Infections in the Immunocompromised Host

Transcription

1 CHAPTER 90 Infections in the Immunocompromised Host Karen Doucette and Jay A. Fishman Introduction The population of immunocompromised patients has expanded greatly due to broader application of immunosuppressive therapies combined with improved survival following organ and stem cell transplantation, cancer chemotherapy, and other chronic diseases requiring immunosuppressive therapy. In addition, monoclonal antibody therapies have revolutionized the treatment of rheumatologic as well as other systemic inflammatory and autoimmune conditions; use of such biologic agents results in selected immune deficits and the associated infectious complications. Despite advances in prophylactic and antimicrobial therapies, infectious complications remain a leading complication of immunosuppressive and immunomodulatory therapies. Familiarity with the clinical presentation, differential diagnosis, and management of infectious complications in immunocompromised patients is essential in critical care medicine. An understanding of the nature of the patient s underlying immune deficits, both innate (e.g., neutropenia) or adaptive (B- or T-cell) immune deficits, and an assessment of the timing, intensity and virulence of epidemiologic exposures, will generally define the most likely pathogens responsible for infectious syndromes. Pathophysiology The risk of infection and spectrum of likely pathogens in the immunocompromised host is determined by the interaction of two factors: The epidemiologic exposures of the patient including the timing, intensity, and virulence of the organisms to which the individual is exposed. The patient s net state of immunosuppression, a conceptual measure of all host factors potentially contributing to the risk for infection (Table 90.1) including anatomic defects and exogenous immunosuppression. Specific immunosuppressive therapies and deficits predispose to specific types of infection (Table 90.2). Consideration of these factors for each patient allows the development of a differential diagnosis for infectious syndromes. Additional clues to possible etiologies of infection can be obtained from a careful epidemiologic exposure history including travel, occupation, hobbies, animal contact, exposure to ill contacts, and recent hospitalizations. In critical care units, the most commonly encountered immunocompromised hosts are those with neutropenia, on systemic corticosteroids, following solid organ or stem cell transplantation and, increasingly, those on immunomodulatory therapies. The Neutropenic Patient Neutropenic patients, generally as a result of cytotoxic chemotherapy for hematologic or solid tumors, are among the most commonly encountered immunocompromised hosts. The relationship between the absolute neutrophil count (ANC) and risk of infection was described by Bodey et al., who correlated the risk for infection with the degree (usually neutrophil counts <500 cells/μl) and duration of neutropenia, notably in leukemic patients (1,2). A reduction in ANC impairs the innate host immune responses of inflammation, phagocytosis, and antigen presentation, making clinical diagnosis more difficult via the absence of erythema or pulmonary infiltrates and predisposing the neutropenic patient to bacterial and fungal infections, usually from endogenous colonization. Historically, gram-negative organisms such as Escherichia coli, Klebsiella species, and Pseudomonas aeruginosa accounted for most bloodstream infections (2); gram-positive organisms, particularly Streptococcus species and coagulasenegative Staphylococcus, are now isolated in almost two-thirds of bloodstream infections (3). This shift from gram-negative to gram-positive infections (recalling a prior shift from grampositive to gram-negative with the early deployment of cephalosporins) is related to the near universal placement of central venous catheters (CVCs) in patients undergoing chemotherapy, as well as the impact of fluoroquinolone prophylaxis on the risk of gram-negative infections (4). The risk of opportunistic fungal infection increases with the duration and severity of neutropenia (5). Up to one-third of febrile neutropenic patients who fail to respond to a 1-week course of empiric antibacterial therapy have systemic fungal infections, most commonly (over 80%) due to Candida or Aspergillus species (6,7). The epidemiology of invasive fungal infections has evolved with the growing at-risk population and increased use of azole prophylaxis. Over half of the bloodstream isolates at most centers are due to non-albicans Candida species with increasing intrinsic (e.g., seen with Candida krusei) or acquired (e.g., seen with Candida glabrata) fluconazole resistance (8). Similarly, neutropenic patients have been found to become infected with highly resistant non-aspergillus molds in addition to Aspergillus species (9,10). The Corticosteroid-Treated Patient Corticosteroids have been used for the treatment of inflammatory, autoimmune, and lymphoproliferative diseases and for prevention of allograft rejection since the 1950s, and remain an integral part of management of many of these conditions today. Corticosteroids have a broad range of effects on the immune system (11). Treatment with corticosteroids results in reduced proliferation of B and T lymphocytes, reduced release of tumor necrosis factor (TNF) and fever, inhibition of neutrophil adhesion to endothelial cells, inhibition of macrophage differentiation, and reduced recruitment of mononuclear cells, including monocytes, to sites of immune inflammation (11,12). In addition, these agents suppress cellular (Th1) immunity and promote humoral (Th2) immunity (11) LWBK1580-CH090_p indd 1112

