Chapter 51: Fungal and Viral Infections in Cancer Patients

Fungal and viral infections remain a significant cause of morbidity and mortality in patients with cancer. Modern management of infections in cancer requires knowledge of the epidemiology, pathogenesis, treatment, and prevention of such infections. Fungal infections range from nosocomial infections with Candida spp to endemic fungi acquired outside the hospital, such as Histoplasma capsulatum. Opportunistic fungi, especially molds, have emerged as a leading cause of death in patients with leukemia or hematopoietic stem cell transplant (HSCT) (¹). Viral infections such as varicella zoster virus (VZV), herpes simplex virus (HSV), or cytomegalovirus (CMV), have been associated with increased morbidity and mortality in patients with cancer, including patients with multiple myeloma or chronic lymphocytic leukemia (CLL), and in HSCT recipients (^2,3,4,5). Respiratory viruses, such as respiratory syncytial (RSV), adenovirus, and influenza, are increasingly recognized as significant pathogens in patients with cancer, particularly as molecular diagnostic methods improve. In addition, viruses such as novel influenza H1N1, West Nile virus, bocaviruses, and noroviruses have emerged as newly recognized pathogens in patients with cancer.

Fungal infections pose a continuing challenge for oncology patients. Exposure to fungi is common, with exposure typically occurring in the environment. Patients with cancer are susceptible not only to new infection with endemic fungi (such as Histoplasma capsulatum), but also to reactivation of latent infections. Opportunistic molds, such as Fusarium spp, Scedosprorium spp, and Zygomycetes cause devastating disease in hematologic patients. Cases of nosocomial infection due to molds are reported in the setting of hospital construction, leading to routine air sampling and filtration. In contrast, Candida spp are a common component of the patient’s or health-care workers’ endogenous microbial flora. Manifestations of infection may not present until the patient receives chemotherapy or undergoes HSCT.

Diagnosis of invasive fungal infections is problematic as well, despite increased use of fungal biomarkers (⁶). The skin and lungs are accessible areas for examination and biopsy as they are commonly affected by fungal pathogens. In our institution, a retrospective study of skin biopsies in patients with leukemia suggested that ulcerated or necrotic skin lesions in the context of bacteremia or fungemia were predictive of infection (⁷). Of note, skin biopsy revealed infection in 39% of all patients undergoing biopsy and 55% of those with severe neutropenia (⁷). Of patients with biopsy-proven skin infection, 39% of those infections were fungal, led by Candida species (25%), Fusarium (19%), Mucorales (13%), Aspergillus species (9%), Alternaria (6%), and Curvularia (3%) (⁷).

In the setting of pulmonary nodules, lung biopsy, utilizing open biopsy or computed tomographic (CT)–guided percutaneous biopsy, has also proven useful in diagnosis. Studies of CT-guided biopsy show a yield of approximately 60% for a specific diagnosis (⁸). In a study at our center of patients with hematologic malignancy, 34% of the specific diagnoses with CT-guided biopsy were previously unidentified infection, predominantly fungal (⁹). A recent retrospective study of open lung biopsy revealed 19% previously undiagnosed infectious etiologies (⁸). Identified organisms included 58% endemic molds (Histoplasma, Coccidioides), 14% Aspergillus species, and 7% Cryptococcus species (⁹).

Despite these efforts, diagnosis is often a challenge if infection is more diffuse or thrombocytopenia is too severe to safely permit biopsy. Autopsy, unfortunately after all diagnostic and treatment efforts failed, has historically been an approach to ultimate diagnosis of etiology, but autopsy rates have fallen almost 90% from 0.63/100 deaths in 1989 to 1993 to 0.06/100 deaths in 2004 to 2008 at our institution (¹⁰). Diagnosis of fungal infections, often manifesting as pulmonary nodules or skin lesions, is challenging, but important, given the modification of therapy that may occur based on identification of a particular species of fungus or discovery of coinfection, malignancy, or other alternative diagnosis. Figure 51-1 suggests an approach to identification of fungal (and other) pulmonary pathogens at our institution.

Risk Factors

Severe neutropenia, particularly prolonged, has long been associated with invasive fungal infections. Chemotherapy resulting in prolonged and severe CD4 lymphocytopenia can also result in infections similar to those seen in patients with untreated human immunodeficiency virus (HIV) or AIDS, such as cryptococcosis and reactivation of endemic fungi, including histoplasmosis and coccidiomycosis. In addition, conditioning regimens for stem cell transplant and immunosuppressives to treat or prevent graft-versus-host disease (GVHD) result in deficient cell-mediated immunity, increasing risk for invasive fungal infection (^4,10). Disruption of mucocutaneous barriers predisposes to invasive candidal infection, exemplified by catheter-related bloodstream infections caused by Candida spp (¹¹).

A recent study from Italy utilized a retrospective cohort of patients with hematologic malignancy to develop a risk prediction score for invasive fungal infections (⁴). The score emphasizes the central roles played by lymphopenia, relapsed or refractory malignancy, prolonged neutropenia (>10 days), and prior history of invasive fungal infection in identifying patients at highest risk of invasive fungal infection. Of interest, the authors found that posaconazole prophylaxis was exclusively beneficial to the group with highest risk of invasive fungal infection (⁴).

Finally, another aspect of importance is the change in flora that takes place with broad-spectrum antibacterial and antifungal therapy. The latter may result in suppression of normal bacterial flora and candidal overgrowth in the oropharynx and gastrointestinal (GI) tract. Antifungal therapy or prophylaxis may result in breakthrough infection with non–Candida albicans species, such as Candida krusei (resistant to fluconazole) (¹¹). Aside from non–Candida albicans species, prophylaxis with non–mold active antifungals (eg, fluconazole) may predispose to infection with molds, such as aspergillosis.

Candidiasis remains the most common invasive fungal infection in patients with cancer. Modern medical care is increasingly complex, involving frequent antimicrobial use and device utilization that alter patient flora and disrupt the mucocutaneous barrier. Candida spp commonly arise from the patient’s endogenous flora, but rare hospital-acquired cases have been reported due to contaminated equipment, solutions, and hospital personnel. Manifestations of candidiasis range from local infection of the skin or oral mucosa to candidemia and widely disseminated infection.

