in the medulla oblongata. The spinal disease similarly can affect a variety of different muscle groups. About 3% of cases involve all four extremities, and 30% affect the lower limbs with either flaccid paralysis or variable degrees of paresis, that is, muscular weakness of neurogenic origin. Trauma and exercise are known to influence the localization of paralysis. Tonsillectomy has long been recognized as a risk factor for bulbar disease. Although the major neurons serving the specific affected muscle groups exhibit lesions acutely, the disease process is often more widespread, with pathological changes being found in many sites in the absence of clinical evidence of paresis. Thus, the early lesions are not confined or restricted to the motor neurons, and extensive tissue damage occurs before clinically recognizable paralysis develops. In the studies of

Bodian (1959), normal-appearing neurons were difficult to locate in the spinal cord early in the clinical disease, even in the absence of significant paralysis. It was later found that as many as 20% of neurons serving a limb might be destroyed in the absence of paresis. Thus, the acute disease can be widespread in the nervous system, but only a relatively small proportion of the motor nerves are irreversibly damaged. Ongoing contemporary research is focused on determining the molecular basis for poliovirus pathogenicity (Gromeier et ah, 1997). While mechanisms remain uncertain, minor changes in the viral genome can dramatically affect neurovirulence in subhuman primate models. The cytological changes developing consequent to poliovirus infection of motor neurons have been studied in primate models and in clinical cases when death occurred early in the course of the disease. The earliest morphologic changes in neurons are observed during the preparalytic stage of the disease. They develop with exceptional rapidity concomitant with local virus replication (Figure 1.2). The initial morphologic change is the dissolution of the Nissel substance with the loss of cytoplasmic basophilia, a process termed chromatolysis. An eosinophilic intranuclear inclusion body (so-called Cowdry type B) appears at this time. Dissolution of the cell follows, accompanied by phagocytosis

STAGES IN MOTOR NEURON DESTRUCTION STAGES IN MOTOR NEURON.RECOVERY 10

Concentration of Virus in CNS

3

4

5

6

Days of Infection F I G U R E 1.2 Schematic representation of the sequential pathological changes in the anterior horn cells of the spinal cord during the course of an acute poliovirus infection. Cytoplasmic chromatolysis of neurons is prominent when maximal concentrations of virus are present in the spinal cord (vertical column virus/grams of tissue). Neurons lyse or recover during convalescence as depicted. Adapted with permission from a diagram by David Bodian (Bodian, 1959).


B

F I G U R E 1.3 (A) Chromatolysis of anterior horn cell. Note the lysis of the stippled basophilic Nissel substance of the cytoplasm resulting in a contracted cell with an eosinophilic cytoplasm. Microglia (macrophages) are located adjacent to the neurons. (B, C) Acute diffuse inflammation and perivascular lymphocytic cuffing of vessels in the brainstem during acute bulbar spinal poliomyelitis. (D) Acute interstitial myocarditis. Note the edema that separates individual muscle bundles and the interstitial influx of a mixture of lymphocytes and macrophages.

carried out by microglia, that is, neuronophagia (Figure 1.3A). These inflammatory cells accumulate to a variable extent in proximity to dying neurons. Initially, polymorphonuclear cells, but later, lymphocytes and microglia are found. In some lesions, the inflammatory response is intense, but it is believed to be a secondary phenomenon and not a causative factor in neuronolysis (Figure 1.3B,C). Wallerian degeneration of the spinal motor nerve fibers follows dissolution of the neurons (Figures 1.4 and 1.5). During the acute stages of poliomyelitis, patients tend to experience muscle weakness, even though paralysis fails to develop. Many investigators believe that infected neurons can recover after brief dysfunctional periods. Morphologically, the motor neurons that are thought to recover exhibit cytoplasmic clearing and clumping of Nissel substance adjacent to the plasma membrane of the cell during the acute stages of the infection. It is unclear whether these cells were actually infected by the virus or exhibit the subtle changes described above as secondary phenomena, perhaps due to cytokines generated during the infection. Unfortu-

nately, in situ localization using modern techniques has not been applied to this question. Post-Poliomyelitis Syndrome (PPS) PPS was initially established as a clinical entity in the 1980s. While difficult to define concisely, this syndrome encompasses a diversity of symptoms experienced by the victim of paralytic poliomyelitis late in life and often after many years of disease quiescence (i.e., 20-30 years). In some, the symptoms include accentuated fatigue of partially paralyzed muscle groups accompanied by pain or discomfort. This is the so-called post-poliomyelitis muscular atrophy syndrome. In other patients, PPS is manifest as an acquired weakness in seemingly uninvolved muscle groups, often occurring in an unpredictable asymmetrical fashion. The prevalence -of PPS is unknown, but it differs among patients, depending upon the degree of residual paralysis after the acute episode years in the past. Patients with little residual paralysis are rarely affected, whereas those with widespread paralysis of various muscle groups (limb, bulbar, or respiratory).

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F I G U R E 1.4 Spinal cord during late convalescence from poliomyelitis (Holtzer stain). The anterior horns of the spinal cord are extensively gliotic and the anterior root trunks (a) leading to the striated muscle are atrophied. Dorsal roots are depicted in (d).

F I G U R E 1.5 Denervation atrophy of striated muscle with partial fatty replacement of the muscle mass.

8


often manifest new muscle weakness and atrophy years after the initial event. One carefully conducted epidemiological study found a PPS prevalence of approximately 28% among paralytic cases of poliomyelitis after a 30-year interval. The pathogenesis of PPS is far from clear, but most studies have ruled out the participation of reactivated infectious polioviruses. Nonetheless, there is molecular evidence suggesting that enteroviral RNA persists in the spinal cord and cerebrospinal fluid (Leon-Monzon and Dalkar, 1995; Muir ei al., 1989). Elevated concentrations of serum and cerebral spinal fluid IgM antibody directed against poliovirus proteins have also been found in occasional patients. An immune pathogenic basis for the syndrome is supported by the histologic finding of perivascular accumulations of B lymphocytes in the spinal cord tissue of a deceased patient with PPS (Miller, 1995). B lymphocyte accumulations have also been described adjacent to the endomysial sites of motor endplates in affected muscle groups. In one study, interleukin-2 was found in the cerebral spinal fluid of many patients suggesting that an active pathogenic process was underway. Taxing neuroanatomic and neurophysiologic studies of peripheral nerves and muscles indicate that the axons of viable recovered neurons sprout and branch during convalescence from acute poliomyelitis to reinnervate collateral muscle fibers "orphaned" by the death of their dedicated neuron (Figure 1.6) (Dalakas, 1992). This remodeling phenomena increases the number of muscle fibers in the motor units of the musculature innervated by the residual anterior horn cells of the cord. While unproven, it is hypothesized that attrition of overbranched and stressed neuronal units later in life may result in slow deterioration and failure of nerves. As a consequence, individual muscle fibers in pathological specimens of the affected muscle drop out and are found as atrophic muscle fibers. They appear angular and rounded in cross-section and exhibit central nuclei and fragmented cytoplasm. These changes, to a variable extent, are superimposed upon the pathologic picture of denervation atrophy resulting from the acute disease decades in the past.

Chronic C N S Infection in the Immunocompromised Patient Chronic enterovirus meningoencephalitis (CEMA) associated with congenital X-linked agammaglobulinemia and other immune deficiency disorders in infants and children is a rare, but now well-established clinical syndrome (McKinney ei al., 1987; Medici ei al., 1978). A predisposition to chronic enterovirus infection

NORMAL

Neuron affected but will survive

ACUTE POLIO Neuron dying

RECOVERY REMODELING Stable Post-polio

PPMA

F I G U R E 1.6 Diagrammatic representation of the state of affected regions of the motor neuron system in the post-polio syndrome. The sequence depicts the hypothetical changes occurring during acute poliomyelitis with loss or damage to neurons. With the passage of time, remodeling is believed to occur wîth enervation of denervated muscle. In the post-polio syndrome, the regenerated nerve twigs that lead to previously denervated muscle begin to atrophy. As a result, individual muscle cells are denervated and undergo atrophy. Adapted with permission from Dalakas (1992).

was first recognized when infants with X-linked agammaglobulinemia developed classical poliomyelitis due to infection with 'Vaccine" strains of poliovirus in the 1960s and 1970s (Davis ei al, 1977; Feigin ei al, 1971). Later, the syndrome was noted in youngsters infected with various echoviruses (Mease ei al, 1985). Interestingly enough, coxsackieviruses have been involved in CEMA only rarely, despite their relative prevalence and pathogenic potential. The syndrome typically is manifest as a slowly progressing neuromuscular disorder with variable expression but generally characterized by the clinical picture of ataxia, dyslexia, dysarthria, loss of cognition.

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changes in personality, seizures, paresthesias, and, on occasion, lower motor neuron disease with paralysis. In most children, the clinical illness is protracted. While a few ultimately recover, the majority die in a coma after progressive neurological deterioration. The prevalence of chronic enterovirus meningoencephalitis and paralytic poliomyelitis due to "wild" and 'Vaccine" strains among those with hypoglobulinemia and combined immunodeficiency disease is low (Feigin et al, 1971). In one study, 5 of some 80 immunologically defective children developed paralytic poliomyelitis, while in a second, 2 of 53 were similarly affected (Wyatt, 1973). Wyatt estimated the incidence of vaccine-associated disease to be 1 x 10^fold greater in those with immune deficiency disorders than among normal healthy persons of comparable age. The prevalence of paralytic disease due to non-polio enteroviruses is also low (Ziegler and Penny, 1975). Medici et al. (1978) described the occurrence of 2 cases among some 176 hypogammaglobulinemic patients in the United Kingdom. CEMA may be a disappearing disease because X-linked agammaglobulinemia and other immune deficiency syndromes are now more frequently recognized earlier in life and treated long term by immunoglobulin administration (Bodensteiner et al, 1979; Chonmaitree et al, 1981; Mease et al, 1981). Since chronically ill children may have unrecognized or subclinical chronic enterovirus infections, the actual incidence remains uncertain. Studies during life and postmortem have demonstrated virus in many scattered organs, in addition to the central nervous system. Because of the relative insensitivity of virus isolation techniques, it is probable that the infection is disseminated widely in the usual case. Support for this notion is based on recent research using PCR to detect systemic infection (Webster et al, 1993). This is of particular interest in view of the lack of clinically recognized dysfunction in organs other than the central nervous system, the liver, and the heart. Information on virus concentrations in tissues and body fluid has not yet accumulated and in situ studies to demonstrate viral genetic material in cells of infected tissue are lacking. As noted above, the clinical course in most affected children is characteristically one of progressive deterioration, with death resulting from the loss of central nervous system function. Autopsy reveals a chronic meningoencephalitis with varying degrees of myelitis and myositis (Webster et al, 1978). With the exception of the liver, which often exhibits hepatitis and a single case report of myocarditis (Mailer et al, 1967), the major organs commonly affected by enteroviruses do not customarily exhibit lesions, although the tissue may

yield virus when isolation attempts are made. As would be expected, the typical pathological changes of X-linked agammaglobulinemia are found in lymphoid tissues, and immunoglobulins are dramatically reduced in the blood serum. In the central nervous system, the meninges show evidence of a chronic inflammatory process with fibrosis in the meningeal spaces accompanied by variable infiltrates of lymphocytes and other mononuclear cells. The substance of the brain is widely involved with prominent changes in the outer neuronal layers of the cerebral cortex and widespread destruction of cerebellar Purkinje cells and Bergmann astrocytes (Hadfield et al, 1985). Frank tissue necrosis is common, and lymphocytic perivascular cuffing as well as both astrocytosis and glial nodules are widespread. The basal ganglion structures and hippocampus are often affected. These neuropathological findings correlate well with evidence of cerebral atrophy demonstrated by radiological imaging pre-mortem and overall deterioration in cortical and cerebellar function. As noted above, the occurrence of poliomyelitis with echo and coxsackievirus infections is variable, but when it occurs the pathological picture strikingly resembles classical poliomyelitis (Liwnicz and Marinkovich, 1979). Patients with chronic enterovirus meningoencephalitis often exhibit slow deterioration of muscle function initially accompanied by a stooped posture, ultimately resulting in contractures of the extremities. As death approaches, the so-called "dermatomyositislike" syndrome develops. It is manifest as "woody" peripheral edema associated with a myofascitis and an erythematous rash, which histologically is reflected as chronic skin inflammation (Webster et al, 1978; Janeway et al, 1956; Bardelas et al, 1977; Bowles et al, 1987; Mease et al, 1981). Enteroviruses are customarily believed to be cytolytic, with a short infectious cycle accompanied by cell death. It comes with some surprise, therefore, to observe these cases of chronic enterovirus infection in which the agent is harbored for long periods within cells and tissues that fail to undergo necrosis. This, of course, occurs in the apparent absence of circulating specific antibody directed against the virus in question. We know little about the biology of the infectious process in the individual cells and tissues under these circumstances. Despite the overwhelming evidence that enterovirus-infected cells undergo lysis in vitro, it is noteworthy that cells chronically infected with group B coxsackieviruses and echoviruses can be maintained in culture. The explanation for this phenomena is not at all clear, but possible explanations are discussed in detail by Schnurr and Schmidt (1988). The influencing

10


factors may either be interferon elaborated by the cells, or defective interfering viral particles that attenuate, but do not abort, the infection. It may be that differentiated cells in intact organs differ with regard to their capacity to undergo lysis in vivo. Alternatively, nonpathogenic mutants or virus variants may evolve. Exogenous antibody cures a chronically coxsackievirusinfected cell culture, an indication that extracellular transmission of virus occurs.

HEART DISEASE Interstitial myocarditis was recognized by pathologists as a complication of infectious disease in the second half of the nineteenth century (Jarcho, 1973). It was Fiedler (1899), however, who brought myocarditis to the attention of the medical public. As a result, the term "Fiedler's myocarditis" is often referred to when physicians describe an idiopathic myocardial inflammatory process in which interstitial infiltrates of mononuclear cells (T cells and macrophages) (Chow et al, 1989) predominate and myocyte necrosis is a subtle or minor feature of the lesion (Figure 1.3D). During this century, pathologists have popularized the concept of viral myocarditis (Woodruff, 1980; Lyon, 1956), and various estimates of its prevalence have been advanced. In an autopsy survey conducted in Sweden, the incidence of myocarditis detected histologically was roughly 1% (Gravanis and Sternby, 1991). In contrast, a myocarditis prevalence of 17% was found in a review of autopsy material from almost 100 children and teenagers dying unexpectedly in the United States, and a comparable incidence (21%) became evident when the hearts of 47 Japanese children who died suddenly were examined (Okuni et aL, 1975). Gore and Saphir (1948) reviewed 40,000 consecutive autopsies and found myocarditis in 3.5%. Of these, only 73 cases were suspected to have a viral etiology. Surveys of autopsy material at large urban hospitals by Blankenhorn and Gall (1958) and de la Chapelle and Kossmann (1954) respectively yielded myocarditis incidences of 3.4 and 3.3%. These estimates, based on retrospective investigations of autopsy material, unfortunately, are flawed by the inevitable variability in the interpretation of microscopical changes in the heart by different observers and the comprehensiveness of the pathologic studies of individual hearts. The inevitable selectivity of cases included in any autopsy series is an important defect. The tendency in these studies to intermix cases of nonbacterial

pericarditis with those exhibiting only myocarditis is a factor that further confuses the issue. Inflammatory myocardial lesions have many etiologies. In his original report, Fiedler referred to the common association of myocarditis with diphtheria and typhoid fever, whereas more recent authors have alluded to the occurrence of myocarditis as a sporadic complication of viral infections of a wide variety of types. More rarely, rheumatic heart disease and hypersensitivity reactions have been associated with myocardial inflammatory lesions. Worldwide Chagas's disease and rickettsial infections are important causes, although geographically confined in their distribution. While in their writings pathologists have generally concluded that myocarditis and pericarditis are relatively acute lesions, the concept of chronic myocarditis is emphasized by some authors. For example, Corvisart (1812) posed this question: "Is the inflammation of the heart always very sharp and acute or does it not sometimes affect an insidious, hidden progress." Clearly, chronic pernicious myocarditis occurs. Patients with progressive but remitting deterioration in cardiac function for periods of as long as 6 years have been described in the literature. The histological features of hearts during the prolonged course of the disease in such cases is not documented.

Clinical Diagnostic Criteria The diagnosis of myocarditis and myopericarditis is frequently tendered by clinicians, but discrepancies between the clinical and pathological findings commonly occur. In the infant and young child, the diagnosis is largely dependent upon physical and radiological findings, with pericardial effusions and cardiac enlargement accompanied by evidence of cardiac failure being common findings (Wood et al, 1978). In adults, chest pain attributable to pleural and pericardial irritation is a frequent complaint. At times, the character of chest pain suggests a myocardial infarction, and the accompanying elevation in serum cardiac enzymes support this possibility (Woods et al, 1973). Pericardial effusions and enlargement of the heart are often observed and constrictive pericarditis sometimes occurs. A diversity of electrocardiographic alterations are documented, with arrythmia, including atrial fibrillation, developing in roughly a third of cases. Ventricular fibrillation and complete heart block are rare outcomes, but do result in death in occasional cases. T-wave abnormalities and either elevation or depression in the ST segment are described. At times, the EKG pattern is

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consistent with a myocardial infarction (Gardiner and Short, 1973).

Pathological Diagnostic Criteria: The "Dallas'' Criteria With the availability of endoscopic cardiac biopsy techniques, pathologists have confronted the need to establish a specific morphologic diagnosis among the diverse cases of clinically suspected myocardial inflammatory disease (Fenoglio et ah, 1983). Invasive approaches are now justifiable in view of the negligible mortality and morbidity of the intraluminal biopsy procedure, and the availability of potentially useful newer antiviral and immunosuppressive therapies. The potential for cardiac transplantation in these patients is an additional consideration. In 1984, a group of eight experienced cardiac pathologists met in Dallas, Texas to establish pathologic criteria for the diagnosis of myocarditis and to begin to classify cases on correlative, clinical, and pathologic grounds (Aretz et ah, 1986; Aretz, 1987). In their deliberations, these pathologists deemed it inappropriate to judge the time course of the process using a single biopsy. Rather, they considered it desirable to evaluate cases by comparing the pathological features in sequential biopsies of subendocardial tissue. It was recommended that a minimum of three and preferably five separate biopsies should be obtained at the time of initial evaluation and a similar number examined later in the course of the illness by follow-up biopsy. Each biopsy was to be serially sectioned and the tissue stained with both hematoxylin and eosin and by the trichrome technique. The initial series of biopsies were then categorized microscopically as: (a) myocarditis, with or without fibrosis; (b) borderline myocarditis; and (c) no myocarditis. After the second series of biopsies, the disease could be further categorized as: (d) ongoing (i.e., persistent myocarditis with or without fibrosis); (e) resolving (healing) myocarditis with or without fibrosis; and (f) resolved (healed) myocarditis with or without fibrosis. It was further recommended that the inflammatory infiltrate should be characterized as lymphocytic, eosinophilic, neutrophilic, giant cell granulomatous, or mixed, and the numbers of cells in the lesion semiquantitated into categories of mild, moderate, or severe and focal, confluent, or diffuse. The amount and distribution of the fibrosis should be described as subendocardial, replacement, or interstitial. These criteria and pathological descriptive approaches, although very general, provide for the first time a basis for a comparative sequen-

11

tial evaluation of cardiac disease suspected to be myocarditis. However, because biopsies are roughly 15 mg in weight, they continue to be a very limited sample of the heart for detection and monitoring of a spotty disease process in an organ weighing several hundred grams. The so-called "Dallas" pathologists defined myocarditis as a cardiac condition in which the inflammatory infiltrate is associated with histological evidence of injury to myocytes (Figures 1.3D and 1.7). Damage to the myocardium was considered to be of paramount importance since it distinguished the condition from a cellular infiltrative processes such as a lymphoma, which on rare occasions could mimic myocarditis. The damage was thought to consist either of frank necrosis or myocyte vacuolization with irregular cellular outlines or disruption of the sarcolemma. Since ischemic damage to the heart is a potential confounding factor, it was felt that the histological changes in the endocardium and subjacent myocardial layer were impor-

F I G U R E 1.7 Endocardial surface of the heart of a 34-year-old man who developed fever and a complete heart block. He died 24 hours after hospitalization. Note the slightly raised grayish-white, patchy area of heart tissue representing necrosis. Reprinted with permission and provided through the courtesy of G. Monif, MD.

12


tant for establishing a diagnosis and differentiating the lesion from one due to ischemia. Borderline myocarditis implies that the infiltrates of inflammatory cells are sparse or that damage to the myocardium is not demonstrable by light microscopy (or both). These changes might be found at the boundary with more severe alterations in the heart tissue and thus might be peripheral lesions. The evaluation of the later second biopsy is considered to be critical with specific regard to determining pathogenesis. If the second lesion is unchanged from the earlier biopsy, the terms ongoing or persistent can be

applied. On the other hand, if the infiltrate has decreased in severity and changes indicative of repair are apparent, the terms resolving or healing myocarditis are considered appropriate. If the inflammatory infiltrate has completely disappeared, the designations resolved or healed myocarditis are suggested. The identity of the infiltrating inflammatory cells is considered to be relevant to etiology, with lymphocytes indicative of viral myocarditis or disease due to collagen vascular problems, sarcoidosis, and Kawasaki's disease. Alternatively, eosinophils suggest the possibility of a hypersensitivity reaction or a parasitic infection, whereas

FIGURE 1.8 (A) Endothelial cell in the heart of a 5-day-old infant who developed fever and cerebrospinal fluid pleocytosis 5 days after birth. Heart and renal failure with acidosis developed and was followed by episodes of cardiac arrest and death 7 days later. The myocardial cells show the ultrastructural changes of degeneration and necrosis, but viral particles are not seen. However, crystalline arrays of particles of a size consistent with an enterovirus are found in endothelial cells (lOOOx). Coxsackievirus B, type 3, was recovered from the heart tissue in cell culture. Electron microscopy of these cells infected in vitro revealed identical crystalline arrays of virions. Reprinted with permission from Haas and Yunis (1970). (B) Skeletal muscle of an 11-year-old child with a chronic neuromuscular syndrome that developed shortly after birth. She died of pneumonia. Autopsy revealed a variable degree of myopathy and atrophy of major muscle groups with occasional sites of focal muscle regeneration. Coxsackievirus A, type 9, was recovered from the muscle tissue. A crystalline lattice of particles having a size consistent with an enterovirus was found in the skeletal muscle (150,000x). Reprinted with permission from Tang et al, 1975. (C) Viral crystalline array (V) in the striated muscle of a suckling mouse 48 hours after inoculation with coxsackievirus A, type 4. Ribosomes (R) of a size roughly comparable to an enterovirus are illustrated. Irregular accumulations of glycogen can also simulate virions in muscle. Reprinted with permission from Harrison et al. (1971).

13

Enteroviruses

neutrophils are found when there is a pressor drug effect or ischemic damage to the heart. Obviously, bacterial infections could also cause neutrophil infiltrates. The presence of giant cells comprised of myocytes or macrophages is a poorly understood pathological observation, for it is consistent with a variety of conditions, but the circumstances under which it occurs are poorly defined. Enterovirus Etiology Enteroviruses are the most common cause of acute serous pericarditis and interstitial myocarditis in both humans and animals of several species. In humans, the enteroviruses are established etiologic agents and account for an estimated Vs to VT. of the clinical cases of myopericarditis occurring in humans. The Coxsackie group B viruses predominate as etiological agents (Kibrick and Benirschke, 1956; Gear, 1958; Null and Castle, 1959; Fechner ei al, 1963; Wright ei al, 1963; Sutton ei al, 1967; Price ei al, 1970; Smith, 1970; Bell and Grist, 1970; Koontz and Ray 1971; Ruffy ei al, 1973; Gear and Measroch, 1973; Hirschman and Hammer, 1974; Chandrasekar ei al, 1975; Levi ei al, 1988); all the established serotypes have been implicated in case reports or surveys (Figure 1.8A,C). Coxsackievirus group B myocarditis occurs in patients of all ages. An estimate by the World Health Organization (WHO) indicates that 3.2% of Coxsackie B infections result in cardiac disease. Most acute and fatal infections that develop in the immediate perinatal period result from transplacental transmission of the virus or fetal contamination during parturition. Frequently, group B coxsackievirus myocarditis in these infants is accompanied by varying degrees of meningoencephalitis and hepatitis. In these severe fatal cases, the heart is commonly enlarged and exhibits evidence of myocardial cell destruction, as well as interstitial infiltrates of mononuclear cells and a few polymorphonuclear leukocytes. The typical features of cardiac failure are usually found in the lungs and liver at the time of postmortem examination. Fatal disease occurs less commonly in adolescents and adults and the pathology is not well described. Many cases have been documented by clinical means among persons in the fourth, fifth, and sixth decades of life, and it has been estimated that roughly 20% of cases of enterovirus myocarditis occur in members of older age groups. For unknown reasons, males are affected twice as often as females. Experimental studies in mice provide insight into why this might occur, as discussed later on. In one study, over half the cases had cardiac enlargement during the acute stages of disease, but evidence that the heart is involved often appears 1 to 2 weeks after the onset of a systemic febrile viral syndrome. As a result, virus frequently cannot be recov-

ered from body secretions, and the diagnosis requires demonstration of a significant increase in serum antibodies against the virus. Meningoencephalitis, hepatitis, and orchitis occasionally occur concomitantly A number of different serotypes of echo viruses have been etiologically associated with myocarditis in infants and children (Mailer ei al, 1967; Monif ei al, 1967; Bell and Grist, 1970; Haynes ei al, 1972; Drew, 1973; MiduUa ei al, 1976) (Figure 1.8A,B), but the number of reported cases is too few for one to know whether or not all serotypes have an equivalent capacity to produce myopericarditis. A WHO study conducted in the 1960s noted the occurrence of cardiac disease in 0.6% of children with documented echovirus infections. While the disease is not well characterized clinically and pathologically, its features would not appear to differ from disease attributable to Coxsackie B viruses, but pericarditis does not occur as commonly Echovirus myocarditis has not been described in adolescents and adults. Myocarditis has been found at autopsy in roughly 10 to 15% of fatal cases of poliomyelitis. However, the poliovirus types responsible for these cases are not known because suitable studies were not done (Laake, 1951; Weinstein and Shelokov, 1951; Saphir and Wile, 1942). Changes in the electrocardiogram often are found in nonfatal cases. Natural History of Group B Coxsackievirus Myocarditis The natural history of acute myocarditis in humans is incompletely defined. Based on studies of experimental murine models, one concludes that acute diffuse inflammation and myonecrosis begin to develop 3 to 4 days after the onset of the systemic infection concomitant with the appearance of virus in heart tissue. During the early stages of infection, virus is present in relatively high concentrations at scattered sites in the myocardium. Infectious virus recoverable by traditional isolation techniques is found in heart tissue for approximately 2 weeks. During this period, many infants and children die with arrhythmias and cardiac failure due to acute myocarditis. An occasional infected adult similarly succumbs. Evidence of inflammation and myonecrosis becomes less prominent in the heart with the passage of time. In some, but not all, survivors of acute myocarditis, dilated cardiomyopathy becomes evident with the passage of time (O'Connell, 1987). Studies by Dec ei al (1985) demonstrated inflammation in endomyocardial biopsies of 89% of patients with a dilated cardiomyopathy. It developed during the first 4 weeks

14

Pathology and Pathogenesis of Human Viral D i s e a s e

^zim :rr*/**'^.v^^

FIGURE 1.9 Examples of inflammatory and fibrotic myocardial changes found at autopsy in the hearts of adult males with fatal end-stage congestive cardiomyopathy. In these cases, variable degrees of lymphocytic and histiocytic infiltration are seen in association with fibrosis.

after the onset of symptoms; 70% of patients had inflammatory lesions in the heart during the following 8-week period (Figure 1.9). Additional published reports attest to the presence of myocarditis in endomyocardial biopsies at intervals after the clinical onset of cardiomyopathy (MacArthur et ah, 1984; O'Connell, 1987; Kandolf, 1993; Zee-Cheng et al, 1984; Olsen, 1993). In recent years, immunohistochemical in situ hybridization and genomic amplification studies have been employed to detect evidence of persistent enteroviral RNA in myocardial cells (Godeny and Gauntt, 1987; Jin et al, 1990; Bowles et al, 1986). In one study viral RNA was demonstrated in the heart tissue of onethird of patients with myocarditis (Satoh et al, 1994), and in a second investigation 52% of endocardial biopsies from patients with dilated cardiomyopathy were positive (Archard et al, 1987). Support for the claim that persistent group B coxsackievirus infections are causatively responsible for dilated cardiomyopathy is provided by the common finding of high concentrations of virus-specific IgM and neutralization antibody

in the blood of many of the patients (MacArthur et al, 1984; Muir et al, 1989; 1996). Pathogenic Mechanisms The pathogenic mechanisms of enterovirus-associated myocarditis in humans is a subject of considerable ongoing research. Arguments have been advanced to indicate that the changes in heart tissue can be attributed to (a) direct viral injury to the cardiac myocytes (McManus et al, 1993), (b) cellular immune mechanisms mediated by either "cytolytic'' T cells (CD8+), or "helper'7 "suppressor" T cells (CD4+), or both (Huber et al, 1988), or (c) the effects of heartspecific antibodies directed against the myosin and other constituents of the cardiac myocytes acting directly on heart tissue or in concert with an antibodydependent cell-mediated cytotoxic reaction (Neumann et al, 1993). These concepts are based almost entirely upon studies in inbred strains of mice experimentally infected with various strains of group B coxsackieviruses. The contrasting conclusions obtained in stud-

Enteroviruses

ies of pathogenesis conducted by various qualified investigators most probably relate to differing patterns of responsivity by various murine genotypes to various laboratory strains of virus having unique pathogenic properties. Accordingly it is likely that conclusions from experimental animal work may prove correct with regard to pathogenic events in individual patients, taking into consideration differences in the properties of the infecting "wild'' strain of virus and the unique genetic features of the individual patient. There may be no common pathogenic mechanism applicable to all cases of human myocarditis, and several mechanisms could be involved simultaneously in individual cases. While the details of the animal experiments are beyond the scope of this section, salient aspects of the studies provide a basis for understanding events that might be expected to occur in humans. Several features of the murine model are particularly intriguing in this regard. Of paramount importance has been the finding that strains of the same serotype of virus recovered from different patients and viruses manipulated in various ways in the laboratory differ intrinsically with regard to their capacity to produce myocarditis in mice. This feature cannot be attributed exclusively to the tropism of the virus for cardiac myocytes since the

15

amounts of virus in the heart tissue of mice infected with different strains of virus are roughly comparable, despite dramatic differences in the severity of the lesions that ultimately develop in the heart. While the genetic basis for the variability between virus strains is ill-defined, the high rate of mutability of picornaviruses during the course of replication in tissue along with the selective pressures attributable to various cellular environments no doubt account for the selections of strains having cardiotropic properties, whereas "wild" strains of the same serotype lack the capacity to cause myocarditis. Most of the mutations affecting pathogenicity are manifest as structural changes in the proteins of the capsid of the virion that ultimately alter either interactions with viral receptors of the cell, or the presentation of antigens to immunologically functional cells, or both (Knowlton et al, 1996; Tu et al, 1995). This conclusion is consistent with the well-documented differences in the clinical manifestations of epidemic strains of naturally occurring virus in various outbreaks, with some virus strains predominantly manifesting their effects as myocarditis, while others cause pleurodynia or aseptic meningitis. Genetic variability among viruses is further compounded by striking differences in susceptibility to myocarditis related to both the age and sex of the

F I G U R E 1.10 Experimental studies in adult mice have established an important role for the major histocompatibility complex (MHC) in dictating susceptibility to myocarditis induced experimentally by coxsackievirus B, type 3, in mice. The results in one such study using transgenic animals are depicted. Myocardium of the infected mouse of the class II lA histocompatibility type (A) and a mouse lacking these class II MHC antigens (B); the myocardium of infected mice of IE MHC type with or without lA antigen (C, D). Note the interstitial inflammation and focal necrosis of the musculature (arrow). Reprinted with permission and provided through the courtesy of S. Huber, PhD.

16


patient as well as the overriding influence of genetic factors that affect both susceptibility to infection and the iramunopathogenetic mechanism involved. Among these influences, perhaps of greatest importance is the complement of antigen-presenting major histocompatibility' proteins exposed on the plasma membrane of the myocardial cell (Figure 1.10). In addition, compelling evidence is now accumulating that implicates certain genetic defects in the metabolism of myocardial cells that predispose to dilated cardiomyopathy in the virus-injured heart of humans (Leiden, 1997). Group B type 3 coxsackievirus-infected adult male mice and pregnant females develop myocarditis readily, whereas virgin female animals are resistant, even though the heart tissue of these animals support the replication of comparable amounts of virus. This observation points to the influence of the sex hormones, testosterone and progesterone, on the susceptibility of mice to myocarditis. Interestingly enough, castration eliminates the male animal's susceptibility to myocarditis, whereas testosterone treatment of virgin females and castrated males creates it (Lyden et al, 1987). These experimental findings are consistent with the clinical observation; that is, among adults, the prevalence of myocarditis is substantially greater in older men and in women during pregnancy The mechanism whereby sex hormones influence the development of myocarditis is incompletely defined, but suppressor T lymphocyte populations may be reduced and nonfunctional in the male and pregnant female animal due to the sex hormone effects (Job et ah, 1986). As noted above, the genetic characteristics of the infected animal appears to influence dramatically the mechanism whereby cardiac damage occurs. For example, in some strains of mice, myocarditis develops as a direct result of viral infection of cardiac myocytes, whereas coxsackievirus B3-infected inbred mice of the A, DBA/2, MRL+/+, and Balb/c strains develop myocarditis by differing mechanisms (Huber, 1997). At the onset, a relatively transient myocardial interstitial inflammatory reaction is found in animals of these three strains a few days after inoculation, but severe persistent infection with chronic myocarditis occurs in A strain mice. In mice of the Balb/c genotype, cardiac damage is mediated by "cytolytic" T cells (CD8+), while in those of the MRL+/+ genotype the "helper" / "suppressor" CD4+ lymphocytes are the key cardiotropic immune mediators (Lodge et al, 1987). In contrast, both of the major T cell types play a contributory role in the development of disease in A strain mice. And, in those of the Balb/c strain, both humoral (i.e., cytotoxic IgG antibody) and cellular mechanisms are involved. Immunocytological studies have demonstrated a diverse complement of macrophages, natural

killer cells, and both CD4+ and CD8+ T cells in the lesions (Godeny and Gauntt, 1987). These complexities are compounded by the finding that immune sensitized lymphocytes differ in their pathogenic effects on the cardiac myocytes and the extent of inflammation and necrosis they cause. Immunological sensitization resulting from prior exposure to an antigen may enhance the severity of the disease. Strong evidence implicating humoral IgG antibodies in the pathogenesis of myocarditis arise from studies of coxsackievirus B3 infected and congenic BIO strains of mice (Neu et al, 1987). In these animals, antibodies reactive with cardiac (but not skeletal) muscle myosin produce heart lesions of a chronic nature. While the development of autoantibodies to myosin is a common, if not a universal, response to cardiac viral injury in mice, the antibody usually does not cause myocarditis (Neu et al, 1987,1990). Indeed, humorally mediated disease occurs only in a limited number of mouse strains. Myocarditis appears to develop in mice when myosin is deposited extracellularly in the interstitial matrix of the heart (Liao et al, 1995). The basis for humoral and cellular immunity against myocardial tissue in the various murine models is unclear, but at least one plausible explanation is antigenic mimicry In one series of experimental studies, antibodies directed against specific epitopes of cardiac myosin neutralize the infectivity of a strain of group B coxsackievirus having cardiotropic properties but had no neutralizing effect on a nonmyocarditic stain of virus (Cunningham et al, 1992). Thus, the immune response of the infected animal to this specific virus strain appears to be unique to the antigenic complement of that virus strain alone, and by one immune mechanism or another acts to alter the integrity of the myosin of the heart muscle cell (presumably because viral antigenic epitopes are shared with myosin). The antibodies to cardiac myosin thus far studied also react with epitopes in the M proteins of strains of group A beta hemolytic streptococcus, which have the capacity to cause rheumatic heart disease. In a broader context, these observations strongly suggest the possibility that antigens to plants and animal constituents elaborated in nature by microbes might contribute to the development of autoimmune disease (Huber et al, 1994; Huber and Cunningham, 1996).

STRIATED MUSCLE DISEASE Coxsackie group A viruses produce an extensive destructive inflammation of striated muscle in infant

17

Enteroviruses

mice inoculated experimentally by various routes (Dalldorf, 1949). This observation raises for consideration the possibility that enteroviruses are involved in the pathogenesis of sporadically occurring clinical cases of polymyositis and dermatomyositis. While this has not proven to be the case, enteroviruses are implicated in the causation of the less severe myositis that occasionally develops in humans, concomitant with a systemic enteroviral illness (Singh and Scheld, 1996). Alas, the concept has not been established by clinical study despite considerable laboratory and epidemiological research. The problems in demonstrating a cause-and-effect relationship between infection and myositis are numerous. They center on the relative unacceptability of biopsies of striated muscle in humans and the apparent relatively transient presence of detectible virus in muscle tissue. In 1953, picornavirus-like particles were demonstrated as crystalline arrays by electron microscopy in the striated muscle of a patient with dermatomyositis (Zweymuller, 1953). This finding triggered a flurry of similar morphological studies that implicated enteroviruses in muscle inflammatory disease, but the work had questionable validity because of the lack of confirmatory virological information (Chou and Gutmann, 1970; Mastaglia and Walton, 1970; de Reuck ei a/., 1977). Moreover, the ultrastructural similarity of the supposed virions to ribosomes and glycogen raised doubt regarding the basic interpretation. Exceptions have been reported. For example. Tang ef al. (1975) documented the isolation of a group A type 9 coxsackievirus from diaphragmatic muscle exhibiting by ultrastructure picornavirus-like virions in a child with a diffuse progressive myopathy and extensive myositis (Josselson ei al., 1980) (Figure 1.8B,C). Muscle from two additional cases of myositis were found to be reactive by immunofluorescence with antiserum directed against coxsackievirus group A-9 (Gyorkey, 1978; Kuroda ei al., 1986). Cases of acute and chronic myositis with or without rhabdomyolysis accompanied by significant increases in serum antibody to coxsackie and echoviruses have also been reported (Jehn and Fink, 1980; Josselson ei al., 1980; Fukuyama ei al., 1977; Berlin ei al, 1974; Travers ei al, 1977; Bowles ei al, 1987). Unfortunately, reports of molecular studies using PCR amplification and in siiu localization are limited. Yousef (1990) examined muscle biopsies using a broadly reacting cDNA probe for enteroviruses. Virusspecific sequences were detected in tissue from 6 of 12 patients with polymyositis or dermatomyositis. The pathogenesis of picornavirus myositis is obscure, since systematic studies in humans have not

been carried out. Work in mice infected with model picornaviruses provide evidence supporting an autoimmune phenomena, possibly with molecular mimicry serving as the pathogenic mechanism (Dalakas, 1995). In siiu localization studies by Cronin ei al. (1988) have documented the presence of the RNA of EMC virus (a coxsackie-like cardiovirus) in striated muscle of experimentally infected mice over periods of as long as 4 weeks. Studies by Ytterberg ei al. (1987) argue that cell-mediated immune processes function to damage skeletal muscle in the coxsackievirus group Bl infected mouse. While noncellular protective mechanisms such as interferon and natural killer cells may act to eliminate the virus from the tissue, presumably T cells (of undetermined type) are responsible for the inflammatory infiltrate and most probably cause muscle damage.

EPIDEMIC MYALGIA: PLEURODYNIA, B O R N H O L M DISEASE The dramatic presentation of patients with lancinating intense chest pain due to an enterovirus infection accounts for the clinical term "devil's grip." The classical description of an outbreak of the disease on the Danish island of Bornholm by Sylvest (1934) documents the clinical features of the syndrome. As the name iraplies, pleurodynia is an acute febrile illness of older children and young adults characterized by the acute onset of insufferable bilateral (or occasionally unilateral) chest pain, exacerbated by deep breathing and cough, and occasionally associated with abdominal wall pain. It develops after the appearance of fever, malaise, and upper respiratory symptoms attributable to infection. Intrinsic pain persists for about 1 week and waxes and wanes thereafter. Coxsackie group B viruses are the customary cause (Weller ei al, 1950; Bain ei al, 1961), but occasionally group A coxsackie and echoviruses are implicated. The pathological basis for this painful syndrome is unclear. Mononuclear cell pleuritis has been described in a few autopsies of infants with systemic infections (Kibrick and Benirschke, 1956; Smith, 1970), and a myositis of the intercostal diaphragmatic muscle has been found in other cases (Sussman ei al, 1959; de Reuck ei al, 1977). However, definitive clinical studies have not been carried out, and it is unclear whether the syndrome is due to a myositis of the thoracic musculature or a pleuritis.

18


LUNG DISEASE In a literature review, Sussman ei al. (1959) noted autopsy descriptions of interstitial pneumonitis in 6 of 15 cases of neonates infected with group B coxsackievirus. Cases with massive pulmonary hemorrhage have also been reported (Hurley et al, 1969; Wong et al, 1989). Fatal interstitial pulmonary disease associated with hyaline membranes has been reported in near-term infants infected with echoviruses type 6, 9, and 11. The viruses were recovered from either lung tissue or tracheal secretions (Cheeseman et al, 1977; Boyd et al, 1987).

TESTICULAR DISEASE Orchitis was recognized as an infrequent complication of Bornholm's disease in the classical description of this disease by Sylvest in 1934. Clinical observations

since that time have confirmed the association (Jamieson and Prinsley, 1947; Warin et al, 1953; Morrison and Baird, 1952), although orchitis has also been reported in patients with coxsackie group B meningitis and myocarditis (Swarm, 1961; Freij et al, 1970). The incidence of orchitis is variable in group B coxsackievirus outbreaks, but it ranges as high as 40%. In one family outbreak, it developed in four of five infected siblings (Morrison and Baird, 1952). Enteroviruses other than group B coxsackieviruses have also been implicated. Coxsackievirus group A, type 9 (Willems et al, 1977), and echovirus type 6 were reported to be the cause of orchitis in individual cases (Welliver and Cherry, 1978). As with mumps, typical symptoms of testicular pain and swelling usually are unilateral, often appearing days or weeks after the development of other clinical complaints attributable to the systemic infection. While adults usually are affected, a 13-year-old boy with bilateral disease has been reported (Willems et al, 1977). We recovered coxsackievirus group B, type 4, at a high concentration from a testicular biopsy of a 23-

B

FIGURE 1.11 Testicular biopsy from a 25-year-old college student. Sixteen days before surgery, he began experiencing fever and bilateral pleural pain consistent with Bornholm disease, i.e., epidemic pleurodynia. Sore throat followed. Seemingly, the patient recovered, but unilateral testicular pain developed 2 days before hospitalization. The patient had experienced mumps in the past. Examination revealed an enlarged, exquisitely tender testicle. Surgical incision of the tunica albuginea revealed dark-blue congested testicular tissue (A). Histologically, necrotic cells and debris obliterated the lumina of some tubules; in other tubules, spermatogenesis was not apparent and Sertoli cells were enlarged and had a clear cytoplasm. Evidence of hemorrhage and edema were found in the interstitium. Perivascular cuffs of lymphocytes were apparent. Coxsackievirus, group B, type 5, was recovered in high concentrations from a small fragment of testicular tissue. Reprinted with permission from Craighead et al. (1962).

19

Enteroviruses

year-old student approximately 2 weeks after the onset of pleurodynia (Craighead et ah, 1962). The biopsy revealed interstitial mononuclear cell infiltration and seminiferous tubular changes that ranged from suppressed spermatogenesis to necrosis (Figure 1.11). The pathological changes resembled those described in cases of mumps orchitis (Gall, 1947). We know of no other pathological studies of testes with orchitis attributable to enteroviruses. However, in mice experimentally infected with the encephalomyocarditis virus, both the Sertoli and germinal cells were infected, and underwent cytological changes (Ueno ei al., 1996). The persistence of relatively large amounts of virus in the testes of a patient with circulating serum antibodies is noteworthy. The common development of orchitis after the subsidence of an acute febrile illness such as pleurodynia, and the pathologic picture in this case, strongly suggest that autoimmune mechanisms are involved.

LIVER DISEASE Neonates with fatal disseminated group B coxsackie and echovirus infections commonly exhibit hepatic parenchymal inflammation and necrosis at autopsy (Benirschke et al, 1958; Hosier and Newton, 1958; Sussman et al, 1959; Morris et al, 1962; Sun and Smith, 1966; Hughes et al, 1972; Krous et al, 1973; Lansky 1979; Gillam et al, 1986; Chambon et al, 1997; Wong et al, 1989). In one study of fatal cases of echovirus type 11 infections (Berry and Nagington, 1982), hepatic necrosis was found in 6 of 12 neonates; the lesions were extensive in three of the cases. Similar observations have been described with other echovirus serotypes (Mostoufizadel et al, 1983; Hughes et al, 1972; Krous et al, 1973; Bose et al, 1983; Gillam, 1986; Garcia et al, 1990; Verboon-Maciolek et al, 1997; Chuang et al, 1993). Electron microscopy has demonstrated virions in hepatocytes (Krous et al, 1973; Gregor et al, 1975) and viral genomic RNA by molecular means (Chambon et al, 1997). Necrotizing hepatic lesions have been reported in neonates infected with all six of the group B coxsackieviruses. Of the over 30 known serotypes of echovirus, 8 have been reported to cause neonatal hepatic disease, presumptively as a result of placental transmission from a mother acutely infected with an enterovirus. Many of these same infants have varying degrees of encephalitis, myocarditis, and adrenal necrosis. In addition, clinical and laboratory evidence of disseminated intravascular coagulation is common with petechia and bleeding being common manifesta-

tions. Thus, the liver lesions are part of a generalized multisystem disease process.

KIDNEY DISEASE Experimentally infected animals and humans with naturally acquired infections excrete polio, coxsackie, and echoviruses in the urine during viremia. Hematuria and proteinuria were noted in a substantial proportion of patients ill during an outbreak of echovirus type 9 (Smith and Aquino, 1971). The demonstration of coxsackievirus antigen in exfoliated renal tubular cells suggests a possible site for viral replication in the kidney, but the evidence to support this possibility is meager. Noteworthy, of course, is the exceptional viral susceptibility of renal epithelial cells in monolayer cultures prepared from primate and human fetuses. Serological evidence of an acute group B type 5 coxsackievirus infection was reported by Aronson and Phillips (1975) in six patients with reversible renal failure of abrupt onset. Kidney biopsies showed rapidly progressive glomerulonephritis, but the details of the renal lesion were not described and infection of the renal parenchyma was not documented. Renal medullary hemorrhages have been reported in several infants with perinatally acquired echovirus infections (Krous et al, 1973; Nagington et al, 1978; Longworth-Krafft and Morgan-Capner, 1980). In addition, glomerulitis accompanied by renal failure have also been documented in neonates infected with echoviruses (Yuceoglu et al, 1966; Huang and Wiegenstein, 1977). The pathogenesis of these parenchymal lesions of the kidney is obscure, and studies designed to identify the site of virus replication in the kidney were not done. In the early 1970s, reports were published associating the hemolytic uremia syndrome with group B coxsackievirus infections. Additional support for an etiological relationship between the syndrome and enterovirus infection is currently lacking (Ray et al, 1971; Austin and Ray 1973).

PLACENTAL LESIONS OF NEONATALLY INFECTED INFANTS Focal villitus with fibrin thrombosis is described in the placental tissue of a few infants born with evidence of in utero enterovirus infection (Batcup et al, 1985; Garcia et al, 1991). In many case reports, pathological studies of the placenta are not described and the over-

20


all prevalence of placental disease in coxsackie and echovirus infection is unknown. Garcia et al. (1990) attempted to determine the prevalence of lesions in a systematic survey of placental tissue, but their evaluation is flawed since infection in the mother was established in only a few cases. In these cases, villitus was observed.

SKIN A N D M U C U S MEMBRANE DISEASE In 1958, an outbreak of a febrile vesicular stomatitis accompanied by an exanthem and vesicular lesions of the hands and feet occurred among children infected with coxsackievirus, group A, type 16 (Robinson et ah, 1958) (Figure 1.12A-C). Subsequent epidemic appearances of these so-called hand, foot, and mouth syndromes were reported from Europe, North America, and Oceania. The skin lesions are transient and only

occasionally associated with generalized symptoms. Vesicular fluid yielded various serotypes of group A coxsackievirus, and virus could also be recovered from the oropharynx a n d / o r stool. Cytological study of cells from infected vesicular fluid in one study demonstrated intracytoplasmic eosinophilic inclusions similar to those occasionally seen in other picornavirus-infected tissue (Froeschle et al, 1967). Scrapings of cells from vesicles by other investigators yielded no cytological evidence of infection (Cherry and Jahn, 1966), but viral particles have been demonstrated in exfoliated cells by electron microscopy (Parra, 1972). The condition is usually seen in young children, although an occasional older person is affected (Adler et al, 1970; Mink et al, 1970; Baker and Phillips, 1979). Echoviruses produce a variety of eruptions in infants and children during the acute febrile illness (Cherry, 1969). Zosteriform vesicular skin lesions have been described (Meade and Chang, 1979). Community outbreaks of hemorrhagic conjunctivitis attributable to unclassified enteroviruses were re-

FIGURE 1.12 Acute ulcerative hand, foot, and mouth disease lesions associated with coxsackievirus type 16 (A,B). (C) Microscopically the preulcerative lesion of the skin shows hyperplasia of the malpighian stratum with ballooning of the cytoplasm of epithelial cells. The rete pegs show accumulations of mononuclear cells. Reprinted with permission from Cherry and Jahn (1966).

Enteroviruses

ported during the 1970s and 1980s in Africa, Europe, Central and Southeast Asia, Japan, American Samoa, and the United States. In addition to the obvious inflammatory features of the conjunctivitis, lymphoid follicles developed in the conjunctival membrane, and a superficial punctate keratitis is seen, but systemic symptoms and fever are generally not observed (Chatterjee et al, 1970; Lemp et al, 1972; Dawson et al, 1974; Kono et ah, 1972; Patriarca et al, 1983; Onorato et al, 1985; Higgins and Scott, 1973). At least one outbreak has been associated with group A type 24 coxsackievirus (Christopher et al, 1982). A case report describes the isolation of group B type 1 coxsackievirus in a worker with conjunctivitis who was exposed in a laboratory (Dietzman et al, 1973).

TYPE I DIABETES MELLITUS Type I (insulin-dependent, juvenile onset) diabetes mellitus is a severe, life-threatening metabolic disease of relatively abrupt onset. It requires prompt insulin therapy inasmuch as most patients are at risk of death due to overt ketoacidosis. Type I diabetes occurs sporadically worldwide but exhibits a marked geographic concentration in Caucasian populations, particularly those in North America and Northern Europe. While persons of all ages can develop the disease, onset usually occurs during or shortly after the arrival of puberty. Roughly 20% of patients have a history of the disease among first-degree relatives. Thus, most cases occur sporadically without known predisposing influences. Nonetheless, an unusually high proportion of those developing the disease possess certain class I and II histocompatibility markers, particularly HLA-DR3, HLA-DR4, and a specific locus in the HLA-DQ complex. This finding suggests an autoimmune pathogenesis. An additional clinical observation supporting the autoimmune hypothesis is the demonstration of a variety of islet of Langerhans-specific antibodies in the blood of patients before and at the time of onset of the disease. The demonstration of lymphocytic infiltrates in and around the islets (so-called insulitis) in the pancreases of many (but not all) of those who die shortly after the onset of the disease further supports the immune hypothesis (Gepts, 1965; Foulis and Stewart, 1984; Foulis et al, 1986). The demonstration of a protective or ameliorating effect of immunosuppressive drug treatment on the progression and severity of diabetes when the therapy is administered shortly after onset of the disease is additional compelling evidence to indicate that the immune mechanisms are involved.

21

Although autoimmunity likely causes or contributes to beta cell damage, the actual etiological trigger initiating the process is unknown. Circumstantial evidence strongly suggests that environmental factors are involved. Support for this notion is provided by studies of monozygotic twinships in which one member has type I diabetes. Interestingly enough, the second twin of the pair develops the disease in only about half the sibships. This observation appears to exclude genetic influences as being the only or predominant factor affecting the development of the disease. Some 70 years ago, a report from Scandinavia claimed an association between outbreaks of mumps in isolated communities and the abrupt onset of diabetes (Gundersen, 1927). Sporadic case reports since that time support the possibility that virus infection could result in pancreatic damage leading to diabetes. Congenitally acquired rubella virus infections have also been associated epidemiologically with type I diabetes; approximately 20% of children with the stigmata of intrauterine infection and the congenital rubella syndrome develop type I diabetes (Forrest et al, 1971). Disease in these patients would appear to result from intrauterine and postnatal pancreatic infection with destruction of the islets of Langerhans (see Chapter 28). Gamble and his associates (1973) documented an unusually high prevalence of coxsackievirus group B serum antibodies in children with type I diabetes. This observation is now supported by seroepidemiological studies conducted in several different population groups, but in some investigations a significant association between infection and disease has not been demonstrated (Banatvala, 1987; Samantray et al, 1977). Further evidence supporting the viral hypothesis is provided by observations on sporadic cases of coxsackievirus group B infections in children who developed abrupt-onset diabetes concomitantly (Gladisch et al, 1976; Sussman et al, 1959; Jenson et al, 1980; Ujevich and Jaffe, 1980). In one of these cases, a group B type 4 coxsackievirus was recovered from the pancreas at autopsy and the virus was found to cause lesions of the islet cells when inoculated into mice (Yoon et al, 1979), thus partially fulfilling the requirements of Koch's postulates. This unique observation has not been repeated with virus isolates from other patients. Although the notion that group B coxsackieviruses might contribute to the development of diabetes in humans is novel, these viruses have long been known to cause necrotizing lesions of the acinar pancreas in the newborn human and of both acinar and insular pancreas of experimentally infected mice (Pappenheimer et al, 1951; Yoon et al, 1978). Sporadic case reports also document pancreatitis in an occasional older pa-

22


tient with a systemic coxsackievirus infection. Interestingly enough, some, but not all, "laboratory-adapted" and "wild" strains of virus have the capacity to cause necrosis of the pancreatic acinar tissue in mice (Dalldorf and Gifford, 1952; Vella ei al, 1992), and genetic influences determine whether or not lesions will develop in various inbred strains (Webb ei al., 1976; Ramsingh ei al., 1989). In these studies, the islets of Langerhans show no pathologic effects, and metabolic abnormalities consistent with diabetes are not apparent. In 1965, the author noted subtle histological changes in the islets of Langerhans of adult male mice infected with selected strains of the encephalomyocarditis virus (Craighead and McLane, 1968), a cardiovirus of the picornavirus genus having many biological similarities to the group B coxsackieviruses. The beta cells of the islets of the acutely infected adult mice were either degranulated or had undergone necrosis, and the animals were diabetic (Craighead and Steinke, 1971) (Figure 1.13). Considerable information has now accumulated on this "new" model of type I diabetes. As with experimental group B coxsackievirus myocarditis in adult mice, sex hormones play a critical role in determining the outcome of infection. Diabetes develops in infected adult male mice, but not in male castrates or females. While exogenous testosterone has no apparent effect on the severity of the infection, its administration

to male castrates and female animals triggers development of insular lesions and metabolic diabetes (Morrow ei al., 1980). Genetic analyses of murine models of diabetes caused by the encephalomyocarditis virus have provided further insights. In some strains of mice, the lesions of the islet beta cells are due exclusively to direct infection of the pancreatic beta cells (Yoon ei al., 1985), whereas in other strains, immune injury mediated by CD4 "helper" lymphocytes is critical to the development of beta cell injury and diabetes (Huber ei al., 1985; Haynes ei al., 1987). The antigen(s) responsible for immune sensitization in these models of diabetes are not known. However, the molecular basis for the unique capacity of the diabetogenic encephalomyocarditis virus to attack the beta cell is largely clarified. An amino acid substitution in the VPl polyprotein of the virion seems to permit viral attachment to a viral receptor on the beta cell (Bae ei al., 1990). "Wild" strains of the same serotype appear to lack this capacity An analysis of clinical, epidemiological, and experimental evidence accumulated over the past twenty years strongly suggests that some, but not all, cases of type I diabetes mellitus develop after group B coxsackievirus infections (Foulis ei al., 1990). As of yet, no markers permitting the identification of such cases have been found. Traditional virological studies most probably would be futile, except in acutely fatal cases of diabetes in which attempts to recover virus might be

FIGURE 1.13 Islet of Langerhans in the pancreas of an adult male mouse infected with the encephalomyocarditis virus, a cardiovirus. Note the coagulation necrosis of the islets. Administration of corticosteroids accentuates the extent of necrosis of beta cells. Alpha cells at the periphery of the islet remain intact. This mouse was diabetic.

Enteroviruses

made at autopsy. In humans, beta cell damage appears to evolve over a period of several years before the overt diabetes becomes evident (Maclaren, 1989). Hypothetically, viral injury could initiate the process, and autoimmune damage to the beta cell mass might develop during this prolonged "latency period" (Harrison et al., 1989). This supposition is supported by the demonstrated appearance of antibodies directed against beta cell components in the serum of prediabetic persons concomitant with a gradual decrease in the capacity of the pancreas to release insulin in response to a glucose challenge. Pathologically, the early events at onset of symptoms are represented by the insulitis (i.e., mononuclear inflammatory response in and around the islet of Langerhans). Later, the disease is characterized by the absence of beta cells in islets that are distorted, shrunken and sometimes fibrotic. Customarily, histologic examination of the pancreatic tissue of children with type I diabetes reveals a sparse insular tissue with islets comprised exclusively of the glucagon elaborating alpha cells and the insular delta cells. Pathological changes in the acinar pancreas customarily are not observed.

References Adler, ]., Mostow, S., Mellin, H., Janney, ]., and Joseph, J. (1970). Epidemiologic investigation of hand, foot, and mouth disease: Infection caused by Coxsackievirus A16 in Baltimore, June through September 1968. Am. J. Dis. Child. 120, 309-313. Archard, L., Bowles, N., Olsen, E., and Richardson, P. (1987). Detection of persistent coxsackie B virus RNA in dilated cardiomyopathy and myocarditis. Eur. Heart J. 8 (Suppl. J), 437440. Aretz, H. (1987). Myocarditis: The Dallas criteria. Hum. Pathol. 18, 619-624. Aretz, H., Billingham, M., Edwards, W., Factor, S., Fallon, J., Fenoglio Jr., J., Olsen, E., and Schoen, F. (1986). Myocarditis: A histopathologic definition and classification. Am. J. Cardiovasc. Pathol. 1, 3-14. Aronson, M., and Phillips, C. (1975). Coxsackievirus B5 infections in acute oliguric renal failure. /. Infect. Dis. 132, 303-306. Austin, T., and Ray, C. (1973). Coxsackie virus group B infections and the hemolytic-uremic syndrome. /. Infect. Dis. 127, 698-701. Bae, Y.-S., Eun, H.-M., Pon, R., Giron, D., and Yoon, J.-W. (1990). Two amino acids, Phe 16 and Ala 776, on the poly protein are most likely to be responsible for the diabetogenicity of encephalomyocarditis virus. /. Gen. Virol. 71, 639-645. Bain, M., McLean, D., and Walker, S. (1961). Epidemic pleurodynia (Bornholm disease) due to coxsackie B-5 virus. Pediatrics 27, 889903. Baker, D., and Phillips, C. (1979). Fatal hand-foot-and-mouth disease in an adult caused by Coxsackievirus 47. JAMA 242, 1065. Banatvala, J. (1987). Insulin-dependent (juvenile-onset, type 1) diabetes mellitus: Coxsackie B viruses revisited. Prog. Med. Virol. 34, 33-54.

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27

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C H A P T E R

2 Rhinoviruses The largest group, about 90% of the recognized strains, attach to the ICAM-1 molecules of the respiratory epithelium (Tomassini and Colonno, 1986; Huguenel et al, 1997). The remaining virus strains comprise the second group. They employ a low-density lipoprotein cell surface receptor that remains to be more specifically identified. Rhinoviruses multiply in the mucosal cells of the nasal cavity and paranasal sinuses of humans and higher primates, as shown by in situ hybridization studies (Bardin et ah, 1994; Arruda et al, 1995) (Figure 2.1A,B). Experimentally infected volunteers appear to be susceptible to exceedingly small amounts of virus. Once infection is established, maximal concentrations of virus accumulate in the nasal cavities within 48 hr (Harris and Gwaltney, 1996). Concomitantly, there is the abrupt onset of the all-too-familiar symptoms of the common cold (Figure 2.2). Respiratory complaints often persist for as long as 7 to 13 days (Gwaltney and Druce, 1997). Biopsies of the nasal mucosa fail to demonstrate cytological changes in the epithelial lining cells during the acute stages of infection, but inflammatory cells are found in increased numbers in the mucosa and submucosa (Winther et ah, 1984). In addition, large numbers of mucosal cells and polymorphonuclear leukocytes as well as both lymphocytes and macrophages are recovered when the nasal cavities are lavaged (Gwaltney et ah, 1984; Levandowski et al., 1988; Turner et ah, 1982). Analysis of these nasal washings yields several cytokines, including gamma interferon and IL-lb, IL-6, and IL-8 (Proud et ah, 1994; Noah et ah, 1995; Johnston, 1995; Gwaltney, 1995; Teran et ah, 1997; Turner et ah, 1998). We can only speculate regarding the role of these in the signs and symptoms of the common cold (Turner and Gwaltney, 1984). Immunological labeling of virus has shown that only rare scattered cells of the nasal mucosa are infected (Arruda et ah, 1997) (Figure 2.3). These cells have an ill-defined topographical distribution (Turner et ah 1982, 1984; Turner and Gwaltney 1984), and not all regions of the mucosa of the nasal turbinate systems

t was only a cluster of barren hospital buildings left over from the war. Located in the rolling vividly green countryside of Wiltshire in Southwest England, The Common Cold Research Unit was / almost obscured by its pastoral surroundings. It was here, however, that much of the important early work that led to our current understanding of simple upper respiratory illnesses was conducted (Tyrrell, 1979). Urban couples would visit for a fortnight's holiday, only to receive as their fee an experimental inoculum possibly containing a candidate for the elusive virus that causes the common cold. It was the carefully recorded symptoms of over 10,000 volunteers (i.e., handkerchief counts, coryza, sneezes, and coughs) that led to identification of the cold-causing agents now known as the rhinoviruses (Andrewes, 1953). Work carried out here and elsewhere in the United Kingdom resulted in two rather simple findings that allowed researchers to grow these fastidious viruses in the laboratory. First, the differentiated respiratory mucosa of human fetuses maintained in organ culture proved to be uniquely susceptible to many. And second, their growth outside the human body was found to be dependent on an environmental temperature of 33°C, rather than the 3637°C customarily used to maintain cells in the laboratory. By growing these viruses in the laboratory, it was soon possible to examine their biological features, and to undertake experiments designed to elucidate their pathogenicity. Rhinoviruses are classified as one of the genre of the picornavirus family. From a molecular and structural perspective, they are strikingly similar to the enteroviruses (see Chapter 1), but differ because they commonly have more fastidious growth requirements in vitro, and the virion is sensitive to acid treatment in a laboratory setting. Thus, rhinoviruses are not believed to replicate in the digestive tract as do their enterovirus cousins (Rowlands, 1995). At present, over 100 distinct serotypes of rhinoviruses have been recovered from humans, but it is likely that many more remain to be identified. These viruses fall into two groups, based on the cell surface receptors they utilize.


29

Copyright © 2000 by Academic Press. All rights of reproduction in any form reserved.

30


F I G U R E 2.1 Nasal epithelium of volunteers experimentally infected with 10^ to 10^ infectious dosages (TCID50) of human rhinovirus-14 three days after inoculation (arrow). Infected ciliated epithelial cells are identified by in situ hybridization. Only a relatively small number of cells are infected despite the large inoculum of virus used. Reprinted with permission from Arruda et al. (1997) and through the courtesy of E. Arruda, MD.

Nasal Secretions

Sneezes

Cough

Sore Throat 0

Headache

Malaise

°^

Days

F I G U R E 2.2 Signs and symptoms of the common cold in volunteers experimentally infected with an unclassified rhinovirus. The illness reached its acme 2 to 3 days after inoculation. Adapted with permission from Tyrrell (1979).

are infected to an equivalent extent. Septal involvement appears to be relatively uncommon (Figure 2.3). Volunteer studies at this time document a decrease in mucociliary function with reduced rates of transport of small (4000 ft. above sea level), where temperatures are more moderate, although malaria is rampant (Figure 9.8). Similar, but more restricted, foci of disease occur in native populations of eastern New Guinea and localized areas of tropical South America, where malaria is also prevalent. An identical lymphoma occurs rarely among somewhat older children in temperate regions of Europe, North and South America, and Japan. Although the tumor's histological features are the basis for its identity, similarities and differences in the organ distribution of the lymphoma in the sporadically and endemically occurring conditions are evident. In Africa, involvement of the orbit of the eye, the jaw, and the ovary are common, whereas these organs are less frequently involved in the disease, occurring sporadically in developed countries. For reasons that are totally unclear, the distribution of lesions in African cases is changing (Table 9.1). The unique lesions of the mandible that so characterize the African disease are age related; they occur much less commonly in older children (Figure 9.9). Worldwide, Burkitt's lymphoma has a striking male predominance and rarely occurs in adults except in association with AIDS. It comprises roughly a third of

F I G U R E 9.9 Typical expansive tumor mass of Burkitt's lymphoma originating in the mandible of an African boy.

the B cell lymphomas developing in untreated patients with human immunodeficiency virus (HIV). The role of EB virus in the pathogenesis of Burkitt's is the central issue in the disease. In Uganda, affected children invariably exhibit high titers of viral-specific capsid antibody (VCA) long before the onset of the disease, and evidence of infection is found by various techniques in almost all of the tumors, that is, 95-98%. In contrast, the tumors in only a small proportion of children with BL in Western countries evidence EBV infection. Similarly, evidence of EBV infection is less commonly found in tumors from patients with BL in North Africa. Although EBV cannot be accorded an etiological role in the Burkitt's form of lymphoma, it most probably plays an important contributory role in tumorigenesis, accounting in part for the relatively high prevalence of the disease in Central Africa and in tropical South America, where infections early in life are the rule. The striking geographic association of Burkitt's lymphoma with holoendemic malaria and endemic malnutrition (particularly kwashiorkor) has served as the basis for hypotheses regarding the pathogenesis of the cancer. In endemic areas, the immunological response to the malaria infections is maximal at the time in life when the incidence of BL is greatest. Moreover, BL is believed to occur less frequently and at an older age when malarial infections are less common. It is speculated that the acquisition of EBV relatively early in life might have a lymphoproliferative effect, possibly in conjunction with the superimposed depressing effect

127

Epstein-Barr Virus TABLE 9.1 Tumor Sites i n E n d e m i c and Sporadic Burkitt's Lymphoma (% of cases) Endemic

Central nervous system Peripheral lymph nodes Mandible Bone (excluding mandible) Abdomen/pelvis Gut Liver Spleen Kidney Adrenals

1967

Sporadic

8 58 50 34

38 NR 21 27

48 44 44 85 70

19 22 19 40 21

11 17 7 4 67 NR NR NR NR NR

Adapted with permission from Templeton (1976). NR = not recorded.

of malaria and malnutrition on immunity, particularly suppressor cells of the T lymphocyte network. Most probably, the virus immortalizes the cells, as occurs in lymphoid cells infected in vitro and in EB-induced nonBurkitt's lymphomas in experimentally infected primates. Luxuriant expansion of the transformed B cell population might be expected to contribute to the characteristic chromosomal translocations described in detail below. Under the circumstances, the immune response to EBV is attenuated by the effect of Falciparum malaria and malnutrition on regulatory T cell immunity. While these concepts are appealing, the evidence is largely circumstantial. Moreover, they do not account for the sporadic occurrence of the disease in temperate developed countries, where the lymphoma no doubt has an entirely different pathogenesis. One could hypothesize that the EBV infection of lymphoblasts in the endemic disease is an epiphenomenon related to the high background prevalence of infection occurring early in life among residents of Central Africa and other tropical regions. Characteristic karyotypic alterations in the tumor cells are the hallmark of endemic Burkitt's lymphoma. They consist of the reciprocal translocations t(8;14), t(8;22), or t(2:8). The incidence of these cytogenetic alterations in the sporadically occurring tumors is not roughly comparable. In one series of 22 African cases in which tumor cell lines were used, 13 t(8;14), 6 t(8;22), 2 t(2;8), and 1 del(8)(q24) were found. Although similar karyotype alterations have been described in lymphomas and leukemias of other types, their occurrence is exceedingly rare except in the Burkitt's lymphomas developing in patients with AIDS. EBV infection of lymphoblastoid cells per se does not appear to be responsible since chromosomal changes do not develop in infected lymphoblastoid lines of cells in the laboratory. The type of translocation correlates with the presence of detectible immunoglobulin heavy and light

chains on the plasma membrane of the tumor cell. Kappa or lambda light chain expression correlates with the t(8;2) and t(8;22) translocations. These observations account for the prevailing view that immunoglobulin promotors of the respective transposed chromosomal segments activate the c-myc oncogene in or adjacent to the breakpoint of the 8th chromosome accounting for malignant phenotypic expression. Under these circumstances, the c-myc regulatory effects on the cell cycle are altered, leading to cell proliferation, rather than to apoptosis. The picture is more complex, however, for, as shown by Pelicci et al. (1986), the breakpoint is located outside the c-myc locus in endemic BL, whereas in the sporadic cases it is found within a 5' region that includes the first intron and exon as well as the flanking sequence of the gene. In addition, in endemic cases of BL with the (8;14) translocation, the breakpoint in the heavy chain gene occurs in the joining region, while in sporadic cases, it is found in the switch region preceding the constant region (Table 9.2). LYMPHOPROLIFERATIVE DISORDERS (LPDs) ASSOCIATED WITH IMMUNOSUPPRESSION (Ziegler, 1981; Lones et al, 1995; Preiksaitis et al, 1992; Purtilo et al, 1992; Saemundsen et al, 1981; Randhawa et al, 1990,1992; Knowles et al, 1995; Craig et al, 1993; Lager et al, 1993)

A number of complex acquired and genetically mediated syndromes of immunosuppression predispose to the development of EBV-associated LPDs of varying degrees of severity and prevalence (Klein and Purtilo, 1981) (Table 9.3). The condition occurs in solid organ allotransplant recipients who are undergoing immunosuppressive drug therapy (Hanto et al., 1981; Abu-Farsakh et al, 1992; Berg et al, 1992; BorischChappuis et al, 1990; Ho et al, 1985) and is seen in

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Pathology and Pathogenesis of Human Viral Disease TABLE 9.2 Characteristics of Endemic and Sporadic Burkitt's Lymphoma Endemic — (African type) Rate: 8-10 cases/100,000/year Mean age — 7 years EBV infection — 97%« Association with holoendemic malaria Chromosomal translocation long 8 to 14 — 86% (heavy chain) long 8 to 2 (kappa light chain) long 8 to 22 (lambda light chain) breakpoint outside of long 8 myc gene Sporadic — (American type) Rate: 0.1 case/100,000/year Mean age — 11 years EBV infection —15-30% Chromosomal translocation as with endemic breakpoint inside of long 8 myc gene AIDS-associated EBV infection - - 35-50% "Approximately 30 gene copies per cell.