2 chapter 90 Infections in the Immunocompromised Host 1113 Table 90.1 Factors Contributing to the Net State of Immunosuppression Immunosuppressive therapy Type Temporal sequence Intensity Cumulative dose Prior therapies Chemotherapy or antimicrobials Mucocutaneous barrier integrity Surgery Catheters Lines Drains Fluid collections Neutropenia, lymphopenia Often drug induced Underlying immune deficiency Hypogammaglobulinemia (e.g., from proteinuria) Complement deficiencies Autoimmune diseases (e.g., systemic lupus erythematosus) Other disease states Human immunodeficiency virus Lymphoma/leukemia Metabolic conditions Uremia Malnutrition Diabetes mellitus Cirrhosis Immunomodulatory viral infections Cytomegalovirus Hepatitis B and C Respiratory viruses The risk of infection in corticosteroid-treated patients is related to the dose and duration of therapy (13,14). Those treated with more than 10 to 20 mg/day of prednisone for more than 3 to 4 weeks are at risk for infectious complications. Corticosteroids place the host at risk for fungal, viral, protozoal, and intracellular bacterial infections. Common pathogens to be considered in corticosteroid-treated patients presenting with a suspected infectious complication include Pneumocystis jirovecii, Listeria monocytogenes, Legionella, and Nocardia species. Bolus treatments with corticosteroids (e.g., for graft-vs.-host or autoimmune disease) may convert colonization (e.g., Aspergillus) to invasive infection. The Solid Organ Transplant Patient With improvements in surgical techniques and immunosuppressive therapy, a growing number of people are living with solid organ transplants. Intensified immunosuppression has decreased the incidence of graft rejection, while infectious complications are an important cause of morbidity and mortality. Interestingly, both a recent case-controlled and retrospective cohort study suggest that in hospital mortality in abdominal organ transplant patients with bacteremia and/or sepsis is lower than in the general population (15,16). Further confirmation of these results as well as additional research to understand the mechanism of this finding are needed. Although all transplant recipients are at increased risk of infection compared to the general population, the risk of infection in an individual recipient is determined largely by the degree of exposure to potential pathogens and the overall or net state of immunosuppression (see Table 90.1) (17). These patients are differentiated from other immunocompromised hosts by the technical aspects (complex surgery) and the need for lifelong immune suppression to maintain graft function. In an individual, the net state of immunosuppression is determined by the immunosuppressive agents selected as well as the dose, duration, and sequence of use. In addition, Table 90.2 Infections Associated with Specific Immune Defects Defect Common Causes Associated Infections Granulocytopenia Neutrophil chemotaxis Neutrophil killing T-cell defects B-cell defects Leukemia, cytotoxic chemotherapy, acquired immunodeficiency syndrome (AIDS), drug toxicity, Felty syndrome Diabetes, alcoholism, uremia, Hodgkin disease, trauma (burns), Lazy leukocyte syndrome, connective tissue disease Chronic granulomatous disease, myeloperoxidase deficiency AIDS, congenital lymphoma, sarcoidosis, viral infection, connective tissue disease, organ transplants, steroids Congenital/acquired agammaglobulinemia, burns, enteropathies, splenic dysfunction, myeloma, acute lymphocytic leukemia Enteric gram negatives, Pseudomonas, Staphylococcus aureus, Staphylococcus epidermidis, streptococci, Aspergillus, Candida, and other fungi S. aureus, Candida, streptococci S. aureus, Escherichia coli, Candida, Aspergillus, Torulopsis Intracellular bacteria (Legionella, Listeria, Mycobacteria), herpes simplex virus, varicella zoster virus, cytomegalovirus, Epstein Barr virus, parasites (Strongyloides, Toxoplasma), fungi (Candida, Cryptococcus) Pneumocystis jirovecii Streptococcus pneumoniae, Haemophilus influenzae, Salmonella and Campylobacter spp, Giardia lamblia Splenectomy Surgery, sickle cell, cirrhosis S. pneumoniae, H. influenzae, Salmonella spp, Capnocytophaga Complement Congenital/acquired defects S. aureus, Neisseria spp, H. influenzae, S. pneumoniae Anatomic Vascular/Foley catheters, incisions, anastomotic leaks, mucosal ulceration, vascular insufficiency Colonizing organisms, resistant nosocomial organisms LWBK1580-CH090_p indd 1113

3 1114 Section 9 Infectious Disease factors such as underlying immune deficiencies, metabolic derangements, the presence of foreign bodies (e.g., surgical drains, CVCs) or fluid collections, and infection with immunemodulating viruses such as cytomegalovirus (CMV), Epstein Barr virus (EBV) or human immunodeficiency virus (HIV) contribute to the risk of infection (17,18). With standardized immunosuppressive regimens, specific infections vary in a predictable pattern depending on the time elapsed since transplantation (Fig. 90.1) (17). This is a reflection of the changing risk factors over time including surgery/ hospitalization, immune suppression, acute and chronic rejection, emergence of latent infections, and exposures to novel community infections. The pattern of infection changes with the immunosuppressive regimen for example, use of pulse dose steroids or T-cell depletion for graft rejection intercurrent viral infections, neutropenia, or significant epidemiologic exposures, such as travel or food. The timeline remains a useful starting point, although it has been altered by the introduction of newer immunosuppressive agents (e.g., sirolimus) and patterns of use including reduced use of corticosteroids and increased use of antibody-based induction therapies. Routine antimicrobial prophylaxis, improved molecular assays, antimicrobial resistance, transplantation in HIV- and hepatitis C virus (HCV)-infected individuals have also impacted the timeline (18). Figure 90.1 demonstrates three overlapping periods of risk for infection after transplantation, each most often associated with unique groups of pathogens. The perioperative period to approximately 4 weeks after transplantation, reflecting surgical and technical complications. Most infections are related to the surgery, similar to those occurring in the complex general surgical population, such as pneumonia, surgical site, urinary tract, and CVC-associated infections caused by typical bacterial and fungal pathogens such as Candida. Nosocomial pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), fluconazole-resistant Candida species, Clostridium difficile, P. aeruginosa, and carbapenem-resistant Enterobacteriaceae are increasingly common. Uncommonly, infections may be transmitted from a bacteremic or fungemic donor with potentially serious complications, including seeding of the vascular suture line. The use of prophylactic antibiotics in the recipient, directed by donor culture results, may allow organs from infected donors to be safely used without compromising transplant outcomes (19 21). The risk for infections in the period from 1 to 6 to 12 months after transplantation are driven largely by the rapidity of tapering of immunosuppression, the use of antilymphocyte induction therapy, the use of antiviral (anti-cmv) and anti-pneumocystis prophylaxis, and the reactivation