Superficial Candidiasis

Oral Infection

Thrush is the most common superficial candidal infection among patients with cancer, typically those with cancers involving the head and neck undergoing chemoradiation (¹²). Oropharyngeal candidiasis is characterized by whitish plaques on the buccal mucosa, palate, or tongue (Fig. 51-2) that may be painful if removed, exposing the erythematous base. Oral thrush may also be a manifestation of esophagitis (¹²). The diagnosis is commonly made clinically but is confirmed by finding yeast and pseudohyphae on scraping or culture.

Esophagitis

Esophageal candidiasis may cause dysphagia, retrosternal pain, and odynophagia in patients with cancer (¹³). Serious complications of this infection can occur, including chronic esophageal strictures, bronchoesophageal fistulas, and mediastinitis. Esophagoscopy with biopsy and culture are necessary to confirm the diagnosis of candidal esophagitis (¹¹). Unfortunately, thrombocytopenia often makes esophagoscopy challenging, so empiric therapy is often used. Esophageal candidiasis requires systemic therapy, typically utilizing fluconazole as initial therapy (¹¹). Caspofungin or other echinocandins may be used if fluconazole fails or is not well tolerated, but it is available only as an intravenous preparation (¹¹). Itraconazole, voriconazole, posaconazole, or amphotericin B formulations are rarely indicated for these infections (¹¹).

Urinary Tract Infection

Patients with cancer, as with many other hospitalized patients, may develop primary infections of the urinary tract in the settings of urinary obstruction and particularly urinary catheters. Differentiating between colonization and infection is challenging in the presence of urinary catheters. Urinalysis may be normal, and high organism counts are not sufficient to confirm infection. In febrile neutropenic patients, candiduria should be considered as a harbinger of disseminated candidiasis. Recent guidelines recommend treatment with fluconazole, with amphotericin B formulations used for resistant Candida spp (¹¹). Of note, echinocandins fail to penetrate the urinary tract, so they should not be used in this setting. Relapse of infection, however, will be likely unless the urinary catheter is removed.

Candidemia

Neutropenia, presence of colonization of oropharynx and other sites, steroid use, presence of central venous catheters, and persistent fever in the setting of broad-spectrum antibacterial therapy suggest the diagnosis of candidemia (¹⁴). A study from a multicenter database demonstrated that C. albicans now represents a minority of candidemia infections (45.6%) (¹⁵). In that study, candidemia resulted in an overall 12-week crude mortality of 35.2%, with highest mortality rate associated with C. krusei (52.9%) and lowest with Candida parapsilosis (23.7%) (¹⁵). Candida parapsilosis candidemia has been associated with central venous catheters (¹⁵). Patients with C. parapsilosis, including nononcology patients from a multicenter database, were less likely to be neutropenic and immunosuppressed, perhaps explaining the lower mortality rate (¹⁵). Candida krusei has been associated with prior antifungal use, hematologic malignancy (including stem cell transplant), neutropenia, and steroid use. These host factors associated with infection suggest why C. krusei exhibits the highest mortality rate of species causing candidemia (52.9%) (¹⁵).

Disseminated Candidiasis

Disseminated candidiasis is difficult to differentiate from other disseminated fungal and bacterial infections. Persistent fever in the setting of antibacterial therapy and liver dysfunction may suggest consideration of disseminated candidiasis (¹⁵). In patients with cancer, disseminated candidiasis typically originates from the GI tract or central venous catheters. Dissemination affects multiple organs, such as the kidneys, heart, GI tract, lung, liver, spleen, and skin (¹⁶). Candida tropicalis is more likely to cause the characteristic skin lesions associated with disseminated candidiasis and occasionally causes a syndrome of skin lesions and painful myositis (¹⁷). Lesions may appear as clusters of pustules or larger nodules and may even develop necrotic centers similar to ecthyma gangrenosum (¹⁸). Common presentation is nontender, firm, nonblanching, raised nodules that are pink to red in color (Fig. 51-3).

Diagnosis

The diagnosis of disseminated candidiasis may be difficult to establish because culture of the organism from sputum, urine, and feces may be positive in patients without infection. On the other hand, 40% of patients with widespread infection demonstrated at autopsy examination had multiple negative blood cultures (¹⁶). Given the challenge of appropriate diagnosis and morbidity associated with failure to treat the severely immunocompromised, empiric therapy is commonly given for those who continue to be ill in the setting of broad-spectrum antibacterial therapy.

Therapy

Therapy for candidiasis includes three classes of medications: azoles (eg, voriconazole), echinocandins (eg, caspofungin), and the polyenes (eg, amphotericin B). Dosing regimens, major toxicities, and general considerations for antifungal agents are shown in Tables 51-1,51-2, 51-3, respectively. Timely appropriate therapy is necessary because the mortality rate for candidemia ranges from 24% for candidemia caused by C. parapsilosis to as high as 53% for C. krusei (¹⁵). Candida glabrata exhibits decreased susceptibility to fluconazole (¹⁴). Mortality, however, is not significantly different from C. albicans candidemia (¹⁴). Candida krusei, inherently resistant to fluconazole, is increasingly isolated in institutions where fluconazole is commonly used for prophylaxis (¹⁹). Candida lusitaniae, more commonly seen in patients with stem cell transplant or neutropenia, is of concern due to amphotericin B resistance (²⁰).

