Introduction

Numerous disease-related and chemotherapy-induced factors render patients with cancer at increased risk for infection.1,2 These factors include the type of cancer (e.g., a solid tumor versus a lymphoma or acute leukemia), the severity and duration of neutropenia, and impairments in cellular function caused by cytotoxic or immunosuppressive drugs; breaches in the integument from surgical procedures, the presence of indwelling plastic venous catheters, or mucositis of the gastrointestinal tract as a result of chemotherapy; and comorbid conditions such as malnutrition, deconditioning, or medical problems such as chronic obstructive lung disease or diabetes. Approaches to prevention, diagnosis, and management of infectious complications in patients with cancer are greatly influenced by the cumulative burden of these risk factors. Neutropenia remains one of the most important predisposing factors for infection, overriding many of the others. This chapter addresses current standards for the management of fever during neutropenia and also highlights contemporary guidelines for the prevention and treatment of common infectious complications in patients with cancer.

The association between neutropenia and increased infection risk was first demonstrated by Bodey and colleagues³ in 1966 in a study of leukemic patients undergoing cytotoxic therapy. The data show that the frequency of infectious complications is inversely related to the degree and duration of neutropenia (Fig. 36-1). Infection risk starts to increase when the absolute neutrophil count (ANC) decreases to less than 1000 cells/mm³ and increases dramatically when the ANC count is less than 500 cells/mm.³ Fewer than half of the neutropenic patients who become febrile will have an identified infection. In roughly 10% to 20% or more of patients with neutrophil counts less than 100 cells/mm³, a bloodstream infection will be identified. More than 50% of all episodes of fever and neutropenia represent “fever of undetermined origin,” with no clear infection source on physical and radiographic examination and cultures.^3,4 In addition to the severity of the ANC nadir, the duration of neutropenia is also an important determinant of both infection risk and infection type. Brief durations of neutropenia, particularly for less than 7 days, are usually associated with a rapid and favorable response to empirical antibiotic therapy. Fever often may be of unknown origin during this early phase of neutropenia, but if a causative pathogen is identified, bacteria and viruses predominate. A neutrophil count persistently less than 500 cells/mm³ for more than 7 days is associated with greater risk for infection-related morbidity and mortality and is the setting in which Aspergillus and other invasive fungal infections most often occur. Other pathogens that may cause infection during the course of prolonged neutropenia (i.e., after 7 days) include antibiotic-resistant bacteria, Candida species, and other molds. Deaths during the state of neutropenia usually are due to these subsequent infections. Overall mortality rates during the state of fever and neutropenia are less than 1% for low-risk patients and approximately 5% for those with more prolonged duration of neutropenia.^5–9

In addition to cytotoxic chemotherapy, circulating neutrophil deficiencies can result from bone marrow incompetence disorders such as myelodysplastic syndrome or crowding out of normal granulocytic precursors by tumor cells. “Functional neutropenia” describes impaired neutrophil microbicidal activity that may be a consequence of the leukemia itself or may be due to therapies such as steroids. In these instances, ineffective neutrophil killing leaves the patient highly vulnerable to infection despite seemingly normal peripheral white blood cell counts.

Sources of Infection

Colonization by pathogenic bacteria, fungi, or viruses generally is a prerequisite for infection. Accordingly, endogenous bacterial and fungal flora and latent herpesvirus infections account for a majority of initial infections in neutropenic patients with cancer.17–17 These infections include skin colonizers such as Staphylococcus aureus and coagulase-negative staphylococci, viridans streptococci, and herpes simplex from the oropharynx and gram-positive bacteria, as well as enteric gram-negative bacteria, from the gut. Candida albicans infections often are derived from the skin or the gastrointestinal or female genital tract. Latent infections that may reactivate during immunosuppression include those due to herpes simplex or varicella-zoster virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV), as well as hepatitis B and C viruses, M. tuberculosis, and Toxoplasma gondii.

Exogenous sources of infection often are found in the hospital and home environments. Contaminated blood products, hospital equipment, water sources, and nosocomial spread of organisms from health care workers represent less common, albeit significant, sources of infection. Common nosocomially spread infections include those due to Clostridium difficile, respiratory viruses, vancomycin-resistant enterococci, and other multiresistant bacteria. Water sources such as faucets and shower heads have been implicated in the spread of Legionella and Aspergillus.¹⁸ Outbreaks of Klebsiella and Enterobacter infection related to intravenous solutions have been well documented.^21–21

Foods can be a potential source of infection, particularly unwashed fruits and vegetables. Neutropenic patients generally are advised to follow safe food-handling guidelines, which include washing fruits and vegetables thoroughly, cooking eggs until the whites and yolks are completely hard, and cooking meat until it is well done.²² Potted plants, mulch, and excavation and building or renovation sites have been implicated as sources of Aspergillus and other molds that may cause disease.²³

Approach to Fever in the Neutropenic Patient

Fever often is the only reliable sign of significant underlying infection in the neutropenic patient. No specific clinical features, such as hypotension, chills or the magnitude of the increase in body temperature can accurately distinguish between fever due to an infection and that due to a noninfectious cause. Nor are laboratory tests such as C-reactive protein or procalcitonin levels considered specific or sensitive or enough to be relied on for making decisions about the use of antibiotics at the time of presentation.26–26 Therefore all febrile neutropenic patients should receive empirical broad-spectrum antibiotics, ideally within 1 hour of presentation. Although a clinically or microbiologically documented source of fever is not found in most febrile neutropenic patients, the rapid initiation of empirical antibiotic therapy remains an important standard of care for all patients in this setting. The choice of specific antibiotic regimens depends on an assessment of the patient’s infection risk during neutropenia, which depends on the duration of neutropenia, the underlying cancer, and comorbid medical conditions. Conditions and findings that may alter the empirical antibiotic regimen are shown in Table 36-1.

Definitions

Guidelines for evaluating antimicrobial therapy for fever and neutropenia have been developed by the Infectious Diseases Society of America and the National Comprehensive Cancer Network.2,26 Fever is defined as a single temperature measurement of 38.3°C (101°F) or greater in the absence of other obvious causes; a temperature of 38°C or greater for an hour or longer is considered to represent a “febrile state” that also requires prompt evaluation and intervention in the setting of neutropenia.^2,26 Neutropenia is defined as an ANC less than 1000 cells/mm³ in some centers but more often is designated by a neutrophil count of less than 500 cells/mm³, which is a level associated with a much higher risk for infection. For practical purposes, an ANC less than 500 cells/mm³, or a count that is anticipated to fall below that level within 48 hours, constitutes a state of neutropenia.

Rarely, a neutropenic patient who is afebrile may exhibit signs or symptoms of infection (e.g., abdominal pain, severe mucositis, and perirectal pain) and should be considered to have an active infection. The concomitant administration of corticosteroids also may initially blunt the fever response. Afebrile neutropenic patients who show signs or symptoms suggestive of an infection should receive empirical antibiotics immediately because of their increased risk for serious invasive infections.

Initial Evaluation

The initial evaluation should be directed toward determining the possible sites of infection and causative organisms and assessing the patient’s level of risk for infection-related complications. A thorough site-specific review of systems is essential. Pertinent history includes recent antibiotic therapy, recent surgery or other invasive procedures such as biopsies or catheter placement, and possible exposure to infections from close contacts and household members, foods, animals, or travel.