of latent viral infections. Opportunistic infections include viral (CMV, varicella zoster virus [VZV], EBV, HCV), bacterial (Nocardia, Listeria, and tuberculosis), fungal (Aspergillus, Pneumocystis, and Cryptococcus), or parasitic (Toxoplasma and Strongyloides) infections. The period beyond 6 to 12 months after transplantation reflect community-acquired exposures and some unusual pathogens based on the level of maintenance immunosuppression. Commonly, these include viral respiratory infections, pneumococcal pneumonia, and gastroenteritis. Herpes simplex, CMV, and shingles infections may emerge. Intense exposure to an opportunistic pathogen may result in disease; transplant recipients should be counseled to avoid high-risk exposures such as unpasteurized milk products (22). Recipients requiring augmentation of immunosuppression for management of graft rejection, as well as those with chronic or recurrent CMV or HCV infections, remain at risk for other opportunistic infections, particularly P. jirovecii, invasive fungal infection, and EBV-associated, posttransplant lymphoproliferative disease (PTLD) (19 25). Timeline of Posttransplant Infections TRANSPLANT NOSOCOMIAL TECHNICAL OPPORTUNISTIC INFECTION Activation of latent infection Residual technical problems COMMUNITY ACQUIRED <4 WEEKS 1 6 MONTHS >6 12 MONTHS MRSA, Candida, VRE, Aspergillus, aspiration, line infection, Clostridrium difficile Nosocomial pathogens Donor derived Recipient colonizers HSV, CMV, HBV, HCV, EBV, Listeria, TB, PJP, BK virus, Nocardia, Toxoplasma, Strongyloides, Leishmania Period of most intensive immune suppression Community-acquired pneumonia, Aspergillus, dermatophytes, CMV colitis, UTI COMMON TO RARE (Based on net state of immune suppression) Figure 90.1 The timeline of infection after transplantation. MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococcus; HSV, herpes simplex virus; CMV, cytomegalovirus; HBV, hepatitis B virus; EBV, Epstein Barr virus; TB, tuberculosis; PJP, Pneumocystic jirovecii; UTI, urinary tract infection. (Adapted from Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med. 1998;338[24]:1741.) LWBK1580-CH090_p indd 1114

4 chapter 90 Infections in the Immunocompromised Host 1115 Hematopoietic Stem Cell Transplant Recipients A growing number of patients undergo allogeneic and autologous hematopoietic stem cell transplantation (HSCT) procedures for both malignant and nonmalignant conditions (26). Despite advances, severe infectious complications are common, with up to 40% of HSCT recipients requiring intensive care unit (ICU) admission, and 60% of these needing mechanical ventilation, which is associated with a high mortality rate (27,28). Although traditionally poor, the outcomes of HSCT recipients admitted to the ICU are improving with advances in infection prevention, diagnosis and management, and ICU care (29); the combination of allogeneic transplantation, mechanical ventilation, and vasopressor use is predictive of mortality (30). Advances in stem cell source and nonmyeloablative conditioning have resulted in shorter periods of neutropenia and less severe mucositis and hepatic venoocclusive disease; the risk of early bacterial infections is decreased while the risks of late viral, fungal, and bacterial infections persist (31,32). In part this reflects increased use of positively selected CD34+ progenitor cells for transplant which results in significant T-lymphocyte and monocyte depletion of the graft and therefore increases the risk of opportunistic infection while reducing malignant cells and reducing graft-versus-host disease (GVHD) (32). Reduced-intensity or nonmyeloablative-conditioning regimens have been developed in attempt to extend these therapies to older and more medically complex patients (34) and although the period of neutropenia is shorter, and potent antitumor effects result from these transplants, patients remain at high risk for GVHD necessitating significant immunosuppression for GVHD prophylaxis (31,33 35). As a result of pretransplant chemotherapy, with or without total-body irradiation, both humoral- and cell-mediated immunity are diminished. Natural host barrier defenses are also impaired by mucositis and the use of vascular access catheters. The timeline of infectious complications in the HSCT recipient is generally divided into three phases. The pre-engraftment phase the period from conditioning therapy to engraftment when patients are neutropenic. Prolonged neutropenia carries the risk for bacterial and fungal infections. Similar to other neutropenic hosts, there has been a shift from predominantly gram-negative to gram-positive coagulase-negative Staphylococci, Streptococci, Enterococci bacterial infections with the use of fluoroquinolone prophylaxis, to which the streptococci are generally resistant (4). Many centers use azole prophylaxis to reduce the incidence of candidemia; however, azole-resistant fungemia remains common (36,37). Herpes simplex virus may also reactivate during this phase but can be prevented with prophylactic acyclovir in seropositive HSCT recipients. The second phase, from engraftment to day 100 or for the duration of treatment for acute GVHD, is characterized by deficits in cellular immunity. The most important pathogens in this period are viral, particularly CMV and adenovirus, and invasive mold infections. The most common manifestations of CMV disease in HSCT recipients are pneumonia and gastrointestinal disease (38). Despite treatment with intravenous ganciclovir and CMV-hyperimmune globulin or intravenous immunoglobulin, the mortality from CMV pneumonitis remains high at 50% or greater (38). The use of ganciclovir or valganciclovir for prophylaxis or preemptive therapy has resulted in a decreased risk of CMV infection during this period, with most infections now occurring after discontinuation (39). Adenovirus may produce severe hepatitis. Interstitial pneumonitis is an important clinical syndrome presenting during the postengraftment phase; etiologies include CMV, respiratory viruses, or idiopathic pneumonia syndrome (IPS, which is overdiagnosed). P. jirovecii can be eliminated as a cause of pneumonitis with TMP-SMX prophylaxis. Respiratory viral infections, such as influenza, respiratory syncytial virus (RSV), parainfluenza virus, and human metapneumovirus are commonly recognized as etiologies of pneumonia in HSCT (40). A number of noninfectious etiologies must also be considered in the differential diagnosis, including IPS and diffuse alveolar hemorrhage. Most