Recently published guidelines suggest that echinocandins be utilized as first-line therapy in neutropenic patients with candidemia, with lipid formulations of amphotericin B as second-line therapy (¹¹). Species-specific recommendations, however, are provided, given inherent differences in resistance. The guidelines emphasize that if a therapeutic approach is resulting in clinical improvement, then current therapy can be continued. For C. glabrata, an echinocandin or lipid formulation of amphotericin B is recommended (¹¹). For infection with C. parapsilosis, an azole or lipid formulation of amphotericin B is recommended. For C. krusei, fluconazole is contraindicated due to innate resistance (¹¹). For neutropenic patients with invasive candidiasis (but not candidemia), lipid formulations of amphotericin B, echinocandins, or voriconazole are recommended (¹¹). In candidemia and invasive candidiasis, fluconazole may be used in patients who have no prior exposure to azoles and are not critically ill (¹¹). If fluconazole is used, the initial recommended dose is 12 mg/kg/d. The guidelines recommend the use of lipid formulations of amphotericin B, rather than amphotericin B deoxycholate (D-AMB), to avoid nephrotoxicity (¹¹).

Caspofungin was the first echinocandin approved by the Food and Drug Administration (FDA), showing broad-spectrum activity against Candida spp. In comparison to D-AMB in a study of invasive candidiasis (80% of which was candidemia), caspofungin showed similar outcomes with fewer adverse events (¹¹). Of note, however, few patients were neutropenic in this study. The three currently available echinocandins (caspofungin, micafungin, and anidulafungin) are comparable in their efficacies, although only one study in patients with nononcologic candidemia directly compared micafungin and caspofungin and showed equivalent outcomes (²¹).

The management of catheter-related bloodstream infections is controversial. Debate exists with respect to need for catheter removal. Patients with indwelling intravascular catheters typically require them for chemotherapy or supportive care. The removal of surgically implanted catheters is particularly difficult, given thrombocytopenia is often present in this patient population and also the high costs of placement. Studies suggest a role for catheter removal, particularly if it is clear that the catheter is the source or in the setting of persistent candidemia without another source. Removal of the catheter may improve response rates and reduce duration of candidemia (¹¹). Infection with C. parapsilosis, in particular, is associated with persistent candidemia without catheter removal (¹¹).

In brief, Candida causes a wide spectrum of syndromes, from superficial oral candidiasis to candidemia, in patients with cancer. The therapeutic approach should take into consideration host risk factors, medication interactions, antifungal toxicities, and comorbidities when selecting a particular agent.

One of the most common and important invasive fungal infections is aspergillosis. Aspergillus spp are the most common invasive mold infections in patients with hematologic cancer (²²). Aspergillus fumigatus is the species most commonly associated with infection, although Aspergillus terreus and Aspergillus flavus, more resistant Aspergillus spp, are becoming increasingly common (²²). Infections are typically acquired by spore inhalation, but construction in hospitals and surrounding areas have been associated with infection (²³). The most important risk factor is prolonged neutropenia (²²). In patients with stem cell transplants, reported risk factors for increased mortality include poor baseline pulmonary status, high doses of steroids (≥2 mg/kg/d), disseminated aspergillosis, proved invasive aspergillosis, increased bilirubin, increased creatinine, HLA-mismatched stem cells, and invasive aspergillosis occurring 40 or more days after transplant (²⁴). A recent retrospective study suggested that elevated serum galactomannan index (GMI), but not bronchoalveolar lavage GMI, is associated with increased mortality (²⁵).

Pulmonary Infection

The most common syndrome associated with aspergillosis is pneumonia. Due to the angioinvasive nature of the infection, symptoms suggesting pulmonary involvement (eg, pulmonary embolism, pleuritic chest pain, fever, hemoptysis, and friction rub) are occasionally encountered (²⁶). Initial chest x-ray may be unremarkable, with fever proceeding in the setting of broad-spectrum antibacterials (²⁶).

Radiologic findings are variable, with wedge-shaped infarcts, necrotizing bronchopneumonia, lobar consolidation, or diffuse infiltrates noted (²⁶). If suspicion is high for infection, early CT scan of the thorax is essential, potentially demonstrating a halo sign (area of low attenuation surrounding a nodular infiltrate), an important early sign that disappears in 75% of cases within the first week (²⁶) (Fig. 51-4). Analysis of radiologic studies from a clinical trial suggested that patients with the halo sign had an improved response to treatment and also improved mortality compared to those who did not exhibit the halo sign (²⁷). Cavitation occurs as the infection progresses, with lesions often increasing in size until neutrophil recovery occurs. Differentiation from infection with other molds (ie, mucormycosis) can be difficult. A study suggested that CT of the thorax with greater than 10 nodules and pleural effusion are more often seen in pulmonary mucormycosis rather than invasive pulmonary aspergillosis (²⁷).

Sinusitis

Immunocompromised patients may exhibit acute sinusitis as a component of invasive diseases, occurring in 15% to 20% of neutropenic patients (²⁸). Fever, headache, cough, epistaxis, and sinus discharge are signs and nonspecific symptoms suggestive of fungal sinusitis (²⁸). On exam, necrotic lesions may be seen in the nose or palate (Fig. 51-5), with accurate diagnosis improved by examination and confirmed by biopsy by experienced otolaryngologists (²⁹). Imaging of the sinuses by CT or magnetic resonance imaging scan may show opacification of the sinuses or bony destruction. Mortality may be as high as 20% in patients with leukemia in remission to 100% for those with invasive sinusitis who have refractory leukemia or are undergoing HSCT (²⁸).

Skin Infection

Aspergillosis as part of dissemination is discussed in the next section, although primary cutaneous infection occurs with direct inoculation. These infections are rarely associated with a central venous access device (³⁰). The mechanism of spread is presumed to be via inoculation during catheter insertion or possibly dressing changes or application. Initially, lesions may appear as erythematous plaques, progressing to necrotic ulcers with black eschars (³⁰). Aspergillus flavus is the most common cause of cutaneous invasive aspergillosis.

Disseminated Infection

Given the angioinvasive nature of aspergillosis, hematogenous dissemination occurs in approximately 20% of patients with active hematologic malignancy or HSCT (³¹). Common sites of dissemination include the central nervous system (CNS), GI tract, and skin. Gastrointestinal involvement is apparent in 40% to 50% of cases, affecting the esophagus and large bowel (³²). Perforation or massive hemorrhage may occur in this setting. Skin infection may also occur, evolving from erythematous plaques to ulcers that ultimately may be covered by black eschar (³³). Given the broad differential diagnosis of skin lesions in this patient population, skin biopsy is critical.