The physical examination should focus on common potential sites of infection. Worthy of emphasis in this regard is that the manifestations of infection are muted in the absence of inflammatory cells. Careful examination of the oropharynx may reveal ulcers, or plaquelike lesions may be due to herpes or thrush, and specimens for appropriate tests should be sent for evaluation. Catheter sites require careful assessment for erythema, tenderness, or discharge. With bacterial cellulitis of the skin or perirectum, induration and erythema may be minimal; pimples or pustules are uncommon without neutrophils to create pus. Similarly, few respiratory signs or symptoms may be noted, and auscultation of the lungs may reveal few adventitial sounds, but an infiltrate may be seen on radiographs. A urinary tract infection may not be associated with dysuria. Gastrointestinal tract mucositis due to cytotoxic chemotherapy can lead to sore throat, oral ulcers, and diarrhea that are indistinguishable from the signs and symptoms of infection. Abdominal pain in neutropenic patients may signify a wide variety of problems, including intestinal tumor necrosis and neutropenic enterocolitis, both of which can result in intraabdominal catastrophe or sepsis.

Initial laboratory evaluation should include a complete blood cell count and differential white cell count to determine the degree of neutropenia, liver and renal function tests, oxygen saturation determination, and urinalysis. Chest radiography should be reserved only for patients who have symptoms of respiratory tract infection. Note that radiographic findings may be minimal in neutropenic patients with pneumonia. At least two blood culture samples, each consisting of 20 to 40 mL of blood, should be obtained from both a peripheral vein and from each catheter lumen.2,4 An adequate volume of blood taken for culture will enhance the chances of recovering a pathogen.²⁷

Drawing blood samples from both a vascular catheter and a peripheral vein can help determine whether the catheter is a source of infection. If the differential time to culture positivity between catheter- and venipuncture-derived cultures is greater than 2 hours, the catheter is implicated as a source.²⁸ In patients with cancer, however, one study showed that catheter-drawn blood cultures without concomitant peripheral cultures do have very good negative predictive value and fairly good sensitivity (89%) and specificity (95%).²⁹ A positive culture result for coagulase-negative staphylococci—a common contaminant—requires two positive blood culture sets to be considered a “true positive.”²⁸

Cultures of any suggestive sites of infection should be performed: Diarrheal stools should be tested for the presence of C. difficile toxin, and specimens from oral or perineal lesions suspected to harbor herpes simplex virus (HSV) should be sent for viral cultures. Polymerase chain reaction (PCR) testing (preferred) or culture/rapid antigen testing should be performed for respiratory viruses on nasal wash or swab specimens in patients with suggestive signs or symptoms during the winter season.

Empiric Antibiotic Therapy

Monotherapy with a broad-spectrum antipseudomonal agent such as an extended-spectrum antipseudomonal cephalosporin (e.g., cefepime or ceftazidime), piperacillin-tazobactam, or a carbapenem (e.g., imipenem-cilastatin or meropenem), constitutes a standard approach to the management of fever and neutropenia in both high-risk and low-risk patients with cancer.2,8,26,38–44 The choice of agent should be based on a review of local institutional bacterial susceptibility patterns. Reports of high rates of multidrug-resistant gram-negative bacteremias in patients with cancer underscores the need to select agents based on a review of local institutional bacterial susceptibility patterns.^47–47 Some institutions routinely use combination therapy with either (1) an aminoglycoside plus either an extended-spectrum antipseudomonal cephalosporin or piperacillin-tazobactam or (2) ciprofloxacin plus an antipseudomonal penicillin. No clear benefit of combination therapy over monotherapy has been demonstrated, and increased renal toxicity has been observed with aminoglycoside use.^{2,8,26,38–44} In an era of increasing bacterial resistance, however, circumstances may arise in which initial empirical antibiotic combinations are advisable.⁴⁸ With the possibility of infection as a result of methicillin-resistant S. aureus, for example, the addition of vancomycin is prudent. If a pneumonia is identified at the outset, then adding an antipseudomonal fluoroquinolone (i.e., ciprofloxacin or levofloxacin) ensures a broadened spectrum against potentially resistant gram-negative or atypical pathogens, as well as “atypical” organisms such as Legionella.⁴⁹ The initial antibiotic regimen may be modified according to clinical, radiographic, or culture data available at the time of presentation, as outlined in Table 36-1.

High-risk patients should receive intravenous antibiotics in the inpatient setting. Again, the choice of specific regimen is highly dependent on institutional profiles of pathogen susceptibility and on potential infection sites in a specific patient. Notably, many of these patients are receiving fluoroquinolone prophylaxis and are therefore at increased risk for resistant gram-negative and gram-positive infections.⁴⁷ It is not clear, however, whether different antibiotic regimens are required for these patients at the onset of fever.

Low-risk patient who can tolerate oral agents may be treated with a combination of oral ciprofloxacin plus amoxicillin-clavulanate. In two randomized double-blind trials, this combination proved as effective as intravenous broad-spectrum monotherapy in selected low-risk patients.33,34 Ciprofloxacin should not be used as a solo agent because of its poor coverage of gram-positive organisms.^2,7 Levofloxacin has better activity against gram-positive organisms but less potent antipseudomonal activity than does ciprofloxacin, and it appears to be a reasonable alternative to combination oral empirical therapy in low-risk patients.⁵⁰

An outpatient treatment course with oral or intravenous (IV) antibiotics may be considered after a brief inpatient stay, during which IV therapy is initiated, fulminant infection is excluded, the patient is deemed to be clinically stable and at low risk for complications, assessment of family support is completed, and the status of initial culture specimens may be ascertained.2,26,31,35 In one large series, oral outpatient treatment for low-risk fever and neutropenia was deemed to be successful in 80% of patients, with 20% of patients requiring readmission to the hospital, primarily for persistent fever. Factors predicting readmission included age greater than 70 years, grade of mucositis greater than 2, poor performance status, and ANC less than 100 cells/mm³ at the outset of fever.⁵¹

Initial Empirical Therapy for Patients Who Are Clinically Unstable

Hypotension or septic shock in a neutropenic patient necessitates very broad empirical antibiotic coverage. Broad coverage is warranted in view of the high mortality rate in neutropenic patients with the systemic inflammatory response syndrome.2,26 Patients should receive multidrug therapy with an antipseudomonal beta-lactam (e.g., cephalosporin, carbapenem, or penicillin, depending on local susceptibilities) plus an aminoglycoside or ciprofloxacin (if the patient is not already receiving fluoroquinolone prophylaxis) and vancomycin or another gram-positive active agent with MRSA activity until culture results are available.

