42 Infections in Hemopoietic Stem Cell Transplant Recipients RAFIK SAMUEL, ALLAN L. TRUANT, AND BYUNGSE SUH COORDINATING...
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42 Infections in Hemopoietic Stem Cell Transplant Recipients RAFIK SAMUEL, ALLAN L. TRUANT, AND BYUNGSE SUH COORDINATING EDITOR
ALLAN L. TRUANT
Cumitech CUMULATIVE TECHNIQUES AND PROCEDURES IN CLINICAL MICROBIOLOGY
Cumitech 1B
Blood Cultures III
Cumitech 2B
Laboratory Diagnosis of Urinary Tract Infections
Cumitech 3A
Quality Control and Quality Assurance Practices in Clinical Microbiology
Cumitech 5A
Practical Anaerobic Bacteriology
Cumitech 6A
New Developments in Antimicrobial Agent Susceptibility Testing: a Practical Guide
Cumitech 7B
Lower Respiratory Tract Infections
Cumitech 12A
Laboratory Diagnosis of Bacterial Diarrhea
Cumitech 13A
Laboratory Diagnosis of Ocular Infections
Cumitech 16A
Laboratory Diagnosis of the Mycobacterioses
Cumitech 18A
Laboratory Diagnosis of Hepatitis Viruses
Cumitech 19A
Laboratory Diagnosis of Chlamydia trachomatis Infections
Cumitech 21
Laboratory Diagnosis of Viral Respiratory Disease
Cumitech 23
Infections of the Skin and Subcutaneous Tissues
Cumitech 24
Rapid Detection of Viruses by Immunofluorescence
Cumitech 25
Current Concepts and Approaches to Antimicrobial Agent Susceptibility Testing
Cumitech 26
Laboratory Diagnosis of Viral Infections Producing Enteritis
Cumitech 27
Laboratory Diagnosis of Zoonotic Infections: Bacterial Infections Obtained from Companion and Laboratory Animals
Cumitech 28
Laboratory Diagnosis of Zoonotic Infections: Chlamydial, Fungal, Viral, and Parasitic Infections Obtained from Companion and Laboratory Animals
Cumitech 29
Laboratory Safety in Clinical Microbiology
Cumitech 30A
Selection and Use of Laboratory Procedures for Diagnosis of Parasitic Infections of the Gastrointestinal Tract
Cumitech 31
Verification and Validation of Procedures in the Clinical Microbiology Laboratory
Cumitech 32
Laboratory Diagnosis of Zoonotic Infections: Viral, Rickettsial, and Parasitic Infections Obtained from Food Animals and Wildlife
Cumitech 33
Laboratory Safety, Management, and Diagnosis of Biological Agents Associated with Bioterrorism
Cumitech 34
Laboratory Diagnosis of Mycoplasmal Infections
Cumitech 35
Postmortem Microbiology
Cumitech 36
Biosafety Considerations for Large-Scale Production of Microorganisms
Cumitech 37
Laboratory Diagnosis of Bacterial and Fungal Infections Common to Humans, Livestock, and Wildlife
Cumitech 38
Human Cytomegalovirus
Cumitech 39
Competency Assessment in the Clinical Microbiology Laboratory
Cumitech 40
Packing and Shipping of Diagnostic Specimens and Infectious Substances
Cumitech 41
Detection and Prevention of Clinical Microbiology Laboratory-Associated Errors
Cumitech 42
Infections in Hemopoietic Stem Cell Transplant Recipients
Cumitechs should be cited as follows, e.g.: Samuel, R., A. L. Truant, and B. Suh. 2005. Cumitech 42, Infections in Hemopoietic Stem Cell Transplant Recipients. Coordinating ed., A. L. Truant. ASM Press, Washington, D.C. Editorial board for ASM Cumitechs: Alice S. Weissfeld, Chair; Maria D. Appleman, Vickie Baselski, B. Kay Buchanan, Mitchell l. Burken, Roberta Carey, Linda Cook, Lynne Garcia, Mark LaRocco, Susan L. Mottice, Michael Saubolle, David L. Sewell, Daniel Shapiro, Susan E. Sharp, James W. Snyder, Allan Truant. Effective as of January 2000, the purpose of the Cumitech series is to provide consensus recommendations regarding the judicious use of clinical microbiology and immunology laboratories and their role in patient care. Each Cumitech is written by a team of clinicians, laboratorians, and other interested stakeholders to provide a broad overview of various aspects of infectious disease testing. These aspects include a discussion of relevant clinical considerations; collection, transport, processing, and interpretive guidelines; the clinical utility of culture-based and non-culture-based methods and emerging technologies; and issues surrounding coding, medical necessity, frequency limits, and reimbursement. The recommendations in Cumitechs do not represent the official views or policies of any third-party payer. Copyright © 2005 ASM Press American Society for Microbiology 1752 N Street NW Washington, DC 20036-2904 All Rights Reserved 10 9 8 7 6 5 4 3 2 1
Infections in Hemopoietic Stem Cell Transplant Recipients Rafik Samuel Section of Infectious Diseases, Temple University School of Medicine, Philadelphia, PA 19140
Allan L. Truant Clinical Microbiology, Immunology, and Virology Laboratories, Temple University Hospital and School of Medicine, Philadelphia, PA 19140
Byungse Suh Section of Infectious Diseases, Temple University School of Medicine, Philadelphia, PA 19140
COORDINATING EDITOR: Allan L. Truant Clinical Microbiology, Immunology, and Virology Laboratories, Temple University Hospital and School of Medicine, Philadelphia, PA 19140
Introduction . . . . . . . . . . . . . . . . . . . Use of Immunosuppressive Agents GVHD . . . . . . . . . . . . . . . . . . . . . . . . Timetable for Infections . . . . . . . . . Immunizations . . . . . . . . . . . . . . . . . Infections . . . . . . . . . . . . . . . . . . . . .
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Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Mycoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Parasitic Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
INTRODUCTION
There are several different types of HSCT. In autologous transplantation, patients function as their own donors; syngeneic transplantation involves identical twins (monozygotic) as donor and recipient; and allogeneic transplantation uses HLA-matched donors of related or unrelated origin. For the last category, donors may be an HLA type that is genotypically identical, phenotypically identical, or nonidentical. The total number of blood and marrow transplants worldwide approaches approximately 45,000 annually, in which autologous and allogeneic represent 30,000 and 15,000, respectively (197). Today, HSCT is widely employed not only in the management of malignant diseases but also in autoimmune and genetic disorders. Major problems of HSCT, contributing to mortality and morbidity, include relapse
A
n early attempt to utilize bone marrow transplantation, more recently termed hemopoietic stem cell transplantation (HSCT), for the therapeutic purpose of treating terminally ill patients with lympho- or myeloproliferative disorders was carried out in the late 1950s (338). This study was based on animal studies indicating that totally ablated bone marrow could be repopulated by the intravenous infusion of a cellular suspension of healthy marrow of the same species (66, 244). Although initial mortality was unacceptably high, since that time many studies have contributed to improve the outcomes of HSCT therapy, both in mortality and morbidity. 1
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of underlying disease, graft-versus-host disease (GVHD), infections, and multiorgan failure. In general, recipients of better-matched hemopoietic stem cells have fewer complications following an HSCT procedure. Autologous HSCT recipients, for example, have no complications of GVHD. Overall, relapse of underlying diseases contributes to 21 to 78% of the mortality, while infections and GVHD are responsible for 5 to 21% and 15% of deaths in HSCT recipients, respectively (197). This review will focus on infectious complications frequently encountered in HSCT recipients. HSCT recipients are more prone to develop infections than the normal population because all HSCT recipients must undergo profound immunosuppressive treatment regardless of the type of transplantation they are going to receive: autologous, syngeneic, or allogeneic. Prior to transplantation, HSCT recipients, except children with severe combined immunodeficiency syndrome, must receive a conditioning procedure. The conditioning regimen may involve the use of cytotoxic agents (e.g., cyclophosphamide, busulphan, melphalan, or thiotepa), with or without radiation, which lead to a profound immunosuppression. This step is necessary to remove as many pathologic cells as possible and to suppress the immunologic ability of recipients to reject transfused cells. This causes transient but severe neutropenia, qualitative defects in phagocytosis, and pronounced defects in both humoral and cellular immunity. In addition, varying degrees of mucositis are inevitable side effects of the conditioning regimen. The combination of neutropenia, defects in immunity, and mucositis induced by conditioning procedures predisposes HSCT recipients to various bacterial, viral, fungal, and parasitic infections. In addition, many HSCT recipients, due to underlying diseases and GVHD, require continued use of immunosuppressive and/or chemotherapeutic agents beyond the conditioning period on a long-term basis, which puts these patients at added risk of infections. The guidelines for preventing opportunistic infections among HSCT recipients by the Centers for Disease Control and Prevention (CDC), the Infectious Diseases Society of America (IDSA), and the American Society of Blood and Marrow Transplantation (47) provided a solid foundation for this review. Various infectious complications commonly observed in the first year following HSCT, the period in which recipients are most vulnerable to opportunistic infections, are depicted in Fig. 1. The most commonly encountered individual infections with selected diagnostic methods and therapeutic regimens are described herein. This review, however, will not detail all of the available manual, automated, and commercially available methods of identification for each pathogen. These procedures and methods can be
CUMITECH 42
reviewed in detail in the Manual of Clinical Microbiology (233), the Manual of Clinical Laboratory Immunology (286), the Manual of Commercial Methods in Clinical Microbiology (346), and the Clinical Microbiology Procedures Handbook (157a), all of which are published by ASM Press.
USE OF IMMUNOSUPPRESSIVE AGENTS Preparation for HSCT requires both a conditioning procedure and ongoing suppression of the immune system to prevent rejection of the transfused cells. Multiple immunosuppressive agents are currently being used. It is important to understand the mode of action of these agents, since they affect the immune system differently and may result in increased or even decreased risk of various infections. Total body irradiation, used to prime a patient for HSCT, may lead to mucositis, lung injury, and even delayed immune reconstitution. Inflamed mucosal surfaces may lead to an increased risk of bacteremia or primary varicella-zoster virus (VZV) infection. There may be an increased risk of cytomegalovirus (CMV) pneumonitis if radiation therapy results in mediastinal injury (44). Azathioprine (Imuran) is a derivative of mercaptopurine that suppresses intracellular inosinic acid synthesis, resulting in decreased purine metabolism and synthesis of DNA, RNA, and proteins (387). A resultant decrease in the number of circulating B and T lymphocytes, reduced immunoglobulin synthesis, and diminished interleukin-2 (IL-2) secretion follows (345). Azathioprine typically leads to an increased number of viral infections, including varicella-zoster infection (318). Corticosteroids have an inhibitory effect on many aspects of the immune system. Once glucocorticoids enter the nucleus of cells, they recruit factors that lead to a release of antiinflammatory mediators and inhibition of many cytokines. As a result, phagocytic cells are less effective and circulating T cells are rapidly depleted. B cells are not significantly affected acutely, but with chronic use, immunoglobulin G (IgG) and IgA levels are decreased (99). All of these factors lead to a significantly increased risk of infection, specifically those related to cellular immunity (332). Cyclosporine (Neoral) and tacrolimus (Prograf) selectively inhibit transcription of IL-2, decreasing circulating helper T cells, suppressor T cells, and cytotoxic T cells (169, 218, 372). Both of these agents also inhibit human prolactin production. Since prolactin is an immune activator, this may have an added cytokine inhibitory effect. These agents have been shown to increase the risk of Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorders (18).
CUMITECH 42
Infections in Hemopoietic Stem Cell Transplant Recipients
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FIGURE 1. Phases of opportunistic infections among allogeneic HSCT recipients (47). Reprinted from reference 47. Pneumocystis carinii has been reclassified as P. jiroveci.
Mycophenolate mofetil (Cellcept) is a prodrug of mycophenolic acid that is a noncompetitive inhibitor of inosine monophosphate. This agent results in an antiproliferative effect on lymphocytes (154). A higher incidence of CMV disease has been noted in patients receiving this agent (299). On the other hand, mycophenolate has potent activity against Pneumocystis jiroveci (250). Sirolimus (Rapamune) is a macrolide that blocks translation of mRNA, leading to decreased cell division. Sirolimus is usually used along with cyclosporine for a synergistic effect on lymphocyte depletion. There is no associated increased risk of CMV disease when this agent is used (154). Sirolimus is fungicidal in vitro against Cryptococcus neoformans and inhibits Candida albicans, Aspergillus spp., and Fusarium spp. (67, 154). Monoclonal antibodies are agents that bind specific receptors critical to immune system function. The earliest agent in use, muromonab CD3 (OKT3), did not have specific targets, which resulted in a more global immunosuppression that led to a high
risk of toxicity and opportunistic infections. Recently, more specific monoclonal antibodies have been developed. These include basiliximab (Simulect) and daclizumab (Zenapax), which are antibodies against the IL-2 receptor and lead to inhibition of T-cell proliferation. There is no associated increased risk of infection with these newer agents (154, 236, 353).
GVHD One of the most feared complications in HSCT recipients is GVHD. This occurs when the transplanted leukocytes recognize the transplant recipient’s body as foreign and damage the organs. This syndrome may occur in up to 50% of allogeneic HSCT recipients. If GVHD occurs in the first 100 days after transplant, it is termed acute. If GVHD occurs after 100 days, it is termed chronic. Development of moderate to severe GVHD has been shown to decrease patient survival and increase risk of infection (354). Acute GVHD manifests in damage to the skin, liver, gastrointestinal tract, or lymphoid tissue. Chronic
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GVHD typically results in damage to the skin, liver, gastrointestinal tract, or lungs. Diagnosis is made clinically along with pathology to confirm the diagnosis (52). Once the patient develops GVHD, the immunosuppressive agents mentioned in the previous section may be added or their doses increased, resulting in increased risk of infections (described elsewhere in this review).
TIMETABLE FOR INFECTIONS After HSCT, the type of transplant received, the agents used in the transplant conditioning, and the presence of GVHD each influence the risk for various infections. It is customary to divide the posttransplant course into three phases defining different infection risks (47) (Fig. 1). These phases are generally termed the preengraftment phase (30 days), the postengraftment phase (30 to 100 days), and the late phase (100 days). During the first 30 days after HSCT (the preengraftment phase), patients develop neutropenia and require indwelling catheters. During this time period, organisms colonizing the gastrointestinal tract, skin, and oropharynx can cause infections. If the neutropenia is prolonged, additional organisms such as fungi can cause serious infections. In addition, organisms such as herpes simplex virus can reactivate. The period including days 30 to 100 is associated with significant cell-mediated dysfunction. Viruses and fungi play a major role in causing infections during this time. For example, infections caused by the herpesviruses (including CMV), P. jiroveci, and Aspergillus spp. can lead to significant morbidity and mortality. The extent of cellular immune dysfunction is significantly affected by GVHD and its resultant treatment if present. After day 100, immune system activity starts to differ depending on the type of transplant received. Autologous HSCT recipients usually have quicker recovery of their immune system and are at lower risk of infections compared to allogeneic HSCT recipients. Viruses that play an important role in the post-100-day period include the herpesviruses and the community respiratory viruses. Bacteria that play an increased role include Haemophilus influenzae and Streptococcus pneumoniae, secondary to impaired reticuloendothelial system function and humoral immunity defects.
IMMUNIZATIONS Immunization, one of the most significant milestones in preventive medicine, is the most effective means of reducing mortality and morbidity due to a variety of infectious agents. Immunization is divided into two
CUMITECH 42
major categories, active and passive. Active immunization involves the administration of a vaccine, which causes the host to develop immunity to the agent contained in the vaccine. Vaccines are available in several different forms: attenuated live, inactivated whole organism, cellular subunit or component, or toxoid. Passive immunization, on the other hand, consists of the administration of preformed antibodies that are protective against the disease in consideration. Passive immunization is accomplished by either intramuscular or intravenous injection of immunoglobulin. In general, active immunization results in long-term protection lasting several decades to a lifetime, mimicking the immunity following natural infection; however, it takes time to produce protective levels of immunity. Immunization with attenuated live vaccine produces longer-term protection than inactivated or toxoid preparation. Passive immunization produces immediate protection, but the immunity is brief and is most often used to prevent the onset of clinical disease either following exposure or prior to anticipated exposure. Infection is a major problem in HSCT recipients, contributing substantially to mortality and morbidity, thus frequently determining the final outcomes of these patients’ diseases. As indicated earlier, HSCT recipients undergo multiple therapeutic modalities that disrupt cellular as well as humoral immunity. Conditioning procedures during the preengraftment period and administration of immunosuppressive agents to prevent acute and chronic GVHD during the postengraftment period cause a significant degree of immune suppression. HSCT recipients, therefore, have a qualitatively and quantitatively diminished level of immune function, and respond to antigenic challenge poorly and unpredictably. Also, antibody titers to vaccine-preventable diseases are known to decline during the 1 to 4 years after transplantation (129, 194, 196, 258, 259) unless revaccinated. HSCT recipients should be routinely revaccinated after HSCT. It is also known that immunity to some infectious diseases in HSCT donors could be transferred to recipients (190). To maximize protection of the recipient against vaccine-preventable infections, the donor’s vaccination status should be as complete as possible before donating the bone marrow cells. A national survey of transplantation centers participating in the National Marrow Donor Program during 1994 (143) led to the national guidelines for optimal doses and timing of vaccinations for HSCT recipients (143). These were published in 2000 under the cosponsorship of the CDC, the IDSA, and the American Society of Blood and Marrow Transplantation (47). The efficacy of recommended vaccinations, for the most part, has not been well studied. A modified vaccination schedule published in the guidelines is
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Infections in Hemopoietic Stem Cell Transplant Recipients
shown in Table 1. Further information on immunization in HSCT is available (47). The recovery rate of the immune system after HSCT varies depending on the type of HSCT performed; therefore, vaccination schedules should ideally be individualized. However, scientific data are still insufficient; hence the same schedule is recommended for all HSCT recipients. Vaccinations of family members, household contacts, and healthcare workers of HSCT recipients are also recommended to minimize the transmission of vaccinepreventable disease from these groups to recipients. Vaccines considered appropriate for this purpose would include, but are not limited to, hepatitis A, influenza, polio, measles-mumps-rubella, and varicella (44). For HSCT recipients who contemplate traveling to areas where vaccine-preventable infections are endemic before a complete recovery of immune status (24 months), only inactivated vaccines and immunoglobulin are recommended. These would include meningococcal, inactivated polio, and immunoglobulin for hepatitis A. Information on the protective efficacy in HSCT recipients of these vaccinations is quite limited, and if feasible it would be best to delay travel until recovery is complete. If, however, the travel cannot be avoided, and the risk for vaccinepreventable disease is high, proceed with vaccinations as mentioned above and other vaccinations such as hepatitis A, meningococcal, parenteral typhoid fever, Japanese B encephalitis, and rabies, depending on the risk. It is advised that no live vaccines be administered, such as Mycobacterium bovis BCG, oral typhoid vaccine, varicella, or yellow fever. More information on travel can be obtained from the CDC’s automated hotline at (404) 332-4559 or on the Internet at http://www.cdc.gov.