Diagnosis

A continuing challenge in management of aspergillosis is early and reliable diagnosis (²⁶). Tissue biopsies from infected tissue may reveal invading hyphae. Paradoxically, cultures of the biopsy specimens fail to grow the fungus in over 50% of cases, although histology and pathology correlate with culture in 78% of those cases (³⁴). Similarly, blood cultures will rarely (except in the case of A. terreus) demonstrate the organism, in contrast to fusariosis (³⁵). Unfortunately, Aspergillus spp fail to grow well from sputum or bronchoscopy, with only 30% of biopsy-proven aspergillosis cases growing mold in sputum cultures (³⁶). Due to these challenges of diagnosis, patients commonly receive empiric antifungal therapy while undergoing workup.

To increase the likelihood of detection of aspergillosis, various non–culture-based tests have been developed. Available tests detect circulating antigens or immune complexes. Galactomannan and 1,3-β-D-glucan are the most commonly used tests. Via a sandwich enzyme-linked immunosorbent assay used to detect the polysaccharide cell wall component of Aspergillus spp, galactomannan can be detected in the serum, and more recently bronchoalveolar lavage fluid, of infected patients (²⁶). Sensitivity ranges from 67% to 100% and specificity from 86% to 99%, but the test has been studied primarily in patients with hematologic malignancy with profound neutropenia. The positive predictive value of this test is poor in patients with solid tumor and other cancer (²⁶). An additional challenge occurs in interpreting a galactomannan in the context of prophylaxis with antimold activity. A recent study suggested up to 86% false-positive results for those on active antimold therapy (³⁷).

1,3-β-D-Glucan is an integral component of the cell wall of several yeasts and fungi (²⁶). Sensitivity ranges from 67% to 100% and specificity 84% to 100%, but false positives are noted due to cirrhosis, hemodialysis, and some chemotherapeutic agents (²⁶).

Therapy

Early diagnosis of aspergillosis utilizing the various available tools has allowed for earlier treatment, but challenges continue in assessing the impact of various treatments, given categorization of infection as proven, probable, or possible (²⁹). Table 51-4 describes various principles for management of aspergillosis. Persistence of neutropenia is a host factor that is critical in determining the outcome of infection, regardless of therapy. In fact, in a study of patients with acute myeloid leukemia (AML), mortality was 90% in those patients who failed to recover from neutropenia (³⁸).

Voriconazole is currently recommended as first-line therapy of invasive pulmonary aspergillosis (²⁸). A randomized trial comparing voriconazole to D-AMB for patients with definite or probable aspergillosis showed decreased mortality in the voriconazole group (71% vs 58%). Both oral and intravenous formulations are available, with decreased nephrotoxicity compared to amphotericin B. Voriconazole does, however, cause visual disturbances, hallucinations, and liver dysfunction in a subset of patients.

Posaconazole, the newest FDA-approved azole, was previously only available as an oral solution. Posaconazole tablets are now available, with considerably improved absorption, with minimal impact from food, mucositis, or elevated gastric pH (³⁹). Despite resultant elevated liver function tests due to dramatically increased posaconazole levels in tablet form, no clinically significant hepatotoxicity occurred (³⁹). Posaconazole was associated with increased response to therapy and decreased mortality compared to Liposomal Amphotericin B (L-AMB) with or without caspofungin (⁴⁰). In addition, nephrotoxicity and change in liver function tests were more likely in the L-AMB–containing regimens.

Lipid formulations of amphotericin B are now recommended in lieu of D-AMB, given the decreased risk of nephrotoxicity. In a randomized study of early treatment of aspergillosis in neutropenic patients, doses of 10 mg/kg/d were compared with 3 mg/kg/d with comparable outcomes (46% high dose vs 50% low dose), but the higher dose resulted in greater nephrotoxicity (32% vs 20%) (²⁸).

Echinocandins inhibit the synthesis of β-(1,3)-D-glucan, an essential component of the fungal cell wall. A disadvantage of echinocandins is that they are available only as an intravenous preparation (²⁸). In a noncomparative trial of 90 patients with definite or probable aspergillosis who had failed other therapy, a complete or partial response occurred in 45% (⁴¹). Responses were observed in 50% of patients with pulmonary infection but in only 26% of those with neutropenia (⁴¹).

Treatment of Invasive Aspergillosis (IA) is challenging, particularly in the setting of prolonged neutropenia. This has led to the use of combination therapy. In a recent randomized, placebo-controlled trial of HSCT and patients with hematologic malignancy, voriconazole combined with placebo or anidulafungin failed to demonstrate a difference in overall or 6-week mortality (⁴²). In a subgroup with radiographic findings consistent with IA and elevated serum galactomannan, the mortality was significantly higher in the monotherapy group (15.7% vs 27.3%, P = .037) (⁴²).

Antifungal agents utilized for prophylaxis against aspergillosis in high-risk patients have included posaconazole, itraconazole, voriconazole, aerosolized or nebulized formulations of amphotericin B, and micafungin (^22,28). Posaconazole is the only agent currently FDA approved for the indication of prevention of invasive aspergillosis in patients with acute leukemia and high-risk stem cell transplant recipients, but significant expense continues to limit the utility of this agent (⁴¹).

Cryptococci are encapsulated yeasts that have a worldwide distribution, with a dramatic increase in incidence corresponding with the advent of HIV/AIDS (⁴³). Cryptococcus neoformans is the most common pathogen, found in pigeon excretions, with infection acquired by inhalation into the lungs. Patients with HIV/AIDS had the highest incidence of infection prior to the initiation of highly active antiretroviral therapy (⁴³). Factors associated with cryptococcosis in patients with cancer include lymphopenia, chemotherapy, and steroid use less than 1 month prior to diagnosis (⁴⁴). Those at particular risk include those with lymphoma or CLL. Risk in patients with hematologic malignancy is low because of widespread use of fluconazole and other agents for antifungal prophylaxis.