Subsequent Modifications of Empiric Antibiotic Regimens

No empirical antibiotic regimen initially administered for fever and neutropenia can be expected to cover all possible infections that may occur during the course of neutropenia. Therefore modifications of the initial regimen—that is, additions or changes of antimicrobial agents—sometimes are required. An important consideration in the management of cancer-related infection is that the mean time to defervescence for febrile patients with neutropenia who receive appropriate initial antibiotic therapy ranges from 2 to 7 days.2,5–7 Therefore at least 3 to 4 days of the initial antibiotic regimen should be given to otherwise stable patients, regardless of continued fever, to determine effectiveness. For patients with a documented infection, it is important to note that tissue-based infections such as pneumonia may take longer to respond to antimicrobial therapy.⁷

Patients who have a fever that persists beyond 4 days of initial antimicrobial therapy and who do not have an identifiable site or source of infection should undergo reassessment of their initial antimicrobial therapy. Any change in antimicrobial agents should be based on the patient’s clinical status, results of examination and cultures, and also the likelihood of early marrow recovery. Although resolution of fever may be slow, persistent fever may suggest a nonbacterial infection, a bacterial infection that is resistant to empirical antibiotics, the emergence of a secondary infection, a closed-space infection, inadequate antimicrobial serum levels, or drug fever. A careful search for these etiologic conditions should be conducted. Frequent and arbitrary antibiotic changes for persistent fever in an otherwise stable patient are to be discouraged. The clinically stable patient with persistent fever may be safely watched without altering the initial antibacterial therapy. If vancomycin was started earlier, it should be discontinued if the patient does not meet the criteria for its use.2,26,54 The addition of vancomycin without specific indications in a blind effort to suppress persistent fever has not been shown to be effective.⁵⁸ If the fever persists beyond 4 to 7 days, initiation of empirical antifungal therapy should be considered (see the next section on Empiric Antifungal Treatment).

Clinically unstable patients who are persistently febrile should be evaluated for changes in antibacterial antibiotics. Double gram-negative bacillary coverage, as reviewed earlier, is recommended. The addition of vancomycin should also be considered, particularly if the clinical indications outlined in Table 36-3 are present.

Empiric Antifungal Therapy

Empiric antifungal therapy traditionally is started when neutropenic patients demonstrate continued or recrudescent fever after 4 days or more of an empiric antibacterial regimen because the risk of invasive fungal disease, particularly invasive aspergillosis, increases with prolonged duration of neutropenia.63,64 The empiric use of amphotericin B in early studies during the 1970s and 1980s showed a reduction in breakthrough fungal infections.^38,65,66 Since then, numerous comparative studies have demonstrated that less toxic alternatives, including liposomal amphotericin B, itraconazole, and caspofungin, are not inferior to amphotericin B desoxycholate.^67–72 Voriconazole is also effective in reducing breakthrough fungal infections.⁷³ The other available echinocandins—anidulafungin and micafungin—are less well studied but presumably are effective in this setting. Itraconazole has been demonstrated to have efficacy in this setting as well, but concerns about liver and cardiac toxicities have discouraged use of this drug.^67,72

Whether all patients with persistent fever require empiric antifungal therapy, and when it should be started, are subjects of long-standing debate. Invasive fungal infections are now relatively infrequent during neutropenia with the advent of more effective antifungal prophylaxis and the use of colony-stimulating factors to abbreviate duration of neutropenia. Furthermore, fever is obviously a nonspecific surrogate marker for fungal infection. Currently, guidelines suggest that an antifungal agent be started at day 4 to 7 in high-risk patients who are not receiving antifungal prophylaxis.2,26 Candidemia is the greatest concern in these patients, and fluconazole, amphotericin B preparation, caspofungin, itraconazole, or voriconazole are considered acceptable choices. If the patient is already receiving fluconazole prophylaxis (which is commonly the case), certain non-albicans species of Candida, including C. glabrata and C. krusei, along with mold infections such as invasive aspergillosis, must be considered. Fluconazole has reduced activity against these Candida species and lacks activity against molds. At present, no data are available to guide the use of empirical antifungal therapy in patients already receiving antimold prophylaxis, such as with voriconazole, posaconazole, or an echinocandin. In all cases, symptoms and signs of invasive fungal pneumonia or sinusitis should be sought; the workup may include computed tomography (CT) scans of chest or sinuses (or both), with follow-up nasal endoscopy or bronchoalveolar lavage as indicated. Biopsy and culture of any suspected lesions should be pursued aggressively to make a definitive mycologic diagnosis that can guide therapy.

A CT scan of the chest is increasingly being used to evaluate the possibility of invasive aspergillosis in patients with prolonged fever and neutropenia; in one study, 90% of persons with proven active disease showed radiographic abnormalities by CT.⁷⁴ Macronodules with or without a halo sign are characteristic of invasive aspergillosis, with the halo sign being an especially important early clue.^75,76 Other manifestations include nodular, wedge-shaped, peripheral, multiple, and cavitary lesions. An air-crescent sign generally is a late finding. Initiation of antifungal agents on the basis of finding a halo sign has been associated with significantly better response to therapy and improved survival.^76,77 Maertens and colleagues⁷⁸ used intensive monitoring for clinical symptoms and signs, serial galactomannan testing (discussed later in this section), and early CT scanning to identify a group of patients with persistent fever while receiving fluconazole prophylaxis in whom antimold therapy did not appear to be required. These data, as well as increasing clinical experience, have led some experts to suggest withholding empiric antifungal therapy if the patient is clinically stable and has no clinical or chest CT scan signs of fungal infection, if no Candida or Aspergillus organisms are recovered from any site, and if neutrophil recovery is imminent. A high-resolution chest CT scan may be a useful screening tool in patients with persistent fever and neutropenia; any abnormalities should be investigated with nasal endoscopy or bronchoalveolar lavage; biopsy and culture of any suspected lesions should be pursued aggressively to make a definitive diagnosis; and treatment with an antimold agent should be initiated.

The serum galactomannan assay specifically detects Aspergillus organisms but not other common fungal pathogens.⁷⁹ Sensitivity varies widely in different patient populations. A recent metaanalysis reported sensitivities of 64% to 78% and specificities of 81% to 95% in patients with neutropenia or neutrophil dysfunction.⁸⁰ Many conditions affect the performance of the galactomannan assay, especially the use of concomitant piperacillin-tazobactam (false-positive) or antimold antifungal agents (false-negative). Although prospective serial galactomannan monitoring may be useful for patients at high risk for Aspergillus infections, routine use in low-risk patients is not advised.^79,80 Furthermore, a single negative test result is of little value in ruling out invasive aspergillosis, although a positive result in concert with abnormalities on the chest CT scan makes the diagnosis highly probable. Galactomannan testing of bronchoalveolar lavage fluid appears to be specific and more sensitive than culture for identifying invasive aspergillosis.^79,81,82

Duration of Antibiotic Therapy

It generally is recommended that empiric antibiotic therapy continue until recovery of the ANC to more than 500 neutrophilic cells/mm³ on one occasion, as long as the patient is clinically stable. In a stable patient who remains febrile despite the return of higher counts, it usually is safe to discontinue antimicrobial drugs and look for a source of fever. In patients who are afebrile and clinically stable but have continued neutropenia, some clinicians recommend a 2-week course of antibiotics at a minimum and then stopping the antibiotics, with close observation.2,26

Documented infections should be treated for a minimum duration of 7 to 14 days with an antibiotic regimen that is narrowed and directed toward any organisms that have been documented microbiologically. Activity against Pseudomonas aeruginosa should be maintained in most patients who remain neutropenic. Most experts prefer to continue antibiotics at least until the ANC returns to more than 500 cells/mm³. A longer course is given if clinically necessary (for example, if a documented infection is ongoing) regardless of neutrophil recovery. Persistent fever of unknown source is not a reason to continue empiric antibiotics beyond ANC recovery.2,26