AIDS (Andiman et ah, 1985). It now commands particular attention in AIDS because of the relatively common occurrence of the syndrome and the propensity for the development of non-Hodgkin's lymphomas (see Chapter 16). LPDs now occur in roughly 2% of allotransplant organ recipients at variable intervals after initiation of immunosuppression. In a study of almost 1000 allotransplant recipients, a lymphoproliferative disorder occurred in 0.8% of patients with kidney grafts, 1.62% with hepatic grafts, and 5.9% of those with cardiac allotransplants (Bhan, 1992). The median interval after transplantation is about 6 months. A higher incidence of disease has been reported from several other transplantation centers. EBV infection immediately before or promptly after transplantation has been associated with a high incidence of LPDs in children. LPDs first became evident in patients who had been administered cyclosporin A. Other therapies such as administration of OKT3 immune serum (which effectively blocks cytolytic T cell action) also predispose to the early onset of the condition. LPDs represent a spectrum of disease conditions, and their clinical stages have been described (Hanto et al, 1982, 1983, 1985; Knowles et al, 1995). In their simplest form, these disorders are reflected as an IM-like syndrome that can be confused with immunologic rejection of the allograft and graft vs. host disease. Pathologically, they are reflected in a polymorphic B cell hyperplasia with limited organ infiltration by B

TABLE 9.3 Clinical Classification of Lymphoproliferative Disorders Associated w i t h I m m u n o s u p p r e s s i o n I. Infectious mononucleosis illness a. Acute febrile illness b. Polymorphic B cell hyperplasia c. Response to acyclovir and withdrawal of immunosuppressive therapy II. Infectious mononucleosis illness involving multiple vital organs a. Acute febrile illness resembling fatal XLP b. Polyclonal or oligoclonal B cell hyperplasia c. Response to acyclovir treatment and to the withdrawal of immunosuppressive drugs is variable III. Lymphomas of predominantly brain and digestive tract a. Monomorphic B lymphoblastoid neoplasm b. No response to acyclovir treatment or withdrawal of immunosuppressive drugs

and T lymphocytes such as may occur in IM (Shearer et al, 1985). Often, the lesions tend to be plasmocytic and are distributed in the oropharynx and lymph nodes (Rizkalla et ah, 1997). Almost invariably, a polyclonal EBV infection can be established in the cells of these infiltrates by in situ hybridization of the viral DNA and immunofluorescent demonstration of EBNA in lymphoid cells of the lesion (Oudejans et al, 1995). At this stage, LPDs are readily reversed by reduction or elimination of immunosuppressive therapy, but this, of course, jeopardizes the transplanted organ. A dramatic response to acyclovir administration often occurs, and this is the therapeutic approach currently employed (Hanto et al, 1982). In a somewhat more complex advanced stage, LPDs are characterized by the infiltrative spread of B lymphocytes and immortalized lymphoblastoid cells into lymphoid organs and into extranodal sites throughout the body. The process usually is polymorphic and polyclonal, although oligoclonal accumulations of cells are often identified in isolated organs. As the disease evolves, a monoclonal population appears, but these cells lack the abnormal protooncogene expression and mutant suppressor genes that characterize a lymphoma (Knowles et al, 1995). Nonetheless, the morphological finding alerts pathologists to the possibility of an incipient lymphoma. Disease at this stage often can be reversed by elimination of immunosuppressive treatment and/or acyclovir administration. In their most devastating form, LPDs are reflected as a large-cell (centroblastic or immunoblastic) nonHodgkin's lymphoma in which is found a monoclonal population of malignant B cells. Lesions of this type can occur at localized sites such as the gastrointestinal tract or brain, and polyclonal infiltrates are found in other more distant organs. Thus, the clinical and patho-

Epstein-Barr Virus

logical evidence strongly suggests that the lymphoma evolves as a clonal population of cells from the more complex polymorphic disease. These lymphomas only rarely respond to elimination of immunosuppressive drug treatment. Southern blot analysis of the EBV DNA in these cells shows that the viral genome is monoclonal and latent in the form of a circular episome. Typically, lymphomas develop in older patients long after initiation of transplantation and commonly involve the central nervous system and abdominal digestive tract.

N O N - H O D G K I N ' S LYMPHOMA EBV is implicated in either the causation or development of B cell lymphomas in the post-transplantation lymphoproliferative disorders, and in non-Hodgkin's lymphomas occurring in AIDS and a variety of other immune deficiency states. It has also been strongly associated with Hodgkin's disease and the Ki-1 positive anaplastic large-cell lymphomas that share the CD30 Ki antigen with Hodgkin's disease and may be of T cell origin (DiGiuseppe et al, 1995) (Figure 9.10A-D). Most

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tumors occurring in patients in an immunosuppressed condition are the so-called high-grade non-Hodgkin's lymphomas. The evidence linking EBV to these tumors is based upon the findings of molecular studies conducted in many different laboratories during the 1990s. However, the infrequent presence of EBV genomic products in spontaneously developing non-Hodgkin's lymphoma in nonimmunocompromised persons, as well as the less than absolute association of the disease with evidence of infection in the immunodeficient patient, raises considerable doubt as to the intrinsic pathogenic role of the virus in tumorigenesis. The common finding of both latent and replicative virus infections in the tumor cells of the immunodeficient patient is compatible with a loss of immune control (Birx et al, 1986). Three different patterns of EBV gene expression are found in various of the different morphologic types of lymphoma. This observation, at present, defies explanation from the perspective of a possible role of EBV gene products in the pathogenesis of these tumors. Does EBV predispose to either the development or clinical progression of non-Hodgkin's lymphoma? In my opinion, the evidence, although incomplete, argues for an affirmative response. Of paramount consideration is the established increase in frequency of these

^t ^ - ^ ^ ^ ^

f

| ^ [ ^ ' # ^

*i§L. ^ % # FIGURE 9.10 (A,B) Anaplastic large-cell lymphoma. Immunochemistry demonstrated the CD30Ki antigen in tumor cells. (C,D) Examples of Reed-Sternberg cells in Hodgkin's lymphoma. Reprinted with permission and through the courtesy of J. Lunde, MD.

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lesions in immunocompromised states accompanied by the finding of EBV latency and gene expression in a substantial proportion of tumor cells. These tumors commonly are aggressive and occur in extranodal sites and atypical locations (such as lymphomas in the brain of patients with AIDS) (Katz et al, 1986; Chang et ah, 1993; Morgello, 1992). The EBV gene product, LMP-1, has an oncogenic role in B cell lymphoma of the immunosuppressed patient. It seems to act as a transmembrane signaling protein that interacts with intercellular transduction molecules, thus mediating transformation (Liebowitz, 1998). Recent additional evidence suggests that the cellular survival protein, bcl-2, is upregulated in the EBV-infected cell, thus inhibiting apoptosis. Infection of the tumor precursor cell appears to occur before the onset of cellular proliferation, inasmuch as the latent episomes in the cell are monoclonal. It is likely that enhanced mitotic activity and inhibition of apoptosis predispose to the diverse cytogenetic aberrations that characterize the tumors at the time of pathologic diagnosis. In turn, these major changes in the cell genome most probably contribute to tumor progression and the aggressive malignant clinical features of the lesions. While EBV may not be the spark that kindles the fire, it may be the oxygen that turns a smoldering flame into a raging inferno. Infection of T cell lymphomas by EBV is now well documented, but detailed systematic information is lacking both with regard to the identity of the infected cells and the expression of the viral genes (Su et ah, 1991; Ott et al, 1992). As noted above, the C3 complement receptor serves as the viral receptor on both B and epithelial cells, but current evidence suggests that this receptor is not present on T cells. Are there then other, still uncharacterized, EBV receptors present on T cells, or are the C3 receptors so sparsely distributed on the cells that they are undetectable with current technology? Alternatively, could receptors be present on progenitor cells and not on the dedifferentiated tumor cells studied by the pathologists in the advanced tumor? Answers to these questions are lacking at present. Using PCR, Tokunaga et al (1993) found EBV DNA in the tumors of 21 out of 96 cases of adult T cell leukemia/lymphoma. EBV EBER-1 and LMP-1 were demonstrated in the cells of the majority of these cases by either in situ hybridization or immunohistochemistry Presumably, this disease can be attributed to HTLV1 infection since the patients resided in the geographic central focus of HTLV-1 in the southern Japanese island of Kyushu. Less information exists with regard to the association of the sporadically occurring systemic and cutaneous T cell lymphomas unrelated to HTLV that occur worldwide (Cheng et al, 1993).

H O D G K I N ' S DISEASE (HD) The association of EBV infection with HD is now well established, yet the role of the virus in causation and progression of the disease is obscure. This is a particularly interesting issue, inasmuch as EBV infection of the tumor does not result in a shortened lifespan or a more aggressive clinical course (Fellbaum et al, 1992). Several unresolved questions continue to obfuscate the problem. Is HD in reality not one but several different disease processes having as the common denominator the Reed-Sternberg cell? Is HD an infectious process that terminates in an uncontrolled malignancy? Do the various morphologic forms of the disease represent a continuum of biologic responses to a hypothetical infectious agent, or do they reflect differing patterns of response to a single etiological agent? What is the biologic significance of the Reed-Sternberg (RS) cell, and what is its origin? Is the fact that the RS cells are aneuploid and monoclonal an indication of the cell's malignant potential despite its rarity in some forms of HD? Epidemiological evidence provides support for an infectious etiology for at least one of the morphologic types of HD, that is, the lymphocyte predominant type (LP). This form characteristically develops in males during the late teenage years or the twenties. It tends to occur in those with a past history of IM and in members of relatively small families having a higher level of educational attainment and socioeconomic status. These latter demographic features are consistent with the pattern of infectious disease that occurs with devastating severity in those protected from endemic infections early in life (e.g., paralytic poliomyelitis). Three other morphologic forms of HD commonly occur: nodular sclerosing, mixed cellularity, and lymphocyte depleted types. While their epidemiology is complex, HD, manifested as these morphological types, tends to occur in somewhat older persons exhibiting none of the demographic associations exhibited by the LP form. Indeed, the mixed cellularity and lymphocyte depleted types usually develop in patients older than 50 years of age, and the peak incidence is in the 8th and 9th decades of life. Cytomorphological and in situ hybridization studies in adult patients with HD who have no known risk factors demonstrate conclusively an association of RS cells and RS-variant cells (so-called Hodgkin's or H cells) with latent clonal EBV genomic components, specifically EBER-1 and LMP-1 (Brousset et al, 1993). No evidence of a replicative infection is found, and the viral genome appears to be monoclonal. This observation implies that the initial infection developed in the

Epstein-Barr Virus

primordial cells of the tumor and that RS and H cells are derived from a common progenitor cell. However, the prevalence of EBV infection appears to be highest in the mixed cell type, intermediate in the nodular sclerosing HD, and uncommon in the LP type (Shibata . ei al., 1991b). In these forms of the disease, an occasional lymphocyte may carry the viral genome (Khan et ah, 1992). Recently, it was also found in the rare primary cutaneous HD (Kumar et al, 1996). These findings argue against the relevance of a pathogenic association of the LP form with IM, and thus EBV infection as suggested in the discussion. They further indicate a stronger association of EBV infection with the more malignant types of disease that tend to occur in older persons. On the other hand, in the rare cases of HD in the pediatric age range, the association with EBV is greatest in children under the age of 4 years. In one study, only 21% of those in the 10-15-year age group were positive (Andriko ei al, 1997). Evidence of rampant EBV infections are found in HD patients with advanced HIV-1 infections (Rubio, 1994). In the tumor, RS and H cells invariably exhibit latent non-episomal infection with EBV (Siebert et al, 1995; Herndier et al, 1993; Carbone et al, 1996). There appears to be an increased prevalence of HD in AIDS, and the disease tends to be more malignant. Prior to modern drug therapy, HD patients with AIDS had a relatively short survival time. This combination of diseases is commonly terminated by overwhelming opportunistic infections, but it is not known whether EBV contributes to the fatal outcome. Advanced HD is often accompanied by a profound degree of T cell-mediated immunosuppression. This defect is thought to be secondary either to deranged antigen processing and presentation by the HD macrophage or, alternatively, T cell unresponsiveness to IL-1 (Jandl, 1996). Whatever the mechanism, HD patients exhibit defects in delayed hypersensitivity in recall skin tests, such as dinitrochlorobenzene sensitization, and manifest an increased tolerance to skin grafts. In view of these findings, one might ask whether a deficiency in T cell immunity predisposes to EBV infection in those with HD. As noted above, RS and H cells exhibit EBV EBER-1 and LMP-1 gene activation, although information on gene copy number in these cells is lacking. It is intriguing to speculate that LMP-1 may contribute to the oncogenicity of the RS and H cells. The products of LMP1 have a diversity of transforming effects when transfected into fibroblasts and B cells in vitro. LMP-1 alters cell growth in vitro and causes the loss of contact inhibition and promotes anchorage independence. By activating the bcl-2 gene, apoptosis is inhibited, thus tend-

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ing to increase the lifespan of these cells (Khan et al, 1993).

NASOPHARYNGEAL C A R C I N O M A (NPC) Undifferentiated carcinomas of the nasopharynx occur with unusually high frequency in residents of southeast China and in emigrant Chinese elsewhere. They comprise approximately 20% of the cancers occurring in these people. Similar tumors are found in the native population of Greenland and in foci in both Africa and the Mediterranean Basin. Undifferentiated nasopharyngeal carcinomas are rarely seen in Caucasians in developed countries of the world. In these areas, the pharyngeal carcinomas are almost invariably comprised of well-differentiated keratinized squamous epithelium, accompanied by variable infiltrates of lymphocytes (Ablashi and Levine, 1983). Latent EBV infections are consistently demonstrated by in situ hybridization in the cells of these undifferentiated tumors in endemic regions of China. In contrast, evidence of infection is infrequently found in the squamous epithelial cells of the well-differentiated nasopharyngeal tumors developing in Caucasians. Latent infections by EBV also do not occur in normal squamous epithelium after a naturally occurring pharyngeal infection. Additional evidence etiologically linking EBV with these tumors is the demonstrated clonal nature of both the tumor cells and the virus within them (Raab-Traub, 1992; Pathmanathan et al, 1995). Almost invariably, exceptionally high levels of circulating antibodies reactive with specific EBV proteins are found in the blood serum of healthy persons destined to develop the tumor. Despite the consistent association of EBV with the undifferentiated nasopharyngeal carcinomas, the contribution of the virus to the events of tumorigenesis remains uncertain. Epidemiological studies suggest, but fail to prove, an etiologic role for dietary factors, the most likely of which is the common consumption of heavily salted fish, particularly at an early age in life (Yu, 1991). The importance of this food or other environmental factors in the pathogenesis of the tumor is suggested by the dramatic decrease in prevalence of nasopharyngeal carcinomas among first- and second-degree Chinese immigrants to North America, who consume a more Western diet (Table 9.4) (Hildesheim and Levine, 1993; Flores et al, 1986). These findings argue against, but do not entirely exclude, a genetic contribution to carcinogenesis, and at the least suggest a cultural influence. The WHO classification assigns tumors of the nasopharynx into three categories based on morphologic

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TABLE 9.4 Incidence of Nasopharyngeal Carcinoma Among Chinese by Sex and Residence No. cases/1 x 10^ Hong Kong Chinese males Chinese females Los Angeles (males) Foreign-born Chinese U.S.-born Chinese U.S.-born Caucasians Canada (males) Foreign-born Chinese 2nd- and 3rd-generation Chinese Caucasians

30 13 14 3.5 0.6 20 1.3 0.22

differentiation of the malignant components. The first of these categories is the well-differentiated keratinizing squamous carcinoma, whereas WHO 2 and 3 represent the undifferentiated carcinomas. The epithelial cell component in these latter tumors is characterized by relatively uniform cells with vesicular nuclei and prominent nucleoli. These cells often form syncytia that can simulate Reed-Sternberg cells. Inflammatory cell infiltrates comprised of small numbers of plasma cells and eosinophils, as well as a predominant population of small T lymphocytes, are found in the lesions. The tumors exhibit two general morphologic patterns that appear to have no influence upon prognosis. The first, termed "Regaud," is characterized by accumulation of neoplastic epithelial cells into the nests and cords interspersed with the inflammatory cell infiltrates (Figure 9.11A,B). In the second pattern, termed "Schmincke,'' the malignant epithelial cells are intermixed with the predominantly lymphoid infiltrates of cells (Figure 9.11C). The latter tumor type must be distinguished from a malignant lymphoma, which it occasionally resembles. Although the clinical and pathologic evidence is limited, NPCs appear to develop from foci of noninvasive epithelial hyperplasia that are presumed to evolve from dysplasia and carcinoma in situ. Virological studies using in situ techniques demonstrate the EBV-encoded RNA (EBER) and the transforming protein LMP1 in dysplastic and noninvasive carcinoma cells, but not in the lymphoid elements that accompany the epithelial components (Brousset et al, 1992). As would be expected, the pharyngeal mucosal tissue from normal control individuals reveals no evidence of infection (Pathmanathan et al, 1995). The same constituents of EBV are consistently found in high copy number in cells of the invasive advanced tumors. In both the pre-

FIGURE 9.11 (A) The "Regaud" morphological form of a poorly differentiated N P C The cytokeratin reactive epithelial cells (B) are arranged in nests interspersed with lymphocytes. (C) The ''Schmincke" morphological form of N P C Although epithelial cells are present, the infiltrating lymphocytes predominate in this poorly differentiated lymphoma. Reprinted with permission and through the courtesy of R. Grenko, MD.

invasive and advanced lesions, the EBV DNA is not integrated into host cell DNA and is found as a circular episome in the cell. Molecular studies have shown that the virion population in both the preinvasive and invasive tumors is clonal. Thus, the malignant cells would appear to be infected with the progeny of a single virion that may have unique biological properties. How the virus and the presumptive environmental fac-

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tors interact is currently a matter for speculation, since no experimental information is available. In Caucasians, lymphoepithelial tumors comprised of variable amounts of undifferentiated carcinoma and squamous carcinomatous elements have been described in the floor of the mouth, tongue, soft palate and uvula, nasal cavity, upper airways and larynx, the upper digestive tract, and the genitourinary tract (Tseng et al, 1997). But, in some of these lesions an association with EBV has not been established (GuUey et al, 1995).

LYMPHOEPITHELIOMATOUS GASTRIC C A R C I N O M A The etiology of gastric carcinoma is obscure, although host genetic predisposition and environmental factors (including diet) are important influencing factors in the causation of these tumors. While the epidemiology and pathogenesis of gastric cancer in general is beyond the scope of this discussion, the possible role of EBV in the pathogenesis of the lymphoepitheliomatous type gastric carcinoma is considered here (Figure 9.12A). Burke and his associates (1990) detected EBV DNA sequences in the malignant epithelial cells of the rare lymphoepitheliomatous poorly differentiated gastric carcinomas (Shibata et al, 1991a). These tumors comprise approximately 4% of the gastric cancers occurring in Japan, where cancer of the stomach continues to be endemic and relatively common (Watanabe et al, 1976). In situ hybridization of these lesions using an EBV-encoded probe complementary to the small early RNA of the virus (EBER) demonstrated infection of the malignant epithelial cells in about 85% of the lesions (Matsunou et al, 1996) (Figure 9.12B,C). Little or no evidence of infection of the infiltrating lymphocyte population was found. Further studies have demonstrated the monoclonality of the virus and its presence as a latent episomal agent in very early lesions as well as in advanced and metastatic tumors (Harn et al, 1995). Additional studies have now shown that EBV infection is not limited to carcinoma with lymphoid stroma, but occurs in 5 to 15% of carcinomas of all morphological types in Japan and in the United States (Shibata and Weiss, 1992; de Bruin et al, 1995; GuUey et al, 1996).

SINONASAL TUMORS Non-Hodgkin's disease, lymphoproliferative disorders of natural killer N K / T cell derivation in the nasal cavity and paranasal sinuses, comprise only a small

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B

*:.^-' • C

^* •-

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FIGURE 9.12 (A) Superficial spreading of lymphoepitheliomatous gastric adenocarcinoma. Note the dense lymphocytic infiltrates with lymphoid follicles. (B) Interface between normal and dysplastic gastric mucosa showing reactivity of the dysplastic elements with EBER antibody of EBV by immunohistochemistry. (C) EBER antibody reactivity of the epithelial elements of a gastric carcinoma. Panels B and C reprinted with permission from GuUey et al. (1996) and through the courtesy of M. Gulley, MD.

proportion of the extranodal lymphomas (fewer than 8%) occurring in the Orient and North America (Petrella et al, 1996). They commonly present clinically as the so-called lethal midline granuloma, a lesion characterized by ulceration and necrosis of the tissues infiltrating in and around the nasal cavities. When the lymphoid cells of the tumor are polymorphic and

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lymphoreticular in character, the lesion is often termed polymorphic reticulosis, particularly when there is an angiocentric pattern. These tumors are clinically aggressive, and patient survival can usually be measured in months. Systematic studies of these unique but rare neoplasms has demonstrated a strong association with latent EBV infection in the clonally derived N K / T cells of the lesions (Jones et al, 1988; Cohen ei ah, 1980; Richel ei al, 1990; Tomita et al, 1995; Arber et al, 1993; Kanavaros et al., 1993). The virus, like its host cells, is clonally derived, an observation suggesting that infection occurred at an early stage in tumorigenesis. Since the infected cells consistently exhibit EBER and LMP-1 when analyzed by in situ techniques, one is obliged to conclude, at least preliminarily, that these oncogenic proteins play an intrinsic role in neoplastic formation (Harabuchi et al, 1990,1996; Arber et al, 1993; Ho et al, 1990). The observations summarized above must be interpreted in the light of studies of lymphocytes in routinely excised nasal polyps. In work carried out in Hong Kong, 85% of the B and T cells in polyps exhibited EBV protein (Tao et al, 1996), and PCR studies of nasal and oral secretions have shown that over 50% of adults have within these tissues actively replicating EBV.

PULMONARY DISEASE During the acute stages of IM, the bronchial epithelial cells are extensively infected with EBV. Chronic infection of the respiratory mucosa also occurs commonly as shown by various virus detection techniques, including in situ hybridization studies on exfoliated cells (Lung et al, 1985). Pulmonary disease, in the form of interstitial pneumonia and lymphoid hyperplasia in the lung, is found in approximately 5% of patients during the acute stages of IM (Mundy, 1972; Sriskandan et al, 1996). Hilar lymphadenopathy occasionally is an accompanying feature (Fermaglich, 1975; Evans, 1967; Baehner and Shuler, 1967). Severe consolidative pneumonia occurs in fatal IM (Custer and Smith, 1948). A diffuse chronic interstitial pneumonitis attributed to EBV in two febrile patients was described by Schooley and his colleagues (1986). EBV infection of pneumocytes and airway cells is demonstrable in over 10% of cases of diffuse interstitial pneumonia examined at autopsy (Oda et al, 1994). In addition, viral capsid antigen indicative of an acute infection was found in the lung tissue of 6 of 12 cases of diffuse interstitial fibrosis of diverse etiologies (Quddus et al.

1997). The importance of the infection in these cases, if any, is unknown. EBV infections of the lymphocytes in lymphoid interstitial pneumonitis (LIP) has been documented by in situ hybridization both in adult patients with a spontaneously developing form of the disease (Barbera et al, 1992) in and children with AIDS-associated LIP (Rubinstein et al, 1986). LIP in the non-HIV-infected patient is a rare condition developing spontaneously in persons of all ages, but most commonly in middle-aged adult women (male:female ratio = 1:5). It is often, but not invariably, associated with a variety of conditions of immune dysregulation, including Sjogren's syndrome, autoimmune hepatitis, pernicious anemia, and myasthenia gravis. Pathologically, LIP is characterized by the presence of a diffuse heterogenous interstitial and peribronchial infiltration of B lymphocytes, plasma cells, and histiocytes. Among 14 selected cases of LIP, 9 had EBV in B cells, but lung tissue from 2 of 10 controls with interstitial fibrosis were also positive (Barbera et al, 1992). About 75% of children with AIDS develop LIP characterized by interstitial infiltration of lymphocytes, predominantly of the CD8+ lineage (Lin et al, 1988; Morris et al, 1987; Guillon et al, 1988). Often, there is a nodular character to the lymphoid accumulations in the lesions that are commonly associated with the walls of the bronchus. Whether or not this lymphoid hyperplastic lesion is pathogenically consistent with the sporadically occurring LIP in the adult is, at present, unclear, but almost invariably, HIV-infected patients exhibit polyclonal hypergammaglobulinemia (Joshi et al, 1985). High titers of EBV capsid antibody are found frequently in the serum. In situ studies by Rubinstein et al (1986) demonstrated EB genomic material in the lymphoid elements of four biopsies from six patients with AIDS manifesting the typical pathological picture of lymphoid hyperplasia. The features of LIP are considered in additional detail in Chapter 16. Fewer than 50 cases of large-cell immunoblastic B lymphomas developing in the pleural cavity after surgically induced pneumothorax for pleural tuberculosis have been reported (Ohsawa et al, 1995). The majority (but not all) of these cases with EBV infections originated in Japan, where this form of treatment for tuberculosis was commonly used in the past. Fukayama (1994) reported elevated EBV LMP-1 and EBNA-1 antigens in tumor cells from all five of the studied patients. EBV infections have also been found in tumors of this type diagnosed in Europe. Lymphoepitheliomatous carcinoma of bronchial origin occurs uncommonly. About 4% of the lung cancers resected surgically in Hong Kong among both smokers and nonsmokers are so classified, but the prevalence in

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Caucasians is much lower (Pittaluga et ah, 1993; Butler et aU 1989; Higashiyama et al, 1995; Chan et al, 1995). An EBV-associated tumor of the lung in an 8-year-old child was reported by Curcio et at. (1997). As in the pharynx, these tumors are comprised of variable-sized islands of poorly differentiated epithelial tumor cells intermingled with lymphocytes and plasma cells. In situ hybridization studies consistently show EBNA in epithelial cells, but not in the lymphocytes. Similar studies of the routinely resected traditional morphological types of bronchogenic carcinomas have consistently proven negative.

LYMPHOMATOID GRANULOMATOSIS This poorly understood lesion was initially described by Leibow and his associates (1972). It is characterized by (i) polymorphic lymphoid infiltrates populated predominantly by T cells and a lesser number of B cells; (ii) angiitis as reflected in the transmural involvement of medium-sized veins and arteries by a lymphoid infiltrate; and (iii) necrosis, resulting in the so-called (but mischaracterized) granulomatosis. The overlap of this lesion with angiocentric T cell lymphomas is vaguely defined, and the two lesions are no doubt confused on occasion (Peiper, 1993). Other possible sources for confusion are the so-called T cell-rich B cell lymphomas (Ramsay et ah, 1988). EBV infection is consistently found in the minor B cell components of the pulmonary lesions of lymphomatoid granulomatosis, but the biological state of the viral genome and its expression have not yet been characterized (Guinee et al., 1994; Haque et al, 1998). Using in situ hybridization, Myers et al (1995) found the EBV DNA to be restricted to the large atypical B cells. T cells were not infected. Lymphomatoid granulomatosis is a rare infiltrative lesion of the skin, lung, liver, kidney, and nervous system in which atypical T lymphocytes, plasma cells, and macrophages accumulate with a distinct relationship to small blood vessels. They are considered by some to be the sinonasal tumors described above. Although believed to be of T cell origin, recent evidence suggests that they may be of natural killer (NK) origin (Salvio, 1996). Interestingly enough, the lymphoid cells in these obscure disease processes are often infected by EBV, as shown by in situ hybridization studies and PCR (Harabuchi et ah, 1996; Katzenstein and Peiper, 1990). Thus, the susceptibility of NK cells requires further study. On the other hand, the large atypical cells in the pulmonary lesions of lymphomatoid granulomatosis prove to be EBV-infected B cells located in a sea of

reactive T cells (Myers et al, 1995). Similarly, the infection has now been found to occur in B-lineage cells of the equally obscure angioimmunoblastic lymphadenopathy and its related lymphomas (Weiss et al, 1992).

INFLAMMATORY PSEUDOTUMORS Inflammatory pseudotumors in lymph nodes, spleen, and liver are commonly infected by EBV as demonstrated by in situ hybridization approaches. The spindle nondendritic reticulum cells are predominantly involved. The importance of this finding remains to be established (Arber et al, 1995; Selves et al, 1996).

SJOGREN'S SYNDROME A N D SALIVARY G L A N D T U M O R S In 1933, the Swedish ophthalmologist H. S. C. Sjogren described the syndrome that now bears his name. It predominantly affects middle-aged women and is characterized by keratoconjunctivitis, sicca (dry eyes), and xerostomia (dry mouth) and is usually accompanied by rheumatoid arthritis. Pathologically, Sjogren's syndrome is characterized by replacement of the involved salivary and lacrimal glands by a dense infiltrate of B cells, often organized into germinal centers, accompanied by T cells, plasma cells, and histiocytes (Figure 9.13A,B). Variable numbers of the so-called epimyothelial islands further typify the lesion. These latter structures represent the residue of the atrophic or apoptotic acinar and ductal epithelial cells. They exhibit varying degrees of dedifferentiation and mitotic activity, resulting in an appearance that can suggest malignancy. EBV DNA is detected focally in the ductal epithelium of the normal adult lacrimal gland, though it is not present in acinar cells (Pflugfelder et al, 1993). A similar distribution of virus genome most probably occurs in the major and minor salivary glands in Sjogren's disease. However, detailed sensitive molecular localization studies have yet to be carried out on these organs. In Sjogren's syndrome, evidence of active virus replication is found in epithelial cells of the salivary and lacrimal glands, and EBV can be recovered from saliva. The infectivity status of the B lymphocytes that characterize these lesions is unclear (DiGiuseppe et al, 1994; Fox et al, 1986; Chan et al, 1994).

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'^VZ

FIGURE 9.13 Parotid gland lesions of Sjogren's syndrome. (A) Epithelial islands are infiltrated and surrounded by dense accumulations of B lymphocytes. In (B) the epithelial island is reticulated and hyalinized. Reprinted from Foote and Frazell (1954).

While Sjogren's syndrome clearly is considered to be an autoimmune process, the skill of the pathologist is occasionally challenged by the necessity to differentiate the lesions of this disease from the much rarer B cell lymphomas that infrequently occur in the salivary glands. A second equally difficult challenge is diagnostic assessment of the Sjogren's lesion for the poorly differentiated lymphoepithelial tumors that occur in these same glands. These lesions strikingly resemble the EBV-associated pharyngeal lymphoepithelial tumors. They predominantly but not invariably (Kotsianti et al, 1996), occur in Orientals and Native American residents of Greenland. In situ DNA hybridization of the salivary glands in these cases has consistently demonstrated evidence of episomal EBV infection of the poorly differentiated tumor cells but not the lymphocytes (Hamilton-Dutoit et al, 1991). Other investigators have detected EBER-1 in lymphoid infiltrates (Wen et al, 1996). Additional studies by Tsai et al (1996) have failed to demonstrate similar viral constructs in 49 other morphologic types of salivary gland cancers. The observation establishes quite clearly the specificity of EBV infection in the poorly differentiated carcinomas (Saito et al, 1989).

While a cause-and-effect relationship between EBV and the development of Sjogren's disease and the epithelial tumors of the lacrimal and salivary glands has not been established, the admittedly incomplete evidence available at present suggests that the lymphoid response in these unique lesions may focus on EBV virus proteins or altered cells in which the virus resides. Could it be that the lymphoid infiltrates introduce an element of immune control of tumor growth, a proposition consistent with the relatively prolonged survival time of patients with these tumors (Tsai et al, 1996)? Whatever its pathogenetic role in neoplasia, EBV virus would not appear to be the sole etiological factor.

HAIRY LEUKOPLAKIA (HCL) HCL is an elevated, verrucous, and somewhat "hairy" whitish proliferative, but nonmalignant, epithelial lesion developing on the lateral surfaces of the tongue and occasionally at other sites in the oral pharynx. EBV is believed to be the etiological agent. HCL

Epstein-Barr Virus

was initially described among homosexual males with AIDS (Greenspan et ah, 1984) but is now known to develop occasionally in recipients of organ allotransplants with iatrogenic immunosuppression (Itin et ah, 1988; Epstein et al, 1988) and rarely among seemingly immunocompetent adults. EBV is known to replicate in the epithelium of the tongue in both immunocompetent and immunocompromised patients who lack clinically evident HCL lesions, and it is claimed that EBV receptors are located on the lateral aspects of the tongue, but this observation requires confirmation (Greenspan et ah, 1985; Corso et ah, 1989). Indeed, replication sites for EBV in the oropharynx must be common. Ferbas et ah (1992) recovered ElBV from the oral pharyngeal secretions of almost 50% of HIV-positive homosexual males, and 16% proved to be HIV-1 seronegative. In typical HCL, luxuriant EBV replication occurs, as established by the consistent demonstration of EBV virions in cells of the lesion, accompanied by expression of LMP-1 and EBNA and the presence of

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liner viral DNA. In addition, the lesions respond to acyclovir treatment. About 25% of HIV-1-infected persons develop the lesion; it seems to be a prognosticator barkening the arrival of AIDS. In one study, 30% of HIV-infected patients with HCL developed overt AIDS within a 3-year period, but the presence of lesions does not correlate with CD4+ cell numbers or other risk factors for AIDS. The tongue lesions are characterized by prominent acanthosis and parakeratosis with loose accumulations of keratin on the surface. This gives the lesion the "hairy" appearance noted clinically (Figure 9.14A,B). A spectrum of structural features result in flat lesions in some cases and corrugation of the surface in others. Squamous epithelial cells with intranuclear inclusions characterize the lesion. The majority of inclusion-bearing cells are located in the stratum spinosum. These cells also typically exhibit a ballooning koniocytosis with an eosinophilic ground-glass appearance to the cytoplasm. Fernandez and colleagues (1990) describe

FIGURE 9.14 Hairy cell leukoplakia showing marked acanthosis and parakeratosis with the resulting superficial ''hairy" projections (A). In (B) the slightly corrugated surface of the lesion results from parakeratosis. Ballooned keratinocytes are seen. (C) Keratinocytes of the superficial spinous layer display intranuclear inclusions (arrow) and (D) ground-glass nucleoplasm with a steel-grey hue after hematoxylin and eosin staining of tissue sections. Reprinted with permission from Fernandez et al. (1990) and through the courtesy of J. Fernandez, MD.

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three characteristic inclusions. The first is the typical eosinophilic Cowdry type A inclusion that is surrounded by a clear halo (Figure 9.14C). In the second form, the nucleus exhibits a ground-glass eosinophilic appearance with clumped chromation adjacent to the periphery of the nuclear membrane (Figure 9.14D). These authors also describe a third type having a steelgrey ground-glass nucleoplasm and a clumped, peripheral chromation. Ultrastructurally, the nuclear inclusions characteristically exhibit nonenveloped virions, as is typical with other herpesviruses (Fowler et ah, 1989). Indeed, the nuclear inclusions described above are morphologically similar to those seen in herpes simplex (herpesvirus type 1) infection. However, studies of numerous HCL lesions appear to have ruled out non-EBV herpesviruses. Immunohistochemistry and in situ hybridization studies suggest that EBV can only be found in the superficial epithelial layers of the HCL lesion, but by using PCR in situ hybridization Brandwein et al. (1996) demonstrated EBV DNA in basal and parabasal cells of the epithelium. The finding of the LMP-1 and EBNA-1 proteins in mucosal cells is consistent with a proliferative effect attributable to the oncogenic products of EBV. It also suggests that EBV may lie latent in the epithelium of the tongue and other epithelial cells of the aerodigestive tract to become activated when immune repression occurs. Recently, Palefsky and associates (1996) detected consistent compositional changes in the amino acid motif of LMP-1 in these infected cells. Since the same alterations are found in the EBV-infected cells of nasopharyngeal carcinoma, these

authors hypothesized that modifications in these proteins may have oncogenic potential. However, HCL lesions do not appear to predispose to the development of lingular cancer.

VIRUS-ASSOCIATED HEMOPHAGOCYTIC SYNDROME Two decades ago, Risdall et al. (1979) described 19 childhood and adolescent patients with fever and diverse constitutional symptoms whose bone marrow exhibited histiocytic hyperplasia and hematophagocytosis. Active infection with members of the herpesvirus family were demonstrated in 14 of the 19 patients. Although cytomegalovirus was the most common infection documented in this series, more recently, the syndrome commonly has been associated with EBV. Significant hematophagocytosis is now recognized to occur in three categories of patients. The first group reflects a rare familial predisposition, in which there is an overlap with the fatal infectious mononucleosis XLP syndrome. Hematophagocytosis almost universally is found at autopsy in patients with this condition (Mroczek et al, 1987; Christensson et al, 1987). T cell lymphomas characterize the second group. In these patients, nonmalignant histocytes engorge erythrocytes, but the malignant T cells prove to be latently infected with EBV in a ringed episomal form (Sullivan et al, 1985; Chen et al, 1991; Wong et al, 1996; Jandl,

FIGURE 9.15 (A) Lymph node with hematophagocytosis in a 39-year-old man. Note the depletion of lymphocytes and the expansion of the sinusoids. (B) Liver of a 65-year-old man with prominent hematophagocytosis by littoral cells. The only other morphological abnormality is mild steatosis of the liver parenchymal cells. Reprinted with permission from Gaffey et al. (1993) and through the courtesy of M. Gaffey MD.

Epstein-Barr Virus

1996). The third group of patients manifest acute viral infections (Wilson et ah, 1981; Look et al, 1981; McKenna et al, 1981; Reisman and Greco, 1984). Of these, EBV again proves to be the most common. In the childhood cases described by Gaffey et al. (1993), in situ hybridization showed the infected cells to be small lymphocytes, but an occasional immunoblast was also reactive. The cell types were not further established. In these cases, hematophagocytosis was consistently found in the bone marrow, lymph nodes, liver, and spleen where infected lymphocytes were also located (Figure 9.15A,B). Ross et al. (1991) reported the clinical and pathological features of a severe febrile systemic illness in which a chronic EBV infection was accompanied by hematophagocytosis demonstrable in the spleen. Recently, Su and colleagues (1994) described a fulminating hematophagocytosis syndrome in 15 previously healthy pediatric-age group patients. Of great interest was the consistent demonstration of EBV RNA in T cells as established by immunolabeling. Because of its sporadic occurrence and the difficulty in recognizing hemophagocytosis pathologically, little fundamental mechanistic information has accumulated to explain the phenomenon. One must conclude that it is the consequence of activation of macrophages by the infection, but the possible role of autoantibodies to erythrocytes elaborated in response to infection remains a pathogenic consideration requiring exploration.

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Epstein-Barr Virus WHO (1969). Histopathological definition of Burkitt's tumour [memorandum]. Bull. WHO 40, 601-607. Wilson, E., Malluh, A., and Stagno, S. (1981). Fatal Epstein-Barr virus-associated hemophagocytic syndrome. /. Pediatr. 98, 260. Wong, K., Chan, J., and Wong, C. (1996). A study of the possible etiologic association of Epstein-Barr virus with reactive hemo-

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phagocytic syndrome in Hong Kong Chinese. Hum. Pathol. 27, 1239-1242. Yu,M. (1991). Nasopharyngeal carcinoma: Epidemiology and dietary factors. lARC Sci. Publ. 103, 3 9 ^ 7 . Ziegler, J. (1981). Burkitt's lymphoma. New Engl. J. Med. 305, 735-745.


C H A P T E R

10

Varicella-Zoster Virus (VZV) years of general practice. This work represents the only published systematic description of the epidemiology and natural history of the condition as it occurs outside the hospital setting. The clinical observations of von Bokay (1909) first raised the possibility of a relationship of herpes zoster in the adult to systemic varicella in childhood. Physicians subsequently noted the occurrence of chickenpox in children exposed to zoster patients, an observation substantiated by experimental induction of the disease in children inoculated with fluid from zoster vesicles. The association was further substantiated by the histological studies of Lipschiitz (1921), who documented the morphological similarity of the lesions in the two conditions. Definitive virological, molecular, and immunological proof of this association ultimately followed isolation of VZV in cultured cells by Weller et al (1958).

INTRODUCTION AND HISTORICAL OVERVIEW 147 DISSEMINATED CHILDHOOD VZV INFECTION OF THE SKIN: CHICKENPOX 147 HEMORRHAGIC VZV INFECTIONS OF THE SKIN 149 CHRONIC VZV INFECTIONS OF THE SKIN 150 NERVOUS SYSTEM DISEASE 151

Herpes Zoster 151 Encephalopathies 154 EYE DISEASE 156 EAR DISEASE 158 PULMONARY DISEASE 158 DIGESTIVE TRACT DISEASE 159 LIVER DISEASE 159 RENAL DISEASE 160 TESTICULAR DISEASE 162 HEART DISEASE 162 JOINT, SYNOVIAL, AND MUSCLE DISEASES CONGENITAL VZV INFECTION 162 REFERENCES 163

162

INTRODUCTION A N D HISTORICAL OVERVIEW

DISSEMINATED C H I L D H O O D VZV INFECTION OF THE SKIN: CHICKENPOX

Few of us recall our initial encounter vvrith varicellavirus (VZV) in the form of chickenpox, but those of US who have experienced herpes zoster will not forget it. Long considered a benign right-of-passage for the youngster, varicella sporadically is responsible for significant disease if the infection occurs in utero or is acquired perinatally, during adulthood, or under circumstances of either immunosuppression or waning immunity. These latter conditions are of increasing importance during the current era of aggressive cancer therapy, organ transplantation, and AIDS. My initial serious thinking about varicella and herpes zoster related to a fortuitous visit with the late R. Edgar Hope-Simpson in Cirencester, England. He was clearly one of medicine's most accomplished family practitioners. He has effectively devoted his intellectual life to the epidemiology of common diseases in the semirural community of the British Isles that he serves. In an extraordinarily insightful paper, Hope-Simpson (1965) summarizes his observations during sixteen PATHOLOGY AND PATHOGENESIS OF HUMAN VIRAL DISEASE

The clinical features of chickenpox are known to most parents and are well described in countless publications. The pathological features of the lesions are less appreciated by pathologists, whose opportunities for examining the skin lesions are limited. In the typical case, the vesicles customarily develop over roughly a 4-day period in multiple waves over the thorax and abdomen some 9 to 21 days after exposure. To a more limited extent, they spread with the passage of time to involve the extremities and head. This central predominance of the skin changes may account for the common later occurrence of herpes zoster lesions in the dermatomes innervated by the thoracic and lumbar sensory neurons. Interestingly enough, sunburned and irritated skin tend to develop particularly prominent crops of vesicular lesions (Muckle, 1978). The characteristic distribution of 147


148


lesions and their cyclic sequence contrast with the eruption of smallpox, which appears as a uniform vesicular rash with a prominent distribution on the extremities, including the palms of the hands and soles of the feet (Chapter 26). The mechanism of acquisition and dissemination of VZV is not completely understood. Presumably, the infection is contracted by the respiratory route, followed by spread of the virus to systemic sites by means of the blood during the clinical latency period. Viremia has been variously documented 1 to 11 days before the appearance of the skin rash, and a virus-specific deoxythymidine kinase is found in the blood 3 to 5 days before the rash appears. Recurrent episodes of viremia presumably seed the endothelial cells of the skin capillaries where viral replication next occurs. Virus has been detected in the blood serum as well as in a variety of circulating cells (i.e., macrophages, B and T cells), but the biologically important mechanism for dissemination of the virus from one site to another is not known. The critical role of the endothelial cell in initiating subsequent viral involvement of the malpighian stratum (but not the stratum basalis) of the epidermis is becoming increasingly appreciated. Although the mechanisms are obscure, the endothelial lesions of the skin capillaries most probably generate vasoactive cytochemicals, locally resulting in the vascular flush that surrounds the developing lesion (the so-called dew drop on a rose petal). Infection of the individual epithelial cells of the skin results in cytoplasm "ballooning'' and the appearance of the intranuclear eosinophilic inclusions that characterize infected cells. The coalescence of adjacent infected "balloon" cells yields multinucleate cells (having, at times, as many as 30 nuclei) and acantholysis in the mal-

phagian stratum that leads to formation of the uniloculate serous fluid-filled vesicles that characterize the early lesion (Figure 10.1 A). The actual mechanistic basis for cell "ballooning" and cell fusion to form giant cells in varicella is unknown. Within days, polymorphonuclear leukocytes accumulate in the vesicle fluid. The superficial granular and keratinizing layers of the epidermis collapse, and the vesicle leaks and then becomes crusted (Figure lO.lB). Because the stratum basalis remains relatively intact and the dermal connective tissue is uninvolved, resolution of the vesicle evolves by epithelial regeneration without scarring (McCormick et al, 1969; McSorley et al, 1974). The immunologically normal child develops detectable humoral and cellular immune responses during the acute stages of the infection. Lymphocyte-mediated immune mechanisms appear to play a key role in resolution of the disease process, but there is no evidence of this response in the form of a mononuclear cell infiltrate in the resolving cutaneous lesions. However, in a wide variety of heritable and acquired cellular immune deficiency conditions, life-threatening systemic disease develops during the initial encounter with the virus, as will be discussed in more detail in what follows (Bullowa and Wishik, 1935; Hook et al, 1968). The importance and role of the humoral antibody in the resolution of skin lesions are uncertain, but antibody is believed to be the critical factor in protective immunity against reinfection. Among enrollees in an HMO in the northeastern United States, the rate of hospitalization proved to be 0.4% (Choo et al, 1995). In one recent study, one of every 200 children under 13 years of age required hospitalization (Yawn and Lydick, 1997). The overall

FIGURE 10.1 (A) Mature skin vesicle of chickenpox. The basal cell and the cornified layers are preserved. Infected cells in the stratum malphagi enlarge by forming cytoplasmic vacuoles — so-called "balloon cells/' The cells subsequently coalesce through the process of acantholysis to form the vesicle. (B) Inflammatory cells, debris, and serum fill the cavity of the vesicle. Regeneration of the basal epithelium occurs during convalescence without scarring.

Varicella-Zoster Virus

death-to-case ratio due to chickenpox is approximately 6.7 per 10,000 cases, but those over the age of 20 years and under 5 are at greatest risk. Thirty-five percent of children with Hodgkin's disease develop VZV infections, and almost a quarter of these manifest disseminated disease (Reboul et ah, 1978). Feldman et al. (1975) reported on the outcome of VZV infections in 60 children receiving cancer chemotherapy. A third of these patients developed visceral disease and 7% died. Although VZV infection clearly is potentially devastating for patients who are chronically ill or immunosuppressed, the majority of the children hospitalized with the complications of chickenpox are believed to be immunologically normal. In one study, 38% of hospitalized children had evidence of viral dissemination with encephalitis, pneumonitis, bacterial super-infection, and Reye's syndrome (Fleisher et al, 1981). Cheatham et al (1956) published detailed autopsy descriptions of the pathological findings in two young children dying with visceral VZV infection. The disease was disseminated and involved all major organs including the nervous system.

HEMORRHAGIC VZV INFECTIONS OF THE SKIN On rare occasions, the vesicular lesions of chickenpox become hemorrhagic during the acute stages of the

149

illness or later during the crusting stage (McKay and Margaretten, 1967). In these cases, thrombocytopenia and capillary fragility occur. The morbidity is low, and fatal complications are exceedingly rare. Purpura fulminans develops on occasion as a complication of VZV infection (Becker and Buckley, 1966). In some of these cases, evidence of intravascular coagulation is observed at autopsy, and hemorrhages are widespread in internal organs. In one series of eight children with purpura fulminans, three died shortly after onset of bleeding, and two additional patients required amputation of an extremity due to hemorrhagic gangrene (Stoesser and Lockwood, 1938). In a comprehensive frequently cited review, Charkes (1961) describes varicella-associated skin conditions that seem to be complications of superimposed bacterial infections (Gonzalez-Ruiz et al, 1995). Leukocytoclastic vasculitis is believed to account for hemorrhagic skin lesions in some patients (Cohen and Trapuckd, 1984; Singh and Deng, 1998) (Figure 10.2). The pathogenesis of hemorrhage in VZV skin infections is unclear, for many cases have not been critically evaluated by biopsy and other modern laboratory approaches. As noted above, thrombocytopenia is common in these patients. Using electron microscopy, Espinoza and Kuhn (1974) documented infection of megakaryocytes in the bone marrow of a fatal case, but additional studies of this phenomenon have not been reported. Intravascular coagulation undoubtedly is a

FIGURE 10.2 Hemorrhagic papulovesicular eruption on the leg of a liver allotransplant recipient. Examination of the dermis showed leukocytoclastic vasculitis, a lesion characterized by fibrinoid degenerative changes of the small blood vessels and infiltrates of leukocytes accompanied by accumulations of nuclear debris. Reprinted with permission from Singh and Deng (1998) through the courtesy of N. Singh, MD.

150


contributing factor in some cases. VZV infects endothelial cells of small blood vessels, and one can readily envision this to be a trigger for thrombosis and the consumption of coagulation products. Acquired protein C deficiency is a complication of the vasculopathy of VZV infections and appears to be an explanation for hemorrhage in some cases. Protein C is a vitamin K-dependent serine protease with antithrombotic properties that is activated by thrombomodulin/thrombin complexes on endothelial cells (Gerson et ah, 1993).

CHRONIC VZV INFECTIONS OF THE SKIN Chronic papillated and verrucous lesions develop in AIDS patients with herpes zoster (HZ). Histologically, there is a marked hyperkerative epidermal hyperplasia with prominent parakeratosis and variable degrees of

acanthoses (Figure 10.3). The cytolysis that contributes to vesicle formation often does not occur, although some lesions are focally necrotic. Keratinocytes with typical intranuclear inclusions and multinucleate cells are consistently found. These lesions are clinically and pathologically reminiscent of the verrucous hairy leukoplakia of the tongue due to EBV that occurs in patients with AIDS. On rare occasions, herpes simplex can produce similar skin changes. PCR analysis of exfoliated or biopsy tissue proves effective in establishing a specific etiological diagnosis (LeBoit et al, 1992). The pathogenesis of these VZV chronic skin lesions is obscure, but it is likely that attenuated cellular immunity plays an important role. Similar skin changes have been described in organ transplant recipients who are receiving immunosuppressive therapy. It has been suggested that the lesions are due to an altered pattern of viral gene expression. Nikkels and colleagues (1997) have hypothesized that

FIGURE 10.3 Verrucous epidermal hyperplasia characterized by marked hyperkeratosis, and pseudocarcinomatous hyperplasia of adnexal epithelium in this lesion caused by VZV. Note columns of the so-called molluscum bodies (A). Numerous multinucleated keratinocytes with the typical HZV nuclear changes are present within the hyperplastic epithelial nests at the base of the lesion (B). Keratinocytes at the sides of the papillations have coarse keratinohyaline granules similar to those seen in verruca vulgaris. An area at the base of the papulation shows laminar keratinization (C). Molluscum bodies form vertical columns in the cornified layer (D). This lesion should not be confused with molluscum contagiosum due to a poxvirus (see Chapter 26).

151


the lesions develop in patients infected with acyclovirresistant VZV strains (Hoppenjans et al, 1990).

NERVOUS SYSTEM DISEASE A diversity of lesions develop in the central nervous system as a consequence of VZV infection. Our understanding of the pathogenesis of these conditions is far from complete, in part because serious nervous system disease develops infrequently and autopsy materials are rarely available for study. Thus, modern tools to establish infection in cells were not applied to this problem until quite recently, and systematic studies using in situ techniques for the identification of virusinfected cells and tissues are only now being reported. While typically VZV induces the so-called Cowdry type A intranuclear inclusions, traditional morphology proves to be an insensitive tool for assessing the localization and distribution of virus in tissue. These problems are confounded by our limited understanding of the virological factors that influence pathogenicity. Herpes Zoster (HZ) Herpes (derived from the same root as herpetology) refers to the serpentine creeping nature of the vesicular eruption. The Greek ''zoster" and "zone'' translate into the English girdle, indicating the distribution of lesions along dermatomes. Cingulus, a Latin word for girdle, is the presumptive derivation of the medical slang term "shingles."

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In immunologically intact persons of all ages, herpes zoster is usually reflected as a unilateral dermatome-limited vesicular rash characteristically closely associated with the distribution of a sensory nerve (Figure 10.4). This relationship was initially suggested by Bright in 1831 and proven 30 years later by Von Barensprung, who first observed evidence of infection in sensory ganglia and nerves at autopsy of patients with HZ. It occurs in persons of all ages and at variable intervals of time after chickenpox. The predisposition of persons of advanced age to HZ (Figure 10.5) was clearly demonstrated by the epidemiological work of Hope-Simpson (1965). In his studies, the overall prevalence of HZ was 3.4 per 1000 in the general population, but 10 per 1000 in octogenarians who had no recognized predisposing medical conditions. Rogers and Tindall (1971) documented an absolute increase in the frequency of trigeminal nerve involvement in geriatric patients (in comparison to patients of all ages). The disease in these older folks was longer in duration and more severe than in younger patients. Its complications are believed to be more severe, and in the elderly the incidence of postherpetic neuralgia increases with age (Kost and Straus, 1996) (Figure 10.6). HZ frequently develops in persons with leukemia, lymphoma (particularly Hodgkin's disease), and a variety of conditions and therapies that result in altered cell-mediated imn\une responsivity. For example, the studies of Atkinson et al. (1980) showed that nearly half of all bone marrow allograft recipients who survive for 6 months or longer develop HZ. Similarly Reboul et al (1978) noted the occurrence of HZ in 20% of children with Hodgkin's

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Lumbar Sacral

40

50

60

Age Groups

Reprinted with permission from LeBoit et al. (1992). FIGURE 10.4 Dermatome involvement by HZ among patients of all ages included in the population-based study of Hope-Simpson (1965). Reprinted with permission.

FIGURE 10.5 Age-specific incidence of HZ in the populationbased study of Hope-Simpson (1965). Reprinted with permission.

152


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FIGURE 10.6 Annual incidence of HZ and the proportion of cases with postherpetic neuralgia. Panel A shows the annual incidence of H Z / I x 10^ persons in a general medical practice. Panel B documents the percentage of patients with pain persisting after onset of the HZ-associated rash. Data are from the placebo group in one large double-blind treatment study. Panel C shows the proportion of patients with postherpetic neuralgia according to age. Reprinted with permission from Kost and Straus (1996).

disease. Fifty percent of patients who received chemotherapy and extensive field irradiation developed HZ. Herpetic lesions in these conditions frequently are not confined to a dermatome distribution and often persist for extended periods. Compelling epidemiological and biological evidence establishes HZ as the reflection of a latent varicella infection acquired earlier in life. Gilden et al. (1992) claim that 90% of adults with serological evidence of past infection are carriers of latent VZV genome in sensory ganglia of the trigeminal or thoracic nerves (or both). The biological nature of the latency is a subject of continued research, but evidence recently

A

Skin

Satellite Cell

summarized by Hay and Ruyechan (1994) indicates that VZV RNA and regulatory proteins are detectable by molecular means in cells of the ganglion in the absence of clinical evidence of disease. They hypothesize that viral replication is downregulated but not inactive during periods of latency. The limited published work suggests that the viral genome is located in satellite cells of the ganglion, but not in the sensory neuron per se during latency (Nagashima et al, 1975; Hay and Ruyechan, 1994) (Figure 10.7). Numerous studies have demonstrated viral particles ultrastructurally in infected ganglion cells, and the virus has been cultured from ganglia at autopsy during and after an attack of

B

Skin

Satellite Cell

FIGURE 10.7 A model for VZV latency based on studies of human ganglia and animal models. Following primary infection with VZV, latency is established in some, but not all, cells of the sensory ganglion (A). The primary site of latency appears to be the satellite cells that surround the neurons, although some neurons may also harbor the latent virus. Upon reactivation that leads to HZ, the virus spreads by means of a lytic infection within the ganglion and via axonal transport. It then infects the skin innervated by the neurons (B). Reprinted with permission from Hay and Ruyechan (1994).


HZ (Esiri and Tomlinson, 1972; Ghatak and Zimmerman, 1973; Bastian et al, 1974). Unfortunately, there are no satisfactory animal models of HZ. The pathology of HZ has been the subject of numerous reports in the past. The classical description was published by Head and Campbell (1900). I quote liberally from their vivid description of the fundamental lesions of this disease. "Changes in the ganglion of the posterior root: If the patient has died with the eruptions still out upon his skin, the affected ganglion will be found to be in a condition of profound inflammation. The interstitial tissue will be crowded with small round cells.... These inflammatory cells may be closely massed into clumps, and such foci may be scattered around the periphery and in the central tissue of the ganglion. These foci of inflammatory cells ... will occasionally be found to be situated around extravasated blood.... In the center of these hemorrhagic foci, the ganglion cells are absolutely destroyed. But in the surrounding zone of small round cells, the remains of ganglion cells can be generally seen.... Over the portion of the ganglion which is inflamed, the sheath generally shows similar changes. The vessels are engorged and occasionally, blood may be extravasated. An arterial branch entering at the distal pole of the ganglion and proceeding towards the lesions differed from similar vessels in the normal part of the ganglion, in that, an abundance of extruded leukocytes occurred along its course.... Ultimately, the focus of inflammation became converted into fibrous tissue and the density and extent of this scar depends on the severity and extent of the original inflammation. Usually, the final result is a scar occurring from 1/6 to 1/2 of the ganglion.... Over the scar is the ganglionic tissue, the sheath is thickened and altered in appearance.... The sheaths may become three times the thickness of the normal, and present a curious nonlaminated appearance, in marked contrast to the normal wavy appearance in the remainder of the sheath.... Thus, in conclusion, the acute changes found in the ganglion in a case of Herpes Zoster consists of (1) extremely acute inflammation with the exudation of small, round deeply-stained cells; (2) extravasation of blood; (3) destruction of ganglion cells and fibers; (4) inflammation of the sheath of the ganglion. "Changes in the posterior nerve-roots: Thirteen days after the eruption first appeared, profound degeneration was found in the posterior roots, and it is probable that this degeneration begins to make its appearance 10 days after the appearance of eruption.... This acute change seems to have reached its height at about 15 days after the appearance of eruption.... If the destruction has been profound, fibrous tissue takes the place of the destroyed nerve fibers.... Fifty-seven days after

153

the eruption, the secondary sclerosis was already quite evident, but 153 days after the eruption, the last remains of the products of acute degeneration could be seen amongst the secondary fibrous tissue. After 272 days, all signs of acute degeneration had disappeared, but the sclerosis was well-marked, more than 1/2 the posterior root being replaced by fibrous tissue.... Thus, the changes we have found in the posterior root correspond to the results that might have been expected from the lesion in the ganglia. They consisted of acute degeneration followed by a greater or lesser amount of secondary sclerosis according to the severity of the acute destruction. "Changes in the peripheral nerves: In the mixed trunks of the peripheral nerves close to the ganglion, these acutely degenerated fibers stand out clearly ... against the normal fibers of the anterior root. The number of these degenerated fibers varies considerably with the severity of the ganglionic lesion.... Eight days after the eruption, no acute degeneration could be found in the peripheral nerves in connection with the affected ganglion, but 13 days after, degeneration was present to a marked degree.... Both posterior primary and anterior primary divisions are markedly affected, but the number of degenerative fibers in the posterior primary division always appears to be greater, probably owing to the almost entirely afferent nature of the branch in the dorsal region. This degeneration can be traced right back to the fine twigs which pass upward into the skin and supply the area over which the eruption is distributed. With time, the products of degeneration are removed from the peripheral nerve, and if the ganglion lesion is not severe, it may be impossible to be certain of any abnormalities in the peripheral nerves. On the other hand, if the lesion has been a severe one of the nerve fibers that have degenerated ... are replaced by fibrous tissue and whole bundles of the nerve may be sclerosed.... Thus, in the peripheral nerves, degeneration seems to appear, to disappear, and to be replaced by sclerotic changes at the same periods after the initial lesions in the ganglion" (also see MuUer and Winkelmann, 1969). "Degeneration in the spinal cord: It is not surprising that such lesions of the ganglion as we have described in the previous section should be attended by acute degeneration of the root-fibers in the posterior columns of the spinal cord. This degeneration probably appears about the 9th or 10th day after the eruption. When dealing with the similar degeneration and the fibers of the posterior roots, we drew attention to the rapidity with which the products of the acute degeneration were removed and replaced by secondary fibrous tissue. In the spinal cord, on the other hand, the products

154


of acute degeneration are removed much more slowly. Thus, ^1 days after the eruption, the products of degeneration in the posterior root showed signs of absorption and these roots were already considerably sclerosed, but the degeneration in the spinal cord was extremely well marked.... One hundred and fifty-three days after the eruption, the acute degeneration in the spinal cord was still profoundly marked, but in 272 days, it had disappeared.... When the degeneration is cleared away from the spinal cord, it leaves no perceptible sclerosis behind it, probably owing to the relatively small number of fibers destroyed" (also see McCarthy and Amer, 1978). Encephalopathies According to Denny-Brown and his colleagues (Denny-Brown el al., 1944), "Four histologic events ... distinguish herpes zoster from other pathological processes." These are: (1) necrotizing ganglionitis; (2) "a poliomyelitis which closely resembles anterior poliomyelitis, but is readily distinguished by its unilaterality segmental localization, and greater involvement of the posterior horn, posterior root and dorsal spinal ganglion"; (3) a mild localized leptomeningitis, and (4) peripheral mononeuritis. Other authors have documented the development of a transverse myelitis in patients with HZ, but the number of cases are small and the incidence of this complication unclear (Hogan and Krigman, 1973; Devinsky ei al., 1991; Gomez-Tortosa et al., 1994; Meylan ei al., 1995; Lionet ei al, 1996; Thomas and Howard, 1972). VZV disease of the central nervous system almost invariably develops in a milieu of relative immunosuppression, yet little quantitative or qualitative information on the status of the immune system in patients with recognized disease has been reported. Thus, our understanding of the immunologic mechanisms influencing the growth and spread of VZV in brain tissues is primitive. Boughton ei al. (1966) documented a wide variety of nervous system disorders in the 2.6% of patients hospitalized with, or following, an episode of chickenpox. These conditions include aseptic meningitis, encephalitis, cerebellar ataxia, optic neuritis, Guillain-Barre syndrome, and Reye's syndrome. The relationship of infection to the neurological problem in these cases has largely been established on the basis of clinical and epidemiological observations and, to a more limited extent, viral serology. Among children with varicella, acute, but generally transient, ataxia attributed to cerebellar infection is the most common neurological problem occurring concomitantly with the rash (Boudewijn ei al., 1978). Almost invariably, this clinical condition is

of limited severity and leaves no residual neurologic abnormalities in its wake. Thus far, pathologic studies have not been reported. Meningoencephalitis of varying degrees of severity have also been described in otherwise healthy children with chickenpox, but often the encephalopathy is first recognized days to weeks after the onset of the rash (Norris ei al., 1970; Wees and Madhavan, 1980) (see Figure 10.15). On rare occasions, it occurs before the appearance of the skin lesions. Autopsy study of these cases has been uncommon (Takashima and Becker, 1979). Perivascular lymphocytic "cuffing" and focal demyelinization of the white matter is found in the brain, but evidence of infection in the form of inclusion-bearing cells is lacking (Appelbaum ei al., 1953). These observations raise for consideration the possibility that many reported cases of alleged varicella encephalitis, in fact, represent post-infectious encephalomyelopathy rather than a specific VZV related lesion. Serious life-threatening VZV encephalopathy sporadically occurs in children with malignant disease, particularly acute lymphogenous leukemia, and Hodgkin's disease, and in adult recipients of chemotherapy and those with AIDS. Commonly, adults who develop an encephalopathy also manifest lesions of herpes zoster. The zosteriform lesions in these cases often are either generalized or involve several dermatomes. Lymphadenopathy occasionally accompanies the rash (Patterson ei al., 1980). However, skin lesions are not invariably present in the so-called zoster sine herpetic syndrome (Lewis, 1958; Manian ei al., 1995). In the study of Jemsek ei al. (1983), 45% of patients with encephalopathy had disease believed to have emanated from cranial or cranial-cervical ganglions. Lesions in the higher levels of the neuraxis are often seen in AIDS. Three fundamental types of lesions have been reported to develop in adults in HZV encephalopathy: 1. Large vessel vasculopathy. The carotid arteries and their various branches into and over the cerebral cortex demonstrate diverse lesions ranging from a lymphocytic angiitis to a granulomatous angiitis. Affected vessels may exhibit intimal proliferation, fibrinoid necrosis, and thrombosis. In the affected vasculature, evidence of infection is found in endothelial cells in the form of intranuclear inclusions or viral particles, demonstrable by electron microscopy, or by in siiu localization of the VZV genome (Bourdette ei al, 1983; Blue and Rosenblum, 1983; Linnemann and Alvira, 1980; Kleinschmidt-DeMasters ei al, 1996; Amlie-Lefond ei al, 1995). Herpes zoster ophthalmicus is the most commonly associated viral lesion. Patients typically exhibit the classical features of a cerebral vascular accident. Because the lesions tend to develop in


155

FIGURE 10.8 Small arterial branches from the circle of Willis showing the active inflammatory stages of VZV vasculitis (A), and the quiescent advanced stage with marked intimal proliferation (B). Reprinted with permission from Kleinschmidt-DeMasters et at. (1996) through the courtesy of B. Kleinschmidt-DeMasters, MD.

older persons, the classical stroke due to atherosclerotic vascular disease is a clinical diagnostic consideration. In varicella vasculopathy, angiograms reveal characteristic segmental irregularities in the appearance of the affected vessels. Although it almost always occurs in adults, two cases of varicella-associated vasculopathy with cerebral infarction were recently reported in boys aged 7 and 9 years (Shuper et ah, 1990; Tucciarone et al, 1992). 2. Encephalitis. Often, the small blood vessels in affected areas show a lymphocytic vasculitis, but they manifest no evidence of endothelial cell infection (Figure 10.8). Scattered, localized, but well-delineated areas of demyelinization and necrosis, often in a perivascular location, characterize this second type of lesion (Figure 10.9). At the periphery of the areas of damage, oligodendroglia exhibit typical intranuclear inclusions, clearly indicating a direct association of the lesion with an active viral infection (McCormick et al, 1969). Astrocytosis may be present depending upon the age of the lesion. Encephalitis of this type results from hematogenous spread of the virus into distal branches of the vasculature. Typically, lesions are located at the junction of grey and white matter. Clinically, this form of VZV encephalopathy results in nonspecific neurological manifestations such as obtundation and problems of mentation (Kleinschmidt-DeMasters et ah, 1996; Jemsek et ah, 1983).

3. Ventriculitis and periventriculitis. Ependymal cells lining the major ventricular systems of the brain commonly show morphological evidence of infection. With the passage of time, the deeper periventricular tissue is affected. Microscopical examination of the lesions reveals nodular astrocytic proliferation on the ependymal surfaces (Gray et ah, 1994). This change can

FIGURE 10.9 A hemorrhagic infarct secondary to a vasculopathy in the occipital lobe of the brain. Several small ovoid ischemic/demyelinating lesions are depicted by arrowheads. Reprinted with permission from Kleinschmidt-DeMasters et al. (1996) through the courtesy of B. Kleinschmidt-DeMasters, MD.

156


FIGURE 10.10 Periventricular ischemic/demyelinating lesion (arrowhead) adjacent to the lateral ventricle at the level of the amygdala. Reprinted with permission from Kleinschmidt-DeMasters et al. (1996) through the courtesy of B. Kleinschmidt-DeMasters, MD.

be detected by radiological imaging techniques and changes in the cerebral spinal fluid that may be diagnostic. The pathological picture is similar to the ventriculitis that occurs with cytomegalovirus infections in neonates (Figure 10.10).

