Karen E. Doucette
Jay A. Fishman
The population of immunocompromised patients has multiplied greatly in recent years due to an expansion of indications for immunosuppressive therapies combined with improved survival following organ and bone marrow transplantation, cancer chemotherapy, and other chronic diseases requiring immunosuppressive therapy. Despite advances in prophylactic strategies and antimicrobial therapies, infectious complications remain a leading complication of immunosuppressive therapy. Familiarity with the clinical presentation, differential diagnosis, and management of infectious complications in immunocompromised patients is essential for the practice of critical care medicine. An understanding of the nature of the patient's underlying immune deficits—neutropenia and humoral- or cell-mediated immune deficit —and their epidemiologic exposure—intensity and virulence of offending pathogens—will often define the most likely pathogens responsible for an infectious syndrome.
The following points should be considered when evaluating any immunocompromised patient presenting with a suspected infection.
Key Points
1. Due to 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.
2. A thorough, repeated history and physical examination remain vital, and are the basis upon which investigations and management are directed in order to achieve a rapid diagnosis and early appropriate therapy. Subtle signs are often the basis for fruitful investigations.
3. Assessment of the immune deficits based on the underlying condition and immunosuppressive therapies, and other therapeutic interventions—surgery, surgical drains, vascular access, antimicrobial therapies—will suggest the most probable pathogens.
4. An aggressive initial approach to diagnosis is generally warranted given the broad spectrum of pathogens potentially causing disease in this population. Routine noninvasive investigations—cultures of blood, urine, and sputum; chest radiograph; and so forth—should be performed, and invasive procedures such as biopsy and bronchoscopy considered early. A delay in arriving at a diagnosis results in delays of appropriate therapy or exposure to toxicities of unneeded therapies, and will compromise treatment outcomes.
5. When tissue or body fluids are collected, histopathologic and microbiologic specimens must be evaluated for both infectious and noninfectious syndromes, such as malignancy, drug toxicity, rejection, and graft versus host disease. Consultation with the pathology and microbiology departments can help ensure maximal yields from clinical specimens.
6. Initial empiric antimicrobial therapy is often warranted due to the severity of initial presentation and/or potential for rapid clinical deterioration. Microbiologic specimens obtained prior to antimicrobial therapy will facilitate microbiologic diagnosis and directed therapy that will limit toxicities and improve patient outcome.
The Immunocompromised Host with Suspected Infection
The risk of infection in the immunocompromised host, as for any individual, 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 measure of all host factors potentially contributing to the risk for infection (Table 115.1) including anatomic defects, as well as exogenous immunosuppression. Specific immunosuppressive therapies and deficits predispose to specific types of infection (Table 115.2).
Consideration of these factors for each patient allows development of a differential diagnosis for “infectious syndromes” and can also be used to direct preventative strategies, such as prophylaxis and vaccination, appropriate to each individual's degree of risk for specific infections. 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 hospitalization.
A thorough physical examination should be completed, with particular focus on organ systems commonly involved with infectious complications in immunocompromised hosts; these include the skin, respiratory tract, central nervous system (CNS), and urinary tract. A careful assessment for cutaneous lesions should be performed, as this may be the earliest manifestation of disseminated infection. Examination of the skin should include the perirectal area, looking for evidence of erythema or tenderness, as this is a common site of infection, such as a perirectal abscess, and source of fever in neutropenic patients. Examination of the respiratory tract should include the paranasal sinuses in addition to the lungs. Signs and symptoms of infection in immunocompromised hosts are often subtle, and minor complaints may be the only clues to localize infection.
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Table 115.1 Factors contributing to the net state of immunosuppression |
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In all immunocompromised patients with fever or suspected infection, routine investigations should include a complete blood count (CBC) with differential, serum creatinine, liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase), and liver function tests (bilirubin, international normalized ratio [INR]) in addition to blood cultures. A chest radiograph should be performed, as signs and symptoms of respiratory infection may be absent despite an active pulmonary process. Chest computed tomography (CT) scans will often reveal important abnormalities missed by routine radiographs. Additional investigations should be guided by the history, examination, and results of the initial investigations.
An aggressive approach to making a specific microbiologic diagnosis should be undertaken, because delays in appropriate therapy may compromise outcome. 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 these are 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 both community-acquired —methicillin-resistant Staphylococcus aureus and multiresistant Pneumococcus—and nosocomial—vancomycin-resistant enterococcus, fluconazole-resistant Candida species—organisms. 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 acid-fast stain for Nocardia, silver stain for Pneumocystis carinii [jirovecii]) or culture media (e.g., for Mycobacteria species). In addition, given that noninfectious etiologies such as organ rejection, drug toxicity, and graft versus host disease (GVHD) are often in the differential diagnosis, histology is integral to making a definitive diagnosis. The diagnosis of virally driven diseases such as tissue-invasive cytomegalovirus (CMV) disease (1) and Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD) (2) also require histology for diagnosis.
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 initially described by Bodey et al., who correlated the risk for infection with the degree and duration of neutropenia, notably in leukemic patients, with neutrophil counts less than 500 cells/µL (3,4). This reduction in ANC impairs the innate host immune response of phagocytosis, thus predisposing the neutropenic patient to an array of bacterial and fungal infections, usually from endogenous colonization.