For low-risk patients who typically have brief periods of neutropenia, some groups of investigators have examined the practice of stopping antibiotics before the ANC reaches 500 cells/mm³. With a clear and steady increase in the ANC or, alternatively, in the absolute phagocyte count (antigen presenting cells = polymorphonuclear neutrophils + bands + monocytes), it appears that the discontinuation of antibiotics before a count of 500 neutrophilic cells/mm³ is achieved can be safe as long as no complicating comorbid conditions are present.51,83–87

Prophylactic use of hemopoietic growth factors is common in the setting of intensive chemotherapy regimens such as stem cell transplantation. Treatment of fever or infection with growth factors, however, is not standard practice. No consistent benefit has been demonstrated in terms of morbidity (i.e., duration of fever and use of antimicrobial agents) or mortality among several randomized controlled trials of the addition of growth factors to an antibiotic regimen at the time of fever during neutropenia.90–90 The routine use of growth factors in treating febrile neutropenic patients is discouraged. Therapy with colony-stimulating factors, however, could be considered for severely neutropenic patients who have serious uncontrolled infections such as bacterial sepsis, pneumonia, severe cellulitis or sinusitis, systemic fungal infections, hypotensive episodes, or multiorgan dysfunction as a result of sepsis. Prophylactic use of the myeloid growth factors is recommended in patients at greater than a 20% risk of febrile neutropenia and in patients with important factors that increase the individual risk of neutropenic complications.⁹⁰

Bloodstream infections occur in about 10% to 20% of febrile patients during neutropenia, most often when neutrophil counts are less than 100 cells/mm³.2,26,45–47,92 The risk of bacteremia is related to the depth of neutropenia, the presence of gastrointestinal mucositis or of an indwelling catheter, or the concomitant presence of a specific site of infection such as pneumonia or soft tissue process. Most bacteremias are due to gram-positive organisms, with coagulase-negative staphylococci and streptococci predominating. Gram-negative pathogens, including Escherichia coli, Enterobacter, Klebsiella, and P. aeruginosa, are important albeit less frequently occurring pathogens.¹⁶

A classification system for bacteremias in febrile neutropenic patients has been developed by Elting and colleagues,⁷ based on the size and presence of associated tissue involvement. Complex bacteremias were those associated with deep-tissue infections of the lung, the liver or spleen, the kidney, the colon, bone and joints, veins and the heart, meninges, and soft tissues with necrosis, or affected skin or soft tissue, wounds, or cellulitis greater than 5 cm in diameter. Simple bacteremias were associated with less tissue involvement (e.g., bacteruria, otitis, pharyngitis, and an affected area of soft tissue less than 5 cm in diameter). The prognostic significance of a complex infection associated with bacteremia on survival was dramatic. At 21 days, 20% of patients with complex infections were dead, compared with only 5% of patients with simple bacteremias (P < .0001). Profoundly neutropenic patients with simple bacteremias had a much higher response rate to antibiotics than was noted in patients with complex bacteremias (94% vs. 70%; P < .0001). The median time to defervescence for patients with simple bacteremias was half that observed for patients with complex bacteremias (2.5 days vs. 5.3 days; P < .0001).

With increasing incidence of MRSA in hospitals and the community, it is recommended that vancomycin be added to standard empirical antibiotic coverage if gram-positive cocci in clusters are isolated from a blood culture, pending identification.16,48,52–54,57 Vancomycin-resistant enterococcus (VRE) also is common in high-risk cancer patients at some institutions. If gram-positive cocci in pairs and chains are identified in blood cultures in settings where VRE is prevalent, then empiric addition of an antimicrobial active against VRE (e.g., linezolid or daptomycin) is prudent, pending definite identification and susceptibility profile. Gram-negative bacteremias in the neutropenic patient are increasingly prevalent in some institutions and are associated with high mortality unless treated promptly and with appropriate antibiotics.^95–95 A variety of resistance mechanisms are evolving among gram-negative organisms. Therefore if gram-negative rods are isolated in blood cultures during fever and neutropenia, an aminoglycoside (which is preferred if the patient was heavily pretreated with fluoroquinolones) or a fluoroquinolone should be added to empiric therapy regimens to ensure coverage of resistant strains until a full susceptibility report is available.

Fungal Infections

Fungal infections are due to yeast or mold pathogens. Candida organisms typically may colonize the gastrointestinal tract and are the most common yeast pathogens in patients with cancer. The spectrum of disease caused by Candida spp. ranges from mild mucocutaneous lesions (e.g., thrush) to disseminated deep tissue involvement (e.g., hepatosplenic candidiasis). An episode of candidemia probably precedes all tissue-invasive infections. Not all candidemias are clinically or microbiologically detected, however, and end organ disease may be the first manifestation of invasive candidiasis. Blood cultures lack sensitivity for Candida and are positive in only perhaps 50% to 70% of the patients with invasive disease.79,102 PCR of fungal genetic material and metabolite or fungal cell wall component detection methods are rapidly being developed for clinical laboratory use and will be much more sensitive.⁷⁹

Neutropenia, the presence of an indwelling venous catheter, and chemotherapy-associated gastrointestinal mucosal injury are important risk factors for invasive candidiasis, rendering patients with cancer at especially high risk. Despite the introduction of newer antifungal agents, recent data showed that the Candida-related overall 30-day crude mortality rate was 38% and the attributable mortality rate was 19% in patients with a hematologic malignancy—similar to older rates.¹⁰³ Because of the difficulty in diagnosing this infection and the associated high mortality, any blood culture found to grow even a single colony of Candida must be regarded as a sign of true infection. Every patient with Candida isolated from the bloodstream should receive at least a 2-week course of antifungal therapy, and in most cases, any indwelling catheters should be removed. Clinical signs of candidemia may range from fever alone to fulminant sepsis. Pustular skin lesions may be a first sign of candidemia. C. albicans accounts for about half of the cases, but non-albicans species, especially C. glabrata and C. krusei, are increasing in incidence. C. glabrata is associated with the highest mortality in patients with cancer. Of note, C. glabrata and C. krusei are somewhat resistant and fully resistant, respectively, to fluconazole and appear to be linked to increased mortality in patients with cancer.^103,104

Catheter-related candidemia should be treated with antifungal therapy, and the catheter should be removed in most cases.28,104,105 Although some studies advocate leaving the catheter in place if the source of candidemia is thought to be the gastrointestinal tract, a recent metaanalysis (n > 1900 patients) indicates that catheter removal is associated with decreased mortality.¹⁰⁶

The availability of echinocandins (e.g., caspofungin, micafungin, and anidulafungin) and newer generation triazoles (e.g., posaconazole and voriconazole), combined with increasing prophylactic use of antifungal agents in certain populations (e.g., those with acute leukemia or GVHD) and the emergence of resistant Candida species in some institutions, has changed the treatment paradigm for candidemia. Certain non-albicans species (e.g., C. glabrata and C. krusei) predictably have reduced susceptibility to fluconazole. Early empiric treatment with an echinocandin (e.g., caspofungin, micafungin, and anidulafungin) is associated with lower mortality.¹⁰⁶ Candidemia that develops during prophylaxis with an azole should be treated with an echinocandin or a amphotericin B preparation. Complications of fungemia may include endocarditis, endophthalmitis, vertebral osteomyelitis, and hepatosplenic candidiasis.¹⁰⁶

Hepatosplenic candidiasis is a form of chronic disseminated candidiasis that almost exclusively affects patients undergoing leukemia induction or stem cell transplantation.15,106–109 It generally manifests only on recovery from neutropenia, as persistent fevers unresponsive to antibacterial agents. Patients may have right upper quadrant tenderness and demonstrate a variety of other gastrointestinal signs and symptoms. Consistent laboratory findings include marked elevation of alkaline phosphatase, with normal or mildly elevated bilirubin and transaminases and a rebound leukocytosis after neutrophil recovery. Blood cultures are almost always negative for fungal growth, as are liver biopsy specimens. Suspected hepatosplenic candidiasis is confirmed by the presence of multiple characteristic well-defined lesions in the liver or spleen, and occasionally in the kidneys on CT scan or ultrasound examination. A prolonged course of therapy, initially with an amphotericin B formulation or an echinocandin, then with oral fluconazole for a number of months, has been advocated. For patients with acute leukemia and hepatosplenic candidiasis, repeated cycles of chemotherapy may be given once the infection is stabilized, and the antifungal agents are continued through the courses of cytotoxic therapy.