invasive mold infections occur during the postengraftment phase, and are associated with treatment of acute GVHD (37). Although Aspergillus continues to be the predominant pathogen, non-aspergillus molds, including Zygomycetes, Fusarium, and Scedosporium species are important pathogens in this population (41,42). Invasive mold infections generally present as pulmonary nodules or pneumonia, but invasive fungemia with septic emboli, sinus disease, and disseminated disease including central nervous system (CNS) involvement are other common presentations. In the late phase, beyond day 100 following engraftment and with chronic GVHD, the incidence of infection is determined by the level of immunosuppression required for the GVHD. Beyond 100 days post transplant, there is gradual recovery of humoral and cellular immune function, but immune reconstitution is often incomplete and antimicrobial prophylaxis may simply shift risk to later periods (43). Up to 40% of HSCT recipients develop VZV infection, generally as a result of reactivation of latent infection, with most cases occurring during the first year. Late CMV disease may occur and is associated with a history of early CMV disease and GVHD (44). Late invasive mold infections may occur, particularly in those with GVHD and preceding viral (CMV) infection. About onethird of patients with chronic GVHD may develop recurrent infection with encapsulated bacteria (sinopulmonary, bacteremia) (45). The predominant pathogen is Streptococcus pneumoniae (often with antimicrobial resistance) as well as Haemophilus influenzae and S. aureus. This risk is related to a deficit in opsonizing antibody (4,36,40,44 52). The Patient Treated with Immunomodulatory Agents There are a growing number of immunomodulatory agents, generally targeting specific cell populations and cytokines, commonly used in clinical practice (53). As more patients are treated with these therapies and with longer-term follow-up, understanding of the risk of infection associated with these biologic compounds will be refined. Tumor necrosis factor-α (TNF-α) antagonists are effective in the treatment of rheumatoid arthritis, active inflammatory bowel disease, psoriasis, and ankylosing spondylitis, and are amongst the best characterized in terms of infectious risk. There are currently five marketed in the United States: Infliximab (Remicade, Centocor Inc.), etanercept (Enbrel, Amgen and Wyeth Pharmaceuticals), adalimumab (Humira, Abbott), certolizumab pegol (Cimzia, UCB Inc.), and golimumab (Simponi, Janssen). Blockade of TNF-α, a proinflammatory cytokine, LWBK1580-CH090_p indd 1115

5 1116 Section 9 Infectious Disease results in improvement in systemic inflammatory conditions; however, TNF-α, along with interferon-γ and other cytokines, is an important component in maintaining cellular immunity and, in animal studies, preventing bacterial deep tissue infections. Tuberculosis has been associated with use of TNF-α antagonists due to cell-mediated immune deficits (54,55). Rates are three- to fourfold higher with adalimumab and infliximab compared to etanercept (56,57). In general, cases have occurred in those with risk factors for latent tuberculosis infection. As a result, tuberculosis skin testing (TST) or interferon-gamma-release assay (IGRA) and chest radiography are recommended in patients prior to the initiation of a TNF-α antagonist as well as the newer biologic agents. Regardless of TST or IGRA data, tuberculosis (and nontuberculous mycobacterial infections) should be considered in the differential diagnosis in a patient presenting with compatible symptoms and after a TNF-α antagonist. Infections with fungi (histoplasmosis, aspergillosis, coccidiomycosis, and candidiasis), bacteria (listeriosis, nocardiosis), parasites (leishmaniasis), and viruses (herpes zoster, hepatitis B and C reactivation) have also been associated with the use of TNF-α antagonists. In 2008 the FDA issued a black box warning regarding endemic mycoses and TNF-α antagonists, although the exact degree of risk appears to vary based on intensity of exposure (55). Rituximab (Rituxan, Genentech Inc. and Biogen Idec) is a chimeric murine/human monoclonal antibody to the CD20 epitope expressed on B lymphocytes but not plasma cells. Treatment with rituximab results in rapid depletion of circulating CD20+ B cells. This agent is approved for the treatment of CD20+ B-cell lymphoma, as well as in combination with methotrexate in rheumatoid arthritis. Rituximab has also been used for the treatment of PTLD, immune thrombocytopenic purpura, autoimmune hemolytic anemia, systemic lupus erythematosus, multiple sclerosis, GVHD, and treatment of antibody-mediated graft rejection (58). Following rituximab therapy, antibody production is maintained by plasma cells. Peripheral B-cell recovery takes 3 to 12 months (59). Approximately 5% of people can develop persistent hypogammaglobulinemia after rituximab treatment, increasing infectious risk (60 62). Fatal hepatitis B reactivation (63,64) and progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the CNS caused by human JC polyomavirus, have been associated with rituximab (65). Numerous other biologic agents are currently approved or undergoing study (53). Table 90.3 summarizes selected approved agents, mechanism of action, associated infectious risks, and approved indications. Diagnosis The signs and symptoms of infection are often muted in immunocompromised hosts with infectious syndromes (66). Minor complaints may be the only clues to localize infections. A physical examination should be completed, with particular focus on organ systems commonly involved with infectious complications including the skin, respiratory tract including sinuses, CNS, and urinary tract. Cutaneous lesions may be the earliest manifestation of disseminated infection. Examination of the skin should include the perirectal area, looking for evidence of erythema or tenderness; this is a common site of infection and source of fever notably in neutropenic patients. In neutropenic patients, fever, defined as a single oral temperature of 38.3 C (101 F) or higher or a temperature of Table 90.3 Selected Biologic Agents, Mechanisms of Action, Food and Drug Administration (FDA)-Approved Indications and Associated Infections Biologic Agent Mechanism of Action FDA-Approved Indications Associated Infectious Risk Natalizumab (Tysabri) Abatacept (Orencia) Ustekinumab (Stelara) Tocilizumab (Actemra) Tofacitinib (Xeljanz) Integrin receptor antagonist Selective costimulation