Presentation, Common Pathogens, and Infectious Disease Syndromes
Fever, defined as a single oral temperature of greater than or equal to 38.3°C (101°F) or a temperature of greater than or equal to 38°C (100.4°F) for an hour or more, is often the only predictor of infection (5). 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 (5).
The gastrointestinal tract, including the oropharynx and periodontium where chemotherapeutic agents induce mucosal damage, is the most common source of infection in febrile neutropenic patients (6). However, this is often difficult to document, making pulmonary infections and bacteremia—especially related to vascular lines—more commonly documented (6). Although historically, Gram-negative organisms such as Escherichia coli, Klebsiella species, and Pseudomonas aeruginosa accounted for most bloodstream infections (4), Gram-positive organisms, particularly Streptococcus species and coagulase-negative Staphylococcus, are now isolated in almost two thirds of bloodstream infections (6). This shift from Gram-negative to Gram-positive bacteremia is related to the now almost universal placement of central venous catheters (CVCs) in patients undergoing chemotherapy, as well as a reduction in the risk of Gram-negative infections with the use of fluoroquinolone prophylaxis (7). The skin, particularly CVC sites, and the lower respiratory and urinary tracts are other common sites of infection.
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Table 115.2 Infections associated with specific immune defects |
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The risk of opportunistic fungal infection increases with the duration and severity of neutropenia (8). 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 (9,10). 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 (11). Similarly, neutropenic patients have been found to become infected with highly resistant non-Aspergillus molds in addition to Aspergillus species (12,13).
Approach to Diagnosis
Signs and symptoms of inflammation may be minimal or absent in the neutropenic host (14). Cutaneous infection often occurs at former sites of intravenous catheters or drains, and may be tender or edematous, without the usual signs of cellulitis. Urinary tract infection may present without pyuria—often with viral pathogens—and the chest radiograph is often normal despite rapidly progressive pneumonia. 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 (15). A daily search for subtle signs and symptoms of infection, particularly pain at the most commonly involved sites—periodontium, oropharynx, perianal, skin, and vascular access sites—should be undertaken.
Basic investigations of the neutropenic patient with possible infection include a CBC with differential, serum creatinine, liver enzymes, and liver function tests in addition to cultures of blood, urine, and sputum. A chest radiograph should be performed. If the chest radiograph is normal but the patient has pulmonary symptoms or no identified source of infection, a CT scan should be performed. Collection of additional specimens is guided by the clinical presentation and preliminary investigations. For example, oral ulcerations should be swabbed for viral (herpes simplex virus [HSV]) studies, skin lesions biopsied for culture and histology, and unexplained pulmonary infiltrates assessed with bronchoscopy and bronchoalveolar lavage and/or transbronchial biopsy, or open lung biopsy, as indicated.
While these investigations are not without risk, it is likely that the patient will become less tolerant of invasive studies as infection progresses. In those recovering from neutropenia with persistent fever, liver function tests and chest and abdominal imaging should be performed to look for hepatosplenic candidiasis, typhlitis, or invasive mold infection. Many infections will be asymptomatic during a neutropenic event, only becoming apparent with recovery.
Management
Identification of the best candidates for empiric therapy and avoiding the excessive use of prophylactic antimicrobial agents and the toxicities associated with many therapies are central goals for the care of the sick, neutropenic host. After obtaining 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 (5). In critically ill neutropenic patients, there is no single empiric regimen appropriate for all patients (5,16,17). The selection of an initial empiric antibiotic regimen should take into consideration the general trend of increasing Gram-positive infections, the local hospital epidemiology, and the susceptibility patterns of isolates from neutropenic patients, in addition to the clinical presentation, epidemiologic exposures, and antimicrobial use history.
Options include monotherapy with (a) a third- or fourth-generation cephalosporin (e.g., ceftazidime or cefepime), (b) a carbapenem such as imipenem or meropenem, or (c) piperacillin-tazobactam. Dual therapy may be used without a glycopeptide, such as an antipseudomonal β-lactam plus an aminoglycoside or fluoroquinolone, 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 empiric addition of vancomycin therapy in febrile neutropenia has not been shown to alter outcomes in those patients without pulmonary infiltrates, septic shock, clinically documented infections likely due to Gram-positive organisms such as central venous catheter or skin and soft tissue infections, or documented Gram-positive infections resistant to the primary empiric therapy (18). Vancomycin use has also been associated with the emergence of vancomycin-resistant enterococci, and thus its use in febrile neutropenic patients should be limited as indicated above.
For those who have a source of infection identified—usually less than half of patients under consideration—antimicrobial therapy can be tailored based on culture results, while those who defervesce on empiric antibacterial therapy should have the antimicrobials continued until neutrophil recovery.
Controversy exists regarding the optimal timing of adding antifungal therapy. In patients who have been in the intensive care unit (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 (Table 115.3) (19,20). 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 (5,8,10). 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 (21). Recently, voriconazole (22), caspofungin (23), other echinocandins (e.g., anidulafungin and micafungin), and posaconazole have been demonstrated to be effective in persistently febrile patients with neutropenia. Renal and hepatic function, potential drug interactions, cost, and suspected source of fungal infection are all considerations when choosing an initial empiric antifungal agent.