Aspergillus spp. are the most common mold pathogens in patients with cancer, but they are seen almost exclusively in two specific settings: during periods of prolonged neutropenia or in patients with GVHD after allogeneic transplantation.¹¹⁰ As discussed earlier (in the Pulmonary Infections section), the vast majority of Aspergillus and other mold infections occur in the lung, whereas fewer organisms disseminate to sinuses, skin, or abdominal organs. Dissemination to the brain occurs in approximately 5% of patients. Unfortunately, the sensitivity of diagnostic tests used to diagnose invasive aspergillosis remains very poor, and delay in diagnosis is all too common, contributing to poor outcome.¹¹⁰ The CT scan has become an essential diagnostic tool for earlier diagnosis of invasive aspergillosis, with characteristic lesions such as nodules, the halo sign, and the crescent sign having high predictive value for the disease.^74,76,77 Despite some improvements in antifungal therapy in recent years, invasive aspergillosis is still associated with at least a 50% mortality rate in patients with cancer.¹¹⁰ Voriconazole has been shown to be superior to amphotericin B for the treatment of proven or probable invasive aspergillosis, and it is now the agent of choice.^2,26,111

On the basis of a few small retrospective studies, combination antifungal treatment appears to be safe and has promising efficacy.111,112 Preliminary results from a randomized multicenter study comparing voriconazole to voriconazole combined with anidulafungin in stem cell transplant and hematology patients with proven or probable invasive aspergillosis demonstrated no statistically significant difference in 6-week survival, but a trend favoring the combination arm was found.¹¹³ More definitive clarification of the efficacy of this combination awaits final publication of the results of this study. The best course in patients who do not respond to first-line therapy is unknown; one open-label trial suggested that oral posaconazole was associated with a 42% response rate in patients who are refractory to or intolerant of conventional therapy for Aspergillus infection, although this response rate is not better than results seen with voriconazole.¹¹⁴

Fusarium is notable for causing tender, red skin nodules and positive blood cultures for mold in approximately half of the cases of this infection.¹¹⁵ Infection with any of the Zygomycetes (Mucor, Rhizopus, and Rhizomucor) is characterized by later onset (after day 90 of the transplant) and a longer median duration of survival. Sinus disease with erosion through tissue planes is a feature of Zygomycetes infections but also may occur with Aspergillus infection. The mortality rate is approximately 80% for transplant recipients with proven infection. In up to 60% of persons who have undergone colonization, progression to invasive infection will occur.¹¹⁶ Other less common molds, including Fusarium, Scedosporium/Pseudallescheria, and Trichosporon, appear to be more susceptible to voriconazole than to amphotericin B. Of note, however, one report recently indicated successful treatment of Fusarium infection with a combination of both agents, and many centers use dual therapy for serious Fusarium infection in high-risk patients.¹¹⁷

An increased incidence of infection with voriconazole-resistant molds such as Rhizopus or Mucor species has been described. This increase may to be related to “breakthrough” infections from voriconazole prophylaxis in high-risk patients with cancer.118,119 Amphotericin B products have been standard therapy for infections due to these pathogens, but the triazole posaconazole has potent in vitro activity against the Zygomycetes and has quickly become an important drug in battling infections with these molds.¹²⁰ It is available only in an oral formulation and has significantly less toxicity than that observed with amphotericin products. Posaconazole has not been evaluated as a first-line agent for treatment of zygomycoses, but reports of posaconazole for salvage therapy are encouraging, and it is considered the second-line agent of choice.¹²⁰ Patients in whom pulmonary lesions with radiologic characteristics suggestive of mold infection (e.g., the halo sign, as noted earlier) develop despite voriconazole prophylaxis should receive treatment for zygomycoses with amphotericin B or posaconazole pending microbiological or histologic diagnosis. Aggressive and repeated surgical débridement is a critically important adjunct to the treatment of zygomycoses of the sinuses.¹¹⁶

Mucositis of the oral cavity and alimentary mucosa is a common consequence of cytotoxic cancer therapies. Disruption of the gastrointestinal mucosa causes erosions and inflammation that can provide a portal of entry for colonizing organisms. Esophageal symptoms of odynophagia, dysphagia, and retrosternal or epigastric discomfort are nonspecific, and it is often difficult to discriminate between drug-induced and infection-induced mucositis. The most common organisms causing local oral or esophageal infection are HSV and Candida spp., although gram-negative and anaerobic bacteria are responsible on rare occasions. The treatment of presumed esophagitis during a period of neutropenia often is based on the empiric administration of antacids or systemic antifungal or acyclovir antiviral therapy. For patients who do not respond to empiric therapy with these agents, careful upper endoscopy may be considered to obtain a more precise diagnosis based on direct visualization of the lesions, as well as on tissue biopsy for histopathological and microbiological examination. Because esophageal endoscopy may be associated with substantial morbidity in profoundly neutropenic or thrombocytopenic patients, it is generally advisable to wait until counts recover before proceeding.

Central Nervous System Infections

In the patient with cancer who demonstrates new mental status changes, focal neurologic signs, or neck stiffness, evaluation for central nervous system (CNS) infection is necessary, because infection is a common cause of neurologic complications.132,133 The initial evaluation begins with cerebral magnetic resonance imaging or contrast-enhanced CT, followed immediately by lumbar puncture if no contraindication exists. Empiric treatment with antibacterial agents with adequate CNS penetration, such as cefepime or meropenem at high doses, is indicated. Of note, neutropenic patients may have few white cells in the cerebrospinal fluid (CSF), even in the setting of meningitis. Impaired T-cell function (e.g., corticosteroids, purine analogs, GVHD, and alemtuzumab) but not neutropenia is a risk factor for Listeria meningitis.¹²⁰ Ampicillin should be added if Listeria infection is suspected in a patient with T-cell impairment. Patients with varicella-zoster virus (VZV) or HSV meningoencephalitis may have suggestive skin lesions; if such infection is suspected, then acyclovir, 10 mg/kg every 8 hours, should be added and a CSF sample sent for PCR testing for both viruses. Cryptococcal meningitis often manifests with fever and subtle mental status changes over several days, and very low CSF cell counts often are seen; serum and CSF cryptococcal antigens are sensitive diagnostic tests. False-positive test results at low titers may occur in patients with plasma cell dyscrasias. Treatment is with amphotericin B preparations combined with 5-fluorocytosine (with monitoring for thrombocytopenia, leukopenia, and diarrhea) initially. A repeat spinal fluid examination must be performed after 2 weeks of therapy to determine if the CSF is culture-negative; if it is, then the patient may be switched to oral fluconazole. Heavily immunosuppressed patients (e.g., recent recipients of an allogeneic hematopoietic stem cell transplant and patients with chronic extensive GVHD) are at risk for meningoencephalitis from reactivation of pathogens such as human herpesvirus–6 (HHV-6), EBV, or T. gondii, although such cases are very rare. CSF PCR assay for these specific herpesviruses or Toxoplasma is used to make the diagnosis; CSF culture typically is negative. Ganciclovir or foscarnet generally is used to treat HHV-6 infection. T. gondii reactivations often are rapidly fatal despite combination therapy with pyrimethamine and sulfadiazine or clindamycin treatment.¹³⁴