Pneumonia

Given inhalation as the mechanism of entry, the lung typically serves as the primary site of infection. Despite this fact, less than 40% of patients present with symptoms suggestive of pneumonia (⁴³). Symptoms may, however, include chest pain, fever, or dyspnea. Chest radiographic findings may include single or multiple nodules, airspace consolidation, reticular patterns, ground-glass opacities, cavitary lesions, and occasionally pleural effusions, with all findings unilateral or bilateral (⁴³). Cryptococcal pneumonia can rapidly progress, resulting in higher mortality in patients with cancer. For susceptible patients, finding of this organism in a patient with chest radiography and symptoms consistent with infection is sufficient indication for therapy. In a series from a cancer center, fine-needle aspiration, bronchoalveolar lavage, and open lung biopsy had a yield of over 90% on culture (⁴⁴).

Central Nervous System Infection

Many series showed a predominance of CNS infection in patients with cancer, primarily with meningoencephalitis, but rarely with meningitis alone or with cryptococcoma. Depending on degree of immunosuppression, patients may exhibit an indolent course, with initial symptoms of fever and headache (⁴³). As the disease progresses, symptoms may include nausea, vomiting, dizziness, somnolence, irritability, confusion, photophobia, or obtundation. Absence of nuchal rigidity (a finding exhibited in only 15% of patients) does not rule out infection (⁴³). Patients infected with Cryptococcus gatti can include those with no apparent immunosuppression but with high predeliction for CNS involvement (⁴³). In patients with CNS disease, findings include elevated opening pressure, decreased glucose, and high protein concentration. Leukocyte count may also be elevated, with lymphocyte predominance (⁴⁴). Available diagnostic tests include India ink, serum cryptococcal antigen, and fungal culture. India ink detects 50% of infections, whereas serum cryptococcal antigen is positive in 90% of cerebrospinal fluid (CSF) and 70% of blood in patients with CNS infection.

Disseminated Infection

Multiple organs, including the liver, prostate, eyes, skin, and bone, may serve as sites of dissemination. Serum cryptococcal antigen has greater than 90% sensitivity and specificity for invasive cryptococcal disease (⁴³). Skin lesions, present in only approximately 10% of patients, tend to be painless and located on the face, neck, and scalp (⁴³). The lesions may appear as papules, plaques, ulcerations, acneiform eruptions, lesions, or even draining sinuses. With wide use of antifungal prophylaxis, skin, soft tissue, and osteoarticular lesions appear to be less common (⁴³).

Therapy

Treatment of cryptococcal disease depends largely on site of infection. Combination of D-AMB with flucytosine is the traditional approach of choice for severe pulmonary cryptococcosis and CNS disease in non–HIV-infected immunocompromised patients as induction therapy (⁴³). Flucytosine is available only as an oral preparation with myelosuppressive toxicity (see Tables 51-1 and 51-2). The recommended dose is D-AMB 0.7 to 1.0 mg/kg/d plus flucytosine 100 mg/kg/d for 2 weeks, as induction therapy, consolidation with fluconazole 400 to 800 mg daily for 8 weeks, and then 200 mg daily maintenance therapy for 6 to 12 months (⁴³). In mild-to-moderate cases of pulmonary disease, fluconazole 400 mg daily alone may be given for 6 to 12 months (⁴³). Of note, synergy has been noted between some antifungal agents and calcineurin inhibitors, associated with improved outcomes for solid-organ transplant patients (⁴⁵), potentially of relevance in patients with HSCT although not established.

Management of cryptococcal meningitis requires monitoring of CSF pressure and appropriate measures if elevated pressures are noted to prevent complications and reduce mortality (⁴³). Complications of elevated intracranial pressures (>200 mm H₂O) include papilledema, hearing loss, vision loss, severe headache, and cognitive impairment. Therefore, management is aggressive, including daily lumbar puncture or, if necessary, ventricular shunt placement (⁴³). Timely intervention is necessary to prevent irreversibile neurologic complications or death.

Humans are exposed to various Fusarium spp found in the air and soil. Superficial (cutaneous, keratitis, onychomycosis), locally invasive, and disseminated infection syndromes are included. The most common species that causes human disease is Fusarium solani (approximately 50% of cases), but others include F. moniliforme, F. oxysporum, and F. dimerum (⁴⁶). Entry points for infection by Fusarium spores are typically skin, onychomycosis, and respiratory tract. Risk factors for invasive fusariosis among patients with hematologic malignancy include uncontrolled cancer (71%), stem cell transplant (47%), and neutropenia (82%) (⁴⁶). Mortality was highest in one retrospective study in patients with fungemia, with an abysmal 6% survival at 12 weeks (⁴⁶). All-cause mortality was 66%, but 50% was attributable to fusariosis.

Sinus infection and pneumonia occur in 80% of patients, and blood cultures are positive in 50% to 70% of cases (⁴⁷). In neutropenic patients, dissemination occurs 75% of the time and is characterized by multiple skin lesions (⁴⁸). Skin lesions may appear as red or gray macules, pustules, or classically papules with central necrosis or eschar (Fig. 51-6). Lesions may also appear to be different types of lesions at different stages of evolution (⁴⁸). Myalgias or subcutaneous lesions are also noted in disseminated fusariosis. In nonneutropenic patients with less-severe immunocompromise, infection may be relatively localized, with paronychia, erythematous nodules, hemorrhagic bullae, or trauma-associated tender, necrotic lesions (⁴⁷).

Therapy

The significance of in vitro susceptibility results is unclear, with conflicting reports of species-specific susceptibility to amphotericin B in some series, whereas others do not demonstrate such an association. Azoles, particularly voriconazole and posaconazole, exhibit variable in vitro activity against different Fusarium species (⁴⁷). Posaconazole and voriconazole have both been used as salvage therapy after initial monotherapy with high-dose lipid formulations of amphotericin B failed (⁴⁷). Combination therapy has been used with anecdotal success, but definitive evidence of effectiveness is lacking. In neutropenic patients, however, neutrophil recovery is the critical component improving outcomes (⁴⁶).