Adjunctive therapies studied in the setting of febrile neutropenia include granulocyte transfusion and the use of hematopoietic growth factors. The role of neutrophil transfusion has been controversial, limited by technical aspects, and made essentially obsolete with the availability of hematopoietic growth factors (24). 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; hence, their use is not routinely recommended (25,26).
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Table 115.3 Risk factors for candidemia in the intensive care unit settinga |
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The Corticosteroid-treated Patient
Corticosteroids have been used for the treatment of inflammatory, autoimmune, and lymphoproliferative diseases as well as for the prevention of graft rejection since the 1950s. Corticosteroids have an effect, both negative and positive, on various components of the immune system (27). Treatment with corticosteroids results in reduced proliferation of B and T lymphocytes, inhibition of neutrophil adhesion to endothelial cells, inhibition of macrophage differentiation, and reduced recruitment of mononuclear cells, including monocytes, into sites of immune inflammation (27,28). In addition, these agents suppress cellular (Th1) immunity and promote humoral (Th2) immunity (27).
The risk of infection in corticosteroid-treated patients is related to the dose and duration of therapy (29,30). Those treated with more than 10 to 20 mg/day of prednisone for more than a month are at risk for infectious complications. Although corticosteroids have a broad effect on the immune system, the primary immune deficit is in cell-mediated immunity, thus placing 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 P. carinii (jirovecii), Listeria monocytogenes, Legionella, and Nocardia species.
Pneumocystis carinii (jirovecii)
The human species of Pneumocystis has recently been renamed P. jirovecii, although considerable controversy persists regarding the appropriate nomenclature of this protozoan (31). P. carinii (jirovecii) has a worldwide distribution and is an important cause of pneumonia in immunocompromised patients, most notably those with human immunodeficiency virus (HIV) infection, but also those immunosuppressed due to malnutrition, organ transplantation, and prolonged corticosteroid use, usually at a dose greater than 15 to 20 mg/day. Those requiring prolonged steroid therapy are appropriate candidates for prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) (32).
Presentation
The onset of symptoms is often associated with recent dose reduction or discontinuation of steroids and/or with intensification of the overall immunosuppressive regimen. Although generally presenting as a subacute illness within weeks of progressive dyspnea and nonproductive cough in HIV-infected individuals, non-HIV immunocompromised patients with Pneumocystis pneumonia (PCP) tend to have a more acute presentation. Patients with PCP are generally hypoxemic with few physical or radiographic findings. In addition to nonproductive cough and dyspnea, low-grade fever is frequently present. Physical examination findings are nonspecific, but may reveal inspiratory crackles on auscultation, with or without hypoxia or other signs of respiratory distress. The illness may progress to respiratory failure requiring intubation and mechanical ventilation.
Diagnosis
The classic chest radiograph appearance of PCP is bilateral interstitial infiltrates with perihilar predominance. The radiographic appearance can be highly variable, however, including patchy airspace disease and small pulmonary nodules. An elevated lactate dehydrogenase level is a nonspecific finding associated with PCP. Since P. carinii (jirovecii) cannot be routinely cultured, a definitive diagnosis relies on the identification of the organism by staining techniques from pulmonary secretions or tissue. The diagnosis may be made by staining secretions obtained through sputum induction with hypertonic saline, which has a 97% negative predictive value (33). If respiratory secretions cannot be obtained by sputum induction, or if this is negative and the diagnosis remains uncertain, bronchoscopy with transbronchial tissue biopsy remains the gold standard for diagnosis of PCP, yielding better results than bronchoalveolar lavage (34). Examination of respiratory secretions may be done quickly by staining with Gomori methenamine silver (GMS) or calcofluor white; however, diagnosis has been improved through the use of immunofluorescent staining with monoclonal antibodies (35).
Treatment
Treatment for PCP is outlined in Table 115.4. First-line therapy for the treatment of PCP is TMP-SMX at a dose of 15 to 20 mg/kg per day of the TMP component, divided every 6 or 8 hours for 21 days (36). In those with severe disease who are allergic to or fail TMP-SMX, alternatives include atovaquone suspension 750 to 1,500 mg orally twice daily, pentamidine 4 mg/kg/day to a maximum of 300 mg, dapsone 100 mg orally plus TMP 15 to 20 mg/kg/day, or clindamycin 600 mg intravenously every 6 hours plus primaquine 15 to 30 mg (as base) per day. Although adjunctive administration of corticosteroids to patients with PCP and HIV has been documented to improve outcomes, this has not been studied in a randomized clinical trial in non-HIV immunocompromised patients with PCP. In practice, a short course of tapering steroids is often beneficial in preventing intubation and in rapidly progressive disease. After completion of therapy, secondary prophylaxis with TMP-SMX should be administered to those who remain at risk due to continued immunosuppression.
Listeria monocytogenes
Listeria monocytogenes is a Gram-positive bacillus capable of intracellular survival after phagocytosis by macrophages (37). Although capable of infecting normal hosts, invasive disease is seen predominantly in those with cell-mediated immune deficits due to such factors as extremes of age (neonates and the elderly), pregnancy, malignancy, organ transplantation, or other immunosuppressive therapy.