Patients with ring-enhancing CNS lesions may have infection with bacteria, Toxoplasma, Nocardia, mycobacteria, or fungal organisms, including cryptococci. Posttransplant lymphoproliferative disease (PTLD) and other malignancies also may manifest as mass lesions. Typically, a brain biopsy is required to make the diagnosis if obvious concurrent infection at a more accessible site is not present (e.g., Nocardia growth from blood cultures or coincident diagnosis of pulmonary invasive Aspergillus infection). First-line therapy for CNS nocardiosis includes high-dose TMP-SMX (15 to 20 mg/kg daily) given in three or four divided doses, usually in combination with a second agent such as meropenem. Sensitivity testing should be performed to further refine therapy.

Treatment of cerebral aspergillosis generally requires voriconazole, which attains high brain tissue levels.¹³⁵ Limited information suggests that posaconazole may be an effective agent for treatment of CNS fungal infections caused by Aspergillus spp, Cryptococcus neoformans, and Pseudallescheria boydii.¹³⁶ Zygomycosis of the CNS is associated with a very high mortality rate; liposomal amphotericin B is considered the best available therapy.¹³⁷

Vascular Access Devices

Indwelling venous access devices are commonly required in patients with cancer for the administration of chemotherapy, blood products, and parenteral nutrition, as well as for withdrawal of blood for therapy monitoring and microbiological evaluation. Infection is a common complication of venous access devices. The risk of infection varies with the device used, the duration of placement, and the extent of the patient’s immunosuppression. Local signs and symptoms, such as erythema and tenderness, are unreliable indicators of catheter infection even in the immunocompetent patient. The evolution of these signs over time, however, is suggestive of infection. Venous access device infections are categorized as entry site infections, tunnel or pocket infections, and catheter-associated bloodstream infections.28,138 (See Chapter 26 on Establishing and Maintaining Vascular Access.)

Entry site infections can be treated effectively with appropriate antimicrobial therapy, without the need for catheter removal. Tunnel infections (i.e., erythema, induration, or tenderness beyond 2 cm from the entry site) and pocket infections necessitate catheter removal, as well as the immediate initiation of an empirical antimicrobial therapy that includes vancomycin to cover methicillin-resistant S. aureus, until culture results are available.

Determining whether a bloodstream infection is related to the venous access device often is difficult, because frequently, no evidence of local catheter inflammation is seen. The concept of “differential time to positivity” has been used to distinguish venous access device–related infections from other types of infection, as follows: If the times at which blood cultures become positive (by machine detection in the clinical microbiology laboratory) are more than 2 hours apart for simultaneously obtained catheter and peripheral vein blood cultures, the catheter is then strongly implicated as the source of infection.¹³⁸ Although this differentiation may help determine whether a catheter can be retained or must be removed, most indwelling catheter–related infections will respond to antimicrobial therapy alone, without catheter removal. Certain exceptions are notable: Catheter removal is advisable for patients with catheters as the likely source of bloodstream infections caused by fungi (yeasts and molds) and nontuberculous mycobacteria (e.g., M. chelonae, M. fortuitum, and M. abscessus). Because S. aureus bacteremia is more likely to result in metastatic seeding and endocarditis, guidelines also suggest catheter removal for patients with S. aureus bacteremia.²⁸ The value of transesophageal echocardiography in the setting of any S. aureus bloodstream infections has been well demonstrated to determine duration of therapy.¹³⁹ Patients with S. aureus bacteremia of brief duration with no evidence of endocarditis by transesophageal echocardiography, no metastatic seeding, and prompt catheter removal may receive a short course (e.g., 14 days) of treatment. Patients who do not meet those criteria should receive 4 to 6 weeks of treatment.²⁸ For other bacteria, the decision concerning the need for catheter removal will depend on the severity of the clinical picture, the degree of immunosuppression, and the availability of an alternative vascular access site in a given patient. In general, if blood cultures remain positive despite appropriate antimicrobial therapy for more than 48 hours, or if the patient is clinically unstable, the catheter should be removed independent of the etiology.

Viral Infections

The incidence of HSV reactivation infections has been reduced with the widespread use of acyclovir prophylaxis. Reactivations not involving the CNS are treated with lower doses of intravenous acyclovir (e.g., 5 mg/kg every 8 hours) or similar drugs given orally, whereas VZV infections are treated with higher doses (e.g., intravenous acyclovir, 10 mg/kg every 8 hours, or oral valacyclovir, 1000 mg every 8 hours). Acyclovir resistance is very uncommon among patients with cancer.¹⁴⁰ HSV infections that break through acyclovir prophylaxis, however, should be considered to be acyclovir-resistant until viral sensitivity testing can be performed, and consideration should be given to initiating treatment with foscarnet or cidofovir. Reports of acyclovir-resistant varicella are extremely rare.¹⁴¹

Patients at highest risk of CMV reactivation include recipients of allogeneic bone marrow transplants in the early period after engraftment (i.e., days 30 to 100 after transplantation), during which time reactivation will develop in 60% of seropositive patients.¹⁴² In addition, patients receiving alemtuzumab and those receiving high-dose corticosteroids for GVHD are at high risk. Universal prophylaxis and preemptive strategies using ganciclovir or valganciclovir have markedly reduced the incidence of CMV disease in these patient groups (see the following discussion on CMV prevention).¹⁴³

End-organ CMV disease most commonly involves the lungs, gastrointestinal tract, or liver.144,145 Definitive diagnosis requires histopathological evidence, but compatible clinical findings (e.g., colonic ulcers and an interstitial pattern on chest radiography) in the setting of CMV viremia diagnosed by PCR or antigen testing is suggestive of invasive disease. CMV treatment is initiated with induction doses of the antiviral agent for at least 2 weeks, followed by a variable course of maintenance dosing, which is half the induction dose. The total duration of treatment depends on clinical response, the results of viremia or antigenemia assays that reflect viral replication activity, and the patient’s overall state of immunosuppression. Intravenous ganciclovir (i.e., an induction dose of 5 mg/kg every 12 hours and a maintenance dose of 5 mg/kg once daily) or oral valganciclovir if absorption is not an issue (900 mg twice daily for at least a 2-week induction and then 900 mg once daily) are first-line treatments when end-organ disease is documented. Foscarnet is a second-line option typically used when the risk of hematologic toxicity precludes the use of ganciclovir or valganciclovir. Electrolyte abnormalities, seizures, and renal dysfunction complicate the use of foscarnet. Cidofovir is a third-line option that is less effective and more toxic than foscarnet.¹⁴⁶

When the end-organ manifestation of CMV infection is pneumonitis, many centers use intravenous immune globulin (IVIG) administered at a dose of 500 mg/kg and typically added on an every-other-day basis for the duration of induction.100,144 When CMV infection manifests in an organ other than the lungs, there is less evidence for the efficacy of IVIG, and thus it is rarely used. However, IVIG can be added if the patient’s total immunoglobulin G (IgG) level is below 400 mg/dL. CMV hyperimmune globulin (prepared from CMV seropositive recipients) has not been shown to be superior to standard IVIG in the treatment of persons with CMV disease, and studies show conflicting results regarding the anti-CMV activity of IVIG versus CMV hyperimmune globulin.^{16,17,100,144,147,148} A typical dose for centers choosing to use CMV hyperimmune globulin is 150 mg/kg on days 1, 4, and 11, with additional doses on day 18 and 25 in critically ill patients.