modulator; inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28 IgG1 k 1 monoclonal antibody that binds with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines Binds specifically to both soluble and membrane-bound IL-6 receptors and inhibits signaling Janus kinase (JAK) inhibitor Relapsing multiple sclerosis moderately to severely active Crohn disease with failure or intolerance to conventional therapies including TNF inhibitors Adult rheumatoid arthritis Juvenile idiopathic arthritis Moderate to severe plaque psoriasis and active psoriatic arthritis Adult rheumatoid arthritis Polyarticular juvenile idiopathic arthritis Systemic juvenile idiopathic arthritis Adult rheumatoid arthritis with inadequate response to methotrexate Progressive multifocal leukoencephalopathy/jc virus herpes encephalitis and meningitis Sepsis Pneumonia Blunted response to immunizations; live vaccines contraindicated Serious bacterial, fungal, and viral infections including disseminated mycobacterial disease, Salmonella and reactivation of hepatitis B Serious infections leading to hospitalization or death including tuberculosis, bacterial (pneumonia, UTI), invasive fungal (Aspergillus), and viral (herpes zoster) infections as well as pneumocystis pneumonia Serious and sometimes fatal infections. The most common serious infections reported include pneumonia, cellulitis, herpes zoster, and urinary tract infection; tuberculosis and other mycobacterial infections, esophageal candidiasis, pneumocystosis, CMV, and BK virus have been reported LWBK1580-CH090_p indd 1116

6 chapter 90 Infections in the Immunocompromised Host C (100.4 F) or higher for an hour or more, may be the only indication of infection (6). About 50% of neutropenic patients with fever have a documented infection, and about 20% of those with neutrophil counts less than 100 cells/μl have bacteremia (2 7,9,10,67,68). Up to 50% of neutropenic patients with a normal chest radiograph and fever lasting 2 days, despite empiric antibiotic therapy, will have findings on chest CT suggestive of pneumonia that were not appreciated on plain radiograph (69). A daily search for subtle signs and symptoms of infection should be undertaken if unexplained fever persists. Basic investigations include a CBC with differential, serum creatinine, liver enzymes, and liver function tests in addition to cultures of blood, urine, and sputum prior to antimicrobial therapy. A chest radiograph should be performed and, if normal, a CT scan should be obtained in the patient with pulmonary symptoms. Collection of additional specimens is guided by the clinical presentation and preliminary investigations (e.g., stool cultures and examination for parasites and C. difficile toxin, blood for CMV nucleic acid testing [NAT], respiratory viral studies, viral swabs for HSV, and VZV from skin lesions). Delays in appropriate therapy may compromise outcome necessitating an aggressive approach to making a specific microbiologic diagnosis. Based upon the clinical stability of the patient, the severity of immune deficits, and the most likely cause of infection, the physician may initiate empiric therapy while awaiting the results of investigations, or therapy may be deferred until clinical data become available. Increasingly, infections in compromised hosts are due to organisms with antimicrobial resistance patterns that make selection of empiric therapy more difficult. Compromised hosts have an increased susceptibility to community-acquired organisms (MRSA, extended-spectrum beta lactamase (ESBL) producing gram negatives and multi drug-resistant Pneumococcus) and nosocomial pathogens (VRE, fluconazole-resistant Candida species and carbapenem-resistant Enterobacteriaceae). All microbiologic isolates require susceptibility testing in immunocompromised patients. Consultation with an infectious diseases specialist may be useful to assist in decisions regarding empiric therapy and for guidance regarding appropriate investigations, specimen collection, and transport. Whenever tissue or body fluids are collected, appropriate histologic and microbiologic investigations should be performed, and consultation with the pathologist and/or microbiologist is recommended to ensure appropriate testing. Diagnosis of many pathogens that cause disease in immunocompromised hosts requires special stains (e.g., modified acidfast stain for Nocardia, silver or immunofluorescent stains for P. jirovecii) or culture media (e.g., for Mycobacteria species). In addition, given that noninfectious etiologies such as organ rejection, drug toxicity, and GVHD are often in the differential diagnosis, histology is integral to making a definitive diagnosis and invasive diagnosis should be considered early in the patient s course. The diagnosis of virally mediated diseases such as tissue-invasive CMV (70) and EBV-associated PTLD (71) may require histology for diagnosis. Treatment The Neutropenic Patient After appropriate microbiologic studies, empiric antimicrobial therapy is indicated in neutropenic patients at the onset of fever or, in the case of suspected infection, without fever (6). In critically ill neutropenic patients, there is no single empiric regimen appropriate for all patients (6,72 74). The selection of an initial empiric antibiotic regimen should take into consideration the general trend of increasing gram- positive infections, the local hospital epidemiology, including the susceptibility patterns of isolates from neutropenic patients, in addition to the clinical presentation, epidemiologic exposures, and prior antimicrobial use. Options include monotherapy with (a) a third- or fourthgeneration cephalosporin (e.g., ceftazidime or cefepime), (b) an antipseudomonal carbapenem such as imipenem or meropenem, or (c) piperacillin tazobactam. Dual therapy, such as an antipseudomonal β-lactam plus an aminoglycoside or fluoroquinolone may be used or, for inpatients with recent surgery or vascular access catheters, a glycopeptide such as vancomycin can be combined with one- or two-drug therapy. The initial empiric addition of vancomycin therapy in febrile neutropenia has not been shown to alter outcomes in patients without pulmonary infiltrates, septic shock, clinically documented infections likely due to gram-positive organisms such as CVC or skin and soft tissue infections, or documented grampositive infections resistant to the primary empiric therapy (75). Vancomycin use has also been associated with the emergence of vancomycin-resistant enterococci; its use in febrile neutropenic