Presentation
Though a food-borne pathogen, L. monocytogenes infection presents as meningitis or primary bacteremia in 80% to 90% of cases (38,39,40). Gastrointestinal symptoms are present in only a minority of cases. Onset of symptoms may be acute or subacute, with fever being nearly universal. CNS involvement may present as meningitis with headache and neck stiffness, focal parenchymal involvement with cerebritis and/or abscess, or meningoencephalitis with impaired level of consciousness.
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Table 115.4 Treatment modalities for the commonest infections |
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Diagnosis
The diagnosis of listeriosis is generally made through culture of blood or cerebrospinal fluid (CSF). Approximately 75% of cases of CNS listeriosis are associated with bacteremia, and a positive blood culture for Listeria should prompt a CSF examination. CSF parameters are variable, but a common presentation is pleocytosis with neutrophil predominance, elevated protein, and normal glucose. The Gram stain is frequently negative.
Treatment
In patients at risk for Listeria who present with meningitis of uncertain etiology, empiric therapy should include ampicillin, 2 g intravenously every 4 hours, as part of the initial regimen. If listeriosis is confirmed, ampicillin is the drug of choice. In vitro data suggest bactericidal synergy of the combination of ampicillin and gentamicin (41). In vitro synergy has also been demonstrated between ampicillin and TMP-SMX; this combination has been demonstrated to be superior to ampicillin and gentamicin in the treatment of Listeria meningoencephalitis (41,42), suggesting that this combination may be indicated in those with severe disease. The minimum duration of therapy recommended is 3 weeks, but this may need to be extended based on the clinical response and radiographic resolution of CNS parenchymal disease if present.
Legionella
Legionella species are small Gram-negative bacilli that are widely distributed in the aqueous environment. Both community and hospital outbreaks have occurred in association with contaminated water sources such as air conditioners, cooling towers, and whirlpools (43). Although capable of causing disease in normal hosts, those with impaired cell-mediated immunity are at highest risk (44).
Presentation
Most commonly, Legionella infection presents as pneumonia—termed Legionnaires disease—although extrapulmonary disease and a self-limited febrile illness—termed Pontiac fever—may occur. The physical and laboratory findings and radiographic appearance of Legionella pneumonia are not specific. Fever with pulse–temperature dissociation, diarrhea, hyponatremia, and elevated liver enzymes may occur, but are not distinctive enough for Legionnaires disease to allow a clinical differentiation from other causes of pneumonia. In patients at risk, Legionella must be considered in the differential diagnosis of pneumonia, and empiric therapy administered when appropriate.
Diagnosis
Legionella is a fastidious organism, and culture of respiratory secretions for diagnosis is both insensitive and time consuming (45); immunofluorescent microscopy can improve the sensitivity of culture techniques. Serology can be used, but also results in delays in diagnosis, as paired sera must be collected. Newer methods that may allow more rapid diagnosis include a urinary antigen test and nucleic acid detection. Urinary antigen tests have a high sensitivity for the detection of Legionella pneumophila serogroup 1, but perform less well in those infected with other serogroups of L. pneumophila, or with other Legionella species. A combination of culture, urinary antigen detection, and serology has been suggested to optimize diagnosis (45).
Treatment
Both macrolides and fluoroquinolones have in vitro activity against Legionella species. Three observational studies have compared the clinical efficacy of macrolides—not including azithromycin—and quinolones, mainly levofloxacin, in patients with Legionnaires disease. The results suggested that quinolones may be superior to macrolides, with fewer complications and shorter hospital stays in those receiving quinolones (46). There are no studies comparing newer macrolides (e.g., azithromycin) to new quinolones.
Nocardia
Nocardia species are part of the aerobic actinomycetes genus, and are ubiquitous environmental saprophytes. While there are several species, the Nocardia asteroides complex—Nocardia asteroides senso strictu, Nocardia farcinica, and Nocardia nova—are the most common cause of disease (47). Immunosuppression is the major risk factor for nocardial infections, and disease is seen most often in solid organ transplant recipients, patients with advanced HIV infection (i.e., with CD4+ counts of less than 100 cells/µL), patients with lymphoreticular malignancy, and those on chronic corticosteroid therapy.
Presentation
Nocardia predominantly causes pneumonia, and the initial presentation includes respiratory symptoms generally in association with fever (48). Chest radiograph typically demonstrates nodular lesions, which may progress to cavitation; however, diffuse infiltrates or consolidation may also occur. Nocardia has a high propensity to disseminate to the CNS, and immunocompromised patients with nocardiosis may present with CNS symptoms with or without concomitant pulmonary symptoms. Although the usual route of infection is inhalational, direct cutaneous inoculation with resultant skin disease—generally subcutaneous nodules—may also be seen.
Diagnosis
Definitive diagnosis of nocardial disease is made through special stain and culture of the organism from the suspected site of infection. Modified acid-fast stain (Kinyoun) demonstrates branching and beading Gram-positive bacilli. Nocardia grow on nonselective media; however, the lab should be notified if this diagnosis is suspected, as selective media can be used to avoid overgrowth by other organisms. Whenever a diagnosis of pulmonary nocardiosis is made, further investigations should include neuroimaging to exclude CNS dissemination.