EYE DISEASE Involvement of the external eye by VZV occasionally occurs in uncomplicated chickenpox. In these cases, the lids and conjunctivae exhibit inflamma-

tion and vesicular lesions. Uncommonly, the cornea is involved, resulting in a superficial or disciform interstitial keratitis (Pavan-Langston and McCuUey, 1973; Karlin, 1993). The lesions are consequent to vesicle formation in the epithelium followed by rupture, leaving shallow ulcerations in the cornea. Direct viral invasion of the internal eye is rare, but it may be a consequence of either hematogenous spread of the virus or transmission along nerves (Cheatham et al, 1956). Under these circumstances, uveitis, cataracts, oculomotor paralysis, and optic neuritis occur (Appel et al, 1988; Robb, 1972; Osfler and Thygeson, 1976; and Lee et al, 1997).

FIGURE 10.11 Residual scarring of the cornea secondary to VZV keratitis involving the nasal branches of the trigeminal nerve. Reprinted with permission from Pavan-Langston and McCulley (1973) through the courtesy of D. Pavan-Langston, MD.


157

OPTHALMIC BRANCH OF THE TRIGEMINAL NERVE Nasociliary Infratrochlear Division | Nasal Division

Lacrimal • Frontal I

FIGURE 10.12 Anatomical distribution of the branches of the sensory nerve of the trigeminal cranial nerve. Some individual variability in distribution can be expected. HZ of this cranial nerve usually involves only a single branch of the nerve, as illustrated in Figure 10.13.

VZV involvement of the eye is more common in herpes zoster when the ophthalmic branch of the trigeminal nerve is involved as a consequence of a latent infection in its gasserian ganglion (Ostler and Thygeson, 1976; Karlin, 1993) (Figure 10.11). The postganglionic nerve further divides into four branches that individually supply specific anatomic components of the internal and external eye (Figure 10.12) (Edgerton, 1945; Duke-Elder, 1965). The distribution of the virus into these various nerve branches ultimately determines the location of the lesion that develops and accounts for the enormous variability in clinical expression of the infection one patient to another (Figure 10.13). Interestingly enough, herpes simplex virus commonly involves the mandibular branch of the fifth cervical nerve, accounting for lesions on the lips. Few pathological studies of the eye involved by VZV are reported since enucleation rarely is required in nonimmunosuppressed adults. Naumann et al. (1968) recorded detailed observations on enucleated orbits with disease developing as a consequence of VZV ophthalmicus. While the details are beyond the scope of this discussion, inflammatory lesions of the nerves and intraorbital vasculitis were prominent features in many cases. Various anatomic structures had undergone necrosis; retinal destruction with detachment and lens opacification were common. Necrotizing lesions of the retina due to various genera of the herpesviruses are occurring with increasing frequency in patients with AIDS and among recipients of chemotherapy for cancer and organ transplantation

(Porter ei al, 1972; Egbert et al, 1980; Friedman et al, 1993; Wunderli et al, 1996; Galindez et al, 1996; Batisse et al, 1996; Garweg and Bohnke, 1997). Of the responsible agents, cytomegalovirus is clearly the most common. Ocular infections with this virus occur in 20 to 25% of patients with AIDS, and in roughly 2% of organ transplant recipients (see Chapters 8 and 16). The syndrome of acute necrotizing retinitis in the literature is usually consequent to VZV (this is a condition variously termed "acute retinal necrosis syndrome,'' "rap-

FIGURE 10.13 Hemorrhagic HZ eruption in the distribution of the frontal branch of the trigeminal nerve. Reprinted wi\h permission from Pavan-Langston and McCuUey (1973) through the courtesy of D. Pavan-Langston, MD.

158


idly progressive outer retinal necrosis/' and "atypical necrotizing retinopathy"). On rare occasions, herpes simplex and herpes simiae are responsible for similar lesions. In immunosuppressed patients, VZV acute necrotizing retinitis develops as a complication of zoster ophthalmicus, but can occur when a distant dermatome is involved, or in the absence of herpetic lesions of the skin. It is rapidly progressive and usually results in destruction and detachment of the retina with blindness. While initially unilateral, it becomes bilateral with the passage of time in Vs to % of patients. Since the clinical manifestations of the various herpesvirus retinopathy are variable, molecular identification techniques have proven most useful in establishing an etiological diagnosis. While the acute necrotizing retinitis syndrome usually occurs in circumstances of immunosuppression associated with clinical herpes zoster, it has developed in healthy adults on very rare occasions after chickenpox (Barondes et al, 1992).

EAR DISEASE In the only report published to date, Bordley and Kapur (1972) described the inner ear lesions of fatal varicella. In three cases, the mucus membranes of the middle ear showed focal necrosis and lymphocytic infiltration. An exudate of polymorphonuclear cells was found in the lumen. Hunt (1907) described so-called Ramsay Hunt syndrome (or herpes zoster oticus) and noted chronic inflammation of the Vllth cranial nerve. As one recalls, this nerve is comprised of both sensory and motor roots. He suggested (but did not demonstrate) that the geniculate ganglion was similarly inflamed. Infection of this ganglion has been established by PCR (Furuta et al, 1992). Ramsay Hunt syndrome assumes several different clinical forms: (1) herpes zoster oticus without apparent nerve disease; (2) herpes zoster oticus with facial palsy; (3) the second pattern accompanied by auditory symptoms; and (4) the second pattern with "Meniere's complex." In temporal bone studies, facial perivascular, perineural, and intraneural lymphocytic infiltrates are found. Vesicular eruption of the conchal area of the external ear occurs in some cases (Harner et al, 1970). The perivascular lesions are consistent with vasculitis, a lesion seen in larger vessels in herpes zoster ophthalmicus syndrome, as discussed earlier. Inflammatory changes are customarily not observed in the cranial nerve and associated vessels in idiopathic Bell's palsy. Zajtchuk and her associates (Zajtchuk et al, 1972) described in detail the pathology of the inner ear in herpes oticus.

PULMONARY DISEASE Pneumonia is a complication of chickenpox in persons of all ages, but the majority of life-threatening cases occurs in healthy young adults who are experiencing their initial infection with VZV (Bagdade and Melmon, 1966; Rotter and Collins, 1961). In the United States, 25% of the deaths attributed to varicella each year are a result of chickenpox pneumonia (Figure 10.14A-D). However, pneumonia also develops in neonates as a reflection of a disseminated infection, and in children receiving chemotherapy. The overall prevalence in adults is difficult to estimate because of the marked predominance of cases among young males and in pregnant women (Weber and Pellecchia, 1965; Pickard, 1968; Harris and Rhoades, 1965; Fish, 1960; Castleman and Kibble, 1963). In military populations, where hospitalization rates are high, approximately 15% of young male soldiers with varicella exhibited clinical or radiological evidence of pneumonia (Triebwasser et al, 1967). The incidence is much higher in adults admitted to civilian hospitals with chickenpox, which no doubt represent either more severe cases of chickenpox or those with diseases predisposing to opportunistic infections (Fitz and Mieklejohn, 1956; Mermelstein and Freireich, 1961). The clinical illness in seemingly normal adults is variable in severity (Table 10.1). It usually develops shortly after the appearance of the rash (Appelbaum et al, 1953) (Figure 10.15). Mortality rates differ in various reported series. Untreated varicella pneumonia in the adult has a mortality of approximately 10%. Pregnant females represent a unique population with a relatively high mortality (Enders, 1984; Qureshi and Jacques, 1996). In one study, 17% of women with clinical varicella developed pneumonia, and 45% of those in the second or third trimester succumbed (Fish, 1960). Pathologically, the lungs exhibit a diffuse interstitial and intra-airspace noncellular exudative process that tends to accumulate in nodular and occasionally hemorrhagic foci. Necrosis of parenchyma is often observed at these sites (Claudy, 1947). This most probably accounts for the pattern of diffuse nodular densities in the X-ray picture during acute illness. It is occasionally represented by calcified nodularity in roentgenograms of the chest after recovery (Knyvett, 1965; Meyer et al, 1986). Small subtle intranuclear inclusions are observed in a variable number of pulmonary epithelial cells and in the endothelium of scattered pulmonary vessels (Figure 10.16A-C). Vascular necrosis and thrombosis appear occasionally in the lung parenchyma, accounting for the sporadic occurrence of lung infarcts (Click et al, 1972). Viral inclusions also are found in the mesothelial cells of the pleura accompa-

159


B

îm^

JH

FIGURE 10.14 Disseminated hemorrhagic VZV infection in a young pregnant school teacher (A). At autopsy, the lungs were deeply congested, heavy (B,C), and consolidated with focal areas of hemorrhagic necrosis. (D) Cross-section of lung after formalin fixation.

nied by pleuritis and effusions. The prevalence of pleural disease is uncertain since many pathology reports fail to mention the pleura. Charles and his associates (1986) established the diagnosis of pleural VZV in one of their cancer patients with a disseminated infection using exfoliative cytology. Multinucleate cells and individual cells with intranuclear inclusions were found (Figure 10.17).

viral infections of infants and children have been associated with this condition (see Chapter 2). Reye's syndrome has been described on a number of occasions in children with varicella (Szalay 1972; Eshchar et ah, 1973; Ey et ah, 1981; Fronstin, 1968; Jenkins et ah 1967;

DIGESTIVE TRACT DISEASE Involvement of the bowel with infarction necrosis is reported in corticosteroid-treated patients with disseminated varicella (Chang et al, 1978; Keene et ah, 1978). More frequently, pseudo-obstruction occurs concomitantly with dermatomal HZ (Tribble et ah, 1993). 8

LIVER DISEASE Reye (1963) described the syndrome of acute encephalopathy accompanied by fatty degeneration of the liver that now bears his name. A number of acute

10

12

14

16

18

Days after Onset of Rash FIGURE 10.15 Time of onset of VZV encephalitis after the appearance of the VZV skin eruption. The development of pneumonia follows a similar time course. Reprinted with permission from Appelbaum et al (1953).

160

Pathology and Pathogenesis of Human Viral Disease TABLE 10.1 Clinical Features of Varicella Pneumonia in 27 Seemingly Normal Adults (>20 years of age, 21 males and 6 females)

Cough Dyspnea Cyanosis Hemoptysis X-ray charges

Severe

Moderate

Mild

None

9 8 5 3 7

6 5 2 4 9

12 3 1 5 10

11 19 15 1

-

Adapted with permission from Tables 32.3 and 32.4 in Krugman et al. (1977).

Norman, 1968; Barr et al, 1968; Click et al, 1970). In some cases the patient had not consumed aspirin, the presumptive critical cofactor in causation of the disease (Click et al, 1970; Belay et al, 1999). Central nervous system signs and evidence of liver dysfunction occur within days after the onset of the rash. The pathology of the liver lesions associated with varicella has been described (Lichtenstein et al, 1983). Hepatitis characterized by mononuclear inflammatory and focal hepatic necrosis of the liver with intrahepatocyte nuclear inclusions is reported infrequently in patients infected with VZV (Figure 10.18) (Eshchar et al, 1973). To a large extent, these liver lesions have been found in immunocompromised patients with disseminated infections and in both children and adults with fatal varicella pneumonia. Ross et al (1980) reported

massive hepatic necrosis in a 64 year-old woman without recognized predisposing conditions and skin lesions. Hepatocytes exhibited intranuclear inclusions and serological studies documented HZV infection.

RENAL DISEASE Henoch et al (1884) described four children with clinical features of the nephrotic syndrome developing 3 to 11 days after the onset of chickenpox. Scattered reports since that time have documented a proliferative nephritis similar to poststreptococcal glomerulonephritis in children and adults with the varicella eruption (Denney and Baker, 1929; Krebs and Burvant,

FIGURE 10.16 HZV pneumonia. (A) Note the two nuclei with subtle intranuclear eosinophilic inclusion in cells of the alveolar inflammatory exudate. (B) Alveolar macrophage and a pneumocyte (arrowhead) with intranuclear inclusions. The pleural surface shows a fibrinous exudate. (C) Deeply congested lung with intra-airspace exudation of fluid. Note the alveolar macrophage with tiny intranuclear inclusion associated with prominent clearing of the surrounding nucleoplasm. In the author's experience, varicella inclusions in cells of the lung are subtler. Their location often demands painstaking microscopy.


161

FIGURE 10.17 Cytological preparation of pleural fluid sediments showing multinucleate mesothelial cells (A) and cells with intranuclear inclusions (B, arrow). Reprinted with permission from Charles et al. (1986).

1972; Minkowitz et al, 1968; Yuceoglu et al, 1967). Viral nuclear inclusions were not observed in pathological material from these patients. Autopsy reports of fatal cases of varicella have not noted the presence of kidney lesions at autopsy. A survey of hospitalized children with varicella documented nephritis in 0.1%. On the other hand, a much higher prevalence of "nephritis with uremia"

was noted among fatal cases of varicella occurring in an outbreak in Cameroon (West Africa). The renal diseases in these alleged cases were not confirmed by pathological study. Recently, a young adult male developed chickenpox accompanied by nephritis 22 months after receiving a single dose of an investigational varicella vaccine (Pillai et al, 1993). The immunological response to the vaccine was apparently poor. This case

FIGURE ^ 10.18 Necrotizing lesion in the liver of an immunocompromised child with a disseminated HZV infection.

162


vividly poses questions regarding the possible role of viral-immune complexes in the genesis of the renal disease.

TESTICULAR DISEASE In a review of the literature, Liu et al. (1994) found six cases of acute orchitis occurring concomitantly with acute varicella. Both children and adults were affected. During convalescence, the testes were atrophic in four of the five patients evaluated.

HEART DISEASE Myocarditis in children with fatal varicella was first reported by Hackel (1953). Focal interstitial inflammation was present in seven cases, but specific involvement of muscle cells was not found. Sporadic reports since that time have documented myocarditis and arrhythmias occurring in children during and immediately after chickenpox and as isolated lesions most probably responsible for death (Tatter et ah, 1964; Moore et al, 1969; Lorber et al, 1988; Waagner and Murphy 1990). Noren et al (1982) found interstitial myocarditis histologically in two-thirds of fatal cases of varicella in a retrospective autopsy study. Myocarditis had not been suspected clinically in these cases. Only rarely are viral inclusions identified in myocardial cells. Morales et al (1971) described inflammatory disease restricted to the conduction system and a cardiac nerve ganglion in one case of sudden death. Fatal myocarditis also occurs during early pregnancy. In a recent case report, a 12-year-old child developed myocarditis that rapidly evolved into a dilated cardiomyopathy requiring cardiac transplantation (Tsintsof et al, 1993).

JOINT, SYNOVIAL, A N D MUSCLE DISEASE Involvement of the synovium and joints in children with otherwise uncomplicated chickenpox is rare. It customarily is monoarticular (DiLiberti et al, 1977; Smith and Sanford, 1967; Mulhern et al, 1971; Ward and Bishop, 1970; Brook, 1977), but cases of polyarthritis are described (Friedman and Naveh, 1971; Sekanina and Frana, 1973). Symptoms appear 1 to 7 days after development of the skin eruption (Priest et al, 1978),

but cases are described in which arthritis precedes the appearance of the rash (Fierman, 1990). Evaluation of joint aspirate usually reveals a prominent number of lymphocytes. However, in some cases, a marked neutrophil response has been seen, indicating a possible superimposed bacterial infection. Resolution of the acute inflammatory process occurs without complications. VZV can be recovered from joint fluid in about a third of cases. Arthritis is not described in many reported cases of systemic varicella, and pathological studies of joints at autopsy are not described. On rare occasions, myositis develops with varicella and herpes zoster. Pratt et al (1995) described rhabdomyolysis in an adolescent and a young adult with primary varicella infection. There were striking increases in blood concentrations of creatine kinase during the acute stage of the illness when myalgia was a prominent complaint. The biopsy from one patient showed individual muscle fiber degeneration and necrosis; PCR yielded viral genomic material. Norris et al (1969) described perivascular cuffing in a muscle biopsy from a patient with HZ and painful muscles.

CONGENITAL VZV INFECTION The incidence of varicella during pregnancy is estimated to range between 0.2 and 7 per 10,000 live births (Qureshi and Jacques, 1996). Two syndromes occur in infants born of women contracting varicella during pregnancy The first results from an infection during the initial 20 weeks of pregnancy In two recently reported studies, pregnancy loss was approximately 67.5% when infection of the mother occurred during the first 20 weeks of gestation (Enders et al, 1994; Balducci et al, 1992). Oyer and colleagues (1998) demonstrated nuclear inclusions in autolyzed embryonic tissue and confirmed the presence of VZV by immunohistochemistry and electron microscopy. Similar findings have been reported by others. An embryopathy is the outcome among those concepti that survive. Characteristically, the infection is manifest as skin, skeletal, and muscle abnormalities accompanied by ophthalmic lesions (cataracts, chorioretinitis, and microphthalmia) and developmental abnormalities of the brain, that is, microencephaly and hydroencephaly (Anglin, 1973; Cotlier, 1978; Laforet, 1947; McKendry and Bailey 1973; Paryani and Arvin, 1986; Srabstein et al, 1974; Frey et al, 1977; Rinvick, 1969; Magliocco et al, 1992; Charles et al, 1977; Savage et al, 1973). The second syndrome is seen in the offspring of women who contract varicella during the last three


weeks of pregnancy. Under this circumstance, disseminated varicella with multiple organ involvement develops (Oppenheimer, 1944; Ehrlich et ah, 1958; Newman, 1965; Da Silva et ah, 1990; Purtilo et al, 1977). Mortality among newborns is roughly 30%, and at autopsy most major organ systems are involved. Until recently, the risk of congenital varicella was uncertain because most information was based on isolated case reports. Several studies of maternal infection during the first trimester have now been conducted. The most meaningful was an investigation controlled for spontaneously occurring nonvaricella-related congenital abnornialities. Two percent of live-born infants exhibited the features of the congenital varicella embryopathy. Similarly, the prevalence of disseminated infections acquired late in gestation from mothers with chickenpox was low (Pastuszak et ah, 1994). In a recent study of over 1300 pregnant women with varicella infections, 9 cases (0.7%) of the congenital varicella syndrome occurred. The highest risk was between the 13th and 20th weeks of pregnancy. The fetuses of women with herpes zoster were not at risk, an indication that immunity acquired by the mother earlier in life was protective (Enders et ah, 1994). A limited number of reports document the placental lesions in maternal VZV infection. Necrotizing and chronic inflammatory lesions of the placental villi characterize the pathological findings, but foci of necrosis and infarction are also described. Inclusion-bearing cells have not been found (Oyer et al, 1998; Garcia, 1963). Qureshi and Jacques (1996) recently summarized the diverse pathology literature on this subject.

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Herpesvirus Type 6 (HHV-6) n 1986, a previously unrecognized lymphotropic (gamma) herpesvirus was recovered from circulating peripheral blood lymphocytes of several patients with lymphoproliferative disorders and / AIDS (Salahuddin et ah, 1986). Since that time, considerable effort has focused on characterizing this new agent and determining its relevance as a cause of disease in humans. Although an impressive body of information has accumulated during the past ten years, the etiological role of HHV-6 in human disease is incompletely defined, and its pathogenic properties poorly understood. The difficulties in establishing a pathogenic role for HHV-6 are based upon the virus' almost universal presence as a latent infection in the tissues of older children and adults (Suga et al, 1995; Luppi et al, 1995; McCullers et al, 1995; Di Luca et al, 1995; Cuende et al, 1994; Caserta and Hall, 1993; Leach et al, 1994; Hall et al, 1994), and its reactivation often during infections with other herpesviruses, immunosuppression therapy, graft-vs.-host disease (Wilborn et al, 1994), and transplant rejection (Hoshino et al, 1995). Additional problems relate to the cumbersome techniques currently required to isolate the virus from human tissue as well as the probable insensitivity of the available immunohistochemical tests currently required for detecting serum antibody. PCR has been used to detect viral DNA in various tissues and body secretions, but this technique does not differentiate between latent and active infections. Thus, the contribution of PCR to our understanding of HHV-6 disease has thus far been limited. Two variants (A and B) of HHV-6 have been defined, but it is not known whether they differ biologically or in pathogenicity. HHV-6 shares DNA molecular homology with the organizational structure of cytomegalovirus, but nonetheless, it possesses unique DNA sequences and is antigenically distinct from other members of the herpesvirus family. It replicates in both B and T lymphocytes, although clinically it is most often demonstrated in the latter cells, particularly, but not exclusively, those of the


CD4+ lineage. Maternal antibody appears to protect newborns until approximately 6 months of age, after which serologic evidence of infection gradually becomes apparent. Over 90% of children possess serum antibodies before 6 years of age. Thus, asymptomatic or unrecognized infections occur commonly among preschool children. The mode of transmission of the virus is unknown. HHV-6, the established etiological agent of exanthema subitum (syn. roseola infantum, sixth disease), exhibits unique clinical and epidemiological features that are consistent with our knowledge of the epidemiology of HHV-6. It rarely is seen before 6 months of age, and usually occurs before age 4 as a sporadic case or in outbreaks of limited size. Secondary cases in family members are rare, no doubt because of the almost universal presence of immunologically mediated resistance, indicating prior infection in most older persons. The exanthema is preceded by fever that subsides with the appearance of a macular or maculopapillary rash on the trunk and to a lesser extent on the face and extremities. Leukopenia and a relative lymphocytosis accompany the exanthema that rarely persists for longer than 24 hr. Many HHV-6 infections manifest only as fever without clinical evidence of a rash. Variant B viruses are more commonly recovered from patients with exanthema subitum. HHV-6 has also been etiologically associated with a non-EBV/non-CMV heterophil-negative mononucleosis syndrome in young adults (Pruksananonda et al, 1992; Akashi et al, 1993). Like other members of the herpesvirus group, latent HHV-6 appears to be activated in states of immunosuppression such as after organ transplantation and in those infected with HIV-1 (Fairfax et al, 1994). Diseases of the central nervous system (i.e., meningoencephalitis), lung, and liver (i.e., hepatitis) have been attributed to HHV-6 under such circumstances, but the evidence in many cases is inconclusive (Ishiguro et al, 1990; Asano et al, 1992; Suga et al, 1993; Achim et al, 1994;

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Carrigan and Knox, 1994; Caserta et ah, 1994; Drobyski et al, 1994; Wilborn et al, 1994; Knox and Carrigan, 1995; Moschettini et al, 1996). HHV-6 has also been demonstrated in pulmonary tissue of immunosuppressed patients with idiopathic interstitial pneumonia (Carrigan et al, 1991; Cone et al, 1993). A cause-and-effect relationship in these cases has not been established, and the sites of viral replication are unknown. Hepatitis and the hematophagocytic syndrome (see Chapter 9) also have been documented in patients with HHV-6 infections (Asano et al, 1990; Huang et al, 1990). Death of a 13-year-old presumptively immunocompetent girl with a rash and multisystem HHV-6 infection has been described (Prezioso et al, 1992). Autopsy revealed atypical lymphocytes with intranuclear inclusions of the herpesvirus type infiltrating multiple organs. Electron microscopy demonstrated herpes virions in the inclusions, and in situ hybridization established the presence of HHV-6. Of particular interest to diagnostic pathologists is the demonstration of HHV-6 by in situ hybridization in the prominent sinus histiocytes of lymph nodes in seven of nine patients with Rosai-Dorfman syndrome (syn. sinus lymphocytosis with massive lymphadenopathy) (Levine et al, 1992) and in histiocyte necrotizing lymphadenitis (syn. Kikuchi's disease). A number of other hematological syndromes of obscure etiology are currently being investigated in consideration of the possible role of HHV-6 in their causation. The near universal presence of genomic DNA in tissue makes this a difficult task. Immunohistochemistry using a monoclonal antibody is claimed to identify virus in tissue (Pitalia et al, 1993). Should such an approach prove sensitive and valid, pathological studies might yield insightful observations on the role of HHV-6 in disease. The virus or viral DNA can readily be detected in circulating mononuclear cells and in the saliva of patients with exanthema subitum. The salivary glands and possibly bronchial glands are suspected to be a common site of subsequent latent infection. Studies by Caserta and colleagues (1994) suggest that the central nervous system may serve as the locus for latent virus, but the evidence is only circumstantial.

References Achim, C , Wang, R., Miners, D., and Wiley, C. (1994). Brain viral burden in HIV infection. /. Neuropathol Exp. Neurol. 53, 284-294. Akashi, K., Eizuru, Y, Sumiyoshi, Y, Minematsu, T., Hara, S., Harada, M., Kikuchi, M., Niho, Y, and Minamishima, Y (1993). Brief report: Severe infectious mononucleosis-like syndrome and primary human herpesvirus 6 infection in an adult. New Engl. ]. Med. 329,168-175.

Asano, Y, Yoshikawa, T., Suga, S., Yazaki, T., Kondo, K., and Yamanishi, K. (1990). Fatal fulminant hepatitis in an infant with human herpesvirus-6 infection [letter]. Lancet 1, 862-863. Asano, Y, Yoshikawa, T., Kajita, Y, Ogura, R., Suga, S., Yazaki, T., Nakashima, T., Yamada, A., and Kurata, T. (1992). Fatal encephalitis/encephalopathy in primary human herpesvirus-6 infection. Arch. Dis. Child. 67,1484-1485. Carrigan, D., and Knox, K. (1994). Human herpesvirus 6 (HHV-6) isolation from bone marrow: HHV-6-associated bone marrow suppression in bone marrow transplant patients. Blood 84, 33073310. Carrigan, D., Drobyski, W., Russler, S., Tapper, M., Knox, K., and Ash, R. (1991). Interstitial pneumonitis associated with human herpesvirus-6 infection after marrow transplantation. Lancet 338, 147149. Caserta, M., and Hall, C. (1993). Human herpesvirus-6. Annu. Rev. Med. 44, 377-383. Caserta, M., Hall, C , Schnabel, K., Mclntyre, K., Long, C , Costanzo, M., Dewhurst, S., Insel, R., and Epstein, L. (1994). Neuroinvasion and persistence of human herpesvirus 6 in children. /. Infect. Dis. 170, 1586-1590. Cone, R., Hackman, R., Huang, M., Bowden, R., Meyers, J., Metcalf, M., Zeh, J., Ashley, R., and Corey, L. (1993). Human herpesvirus 6 in lung tissue from patients with pneumonitis after bone marrow transplantation. New Engl. J. Med. 329,156-161. Cuende, J., Ruiz, J., Civeira, M., and Prieto, J. (1994). High prevalence of HHV-6 DNA in peripheral blood mononuclear cells of healthy individuals detected by nested-PCR. /. Med. Virol. 43,115-118. Di Luca, D., Mirandola, P., Ravaioli, T., Dolcetti, R., Frigatti, A., Bovenzi, P., Sighinolfi, L., Monini, P., and Cassai, E. (1995). Human herpesvirus 6 and 7 in salivary glands and shedding in saliva of healthy and human immunodeficiency virus positive individuals. /. Med. Virol. 45, 462^68. Drobyski, W., Knox, K., Majewski, D., and Carrigan, D. (1994). Brief report: Fatal encephalitis due to variant B human herpesvirus-6 infection in a bone marrow-transplant recipient. New Engl. J. Med. 330, 1356-1360. Fairfax, M., Schacker, T., Cone, R., Collier, A., and Corey L. (1994). Human herpesvirus 6 DNA in blood cells of human immunodeficiency virus-infected men: Correlation of high levels with high CD4 cell counts. /. Infect. Dis. 169,1342-1345. Hall, C , Long, C , Schnabel, K., Caserta, M., Mclntyre, K., Costanzo, M., Knott, A., Dewhurst, S., Insel, R., and Epstein, L. (1994). Human herpesvirus-6 (HHV6) infection in children: Prospective evaluation for complications and reactivation. New Engl. ]. Med. 331, 432-438. Hoshino, K., Nishi, T., Adachi, H., Ito, H., Fukuda, Y, Dohi, K., and Kurata, T. (1995). Human herpesvirus-6 infection in renal allografts: Retrospective immunohistochemical study in Japanese recipients. Transpl. Int. 8, 169-173. Huang, L., Lee, C , Lin, K., Chuu, W., Lee, P., Chen, R., Chen, J., and Lin, D. (1990). Human herpesvirus-6 associated with fatal haemophagocytic syndrome [letter]. Lancet 336, 60-61. Ishiguro, N., Yamada, S., Takahashi, T., Takahashi, Y, Togashi, T., Okuno, T., and Yamanishi, K. (1990). Meningo-encephalitis associated with HHV-6 related exanthem subitum. Acta Paediatr Scand. 79, 987-989. Knox, K., and Carrigan, D. (1995). Active human herpesvirus (HHV6) infection of the central nervous system in patients with AIDS. /. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 9, 69-73. Leach, C , Newton, E., McParlin, S., and Jenson, H. (1994). Human herpesvirus 6 infection of the female genital tract. /. Infect. Dis. 169, 1281-1283.

Herpesvirus Type 6 Levine, P., Jahan, N., Murari, P., Manak, M., and Jaffe, E. (1992). Detection of human herpesvirus 6 in tissues involved by sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). J. Infect. Dis. 166, 291-295. Luppi, M., Barozzi, P., Maiorana, A., Marasca, R., Trovato, R., Fano, R., Ceccherini-Nelli, L., and Torelli, G. (1995). Human herpesvirus-6: A survey of presence and distribution of genomic sequences in normal brain and neuroglial tumors. /. Med. Virol. 47,105-111. McCuUers, J., Lakeman, R, and Whitley, R. (1995). Human herpesvirus 6 is associated with focal encephalitis. Clin. Infect. Dis. 21, 571-576. Moschettini, D., Balestri, P., Fois, A., and Valensin, P. (1996). Acute encephalitis due to human herpesvirus 6. Clin. Infect. Dis. 23, 397-398. Pitalia, A., Liu-Yin, J., Freemont, A., Morris, D., and Fitzmaurice, R. (1993). Immunohistochemical detection of human herpes virus 6 in formalin-fixed, paraffin-embedded lung tissues. /. Med. Virol. 41,103-107. Prezioso, P., Cangiarella, J., Lee, M., Nuovo, G., Borkowsky, W., Orlow, S., and Greco, M. (1992). Fatal disseminated infection with human herpesvirus-6. /. Pediatr 120, 921-923.

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Pruksananonda, R, Hall, C., Insel, R., Mclntyre, K., Pellett, P, Long, C., Schnabel, K., Pincus, P., Stamey, R, and Damgaugh, T. (1992). Primary human herpesvirus 6 infection in young children. New Engl. J. Med. 326,1445-1450. Salahuddin, S., Ablashi, D., Markham, P., Josephs, S., Sturzenegger, S., Kaplan, M., Halligan, G., Biberfeld, P, Wong-Staal, K, and Kramarsky, B. (1986). Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 234, 596-601. Suga, S., Yoshikawa, T., Asano, Y, Kozawa, T., Nakashima, T., Kobayashi, L, Yazaki, T., Yamamoto, H., Kajita, Y, and Ozaki, T. (1993). Clinical and virological analysis of 21 infants with exanthem subitum (roseola infantum) and central nervous system complications. Ann. Neurol. 33, 597-603. Suga, S., Yazaki, T., Kajita, Y, Ozaki, T., and Asano, Y (1995). Detection of human herpesvirus 6 DNAs in samples from several body sites of patients with exanthem subitum and their mothers by polymerase chain reaction assay. /. Med. Virol. 46, 52-55. Wilborn, R, Schmidt, C., Brinkmann, V., Jendroska, K., Oettle, H., and Siegert, W. (1994). A potential role for human herpesvirus type 6 in nervous system disease. /. Neuroimmunol. 49, 213-214.


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12 Kaposi Sarcoma-Associated Herpesvirus (KSHV, HHV-8) INTRODUCTION

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progressive neoplastic process of children and male adult residents of the highlands of equatorial subSaharan Africa (Lothe, 1963; Templeton, 1981; Hutt, 1984). More recently, it garnered attention when KS was found with increasing frequency among organ allotransplant recipients being administered immunosuppressive agents (Harwood et ah, 1979; Klepp et ah, 1978; Akhtar et ah, 1984; Vella et ah, 1997). As it turned out, most of these patients proved to be of Jewish origin. They experienced a progressive life-threatening disease that often became systemic and involved internal organs. As already noted, KS was dramatically reintroduced to the medical and general public when it appeared unexpectedly among male homosexuals with HIV-1 infections prior to development of fullblown AIDS (Friedman-Kien, 1981) (see Chapter 16). The infrequent occurrence of KS among aging males, particularly those of Jewish or Mediterranean heritage, provides little hint as to its causation, but over the past century etiologic speculation has been rampant. The common occurrence of the disease in the highlands of Central Africa suggested a likely role of either environmental influences or an infectious agent (or both) in its causation. The epidemiology of KS in male homosexuals conducting unprotected sexual acts with multiple partners of the same gender seemed to be most compatible with a transmissible venereal-acquired infection. But the infrequent occurrence of KS among hen\ophiliacs inadvertently infected with HIV1 by means of blood transfusions or blood concentrates strongly suggested that KS was not caused by HIV-1. The demonstration of a new gammaherpesvirus, now termed KSHV, or HHV-8, in the lesions (Chang et ah, 1994) and in mononuclear cells of the blood of patients with HIV-1 infections before the appearance of the disease (Whitby et ah, 1995) strongly suggests, but does not prove, an etiologic relationship between this "new" virus and the disease. As of yet, HHV-8 has not been shown to induce lesions similar to KS in experimental animals, and attempts to thwart the progression of KS

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BODY CAVITY-BASED NON-HODGKIN'S

LYMPHOMA (BCBL)

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ANGIOFOLLICULAR LYMPH NODE HYPERPLASIA REFERENCES

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INTRODUCTION As a pathologist, I first confronted Kaposi's sarcoma (KS) as a diagnostic problem in a mission hospital in the central highlands of northern Tanzania. To my inexperienced eye, it proved to be a challenge w^hen attempting to differentiate the atypical lesion from pyogenic granuloma, infected traumatized hemangiomas, and an assortment of other chronic conditions of the skin that commonly occur in the indigenous African population. The frequency of these diagnostic encounters peaked my interest and stimulated further exploration of the clinical problem. The issue proved particularly intriguing, since at the time KS was blossoming forth in the United States in a quite different form among young male homosexuals destined to die of AIDS (see Chapter 16). The outcome of the inquiries by my colleagues and I wâs a paper that addressed the subtle immunologic deficiencies of patients vvîth endemic KS in Africa who had not experienced an HIV-1 infection (Craighead et ah, 1988). While the research answered a few questions, it engendered a deep curiosity focused on this enigmatic lesion. Many other medical scientists have been similarly intrigued. In 1872, the Hungarian dermatologist, Moritz Kaposi (Figure 12.1) described the unique disease of the skin that now bears his name. It was initially recognized as a rare affliction, primarily occurring in older men of Mediterranean and Jewish heritage (Ross et al., 1985). It was later found to be a relatively common


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FIGURE 12.2 Typical skin lesion of KS of roughly 2 to 3 months duration on the arm of a 60-year-old truck driver with chemotherapy-treated chronic lymphocytic leukemia.

FIGURE 12.1 Moritz Kaposi, the Austrian dermatologist who described the unique lesion of the skin that now carries his name.

with specific antiviral agents directed against HHV-8 are only in their infancy. Although Kock's postulates have yet to be satisfied, the cumulative evidence supporting an etiologic role for HHV-8 in KS is compelling. KS exhibits a number of fascinating clinical and pathological features. With the possible exception of preadolescent children in Africa, it invariably affects males substantially more often than females, even when male homosexuals are excluded (Templeton, 1981). Its appearance seems to be triggered by a defect(s) in immunosurveillance, but HIV-1-infected patients do not typically exhibit the rampant opportunistic infections that characterize advanced AIDS. Hemangiomatous lesions on the trunk and head are common, and progression of the disease with involvement of the upper aerodigestive tract and internal organs is relatively rapid. It accompanies the premorbid deterioration of cellular immunity. To this extent, KS has been a causative or contributing factor in the death of many patients infected with HIV-1. In these cases, fatal involvement of the respiratory and digestive tract by the neoplasm is common (Gottlieb and Ackerman, 1982; Martin et al, 1993). In contrast, the disease is chronic in the sporadically occurring cases (that have no associa-

tion with HIV-1) in the Mediterranean Basin and subSaharan East Central Africa. Overt immunodeficiency is not evident in these patients (Matondo and Zumla, 1996). It initially appears as an indolent superficial violaceous lesion usually of the extremities (Figure 12.2) and evolves through a series of tumors (Figure 12.3), progressing centripetally in the distribution of the lymphatics to later involve the upper extremities, neck, and head (Reynolds et al, 1965; Lospalluti et al, 1995). Later, a "woody" edema of the feet and hands develops (Figure 12.4). Visceral organs are rarely affected until late in the disease (Lothe and Murray 1962; Reed et al, 1974; Port et al, 1982) (see Table 16.11). Chang and his colleagues (1994) reported the identification of a previously unrecognized herpesvirus in

FIGURE 12.3 Multiple confluent tumorous masses of KS on the dorsum of the hand and wrist of a young African man who was otherwise active and relatively healthy Note the edema of the digits. Reprinted with permission from Craighead et al. (1988).

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sified as a gammaherpesvirus and assigned the designation HHV-8 (Moore et al, 1996a,b). This classification now seems fully appropriate inasmuch as the virus can usually be demonstrated in the circulating CD19-positive B cells of patients with KS. More recently, electron microscopy has shown that the virion of HHV-8 is structurally similar to other herpesviruses. In addition, it has been claimed that HHV-8 can be grown in a continuous line of embryonal human kidney epithelial cells by cocultivating susceptible cells with those derived from KS lesions (Foreman et al, 1997). The validity of this finding has been questioned (Blauvelt et al, 1997a). At present, we know very little about KSHV/HHV-8 and the viral genes responsible for the distinctive character of the lesions for which it appears to be responsible. Information is only now accumulating in sufficient depth to permit some understanding of the means by which HHV-8 infection is contracted and disseminated.

EPIDEMIOLOGY

FIGURE 12.4 "Metastatic'' tumor nodules on the leg of a young African male with a KS lesion on the plantar surface of the foot.

homogenates of KS tumor tissue using a relatively new clinical isolation technique (representational difference analysis) and the polymerase chain reaction (PCR) to amplify a 233-bp herpesvirus-like sequence. This observation was confirmed and has been expanded upon by many others since that time (Moore and Chang, 1995; Chuck et al, 1996; Dictor et al, 1996). The viral gene segments originally identified in these experiments represented components coding for elements of the capsid and tegmentum proteins that share genetic markers with Herpesvirus simiae and, to a lesser extent, Epstein-Barr virus (EBV). On this basis, KSHV is clas-

Gaps of enormous proportion exist with regard to our understanding of the distribution of HHV-8 in members of the general population, both in developed countries and in regions of the Mediterranean Basin and Africa with a high prevalence of KS. Much of the currently available information is based on studies of small groups of incompletely characterized persons, using serological tests of unverifiable accuracy and molecular approaches predisposed to error. Thus, apparent conflicts in published data may reflect technical artefacts. Although it is currently impossible to develop firm conclusions, the evidence indicates that the prevalence of latent or active HHV-8 infections among members of the general population is low in the endemic areas of sub-Saharan Africa and the Mediterranean Basin, as well as in members of the United States and Europe populations (Marchioli et al, 1996; Lennette et al, 1996; Corbellino et al, 1996a; Blauvelt et al, 1997b; Cathomas et al, 1998). In various surveys, roughly 10 to 50% of homosexual males have been found to be infected when the peripheral blood mononuclear cells are analyzed (Lefrere et al, 1996; Moore et al, 1996a; De Milito et al, 1996). Almost all patients with AIDS who exhibit KS lesions carry the virus in peripheral blood mononuclear cells. Similarly, there is a strong association between HHV-8 with KS in cases occurring in the Mediterranean Basin and in subSaharan Africa (Dupin et al, 1995; Huang et al, 1995).

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The mode of transmission of HHV-8 among male homosexuals destined to develop KS is uncertain. Epidemiological analysis suggests the possibility of fecal-oral transmission, and studies by Thomas et al. (1996) indicate that HHV-8 is elaborated in the mucosa of the duodenum and small intestine. In this work, HHV-8 was detected in the digestive tract mucosa of 47% male homosexuals by means of endoscopic biopsy, but the identity of the actual cells supporting virus growth was not established. Oral secretions and tissues have proven positive in 75% of AIDS patients with KS (Koelle et al, 1997; Di Alberti et al, 1997), and semen, as well as both prostatic and testicular tissues, also yield evidence of infection in most, but not all, studies (Lin et al, 1995; Monini et al, 1996; Corbellino et al, 1996b; Gupta et al, 1996; Howard et al, 1997; Diamond et al, 1997). While body secretions may serve as a means for spreading the virus, it is not entirely clear whether the infection is intrinsic to epithelial or germinal cells of the reproductive organs, or reflects HHV-8 in resident and inflammatory mononuclear cells of blood origin. In a detailed study of semen using PCR in situ technology, Huang et al (1997) found evidence in both spermatozoa and mononuclear cells. Recently, viral genomic material was demonstrated in the epithelium of the prostate gland by in situ methodology (Staskus et al, 1997). Vertical transmission of HHV-8 from an HlV-l-infected mother with KS to her offspring is reported (McCarthy et al, 1996). On rare occasions, familial occurrence of KS has been documented (Greco et al, 1938; Zeligman, 1960; Finlay and Marks, 1979; Digiovanna and Safai, 1981), and cases of KS occurring among very young African children are recorded in the literature. This suggests, but certainly does not prove, vertical transmission (Lothe, 1963; Dutz and Stout, 1960).

PATHOGENESIS A N D PATHOLOGY The pathogenesis of the lesions of KS is an enigma that remains largely unexplained despite considerable research. Indeed, it is unclear whether the "tumor" represents a "true" neoplasm resulting from malignant cellular transformation or is a localized proliferation of vascular and stromal elements possibly resulting from the autocrine or paracrine influences of a panoply of growth factors elaborated in response to infection (Cornali et al, 1996; Ensoli et al, 1994; Koster et al, 1996; Nickoloff and Foreman, 1996; Nair et al, 1992; Nakamura et al, 1997; Boshoff et al, 1997). Impressive arguments support both possibilities. Evidence arguing for the concept of malignancy is the demonstration of monoclonality among the cells of the multiple "tu-

mors" in some but not all patients (Rabkin et al, 1997), and the seemingly unrestricted invasive and metastasizing growth characteristics of the disease in immunosuppressed patients. Contrariwise, our inability to transplant the "tumor" into animals and to grow "tumor cells" in culture in the absence of growth factors (Nakamura et al, 1988, 1997) is evidence supporting the view that the lesion may be a nonmalignant cellular proliferation responding to a stimulus yet to be defined. Whatever its nature, HHV-8 is intimately involved, as demonstrated by in situ localization of the virus in endothelial cells and the spindle cell elements of the lesions at progressive stages in the development of KS (Boshoff et al, 1995; Li et al, 1996; Dictor et al, 1996; Staskus et al, 1997; Cathomas et al, 1998). However, the finding of the virus in "tumor" cells must be interpreted with caution, for, as noted earlier, many of these patients have evidence of a systemic HHV-8 infection. This large and complex virus is currently being characterized; its pathogenic mechanisms remain to be elucidated (Ganem, 1996; Chang et al, 1996). Immunological influences clearly are reflected in the development and progression of the lesions of KS, but at what stage in the evolution of the infection do they act? Studies of KS in Africa (Craighead et al, 1988) and our understanding of transplantation immunosuppression (Klepp et al, 1978; Harwood et al, 1979; Hoshaw and Schwartz, 1980; Stahl et al, 1982; Rasmussen et al, 1982) and AIDS argue that cell-mediated mechanisms are involved. There would appear to be a delicate imbalance of the various T cell elements since reduction or elimination of immunosuppressive drugs in the transplant recipient (Vadhan-Raj et al, 1986; Santucci et al, 1988; Erer et al, 1997), or the treatment of AIDS often reverses the course of KS (Real and Krown, 1985; Soler et al, 1996). The histopathogenesis of KS is the subject of an abundant literature. The subject is particularly confusing since classification schemata based on epidemiological/clinical staging and microscopical morphology are often used interchangeably in the literature. Clinically, there are four general categories of disease: 1. Classical. The disease initially described by Kaposi. It occurs predominantly among elderly male Jews and men residing in restricted geographic regions of the Mediterranean Basin. This form is frequently manifest as indolent lesions of the extremities, and rarely is a cause of death, despite its chronicity. 2. Endemic. The disease occurs with a relatively high frequency in the equatorial highlands of East and


Central Africa with a maleifemale ratio of roughly 15:1. This chronic disease form is often multifocal and evolves as tumorous nodules predominantly on the lower extremities. 3. Lymphadenopathic. A condition observed in African children of both sexes, and in an occasional patient with AIDS. In this fulminating form of KS, the prototypic lesions are found in isolated lymph nodes and the condition is manifest as generalized disease of the lymphoid system. 4. Invasive. Infiltrating tumor invades internal organs, particularly those of the respiratory and digestive tracts. This form is occasionally seen late in the course of African endemic KS and as a fulminating aggressive disease in patients with AIDS and recipients of immunosuppression. See Templeton (1981), Krigel et al (1983), and Lospalluti et al (1995). An understanding of the histogenesis of KS lesions is intrinsic to an appreciation of the variable pathologic features of the disease (see Figure 12.5). Of critical importance is the question of a cell of origin for the proliferating vascular structures that are an intrinsic hallmark of the lesion. Are they derived from blood vessels or lymphatics or primitive mesenchyma? While a restrictive approach to this question may be naive, the bulk of the histologic ultrastructural and immunochemical evidence indicates that the fundamental vascular structures reflect an aberrant series of interconnections between lymphatics and venules (Figure 12.6A,B). Simply, in the earliest lesions, there appear to be lymphatic-to-venous shunts with pooling of lymph and blood in the slit-like and sinusoidal structures of infinite complexity that are found in the lesions (Dictor, 1986; Leibowitz et al, 1980; Cossu et al, 1997). The immunohistochemistry strongly suggests that many of these abnormal vascular channels have a reaction pattern consistent with lymphatics (Beckstead et al, 1985; Jones et al, 1986). Additionally, the fine structural features of these lesions are consistent with this notion of histogenesis as shown by the elegant studies of McNutt et al (1983). As seen by these investigators, capillary dendritic pericytes are consistently lacking in the typical vascular structures of the lesion, and there is a discontinuity between the endothelial cells. In addition, the basal lamina of the vascular channels prove to be thin and fragmented. These features are consistent with an origin in lymphatic vessels (Dorfman, 1986) (Figure 12.6A~D). The origin of the sarcomatous elements of the evolving KS lesion is the second question, particularly when

175

the tumors become large and nodular and exhibit the features of a fibrosarcoma (Figure 12.6C,D). To date, the immunohistochemistry indicates that these proliferating "sarcomatoid" cellular elements are of endothelial origin, although the cells exhibit none of the fine structural features of endothelial cells (Schulze et al, 1987). Assuming the correctness of these conclusions, one could envision KS to be an evolutionary disease process in which the early lesions represent lymphatic proliferations that are potentially multifocal, with semiautonomous growth. Progression occurs when immunological controls are aborted. Where HHV-8 fits into this scenario is totally unclear. It may provide the stimulus for growth through generation of chemokines yet to be elucidated (Li et al, 1996; Boshoff et al, 1997). Typical skin lesions evolve clinically through stages nominally termed (1) patch, (2) plaque, and (3) nodular. In HIV-1-infected patients, the patch stage clinically presents as a small violaceous-pink irregular discoloration of the skin surface often seen initially on the forehead, conjunctiva, tip of the nose, and the glans penis. To me, this pattern suggests that the causative agent may be sensitive to internal body heat, such as is the case with Treponema pallidum. Histologically, these lesions are comprised of irregular loosely organized vascular slits lined by a thin attenuated endothelium. Usually, there is an associated mononuclear inflammatory infiltrate comprised of lymphocytes and plasma cells (Ackerman, 1979). In the plaque stage that follows, the vascular so-called "glomeruloids" become more prominent, with the vascular structures exhibiting a jagged configuration. Occasionally, vascular structures are dilated into sinusoids. A chronic inflammatory infiltrate is evident, and loosely organized spindle cells are interposed between bundles of collagen adjacent to the abnormal vascular structures. Congestion and extravasation of erythrocytes are often prominent in these lesions, and variable amounts of hemosiderin are seen. In the nodular stage that follows, inflammation is not a prominent feature, but the well-circumscribed nodules are comprised of mildly pleomorphic spindle cells and collagen fibers. Templeton (1981) describes a very aggressive form of the disease that evolves from the lesions of nodular KS on the extremities in African patients. I have seen similar cases in East Africa. These tumors transgress the deep fascia of the lower extremities and infiltrate subcutaneously. There is an associated "woody" consistency to the lower extremities, as described above. Sporadic reports from the United States in the preAIDS era document KS occurring in adults in a single, or in a cluster, of lymph nodes (Lee and Moore, 1965; Ramos et al, 1976; Berman et al, 1986; Dutz and Stout,

176


Multiple Pathways Involving HHV-8, Integrins^ CD40 and Bcl-x Leading to Emeiênce and Survival of KS Tumor Cells HIV-1 Infected a T-cells

Macrophages | and Dermal Dendritic Cells

Oncostatin M Tat bFGF Scatter Factor Other Gytokines

Resting Endothelial Cells (Epithelioid)

Proliferation via Secretion of Mitogens and Cytokines Activated Endothelial Cells (Spindle Shaped)

Proliferating KS Tumor [Cells and Endothelial Cells 4Cell Survival 4 BCI-XL 4lniegrins ^ Apopiosis 4CD40 FIGURE 12.5 Multistep pathwây leading to formation of KS lesions highlighting roles for HHV-8 and other proteins that regulate apoptosis. In the upper portion of this diagram, involvement of HIV-1, various grov^th factors, and cytokines in the initiation and transdifferentiation-dependent phases are portrayed, leading to emergence of activated endothelial cells. The subsequent steps involving proliferation of KS tumor cells and neovascularization are suggested to involve active participation and infection by HHV-8 and overexpression of integrins, extracellular matrix, and various proteins that can prolong the longevity of KS tumor cells and endothelial cells such as BC1-XL and CD40. It is conceivable that certain viral gene products derived from the novel y-herpesvirus HHV-8 can directly influence the biology of the KS tumor cell and endothelial cell. HHV-8 is known to be present in circulating B lymphocytes, and in situ polymerase chain reaction has demonstrated viral transcripts wîthin the tumor cells and endothelial cells. A vicious cycle can be envisioned in w^hich the activated KS tumor cells and endothelial cells produce cytokines capable of autocrine grov\^th stimulation and recruitment of additional tumor cells into the neoplastic lesion. The exact relationship betvêen participation of the immune system and the presence of HIV-1 and/or HHV-8 in formation of KS lesions is uncertain at this time. It is possible that KS lesions may not be truly sarcomatous lesions but rather represent an abortive immune response to a heterogenous group of virally infected mesenchymal cell types. Nonetheless, the angioproliferative lesions can produce deadly consequences secondary to extensive and uncontrollable hemorrhage. There is precedent for an infectious agent to produce a KS-mimetic phenotype knovv^n as bacillary angiomatosis, which is relatively easily treated by antibiotics. It may be feasible to treat KS lesions most effectively by targeting the infectious agent rather than using cytotoxic chemotherapeutic agents that may exacerbate the immunosuppression associated with HIV-1 infection. In any event, it should be clear that many new therapeutic opportunities exist based on progress made in clarifying etiological and pathophysiological issues related to KS. Reprinted with permission from Nickoloff and Foreman (1996).


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FIGURE 12.6 (A) Subepidermal plaque lesions of KS exhibiting the slit-like vascular structures and the interposed accumulations of mononuclear cells. The absence of erythrocytes in the spaces suggest interconnections with lymphatics. (B) Mixed subepithelial tumorous lesion of KS showing the superficial infiltrating fibroblastoid elements and the deeper sinusoids and accumulations of complex small vascular structures. (C) Sinusoids of a mixed lesion of KS with nodular fibroblastoid lesion at the base. (D) Sarcomatous lesion of KS in a nodular lesion similar to Figure 12.3. Note the prominent pleomorphism and the tumor giant cells. Reprinted with permission from Craighead et ah (1988).

I960; Ecklund and Valaitis, 1962). As noted above, childhood cases with generalized lymph node involvement are relatively common in Africa (O'Connell, 1977; Lothe, 1963). Templeton (1981) claims that these cases comiprise roughly 4% of the KS occurring in Uganda. In contrast to adults, this form of disease generally devel-

ops with equal frequency in boys and girls. In association with the HIV-1 epidemic, involvement of lymph nodes is occurring with increasing frequency among African children and adults (Marquart et ah, 1987), and in male homosexuals in North America and Europe (Finkbeiner et al, 1982).

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Bhana et at. (1970) described two morphologic forms of KS in lymph nodes, a finding confirmed by other authors (O'Connell, 1977). In the first, the node is extensively involved with the KS lesion, and the process seems to emanate from the medulla of the node. Multiple lymph nodes exhibit disease, and the condition tends to progress rapidly. In the second, only a portion of a node is involved, with the KS lesion usually being found in sinusoids and involving the capsule (Ramos et ah, 1976). This form seems to occur in the drainage pattern of cutaneous KS lesions and resembles a metastasis. However, cases are reported in which primary skin lesions are not present (Lee and Moore, 1965). In reviewing the histologic description in numerous early reports, I note the common observation of nodular lymphoid hyperplasia with plasma cell infiltrates and a small blood vessel proliferation developing in portions of the node not involved by KS. The picture strikingly resembles Castleman's disease. Recent authors have described the lesions of KS in nodes exhibiting classical features of Castleman's disease (Rywlin et ah, 1983; Chen, 1984) (see below).

A N G I O S A R C O M A S A N D OTHER VASCULAR LESIONS Malignant non-KS vascular sarcomas occur rarely (ca. 1% of all sarcomas in North Americans) and exhibit diverse morphological and clinical features. To a large extent, these lesions are idiopathic, although some are causatively related to chronic irradiation secondary to thorotrast administration and long-term lymphatic obstruction (i.e., postmastectomy). A relatively large number of angiosarcomas and related lesions have now been examined by PCR in an effort to detect a possible association with HHV-8 infection. The results, at present, are inconclusive and conflict from one report to another. McDonagh et al (1996) found evidence of HHV-8 infection in almost 30% of the angiosarcomas they studied, but only 1 of 20 hemangiomas proved positive. Hemangiopericytomas consistently proved negative. Only 1 of the 50 patients yielding these specimens was immunocompromised. On the other hand, an evaluation of 11 primary vascular tumors of body cavity origin (Lin et al, 1996), 15 capillary hemangiomas (Smoller et al, 1997), and 138 assorted vascular lesions (Jin, 1996) yielded no evidence of HHV-8 infection. Clearly, the possible role of HHV-8 in the pathogenesis of non-KS vascular lesions will require further study, work that no doubt will be published in future years.

BODY CAVITY-BASED NON-HODGKIN'S LYMPHOMA (BCBL) Lymphomatous effusions into the pleural and peritoneal cavities, in the absence of solid non-Hodgkin's lymphomatous masses, are known as BCBLs (Carbone et al, 1996; Hermine et al, 1996). BCBLs are usually comprised of large neoplastic cells with abundant cytoplasm and an irregular pleomorphic nucleus. Several nucleoli are present. The cell populations appear to be a mixture of anaplastic, multilobulated, and multinucleated large cells, many of which have immunoblastic features (Carbone et al, 1996; Hsi et al, 1998) (Figure 12.7). These cancers are rare and occur predominantly, but not exclusively, in males (Said et al, 1996). Patients occasionally develop KS before or after the appearance of the tumor, but die as a result of the complications of the lymphoma, usually less than 6 months after diagnosis. Thus, KS may not have had an opportunity to develop in many cases (Strauchen et al, 1996). BCBLs develop predominantly in patients with AIDS (DePond et al, 1997). EBV infection of the cells with expression of the oncogenic LMP-1 and EBNA-2 proteins is common in AIDS-associated cases, but evidence of EBV customarily is not found in the tumors of patients uninfected with HIV-1. In contrast to most AIDS-associated lymphomas that are of B cell lineage (see Chapter 7), most BCBLs have an indeterminant immunophenotype, although they exhibit a clonal rearrangement of the immunoglobulin genes (Karcher and Alkan, 1997). Individual cells of BCBLs prove to be latently infected with HHV-8 in the form of a circular episome of the viral DNA at a high copy number, but no information is available at present as to the clonality of the virus in the individual tumor cells of a particular patient. Cells of BCBLs from an EBV serologically negative patient with AIDS were recently reported to exhibit enveloped virus particles and in situ genomic signals consistent with HHV-8 (Hsi et al, 1998) (Figure 12.8). Treatment of cultured tumor cells with a chemical tumor promoter has been shown to induce the formation of morphologically identifiable viral particles within the cell, but not their release from the cell (Miller et al, 1997). Surveys using PCR have shown that benign lymphoid proliferations and solid lymphomas of a wide variety of morphological types in non-AIDS patients exhibit no evidence of HHV-8 infection (Pastore et al, 1995; Cesarman et al, 1996; Gaidano et al, 1996; Chadburn et al, 1997).


FIGURE 12.7 Representative morphology of body cavity-based lymphoma from HIV-positive males with Kaposi's sarcoma. (A,B) Cytocentrifuge preparation of pleural fluid and histological preparation of pleural biopsy showing large neoplastic cells of relatively uniform size and shape with immunoblastic features (A, WrightGiemsa stain, original magnification x750; B, hematoxylin-eosin stain, original magnification x300). (C) Cytocentrifuge preparation of pleural fluid showing neoplastic immunoblasts with moderate nuclear pleomorphism, mitotic activity, and prominent cytoplasmic vacuoles (Wright-Giemsa stain, original magnification x750). (D) Cytocentrifuge preparation of pleural fluid showing immunoblastic features, marked variation in cell size, and abundant mitotic activity (Wright-Giemsa stain, original magnification x750). Reprinted with permission from Karcher and Alkan (1997) and through the courtesy of D. Karcher, MD, and S. Alkan, MD.

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180


FIGURE 12.8 A 38-year-old HIV-positive IV drug user with Kaposi's sarcoma. He presented with a pericardial effusion consequent to the neoplasm described here. He died shortly thereafter. (A) Cytologic smear of premortem pericardial fluid showing noncohesive lymphomatous cells with large pleomorphic nuclei and prominent nucleoli. (B) Papanicolaou stain. Electron micrograph of a pericardial lymphoma cell containing 100 nm of nuclear viral particles (arrows) consistent with the appearance of human herpesvirus-8. Inset: high magnification showing enveloped virus budding from nuclear membrane (arrow) with adjacent nucleocapsids also in the cytoplasm. (C) Section of heart that shows pericardial lymphomatous infiltrate that forms a tumor nodule. Inset: high magnification showing infiltration of myocardium. Hematoxylin and eosin (H&E). (D) Lymphomatous infiltrate in pericardium (H&E). (E) Section of heart with lymphomatous infiltrate. Inset: high magnification. Lymphoma cells express epithelial membrane antigen in a Golgi pattern. Immunohistochemical stain with anti-epithelial membrane antigen. (F) Interstitial pulmonary lymphomatous infiltrate (H&E). (G) Hepatic involvement by lymphoma. Note tumor formation at the right side of the panel (arrows) (H&E). Reprinted with permission from Hsi et ah (1998) and through the courtesy of B. Nickoloff, MD.

ANGIOFOLLICULAR LYMPH N O D E HYPERPLASIA (syn. AFLH, multicentric angiofoUicular lymph node hyperplasia, Castleman's disease) (Shahidi et ah, 1995)

In 1956, Castleman and his associates described a localized lymphadenopathy of the mediastinum in which lymph nodes histologically resembled the thy-

mus. However, the so-called Hassel's bodies proved to be vascularized lymphocyte-depleted germinal follicles exhibiting hyalinized collagen, located in a sea of concentrically layered lymphocytes. The condition proved to be benign, and the masses were effectively treated by surgical excision or radiation therapy. A second clinical variant of the disease was reported by Flendrig (1969) and Keller et al (1972). In this condi-

181


tion, the patients were febrile and had both generalized lymphadenopathy and splenomegaly accompanied by anemia and hypergammaglobulinemia. Later reports by Gaba et al (1978) and Weisberger et al (1985) described similar cases having a high mortality and short survival period. The histology of the lymph nodes in these cases resembled the original lesions described by Castleman et al (1956), but exhibited sheets of plasma cells in addition to the uniquely vascularized hyaline structures replacing the lymphoid follicles (Figure 12.9). During the 1980s, additional cases of AFLH with generalized or multicentric lymphadenopathy and systemic symptoms were reported in male homosexuals with AIDS (Dickson et al, 1985; Oksenhendler et al, 1996). Many of these patients had KS. With the discovery of HHV-8, an association with AFLH with infection was established (Soulier et al 1995; Gessain et al, 1996;

Chadburn et al, 1997). Among patients with AIDS, the virus was invariably discovered by PCR in the diseased lymph nodes, whereas fewer than half of the nodes from HIV-1-negative cases with multicentric AFLH proved to be HHV-8 positive. Many of the later patients were men older than 50 years of age who had clinical evidence of immune dysregulation. Further studies documented the presence of HHV-8 genomic material in the circulating blood mononuclear cells of HIV-1-infected patients with AFLH (Grandadam et al, 1997). Although our understanding of this complex disorder is currently quite limited, one might hypothesize that AFLH represents a dysplastic lymphoproliferative disorder, the expression of which is modulated by immunological influences (Ohyashiki et al, 1994). The pathogenic role of HHV-8 in AFLH remains to be clarified, but in a recent report antiviral therapy was associated with clinical resolution of the lesions (Revuelta and Nord, 1998). As noted above, KS lesions have been found in lymph nodes exhibiting the classical features of AFLH (Rywlin et al, 1983; Chen, 1984; Tirelli et al, 1996). Currently, evidence to indicate that EBV contributes to development of the lesions is lacking.

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FIGURE 12.9 Angiofollicular lymph node hyperplasia. Note the hyalinized follicular lesion with associated radiating vascular structure at 8:00 o'clock surrounded by mixed population of mononuclear cells. Reprinted with permission and through the courtesy of J. Lunde, MD.

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C H A P T E R

13 Herpesvirus Simiae Virus (Herpes B) appears to be a major means for spread of the virus in breeding colonies (Weigler et al, 1993, 1995). While herpes B infection in its natural host is relatively benign, when the virus is inoculated into subhuman primates of unrelated species devastating central nervous system infections often evolve. The occurrence of fatal disease in humans appears to be comparable. After cutaneous inoculation of a primate, the virus replicates locally, resulting in a crop of vesicles and localized inflammation before spreading by means of the lymphatics to regional lymph nodes. Lymphadenitis often develops, and focal areas of necrosis and hemorrhage are found in the nodes. Similar lesions are occasionally found in HSV-infected humans (see Figures 7.23 and 7.24). Systemic spread of the virus usually follows with the development of circumscribed necrotic lesions in the liver, adrenals, spleen, and kidney. The neural route of centripetal spread of the virus by means of peripheral nerves to the central nervous system results in a myelitis, ultimately followed by development of a diffuse encephalitis. In striking contrast to HSV, herpes B does not favor the limbic system of the brain (Weigler, 1992). Detailed information on the pathological features of herpes B in humans is surprisingly limited. Although considerable variability between individual cases is well documented, in general, the neuropathological picture is one of a diffuse chronic active infection involving the spinal cord, brainstem, and cerebral cortex (Hummeler, et al, 1959; Sabin and Wright, 1934; Sabin, 1949; Nagler and Klotz, 1958). Typical intranuclear eosinophilic inclusions are the hallmark of the virus. The overt hemorrhagic necrosis of the temiporal lobe so characteristic of HSV encephalitis (see Figures 7.9 and 7.14) is not observed. With increasing awareness, the risk for workers in research facilities and in vaccine production has been substantially reduced. Considerable effort now focuses on identification of latent and subclinical infections in subhuman primates and establishment of

^/% oughly 35 different herpesviruses are known ^ ^ X to infect various species of nonhuman priM^L mates. Of these agents, only "herpes B" (syn. r • ^ Herpesvirus simiae, Cercopithecine Herpesvirus 1) is a recognized pathogen for man. It is an enzootic virus of the Old World Macaca mulatta rhesus monkey that has virological similarities to Herpes simplex virus (HSV). Twenty-five cases of disease in humans have been documented, and several additional cases are suspected but not proven. To a large extent, these infections were acquired inadvertently in an occupational setting as the result of monkey bites or exposure to cultured cells of Macaca origin. One instance of person-to-person spread by mechanical means has been documented (Holmes et al, 1990). Twenty-two of the 25 recognized infections in humans progressed to encephalomyelitis, resulting in 16 deaths (Weigler, 1992). Many of the surviving patients had significant residual neurological disease, some requiring institutionalization. In contrast to HSV, herpes B infections result in a diffuse encephalitis and transverse myelitis, anatomically related to the initial primary site of infection. The incubation period before development of local lesions ranges from 2 days to more than 10 years. At the local site of inoculation, vesicles and a promiinent soft tissue reaction are observed in some patients. In one case, an ophthalmic herpes zoster clinical picture developed initially, to be followed by a rapidly evolving encephalomyelitis (Fierer et al, 1973). Based on studies of naturally and experimentally infected subhuman primates, it is reasonable to conclude that the biological properties of herpes B and HSV are similar. For example, the incidence of subclinical infections in primate colonies increases with age. Although these infections usually become latent and are clinically unimportant, virus can be recovered sporadically from the oral cavity, conjunctiva, and genital secretions of individual, seemingly healthy, monkeys (Weigler, 1992). Indeed, infection by the venereal route


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virus-free colonies of animals for research purposes and tissue culture production. Herpes B infections should rarely occur in the future (Wells ei a\., 1989; Holmes ei al, 1995).

References Fierer, J., Bazeley, P., and Braude, A. (1973). Herpes B virus encephalomyelitis presenting as ophthalmic zoster: A possible latent infection reactivated. Ann. Intern. Med. 79, 225-228. Holmes, G., Hilliard, J., Klontz, K., Rupert, A., Schindler, C , Parrish, E., Griffin, D., Ward, G., Bernstein, N., Bean, T., Ball, M., Brady J., Wilder, M., and Kaplan, J. (1990). B virus {Herpesvirus simiae) infection in humans: Epidemiologic investigation of a cluster. Ann. Intern. Med. Ill, 833-839. Holmes, G., Chapman, L., Stewart, J., Straus, S., Hilliard, J., and Davenport, D. (1995). Guidelines for the prevention and treatment of B-virus infections in exposed persons. Clin. Infect. Dis. 20, 421-439. Hummeler, K., Davidson, W, Henle, W, LaBoccetta, A., and Ruch, H. (1959). Encephalomyelitis due to infection with Herpesvirus

simiae (Herpes B virus): A report of two fatal, laboratory-acquired cases. New Engl. ]. Med. 261, 64-68. Nagler, R, and Klotz, M. (1958). Fatal B virus infection in person subject to recurrent herpes labialis. Can. Med. Assoc. J. 79, 743-745. Sabin, A. (1949). Fatal B virus encephalomyelitis in physician working with monkeys. /. Clin. Invest. 28, 808. Sabin, A., and Wright, A. (1934). Acute ascending myelitis following monkey bite, with isolation of virus capable of reproducing disease. /. Exper. Med. 59,115-136. Weigler, B. (1992). Biology of B virus in Macaque and human hosts: A review. Clin. Infect. Dis. 14, 555-567. Weigler, B., Hird, D., Hilliard, J., Lerche, N., Roberts, J., and Scott, L. (1993). Epidemiology of cercopithecine herpesvirus 1 (B virus) infection and shedding in a large breeding cohort of Rhesus macaques. /. Infect. Dis. 167, 257-263. Weigler, B., Scinicariello, R, and Hilliard, J. (1995). Risk of venereal B virus (Cercopithecine Herpesvirus 1) transmission in Rhesus monkeys using molecular epidemiology. /. Infect. Dis. 171,1139-1143. Wells, D., Lipper, S., Hilliard, J., Stewart, J., Holmes, G., Herrmann, K., Kiley, M., and Schonberger, L. (1989). Herpesvirus simiae contamination of primary Rhesus monkey kidney cell cultures: CDC recommendations to minimize risks to laboratory personnel. Diagn. Microbiol. Infect. Dis. 12, 333-336.