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Passive immunizations are available for HSCT recipients who were exposed to certain vaccinepreventable diseases (47). These preparations include hepatitis B immunoglobulin for parenteral or mucous exposure to hepatitis B virus; human rabies immunoglobulin for a high-risk rabies exposure; respiratory syncytial virus (RSV) immunoglobulin for ill patients with upper or lower respiratory infections suspected of RSV infection; tetanus immunoglobulin for high-risk tetanus exposure; varicella-zoster immunoglobulin (VZIG) after close contact with a person with varicella or shingles; intramuscular immunoglobulin after exposure to hepatitis A or measles exposure; and intravenous immunoglobulin for severe hypogammaglobulinemia.
INFECTIONS Bacterial Infections Many bacterial species can cause significant morbidity and mortality in HSCT recipients. This section will focus on those infectious agents that cause disease at an increased rate in HSCT recipients compared to the general population. These include mycobacterial infections and infections due to Listeria monocytogenes, Legionella pneumophila, Nocardia spp., and Rhodococcus equi. Other bacterial infections seen less commonly in HSCT recipients are mentioned briefly. Mycobacterial Infections Mycobacterial infections may occur in HSCT recipients and have been reported extensively (3, 41, 113, 117, 174, 176, 237, 289). The incidence of mycobacterial infections in HSCT recipients is 0.006 to 3.3%.
Table 1. Recommended vaccinations for HSCT recipients, including both allogeneic and autologous recipientsa Vaccination at indicated time after HSCT Vaccine or toxoid Inactivated vaccine or toxoid Tetanus, diphtheria (Td), pertussis (DTP) Children aged 7 years Children aged 7 years H. influenzae type b conjugate Hepatitis B (HepB) 23-valent pneumococcal polysaccharide (PPV23) Inactivated polio (IPV) Influenza
Live-attenuated vaccine Measles-mumps-rubella (MMR) Varicella vaccine a
12 mo
14 mo
24 mo
DTP or DT Td Hib conjugate HepB PPV23 IPV Lifelong, seasonal administration, beginning before HSCT and resuming at 6 months after HSCT
DTP or DT Td Hib conjugate HepB
DTP or DT Td Hib conjugate HepB PPV23 IPV
IPV
MMR Contraindicated for HSCT recipients
Adapted from reference 47. Td, adult tetanus combined with diphtheria; DT, pediatric tetanus and diphtheria vaccine; DTP, pediatric diphtheria, tetanus, and pertussis.
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It is slightly higher than in the general population but much lower than in human immunodeficiency virus (HIV)-infected patients or solid organ transplant recipients. The largest study reporting on mycobacterial infections is from the University of Minnesota (289). This study reported on 2,241 patients who were followed over a 20-year period. The investigators identified two patients with infections due to Mycobacterium tuberculosis, two with Mycobacterium avium complex, and nine with rapidly growing mycobacterial species. Mycobacterial infections in HSCT often have atypical presentations. Instead of presenting with cavitary pulmonary lesions, they presented with fever, pneumonitis, osteomyelitis, and most frequently, catheter-related infections. The catheter-related infections were all caused by rapidly growing mycobacteria. Other studies confirm these results (3, 41, 113, 117, 174, 176, 237, 289). Diagnosis of mycobacterial disease is usually made by culture (broth and/or tube culture) followed by either traditional biochemical testing or DNA probe analysis for species identification (346). Molecular amplification methods are also growing in their use (particularly for diagnosis of M. tuberculosis) and may soon be available to detect point mutations responsible for antimicrobial drug resistance. Histopathology, however, may be needed to demonstrate tissue involvement. Since response to therapy varies between species, it is extremely important to accurately identify the organism and its antimicrobial susceptibilities. Treatment of mycobacterial disease in patients with HSCT is similar to treatment of those with normal immunity. Interactions of rifampin with cyclosporine and tacrolimus must be taken into consideration. Listeria monocytogenes L. monocytogenes is a motile (umbrellalike in semisolid medium), gram-positive bacillus that can be found in many different foods including meats and dairy products and is routinely cultured on standard bacteriologic culture media. Listeria is a relatively uncommon cause of infection in HSCT recipients, accounting for only 0.47% of patients evaluated in two studies (200, 294). Early clinical symptoms include fever, diarrhea, abdominal cramps, and vomiting. Almost all HSCT patients with Listeria develop bacteremia and up to two-thirds develop meningitis (320). When meningitis is present, the spectrum of symptoms is diverse, varying from personality changes to classical meningismus. Cerebrospinal fluid (CSF) findings include pleocytosis with a mixture of neutrophils and lymphocytes, elevated protein, and decreased glucose. However, these parameters may be within normal
CUMITECH 42
limits. Listeria can also cause brain abscesses or rhombencephalitis; these abscesses have a predilection for the brain stem. Mortality reaches 30% in patients with central nervous system (CNS) involvement (320). The therapy of choice for Listeria infection is high-dose ampicillin (200 mg/kg divided every 4 h), and in those with meningitis, aminoglycosides (gentamicin, 5 mg/kg divided every 8 h) should be added (85, 200). Trimethoprim-sulfamethoxazole (TMP-SMZ) (15 mg/kg divided every 6 h) is a reasonable alternative for the penicillin-allergic patient. Preventing listerial infections is highly recommended in HSCT recipients. Thorough cooking of raw meat, washing of fresh fruits and vegetables, and avoiding foods that may harbor Listeria such as unpasteurized milk, deli meats, and soft cheeses are recommended (48). Legionella Legionella spp. are fastidious, aerobic gram-negative bacilli that are ubiquitous in nature. Infections caused by Legionella in transplant recipients can be acquired either in the community or in the hospital. Outbreaks are usually related to exposure to a contaminated water source or soil. Infection can occur at any time after transplant but particularly in the first 100 days. Patients present with fever, chills, myalgias, malaise, dyspnea, and a nonproductive cough associated with pleuritic chest pain. Other symptoms include diarrhea and headache. On chest radiograph, multilobar alveolar infiltrates are found. Pleural effusions or cavities may occur. Diagnosis can be made by growing the organism in culture or by direct specimen testing. The organism is usually not seen on routine sputum Gram stain, and growing the organism is difficult due to slow growth and the requirement of supplemented media and carbon dioxide. Testing of sputum by direct fluorescent antibody staining is rapid; however, it has only 50 to 70% sensitivity but high specificity (95%). Serology may be helpful, but not in the acute phase of the disease. Detection of urine antigen by enzyme immunoassay demonstrates 85% sensitivity for Legionella pneumophila serogroup 1, but it is not available for other serogroups. Nucleic acid amplification tests, although occasionally used as a “home brew” assay, are not available commercially (346). Treatment of Legionella infection includes one of the macrolides (azithromycin, 500 mg for 1 day followed by 250 mg for 13 more days) or fluoroquinolones (levofloxacin, 500 mg daily for 14 days). Rifampin also has activity against the organism but should not be used alone. Nocardia Nocardia spp. are filamentous, branching aerobic gram-positive rods that are found in soil and decay-
CUMITECH 42
Infections in Hemopoietic Stem Cell Transplant Recipients
ing organic material. These bacteria cause infection after inhalation or inoculation of the skin. In two large studies of HSCT recipients, the rate of nocardiosis was 0.3 and 1.7% (57, 348) and it occurred between 1 and 6 months after transplantation. Approximately 90% of patients present with chronic pulmonary symptoms that include fever, productive cough, pleuritic chest pain, and dyspnea that are subacute, manifesting over one week or longer. Nocardia spp. disseminate in about one-third of the cases and usually cause disease in the CNS, skin, and soft tissue (57, 348). Diagnosis is usually made by biopsy or culture of the likely infected site. Gram stain reveals filamentous, branching, beaded gram-positive rods that also stain weakly positive by modified acid-fast stain (17). The cultures usually require more than 4 to 5 days for growth and will grow readily on mycobacterial media. Species are commonly identified biochemically and by observation of hydrolysis of acetamide, adenine, casein, esculin, hypoxanthine, tyrosine, and xanthine. Sulfonamides are the treatment of choice (TMP-SMZ, 15 to 20 mg/kg divided every 6 h); however, amikacin, imipenem, ceftriaxone, and minocycline are effective as well. Duration of treatment is 3 months for isolated pulmonary disease and more than a year for disseminated or CNS disease (222). Prevention of this disease is easily achieved with prophylactic administration of TMP-SMZ (57). Rhodococcus equi R. equi is a gram-positive coccobacillus causing disease in humans with impaired cellular immunity (270). Symptoms include fever, dyspnea, nonproductive cough, and hemoptysis. Chest X rays reveal infiltrates or nodules. The infection generally is confined to the lungs, but patients may occasionally present with disseminated disease. Blood cultures are usually positive (232, 270). The organisms grow on routine bacteriologic media within 2 to 3 days and have a characteristic salmon-colored mucoid appearance. R. equi is differentiated from other species (such as R. erythropolis, R. rhodnii, and R. rhodochrous) by pigment color, decomposition of adenine and tyrosine, and utilization of different sugars. Macrolides, ciprofloxacin, imipenem, vancomycin, and rifampin are all clinically effective. Treatment usually entails combination therapy (erythromycin, 500 mg every 6 h, and rifampin, 600 mg daily) for several months (369). Gram-Positive and Gram-Negative Bacteria Gram-positive infections caused by Enterococcus spp., Streptococcus spp., and Staphylococcus spp. have been implicated in localized postoperative infections as well as bacteremia during the postoperative period. In the long term, they also present a serious
7
concern, especially in patients with GVHD. The source of these infectious agents is usually the patient’s own flora (92). Infections caused by gramnegative organisms usually are seen in the urinary tract, gastrointestinal tract, or the biliary tract. These pathogens are commonly members of the family Enterobacteriaceae such as Escherichia coli or Klebsiella spp. Primary bacteremia may also be seen in the early posttransplant period secondary to infected invasive catheters. These may be caused by members of the Enterobacteriaceae family, or the nonfermentative gram-negative bacilli such as Pseudomonas or Acinetobacter spp. (92). Viral Infections Viruses are often grouped by their families (e.g., Herpesviridae) or by their mode of transmission (respiratory viruses). This section focuses on the herpesviruses, the community-acquired respiratory viruses, parvovirus, and polyomaviruses. There are many other viruses that have not been included in this review because they do not play a significant role in HSCT recipients (e.g., hepatitis viruses, enteroviruses, West Nile virus, the coronavirus causing severe acute respiratory syndrome (SARS), or metapneumoviruses). Herpesviridae The herpesviruses are DNA viruses that become latent in either neurons or lymphocytes. Changes in cellmediated immunity can lead to reactivation of these viruses resulting in disease. Herpes simplex virus (HSV), CMV, and EBV each have a seroprevalence of over 50% in adults, while VZV, human herpesvirus 6 (HHV-6), and human herpesvirus 7 (HHV-7) are almost universal. Most infections occur in childhood and reactivate after HSCT. However, if the primary infection occurs after the HSCT, the symptoms are usually prolonged and severe. Of all the herpesviruses that can cause infection after transplantation, CMV is the most common, followed by HSV, VZV, and EBV (397). The clinical manifestations of the herpesviruses are more frequent, severe, and prolonged in HSCT recipients when compared to immunocompetent hosts. The Alphaherpesvirinae
HSV. HSV-1 and HSV-2 are contracted by direct skin or mucosal contact, after which they are taken into neurons and remain dormant in nerve ganglia (63). Seventy-five percent of HSV infections in HSCT recipients occur in the first month after transplant and represent reactivation of latent virus (298). Significant disease is rare after the second month (149). Reactivation in the skin presents as painful papules that develop into clusters of vesicles, which
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Samuel et al.
subsequently open and lead to superficial ulcers that crust over. These lesions may take up to 4 weeks to heal. Reactivation may also occur in the orolabial, genital, or perianal regions. They may take the form of painful ulcers that persist for weeks or even months if not treated (43). Diagnosis is usually made clinically; however, if the lesions are not characteristic, a Tzanck smear (not very sensitive), a direct immunofluorescence assay (DFA), occasionally incorporating a cytocentrifugation step (cytospin DFA), PCR, or culture are helpful (177, 295); enzyme immunoassay, in situ hybridization, and hybrid capture have also been used. The most sensitive method remains PCR, and serology plays no role in the diagnosis. If HSV gingivostomatitis spreads to the esophagus or trachea, esophagitis or pneumonitis may develop. If esophagitis develops, patients have dysphagia and odynophagia that can lead to significant pain and decreased oral intake. The differential diagnosis in this setting includes candidiasis, CMV, or GVHD (220). Diagnosis is usually made via endoscopy and biopsy, with cultures and histopathology demonstrating changes compatible with HSV. If pneumonia develops, the patient’s chest X ray demonstrates focal or multifocal infiltrates. Since HSV is shed in oral secretions when no disease is present, a positive culture is not enough to make the diagnosis. Visualization of the bronchial tree demonstrates severe erosive disease and hemorrhage. Histopathology demonstrating multinucleated giant cells is important to make the diagnosis (274). Other manifestations of HSV infection, including hepatitis, encephalitis, and disseminated disease, may occur. Treatment includes acyclovir given orally or intravenously. Oral acyclovir should be adequate for mucocutaneous disease (400 mg every 8 h), but intravenous administration may be beneficial for visceral or disseminated disease. In patients with mucocutaneous disease, oral or intravenous acyclovir shortens duration of shedding and time for lesion healing. Treatment should be given until complete healing of the lesions occurs (226, 274, 315, 330). Other agents that may be used to treat HSV include famciclovir, valacyclovir, ganciclovir, valganciclovir, foscarnet, and cidofovir (120). Studies with these agents are limited in HSCT patients. Since HSV disease is very common, prophylaxis is recommended. Acyclovir prophylaxis in HSCT patients decreases risk of infection from 70% to less than 5% (355). VZV. VZV is acquired via inhalation of airborne virus into the respiratory tract. Viremia ensues, leading to disseminated disease. About 7 days after viremia, cutaneous vesicles erupt. The patient is infectious for about 2 days prior to the rash and up to 5 days afterwards. Some virions reach the dorsal root ganglia via sensory nerves and establish latency.
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When cellular immunity wanes, the VZV reactivates and travels along nerves to the skin, leading to characteristic herpes zoster (371). Interestingly, herpes zoster in HSCT recipients usually occurs after day 100 (HSV is usually earlier). In addition, the underlying malignancy predicts the risk of zoster after HSCT: it is 46% in Hodgkin’s lymphoma, 23% in leukemia, and 9% in solid tumors (311). Usually VZV presents along one dermatome; however, in 15 to 20% of patients, an atypical generalized zoster presentation occurs. This atypical presentation is associated with a higher risk for visceral involvement, reaching approximately 40% (198). Visceral disease is commonly seen with cutaneous disease. Organs that have been involved include the lung, brain, liver, kidney, pancreas, and the gastrointestinal tract. However, it may present with fever and gastrointestinal symptoms alone (308). Culture of the involved tissue or fluid by isolation in tissue culture, immunofluorescence, in situ hybridization, serology, and/or PCR may be helpful to make the diagnosis (22, 235). Unlike HSV, VZV is not shed asymptomatically. Diagnostic advantages of PCR include that the infectious virus is more labile than its DNA, thus allowing higher sensitivity with PCR, and that vaccine-type and wild-type VZV can be differentiated by PCR. PCR analysis has therefore been useful in describing the etiology of rashes as caused by vaccine or wild-type virus. Treatment with highdose acyclovir (5 mg/kg every 8 h) should be initiated (195). Prophylaxis of HSV and CMV is also adequate prophylaxis of VZV, with the risk of VZV infection decreasing from 18% to 0 (203). Primary infection may be severe, so prevention of disease is important in HSCT recipients who are varicella seronegative. Prior to HSCT, if serology indicates no previous exposure, the patient should receive vaccination if possible (137). If a seronegative transplant recipient has an exposure to VZV, he should receive VZIG within 96 h of exposure. VZIG may not prevent chickenpox, but it reduces the severity of the disease (248). The Betaherpesvirinae
CMV. CMV is the most common herpesvirus infection in HSCT recipients. CMV is a ubiquitous virus that is acquired in childhood. By adulthood, approximately 80 to 90% of people have antibodies to CMV. Primary infection usually presents as a mononucleosislike syndrome. The infection is contained; however, the virus is not eliminated but becomes latent with intermittent reactivation. The virus usually resides in mononuclear cells, polymorphonuclear cells, and macrophages. The balance of immune control and reactivation is maintained by the combination of cell-mediated and humoral immunity.