patients should be limited as indicated above. For those with an identified source of infection, usually less than half of patients, antimicrobial therapy can be tailored based on culture results. Those who defervesce on empiric antibacterial therapy should have the antimicrobials continued to complete a therapeutic course appropriate for the defined infection and until neutrophil recovery. Controversy persists regarding the optimal timing of adding antifungal therapy. In patients who have been in the ICU for more than 5 to 7 days and have been hypotensive or otherwise critically ill, anti-candida therapy may be added after cultures are obtained (76,77). In others who have failed to defervesce on empiric antibiotic therapy after 5 to 7 days, and in whom no source of infection is identified, there is a high risk of systemic fungal infection, and empiric antifungal therapy should be added (5 7,72). Amphotericin B is the historical gold standard for empiric therapy in this setting; however, lipid products of amphotericin B (e.g., liposomal amphotericin B [AmBisome, Astellas] and amphotericin B lipid complex [Abelcet, Elan]) have similar efficacy with less toxicity (78). In the United States, liposomal amphotericin or echinocandins (caspofungin (79)) are approved for empiric therapy of fever in neutropenia. Other agents may have efficacy such as voriconazole (80), other echinocandins (e.g., anidulafungin and micafungin), and posaconazole (81). Renal and hepatic function, potential drug interactions, cost, and suspected source of fungal infection are all considerations when choosing an initial empiric antifungal agent. In those with confirmed invasive aspergillosis, voriconazole is the drug of choice although no direct clinical trial comparison with liposomal amphotericin has been performed. Limited data suggest that combination therapy with these agents with an echinocandin may improve outcomes in highly selected patients (52,82,83). Although the use of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) increase the neutrophil count, they have not been shown to have benefit in the management of febrile neutropenia and routine use is not recommended (84,85). LWBK1580-CH090_p indd 1117

7 1118 Section 9 Infectious Disease Table 90.4 Treatment Modalities for Common Opportunistic Infections Infectious Agent Primary Therapy Secondary Therapy Other Considerations Pneumocystis jirovecii (PCP) Listeria monocytogenes Legionella pneumophila and other species Nocardia spp TMP-SMX, dosed as mg/ kg/day of TMP component, divided every 6 8 hrs 21 days Empiric or confirmed: Ampicillin 2 g IV every 4 hrs 21 days or more For synergy: Ampicillin plus TMP-SMX 20 mg/kg/day divided every 6 hrs Levofloxacin mg IV every 24 hrs 7 14 days TMP-SMX, dosed as 15 mg/ kg/day of TMP component, divided every 6 12 hrs, PO or IV Atovaquone 750 1,500 mg orally bid Dapsone 100 mg orally plus TMP as above Clindamycin 600 mg IV every 6 hrs plus primaquine mg/day (as base) Ampicillin plus gentamicin 2 mg/kg IV load, then 1.7 mg/kg IV every 8 hrs Azithromycin 500 mg daily for 7 14 days Imipenem 500 mg IV every 6 hrs plus amikacin 7.5 mg/kg IV every 12 hrs (with normal renal function) both 3 4 wks, then switch to PO regimen Linezolid mg orally bid Ceftriaxone 2 g bid Adjunctive use of corticosteroids common but not evidence based in non-hiv patients Based on antimicrobial susceptibility pattern Surgical resection of necrotic material often necessary Therapy duration is 6 12 mo; for central nervous system infection 9 12 mo The Corticosteroid-Treated Patient Common pathogens to be considered in corticosteroid-treated patients presenting with suspected infection include bacterial sepsis, P. jirovecii (PCP), L. monocytogenes, Legionella, and Nocardia species. Those requiring prolonged steroid therapy are appropriate candidates for prophylaxis with TMP-SMX which has broad antibacterial as well as anti-pneumocystis and anti-toxoplasma activity (86); in the absence of prophylaxis, PCP remains common. Overly rapid tapering of corticosteroids may provoke adrenal insufficiency including nausea, abdominal pain, hypotension, and confusion, and may be precipitated by simultaneous infections. Table 90.4 summarizes the antimicrobial treatment of these common opportunistic infections (86 104). The Solid Organ Transplant Patient Treatment of infections in transplant recipients may be complicated by rapid progression, precipitation of rejection, and antimicrobial toxicity related to drug interactions or nephrotoxicity; whenever possible, prevention of infections is therefore a principal goal. Approaches to prevention include donor and recipient history and serologic screening, TST or IGRA screening, and pretransplant immunization of recipients. All potential organ donors and recipients should undergo a thorough history and physical examination to identify risk factors for infection and potential latent infections. This includes information regarding travel/residence, occupational, and risk behavior (e.g., injection drug use) and exposure histories (e.g., tuberculosis). Commonly utilized serologic tests for screening donors and recipients include HIV-1 and -2; HCV antibodies; hepatitis B surface antigen (HBsAg); hepatitis B core antibody (anti-hbc total ± IgM); hepatitis B surface antibody (anti-hbs) (some centers); CMV-IgG antibodies; EBV antibody panel; syphilis screen (rapid plasma reagin [RPR] or syphilis enzyme immune assay); Toxoplasma antibody; HSV IgG (some centers); and VZV IgG in recipients. Optimally, immunization against vaccine-preventable diseases should be completed prior to transplantation and as early in the course of the disease as possible. This is based on three principal factors (a) the response to vaccine declines with progressive end-organ failure; (b) despite this, the response to vaccination may be better before transplantation than after; and (c) live viral vaccines (e.g., mumps, measles, rubella [MMR], varicella/herpes zoster) are generally contraindicated post transplant. Attention to the appropriate and timely administration of as many immunizations as possible is of particular importance in pediatric transplant candidates. National immunization guidelines should be followed by consultation with an infectious diseases specialist. In addition to routine vaccinations, all transplant candidates should receive a pneumococcal vaccine, yearly influenza vaccine, and hepatitis B vaccine. Hepatitis B vaccination, with a documented serologic response, allows for the safe use