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14 Adenoviruses INTRODUCTION

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EPIDEMIOLOGY

RESPIRATORY TRACT DISEASE

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DISEASE IN IMMUNOSUPPRESSED PATIENTS GENITOURINARY TRACT DISEASE DIGESTIVE TRACT DISEASE MYOCARDIAL DISEASE

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CENTRAL NERVOUS SYSTEM DISEASE EYE DISEASE

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Since the time of this initial work in the early 1950s, an enormous body of information has accumulated on what has proven to be a large family of viruses that has the capacity to infect a diversity of organs. At the time of this writing, 42 antigenically distinct serotypes of adenoviruses have been recovered from humans, and many more types are found in lesser animal species. The human adenoviruses are now nominally classified into seven groups, based largely on their biological features (Table 14.1). While they share similar structural and biochemical features, only about a third of the 42 strains are commonly recovered from clinical specimens, and only a few of these strains are known to cause disease. The adenovirus virions range from 60 to 90 nm in diameter. The viruses are comprised of a linear cord of double-stranded DNA made u p of nine translational units surrounded by a complex capsid of 252 unit capsomeres arranged in icosahedral symmetry. Pentamers, to which are attached fibers of variable length, form at the 12 vertices of the capsid, whereas the remaining capsomeres are hexamers. The fibers of the pentamers functionally serve to attach the virus to receptors of an unidentified composition on cell surfaces. Internalization of the virions into the cell is facilitated by integrins (Goldman and Wilson, 1995). After pinocytosis, the virion is uncoated, and synthesis of the "early" proteins (E1/E3) begins using the molecular machinery of the cell. These proteins turn off cellular DNA and protein synthesis, inducing apoptosis. Elaboration of the structural so-called "late" proteins of the virus follows, after which assembly of the progeny virions occurs in the nucleus (Figure 14.1). These particles are often organized into crystalline arrays (Figure 14.2). Because of the distinctive morphological features of the virus crystals, adenovirus-infected cells are readily detected by electron microscopy in human tissue. A substantial excess of the structural components of the virus are manufactured and accumulate in the cell nucleus during the replication cycle. These deposits appear to account, in part, for the intranuclear inclusions that are

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INTRODUCTION Inflammation and hyperplasia of the tonsils and adenoids invariably develop during the countless episodes of acute respiratory disease experienced by otherwrise healthy infants and young children. Despite its almost universal occurrence, the pathogenesis of common childhood oropharyngeal lymphoid hyperplasia is incompletely understood. To explore this intriguing question, Wallace Rowre and his colleagues (1953) cultured tonsillar and adenoid tissue for viruses and tediously monitored the events that evolved in the cells that grew in vitro from these tissues. Over the ensuing wreeks, the cells gradually developed the cytopathology of a new and previously unrecognized family of viruses. Not one, but several, antigenically different agents were recovered from lymphoid tissues in this manner. One group proved to be the prototype strains of what were initially termed the adenopharyngeal conjunctival (APC) agents, now known as adenoviruses. The second was cytomegalovirus (see Chapter 8). Subsequent studies have shown that adenoviruses of several different serotypes can be recovered from 60 to 75% of tonsil and adenoid specimens evaluated in the manner explored by Rowe (Van der Veen and Lambriex, 1973; Strohl and Schlesinger, 1965). More recent studies have shown that the virus is fully assembled and is present in a latent state in roughly 1 of every 10^ lymphoid cells in the oropharynx. On rare occasions, intranuclear inclusions typical of this family of viruses have been found in the squamous epithelial cells of the tonsils and adenoids (Brown, 1974).


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Pathology and Pathogenesis of Human Viral D i s e a s e TABLE 14.1 Classification of A d e n o v i r u s Serotypes Origin and group Respiratory C Bl Urinary Tract B2 Keratoconjunctivitis Bl D E Enteric Infections A F

Disease associations

Serotype

I, 2, 5, 6 3, 7, 16, 21

Minor acute upper respiratory illnesses; commonly are latent; persist in tonsils/adenoids Pneumonia

II, 14, 34, 35

Cystitis and nephritis; types 34 & 35 commonly disseminate in immunocompromised patients

3,7 Multiple serotypes 4

Sporadic and epidemic keratoconjunctivitis

12,18, 31 40,41

Diarrhea

FIGURE 14.1 The nucleus of a cultured epithelial cell 48 hr after infection with adenovirus type 2. The arrow depicts inclusions of several types (I, II, and III), the most prominent of which is the paracrystalline array. These components contribute to the inclusions observed by light microscopy N defines the nucleolus. Virions are distributed throughout the nucleus in this cell but not in crystalline arrays (12,000x). Reprinted with permission from Weber and Stich (1969).

the typical cytological features of the adenovirus-infected epithelial cell. The presence of viral proteins in the so-called "smudge" cells that typify adenovirus-infected tissues has not been established. However, infected epithelial cells often fail to exhibit diagnostic morphological changes (Ladenheim et ah, 1995). Adenoviruses are ubiquitous and most of us, no doubt, are latent carriers. Infections with the common endemic types (1-2, 5-7,14) customarily occur in childhood, resulting in relatively transient upper respiratory illnesses characterized by rhinitis, pharyngitis, tracheitis, and more generalized systemic symptoms. When patients exhibit unilateral or bilateral follicular conjunctivitis, the illness is termed pharyngeal conjunctival fevers. Overall, adenoviruses are responsible for roughly 5% of the upper respiratory illnesses of children. Perhaps 10% of the uncomplicated cases of childhood pneumonitis are due to these viruses. Thus, adenovirus infections are a "right of passage" for us all, and they cause serious illness on only rare occasions. The diseases considered in this chapter prove to be the more serious and often life-threatening. In the discussion, I have deliberately avoided a listing of specific adenovirus serotypes associated with various syndromes, since the information can be found in any standard virology text, and this detail to a large extent is meaningless when dealing with a clinical problem. Adenoviral lesions are characterized by a distinctive cytopathology and an associated acute inflammatory response. The cellular necrosis that follows is attributed to both the turn-off of cell protein synthesis and cell-mediated immune mechanisms (Ginsberg et al, 1990). However, information on the immunopathology of adenovirus infections is limited, and the relative contribution of immune mechanisms in the clearance of virus and recovery is uncertain. The common occurrence of fulminating adenovirus disease in recipients of

Adenoviruses

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FIGURE 14.2 Region of the nucleus of a cultured epithelial cell 96 hours after infection with adenovirus type 18. Note the fine structural features of the paracrystalline arrays (A). In (B) a similar array is closely associated with a crystal of virions (v) (42,000x). Reprinted with permission from Weber and Liao (1969).

immunosuppressive agents such as organ allograft recipients, and in patients with AIDS, emphasizes the important role of immunity in the control of infection. Recent experimental evidence indicates that the E1/E3 "early" proteins elaborated by the virus increase the expression of ICAM and class I major histocompatibility antigens by an infected cell (Pilewski et ah, 1995; Ginsberg et al, 1989). Epithelial cell susceptibility to the destructive effects of tumor necrosis factor alpha and other cytokines may also be influenced by these products elaborated "early" in the replicative cycle (Duerksen-Hughes, 1989). The inflammatory response customarily observed in the submucosa of the infected respiratory tract appears to contribute to both virus eradication and destruction of the mucosa.

RESPIRATORY TRACT DISEASE Most children are infected with adenoviruses at an early age, and by the age of 5 years, at least 50% of children have serological evidence of a past experience with as many as four different viruses of the pneumotropic groups Bl and C. The infection may be asymptomatic or manifest as a nonspecific transient respiratory illness, ranging in severity from nasal congestion to croup, but usually accompanied by fever. Thus, adenovirus illnesses cannot be differentiated clinically

from minor respiratory disease due to a variety of other common viruses. In total, however, adenoviruses account for only about 5% of the relatively mild respiratory infections experienced by infants and young children. The virus is usually transmitted by either the fecal-oral route, or by the respiratory droplet route, and customarily does not spread in epidemic form. In children, approximately 5% of adenovirus infections of the oropharynx spread to involve the lower respiratory tract, with bronchitis, bronchiolitis, and pneumonia being the most common clinical manifestations. They represent a substantial component of the pneumonias of young children requiring hospitalization. Adenoviruses types 3, 5, 7, and 21 are the most frequently involved serotypes (Collier et ah, 1966; Chany et al, 1958; Becroft, 1967; Benyesh-Melnick and Rosenberg, 1964). Newborn infants are affected uncommonly, although neonatal infections acquired in the birth canal or transplacentally from an infected mother are reported (Pinto et al, 1992; Benyesh-Melnick and Rosenberg, 1964; Abzug and Levin, 1991; Chiou et al, 1994). Outbreaks of nosocomial disease in hospital settings are particularly devastating (SinghNaz et al, 1993). About 15% of infected children died in the largest outbreak of adenovirus pneumonia thus far studied. The clinical features of this febrile respiratory infection focus on the airways and lungs, with a pertussis-like cough being common (Collier et al, 1966). Heart failure and evidence of central nervous system

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B

''¥M-SA\7 FIGURE 14.3 (A) Adenovirus pneumonia with destruction of the bronchial mucosa and plugging of the lumina with mucus secretions and debris. A proteinaceous exudate and focal interstitial pneumonitis are seen in the parenchyma of the lung. (B) The cytolytic changes in the bronchial mucosal cells are seen at higher magnification.

involvement are common features in severe cases (Connor, 1970; Klenk et al, 1972; Schonland et al, 1976). Some reports suggest that Asians are unusually susceptible to adenovirus pneumonia (Lang et al, 1969). Inclusion-body pneumonia in children was first described by Goodpasture et al. (1939), although its viral etiology was not appreciated at the time. The causative role of adenoviruses in this disease is now established, and numerous case reports document the devastating pathological features. Typically, the respiratory mucosa of the bronchi and bronchioles is destroyed and desquamated, with chronic inflammatory cell accumulations being evident in the lumina and submucosal tissues (Figure 14.3A,B). The submucosal glands in the trachea and bronchi are often involved and exhibit a necrotic epithelium. This appears to be a characteristic of adenovirus infections of the airways. In the distal branches of the bronchial tree, accumulated debris comprised of necrotic epithelium accompanied by serous and cellular exudates form eosinophilic plugs that obliterate the lumina of these channels. In situ hybridization establishes the presence of the virus in epithelial cells lining airways (Hogg et al, 1989). Cytological evidence of infection in the form of smudge and inclusion-bearing cells is variable in large part, because the destructive effects of the virus leave few intact mucosal cells (Figures 14.4A-F and 14.5A-F) (Kawai, 1959; Pinkerton and Carroll, 1971; Becroft, 1971; Herbert et al, 1977). Similar cytological changes can be seen in type II cells of the pulmonary alveolar parenchyma when the lungs are involved. In these cases, interstitial inflammation is often evident. A substantial body of evidence attests to the devastating long-term effects of adenovirus infections on the airways and lung parenchyma (Figure 14.6). To a variable extent, bronchiolitis obliterans, bronchiectasis (Becroft, 1971), and interstitial pulmonary fibrosis and

FIGURE 14.4 Adenovirus type 7 infection of an organ culture of differentiated human trachea. (A-D) illustrate the ''honeycombing'' of the nucleus and the small compartmentalized inclusions characteristic of the early virus-induced nuclear alterations. E demonstrates the nucleus of a typical smudge cell and F illustrates a distinctive intranuclear inclusion. The changes in E and F develop relatively late in the course of the infection.

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Adenoviruses

B

FIGURE 14.5 Diverse cytological alterations observed in an organ culture of human tracheal epithelium infected with adenoviruses. They can be characterized as intranuclear inclusions (A-C) and smudge cells (D-F). In evaluating tissue, the pathologist must be acquainted with the spectruni of changes that customarily develop as a result of an adenovirus infection.

chronic inflammation have been described in these cases (Kawai et ah, 1976; Simila et al, 1971; Warner and Marshall, 1976; Lanning et al, 1980; Zarraga et al., 1992). Although the prevalence of these late complications is difficult to assess, a follow-up report of an outbreak of type 21 adenovirus documented permanent residual lung damage in 60% of infected young children and saccular bronchiectasis in 20% (Lang et al, 1969). Chany et al (1958) detected long-term radiological changes in 27% of children 9 to 12 years after recov-

ery from adenovirus pneumonia. On the other hand, Simila et al (1971) noted radiologic evidence of pulmonary fibrosis in only 2 of 29 (7%) documented cases of adenovirus pneumonia and bronchiectasis in an additional 7%. An approximate 50% reduction in the caliber of the small airways was found in the lungs of young dogs experimentally infected with a canine strain of adenovirus (Castleman, 1985). The anatomic changes were attributed to scarring of the airway walls (Wright et al, 1979,1964).

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FIGURE 14.6 A 38-year-old man with AIDS and adenovirus pneumonia established by lung biopsy. Computer axial tomograph demonstrates nodular and alveolar densities with airspace consolidation in both lungs. Reprinted with permission from Maslo et al. (1997).

Chronic persistent adenovirus infections of the respiratory tract have been documented in humans (Chanock, 1974) and experimentally infected animals. Using PCR, Pacini ei al (1984) and Matsuse et al (1992) claimed to have found the adenovirus ElA gene in the lung tissue of a substantial proportion of patients with chronic obstructive pulmonary disease. The significance of these findings with regard to the pathogenesis of chronic lung disease is uncertain. Studies by Hogg et al (1989) and Bateman et al (1995) fail to document an increased prevalence of chronic adenovirus infections in the bronchial tree of patients with follicular bronchitis. This lesion is characterized by the accumulation of prominent lymphoid follicles within the dilated bronchiectatic walls of the airways and associated lung. While saccular bronchiectasis can be a residual effect of adenovirus infections, there is currently no evidence to suggest that chronic adenovirus infections contribute to development of the lesion. As noted above, chronic bronchiolitis and bronchiolitis obliterans are often found in the lungs of those recovering from adenovirus infections. Adenovirus lower respiratory tract disease occurs on sporadic occasions in members of the adult population, but the infection is not an important cause of pneumonia in older age groups. In contrast, outbreaks of infection with certain virus strains prove to be a common cause of pneumonia among recent inductees

into the military in the United States and Europe. The responsible strains of virus in the two geographic regions thus far studied differ, with serotypes 4 and 7 being prevalent in the United States and types 14 and 21 in Europe. The respiratory droplet mode of transmission appears to account for outbreaks on military bases (Chanock, 1974). Although asymptomatic infections are common among recruits, acute respiratory illness develops in approximately 50%, and pneumonia occurs in 5 to 15% of military inductees. Rare fatalities have occurred as a consequence of a progressive pneumonia (Dudding et al, 1972; Loker et al, 1974; Field et al, 1978). Autopsy reveals an extensive acute bacterial pneumonia, and the typical cytological changes indicative of adenovirus infection are not found, even though virus, in high concentrations, can occasionally be recovered from lung tissue. In some of these cases, disseminated intravascular coagulation and rhabdomyolysis of striated muscular masses has been documented (Wright et al, 1979). Because of its common occurrence in young military recruits, oral vaccines were developed, and, to a large extent, routine prophylaxis has eliminated the problem on military bases. It is surprising and unexplained why similar adenovirus outbreaks do not occur in other semiclosed populations such as among college students. However, a recent report documents an outbreak of pneumonia in a semiclosed chronic psychiatric facility. Fourteen

Adenoviruses

percent of the residents developed pneumonia sufficiently severe that 36% of them required mechanical ventilation and 7% died. An uncommon serotype of adenovirus (type 35) was responsible (Sanchez et ah, 1997; Klinger et al, 1998).

DISEASE IN I M M U N O COMPROMISED PATIENTS Disseminated adenovirus infections occur commonly in immunocompromised patients with genetically acquired defects in cellular immunity such as thymic aplasia (Wigger and Blanc, 1966; Aterman et ah, 1973; Charles et al, 1995), X-linked lymphoproliferative syndrome (Purtilo et al, 1985), AIDS (Gelfand et al, 1994; Maddox et al, 1992; Anders, 1990-91), cancer patients undergoing chemotherapy, and after renal (Myerowitz et al, 1975), lung (Ohori et al, 1995), hepatic (Michaels et al, 1992), and bone marrow (Flomenberg et al, 1994) transplantation (Strickler et al, 1992). Infections in allotransplant recipients seem to develop during episodes of graft-vs.-host disease, as documented either clinically or in kidney biopsies (Umekawa and Kurita, 1996; Yagisawa et al, 1995), and during epi-

195

sodes of rejection. Both endogenous reactivation (Shields et al, 1985; Ohori et al, 1995) and exogenous nosocomial acquisition of the virus occur (Pingleton et al, 1978). In addition to the lungs, a wide variety of organs exhibit lesions in individual cases, with the parotid (Gelfand et al, 1994), liver (Wigger and Blanc, 1966; Rodriguez et al, 1984; Koneru et al, 1987; Krilov et al, 1990; Purtilo et al, 1985), lung, gall bladder (Hedderwick et al, 1998), colon (Figure 14.7) (Michaels et al, 1992; Janoff et al, 1991; Maddox et al, 1992), brain (Anders et al, 1990-91), pancreas (Niemann et al, 1993), kidney (Figure 14.8), and the lower urinary tract (Ito et al, 1991) being sites of disease. In a systematic study of patients with AIDS, viremia proved to be common (Ferdman and Ross, 1997). In disseminated disease among immunocompromised adult patients, the pulmonary lesions are similar to those described earlier in this chapter (Maslo et al, 1997; Sencer et al, 1993; Zaltzman et al, 1994; Yagisawa et al 1995; Umekawa and Kurita, 1996). The liver exhibits multiple circumscribed foci of coagulation necrosis, with occasional hepatocytes showing the cytologic features of infection. In the colon, adenovirus-infected mucosal cells are readily identified microscopically They exhibit intranuclear inclusions that can be differentiated from the typical "owl eye"

FIGURE 14.7 (A) Colonic mucosa exhibiting typical smudge cells (arrow) established to be due to adenovirus by immunohistochemistry (arrow) (B). The patient died with AIDS. Reprinted with permission from Hedderwick et al. (1998) and through the courtesy of S. Hedderwick, MD, and J. Greenson, MD.

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F I G U R E 14.8 Kidney of a 17-year-old bone marrow recipient who died with cytomegalovirus pneumonia 3 months after transplantation. Adenovirus was isolated from the kidney tissue postmortem but not from the lungs and other major organs. In (A) the tubules are mildly dilated and show focal changes in the epithelial lining cells. Immunohistochemistry (B) with antibody against the adenovirus hexon protein demonstrated viral infection of tubular lining cells without involvement of the glomerulus. Photographs reprinted with permission and through the courtesy of R. Hackman, MD.

inclusions of cytomegalovirus. Superficial cells of the mucosa, but not those of crypts, are usually involved; frequently, the infected cells appear necrotic. The submucosa usually exhibits a chronic inflammatory cell infiltrate. In contrast, cytomegalovirus commonly infects macrophages, vascular endothelial cells, and stromal cells, that is, fibroblasts and smooth muscle cells of the colon in immunosuppressed patients. Involvement of mucosal epithelial cells by cytomegalovirus is less common. In a prospective study of bone marrow transplant recipients, adenoviruses were the most frequently recovered enteric virus. The majority of the patients had diarrhea and many died, but the cause of death and the possible contribution of the adenovirus were not established (Yolken et al, 1982).

GENITOURINARY TRACT DISEASE Renal and tubulo-interstitial disease and hemorrhagic cystitis are major causes of morbidity in allotransplant recipients. In a study of 977 bone marrow transplant recipients, 135 (14%) developed hematuria and dysuria. Of these patients, 60 had severe cystitis requiring aggressive treatment. Twenty-two percent also developed renal failure, presumably attributable to nephritis (Steigbigel et al, 1978; Ito et al, 1991; Tomoe et al, 1994; Green et al, 1994; Usami et al, 1997; Hackman et al, 1997). In kidney biopsies, there are extensive changes in the tubular lining cells attributable to the adenovirus infection and interstitial chronic inflamma-

tion (Figure 14.8). Some, but not all, of the patients studied yielded virus when the urine was cultured. A canine strain of adenovirus (the etiology of an often fatal systemic disease in immunologically intact dogs) induces lesions in the kidney that are similar to those found in immunosuppressed humans (Morrison et al, 1976). Numazaki et al (1968) described the spontaneous occurrence of acute hemorrhagic cystitis in otherwise healthy children associated with infection by type 11 adenovirus. Subsequent studies by these and other investigators (Numazaki et al, 1973; Mufson et al, 1971, 1973; Mufson and Belshe, 1976; Lee et al, 1996) confirmed these findings and established a causative relationship between viruria and disease of the urinary bladder and kidneys. Adenovirus type 11 is rarely found to infect sites other than the urinary tract; it appears to account for approximately 80% of the cases of hemorrhagic cystitis developing spontaneously in children in Japan, but only 23% of cases in the United States. The mode of infection of the urinary tract is not understood, and it is possible the cystitis results from an activated latent virus. The clinical evidence, although incomplete, suggests that disease of the urinary tract is not acquired as a result of viremia and is not a complication of a generalized infection. In both Japan and the United States, males are 2 to 4 times more likely to be affected than females. Systematic studies have not been conducted among persons of various age groups, and the occurrence of this syndrome other than in Japan and the United States has not been documented. The accumulated information is largely clinical. Pathological studies have not been reported, although im-

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Adenoviruses

munocytochemical studies of exfoliated urinary tract epithelial cells document infection. A case of orchitis in a 5-year-old child with a concomitant adenovirus infection has been reported (Naveh and Friedman, 1975).

DIGESTIVE TRACT DISEASE Adenoviruses often are recovered using traditional cell culture techniques from the stools of healthy children and those with diarrheal disease. Early attempts to associate these virus isolates with disease proved futile, for they were so frequently recovered from health study subjects (Sterner et al, 1961; Richmond et ah, 1979). During the early 1970s, a new class of adenovirus was demonstrated in the stools of children with diarrhea using the technique of immune electron microscopy. It proved impossible to recover these viruses using traditional cell cultures, and they were therefore considered to be uniquely fastidious (Whitelaw et al, 1977). Accordingly, other sensitive diagnostic approaches were developed (i.e., the ELBA and DNA restriction analyses). Only somewhat later were cell cultures found that proved susceptible to these so-called fastidious adenoviruses (Cukor and Blacklow, 1984). Systematic studies have now established specific serotypes (40 and 41) of adenovirus as a cause of diarrhea in infants and children. Indeed, these agents are believed to be the second most common etiology of viral diarrhea (Kapikian, 1993). Affected children usually experience a protracted illness of as long as 10 days, accompanied by fever and occasional respiratory symptoms (Uhnoo et al., 1986). Pathological studies of the digestive tract tissue of children with adenovirus diarrheal disease have not been reported. Intussusception, an acute and often life-threatening surgical emergency in infants and young children, has many causes. However, in the majority of cases, pathologic study demonstrates hyperplasia of the lymphoid tissue of Peyer's patches at the lead point of the intussusception in the ileum, or at the ileocecal junction. Boys are affected twice as often as girls. A growing body of information associates adenovirus infections of the intestinal mucosa and mesenteric lymph nodes with this condition (Prince, 1979). Children hospitalized with intussusception may be more susceptible to infection, as they appear to have a lower prevalence of serum antibodies to the common adenovirus serotypes and virological work has documented infection of the gut in a substantial proportion of cases. In the studies of Ross et al. (1962), serotypes 1, 2, 5, 6, and 7 were

isolated. In other reports, no specific virus type predominated (Bell and Steyn, 1962; Ross et al, 1962). The so-called enteric adenoviruses that are commonly associated with diarrheal disease are not customarily recovered from patients with intussusception (Bhisitkul et al, 1992). Morphologic evaluation of the mucosa of surgically excised gut and appendices have demonstrated typical adenovirus cytopathology in the intestinal mucosa of roughly one-third of cases (Yunis et al, 1975; Montgomery and Popek, 1994).

MYOCARDIAL DISEASE Several case reports document the sporadic occurrence of lymphocytic interstitial myocarditis in newborns and children infected with adenoviruses (Towbin et al, 1994). To date, virus has not been recovered from heart tissue, and cells exhibiting the typical cytological features of an adenovirus infection have not been found in the myocardium; but in two cases, PCR of formalin-fixed paraffin-embedded heart tissue demonstrated the presence of adenovirus DNA (Lozinski et al, 1994). The evidence supporting an adenovirus causation in many clinical cases is circumstantial, based largely on the demonstration of a concurrent infection in other body tissues (Chany et al, 1958; Sterner, 1962; Van Zaane and Van der Veen, 1962; Berkovich et al, 1968; Henson and Mufson, 1971). In mice, a murine strain of adenovirus replicates in endothelial cells and myocytes, causing a destructive interstitial myocarditis and a valvulitis (Blailock et al, 1968). Towbin and his colleagues (1994) recently accomplished the diagnosis by PCR using blood from an acutely ill mother and her fetus, which had dilated cardiomyopathy and hydrops. In a case of sudden death with myocarditis, adenovirus DNA was demonstrated in myocardial cells (Shimizu et al, 1995). By their nature, the reports referred to above document fatal cases studied pathologically. The prevalence of myocarditis in adenovirus-infected persons with a nonfatal outcome is unknown.

CENTRAL NERVOUS SYSTEM DISEASE Meningoencephalitis of varying degrees of severity has been described in infants and children and, on occasion, in adults with and without systemic manifestations of infection, in particular, pneumonia (Chany et al, 1958; Gabrielson et al, 1966; Huttunen, 1970; Simila et al, 1970; Chou et al, 1973; Kelsey 1978; Kim and Gohd, 1983; Koskiniemi and Vaheri, 1982; Lelong et al.

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1956; West et a/., 1985; Anders et al, 1990-91). Brain biopsies have yielded adenoviruses type 2 (West et al, 1985), type 3 (Faulkner and van Rooyen, 1962), type 4, type 5 (Faulkner and van Rooyen, 1962), type 7 (Lord et al, 1975), type 11 (Osamura et al, 1993), and type 32 (Roos et al, 1972). In the small number of surgical brain biopsies thus far studied, the pathological changes have ranged from perivascular cuffing and gliosis to frank necrosis of parenchyma. Comprehensive autopsy studies have not been reported, and much remains to be learned about the pathological features of the central nervous system disease and its pathogenesis. On rare occasions, Reye syndrome has been reported in children with adenovirus pneumonia (Ladisch et al, 1979).

EYE DISEASE During mobilization for the Second World War, workers at scattered shipyards in the United States developed a severe, unilateral or bilateral, painful, and purulent chronic conjunctivitis. The condition often followed visits to eye clinics for the treatment of minor industrial injuries to the eyes. Commonly, the disease occurred in outbreak form and was ultimately traced to the instrumentation, solutions, and hands of ophthalmologists. The work of Jawetz (1959) established the etiological role of adenoviruses of several different serotypes. Later outbreaks were documented in family clusters, such as among playmates attending swimming pools, and among sexual partners (where venereal transmission by means of the adenovirus-infected genital secretions was a consideration). In a recent study, 5% of cases of conjunctivitis occurring over a 10-year period were attributed to adenovirus with, types 3, 4, and 7 being the predominant serotypes isolated (O'Donnell et al, 1993). During the acute stages of the infection, pseudomembranes often form on the corneal surfaces followed by the appearance of subepithelial corneal infiltrates. Occasionally, hemorrhage occurs in the eyes. Finally, a superficial punctate keratitis develops. These exudative lesions, and the associated visual problems persist for weeks or months, or at times even longer. Immunohistochemistry, in situ hybridization, and negative staining electron microscopy can be used to establish the diagnosis in scrapings from the cornea. Adenoviruses are often readily recoverable from the conjunctival exudates during the acute stages of the illness. In the exudates, polymorphonuclear leukocytes predominate. Cells with the specific cytopathic effects of adenoviruses have not been described.

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C H A P T E R

15 Retroviruses: General Principles

r

he family Retroviridae is comprised of three subfamilies. These are the spumaviruses, the oncoviruses, and the lentiviruses. The spumaviruses are curiosities. To the best of our knowledge, they play no role in disease of humans and lower animals. The oncoviruses are endogenous to a variety of animal species, including subhuman primates. They are the traditional tumor viruses that were the subject of considerable cancer research in the past. This large and complex subfamily of viruses infect a wide variety of animal species (at last count, over 20) but are not known to be pathogenic for humans. The oncoviruses are now divided into five genera. The

virions are often carriers of integrated protooncogenes that represent biologically important genes acquired from the animal host in which the virus is replicated. Familiar agents of historical importance are the Rous sarcoma virus of avian species, various murine leukemia viruses, the feline leukemia virus, and the mouse mammary tumor virus. The human T cell leukemia/lymphoma viruses 1 and 2 (HTLV-1 and HTLV-2) are pylogenetically related to agents endogenous to certain subhuman primates. They are genetically distinct and only distantly related to the two lentiviruses of great human importance: human immunodeficiency viruses types 1 and 2 (HIV-1

FIGURE 15.1 Budding of HIV-1 virions from the surface of a cultured cell as demonstrated by scanning electron microscopy (7000x). Reprinted with permission and through the courtesy of P. Roingeard and D. Brand.


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and HIV-2). The genome of the human T cell leukemia/lymphoma viruses and the human immunodeficiency viruses are similar. The RNA of the virion is comprised of three critical structural genes {gag, pol, and env) and two accessory regulatory genes. The pol gene codes the reverse transcriptase enzyme that is characteristic of this family of viruses. This enzyme converts the two identical 9.2-kb single strands of viral RNA to double-stranded DNA and, in turn, integrates this DNA with the DNA of the cell, ultimately resulting in formation of the progeny provirus. The env gene is responsible for formation of the viral envelope, and the gag gene directs synthesis of the virions matrix protein. The regulatory genes of HIV-1 and -2 {rev and tat) and of HTLV-1 and -2 {tax and rex) play important roles in the pathogenicity of the viruses, and contribute to the unique functions of the virus. HIV-1 and -2 have sev-

eral luxury genes, the roles of which are incompletely defined, but they no doubt endow the virion with important biological properties yet to be elucidated. Structurally, the nucleocapsid of the virion encompasses its genetic reservoir. It is surrounded by the envelope, which is formed as the virus buds from the surface of the infected cell (Figures 15.1 and 15.2). The lentiviruses of hun\ans are similar to several virus agents of importance in domestic animals. These include visna/maedi, sheep viruses of historical significance, and the more recently recognized feline and bovine immunodeficiency viruses. There are, in addition, a number of endogenous lentiviruses of subhuman primates. Several of these, the simian immunodeficiency viruses (SIVs), have proven to be valuable models for HIV-1 infection in hunnans.

FIGURE 15.2 Murine leukemia virus, a nonhuman retrovirus. (A) Budding of virions from the plasma membrane of a cultured cell. (B) Electron microscopy of negatively stained virions showing surface features. (C) The concentric arrangement of the core, shell, and nucleoid of the virion. (D) The hexagonal arrangement of the subunits of the shell around the core of the virion is recognizable. Bars = 100 nm. Reprinted with permission from and through the courtesy of H. Frank and W. Schafer.

C H A P T E R

16 Human Immunodeficiency Viruses HUMAN IMMUNODEFICIENCY VIRUSES 1 AND 2 (HIV-1 AND HIV-2) 205 HIV-1 CLINICAL COURSE IN ADULTS 207 HIV-1 CLINICAL COURSE IN INFANTS AND CHILDREN 210 PERSISTENT GENERALIZED LYMPHADENOPATHY (PGL) (SYN. PROGRESSIVE GENERALIZED LYMPHADENOPATHY) 212 DISEASES OF THE HEMATOPOIETIC SYSTEM 215 DISEASES OF THE CENTRAL NERVOUS SYSTEM 216 Acute Meningitis 216 HIV-1 Encephalopathy 216 Cognitive/Motor Complex (Syn. Dementia Complex) 217 Myelopathy and Myelitis 219 Neuropathy 219 Myositis 220 Opportunistic CMV Infections of the Central and Peripheral Nervous Systems 221 DISEASES OF THE RESPIRATORY TRACT 222 Diffuse Alveolar Damage (DAD) 222 Lymphoid Interstitial Pneumonia (LIP), Nonspecific Interstitial Pneumonia (NIP), Follicular Bronchitis/Bronchiolitis (FBB) 222 Pulmonary Hypertension and VascularOcclusive Disease 223 Opportunistic Infections of the Lung 225 DISEASES OF THE HEART 226 DISEASES OF THE VASCULATURE 227 DISEASES OF THE KIDNEY 228 DISEASES OF THE TESTIS 229 DISEASES OF THE DIGESTIVE TRACT 230 TUBULORETICULAR STRUCTURES (TRSs) AND CYLINDRICAL CONFRONTING CISTERNAE (CCC) 231 LYMPHOMAS 231 KAPOSI'S SARCOMA 232 CERVICAL CANCER 234 REFERENCES 234

promiscuity in the early 1980s. The origin of the virus is shrouded in mystery. Very recent evidence suggests that it may have been a naturally infected chimpanzee. The route by which it gained access to the homosexual community is unknown. However, the environment for the dissemination by sexual means of this heretofore unrecognized highly infectious agent was propitious at the time. The clinical appearance of cases of Kaposi's sarcoma (due to sexually transmitted HHV-8; see Chapter 12) and Pneumocystis carinii pneumonia (originating from obscure sources) proved to be harbingers of the cellular immune deficiency caused by the agent originally termed human T cell lymphotropic virus (HTLV-3) and later. Type 1 Human Deficiency Virus (HIV-1). The clinical term Acquired Immunologic Deficiency Syndrome (AIDS) was coined soon thereafter, but the clinical definition of this syndrome underwent several revisions as our knowledge grew. The appearance of the virus in male homosexuals in San Francisco was soon followed by outbreaks in Los Angeles and New York, where concentrations of sexually active male homosexuals clustered. The pandemic had begun, and it was not long before a new population of susceptibles turned up with AIDS, that is, the sufferers of hemophilia who were recipients of blood concentrates derived from pooled human plasma. As events unfolded, the source of the blood products used for treatment of these unfortunate patients all too frequently proved to be a donor with a subclinical HIV-1 infection. In 1985, HIV-1 was recovered in laboratories in Paris and Bethesda, Maryland. Sadly, the unfortunate controversy of priority tarnished the brilliance of the pathfinding virological work conducted on both sides of the Atlantic. The more recent history of the worldwide AIDS pandemic is only too well known. While HIV-1 continues to be a threat for male homosexuals engaging in sexual interactions without prophylaxis, it is a latent hazard for the i.v. drug abuser and his/ her sexual consort. Heterosexual intercourse is increasingly serving as a major route of viral transmission, by means of semen, saliva, and genital secretions, in

H U M A N IMMUNODEFICIENCY VIRUSES 1 A N D 2 (HIV-1 A N D HIV-2) The sexual revolution of the 1970s set the stage for the appearance of HIV-1 in epicenters of homosexual PATHOLOGY AND PATHOGENESIS OF HUMAN VIRAL DISEASE

205


206


populations where the background prevalence of infection is high and promiscuity an accepted practice. Increasingly, sex workers (e.g., prostitutes) serve as the vector. In Africa, where the prevalence of subclinical infection among the members of the general population is exceedingly high, transmission appears to occur largely by heterosexual routes. A recent report from New York illustrates the changing patterns of viral dissemination, as reflected in the prevalence of autopsies on patients with AIDS in a major metropolitan hospital. During the 1980s, male homosexuality was a risk factor in 25% of HIV-1 cases coming to autopsy, whereas in the period 1989-95 it comprised only 13% of AIDS autopsies. Twenty-four percent of AIDS autopsies were done on heterosexual patients in the 1980s, while in the 1989-95 time period the incidence was 36%. The number of cases of AIDS occurring in intravenous drug users proved to be stable over the period 1980-96 (Concepcion et al., 1996). As illustrated by Tables 16.1, 16.2, and 16.3, opportunistic infections are the hallmark of the AIDS syndrome. In these patients, the commonest lifetime opportunistic infection is Pneumocystis carinii, with lifethreatening pneumonia occurring in about two-thirds of AIDS cases. Kaposi's sarcoma develops in about 50% of cases, and disseminated infections by bacteria of the Mycobacterium avium complex or Mycobacterium tuberculosis are documented in approximately a third. Cytomegalovirus-related disease in various organ systems are observed in 20% of patients with AIDS, although subclinical infections with this virus exist in the majority of those with clinical AIDS. As discussed in more detail below, the number of cases of Kaposi's sarcoma has decreased since the early 1980s, whereas mycobacterial infections are increasingly common. Undoubtedly, the opportunistic infections of importance to AIDS patients will continue to change as new antimicrobial therapies are introduced and treatment of the primary disease improves. As with other lentiviruses, HIV-1 and its less common sibling, HIV-2, possess two identical strands of RNA of about 9.2 kb that are converted into a proviral double-stranded DNA in the nucleus of the infected cell by a unique enzyme, reverse transcriptase, during the early stages of replication. The viruses exhibit similar morphological features and are approximately 120 nm in diameter. An enormous amount of new information has accumulated on the composition of the human lentivirus genome, and on the genes unique to both HIV-1 and HIV-2. The virus genes code for a functionally complex panoply of enzymes and proteins that are elaborated and produced during the course of replica-

TABLE 16.1 C o m m o n Opportunistic Central N e r v o u s S y s t e m Infections and D i s e a s e of Patients w i t h A I D S (in order of frequency) Clinical/pathological process

Etiologic agents

Encephalitis and polyradiculitis

Cytomegalovirus Herpes simplex, type 1 (Chapters 7, 8)

Pseudotumor

Toxoplasma gondii

Meningitis

Cryptococcus neoformans Mycobacterium avium complex

Progressive leukoencephalopathy

Papovirus (BK, JC) (Chapter 22)

B cell lymphoma

Epstein-Barr virus (Chapter 9)

TABLE 16.2 C o m m o n Opportunistic Lung Infections and D i s e a s e i n Patients w i t h A I D S (in order of frequency) Clinical/pathological process

Etiologic agents

Interstitial pneumonia

Cytomegalovirus (Chapter 8) Pneumocystis carinii

Abscess-forming pneumonia with granulomatous and purulent inflammation

Cryptococcus neoformans Mycobacterium tuberculosis Histoplasma capsulatum Coccidioides immitis

Purulent pneumonia with or without abscesses

Streptococcus pneumoniae Haemophilus influenzae Pseudomonas aeruginosa Klebsiella pneumoniae Staphylococcus sp.

TABLE 16.3 C o m m o n Opportunistic D i g e s t i v e Tract Infections i n pre-AIDS and A I D S (in order of prevalence) Oral/oral pharynx^ Candidiasis

Intestinal^ Candidiasis

Hairy cell leukoplakia (Chapter 9)

Cytomegalovirus (Chapter 8)

Kaposi's sarcoma (Chapter 12)

Microsporidiasis

Melanotic macules

Mycobacterium avium complex

Herpes simplex virus, type 1 (Chapter 7)

Cryptosporidia

Condyloma accuminatum (Chapter 21) Amoeba sp. Molluscum contagiosum (Chapter 25) Bacterial glossitis ''Barone et al (1990). ^Greenson et al (1991).

Salmonella sp.


tion. The enveloping lipid membrane of the virion and its constituent glycoproteins are critical to viral attachment and replication, as well as the tropism of the virus for the specific receptors on the target cell. Of these, the external surface glycoprotein, gpl20, and the transmembrane glycoprotein, gp41, are key. In addition, the membrane incorporates several of the important marker antigens of the virus. Infection of susceptible cells by HIV-1 (and, presumably, HIV-2) requires interaction of the major capsid glycoprotein, gpl20, with the CD44- receptor on its surface. Other receptors of the CCR4/CCR5 chemokine family serve as coreceptors and are required for uptake of the virus by the cell. The coreceptor for virions that are macrophage-tropic are CCR5, whereas the comparable coreceptor for the CD4+ cell is CCR4. These receptors are found on the dendritic cells (the so-called Langerhans cells) of the skin and mucus membranes that are the usual primary site of infection. The gp41 protein also participates by facilitating transport of the virion across the plasma membrane, where it is subsequently uncoated. The gene coding membrane glycoprotein gpl20 has highly mutable segments that serve to alter the antigenic makeup of the virus. Since the antigens on the surface of the virions in an individual patient are in an evolutionary state of flux, traditional host immune mechanisms often prove impotent as control measures. Major antigenic differences in gpl20 also serve as the basis for classification of the viral genotypes currently catalogued by the designations A through I. These represent families of viruses that predominate in various regions of the world. There is currently no evidence to indicate that the members of these various families differ in pathogenicity (Janssens et aU 1997). HIV-2 is a genetically distinct lentivirus closely related to a simian immunodeficiency virus endemic in West African Sooty Mangabey monkeys. While virologically similar to HIV-1, the RNA molecular sequences of the two viruses differ. HIV-2 occurs commonly in the coastal equatorial countries of the West African bulge (Guinea Bissau, Senegal, and Gambia), with a much lower frequency elsewhere in Africa, Europe, and North America. HIV-2 is believed to spread by heterosexual intercourse. The virus appeared before HIV-1 in its endemic areas of West Africa, but it is gradually diminishing in prevalence among the population. On the other hand, HIV-1 is spreading into West Africa, even though the incidence of new infections is still substantially lower than in East and Central Africa. Among women of reproductive age in Abidjan, Cote de Ivoire during 1992, the incidence of HIV-2 infection was 1.7%, whereas 9.4% of the same population had serological evidence of HIV-1 infection

207

(De Cock et al, 1993). In the United States, the prevalence of infection, as determined by screening of blood donors between 1992 and 1995, was 2 cases per 7.4 x 10^ units of blood. HIV-2-associated AIDS has not been reported in North America (O'Brien et a/., 1992). HIV-2 appears to be less infectious, and blood concentrations of the virus tend to be lower than in persons infected with HIV-1. While the development of AIDS from HIV2 is well documented in its endemic region, the clinical illness seems to be less severe (De Cock et al, 1993; Ariyoshi et al, 1996), although the distribution and types of lesions occurring in HIV-2- and HIV-1-infected patients with AIDS are similar (Lucas et al, 1991). Thus, the epidemiological and clinical evidence strongly suggests that HIV-2 originated in West Africa as the result of one or more interactions between humans and the Sooty Mangabey monkey. Because of its relatively low infectivity the virus may have now reached an epidemic peak and is on the decline. There is little evidence to suggest that it will spread pandemically in a fashion similar to HIV-1.

HIV-1 CLINICAL COURSE IN ADULTS HIV-1 infections typically are acquired when the virus transits the genital or oral mucosa and is taken u p by the dendritic Langerhans cells in the lamina propria of the epithelium. The transmitted viruses (the socalled R5 strains) customarily are the macrophagetropic variants that use the gpl20 receptor and the CCR5 coreceptor on the plasma membrane of the Langerhans cell to facilitate uptake. The nasopharyngeal tonsils and adenoids are also richly endowed with dendritic cells, and no doubt can serve as a site of virus entry. Thus, the Langerhans macrophage appears to ''screen" a heterogenous population of viruses, permitting entry of R5 variants, agents that are much less pathogenic than the T cell-tropic syncytialforming R4 variant viruses that evolve relatively late in the course of a naturally acquired infection. Persons whose cells lack CCR5 coreceptors through a homogenous deletion of its genes are relatively resistant to infection with "wild" strains of HIV-1. Clearly, defects in cytokine receptors, of which there may be many, dictate, at least in part, the ultimate course of the infection (McNicholl et al, 1997; Smith et al, 1997). After acquisition of the virus, Langerhans cells fuse with circulating CD4+ T lymphocytes, which, in turn, disseminate the virus. Lymph nodes draining the site of infection yield virus when tested 48 hours after exposure.

208

Pathology and Pathogenesis of Human Viral Disease 1200

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FIGURE 16.1 Clinical course of HIV-1 infection in typical patient demonstrating a dramatic reduction of CD4+ cells during the acute episode shortly after infection and subsequent gradual deterioration in the CD4+ T cell reserves until the AIDS syndrome evolves. The concentrations of virus in the blood increase dramatically during the ''acute'' episode of illness that occurs shortly after infection, and during the terminal AIDS syndrome. The concentrations of HIV-1 RNA in the blood parallel the virus concentrations. Reprinted with permission from and through the courtesy of A. Fauci, MD.

and viremia can be documented shortly thereafter. Persons who inadvertently acquire the virus parentally from patients with advanced HIV-1 infections may receive an inoculum of the more pathogenic R4 variants. Figure 16.1 depicts certain parameters of the typical clinical course of disease progression. In 50 to 70% of patients, the first evidence of HIV-1 infection proves to be a "mononucleosis-like" syndrome that develops several weeks after exposure and persists for about 2 to 4 weeks thereafter (mean duration = 25 days) (Table 16.4) (Clarke et al, 1991; Vanhems et al, 1997; Kahn and Walker, 1998). The syndrome is often not diagnosed because HIV-1 antibodies are not yet detectible in the blood. There is a high level of viremia with widespread dissemination of the virus, but the major sites of virus replication at this stage are undefined. Virological and immunological events may dictate the future course of the infection. CD8+ cytotoxic T cells targeted against the virus appear to play a key role in the host's initial response to the virus. As they appear in the blood, viremia abates. Humoral antibodies appear much later and do not seem to be important actors in the body's initial response to infection. The relative height of the viremia in the early stages of the infection (often greater than 10^ RNA molecules per milliliter) correlates inversely with the duration of patient survival (Wong et al, 1996). Although the

TABLE 16.4 Percentage of Patients w i t h Acute HIV-1 Infections Manifesting S i g n s and S y m p t o m s >50%

Fever (temperature >38°C) Lethargy Cutaneous rash Myalgia Headache

>25%-50%

Pharyngitis or sore throat Cervical adenopathy Arthralgia Oral ulcer Odynophagia

5-25%

Weight loss Nausea Diarrhea Night sweats Cough Anorexia Abdominal pain Vomiting Photophobia Sore eyes Tonsillitis Depression Dizziness Adenopathy Oral candidiasis Genital ulcers

Adapted with permission from Vanhems et al. (1997).


relative pathogenicity of the virus may be a factor accounting for the duration of the latency period, as has been found in a few cases (Cao ei al, 1995; Operskalski et al, 1997), host factors appear to be of primary importance. Of these, the major histocompatibility complex (MHC) type of host cells, and its complement of cytokine receptors, may be critical. At present, evidence supporting the notion that histocompatibility antigens may dictate the intensity of the infection or the luxuriance of the immune response is limited and based largely on the finding of a loose but statistically significant association of AIDS with certain MHC types. Several mechanisms whereby molecules encoded by MHC genes might predispose an individual to infection are worthy of brief consideration. First, certain MHC class I and II alleles could limit progression of the HIV-1 infection by serving as a restriction element for one of several immunodominant HIV-1 T helper or cytolytic T cell epitopes (thus promoting a salutary immune response to HIV-1). Alternatively, a lack of protective MHC alleles could predispose to development of AIDS because of a poor immune response. Certain MHC alleles could also predispose an individual to pathogenic immune responses against viral epitopes in various tissues. Lack of an AIDS-promoting MHC allele type might protect against pathogenic responses of the immune system to HIV-1 (Haynes et al, 1996; Hill, 1996). The duration of the clinical latency period and its outcome appear to be dictated at least in part by the cellular and antibody-mediated immune responses to HIV-1 antigens. CD8+ cytolytic T cells are of paramount importance, for they can destroy virus-producing dendritic cells. The elaboration of neutralizing antibodies also may contribute to control and dissemination of extracellular virus, but the role of humoral immunity is less clearly defined. It may also participate in antibody-dependent cell-mediated immunity. For unknown reasons, individual infected patients differ substantially in terms of the briskness and degree of their immune response to the virus. This ultimately determines virus concentrations in the blood and tissue, considerations that appear to influence the duration of the latency period. Differences in the immunoresponsivity of the host are compounded by evolving rapid changes in the antigenic makeup of the virion due to the hypermutability of certain viral genes. On a continuous basis, this may abrogate the effectiveness of a previously elaborated protective antibody. One can envision an evolving immune response to an ever-changing series of viral epitopes.

209

About 10% of HIV-infected persons develop AIDS within 2 to 3 years after acquisition of the virus. Disease in these patients can be fulminating (Michael et al, 1997) with, for example, a rapidly progressive dementia (Bassiri et al, 1995; Holland et al, 1996). Roughly 10 to 15% of those infected with HIV-1 will remain AIDSfree indefinitely, whereas the remainder (about 75%) develop the disease with a median latency period of 10 years (Haynes et al, 1996). The basis for these differences in disease progression is currently unclear, although much new information relevant to the question is accumulating. Race and gender do not appear to influence susceptibility and progression of HIV-1 infections. The factors that correlate with the duration of the latency period are: (1) the levels of cell-associated virus in the blood, and the plasma RNA concentration (Fang et al, 1997), (2) the relative proportion of circulating syncytium-inducing (SI) variants of the virus (Koot et al, 1996; Spijkerman et al, 1998). Patients infected initially with the syncytium-inducing HIV-1 variant usually develop AIDS within 5 years. These variants have the ability to infect and replicate in both macrophages and T cells (Yu et al, 1998). The tendency of infected CD4+ cells to undergo apoptosis (Liegler et al, 1998) is an additional factor. Certain virus variants are highly pathogenic and have specific tropism for the CD4+ T lymphocytes. The blood virus and RNA concentrations correlate inversely with CD4+ cell counts, and the amounts increase substantially as the CD4+ cell numbers fall to a critical level. At this stage, the CD4+-tropic SI virions predominate in the blood and tissues. Longterm HIV-1 survivors possess CD4+ T cells that are resistant to apoptosis, whereas the disease in patients with T cells that readily undergo apoptosis tends to progress more rapidly (Liegler et al, 1998). AIDS in the adult is a clinical syndrome that customarily appears when CD4+ lymphocyte counts in the blood fall to less than 200/mm^ (see Figure 16.1) and high concentrations of virus and viral RNA are found in the blood and tissues (Bagasra et al, 1996). It is usually manifest as one or a combination of opportunistic infections and, to a variable extent, Kaposi's sarcoma and malignant lymphoma. The U.S. Centers for Disease Control and Prevention (CDC) has established a schema for categorizing individual cases, primarily for use in research and epidemiology (Table 16.5). It distinguishes between category B illnesses and lifethreatening infections of major organ systems of category C (Table 16.6). In this chapter, the more common infections and neoplasms associated with AIDS will be considered below.

210

Pathology and Pathogenesis of Human Viral Disease TABLE 16.5 1993 R e v i s e d Classification S y s t e m for HIV-1 Infection and Expanded A I D S Surveillance Case D e f i n i t i o n for A d o l e s c e n t s and A d u l t s Clinical category (A) asymptomatic acute (primary) HIV or PGL''

CD4+ Tcell category

(B) symptomatic. not (A)or(C) conditions

(C) AIDS-indicator conditions*"

(1)>500/^1

Al

(2)200-199/^1

A2

Bl B2

CI C2

(3)
Kahn, J., and Walker, B. (1998). Acute human immunodeficiency virus type 1 infection. Curr. Concepts 339, 33-39. Kalayjian, R., Cohen, M., Bonomo, R., and Flanigan, T. (1993). Cytomegalovirus ventriculoencephalitis in AIDS: A syndrome with distinct clinical and pathologic features. Medicine 72, 67-77. Ketzler, S., Weis, S., Huag, H., and Budka, H. (1990). Loss of neurons in the frontal cortex in AIDS brains. Acta Neuropathol. 80, 92-94. Khalil, S., Nounou, R., Frayha, H., Halim, M., Ellis, M., and Black, F. (1996). Bone marrow morphologic findings in patients with human immunodeficiency virus (HIV) infection. Ann. Saudi Med. 16, 16-19. Kim, K., and Factor, S. (1987). Membranoproliferative glomerulonephritis and plexogenic pulmonary arteriopathy in a homosexual man with acquired immunodeficiency syndrome. Hum. Pathol 18,1293-1299. Kimmel, P., Phillips, X, Ferreira-Centeno, A., Farkas-Szallasi, T., Abraham, A., and Garrett, C. (1992). Brief report: Idiotypic IgA nephropathy in patients with human immunodeficiency virus infection. New Engl J. Med. 327, 702-706. Kiviat, N., Critchlow, C , Hawes, S., Kuypers, J., Surawicz, C , Goldbaum, G., van Burik, J., Lampinen, T., and Holmes, K. (1998). Determinants of human immunodeficiency virus DNA and RNA shedding in the anal-rectal canal of homosexual men. /. Infect. Dis. 177, 571-578. Klatt, E., and Meyer, P. (1988). Pathology of the heart in acquired immunodeficiency syndrome (AIDS). Arch. Pathol. Lab. Med. 112, 114. Knowles, D., Chamulak, G., Subar, M., Burke, J., Dugan, M., Wernz, J., Slywotzky, C , Pelicci, P., Dalla-Favera, R., and Raphael, B. (1988). Lymphoid neoplasia associated with the acquired immunodeficiency syndrome (AIDS). Ann. Intern. Med. 108, 744-753. Koeppin, A., Lansing, L., Peng, S., and Smith, R. (1981). Central nervous system vasculitis in cytomegalovirus infection. /. Neurol. Sci 51, 395-410. Koot, M., van't Wout, A., Kootstra, N., de Goede, R., Tersmette, M., and Schuitemaker, H. (1996). Relation between changes in cellular load, evolution of viral phenotype, and the clonal composition of virus populations in the course of human immunodeficiency virus type 1 infection. /. Infect. Dis. 173, 349-354. Kornfeld, H., and Axelrod, J. (1983). Pulmonary presentation of Kaposi's sarcoma in a homosexual patient. Am. Rev. Respir. Dis. 127, 248-249. Kornstein, M., Pietra, G., Hoxie, J., and Conley M. (1986). The pathology and treatment of interstitial pneumonitis in two infants with AIDS. Am. Rev. Respir. Dis. 133, 1196-1198. Lairmore, M., Rosadio, R., and DeMartini, J. (1986). Ovine lentivirus lymphoid interstitial pneumonia. Am. J. Pathol. 125, 173-181. Lamperth, L., Dalakas, M., Dagani, F., Anderson, J., and Ferrari, R. (1991). Abnormal skeletal and cardiac muscle mitochondria induced by zidovudine (AZT) in human muscle in vitro and in an animal model. Lab. Invest. 65, 742-751. Landesman, S., Kalish, L., Burns, D., Minkoff, H., Fox, H., Zorrilla, C , Garcia, P., Fowler, M., Mofenson, L., and Tuomala, R. (1996). Obstetrical factors and the transmission of human immunodeficiency virus type 1 from mother to child. New Engl J. Med. 334,1617-1623. Langston, C , Lewis, D., Hammill, H., Popek, E., Kozinetz, C , Kline, M., Hanson, I., and Shearer, W. (1995). Excess intrauterine fetal demise associated with maternal human immunodeficiency virus infection. /. Infect. Dis. 172,1451-1460. Lathey, J., Spector, D., and Spector, S. (1994). Human cytomegalovirus-mediated enhancement of human immunodeficiency virus type-1 production in monocyte-derived macrophages. Virology 199, 98-104.

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17 Human T Cell Leukemia/Lymphoma Viruses (HTLV-1 and -2) INTRODUCTION 243 T CELL LEUKEMIA/LYMPHOMA (TLL) SYNDROME TROPICAL SPASTIC PARAPARESIS (TSP) 247 INFLAMMATORY CONDITIONS ASSOCIATED WITH

bution in certain population groups. These various strains of HTLV-1 do not appear to differ in pathogenicity. It is estimated that 10 to 20 million persons have contracted HTLV-1 worldwide, with there being an approximate 5% life risk of serious disease developing as a consequence of this infection. Although the virus is now widely distributed among residents of developed countries, the initially endemic foci were first identified in the southern islands of the Japanese archipelago (including Okinawa) (Figure 17.1), the Caribbean Islands and adjacent regions of northeast South America, and West Africa, particularly the Congo Basin. It also occurs sporadically in residents of the southeastern United States and in restricted clusters of Iranian Jewish immigrants in Israel, Native Americans in British Columbia, and in certain tribes in New Guinea. Members of these latter clusters are infected with strains carried during tribal migrations in the distant past (Yamashita et ah, 1996). Three modes of transmission of the virus are documented. Maternal infection of infants by breastfeeding is the primary route in most endemic societies. Transplacental infection is believed to be an unlikely route. In Japan, viral transmission in endemic regions is substantially reduced when seropositive mothers abstain from breastfeeding, or when breast milk is stored at 4°C for 24 hr. Acquisition of infection in the postnatal period appears to result in the greatest risk of acquiring T cell leukemia/lymphoma. Infection also occurs commonly by means of blood transfusion and to a lesser extent by intravenous drug usage. Fresh frozen plasma is not infectious, an indication that the cellular components of the blood serve as the vector of the virus. As might be expected, storage of blood at 4°C for 24 hr reduces infectivity substantially. The rate of acquisition of infection from transfused blood increases dramatically when the cell con-

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HTLV-llNFECTION 248

HTLV-2 249 REFERENCES

250

INTRODUCTION HTLV-1 and -2, 90 run in diameter, are C-type retroviruses having specific tropism for human helper/inducer T cells. HTLV-1 was initially isolated from the T cells of a patient with a cutaneous lymphoma mistakenly thought to be mycosis fungoides/Sezary syndrome (Poiesz ei ah, 1980). Cell cultures of hairy cell leukemia yielded the first strains of HTLV-2. The molecular make-up of these two viruses is similar to other retroviruses, but they possess, in addition, a unique X region in the genome that endows the viruses with exceptional biological properties. The two genes in this X region are now termed tax and rex. HTLV-1 and -2 are closely related to a leukemia/lymphoma virus of bovine origin that has a cosmopolitan distribution and sporadically causes malignant disease in infected cattle. Detailed molecular analyses establish a close link between HTLV-1 and similar agents in subhuman Old and New World primates. Transmission of HTLV-like simian virus to humans may have happened on at least three occasions, but these rare hypothetical events most probably occurred in man's ancient past. As a result, three different subtypes of HTLV-1 are established in various populations worldwide. The most widely distributed type was most probably disseminated by means of the slave trade in centuries past. The other strains of HTLV-1 exhibit a more endemic distri-


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•

Bi \m \m •

110SB-iie M~ 88 20~5B ~20

Kyushu F I G U R E 17.1 Adult T cell leukemia/lymphoma incidence rates (per 1 x 10^ persons) in the Japanese archipelago. Reprinted with permission from Anonymous (1996).

centration of virus is greater than 10^. The risk of infection from a unit of contaminated blood is estimated to range from 15 to 60%. Persons acquiring the virus by means of transfusion seem to be at particularly high risk of developing the HTLV-1 neurological disease described below. Serological screening for HTLVl/HTLV-2 blood for transfusion was initiated in the United States in 1988. Sexual transmission also serves as a route of infection; women are almost invariably at risk. In one Japanese study, the risk for transmission from husband to wife over a 10-year period was estimated to be 60%, whereas wife-to-husband transmission almost never occurred. In another study from Japan, 50% of wives of HTLV-1 seropositive men were infected after 4 years of marriage. Horizontal infection of the wife by the husband and vertical infection of children from the mother most probably account for the clustering of cases in individual families and in communities. The incidence of HTLV-1 among female sex workers in a South American city was found to increase with duration of prostitution. After 6 years the prevalence of seropositivity was 16%. There is currently circumstantial evidence to indicate that an infection acquired sexually can result in disease, although it occurs later in life (Araujo and Andrada-Serpa, 1996), but the possibility exists that sexually transmitted infections of other types may enhance replication of HTLV-1 in infected persons (Anonymous, 1996).

T-CELL LEUKEMIA/LYMPHOMA (TLL) SYNDROME In 1977, Japanese hematologists described a unique T cell lymphoproliferative disease affecting middleaged adults in Kyushu, the southernmost island of the Japanese archipelago (Uchiyama et ah, 1977). Five years later, Catovsky ei al. (1982) documented a cluster of black adults in the Caribbean with a clinical and pathological entity identical to the Japanese syndrome. Later studies in the United States further characterized the leukemia and ultimately resulted in recovery of the etiologically responsible retrovirus (Poiesz et al, 1980; Bunn et al, 1983). HTLV-1 TLL is characterized by an indolent progressive course that may or may not terminate in a precipitous acute phase. Initially, an HTLV-1 carrier is asymptomatic, although a few abnormal lymphocytes may be found in the blood. Occasionally, there is fever and ill health. The outcome of this phase is variable in duration, but most HTLV-1 carriers manifest no further progression of the disease. A smoldering form of TLL is also recognized. In this condition, erythematous, papillary, and nodular skin lesions develop in association with the presence of atypical lymphocytes in the blood as described above. The clinically overt stage of TLL due to HTLV-1 is rapidly progressive and of short duration, presumably

Human T Cell Leukemla/Lymphoma Viruses

occurring after a prolonged prodromal period. It is characterized by lymphocytosis comprised of morphologically distinctive malignant CD4+ cells. While the numbers of lymphocytes in the peripheral blood are variable over a wide range, the numbers are on average in the neighborhood of 25,000 mm^. Anemia is seen in fewer than half of patients, and thrombocytopenia does not occur. Lymphadenopathy, hepatosplenomegaly and hypercalcemia with or without accompanying lytic bone lesions occur concomitantly. About 60% of patients with adult TLL exhibit infiltrative skin lesions that pathologically show both dermal and epidermal involvement with Pautrier's microabscesses. Adult TLL leukemia is characterized by the presence of medium-sized, often pleomorphic, lymphocytes in the blood (Figure 17.2A-D). These cells have a convoluted multilobulate nucleus. They are sometimes termed "flower cells." The cells vary in size in individual patients, as well as among patients of the same ethnic background. They exhibit the T3+T4+T8- phenotype of mature peripheral helper T cells. The cells typically demonstrate chromosomal abnormalities during the acute stages of disease, but the patterns of the karyotype abnormalities do not measurably differ from those found in T cell leukemias not associated with HTLV-1 infection. TLL peripheral blood cells can, at times, be confused with the circulating cells of Sezary syndrome, which have a typical hyperchromatic cerebriform nucleus. Bone marrow examination reveals variable numbers of malignant lymphoid cells and, at times, osteoclastic activity with evidence of bone reabsorption. In one series, 40% of patients had radiologically demonstrable lytic bone lesions (Jaffe et ah, 1984). Hypercalcemia was consistently present in those with bone disease, but it can be seen in the absence of a leukemic infiltrate. The enlarged lymph nodes accompanying the disease exhibit a diffuse loosely scattered population of cells of mixed size, including a large pleomorphic variant cell. Follicular nodularity is not evident (Lukes and Collins, 1992) (Figure 17.2E-G). The liver shows infiltrates in the portal region that extends into the adjacent parenchyma. Other sites of infiltrative involvement are the lung, digestive tract, and kidney, as well as the meninges of the central nervous system. The predominant form of adult lymphatic leukemia is of B cell origin. It exhibits a relatively indolent prolonged course, extending over years or decades. In contrast, T cell leukemias in adults are much less common but have a more aggressive clinical course and are often rapidly fatal. Mycosis fungoides/Sezary syndrome is a chronic largely cutaneous form of T cell

245

lymphoma. The skin lesions of this syndrome must be differentiated from those occurring in TLL. Systematic molecular studies of skin lesions from cases of cutaneous T cell lymphoma, large cell lymphoma, lymphomatoid papulosis, and Hodgkin's disease have failed to reveal any evidence to suggest that these conditions are HTLV-1 related (Kikuchi ei al, 1997; Arai et al, 1994; Wood et al., 1997). Finally, some hematologists include lymphoproliferative disorders comprised of T-gamma cells and characterized by the presence of large granular lymphocytes. The lesions have the features of malignant natural killer cells (Knowles, 1986; Pandolfi et al, 1992). While the classical clinical features of these various skin conditions are distinctive, exclusion of an HTLV-1 etiology for a skin problem in individual cases of leukemia/lymphoma may require virological evaluation. What mechanisms are involved in the transformation of CD4+ T lymphocytes by HTLV-1? At present, we have no specific answers to this question, but intriguing observations support feasible hypotheses. As noted above, TLL occurs sporadically and is rare, even in populations with a high frequency of endemic infection. The disease requires many decades to develop, during which time evidence of a reversible preleukemic state slowly evolves. When leukemia develops, only a small proportion of malignant cells contain identifiable viral protein or virions, whereas most cells exhibit no evidence of viral transcription. Unlike many of the retroviruses of lesser species, that is, the so-called oncornaviruses, the HTLV-1 genome does not incorporate cellular oncogenes acquired during growth in animal tissue. In addition to the constitutive retrovirus genes (gag, pol, and env), the HTLV-1 genome contains a sequence known as pX. The pX gene codes at least three proteins — p21. Tax and Rex. The latter two proteins are intrinsic to viral replication. Tax activates transcription of the viral genome, whereas Rex is a negative regulatory factor. Thus, the interaction of these two gene products plays an intrinsic role in continued virus expression and, accordingly, replication. However, Tax has additional functions, for it activates a plethora of cellular genes including those of the lymphokines such as IL-2 and IL-6, and their receptors, as well as various nuclear protooncogenes and cell surface molecules. It is not surprising that in experimental settings the Tax protein can extend the lifespan of lymphocytes, increase the growth of fibroblasts in agar, and act synergistically with the Ras oncogene to transform rodent cells. Incorporation of the Tax gene in the germline of mice results in a transgenic animal having a marked predisposition for the development of neurofibromas. Findings of this

246


F I G U R E 1 7 . 2 Adult T cell leukemia associated with HTLV-1 infection. The illustrations are from from a single case and are reprinted with permission from Lukes and Collins (1992). (A) Peripheral blood. A peripheral blood smear shows small lymphocytes with extraordinary variation in nuclear configuration with deep indentation and cloverleaf patterns. The cytoplasm is slightly azurophilic and vacuolated. Small nucleoli are noted. Wright's stain. xlOOO. (B) Peripheral blood. Occasional large blasts are present in this peripheral blood smear, although their percentage is usually low. They have finely acidophilic nuclear chromatin and small nucleoli. The cytoplasm is azurophilic and contains multiple small vacuoles. Wright's stain. xlOOO. (C) Peripheral blood. A cytospin preparation of peripheral blood reveals marked accentuation of the nuclear configurational changes with indentation and lobulation. Wright's stain. xlOOO. (D) Peripheral blood. A plastic-embedded section of buffy coat shows only limited nuclear invagination, illustrating that the degree of indentation and lobulation varies considerably with the conditions of the preparation. xlOOO. (E) Lymph node. In this illustration, there is diffuse involvement without any follicular nodulation. Sinuses are dilated and often contain loosely scattered neoplastic cells. The capsule is not involved. H&E. x32. (F) Lymph node. This section shows remarkable variation in size and nuclear configuration of neoplastic cells. This variation is more apparent than in the peripheral blood illustrations. H&E. x600. (G) Lymph node. An MGP stain emphasizes the abundance of the lightly pyroninophilic character of the cytoplasm. Prominent nucleoli are seen. MGP. x600.

Human T Cell Leukemia/Lymphoma Viruses

type show that Tax is, in fact, a classical oncogene. Conceivably, then. Tax and its cell products could play both an autocrine and a paracrine role in stimulating the growth of infected populations of cells. The extraordinary Tax protein has additional capabilities, for it binds cell cycle inhibitors in a manner similar to protein products of classical DNA tumor viruses. These proteins appear to suppress the naturally occurring cell negative regulators, Rb and p53, thus allowing for runaway cell growth. The various Tax functions described above have, to a large extent, been documented by in vitro studies. What occurs in humans is unclear. The evidence thus far presented does not necessarily serve as a basis for concluding that infection can result in malignant transformation. Rather, one might hypothesize that, as of yet, unidentified cofactors are critical determinants of malignancy. Chromosomal alterations in the HTLV-1infected cell, not dissimilar from those found in nonviral T cell leukemia, may result in a malignant genotype. At present, we just don't know (Hjelle, 1991; Pandolfi et al, 1992; Hollsberg and Hafler, 1993; Yoshida, 1996).

TROPICAL SPASTIC PARAPARESIS (TSP) (syn. HTLV-1-Associated Myelopathy [HAM])

TSP was initially associated with HTLV-1 infection by serological means in studies of patients residing in Jamaica (Cruickshank, 1956; Gessain et ah, 1985). A similar syndrome was found to occur throughout the Caribbean basin as well as in the Cote dTvoire and in the Seychelle Islands. Shortly thereafter, the syndrome was described in Japan, but the designation of HAM was applied there. TSP and HAM are now believed to be identical clinical and pathological entities associated worldwide with HTLV-1 infection (Touze et ah, 1996). Although the etiological relationship of HTLV-1 with TSP/HAM is now well established, the incidence in endemic clusters is low, that is, 0.25% in Jamaica. However, the prevalence of the disease among seropositive persons differs greatly in various geographic regions. For example, the incidence in Martinique is roughly 1.5 to 3%, while in southern Japan it is less than 0.1%, a 15to 30-fold difference (Kaplan et al., 1990). In the same geographic region of the Democratic Republic of the Congo, a threefold difference in prevalence of the disease among various isolated tribes is found. Environmental factors and host genetic influences may be important considerations in the pathogenesis of the

247

disease, but the relative virulence of different virus strains and the mode of acquisition of the virus could play an important role. TSP/HAM is a chronic, but progressively evolving, demyelinating myelopathy primarily, but not exclusively, involving the lateral corticospinal, spinocerebellar, spinothalamic, and posterior corticocerebral tracts (Figure 17.3). Posterior sensory tracts are occasionally affected, but to a relatively minor degree. The lesions are most prominent in the cervical and thoracic cord. At autopsy, axonal loss is often extensive in the cord areas of demyelinization (Levin et al, 1997) (Figure 17.4). Foci of gliosis and chronic perivascular lymphocytic infiltration are sometimes seen (Rosenblum et al., 1992). Typically, the leptomeninges are thickened by fibrosis and hyalinized perivascular fibrosis is seen. Variable numbers of lymphocytes are found in association with small blood vessels in the meninges. In the brain, lymphocytic perivascular cuffing is occasionally found in the medulla and pons, as well as in the white matter of the cerebrum and cerebellum (Akizuki et al, 1987). Patients exhibit a spastic paresis of the lower extremities accompanied by urinary bladder sphincter problems, male impotency, and intestinal obstipation (Domingues et al, 1995). Sensory complaints occur, but they are not a prominent feature of the syndrome. In Japan, the mean age of onset is 44 years, but children in the first decade of life are occasionally affected. The latency period proved to be less than 3.4 years in half of those who developed the infection consequent to blood transfusion (Ijichi et al, 1996). The pathogenic role of HTLV-1 in TSP/HAM is unclear, but there is no evidence to indicate that the disease results from direct involvement of the spinal cord by the virus. Indeed, the clinical data suggest that a chronic inflammatory process (in which HTLV-1-infected CD4+ and CD8+ lymphocytes are found) precedes development of the destructive lesions of the cord. This observation has led some investigators to conclude that TSP/HAM is an idiosyncratic hypersensitivity process mediated immunologically. If so, the target antigen(s) have yet to be identified (Jacobson, 1996). Alternatively, other observations indicate that the infiltrating activated virus-infected lymphocytes may release cytochemicals and cytokines directly, damaging nervous system tissue (Ijichi et al, 1996). Patients tend to have a hyperactive immune system with high concentrations of CD8+ HTLV-1-sensitized lymphocytes and HTLV-1 DNA in the blood and spinal fluid (Levin et al, 1997). Additional pathological characterization of the early stages of this fascinating but

248


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FIGURE 17.3 HTLV-1 spinal cord demyelinating lesion. Cervical cord (top) showing the loss of myelinated axons, largely from lateral corticospinal and posterior spinocellular tracts, but also to an extent in fasciculi gracii as reflected in pallor and shrinkage of these regions. Thoracic segment of cord (bottom) exhibiting diffuse pallor of the lateral and anterior columns. Both HTLV-1-infected patients had HIV-1 associated AIDS. Vacuolar changes are not conspicuous in these specimens, but circumferential leptomeningeal fibrosis and thickening of meningeal blood vessels is evident (Luxol fast blue/hematoxylin-eosin stains). Reprinted with permission from Rosenblum et al. (1992).

poorly understood myelopathy are needed in order for us to assess more critically assess the pathogenic mechanisms involved in this disease.