HHV-6, a virus acquired by 95% of humans during childhood, reactivates asymptomatically in up to 50% of patients after allogeneic hematopoietic stem cell transplant.149,150 Clinical disease is uncommon but may include interstitial pneumonitis, encephalitis, rash, cytopenias, and delayed engraftment.^149,150 PCR assay performed on plasma, tissue biopsy material, or CSF can be useful in suggesting HHV-6–associated disease. HHV-6 has 60% DNA homology with CMV, and treatment of documented infection usually is initiated with induction doses of foscarnet or ganciclovir, although responses are variable and it is unclear which drug is more effective.¹⁵¹

RSV and influenza virus infections generally are seasonal, whereas parainfluenza and adenovirus infections may occur year round. Upper respiratory infections may progress to pneumonia, with mortality rates between 6.6% and 80% in heavily immunosuppressed patients.152,153 Preengraftment hematopoietic stem cell transplant recipients are likely at the highest risk of mortality from RSV infection. Inhaled ribavirin reduces RSV shedding, but clinical efficacy has not been demonstrated¹⁵⁴; furthermore, difficulty of administration and occupational exposure issues limit use of this agent. Oral ribavirin at a dose of 600 mg three times a day is more convenient and has been safely used, but efficacy is unknown¹⁵⁵ A neuraminidase inhibitor commonly is used to treat influenza and may prevent progression from upper respiratory infection to pneumonia, but prolonged shedding and the development of resistance may occur.¹⁵⁶ Adenovirus may cause pneumonia, colitis, hemorrhagic cystitis, hepatitis, or disseminated disease with a sepsis-like presentation in patients undergoing allogeneic hematopoietic stem cell transplant.^128,157 Asymptomatic reactivation is common in adults, but rising levels of viremia or isolation from multiple sites has been associated with an increased risk of severe disease. No standard treatment has been validated, but cidofovir (1 mg/kg three times a week or 5 mg/kg weekly) has been associated with a reduction in levels of viremia.¹⁵⁸

Reactivation of the BK virus in the uroepithelium may lead to hemorrhagic cystitis in allogeneic transplant recipients, and a quantitative PCR assay for BK virus in the urine and plasma may be helpful both diagnostically and in assessing response to treatment.159,160 Low-dose cidofovir (1 mg/kg weekly) has been used for treatment, but its efficacy is unknown.¹⁶¹

Prevention of Infections in Selected Risk Groups

General guidelines for prevention of infections are shown in Table 36-5.

Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

A comprehensive guideline for preventing infectious complications among hematopoietic cell transplantation recipients was recently published and is an excellent resource for practioners.¹⁴³ Bacterial infections may cause more than 25% of fevers in the preengraftment phase of allogeneic hematopoietic stem cell transplant, and thus antibacterial prophylaxis (usually with a newer fluoroquinolone) is often used during this period¹⁶⁸ (Fig. 36-2). This practice has been shown to reduce the incidence of infections, particularly those due to gram-negative organisms, in other high-risk groups (see Risk Assessment), but it has not been consistently associated with a decrease in mortality.^164,165 Because of the risk of resistant organisms and C. difficile infection, some centers choose not to use routine prophylaxis for allogeneic transplant recipients.^169,170 After engraftment, prophylaxis against encapsulated organisms is indicated. Penicillin prophylaxis has decreased the incidence of infection-related morbidity and mortality from Streptococcus pneumoniae, H. influenzae type b, and N. meningitidis significantly. Prophylaxis generally is discontinued 1 or 2 years after transplantation or later if immunosuppression is ongoing at the 2-year point. Prophylaxis with TMP-SMX (or atovaquone, dapsone, or aerosolized pentamidine, if the patient is intolerant to TMP-SMX) for 6 months after transplantation is indicated to prevent pneumocystis pneumonia. Prophylaxis is generally extended if GVHD develops.

Fluconazole prophylaxis has been clearly demonstrated to prevent candidemia and hepatosplenic candidiasis among allogeneic transplant recipients, with treatment generally continuing to day 75 after transplantation.171–174 Fluconazole, however, does not have activity against yeasts such as C. glabrata (some strains) and C. krusei or against molds such as Fusarium, Aspergillus, and the Zygomycetes. Some centers use prophylaxis with an agent active against mold, such as voriconazole, in high-risk patients (i.e., mismatched or matched unrelated donor transplants). A recent trial demonstrated no statistically significant benefit of voriconazole compared with fluconazole for the prevention of fungal infections when it was administered for the first 100 days (180 days for those receiving prednisone at a dose of ≥1 mg/kg/day or for recipients of T-cell–depleted grafts with CD4⁺ counts <200 at day 100) after transplantation.¹⁷⁵

Prevention of CMV disease after allogeneic hematopoietic stem cell transplantation can be effectively accomplished with use of either universal prophylaxis or preemptive therapy with ganciclovir or valganciclovir.² The preemptive strategy uses weekly or twice monthly blood antigenemia or PCR viral load monitoring tests to guide initiation of antiviral agents, whereas universal prophylaxis involves providing the drug to all patients at risk (all but seronegative donors and recipients). In the absence of prophylaxis, CMV will reactivate in about 60% of CMV seropositive recipients¹⁴² and a much smaller percentage of CMV seronegative recipients. However, a majority of transplant recipients will initially present with CMV reactivation silently; this reactivation typically is detected by the weekly monitoring test before the development symptoms (e.g., fever) or end-organ disease. Severe end-organ disease can occur if subclinical reactivations are not treated. The preemptive strategy is preferred to universal CMV prophylaxis for two reasons: First, it decreases exposure to this marrow-toxic drug, and second, in allowing for some low-level replication of CMV, recovery of CMV-specific immunity may be enhanced. Both strategies, however, appear to shift the timing of CMV reactivations to later (after day 100, when monitoring often stops) in the postengraftment course, after it is discontinued in transplant recipients at higher risk. Strategies for preemptive therapy vary; typically, intravenous ganciclovir or oral valganciclovir is administered at induction dosing for 7 to 14 days and then reduced to maintenance dosing if a reduction in viremia or antigenemia is observed.¹⁷⁶ Treatment may be continued for 2 to 3 weeks after a negative result on a viremia or antigenemia test, and then weekly monitoring is resumed. In most centers, weekly monitoring is continued for at least 100 days, and longer if immunosuppression for GVHD is needed. In some patients receiving intense immunosuppression to treat GVHD, CMV viremia or antigenemia may respond poorly to initial treatment. Management of these patients is difficult, but as long as induction doses are maintained, the development of end-organ disease appears to be uncommon.¹⁷⁷

For patients seropositive for HSV and VZV, most centers use antiviral prophylaxis with acyclovir or an equivalent agent (e.g., valacyclovir or famciclovir) during the neutropenic period, and some centers continue for up to a year to prevent VZV reactivation. These agents should be stopped if a patient is receiving CMV-active agents such as ganciclovir, valganciclovir, or foscarnet.