of anti HBc-positive nonhepatic donors, thus expanding the donor pool (105). Susceptible individuals should receive varicella vaccine (live vaccine) a minimum of 4 weeks prior to transplantation. The optimal treatment of HCV (pre- or posttransplant) is under investigation. Transplant candidates should undergo TB screening with TST/IGRA and risk factor assessment prior to transplantation. There is a 50- to 100-fold increased risk of tuberculosis (TB) following organ transplantation, with an increased risk of dissemination compared to the general population (106,107). Management of TB post transplant is also associated with significant morbidity and mortality, and its therapy is complicated by the multiple drug interactions between antituberculous and antirejection medications (107,108). Disease-Specific Prevention and Management Cytomegalovirus. CMV remains a significant cause of morbidity in organ transplant recipients; strategies for prevention have decreased the morbidity of CMV. The risk of CMV disease depends on a number of factors, including the donor and recipient serostatus, as well as the immunosuppression, LWBK1580-CH090_p indd 1118

8 chapter 90 Infections in the Immunocompromised Host 1119 particularly the use of antilymphocyte antibody (ALA) preparations for induction or treatment of rejection. The American Society of Transplantation Guidelines on CMV prevention and management (109) should be used to guide institutional approaches to CMV prevention in conjunction with local CMV epidemiology, available laboratory support, and infrastructure. If both the donor and recipient are CMV-negative, antiherpes virus prophylaxis (for HSV and VZV) is generally used for the first 3 to 12 months post transplantation. However, 5% to 10% of such patients may develop community-acquired CMV at some time post transplant. Those who are CMV-seronegative and receive a seropositive organ are at greater risk of a primary CMV infection. Such patients should receive prophylaxis with valganciclovir (900 mg/day corrected for renal function) for 100 days; 200 days in kidney recipients and 12 months in lung recipients ( ). In CMV-seropositive recipients, either prophylaxis with valganciclovir or preemptive therapy based on routine monitoring via a sensitive assay (e.g., quantitative CMV NAT) have been used. Given the high risk of CMV infection and disease in seropositive lung and heart lung recipients, prophylaxis is generally preferred. All patients at risk for CMV who receive lymphocyte-depleting agents for induction or treatment of rejection should receive antiviral prophylaxis. CMV disease refers to the presence of symptoms attributable to CMV in the face of viral replication, and can be further divided into (a) CMV syndrome and (b) tissue-invasive disease. CMV syndrome is defined by the constellation of fever greater than 38 C, neutropenia or thrombocytopenia, and the detection of CMV in the blood by antigenemia, PCR, or shell viral culture. Tissue-invasive disease requires a biopsy for confirmation, except in the case of retinitis, and is defined by the presence of signs or symptoms of organ dysfunction in association with histologic evidence of CMV in the affected tissue (113). Established CMV syndrome or tissue-invasive disease should be treated with intravenous ganciclovir, 5 mg/kg every 12 hours or valganciclovir 900 mg orally twice daily (114). Therapy should be continued for a minimum of 14 days and until symptoms have resolved and viremia has cleared (i.e., until the CMV PCR/ antigenemia is undetectable) in order to minimize the risk of relapse (115,116). Gastrointestinal disease may present with diarrhea and with negative NAT testing of blood samples. Ganciclovir-resistant CMV is an emerging problem; risk factors include donor recipient mismatch, in which the donor is seropositive and the recipient seronegative; prolonged use of ganciclovir/valganciclovir; suboptimal ganciclovir levels; intense immunosuppression; and high CMV viral load. If ganciclovir resistance is suspected, infectious diseases/microbiology should be consulted for consideration of molecular resistance testing and either alternative (e.g., foscarnet, cidofovir) or adjunctive (CMV-Ig) therapies (117). Epstein Barr Virus and Posttransplant Lymphoproliferative Disease. Primary EBV infection after transplantation has been identified as the most important risk factor for PTLD, a complication with mortality reported to range as high as 40% to 60%. This risk is exacerbated by the occurrence of CMV disease and treatment with polyclonal or monoclonal ALA. Use of belatacept immunosuppression has been associated with increased risk of PTLD in the EBV D+/R- transplant population, notably involving the central nervous system (118,119). Studies comparing transplant recipients having received antiviral prophylaxis with either acyclovir or ganciclovir to historical controls suggest some benefit of antiviral prophylaxis (120). More recently, quantitative EBV viral load monitoring has also been shown to decrease the risk of PTLD (121). In those at high risk for PTLD (i.e., EBV donor seropositive/recipient seronegative), preventative strategies with antiviral prophylaxis and/or EBV viral load monitoring may be considered. If EBV viremia is detected, immunosuppression reduction should be considered. PTLD represents a highly diverse spectrum of disease with variable clinical presentation, from benign B-cell proliferation (mononucleosis) to true monoclonal malignancy. It may be nodal or extranodal, localized or disseminated, and commonly involves the allograft. The diagnosis of PTLD requires histologic confirmation and staging of the disease (122). Options for the treatment of PTLD depend on the histology and stage of the disease; however, in all cases, attempts should be made to reduce or withdraw immunosuppression. Additional considerations for treatment will depend on the clinical presentation, histology, and stage of disease (122). A multidisciplinary approach to management is generally indicated with collaboration of the transplant physician with hematology/ oncology, infectious diseases, and surgery specialists, depending on the clinical setting. In addition to immunosuppression reduction or withdrawal, potential options for therapy include antiviral agents, intravenous immunoglobulin, surgical resection, and local radiation. The use of rituximab, the anti-cd20 monoclonal antibody, is an attractive second-line option if reduction in immunosuppression alone fails, given its low toxicity and