INFLAMMATORY C O N D I T I O N S ASSOCIATED WITH HTLV-1 INFECTION Several inflammatory disorders of presumptive autoimmune pathogenesis have been described in HTLV-1-infected persons, some of whom are also afflicted with TSP/HAM. Of these, polymyositis, arthritis, and uveitis are best documented. At present, a mechanistic basis for these various lesions is lacking, but the evidence suggests that activated infiltrating HTLV-1-infected CD4+ cells initiate the release of a

plethora of cytokines and cell surface receptors, thus triggering localized inflammation. Interestingly enough, transgenic mice carrying the Tax gene of HTLV-1 develop an inflammatory arthritis and a Sjogren-like parotitis (Green et al, 1989; Iwakura et al, 1991). The polymyositis is characterized by the gradual onset of proximal muscle weakness and an electromyographic picture consistent with inflammation. Histologically, the striated muscles exhibit atrophy, necrosis, and fibrosis associated with prominent infiltrates of macrophages and lymphocytes. The predominant infiltrating lymphocytes are CD8+, cytolytic T cells. These cells have been shown to carry the HTLV1 genome (Osame et al, 1986; Sherman et al, 1995); however, there is no evidence to suggest that muscle cells are infected.

249

Human T Cell Leukemla/Lymphoma Viruses

B

FIGURE 17.4 Immunohistochemical analysis of inflammatory cell infiltrates in spinal cord of HTLV-1-infected women with paraplegia accompanied by dysphagia and dysarthria. Reactive cells stain brown. (A) Perivascular T cell infiltrates. The infiltrate is largely comprised of CD8+ cells (B) that are activated, as shown by their reaction with CD45RO antibody (C). Panel D documents a robust macrophage response. Reprinted with permission from Levin et al. (1997).

The arthropathy is chronic and customarily monarticular. It involves predominantly, but not exclusively, the large joints. Older women who are long-term carriers of HTLV-1 comprise the majority of those so affected. Rheumatoid factor is not elaborated in response to the disease. Arthroscopy shows a villous synovial hyperplasia, an observation confirmed by biopsy. There is, in addition, radiological documentation of destructive changes in the bone and cartilage of the joint. Pathological study reveals synovial cell atypicalities and infiltrates of CD8+ lymphocytes. Some studies have suggested that the synovial cells are infected, but the matter remains to be resolved. Both the infiltrating lymphocytes and synovial fluid are infected with HTLV-1, as demonstrated by PCR. An increased prevalence of uveitis in young adults with HTLV-1 antibodies has been reported from Japan. Bronchitis and alveolitis are also believed to occur in some HTLV-1-infected patients. The inflammatory cell infiltrates in the eye carry the HTLV-1 genome (Mochizuki et ah, 1996). In endemic areas, both thyroiditis of the Hashimoto stroma type and Sjogren's syndrome are found, with

increased prevalence in persons who possess HTLV-1 serum antibodies (Nishioka, 1996).

HTLV-2 Although HTLV-1 and HTLV-2 share 65% of their nucleotide sequences and are morphologically similar, the two viruses differ with regard to their disease-causing potential and population distribution. HTLV-2 was first recovered from a patient with atypical hairy cell leukemia in 1982 (Kalyanaraman et al., 1982); and a second isolate from a similar case was reported 4 years later (Rosenblatt et ah, 1986). This uncommon leukemia tends to occur in middle-aged men (Chang et ah, 1992) and is probably of B cell origin. The possible association of HTLV-2 with hairy cell leukemia would, in retrospect, seem to be fortuitous, for no evidence of an etiologic relationship has accumulated in more recent years. Similarly, infection with HTLV-2 has been demonstrated in a few patients with TSP/HAM, but a

250


causative link has not been established. Thus, at present, HTLV-2 reniains an orphan with no recognized disease-causing potential for humans. HTLV-2 has a unique geographic distribution, with endogenous clusters having been identified in many, but certainly not all American Indian tribes in North, Central, and South America (Figure 17.5). These include the Pueblos of New Mexico/Arizona, the Seminoles of Florida, and the Yakima of the Pacific Northwest. In Panama, a focus exists in the Guaymi tribes, but not in the nearby closely related San Bias tribal groups. In South America, the virus is distributed widely among scattered tribes from the Caribbean coast to southern Argentina, but no apparent ethnic link serves as a common denominator (Figure 17.5).

YAKIMA NAVAJO

PUEBLO

(nb) GUAYMI

(nb) TOBA

(nb) MATACX)

(nb) FIGURE 17.5 Native American populations with endemic HTLV-2 infections. Reprinted with permission from Anonymous (1996).

In a carefully conducted study of members of the Gran Chaco tribe in western Paraguay and northern Argentina, the overall prevalence of serological reactivity proved to be 22%, with the incidence increasing with advancing age. As with HTLV-1, infection appeared to be transmitted sexually by the male, and postnatally by breastfeeding (Ferrer et al., 1996). As a result, clustering of cases within families proved to be common. For reasons that are totally unclear, serologic evidence of infection is found commonly in i.v. drug users in North America and Europe. In the United States, HTLV-1 seropositive donors of blood are more often infected with HTLV-2 than with HTLV-1. There is also epidemiologic evidence to suggest that HTLV-2 is

spread sexually by non-Native American populations (Weiss, 1994; Khabbaz et al, 1992). Because HTLV-1 and -2 share antigenic determinants, some concern exists regarding the accuracy of the customary ELISA screening methods. More refined techniques (i.e.. Western blot analysis and radioimmunoprecipitation assays) are required to differentiate the two viruses. The sensitivity of the serological assays also proves it to be a potential problem. As a result, serological survey results and populations studies may not detect all who have been infected (Hall et al, 1994; Rios et al, 1994). References Akizuki, S., Nakazato, O., Higuchi, Y, Tanabe, K., Setoguchi, M., Yoshida, S., Miyazaki, Y, Yamamoto, S., Sudou, S., Sannomiya, K., and Okajima, T. (1987). Necropsy findings in HTLV-I associated myelopathy. Lancet 1,156-157. Anonymous (1996). '"Human Immunodeficiency Viruses and Human T-Cell Lymphotropic Viruses.'' "lARC Monographs on the Evaluation of Carcinogenic Risks to Humans/' Vol. 67. WHO, Lyons. Aral, E., Chow, K., Li, C , Tokunaga, M., and Katayama, I. (1994). Differentiation between cutaneous form of adult T cell leukemia/lymphoma and cutaneous T cell lymphoma by in situ hybridization using a human T cell leukemia virus-1 DNA probe. Am. J. Pathol. 144,15-20. Araujo, A.-C, and Andrada-Serpa, M. (1996). Tropical spastic paraparesis/HTLV-I-associated myelopathy in Brazil. /. Acquit. Immune Defic. Syndr. Hum. Retrovirol. 13 (Suppl. 1), S33-S37. Bunn Jr., R, Schechter, C , Jaffe, E., Blayney, D., Young, R., Matthews, M., Blattner, W., Broder, S., Robert-Guroff, M., and Gallo, R. (1983). Clinical course of retrovirus-associated adult T-cell lymphoma in the United States. New Engl. J. Med. 309, 257-264. Catovsky, D., Greaves, M., Rose, M., Galton, D., Goolden, A., McCluskey, D., White, J., Lampert, L, Bourikas, G., Ireland, R., Brownell, A., Bridges, J., Blattner, W, and Gallo, R. (1982). Adult T-cell lymphoma-leukaemia in blacks from the West Indies. Lancet 1, 639-643. Chang, K., Stroup, R., and Weiss, L. (1992). Hairy cell leukemia: Current status. Am. J. Clin. Pathol 97, 719-738. Cruickshank, E. (1956). A neuropathic syndrome of uncertain origin: Review of 100 cases. West Indian Med. J. 5,147-158. Domingues, R., Muniz, M., Pinho, J., Bassit, L., Jorge, M., Alquezar, A., Marchiori, R, Chamone, D., and Scaff, M. (1995). Human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis in Sao Paulo, Brazil. Clin. Infect. Dis. 20,1540-1542. Ferrer, J., Esteban, E., Dube, S., Basombrio, M., Segovia, A., PeraltaRamos, M., Dube, D., Sayre, K., Aguayo, N., Hengst, J., and Poiesz, B. (1996). Endemic infection with human T cell leukemia/lymphoma virus type IIB in Argentinean and Paraguayan Indians: Epidemiology and molecular characterization. /. Infect. Dis. 174, 944-953. Gessain, A., Barin, R, Vernant, J., Gout, O., Maurs, L., Calender, A., and De The, G. (1985). Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet 2, 407410. Green, J., Hinrichs, S., Vogel, J., and Jay, G. (1989). Exocrinopathy resembling Sjogren's syndrome in HTLV-1 tax transgenic mice. Nature 341, 72-74.

Human T Cell Leukemia/Lymphoma Viruses Hall, W., Kubo, T., Ijichi, S., Takahashi, H, and Zhu, S. (1994). Human T cell leukemia/lymphoma virus, type II (HTLV-II): Emergence of an important newly recognized pathogen. Sem. Virol. 5,165-178. Hjelle, B. (1991). Human T-cell leukemia/lymphoma viruses: Life cycle, pathogenicity, epidemiology, and diagnosis. Arch. Pathol. Lab. Med. 115, 440^50. HoUsberg, P., and Hafler, D. (1993). Pathogenesis of diseases induced by human lymphotropic virus type I infection. New Engl. J. Med. 328,1173-1182. Ijichi, S., Nakagawa, M., Umehara, R, Higuchi, I., Arimura, K., Izumo, S., and Osame, M. (1996). HAM/TSP: Recent perspectives in Japan. /. Acquir Immune Defic. Syndr. Hum. Retrovirol. 13 (Suppl. 1), S26-S32. Iwakura, Y, Tosu, M., Yoshida, E., Takiguchi, M., Sato, K., Kitajima, I., Nishioka, K., Yamamoto, K., Takeda, T., and Hatanaka, M. (1991). Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-I. Science 253,1026-1028. Jacobson, S. (1996). Cellular immune responses to HTLV-I: Immunopathologic role in HTLV-I-associated neurologic disease. /. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 13 (Suppl. 1), SIOOS106. Jaffe, E., Blattner, W., Blayney, D., Bunn Jr, P., Cossman, J., RobertGuroff, M., and Gallo, R. (1984). The pathologic spectrum of adult T-cell leukemia/lymphoma in the United States. Am. J. Surg. Pathol. 8, 263-275. Kalyanaraman, V., Sarngadharan, M., Robert-Guroff, M., Miyoshi, I., Blayney, D., Gould, D., and Gallo, R. (1982). A new subtype of human T-cell leukemia virus (HTLV-II) associated with a T-cell variant of hairy cell leukemia. Science 218, 571-573. Kaplan, J., Osame, M., Kubota, H., Igata, A., Nishitani, H., Maeda, Y, Khabbaz, R., and Janssen, R. (1990). The risk of development of HTLV-I-associated myelopathy/tropical spastic paraparesis among persons infected with HTLV-I. /. Acquir. Immune Defic. Syndr. 3,1096-1101. Khabbaz, R., Onorato, I., Canon, R., Hartley, T., roberts, B., Hosein, B., and Kaplan, J. (1992). Seroprevalence of HTLV-I and HTLV-II among intravenous drug users and persons in clinics for sexually transmitted diseases. New Engl. J. Med. 326, 375-380. Kikuchi, A., Ohata, Y, Matsumoto, H., Sugiura, M., and Nishikawa, T. (1997). Anti-HTLV-1 antibody positive cutaneous T-cell lymphoma. Cancer 79, 269-274. Knowles III, D. (1986). The human T-cell leukemias: Clinical, cytomorphologic, immunophenotypic, and genotypic characteristics. Hum. Pathol. 17,14-33. Levin, M., Lehky, T., Flerlage, A., Katz, D., Kingma, D., Jaffe, E., Heiss, J., Patronas, N., McFarland, H., and Jacobson, S. (1997). Immunologic analysis of a spinal cord-biopsy specimen from a patient with human T-cell lymphotropic virus type I-associated neurologic disease. New Engl. J. Med. 336, 839-845. Lukes, R., and Collins, R. (1992). ''Tumors of the Hematopoietic System,'' 2nd ed., 28, p. 409. Armed Forces Institute of Pathology, Washington, DC.

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Mochizuki, M., Ono, A., Ikeda, E., Hikita, N., Watanabe, T., Yamaguchi, K., Sagawa, K., and Ito, K. (1996). HTLV-I uveitis. /. Acquir Immune Defic. Syndr Hum. Retrovirol. 13 (Suppl. 1), S50-S56. Nishioka, K. (1996). HTLV-I arthropathy and Sjogren syndrome. /. Acquir. Immune Defic. Syndr Hum. Retrovirol. 13 (Suppl. 1), S57S62. Osame, M., Usuku, K., Izumo, S., Ijichi, N., Amitani, H., Igata, A., Matsumoto, M., and Tara, M. (1986). HTLV-I associated myelopathy, a new clinical entity. Lancet i, 1031-1032. Pandolfi, F., Zambello, R., Cafaro, A., and Semenzato, G. (1992). Biologic and clinical heterogeneity of lymphoproliferative diseases of peripheral mature T lymphocytes. Lab. Invest. 67, 274302. Poiesz, B., Ruscetti, R, Gazdar, A., Bunn, P., Minna, J., and Gallo, R. (1980). Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc. Natl. Acad. Sci. U.S.A. 77, 7415-7419. Rios, M., Khabbaz, R., Kaplan, J., Hall, W., Kessler, D., and Bianco, C. (1994). Transmission of human T cell lymphotropic virus (HTLV) type II by transfusion of HTLV-I-screened blood products. /. Infect. Dis. 170, 206-210. Rosenblatt, J., Golde, D., Wachsman, W., Giorgi, J., Jacobs, A., Schmidt, G., Quan, S., Gasson, J., and Chen, I. (1986). A second isolate of HTLV-II associated with atypical hairy-cell leukemia. New Engl. J. Med. 315, 372-377. Rosenblum, M., Brew, B., Hahn, B., Shaw, G., Haase, A., Maroushek, S., and Price, R. (1992). Human T-lymphotropic virus type I-associated myelopathy in patients with the acquired immunodeficiency syndrome. Hum. Pathol. 23, 513-519. Sherman, M., Amin, R., Rodgers-Johnson, P., Morgan, O., Char, G., Mora, C , lannone, R., Collins, G., Papsidero, L., Gibbs Jr., C , and Poiesz, B. (1995). Identification of human T cell leukemia/lymphoma virus type I antibodies, DNA, and protein in patients with polymyositis. Arthritis Rheum. 38, 690-698. Touze, E., Gessain, A., Lyon-Caen, O., and Gout, O. (1996). Tropical spastic paraparesis/HTLV-I-associated myelopathy in Europe and in Africa: clinical and epidemiologic aspects. /. Acquir Immune Defic. Syndr. Hum. Retrovirol. 13 (Suppl. 1), S38-S45. Uchiyama, T., Yodoi, J., Sagawa, K., Takatsuki, K., and Uchino, H. (1977). Adult T-cell leukemia: Clinical and hematologic features of 16 cases. B/oorf 50, 481-492. Weiss, S. (1994). The evolving epidemiology of human T lymphotropic virus type II. /. Infect. Dis. 169,1080-1083. Wood, G., Schaffer, J., Boni, R., Dummeer, R., Burg, G., Takeshita, M., and Kikuchi, M. (1997). No evidence of HTLV-I proviral integration in lymphoproliferative disorders associated with cutaneous T-cell lymphoma. Am. J. Pathol. 150, 667-673. Yamashita, M., Ido, E., Miura, T., and Hayami, M. (1996). Molecular epidemiology of HTLV-I in the world. /. Acquir Immune Defic. Syndr. Hum. Retrovirol. 13 (Suppl. 1), S124-S131. Yoshida, M. (1996). Multiple targets of HTLV-1 for dysregulation of host cells. Sem. Virol. 7, 349-360.


C H A P T E R

18 Hepatitis Viruses Although hepatitis has been recognized clinically since the time of the earliest recorded medical history, knowledge of its epidemiology was exclusively observational. Perhaps the most insightful information on the illness developed in the 1960s, when the late Saul Krugman and his associates conducted studies on the residents of Willowbrook State Hospital in Staten Island, New York. This work provided for the first time definitive clinical evidence that two different transmissible agents with clearly defined incubation periods were involved. Their insightful work, which later proved to be the target of much public criticism, was based on inoculation of experimental samples of blood containing virus into institutionalized mentally handicapped children, who would have otherwise naturally contracted the infections early in the course of their residence in this long-term custodial setting. My next experience with hepatitis occurred in the early 1970s, when I worked with June Almeida, whose unique skill was with negative staining of viruses, and whose interest at the time was the newly discovered Australian antigen, a morphologic enigma in the blood of patients with the long-incubation form of hepatitis (Almeida et al., 1971). At the time, I was astonished when we regularly discovered this antigen in the blood of healthy Africans while conducting studies on serum samples brought to us from his homeland by the dynamic young Nigerian pathologist A. O. Williams. This finding provided a preliminary insight into the medical importance of chronic subclinical hepatitis B virus infections in Africa, and the potential importance of the viral carrier state so common in Africans and Asians. During the ensuing years, as work with hepatitis B provided interest for legions of investigators, others turned to explore the etiology of the short-incubation hepatitis described as MS-1 by Krugman and his colleagues at Willowbrook. Using the electron-microscopic technique of negative staining, Feinstone and his colleagues (1973) demonstrated the presumptive causative virus in stool samples from patients with acute hepatitis; six years later. Provost and Hilleman

INTRODUCTION 253 ORALLY ACQUIRED SHORT-INCUBATION-PERIOD ACUTE HEPATITIS 254

Hepatitis A Virus (HAV) 254 Hepatitis E Vims (HEV) 255 PARENTALLY ACQUIRED LONG-INCUBATION-PERIOD ACUTE AND CHRONIC HEPATITIS 257

Hepatitis B Virus (HBV) 257 Hepatitis D Virus (HDV) (Delta Agent) 260 Hepatitis C Virus (HCV) 260 CHRONIC HEPATITIS ( C H ) 262 HEPATOCELLULAR CARCINOMA ( H C C ) 264 AUTOIMMUNE HEPATITIS (AH) 270 PAPILLARY ACRODERMATITIS (GIANOTTI-CROSTI SYNDROME; GCS) 271 GLOMERULONEPHRITIS 272 REFERENCES 273

INTRODUCTION It was one of those inadvertent needle pricks self-inflicted while culturing the blood of my newly admitted patient with a fever of unknown origin. I thought little about it at the time, but in retrospect, I was pleased to learn a few days later that the bacterial blood cultures were sterile. The patient was soon discharged afebrile, but without a diagnosis. I can only assume now that it was subclinical hepatitis, for just 30 days later the incident immediately came to mind when my urine exhibited the deep mahogany tint that can only be attributed to bilirubin. I suddenly felt ill, and indeed I soon was, with fever, overwhelming malaise, anorexia, and the obvious jaundice that serves as the basis for the clinical diagnosis of acute hepatitis. At the time, I was aware of the so-called hepatitis A, that is, the short-incubation form, and hepatitis B, the so-called long-incubation form of hepatitis, but little else. As an intern in 1957,1 also possessed some knowledge of postnecrotic cirrhosis, but how and under what circumstances it developed was obscure. There were no diagnostic tests for the hepatitis viruses, and treatment was limited to bed rest and a good diet.


253


254


TABLE 18.1 Features of Hepatitis Viruses: Their Associated Liver Disease Typical transmission mechanism Virus Virus family Nucleic acid type Virion diameter Genotypes Incubation period (days) Viremia Virus in stool Acute mortality Chronic hepatitis Cirrhosis Hepatocellular carcinoma

Perinatal/ parenteral/ sexual

Fecal-oral/ ,waterborne HAV Picornavirus RNA 28 7 15-50 Brief +
"™-HBsAg (Envelope) —HBcAg/HBeAg {Nucleocapsid) [—DNA polymerase --Circular DNA (HBV genome)

-~-™-? X protein FIGURE 18.3 (A) HBV particles in the blood as demonstrated by negative staining immune electron microscopy (122,000x). Reprinted with permission from Huang and Groh (1973). (B) Schematic representation of HBV illustrating key antigenic components. Reprinted with permission from Gerber and Thung (1985).

258


FIGURE 18.4 (a) ''Ground glass" hepatocytes in a liver biopsy from a patient with asymptomatic chronic hepatitis, (b) Hepatocytes stained by immunochemistry to identify HBsAg. Reprinted with permission from Afroudakis et ah (1976).

cytes of the infected liver do not lyse as a result. In general, HBsAg is synthesized in excess; it accumulates in the cytoplasm, resulting in the typical ground-glass appearance of the infected cell cytoplasm (Figure 18.4). It also spills over into the blood, where it is found as the pleomorphic spherical and tubular noninfectious antigen particles known as Australian antigen (see Figure 18.2). Customarily, these particles are intermixed with variable numbers of the so-called Dane particles, which are the true virions of HBV in the blood. In the developed countries of North America and Europe, HBV is transmitted in blood products and by the needles and syringes used by consumers of illicit addictive drugs. Sexual interactions are an additional means of transmission, but the mechanism involved is not understood. With rigorous but highly effective screening of blood products for transfusion, new infections are now almost exclusively limited to the subculture of drug abusers and those who engage in promiscuous sexual activity. Many of these individuals are also HIV-1 positive. Subclinical, anicteric hepatitis proves to be the rule in infants and children. Asymptomatic anicteric hepatitis occurs in roughly 60 to 80% of those acquiring the virus during adulthood. The remainder exhibit chemical or overt clinical acute hepatitis after latency periods of 1.5 to 4 months. While the majority of patients recover after variable periods of illness without significant liver damage, about 1% develop fatal fulminating hepatitis with massive destruction of the liver. The disease in a small number (2-10%) evolves into chronic

hepatitis. The risk of a chronic infection inversely relates to age. Ninety percent of infants infected in the perinatal period fail to clear the virus, whereas only 10% of newly infected adults develop chronic disease. These clinical conditions and their pathogenesis will be considered below. In subSaharan Africa, Southeast Asia, the People's Republic of China, and the Mediterranean Basin, transmission of HBV commonly occurs during the perinatal period. The likelihood that the infant will be infected at the time of parturition relates to the replicative activity of the virus in the mother at the time and, consequently, her virus load. The means by which the virus is transmitted from mother to infant are not well defined, but transplacental infection is likely, and bleeding at the time of birth must result in infection of some newborns. Presumably, the immature immune system of the very young child permits the virus to replicate and spread in the liver without a significant protective response. Infection of newborns is common, and 90% of these infants develop chronic hepatitis. In contrast, only 30% of children exposed after the perinatal period, but before the age of 6 years, develop chronic liver disease. Worldwide, over 2 x 10^ people are chronically infected with HBV. The pathogenesis of HBV hepatitis has been the subject of considerable research. The availability of animal models, including transgenically infected mice, and an abundance of clinical information from naturally infected humans, has made major advances possible.

259

Hepatitis Viruses

However, despite the elegance and comprehensiveness of the investigative work, gaps of considerable magnitude preclude a full appreciation of the pathogenesis of clinical hepatitis and the variable outcomes in humans of different ages and societies. Our current understanding of the mechanisms involved in HBV hepatitis are summarized in great detail in a recent review by Chisari and Ferrari (1997). The evidence now indicates that cellular immune mechanisms are key factors in the development of the hepatic lesions. CD8+ cytolytic T cells appear to be the major actors. These cells directly interact with HLA class I-expressing hepatocytes that are endogenously generating the virus. As a consequence, two independent mechanisms of cell injury may be invoked, resulting in either apoptosis or cytolysis of the liver cells (Figures 18.5 and 18.6). The first is a direct consequence of the actions of at least two types of molecules released after contact of the effector lymphocyte with its target, the infected hepatocyte. The pore-forming perforins and a lymphocyte-specific granular serine esterase are the products released by the T cells that are believed to cause cytolysis of the

hepatocytes. Apoptosis, on the other hand, may be due to a Fas-based mechanism, whereby receptors on infected target cells interact with the Fas ligands of the effector T cell (Figure 18.7). The complex mechanisms involved in these events have been recently reviewed (Schulte-Hermann et ah, 1995; Moretta, 1997). Presumably, through cytolysis or apoptosis of the hepatocyte, the infection is terminated. Regenerating liver cells are protected from reinfection either by means of cellular or humoral immune mechanisms. Contemporary thinking suggests that certain cellularly immune mechanisms downregulate the infections in the liver cells. However, direct evidence indicating that this occurs in human HBV hepatitis is currently lacking.

FIGURE 18.6 Liver of a patient infected with HCV. Note the apoptotic hepatocytes (a) and cells exhibiting ballooning of the cytoplasm (b). These are the two major nonspecific changes observed in liver parenchymal cells during hepatitis.

cytotoxic lymphocyte macrophages lymphocytes

EXECUTION

FIGURE 18.5 Electron micrograph of an apoptotic body derived from liver cells. Note the infiltrating lymphocyte (L). The hepatocyte (H) at the top of the figure appears to be unaffected. The electrondense granules in the hepatocyte are glycogen. Reprinted with permission from Ishak (1994).

HEPATOCYTE

FIGURE 18.7 Three major factors are believed to contribute to apoptosis and death of liver cells. TGFp and TNF may interact with plasma membrane receptors, resulting in cell injury. The FAS ligand also can interact APO-FAS to promote apoptosis. DAG = diacylglycerol; TCR = T cell receptor; CTL = cytotoxic lymphocytes. Reprinted with permission from Schulte-Hermann ei al. (1995).

260


While the above mechanisins most probably account in whole, or in part, for cell injury and recovery as a consequence of HBV infection in the liver of adults, the pathogenic basis for chronic hepatitis remains poorly understood. In neonatally infected infants, immunologic tolerance would appear to be the likely explanation, but in the adult with chronic hepatitis our understanding is less clear.

Hepatitis D Virus (HDV) (Delta Agent) About 1% of those infected with HBV develop acute liver failure associated with massive hepatic necrosis. Roughly 10% of newly infected adults and a much larger percentage of infants progress to chronic hepatitis, as noted above. When patients with unresolved HBV infections manifest fulminating necro-inflammatory disease or chronic hepatitis that evolves into cirrhosis, the possibility of a superinfection with the delta agent (HDV) is a consideration (Rizzetto el al, 1983; Lee, 1993; Smedile ei al, 1982). HDV is a defective virus that relies on HBV to provide its envelope protein. Thus, it parasitizes the intracellular synthetic systems of the HBV-infected cell to complete its own replicative cycle. This allows the virus to spread from cell to cell. HDV is a small (36 nm in diameter) virion that has a limited store of genetic material in a single strand of RNA that is circularized when located in liver cells (Wang ei al., 1986). While HDV is cosmopolitan in its distribution, it is usually found when the HBV carrier status of a population is relatively high, or when i.v. drug use is prevalent. However, it has also been associated with outbreaks of severe hepatitis among native populations in South America, where these risk factors are not found (Adler ei al., 1984; Ljunggren ei al., 1985; Fonseca and Simonetti, 1987). The means whereby the virus was introduced into these isolated native populations is obscure, and it is not known how the virus spreads from person to person in this setting. In developed areas such as the United States and Western Europe, fewer than 20% of the blood donors who have evidence of chronic HBV infections are also infected with HDV The acute hepatitis due to HBV cannot be dififerentiated clinically and pathologically from HBV associated with HDV (Verme ei al., 1986). Evidence of infection is detected by immunohistochemistry, or by means of in siiu hybridization. Generally, only a small proportion of the liver cells of patients with acute HBV hepatitis are positive for HDV The virus is found more commonly in the livers of patients with chronic hepatitis and cirrhosis. Not surprisingly, chronic hepatitis is the

outcome in about 20 to 25% of HDV-infected patients, and the disease frequently progresses to cirrhosis in these individuals (Rizzetto ei al., 1983). Like other hepatitis viruses, HDV is not cytolytic in vitro, and the mechanism whereby it causes liver cell injury is not understood. Hepatitis C V i m s (HCV) Before the discovery of HCV in 1989, approximately 20 to 25% of recipients of blood transfusions in urban North America and Europe developed the so-called non-A and non-B hepatitis, that is, acute hepatitis of unknown but presumptive viral etiology. More than 80% of these infections progressed to chronic hepatitis, and in a few the disease evolved into cirrhosis and hepatocellular carcinoma. By screening cDNA "expression" vectors derived from RNA in the plasma of chimpanzees inoculated with serum from patients with non-A/non-B hepatitis, clones of a new virus, termed HCV, were found. This finding, the outgrowth of a truly unique laboratory approach to viral diagnosis, was followed by an extraordinary effort to elucidate the biology of HCV and establish its clinical and epidemiological features. The development of several efficient blood screening methodologies has now largely eliminated this virus as a threat for the recipient of blood transfusions. At present, HCV is unclassified virologically, but it possesses many of the molecular and structural features of members of the flaviviridae family (see Chapters 19 and 24) (Cuthbert, 1994). It is a 30- to 34-nm-indiameter enveloped virus having a single-stranded RNA genome surrounded by an envelope derived from the cell in which it grows. The virus has not been successfully grown in cultured cells; thus, much of the information we possess today is derived from investigations conducted in experimentally infected chimpanzees. HCV has a long open reading frame that contains genomic material for the synthesis of several component proteins of the virion, and one of these genes is highly mutable. Accordingly, as many as 12 genotypes of HCV have already been identified, and because of the high mutation rate, it is quite likely that new mutations appear in the patients as a virus adapts to its host. Thus, changes in the antigenicity of the virus may account for the chronicity of the infection as the virus eludes the infected person's immune response. Although immunologic studies at present are limited, both humoral and cellular immune mechanisms are involved in the host's response to infection. However, there is presently no evidence to suggest that the lesion in the liver of the HCV-infected patient has an immunopathologic basis, as is the case in HBV infection. As

Hepatitis Viruses

would be expected, the humoral immune response does not have the capacity to resolve the infection when the virus is sequestered in hepatocytes. Indeed, humoral immunity may promote selection of new pathogenic mutants in vivo on an ongoing basis. Worldwide, the incidence of HCV infection as assessed by immunologic surveys of the population varies. In Scandinavia, fewer than 1% of the general population are infected, whereas in Egypt a prevalence of 12% has been reported. Four million An\ericans are currently believed to be chronically infected with HCV and approximately 8 x 10^ to 1 x 10^ deaths occur annually as a result of this infection. The great majority of infections with HCV have, in the past, resulted from blood transfusions, but transplacental infection of the fetus and perinatal infections are documented (Lin et ah, 1994; Ohto et ah, 1994; Tovo et al, 1997), particularly in the offspring of women with high blood concentrations of virus. Sexual transmission has not been established as a mode of spread, but evidence of familial clustering of seroreactivity exists and female sex workers who have not been the recipients of blood transfusions exhibit a higher incidence of seroreactivity to the

261

virus than do female members of the general population. After exposure, HCV RNA is detected in the blood within 1 to 3 weeks. Studies in chimpanzees have shown that concentrations of virus in the liver are exceedingly high at this time. Evidence of liver cell injury in the form of increased blood levels of serum alanine aminotransferase is demonstrated, but most patients are asymptomatic and jaundice develops infrequently. An occasional patient complains of malaise, weakness, and anorexia, and a few become anoretic. The morphological features of the acute disease are illustrated in Figure 18.8. Only about 15 to 25% of patients appear to recover, whereas the remainder enter the chronic hepatitis stage during which an insidious progression of liver disease evolves over a period of decades. Nonspecific symptoms of hepatitis are noted by the occasional patient with chronic HCV hepatitis, but the disease is rarely symptomatic, and almost never disabling. Over a period of two or more decades, about 20% of patients with chronic hepatitis due to HCV develop cirrhosis, and roughly 5% of these patients subsequently develop hepatocellular carcinoma. It is likely that differences in

FIGURE 18.8 (A) Chronic hepatitis. Note the subtle disorganization of the liver parenchyma and the accumulation of lymphocytes adjacent to a necrotic hepatocyte. (B) Prominent "balloon" degeneration of hepatocytes. Note the inflammatory cells and the "dropout" of liver parenchymal cells. (C) Note the aggregates of lymphoid cells in the portal areas. (D) At higher resolution, the lymphoid cell accumulations in the liver illustrated in A encompass bile ducts. Note the normal appearance of the glycogenated cytoplasm of the hepatocyte. Reprinted with permission from Ishak (1994).

262


the pathogenicity of virus strains may account for differing degrees of disease progression. Cofactors influencing host susceptibility to the infection most probably are also an important consideration. Patients infected with both HBV and HCV seem to develop progressive disease frequently (Hytiroglou ei al., 1995). Alcoholic beverage consumption in excess is believed to be a risk factor. Although intravenous drug users with HIV-1 also develop HCV infections, HIV-1 does not appear to significantly influence the course of the disease. While fulminating hepatitis is a rare complication of HCV infection, an occasional liver transplant recipient will develop rapidly progressive hepatic disease due to the virus. Currently, a substantial proportion of the liver transplantations done in the United States are due to HCV liver damage. Recurrence of HCV infections in the grafted livers invariably occurs after transplantation. Interestingly enough, in one study the infection did not affect the life expectancy of the graft recipient over a 4-year period, but there was a higher incidence of graft rejection among HCV-infected patients (Lumbreras ei al., 1998). The majority of the recipients of these liver transplants exhibit a relatively benign course. This contrasts with the substantial mortality observed in liver transplant patients infected with HBV (Lake and Wright, 1991). The majority of the recipients of these liver transplants exhibit a relatively benign course. In one study, moderately severe chronic hepatitis developed after transplantation in 27% of patients over the 3-year period, and cirrhosis was found after a latency period of 4 years in 8% (Cane ei al., 1996). An etiological association of mixed cryoglobulinemia with HCV chronic hepatitis is now established (Ferri ei al, 1991; Agnello ei al, 1992). Most Italian patients with mixed cryoglobulinemia appear to possess HCV antibodies, but in the United States the prevalence is somewhat lower (Levey ei al, 1994). These patients exhibit petechial hemorrhages and ecchymoses in the skin of the lower extremities, and often have arthralgias, hepatosplenomegaly and glomerulonephritis. In the serum, viral RNA and virions are complexed with the cryoproteins. Three clinical categories of cryoglobulinemia have been identified (Brouet ei al, 1974). In type I, the immunoglobulins are homogenous and monoclonal. They are generally the result of a lymphoproliferative disorder such as multiple myeloma or Waldenstrom's macroglobulinemia. In the type II form, mixtures of a monoclonal immunoglobulin with anti-IgG activity (rheumatoid factor) and polyclonal IgG are found. Most cases of HCV-associated cryoglobulinemia are of this type (Agnello ei al, 1992). In the type III form, a mixture of heterogenous, and

polyclonal IgM and IgG molecules are present in the blood. Type II is associated with a diversity of infectious processes and autoimmune diseases (Bloch, 1992). The pathogenesis of cryoglobulinemia in HCV is obscure. Other forms of hepatic disease do not produce these profound abnormalities of serum proteins. About 15% of transfusion-associated hepatitis is not attributable to HBV and HCV, and it is not due to HAV or HEV. In 1967, a candidate virus was isolated from the blood of a surgeon (whose initials were G. B.) with acute hepatitis. The virus, which proved to be a flavivirus, was similar to HCV, for it was found to induce hepatitis in marmosets, a small New World primate. With further study, the agent proved to be not one but two viruses, termed GBV-A and GBV-B. These agents now appear to be indigenous to Tamarin monkeys and may be members of an entirely new, previously unrecognized genus of flaviviruses (Bukh and Apgar, 1997). Later, a third, similar virus, GBV-C, was isolated from patients (Fiordalisi ei al, 1996) with hepatitis, and a fourth, designated HGV, was similarly recovered (although it may be a genotype of GBV-C). The discovery of this confusing plethora of incompletely characterized viruses created a stir in the hepatitis research community, but it may be that the interest was unwarranted. Despite the persistence of these viruses in humans, and their association with HCV infections, the GB viruses do not appear to cause hepatitis in humans and do not play a copathogenic role with HCV in enhancing the severity of the liver disease (Alter ei al, 1997; Colombatto ei al, 1997; Hadziyannis, 1998; Loya, 1996; Brown ei al, 1997). We now know that GBVC / HGV is carried in a chronic viremic state by roughly 1 to 2% of Americans and can be transmitted by transfusion and from mother to offspring (Linnen^f al, 1996; Lin ei al, 1998; Masuko ei al, 1996; Stark ei al, 1996; Thomas ei al, 1997).

C H R O N I C HEPATITIS Chronic hepatitis is a clinical and pathologic syndrome, not a single disease. Patients may be asymptomatic, but more often they experience variable degrees of malaise and fatigue intermittently. Serum concentrations of the liver enzymes alanine and aspartate aminotransferase are usually increased, but alkaline phosphatase and gamma-glutamyl transpeptidase, bilirubin, albumin, and the various coagulation factors are customarily found in normal concentrations. Thus, the synthetic capacity of the liver parenchyma is intact.

263

Hepatitis Viruses

• .

.

•

W

0 FIGURE 18.9 Chronic hepatitis, low-power assessment of morphologic patterns. (A) Portal hepatitis involves an increase in mononuclear cells (dots), almost entirely confined to portal areas. At scanning magnification, this results in the portal areas being sharply delimited. (B) In periportal hepatitis, an increase in mononuclear cells (dots) in the periportal parenchyma (zone 1) occurs, commonly associated with piecemeal necrosis and lobular inflammation of variable degree. The result is a low-power impression of portal-dominant inflammation; however, the portal areas are less sharply defined than in portal hepatitis. (C) Lobular hepatitis is characterized by lobular inflammation, with or without disarray and necrosis. Pure lobular hepatitis is a feature of acute hepatitis; however, lobular hepatitis in conjunction with considerable portal and periportal inflammation is typical of '"flares" of chronic viral or autoimmune hepatitis. Reprinted with permission from Batts and Ludwig (1995).

Pathologically, chronic hepatitis is defined as a progressive necro-inflammatory disease of variable severity not associated with the features of chronic cholestasis, steatosis, and Mallory body formation (Ishak, 1994) (Figure 18.9). Portal fibrosis, cirrhosis, and, in some cases, hepatocellular carcinoma, are the final outcome. The term "chronic hepatitis'' commits to obsolescence a confusing nomenclature that has accumulated in the field of hepatology since the 1960s (Table 18.2) (Desmet et al, 1994; Party 1995). HBV, with or without the delta agent, and HCV are the common etiologies of chronic hepatitis in most clinical situations, but autoimmune hepatitis is responsible in sporadic cases. Superimposed infections and nutritional or toxic insults to the liver may accentuate the severity of the process. Piecemeal necrosis is the hallmark of chronic hepatitis. It is reflected as the expansive degeneration and destruction of the periportal limiting plate of liver cells, ultimately resulting in the confluence of adjacent portal areas and leading to bridging fibrosis between portal triads. The fibrosis that follows in the wake of the liver parenchymal injury (Figures 18.10-18.12) is progressive and can ultimately terminate in cirrhosis (Figure

18.13). Degenerative changes in individual liver cells consist of either cytoplasmic swelling and rarefaction or the clumping of cytoplasmic organelles (or both). Apoptotic bodies (syn. acidophilic bodies) are also seen (see Figure 18.5). To a variable extent, the portal areas

TABLE 18.2 Chronic Hepatitis and Cirrhosis: Obsolete Terms Chronic hepatitis and related conditions Chronic active hepatitis, chronic aggressive hepatitis, chronic active liver disease, plasma cell hepatitis, lupoid hepatitis, and other synonyms for autoimmune hepatitis Chronic persistent hepatitis Chronic lobular hepatitis Chronic nonsupportive destructive cholangitis Pericholangitis Cirrhosis Portal cirrhosis Postnecrotic cirrhosis Posthepatitic cirrhosis Reprinted with permission from Batts and Ludwig (1995).

264

Pathology and Pathogenesis of Human Viral Disease TABLE 18.3 Scoring S y s t e m for Grading and Staging of Liver S p e c i m e n s w i t h Chronic Hepatitis Grade of necro-inflammatory activity

Stage of fibrosis/ cirrhosis

0 = no necro-inflammatory activity

0 = no fibrosis

1 = mild piecemeal necrosis and lobular activity

1 = mild fibrosis (= portal fibrosis without fibrous septum formation)

2 = moderate piecemeal necrosis and lobular activity

2 = moderate fibrosis (= fibrous septa extending into lobules, but not reaching terminal hepatic venules and other portal tracts)

3 = Severe piecemeal necrosis and lobular activity with or without bridging necrosis

3 = severe fibrosis (= fibrous septa extending to adjacent portal tracts and terminal hepatic venules, indicating transition to cirrhosis) 4 = cirrhosis

Reprinted with permission from Batts and Ludwig (1995).

are infiltrated by B lymphocytes, plasma cells, and macrophages, which, on occasion, accumulate into follicles. Intraacinar infiltrates of inflammatory cells and activated Kupffer cells line sinusoids in the usual histological picture (Figure 18.14). The pathological changes in chronic hepatitis have been categorized semiquantitatively by Batts and Ludwig (1995) into a grading schema for clinical application (Table 18.3; Figure 18.15).

HEPATOCELLULAR CARCINOMA (HCC) (see Figures 18.16-18.19)

Numerous risk factors have been identified that are believed to cause, or contribute to, the development of HCC (Table 18.4). HCC most probably is an example of multistage carcinogenesis in which endogenous and exogenous influences act in concert to transform the hepatocyte, possibly in persons who are genetically

FIGURE 18.10 Post-transfusion HBV with submassive necrosis in a leukemic patient. A tongue of necrotic tissue bridges between lobules of liver. Reprinted with permission from Ishak (1976).

265

Hepatitis Viruses

FIGURE 18.11 Chronic hepatitis. Adjacent portal areas expanded by fibrosis are linked as demonstrated by a reticulin stain that denotes collagen. Reprinted with permission from Ishak (1994).

^"*4SS»%%'i'^V--?vt'*>/'r •'••• •:••

FIGURE 18.12 Marked periportal fibrosis with extension into the lobular structure of liver.

FIGURE 18.13 Nodular cirrhosis secondary to HCV chronic hepatitis. Note the regenerating nodules of liver parenchymal cells separated one from another by bands of connective tissue. Chronic inflammatory cell infiltrates in the fibrous tissue constitute a nonspecific change.

266


FIGURE 18.14 Mixed inflammatory cell infiltrate comprised of lymphocytes, plasma cells, and macrophages in the parenchyma of the liver from a case of chronic HCV infection.

FIGURE 18.15 Staging of chronic hepatitis, schematic diagram. (A) Portal fibrosis (stage 1) characterized by mild fibrous expansion of portal tracts. (B) Periportal fibrosis (stage 2) showing fine strands of connective tissue in zone 1 with only rare portal-portal septa. (C) Septal fibrosis (stage 3) manifested by connective tissue bridges that link portal tracts with other portal tracts and central veins, minimally distorted architecture, but no regenerative nodules. (D) Cirrhosis (stage 4) showing bridging fibrosis and nodular regeneration. Reprinted with permission from Batts and Ludwig (1995).

Hepatitis Viruses TABLE 18.4 Nonviral Risk Factors for Hepatocellular Carcinoma (HCC)

267 TABLE 18.5 Geographic Distribution of H C C 5-20«

20-15(F Aflatoxin Bj contamination of food Alpha 1 antitrypsin deficiency Anabolic and estrogenic steroid consumption Ethanol consumption Hemochromatosis Nutritional deficiencies Thorotrast diagnostic procedures Tobacco smoking

FIGURE 18.16 Extensive involvement of the liver by hepatocellular carcinoma. Note the hemorrhage and necrosis in the large central nodular mass. Elsewhere, the parenchyma is interdigitated by bands of connective tissue of varying thickness. At the resolution of the naked eye, it is often impossible to differentiate neoplastic tumor from cirrhotic liver. Reprinted from Craig et ah (1989).

predisposed. To date, no specific molecular markers have been associated with the transformational event. The pathogenic role of HBV and HCV in the neoplastic process should be considered in this context. Worldwide, some 7 X 10^ HCC deaths occur annually. The incidence of HCC exhibits great geographic variability (Table 18.5), being highest in subSaharan Africa and Southeast Asia, and lowest in the developed countries of Europe and North America. However, pockets of increased prevalence are found where immigrants from endemic areas have settled and retained their traditions as well as the diets of their former homes. HCC in North America is typically a disease of the sixth or seventh decades of life, but in areas of endemicity, it tends to appear clinically at an earlier age. For unknown reasons, HCC occurs predominantly in males in endemic areas of high disease prevalence.

80%), one can conclude that the pulmonary edema is noncardiac. However, a shock state readily evolves in many patients with a low cardiac stroke volume and high vascular resistance. Death follows in about 75% of patients (Hallin et ah, 1996). Recovery can be rapid in patients who survive, with the prompt return of respiratory sufficiency and cardiovascular stability. No clinical evidence of intrinsic disease of the heart, liver, and kidney are observed, and hemorrhages do not appear, despite the profound thrombocytopenia detected in 50% of patients. Pathological examination (Nolle et al, 1995; Zaki et al., 1996) documents the presence of pulmonary edema with intra-airspace protein exudate, but without evi-

TABLE 20.1 Major S y m p t o m s of Young A d u l t Patients w i t h Hantavirus Pulmonary S y n d r o m e Fever Myalgia Headache Cough Nausea and Vomiting Malaise Diarrhea Shortness of breath

100% 100% 71% 71% 71% 59% 59% 53%

Reprinted with permission from Duchin et al. (1994).

B TABLE 20.2 Laboratory Findings in Young A d u l t s w i t h Hantavirus Pulmonary S y n d r o m e Leukocytosis and left shift

64%

Platelets (37 sec)

71%

Adapted with permission from Moolenaar et al. (1995) and Zaki et al. (1995).

FIGURE 20.1 Lung of typical case of HPS showing pulmonary edema with fibrin accumulation and slight interstitial inflammation. Note the intact alveolar pneumocytes. Reprinted with permission from Zaki et al. (1995). Interested readers are referred to the comprehensive and amply illustrated report on HPS by Dr. Zaki and his associates (''Hantavirus pulmonary syndrome: Pathogenesis of an emerging infectious disease," Am. ]. Pathol. 146, 552-579, 1995).

Hantavirus Pulmonary Syndrome

dence of cytolytic changes in the alveolar pneumocytes lining airspaces, and the endothelium of the pulmonary vasculature (Figure 20.1A,B)- Electron microscopy confirms the light microscopic findings and shows that the type I and II pneumocytes, and the vascular endothelium of the interstitium, are intact. The airspaces contain protein-rich fluid and lungs weigh two- to threefold greater than normal. While hyaline membranes are variably present, they are not a prominent feature. Interstitial edema and modest interstitial infiltrates by large immuoblastoid T cells and monocytes/macrophages are seen. Respiratory insufficiency in these patients is compounded by the universal presence of pleural effusions with combined volumes of pleural fluid from the two chest cavities ranging from 210 to 8420 ml. Lesions of the heart, liver, and kidney are not evident by light microscopy. Electron microscopy demonstrates the so-called Hantavirus inclusions and individual virions in the cytoplasm of endothelial cells of capillaries in the pulmonary interstitium (Figures 20.2 and 20.3). Virions are also found in alveolar macrophages (Figure 20.4A,B) (Zaki ei al., 1995). Immunocytochemistry establishes the antigenic specificity of virus particles in these cells (Figure 20.5A). The finding of viral antigen in promi-

FIGURE 20.2 Low-magnification electron micrograph of a capillary in the lung exhibiting a characteristic Hantavirus inclusion in the cytoplasm of an endothelial cell. Reprinted with permission from Zaki ei al. (1995).

299

nent amounts in the endothelial cells of myocardial capillaries and endocardial cells is of particular interest. As noted above, patients with HPS terminally often exhibit noncardiogenic shock; thus, viral involvement of the myocardial capillary network would appear to have little or no effect on the function of the heart. In the liver, endothelial cells appear to be involved only rarely, although antigen is found in an occasional Kupffer cell. Hepatic parenchymal cells are intact and exhibit no evidence of infection. In the kidneys, abundant amounts of viral antigen are detected in capillaries of both the glomeruli and the medullary interstitium (Figure 20.5B). Zaki ei al (1995) speculate that this finding may account for the proteinuria seen in many patients with HPS. Finally, antigen is localized in the endothelium of the sinusoids of the spleen and lymph nodes. It is also detected in dendritic cells of lymphoid

FIGURE 20.3 High-resolution electron micrograph of the inclusion shown in Figure 20.2. Note the filamentous composition (x64,000). Ultrastructural immunochemistry demonstrates viral antigen in these structures. Similar inclusions were described by Tao ei al. (1987) in the tissues of animals infected with Oriental strains of Hantavirus. Those authors described three morphological types of inclusions (granular, granulofilamentous, and filamentous) and demonstrated their association with the virus by ultrastructural immunological labeling. Although virus particles are seen by electron microscopy in scattered endothelial cells, they are not found in proximity to the inclusions. Reprinted with permission from Zaki ei al. (1995).

300


FIGURE 20.4 Virus-like particles in a pulmonary interstitial macrophage. (A) The virions are associated with phagolysosomes containing fragmented cellular debris. Scale: bar = 1 micron. (B) Higher magnification of boxed area of A showing virus particles, one of which is budding from a cell membrane (arrow). Reprinted with permission from Zaki et at. (1995).

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FIGURE 20.6 Immunoblastic cells in the interstitium of the spleen of a patient with HPS. Reprinted with permission from Zaki ei al. (1995).

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Hantavirus Pulmonary Syndrome

follicles. Immunoblastic cells commonly accumulate in these lymphoid organs (Figure 20.6A,B). References Armstrong, L., Zaki, S., Goldoft, M., Todd, R., Khan, A., RF, K., Ksiazek, T., and Peters, C. (1995). Hantavirus pulmonary syndrome associated with entering or cleaning rarely used, rodentinfested structures. /. Infect. Dis. 172,1166. Butler, J., and Peters, C. (1994). Hantaviruses and hantavirus pulmonary syndrome. Clin. Infect. Dis. 19, 387-395. Childs, J., Ksiazek, T., Spiropoulou, C , Krebs, J., Morzunov, S., Maupin, G., Gage, K., RoUin, P., Sarisky, J., Enscore, R., Frey, J., Peters, C., and Nichol, S. (1994). Serologic and genetic identification of Peromyscus maniculatus as the primary rodent reservoir for a new hantavirus in the Southwestern United States. /. Infect. Dis. 169,1271-1280. Duchin, J., Koster, R, Peters, C., Simpson, G., Tempest, B., Zaki, S., Ksiazek, T., Rollin, P., Nichol, S., Umland, E., Moolenaar, R., Reef, S., Nolte, K., Gallaher, M., Butler, J., Breiman, R., and Group, A. T. H. S. (1994). Hantavirus pulmonary syndrome: A clinical description of 17 patients with a newly recognized disease. New Engl. J. Med. 330, 949-955. Hallin, G., Simpson, S., Crowell, R., James, D., Koster, R, Mertz, G., and Levy, H. (1996). Cardiopulmonary manifestations of hantavirus pulmonary syndrome. Crit. Care Med. 24, 252-258. Hjelle, B. (1996). Hantavirus pulmonary syndrome, renal insufficiency, and myositis associated with infection by Bayou hantavirus. Clin. Infect. Dis. 23, 495-500. Hjelle, B., Torrez-Martinez, N., Koster, R, Jay, M., Ascher, M., Brown, T., Reynolds, P., Ettestad, P., Voorhees, R., Sarisky, J., Enscore, R., Sands, L., Mosley, D., Kioski, C., Bryan, R., and Sewell, C. (1996). Epidemiologic linkage of rodent and human hantavirus genomic sequences in case investigations of hantavirus pulmonary syndrome. /. Infect. Dis. 173, 781-786. Huang, C., Campbell, W., Means, R., and Ackman, D. (1996). Hantavirus S RNA sequence from a fatal case of HPS in New York. /. Med. Virol. 50, 5-8. Jay, M., Hjelle, B., Davis, R., Ascher, M., Baylies, H., Reilly, K., and Vugia, D. (1996). Occupational exposure leading to hantavirus pulmonary syndrome in a utility company employee. Clin. Infect. Dis. 22, 841-844. Levis, S., Rowe, J., Morzunov, S., Enria, D., and St. Jeor, S. (1997). New hantaviruses causing hantavirus pulmonary syndrome in central Argentina [letter]. Lancet 349, 998-999. Levy, H., and Simpson, S. (1994). Hantavirus pulmonary syndrome. Am. J. Respir. Crit. Care Med. 149,1710-1713.

301

Mackow, E., Luft, B., Bosler, E., Goldgaber, D., and Gavrilovskaya, I. (1995). More on hantavirus in New England and New York. New Engl. J. Med. 332, 337-338. Moolenaar, R., Dalton, C , Lipman, H., Umland, E., Gallaher, M., Duchin, J., Chapman, L., Zaki, S., Ksiazek, T, Rollin, P., Nichol, S., Cheek, J., Butler, J., Peters, C , and Breiman, R. (1995). Clinical features that differentiate hantavirus pulmonary syndrome from three other acute respiratory illnesses. Clin. Infect. Dis. 21, 643649. Morzunov, S., Feldmann, H., Spiropoulou, C , Semenova, V., Rollin, P., Ksiazek, T, Peters, C , and Nichol, S. (1995). A newly recognized virus associated with a fatal case of hantavirus pulmonary syndrome in Louisiana. /. Virol. 69,1980-1983. Nolte, K., Feddersen, R., Foucar, K., Zaki, S., Koster, R, Madar, D., Merlin, T., McFeeley, R, Umland, E., and Zumwalt, R. (1995). Hantavirus pulmonary syndrome in the United States: A pathological description of a disease caused by a new agent. Hum. Pathol. 26,110-120. Padula, P., Edelstein, A., Miguel, S., Lopez, N., Rossi, C , and Rabinovich, R. (1998). Hantavirus pulmonary syndrome outbreak in Argentina: Molecular evidence for person-to-person transmission of Andes virus. Virology 241, 323-330. Schmaljohn, C , and Hjelle, B. (1997). Hantaviruses: A global disease problem. Emerging Infect. Dis. 3, 95-103. Shefer, A., Tappero, J., Bresee, J., Peters, C , Ascher, M., Zaki, S., Jackson, R., Werner, S., Rollin, P., Ksiazek, T., Nichol, S., Bertman, J., Parker, S., and Failing, R. (1994). Hantavirus pulmonary syndrome in California: report of two cases and investigation. Clin. Infect. Dis. 19,1105-1109. Tao, H., Semao, X., Zinyi, C , Gan, S., and Yanagihara, R. (1987). Morphology and morphogenesis of viruses of hemorrhagic fever with renal syndrome, II: Inclusion bodies — ultrastructural markers of hantavirus-infected cells. Intervirology 27, 45-52. Wells, R., Young, J., Williams, R., Armstrong, L., Busico, K., Khan, A., Ksiazek, T., Rollin, R, Zaki, S., Nichol, S., and Peters, C. (1997). Hantavirus transmission in the United States. Emerging Infect. Dis. 3, 361-365. Zaki, S., Greer, R, Coffield, L., Goldsmith, C , Nolte, K., Poucar, K., Feddersen, R., Zumwalt, R., Miller, G., Khan, A., Rollin, R, Ksiazek, T., Nichol, S., Mahy, B., and Peters, C. (1995). Hantavirus pulmonary syndrome: Pathogenesis of an emerging infectious disease. Am. J. Pathol. 146, 552-579. Zaki, S., Khan, A., Goodman, R., Armstrong, L., Greer, P., Coffield, L., Ksiazek, T., Rollin, R, Peters, C , and Khabbaz, R. (1996). Retrospective diagnosis of hantavirus pulmonary syndrome, 19781993: Implications for emerging infectious diseases. Arch. Pathol. Lab. Med. 120,134-139.


C H A P T E R

21 Papillomaviruses INTRODUCTION 303 DISEASE OF THE SKIN 305 DISEASE OF THE FEMALE GENITAL TRACT

proved to be out of the mainstream of experimental cancer research at the time. Accordingly, an appreciation of their importance awaited the modern revolution of molecular virology during the last three decades of the twentieth century. Papillomaviruses and the papovaviruses (see Chapter 22) are classified as subfamilies of the Papovavirus family. Although the two have similarities, the viruses of these two subfamilies differ in size, and their DNA genomes are dissimilar. Papillomaviruses of humans (HPVs) are obligate parasites of epithelial cells, and their replication is intimately tied u p with host cell multiplication and differentiation. HPVs are about 55 nm in diameter. They have a capsid comprised of 72 capsomeres arranged in icosahedral symmetry. The capsomeric protein is the major antigen of the virion, but the antigenic makeup of the virus has not been utilized for classification or typing purposes. Based on molecular analysis of the viral doublestranded DNA, 70 distinct types of papillomavirus have now been identified in human tissues.^ The pathogenic importance of many of these virus types has yet to be established. While several individual types tend to be associated with distinct pathologic lesions in specific anatomic sites, considerable overlap exists. To a large extent, HPVs are not believed to be infectious for lesser species of animals, but the basis for this conclusion has not been rigorously examined. Similarly, the countless papillomaviruses of subhuman mammalian and avian species are not thought to be infectious for humans, but, for obvious reasons, experimental proof is lacking (Rowson and Mahy, 1967). Many gaps currently exist in our knowledge of the papillomaviruses and their pathogenic mechanisms. In part, these shortcomings and our lack of understanding of papillomaviruses relate to our inability to grow these agents in cultured cells in vitro. Thus, experimental work has largely been done with virus extracted from tumor tissue.

308

Vulva and Vagina 309 Cervix Uteri 311 Endometrium 314 DISEASE OF THE GLANS PENIS 314 DISEASE OF THE DIGESTIVE TRACT 315

Oropharynx 315 Esophagus 315 Anus 317 DISEASE OF THE LARYNX AND TRACHEOBRONCHIAL TREE 317 DISEASE OF THE EYE 321 DISEASE OF THE MIDDLE EAR 322 REFERENCES 322

INTRODUCTION I only heard him speak once! Elderly, but alert and engaging, Richard Shope described for his audience the fascinating story of the discovery of the rabbit papilloma virus (RPV) (Shope, 1933). He related subsequent experiments that established this common epidemic infectious agent of wild rabbits as a model for human viral carcinogenesis. RPV, once passed through a bacteria-tight filter, proved to be transmissible in serial from the skin of one animal to another of the same species, but it could not be passaged serially in domestic rabbits, although it caused benign cutaneous papillomas and squamous carcinomas in this species (Rous and Beard, 1935; Amelia et al, 1994). In these domesticated animals, the infectious virus became masked, although its genes persisted, an event now^ observed in human cervical carcinoma associated with papillomavirus infection (Kidd and Rous, 1940). Additional work (Rous and Kidd, 1936) had shown that the application of coal tar to the skin of papillomavirus-infected rabbits accelerated development of tumors at this site. These uniquely simple, but insightful, experiments

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and bath houses is common. Plantar warts exhibit full thin papillae invested with a prominent layer of cells containing keratohyalin and invested by a thick layer of keratin. The lesions are well circumscribed, allowing them to be easily removed with a curette. Plantar warts result from infection by HPVl (Figure 21.5). Large numbers of virus particles are found in the intranuclear particles in the horny layer. Epidermodysplasia verruciformis (EV) is an exceedingly rare lifelong generalized eruption of flat warts having malignant potential. There is a familial predisposition (Jablonska et a/., 1968), but the heritable mode of transmission has not been established. Described by Lewandowsky and Lutz in 1922, our understanding of the pathogenesis of these lesions is gradually increasing, even though the mode of inheritance of the predisposition to EV has not been defined. The disease represents the unique influences of both environmental (i.e., UVB irradiation) and immunological factors on the course of an HPV infection. The disease first becomes apparent as generalized crops of (colored or colorless) macular or pityriasis versicolor-like lesions occurring in the very young. It progresses over time to form multiple large flat, often confluent, lesions

307

(Figure 21.6). After some 25 years, roughly a third of patients have developed skin cancers that predominately occur on the sun-exposed skin. Persons with the disease exhibit anergy to antigens known to induce skin hypersensitivity reactions. Thus, cellular immunity appears to be defective. EV is frequently seen in patients with AIDS and in organ allograft recipients being administered immunosuppressive regimens (de Jong-Tieben et ah, 1994). More than 20 different types of HPV have been recovered from various cases, but types 3, 5, 8, 9, 10, and 12 predominate. Interestingly enough, the virus types customarily associated with EV are commonly found in skin lesions of various kinds (including squamous carcinomas of the skin), occurring in organ allotransplant recipients and in AIDS (Soler et al, 1993; Stark et al, 1994; Shamanin et a/., 1996; Leigh and Glover, 1995; Meyer et al, 1998; de Jong-Tieben et al, 1994). EV patients infected with HPV types 5 and 8 are said to be unusually predisposed to development of actinic keratoses and invasive squamous cell carcinoma on UV-exposed areas of the skin (Majewski and Jablonska, 1995). The DNA of these two types is found in more than 90% of EV-associated cancers as a nonintegrated episome (Pfister, 1992).

F I G U R E 21.5 Verruca plantaris. The lesion exhibits the features of a verruca vulgaris but is compressed deep into the subjacent dermis. The convergence of the rete ridges allows the lesion to be curretted out and removed.

308


FIGURE 21.6 Epidermodysplasia verrucaformis. The typical lesion exhibits hyperkeratosis and large cells with an abundant pale-staining cytoplasm. Because they resemble cells observed in well-differentiated squamous cell carcinomas, some authors have suggested, without good basis, that they represent a premalignant change.

DISEASE OF THE FEMALE GENITAL TRACT Almost 50% of sexually active college women have detectable HBV of one or more types in their genital tract tissue. Often, there is no clinical or cytopathological evidence of infection. In an exfoliative cytology study of over 1 x lO'* women with healthy cervices, almost 9% were found to have HBV infections (this is a minimal number because of the methodology used in the study) (see de Villiers et ah, 1992). The male partner of women with clinically evident HPV-associated genital warts or cervical dysplasia often has penile lesions when carefully studied by colposcopy. In some, but certainly not all, cases, the HPV type infecting these men proves to be identical to the virus of their sexual consort (Kyo et al, 1994). The relative risk of infection with some, but not all, HPV types increases in inverse relationship to the age of the woman at first intercourse and parallels the number of sexual partners (Franco et ah, 1995). Cross-sectional analyses in which population groups are surveyed measure the recently acquired infections as well as the persistent strains acquired in the past, that is, the prevalence. Thus, the results reflect the cumulative virus burden of the population under study, not the incidence of new infections per unit of time. In younger women (i.e., less than 30 years of age), the HPV seem to persist for a shorter period of time

than in older women. The "high-risk" virus types known to be associated with cancer of the cervix and vulva tend to persist longer than types thought not to be pathogenic (Hildesheim et al, 1994). The recognition of koilocytic atypia as a reflection of HPV infection in the cervical epithelium proved to be the first hint that HPV might be involved in the pathogenesis of cervical cancer (Meisels and Fortin, 1976; Purola and Savia, 1977). The term "koilocytosis" was coined by Koss and Durfee (1956) to refer to cells having irregular hyperchromatic nuclei surrounded by a clear cytoplasmic halo. These cells are now considered to be pathognomonic of HPV infection of squamous epithelium. Some investigators believe koilocytosis appears in a cell when the protein elaborated by the E4 "early" gene of the virus binds with and collapses the cytokeratin framework of the cell. Koilocytic atypia exists when the squamous epithelial cells display perinuclear halos and nuclear atypia with numerous bi- and multinucleate cells. Mitotic activity in these lesions is increased, but atypical mitotic figures are not evident (Nuovo et al, 1989). Nuovo (1990) detected HPV in 77% of condylomatous lesions with koilocytic atypia, but 20% of the lesions they studied that lacked these pathognomonic features were also positive. The etiology and possible role of HPV in the remaining condylomata is unknown.

309

Papillomaviruses

Vulva and Vagina Condylomata acuminatum involves multifocal lesions of the vulva and vagina almost invariably accompanied by infection with so-called "low-risk" HPV type 6 and 11. As would be expected, it occurs with increased frequency in women who have had intercourse with multiple sexual partners. The prevalence of these so-called genital warts seems to be increasing among sexually active young women. Relatively little clinical and biological information is available that documents sequentially the mode of appearance, the evolution, and the natural resolution of these lesions. They occur commonly in pregnant women and users of oral contraceptives and appear to regress when endocrine stimulation to the genital tissue ceases. The epithelium of the skin adjacent to condylomata and elsewhere in the perineum is commonly infected with HPV even when histological evidence of infection in the skin is lacking (Ferenczy et ah, 1985). This observation most probably accounts for the relatively high recurrence rates of condyloma after removal chemically or by cautery. Condyloma of the vagina and cervix are often found in women with these vulvar lesions. As might be expected, condyloma acuminata are epidemiologically associated with an increased risk of anogenital neoplasia, particularly cancer of the vulva. However, the lesions customarily are not due to infection by "high-risk" HPV types. Thus, they are not premalignant lesions (Friis et a/., 1997). Condyloma acuminatum generally develops on the vulvar vestibule and on the medial aspects of the labia (Figure 21.7). It must be differentiated by the pathologist from the common squamous papillomas and fibroepitheliomatous "tags." These exophytic cauliflower-like lesions exhibit a complex branching papillary configuration associated with epithelial proliferation (Figure 21.8). Koilocytotic atypia in the superficial granular layer of the epithelium is diagnostic of the lesions. Squamous carcinoma of the vulva is a relatively uncommon disease with an incidence approximately onefifth that of invasive cervical carcinoma (Ries et at., 1996). Two biologically different categories of disease are now recognized (Table 21.2). The first is represented by lesions infected with the so-called "high-risk" HPV types, 16 and 18. They tend to occur in younger women. The appearance of these cancers is preceded by vulvar intraepithelial neoplasia (VIN) of an advanced grade (Figure 21.9). As discussed in more detail below, the lesions have distinct morphological features and a better prognosis than the second category of squamous cancer (Bloss et al, 1991; Haefner et ah, 1995). The latter tumors develop in older women, often those

FIGURE 21.7 Multiple condylomata developing on the vulvar vestibule. The lesions are discrete, nonconfluent, raised "cauliflowerlike" excrescences. There is an absence of congestion and inflammation adjacent to the lesion.

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FIGURE 21.8 Condyloma acuminatum exhibit complex branching papillae with a flbrovascular core. The acanthotic folds exhibit to a varying degree koilocytosis in the upper third of the epithelium. As shown here, poikilocytosis is characterized by cytoplasmic vacuolization surrounding enlarged nuclei that show varying degrees of atypia. The clearing of the cytoplasm most probably is a fixation artefact resulting from viral-induced changes in the cytokeratin skeleton of the cell (see text).

310


***^W* FIGURE 21.9 Morphological spectrum of HPV type 16-associated vulvar intraepithelial neoplasia (VIN) or squamous intraepithelial lesion (VIL) exhibiting (A) warty or Boenoid features, (B) hyperkeratosis, (C) acanthosis with minimal hyperkeratosis, and (D) near-complete absence of differentiation. A consistent feature of these lesions is the nuclear atypia extending upward through at least two-thirds of the epithelial layer. Reprinted with permission and through the courtesy of J. Crum, MD.

with the chronic inflammatory and degenerative disease known as lichen sclerosis (Toki et ah, 1991). This latter condition is characterized by atrophy of the vulvar skin, but with focal hyperplasia of the epidermis to a variable degree. The presence of atypical cells in the

epithelium portend the ultimate neoplastic outcome in some patients, and Tate et al. (1997) have demonstrated the monoclonality of the epithelial cells in these lesions. These invasive squamous carcinomas have a relatively poor prognosis. In one series, the mean age of the pa-

311

Papillomaviruses TABLE 21.2 A g e of W o m e n w i t h Vulvar Carcinoma b y M o r p h o l o g i c Type Tumor type Age (years) ^-

.»

-

FIGURE 22.4 Ureter at 200x (A) and 400x (B), exhibiting diffuse cytological alterations typical of BKV infection. Note the cellular and nuclear pleomorphism and the homogenous ground-glass appearance of the intranuclear inclusions. Prepared from autopsy specimens obtained from a 48-year-old man with non-Hodgkin's lymphoma treated with repeated cycles of combined drug chemotherapy. Photomicrographs reprinted with permission and through the courtesy of K. Nagashima, MD.