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Infections in Hemopoietic Stem Cell Transplant Recipients
Historically, after HSCT, CMV infection had a mortality rate of 25%, most of which was secondary to pneumonitis, which carried a 90% mortality rate. It is therefore critical to understand which patients are at highest risk of either reactivation or primary infection. The most important risk factor to the patient is the serologic status of the recipient and donor. If both the patient and the donor are seronegative, there is a very low likelihood of developing disease. If the donor is seropositive and the recipient is seronegative, there is a 30% chance of primary CMV infection. Not only did these patients acquire CMV infection, but their mortality from any infectious agent was doubled (18.3 versus 9.7%) (240). If the patient is seropositive prior to transplant, he has a 20 to 35% risk of reactivation of CMV whether the donor is seropositive or seronegative (23). CMV can cause significant disease of many organs if reactivated after HSCT. These diseases include pneumonitis, gastroenteritis, hepatitis, encephalitis, and retinitis, of which the most severe is pneumonitis (95). Symptoms of pneumonitis include a nonspecific dry cough, with hypoxemia and low-grade fevers. Radiographically, a bilateral interstitial pattern is typically seen. Unfortunately, these are not specific findings and can be confused with other infections. The diagnosis of CMV pneumonitis relies on identifying the organism from bronchoalveolar lavage (BAL), transbronchial biopsy, or open-lung biopsy. In one study, BAL and biopsy were equivalent in leading to a diagnosis (64). The difficulty with diagnosis by BAL is that CMV isolation alone does not indicate disease, since CMV may be present in asymptomatic infection. However, the presence of CMV in the BAL in asymptomatic patients at day 35 may be a predictor of pneumonitis in the future in 67% of those patients (310). PCR has been used on BAL specimens and had an extremely high negative predictive value but very poor positive predictive value (46). Immunostaining the alveolar cells as an adjunct to the PCR may raise the positive predictive value (224). One study evaluated quantitative CMV PCR from the lungs (322); however, in HSCT recipients this was not predictive of disease. Visualization of the organism along with multinucleated giant cells on cytopathology is very suggestive of disease. CMV PCR alone from a pulmonary source is currently not accepted as diagnostic of CMV pneumonitis (290). Treatment of CMV pneumonitis with either antivirals alone or hyperimmunoglobulin alone was not successful, resulting in survival of only 0 to 20% of patients (14, 276, 314). Multiple noncontrolled studies with combination therapy including ganciclovir and CMV hyperimmune globulin (IVIG) demonstrated a survival of 50 to 70% (91, 193, 277, 309).
9
Thus, current recommendations for the treatment of CMV pneumonitis are to use ganciclovir 5 mg/kg twice daily for 2 to 3 weeks, followed by once daily maintenance therapy for another 2 weeks. In addition, IVIG is recommended at doses of 0.5 g/kg given every other day for 2 weeks. Despite this treatment recommendation, mortality remains above 50% (23). Another significant manifestation of CMV disease is involvement of the gastrointestinal tract. Symptoms vary depending on the area infected. Ulcerations are usually seen on endoscopy, but are not specific. Other etiologies to consider are HSV infection and GVHD. The diagnosis is made by biopsy of the ulcer and analysis by histopathology. CMV DNA alone is not sufficient to diagnose CMV disease, since shedding of the virus can occur in asymptomatic patients (131). Ganciclovir 5 mg/kg twice daily for 2 weeks followed by 5 mg/kg/day for 2 to 4 weeks is recommended for therapy. The addition of IVIG has not shown any benefit in gastrointestinal infection (191, 278). CMV encephalitis may also occur and symptoms include headache, confusion, and fatigue. CSF PCR for CMV DNA is highly specific and sensitive for making the diagnosis of CMV encephalitis (58). Therapy for encephalitis includes ganciclovir 5 mg/kg twice daily for 2 weeks followed by 5 mg/kg/day; foscarnet (60 mg/kg every 8 h for 3 weeks followed by 90 mg/kg/day); or a combination of the two. CMV retinitis occurs but is relatively uncommon when compared to the other manifestations of CMV infection. The diagnosis of retinitis is made by fundoscopic examination demonstrating typical retinal lesions (65, 393). Therapy for retinitis includes systemic ganciclovir 5 mg/kg twice daily for 2 weeks followed by 5 mg/kg/day indefinitely. Since CMV can cause such significant morbidity and mortality in HSCT recipients, preventing CMV in CMV-negative patients and preventing reactivation in patients with CMV antibodies are extremely important. For patients who are CMV seronegative and donor negative, the risk of acquiring CMV is through receiving contaminated blood products. The use of CMV seronegative blood or leukocyte-filtered blood products can limit transmission (34). Patients who are CMV seropositive can be given prophylaxis to prevent reactivation. The agents available include acyclovir, valacyclovir, ganciclovir, foscarnet, and valganciclovir. Acyclovir has been shown to decrease primary CMV infection and CMV reactivation, and to increase survival (225). Prophylaxis with high-dose intravenous acyclovir followed by oral acyclovir for 210 days following transplant has been shown to be successful at preventing CMV infection (26, 269). A follow-up study comparing valacyclovir
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to acyclovir demonstrated a reduction in risk of CMV infection from 40 to 28%. No difference in CMV disease or survival was demonstrated when comparing these two agents (192). Three randomized double-blind studies have evaluated ganciclovir for CMV prophylaxis. All three studies showed a decrease in infection and disease due to CMV to 35% (37, 125, 388). However, no survival benefit was demonstrated. In addition, increased invasive bacterial and fungal infections were seen in the patients who received ganciclovir (27, 125, 297). Because of the concerns of increased infections from bacterial and fungal organisms and even bone marrow toxicity from ganciclovir, a different approach may be taken to prevent CMV reactivation, which is commonly termed preemptive therapy. This is based on the detection of CMV reactivation using a rapid diagnostic technique, followed by the initiation of antiviral therapy. The advantage is that only patients at high risk receive antiviral treatment. The disadvantage is that there is a need to monitor patients, and the possibility of developing disease before the test is positive is an important consideration. There are multiple methods to detect CMV. One can grow the virus (shell vial assay); quantify the amount of virus (PCR, pp65 antigenemia, or branched DNA amplification); or use the hybrid capture assay. The easiest way to culture CMV is by rapid shell vial centrifugation. This test is limited by a relatively low sensitivity (24). PCR for CMV DNA is currently considered more sensitive than shell vial cultures (a rapid but less sensitive method to detect infection) (346) and has been used as a basis for preemptive therapy (21, 140, 275). The threshold for a positive test is 104 DNA copies per ml of plasma (24). The incidence of CMV disease and CMV mortality was decreased using the preemptive technique with PCR when compared to standard prophylaxis with ganciclovir (158). Another very sensitive test is the pp65 antigenemia assay, which is based on the detection of CMV lower matrix protein pp65 in polymorphonuclear leukocytes by immunostaining with monoclonal antibodies. This test is also considered more sensitive than shell vial isolation (24). The pp65 antigenemia assay was studied in preemptive therapy with excellent results (25, 27, 159, 344). Some have reported that the threshold for this test ranges between 1 and 15 per 50,000 cells (24). Another method to quantify CMV is the hybrid capture CMV DNA assay. This test uses a CMV RNA probe to target DNA (CMV). There is a resultant RNA-DNA hybrid that can then be measured (24). One study comparing pp65 antigenemia to PCR has been reported (393). This study demonstrated a higher sensitivity for the PCR than the antigenemia
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test; however, there was no clinical difference in predicting activation of CMV in the 51 patients studied. In one study, the hybrid capture CMV DNA assay was compared to pp65 antigenemia, revealing a 95% sensitivity rate (219). One other study compared the hybrid capture assay to PCR and demonstrated a 90% concordance between the two assays (140). If the approach to preventing CMV disease is one of preemptive therapy, all CMV seropositive recipients and all seronegative recipients of a seropositive graft should have weekly tests until day 100 after transplant. Once the DNA or antigen is positive, treatment is recommended, and the most commonly used agent is ganciclovir. The threshold of a positive test is controversial. Some studies report on two consecutive elevated levels of DNA, or antigenemia of greater than 10 per 50,000 cells, while others use any single elevated level to initiate treatment. The concern is that disease may begin before elevated levels of DNA are detected or the progression is rapid. Once treatment is initiated, it should be continued until the DNA or antigenemia test is negative. In patients who have had CMV preemptive treatment, weekly monitoring should continue beyond 100 days and possibly for one year, since up to 33% might recur in the first year (28). HHV-6. HHV-6 is usually acquired early in life and is transmitted via saliva. It is associated with a febrile illness with the classic rash of roseola infantum. After acute infection, the viral genome persists in CD4-positive T cells and salivary glands (45). In HSCT recipients, approximately 30 to 45% of them develop HHV6 viremia in the first month following transplantation. In these patients, there have been multiple clinical associations with HHV-6. However, the precise causal relationship between HHV-6 and clinical disease has not been clearly defined. Association of fever and rash has been reported (45). In addition, association with bone marrow suppression, pneumonitis, and encephalitis has been reported (319, 399). Sophisticated isolation procedures may be performed in primary cell cultures or continuous cell cultures and confirmed using monoclonal antibodies. By electron microscopy, HHV-6 virions have typical herpesvirus morphology. In situ hybridization and in situ PCR have also been used in a few studies for detection of HHV-6 DNA in brain tissue from nonHSCT patients (233). Detection of the virus by single target, multiplex, qualitative, and quantitative PCR may also be helpful to make a diagnosis (156). Various serologic tests have also been used to detect IgG or IgM. However, none of the current assays differentiate antibodies to HHV-6A versus HHV-6B, and cross-reactivity with antibodies to HHV-7 has been observed. HHV-6 appears to respond to both ganciclovir and foscarnet (365, 400).
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Infections in Hemopoietic Stem Cell Transplant Recipients
HHV-7. HHV-7 is usually acquired early in life and is transmitted via saliva, as is HHV-6. It also may be the etiology of roseola infantum. After acute infection, the virus persists in CD4 T lymphocytes (1). It is unclear what role this organism may have in HSCT. There may be a role as a cofactor in CMV disease, and there is one report of fatal encephalitis in the literature (49, 50). Diagnosis may be made using a combination of the methods described above (for HHV-6), including sophisticated cell culture procedures, electron microscopy, serologic tests and molecular analyses (including PCR) (209). It is unclear what the best agent is to treat HHV-7 in vivo; however, ganciclovir, foscarnet and cidofovir have in vitro activity (364). The Gammaherpesvirinae
EBV. EBV is a ubiquitous virus that is transmitted via saliva. Individuals are typically infected in childhood or adolescence and may develop infectious mononucleosis. Up to 90% of adults have antibodies against EBV. After acute infection, EBV persists in B lymphocytes and rarely in nasopharyngeal cells (61). If a recipient of an HSCT is seronegative for EBV and the donor is positive, it is almost assured that the recipient will develop primary infection that manifests as a mononucleosis syndrome. Posttransplant lymphoproliferative disease (PTLD) is a feared complication of EBV infection in HSCT recipients. In a study of over 18,000 patients who underwent HSCT, the incidence of PTLD is 120 per 10,000 patient years during the first 5 months after transplant, and decreases to 5 per 10,000 patient years after 1 year (69). The major risk factors for the development of early-onset PTLD (within the first year after transplant) include the use of unrelated or mismatched donors, T-cell depletion of donor marrow, and the use of antithymocyte globulin or antiCD3 monoclonal antibody (6). In patients with three of these risk factors, the incidence of PTLD was 22%. The development of GVHD is the only identified risk factor for development of late-onset PTLD (after the first year after transplant) (69). PTLD typically presents in one of three ways. The first is a benign polyclonal lymphoproliferation, leading to enlarged lymph nodes. Similar to infectious mononucleosis, it is characterized by polyclonal B-cell proliferation with normal cytogenetics and no malignant transformation. The second is similar to the first but with clonal transformation suggesting malignancy. These are the most common presentations of early-onset PTLD. The third disorder (usually seen in late-onset PTLD) is extranodal, with solid tumors characterized by monoclonal B-cell proliferation and malignant transformation (134, 402). Diagnosis of PTLD is usually made by pathology
11
and detection of EBV DNA by in situ hybridization, Southern blot, Western blot, or immunohistochemistry (112, 268, 288). Serodiagnosis and antigen detection by immunofluorescence have also been used. Electron microscopy has rarely been used with success since EBV, usually latent, may be present in infected tissue in extremely low numbers. One possible exception may be tongue lesions in oral leukoplakia, which may show elevated numbers of EBV. Another method of diagnosis includes measuring EBV viral load in plasma (327). A low viral load has a negative predictive value of 100% in HSCT patients (1,000 EBV genomes/l of plasma). However, the positive predictive value of a high viral load (5,000 EBV genomes/l of plasma) is only 39% (356). This test may be useful to monitor response to treatment. In one study of 13 patients, all responders had a decrease in EBV DNA, while every nonresponder had an increase in EBV DNA in 72 h (350). Effective treatment of the polyclonal disorders with reduction of immunosuppression and possibly antiviral therapy with acyclovir has been demonstrated (135). The third condition, which is usually a lymphoma, is treated with chemotherapy and radiation therapy. There have been other approaches to the treatment of PTLD in HSCT. Researchers have studied recipients of T-cell-depleted HSCT who developed PTLD and received infusions of donor leukocytes; GVHD was a significant complication (251, 329). Another approach, treatment with rituximab, an antibody directed against CD 20, was evaluated in two studies. The complete response rate was 62% and 67% (100, 228). A major side effect includes B-cell lymphopenia and resultant hypogammaglobulinemia. In addition, reactivation of CMV has been noted (334). Other reported manifestations of EBV after HSCT include aplastic anemia (157), meningoencephalitis (76), and oral hairy leukoplakia (96). HHV-8. HHV-8 is found more commonly in men and in individuals from Saudi Arabia and South Africa. Infection usually occurs early in life. It induces host cells to initiate angiogenesis, putting the patient at risk for bleeding or Kaposi’s sarcoma (KS). The cells seen on pathologic specimens are called spindle cells and are likely a transformation of pluripotent mesenchymal progenitor cells (29). HHV-8 infection in HSCT has been reported. In two separate case reports, infection with this virus led to bone marrow failure (72, 204). In addition, HHV-8 has been linked to KS. KS involves the skin, lungs, bladder, and gastrointestinal tract. Since angiogenesis is the predominant feature, bleeding may be the presenting manifestation (204). Even though there are no reports of KS in HSCT, it is thought that it can develop in this population. In
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Table 2. Community-acquired respiratory virus infections in HSCT recipients Type of Infection Overall number Influenza viruses Adenoviruses Parainfluenza viruses RSV Rhinoviruses
No. of infections FHCRC
a
127 14 0 38 44 31
HUHb
MDACCc
39 15 8 8 8 0
67 12 4 6 33 12
a
FHCRC, Fred Hutchinson Cancer Research Center, Seattle, Wash.; data acquired during a 6-year period. HUH, Huddinge University Hospital, Huddinge, Sweden; data acquired during a 7-year period. c MDACC, M. D. Anderson Cancer Center, Houston, Tex.; data acquired during a 1-year period. b
respiratory disease, usually in late fall, winter, and early spring (214); nosocomial transmission has been reported (145). Symptoms include rhinorrhea, sinus congestion, sore throat, and otitis media. The progression to pneumonia can be as high as 80% if infection occurs in the first month after transplant, but only 25% if infection occurs after the first month. Mortality rates of over 80% have been reported in RSV pneumonia (136, 381). Treatment includes aerosolized ribavirin (6 g/day by aerosol) and RSV-titered immunoglobulin (500 mg/kg every other day), which reduces mortality to 33% (119). Treatment should be initiated early, since there is a 100% mortality rate if treatment is initiated after respiratory failure (382). Influenza Virus
solid organ transplants, KS presents early posttransplantation, with a median time of onset of 22 months (260). Identification of HHV-8 can be accomplished by PCR, by hybridization with nucleic acid probes, serologically, and with the use of monoclonal antibodies. As with HHV-6 and HHV-7, HHV-8 virions have electron microscopic morphology similar to other herpesviruses (233). Treatment may include reduction of immunosuppression if possible. Chemotherapy may be beneficial. Antivirals such as ganciclovir, foscarnet, and cidofovir are active in vitro (239); however, clinical data are lacking in the HSCT population. Community-Acquired Respiratory Viruses Community-acquired respiratory viruses have the potential to be life threatening in individuals who have received HSCT. These viruses include RSV, influenza viruses, parainfluenza viruses, adenoviruses, rhinoviruses, and coronaviruses. There have been three large studies describing the rates of community respiratory virus infections in HSCT recipients (33, 189, 381) (Table 2). They occur frequently and carry a high mortality rate of 9% (94). The methods for diagnosis of these agents are demonstrated in Table 3.
Influenza virus is a major cause of morbidity and mortality in all individuals. Because it can undergo antigenic variation, the virus continues to be a significant cause of upper respiratory infections in the late fall through early spring. In transplant recipients, infection is much more severe than in nontransplant patients. In one study from the M. D. Anderson Cancer Center in Houston, researchers isolated influenza in 100 HSCT recipients (395). The progression to pneumonia occurred at a high rate of 60%, and mortality secondary to influenza pneumonia was 40% (94). Prophylaxis against influenza includes vaccination of the patients, their families, and their close contacts (138). If given during the early posttransplantation period or in those patients with chronic GVHD, the vaccine may not be effective. Historically, amantadine (100 mg twice daily) and rimantadine (100 mg twice daily) have been used for the treatment of influenza A (93). A review of 100 patients receiving these agents showed a significantly decreased risk of progression to pneumonia when therapy was initiated early (180). Newer agents including zanamavir (2 inhalations twice daily) and oseltamivir (75 mg twice daily) are being used; however, no prospective studies have been reported (139, 343).