response rates, which range from 61% to 76% (123). Cytotoxic chemotherapy is generally considered a third-line option due to a high incidence of toxicity in this population. Pneumocystis jirovecii (formerly P. carinii). In the absence of prophylaxis, Pneumocystis pneumonia occurs in 5% to 15% of solid organ transplant recipients. Prophylaxis with TMP-SMX, one single-strength tablet daily, essentially eliminates this risk and is indicated in all nonallergic transplant recipients for a minimum of 6 months following transplantation. This also acts as prophylaxis for a number of other infections such as Nocardia, Listeria, and community-acquired pneumonia. In sulfa-allergic patients, dapsone 100 mg daily or atovaquone 1,500 mg daily are alternatives (124). Toxoplasmosis. Toxoplasmosis is of particular concern among cardiac transplant recipients given that the site of latency is the cardiac muscle. Seronegative recipients of a seropositive heart are at risk due to donor transmission and primary infection, and therefore require prophylaxis. TMP- SMX has been used effectively for prophylaxis as one doublestrength tablet daily; lifelong prophylaxis is recommended (125). Treatment of Infectious Syndromes in Immunocompromised Hosts The management of infectious complications in immunocompromised hosts can be complex, and thus, consultation with local infectious diseases specialists is recommended. Fever and Pulmonary Infiltrate Immunocompromised hosts are susceptible to both common and unusual respiratory pathogens. In those presenting with fever and a pulmonary infiltrate, the differential diagnosis is broad and includes both infectious and noninfectious LWBK1580-CH090_p indd 1119

9 1120 Section 9 Infectious Disease Table 90.5 Differential Diagnosis of Fever and Pulmonary Infiltrate in Organ Transplant Recipients Chest Radiograph Finding Acute Onset etiologies. Infection is ultimately identified in 75% to 90% of such cases in organ transplant patients, and dual processes or sequential infections are common. Because pneumonia may rapidly progress in immunocompromised hosts with a resultant high mortality, initial empiric therapy directed at the most likely pathogens should be considered following the collection of blood and sputum cultures, viral respiratory studies, a complete blood count, and serum creatinine; consultation with pulmonary and infectious diseases specialists is recommended. Identification of the pathogen is key to directing appropriate therapy, and thus, early invasive diagnostic tests (e.g., bronchoscopy, lung biopsy) should be considered, particularly in those who are critically ill or fail to respond to initial empiric therapy. Findings on chest radiograph combined with the clinical presentation, rate of progression, exposure history, and assessment of the net state of immunosuppression can help narrow the differential diagnosis. Table 90.5 summarizes the differential diagnosis based on chest radiographic findings and clinical presentation. Chest CT may be useful to delineate the extent of pulmonary disease and guide invasive diagnostic tests. Central Nervous System Infections Subacute/Chronic Onset Consolidation Bacteria Fungal Pulmonary Nocardia embolism Hemorrhage Tuberculosis Pulmonary edema Viral (adenovirus) Reticulonodular Pulmonary edema Pneumocystis carinii (jirovecii) Viral Drug reaction (including sirolimus) P. carinii (jirovecii) Bacterial Viral Nodular Bacterial Fungal Nocardia Tuberculosis Tumor (including PTLD) PTLD, posttransplant lymphoproliferative disease. Similar to pulmonary infections, the presentation of CNS infection in compromised hosts may differ from the general population due to immunosuppression. Fever may or may not be present, and the presentation can be subtle, with headache or minor changes in mental status. The differential diagnosis in those presenting with neurologic symptoms with or without fever is broad, including both infectious and noninfectious etiologies. Clinical presentations include meningitis acute or subacute/chronic encephalitis, seizures, focal neurologic deficits, and progressive cognitive impairment. Among the common causes of infection are L. monocytogenes and Cryptococcus neoformans, as well as the common community-acquired bacteria pathogens. Metastatic infection due to Aspergillus, Mucormycoses, and Nocardia species are observed. In those with underlying solid tumor or hematologic malignancy, metastatic disease including meningeal involvement must also be Table 90.6 Common Central Nervous System Infections in Transplant Recipients Community-acquired pathogens Pneumococcus Meningococcus Listeria monocytogenes Herpes simplex virus Cryptococcus neoformans Lyme disease Metastatic infection Bacteremia (endocarditis) Mycobacterium tuberculosis Aspergillus Nocardia species Strongyloides stercoralis (gram-negative meningitis) Mucoraceae (sinuses) Dematiaceae cerebral phaeohyphomycosis (skin) Histoplasma and Pseudallescheria/Scedosporium, Fusarium Other central nervous system processes Cytomegalovirus (nodular angiitis) Varicella zoster virus Human herpesvirus 6 Toxoplasma gondii JC virus (progressive multifocal leukoencephalopathy) West Nile virus, lymphocytic choriomeningitis virus Lymphoma (PTLD) Naegleria/Acanthamoeba considered. Table 90.6 lists the most common causes of these symptoms. Consultation with infectious diseases/microbiology should be considered to assist in diagnosis and to ensure that appropriate samples are collected for diagnostic testing. Cerebral spinal fluid analysis after neuroimaging with CT and/or magnetic resonance imaging (MRI) should be obtained in all such individuals. Key Points Because of the impaired inflammatory response, the classic signs and symptoms of infection may be absent in immunocompromised patients. For example, an organ transplant recipient with a perforated viscus may present with fever but without clinical evidence of peritonitis; a neutropenic patient with pneumonia may have cough but absence of a pulmonary infiltrate on chest radiograph. A thorough, repeated history and physical examination is vital, and is the basis upon which investigations and management are directed in order to achieve a rapid diagnosis and early appropriate therapy. Assessment of the immune deficits based on the underlying condition, immunosuppressive/immunomodulatory therapies, and other risk factors surgery, surgical drains, vascular access, antimicrobial therapies, mucositis, epidemiology will suggest the most probable pathogens. LWBK1580-CH090_p indd 1120