Preskorn, 1976). And, immunocytochemistry has convincingly demonstrated JCV DNA, Tag antigen, and p53 protein in intranuclear inclusions of the astrocytes, often in the absence of antigenic viral protein (Aksamit et ah, 1986; Stoner et al, 1986). It would appear that p53 binding by viral Tag results in an unstable state of cellular transformation by astrocytes that may inefficiently fabricate virus (Ariza et al, 1994). In virological terminology, the astrocytes may be semipermissive because they often do not complete the replicative cycle and produce capsid proteins. This conclusion is based on studies of Aksamit et al. (1986). These investigators found that only a small proportion of infected astrocytes (as established by in situ hybridization) displayed evidence of viral capsid protein synthesis (as evaluated by immunochemistry). Usually, but not invariably, PML is a rapidly progressive disease with a survival period of 3 to 6 months. However, chronic cases have been reported (Hedley-Whyte et al, 1966). Almost invariably, it occurs in patients with immunodeficiency disorders (Bolton and Rozdilsky, 1971). Although relatively common in cases of leukemia and lymphoma, the disease assumes its most overt form in AIDS. The rapidity of disease progression seems to relate to the degree of immunosuppression of the patient. PML is now considered an indicator sentinel of AIDS, affecting roughly 4% of these patients. JCV infection in PML is a systemic process, for in rare cases typical viral inclusions are found in numerous organs at autopsy (Martin and Banker, 1969; Castaigne, 1965).

URINARY TRACT INFECTION A N D DISEASE BKV possesses the capacity to infect cells lining the renal tubules and the transitional epithelium throughout the urinary tract (Chesters et al, 1983). Involvement of these epithelia is readily apparent morphologically and can be confirmed by histochemistry (Shinohara et al, 1993) (Figures 22.4A,B and 22.5A-D). Rare cases of interstitial nephritis with evidence of BKV inclusions in tubular lining cells are reported (Figure 22.6A-C). One patient among the cases known to me was a 6-year-old immunocompromised boy who developed renal failure and died. Large amounts of viral DNA were found in the kidneys at autopsy, with substantially lesser amounts being detected in the lungs, spleen, and lymph nodes (Rosen et al, 1983). A second case is of interest. This young male with AIDS also developed an interstitial nephritis with inclusion-bearing cells in the renal tubules. In addition, he had an interstitial pneumonia and meningoencephalitis with ventriculitis attributable to the virus (Vallbracht et al, 1993). Pappo and associates (1996) found 15 reported cases of urinary tract involvement with BKV-like papovavirus among renal allograft recipients. This review brought to light the common occurrence of graft rejection in association with infection. Urinary tract strictures were a clinical problem in five cases. Whether or not these complications are a consequence of BKV infection remains to be established. Arthur and his colleagues (1986) associated BKV infection with hemorrhagic cys-

332


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fel FIGURE 22.5 (A) Urinary bladder epithelium displaying the widespread cytological abnormalities typical of BKV infection as established by immunohistochemistry using an anti-JCV polyclonal antibody (B). (C) This electron micrograph (3500x) of the infected urinary bladder epithelium displays the viral nucleocapsids that are illustrated in detail in (D) (40,000x). Prepared from autopsy specimens obtained from a 48-year-old man with non-Hodgkin's lymphoma treated with repeated cycles of combined drug chemotherapy. Photomicrographs provided through the courtesy of K. Nagashima, MD.

FIGURE 22.6 Kidney of patient described in Figure 22.1. (A) Degeneration and necroses of the renal tubules. Some of the epithelial cells lining the tubules have enlarged and hyperchromatic nuclei (x210). (B) Abnormal nuclei contain granular basophilic material (arrowheads). Intranuclear bodies (arrows) in degenerated epithelial cells (x800). (C) Typical intranuclear inclusion body with halo (xSOO). Reprinted with permission from Vallbracht et al. (1993).

Papovaviruses

titis in bone marrow transplant recipients. Half of the patients who received allogenic grafts were infected, and hemorrhage cystitis developed in 71%. Reports of hemorrhagic cystitis attributed to BKV have not been reported in the literature in recent years, and a causative role for the virus has not been established. References Aksamit, A., Sever, J., and Major, E. (1986). Progressive multifocal leukoencephalopathy: JC virus detection by in situ hybridization compared with immunohistochemistry. Neurology 36, 499-504. Ariza, A., Mate, J., Fernandez-Vasalo, A., Gomez-Plaza, C , PerezPiteira, J., Pujol, M., and Navas-Palacios, J. (1994). p53 and proliferating cell nuclear antigen expression in JC virus-infected cells of progressive multifocal leukoencephalopathy. Hum. Pathol. 25, 1341-1345. Arthur, R., and Shah, K. (1989). Occurrence and significance of papovavirus BK and JC in the urine. In "Progress in Medical Virology" (J. Melnick, ed.). Vol. 36, pp. 42-61. Karger, Basel. Arthur, R., Shah, K., Baust, S., Santos, C , and Saral, R. (1986). Association of BK viruria with hemorrhagic cystitis in recipients of bone marrow transplants. New Engl. J. Med. 315, 230-234. Astrom, K., Mancall, E., and Richardson, E. (1958). Progressive multifocal leukoencephalopathy. Brain 81, 93-110. Ault, G., and Stoner, G. (1994). Brain and kidney of progressive multifocal leukoencephalopathy patients contain identical rearrangements of the JC virus promoter / enhancer. /. Med. Virol. 44,298-304. Bastian, R (1971). Papova-like virus particles in a human brain tumor. Lab. Invest 25,169-175. Bergsagel, D., Finegold, M., Butel, J., Kupsky, W., and Garcea, R. (1992). DNA sequences similar to those of simian virus 40 in ependymomas and choroid plexus tumors of childhood. New Engl. J. Med. 326, 988-993. Bolton, C , and Rozdilsky, B. (1971). Primary progressive multifocal leukoencephalopathy: A case report. Neurology 21, 72-77. Carbone, M., Rizzo, P., Grimley, P., Procopio, A., Mew, D., Shridhar, v., de Bartolomeis, A., Esposito, V., Giuliano, M., Steinberg, S., Levine, A., Giordano, A., and Pass, H. (1997). Simian virus-40 large-T antigen binds p53 in human mesotheliomas. Nature Med. 3, 908-912. Castaigne, P. (1965). La leucoencephalopathie multifocale progressive. Presse Med. 73,1167-1170. Chesters, P., Heritage, J., and McCance, D. (1983). Persistance of DNA sequences of BK virus and JC virus in normal human tissues and in diseased tissues. /. Infect. Dis. 147, 676-684. Coleman, D., Gardner, S., and Field, A. (1973). Human polyomavirus infection in renal allograft recipients. Br. Med. J. 3, 371-375. Coleman, D., Russell, W., Hodgson, J., Pe, T., and Mowbray J. (1977). Human papovavirus in Papanicolaou smears of urinary sediment detected by transmission electron microscopy. /. Clin. Pathol. 30, 1015-1020. Coleman, D., Wolfendale, M., Daniel, R., Dhanjal, N., Gardner, S., Gibson, P., and Field, A. (1980). Infectious diseases: A prospective study of human polyomavirus infection in pregnancy. /. Infect. Dis. 142,1-8. Gardner, S., Field, A., Coleman, D., and Hulme, B. (1971). New human papovavirus (B.K.) isolated from urine from renal transplantation. Lancet 1,1253-1257.

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Gribble, D., Haden, C , Schwartz, L., and Henrickson, R. (1975). Spontaneous progressive multifocal leukoencephalopathy (PML) in macaques. Nature 254, 602-604. Hedley-Whyte, E., Smith, B., Tyler, H., and Peterson, W. (1966). Multifocal leukoencephalopathy with remission and five year survival. /. Neuropathol. Exp. Neurol. 25,107-116. Holmberg, C , Gribble, D., Takemoto, K., Howley, P., Espana, C , and Osburn, B. (1977). Isolation of simian virus 40 from Rhesus monkeys (Macaca mulatta) with spontaneous progressive multifocal leukoencephalopathy. /. Infect. Dis. 136, 593-596. Houff, S., Major, E., Katz, D., Kufta, C , Sever, J., Pittaluga, S., Roberts, J., Gitt, J., Saini, N., and Lux, W. (1988). Involvement of JC virusinfected mononuclear cells from the bone marrow and spleen in the pathogenesis of progressive multifocal leukoencephalopathy. New Engl. J. Med. 318, 301-305. Manz, H., Dinsdale, H., and Morrin, P. (1971). Progressive multifocal leukoencephalopathy after renal transplantation: Demonstration of papova-like virions. Ann. Intern. Med. 75, 77-81. Markowitz, R., Thompson, H., Mueller, J., Cohen, J., and Dynan, W. (1993). Incidence of BK virus and JC virus viruria in human immunodeficiency virus-infected and -uninfected subjects. /. Infect. Dis. 167, 13-20. Martin, J., and Banker, B. (1969). Subacute multifocal leukoencephalopathy with widespread intranuclear inclusions. Arch. Neurol. 21, 590-602. Narayan, O., Penney Jr., J., Johnson, R., Herndon, R., and Weiner, L. (1973). Etiology of progressive multifocal leukoencephalopathy: Identification of papovavirus. New Engl J. Med. 289,1278-1282. O'Reilly, R., Lee, F., Grossbard, E., Kapoor, N., Kirkpatrick, D., Dinsmore, R., Stutzer, C , Shah, K., and Nahmias, A. (1981). Papovavirus excretion following marrow transplantation: Incidence and association with hepatic dysfunction. Transplant. Proc. 13, 262-266. Padgett, B., Walker, D., ZuRhein, G., and Eckroade, R. (1971). Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet 1,1257-1260. Padgett, B., Walker, D., ZuRhein, G., Hodach, A., and Chou, S. (1976). JC papovavirus in progressive multifocal leukoencephalopathy. /. Infect. Dis. 133, 686-690. Pappo, O., Demetris, A., Raikow, R., and Randhawa, P. (1996). Human polyoma virus infection of renal allografts: Histopathologic diagnosis, clinical significance, and literature review. Mod. Pathol. 9,105-109. Rosen, S., Harmon, W, Krensky, A., Edelson, P., Padgett, B., Grinnell, B., Rubino, M., and Walker, D. (1983). Tubulo-interstitial nephritis associated with polyomavirus (BK type) infection. New Engl. J. Med. 308,1192-1196. Sangalang, V., and Embil, J. (1982). Recovery of papovavirus in cell culture explants of brain tissue from case of progressive multifocal leukoencephalopathy. Lancet 2, 329-330. Shah, K., and Nathanson, N. (1976). Human exposure to SV40: Review and comment. Am. J. Epidemiol. 103,1-12. Shinohara, T., Matsuda, M., Cheng, S., Marshall, J., Fujita, M., and Nagashima, K. (1993). BK virus infection of the human urinary tract. /. Med. Virol. 41, 301-305. Stoner, G., Ryschkewitsch, C , Walker, D., and Webster, H. (1986). JC papovavirus large tumor (T)-antigen expression in brain tissue of acquired immune deficiency syndrome (AIDS) and non-AIDS patients with progressive multifocal leukoencephalopathy. Proc. Natl. Acad. Sci. U.S.A. 83, 2271-2275.

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Sundsfjord, A., Flaegstad, T., Flo, R., Spein, A., Pedersen, M., Permin, H., Julsrud, J., and Traavik, T. (1994). BK and JC viruses inhuman immunodeficiency virus type 1-infected persons: Prevalence, excretion, viremia, and viral regulatory regions. /. Infect. Dis. 169,485^90. Vallbracht, A., Lohler, J., Gossmann, J., Gluck, T., Petersen, D., Gerth, H., Gencic, M., and Dorries, K. (1993). Disseminated BK type polyomavirus infection in an AIDS patient associated with central nervous system disease. Am. J. Pathol. 143, 29-39. Walker, D. (1978). Progressive multifocal leukoencephalopathy: An opportunistic viral infection of the central nervous system. In ''Handbook of Clinical Neurology" (P. Vinken and G. Bruyn, eds.). Vol. 34, pp. 307-329. North-Holland, Amsterdam.

Watanabe, I., and Preskorn, S. (1976). Virus-cell interaction in oligodendroglia, astroglia and phagocyte in progressive multifocal leukoencephalopathy: An electron microscopic study Acta Neuropath. 36,101-115. Weiner, L., Herndon, R., Narayan, O., Johnson, R., Shah, K., Rubinstein, L., Preziosi, T., and Conley, R (1972). Isolation of virus related to SV40 from patients with progressive multifocal leukoencephalopathy New Engl. J. Med. 286, 385-431. ZuRhein, G., and Chou, S. (1965). Particles resembling papovaviruses in human cerebral demyelinating disease. Science 148,1477-1479.

C H A P T E R

23 Parvoviruses INTRODUCTION 335 JOINT DISEASE 337 ERYTHROPOIETIC SYSTEMIC DISEASE INFECTIONS IN PREGNANCY 339 INFLAMMATORY LESIONS 340 TISSUE DIAGNOSIS 340 REFERENCES 340

blocks required for replication. Thus, they tend to parasitize rapidly replicating cells such as the precursors of the erythroid elements in the bone marrow. As a family, the parvoviruses infect a diversity of plants and animals, and some are parasites of other much larger viruses, such as the adenovirus-associated viruses (a virus that infects another more complex virus but is not a pathogen for humans). Only one serotype, termed B19, has thus far been found to infect humans with resulting disease, an observation first reported by Cossart et at. (1975). Adenovirus-associated viruses are poorly understood agents that were once recovered from a few patients with rheumatoid arthritis. They are believed to infect humans (Simpson et al, 1984), but there is no known accompanying disease. Other parvoviruses of lesser mammalian species go by the terms rat virus, minute virus of mice, and the virus of Aleutian mink disease (Porter, 1986). These agents have been the subject of considerable basic research, but this experimental work at present provides little insight into the pathogenesis of parvovirus disease in humans (Margolis and Kilham, 1970). Human parvovirus B19, appears to infect persons of all ages. Community outbreaks tend to erupt in late winter and spring, but infections are known to occur sporadically throughout the year. Because it has been difficult to conduct traditional virological studies on large population groups due to the unavailability (until recently) of susceptible cell cultures, detailed epidemiological information is still lacking. Seroepidemiological studies have documented infection in about 2 to 15% of infants under the age of 5 years. Roughly 15 to 60% of children and adolescents (aged 5 to 19 years) are seropositive, and 30 to 60% of adults have evidence of infection in the distant past. Thus, at any one time, abundant numbers of susceptibles of all ages are found in the general population. Much of what we know about the epidemiology of this virus is derived from studies in North America and Europe; little information is available from developing countries. Human volunteer studies at the Common Cold Research Unit in the United Kingdom have provided

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INTRODUCTION The parvovirus strain B19 is a relatively new addition to the diverse family of viruses causing erythematous rashes. Erythema infectiosum (so-called fifth disease) was first established as a clinical syndrome by Herrick in 1962. The rash appears on the cheeks, and progresses over a short period to involve the limbs and trunk. The transient skin lesions are described as lacy or reticular. In young women (but rarely in men), a symmetrical polyarthritis primarily affecting the peripheral joints develops shortly after the appearance of the rash and commonly disappears without complications within a few days. Parvoviruses would be of little further interest to those of us who do not practice office pediatrics if it were not for the unique capacity of the so-called B19 strain of the virus to infect red blood cell precursors in the bone marrow. As a result, the virus causes erythroblastic crises in patients whose erythron has been stimulated by hemolytic anemia. It is also responsible for fetal loss with hydrops fetalis when infection occurs in utero. With the advent of chemotherapy and AIDS, parvovirus B19 has also been recognized as a cause of anemia in an occasional immunocompromised patient. This chapter provides an overview of our current understanding of this interesting virus and the diseases attributed to it. The family Parvoviridae comprises a large number of nonenveloped agents made up of a single-stranded DNA genome surrounded by a capsid comprised of protein capsomeres arranged in an icosahedral symmetry. Parvoviruses are the smallest of the human DNA pathogens and lack many of the biochemical building PATHOLOGY AND PATHOGENESIS OF HUMAN VIRAL DISEASE

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insightful perspectives into the natural-occurring infection in the immunologically naive adult (Anderson et al, 1984). Figure 23.1 depicts the major parameters of illness in a middle-aged woman inoculated intranasally with approximately 100 infectious viruses present in a serum specimen from a naturally infected blood donor. Both the virus and its DN A were detected in the blood of this volunteer 6 days after inoculation, accompanied by mild systemic symptoms including fever, but a rash was not evident. Neutropenia, lymphopenia, and thrombocytopenia occurred shortly thereafter. Of particular note was the decrease in reticulocytes in the blood followed by a gradual reduction in the hemoglobin concentration. On day 15, itching first was noted, and shortly thereafter a maculopapillary rash developed. Symmetrical arthralgias and arthritis of the smaller joints of the extremities then appeared and persisted for a period of about 3 weeks. At this time, fever was no longer present. As might be expected, virus-

specific IgM antibodies developed during the second week after inoculation and IgG antibody was detected in the blood a few days later. This experiment reproduced dramatically the syndrome of erythema infectiosum so amply documented clinically in association with parvovirus B19 infection (Plummer et al, 1985; Anderson et al, 1984). However, the work failed to establish the pathogenesis of the salient clinical features of the illness. Assays for interferon in the blood were consistently negative, and IgM immune complexes were present transiently during the time of maximum symptoms, but they were not detected during periods when the rash and arthritis were present. Thus, symptomatology attributable to circulating interferon or immune complexes would not appear to account for the systemic symptoms, rash, and arthralgias that accompanied this parvovirus infection. The pathogenesis of the rash of erythema infectiosum is not understood. Schwarz et al (1994) detected

Symptoms I Haemoglobin(g/dI)

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FIGURE 23.1 Features of primary parvovirus infection in a seronegative volunteer inoculated intranasally on day 0. Reprinted with permission from Anderson et al. (1985).

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Parvoviruses

viral capsid proteins by immunofluorescence and by DNA in situ hybridization in cells of the stratum basalis of the erythematous skin in a biopsy from a 5-year-old tot with typical lesions. This interesting finding has not been confirmed, and its relevance to our understanding of the skin lesions is uncertain. Experiments in animals strongly suggest that endothelial cells may be infected by parvoviruses, a finding of some possible relevance to our understanding (Margolis and Kilham, 1975), but replication of parvoviruses in the endothelial cells of human tissues has yet to be established.

JOINT DISEASE During and after an episode of erythema infectiosum, a few (i.e., less than 10%) children and adolescents experience arthralgias and arthritis. More than 75% of adults have joint symptoms, but females are more commonly affected than males (Ager et al, 1966; Anderson et al, 1984). In general, the clinical syndrome in these patients does not simulate rheumatoid arthritis, and the traditional serological markers of rheumatic disease (rheumatoid factor, latex agglutinins, and antinuclear antibody) are not found in the blood, although exceptions have been reported (Luzzi et al., 1985). Surveys of patients in general rheumatology clinics have been carried out in an effort to assess the prevalence of parvovirus B19 infections among those presenting with acute-onset arthralgias and arthritis. Elevated serum concentrations of virus-specific IgM antibody were employed as a marker. In one study, 19 of some 153 patients so affected exhibited evidence of recent parvovirus infection. Most of the symptoms in these patients improved within weeks, but several had persistent complaints for more than 2 years and three patients were symptomatic for more than 4 years (White et ah, 1985). In many of these patients, a rash preceded the onset of joint symptoms (Reid et al, 1985; Naides et al, 1990). The pathogenic mechanisms involved in parvovirus arthritis are unknown. One would anticipate that the joint spaces are seeded during viremia, and virus replication might be expected to occur in synovial tissue, but we just don't know! Because of the relatively brisk antibody response to these viruses and the high concentrations of viral DNA detected in the blood, immune complexes might serve as a means whereby arthritis could develop, but as noted above, clinical and experimental evidence supporting this conjecture is lacking.

ERYTHROPOIETIC SYSTEMIC DISEASE An infectious etiology for transient aplastic crises in children with sickle cell disease was first suggested by the occurrence of outbreaks among members of families with this heritable disease (Pattison et al, 1981). Moreover, the observation that a crisis of this type only occurs in the same patient on a single occasion (Rao et al, 1992) indicated that the first attack conferred protection, which we now know is the result of acquired immunity. The discovery that these episodes of erythroid aplasia were due to an obscure parvovirus was a startling revelation to hematologists. Because of its small size and limited informational capacity of its DNA, parvovirus B19 preys upon the synthetic tools of the host cell to support its replication (Ozawa et al, 1986). No patient could be more susceptible than one with hemolytic anemia in which a high turnover of erythroid cells is due to a hemoglobinopathy or a heritable defect of the erythrocyte (such as spherocytosis or glucose-6PD deficiency). Erythroid and burst colony-forming units as well as proerythroblasts entering the S phase prove to be the target cells because they are endowed with a specific virus receptor, the P membrane globoside that confers susceptibility (Young, 1988). As a result, the replicative capability of the cell is destroyed (Figure 23.2), resulting in a transient aplastic state characterized by the abrupt onset of anemia and reticulocytopenia. Because

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Parvovirus B19 (particles/plate) F I G U R E 23.2 Erythroid colony formation is completely inhibited by parvovirus B19 infection in bone marrow specimens from normal controls with the P erythrocyte phenotype. In contrast, replication of erythroid elements with the p phenotype is not impeded. Reprinted with permission from Brown et al. (1994).

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these patients are so dependent upon the accelerated synthesis of new erythroid elements, anemia develops rapidly due to the combined effects of acute bone marrow depression and hemolysis. It has been suggested that the severity of hemolytic disease correlates with parvovirus B19 attack rate, thus accounting for the relatively high prevalence of the condition in patients with sickle cell anemia (SS hemaglobinopathy). In a study conducted over a 7-year period at a large urban hospital, 68% of children and adolescents with SS disease developed an aplastic crisis accompanied by evidence of B19 parvovirus infection (Rao et al, 1992). As noted above, the specific P blood group globoside was recently found to be the specific cell receptor for B19 parvovirus on erythrocyte precursors, and presumably on other target cells. In actuality, there are three P antigens (P, P^ and P^), but for practical purposes the dominantly inherited P is the critical factor, since P^ is extremely rare, except in Scandinavia. The erythroid precursors of the cells that lack P (that is, P genotype), are resistant to parvovirus infection, as shown in Figure 23.2. Persons lacking P consistently possess no circulating antibody to B19 parvovirus and thus appear to be completely resistant to infection (Brown et al, 1994). The temporal association of transient aplastic crises with erythema infectiosum has been documented in individual case reports. Figure 23.3 depicts the epidemic curve of a community outbreak of the acute erythematous skin disease followed temporally by aplastic crises among patients with SS disease (Chorba et al, 1986). The erythematous rash is often difficult to detect in black patients. Thus, artefactually, the aplastic crises developing in some of these patients appear to be spontaneous, and unrelated to the occurrence of

erythema infectiosum. Since those with hemolytic disease are often recipients of blood transfusions, exogenous blood is a likely source of infection in some patients (Cossart et al, 1975). The bone marrow of patients with aplastic crisis due to parvovirus is typically hypoplastic and, on rare occasions, exhibits variable degrees of necrosis. The pathognomonic morphological feature of the infection, however, is an enlarged dysplastic erythrocyte precursor cell having a diffuse amphophilic nuclear inclusion lacking a halo (Figure 23.4). These cells are said to have a megaloblastoid appearance. Krause et al (1992) suggested that formalin fixation of both the bone marrow smears and biopsies accentuates the appearance of inclusions in cells. As would be expected, the serum ironbinding capacity and saturation are increased in patients with aplastic disease (Figures 23.5 and 23.6A,B).

F I G U R E 23.4 Aspiration smear of bone marrow showing the giant proerythroblasts exhibiting an intranuclear inclusion. The marrow aspirate shows erythroid hypoplasia and these scattered bazaar erythroid precursor cells. Wright's stain. Reprinted with permission from Schwartz et al. (1991).

Months

F I G U R E 23.3 Temporal association of community outbreak of erythema infectiosum with the subsequent appearance of new cases of aplastic crises. Adapted with permission from Chorba et al. (1986).

FIGUfRE 23.5 Bone marrow biopsy specimen. Clusters of erythroid cells with distinct intranuclear inclusions are seen. Reprinted with permission from Krause et al. (1992) and through the courtesy of J. Krause, MD.

Parvoviruses

339

B

FIGURE 23.6 Formalin-fixed air-dried smear of an aspirate of bone marrow showing erythroblastic cells bearing intranuclear inclusions. Reprinted with permission from Krause et ah (1992) and through the courtesy of J. Krause, MD.

Chronic parvovirus B19 infections with varying degrees of erythroid depression have been reported in immunologically intact persons, as well as in patients with a variety of aberrations of cellular and humoral immune responsivity (Faden et ah, 1992; Kurtzman et al, 1987, 1989; Graeve et a/., 1989). Case reports document parvovirus B19 infections in patients with AIDS accompanied by chronic anemia (Frickhofen et ah, 1990; Bowman et ah, 1990; Griffin et ah, 1991). However, surveys fail to indicate that this virus is a common cause of the anemia that afflicts about 80% of those with AIDS (van Elsacker-Niele et ah, 1996; Chernak et ah, 1995). Defects in myelopoiesis and thrombocytopoiesis have been reported in some cases. Some incomplete evidence suggests that the progenitors of these blood elements may also be infected, but the clinical evidence is incomplete. It should be recalled that neutrophil depression and thrombocytopenia were noted in the human volunteer studies described above (Anderson et ah, 1985) (Figure 23.1).

INFECTIONS IN PREGNANCY Parvovirus infections of pregnant domestic and experimentally infected animals are believed to result in congenital anomalies and stillbirths (Margolis and Kilham, 1975). Hartwig and his colleagues (1989) demonstrated parvovirus B19 DNA in the tissues of a human abortus in which developmental abnormalities of the eye were noted and a vasculitis was found in several organs. Maternal B19 infections in early pregnancy are believed to result in death of the conceptus (Woernle et ah, 1987; Kinney et ah, 1988; Hall and Cohen, 1990; Garcia-Tapia et ah, 1995; Gratacos et ah, 1995). It is

somewhat surprising that intrauterine parvovirus B19 infections have not been accompanied more frequently with teratological catastrophes in view of the predisposition of parvovirus B19 for rapidly multiplying cells. The association of hydrops fetalis with fetal parvovirus infection was first demonstrated by Brown et ah (1984). The actual prevalence is low. Only two cases are known to have occurred in Scotland during a parvovirus epidemic affecting some 500,000 persons (Anand et ah, 1987), whereas an incidence of 1.7% was reported among 60 pregnant women with serologically established infections occurring in an epidemic in Spain (Gratacos et ah, 1995). On the other hand, there was a recorded incidence of 14% among 197 cases of hydrops attributed to fetal anemia (Machin, 1989). And, 5 cases of parvovirus infection were found among 32 autopsies of hydropic stillbirths (16%) at a major urban obstetrical hospital in the United States. This latter study employed the diagnostic approach of searching for inclusions in postmortem material by light microscopy (Rogers et ah, 1993). Profound anemia due to virus replication in the fetal erythrocyte progenitor cells is the fundamental pathogenic mechanism involved in the development of hydrops fetalis, but the virus apparently also grows in the fetal heart and liver. Vasculitis is also described in fetal tissue. A high-output heart failure develops as a consequence of anemia, but the process may be compounded in some cases by myocarditis and hypoalbuminemia due to liver disease. The end result is collection of massive amounts of fluid in the tissues and the placenta of the maturing fetus. At autopsy, the tissues of these stillbirths typically reveal prominent numbers of erythroblastic cells with inclusions in the vasculature of the placenta and major organs (Figures 23.7 and 23.8). The liver can show evidence of parenchymal cell

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FIGURE 23.7 A nucleated red blood cell within the vessel of a placental villus shows the characteristic dark-staining intranuclear inclusion characteristic of parvovirus. Reprinted with permission and through the courtesy of Brenda Waters, MD.

FIGURE 23.8 Even in autolyzed tissue such as this spleen, the dark staining cells infected with parvovirus are recognizable. Reprinted with permission and through the courtesy of Brenda Waters, MD.

involvement by the virus, but characteristically, it exhibits massive extrameduUary hematopoiesis and prominent deposits of hemosiderin in Kupffer cells and hepatocytes. The latter finding suggests that hemolysis occurs during the acute infection, but this is not documented.

istry facilitates diagnosis in tissue sections but does not appear to be more sensitive than careful microscopical examination of routinely stained tissue sections for inclusion-bearing cells. Transmission electron microscopy employing traditional methodology readily demonstrates characteristic virions in the nuclear inclusions, but the technique is time-consuming, since infected cells must be found by the microscopist. Negative stain electron microscopic detection of virions in the blood serum of infected children has been effectively employed, but considerable technical skill and painstaking effort is required. Serum assays for IgM antibody is the most useful rapid diagnostic approach for evaluation of infection in cases of aplastic crises. Rapid diagnosis for these patients is important since treatment with virus-specific immunoglobulin may prove effective. The isolation of virus from tissues is not a practical approach because sensitive cell culture methodologies applicable to routine studies have not yet been developed.

INFLAMMATORY LESIONS On rare occasions, myopericarditis, aseptic meningitis, and encephalitis are associated with acute parvovirus infections in children and adults (Enders et ah, 1998). Scattered reports claim an association of vasculitis (i.e., giant cell vasculitis, polyarteritis nodosa, and a leukoclastic vasculitis) with parvovirus B19 infections (Torok et ah, 1992; Stand and Corman, 1996; Cooper and Choudri, 1998). It is possible that immune complexes contribute to the development of the vascular lesions in such cases if they are, in fact, virus related (Garcia-Tapia et al, 1995). Thus far, detailed pathological studies are not reported, and virological evaluation of the involved organs has been limited (Cassinotti et ah, 1993; Okumura and Ichikawa, 1993; Watanabe et al., 1994; Saint-Martin et al, 1990; Koduri and Naides, 1995; Chia and Jackson, 1996).

TISSUE D I A G N O S I S Immunohistochemistry, in situ hybridization, and the polymerase chain reaction are now commonly used sensitive approaches for the detection of virus in tissues (Porter et al, 1988; Schwarz et al, 1991, 1992; Torok, 1992; Goldstein et al, 1995). Immunohistochem-

References Ager, E., Chin, T., and Poland, J. (1966). Epidemic erythema infectiosum. New Engl. J. Med. 275,1326-1331. Anand, A., Gray, E., Brown, T., Clewley J., and Cohen, B. (1987). Human parvovirus infection in pregnancy and hydrops fetalis. New Engl ]. Med. 316,183-186. Anderson, M., Lewis, E., Kidd, I., Hall, S., and Cohen, B. (1984). An outbreak of erythema infectiosum associated with human parvovirus infection. /. Hyg. (Cambridge) 93, 85-93. Anderson, M., Higgins, P., Davis, L., Willman, J., Jones, S., Kidd, I., Pattison, J., and Tyrrell, D. (1985). Experimental parvoviral infection in humans. /. Infect Dis. 152, 257-265. Bowman, C , Cohen, B., Norfolk, D., and Lacy C. (1990). Red cell aplasia associated with human parvovirus B19 and HIV infection: Failure to respond clinically to intravenous immunoglobulin. A/DS 4,1038-1039.

Parvoviruses Brown, T, Anand, A., Ritchie, L., Clewley, J., and Reid, T. (1984). Intrauterine parvovirus infection associated with hydrops fetalis. Lancet 2, 1033-1034. Brown, K., Hibbs, J., Gallinella, G., Anderson, S., Lehman, E., McCarthy, R, and Young, N. (1994). Resistance to parvovirus B19 infection due to lack of virus receptor (erythrocyte P antigen). New Engl J. Med. 330,1192-1196. Cassinotti, R, Schultze, D., Schlageter, P., Chevili, S., and Siegl, G. (1993). Persistent human parvovirus B19 infection following an acute infection with meningitis in an immunocompetent patient. Eur. J. Clin. Microhiol. Infect. Dis. 12, 701-704. Chernak, E., Dubin, G., Henry, D., Naides, S., Hodinka, R., MacGregor, R., and Friedman, H. (1995). Infection due to parvovirus B19 in patients infected with human immunodeficiency virus. Clin. Infect. Dis. 20,170-173. Chia, J., and Jackson, B. (1996). Myocarditis due to parvovirus B19 in an adult. Clin. Infect. Dis. 23, 200-201. Chorba, T., Coccia, P., Holman, R., Tattersall, P., Anderson, L., Sudman, J., Young, N., Kurczynski, E., Saarinen, U., Moir, R., Lawrence, D., Jason, J., and Evatt, B. (1986). The role of parvovirus B19 in aplastic crisis and erythema infectiosum (fifth disease). /, Infect. Dis. 154, 383-392. Cooper, C , and Choudhri, S. (1998). Diagnosis: Leukocytoclastic vasculitis secondary to parvovirus B19 infection. Clin. Infect. Dis. 26, 989. Cossart, Y, Cant, B., Field, A., and Widdows, D. (1975). Parvoviruslike particles in human sera. Lancet 1, 72-73. Enders, G., Dotsch, J., Bauer, J., Nutzenadel, W., Hengel, H., Haffner, D., Schalasta, G., Searle, K., and Brown, K. (1998). Life-threatening parvovirus B19-associated myocarditis and cardiac transplantation as possible therapy: Two case reports. Clin. Infect. Dis. 26, 355-358. Faden, H., Gary Jr., G., and Anderson, L. (1992). Chronic parvovirus infection in a presumably immunologically healthy woman. Clin. Infect. Dis. 15, 595-597. Frickhofen, N., Abkowitz, J., Safford, M., et al. (1990). Persistent B19 parvovirus infection in patients infected with human immunodeficiency virus type 1 (HIV-1): A treatable cause of anemia in AIDS. Ann. Intern. Med. 113, 926-932. Garcia-Tapia, A., del Alamo, C , Martinez-Rodriguez, A., Martin-Reina, M., Lopez-Caparros, R., Caliz, R., Caballero, M., and Bascunana, A. (1995). Spectrum of parvovirus B19 infection: Analysis of an outbreak of 43 cases in Cadiz, Spain. Clin. Infect. Dis. 21, 1424-1430. Goldstein, L., Strenger, R., King, T., Le, S., and Rogers, B. (1995). Retrospective diagnosis of sickle cell-hemoglobin C disease and parvovirus infection by molecular DNA analysis of postmortem tissue. Hum. Pathol. 26,1375-1378. Graeve, J., de Alarcon, P., and Naides, S. (1989). Parvovirus B19 infection in patients receiving cancer chemotherapy: The expanding spectrum of disease. Am. ]. Fed. Hematol.lOncol. 11, 441-444. Gratacos, E., Torres, P.-J., Vidal, J., Antolin, E., Costa, J., Jimenez de Anta, M., Cararach, V., Alonso, R, and Fortuny A. (1995). The incidence of human parvovirus B19 infection during pregnancy and its impact on perinatal outcome. /. Infect. Dis. 171,1360-1363. Griffin, T., Squires, J., Timmons, C , and Buchanan, G. (1991). Chronic human parvovirus B19-induced erythroid hypoplasia as the initial manifestation of human immunodeficiency virus infection. /. Pediatr. 118, 899-901. Hall, S. and Cohen, B. (1990). Prospective study of human parvovirus B19 infection with pregnancy. Br. Med. J. 300,1166-1170.

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Hartwig, N., Vermeij-Keers, C , Van Elsacker-Niele, A., and Fleuren, G. (1989). Embryonic malformations in a case of intrauterine parvovirus B19 infection. Teratology 39, 295-302. Herrick, T. (1962). Erythema infectiosum: Clinical report of 74 cases. Am. ]. Dis. Child. 31, 486^95. Kinney, J., Anderson, L., Farrar, J., et al. (1988). Risk of adverse outcomes of pregnancy after human parvovirus B19 infection. /. Infect. Dis. 157, 663-667. Koduri, P., and Naides, S. (1995). Aseptic meningitis caused by parvovirus B19 [brief report]. Clin. Infect. Dis. 21,1053. Krause, J., Penchansky, L., and Knisely, A. (1992). Morphological diagnosis of parvovirus B19 infection: A cytopathic effect easily recognized in air-dried, formalin-fixed bone marrow smears stained with hematoxylin-eosin or Wright-Giemsa. Arch. Pathol. Lab. Med. 116,178-180. Kurtzman, G., Ozawa, K., Cohen, B., Hanson, G., Oseas, R., and Young, N. (1987). Chronic bone marrow failure due to persistent B19 parvovirus infection. New Engl. ]. Med. 317, 287-294. Kurtzman, G., Frickhofen, N., Kimball, J., Jenkins, D., Nienhuis, A., and Young, N. (1989). Pure red-cell aplasia of 10 years' duration due to persistent parvovirus B19 infection and its cure with immunoglobulin therapy. New Engl. J. Med. 321, 519-523. Luzzi, G., Kurtz, J., and Chapel, H. (1985). Human parvovirus arthropathy and rheumatoid factor. Lancet, May 25, p. 1218. Machin, G. (1989). Hydrops revisited: Literature review of 1,414 cases published in the 1980s. Am. J. Med. Genet. 34, 366-390. Margolis, G., and Kilham, L. (1970). Parvovirus infections, vascular endothelium, and hemorrhagic encephalopathy. Lah. Invest. 22, 478-488. Margolis, G., and Kilham, L. (1975). Problems of human concern arising from animal models of intrauterine and neonatal infections due to viruses: A review, II: Pathological studies. Prog. Med. Virol. 20, 144-179. Naides, S., Scharosch, L., Foto, R, and Howard, E. (1990). Rheumatologic manifestations of human parvovirus B19 infection in adults: Initial two-year clinical experience. Arthr. and Rheum. 33, 1297-1309. Okumura, A., and Ichikawa, T. (1993). Aseptic meningitis caused by human parvovirus B19. Arch. Dis. Child. 68, 784-785. Ozawa, K., Kurtzman, G., and Young, N. (1986). Replication of the B19 parvovirus in human bone marrow cell cultures. Science 233, 883-886. Pattison, J., Jones, S., Hodgson, J., Davis, L., White, J., Stroud, C , and Murtaza, L. (1981). Parvovirus infections and hypoplastic crisis in sickle cell anemia. Lancet 1, 664-665. Plummer, R, Hammond, G., Forward, K., Sekla, L., Thompson, L., Jones, S., Kidd, I., and Anderson, M. (1985). An erythema infectiosum-like illness caused by human parvovirus infection. New Engl. J. Med. 313, 74-79. Porter, D. (1986). Aleutian disease: A persistent parvovirus infection of mink with a maximal but ineffective host humoral immune response. Prog. Med. Virol. 33, 42-60. Porter, H., Khong, T, Evans, M., et al. (1988). Parvovirus as a cause of hydrops fetalis: Detection by in situ DNA hybridization. /, Clin. Pathol. 41, 381-383. Rao, S., Miller, S., and Cohen, B. (1992). Transient aplastic crisis in patients with sickle cell disease: B19 parvovirus studies during a 7-year period. Am. ]. Dis. Child. 146,1328-1330. Reid, D., Brown, T., Reid, T., Rennie, J., and Eastmond, C. (1985). Human parvovirus-associated arthritis: A clinical and laboratory description. Lancet, February 23, pp. 422-425.

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Rogers, B., Mark, Y, and Oyer, C. (1993). Diagnosis and incidence of fetal parvovirus infection in an autopsy series, I: Histology. Ped. Pathol. 13, 371-379. Saint-Martin, J., Choulot, J., Bonnaud, E., and Marinet, R (1990). Myocarditis caused by parvovirus. /. Pediatr. 116,1007-1008. Schwarz, T., Nerlich, A., Hottentrager, B., Jager, G., Wiest, I., Kantimm, S., Roggendorf, H., Schultz, M., Cloning, K., Schramm, T., Holzgreve, W., and Roggendorf, M. (1991). Parvovirus B19 infection of the fetus: Histology and in situ hybridization. Am. J. Clin. Pathol. 96, 121-126. Schwarz, T., Jager, G., Holzgreve, W., and Roggendorf, M. (1992). Diagnosis of human parvovirus B19 infections by polymerase chain reaction. Scand. J. Infect. Dis. 24, 691-696. Schwarz, T, Wiersbitzky, S., and Pambor, M. (1994). Case Report: Detection of parvovirus B19 in a skin biopsy of a patient with erythema infectiosum. /. Med. Virol. 43,171-174. Simpson, R., McGinty, L., Simon, L., Smith, C , Godzeski, C., and Boyd, R. (1984). Association of parvoviruses with rheumatoid arthritis of humans. Science 223,1425-1428. Staud, R., and Gorman, L. (1996). Association of parvovirus B19 infection with giant cell arteritis. Clin. Infect. Dis. 22, 1123.

Torok, T. (1992). Parvovirus B19 and human disease. Adv. Int. Med. 37, 431-455. Torok, T., Wang, Q.-Y, Gary Jr., G., Yang, C.-R, Finch, T., and Anderson, L. (1992). Prenatal diagnosis of intrauterine infection with parvovirus B19 by the polymerase chain reaction technique. Clin. Infect. Dis. 14,149-155. van Elsacker-Niele, A., Kroon, R, van der Ende, M., Salimans, M., Spaan, W., and Kroes, A. (1996). Prevalence of parvovirus B19 infection in patients infected with human immunodeficiency virus. Clin. Infect. Dis. 23, 1255-1260. Watanabe, T., Satoh, M., and Oda, Y (1994). Human parvovirus B19 encephalopathy [letter]. Arch. Dis. Child. 70, 71. White, D., Mortimer, R, Blake, D., Woolf, A., Cohen, B., and Bacon, R (1985). Human parvovirus arthropathy. Lancet 1, 419-421. Woernle, C , Anderson, L., Tattersall, R, and Davison, J. (1987). Human parvovirus B19 infection during pregnancy. /, Infect. Dis. 156, 17-20. Young, N. (1988). Hematologic and hematopoietic consequences of B19 parvovirus infection. Sem. Hematol. 25,159-172.

C H A P T E R

24 Neurotropic ArthropodTransmitted Viruses INTRODUCTION

yield an enormous amount of information over time. Much of our current understanding of the ecology of mosquito-borne viruses and the diseases they cause in humans has accumulated by correlating the observations of field entomologists, who classify the mosquitos and characterize their habitat, with the outcome of these virological studies. Of course, this is only half the story, for establishing a virus isolate as the cause of a human disease proves to be an imposing challenge. As it turns out, only a small proportion of the countless different viruses recovered from wild-caught mosquitos play a role in disease. To decipher the ecology of the viruses of human importance and to relate them to the epidemiology of the disease occurring in the rare patient with meningoencephalitis is a demanding task. Subclinical infections tend to be the rule, and clinical disease the exception, thus confounding the problem of associating a virus with disease. The work in developed countries has progressed to the point where many potentially devastating outbreaks of infection are now averted, largely by interrupting the life cycle of the vector. Worldwide, arthropod-borne viruses are a significant cause of morbidity and mortality. Several dozen of these viruses proved to be the etiologic agents for specific illnesses, each with its own natural history and ecological niche. These viruses circulate in nature in biologic cycles that usually involve specific species of mosquito having unique habitat requirements, and one or more nonhuman vertebrate intermediate hosts. Thus, two viral replicative cycles occur in nature; one in the insect, and the second in a warm-blooded (e.g., a subhuman primate, rodent, or swine) or cold-blooded animal (e.g., birds or snakes). It is usually when we humans invade the natural habitat of the vector and are bitten that infection occurs. Thus, humans are an incidental "dead-end" host.

343

TOGAVIRUSES (ALPHAVIRUSES)

344

Eastern Equine Encephalitis (EEE) 346 Western Equine Encephalitis (WEE) 347 Venezuelan Equine Encephalitis (VEE) 348 FLAVIVIRUSES 349

St. Louis Encephalitis (SLE) 351 Japanese B Encephalitis (JBE) 352 Other Flavivirus Encephalitides 353 BUNYAVIRUSES 354

LaCrosse (California Encephalitis Group) 354 REOVIRUSES 354 REFERENCES 355

INTRODUCTION Pedro Galindo was a robust engaging man! Enthusiastic and energetic, he invariably radiated excitement when discussing the biology of the mosquito. He was also much more than an enthusiastic entomologist. Galindo was a "Depudado" in the national legislature of the Republic of Panama, where he lived and worked. Somehow, he balanced his life, dividing his time between politics and entomology. But, he seemed to have an enormous amount of time for his true love — the collection and speciation of the mosquitos in the canapes of the virgin forests of the Isthmus of Panama. Both Pedro and our lab benefitted. We helped to finance his expeditions and paid some of his field staff; in return, he brought us the carcasses of freshly caught mosquitos to be used in our attempts to isolate in the laboratory and then characterize the arthropod-borne viruses of the Panamanian jungles. Our work was deceptively simple. Groups of 20 or so field-caught mosquitos were homogenized in a mortar using a pestle, and the suspended tissue inoculated into the brains of newborn mice. These tiny animals were then monitored for illness, which occasionally proved to be due to a virus. This rather traditional approach employed in laboratories worldwide can PATHOLOGY AND PATHOGENESIS OF HUMAN VIRAL DISEASE

Members of four families of virus are responsible for the arthropod-transmitted meningoencephalitides of humans worldwide. When clinical disease occurs, the 343


344


physician is only detecting the "tip of the iceberg/' for, beneath the "waterline," there exists a complex ecology in which humans play only a minor role. In general, these RNA viruses are highly mutable, and "wild" strains with a diversity of biological characteristics circulate in nature. Thus, the viruses humans confront may differ both in infectivity and pathogenicity over time and in different geographical locales. Based on analogies with experimental observations in laboratory animals, there is every reason to believe that the outcome of infection in humans is influenced by virological factors as well as genetically acquired and age-associated influences unique to the human host. For example, strains of wild-caught viruses of the same serotype differ substantially in their infectivity for laboratory mice, even though various virus isolates may be antigenically identical, and exhibit only the slightest dissimilarity from a molecular perspective. For unknown reasons in humans, some viruses cause devastating disease almost exclusively in children, whereas the elderly are more severely affected with others (see below). In endemic regions of virus dissemination, it is common for serum antibodies to be found in a proportion of the adult population. This indication of an earlier subclinical infection proves to be particularly the case where vectors breed with relative abandon such as in areas of Asia where Japanese B encephalitis is endemic. In this vast region, clinical infections tend to occur in children, most probably because they are highly susceptible, but also because a relatively large number of adults are immune. Contrariwise, along the Eastern Seaboard of the United States, relatively few adult members of the population possess serum antibodies to the virus of eastern equine encephalitis, most probably because it rarely circulates in an anthrophilic mosquito species. While devastating infections occur in young children, encephalitis is very uncommon in adults. Older persons may be intrinsically resistant, as proves to be the case when adult mice are inoculated experimentally with "wild" strains of many of the arthropod viruses. Three clinical forms of infection occur in exposed persons after incubation periods of usually less than a week: (a) asymptomatic subclinical infections; (b) febrile illnesses with or without systemic symptoms, such as headache, muscle aches, and pain; and (c) meningoencephalitis with or without focal neurological signs, ranging in severity from irritability to somnolence, to death. Clinical signs of meningeal inflammation are a variable component of the clinical illness, but meningitis usually is not a prominent feature of these diseases.

TOGAVIRUSES (ALFHAVIRUSES) The virus family Togaviridae derives its name from the morphologic features of the viral envelope, which reminded electron microscopists of the togas worn by citizens of Imperial Rome. The family is comprised of the alphaviruses, which are the subject of this section, and the rubiviruses, represented solely by rubellavirus (see Chapter 28). Over 25 different alphaviruses have been recovered from nature, but only a small number are human pathogens (Table 24.1). The genus alphavirus may be further divided into two subgenera based upon nucleotide sequence analysis and the diseases they cause. The first group includes the encephalitis viruses. In the second are categorized a group of exotic agents that cause nonfatal febrile arthropathies (Table 24.2). These agents will not be considered further in this book. The diseases they cause, while highly symptomatic, are relatively uncommon and geographically restricted. In addition, pathological information from humans is nonexistent and our knowledge of the pathogenesis of the arthropathy is limited. Togaviruses have a traditional structure in which a single strand of RNA is surrounded by a protein capsid comprised of 240 capsomeres arranged in icosahedral symmetry. In turn, the capsid shell is surrounded by a membrane comprised of a lipid bilayer of host cell origin in which are embedded two viral-encoded glycoproteins. These glycoproteins, termed El and E2, project from the envelope surface. Their biochemical composition plays an important role in viral pathogenicity since amino acid substitution at critical sites dramatically influences infectivity. The El and E2 proteins are the major antigens of the alphaviruses. Circulating immunoglobulins directed against viral glycoproteins are elaborated early in the course of infection. These antibodies appear to play an important role in viral clearance and protect against reinfection. The importance of cell-mediated immunity in alphavirus infections is not known. Alphavirus attachment to target cells reflects the interaction of the viral G2 glycoprotein with the plasma membrane. The virion is taken up by the cell and uncoated promptly, after which replication of the next generation of progeny virion begins. The viral RNA serves as the messenger. Production of viral components by the infected cell is associated with cytolysis. In animals, this appears to be the basis for the destructive effects of alphaviruses in tissue since immunopathologic process seem not to play a role. However, the generation of cytokines during the process of infection of viral target cells may serve to amplify the host response to infection and injury to tissue.

345

Neurotropic Arthropod-Transmitted Viruses TABLE 24.1 Neurotropic Arthropod-Borne Viruses

Genus

Reservoir and amplifying host

Vector

Endemic area for human disease

Alphaviruses Eastern equine encephalitis (EEE)

Culiceta melanuria Aedes sp.

Passerine birds

Eastern US & Gulf Seaboard

Western equine encephalitis (WEE)

Culex sp.

Birds; snakes

US & Canada; West of Mississippi River; Argentina

Horse

Caribbean Basin

Venezuelan equine encephalitis (VEE) Flaviviruses JB Complex St. Louis Encephalitis (SLE)

Culex sp.

Passerine birds

South central US; Florida; California

Japanese B Encephalitis (JBE)

Culex sp.

Pigs; Water birds

Maritime Southeast Asia; China; Japan; India, Indochina

West Nile Encephalitis (WNE)

Culex sp.

Birds; mammals

Egypt; Israel

Murray Valley Encephalitis (MVE)

Culex sp.

Water birds; small mammals

Eastern Australia

TBE Complex Central Europe/Russian Spring-Summer Encephalitis (RSSE)

Ixodid ticks

East Central Europe; East/Central/ West former USSR

Powassan

Ixodid ticks

Small field mammals

Russia; Canada; Northern US

Aedes triseriatus

Small field mammals

North Central US

Dermacentor andersonia

Various field mammals

Rocky Mountains, US; Great Basin, US

Bunyavirus (California serogroup viruses) LaCrosse (LAV) Reoviruses Colorado Tick Fever (CTF)

TABLE 24.2 Alphavirus Febrile Arthropathies

Disease

Geographic distribution

Vector

Chikungunya

Aedes aegypti Mansonia sp. Aedes aegypti person-to-person

O'nyong-nyong

Anophales sp.

East Africa

Igbo Ora

Anophales sp.

West Africa

Ross River New Guinea

Aedes sp.

East & North Australia

Alphaviruses are highly mutable, and subtle amino acid substitutions in the capsid glycoproteins appear to influence the outcome of infection. Wie know very little about the molecular make-up of the virions transmit-

sub-Saharan Africa Indian subcontinent Indochina

ted by the insect vector to the human host. Unfortunately, most experimental studies are carried out with laboratory-adapted strains of virus that have been passaged from animal to animal before investigative work

346 is undertaken. This allows for selection of numerous subtle mutations that most probably have no relevance to disease in humans. After an arthropod "bite," virus replicates at the local site, possibly in resident cells or inflammatory cells such as macrophages. Viremia then occurs. The virus concentration of the blood probably determines, at least in part, whether or not the central nervous system is infected. In the brain, alphaviruses appear to replicate in endothelial cells before they broach the vascular barrier that precludes their access to the rich source of target neurons and glial cells in the brain. Alphaviruses appear to be primarily neurotropic and disseminate throughout the brain with apparent ease, although we understand very little about the intracerebral events associated with infection. Experimentally, some viruses of this family are only infectious for young mice when inoculated subcutaneously or directly into the brain, whereas other viruses infect the central nervous system of animals of all ages, regardless of the route of inoculation. Major organs other than the brain do not develop significant lesions in most alphavirus infections. Venezuelan equine encephalitis virus is an exception, for it uniquely infects and destroys lymphoid and myeloid cells indiscriminately in its natural host, the horse, as well as in a variety of small experimental animals. Necrosis of lymphoid tissues is also reported in humans, but the information available from autopsies is limited.

1986

1987

198S

Eastern Equine Encephalitis (EEE)

FIGURE 24.1 Annual incidence (1985-94) of cases of EEE (A) and WEE (B) reported to the Centers for Disease Control and Prevention.

The initial outbreak of encephalitis known to be caused by EEE occurred in Massachusetts during the late summer of 1938. Two-thirds of the cases were children and 74% died (Feemster, 1958). Among the few survivors, severe neurological sequelae (mental retardation, seizure disorders, emotional lability, and impaired motor activity, speech, and hearing) proved to be common. Since that time, outbreaks of limited size have occurred along the Eastern Seaboard and the Gulf Coast, but, customarily, only sporadic cases are reported. Between 1955 and 1993, the U.S. Centers for Disease Control and Prevention documented 223 human cases of EEE in the United States. The high mortality among children has continued with a substantially reduced death rate among adults (Figure 24.1 A). In the freshwater wetlands of its endemic range, EEE transmission in nature appears to go unrecognized. Culiceta melanura is the major vector, and passerine birds are the amplifying host. Many of these familiar songbirds enjoy a winter vacation in South and Central America, where they most probably overwinter the virus. When virus activity in reservoirs reaches a threshold during the summer months in North America, species of the Aedes mosquito may also serve as vectors

transmitting the viruses to horses and to upland birds, such as the exquisitely susceptible pheasant. Only on occasion do humans intervene. Mammalian intermediate hosts are not known to be important reservoirs for EEE in nature. A strain of EEE virus that is less pathogenic than the North American virus circulates in the American tropics. A small number of healthy adult residents of these endemic regions possess serological evidence of past subclinical infection with this virus. A clinically severe encephalitis is the usual outcome of an EEE virus infection in children in North America. The pathological features of the acute disease have been elegantly described by many earlier authors (Farber et al, 1940; Wesselhoeft et al, 1938; Dent, 1955; Herzon et al, 1957; Haymaker, 1958a; Moulton, 1960; Jordan et al, 1965). The outstanding histopathologic feature in these cases is the presence of luxuriant focal polymorphonuclear leukocyte infiltrates extensively involving the brain (Figure 24.2A-D). Both the cerebral cortices and midbrain structures (thalamus, basal ganglia, substantia nigra, and pars basalis) are affected. Lesions in the cerebellum, brainstem, and spinal cord

Neurotropic Arthropod-Transmitted Viruses

347

B

-*/'/»

P'X;

^';^^^«ik^^

F I G U R E 24.2 Lesions in the brain of a young child infected with, and dying of, EEE. (A) Acute destructive encephalitis. Note the diffuse infiltrates of polymorphonuclear leukocytes. The severe widespread acute inflammation seen here is typical of EEE, but not of most other types of arthropod-borne virus encephalitis. (B) Glial nodule. (C) Perivascular cuff. (D) Thrombosed small vessels. Note the endothelial cell changes in the vessels and the scattered inflammatory cells.

are not prominent. Recently, magnetic resonance imaging has been used to document destructive inflammatory changes (Figure 24.3) (Deresiewicz et ah, 1997; Piliero et ah, 1994). Meningeal infiltrates and perivascular inflammatory cell "cuffs" are prominent in acute lesions. Electron microscopy of the acutely infected brain documents profound changes in neurons and glia, alterations also readily apparent at lower levels of resolution. In the studies of Kim and colleagues (1985), the so-called tubular reticular complexes (ultrastructural cellular alterations seen in HIV-1-infected cells and lupus erythematosus) were evident in macrophages. These cells seem to support virus replication. With the passage of time, the pathological picture changes with subsidence of the polymorphonuclear response, and the appearance of lymphocytes and macrophages in areas where destructive changes and rarefaction of brain substance are apparent. Western Equine Encephalitis (WEE) WEE was first isolated in California from a horse during an equine epizootic in 1930 and from a child with encephalitis in 1938. This interesting virus pos-

sesses molecular features of EEE, and antigenic determinants of Sindbis virus, an Old World alphavirus that apparently lacks the ability to cause central nervous system disease in humans. Thus, it has been hypothesized that WEE is a recombinant, reflecting a clandestine interaction of these two disparate viruses aeons in the past (Hahn et ah, 1988). WEE is endemic throughout the Midwestern United States and California (Figure 23.1B), where its vector is Culex tarsalis, a common mosquito of agricultural lands, and its intermediate amplifying hosts are birds and small animals, including snakes. In the American Mid- and Far West, enzootics in horses are common, with roughly 22 to 100 equine cases of encephalitis occurring for each clinical case in humans (Figure 24.IB). WEE is infectious for persons of all ages, but about 20% of cases are infants and small children (Cohen et al, 1953). As with other viral encephalitides, the signs and symptoms of nervous system involvement are variable and may be so mild as to be overlooked. The initial fever is followed by headache, and as the infection progresses, drowsiness, malaise, mental symptoms, and seizures intervene. Stupor and coma, followed by death in some cases, generally occurs 4 to 7

348


FIGURE 24.3 Lesions of the basal ganglia and cortex in a 14-year-old boy who died of EEE. Panel A shows an MRI scan taken 3 days after the onset of neurologic symptoms. Large asymmetric lesions are present in the caudate nuclei, putamen, and thalami (arrowheads). Panel B shows a CT scan taken 7 days after the onset of neurologic symptoms. Large lesions of the basal ganglia and thalami are again evident (outlined by arrowheads). There is diffuse swelling of the brain. Panel C shows an image from the same MRI as shown in A. Lesions are present in the medial temporal lobes (arrows) and right insula (not shown). Autopsy revealed diffuse encephalomalacia, marked perivascular chronic inflammatory changes, and focal intraparenchymal perivascular hemorrhage in the caudate nucleus and putamen. Several microglial nodules were evident. A necrotic and hemorrhagic area measuring 3 by 2 cm was present in the anterior portion of the right temporal lobe. Reprinted with permission from Deresiewicz et al. (1997).

days after the onset of symptoms. A variety of neurological signs are detected, but in general, the encephalitis is not as severe as in EEE (Baker, 1958b). WEE is less pathogenic than EEE, and thus has a substantially lower case:infection ratio (Reeves et al, 1962). Subclinical infections occur in more than 1000 adults for each clinical case of encephalitis. However, as with EEE, clinically inapparent infections are uncommon in infants and devastating life-threatening encephalitis often occurs. Findings at autopsy are limited to the central nervous system, where, in order of decreasing frequency, lesions are found in the globus pallidum, central cortex, thalamus, and pontine tegmentum (Haymaker, 1958b). Histologically, pathologists find a mixed infiltrate of polymorphonuclear cell, lymphocytes, and macrophages involving the meninges and perivascular spaces. Areas of rarefaction necrosis stud the brain, where reactive gliosis and variable numbers of inflammatory cells are often present. Customarily, encephalitis persists for 10 days and then subsides. The severity of the clinical sequelae is variable and related to age (Baker, 1958b). In infants, motor involvement, behavioral retardation, and seizure disorders occur (Finley, 1958). Similar sequelae are seen in older children and adults, but residual com-

plications are uncommon. Severe destructive changes may be seen morphologically in the brains of those who linger with significant disabilities after the acute stages of illness. Venezuelan Equine Encephalitis (VEE) Epizootics of VEE in horses, and concurrent epidemics in humans, occur periodically in northern South America, primarily Colombia and Venezuela. These outbreaks seem to develop along with heavy rains and flooding during the traditional dry season. Horses are the principal amplifying hosts because they sustain a prolonged high level of viremia and attract a variety of mosquitos. In addition, horse-to-horse contact transmission occurs (Kissling et al, 1956). Epidemiologically differences in the pathogenic properties of various "wild" viral strains may be a significant factor. Molecular analyses indicate that the virus responsible for some 1.3 X 10^ human infections in northwest Venezuela in 1994 is linked to a strain responsible for another larger epidemic in the same region some 20 years earlier in 1973 (MMWR, 1995; Sidwell et al, 1967). VEE readily circulates in horses as epidemics in northern South America, and variably "spills over"


into humans. When humans are infected, the disease is customarily manifest as a "flu-like" syndrome with fever, headache, muscle pain, and prostration. Evidence of neurological disease occurs predominantly in children and the elderly, with an overall attack rate of about 4%, and a case fatality rate of less than 1%. Deaths occur predominantly in children. Few autopsy reports of fatal human cases are published. Deaths among VEE-infected persons occur as a result of encephalitis or a fulminating lymphocytolytic reaction with disseminated intravascular coagulation (de la Monte ei al., 1984). Meningoencephalitis is the predominant lesion, with focal accumulations of a mixed inflammatory cell infiltrate in the meninges and brain. A necrotizing vasculitis is observed rarely. In most patients, there is striking necrosis of lymphoid cells in the lymph nodes and spleen. This unique lesion is also observed in horses and animals of several different species experimentally infected in the laboratory (Victor et al., 1956). Finally, widespread hepatocellular degeneration and necrotic changes are observed in over 60% of patients at autopsy, and interstitial pneumonia is seen in most patients.

FLAVIVIRUSES The features of the viruses of this large family were summarized in Chapter 19. In brief, the flaviviruses of

349

human importance are small RNA-containing agents having a nucleocapsid surrounded by a bilayer envelope derived from the host cell. The viral E protein embedded in the membrane is the major antigen. It confers antigenic identity to the virus and provokes both humoral and cell-mediated immune responses. The role of humoral antibody in viral clearance and protection against reinfection is well established, but the importance of cellular immunity is unclear. Flaviviruses appear to replicate at the local site of the insect "bite" before disseminating to regional lymph nodes and to various solid organs (heart, liver, pancreas), where a second stage of replication occurs. The subsequent viremia carries the agent to the central nervous system, where it may multiply in endothelial cells before gaining access to the brain. The mode by which the virus subsequently spreads in the central nervous system is unclear. Flaviviruses attack both glia and neurons. The virus destroys neurons by a pathological process that morphologically appears remarkably similar to events in the poliovirus-infected anterior horn cell (see Chapter 1). The earliest changes in the cells accompany viral maturation. Virion cores accumulate in the cytoplasm and appear to acquire their membrane by budding into the internal cisternae of the cell cytoplasm (Figure 24.4). Cell dissolution occurs 2 or more days after the cell sustains the initial infection (Murphy ei al., 1968). Centers in the brain differ with regard to their susceptibility to infection, and the spinal cord is rarely involved. It may be that the virus gains

F I G U R E 24.4 Enveloped virions in the cisterna of the endoplasmic reticulum of a neuron in the brain of an infant mouse infected with SLE. The arrowheads point out ribosomes and irregular particles of approximately the same size that are believed to be precursors of viral particles. Envelopment occurs when the precursor particles pass through the wall of the endoplasmic reticulum. Reprinted with permission from Murphy ei al. (1968).

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access to the brain at multiple sites as a result of viremia. During the course of infection, mixed inflammatory cell responses are discerned at scattered sites in the brain by the pathologist. The infiltrate is comprised of lymphocytes, plasma cells, and macrophages. The prominent accumulations of polymorphonuclear leukocytes seen in EEE and, to a lesser extent in WEE-infected brains, are not observed. Many gaps in our understanding of the pathogenesis of flavivirus infections of the nervous system remain to be filled by the work of future investigators. Based on both molecular and antigenic similarities, the flaviviruses of human importance are categorized

into two groups. The first group, termed JE, incorporates major endemic viruses of five continents that are transmitted by culicine mosquitos, and use a variety of birds and mammals as intermediary and overwintering hosts (Table 24.1, Figure 24.5). Each of these viruses has the potential to cause encephalitis in humans, but they are also responsible for a large number of inapparent infections throughout endemic ranges. Viruses of the second group (TBE) are transmitted by the ixodid tick but employ mammals and birds to amplify and overwinter the virus. While these viruses cause encephalitis on occasion, disease of the central nervous system is an uncommon outcome (Table 24.1).

Birds and/or Mamrrrals

Dead-end Hosts

Migratory Birds, Bats

Maintenance Mechanisms F I G U R E 24.5 Generalized transmission cycle of mosquito-borne flaviviruses causing encephalitis, showing summertime amplification and presumptive overwintering mechanisms. Humans are "dead-end" hosts and do not perpetuate virus transmission. Vector species vary, but culicine mosquitos (principally Culex spp.) are responsible for the amplification cycles. Wild birds are the most important intermediate viremic hosts for most viruses because they sustain a viremia, but in the case of Japanese encephalitis domestic swine play an important role. The pattern shown here applies to St. Louis, Japanese, Murray Valley, and West Nile encephalitis viruses and possibly other flaviviruses, but with individual variations. Reprinted with permission from Monath and Heinz (1996).


St. Louis Encephalitis (SLE) Several late summer outbreaks in the American Midwest during the early 1930s established SLE as a major cause of arthropod-borne encephalitis among adults in North America. The virus has continued to plague residents of the southern and central states, posing an ever-present threat when weather conditions favor multiplication of its vector, the culicine mosquito (Figure 24.6). SLE virus is widely disseminated in North and Central America. Virus activity in nature has been documented at one time or another throughout the continental United States, except for maritime New England, and from Canada to the Darien jungle of Panama.

A

j^

-. ft. \\

A 1992

K

351

factor influencing the occurrence of an epidemic. In recent years, public health mosquito eradication programs have played an important role in curtailing many of these outbreaks. Encephalitis due to SLE virus is primarily a disease of persons of advanced age, in contrast to the alphaviruses considered above, and Japanese B encephalitis discussed below. In one outbreak (Jones, 1934), the mortality rate was 335 per 1 x 10^ population among octogenarians, but less than 4 per 1 x 10^ in persons under 40 years of age — nearly a 100-fold difference! Hypertensive and atherosclerotic vascular disease are risk factors predisposing to encephalitis among those who are infected. The pathogenic basis for this observation is obscure. In middle-aged patients with hypertension, mortality is increased some ninefold (Broun, 1958). The onset of SLE is usually sudden, with high fever and the signs and symptoms of meningeal irritation accompanied by drowsiness and mental confusion. Stupor and coma evolve subsequently. About Vs to V2 of patients who recover from encephalitis of varying degrees of severity experience residual symptoms (Table 24.3) and exhibit a diversity of significant organic neurological defects (Table 24.4) (Figure 24.7).

!\

1993

FIGURE 24.6 Evidence of SLE virus epidemicity in the United States during the 10-year period 1985-94 based on the annual incidence of cases of encephalitis reported to the Centers for Disease Control and Prevention (MMWR, 1994).

The virus of SLE would be better considered a family of antigenically identical agents that differ greatly in pathogenicity (Monath ei al., 1980). The basis for the high degree of mutability of this family of viruses has not been established, but it has significant implications with regard to the epidemiology of SLE. In endemic areas of virus activity, the prevalence of seropositive adults in the general population is relatively high. According to Monath and Heinz (1996), the ratio of inapparent: apparent infection varies with age, being 806:1 in children and 85:1 in the elderly. During outbreaks, inapparent and mild infections are prevalent. One might speculate that these infections do not involve the central nervous system because the virus lacks neurotropic pathogenicity. However, host factors also play an important role. In the United States, sporadic devastating outbreaks in heavily populated areas of the country have been documented over the past half century. Climatic conditions favoring multiplication of the vector mosquito are perhaps the most important

TABLE 24.3 Outstanding General S y m p t o m s in 18 Patients w i t h Organic D e f e c t s D u r i n g Convalescence from SLE Impaired memory Nervousness Irritability Weakness Dizziness Inability to walk firmly Inability to work Sleeplessness Adapted with permission from Smith (1958).

In fatal cases, the brain reveals a mononuclear meningitis (Figure 24.8) and a diffuse perivenular and periarteriolar infiltrate, predominantly, but not exclusively, located in the grey matter. Lesions in the cord are occasionally prominent. Cranial nerves are generally not affected. Focal accumulations of microglial nodules and variable degrees of neuronolysis are observed (Gardner and Reyes, 1980). The lesions of SLE predominate (and are most severe) in the thalamus and substantia nigra. The cerebral cortices, cerebellum, hypothalamus, and brainstem are less frequently affected and the lesions are less severe (McCordock ei al., 1934;

352


FIGURE 24.7 Late stages in the recovery of a flavivirus-infected infant mouse. Note the destructive loss of brain parenchyma (A) and the accumulations of mononuclear cells and granulation tissue (B). Resolution of the lesion is associated with the gliosis and scarring.

Weil, 1934; Haymaker, 1958c; Shinner, 1963; Suzuki and Phillips, 1966; Gardner and Reyes, 1980) (Figure 24.8). The pathological effects appear to be largely due to viral damage to neurons. The degree and distribution of the inflammation does not necessarily correspond to the distribution of neuronal lesions, suggesting that the infection is more widespread. When patients recover, newly elaborated antibodies appear to be of paramount importance in clearing the virus from the central nervous system. Cellular immune mechanisms have not been found to be significant factors influencing viral infectivity. SLE disease in HIV-1infected patients is not inordinately severe (Okhuysen et al, 1993). TABLE 24.4 Nature of Organic Defects Found in 18 Patients 3 Years After Infection w i t h SLE Organic Defects Defects in speech Difficulty in walking Disturbances in vision Positive Romberg sign Deafness Positive Oppenheim and Babinski signs Change in acuity of smell Lateral nystagmus Paralysis of both lower extremities Partial paralysis of upper extremities Right hemiplegia Epileptiform convulsions Adapted with permission from Smith (1958).