Vaccination after autologous or allogeneic hematopoietic stem cell transplant should be initiated once cellular immunity is thought to be reconstituted, which typically occurs at approximately 12 to 18 months after transplantation if GVHD does not occur.¹⁴³ A full immunization series, similar to that given to young children, is recommended because posttransplant patients are considered immunologically naïve.

Because of the high risk of invasive disease with pneumococcus and evidence of serologic response when a conjugate vaccine is administered earlier, many centers begin pneumococcal vaccination 3 to 6 months after transplantation. In order to provide protection against serotypes not included in the conjugate vaccine, some centers administer a fourth dose with the polysaccharide vaccine 12 to 18 months after the initial three-shot conjugate vaccination series is completed.143,178 Some centers will check titers for response, but this approach is not standardized. Because of poor response, most centers defer influenza vaccination until at least 6 months after transplantation. Hepatitis B surface antibody should be checked after completion of the vaccine series, with revaccination using a double dose a reasonable approach for persons who do not seroconvert. Autologous transplant recipients also require revaccination, and most centers use a similar schedule as is used for allogeneic transplant recipients. Table 36-6 shows a standard immunization schedule to be used after transplantation.

The serostatus of herpesviruses (HSV, VZV, CMV, and EBV) that may be present in latent form in the body should be checked before transplantation to determine if the patient is at risk for reactivation. Current testing of both the donor and recipient before the transplant preparative regimen begins includes not only herpesvirus antibodies but also hepatitis virus panels, human T-cell lymphotrophic virus I and II antibodies, human immunodeficiency virus (HIV), and syphilis serology.

The only test result that could lead to immediate cancellation of the transplantation procedure would be a positive result on HIV testing in a patient not known to be seropositive. If the screening test for HIV is positive from either the donor or the recipient, a Western blot study should be completed to confirm the result before informing the affected person of the screening test result. Any time a positive HIV test result is conveyed to a patient, appropriate counseling must be provided.

Stem cell or marrow donor infectious diseases screening protocols (similar to those for solid organ donors) aim to identify donors who may transmit latent infections to the recipient.143,184 Several serostatus test results, if positive, would not constitute an indication to cancel the transplant but would lead to a different action plan.¹⁸⁴ If the indirect screening test for syphilis, such as the rapid plasma reagin or Venereal Disease Research Laboratory test, yields a positive result and is confirmed by a direct test, that is, the fluorescent treponemal antibody test, then the patient should receive high-dose penicillin treatment for 10 to 14 days.

Hepatitis B (core antibody, surface antibody, and surface antigen) and C serologic studies are performed in donor and recipient before transplantation; if results are positive, viral load testing should be performed. Because of the decreased sensitivity of hepatitis C serologies in immunosuppressed patients, some centers screen with nucleic acid tests. Hepatitis B or (much less commonly, hepatitis C) may flare after transplantation, leading to life-threatening hepatic dysfunction.187–187 Recipients with detectable hepatitis B DNA should be treated with antiviral medications, possibly in combination (e.g., tenofovir, lamivudine, adefovir, entecavir) if possible before transplantation and for 6 months after transplantation (longer if GVHD occurs).¹⁴³ Patients with a history of hepatitis B but no detectable hepatitis B DNA may receive prophylactic antiviral agents or be monitored for hepatitis flare. Treatment for hepatitis C in a patient requiring stem cell transplantation is usually not practical prior to transplantation. In this circumstance, transplantation is not contraindicated, but an assessment of hepatic status before transplantation and an attempt to reduce the hepatoxicity of the conditioning regimen is reasonable in patients with cirrhosis or significant fibrosis.

A person infected with a hepatitis virus may serve as a donor if no alternative donor is available or if the intended recipient is already seropositive. The risk of transmission is lowest when a hepatitis B-positive or hepatitis C-positive donor has an undetectable viral load. Accordingly, donors found to have high viral loads on testing for hepatitis B or C should receive treatment with appropriate antiviral agents to reduce viral loads before transplantation and before donation, in conjunction with hepatology consultation.185–189 Recipients who receive cells from a seropositive donor should have viral load levels monitored before and after transplantation and also may require treatment.

CMV, HSV, and VZV serologic studies are routinely performed before transplantation. If either the donor or the recipient is seropositive, a prevention strategy (as presented earlier) is used.¹⁴³ If both the recipient and the donor are CMV seronegative, seroconversion with blood products is possible, and thus CMV seronegative or filtered, leukoreduced blood products are commonly used.^190,191 Patients seropositive for HSV or VZV (or with a reliable history of chickenpox) receive prophylaxis as discussed. VZV-seronegative patients should receive varicella-zoster immune globulin prophylaxis within 96 hours of significant exposure.¹⁴³ If varicella-zoster immune globulin is not available, most experts would treat with IVIG, acyclovir, or valacyclovir for 3 weeks.

Knowing the EBV serostatus before transplantation is not mandatory because 95% of adult patients can be assumed to be seropositive for this virus. EBV-driven PTLD occurring as a consequence of EBV reactivation is in the differential diagnosis for any space-occupying mass after transplantation, but this disease usually appears several months after the neutropenic phase.¹⁹² Major risk factors for the development of PTLD include primary EBV infection after transplantation in a seronegative recipient, the use of antithymocyte globulin or anti-CD3 monoclonal antibodies for immunosuppression, and CMV primary infection or reactivation.^195–195 Mismatched or unrelated donor stem cell grafts or T-cell–depleted grafts also are associated with an increased risk for PTLD. Although the incidence of PTLD after allogeneic hematopoietic stem cell transplant is as low as 0.5% in patients without major risk factors, it increases to 22% in patients with three or more risk factors. Routine monitoring of EBV viral load appears to be of limited value after transplantation.¹⁹⁵ However, in patients with high-risk profiles for PTLD and a rising viral load, preemptive rituximab treatment appears to effectively reduce EBV viral load and, accordingly, the incidence of PTLD after transplantation.^196,197

Historically, 15% of patients receiving transplants in the United States are seropositive for T. gondii, but this percentage may be higher in European centers.¹⁹⁸ The risk of reactivation leading to disease among seropositive patients is 2% to 6%, and parasitemia can be detected by PCR in 16% of seropositive recipients and may precede disease, leading to an opportunity for a preemptive prevention strategy.^200–200 Because serologies for T. gondii may be unreliable after transplantation, serologies should be obtained before transplantation because this information can be useful in evaluating patients in whom syndromes compatible with toxoplasmosis (e.g., a CNS mass lesion) later develop. It is likely that low-dose sulfa-based regimens such as those used to prevent PCP also are effective in preventing Toxoplasma infection.^199,201