Mucormycosis is an infection caused by molds of the order Mucorales present in the environment, acquired by inhalation of spores (⁴¹). These molds, similar to Aspergillus spp, are angioinvasive, causing thrombosis and infarction. Macrophages and neutrophils are key components of the immune response to mucormycosis. Patients with acute leukemia, diabetic ketoacidosis, or iron overload; HSCT recipients; and those treated with adrenal corticosteroids (⁴¹) may be affected by mucormycosis. Syndromes include rhinocerebral, pulmonary, GI, and cutaneous involvement (⁴⁹). Patients with hematologic malignancy tend to have pulmonary or disseminated disease, whereas those with diabetes have predominantly sinus involvement (⁵⁰).

Overall mortality is 44%, but patients with cancer with definite or probably mucormycosis have a mortality rate of 71% (⁴¹). Patients with neutropenia are more likely to have disseminated disease, which has a mortality over 90%.

Therapy

Amphotericin B, more recently in lipid formulations, has been the most commonly used approach to treatment of mucormycosis (^49,50). High doses of amphotericin B (5-10 mg/kg/d) can be provided with lipid formulations (⁵⁰). Other modalities that have been used include hyperbaric oxygen, iron-chelating agents (deferasirox), surgical intervention, immunomodulatory therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interferon gamma and granulocyte transfusions (⁵⁰). The addition of posaconazole typically occurs in transition to oral therapy, but rarely may be used as a frontline agent if there is a contraindication to amphotericin B formulations or relatively mild, localized disease that has been surgically resected (⁵⁰). In addition to monotherapy with amphotericin B formulations, various combinations of antifungals, including echinocandins, are given with any or all of the modalities mentioned (⁵⁰). A review of the common nonendemic fungi and associated syndromes is provided in Table 51-5.

The list of common endemic fungi that may infect patients with cancer in North America includes Coccidioides immitis and Histoplasma capsulatum (⁵¹). The distribution of these organisms is determined by climate and geography. These may infect patients without severe immunosuppression and may manifest as lung lesions that may even be confused with malignancy, such as lung cancer, or as disseminated disease (⁵¹). In patients with hematologic malignancies with cellular immunity impaired by the disease process or by treatments, including steroids (eg, CLL), these infections may represent reactivation of latent infection (⁵¹).

Histoplasmosis

Presentation of histoplasmosis is with pulmonary lesions in patients with solid tumor, but predominantly is disseminated disease in patients with hematologic malignancy (⁵¹). In the United States, histoplasmosis is most common in the Ohio and Mississippi River valleys. Hepatosplenomegaly and mucocutaneous ulcerations, particularly in the oral cavity, may be present (⁵¹). Histoplasmosis is identified by culture from infected tissues, including respiratory samples and rarely the bloodstream on culture. Histoplasmosis antigen testing can be used to detect evidence of histoplasmosis in urine (⁵²). Recent guidelines suggest utilizing liposomal amphotericin B (3-5 mg/kg/d) for severe pulmonary or disseminated disease, followed by itraconazole (200 mg twice daily for 2 days, then 200 mg daily) (⁵²). For most infections requiring treatment, therapy is provided for 6 to 9 months (⁵²). Severely immunocompromised patients may require even more prolonged therapy. Successful therapy with voriconazole has been used for histoplasmosis (⁵³).

Coccidioidomycosis

Coccidioides immitis is reported to cause fever, hypoxemia, and diffuse pulmonary infiltrates in immunocompromised patients (⁵¹). In the United States, coccidioidomycosis is endemic to western Texas, central California, southern New Mexico, and southern Arizona. Disseminated infection may involve the skin and bone. In patients with hematologic malignancy, serologic tests may be negative. In most cases, specimens from the lung, CSF, or other tissue provide the best approach for diagnosis (⁵⁴). Current guidelines recommend therapy for severe pulmonary or severe disseminated infection should begin with an amphotericin B formulation, D-AMB (0.7-1.0 mg/kg/d) or liposomal amphotericin B (3-5 mg/kg/d). For meningitis, guidelines recommend fluconazole (400 to 800 mg/d), possibly combined with intrathecal amphotericin B (⁵⁴). After completing initial aggressive therapy according to syndrome on presentation, fluconazole (400 mg/d) or itraconazole (400 mg/d) is continued for at least a year for most cases and indefinitely for immunocompromised patients (⁵⁴). Lifelong therapy with fluconazole or voriconazole, which penetrate the CNS, are recommended for those with meningitis (⁵⁴).

White Blood Cell Transfusions

Recovery of neutropenia is essential for recovery from invasive fungal infection. Almost five decades ago, transfusions of leukocytes were first utilized to assist neutropenic patients in recovery. Some studies have suggested that this approach could be effective in management of invasive fungal infection, but doubts remain. Issues include the challenge of the dose of cells and the length of time during which they remain active (⁵⁵). Administration of granulocyte colony-stimulating factor (G-CSF) has allowed healthy volunteers to provide adequate numbers of cells (⁵⁵). The effectiveness of this approach may be as a bridge to recovery of bone marrow. Finally, clinical issues with granulocyte transfusions include an initial worsening of respiratory symptoms, although skin and soft tissue infections appear to improve.

Cytokines

Proinflammatory cytokines, exemplified by interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin (IL) 2, are produced by Th1 lymphocytes, activating effector immune cells (⁵⁶). Treatment with IFN-γ, sometimes in combination with GM-CSF, has been used to stimulate the immune response to fungal infections (⁵⁶). The IFN-γ enhances hyphal damage to fungal pathogens by neutrophils and monocytes (⁵⁶).

The duration and depth of neutropenia can be decreased using colony-stimulating factors, including G-CSF (filgrastim) and GM-CSF (sargramostim, molgramostim) (⁴¹). Here, GM-CSF may be of particular use because it not only increases the number of granulocytes but also improves the function of macrophages and granulocytes (⁵⁶). Case reports and case series have suggested the potential benefit of several of these adjunct therapies, although data are not adequate to make firm recommendations for use of these immunomodulators.