33%

11%

6%

Japanese B Encephalitis (JBE) This virus is distributed over a vast densely inhabited region of the earth's surface. It is widespread in the Indian Subcontinent to the southwest, and in the Japanese archipelago on the northeast. Much of mainland China and Southeast Asia are also areas of endemicity. In tropical regions, the virus appears sporadically in individual cases and in small outbreaks throughout the year. Where climatic conditions are seasonal, virus outbreaks occur during and after the monsoon rains (in the summer months, June through September). The human toll of JBE is incalculable, but undoubtedly it is the world's most consequential arthropod-borne viral infection in terms of morbidity and mortality. The ecology of JBE is influenced over its broad range by a variety of environmental factors, but it appears to be disseminated to humans by various species of culicine mosquito, with birds and mammals being amplifying and overwintering hosts. In Japan, where extensive ecological studies have been done, the domestic pig and various species of heron are major intermediaries (Scherer, 1959). In contrast to SLE, JBE encephalitis commonly occurs in infants and children where the mortality rate is high. Because inapparent subclinical infections are so common in the general population in these endemic regions, young people represent a highly susceptible population. The molecular characteristics of various JBE strains differ over the geographic range of the virus, and the pathogenicity of field isolates for laboratory animals, and presumably humans, is variable (Huang and Wong, 1963).


353

F I G U R E 24.8 An inflammatory infiltrate in the meninges of the brain of an infant mouse experimentally infected with a flavivirus. The cells are a mixture of lymphocytes and macrophages.

The pathological features of JBE are similar to those of SLE described above. However, the reports of Japanese pathologists suggest that areas of rarefaction in the brain are frequently present (Miyake, 1964). Mortality is variable and highly influenced by the quality and availability of medical care. Among young adult members of the American military stationed in Japan, it is lower than 10%. In children, death is common and residual neurological defects are a frequent outcome. Zimmerman (1946) has provided us with a detailed description of the central nervous system disease in young Okinawa native residents dying within a 2week period after the onset of symptoms. Lesions were found throughout the brain and spinal cord. "The degree of neuronal involvement varied from case to case, and from zone to zone in each case." Injured cells were as few as two to three in some cases, whereas larger areas of disease incorporating 20 to 30 cells were also present. The cytological features ranged from chromatolysis of ganglion cells to eosinophilic pycnotic neurons. In the substantia nigra, melanin-containing cells were damaged and the melanin scattered in the interstitium. A neutrophilic infiltrate was sporadically observed, and at times the acute inflammation resembled a pyogenic abscess. "In the anterior horn of the spinal cord, the glia and leukocyte reactions duplicated the histolytic picture of acute poliomyelitis" (Zimmerman, 1946). Perivascular cuffs of lymphocytes and glial

nodules comprised of polymorphonuclear cells and mononuclear cells were scattered throughout the brain and cord.

Other Flavivirus Encephalitides Worldwide, several additional arthropod viruses cause sporadic cases of encephalitis in diverse endemic areas. These include: (1) the Central European and Russian spring/summer complex of immunologically related viruses that are tick-borne and range over a vast geographic region from south central East Europe into much of the southern reaches of the former Soviet Union; (2) Powassen, a member of the Russian spring/ summer complex that appears sporadically in eastern Canada and the Northeast United States; (3) West Nile encephalitis, a mosquito-borne agent distributed throughout the Middle East and in Africa south to the Cape; (4) Murray Valley encephalitis, a mosquito virus that is widely distributed in eastern Australia; and (5) Rocio, an uncommon cause of encephalitis in the Brazilian state of Sao Paulo. The illnesses caused by these exotic viruses generally are mild and not associated with neurological signs and symptoms. On occasion, however, meningoencephalitis of varying degrees of severity occurs. Mortality rates are customarily low. Unfortunately, the pathological features of the disease

354


in virologically verified cases are poorly characterized, and published reports are limited to observation in one or a small number of cases. The interested reader is referred to the relevant literature: Russian spring/summer encephalitis (Jervis and Higgins, 1953); Powassan (Smith et al., 1974), West Nile encephalitis (Pruzanski and Altman, 1962; Manuelidis, 1956; Marberg et al, 1969; Gadoth et al, 1979; Southam and Moore, 1951, 1954), Murray Valley encephalitis (Robertson, 1952).

BUNYAVIRUSES As discussed in more detail in Chapter 19, the family Bunyaviridae is comprised of four genera of viruses having human health importance. Members of the genera Hantavirus, Phlebovirus, and Nairovirus are the etiological agents of various hemorrhagic disease in humans. The pathogenic arthropod-transmitted Bunyaviruses are considered here.

50% experience seizures and exhibit focal neurological signs. Indeed, focal seizures and generalized convulsions prove to be the most distinguishing clinical features of acute LAC infection (Deering, 1983). In one study, seizures occurred during convalescence in 6% of children (Chun, 1983). Neuropathological information is limited because of the low mortality rate of LAV infections (Kalfayan, 1983). Evidence of elevated intracranial pressure is found at autopsy. In the reported cases, congestion of the leptomeninges is observed, and only minimal mononuclear cell accumulations are present. The grey matter of the cerebral cortices exhibits focal, patchy clusters of mononuclear cells, and localized areas of necrosis. Polymorphonuclear leukocytes are rarely observed in infiltrates. Perivascular lymphocytic cuffs are also a prominent feature. Additional but mild changes are seen in the basal nuclei and brainstem. The cerebral white matter, cerebellum, medulla, and spinal cord fail to exhibit lesions. The prominent involvement of the cerebral cortices in these patients no doubt accounts for the high prevalence of seizure disorders and focal neurological signs.

LaCrosse (California Encephalitis Group) (Calisher and Thompson, 1983) The classification of the viruses categorized in the genus Bunyavirus proves confusing. The genus includes almost 150 interrelated viruses that share antigenic and molecular characteristics but are not human pathogens. California encephalitis virus was initially recovered in the Golden State from a human case of encephalitis in 1943. Although it is the prototype virus of the group, infection by California encephalitis virus has been associated with neurological disease on only rare occasions since that time. On the other hand, an antigenically closely related member of the California complex, termed LaCrosse (LAC), is a major cause of encephalitis among children and adolescents in the Midwest and Eastern United States. During the past several decades, roughly 70 cases of LAC encephalitis have occurred each year in the United States, with the highest annual incidence in the Middle American states of Indiana, Kentucky, Wisconsin, Minnesota, and Iowa. The case fatality rate over this period has been 0.3%. Related viruses (Snowshoe hare and Jamestown) are etiologically associated with meningoencephalitis in humans in Canada and New York State, but they are exceedingly rare causes of disease. Most patients with meningoencephalitis due to LAC are 5 to 10 years of age. They present clinically with fever, headache, signs of meningeal irritation, and an altered sensorium (Gundersen and Brown, 1983). Over

REOVIRUSES The virus of Colorado tick fever (CTF) is classified in the genus Coltivirus of the family Reoviridae. The reoviruses are ubiquitous, with a worldwide distribution. They have been recovered from a number of arthropod species and a vast variety of vertebrates. CTF virus is biologically related to several agents of veterinary and wildlife importance, but it represents the only established human pathogen in this large genus of interesting viruses. On rare occasions, two antigenically related viruses have been recovered from humans, but their causative role in disease is not established. CTF is a febrile, rarely fatal, systemic illness that on occasion is manifest with an erythematous maculopapillary skin rash and uncommonly with hepatitis, arthritis, pneumonitis, myocarditis/pericarditis (Emmons, 1985) and meningoencephalitis (Spruance and Bailey 1973; Goodpasture et al, 1978; Tsai, 1991). It is transmitted in the field by the so-called hard-shelled tick Dermacentor andersonia. Thus, a disproportionate number of those with an infection are young adult males who acquired the virus vocationally or avocationally About 175 cases occur in the United States annually, throughout the endemic area of virus activity, which includes the Rocky Mountain and Great Basin states of America.


Coltivirus infections are unique, for the virus parasitizes erythrocytes and mononuclear cells in the blood as well as their precursors in the bone marrow and lymphoid tissues. In this fashion, CTL avoids the onslaught of the immune response to infection. Chronic infections of red cells have been demonstrated for as long as 4 months in animals (Philip et ah, 1975; Philipp et al, 1993). In experimentally infected animals, the virus of CTF exhibits neurotropic properties. However, studies applicable to understanding the pathogenesis of the meningoencephalitis in humans are lacking. The incidence of CNS disease (meningitis, meningoencephalitis, and encephalitis) has been estimated to be 3 to 7% (Monath and Guirakhoo, 1996). Case reports are scattered in the literature (Silver et ah, 1961; Fitz and Meiklejohn, 1958; Ecklund et al, 1959; Fraaer C , and Scheff, 1962). Since patients recover without significant neurologic residue, detailed neuropathological studies have not been carried out.

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Robertson, E. (1952). Murray Valley encephalitis: Pathological aspects. Med. J. Aust. 1,107. Rous, P., and Kidd, J. (1936). The carcinogenic effect of a virus upon tarred skin. Science 83, 468-469. Scherer, W (1959). Ecological studies of Japanese encephalitis in Japan, parts I-IX. Am. J. Trop. Med. Hyg. 8, 644-722. Shinner, J. (1963). St. Louis virus encephalomyelitis. Arch. Pathol. 75, 309-322. Sidwell, R., Gebhardt, L., and Thorpe, B. (1967). Epidemiological aspects of Venezuelan equine encephalitis virus infections. Bacteriol. Rev. 31, 65-81. Silver, H., Meiklejohn, G., and Kempe, C. (1961). Colorado tick fever. Am. J. Dis. Child. 101, 56-61. Smith, J. (1958). St. Louis encephalitis: Sequelae. Neurology 8,884-887. Smith, R., Woodall, J., Whitney E., Deibel, R., Gross, M., Smith, V, and Bast, T. (1974). Powassan virus infection: A report of three human cases of encephalitis. Am. J. Dis. Child. 127, 691-693. Southam, C , and Moore, A. (1951). West Nile, Ilheus, and Bunyamwera infections in man. Am. J. Trop. Med. 31, 724. Southam, C , and Moore, A. (1954). Induced virus infections in man by the Egypt isolates of West Nile virus. Am. J. Trop. Med. Hyg. 3, 19. Spruance, S., and Bailey, A. (1973). Colorado tick fever: A review of 115 laboratory confirmed cases. Arch. Intern. Med. 131, 288-293. Suzuki, M., and Phillips, C. (1966). St. Louis encephalitis: A histopathologic study of the fatal cases from the Houston epidemic in 1964. Arch. Pathol. 81, 47-54. Tsai, T. (1991). Arboviral infections in the United States. Infect. Dis. Clin. North Am. 5, 73-102. Victor, J., Smith, D., and Pollack, A. (1956). The comparative pathology of Venezuelan equine encephalomyelitis. /. Infect. Dis. 9, 5566. Weil, A. (1934). Histopathology of the central nervous system in epidemic encephalitis (St. Louis epidemic). Arch. Neurol. Psych. 31, 1139-1152. Wesselhoeft, C , Smith, E., and Branch, C, (1938). Human encephalitis: Eight fatal cases, with 4 due to the virus of equine encephalomyelitis. JAMA 111, 1735-1741. Zimmerman, H. (1946). The pathology of Japanese B encephalitis. Am. J. Pathol. 22, 965-975.

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25 Rabiesviruses INTRODUCTION 357 EPIDEMIOLOGY 357 CLINICAL DISEASE 358 PATHOGENESIS 359 CENTRAL NERVOUS SYSTEM DISEASE REFERENCES 362

cause they are exceedingly uncommon causes of disease and we know so little about them. The vesiculoviruses are the second genus of the family to infect vertebrates. The only virus of human importance is vesicular stomatitis virus, an agent of economic significance, for it causes outbreaks of a nonfatal vesicular disease of the mucus membranes of cattle and other hoofed animals. On rare occasions, humans who work in close contact with infected animals develop mild vesicular eruptions. The virion of rhabdoviruses are relatively large and bullet-shaped when examined by electron microscopy. They have a helical nucleocapsid enveloped by a lipid and glycoprotein bilayer membrane. Despite the virion's size, it contains a limited complement of genes in the form of a single-stranded RNA that codes viral polymerases and structural proteins. When infecting a cell, the rhabdovirus passively attaches to the plasma membrane and is taken into the cell. The nucleocapsid is then uncoated and replication begins in the cytoplasm. The viral polymerase catalyzes RNA synthesis, and structural components of the virus are fabricated under the direction of viral genes using cell metabolites. These components assemble subjacent to the plasma membrane of the cell, where they bud off as infectious virions. Much of what we know about rabiesvirus replication is drawn from analogies with its cousin, the vesicular stomatitis virus. Relatively little scientific research on this aspect of rabiesvirus biology has thus far been conducted. Vesicular stomatitis virus replicates rapidly in susceptible cells while destroying them, whereas in vitro growth of rabiesvirus is slow and cytotoxicity limited. Thus, comparisons between the two must be evaluated with caution.

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Take heed of yonder dog! Look when he fawns; he bites; and when he bites his venom tooth will rankle to the death; have not to do with him; beware of him; sin, death, and hell, have set their works on him. William Shakespeare

INTRODUCTION Rabies (Latin rahhos, meaning "to do violence") is a disease of antiquity documented by authors and historians long before the birth of Christ. The public health importance, indeed the fear of rabies, was profound among our distant forefathers. At the time of Pasteur, the French government sponsored a rabies commission, and Pasteur's accomplishments were followed with great interest by the general public as well as the scientific community. His work culminated in successful postexposure immunization of a young boy who had been extensively bitten by a rabid dog using an attenuated live-virus vaccine (Fisher, 1995). Rabiesvirus is the only member of the Rhabdoviridae family having human importance. This large family of viruses comprises five genera in which are classified viruses of both warm- and cold-blooded fauna, including insects and several species of flora. Rabies is the dominant member of the Lyssavirus {Lyssa = Greek for "madness") genus. There are several distant relatives of rabiesviruses in this family, namely, Lagos bat virus, Mokolavirus, and Duvenhago (Mebatsion et ah, 1992). They are indigenous to bats in Africa, but on rare occasions these viruses have caused encephalopathies in humans. I will not consider them further here, bePATHOLOGY AND PATHOGENESIS OF HUMAN VIRAL DISEASE

EPIDEMIOLOGY Rabiesviruses are infectious for a wide variety of warm-blooded animals, and silent transmission in the wild among various species occurs largely unrecognized by humans. The virus infecting these diverse 357

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species of animals possesses in nature unique molecular and antigenic markers that allow the investigator to identify the origin of a particular virus strain (Smith et al., 1992). While infections of human importance are customarily acquired from dogs, wolves, and coyotes, insectivorous and fruit-eating bats are increasingly serving as a source of human disease. Infected bats have now been documented in all of the 48 contiguous United States, and 11 of the 21 cases of rabies occurring in the United States over the period from 1980 through 1995 are attributed to an infected bat (MMWR, 1995a, 1996). On rare occasions, the origin of the infection in humans is never established (Mrak and Young, 1993), and in other cases, direct contact and a penetrating wound inflicted by a suspect animal are not documented. For example, only 27% of the 33 human rabies deaths occurring in the United States over the period from 1977 through 1994 had clearly documented histories of an animal bite (MMWR, 1995b, 1992). Although considerable concern is voiced in the United States about the hazards of rabies epizootics among raccoons, skunks, and foxes living in close proximity to humans, these infected animals have not proven to be a substantial threat, even in densely populated communities. Apparently, these wild animals usually develop "dumb" rabies and do not exhibit the aggressive behavior of dogs and wolves. In addition, the virus strains that infect animals may be relatively lacking in pathogenicity or the virus concentrations in the salivary gland secretions may be relatively low. These mysteries remain to be solved. Worldwide, rabies is of greatest human importance in countries where the populations of stray dogs and wolves are high. In recent years, several cases of rabies imported into the United States have exhibited extraordinarily long incubation periods, that is, as long as 7 years (Smith et ah, 1991). In a comprehensive review of the literature. Dean (1963) found that almost 10% of published cases of rabies had an incubation period longer than 90 days. Thus, clinically unexplained cases of encephalopathy should trigger a consideration of rabies among physicians and pathologists. As discussed in more detail below, the neuropathologic features of rabies are sufficiently obscure (Anonymous, 1978) that the unsuspecting pathologist could easily overlook the diagnosis, while unknowingly conducting an autopsy on an unusually hazardous cadaver. This concern is illustrated by therapeutic misadventures when rabies-infected corneas have been unknowingly transplanted into susceptible patients (Houff et al, 1979).

CLINICAL DISEASE Two clinical forms of rabies occur in humans — the so-called "furious" rabies and "dumb" rabies. In the former, the brainstem, cranial nerves, and limbic system of the brain are extensively involved, whereas in "dumb" rabies the lesions are customarily restricted to the brainstem and spinal cord. In most cases, the illness is initially expressed as a nonspecific syndrome of chills and fever, myalgias and headaches, as well as vague respiratory and digestive tract complaints. Pain and paresthesias appear in proximity to the site of the animal bite in a substantial number of patients. The prodroma in the "furious" form is expressed as episodes of generalized arousal, accompanied by hydrophobia. The latter symptoms reflect an overwhelming terror of water resulting from violent contractions of the respiratory chest muscles and those of the hypopharynx. Arousal episodes are followed by agitation, confusion, and maniacal behavior interspersed with episodes of lucidity and calmness. Paralysis of the muscles of deglutition is common and accompanied by salivation. Coma and death follow, usually despite respiratory support (Anonymous, 1975). Although encephalitic rabies is customarily believed to be uniformly fatal, survival without residual neurological abnormalities has been documented. Unfortunately, in many of the cases, sound documentation of rabies was not reported. A virological substantiated childhood case was published by Hattwick et al. (1972). The 7-year-old child lapsed into a coma and a brain biopsy demonstrated encephalitis with neuronal damage and Babes nodules (see below). The patient recovered over a 3-month period without neurological disability. It was unclear whether or not cognitive capabilities were impaired. "Dumb" rabies is less familiar to clinicians, for it occurs in only about 20% of cases. Neurologic symptoms, pain, and sensory abnormalities and flaccid paralysis are confined to, or are most severe in, the bitten extremity. Transverse and ascending myelitis may follow with death resulting from paralysis of the muscles of deglutition and respiration. Demyelinization and remyelinization as well as fiber loss in peripheral nerves is frequently seen when pathological studies of teased nerves are done. Axonal loss and Wallerian degeneration is seen in some cases. Dorsal route ganglia often exhibit chronic inflammatory infiltrates (Chopra et al, 1980). Survival may be more protracted than in "furious" rabies because encephalitis does not develop and, as a result, some patients do not die (Anonymous, 1978; Pawan, 1939).

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Despite localization of the clinical disease to the central nervous systems, rabies is a systemic infection involving multiple organs. But, in contrast to most other viral diseases, the virus of rabies is spread to peripheral sites centrifugally along nerve trunks. Sensory nerves seem to be particularly important in this role, but the autonomic nervous system is also involved. Transport of virus by means of autonomic nerves may account for the interstitial myocarditis, sialoadenitis, and adrenal medullitis that commonly occurs in rabiesvirus-infected patients (Lopez-Corella et al, 1997; Ross and Armentrout, 1962; Cheetham et al, 1970). In some cases, the myocarditis is severe and may have contributed to death. Cardiac dysrhythmias commonly are observed (Bhatt et al, 1974). The diagnostic approaches currently employed are dependent upon this peripheral dissemination of the virus. Corneal impression smears and skin biopsies from body sites with a high density of hair follicles (such as the back of the neck) are commonly used techniques (Koch et al, 1975; Leach and Johnson, 1940; Smith et al, 1972). These approaches are relatively insensitive indicators of infection, even when immunohistochemistry is employed (Johnson et al, 1980). Information using PCR to increase sensitivity has not been reported.

PATHOGENESIS Over 100 years before Pasteur attempted his first immunization of a human, Morgagni noted that rabies "does not seem to be carried through the veins, but by the nerves, up to their origins." Experimentally pursuing this concept, DiVestea and Zagari (1889) induced rabies in dogs by inoculating the sciatic nerve with virus. They then prevented it by severing the nerve shortly after injection. Rabiesvirus appears to move in a retrograde fashion by axonal flow to the central nervous system (Gosztonyi, 1978; Jenson et al, 1969; Gillet et al, 1986). This process depends upon intact microtubules in the nerves, for it is inhibited by colchicine treatment (an agent possessing the capacity to disrupt microtubules) (Tsiang, 1979). At nerve synapses, rabiesvirus appears to bind to the acetylcholine receptor involved in cholinergic conductance (Lentz et al, 1984), thus facilitating neural transport. Centripetal movement of the virus in peripheral nerves occurs at a rate of about 5 to 10 cm per day. Based on this observation, it is difficult to account for the prolonged clinical latency period between the time of exposure and manifestation of infection. Perhaps rabiesvirus lies dormant

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at the site of introduction. For example, it might proceed through one or more replicative cycles locally in muscle cells before entering the nerve, as suggested by Murphy (1977) and Charlton and Casey (1979). However, in the murine model in which animals are infected by footpad inoculation, amputation of the extremity must be carried out within 4 hours to protect the animals from central nervous system disease. In a more recent study, masseter muscle inoculation was followed by the appearance of viral RNA in the trigeminal ganglion 18 hours later and in the brainstem after 24 hours (Shankar et al, 1991). Thus, entry of the virus into the peripheral nervous system appears to occur rapidly. One might conclude that local replication of the virus in muscle at the site of inoculation is of limited pathogenic importance. Clinically, infection resulting in death occurs with relative infrequency among those who are bitten on the distal extremities, but it is common in patients with facial and head wounds inflicted by a rabid animal. Neural transmission of the virus to the central nervous system may be a relatively inefficient process in humans. Passage of the wild so-called "street" strains of rabiesvirus in a susceptible host (such as the mouse) by inoculating brain suspensions intracerebrally shortens the latency period and increases the virulence of the virus. One concludes that highly pathogenic virions are selected by this process. In contrast, serial intracerebral passage of virus in relatively resistant animals results in attenuation and a relative loss of virulence, as originally demonstrated by Pasteur (Miyamoto and Matsumoto, 1967). Pathogenicity appears to relate to the make-up of the G glycoprotein on the surface of the enveloping membrane of the virion. This protein is a key factor in the interaction of the virus with cells of the central nervous system. Amino acid substitution at specific sites in the protein molecule dramatically affects the virulence of the virus (Rupprecht and Dietzschold, 1987). Much remains to be learned about the factors that influence pathogenicity and the role of G protein variability in this infectious process (Tuffereau et al, 1989; Lafay et al, 1991). Rabiesvirus G protein is highly antigenic in humans, as demonstrated by the prompt elaboration of specific immunoglobulins in response to administration of attenuated virus vaccines. Under natural circumstances of infection, the immune response to the naturally occurring "street" virus is comparatively slow, perhaps due to the relatively low concentration of virus in the inoculum and the sequestered nature of the virus in the nervous tissue. Circulating antibody is key to protection against reinfection, but probably plays little or no role in attenuating an established infection. In experi-

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mental models, cellular immune mechanisms are involved in modulating the course of the disease, but paradoxically, they may accentuate neuropathogenicity under certain circumstances (Soave et ah, 1961; Sugamata et ah, 1992). For example, administration of rabies-sensitized T cells to infected mice shortens survival time and increases the severity of the neurological disease. Pathologically, there is a prominent meningitis and perivenular infiltrate of mixed lymphocytes and macrophages in the brain of these experimental animals (Sugamata et al, 1992; Shope et al, 1979). Cellular immune mechanisms may explain the incompletely documented so-called "early death phenomena" in which previously immunized subhuman primates and

naturally infected humans experience a shortened latency period of disease when infected. CENTRAL NERVOUS SYSTEM DISEASE In 1903, Negri reported his finding of a structure reminiscent of an amoeboid parasite in the brain cells of a rabid dog. Almost simultaneously, Bosc (1903) independently discovered a similar structure associated with rabies, but credit for his observation rarely finds its way into the literature. Although the morphologically obvious Negri body led to the conclusion that rabies was due to a parasite, the concept was readily

FIGURE 25.1 Examples of Negri bodies in cells from different locations in the brain of different species of animals. (A) Neuron in the hippocampus of a rabid dog. (B) Hippocampus of a rabid skunk. Note the internal body so-called innerkorperchen. (C) Multiple Negri bodies in a neuron of the pons of an experimentally infected monkey. (D) Neuron in basal ganglion cell of skunk. Note the unusually large-sized Negri body (arrow). (E) Anterior Horn cell of spinal cord of rabid raccoon. Note the small Negri body (arrow). (F) Axon of hippocampus of human. Reprinted with permission from Perl (1975) and kindly provided by D. Perl, MD.

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FIGURE 25.2 Ultrastructure of a neuron from the caudate nucleus of an experimentally infected monkey. Several Negri bodies of differing size are seen (arrows). The smaller bodies are not demonstrable by light microscopy. Note the bullet-shaped dense-staining virions associated with the Negri bodies. Reprinted with permission from Perl (1975) and kindly provided by D. Perl, MD.

FIGURE 25.3 Ultrastructure of a Negri body exhibiting the bulletshaped virions raised at the periphery. The invagination in this cell is thought to represent the internal body demonstrated in Figure 25.IB. Reprinted with permission from Perl (1975) and kindly provided by D. Perl, MD.

disproved when it was found that the infectious agent passes through a bacterial-type filter. The biological nature of the eosinophilic intracytoplasmic body that bears Negri's name has perplexed countless investigators in part because it is inconsistently found in cells of the central nervous system and because the bodies vary greatly in their morphological features in different cells and at various sites in the brain. Moreover, Negri bodies in different infected animal species are often morphologically dissimilar. Thus, the Negri body of a cow is very large in comparison to the bodies found in the nervous system of rabbits and raccoons, where, in fact, multiple small inclusions are evident (Figure 25.1C). As one might expect, pathologists applied new names to describe some of these morphologic variants. Goodpasture (1925) described the Lyssa body as a Negri-like structure lacking the small basophilic internal body (Innerkorperchen) that typifies the classical Negri body. Some observers thought that the Negri body represented a degenerate cell, and that the innerkorperchen was the etiological agent. Others doggedly persisted in considering the Negri body a para-

site, despite its morphologic variability and the demonstrated capacity of the rabies agent to pass through an ultrafilter. Although the Negri body has been the topic of much research and discussion since its discovery in the early years of the twentieth century, we know now that these bodies not only differ morphologically, but biologically as well. Matsumoto (1963) was the first pathologist to provide insight into the fine structural features of the Negri body Figures 25.2 and 25.3 illustrate the ultrastructural features of Negri bodies studied by Perl (1975). In rabies encephalitis, the brain tissue is extensively involved, as shown by electron microscopy and immunohistochemistry, even when traditional histologic examination of the tissue reveals surprisingly few changes. Although incompletely studied, the evidence indicates that the virus is rapidly disseminated along multiple neural channels and by contiguous spread from cell to cell in the brain. Careful study reveals scattered areas of neuronophagia and microglial nodules (so-called Babe's nodules) (Figure 25.4). The latter abnormalities are observed in many forms of encepha-

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m.\

FIGURE 25.4 (A) Babe's nodule in the thoracic spinal cord of an experimentally infected monkey. The reactive inflammatory cells are accumulated around a neuron. In (B) neuronophagia is evident. Note the perivascular lymphocytic infiltrate in (A). Reprinted with permission from Perl (1975) and kindly provided by D. Perl, MD.

litis and indicate accumulations of activated microglia in localized areas of tissue damage. In addition, perivascular meningeal lymphocytic infiltrates are seen to a variable extent (Figure 25.5). Thus, the elusive and often difficult-to-detect Negri body remains a critical marker of infection, although it may often not be found even after careful histologic study and its distribution may prove highly variable. The important role of immunohistochemistry in establishing the diagnosis of rabies under these circumstances is apparent (Johnson

et ah, 1980). Indeed, the pathologist conducting postmortem studies on patients with unexplained encephalitis should carefully consider the advisability of exploratory immunolocalization studies when the pathological changes do not readily account for the clinical disease (Figure 25.6). References Anonymous (1975). Editorial: Diagnosis and management of human rabies. Br. Med. ]. 3 (5986), 721-722.

FIGURE 25.5 Extensive perivascular infiltrates in the midbrain of a human case of rabies. Reprinted with permission from Perl (1975) and kindly provided by D. Perl, MD.

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FIGURE 25.6 The more typical appearance of the cerebral cortex in a human with rabies. Negri bodies are present on close microscopical inspection of the tissue, but they could be easily missed by the pathologist. In this case, no perivascular infiltrates and Babe's nodules are observed.

Anonymous (1978). Editorial: Dumb rabies. Lancet 2,1031-1032. Bhatt, D., Hattwick, M., Gerdsen, R., Emmons, R., and Johnson, H. (1974). Human rabies. Am. J. Dis. Child. 127, 862-869. Bosc, F. (1903). C.R. Soc. Biol. 55,1284. Charlton, K., and Casey, G. (1979). Experimental rabies in skunks: Immunofluorescence light and electron microscopic studies. Lah. Invest. 41, 36-44. Cheetham, H., Hart, J., Coghill, N., and Fox, B. (1970). Rabies with myocarditis: Two cases in England. Lancet 1, 921-922. Chopra, J., Banerjee, A., Murthy, J., and Pal, S. (1980). Paralytic rabies: A clinico-pathological study. Brain 103, 789-802. Dean, D. (1963). Pathogenesis and prophylaxis of rabies in man. N.Y. State]. Med. 74, 3507-3513. DiVestea, A., and Zagari, G. (1889). Sur la transmission de la rage par voie nerveuse. Ann. Inst. Pasteur (Paris) 3, 237-248. Fisher, D. (1995). Resurgence of rabies: A historical perspective on rabies in children. Arch. Pediatr. Adolesc. Med. 149, 306-312. Gillet, J., Derer, P., and Tsiang, H. (1986). Axonal transport of rabies virus in the central nervous system of the rat. /. Neuropathol. Exp. Neurol. 45, 619. Goodpasture, E. (1925). A study of rabies with reference to a neural transmission of the virus in rabbits and the structural and significance of Negri bodies. Am. J. Pathol. 1, 547-582. Gosztonyi, G. (1978). Axonal and transsynaptic spread of viral nucleocapsids in fixed rabies encephalitis. /. Neuropathol. Exp. Neurol. 37, 618. Hattwick, M., Weis, T., Stechschulte, C , Baer, G., and Gregg, M. (1972). Recovery from rabies (a case report). Ann. Intern. Med. 76, 931-942. Houff, S., Burton, R., Wilson, R., Henson, T., London, W., Baer, G., Anderson, L., Winkler, W, Madden, D., and Sever, J. (1979). Human-to-human transmission of rabies virus by corneal transplant. New Engl. J. Med. 300, 603-604. Jenson, A., Rabin, E., Bentinck, D., and Melnick, J. (1969). Rabiesvirus neuronitis. /. Virol. 3, 265-269.

Johnson, K., Swoveland, P., and Emmons, R. (1980). Diagnosis of rabies by immunofluorescence in Trypsin-treated histologic sections. JAMA 244, 41-43. Koch, R, Sagartz, J., Davidson, D., and Lawhaswasdi, K. (1975). Diagnosis of human rabies by the corneal test. Am. J. Clin. Pathol. 63, 509-515. Lafay, F., Coulon, P., Astic, L., Saucier, D., Riche, D., Holley, A., and Flamand, A. (1991). Spread of the CVS strain of rabies virus and of the avirulent mutant AvOl along the olfactory pathways of the mouse after intranasal inoculation. Virology 183, 320-330. Leach, C , and Johnson, H. (1940). Human rabies with special reference to virus distribution and titer. Am. ]. Trop. Med. 20, 335-340. Lentz, T., Wilson, P., Hawrot, E., and Speicher, D. (1984). Amino acid sequence similarity between rabies virus glycoprotein and snake venom curaremimetic neurotoxins. Science 226, 847-848. Lopez-Corella, E., Ridaura-Sanz, C , and Samayoa-Patma, J. (1997). Human rabies: Systemic pathology in 33 cases. Proc. Acad. Pathol., Orlando, FL. Matsumoto, S. (1963). Electron microscope studies of rabies virus in mouse brain. /. Cell. Biol. 19, 565-591. Mebatsion, T., Cox, J., and Frost, J. (1992). Isolation and characterization of 115 street rabies virus isolates from Ethiopia by using monoclonal antibodies: Identification of 2 isolates as Mokola and Lagos bat viruses. /. Infect. Dis. 166, 972-977. Miyamoto, K., and Matsumoto, S. (1967). Comparative studies between pathogenesis of street and fixed rabies infection. /. Exp. Med. 125, 447-475. MMWR (1992). Human rabies — California. Morb. Mortal Weekly Rep. 41, 461-463. MMWR (1995a). Human rabies — West Virginia, 1994. Morh. Mortal. Weekly Rep. 44, 86-87. MMWR (1995b). Human rabies — Alabama, Tennessee, and Texas, 1994. Morb. Mortal. Weekly Rep. 44, 269-272. MMWR (1996). Human rabies — Connecticut, 1995. Morb. Mortal. Weekly Rep. 45, 207.

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Mrak, R., and Young, L. (1993). Rabies encephalitis in a patient with no history of exposure. Hum. Pathol 24,109-110. Murphy, R (1977). Rabies pathogenesis [brief review]. Arch. Virol. 54, 279-297. Negri, A. (1903). Beitrag zum Studium der Aetiologie der Tollwuth. Z. Hyg. Infektionskr. 44, 519-540. Pawan, J. (1939). Paralysis as a clinical manifestation in human rabies. Ann. Trop. Med. Parasitol 33, 21. Perl, D. (1975). The pathology of rabies in the central nervous system. In 'The Natural History of Rabies'' (G. Baer, ed.). Vol. 1, pp. 235-272. Academic Press, New York. Ross, E., and Armentrout, S. (1962). Myocarditis associated with rabies. New Engl. J. Med. 266,1087-1089. Rupprecht, C , and Dietzschold, B. (1987). Perspectives on rabies virus pathogenesis [editorial]. Lah. Invest. 57, 603-606. Shankar, V, Dietzschold, B., and Koprowski, H. (1991). Direct entry of rabies virus into the central nervous system without prior local replication. /. Virol. 65, 2736-2738. Shope, R., Baer, G., and Allen, W. (1979). Summary of a workshop on the immunopathology of rabies. /, Infect. Dis. 140, 431^35. Smith, J., Fishbein, D., Rupprecht, C., and Clark, K. (1991). Unexplained rabies in three immigrants in the United States: A virologic investigation. New Engl. J. Med. 324, 205-211.

Smith, J., Orciari, L., Yager, R, Seidel, H., and Warner, C. (1992). Epidemiologic and historical relationships among 87 rabies virus isolates as determined by limited sequence analysis. /. Infect. Dis. 166, 296-307. Smith, W., Blenden, D.C., Fuh, T., and Hiler, L. (1972). Diagnosis of rabies by immunofluorescent staining of frozen sections of skin. /. Am. Vet. Med. Assoc. 161,1495-1501. Soave, O., Johnson, H., and Nakamura, K. (1961). Reactivation of rabies virus infection with adrenocorticotropic hormones. Science 133,1360-1361. Sugamata, M., Miyazawa, M., Mori, S., Spangrude, G., Ewalt, L., and Lodmell, D. (1992). Paralysis of street rabies virus-infected mice is dependent on T lymphocytes. /. Virol. 66,1252-1260. Tsiang, H. (1979). Evidence for an intraaxonal transport of fixed and street rabies virus. /. Neuropath. Exp. Neurol. 38, 286-299. Tuffereau, C., Leblois, H., Benejean, J., Coulon, P., Lafay, P., and Flamand, A. (1989). Arginine or lysine in position 333 of ERA and CVS glycoprotein is necessary for rabies virulence in adult mice. Virology 172, 206-212.

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Poxviruses genera infect humans. The orthopoxviruses are: variola major and its less pathogenic variant variola minor, cowpox and its variant vaccinia, and monkeypox. These viruses cause disseminated infections of the skin and mucus membranes. Variola major and minor appear to be obligate human parasites, although they infect certain species of subhuman primates in the laboratory (Brinckerhoff et al, 1906). Monkeypox virus is indigenous to subhuman primates in West Africa, and it occasionally infects humans residing near the central west coast of that continent. Clinically, monkeypox can be confused with its much more virulent cousin, smallpox. Cowpox is an uncommon cause of vesicular disease in cattle. It occasionally infects herdsmen by direct contact. Recognized human outbreaks have been restricted to Europe. The virus appears to originate in wild rodents from which cattle are infected in the pasture. It is believed to be the "seed" from which vacciniavirus was derived. The virus of cowpox should be differentiated from the parapoxvirus responsible for milker's nodules, an infection discussed in more detail later. Once introduced into a herd, cowpox spreads rapidly, causing short-lived lesions of the teats and skin. As is well known, vaccinia is a laboratorymanipulated virus of uncertain derivation that has long been used for so-called jennerian immunization. While infection by direct inoculation causes a localized lesion, dissemination occurs to involve preexisting skin lesions, particularly in infants and the immunosuppressed patient. It is believed that an endemic poxvirus disease of the water buffalo in the Indian Subcontinent is caused by a strain of vacciniavirus initially derived from recently vaccinated humans. The parapoxviruses (milker's nodules, bovine popular stomatitis, and orf) are zoonotic causes of localized vesiculonodular lesions that are acquired from infected domestic animals. The moUuscipoxvirus genus has within it only one agent of human importance: the virus responsible for molluscum contagiosum (MC). This is customarily a childhood disease of the skin, but it is now an imposing threat to the immunosuppressed patient.

INTRODUCTION 365 ORTHOPOXVIRUSES 366

Variola (Major and Minor) 367 Vacciniavirus 371 Monkeypox 373 PARAPOXVIRUSES

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Milker's Nodules 377 Bovine Papular Stomatitis (BPS) 377 Ecthyma Contagiosum (orf) 377 MOLLUSCIPOXVIRUSES 377 REFERENCES 379

INTRODUCTION He is an impressive, quiet spoken, former Dean of the Johns Hopkins School of Hygiene, but in another era he successfully led the WHO effort to eliminate the virus of smallpox from its last haunts in obscure corners of Africa and Asia. Donald Henderson's task was conducted deliberately and with single-minded purpose. No physician has previously been privileged to serve in a leadership role to eliminate a disease from the face of the planet (Figure 26.1). Although smallpox virus is now thought to be securely sequestered in laboratory freezers in the United States and the former Soviet Union, concern mounts in this time of terrorism that, in some clandestine way, the virus will be unleashed to decimate selected populations. Now lacking immunity, our children and many young adults worldwide are highly susceptible and thus defenseless against this imposing potential threat (Breman and Henderson, 1998; Mahy ei ah, 1993). The poxviruses of humans and a wide variety of lesser animals share biological properties, and their clinical manifestations in mammals largely relate to their capacity to grow in the epithelium of the skin, and, to a variable extent, the mucus membranes of the oropharynx and eye. Poxviruses infect a number of species of animals, and several kinds of insects. The viruses of vertebrates are members of the chordopoxviridae subfamily; members of four of its eight PATHOLOGY AND PATHOGENESIS OF HUMAN VIRAL DISEASE

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FIGURE 26.1 The last case of smallpox within a 20-nation area of West and Central Africa (May 21, 1970). This 27-year-old patient was vaccinated about 10 days before the photographs were prepared (note the primary vaccination lesion on the arm in B). The classical features of smallpox are exhibited here. The patient appeared weak and/or fatigued and the lesion had a predominant peripheral distribution. The lesions are deep-seated and firm in appearance. Reprinted with permission from Hernon (1996) and through the courtesy of C. Hernon, MD.

B The largest of the viruses that infect humans, the virions of the poxvirus family have a complex structure. The genetic material of the various members of this large family is found in a linear double-stranded DNA approximately 180-190 kb in length. This sizable genome provides sufficient information to code roughly 150 proteins of average size. Although poxviruses have been the subject of considerable basic research, our understanding of the function of many of the proteins is limited. In addition, some are most probably not essential for viral replication and may only play a role in certain less critical aspects of the virion life cycle. Poxviruses replicate in the cell cytoplasm independent of the nucleus and are not dependent upon the cell's synthetic tools. Thus, the virus employs a panoply of enzymes of its own making to manufacture new progeny virions. The individual infectious units — known as elementary bodies, or Guarnieri bodies, in the earlier literature — can be seen in the cytoplasm of the infected cell by light microscopy, for they are enormous: 230 to 240 |Lim in diameter. Customarily, the virions accumulate in well-defined amphophilic cyto-

plasmic inclusions, although these inclusions are often not found histologically. Electron microscopy of the infected cells and the vesicle fluid from skin lesions makes possible a diagnosis based on virion morphology (Figure 26.2). The vesicles caused by an orthopoxvirus can also be differentiated histologically from similar lesions due to other common human viruses such as the herpesviruses (see Chapter 7).

ORTHOPOXVIRUSES The lesions caused by these viruses characteristically are vesicular, but there is an associated, sometimes dramatic, localized proliferation of the adjacent epithelium (Figure 26.3). Vacciniavirus elaborates an epidermal growth factor-like product during infection, and it is believed that this or similar growth factors account for the epithelial proliferation so commonly evident at the margins of poxvirus vesicles. The cytoplasm of infected cells of the superficial epidermal layers of the skin initially becomes vacuolated, that is.

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Poxviruses

FIGURE 26.2 Electron micrograph illustrating typical poxvirus morphology. The seemingly bilobate nucleosome is surrounded by an outer membrane. Illustrated here are accumulations of the virus of molluscum contagiosum in a cytoplasmic inclusion. Note the seemingly compressed nucleus of the infected cell at the right base. Reprinted with permission and through the courtesy of V. Burmeister, PhD.

the so-called "balloon" change. Surprisingly, we know very little about the mechanistic basis for these alterations in the infected cell structure. The cells also exhibit the classical poxvirus eosinophilic cytoplasmic inclusions. As the lesions evolve, suprabasal compartmentalized vesiculations develop in the epidermis. Later, as infected cells undergo necrosis, fluid accumulates and the vesicles expand. Ultimately, the basal cells lyse and the vesicle is encompassed by a cap comprised of the compressed granular and cornified layers. While the vesicular fluid initially is clear, polymorphonuclear leukocytes and cell debris gradually accumulate in the fluid, resulting in the pustule. Several pathogenic mechanisms no doubt account for cell damage, but their relative contribution to the development of lesions in humans is far from clear. In general, the orthopoxviruses inhibit cell macromolecular synthesis during the course of replication, and cytokines are generated by the cells. Early in the infection, viral antigens are introduced into the plasma membrane of the infected cell; they are the potential targets for cytolytic T cells. Studies employing the modern tools of cell biology and immunopathology remain to be focused on

the immune mechanisms involved in the formation of the vesicle and its subsequent resolution. Variola (Major and Minor) Smallpox has been a plague on humans since prehistory. Its extraordinary infectivity and its high mortality rate have long made it a feared scourge on civilization. Mortality due to smallpox ranges from 20 to 40% in various outbreaks, but the death toll is highest in infants and the elderly. Nutritional factors and the overall health of the patient no doubt influence survival. Antibacterial drug therapy also reduces the death rate. Although classical smallpox is spread in epidemic form by means of the respiratory route, histologically evident lesions in the airways and lung are not a feature of the disease at autopsy. The virus is transmitted from the respiratory tract to regional lymph nodes, where the initial phase of virus replication occurs. After about 10 to 12 days, viremia develops and persists for a short period. Fever and generalized symptoms accompany the viremic stage. The skin lesions initially develop on the mucus membranes of the oropharynx;

368


Inclusion bodies Ballooning degeneration

_

\ ';'^-,-;^

l $ & ^ * % ^ y ^ infiltrate Oedema of

Separation of epithelial cells

m i

j j ^ ^ Dilated and engorged vessels .Perivascular infiltrate Haemorrhages In dermis

Polymorpho nuclear cell infiltrate Reticulating degeneration

Ballooning degeneration

Nevs^ epithelium

Proliferated epithelium

Crust

Densely massed polymorphonuclear cells

rm..^:-FIGURE 26.3 Stages in the development and evolution of a typical skin lesion of smallpox. (A) The earliest change is oedema of the dermis, leading to separation of epithelial cells of the papillae and lymphocytic infiltration in the dermis, especially around small vessels. Balloon degeneration is seen in a few cells in the lower malpighian layer. (B) These changes progress, and the small vessels become dilated and engorged. Inclusion bodies are also visible adjacent to cells showing balloon degeneration. In early hemorrhagic-type smallpox, illustrated here, evidence of hemorrhage into the dermis was pronounced. (C) As the pathological process progresses, the epithelial cells break down by reticulating degeneration to produce a multilocular vesicle. (D) The vesicle formed by coalescence of the smaller cavities is infiltrated with polymorphonuclear leukocytes to form a pustule, around which are found cells containing inclusion bodies. (E) The fully developed pustule is packed with polymorphonuclear leukocytes and the epithelium on either side of the pustule has proliferated. (F) Eventually, the pustule forms a crust, beneath which new epithelium grows to repair the surface. Such lesions, in which the sebaceous glands are not involved, heal without leaving a scar. Reprinted with permission from Fenner ei a\. (1988).

369

Poxviruses

»

c

FIGURE 26.4 The characteristic palmar and plantar lesions in variola major. Reprinted with permission from Fenner et al. (1988).

24 hours later, a macular erythematous rash appears on the face and distal extremities, including the palms and soles. The rash rapidly spreads centrally in a centripetal fashion to involve the body as a whole (Figure 26.4), but lesions are often relatively sparse on the trunk (Figure 26.5). Histologically, the developing skin lesions take several forms. Initially, they evolve through vesicular and pustular stages. By the end of the second week of clinical illness, scabs form over the pustules, the fever defervesces, and the patient gradually recovers. The cause of death in patients with smallpox is unclear, despite careful autopsy study. Lesions in internal organs are customarily sparse, if they exist at all, and they are not believed to be a contributing factor in the progression or severity of the disease. Death is generally stated to be due to a generalized toxemia, but the pathophysiologic basis is obscure. Confluent and hemorrhagic disease is highly fatal (Table 26.1).

In smallpox, scarring of the face is one of the devastating long-term residual lesions among survivors. These scars appear to result from sebaceous gland involvement by the virus, ultimately resulting in accumulation of necrotic debris in the lumina of the glands. A granulation tissue response contributes to the scarring process. There is no evidence to suggest that smallpox virus invades the dermis. Although variola major is generally considered to be a uniformly severe disease, attenuated strains circulated in outbreak form in the past. The term "alastrim" refers to a virus of a relatively low order of pathogenicity that was endemic to South America. The variola minor viruses appeared sporadically elsewhere in the world (Gordon et ah, 1966). In the latter infections, patients (by definition) develop fewer than 100 pox on the face and lesser numbers elsewhere (Figures 26.6 and 26.7). The mortality rate is roughly 1%. In the laboratory, the various so-called "wild" strains act in a some-

370


FIGURE 26.5 Variola major in an infant. Note the relative paucity of lesions on the trunk and their predominance on the face and extremities. Reprinted with permission from Fenner et at. (1988).

FIGURE 26.6 A 17-year-old girl with variola minor who was hospitalized with the admitting diagnosis of chickenpox. Reprinted with permission from Gordon et al. (1966).

Poxviruses

371

TABLE 26.1 Mortality of Various Clinical Types of Variola Major in Unvaccinated Patients in India Clinical types of lesion

Ordinary" Confluent Semiconfluent Discrete Total

Percent of patients

Mortality rate (%)

23 24 42

62 37 9

89

30

Flat Type^

7

97

Hemorrhagic

2

96

Modified

2

_0

Overall mortality

36

Modified with permission from Fenner et al. (1988). ''Raised pustule lesions. ^Flat confluent or semiconfluent pustules.

what dissimilar fashion, but the molecular basis for differences in pathogenicity between the viruses of variola major and minor remain to be deciphered. Vacciniavirus Localized inoculation of variola virus (using infected scabs from healing lesions) into the skin of susceptibles was a well-established immunization practice before the introduction of vaccination by Jenner in 1798 (Bloch, 1993). Variolation causes an attenuated, rarely fatal, localized smallpox having a shortened incubation period. However, the virus that grew in these lesions proved to be highly contagious for contacts, thus potentially triggering outbreaks. Cowpox virus from which vacciniavirus was derived shares many molecular and biological properties with variola, including antigenicity. Perhaps it was, in fact, a smallpox virus modified by passage for centuries in field rodents and cattle. Further repeated passage of cowpox in humans and laboratory animals ultimately yielded vacciniavirus. There are n\any laboratory and vaccine strains that differ somewhat in pathogenicity for humans. Systemic Complications of Vaccination (see Figure 26.8)

Before the eradication of smallpox, immunization with vacciniavirus was a routine procedure for preschool children and travelers, but its use was a concern inasmuch as complications were an inevitable outcome in a small number of cases (Lane et al, 1969). For example, in the United States during 1968 (the last year

F I G U R E 26.7 Self-portrait by a photographer with the skin lesions of variola minor. This case of variola minor occurred in the United Kingdom in the mid-1960s. Patients during the outbreak had a prodromal illness of 3 days, but they were not seriously ill and were afebrile, or had only a slight fever. The rash appeared initially on the face and then on the extremities, including the palms and soles. Vesicles were 6 to 8 mm in diameter. Pustules became evident on day 5 and scabs formed on about day 8. The illness is described in detail by Gordon et al. (1966). Reprinted with permission from Gordon et al. (1966).

for which comprehensive survey data are published), almost 600 persons were reported to have developed vaccination complications, and there were nine deaths. Thus, approximately 74 complications, and 1 death occurred per 1X10^ primary vaccinations. Morbidity and mortality proved to be highest in infants, with 112 complications and 5 deaths per 1 x 10^ primary vaccinations. While vacciniavirus usually causes a benign inflammatory reaction at the local sites of primary inoculation into the skin (Figure 26.9), it is potentially pathogenic for (1) the fetus in utero; (2) patients with naturally occurring, or acquired immunodeficiency; and (3) those with chronic open skin lesions, particularly eczema. In addition, for unknown reasons, encephalitis develops sporadically in otherwise healthy young persons with an approximate incidence of 2 to 3 cases per 1 x 10^ immunizations. A rare patient experiences ocular vaccinia (Ruben and Lane, 1970; Ellis and Winograd, 1962). Arthritis (Silby et al, 1965), pericarditis, myocarditis (Cangemi, 1958; Finlay-Jones, 1964; Matthews and Griffiths, 1974) and nonbacterial

372


>.

FIGURE 26.8 Vacciniavirus infections. (A) Eczema vaccinatum in a young black child. Note the ichthyotic scaling of the skin over the trunk. (B) Progressive vaccinia in a child with an immunologic deficiency of unknown type. Note the extensive lesions with satellites. There is generalized erythema and edema of the shoulder and upper extremity. (C) Benign generalized vaccinia of 10 days duration. Note the primary lesion on the left arm. (D) Autoinoculation of the eye resulting in ocular and conjunctival vaccinia. Reprinted with permission from Fenner et al. (1988).

osteomyelitis (Sewall, 1949; Haar and Meinertz, 1954; Cochran et al, 1963; Elliot, 1959) are additional uncommon complications. Progressive vaccinia, an often fatal dreaded complication of immunization, is an infrequent outcome of the inadvertent vaccination of infants and children with congenital forms of hypogammaglobulinemia and combined immunologic deficiency (Hathaway et ah, 1965). It is also seen in children and adult recipients

of chemotherapy and those with malignant hematological disease (Neff and Lane, 1970; Freed et al, 1972). Rather than resolve over a period of weeks, the localized primary lesion continues to enlarge and the virus disseminates. In the survey conducted by Lane and his colleagues (1969), 7 of 11 patients with progressive localized lesions developed "metastatic" lesions of vaccinia, and 4 died. Clinically milder forms of generalized vaccinia are believed to be the sequelae of a pro-

373

Poxviruses

F I G U R E 26.9 Uncomplicated primary vaccination, vesicular lesion at 20 days.

tracted inadequate immune response to immunization. Such an infection eventually resolves and is customarily not fatal (Annotations, 1964). Generalized disease also develops as a complication of eczema, even when the disease is in a state of remission. Patients with other forms of chronic skin disease are also at risk. In the past, those with active dermatological conditions were rarely immunized; thus, disseminated vaccinia generally occurred inadvertently among contacts of vaccinees who had chronic skin disease. Assuming an adequate immune capability, these patients recovered, but they were often severely ill for protracted periods of time, and the infection occasionally left ugly scars in its wake. Neurological Complications of Vaccination Postvaccinial central nervous system disease typically develops spontaneously in otherwise healthy vaccinees in the absence of recognized predisposing conditions. It encompasses a diversity of neurological syndromes, ranging from febrile seizures to encephalopathy with coma. In one study, 4 of the 14 encephalitic patients died. There are no characteristic neuropathological findings. In some cases, a nonspecific encephalitis with edema and perivascular infiltrates are found in the brain at autopsy, whereas in others the nervous system exhibits demyelinating changes in a pattern consistent with postinfectious encephalopathy. It would appear that certain vaccine strains of virus more commonly caused encephalitis. The pathogenesis of the disease of the central nervous system is not understood, and it is not clear to what extent the virus directly invades the brain. Gestational Complications of Vaccination Fewer than 20 cases of generalized vaccinia acquired in utero as a complication of the primary vaccination of

a pregnant woman have been reported. In these cases, immunization was carried out as early as the third week of pregnancy, and as late as the sixth month. When the fetus was infected, parturition occurred from 4 to 12 weeks later. The fetuses from early pregnancies are invariably stillbirths, whereas more mature but infected fetuses often survive for varying periods. Characteristic skin lesions are scattered over the body at autopsy. They consist of red circular ulcers up to 2 cm in diameter with sloughed centers. The placenta and viscera exhibit numerous abscess-like lesions, some of which are umbilicated. These punctate lesions are up to 3 mm in diameter and have irregular margins. Histologically, they exhibit necrosis, but no evidence of the vacciniavirus is found (Green et al, 1966; Naidoo and Hirsch, 1963). Lymphadenitis

Secondary to Vaccination

Clinical enlargement and tenderness of regional lymph nodes commonly occurs after vaccination and persists for varying periods. This is not surprising in view of the local inflammatory response to the vaccine in the skin, and the numerous antigens of the virus generated during infection. Vacciniavirus has been demonstrated in the lymph nodes (McMaster and Kidd, 1936; Hartsock and Bellanti, 1966). Lukes and colleagues (1966), Rappaport (1966), and Hartsock (1968) have described the pathological changes in these nodes and noted the potential for confusion with lymphoma, including Hodgkin's disease. As noted by these authors, there is an apparent effacement of the architecture by a diffuse or follicular hyperplasia in which immunoblasts are a prominent cellular component. Lymphocytes, plasma cells, and eosinophils are present in variable numbers. Focal vascular changes and dilated small vessels are evident. The changes are not unlike those observed in infectious mononucleosis (see Chapter 9) and herpes zoster (see Chapter 10). Monkeypox A virus similar to variola was first isolated from subhuman primates in the late 1950s (von Magnus et al., 1959). In 1970, the so-called monkeypox was first isolated in the Democratic Republic of the Congo from a human with an illness similar to smallpox (Ladnyi etal, 1972). Additional patients with monkeypox were reported from Nigeria, Liberia, and Sierra Leone during the 1970s; a total of 55 cases were documented in West Africa during that decade. Over the ensuing 24 years, some 350 clinically recognized cases were reported. Substantially fewer cases occurred over the subsequent years until 1996, when an outbreak developed in the former Zaire (Mukinda et ah, 1997; Cohen, 1997).

374


The clinical illness caused by the monkeypox virus in an unvaccinated human strikingly resembles smallpox (Fenner et ah, 1988) (Figure 26.10), but the mortality is substantially lower (11%) and the secondary attack rate proves to be only about 9% (in comparison to the rate for variola, which is 25 to 30%) (Breman and Henderson, 1998). Although the infectivity and mortality resulting from the infection is substantially lower than in smallpox, concern has arisen as to whether monkeypox could replace smallpox as a pandemic scourge on humanity. Computer simulations have now provided considerable assurance that this will not prove to be the case. The model forecasts that the virus would be expected to "die out" after 14 generations of human-tohuman transmission in a nonimmune population (Breman and Henderson, 1998). Thus far, natural transmission in humans has only been documented over a series of four generations. We can conclude that this virus, although similar to variola, poses little threat as a future epidemic/pandemic virus of worldwide im-

F I G U R E 26.10 Monkeypox in a child in the Democratic Republic of Congo. Reprinted with permission from Breman and Henderson (1998).

portance. Primary cases resulting from monkey to human transmission most likely will continue to occur in west central Africa. Sporadic reports of primate-to-human transmission of unclassified poxviruses not related to variola and monkeypox have been reported (Downie et al, 1971; McNulty et al, 1968). These incompletely characterized agents have proven to be relatively nonpathogenic for humans, although they cause localized skin lesions after both natural infection and experimental inoculation into human volunteers. It would appear that numerous species of subhuman primates host poxviruses having pathogenic potential for humans. Of particular interest is a West African poxvirus (Yaba) of primate origin (unrelated to recognized human poxviruses). It produces subcutaneous tumors in its natural host (Bearcroft and Jamieson, 1958). It also causes tumors when introduced into the skin of human volunteers, and after accidental inoculation of a laboratory worker (Grace et ah, 1962). The lesions exhibit a sarcomatoid microscopi-

Poxviruses

375

cal appearance and have been classified pathologically as histiocytomas (Sproul et ah, 1962).

PARAPOXVIRUSES The three members of this genus having human importance cause localized skin lesions at inoculation sites (often the hands) in farmers and tradesmen who work with cattle and sheep, or their products (Figure 26.11). The parapoxviruses are antigenically distinct

FIGURE 26.11 Lesion of ecthyma contagiosum (orf) on the proximal phalanx of the hand of a sheepherder.

from the orthopoxviruses, and cross-protection apparently does not exist. Acquisition of immunity by the infected human presumably results in imn\une-mediated protection against reinfection, but this conclusion has not been critically tested. Indeed, our understanding of the immune mechanisms involved are limited. Several stages in the evolution of the skin lesion have been described. The first is an elevated macular papular excrescence. Shortly thereafter, the so-called "target" lesion appears. It exhibits a red papular center surrounded by concentric alternating white and red halos. A vesicular-pustular nodule then develops. Subsequently, there is a regenerative phase during which the epithelium proliferates. Finally, the lesion regresses, generally 5 to 7 weeks after inoculation (Figure 26.12). Histologically, the erythematous papule that appears within a week after inadvertent inoculation exhibits spongiotic vacuolization of the squamous cells in the upper third of the epidermis. These cells display characteristic intracytoplasmic inclusions and rarely intranuclear inclusions (Figure 26.13) (Evins et ah, 1971; Leavell et al, 1968). The vesicular papule then becomes necrotic and develops a crust. The lesion then grows centrifugally forming in its wake multilobulate vesicles. The white halo that forms around the central papule in the so-called "target" lesions consists of a

FIGURE 26.12 The complex lesion of orf shows hyperplasia of the stratum malpighii and a marked parakeratosis with interlinked vesicles of varying dimensions. While the lesions of the paravaccinia group are vesicular, hyperplasia of the epithelium predominates, resulting in the nodular lesions that characterize the clinical appearance of the lesion.

ring of vacuolated cells, and the surrounding red halo results from inflammation in the dermis with the accompanying vascular dilatation. As the skin lesion evolves, the parakeratotic crust sloughs. The subjacent dermis exhibits a prominent but relatively circumscribed, but often intense, infiltrate of both lymphocytes and macrophages. The nodular stage evolves subsequently. It is characterized by extreme degrees of acanthosis, resulting in downward projections of tongues of the epidermis into the dermis. This is one of the distinguishing histological features of the lesion. At this late stage, viral inclusions rarely are observed in epithelial cells. The papillomatous stage that evolves reflects continued epidermal proliferation. By 5 weeks, regression begins. Some pathologists have described capillary proliferation and edema at the base of these lesions. Resolution of parapoxvirus lesions appears to depend upon an immune response. In patients with altered immunity, massive tumorous lesions have been described. In a case reported by Savage and Black (1972), a lesion on the finger of a patient with lymphoma grew luxuriantly, requiring amputation (Figure 26.14). On occasion, these parapoxvirus lesions have been confused clinically with malignant tumors of the skin.

376


^•'- . .jfî'x........m..\..

«--::i%

#J*--

W

.vie., ?.•.4 volumes of 5% hypochlorite bleach should be added to the water and left for at least 2 hr before being discarded. Before it leaves the autopsy room, the body should be sponged with 5% sodium chlorite. All tissues should be considered fully infectious, even after prolonged fixation in formalin and histologic processing. Tissues may be washed in several changes of water on a shaker, rather than in running tap water; this water, the formalin, and

subsequent aqueous or alcoholic washes should be pooled and decontaminated. Glassware, forceps, and tissue carriers can also be decontaminated by soaking in 5% sodium hypochlorite or autoclaving. Xylene, toluene, or other organic solvents should be autoclaved and discarded, rather than reused. The microtome blade used to cut such tissue can be decontaminated by flaming, autoclaving, or soaking in disinfectants. Special care must be taken to avoid cuts with potentially contaminated glassware or blades. Remains of patients dying of the disease should not be accepted for teaching of gross anatomy to students, and specimens and pathological teaching collections should be handled with caution. Morticians and mortuary workers should be warned of possible hazards posed by tissue of patients with CJD and provided with advice about proper use of disinfectants. (Gajdusek et al, 1977)

The more recent experimental evidence to date (see Brown et al, 1986a) recommends the following for decontamination of suspected infectious material on instruments: 1 hour exposure to temperature of 132°C in a steam autoclave, or to 1 N sodium hydroxide (NaOH) at room temperature; nearly complete decontamination was possible with 1-hr exposure to a temperature of 121 °C or to 2.5% sodium hypochlorite.

424


However, the authors warn that the recommended treatments are not the "final solution" to the problem of decontamination. Tissue for histology should be treated for 1 hour in concentrated formic acid and then immersed in a 4% formaldehyde solution for 48 or more hours (Budka et al, 1995). ANCILLARY NONHISTOPATHOLOGICAL DIAGNOSTIC APPROACHES OF THE PRION DISEASES PypSc J5 protease resistant, allowing separation from the PrP^ present in normal tissue. It is antigenic. Thus, immunohistochemical and immunochemical assays could be of diagnostic usefulness in cases of prion disease in which the clinical or pathological picture is uncertain or atypical. In several recent studies. Western Blot analysis of brain biopsies permitted a specific diagnosis when pathological diagnosis was not possible (Brown et al, 1986b; Castellani et ah, 1997). In one case report, a 16-mg fragment of grey matter provided sufficient material for assay. Of greater interest was demonstration of the usefulness of biopsy tissue from a case of vCJD to accomplish diagnosis by Western Blot analysis (Hill et al, 1997). This approach, and most probably future modification, could permit diagnosis without the necessity for brain biopsy. In familial CJD and autosomal-dominant CSS, PCR analysis of DNA from nonnervous tissue permits specific diagnosis without histopathological examination of brain tissue (CoUinge et al, 1989). Hsich and colleagues (1996) have claimed that a specific diagnostic protein is present in the cerebrospinal fluid of CJD patients. It is demonstrated by SDS-PAGE. Confirmation of this interesting observation will be required.

References Adomato, B., and Lampert, P. (1971). Status spongiosis of nervous tissue: Electron microscopic studies. Acta Neuropath. (Berlin) 19, 271-289. Brown, P. (1996). Environmental causes of human spongiform encephalopathy. In "Methods in Molecular Medicine: Prion Diseases'' (H. Baker and R. Ridley, eds.), pp. 139-154. Humana Press, Totowa, NJ. Brown, P., Gibbs, C , Amyx, H., Kingsbury, D., Rohwer, R., Sulima, M., and Gajdusek, D. (1982). Chemical disinfection of Creutzfeldt-Jakob disease virus. N. Engl J. Med. 306,1279-1282. Brown, P., Rohwer, R., and Gajdusek, D. (1986a). Newer data on the inactivation of scrapie virus or Creutzfeldt-Jakob disease virus in brain tissue. /. Infect Dis. 153,1145-1148.

Brown, P., Coker-Vann, M., Pomeroy, K., Franko, M., Asher, D., Gibbs, C , and Gajdusek, D. (1986b). Diagnosis of Creutzfeldt-Jakob disease by Western blot identification of marker protein in human brain tissue. N. Engl J. Med. 314, 547-551. Bruce, M., McBride, P., and Farquhar, C. (1989). Precise targeting of the pathology of the sialoglycoprotein, PrP, and vacuolar degeneration in mouse scrapie. Neurosci. Lett. 102,1-6. Budka, H., Aguzzi, A., Brown, P., Brucher, J., Bugiani, O., Collinge, J., Diringer, H., Gullotta, F., Haltia, M., and Hauw, J. (1995). Tissue handling in suspected Creutzfeldt-Jakob disease (CJD) and other human spongiform encephalopathies. Brain Pathol 5, 319-322. Castellani, R., Parchi, P., Madoff, L., Gambetti, P., and McKeever, P. (1997). Biopsy diagnosis of Creutzfeldt-Jakob disease by Western blot: A case report. Hum. Pathol 28, 623-626. Chou, S., Payne, W, Gibbs, C , and Gajdusek, D. (1980). Transmission and scanning electron microscopy of spongiform change in Creutzfeldt-Jakob disease. Brain 103, 885-904. Collinge, J., Owen, F., Lofthouse, R., Shah, T, Harding, A., Poulter, M., Boughey, A., and Crow, T. (1989). Diagnosis of GerstmannStraussler syndrome in familial dementia with prion protein gene analysis. Lancet 2,15-17. Collinge, J., Sidle, K., Meads, J., Ironside, J., and Hill, A. (1996). Molecular analysis of prion strain variation and the aetiology of "new variant" CJD. Nature 383, 685-690. Creange, A., Gray, F., Cesaro, P., Adle-Biassette, H., Duvoux, C , Cherqui, D., Bell, J., Parchi, P, Gambetti, R, and Degos, J. (1995). Creutzfeldt-Jakob disease after liver transplantation. Ann. Neurol 38, 269-272. Creutzfeldt, H. G. (1920). Uber eine eigenartige herdformige Erkrankung des Zentralnervensystems. Z, Gesamt. Neurol Psychiat. 57,1-18. DeArmond, S., and Prusiner, S. (1995). Etiology and pathogenesis of prion diseases. Am. J. Pathol 146, 785-811. Gajdusek, D. (1979). Observations on the early history of kuru investigation. In "Slow Transmissible Diseases of the Nervous System" (S. Prusiner and W. Hadlow, eds.). Vol. 1, pp. 7-35. Academic Press, New York. Gajdusek, D., Gibbs, C , Asher, D., Brown, R, Diwan, A., Hoffman, R, Nemo, G., Rohwer, R., and White, L. (1977). Precautions in medical care of, and in handling materials from, patients with transmissible virus dementia (Creutzfeldt-Jakob disease). New Engl J. Med. 297,1253-1258. Gerstmann, J., Straussler, E., and Scheinker, I. (1936). Uber eine eigenartige hereditar-familiare Erkrankung des Zentralnervensystems zugleich ein Beitrag zur frage des vorzeitigen lokalen Alterns. Z. Neurol 154, 736-762. Hadlow, W. (1959). Scrapie and kuru. Lancet 2, 289-290. Haywood, A. (1997). Transmissible spongiform encephalopathies. New Engl J. Med. 337,1821-1828. Hill, A., Zeidler, M., Ironside, J., and Collinge, J. (1997). Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet 349, 99-100. Holman, R., Khan, A., Belay, E., and Schonberger, L. (1996). Creutzfeldt-Jakob disease in the United States, 1979-1994: Using national mortality data to assess the possible occurrence of variant cases. Emerg. Infect. Dis. 2, 333-337. Horwich, A., and Weissman, J. (1997). Deadly conformations: Protein misfolding in prion disease. Cell 89, 499-510. Hsich, G., Kenney, K., Gibbs, C , Lee, K., and Harrington, M. (1996). The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. New Engl ]. Med. 335, 924-930.

Transmissible Spongiform Encephalopathy Hunter, G. (1972). Scrapie: A prototype slow infection. /. Infect. Dis. 125, 427-440. Jakob, A. (1921). Uber eigenartige Erkrankungen des Zentralnervensystem mit bemerkenswerten anatomischen Befunden. Z. Gesamt. Neurol. Psychiat. 61,147-228. Johnson, R., and Gibbs, C. (1998). Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies. New Engl. J. Med. 339,1994-2004. Kitamoto, T., Shin, R.-W., Doh-ura, K., Tomokane, N., Miyazono, M., Muramoto, T., and Tateishi, J. (1992). Abnormal isoform of prion proteins accumulates in the synaptic structures of the central nervous system in patients with Creutzfeldt-Jakob disease. Am. J. Pathol. 140,1285-1294. Klein, R., and Dumble, L. (1993). Transmission of Creutzfeldt-Jakob disease by blood transfusion. Lancet 341, 768. Lampert, R, Gajdusek, C , and Gibbs, C. (1972). Subacute spongiform virus encephalopathies. Am. J. Pathol. 68, 626-646. Lugaresi, E., Medori, R., Montagna, R, Baruzzi, A., Cortelli, P., and Lugaresi, A. (1986). Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. New Engl. ]. Med. 315(16), 997-1003. Manuelidis, E., Kim, J., Mericangas, J., and Manuelidis, L. (1985). Transmission to animals of Creutzfeldt-Jakob disease from human blood. Lancet 2, 896-897. Masters, C , and Richardson, E. (1978). Subacute spongiform encephalopathy (Creutzfeldt-Jakob disease). Brain 101, 333-344. Masters, C , Harris, J., Gajdusek, D., Gibbs, C , Bernoulli, C , and Asher, D. (1979). Creutzfeldt-Jakob disease: Patterns of worldwide occurrence. In ''Slow Transmissible Diseases of the Nervous System" (S. Prusiner and W. Hadlow, eds.). Vol. 1, pp. 113-142. Academic Press, New York. Masters, C , Gajdusek, D., and Gibbs, C. (1980). The GerstmannStraussler syndrome and the various forms of amyloid plaques which occur in the transmissible spongiform encephalopathies [abstract]. /. Neuropathol. Exp. Neurol. 39, 374. Medori, R., Tritschler, H., LeBlanc, A., Villare, R, Manetto, V., and Chen, H. (1992). Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. New Engl. J. Med. 326, 444-449. Muramoto, T., Kitamoto, T., Tateishi, J., and Goto, L (1992). The sequential development of abnormal prion protein accumulation in mice with Creutzfeldt-Jakob disease. Am. J. Pathol 140,1411-1420. Pammer, J., Weninger, W., and Tschachler, E. (1998). Human keratinocytes express cellular prion-related protein in vitro and during inflammatory skin diseases. Am. J. Pathol. 153,1353-1358.