RSV
RSV is a major cause of lower respiratory tract infection in children; however, natural immunity is incomplete and repeat infections can occur (133). In HSCT recipients, RSV infection presents as an acute Table 3.
Parainfluenza virus is the major cause of croup in young children. It has been noted to cause significant morbidity and mortality in HSCT recipients. The
Available rapid tests to diagnose community-acquired respiratory viruses
Infective agent RSV Influenza viruses Parainfluenza viruses Adenoviruses Rhinoviruses a
Parainfluenza Virus
Specimen source Respiratory Respiratory Respiratory Respiratory Respiratory
a
specimen specimen specimen specimen or blood specimen
Available tests Antigen Antigen Antigen Antigen PCR
detection, immunofluorescence, or PCR detection, immunofluorescence, or PCR detection,b immunofluorescence, or PCR detection, immunofluorescence, or PCR
Includes throat swab, nasal swabs, nasal wash, nasopharyngeal aspirate, and bronchoalveolar lavage. Commercial test kits are not currently available, but reagents are available as single components.
b
Cultures Yes Yes Yes Yes Yes
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Infections in Hemopoietic Stem Cell Transplant Recipients
clinical course is one of upper respiratory symptoms such as cough, sore throat, and odynophagia, which proceed to pneumonia (51). In a study from the M. D. Anderson Cancer Center, 45 consecutive parainfluenza-infected HSCT recipients were reported (185). Pneumonia complicated the illness in 58% of patients, and the mortality rate of pneumonia was 39%. There is no licensed treatment or vaccine available for parainfluenza and the treatment is mainly supportive. Adenovirus
Adenoviruses commonly affect children under 5 years of age. Outbreaks in adults have been observed when individuals are in close quarters, such as with military recruits or in nursing homes (221). Infections in HSCT recipients occur within the first few months after transplantation. Outbreaks of adenovirus among transplant recipients have been reported (394). The incidence of adenovirus infection after HSCT ranges from 3 to 21% (101, 317). One study reported a 3% incidence among 3,000 adults (179); another study reported 20.9% incidence in adults and 31% in children (101). Adenovirus was cultured from throat, urine, or stool cultures. Infection in children occurred in the first 3 months posttransplantation, while in adults it usually occurred after that period (394). Clinical manifestations of adenovirus infection after HSCT range from fever to fatal disseminated disease. Up to 20% develop invasive disease and up to half of these patients can die (101, 316, 366, 394), usually from interstitial pneumonia. Other sites of infection include the kidneys (presenting as hematuria), the colon (presenting as colitis), and the liver (presenting as hepatitis). Risk factors noted for disease include GVHD (179), allogeneic HSCT, and young age. Diagnosis is difficult to make, and adenovirus should be considered in any patients with unexplained high-grade fevers. Since adenovirus is shed asymptomatically, culture of the organism does not denote an etiology of disease. Cultures of the site of possible infection are helpful, but biopsy showing adenovirus inclusions and immunohistochemical staining can confirm the diagnosis. In addition, detection of adenovirus in blood by PCR may predict disseminated disease (84, 307). In one study, patients with disseminated disease had adenovirus DNA positive from serum; however, patients with gastroenteritis and cystitis had negative DNA PCR (84). Another study found that the magnitude of the PCR might indicate the severity of disease (307). There is no specific treatment for adenoviral infections. Ribavirin may play a role in treatment; however, there is little clinical data. Ganciclovir plays no role in treatment. There has been one study using cidofovir for
13
adenoviral infection. Other possible adjuncts to treatment include intravenous immunoglobulin for pneumonia (74), donor leukocyte infusion (153), and possibly even reduction of immunosuppression. Other respiratory viruses such as rhinoviruses and coronaviruses are the cause of the common cold. In HSCT recipients, a study from M. D. Anderson Cancer Center reported significant morbidity and mortality associated with rhinovirus infection (118). In approximately one-third of the patients in whom they identified rhinovirus infection, pneumonia developed. All of the patients who developed pneumonitis died. Lung biopsies or autopsies were performed and were consistent with pneumonitis and/or acute respiratory distress syndrome. However, no cultures for rhinovirus were performed. In another study, only 1 of 29 patients developed pneumonia (32). The exact role of these viruses in HSCT is still unclear. Parvovirus B19 Parvovirus B19 is a single-stranded DNA virus that typically causes disease in childhood leading to erythema infectiosum. It has been associated with red cell aplasia in individuals with sickle cell anemia or HIV. Up to 60% of individuals are seropositive for parvovirus B19 by adulthood (10). In the HSCT recipient, infection with parvovirus B19 can result in red cell aplasia. Patients have inadequate reticulocytosis and possibly thrombocytopenia and leukopenia. Up to one-third of the patients have fever and malaise. Rash and arthritis, frequent in immunocompetent hosts, are uncommon in this population (15, 102). Positive IgM and elevated IgG levels (tests available commercially) to parvovirus B19 in suspected patients assist in making the diagnosis. Although PCR is the most sensitive diagnostic method to detect parvovirus B19 DNA, other molecular methods such as dot blot hybridization and in situ hybridization have been used with success. Most routine cell cultures, although permitting a low level of B19 replication, are not reliable for isolation and identification. The pathogenesis of disease includes viremia beginning approximately 5 days after infection and lasting for 3 to 10 days in the immunocompetent patient. IgM antibodies are present by week 2, but viremia does not decrease until IgG antibody rises. In patients without an adequate IgG response, persistent viremia continues and chronic anemia results (10). Recommendations for treatment include IVIG infusion for 3 to 10 days (175). Polyomaviruses Polyomaviruses are DNA viruses that lead to asymptomatic infection. These viruses include JC virus (JCV) and BK virus (BKV); 90% of adults have antibodies to BKV, and up to 60% have antibodies to
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JCV. These viruses establish persistent infection in kidneys, peripheral blood cells, and the brain (90, 339, 340). In HSCT recipients, BKV can lead to hemorrhagic cystitis. As with many other viruses, isolating the virus from urine is not reflective of disease etiology. In patients with AIDS, JCV is associated with progressive multifocal leukoencephalopathy; however, this is rarely reported to occur in HSCT recipients. Documenting disease caused by these viruses usually requires histological findings in addition to microbiological identification. Although cell cultures can be used to isolate human polyomaviruses from clinical specimens, they are not routinely used due to relatively long growth cycles and limited host cell ranges. BKV and JCV can be detected by electron microscopy, antigen detection (commonly by immunohistochemistry), and very reliably by sensitive and specific PCR methods. Studies supporting the use of cidofovir in HSCT patients with BKV-associated hemorrhagic cystitis have been reported (123, 141). Adjusting immunosuppression may be of use as well. Mycoses In this section, fungal infections that are frequently encountered in HSCT are described. Fungal infections are divided into three categories: yeast, mold, and endemic fungal infections. Yeast Infections Candida
Candida species are the third most common cause of nosocomial bloodstream infections in the United States (86) and are the most common cause of fungal infections. In the early stages of HSCT, during the first month, conditioning regimens invariably cause severe neutropenia and mucositis involving oral, gastrointestinal, genitourinary, and pulmonary systems. After the first month following HSCT, mucosal immunity is compromised secondary to GVHD of the skin, intestines, and liver, rendering the patients at risk for yeast infections involving Candida, Trichosporon, and Malassezia infections. Candidemia carries a high mortality rate of 40 to 60% (87, 107, 128). Among Candida species, C. albicans is most frequently encountered, accounting for roughly one-half of candidemia cases. Candida species other than C. albicans are responsible for the other half of the cases (7, 263). These species are C. glabrata, C. tropicalis, C. parapsilosis, C. krusei, and C. lusitaniae. Another Candida species that is occasionally seen in HSCT recipients and may easily develop fluconazole resistance is C. dubliniensis, which can be misidentified as C. albicans because both species are capable of germ tube formation (223). Candida
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species are easily grown on routine media used in mycology laboratories and detected and identified by commercially available methods (389). Chromogenic isolation media are also available to correctly detect and identify C. dubliniensis (130). Experimental evidence indicates that the Candida species are usually from the patient’s own gastrointestinal tract (242), where they are normal commensals. In addition, vascular access also serves as a major route of entry (241). C. parapsilosis is associated more often with vascular catheters and lipid formulation infusion for total parenteral nutritional supplementation (172, 367). Candidemia may lead to either acute or chronic disseminated candidiases (31, 391). Acute disseminated candidiasis commonly involves multiple organs including the kidney, heart, skin, and musculoskeletal system. C. tropicalis is often isolated in neutropenic patients with this syndrome (386), whereas chronic disseminated candidiasis often affects the liver and spleen in addition to other organs, often referred to as “hepatosplenic candidiasis.” This condition is a relatively common complication of severe mucositis (11). The incidence of hepatosplenic candidiasis in patients with acute leukemia was 6.8% (38, 164) during the period from 1980 to 1993 and carried a high mortality rate at 74% (11). Premortem diagnosis of disseminated candidiasis is difficult to make and remains a clinical diagnosis. Persistent fever may be the only symptom present. Imaging studies such as computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound evaluation, often combined with laparoscopic liver biopsy, may lead to the diagnosis. The management of uncomplicated candidemia consists of systemic antifungal therapy with fluconazole or an amphotericin B preparation such as amphotericin B lipid complex (ABLC; Abelcet) (5 mg/kg daily) or liposomal amphotericin B (AmBisome) (3 mg/kg daily) in appropriate doses for a minimum of 2 weeks after the last positive blood culture (254). When fluconazole-resistant non-albicans Candida, such as C. glabrata, C. krusei, C. lusitaniae, or C. dubliniensis, is involved, an echinocandin or voriconazole should be used instead. In patients with disseminated candidiasis, similar agents to those used in candidemia are recommended. Fungal susceptibility tests are not universally available but may guide treatment in difficult cases. The duration of treatment, however, must be prolonged 8 weeks or longer (164). Removal of Candida-infected catheters is considered to be a standard of care (243). Oropharyngeal Candida infection, commonly known as “thrush,” typically shows adherent white “cottage cheese”-like plaques distributed over the buccal mucosa, gingiva, soft palate, tonsils, tongue, and hypopharynx. When more severe, it may extend
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Infections in Hemopoietic Stem Cell Transplant Recipients
to involve the esophagus, resulting in esophageal candidiasis. This typically manifests with pain on swallowing (odynophagia). A wet mount or Gram stain of scrapings obtained from the mucosal lesions revealing pseudohyphae usually establishes the diagnosis. Therapy for oropharyngeal candidiasis can be accomplished by local treatments such as nystatin or clotrimazole troches in mild cases, but in moderate to severe cases including esophageal lesions, a systemic antifungal therapy with the newer azoles is indicated. Oral fluconazole appears to be the drug of choice for infections caused by C. albicans, although topical clotrimazole or oral itraconazole offer a comparable mycological cure (75, 254). For other non-albicans Candida infections, the echinocandins such as caspofungin or a second-generation azole such as voriconazole is the preferred choice. Amphotericin B is also highly effective but more toxic. Cryptococcus neoformans
Cryptococcus neoformans is distributed worldwide in nature, including in soil, and it grows to high concentrations in aged pigeon feces. Birds are not infected (186), and hence fresh pigeon droppings do not contain the organism. Most cryptococcal infections begin with inhalation of the organisms, which become localized in the lungs. In immunocompetent hosts, they are eliminated by host defense mechanisms. In immunocompromised individuals, however, the organisms are hematogenously spread to extrapulmonary organs. They have a predilection for the CNS, although other organs such as the musculoskeletal system and cutaneous tissue may be involved. Prolonged hypercortisolism brought on by either endogenous or exogenous means is well known to predispose patients to invasive fungal infections, including cryptococcosis (80, 188). High doses of glucocorticoids are often administered in allogeneic recipients with GVHD. The most common manifestation of CNS cryptococcosis is meningitis, which is usually subacute but may be acute in onset. Complications may include hydrocephalus, elevated intracranial pressure, encephalitis, sudden hearing loss, visual disturbance or loss, and facial numbness or weakness. Seizures may occur as a late complication. Occasionally, mass lesions in the brain or spinal cord can be seen. Clinical course and manifestations may vary greatly depending on the immune status of the host. Typical meningismus that is seen in acute bacterial meningitis may not be present in cryptococcal meningitis. Factors predisposing to a poor clinical outcome are lymphoreticular malignancy or corticosteroid therapy, CSF with high opening pressure, a low glucose level, less than 20 leukocytes/mm3, cryptococci seen in smear, cryptococci isolated from extraneural sites,
15
and high titers of cryptococcal antigen in CSF or serum (80). Culturing the organism from specimens obtained from the infection site makes a definitive diagnosis of cryptococcosis. Diagnosis of CNS cryptococcosis is usually made by latex agglutination or enzyme immunoassay technique for the detection of cryptococcal capsular polysaccharide antigen in serum or CSF. These tests are reliable, with sensitivity and specificity approaching 100% (166, 234). The India ink preparation is positive in 25 to 50% of patients with cryptococcal meningitis, and this detection method is still used, but only to support a presumptive diagnosis or for teaching purposes. The therapeutic regimen of choice before the HIV era (non-HIV patients) was the combination of amphotericin B and flucytosine given for 6 weeks (20, 82). The current treatment regimen of choice for HIV patients is amphotericin B or lipid formulation amphotericin B (Abelcet or AmBisome) with or without flucytosine for 2 weeks followed by fluconazole for 8 weeks and a maintenance daily dose of fluconazole indefinitely (183, 292, 313, 349). Similar data for HSCT recipients are currently lacking. The practice guidelines for cryptococcal disease in HIVnegative patients (293) classify the patients into two different categories: pulmonary and CNS cryptococcal diseases. Patients with mild to moderately symptomatic pulmonary cryptococcosis should be treated with either fluconazole (200 to 400 mg/day) or itraconazole (200 to 400 mg/day) for 6 to 12 months or amphotericin B, 0.5 to 1 mg/kg/day for a total dose of 1,000 to 2,000 mg. On the other hand, patients with severe pulmonary cryptococcal disease or CNS involvement should be given induction therapy with amphotericin B (0.7 to 1 mg/kg/day) plus flucytosine (100 mg/kg/day) for 2 weeks followed by fluconazole (400 mg/day) for a minimum of 10 weeks. Other alternate treatment regimens include amphotericin B (0.7 to 1 mg/day) alone, or lipid formulation of amphotericin B (3 to 6 mg/kg/day) for 6 to 10 weeks. Nephrotoxicity is a major drawback of amphotericin B deoxycholate. The lipid formulations of amphotericin B carry significantly less nephrotoxicity than the conventional preparation (390). The use of flucytosine is associated with significant myelosuppression and its use in immunocompromised hosts needs to be followed closely. In addition, flucytosine causes a high incidence of gastrointestinal adverse effects. The presentation of pulmonary cryptococcosis is highly variable, although in typical cases, radiographic findings may reveal either patchy pneumonia or solitary or multiple small nodules. Patients are usually asymptomatic. An additional uncommon clinical manifestation of disseminated cryptococcosis is cellulitis, which may mimic bacterial cellulitis but
16
Samuel et al.