Treatment
Antimicrobial therapy is the foundation of treatment of nocardiosis, although adjunctive surgical resection of necrotic tissue is necessary on occasion. TMP-SMX, dosed as the TMP component at 15 mg/kg/day divided in two or four doses and administered either orally or intravenously, is the preferred agent for treating nocardial infections; this agent achieves high concentrations in lung, brain, skin, and bone (49). Given that some species may be resistant to TMP-SMX, combination therapy may be considered until susceptibilities are available. Other antimicrobial agents with activity against Nocardiaspecies include imipenem, amikacin, minocycline, ceftriaxone, linezolid, ciprofloxacin, and amoxicillin/clavulanate. While the duration of therapy should be individualized based on clinical response, pulmonary and cutaneous disease should be treated for at least 6 to 12 months, and CNS disease for at least 9 to 12 months. Immunosuppression should be reduced as much as possible to aid in treatment.
Patients Treated with Immunomodulatory Agents
In recent years, a number of monoclonal antibody therapies have been developed and have revolutionized the treatment of rheumatologic as well as other systemic inflammatory and autoimmune conditions (Table 115.5). Immune modulation using these agents results in selected immune deficits and infectious complications have been recognized in association with several of these agents. As more patients are treated with these therapies, with a longer-term follow-up, our understanding of the risk of infection associated with these biologic compounds will undoubtedly be refined.
Tumor Necrosis Factor-α Antagonists
Three tumor necrosis factor-α (TNF-α) antagonists are currently marketed in the United States: Infliximab (Remicade, Centocor Inc.), etanercept (Enbrel, Amgen and Wyeth Pharmaceuticals), and adalimumab (Humira, Abbott). These agents are effective in the treatment of rheumatoid arthritis, active Crohn disease, and ankylosing spondylitis. Blockade of TNF-α, a proinflammatory cytokine, 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.
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Table 115.5 Selected therapeutic antibodies |
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Tuberculosis has been associated with use of TNF-α antagonists, probably as a result of the resultant cell-mediated immune deficits (50,51). The majority of cases have occurred in patients receiving infliximab; however, cases have also been described in association with etanercept and adalimumab. In general, cases have occurred in those with risk factors for latent tuberculosis infection. As a result, tuberculosis skin testing (TST) is recommended in all patients prior to the initiation of a TNF-α antagonist. Regardless of TST results, tuberculosis should be considered in the differential diagnosis in a patient presenting on a TNF-α antagonist with compatible symptoms.
A number of other infections including histoplasmosis, listeriosis, aspergillosis, coccidiomycosis, and candidiasis have been associated with the use of TNF-α antagonists; however, the magnitude of risk and whether or not a causative association exists are unclear (51).
Rituximab
Rituximab (Rituxan, Genentech Inc. and Biogen Idec) is a chimeric murine/human monoclonal antibody that binds the CD20+ marker, expressed on B lymphocytes. 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 for the treatment of rheumatoid arthritis. In addition to these conditions, rituximab has been used for the treatment of posttransplant lymphoproliferative disease, immune thrombocytopenic purpura, autoimmune hemolytic anemia, systemic lupus erythematosus, multiple sclerosis, graft versus host disease, and treatment of antibody-mediated graft rejection (52).
Following rituximab therapy, antibody production is maintained by plasma cells, which are CD20, negative. Peripheral B-cell recovery takes 3 to 12 months (53). Despite this B-cell deficiency and extensive use of rituximab for the treatment of malignant and autoimmune conditions, there has been no evidence of an increased risk of infection in patients treated.
Natalizumab
Natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals) is a recombinant humanized monoclonal antibody that binds to α4-integrin, thereby inhibiting α4-integrin–mediated leukocyte adhesion. Disruption of binding prevents the transmigration of leukocytes across the endothelium into inflamed tissue. Natalizumab is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis and in those with inadequate response to, or who are unable to tolerate, alternate therapies (54). It also increases the rate of remission and improves the quality of life in patients with active Crohn disease (55).
Progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the central nervous system caused by the human polyomavirus JC virus, has been reported in three patients who received natalizumab (56,57,58). The U.S. Food and Drug Administration (FDA) approved an application for resumed marketing in June of 2006. Given the mechanism of action and inhibition of leukocyte migration, it is possible that further opportunistic infections may be associated with the use of this agent.
The Solid Organ Transplant Recipient
With improvements in surgical techniques and immunosuppressive therapy, a growing number of people are living with solid organ transplants. With intensified immune suppression, the incidence of graft rejection has decreased, while infectious complications are an important cause of morbidity and mortality. 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 two factors: the degree of exposure to potential pathogens and the overall or “net state of immunosuppression” (Table 115.1) (59). These patients are differentiated from other immunocompromised hosts by the technical aspects (complex surgery) and, in general, the need for lifelong immune suppression to maintain graft function.
In an individual, the net state of immunosuppression is determined not only by the immunosuppressive agents used, but also by their dose, duration, and sequence of use. In addition, factors such as underlying immune deficiency, metabolic derangements, the presence of foreign bodies (e.g., central venous catheters) or fluid collections, and infection with immune-modulating viruses such as CMV or EBV all contribute to overall immunosuppression and the risk of infection (59).