Surgical Resection

The role of surgical resection is characterized for fungal infection by organism, but a recent study described patients undergoing resection as a component of therapy for a broad array of fungal infections from 1984 through 2009; the study provided insight into use of this approach (⁵⁷). Patients with hematologic malignancy and suspected pulmonary invasive fungal infection on appropriate systemic antifungal therapy underwent resection in select circumstances. These included progression of fungal infection despite therapy, with neutropenia not considered a contraindication. Platelets were transfused over 50 times 10⁹/L. After surgery, nearly 90% of patients underwent further chemotherapy or stem cell transplant, with mortality of 7% and 48% at 30 days and 1 year, respectively (⁵⁷). Fungal organisms isolated were predominantly Aspergillus species (88%) and Mucorales (8%). Bacterial infection was noted in 8% of patients, with lung infarction in another 3%, with no evidence of fungal infection, obviating the need for active antimold therapy. Over the time of the retrospective study, the surgical procedures became less invasive, shifting from lobectomy and open limited resections to video-assisted thoracoscopic procedures (⁵⁷). Surgical resection, via open or video-assisted thoracoscopy, presents a viable option for management of focal fungal infection that fails to respond to antifungal therapy alone, even with patients with hematologic malignancies. In fact, these procedures have successfully been followed by subsequent chemotherapy and stem cell transplant.

Viral infections are an important cause of morbidity and mortality in patients with cancer. Although morbidity and mortality are greater for patients with hematologic malignancies or after HSCT, viral infections, such as norovirus or influenza virus, can increase length of hospital stay and delay chemotherapy, radiation, or surgery in a broad patient population. The most common viral infections are respiratory viral infections, including adenovirus, influenza, parainfluenza, RSV, rhinovirus, and human metapneumovirus (⁵). DNA viruses, such as herpes simplex, varicella, and CMV, are well known to cause serious infections in patients with hematologic malignancies or after HSCT, resulting in intense monitoring and prophylaxis directed against such viruses (⁵⁸). Patients with hematopoeitic stem cell transplant are at particular risk for severe viral infections. Modern tools of diagnosis can quickly identify infection, but treatment options are limited for many viral infections. The following sections provide an overview of viral infections in patients with cancer. Special focus is placed on those with hematologic malignancies and patients after HSCT because this population is uniquely susceptible to viral infections.

Human Herpesviruses

Human herpesviruses are among the most common causes of viral infections in immunocompetent as well as in immunocompromised patients. Morbidity and mortality from these viruses are high among immunosuppressed patients. Herpesviruses are double-stranded DNA viruses. The herpesvirus group has eight members, six of which are important pathogens in immunosuppressed patients (ie, patients with hematologic malignancies and solid-organ or stem cell transplant recipients) (^58,59). This group of pathogens includes HSV 1 and 2, VZV, CMV, Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6).

Herpesviruses establish a latent phase after primary infection. The reactivation of these DNA viruses can be triggered by several stimuli; this is perhaps best recognized in the recurrent blisters and ulcers associated with HSV. The likelihood of reactivation of these viruses is increased during profound T-cell immunosuppression, as host defenses against these viruses are dependent on virus-specific helper and cytotoxic T lymphocytes. Over the past decade, substantial improvements have been made in the techniques used to detect these infections, such as real-time polymerase chain reaction (PCR), as well as the development of effective antiviral agents and the use of different strategies for prophylaxis and treatment.

Herpes Simplex Viruses

Among the most common causes of mucocutaneous lesions in immunocompromised patients are HSV types 1 and 2 (⁵⁹). Approximately 40% to 60% of seropositive patients undergoing induction chemotherapy for leukemia or conditioning for HSCT will experience HSV reactivation, usually in early stages, when immunosuppression is most intense (⁵⁹). Reactivation of HSV may cause severe disease during neutropenia. Patients with a CD4 count less than 50 who received purine analogs or alemtuzumab are at highest risk of reactivation (⁵⁹). Oropharyngeal and esophageal disease is usually but not exclusively caused by HSV-1. The clinical manifestations of oropharyngeal HSV disease can range from gingivitis to stomatitis and cheilitis. Esophagitis from HSV may occur from local spread. Clinical presentation ranges from fever, malaise, myalgia, dysphagia, and bleeding to severe oral pain and odynophagia. Disease caused by HSV-2 is more likely to cause genital and anal disease.

Diagnosis

The diagnosis of HSV infection can be made by isolating the virus in culture or by performing a biopsy showing the characteristic inclusions by immunohistochemistry. Direct detection methods of the virus in clinical specimens are generally not as sensitive as culture methods but offer the advantage of a rapid diagnosis. Direct or indirect immunofluorescence can be used to detect HSV-1, HSV-2, and VZV from specimens of cutaneous lesions.

Prophylaxis

Antiviral prophylaxis should be strongly considered in HSV-seropositive patients at risk for reactivation during intensive chemotherapy for acute leukemia and during early stages of HSCT (^58,59). Oral acyclovir and valacyclovir are the agents of choice for prophylaxis. If patients are receiving intravenous foscarnet or ganciclovir for treatment of another viral infection, then they do not need to continue acyclovir prophylaxis (⁶⁰). Guidelines suggest that continuing prophylaxis for over a year post-HSCT significantly reduces reactivation, with a finding that this may even decrease the risk of acyclovir-resistant HSV (^59,60,61).

Therapy

The available antiviral agents for the treatment of HSV disease include acyclovir, valacyclovir, famciclovir, foscarnet, and cidofovir (Tables 51-6 and 51-7) (^58,60). The bioavailability of oral valacyclovir and famciclovir is three to five times superior to that of oral acyclovir. All of these drugs are dependent on the virus-encoded thymidine kinase for their intracellular phosphorylation for activity.