fails to respond to empiric antibiotic therapy (9). These lesions are warm to the touch, erythematous, indurated, and tender. Diagnosis is made by tissue biopsy for culture and histologic examination. Trichosporon beigelii
T. beigelii is occasionally isolated as part of the normal flora of human skin and also is known to cause colonization of the gastrointestinal or respiratory tracts in immunosuppressed patients (363). It is isolated and identified on routine media used in the mycology laboratory, and identified by commercially available methods (389). In profoundly neutropenic patients who are receiving immunosuppressive agents, it may cause disseminated infection with a high mortality rate of 74% (152). Disseminated trichosporonosis may involve fungemia, funguria, endocarditis, endophthalmitis, cutaneous lesions, renal failure, and pneumonia (110, 201, 358, 363). Therapy with amphotericin B alone has been unsatisfactory, although it has some in vitro activity. It has been shown that amphotericin B at achievable serum levels is only inhibitory but not fungicidal (362). Fluconazole shows significant activity in vitro and in vivo in animal models. In a small number of patients, fluconazole was shown to be effective in patients with Trichosporon infections (5). Perhaps combination therapy with amphotericin B and fluconazole may have an even more favorable outcome (7). Voriconazole shows even more enhanced activity than fluconazole in vitro, but clinical data are lacking (97). In an animal model of disseminated trichosporonosis, administration of a macrophage colony-stimulating factor improved survival (206), so it might be prudent to use it in patients with disseminated trichosporonosis to augment newer triazoles with or without amphotericin B. Malassezia
The genus Malassezia, formerly known as Pityrosporum, consists of lipophilic yeasts found on the skin as commensals, and it is associated with a folliculitis which is typically maculopapular but occasionally is pustular. These pruritic lesions involve the chest, upper back, and shoulders (42, 231). There are seven species in the genus, including the most frequently encountered, M. furfur. This species has also been associated with catheter-related fungemia in patients receiving parenteral lipid through central venous catheters. However, disseminated Malassezia infections are rare complications in HSCT recipients (231). These infections, cutaneous or systemic, appear to have a more benign course than other disseminated fungal infections. The folliculitis is usually diagnosed by the microscopic examination of skin scrapings from the lesion in a KOH (potassium hydroxide) preparation. To isolate M. furfur, the
CUMITECH 42
growth medium must be supplemented with a lipid component by overlaying Sabouraud’s glucose agar with a few drops of sterile olive oil (227). Malassezia spp. are usually susceptible to amphotericin B and azole compounds. Fluconazole has been used successfully to treat Malassezia folliculitis in cardiac transplant recipients (279). Mold Infections Although yeasts remain the most common cause of fungal infections, mold infections remain the most dreaded infectious complication in HSCT recipients. These infections carry a very high mortality rate, approaching near 100% unless immune function recovers. The 1-year survival estimate for patients with invasive aspergillosis in HSCT recipients was only 7% (357). With effective prophylaxis for C. albicans in place, Aspergillus may appear as an important pathogen early after transplantation (20 to 30 days). Due to the common modality of GVHD prophylaxis (up to 180 days), the recipients remain severely immunosuppressed, rendering them at high risk for infections. In addition to Aspergillus, several other molds, including Fusarium, Scedosporium, and Zygomycetes, play an important role as pathogens in these patients. Aspergillus
Aspergillus species that cause disease in humans are ubiquitous in the environment and have been isolated from soil, air, decaying vegetables, compost, stored grain, and building material. They are also easily isolated from basements, furniture, and potted plants. Aspergillosis is the second most common systemic fungal infection requiring hospitalization in the United States, next to candidiasis. The most common species infecting humans are A. fumigatus, A. flavus, A. niger, A. terreus, and A. nidulans. Of these, A. fumigatus causes approximately 90% of invasive aspergillosis. Of these species, A. terreus may be resistant to amphotericin B (261), while the others are not. Risk factors for invasive aspergillosis include neutropenia, high-dose corticosteroid therapy, and cytotoxic drug therapy. The respiratory tract is the usual portal of entry by inhalation of airborne conidia, with diameters of approximately 2 to 3 m, that are small enough to reach the alveoli (213). Damaged skin, surgical wounds, or the external ear may serve as entry sites. The first line of host cellular defense against the conidia includes macrophages that ingest and process conidia further by secreting cytokines and chemokines (304, 306). If the macrophage surveillance fails, germinating conidia or hyphae will be phagocytized by neutrophils and monocytes (285, 305). In HSCT recipients, these cellular defense mechanisms are compromised. The incidences of invasive aspergillosis in allogeneic and
CUMITECH 42
Infections in Hemopoietic Stem Cell Transplant Recipients
autologous HSCT patients are reported to be 4 to 9% and 0.5 to 6%, respectively, and pulmonary infections account for 80 to 90% of invasive aspergillosis (77). In an analysis of 2,496 patients who underwent HSCT during a 6-year period, 158 (139 proven and 19 probable) developed Aspergillus infection. A bimodal distribution of onset was shown, peaking 16 and 96 days after transplantation (357). Similar findings were recorded in another large review (257). Invasive aspergillosis in HSCT recipients commonly involves lungs, sinuses, and brain. Blood cultures of patients with invasive aspergillosis are invariably negative. Aspergillus hyphae in tissue are best visualized by silver stain; they are 2 to 4 m wide, are frequently septate, and branch acutely at 45 degrees. The clinical presentation of invasive pulmonary aspergillosis is variable and nonspecific, although the more immunocompromised the patient, the less likely symptomatic. A typical presentation is fever, dry cough, hemoptysis, shortness of breath, and pleuritic chest pain. The patients are unresponsive to empiric antibiotic therapy. Chest roentgenograms or CT scans are almost always abnormal, but the findings are nonspecific. Radiographic findings vary showing single or multiple nodules with or without cavitation. Diffuse pulmonary infiltrates or wedge-shaped infiltrates are also seen. The most characteristic early lesions, which may best be demonstrated by CT scans, are small, pleural-based nodules with surrounding low attenuation (the “halo” sign). Nodules may cavitate, usually as the patients recover from neutropenia, and reveal an “air-crescent” sign. The halo and air-crescent signs are quite typical of invasive pulmonary aspergillosis but are not definitive. Other molds and Pseudomonas aeruginosa are known to cause similar changes. Definitive diagnosis requires demonstration of the organism in lung tissue with a positive culture and identification of Aspergillus. The monitoring of galactomannan, a cell-wall polysaccharide produced by Aspergillus species, as a potential marker for early detection of invasive aspergillosis has been the subject of many investigations. In a recent study with HSCT recipients, 986 serum samples from 67 patients were serially monitored for galactomannan levels by a galactomannan enzyme immunoassay (EIA). The study demonstrated that the galactomannan EIA could be a potentially useful method in early diagnosis and for therapeutic monitoring of invasive aspergillosis, with a sensitivity of 87.5% when the index cutoff for positivity is decreased to 0.5 (212). Aspergillus may disseminate hematogenously to extrapulmonary sites including the brain, myocardium, liver, spleen, skin, and kidneys. The brain is the most commonly involved in 25 to 40% of invasive
17
pulmonary aspergillosis cases (303, 385). Typically, patients present with altered mental status, confusion, cranial nerve palsy, and hemiparesis (217). Meningismus is rarely present (77). CT scans may reveal single or multiple hypodense and well-demarcated lesions. For patients with adequate peripheral white blood cell counts, the ring enhancement and surrounding edema are more frequently demonstrated (396). MRI images often reveal lesions that were not detected by CT scans (132). Definitive diagnosis of cerebral aspergillosis requires brain biopsy or aspiration; however, these procedures are not always feasible. Aspergillus rhinosinusitis is a potentially lethal complication of severe neutropenia in patients with acute leukemia (335) or HSCT (83). The sinus infection should be suspected when a neutropenic patient develops fever with no apparent source, with signs and symptoms of sinusitis, orbital or cavernous sinus disease, cutaneous changes over the nose, or an ulcerative lesion or perforation of the hard palate (335). A thorough examination with rhinoscopy followed by CT or MRI imaging studies may lead to the correct diagnosis. CT and MRI imaging studies may not distinguish Aspergillus infection from bacterial infection. T2-weighed MRI images show decreased signal intensity in cases of Aspergillus infections compared to those of bacterial infections (77). Until recently, treatment of invasive aspergillosis was entirely dependent upon administration of highdose amphotericin B. However, lipid preparations of amphotericin B are less nephrotoxic, but definite superiority to amphotericin B deoxycholate in patients with invasive aspergillosis needs to be confirmed (59, 147, 361, 383, 384). Itraconazole, in both intravenous and oral formulations, is considered an alternative agent for invasive aspergillosis, but again, well-controlled studies comparing this agent to amphotericin B are lacking. A new class of antifungal agents, echinocandins, was introduced for use as salvage agents in patients with invasive aspergillosis who are refractory to standard therapy or show unacceptable toxicities. In a clinical trial study in patients with invasive aspergillosis, caspofungin showed promising results (J. Maertens, I. Raad, C. A. Sable, A. Ngai, R. Berman, T. F. Patterson, D. Denning, and T. Walsh, Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 1103, 2000). Other similar compounds such as micafungin (Fujisawa Healthcare, Inc., Deerfield, Ill.) and anidulafungin (Vicuron Pharmaceuticals, Inc., King of Prussia, Pa.) are undergoing phase 3 clinical trial studies. These compounds carry a benign side effect profile. Voriconazole has recently been introduced as an agent for treatment of invasive aspergillosis, available in both intravenous and oral preparations.
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Samuel et al.
When therapeutic efficacy and tolerance were compared to those of amphotericin B, it showed better efficacy than that of amphotericin B with fewer side effects (144). Voriconazole, however, has significant drug interactions. Voriconazole is metabolized by the hepatic cytochrome P450 enzyme system including CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these enzymes may increase or decrease voriconazole systemic exposure. Coadministration of voriconazole and the following drugs is contraindicated: rifampin, rifabutin, sirolimus, terfenadine, astemizole, cisapride, quinidine, and ergot alkaloids. Significant drug interactions may require dose adjustments of voriconazole or the following drugs: phenytoin, omeprazole, cyclosporine, tacrolimus, warfarin, statins, benzodiazepine, calcium channel blockers, sulfonylurea, protease inhibitors except indinavir, and nonnucleoside reverse transcriptase inhibitors. The drugs listed above are only representative therapeutic agents and are not a complete listing. Therefore, when voriconazole is administered to patients who are taking other medications, it is recommended that drug interactions should be thoroughly reviewed. In a multicenter, retrospective analysis of therapeutic outcomes in patients infected with A. terreus, where 38 of 83 patients were HSCT recipients, the voriconazole group showed lower mortality (55.8%) than the group treated with other fungal agents (73.4%) (326).
CUMITECH 42
sites is seen in as many as 70% of cases (213). The most common extra-pulmonary site is the skin, which evolves from widespread and multiple erythematous subcutaneous nodules that undergo necrosis (6, 281). These lesions are seen in two-thirds of all cases. They are painful, expand in size, and tend to concentrate on the extremities. In immunocompetent patients, localized skin lesions and ophthalmologic infections have been described. Diagnosis is usually made by biopsy demonstrating the presence of acutely branched and septate hyphae when prepared with methenamine silver or periodic acid-Schiff (PAS) stains. Fungal cultures are mandatory to confirm and to differentiate it from Aspergillus species. Unlike disseminated aspergillosis, blood cultures are positive in approximately 50% of disseminated fusariosis cases (30). The common presentation of fusariosis is fever in a patient with hematologic malignancy that is refractory to broadspectrum antibiotics and reveals multiple skin lesions with positive blood cultures for fungal species. Therapeutic response to conventional amphotericin B alone or in combination with flucytosine or rifampin is reported to be poor (8, 127), although lipid formulations of amphotericin B (5 mg/kg/day) appear to have improved activity. Amphotericin B combined with caspofungin shows synergistic or synergistic/additive activity in vitro (13). Recently, new triazoles such as voriconazole and posaconazole showed better activity in vitro and in vivo against Fusarium than older triazoles (202, 252).
Fusarium
Organisms belonging to the genus Fusarium are common in soil and organic debris, as is the case with Aspergillus and Zygomycetes. They commonly cause disease in plants but disease in humans is rare. This organism is the second most common filamentous fungal pathogen in HSCT recipients after Aspergillus (6, 325). The portal of entry is usually the respiratory tract, but direct inoculation into traumatized skin also leads to fusariosis. Risk factors for fusariosis are similar to those of aspergillosis, namely, profound neutropenia and corticosteroid treatment. Fusariosis shows a bimodal distribution in terms of its onset of clinical manifestations in HSCT recipients (213, 360). The most common species to cause human infections is Fusarium solani, accounting for approximately 50% of the cases, while other species such as F. moniliformis, F. oxysporum, F. dimerum, and F. proliferatum account for the rest (265). Fusariosis in immunocompromised patients often begins with nonspecific symptoms such as fever and myalgias that are unresponsive to broad-spectrum antibiotic coverage. The most common presentation of fusariosis in immunocompromised hosts is pulmonary infection, and dissemination to extra-pulmonary
Zygomycetes
Zygomycosis, previously known as phycomycosis or mucormycosis, refers to uncommon diseases caused by a group of fungi belonging to the class Zygomycetes. The majority of organisms causing zygomycoses belong to three genera: Rhizopus, Mucor, and Rhizomucor (168, 333). These fungi are ubiquitous and can be easily isolated from soil, decomposing organic matter, fruits, and vegetables. When histologically examined, the Zygomycetes are broad, nonseptate or pauciseptate thick-walled, irregularly shaped hyphae with right-angle branching. Culture is positive in only 25% of histologically documented cases of pulmonary zygomycosis (170). These molds differ from Aspergillus, which has thin septate hyphae and which branches at acute 45degree angles (280). Determination of species requires culture of the fungus, although speciation is not necessary for treatment. As with invasive aspergillosis in HSCT recipients, there is a bimodal distribution of onset, early and late, but zygomycosis tends to occur later after allogeneic transplantation, corresponding to the severity of GVHD and the intensity of corticosteroid treatment (210).
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Infections in Hemopoietic Stem Cell Transplant Recipients
The major mode of transmission is believed to be by the inhalation of spores. However, other means such as trauma-related inoculation, or ingestion of contaminated foodstuff or herbal products has also been implicated (247, 280). Host factors that predispose to zygomycosis include immunosuppression, uncontrolled diabetes mellitus, deferoxamine therapy, skin breakdown, intravenous drug abuse, and malnourishment (122). Of these, the best-known condition associated with zygomycosis is uncontrolled diabetes mellitus with ketoacidosis. There is evidence that the incidence of zygomycosis is increasing in HSCT recipients (170, 213). Clinical manifestations can be classified by the tissue site involved: rhinocerebral, sinus, pulmonary, gastrointestinal, cutaneous, abdominopelvic, and disseminated (122). Rhinocerebral zygomycosis typically originates in the nares, palate, or paranasal sinuses with gradual or rapid involvement of the eye and brain, depending on the host factors. Symptoms may include fever, malaise, headache, nasal congestion, and occasionally brown, blood-tinged rhinorrhea. Symptoms may progress to facial and periorbital swelling and numbness with blurred vision or diplopia. Examination may show a black eschar on the palate, proptosis, chemosis, and cranial nerve involvement. Cavernous sinus thrombosis may occur with manifestations including loss of vision, corneal anesthesia, ophthalmoplegia, and facial anhidrosis. Once the brain is involved, there may be a deterioration of mental status, onset of seizures, or cerebrovascular accident. Radiographic procedures such as CT scan and MRI are required to determine the extent of disease process and to guide surgical procedures (19). Epidemiologically and clinically, pulmonary zygomycosis resembles aspergillosis. Again, patients with pneumonia in the setting of profound neutropenia or on prolonged high-dose corticosteroid therapy who fail to respond to empiric antibiotic treatment should be suspected of suffering from possible fungal pneumonia including zygomycosis (170, 182, 337). Zygomycosis also tends to cause vascular invasion as with aspergillosis, resulting in thrombosis, hemorrhage, and infarction. As pointed out above, if a lung biopsy specimen reveals the presence of definite fungal elements but culture fails to grow, the presumptive diagnosis favors zygomycosis over aspergillosis. Cutaneous zygomycosis can be precipitated by hematogenous spread as part of disseminated disease, but more often it is caused by direct invasion of preexisting wounds. The lesions may be unusually invasive, and they may involve not only superficial layers but also deeper tissues such as muscle, fascia, and bone (2, 256). Typically the lesion is very painful, erythematous, and indurated and may progress to a black necrotic ulcer. The diagnosis is made primarily
19
by direct histopathologic examination and by fungal culture. Therapy of zygomycosis is almost always accomplished using a combination of effective surgery and intense antifungal treatment. However, the overall mortality is still estimated at approximately 80% and in disseminated cases it approaches 100% (337). Currently, amphotericin B is the only dependably active agent. Lipid formulations of amphotericin B (i.e., Abelcet, AmBisome) have a theoretical advantage over the conventional preparation because they can deliver much higher doses of amphotericin B with reduced toxicity, but the added benefit of these newer preparations has yet to be proven. Among the newer azole compounds, posaconazole has demonstrated promising results, both in vitro and in vivo (E. Dannaoui, J. F. G. Meis, D. Loebenberg, and P. E. Verweu, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-193, 2002; L. K. Najvar, Q. N. Sun, R. Bocanegra, D. Loebenberg, and J. R. Graybill, Abstr. 41st Intersci. Conf. Antimicrob. Agents Chemother., abstr. J-1616, 2001). Voriconazole, on the other hand, is not active against Zygomycetes (F. M. Marty, L. Cosimi, W. A. Marasco, R. H. Rubin, and L. R. Baden, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M985, 2003). Endemic Mycoses Histoplasmosis, coccidioidomycosis, and blastomycosis are collectively called endemic mycoses because they occur in a geographically specific area. Thus, an infection with these fungi will occur only if the patient has previously been in the specific area. These infections are caused by Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis, respectively. These organisms exhibit thermal dimorphism: at temperatures below 35°C in the laboratory and in natural habitat they are molds, whereas at 37°C they are yeasts, except C. immitis, which in tissue phase is a spherule. Although these organisms can infect both normal hosts and immunocompromised subjects, hematogenously disseminated diseases occur more frequently in the latter patient population. The initial infections can be dormant for many years, and they may reactivate to reveal clinical manifestations as the host undergoes immunosuppression due to various reasons. Histoplasma
Histoplasmosis is worldwide in distribution, with high prevalence in tropical and temperate zones including South and Central America, Africa, and southeastern Asia. Within the United States, the disease is endemic in the south-central and north-central states, especially in the Mississippi and Ohio River drainage basins. A high prevalence has also been
20
Samuel et al.
noted in selected areas of the eastern United States. In two large urban outbreaks in the United States, it has been shown that dissemination and a higher mortality are observed in patients with immunosuppression, including solid organ transplant recipients (379, 380). Histoplasmosis in HSCT recipients has been reported in only a small number of patients (230, 262, 341, 359). Aerosolized microconidia of H. capsulatum are inhaled into the lungs and transformed into yeast forms at body temperature, which are phagocytized by macrophages in immunocompetent hosts. This process, however, is incomplete in immunocompromised patients; the yeasts multiply intracellularly and disseminate to mediastinal lymph nodes and other sites throughout the reticuloendothelial system. This organism has the tendency to stay latent unless the host defense system, especially cellular immunity, is impaired. In normal hosts with low-level exposure, fewer than 5% develop symptomatic disease, whereas most patients develop symptomatic infection with heavy exposure (373, 374). Flulike pulmonary illnesses, pericarditis, arthritis, or arthralgias with erythema nodosum are the most common manifestations of histoplasmosis in this patient population (373). In immunosuppressed patients, however, widely disseminated infection occurs in the majority of patients (88%), with predominant involvement of the lungs and other organs throughout the reticuloendothelial system (165). In transplant recipients, although pulmonary infections can occasionally be seen, disseminated infections are more common (165, 262). Patients with pulmonary infections present with fever, chills, cough, and shortness of breath. Mediastinal and hilar lymphadenopathies, which are common in healthy subjects with acute pulmonary syndrome, are not commonly demonstrated on chest radiographs in immunosuppressed patients. Clinical presentation of disseminated histoplasmosis is nonspecific, although most patients complain of fever, chills, fatigue, anorexia, and weight loss. On physical examination, one should look for hepatosplenomegaly, oropharyngeal ulcers (25 to 75%), and cutaneous lesions, including papules, pustules, plaques, ulcers, abscesses, and cellulitis. When CNS involvement is present, patients may present with headache, confusion, and seizures (126, 165, 300). Laboratory findings to support the diagnosis include pancytopenia, elevated alkaline phosphatase, elevated erythrocyte sedimentation rate, and electrolyte abnormalities suggestive of adrenal insufficiency (126, 300). The definitive diagnosis of histoplasmosis can be made by culture confirmation of the etiologic agent,
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but is often difficult. Routine blood cultures in broth usually do not yield positive results. The Isolator system (Wampole Laboratories, Princeton, N.J.), also known as the lysis-centrifugation blood culture method, appears to be superior for Candida, Cryptococcus, and Histoplasma to the Organon Teknika Corp. (Raleigh, N.C.) BacT/Alert system (207, 389), and may be superior to other manual and automated blood culture systems as well. The Isolator system has also been shown to be superior to MYCO/F Lytic medium for use in the BACTEC 9000 instruments (BD Biosciences, Sparks, Md.), equipped with a fluorescent sensor to detect a decreasing oxygen concentration rather than an increasing carbon dioxide concentration with microbial growth (368). Serologic tests for histoplasma antibody such as complement fixation and immunodiffusion tests are useful in normal hosts, but effective antibody levels often do not appear in immunosuppressed patients (165, 262). The detection of H. capsulatum capsular antigen by EIA of body fluids, such as serum, urine, and CSF, is extremely useful in the initial diagnosis and subsequent monitoring of disease progression during therapy in disseminated histoplasmosis (375, 377). The sensitivity of several diagnostic laboratory tests for histoplasmosis is summarized in Table 4 (376), which is separated into disseminated, chronic pulmonary, and self-limited categories. The last category includes acute pulmonary, rheumatologic, and pericarditis syndromes that characteristically improve in 2 to 3 weeks without treatment. Treatment guidelines for histoplasmosis from the IDSA have recently been published (378). Acute pulmonary histoplasmosis with hypoxemia or symptomatic for 1 month, chronic pulmonary infection, esophageal compression and/or ulceration, granulomatous mediastinitis with obstruction and/or invasion of tissue, and disseminated histoplasmosis need to be treated. On the other hand, acute self-limited syndrome, rheumatologic manifestations, pericarditis, histoplasmoma, broncholithiasis, and fibrosing mediastinitis need not be treated. The recommended treatment schedule for severe manifestations of histoplasmosis usually requires amphotericin B (35 mg/kg) Table 4.