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Pattison, J. (1998). The emergence of bovine spongiform encephalopathy and related diseases. Emerg. Infect. Dis. 4, 390394. Piccardo, R, Safar, J., Ceroni, M., Gajdusek, D., and Gibbs, C. (1990). Immunohistochemical localization of prion protein in spongiform encephalopathies and normal brain tissue. Neurology 40, 518-522. Prusiner, S. (1987). Prions and neurodegenerative diseases. New Engl. J. Med. 317,1571-1581. Prusiner, S. (1997). Prion diseases and the BSE crisis. Science 278, 245-251. Prusiner, S., Telling, G., Cohen, R, and DeArmond, S. (1996). Prion diseases of humans and animals. Sem. Virol. 7,159-173. Ricketts, M., Cashman, N., Stratton, E., and El Saadany S. (1997). Is Creutzfeldt-Jakob disease transmitted in blood? Emerg. Infect. Dis. 3,155-163. Rosenberg, R., White, C , Brown, P., Gajdusek, D., Volpe, J., Posner, J., and Dyck, P. (1986). Precautions in handling tissues, fluids, and other contaminated materials from patients with documented or suspected Creutzfeldt-Jakob disease. Ann. Neurol. 19, 75-77. Scully R., Galdabini, J., and McNeely B. (1980). Case records of the Massachusetts General Hospital: Case 45-1980. New Engl. ]. Med. 303,1162-1171. Scully R., Mark, E., McNeely W., and McNeely B. (1993). Case records of the Massachusetts General Hospital: Case 17-1993. New Engl. J. Med. 328, 1259-1266. Sigurdsson, B. (1954). Rida, a chronic encephalitis of sheep with general remarks on infections which develop slowly and some of their special characteristics. Br Vet. ]. 110, 341-354. Tateishi, J. (1985). Transmission of Creutzfeldt-Jakob disease from human blood and urine into mice. Lancet 2,1074. Traub, R., Gajdusek, D., and Gibbs, C. (1974). Precautions in conducting biopsies and autopsies on patients with presenile dementia. /. Neurosurg. 41, 394-395. Traub, R., Gajdusek, D., and Gibbs, C. (1975). Precautions in autopsies on Creutzfeldt-Jakob disease. Am. ]. Clin. Pathol. 64, 287. Will, R., Ironside, J., Zeidler, M., Cousens, S., Estibeiro, K., Alperovitch, A., Poser, S., Pocchiari, M., Hofman, A., and Smith, P. (1996). A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 347, 921-925. Zeidler, M., Stewart, G., Barraclough, C , Bateman, D., Bates, D., Bum, D., Colchester, A., Durward, W, Fletcher, N., Hawkins, S., Mackenzie, J., and Will, R. (1997). New variant Creutzfeldt-Jakob disease: Neurological features and diagnostic tests. Lancet 350, 903-907.


C H A P T E R

31 Lymphocytic Choriomeningitis Virus (LCMV) ^ ^ h a r l e s Armstrong was a lifelong Public Health y ^ ^ / S e r v i c e virologist. In 1933, he and his col/ 0 leagues isolated LCMV for the first time while ^ ^ evaluating a case of central nervous system disease during an outbreak of arthropod-borne encephalitis in St. Louis, Missouri (see Chapter 24) (Armstrong and Sweet, 1939). While it is improbable that the illness was due to LCMV, the finding introduced the scientific community to a new virus later to be classified in the arenavirus family. I first met Armstrong many years later, when he called me into his laboratory at the National Institutes of Health to demonstrate the convulsions that occur in mice shortly after intracerebral inoculation of LCMV. By spinning an infected animal by its tail, he could routinely induce seizures and muscular spasms. This proved to be the first evidence of a developing fatal meningitis. The origin of Dr. Armstrong's initial viral isolate is uncertain, since it was recovered during a series of passages of infectious human material through monkeys. Subsequently, LCMV was isolated from a laboratory mouse (Traub, 1935) and, shortly thereafter. Rivers and Scott (1935) established an association of LCMV with meningitis in a naturally infected human. The overall medical importance of LCM virus for humans is difficult to assess because we lack detailed comprehensive epidemiological survey information on human populations. Three studies in the past provide some insight into the prevalence of human infections, but they yield little information on the frequency of subclinical and nonspecific illness due to LCMV worldwide. Almost 20% of adults were found to possess what were believed to be serum antibodies against LCMV in a survey of prison inmates in institutions scattered around the United States (Wooley ef al., 1937). In a more recent study, 5% of inner-city Baltimore residents proved to have serological evidence of past infection with LCMV (Childs ei al,, 1991). In one survey conducted in northwest Germany, over 3% of the population was found to be positive (Ackermann ei al.,


1974), whereas in southern Germany there was no serological evidence of past infection among residents (Blumenthal ei al., 1970). These data provide only meager insight into the prevalence of infection in developed countries and fail to indicate how often clinical disease occurs. Moreover, the work is subject to methodological shortcomings, both with regard to the specificity and sensitivity of assays used. Clearly, we know very little about the prevalence of naturally occurring infections in the world's population overall. About 8% of cases of aseptic meningitis in North America are due to LCMV (Baird and Rivers, 1938; Adair ei al., 1953; Meyer ei al., 1960; Farmer and Janeway, 1942). On exceedingly rare occasions, a fatal encephalomyelitis with nonspecific pathological brain changes has been described (Smadel ei al., 1942; Adair ei al., 1953; Warkel ei al, 1973). LCMV infections in humans more commonly result in a febrile systemic influenza-like syndrome replete with many generalized signs and symptoms (Table 31.1) (Baum ei al., 1966; Lewis and Utz, 1961). Based on fragmentary clinical and experimental information, in severe cases the pathologist might expect to find evidence of mononuclear cell infiltration in a variety of parenchymal organs, including the liver, pancreas, salivary gland, and testicles. Autopsy verification of these hypothesized organ lesions is lacking. The results of serological surveys indicate that clinically inapparent and nonspecific febrile illnesses occur commonly as a result of LCMV infections. LCMV is the prototype arenavirus, although it is clearly less pathogenic than many other members of the family (see Chapter 19). The virions are approximately 110 to 130 nm in diameter and membrane bound. They utilize RNA as genetic material. In viiro, the viruses "bud" from the plasma membrane surface of the infected cell but cause no noteworthy morphologically recognizable cytopathic effects. Thus, the virus can be maintained as a chronic infection for

427


428


TABLE 31.1 Features of G e n e r a l i z e d Illness D u e to LCM Virus in Ten A d u l t Laboratory Workers and A n i m a l (Hamster) Caretakers Duration of illness (median) Signs and symptoms Fever Retroorbital headache Meningeal signs and symptoms Malaise and anorexia Arthralgia Arthritis Myalgia Adenopathy Orchitis Partial alopecia Laboratory Findings Leukopenia Thrombocytopenia

10 days 10/10'' 10/10 0/10 10/10 10/10 1/10 10/10 3/10 3/9 2/10 4/4 1/4

Adapted with permission from Baum et ah (1966). "This column provides number positive/number infected.

indefinite periods of time in the laboratory. As abundant experimental and pathological evidence now indicates, the capacity of LCMV to cause disease is intimately linked to the immune system of the host: specifically, the cytolytic CD8+ T cell response that accompanies infection appears to be involved (Hotchin, 1962). Spontaneous abortions and congenital infections due to LCMV have been reported in recent years. Infected infants are often underdeveloped and, to a variable extent, manifest microcephaly, internal hydrocephalus, cerebral calcifications, and chorioretinitis (Komrower et al, 1955; Ackermann et al, 1974; Sheinbergas, 1976; Sheinbergas et al, 1977; Chastel et al, 1978; Larsen et al, 1993; Barton et al, 1996). The pathologic features of congenital infections have been briefly described in the Russian literature (Sheinbergas et al, 1977). Like other members of the arenavirus family, LCM virus is maintained in nature in rodents. However, surprisingly little data exist to indicate the diversity of small animal species that are naturally infected. Laboratory mice and hamsters have served as reservoirs for the virus responsible for many of the reported human outbreaks (Traub, 1939; Biggar et al, 1975; Smadel et al, 1942; Lewis et al, 1965; Dykewicz et al, 1992). In developed countries, most of these outbreaks have occurred among laboratorians working with infected mice and Syrian hamsters. Additional cases among pet owners have been reported (Ackermann et al, 1975). Zoo animals also appear to be potential sources of human infection. Fatal LCM hepatitis has been described in marmosets (but not in humans) (Stephensen et al, 1991).

The domestic house mouse {Mus musculus) is believed to be the common host in nature. Infection under natural conditions of transmission appears to occur in the perinatal period, when the mouse is immunologically tolerant to the virus and the thymus underdeveloped. A chronic systemic nonpathogenic infection evolves, with large amounts of virus being present in various organs and the excreta. In the laboratory, nonimmune adult mice are exceptionally susceptible when inoculated intracerebrally. These animals develop a fatal lymphocytic meningoencephalitis that, interestingly enough, can often be aborted by prophylactic irradiation or chemotherapy. As might be expected, adult nude athymic mice only develop inapparent infections (Dykewicz et al, 1992). Compelling evidence now indicates that disease in the rodent, and presumably in humans, is an immunopathologic process (Hotchin, 1962). In the countless experimental animal studies that have been carried out over the past 50 years, variability in results can best be attributed to differences in the susceptibility of the strains of mouse and the pathogenic properties of the virus variant used in the experiment. Arenaviruses exhibit a high rate of mutability during transmission in laboratory mice, and it is highly probable that so-called ''wild" strains in nature vary considerably in pathogenicity for humans. This may account for the differing outcomes of naturally acquired infections, with most being subclinical, and a rare few cases that result in meningitis, encephalitis, and death. One might ask whether the voluminous laboratory research conducted with LCMV is relevant to clinical disease caused by this virus. The mouse appears to be a natural host, and humans prove to be infected incidentally when unusually intimate contact with rodents occurs. I believe the many interesting studies carried out experimentally have provided science with unique insights into the immunopathology of virus disease, but the results do not appear to be directly translatable into an understanding of the pathogenesis of clinical illness in humans caused by LCMV.

References Ackermann, R., Korver, G., Turss, R., Wonne, R., and Hochgesand, R (1974). Prenatal infection with the lymphocytic choriomeningitis virus. Dtsch. Med. Wochenschr. 13, 629-632. Ackermann, R., Stammler, A., and Armbruster, B. (1975). Isolierung von Virus der lymphozytaren Choriomeningitis aus Abrasionsmaterial nach Kontakt der Schwangeren mit einem Syrischen Gold-hamster {Mesocricetus auratus). Infection. 3, 47-49. Adair, C., Gauld, R., and Smadel, J. (1953). Aseptic meningitis, a disease of diverse etiology: Clinical and etiologic studies on 854 cases. Ann. Intern. Med. 39, 675-704.

Lymphocytic Choriomeningitis Virus Armstrong, C , and Sweet, L. (1939). Lymphocytic choriomeningitis. Publ Health Rep. 54, 673-684. Baird, R., and Rivers, T. (1938). Relation of lymphocytic choriomeningitis to acute aseptic meningitis. Am. J. Pub. Health 28, 47. Barton, L., Peters, C , Seaver, L., and Chartrand, S. (1996). Congenital lymphocytic choriomeningitis virus infection. Arch. Pediatr. Adolesc. Med. 150, 440. Baum, S., Lewis, A., Rowe, W., and Huebner, R. (1966). Epidemic nonmeningitic lymphocytic choriomeningitis-virus infection: An outbreak in a population of laboratory personnel. New Engl. J. Med. 274, 934-936. Biggar, R., Woodall, J., Walter, R, and Haughie, G. (1975). Lymphocytic choriomeningitis outbreak associated with pet hamsters. Fifty-seven cases from New York State. JAMA 232, 494-500. Blumenthal, W., Kessler, R., and Ackermann, R. (1970). Uber die Durchseuchung der landlichen Bevolkerung in der Bundesrepublik Deutschland mit dem Virus der Lymphocytaren Choriomeningitis. Zentralbl Bakteriol. Abt. I Orig. 213, 36-48. Chastel, C , Bosshard, S., Le Goff, R, Quillien, M., Gilly, R., and Aymard, M. (1978). Infection transplacentaire par le virus de la choriomeningite lymphocytaire: Resultats d'une enquete serologique retrospective en France. Nouv. Presse Med. 7,1089-1092. Childs, J., Glass, G., Ksiazek, T., Rossi, C , Barrera Oro, J., and LeDuc, J. (1991). Human-rodent contact and infection with lymphocytic choriomeningitis and Seoul viruses in an inner-city population. Am. J. Trop. Med. Hyg. 44,117-121. Dykewicz, C , Dato, V., Fisher-Hoch, S., et al. (1992). Lymphocytic choriomeningitis outbreak associated with nude mice in a research laboratory. ]AMA 1&7,1349-1353. Farmer, T., and Janeway, C. (1942). Infections with the virus of lymphocytic choriomeningitis. Medicine 21,1-64. Hotchin, J. (1962). The biology of lymphocytic choriomeningitis infection: virus-induced immune disease. Cold Spring Harbor Symp. Quant. Biol. 27, 479^99. Komrower, G., Williams, B., and Stone, R (1955). Lymphocytic choriomeningitis in the newborn, probable transplacental infection. Lancet 1, 697-698.

429

Larsen, P., Chartrand, S., Tomashek, K., Hauser, L., and Ksiazek, T. (1993). Hydrocephalus complicating lymphocytic choriomeningitis virus infection. Pediatr Infect. Dis. J. 12, 528-531. Lewis, J., and Utz, J. (1961). Orchitis, parotitis and meningoencephalitis due to lymphocytic choriomeningitis virus. New Engl. J. Med. 265, 776-780. Lewis, A., Rowe, W, Turner, H., and Huebner, R. (1965). Lymphocytic choriomeningitis virus in Syrian hamster tumor. Science 150, 363. Meyer, H,, Johnson, R., Crawford, I., Dascomb, H., and Rogers, N. (1960). Central nervous system syndromes of 'ViraF' etiology: A study of 713 cases. Am. J. Med. 29, 334-347. Rivers, T., and Scott, T. (1935). Meningitis in man caused by a filtrable virus. Science 81, 439. Sheinbergas, M. (1976). Hydrocephalus due to prenatal infection with the lymphocytic choriomeningitis virus. Infection 4,185-191. Sheinbergas, M., Pmashekas, R., Pikelite, R., et al. (1977). Clinical and pathomorphological data on hydrocephalus caused by prenatal infection by the lymphocytic choriomeningitis virus. Zh. Nevropatol. Psikhiatr 77,1004-1007. Smadel, J., Green, R., Paltauf, R., and Gonzales, T. (1942). Lymphocytic choriomeningitis: Two human fatalities following an unusual febrile illness. Proc. Soc. Exp. Biol. Med. 49, 683-686. Stephensen, C , Jacob, J., Montali, R., et al. (1991). Isolation of an arenavirus from a marmoset with Callitrichid hepatitis and its serologic association with disease. /. Virol. 65, 3995-4000. Traub, E. (1935). A filtrable virus recovered from white mice. Science 81, 439. Traub, E. (1939). Epidemiology of lymphocytic choriomeningitis in a mouse stock observed for four years. /. Exp. Med. 69, 801-817. Warkel, R., Rinaldi, C , Bancroft, W, Cardiff, R., Holmes, G., and Wilsnack, R. (1973). Fatal acute meningoencephalitis due to lymphocytic choriomeningitis virus. Neurology. 23,198-203. Wooley, J., Armstrong, C , and Onstott, R. (1937). The occurrence in the sera of man and monkeys of protective antibodies against the virus of lymphocytic choriomeningitis as determined by the serum-virus protection test in mice. Publ. Health Rep. 52,1105-1115.


C H A P T E R

32 Enteric Viral Disease INTRODUCTION 431 NORWALK-LiKE VIRUSES (NLVs) 432 ROTAVIRUSES (RVs) 433 ADDITIONAL ENTERIC VIRUSES 438 PATHOPHYSIOLOGY OF VIRAL ENTERITIS REFERENCES 439

diarrhea. When pathogenic bacteria are excluded, roughly 80% of the episodes of diarrhea (>3 nonsolid stools per day) are either of unknown etiology or are due to viruses. With the discovery of the enteroviruses (see Chapter 1) and the demonstration of their chronic presence in the stools of many of those who are infected, it was thought that the search for the cause of nonbacterial diarrhea would soon be over. But despite the presence of high concentrations of enteroviruses in the stools of both ill and healthy children, it shortly became apparent that these viruses were not common etiologic agents of enteritis, but merely nonpathogenic "passengers'' in our digestive tracts. Other viruses such as members of many of the common serotypes of the adenoviruses similarly can often be found in the gut, but they too usually fail to cause disease. As an outgrowth of an enormous amount of laboratory work, it was ultimately concluded that the elusive viruses of childhood enteritis are sufficiently fastidious that they cannot be easily grown in tissue culture and in laboratory animals. Thus, in the early 1970s, investigators initiated attempts to identify viral particles in stool extracts using electron microscopy. To accomplish this, the background was stained (so-called negative staining), with the virions in startling contrast, that is, like stars in a dark sky. Should the virions be present in sufficient number, and should their morphology be sufficiently distinctive, infection could be established. By adding specific antibody (or serum from a previously infected patient) to the suspension, the virions would clump with the antibody and an antigenic identification of the virus accomplished. This also proved a means for assaying the relative concentration of antibody in the blood of those who were infected. The technique of negative-staining electron microscopy using clinical enteric specimens is an arduous art form that requires exceptional skill and attention to detail, clearly not a characteristic of many of our species. But, this painstaking approach has now yielded evidence to indicate that viruses of at least six families may contribute to enteric illness in children and in adult citizens

439

INTRODUCTION Al Kapikian learned immune electron microscopy from the talented British investigator June Alameda, who had perfected the technique into an art form, as much as a skill. In the early 1970s, Kapikian focused on this approach to the search for the elusive viruses believed to be responsible for nonbacterial gastroenteritis. It was not long before he identified the virions of the so-called Norwalk agent in a diarrheal stool from an adult volunteer who had been challenged with a fecal sample from a child ill during an outbreak of diarrhea. This virus and its soon-to-be-discovered close relatives (the so-called Norwalk-like viruses [NLVs]) proved to be important causes of explosive outbreaks of diarrhea in both children and adults. NLVs were first reported in 1972 (Kapikian et al, 1972; Kapikian, 1994). Only a year later, Ruth Bishop and her colleagues (1973) found virions of a different size and appearance in cells of the duodenal mucosa of infants with gastroenteritis. These agents proved to be the prototype for a new genus, the rotaviruses (RVs), members of which are infectious for humans and a wide variety of domestic animals. Rotaviruses, classified into Group A, are now recognized to be the major cause of severe diarrheal disease in infants and young children worldwide. Cholera morbus has plagued and threatened the lives of infants and children since the beginning of recorded history. Morbidity is universal, and the resulting mortality, particularly in developing areas of the world, continues to be tragic. Overall, as many as a third of the deaths in children under the age of 5 in the less-developed countries of the world are attributed to


431


432


whose immunity has waned (Figure 32.1, Table 32.1). Studies in domestic animals have also shown that diarrheal disease of economic importance is caused by members of these same virus families, possibly by strains of virus that are host-specific. With the development of refined rnolecular and immunological tools, more sensitive and less laborious diagnostic approaches fortunately are now replacing negative-staining electron microscopy of stool specimens.

Q Bacteria 0

Parasites

•

Rotavirus

H Enteric Adenovirus

TABLE 32.1 Enteric Viruses D e f i n i t e l y or Possibly Causing Gastroenteritis i n H u m a n s Endemic disease Rotaviruses Group A Groups B and C

Epidemic outbreaks

Worldwide importance

+

++++ +

Calciviruses Norwalk-like viruses Unclassified

+ +

Enteric adenoviruses

+

Toroviruses

+

Astroviruses

+?

Coronaviruses

++ +? ?

TABLE 32.2 G e n o t y p e s of Norwalk-Like Viruses Based o n Molecular A n a l y s e s

i l Astrovirus •

Other viruses

n

Unknown

FIGURE 32.1 Estimated median percentage of diarrheal episodes associated with specific viruses and categories of enteropathogens in developed countries. Reprinted with permission from Kapikian (1994).

NORWALK-LIKE VIRUSES (NLVs) A number of antigenically distinct, nonenveloped, round, 27- to 32-nm RNA viruses classified into a newly proposed genus of the calcivirus family have been found to cause sporadic outbreaks of transient severe enteritis in both children and adults. The etiological role of these viruses as a cause of intestinal disease was established by demonstrating a temporal association of naturally occurring infections (as demonstrated by stool examination using electron microscopy) with illness and by experimental induction of disease in both human volunteers and experimental animals (Hall et al, 1984). The NLVs are provisionally divided for classification purposes into two distinct groups based on genetic analysis (Table 32.2). The relative clinical importance of the viruses of the various groups listed in Table 32.2 has yet to be established, but they are believed to be responsible for a substantial proportion of the nonbacterial outbreaks of acute vomiting and diarrhea that occur in families and institutions.

Genotype I Norwalk" Southampton Cruise ship Desert Shield Genotype II Gwynedd Toronto Lardsdale Snow Mountain White River Hawaii "The geographic name customarily refers to the site where the virus was initially isolated.

Although survey information is incomplete, infections with NLV are thought to occur worldwide. In developing countries, the majority of children are infected during the first 10 years of life (Figure 32.2), whereas in North America infection is relatively uncommon in children, and by the fifth decade of life only 50% of the population possess serological evidence of past infection. It is not clear what proportion of these infections are accompanied by clinical illness, and we possess only limited information on the persistence of serum antibodies during convalescence from infection. Thus, NLV-related disease may occur more commonly than serological surveys of the population now suggest. Outbreaks of illness develop as a result of a contaminated common source, such as a water supply or food, or as a consequence of person-to-person transmission (Fankhauser et ah, 1998). The mean incubation period is approximately 40 hours, and symptoms persist for 12

433

Enteric Viral Disease

100 r

TABLE 32.3 Symptoms of Norwalk Virus Infections among Children during a Naturally Occurring Outbreak

(12)

(3) o

/fSiO^ 90

-

Percent \ .

Q O

80h

m z

\

L

32 85 84 62 bl 44

Reprinted with permission from Kapikian (1994). mi)

50 \-

40

h

g 30

l

I

10 stools/day) Vomiting Vomiting (>5 x/day) Fever Temperature >39°C Respiratory symptoms Dehydration

94 28 92

sr

86 35 32 72«

Percentage of nonhospitalized 100 17 83 28 83 47 34 30

Reprinted with permission from Uhnoo et al. (1986). "Statistically significant (p > 0.05) difference between hospitalized and nonhospitalized patients.

TABLE 32.5 S y m p t o m s i n North American A d u l t s w i t h Familially Acquired Rotavirus Infections Symptoms

Percent

Diarrhea Abdominal cramps Vomiting Respiratory Fever

32 24 10 7 6

Reprinted with permission from Wenman et al. (1979).

FIGURE 32.5 Experimentally induced rotavirus infection in gnotobiotic piglets. Villous epithelium in the top panel shows a viroplasm with viral particles budding into the distended cisternae of endoplasmic reticulum. In the middle panel, enveloped virus particles are situated within (arrow) and at the edge of convoluted smooth membrane. The bottom panel displays the fine structural features of the viroplasm shown in Figure 32.6. Reprinted with permission from Saif et al. (1978).


437

FIGURE 32.6 Experimentally induced rotavirus infection in gnotobiotic piglets. Electron micrographs of villous epithelium. Note distended cisternae of the rough endoplasmic reticulum and rarefaction of cytoplasm in panel A. The affected cell is situated between two seemingly normal cells. Panel B shows cells with shortened irregular microvilli and a break in the viroplasm-VP border (arrow) (see Figure 32.5). Reprinted with permission from Saif et al. (1978).

§ o

^^ 10'

0

I

n

I Immunofluorescence

i L

•

40 60 80 100 hours after infection

2 3 weeks after infection

FIGURE 32.7 Experimentally induced rotavirus infections in gnotobiotic piglets. Temporal evidence of infectivity as based on assays of bowel content and immunofluorescence of mucosal lining cells for the presence of virus. The associated changes in the villus lengthicrypt length ratio is shown for infected (solid black) and control (broken line) animals. Note the protracted recovery time. Reprinted with permission from Crouch and Woode (1978).

showed that disaccharidase concentrations were reduced in the epithelium. Repeat biopsies were done on several children during convalescence (3 to 8 weeks), and regeneration of the mucosa was found. As noted above, a wide variety of wild and domesticated mammals and poultry (Domermuth and Gross, 1985) acquire RV infections naturally. Experimental studies in calves (Reynolds et al, 1985), lambs (Snodgrass et al, 1977, 1979), and piglets (Theil et al, 1978; Crouch and Woode, 1978) have provided insight into the location of viral replication in the gut and the associated histologic changes (Figure 32.7). To a large extent, the changes observed in children (Davidson and Barnes, 1979) were found in these animals. In calves, the lesions tended to be more prominent in the proximal small intestine, whereas in lambs the distal ileum was more severely affected. Table 32.6 summarizes the results of immunohistochemical studies that document viral replication in the gut of lambs after experimental infection per os. In general, the sites of RV replication correlate with the pathological changes found in the intestinal mucosa (Snodgrass et al, 1977). As might be expected, the concentrations of virus in the gut of these piglets were highest before lesions in the mucosa appeared (Crouch and Woode, 1978).

438

Pathology and Pathogenesis of Human Viral D i s e a s e TABLE 32.6 Immunofluorescent Staining of the Intestine of an Experimentally Infected Lamb for Rotavirus Antigen

Time killed (hours p.i.) 12 18 27 42 48 72 96 144 Control Control

Small intestine

Large intestine

Anterior

Middle

Posterior

_

++++ +++

++++ +++ ++

++

-

+

-

++ +

++

+ +

-

+

•

-

+

Colon

Caecum

++ +

++ ++ ++

-

+

Reprinted with permission from Snodgrass et al. (1977). ++++ = Continuous fluorescent epithelial cells present over at least distal half of the villi. +++ = Continuous fluorescent epithelial cells present over tip or distal third of the villi. ++ = Sporadic fluorescent epithelial cells present in most villi. + = Sporadic fluorescent epithelial cells present in a few villi.

A D D I T I O N A L ENTERIC VIRUSES

FIGURE 32.8 Photomicrographs of histological cross-sections from the small intestines of two piglets. (Top) Observe the long slender villi with lightly stained epithelium that dominate the mucosa in the normal animal. There is a narrow band of crypts with a darkly stained epithelium around the base of the mucosa. (Bottom) Severe villous atrophy caused by the swine coronavirus responsible for transmissible gastroenteritis. Reprinted with permission from Moon (1994).

Viruses of several additional families have been implicated in human enteritis, but, in general, the disease is relatively mild and not life threatening (Table 32.1). Information concerned with the pathological effects of these viruses on the gut mucosa is lacking. In many studies, the common occurrence of asymptomatic enteric infections often makes it difficult to establish, on epidemiological grounds, an etiological relationship between the infection and disease; yet, under certain circumstances, these viruses may be pathogenic for humans. The enteric adenoviruses types 40 and 41 are recognized causes of enteritis, but they account for fewer than 10% of cases (see Chapter 14) (Brandt et al, 1985). In two recent studies, toroviruses were associated with enteritis manifest in children as both vomiting and diarrhea. Although not severe, the stools commonly were bloody and disease persisted for several days (Koopmans et ah, 1997). Enteritis due to toroviruses also occurs in cattle and horses (Weiss and Horzinek, 1987; Woode et al, 1982; Jamieson et al, 1998). Astroviruses and coronaviruses have been implicated as causes of diarrheal disease in humans, but the evidence supporting a cause-and-effect association is weak (Phillips et al, 1982; Lew et al, 1990). These latter viruses are etiologically responsible for disease in young domestic animals (Mebus et al, 1973; Thake et al, 1973; Gray et al, 1980; Kurtz et al, 1979) (Figures 32.8 and 32.9).

439


FIGURE 32.9 Degeneration of mucosal lining cell in the midgut of a lamb infected with an astrovirus. Note the changes in the microvilli (arrows) and virions in a lysosome (V). Reprinted with permission from Gray et al. (1980).

PATHOPHYSIOLOGY OF VIRAL ENTERITIS Pathological observations provide insight into the physiological basis for enteritis in those infected with enteropathic viruses. At present, relatively few clinical studies have addressed these issues in detail. Involvement of the upper intestinal tract (duodenum and jejunum) may account for the vomiting that so frequently occurs in NLV infections. Diarrheal disease no doubt is consequent to the profound changes in the intestinal mucosa that occur during the acute illness. Reduction in the surface area of the gut mucosa and functional alterations in the individual enterocytes that line villi reduce absorption of fluids and solids beyond the capacity of the colon to compensate. The loss of disaccharidases in the mucosal cells of the small intestine increases the carbohydrate concentrations of the large bowel content, resulting in the generation of fermentation products.

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Davidson, G., and Barnes, G. (1979). Structural and functional abnormalities of the small intestine in infants and young children with rotavirus enteritis. Acta Paediatr. Scand. 68,181-186. Dolin, R., Blacklow, N., DuPont, H., Formal, S., Buscho, R., Kasel, J., Chames, R., Hornick, R., and Chanock, R. (1971). Transmission of acute infectious nonbacterial gastroenteritis to volunteers by oral administration of stool filtrates. /. Infect. Dis. 123, 307-312. Dolin, R., Levy, A., Wyatt, R., Thornhill, T., and Gardner, J. (1975). Viral gastroenteritis induced by the Hawaii agent: Jejunal histopathology and serologic response. Am. J. Med. 59, 761-768. Domermuth, C., and Gross, W. (1985). Hemorrhagic enteritis of turkeys. In ""Animal Models for Intestinal Disease'' (C. Pfeiffer, ed.), chap. 22. CRC Press, Boca Raton, FL. Dryden, M., and Shanson, D. (1988). The microbial causes of diarrhoea in patients infected with the human immunodeficiency virus. /. Infect. 17,107-114. Eiden, J., Losonsky, G., Johnson, V, and Yolken, R. (1985). Rotavirus RNA variation during chronic infection of immunocompromised children. Pediatr. Infect. Dis. 4, 632-637. Fankhauser, R., Noel, J., Monroe, S., Ando, T., and Glass, R. (1998). Molecular epidemiology of "Norwalk-like viruses'' in outbreaks of gastroenteritis in the United States. /. Infect. Dis. 178,1571-1578. Gray, E., Angus, K., and Snodgrass, D. (1980). Ultrastructure of the small intestine in astrovirus-infected lambs. /. Gen. Virol. 49,71-82. Greenberg, H., Valdesuso, J., Kapikian, A., Chanock, R., Wyatt, R., Szmuness, W., Larrick, J., Kaplan, J., Gilman, R., and Sack, D. (1979). Prevalence of antibody to the Norwalk virus in various countries. Infect. Immunol 26, 270-273. Hall, G., Bridger, J., Brooker, B., Parsons, K., and Ormerod, E. (1984). Lesions of gnotobiotic calves experimentally infected with a calcivirus-like (Newbury) agent. Vet. Pathol. 21, 208-215. Hrdy, D. (1987). Epidemiology of rotaviral infection in adults. Rev. Infect. Dis. 9, 461-^69. Jamieson, F., Wang, E., Bain, C., Good, J., Duckmanton, L., and Petric, M. (1998). Human torovirus: A new nosocomial gastrointestinal pathogen. /. Infect. Dis. 178, 1263-1269. Kaljot, K., Ling, J., Gold, J., Laughon, B., Bartlett, J., Kotler, D., Oshiro, L., and Greenberg, H. (1989). Prevalence of acute enteric viral pathogens in acquired immunodeficiency syndrome patients with diarrhea. Gastroenterology 97,1031-1032. Kapikian, A. (1994). Norwalk and Norwalk-like viruses. In "Viral Infections of the Gastrointestinal Tract," 2nd ed. (A. Kapikian, ed.), pp. 471-518. Marcel Dekker, New York. Kapikian, A., Wyatt, R., Dolin, R., Thornhill, T, Kalica, A., and Chanock, R. (1972). Visualization by immune electron microscopy of a 27-nm particle associated with acute infectious nonbacterial gastroenteritis. /. Virol. 10,1075-1081. Koopmans, M., Goosen, E., Lima, A., et at. (1997). Association of torovirus with acute and persistent diarrhea in children. Pediatr. Infect. Dis. 16, 504-507. Kurtz, J., Lee, T, Craig, J., and Reed, S. (1979). Astrovirus infection in volunteers. /. Med. Virol. 3, 221-230. Lew, J., Glass, R., Petric, M., Levaron, C , Hammond, G., Miller, S., Robinson, C , Boutilier, J., Riepenhoff-Talty, M., Payne, C , Franklin, R., Oshiro, L., and Jaqua, M. (1990). Six-year retrospective surveillance of gastroenteritis viruses identified at ten electron microscopy centers in the United States and Canada. Pediatr. Infect. Dis. ]. 9, 709-714.

Lewis, D., Lightfoot, N., Cubitt, W, and Wilson, S. (1989). Outbreaks of astrovirus type 1 and rotavirus gastroenteritis in a geriatric inpatient population. /. Hosp. Infect. 14, 9-14. Mebus, C , Stair, E., Rhodes, M., and Twiehaus, M. (1973). Pathology of neonatal calf diarrhea induced by a coronavirus-like agent. Vet. Path. 10, 45-64. Moon, H. (1994). Pathophysiology of viral diarrhea. In "Viral Infections of the Gastrointestinal Tract," 2nd ed. (E. Kapikian, ed.), pp. 27-52. Marcel Dekker, New York. Moulton, L., Staat, M., Santosham, M., and Ward, R. (1998). The protective effectiveness of natural rotavirus infection in an American Indian population. /. Infect. Dis. 178,1562-1566. Phillips, A., Rice, S., and Walker-Smith, J. (1982). Astrovirus within human small intestinal mucosa. Gut. 23, A923-A924. Qui, F, Tian, Y, Liu, J., Zhang, X., and Hao, Y (1986). Antibody against adult diarrhoea rotavirus among healthy adult population in China. /. Virol. Methods 14,133-140. Reynolds, D., Hall, G., Debney, T, and Parsons, K. (1985). Pathology of natural rotavirus infection in clinically normal calves. Res. Vet. Sci. 38, 264-269. Saif, L., Theil, K. W, and Bohl, E. H. (1978). Morphogenesis of porcine rotavirus in porcine kidney cell cultures and intestinal epithelial cells. /. Gen. Virol. 39, 205-217. Schreiber, D., Blacklow, N., and Trier, J. (1973). The mucosal lesion of the proximal small intestine in acute infectious nonbacterial gastroenteritis. New Engl. ]. Med. 288, 1318-1323. Schreiber, D., Blacklow, N., and Trier, J. (1974). The small intestinal lesion induced by Hawaii agent acute infectious nonbacterial gastroenteritis. /. Infect. Dis. 129, 705-708. Snodgrass, D., Angus, K., and Gray, E. (1977). Rotavirus infection in lambs: Pathogenesis and pathology. Arch. Virol. 55, 263-274. Snodgrass, D., Ferguson, A., Allan, F., Angus, K., and Mitchell, B. (1979). Small intestinal morphology and epithelial cell kinetics in lamb rotavirus infections. Gastroenterology 76, 477^81. Thake, D., Moon, H., and Lambert, G. (1973). Epithelial cell dynamics in transmissible gastroenteritis of neonatal pigs. Vet. Path. 10, 330-341. Theil, K., Bohl, E., Cross, R., Kohler, E., and Agnes, A. (1978). Pathogenesis of porcine rotaviral infection in experimentally inoculated gnotobiotic pigs. Am. ]. Vet. Res. 39, 213-220. Uhnoo, I., Olding-Stenkvist, E., and Kreuger, A. (1986). Clinical features of acute gastroenteritis associated with rotavirus, enteric adenoviruses, and bacteria. Arch. Dis. Child. 61, 732-738. Ward, R., and Bernstein, D. (1994). Protection against rotavirus disease after natural rotavirus infection. /. Infect. Dis. 169, 900-904. Weiss, M., and Horzinek, M. (1987). The proposed family, Toroviridae: agents of enteric infections. Arch. Virol. 92,1-15. Wenman, W, Hinde, D., Feltham, S., and Gurwith, M. (1979). Rotavirus infection in adults: Results of a prospective family study. New Engl. J. Med. 301, 303-306. Wood, D., David, T, Chrystie, L, and Totterdell, B. (1988). Chronic enteric virus infection in two T-cell immunodeficient children. /. Med. Virol. 24, 435^44. Woode, G., Reed, D., Runnels, P, Herrig, M., and Hill, T. (1982). Studies with an unclassified virus isolated from diarrheic calves. Vet. Microbiol. 7, 221-240.

Index

Acquired immunodeficiency syndrome, see also Human immunodeficiency virus cervical cancer association, 234 clinical course of HIV-1 infection adults, 207-209 children and infants, 210-211 epidemiology, 205-206 history 205-206 Kaposi's sarcoma AIDS association, 171-172, 232-233 classification, 174-175 clinical features, 171-172, 233 lymph node involvement, 177-178 pathogenesis, 174-175,177-178 staging, 175 tissue distribution, 233-234 opportunistic infections adenovirus, disseminated disease, 195-196 bacterial pneumonias, 206, 225-226 chronic enterovirus meningoencephalitis, 8-10 cytomegalovirus, see Cytomegalovirus digestive tract, 206 human herpesvirus type 6,167-168 measles, 403-404 moUuscum contagiosum, 377-378 overview, 206 Adenovirus central nervous system disease, 197-198 classification, 189-190 digestive tract disease, 197 discovery, 189 disseminated disease in immunocompromised patients, 195-196 enteric virus, 438 epidemiology, 189-191 eye disease, 198 genitourinary tract disease, 196-197 heart disease, 197 immune response, 191

respiratory tract infection chronic infection, 194 inclusion-body pneumonia, 192 late complications, 192-193 serotypes, 191,194-195 transmission, 191,194 structure, 189-190 AIDS, see Acquired immunodeficiency syndrome Alphaviruses classification, 344 eastern equine encephalitis, 346-347 infection cycle, 344, 346 strains, 345-346 structure, 344 Venezuelan equine encephalitis, 348-349 western equine encephalitis, 347-348 Angiofollicular lymph node hyperplasia, Kaposi's sarcoma-associated herpesvirus as cause, 180-181 Angiosarcoma, Kaposi's sarcomaassociated herpesvirus as cause, 178 Arenavirus, see also Lymphocytic choriomeningitis virus Guanarito virus, 280 Junin virus, 278-279 Lassa virus, 280-292 Machupo virus, 278-279 Sabia virus, 280 structure and classification, 277-278 Argentinian hemorrhagic fever, see Junin virus Arthropod-transmitted viruses alphaviruses classification, 344 eastern equine encephalitis, 346-347 infection cycle, 344, 346 strains, 345-346 structure, 344 Venezuelan equine encephalitis, 348-349 western equine encephalitis, 347-348 Colorado tick fever, 354-355

441

flaviviruses classification, 350 infection cycle, 349-350 Japanese B encephalitis, 352-353 miscellaneous encephalitides, 353-354 overview, 349 St. Louis encephalitis, 351-352 LaCrosse, 354 overview of viruses and diseases, 343-344 Atherosclerosis, cytomegalovirus role, 107-109 Autoimmune hepatitis, features, 270

B BK virus, see also Papovavirus discovery, 327 urinary tract infection and disease, 331, 333 viremia, 328-329 Bolivian hemorrhagic fever, see Machupo virus Bornholm disease. Coxsackievirus infection, 17 Bovine papular stomatitis, features, 377 Bunyaviruses Congo-Crimean hemorrhagic fever virus, 286-287 Hantavirus, hemorrhagic fever with renal disease epidemiology, 282 Hantaan virus and Korean hemorrhagic fever, 282-284 Puumala virus and nephropathia endemica, 284-285 Seoul virus, 282-284 LaCrosse, 354 overview, 282, 354 Rift Valley fever virus, 285-286 Burkitt's lymphoma AIDS-associated disease, 232 chromosome translocations, 127 discovery of Epstein-Barr virus association, 117,125 epidemiology, 125-126 pathogenesis, 127

442

Castleman's disease, see AngiofoUicular lymph node hyperplasia Cervical cancer AIDS association, 234 human papillomavirus association, 311-314 Chickenpox clinical features, 147-148 course, 148-149 immune response, 148 transmission, 148 Chronic enterovirus meningoencephalitis, enterovirus disease in immune deficiency, 8-10 CJD, see Creutzfeldt-Jacob disease CMV, see Cytomegalovirus Coxsackievirus, see also Enterovirus Bomholm disease, 17 classification, 1 diabetes mellitus type I, group B infection role, 21-23 group B myocarditis epidemiology, 13 natural history, 13-14 pathogenesis, 14-16 Colorado tick fever, features, 354-355 Common cold, see Rhinovirus Congo-Crimean hemorrhagic fever virus, hemorrhagic fever, 286-287 Cowpox virus, features and diseases, 365, 371, 377 Creutzfeldt-Jacob disease, see also Transmissible spongiform encephalopathy clinical features, 413-414 iatrogeruc Creutzfeldt-Jacob disease, 422 new variant Creutzfeldt-Jacob disease (vCJD), 421-422 pathological features, 415-417 Cylindrical confronting cisternae, human immunodeficiency virus-infected cells, 231 Cytomegalovirus, see also Herpesvirus atherosclerosis role, 107-109 congenital infection and disease, 90, 92 digestive tract disease, 100-101 discovery, 87 ear disease, 107 epidemiology and natural history of infection, 89-90 eye disease, 106-107 genital disease, 103-105 heart disease, 105-106 immunologically intact patient infection, 92-93 inclusion body cells, 87-89 kidney disease, 103 liver disease, 101-102 lung disease course, 97-99 immunocompromised patients, 96, 99, 206 lesions, 99-100 pneumonia models, 99 mononucleosis, 93

Index nervous system disease adults, 94-95 children, 93-94 immunocompromised patients, 95-96, 221-222 pancreas disease, 102 placental disease, 92 posttransfusion syndrome, 93 transplant recipient infection, 88, 96 urinary tract disease, 102-103

D Dengue virus epidemiology, 292 hemorrhagic fever, 292-293 shock syndrome, 292-293 Diabetes mellitus type I autoimmunity in pathogenesis, 21 mumps role, 385-386 virus infection role, 21-23 Diffuse alveolar damage, AIDS-associated disease, 222 Digestive tract adenovirus disease, 197 AIDS-associated diseases, 230-231 cytomegalovirus disease, 100-101 herpes simplex virus disease, 76-77 human papillomavirus diseases anus, 317 esophagus, 315-317 oropharynx, 315 varicella-zoster virus disease, 159 Duncan's disease, see X-linked lymphoproliferative disease

Ear cytomegalovirus disease, 107 human papillomavirus and middle ear disease, 322 mumps and middle ear disease, 407 mumps manifestations, 386 varicella-zoster virus disease, 158 Eastern equine encephalitis, features, 346-347 Ebola virus clinical features of disease, 287-289 outbreaks, 287 pathology 288-289 EBV, see Epstein-Barr virus Echovirus, see Enterovirus Ecthyma contagiosum, features, 377 Encephalitis, see also Nervous system disease cytomegalovirus adults, 94-95 children, 93-94 immunocompromised patients, 95-96 enterovirus disease, 4 flaviviruses Japanese B encephalitis, 352-353 miscellaneous encephalitides, 353-354 St. Louis encephalitis, 351-352

herpes simplex virus diagnosis, 71-72 distribution in brain, 72-73 epidemiology, 71 immunocompromised patients, 74 seizures, 74-75 treatment, 71-72 rabies, 360-362 Enteric viral disease adenoviruses, 438 astroviruses, 438 coronaviruses, 438 diagnosis, 431^32 mortality, 431 Norwalk-like viruses clinical course of infection, 432-433 discovery, 431 epidemiology, 432 pathology, 433 structure and classification, 432 pathophysiology, 439 rotaviruses clinical features of infection, 434-435 epidemiology, 433^34 pathology 435, 437 structure and classification, 434 toroviruses, 438 Enterovirus, see also Coxsackievirus; Poliovirus Bomholm disease from Coxsackievirus infection, 17 classification, 1 diabetes mellitus type I, virus infection role, 21-23 heart disease Coxsackievirus group B myocarditis, 13-16, see Coxsackievirus diagnostic criteria, 10-13 epidemiology, 10 infection route, 2 kidney disease, 19 liver disease, 19 lung disease, 18 mutability, 1 neurological disease aseptic meningitis, 3-4 chronic enterovirus meningoencephalitis in immune deficiency, 8-10 encephalitis, 4 poliomyelitis, 4-6 post-poliomyelitis syndrome, 6, 8 placental disease, 19-20 receptors, 2 skin lesions, 20-21 striated muscle disease, 16-17 structure, 2 testicular disease, 18-19 transmission, 2-3 virulence factors, 3 Epstein-Barr virus, see also Herpesvirus Burkitt's lymphoma chromosome translocations, 127 discovery 117,125 epidemiology, 125-126 pathogenesis, 127

Index discovery, 117 hairy leukoplakia association, 136-138 hemophagocytic syndrome, 138-139 Hodgkin's disease role, 130-131 infectious mononucleosis clinical features, 120 discovery of viral etiology, 117 female genital tract, 123 kidney disease, 123 lymph node pathology, 120-121 myocarditis, 123 neuromuscular disease, 122-123 pancreatitis, 123 pericarditis, 123 inflammatory pseudotumor association, 135 lung disease, 134-135 lymphoepitheliomatous gastric carcinoma role, 133 lymphomatoid granulomatosis association, 135 lymphoproliferative disorders associated with immunosuppression, 127-129 nasopharyngeal carcinoma role, 131-133 non-Hodgkin's lymphoma role, 129-130 receptors, 118 replication, 118 sinusoidal tumor role, 133-134 Sjogren's syndrome, infection in salivary gland tumors, 135-136 strains, 118 X-linked lymphoproliferative disease, 123-124 Exanthema subitum, human herpesvirus type 6 infection, 167 Eye adenovirus disease, 198 cytomegalovirus disease, 106-107 herpes simplex virus disease, 78-81 human papillomavirus disease, 321-322 mumps disease, 407 varicella-zoster virus disease, 156-15

Fatal familial insomnia, see also Transmissible spongiform encephalopathy clinical features, 415 pathological features, 415-417 FBB, see Follicular bronchitis/bronchiolitis FFI, see Fatal familial insomnia Filoviruses Ebola virus clinical features of disease, 287-289 outbreaks, 287 pathology 288-289 Marburg virus disease, 287 overview, 287 Flaviviruses classification, 350 dengue virus epidemiology, 292 hemorrhagic fever, 292-293 shock syndrome, 292-293

infection cycle, 349-350 Japanese B encephalitis, 352-353 miscellaneous encephalitides, 353-354 overview, 289-290, 349 St. Louis encephalitis, 351-352 yellow fever virus clinical phases of illness, 291 epidemiology, 290-291 history of study 290-291 pathology 291-292 Follicular bronchitis /bronchiolitis, AIDS-associated disease, 222-223

GB virus, discovery and features, 262 Genitals, see also Testicles adenovirus disease, 196-197 cytomegalovirus disease, 103-105 Epstein-Barr virus and infectious mononucleosis of female genital tract, 123 herpes simplex virus disease females, 66-68 males, 69 human papillomavirus diseases cervix uteri, 311-314 endometrium, 314 epidemiology, 308 glans penis, 314-315 vulva and vagina, 309-311 German measles, see Rubella Gerstmann-Straussler-Scheinker disease, see also Transmissible spongiform encephalopathy clinical features, 414 pathological features, 415-417 Gianotti-Crosti syndrome, features, 271-272 Giant cell pneumonia mumps virus, 400^02 parainfluenza virus, 49-50 respiratory syncytial virus, 55 Gingivostomatitis, herpes simplex virus, 65 Glomerulonephritis, hepatitis virus association, 272-273 GSS, see Gerstmann-Straussler-Scheinker disease Guanarito virus, hemorrhagic fever, 280

H Hairy leukoplakia, Epstein-Barr virus association, 136-138 Hantaan virus, Korean hemorrhagic fever, 282-284 Hantavirus hemorrhagic fever with renal disease epidemiology, 282 Hantaan virus and Korean hemorrhagic fever, 282-284 Puumala virus and nephropathia endemica, 284-285 Seoul virus, 282-284 strains, 297

443 Hantavirus pulmonary syndrome clinical features, 298 epidemiology, 297 origins, 297 pathology 298-299, 301 Heart adenovirus disease, 197 AIDS-associated disease, 226-227 congenital rubella effects, 394 cytomegalovirus disease, 105-106 enterovirus diseases Coxsackievirus group B myocarditis, 13-16, see Coxsackievirus diagnostic criteria, 10-13 epidemiology, 10 Epstein-Barr virus and infectious mononucleosis, 123 influenza virus disease, 41-44 Hematopoietic system, human immunodeficiency virus infection effects, 215 Hemophagocytic syndrome, Epstein-Barr virus, 138-139 Hemorrhagic fever viruses, see also specific viruses arenaviruses, 277-282 bunyaviruses, 282-287 tiloviruses, 287-289 flaviviruses, 289-293 overview, 277 Hepatitis virus autoimmune hepatitis features, 270 chronic hepatitis diagnosis, 262 pathology 263-264 Gianotti-Crosti syndrome features, 271-272 glomerulonephritis association, 272-273 hepatitis A virus clinical features of disease, 254-255 epidemiology 254 pathogenesis, 255 structure, 254 hepatitis B virus discovery, 257 pathogenesis, 257-260 structure, 257 transmission, 258 hepatitis C virus clinical features of disease, 261-262 epidemiology, 261 immune response, 260-261 liver transplantation in treatment, 262 mixed cryoglobulinemia association, 262 structure, 260 hepatitis D virus, replication and clinical features of infection, 260 hepatitis E virus clinical features of disease, 256 epidemiology, 256 structure, 255 hepatocellular carcinoma association, 264, 267, 269 history of study 253-254

444 Hepatocellular carcinoma, hepatitis virus association, 264, 267, 269 Herpes simplex virus, see also Herpesvirus digestive tract disease, 76-77 encephalitis diagnosis, 71-72 distribution in brain, 72-73 epidemiology, 71 immunocompromised patients, 74 seizures, 74-75 treatment, 71-72 eye disease, 78-81 generalized systemic disease, 69-71 genital disease females, 66-68 males, 69 genome, 61 gingivostomatitis, 65 liver disease, 77-78 lymph node disease, 78 respiratory tract disease, 75-76 skin lesions, 65-66 Herpesvirus, see also Cytomegalovirus; Epstein-Barr virus; Herpes simplex virus; Human herpesvirus type 6; Kaposi's sarcoma-associated herpesvirus; Varicella-zoster virus classification, 61 cytopathology, 63 herpes B, 187-188 latency 62-63 replication, 61-62 structure, 61 Herpes zoster epidemiology 151-152 latency, 152 pathology 153-154 HHV, see Human herpesvirus HIV, see Human immunodeficiency virus Hodgkin's disease AIDS-associated disease, 232 Epstein-Barr virus role, 130-131 HPV, see Human papillomavirus HPS, see Hantavirus pulmonary syndrome HSV, see Herpes simplex virus HTLV, see Human T cell leukemia / lymphoma virus Human herpesvirus type 6 exanthema subitum, 167 immunocompromised patient infection, 167-168 pathogenicity, 167 Human herpesvirus type 8, see Kaposi's sarcoma-associated herpesvirus Human immunodeficiency virus, see also Acquired immunodeficiency syndrome; Retrovirus clinical course of HIV-1 infection adults, 207-209 children and infants, 210-211 comparison of types, 207 digestive tract diseases, 230-231 discovery, 205 epidemiology, 205-206 genome, 204, 206 heart disease, 226-227

Index hematopoietic system effects, 215 kidney disease, 228-229 lymphoma association Burkitt's lymphoma, 232 Hodgkin's disease, 232 non-Hodgkin's lymphoma, 231-232 myositis, 220-221 nervous system diseases acute meningitis, 216 dementia complex, 217-219 encephalopathy, 216-219 mechanisms of neuronal damage, 218-219 myelopathy and myelitis, 219 neuropathy, 219 origins, 205 pancreatitis, 230-231 persistent generalized lymphadenopathy nonprogressive disease, 214-215 pathogenesis, 212 stages, 213-214 receptor, 207 respiratory tract diseases diffuse alveolar damage, 222 follicular bronchitis /bronchiolitis, 222-223 lymphoid interstitial pneumonia, 222-223 nonspecific interstitial pneumonia, 222-223 pulmonary hypertension and vascular-occlusive disease, 223, 225 structure, 206-207 testicular disease, 229 ultrastructure of infected cells, tubuloreticular structures and cylindrical confronting cisternae, 231 vasculature disease, 227-228 Human papillomavirus classification, 303 digestive tract disease anus, 317 esophagus, 315-317 oropharynx, 315 E6 and E7 proteins in pathogenesis, 304-305 eye disease, 321-322 genital diseases cervix uteri, 311-314 endometrium, 314 epidemiology, 308 glans penis, 314-315 vulva and vagina, 309-311 infection cycle, 304 laryngeal papillomas, 317-319 middle ear disease, 322 skin lesions epidermodysplasia verruciformis, 307 verruca plana, 305 verruca plantaris, 305, 307 verruca vulgaris, 305 structure, 303 tracheobronchial tree papillomas, 319, 321 Human T cell leukemia/lymphoma virus, see also Retrovirus cell transformation mechanism, 245, 247

comparison between types, 243, 249 epidemiology, 243, 250 genome, 204, 243, 245, 247 HTLV-2 distribution and diseases, 243, 249-250 inflammatory conditions associated with HTLV-1 infection, 248-249 T-cell leukemia/lymphoma syndrome, HTLV-1 infection clinical course, 244-245 pathogenesis, 245, 247 transmission, 243-244 tropical spastic paraparesis, HTLV-1 infection, 247-248

I Inclusion body cells, cytomegalovirus association, 87-89 Infectious mononucleosis, see Mononucleosis Inflammatory pseudotumor, Epstein-Barr virus association, 135 Influenza virus central nervous system disease, 43 classification, 35-36 course and features of infection adults, 38-39 children, 38 epidemics, 36-38 heart disease, 4 1 ^ 4 infection route, 35-36 lung disease, 40-41 muscle disease, 43 receptors, 35 Reye-Johnson syndrome, 43-44 risk factors for infection, 39-40 salivary gland disease, 43

J Japanese B encephalitis, features, 352-353 JC virus, see also Papovavirus progressive multifocal leukoencephalopathy clinical course, 331 pathology, 330-331 viruses, 329-330 viremia, 328-329 Joint disease mumps manifestations, 386 parvovirus B19, 337 varicella-zoster virus, 162 Junin virus, hemorrhagic fever, 278-279

K Kaposi's sarcoma AIDS association, 171-172, 232-233 classification, 174-175 clinical features, 171-172, 233 lymph node involvement, 177-178

445

Index pathogenesis, 174-175,177-178 staging, 175 tissue distribution, 233-234 Kaposi's sarcoma-associated herpesvirus angiofollicular lymph node hyperplasia, 180-181 angiosarcomas and vascular lesions, 178 body cavity-based non-Hodgkin's lymphoma, 178 discovery 172-173 epidemiology 173-174, 233 Kidney AIDS-associated disease, 228-229 cytomegalovirus disease, 103 enterovirus disease, 19 Epstein-Barr virus and infectious mononucleosis, 123 glomerulonephritis, hepatitis virus association, 272-273 Hantavirus, hemorrhagic fever with renal disease epidemiology, 282 Hantaan virus and Korean hemorrhagic fever, 282-284 Puumala virus and nephropathia endemica, 284-285 Seoul virus, 282-284 varicella-zoster virus disease, 160-162 KSHV, see Kaposi's sarcoma-associated herpesvirus Kuru, see also Transmissible spongiform encephalopathy clinical features, 414^15 pathological features, 415-417

LaCrosse, features, 354 Laryngeal papillomas, human papillomavirus and cancer role, 317-319 Lassa virus, hemorrhagic fever, 280-292 Liver, see also Hepatitis virus congenital rubella effects, 394 cytomegalovirus disease, 101-102 enterovirus disease, 19 herpes simplex virus disease, 77-78 Lassa virus lesions, 280-282 varicella-zoster virus disease, 159-160 Lung adenovirus infection chronic infection, 194 disseminated disease in immunocompromised patients, 195-196 inclusion-body pneumonia, 192 late complications, 192-193 serotypes, 191,194-195 transmission, 191, 194 AIDS-associated diseases diffuse alveolar damage, 222 follicular bronchitis / bronchiolitis, 222-223 lymphoid interstitial pneumonia, 222-223 nonspecific interstitial pneumonia, 222-223

pulmonary hypertension and vascular-occlusive disease, 223, 225 cytomegalovirus disease course, 97-99 immunocompromised patients, 96, 99 lesions, 99-100 pneumonia models, 99 enterovirus disease, 18 Epstein-Barr virus disease, 134-135 herpes simplex virus disease, 75-76 influenza virus disease, 4 0 ^ 1 mumps giant cell pneumonia, 400^02 mortality 399^00 persistence, 399, 401 parainfluenza virus disease, 47-50 respiratory syncytial virus disease, 53-58 rhinovirus disease, 31-32 varicella-zoster virus disease, 158-159 Lymph node, see also Angiofollicular lymph node hyperplasia; Persistent generalized lymphadenopathy herpes simplex virus disease, 78 Kaposi's sarcoma involvement, 177-178 lymphadenitis in vaccination by vacciniavirus, 373 Lymphocytic choriomeningitis virus aseptic meningitis, 427 isolation, 427 pathogenicity in humans, 427-428 rodent hosts, 428 structure, 427 Lymphoepitheliomatous gastric carcinoma, Epstein-Barr virus role, 133 Lymphoid interstitial pneumonia, AIDS-associated disease, 222-223 Lymphomatoid granulomatosis, Epstein-Barr virus association, 135

M Machupo virus, hemorrhagic fever, 278-279 Marburg virus disease, hemorrhagic fever, 287 Measles virus atypical measles syndrome following vaccination, 402-403 central nervous system disease, see Meningoencephalitis meningoencephalitis, 404-404 overview of syndromes, 403 subacute sclerosing panencephalitis, 404-407 classification, 398-399 epidemiology, 397 eye disease, 407 immune response, 397-398 immunosuppression, 399 isolation, 399 lesions, 397 middle ear disease, 407 pregnancy effects, 407-408 respiratory tract disease giant cell pneumonia, 400-402 mortality 399-400 persistence, 399, 401 structure, 399

Meningoencephalitis, 403-404 immunized patients, 404 immunocompromised patients, 403-404 natural infection, 403 Meningitis enterovirus disease, 3-4 human immunodeficiency virus association, 216 lymphocytic choriomeningitis virus, 427 Milker's nodules, cowpox, 377 Molluscum contagiosum, features, 377-378 Monkeypox virus discovery, 373 epidemiology, 365, 374 modern threat, 374 Mononucleosis cytomegalovirus association, 93 Epstein-Barr virus and infectious mononucleosis clinical features, 120 discovery of viral etiology, 117 female genital tract, 123 kidney disease, 123 lymph node pathology, 120-121 myocarditis, 123 neuromuscular disease, 122-123 pancreatitis, 123 pericarditis, 123 Mumps central nervous system disease, 382 clinical course, 381-382 diabetes mellitus, role in type 1 disease, 385-386 ear disease, 386 history 381 joint disease, 386 pancreatic disease, 384-385 salivary gland disease, 382 testicular disease, 383-384 virus features, 381 Muscle influenza virus disease, 43 myositis in AIDS, 220-221 striated muscle disease, enterovirus, 16-17 varicella-zoster virus disease, 162 Myocarditis, see Heart

N Nasopharyngeal carcinoma, Epstein-Barr virus role, 131-133 Nervous system disease, see also Encephalitis; Transmissible spongiform encephalopathy adenovirus, central nervous system disease, 197-198 congenital rubella effects on central nervous system, 393-394 cytomegalovirus disease adults, 94-95 children, 93-94 immunocompromised patients, 95-96 enterovirus diseases aseptic meningitis, 3-4

446 chronic enterovirus meningoencephalitis in immune deficiency, 8-10 encephalitis, 4 poliomyelitis, 4-6 post-poliomyelitis syndrome, 6, 8 Epstein-Barr virus and infectious mononucleosis, 122-123 human immunodeficiency virus association acute meningitis, 216 dementia complex, 217-219 encephalopathy, 216-219 mechanisms of neuronal damage, 218-219 myelopathy and myelitis, 219 neuropathy, 219 influeiLza virus, central nervous system disease, 43 measles, see Meningoencephalitis meningoencephalitis, 403-404 overview of syndromes, 403 subacute sclerosing panencephalitis, 404-407 mumps manifestations, 382 rabies, 360-362 varicella-zoster virus diseases encephalopathies, 145-156 herpes zoster, 151-154 NHL, see Non-Hodgkin's lymphoma NLVs, see Norwalk-like viruses Non-Hodgkin's lymphoma AIDS-associated disease, 231-232 Epstein-Barr virus role, 129-130 Kaposi's sarcoma-associated herpesvirus and body cavity-based lymphomas, 178 Nonspecific interstitial pneumonia, AIDS-associated disease, 222-223 Norwalk-like viruses clinical course of infection, 432-433 discovery, 431 epidemiology, 432 pathology, 433 structure and classification, 432 NPC, see Nasopharyngeal carcinoma

Pancreas AIDS-associated disease, 230-231 congenital rubella effects, 394 cytomegalovirus disease, 102 Epstein-Barr virus and infectious mononucleosis, 123 mumps manifestations, 384-385 Papillary acrodermatitis, see Gianotti-Crosti syndrome Papillomavirus, see Human papillomavirus Papovavirus, see also BK virus; JC virus; SV40 infection cycle, 327-328 structure, 327 Parainfluenza virus classification, 47 discovery, 47

Index giant cell pneumonia, 49-50 respiratory infections, 47-48 Sendai virus infection in mice, 48 Parvovirus B19 epidemiology, 335 erythropoietic systemic disease, 337-339 fifth disease, 335-337 infection course, 336 inflammatory lesions, 340 joint disease, 337 pregnancy infections, 339-340 structure, 335 tissue diagnosis of infection, 340 Penis, see Genitals Pericarditis, Epstein-Barr virus and infectious mononucleosis, 123 Persistent generalized lymphadenopathy nonprogressive disease, 214-215 pathogenesis, 212 stages, 213-214 PGL, see Persistent generalized lymphadenopathy Placenta cytomegalovirus disease, 92 enterovirus disease, 19-20 PML, see Progressive multifocal leukoencephalopathy Poliovirus, see also Enterovirus classification, 1 poliomyelitis, 4-6 post-poliomyelitis syndrome, 6, 8 receptor, 2 Post-poliomyelitis syndrome, see Poliovirus Posttransfusion syndrome, cytomegalovirus association, 93 Poxvirus cowpox virus, 365, 371, 377 molluscum contagiosum, 377-378 monkeypox virus discovery, 373 epidemiology, 365, 374 modern threat, 374 orthopoxviruses, 365-367, 369, 371-375 parapoxviruses, 375, 377 replication, 366 smallpox clinical course, 367, 369 modem threat, 365 mortality 367, 369, 371 transmission, 367 structure, 366 vacciniavirus complications of vaccination, 371-373 development of virus, 371 dissemination, 365 epidermal proliferation, 366 Pregnancy complications in vaccination by vacciniavirus, 373 congenital infection cytomegalovirus, 90, 92 rubella, 391-394, see Rubella varicella-zoster virus, 162-163 measles effects, 407-408 parvovirus B19 infection, 339-340 Prion disease, see Transmissible spongiform encephalopathy

Progressive multifocal leukoencephalopathy clinical course, 331 JC virus role, 329-330 pathology 330-331 SV40 role, 327, 329-330 Pulmonary hypertension, vascular-occlusive disease in AIDS, 223, 225 Puumala virus, nephropathia endemica, 284-285

R Rabies central nervous system disease, 360-362 clinical forms, 358-359 epidemiology, 357-358 immunization, 357 pathogenesis, 359-360 viruses classification, 357 structure, 357 Respiratory syncytial virus classification, 53 epidemiology, 53, 57 immune-mediated disease, 54-55 risk factors for infection, 53, 55-56 symptoms of infection, 57-58 Retrovirus, see also Human immunodeficiency virus; Human T cell leukemia/lymphoma virus classification, 203 genomes, 204 Reye-Johnson syndrome, influenza virus association, 43-44 Rhinovirus cell distribution, 29-30, 32 classification, 29 discovery, 29 diseases, 31-32 receptors, 29 symptoms of infection, 31 Rift Valley fever virus, hemorrhagic fever, 285-286 Rotavirus clinical features of infection, 434-435 epidemiology, 433-434 pathology 435, 437 structure and classification, 434 RSV, see Respiratory syncytial virus Rubella congenital infection central nervous system effects, 393-394 fetal growth effects, 391 heart effects, 394 liver effects, 394 organ malformations, 392 pancreas effects, 394 persistence, 392 timing and organ abnormalities, 391 history of study 389 postnatal infection features, 390 virus classification and structure, 389 isolation and culture, 389-390 Rubeola, see Measles virus

447

Index

Sabia virus, hemorrhagic fever, 280 St. Louis encephalitis, features, 351-352 Salivary gland influenza virus disease, 43 mumps manifestations, 382 Sjogren's syndrome, Epstein-Barr virus infection in tumors, 135-136 Scrapie, features, 412 Sendai virus, see Parainfluenza virus Seoul virus, hemorrhagic fever, 282-284 Shingles, see Herpes zoster Sinusoidal tumor, Epstein-Barr virus role, 133-134 Sixth disease, see Exanthema subitum Sjogren's syndrome, Epstein-Barr virus infection in salivary gland tumors, 135-136 Skin, see also Measles virus; Poxvirus enterovirus lesions, 20-21 herpes simplex virus lesions, 65-66 human papillomavirus lesions epidermodysplasia verruciformis, 307 verruca plana, 305 verruca plantaris, 305, 307 verruca vulgaris, 305 parvovirus B19 and fifth disease, 335-337 varicella-zoster virus infection chickenpox (see Chickenpox), 147-148 chronic skin infections, 150-151 hemorrhagic skin infections, 149-150 Smallpox clinical course, 367, 369 modern threat, 365 mortality, 367, 369, 371 transmission, 367 Striated muscle, enterovirus disease, 16-17 Subacute sclerosing panencephalitis, mumps association, 404-407 SV40, human infection, 327, 329-330

T-cell leukemia/lymphoma syndrome, HTLV-1 infection clinical course, 244-245 pathogenesis, 245, 247 Testicles AIDS-associated disease, 229 enterovirus disease, 18-19 mumps manifestations, 383-384 varicella-zoster virus disease, 162 Tracheobronchial tree, human papillomavirus papillomas, 319, 321

Transmissible spongiform encephalopathy clinical features Creutzfeldt-Jacob disease, 413^14 fatal familial insomnia, 415 Gerstmann-Straussler-Scheinker disease, 414 kuru, 414^15 diagnosis by nonhistopathological methods, 424 history of study, 411 iatrogenic Creutzfeldt-Jacob disease, 422 new variant Creutzfeldt-Jacob disease, 421^22 pathological features, 415^17 prion-related protein accumulation in plaques, 418-419 mutations, 419 physical properties, 417-418, 422 structure, 417 properties, 411 safety precautions for pathologists, 422-424 scrapie, 412 species specificity, 411-412 Transplant recipient cytomegalovirus infection, 88, 96 liver transplantation in hepatitis B treatment, 262 Tropical spastic paraparesis, HTLV-1 infection, 247-248 TSP, see Tropical spastic paraparesis Tubuloreticular structures, human immunodeficiency virus-infected cells, 231

Varicella-zoster virus, see also Herpesvirus chickenpox clinical features, 147-148 course, 148-149 immune response, 148 transmission, 148 chronic skin infections, 150-151 congenital infection, 162-163 digestive tract disease, 159 ear disease, 158 eye disease, 156-158 hemorrhagic skin infections, 149-150 historical overview, 147 joint disease, 162 kidney disease, 160-162 liver disease, 159-160 lung disease, 158-159 muscle disease, 162 nervous system diseases encephalopathies, 154-156 herpes zoster, 151-154 testicular disease, 162 Variola, see Smallpox Vasculature, AIDS-associated disease, 227-228 vCJD (new variant Creutzfeldt-Jacob disease), 421-422 Venezuelan equine encephalitis, features, 348-349 Venezuelan hemorrhagic fever, see Guanarito virus

w

u Urinary tract, see also Kidney adenovirus disease, 196-197 BK virus infection and disease, 331, 333 cytomegalovirus disease, 102-103

West African hemorrhagic fever, see Lassa virus Western equine encephalitis, features, 347-348

X-linked lymphoproliferative disease, Epstein-Barr virus infection, 123-124 Vacciniavirus con\plications of vaccination central nervous system, 373 lymphadenitis, 373 pregnancy, 373 systemic complications, 371-373 development, 371 dissemination, 365 epidermal proliferation, 366

Yellow fever virus clinical phases of illness, 291 epidemiology, 290-291 history of study 290-291 pathology, 291-292

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