Timeline of Posttransplant Infections
With standardized immunosuppressive regimens, specific infections vary in a predictable pattern depending on the time elapsed since transplantation (Fig. 115.1) (59). 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 (e.g., pulse dose steroids or the intensification 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 and patterns of use; the reduced use of corticosteroids and calcineurin inhibitors; the increased use of antibody-based induction therapies or sirolimus; routine antimicrobial prophylaxis; improved molecular assays; antimicrobial resistance; transplantation in HIV- and hepatitis C virus (HCV)-infected individuals; and broader epidemiologic exposures, again, such as travel. Figure 115.1 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
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Figure 115.1. 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; PCP, Pneumocystic carinii; UTI, urinary tract infection. (Adapted from Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med. 1998;338[24]:1741.) |
· The period 1 to 6 months after transplantation, depending on the rapidity of tapering immune suppression and the use of antilymphocyte “induction” therapy, reflecting intensive immune suppression with viral activation and opportunistic infections
· The period beyond 6 to 12 months after transplantation, reflecting community-acquired exposures and some unusual pathogens based on the level of maintenance immune suppression
In the first month after transplantation, most infections are related to the surgery, similar to those occurring in the complex general surgical population. These include pneumonia and surgical site, urinary tract, and central venous catheter–associated infections caused by typical bacterial and fungal pathogens such as Candida. Exposure to nosocomial pathogens and colonization will alter the use of empiric antimicrobial therapy, including for methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococcus (VRE), fluconazole-resistant Candida species, Clostridium difficile, and P. aeruginosa.Opportunistic infections rarely occur within the first month posttransplant unless there has been pretransplant immunosuppression. In the absence of prophylaxis, however, 24% to 34% of transplant recipients will have HSV disease, with most cases of HSV occurring as orolabial or genital disease due to reactivation of latent infection in the recipient during the first post transplant month (60).
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, allows organs from donors with bacteremia and/or meningitis to be safely used without compromising transplant outcomes (61,62,63).
The first month through the sixth month post transplant is the highest-risk period for opportunistic infections, since the effects of immunosuppression are greatest during this period. These infections may include viral (CMV, varicella-zoster virus [VZV], EBV, and hepatitis B), bacterial (Nocardia, Listeria, and tuberculosis), fungal (Aspergillus and Cryptococcus), or parasitic (Pneumocystis, Toxoplasma and Strongyloides) infections.
Beyond 6 months post transplant, most recipients are on reduced levels of maintenance immunosuppression with good graft function and at low risk for opportunistic infections. Most infectious complications during this time are due to conventional community-acquired pathogens occurring in the general population. These include viral respiratory infections, pneumococcal pneumonia, and gastroenteritis. Intense exposure to an opportunistic pathogen, however, may still result in disease, and transplant recipients should be counseled regarding strategies to avoid high-risk exposures (64). Recipients requiring augmentation of immunosuppression for management of acute chronic rejection, as well as those with chronic or recurrent CMV infection, remain at risk for other opportunistic infections, particularly P. carinii (jirovecii), invasive fungal infection, and EBV-associated, posttransplant lymphoproliferative disease.
Prevention of Infections
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, tuberculin skin testing, and pretransplant immunization of recipients.
Donor and Recipient Screening
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 a complete medical history, as well as travel/residence, occupational, and risk behavior (e.g., injection drug use) and exposure history (e.g., tuberculosis). Commonly utilized serologic tests for screening donors and recipients include HIV-1 and -2, human T-lymphotropic virus (HTLV)-I/II, and HCV antibodies; hepatitis B surface antigen (HBsAg); hepatitis B core (HBcAb total ± IgM); hepatitis B surface (HBsAb) (some centers); CMV IgG antibodies; EBV antibody panel; syphilis screen (rapid plasma reagin [RPR] or venereal disease research laboratory [VDRL]); Toxoplasma antibody; HSV IgG (some centers); and VZV IgG in recipients.
Immunization
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) 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 as needed and, based on vaccine type and urgency of transplant, accelerated vaccination schedules used prior to transplant where appropriate. 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 HBcAb-positive donors, thus expanding the donor pool (65). Susceptible individuals should receive varicella vaccine (live vaccine) a minimum of 4 weeks prior to transplantation.
Tuberculosis Screening
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 (66,67). 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 (68,69). Transplant candidates should undergo TB screening with TST and risk factor assessment prior to transplantation.
Disease-specific Prevention and Management
Cytomegalovirus
CMV remains a significant cause of morbidity in organ transplant recipients; however, strategies for prevention have decreased the morbidity and mortality from CMV. The risk of CMV disease depends on a number of factors, including the donor and recipient serostatus, as well as the immunosuppression, 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 (70) 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) are 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 greatest risk of a primary CMV infection. Such patients should receive prophylaxis with valganciclovir (900 mg/day) for 100 days (70,71). In CMV-seropositive recipients, either prophylaxis with valganciclovir or preemptive therapy based on the results of a sensitive monitoring assay (e.g., CMV antigenemia or polymerase chain reaction [PCR]) 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 vial 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 (1).