Sensitivity of laboratory tests for histoplasmosisa H. capsulatum diagnostic sensitivity (% true positives)
Test
Antigen Culture Histopathology Serology a
Disseminated
Chronic pulmonary
Self-limited
92 83 43 71
21 85 17 100
39 13 9 98
Adapted from reference 376 with permission of Elsevier.
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Infections in Hemopoietic Stem Cell Transplant Recipients
over 3 to 4 months initially followed by itraconazole (200 to 400 mg daily) for 6 to 24 months, or fluconazole (400 to 800 mg daily) for 12 months in cases of meningitis. Moderately severe or mild cases can be treated with itraconazole for the entire course (6 to 24 months) without the necessity of initial amphotericin B (378). The data on the use of lipid formulations of amphotericin B in histoplasmosis are limited. However, the preliminary results of comparing standard preparation of amphotericin B to liposomal amphotericin B (AmBisome) in AIDS patients with disseminated histoplasmosis showed that liposomal amphotericin B may be the preferred drug (P. Johnson, L. Wheat, G. Cloud, W. Powderly, D. Lancaster, D. Bamberger, M. Goldman, R. Hafner, W. Dismukes, and the NIAID Mycosis Study Group, Abstr. 7th Conference on Retroviruses and Opportunistic Infections, abstr. 232, 2000). Coccidioides immitis
Regions where coccidioidomycosis is endemic follow the climatologic Sonoran life zone, which is characterized by hot summer months, modest rainfall, few winter freezes, low humidity, and alkaline soil. The etiologic agent Coccidioides immitis grows in a soil layer a few centimeters below the surface. Disruption of the soil layer in the area of endemicity causes the release of the fungal elements into the air. In the United States, this condition is found in the southwest, including the deserts of Arizona, Central Valley of California, Nevada, parts of New Mexico, and Texas. Also, areas throughout northern Mexico and parts of Central and South America are involved (253). Most of the population in the area of endemicity becomes infected during childhood. It is estimated that 100,000 infections occur annually in the United States, but patients with compromised cellular immunity are at higher risk for development of extrapulmonary disseminated disease. These include patients with AIDS and transplant recipients. Also, pregnant women and persons of African and Filipino descent have a higher risk for disseminated disease. Most coccidioidomycosis cases reported in the immunocompromised are in solid organ transplant recipients, and only a few HSCT recipients have been described (282, 341). Two cases of disseminated coccidioidomycosis and a case of localized pulmonary coccidioidomycosis in HSCT recipients were described; both disseminated cases died while the single case of localized pulmonary infection survived (282). C. immitis is a dimorphic fungus: the mold form represents a saprophytic phase and grows in soil, whereas inhalation of the conidia into the lungs results in a morphologic change, forming large, thickwalled spherules that become filled with hundreds of
21
endospores. When this spherule ruptures, numerous endospores are released, each of which has the potential to form a new spherule, thus continuing the infection cycle. Healthy individuals with acute pulmonary infection are asymptomatic 60% of the time. Others develop an influenzalike illness that includes cough, fever, drenching night sweats, or pleuritic chest pain. Arthralgias and myalgias may be prominent, and erythema multiforme or erythema nodosum may also be present. Chest radiographs are abnormal in half of symptomatic patients, typically with ipsilateral perihilar adenopathy. Eosinophilia is frequently a prominent finding in peripheral blood. Symptoms clear in a few weeks and a very small portion go on to develop residual pulmonary lesions or extrapulmonary disease (56). In transplant recipients, C. immitis tends to disseminate, with the skin, subcutaneous tissue, bones, and meninges being the common sites involved. Blood cultures are usually positive in this patient population (4). The skin lesions are papulopustular, nodular, verrucous, and often ulcerate. The vertebral bodies are the usual sites of osteomyelitis. Usual symptoms of meningeal involvement include headache, cranial nerve palsies, and increased intracranial pressure. Coccidioidomycosis in solid organ transplant recipients carries a dismal prognosis, and the mortality with treatment usually approaches between 50 and 63% in liver and renal transplant recipients, respectively (60, 151). The definitive diagnosis of coccidioidomycosis is made by the isolation of the organism from a clinical specimen. Appropriate specimens for culture include tissue aspirate or biopsies, sputum, and body fluids. The fungus grows well on routine mycology culture media, and it takes only 3 to 7 days, although it may grow as early as 2 days. A DNA-specific probe is now available, making identification possible as soon as growth is obtained (328). Whenever a diagnosis of C. immitis infection is suspected, it is important to notify the laboratory personnel so that they can take the necessary precautions to protect themselves from accidental exposure. Demonstration of typical spherules, measuring 20 to 80 m in diameter on wet mounts with KOH preparation, may lead to more rapid diagnosis. C. immitis spherules in tissue are readily identified by routine hematoxylin and eosin, Gomori methenamine silver, and PAS staining. Serology plays an important role in the diagnosis and follow-up of patients with coccidioidomycosis in immunocompetent patients, although serologic response in immunocompromised hosts may be poor (282, 352). Tube precipitin-reacting antibodies represent IgM antibodies that are present in primary infection and disappear as the infection enters the chronic phase.
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Samuel et al.
IgG antibodies detected by complement fixation or other methods appear instead during the chronic phase of infection and persist (103). For immunocompromised patients, however, serologic response may be poor (282, 352). The IDSA published a set of practice guidelines for major mycoses including coccidioidomycosis (104). Primary uncomplicated respiratory infections in healthy subjects usually require periodic reassessment to ensure resolution without antifungal treatment. However, immunosuppressed hosts and women in the third trimester of pregnancy or in the immediate postpartum period should be considered for antifungal treatment. Also, persons of African or Filipino descent who have a higher risk for dissemination should be considered for treatment. Usually, triazoles at their recommended doses for a period of 3 to 6 months are sufficient. In pregnant women, amphotericin B is the treatment of choice, since triazoles carry a teratogenic potential. Patients with diffuse pneumonia should receive several weeks of amphotericin B until there is clear evidence of improvement. Afterward, oral azoles, fluconazole, itraconazole, or ketoconazole should be administered for at least 1 year. A solitary lung nodule usually does not require antifungal therapy; however, if significant immunosuppression is necessary, therapy should be considered. Patients with asymptomatic pulmonary cavities do not require therapy, whereas those with symptomatic cavities are preferably treated with surgical resection and oral azole therapy. For patients with disseminated disease without CNS involvement, although high-dose oral azole therapy is preferred, amphotericin B is used as an alternative agent, especially in cases where responses to oral agents are less than expected. When the CNS is involved, high-dose fluconazole is preferable (104, 105), although itraconazole can also be used (347). Some investigators, however, prefer intravenous amphotericin B along with intrathecal amphotericin B. In transplant recipients, clinical relapse is common when therapy is discontinued, and most of the patients require indefinite or lifelong maintenance therapy. As an investigational triazole, posaconazole (Schering-Plough Research Institute, Kenilworth, N.J.) has been shown to be effective in animal models (205) and is currently undergoing human clinical trial studies. Caspofungin has also been shown to be active in animal models, but human data are limited. B. dermatitidis
Blastomycosis is endemic in the southeastern, central, and mid-Atlantic United States; Canadian provinces bordering the Great Lakes; and certain areas of New York and Canada adjacent to the St. Lawrence River
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(168). Isolated cases of blastomycosis are also reported in other parts of the world, including Africa and Central and South America. The etiologic agent, B. dermatitidis, which is the asexual stage of Ajellomyces dermatitidis, is a dimorphic fungus. It grows at room temperature as a whitish/tan mold and grows within the host or at 37°C as budding yeastlike cells with a thick, refractile cell wall that reproduce by single broad-based buds. B. dermatitidis tends to proliferate in warm and moist soil rich with decaying organic matter. Consequently, persons with occupational exposure to soil appear to have the highest risk for acquiring this infection. Blastomycosis is the least common endemic mycosis and primarily affects noncompromised hosts. However, recently an increasing number of blastomycosis cases have been described among transplant recipients, more solid organ transplant recipients than HSCT recipients (162, 341). There have been no cases of blastomycosis transmitted by a donor organ (162). Human blastomycosis usually occurs through inhalation of conidia into the lungs, which leads to asymptomatic or self-limited infections, but occasionally leads to chronic pneumonia. Most patients with pulmonary blastomycosis require treatment, but occasionally spontaneous cure occurs in immunocompetent persons (54). Blastomycosis involves the lungs, skin, bone, and genitourinary tract, in decreasing order of frequency. The pulmonary lesions in transplant recipients are similar to those of healthy hosts and include lobar pneumonia, diffuse infiltrates, and cavitary lesions (255). The infection may occasionally disseminate, more often in transplant recipients than in healthy subjects, to extrapulmonary sites such as the skin, skeletal system, and male genitourinary tract. Mortality rates approach 30 to 40% and most deaths occur during the first few weeks of therapy (54). The most common extrapulmonary site is the skin. Most patients with cutaneous blastomycosis show multiple skin lesions, which are papulonodular, pustular, and ulcerative (255, 312). Men are more likely to have genitourinary involvement, which may include prostatitis, epididymitis, and orchitis. Disseminated blastomycosis may involve the CNS in 5 to 10% of cases and manifestations include meningitis and epidural or cranial abscesses (36, 171). Either demonstrating the yeast from clinical specimens or growth of the fungus in culture usually makes the diagnosis from tissues suspected of the infection. The former is much speedier and highly reliable while the latter confirms the diagnosis, but it takes 2 to 4 weeks of incubation. The presence of the yeast is unique and signifies blastomycosis, unlike Candida or Aspergillus, which may represent a contaminant. The fungus is most commonly identified by KOH preparation followed by direct microscopy,
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Infections in Hemopoietic Stem Cell Transplant Recipients
and tissue biopsy specimens can be prepared for standard fungal staining such as PAS or methenamine silver stain (53, 163). The organism can be identified morphologically as B. dermatitidis and also by employing highly specific and sensitive DNA probes (163). Serology as well as skin testing are neither specific nor sensitive and have low clinical utility (12). Another common method used to identify fungi including Pneumocystis is calcofluor white stain, which specifically binds to 1,3- and 1,4-polysaccharides (cellulose and chitin) of cell wall in fungi. This technique enhances the detection of fungi; however, one minor disadvantage of this technique is the need for a fluorescence microscope equipped with a barrier filter to protect the eye. Organisms will exhibit a green fluorescence (178). Guidelines for treatment of blastomycosis have been published by the IDSA (54), and amphotericin B (0.7 mg to 1 mg/kg/day; total dose of 1.5 g to 2.5 g) is recommended. In some patients, once improvement or stabilization is seen after receiving a total dose of 500 mg of amphotericin B, therapy can be changed to itraconazole. In severely immunocompromised patients, amphotericin B in a total dose of at least 2 g is preferred, followed by itraconazole. Total duration of treatment is usually 6 to 12 months for all patients. For patients with CNS involvement who cannot tolerate itraconazole, fluconazole can be given instead. For pregnant or pediatric patients, amphotericin B only is recommended. P. jiroveci (P. carinii) Pneumocystis is distributed worldwide in humans as well as a variety of animals, and these organisms show a high degree of genetic diversity and host specificity. The taxonomic status of organisms known as P. carinii has been debated for several decades, since morphologically they resemble protozoa, but gene sequence studies indicate that they should be categorized as fungi. These organisms show 60 and 20% homology with fungi and protozoa, respectively, and are not culturable outside lung tissue; thus, detailed studies on its life cycle, biochemistry, and metabolism are limited. They are currently placed, on the basis of genetic and morphologic criteria, in the phylum Ascomycota within a newly described class, Archiascomycetes. The new nomenclature for the Pneumocystis species that causes human disease is now P. jiroveci, since P. carinii can cause disease only in rats (70). Scientific evidence indicates that very few Pneumocystis organisms are required to initiate the infection, and fewer than 10 organisms could establish a fulminant infection in immunocompromised rats (71). Most humans become seropositive by 2 to 4 years of age, and the organism therein can survive
23
indefinitely without causing any ill effects until the host immune system is severely compromised. In AIDS patients (who develop most of the Pneumocystis pneumonia today), 95% of Pneumocystis cases occur in patients with CD4 counts less than 200/mm3 with an annual incidence of 8% (148). Clinical signs and symptoms of Pneumocystis pneumonia are that of atypical pneumonia. Typically there is a gradual onset over a 2- to 4-week period with fever, nonproductive cough, and slowly increasing dyspnea. However, the clinical picture can be quite variable; in some patients, no symptoms may be present at the time of diagnosis. The chest radiograph typically shows bilateral diffuse infiltrates, perihilar in distribution. The chest radiograph may also vary a great deal, ranging from normal films to unilateral or bilateral infiltrates, nodules, cavitary lesion, or effusion. There is no large prospective study comparing signs and symptoms specifically in the HSCT recipients to those of other patient populations such as AIDS patients. It is prudent to believe that the clinical picture and laboratory findings would be similar to those in HIV-positive patients. The most frequent laboratory abnormality is impaired oxygenation. Another abnormality, which may be reflective of Pneumocystis pneumonia, is serum lactic dehydrogenase levels, which are elevated in active pulmonary disease and which fall with successful treatment (398). Pneumocystosis should be in the differential diagnosis of any subacute pneumonia in immunocompromised patients. Histopathologic staining makes a definitive diagnosis. Fiberoptic bronchoscopy with BAL provides an adequate specimen for the diagnosis of P. jiroveci. Methenamine silver, toluidine blue, and cresyl echt violet are most commonly used to selectively stain the cell wall. The Wright-Giemsa stain is used to stain the nuclei of all developmental stages of the organism. In addition, immunofluorescence has been used with success. TMP-SMZ is considered the drug of choice for treatment of all different forms of pneumocystosis. The usual daily doses of 15 to 20 mg of TMP and 75 to 100 mg of SMZ in 3 to 4 divided doses for 2 weeks for non-HIV patients and 3 weeks for HIV patients are well-accepted treatment regimens. Alternative agents include pentamidine (4 mg/kg) given intravenously and trimetrexate (daily dose of 45 mg/m2) combined with folinic acid (20 mg/m2 every 6 h) for the same duration as TMP-SMZ. Several other regimens are atovaquone (750 mg twice daily), TMP (15 mg/kg daily) plus dapsone (100 mg daily), and clindamycin (600 mg intravenously every 6 h or 300 to 450 mg orally) plus primaquine (15 to 30 mg daily). Use of glucocorticoids at moderate doses (40 mg twice daily) with a taper over 20 days, for
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Samuel et al.
patients with a pulmonary alveolar oxygenation of 70 mm Hg or an alveolar-arterial gradient of 35, is advocated. Prophylaxis is indicated for patients with HIV and CD4 200/mm3. TMP-SMZ, taken as one doublestrength tablet orally once daily, is the regimen of choice. Other doses of TMP-SMZ, such as one singleor double-strength tablet three times weekly, are also used. Other regimens, such as dapsone 100 mg daily or 50 mg daily combined with a weekly oral dose of pyrimethamine (50 mg) and folinic acid (25 mg), are also employed. In allogeneic HSCT recipients, Pneumocystis infection develops in 10 to 20% of patients, typically during the period immediately after engraftment until 6 months following HSCT. During this period and beyond for those requiring immunosuppressive agents such as prednisone or cyclosporine, Pneumocystis prophylaxis should be maintained (73). Parasitic Infections A parasite is an organism that lives within a host and obtains an advantage unilaterally. These include and are often limited to infections caused by protozoa and helminths. Protozoa are unicellular and microscopic and replicate within mammalian hosts, whereas helminths are multicellular and macroscopic and do not typically multiply within mammalian hosts. Because each parasitic infection has a unique set of circumstances under which human malady is observed, special attention should be paid to a patient’s exposure history, immune status, and presenting laboratory parameters, especially eosinophilia. Exposure history should include a detailed account of remote and recent travel, dietary habits, and transfusion of blood products. Eosinophilia is not associated with protozoan infections except Isospora belli and occasionally Dientamoeba fragilis. Eosinophilia is frequently observed in helminthic infections, especially in the tissue-invasive phase of nematodes, such as Ascaris, and hookworm infections, and the early stages of fluke infections such as schistosomiasis, paragonomiasis, clonorchiasis, and fascioliasis. Chronic eosinophilia lasting more than a year may be indicative of strongyloidiasis, visceral larva migrans, filariasis, and cysticercosis. Understanding the geographic distribution of parasitic infections is very helpful in the search for clues. Parasitic infections encountered in the United States as well as other countries include cryptosporidiosis, cyclosporiasis, echinococcosis, giardiasis, enterobiasis, strongyloidiasis, toxoplasmosis, and trichinellosis. Certain infections such as filariasis, leishmaniasis, malaria, schistosomiasis, and trypanosomiasis are endemic in many developing coun-
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tries. Among these infections, only those that appear to be important in immunosuppressed hosts will be described. Toxoplasma gondii The etiologic agent T. gondii is an intracellular protozoan organism that is ubiquitous in nature and infects both mammals and birds throughout the world. The organism exists in three forms during its life cycle: the tachyzoite, the tissue cyst (containing bradyzoites), and the oocyst. The tachyzoite is the asexual invasive form (equivalent to the trophozoite of other protozoal infections); the tissue cyst is found in the infected tissue during the chronic phase of infection; and the oocyst is produced during the sexual cycle in the definitive host, the cat. In the United States, roughly 5 to 30% of individuals 10 to 19 years old and 10 to 67% of the population over age 50 show serologic evidence of past exposure (217). Human infection occurs mainly by the ingestion of undercooked meat harboring tissue cysts or of sporulated oocysts from contaminated soil, or by transfusion of blood products or organ transplantation infected with the organism. Also, in women infected with T. gondii, during the first trimester of pregnancy maternally acquired toxoplasmosis leads to infection in the fetus in approximately 15% of cases, although the disease in the infant is more severe. Congenital acquisition increases to 25% in the second trimester and up to 65% in the third trimester, although the disease may be milder or asymptomatic (40, 171). Women who are serologically positive before pregnancy are protected and their children do not have a risk of congenital neonatal infection. Most infants (70%) affected by the syndrome can have normal development if appropriately handled with early diagnosis and prompt treatment (156). In an immunocompetent population, 80 to 90% of acute toxoplasmosis cases are usually asymptomatic. However, rare complications may involve pneumonia, myocarditis, encephalopathy, meningoencephalitis, pericarditis, and polymyositis. Toxoplasmosis in HSCT recipients is relatively rare when compared to AIDS patients, yet a fair number of cases have been described (78, 161, 216, 284, 321, 323). The frequency of documented toxoplasmosis in this population varies from 0.4 to 3%, depending on the prevalence of seropositivity in HSCT recipients prior to the procedure (215). Clinical onset may be early after allogeneic HSCT, with a median of 64 days (range, 4 to 516 days) (216). Late cases are encountered in chronic GVHD patients requiring immunosuppressive treatment (215). Acute GVHD has been suggested as a predisposing factor for toxoplasmosis in HSCT recipients, such that 73% developed moderate to severe acute GVHD prior to infec-
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Infections in Hemopoietic Stem Cell Transplant Recipients
tion (216). The brain is the most commonly affected site, followed by the lung and the heart. Motor weakness is the most common presenting focal neurologic sign, although other abnormalities including change in mental status, cranial nerve abnormalities, speech disturbances, sensory disturbances, cerebellar signs, seizures, and movement disorders may also be detected. Meningeal signs are rare. Lung involvement by T. gondii is rather nonspecific and mimics interstitial pneumonia of other etiologies (114, 291). Cardiac involvement is also nonspecific and may present with arrhythmia, pericarditis, and heart failure; diagnosis is frequently made at autopsy (323). The definitive diagnosis of acute infection with Toxoplasma is either to isolate the etiologic agent using xenodiagnosis from human tissue inoculated into test animals or to demonstrate typical tachyzoites from the tissue specimen. Demonstration of typical cysts containing bradyzoites signifies chronic infection. However, xenodiagnosis is laborious and not available in most laboratories, and finding tachyzoites requires deep-tissue biopsy. Radiographic imaging studies such as a CT or an MRI of the brain revealing multiple focal lesions in immunocompromised patients strongly favor the diagnosis of CNS toxoplasmosis, but it is not pathognomonic. An MRI is more sensitive in detecting T. gondii lesions than a CT scan, but it also is not pathognomonic. All HSCT recipients undergo serologic tests for toxoplasmosis preoperatively as part of the screening process, and are given appropriate treatment and/or prophylaxis accordingly before the procedure. Under the best of circumstances, serologic tests for toxoplasmosis are not dependably reproducible or specific. Toxoplasmosis in seronegative HSCT recipients is extremely rare. The antibody response to a Toxoplasma infection, as in other infections immediately following an HSCT procedure, is poor; therefore, standard serology during this period is not reliable. PCR methodologies detecting Toxoplasma DNA have been developed for the diagnosis of neonatal toxoplasmosis (148), and the same technologies have been used in the evaluation of toxoplasmosis in AIDS patients where the sensitivity and specificity in the blood and CSF have been shown to be 50 to 65% and 95 to 100%, respectively (89). Similar data are not available for HSCT patients, but in one study, 46% of the patients with Toxoplasma disease and all 6 with infection had 1 positive PCR result (39). The PCR technologies have not undergone standardization. The significance of the positive test for T. gondii DNA in blood without clinical manifestations is not certain. This may represent a transition from tissue cysts into trophozoites (tachyzoites), which
25
would be favored by intense immunosuppression (39). Conversely, in HSCT recipients, well-documented disseminated toxoplasmosis as demonstrated by positive cytology has failed to give a positive PCR (142), emphasizing the importance of cytologic examination if clinically indicated whenever a proper specimen can be submitted for cytologic examination. Treatment is usually a combination of pyrimethamine (200 mg loading, then 50 to 70 mg daily) with folinic acid (10 to 20 mg daily) and either sulfadiazine (1 to 1.5 g every 6 h) or clindamycin (600 mg every 6 h). The duration of therapy should last at least 4 to 6 weeks beyond complete resolution of toxoplasmosis. Prophylaxis of toxoplasmosis in seropositive HSCT recipients consists of TMP-SMZ (2 double-strength tablets per day twice weekly) or pyrimethamine-sulfadoxine (Fansidar) (1 tablet twice weekly) (215). Toxoplasmosis in HSCT recipients carries a grave prognosis, with nearly 90% of the patients dying of the disease, in contrast to the similar disease in AIDS patients where 70 to 80% respond to therapy (215). Malaria Malaria is the most important parasitic disease in the world. It affects more than 1 billion people and causes between 700,000 and 2.7 million deaths annually. More than 90% of malaria cases occur in subSaharan Africa (38). Earlier global efforts to eradicate malaria from the 1940s to the 1970s have virtually eliminated the disease in the subtropics and have eradicated it in North America, Europe, and Russia. Malaria is a protozoan disease transmitted by the bite of infected Anopheles mosquitoes and is endemic in many parts of the tropics. There are four species of the genus Plasmodium that cause nearly all human malaria: P. vivax, P. ovale, P. malariae, and P. falciparum. Of these four species, P. falciparum is the most malignant form of malaria, causing the most serious complications including death. Anopheles gambiae is the major vector of P. falciparum. Although malaria is an uncommon complication in HSCT recipients, the infection, which can be transmitted by many different modalities, has been documented in both autologous and allogeneic HSCT recipients. Some example cases will be described to demonstrate the importance of previous known or circumstantial exposure to malaria. Two patients, one autologous and one allogeneic HSCT recipient with probable geographic exposure to malaria, developed malaria caused by P. vivax at days 20 and 70, respectively (272, 296), and both patients responded to chloroquine. In another case, malaria due to P. falciparum developed in an HSCT recipient on day 12, where both this recipient and the donor were exposed to malaria by history (184). In a different
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Samuel et al.
case, a thalassemia patient with no past exposure who had required multiple transfusions prior to HSCT developed spiking fevers with a diagnosis of malaria due to P. falciparum on day 6 after undergoing HSCT (342). Additionally, a case of malaria due to P. falciparum was documented in an HSCT recipient with no endemic exposure from an unrelated volunteer donor who previously had malaria and was treated (245). Finally, a fatal case of malaria transmitted by improperly prepared donor’s hemopoietic cells before transplantation has been documented (79). These cases emphasize the necessity of eradicative antimalarial treatment of the recipients and/or donors before the HSCT procedure is performed, where there exists a risk of previous exposure. The life cycle of Plasmodium consists of an asexual erythrocytic phase and a sexual phase where male and female gametocytes in the gut of a female mosquito mature to produce sporozoites. Infection begins as the infected female Anopheles mosquito bites to feed on blood, and during the blood meal, sporozoites in the salivary gland of the insect are injected into the skin. From the skin, they enter the bloodstream and are carried to the liver, where they multiply and mature in the hepatocytes to become tissue schizonts and the hepatocytes burst to release merozoites. Through this maturation process, a single sporozoite becomes up to 30,000 merozoites, which go on to invade and destroy red blood cells. In the case of P. vivax and P. ovale, however, some parasites remain in the liver and become dormant (hypnozoite) and can be reactivated to produce clinical malaria months to years later. The merozoite in the red blood cell matures to ring form, trophozoite, and schizont. Schizonts mature, lyse their host red blood cells, and release the next generation merozoites, which go on to invade uninfected red blood cells. At this juncture some parasites differentiate to male and female gametocytes. If taken up by the female Anopheles mosquito, the gametocytes mature to male and female gametes, which in turn produce zygotes. In the mosquito gut, the zygotes develop into an oocyst, the mature form of which produces sporozoites. These sporozoites travel to the salivary glands of the mosquito. The hallmark of malaria is acute cyclic fevers. Malaria caused by P. vivax or P. ovale typically shows 48-h cycles (tertian malaria), whereas that caused by M. malariae manifest with 72-h cycles (quartan malaria). Patients with P. falciparum, however, more often present with continuous or irregular spikes and rarely present with well-synchronized 48-h cycle symptoms, although the parasitic cycle is 48 h. Malaria paroxysm characteristically goes through three stages. The first is a “cold or chilling” stage, which lasts 15 minutes to several hours during which
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patients may experience true rigors. The second is a “hot stage” lasting several hours, when the patient’s temperature may rise to 104°F or higher with minimal diaphoresis. During this stage, patients may develop serious complications such as febrile seizures and hyperthermic brain damage. Other clinical manifestations include tachycardia, hypotension, headache, cough, backache, abdominal pain, vomiting, diarrhea, and changing mental status. The third is a “sweating” stage, which occurs within 2 to 6 h after the second stage with resolution of fever. At this stage, patients experience marked fatigue and often fall asleep. The most dreadful complication of P. falciparum infection is cerebral malaria, which leads to coma. This complication carries a significant fatality rate (20%) and is believed to be attributable to several factors, including the blockage of capillaries due to parasitized red blood cells, hypoglycemia, and the effects of cytokines such as tumor necrosis factor (173). Other complications including acute renal failure and pulmonary edema may also develop. Diagnosis of malaria is best made by microscopy of Giemsa-stained thick or thin blood smears under oil-immersion magnification (1,000). Thick-film preparations increase the possibility of detecting light infections by screening a large amount of blood cells, while thin-film preparations are most suitable for identifing morphological characteristics of the blood parasites. It is important to repeat blood smears every 12 h for 2 days if the first smear is negative. Also, more than one Plasmodium species may be involved in about 5% of patients infected with malaria. Although characteristic gametocytes (if found) are diagnostic, they are often absent. Other technologies such as malaria antigen or antibody detection, DNA probes, and PCR methods are available in specialized laboratories, but they are not widely available. Differential diagnosis of an acute febrile illness in a patient from a malarious area or with exposure history should include malaria. Diagnostic approaches to confirm the diagnosis should be undertaken immediately. Once a diagnosis is confirmed, treatment should be instituted as soon as possible. Knowing the resistance status and the exact species of the infecting organism is extremely important. Chloroquine is the treatment of choice for chloroquine-susceptible malaria. In patients who are able to take oral medication, chloroquine phosphate (Aralen) is administered at 1,000 mg (600 mg base or 10 mg base/kg), followed by 500 mg (300 mg base or 5 mg base/kg) after 6 h, and the same dose is repeated on days 2 and 3. For patients unable to tolerate oral administration, chloroquine can be given either as an intramuscular (2.5 mg base/kg every 4 h or 3.5 mg base/kg every 6 h, not to exceed a total dose of 25 mg base/kg) or an intravenous (10 mg base/kg over 4 h,
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Infections in Hemopoietic Stem Cell Transplant Recipients
followed by 5 mg base/kg every 12 h over a 2-h infusion, not to exceed a total dose of 25 mg base/kg) injection. For patients with chloroquine-resistant P. vivax malaria who are able to take oral medications, mefloquine (Lariam) (750 mg followed by 500 mg in 8 to 12 h) or halofantrine (500 mg every 6 h, a total of 3 doses over 24 h) is effective. For a patient infected with chloroquine-resistant but mefloquine-susceptible P. falciparum, mefloquine (same doses as above) can be used, but patients infected with chloroquine- and mefloquine-resistant strains should be treated with a combination of quinine sulfate (650 mg orally every 8 h for 3 to 7 days) and doxycycline (100 mg twice daily for 7 days), or pyrimethamine-sulfadoxine (Fansidar) (3 tablets as a single dose on the last day of treatment), or clindamycin (900 mg every 8 h for 5 to 7 days). Other regimens such as atovaquone/ proguanil (Malarone) (2 Malarone tablets twice a day for 3 days) or atovaquone/proguanil with artesunate (4 mg/kg/day for 3 days), or artesunate alone can be used. For patients who are unable to tolerate oral medications, several parenteral regimens are available: quinine dihydrochloride given intravenously (20 mg/kg over 4 h, followed by 10 mg/kg over 1 to 2 h every 8 h until patient tolerates oral medications); quinidine gluconate given intravenously (10 mg/kg, maximum 600 mg over 1 to 2 h, followed by 0.02 mg/kg/h until patient tolerates oral medications); and artemether given intramuscularly (3.2 mg/kg initially, followed by 1.6 mg/kg/day for 5 to 7 days) (173). For the HSCT recipient who travels, prophylaxis of malaria can be achieved. Chemoprophylaxis of chloroquine-susceptible malaria is quite readily accomplished by the use of chloroquine phosphate (500 mg) taken weekly, beginning 1 to 2 weeks before entering the malarious area, during exposure, and for 4 weeks after leaving the area of endemicity. For chloroquine-resistant malaria, mefloquine (250 mg) is used on the same schedule. Recently another regimen known as atovaquone-proguanil (Malarone) (250 mg/100 mg) became available. It is taken daily, beginning 1 to 2 days before one enters the area of endemicity, during exposure, and for 1 week after leaving the area of endemicity. Doxycycline (100 mg daily) is an alternative to mefloquine or atovaquone/ proguanil; it needs to be taken 1 to 2 days before entering the malarious area, during exposure, and for 4 weeks after leaving the malarious area. Resistance of Plasmodium spp. to first-line drugs such as chloroquine and pyrimethamine-sulfadoxine, and that of vector mosquitoes to a major insecticide (DDT) are widespread. Thus, eradication of malaria appears impossible. Continued efforts to develop new drugs and especially effective vaccines appear
27