Established CMV syndrome or tissue-invasive disease should be treated with intravenous ganciclovir, 5 mg/kg every 12 hours. Although oral ganciclovir and valganciclovir have been shown to be effective in the prevention of CMV infection, there are, as yet, no data to support their use in the treatment of disease due to CMV. Therapy should be continued for a minimum of 14 days 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 (72,73).
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; suboptimal ganciclovir levels; intense immunosuppression; and high CMV viral load. Ganciclovir-resistant CMV should be suspected in the setting of a stable, or rising, viral load in patients treated with ganciclovir; no decrease in antigenemia after 7 days of therapy; lack of clinical improvement after 14 days of full-dose intravenous ganciclovir; or CMV infection developing shortly after a prolonged course of low-dose ganciclovir. 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 (74).
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. Studies comparing transplant recipients having received antiviral prophylaxis with either acyclovir or ganciclovir to historical controls suggest some benefit of antiviral prophylaxis (75). Recently, quantitative EBV viral load monitoring has also been shown to decrease the risk of PTLD (76). 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 and localized or disseminated, and commonly involves the allograft. The diagnosis of PTLD requires histologic confirmation and staging of the disease (2).
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. 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% (77). Cytotoxic chemotherapy is generally considered a third-line option due to a high incidence of toxicity in this population.
Pneumocystis carinii (jirovecii)
In the absence of prophylaxis, P. pneumoniae occurs in 5% to 15% of solid organ transplant recipients. Prophylaxis with trimethoprim-sulfamethoxazole, 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, aerosolized pentamidine 300 mg monthly, or atovaquone 1,500 mg daily are alternatives (32).
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 double-strength tablet daily; lifelong prophylaxis is recommended (78).
Diagnosis and Treatment of Infectious Syndromes
The diagnosis and management of infectious complications in transplant recipients can be complex, and thus, consultation with local infectious diseases specialists is recommended. The initial approach to the transplant patient with suspected infection includes a thorough history and physical examination to assess the overall state of immune function and exposure history and localize the potential site of infection. Basic testing should include a complete blood count, creatinine, liver enzyme and function studies, blood cultures, and a chest radiograph. Additional specimens for microbiologic testing should be obtained as directed by the history and physical examination (e.g., urine cultures, stool for bacterial culture, Clostridium difficile toxin, ova and parasites, blood for CMV antigenemia, or PCR).
Identification of the etiologic agent of infection is extremely important and, hence, early aggressive testing (e.g., tissue biopsy, bronchoscopy) should be considered. Due to the possibility of unusual pathogens, close coordination with microbiology and pathology is recommended to ensure proper collection and testing of specimens. Because infections may progress rapidly in immunocompromised hosts, empiric therapy directed at likely pathogens may be considered after collection of appropriate diagnostic samples.
Fever and Pulmonary Infiltrate
Transplant recipients are susceptible to both common and unusual respiratory pathogens. In transplant patients presenting with fever and a pulmonary infiltrate, the differential diagnosis is broad and includes both infectious and noninfectious etiologies. However, infection is ultimately identified in 75% to 90% of such cases, and dual 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 115.6 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
Similar to pulmonary infections, the presentation of CNS infection in transplant patients 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 transplant patients 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 and Nocardia species are also common.
Table 115.7 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.
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Table 115.6 Differential diagnosis of fever and pulmonary infiltrate in organ transplant recipients |
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Table 115.7 Common central nervous system infections in transplant recipients |
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The Hematopoietic Stem Cell Transplant Recipient
A growing number of patients are undergoing allogeneic and autologous hematopoietic stem cell transplantation (HSCT) procedures for both malignant and nonmalignant indications (79). Despite the advances, severe infectious complications are not uncommon, with up to 40% of HSCT recipients requiring ICU admission, and 60% of these needing mechanical ventilation, which is associated with a high mortality rate (80,81). 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 (82).
Historically, bone marrow has been relied upon as a source of stem cells, but recent developments now include the use of peripheral blood stem cell (PBSC) and umbilical cord blood (UCB) for transplantation. In an attempt to eliminate malignant cells and decrease the risk of graft versus host disease, positively selected CD34+ progenitor cells may be used for transplantation; however, this results in significant T-lymphocyte and monocyte depletion of the graft, and therefore an increased risk of opportunistic infection (83). In an attempt to extend treatment by allogeneic HSCT to older patients and those with comorbid conditions, reduced-intensity or nonmyeloablative-conditioning regimens have been developed (84). Although the period of neutropenia is shorter, and potent antitumor effects result from this type of transplant, patients remain at high risk for GVHD and require GVHD prophylaxis (85). Thus, despite shorter periods of neutropenia and less severe mucositis, and though the risk of early bacterial infections appears to be decreased, the risk of late viral, fungal, and bacterial infections persists (86).
As a result of pretransplant conditioning 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 risk of infectious complications in the HSCT recipient is generally divided into three phases: (a) the period from conditioning therapy to engraftment when patients are neutropenic—the pre-engraftment phase—carries a high risk of bacterial and fungal infections; (b) the second phase, from engraftment to day 100—or during the period of treatment for acute GVHD—in which viral and filamentous fungal infections predominate; and (c) beyond day 100—late phase or with chronic GVHD—the incidence of infections is reduced, and is determined by the level of immune suppression needed for chronic GVHD.