essential for better control of malaria. The three major parasite stages in humans (sporozoite, merozoite, gametocyte) are antigenically distinct. Therefore, an effective vaccine must contain all three antigenic types. Recently, complete genome sequencing of the principal vector A. gambiae (150) and the parasite P. falciparum (35, 111) has been completed. These scientific accomplishments should provide a wealth of information for a better understanding of the mechanisms involved in the pathogenesis, and resistance mechanisms of the vector and malaria parasite as well. Strongyloides stercoralis S. stercoralis infection is endemic in warm climates worldwide, including parts of the southern United States. Unlike other helminths, S. stercoralis is able to replicate in the human host. Adult parasitic females are parthenogenetic, whereas parasitic males do not seem to exist. S. stercoralis is a soil-dwelling nematode that requires warm, moist conditions to survive. The parasite exists in two different forms: the freeliving rhabditiform larvae and the infective filariform larvae that can penetrate intact skin or mucosa upon contact. Soil contaminated by feces infected with S. stercoralis allows rhabditiform larvae to mature into free-living adult male and female nematodes in the soil. Adult females produce eggs that generate the production of rhabditiform larvae. The free-living larvae can turn into the infective filariform larvae. Human infection is usually acquired through exposure to either feces or fecally contaminated soil in developing countries, yet can also be acquired from ingestion of fecally contaminated food. Once the parasite enters the human body by penetrating the integument or mucosa of the gastrointestinal tract, the infective larvae are carried by the capillaries to the right side of the heart. According to a dog model experiment, the process from dermal infection to appearance of the larvae in the venous blood takes only 15 min (115). The parasite then travels to the lung and the alveoli and then ascends to the oral cavity via the tracheobronchial tree. It is then swallowed and enters the gastrointestinal tract, where the larva matures into an adult female and upon fertilization deposits up to 40 eggs in the proximal small bowel. The eggs hatch to produce rhabditiform larvae, which are usually expelled in stool. It takes 3 to 4 weeks after infection to detect the rhabditiform larvae in stool (199). Occasionally, some of the rhabditiform larvae turn into the infective filariform larvae within the colon and are able to penetrate the mucosa, thus establishing a perpetual infection within a host, referred to as autoinfection. S. stercoralis may infect anyone who has lived in an area where it is endemic. As a result of autoinfec-
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tion, strongyloidiasis can persist for a few years to decades. In immunocompetent patients, S. stercoralis infection is asymptomatic in more than 50% of infected individuals (37). In patients with steroid use, S. stercoralis multiplies much more efficiently, such that the parasite load can be very high, precipitating hyperinfection syndrome. Cyclosporine, on the other hand, has an intrinsic antiparasitic effect and does not enhance the parasite burden. Patients with a high parasitic load may show clinical signs and symptoms ranging from vague epigastric pain, bloody diarrhea, and bowel obstruction to a malabsorption syndrome. When the pulmonary system is involved with hyperinfection syndrome, the symptom complex may mimic adult respiratory distress syndrome with an acute onset of dyspnea, hemoptysis, and diffuse infiltrates on chest radiograph. A fatal case of disseminated strongyloidiasis has been reported in an HSCT recipient presenting with shortness of breath and fever (271). Mortality rates due to disseminated strongyloidiasis have been reported to be high (87%) (181). This syndrome may involve the CNS to produce meningitis and brain abscesses. Hyperinfection may also be complicated by monomicrobial or polymicrobial bacteremia (155) or candidemia (C. G. Fumberg, J. R. Kostman, A. L. Truant, and B. Suh, Abstr. 34th Infectious Disease Society of America, p. 131, 1996), which are believed to be transported by a “piggyback” phenomenon, whereby S. stercoralis migrates through the gastrointestinal wall carrying the organisms. A definitive diagnosis depends on the demonstration of S. stercoralis larvae in either the feces or duodenal aspirate. Serial freshly passed specimens should be examined to increase the yield. A modified agar plate method has been shown to be superior to the conventional test with higher sensitivity (96%) (302). The eggs are almost never found because they hatch in the intestine. Eosinophilia can be a clue to the diagnosis of strongyloidiasis, but eosinophilia may not be present in immunocompromised patients. An enzyme-linked immunosorbent assay for antibodies to S. stercoralis (301) and the use of molecular probes (273) are more sensitive. The strongyloides antibody tests may cross-react with other helminthic infections such as Ascaris lumbricoides, hookworm, filarial, and schistosome infections (317). Antibody detection is more convenient for screening populations at risk, sensitivity is good (84 to 90%) (317), and the test is available commercially. In cases of hyperinfection syndrome or disseminated strongyloidiasis, diagnosis is made by the demonstration of infective filariform larvae in gastrointestinal or pulmonary secretions or other tissue or tissue fluids such as CSF, urine, or peritoneal fluid. Treatment of choice for uncomplicated strongy-
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loidiasis is ivermectin (200 g/kg daily for 1 to 2 days), and the treatment should be extended for at least 5 to 7 days for disseminated cases. An alternative agent is thiabendazole (25 mg/kg twice daily for 2 days) for uncomplicated cases, and the same dose schedule for 5 to 7 days for disseminated cases, but this regimen carries a lower cure rate and higher adverse effects (106). Chagas’ Disease (American Trypanosomiasis) Chagas’ disease, also known as American trypanosomiasis, is caused by Trypanosoma cruzi, a protozoan transmitted from animals to humans by reduviid or triatomid bugs. As the infected bug feeds, it defecates on the skin, and as the host scratches the site, the organism is inoculated. In a majority of cases (80%), transmission is through mucous membranes or skin breaks that are contaminated by the feces of the triatomine bug. Many domestic and wild animals including rodents and armadillos serve as reservoirs of the infection. The infection can also be transmitted by unscreened blood transfusions, from an infected mother to her fetus, via organ transplantation, and by laboratory accidents (167, 283). The geographic distribution of the disease extends from the southern United States to the southern tip of Argentina, affecting a total of approximately 16 million to 18 million people (392). The parasite characteristically appears in the blood in flagellate trypanosomal (trypomastigote) form; in the tissue, it shows in nonflagellate leishmanial (amastigote) form. The disease typically follows three stages: acute, intermediate, and chronic. The acute stage is usually subclinical, and when clinically symptomatic it may be manifested by nonspecific symptoms such as fever, general edema, lymphadenitis, and anemia. Occasionally, it may proceed to severe life-threatening complications such as myocarditis or meningoencephalitis (238). The parasite at this stage may be demonstrable in the peripheral blood by direct microscopy. The signs and symptoms of acute Chagas’ disease usually subside within a few weeks to several months even without a specific treatment. The disease then enters the intermediate stage, during which the disease can be detected only by serology or sensitive parasite detection methods such as xenodiagnosis, hemocultures, or PCR (267). This stage may last a few years to decades. There are no clinical or laboratory indicators to predict when the chronic stage would manifest. As the disease process enters the chronic stage, the most common presenting symptoms are those of myocardial involvement showing precordial discomfort and/or arrhythmias including palpitations, heart block, and premature ventricular contractions. This may eventually lead to congestive heart failure. The
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Infections in Hemopoietic Stem Cell Transplant Recipients
second most common manifestation is a hugely dilated esophagus and/or colon, known as megaesophagus and megacolon, respectively. Clinical manifestations of the megaesophagus include achalasia, chest pain, and regurgitation, while those of the megacolon are chronic constipation and abdominal pain. Thus, Chagas’ disease may be a convoluted course of illness. For suspected cases of Chagas’ disease, a history of exposure or transfusion from a chronically infected donor should be sought. Some reactivation cases have been described in HSCT recipients after engraftment, and some before the infusion of the marrow cells during the conditioning chemotherapy (78). The Infectious Disease Advisory Committee of the INCUCAI (Unique Central National Institute Ablation Coordinator and Implants) and members of the Argentine Chagas’ Disease Diagnosis Laboratory network recommend that patients with Chagas’ disease be acceptable candidates for solid organ transplantation and HSCT; however, infected donors are considered unacceptable for all heart transplantation (238). A definitive diagnosis of the acute disease depends on the demonstration of parasites (trypomastigotes) in the fresh anticoagulated blood or in a buffy coat preparation. The yield can be improved by concentration using centrifugation after lysis of the red blood cells using a weak ammonium chloride (0.083%) solution (Strout test) (331). Other diagnostic methods such as xenodiagnosis and hemoculture techniques are 100% specific and 50 to 80% sensitive, yet are very labor intensive, and the time required for completion of the study is rather long (1 to 3 months) (81, 336). In the intermediate or chronic phase of the disease, the most commonly used methods to look for serological evidence of antibodies against T. cruzi are indirect fluorescence, indirect hemagglutination, and enzyme-linked immunoassay methods (181, 264). PCR detection of T. cruzi DNA from the blood is likely to eventually replace the other methods (121, 370). Currently, two drugs are used to treat Chagas’ disease: a nitrofuran derivative, nifurtimox; and a nitroimidazole derivative, benznidazole (238). In the United States only, the first preparation of nifurtimox is available as an investigational drug from the CDC Drug Service [phone, (404) 639-3670]. It is used in a dose of 8 to 10 mg/kg/day for 90 to 120 days. The efficacy of benznidazole appears to be about equal to that of nifurtimox, but it has been less widely tested. Drug toxicity of either preparation is a serious problem. The most common side effects of nifurtimox include gastrointestinal intolerance such as anorexia, nausea, vomiting, and abdominal pain. Neurological adverse effects and rash are also frequently encountered. Peripheral neuropathy and bone marrow sup-
29
pression are seen with benznidazole use. These drugs have been shown to be effective in treatment of acute Chagas’ disease; however, their efficacy in intermediate and chronic cases has not been well established. Cryptosporidium Cryptosporidium parvum, first recognized as a human pathogen in 1976, is now a leading cause of endemic and epidemic diarrheal disease worldwide. It emerged as a major cause of chronic diarrhea in patients with AIDS in the 1980s, and, in 1993, a massive outbreak of waterborne Cryptosporidium infection involving more than 400,000 individuals in Milwaukee, Wis., attracted public attention (207). C. parvum is an intracellular protozoan parasite, which has a complex life cycle. It is capable of completing all stages of its life cycle in the gastrointestinal tract within a single host without extraintestinal development. Oocysts of Cryptosporidium, which are equipped with a thick, two-layered and environmentally resistant wall, sporulate while within the host cells and are infective when they are released in the feces (68). The oocysts are remarkably resistant to most commonly used disinfectants, including routine chlorination of drinking water. Humans are infected when they ingest Cryptosporidium oocysts. Persons at increased risk for the infection include household contacts and sexual partners of infected persons, day-care personnel, users of communal swimming pools, and travelers to regions of high endemicity. Transmission can result from contact with domestic animals such as sheep and cows, and ingestion of contaminated water with Cryptosporidium oocysts (208). Cryptosporidial infection accounts for 2.2 and 6.1% of the diarrheal diseases in immunocompetent persons in developed and developing countries, respectively. Cryptosporidial infection rates are much higher in immunocompromised patients. In patients with AIDS and diarrhea, for instance, the incidence of Cryptosporidium runs 14 and 24% in developed and developing countries, respectively (55). In renal transplant recipients, a prevalence of 20% has been observed (246). On the other hand, a prospective analysis of 65 HSCT recipients in India revealed only a 4.61% incidence rate (160), and another similar study with 60 HSCT recipients in the Netherlands revealed only one patient infected with Cryptosporidium (351). Infection with Cryptosporidium in HSCT recipients has not been shown to be associated with increased mortality (160, 266), although severe diarrheal disease (211, 266) and pulmonary involvement (116) have been documented. Cryptosporidial infection appears to involve only the superficial epithelia of the gastrointestinal tract. The incubation period is 7 to 10 days. Although
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cryptosporidiosis may be asymptomatic, most patients (90%) have profuse watery diarrhea containing mucus, but rarely blood or leukocytes. The diarrhea lasts approximately 2 weeks, accompanied by nausea, vomiting, and abdominal cramps. In the Milwaukee outbreak, the major clinical manifestations observed include watery diarrhea (93%) with median maximal number of stools per day of 12, abdominal cramps (84%), fever (57%), vomiting (48%), and weight loss (75%) (55, 208). Clinical manifestations may vary depending upon the immune status of the host. In patients with AIDS, fulminant infection is observed in patients with CD4 T-cell counts below 50/mm3, whereas less symptomatic infections are associated with higher CD4 cells (98). The diagnosis of cryptosporidiosis should be considered in all patients with persistent watery diarrhea, especially in transplant recipients. The acid-fast stain technique using modified Ziehl-Nielsen or Kinyoun staining of fixed fecal specimens demonstrates the presence of bright pink round oocysts measuring 4 to 6 m in diameter. The destaining reagent should be 1 to 3% sulfuric acid, not alcoholacid decolorizer (249). The modified acid-fast staining can visualize not only the oocysts of Cryptosporidium but also those of Cyclospora (8 to 10 m) and Isospora (10 to 19 m by 20 to 30 m) (124); therefore, differentiating them on the basis of morphology and size requires laboratory expertise. The sensitivity can be improved by examining multiple specimens and by employing concentration techniques (324). Newer and more sensitive methods are now available, including immunofluorescence assays and antigen-capture enzyme-linked immunosorbent assays, for which sensitivity and specificity have been shown to be 100% (108, 109). These methods are commercially available. Highly sensitive PCR methods for the detection of Cryptosporidium in fecal specimens also exist (229, 401), but they are not yet commercially available. Recently, nitazoxanide was approved by the Food and Drug Administration for the treatment of giardiasis and Cryptosporidium in children and for giardiasis in adults. There was an 80% cure of Cryptosporidium in immunocompetent individuals following a 3-day course of therapy. Use of this drug in immunocompromised patients remains controversial (16). Paromomycin (Parke-Davis/Warner-Lambert Company, Ann Arbor, Mich.) and nitazoxanide (Romark Institute for Medical Research, Tampa, Fla.) have been subjected to placebo-controlled clinical trials in advanced AIDS patients (146, 287). Paromomycin was proven to be no more effective than placebo. Other agents including spiramycin, paromomycin with azithromycin, TMP-SMZ, and somatostatin have been used in AIDS patients with conflicting
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results. Of these compounds, spiramycin appears to be the best prospect for the treatment of cryptosporidiosis, and it was successfully used (1 g orally three times a day for 21 days) in an HSCT recipient (62).
CONCLUSION HSCT recipients are at risk for multiple infections as a result of significant immune suppression. These infections can lead to a high amount of morbidity and mortality. Understanding which infections these individuals could acquire may allow us to vaccinate and prophylax patients to decrease their risk of infections. Recognizing the clinical presentations of these infections can lead to a quicker diagnosis, which may mean earlier treatment and possible cure of these usually serious infections. In addition, since many of these infections are either rare or difficult to diagnose, it is important for microbiologists and pathologists to understand the diagnostic methods and tests to make the quickest diagnosis possible. This review, although comprehensive, is not meant to be encyclopedic. The field of infections in HSCT recipients is dynamic, with new diagnostic tests, procedures, and even manifestations of infections emerging. In addition to this review, one must keep abreast of new information. REFERENCES 1. Ablashi, D. V., Z. N. Berneman, B. Kramarsky, D. M. Ferguson, and A. L. Komaroff. 1994. Human herpesvirus-7. In Vivo 8:549–554. 2. Adam, R. D., G. Hunter, J. DiTomasso, and G. Comerci, Jr. 1994. Mucormycosis: emerging prominence of cutaneous infections. Clin. Infect. Dis. 19:67–76. 3. Aljurf, M., M. Gyger, A. Alrajhi, E. Sahovic, N. Chaudhri, M. Musa, O. Ayoub, P. Seth, M. Aslam, and F. Al-Fiar. 1999. Mycobacterium tuberculosis infection in allogeneic bone marrow transplant patients. Bone Marrow Transplant. 24:551–554. 4. Ampel, N. M., K. J. Ryan, P. J. Carry, M. A. Wieden, and B. Schiffman. 1986. Fungemia due to Coccidioides immitis. An analysis of 16 episodes in 15 patients and a review of the literature. Medicine 65:312–321. 5. Anaissie, E., A. Gokaslan, R. Hachem, R. Rubin, G. Griffin, R. Robinson, J. Sobel, and G. Bodey. 1992. Azole therapy for trichosporonosis: clinical evaluation of eight patients, experimental therapy for murine infection, and review. Clin. Infect. Dis. 15:781–787. 6. Anaissie, E., H. Kantarjian, J. Ro, R. Hopfer, K. Rolston, V. Fainstein, and G. Bodey. 1988. The emerging role of Fusarium infections in patients with cancer. Medicine 67:77–83.
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7. Anaissie, E. J., R. Hachem, N. C. Karyotakis, A. Gokaslan, M. C. Dignani, L. C. Stephens, and C. K. Tin-U. 1994. Comparative efficacies of amphotericin B, triazoles, and combination of both as experimental therapy for murine trichosporonosis. Antimicrob. Agents Chemother. 38:2541–2544. 8. Anaissie, E. J., R. Hachem, C. Legrand, P. Legenne, P. Nelson, and G. P. Bodey. 1992. Lack of activity of amphotericin B in systemic murine fusarial infection. J. Infect. Dis. 165:1155–1157. 9. Anderson, D. J., C. Schmidt, J. Goodman, and C. Pomeroy. 1992. Cryptococcal disease presenting as cellulitis. Clin. Infect. Dis. 14:666–672. 10. Anderson, L. J. 1990. Human parvoviruses. J. Infect. Dis. 61:603–608. 11. Anttila, V. J., E. Elonen, S. Nordling, A. Silvonen, R. Ruutu, and P. Ruutu. 1997. Hepatosplenic candidiasis in patients with acute leukemia: incidence and prognostic implications. Clin. Infect. Dis. 24:375– 380. 12. Areno, J. P., G. D. Campbell, and R. B. George. 1997. Diagnosis of blastomycosis. Semin. Respir. Infect. 12:252–262. 13. Arikan, S., M. Lozano-Chiu, V. Pactznick, and J. H. Rex. 2002. In vitro synergy studies with caspofungin and amphotericin B against Aspergillus and Fusarium spp. Antimicrob. Agents Chemother. 46:245– 247. 14. Aschan, J., O. Ringden, P. Ljungman, P. Lonnqvist, and S. Ohlman. 1992. Foscarnet for treatment of cytomegalovirus infections in bone marrow transplant recipients. Scand. J. Infect. Dis. 24:143–150. 15. Azzi, A., R. Fanci, S. Ciappi, K. Zakrzewska, and A. Bosi. 1993. Human parvovirus B19 infection in bone marrow transplantation patients. Am. J. Hematol. 44:207–209. 16. Bailey, J. M., and J. Erraamouspe. 2004. Nitazoxanide treatment for giardiasis and cryptosporidiosis in children. Ann. Pharmacother. 38:634–640. 17. Beaman, B. L., and I. Beaman. 1994. Nocardial species, host-parasite relationship. Clin. Microbiol. Rev. 7:213–264. 18. Beatty, P. R., S. M. Krams, C. O. Esquivel, and O. M. Martinez. 1998. Effect of cyclosporine and tacrolimus on the growth of Epstein-Barr virus–transformed B-cell lines. Transplantation 49:191–194. 19. Bennett, J. E. 1998. Mucormycosis, p. 1158. In A. S. Fauci, E. Braunwald, K. J. Isselbacher, J. D. Wilson, J. B. Martin, D. L. Kasper, S. L. Hauser, and D. L. Longo (ed.), Harrison’s Principles of Internal Medicine, 14th ed. McGraw-Hill, New York, N.Y. 20. Bennett, J. E., W. E. Dismukes, R. J. Duma, G. Medoff, M. A. Sande, H. Gallis, J. Leonard, B. T. Fields, M. Bradshaw, H. Haywood, Z. A. McGee, T. R. Cate, C. G. Cobbs, J. F. Warner, and D. W. Alling. 1979. A comparison of amphotericin B alone and
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