Phase 1: Pre-engraftment Infections
The early pre-engraftment, neutropenic phase usually lasts 10 to 15 days in most current nonmyeloablative HSCT patients, and longer with ablative regimens. The predominant infections seen during conditioning chemotherapy to the time of engraftment are similar to those seen in association with neutropenia (see previous section on the neutropenic patient). 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 (7). Although azole prophylaxis has reduced the incidence of candidemia, this continues to be an early cause of bloodstream infection with an increase in the risk of azole-resistant Candida (87). Herpes simplex virus may also reactivate during this phase but can be prevented with prophylactic acyclovir in seropositive HSCT recipients.
Phase 2: Engraftment to Day 100 (Acute Graft versus Host Disease)
This phase is characterized by deficits in cellular immunity; therefore, the most important infectious complications are viral infections, particularly CMV and invasive mold infections. The most common manifestations of CMV disease in HSCT recipients are pneumonia and gastrointestinal disease (88). The highest risk of disease occurs in seropositive recipients of seronegative transplants (89), and CD34+selected PBSC transplantation is associated with an increased risk of CMV infection due to T-lymphocyte depletion. The use of ganciclovir for prophylaxis or preemptive therapy has resulted in a decreased risk of CMV infection during this period, with most infections now occurring after ganciclovir has been discontinued.
Interstitial pneumonitis is an important clinical syndrome presenting during the postengraftment phase, and etiologies include CMV, respiratory viruses, Pneumocystis, or idiopathic pneumonia syndrome (IPS). The diagnosis of CMV pneumonitis requires histology for definitive diagnosis; however, this is often impractical, and a presumptive diagnosis may be made on the basis of the presence of interstitial pneumonia, detection of CMV antigen or nucleic acid in the peripheral blood, and/or respiratory secretions combined with negative investigations for other etiologies of pneumonitis. Despite treatment with intravenous ganciclovir and CMV hyperimmune globulin or intravenous immunoglobulin, the mortality from CMV pneumonitis remains high at 50% or greater (90).
P. carinii (jirovecii) has essentially been eliminated as a cause of pneumonitis with the use of TMP-SMX prophylaxis. Respiratory viral infections, such as respiratory syncytial virus, parainfluenza virus, and human metpneumovirus, have been increasingly recognized as an etiology of pneumonia in HSCT (91). A number of noninfectious etiologies of pneumonia also exist, including IPS and diffuse alveolar hemorrhage, which must also be considered in the differential diagnosis of HSCT recipients with pneumonitis.
The majority of invasive mold infections occur during the postengraftment phase, and are associated with treatment of acute GVHD (92). Although Aspergillus continues to be the predominant pathogen, non-Aspergillus molds, including Zygomycetes, are emerging pathogens in this population (93). Invasive mold infections generally present as pulmonary nodules, but invasive sinus disease and disseminated disease including CNS involvement are other common presentations. Given the high mortality associated with invasive mold infections, empiric antifungal therapy should be initiated while a definitive diagnosis is aggressively pursued. Empiric therapy with liposomal amphotericin is preferred to voriconazole in HSCT patients with fever or pulmonary infiltrates, given that it has the broadest spectrum of activity. By contrast, the treatment of choice for documented invasive aspergillosis is voriconazole, which has a survival benefit over amphotericin B deoxycholate therapy and is associated with less toxicity, particularly nephrotoxicity (94). Despite appropriate therapy, the mortality of invasive mold infections remains high in HSCT recipients, particularly in those with disseminated or CNS disease, where the mortality reaches 80% to 100%. Newer antifungal agents, such as posaconazole, and combination therapies have not yet been fully studied for therapy in these populations.
Phase 3: Late Infections beyond 100 Days
Beyond 100 days post transplant, there is gradual recovery of humoral and cellular immune function, but infection risk is driven to a large extent by the additional immunosuppression induced by chronic GVHD and its treatment. Up to 40% of HSCT recipients develop varicella-zoster virus infection, generally as a result of reactivation of latent infection, with most cases occurring during the first year. Disseminated disease is associated with a high mortality rate and should be treated with intravenous acyclovir, 10 mg/kg every 8 hours. Late CMV disease may occur and is associated with a history of early CMV disease and GVHD (95). Late CMV disease is treated the same as that occurring early; the outcome of late disease is poor, particularly for CMV pneumonia. Late invasive mold infections may also occur, particularly in those with GVHD and preceding viral (CMV) infection. As with CMV, the management of late mold infections mimics that of early infections. Every attempt should be made to decrease immunosuppression to assist in the treatment of infection.
About one third of patients with chronic GVHD may develop recurrent infection with encapsulated bacteria (sinopulmonary, bacteremia) (96). The predominant pathogen is Streptococcus pneumoniae, with Haemophilus influenzae and S. aureus also commonly isolated. This risk is related to a deficit in opsonizing antibody (97). Because HSCT recipients respond poorly to pneumococcal vaccine within the first 1 to 2 years post transplant, antibiotic prophylaxis with penicillin or TMP-SMX is recommended in those with chronic GVHD. In patients with chronic GVHD admitted with sepsis, broad-spectrum empiric antibiotic therapy is recommended pending microbiologic identification.
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