Established HSV disease can be treated either orally or intravenously. The most commonly used drug is acyclovir. Immunosuppressed patients with disseminated or severe HSV disease should be treated with intravenous acyclovir (5-10 mg/kg every 8 h). Otherwise, an oral regimen can be used for milder HSV disease (famciclovir, 500 mg three times a day, or valacyclovir, 1 g three times a day) (^58,59). Foscarnet and cidofovir can be used for resistant disease but are only available in intravenous formulations (⁶⁰).

Varicella Zoster Virus

Reactivation of VSV occurs primarily in elderly individuals, seropositive organ transplant and HSCT recipients, patients with cancer, and those with AIDS. Disseminated VZV infection can be life threatening in HSCT recipients and patients receiving intensive corticosteroid therapy (⁵⁹).

The clinical manifestations of VZV infection are primary varicella infection (chickenpox) and herpes zoster. The clinical presentation includes low-grade fever, malaise, and a vesicular rash that evolves to scabs. Constitutional symptoms usually develop after the onset of rash and include pruritus, anorexia, and listlessness. Primary VZV infection (chickenpox) occurs mainly in children under 10 years of age.

Reactivation of latent VZV or herpes zoster is frequently observed among patients with cancer, mainly patients with leukemia or lymphoma, as well as in HSCT recipients (^58,59). Visceral herpes zoster may follow cutaneous dissemination in immunocompromised patients and can result in pneumonia, encephalitis, retinal necrosis, hepatitis, and small bowel disease. Cutaneous VZV eruption can be complicated by secondary bacterial infections, thrombocytopenia, and vasculitis (Fig. 51-7).

Diagnosis

Immunocompromised patients may exhibit single dermatomal disease, but more commonly develop multidermatomal or disseminated cutaneous disease, which can make the clinical diagnosis less certain on visual inspection alone. The diagnosis can be established within hours by the direct method of immunofluorescent staining on material collected from a skin lesion or from a skin biopsy. Viral culture should also be performed. In some cases, a biopsy is required to establish the diagnosis because other diseases can mimic VZV, such as streptococcal impetigo, GVHD, and various noninfectious bullous diseases.

Therapy

The treatment of choice for chickenpox or VZV in immunocompromised patients is high-dose intravenous acyclovir (10 mg/kg every 8 h) (see Tables 51-6 and 51-7). Early initiation of acyclovir is paramount because it may reduce progression to end-organ disease and usually prevents death in patients with reactivated disease. Therapy can be changed to an oral agent once clinical improvement has occurred, including resolution of fever or healing/crusting of lesions. The options for an oral regimen for treatment of localized herpes zoster among patients with mild immunosuppression include acyclovir (rarely used because of bioavailability and pill burden), valacyclovir, and famciclovir (⁶²).

Prevention of Infection

Varicella zoster virus can be transmitted from person to person, and this can become problematic in a hospital or clinic setting. To prevent nosocomial transmission, immunocompromised patients with cutaneous lesions suspicious of VZV eruption and those with disseminated zoster should be placed under contact and respiratory isolation. In addition, it is recommended that the family members, caregivers, and visitors of patients scheduled to undergo transplant be vaccinated against VZV, preferably at least 4 weeks prior to conditioning regimen (^59,60).

Immunosuppressed patients with negative VZV titers and no history of chickenpox should be offered VZV immune globulin after being in close contact with individuals with either chickenpox or herpes zoster. Close contact includes prolonged face-to-face contact, a household or playmate contact, or exposure to a roommate in a shared hospital room. Varicella zoster immune globulin, if available, should be administered within 96 h of exposure to be most effective in preventing infection (⁵⁹).

Immunocompromised persons should avoid contact with individuals who developed a rash after receiving zoster vaccine. No additional precautions are required if a rash has not developed (^59,60). A study of an inactivated varicella vaccine in HSCT patients resulted in decreased incidence and severity of zoster but is not commercially available (⁵⁹).

Cytomegalovirus

Evidence of prior CMV infection is present in approximately 85% of the US population (⁵⁹). Therefore, reactivation of latent CMV infection is the primary concern in the hematologic malignancy and HSCT patient populations (^59,60). Reactivation can manifest as viremia alone, a mononucleosis-like syndrome with lymphadenopathy, or more severe disease with end-organ damage. Other symptoms of CMV reactivation include fever, lymphadenopathy, splenomegaly, lymphocytosis, and polyradiculopathy. Manifestations of end-organ disease include retinitis, encephalitis, and hepatitis, but pneumonitis and GI disease are the most common and can be life threatening (⁵⁹).

The most common sites of CMV infection in the GI tract are the esophagus and colon. The hallmarks of CMV colitis are abdominal pain and diarrhea. Esophagitis caused by CMV is associated with pain and dysphagia. On upper GI endoscopy, ulcerations can be seen in the esophagus, and a biopsy must be obtained to rule out other infectious etiologies, such as HSV or candida esophagitis. As with esophagitis, the diagnosis of colitis requires biopsy. In a retrospective study at our institution, 72% of patients diagnosed with GI CMV disease had hematologic malignancies, 25% had AIDS, and overall CMV-attributable mortality rate was 42% (⁶³). Independent predictors of mortality were disseminated CMV and diagnosis of AIDS (⁶³).

Cytomegalovirus pneumonitis is associated with a mortality rate of 80% to 100% in patients with high-risk leukemia and HSCT (⁵⁹). Pneumonitis typically presents with severe dyspnea, hypoxia, and interstitial disease on chest radiograph. Similar to GI disease, finding of CMV from bronchoscopy specimens without accompanying pathology is of unclear significance. The thrombocytopenia present in most patients with leukemia and HSCT often prevents acquisition of a biopsy specimen that can accurately confirm diagnosis of CMV pneumonitis. A study of autopsy-proven CMV pneumonia in patients with HSCT and hematologic malignancy showed that incidence decreased over the time of the study (from 1990 to 2004) (⁶⁴).

Risk Factors

Patients with HSCT and hematologic malignancies are at highest risk for CMV infection and reactivation. In patients with leukemia, those at highest risk include patients who have received purine analogues (eg, fludarabine) and T-cell–depleting monoclonal antibodies (eg, alemtuzumab) (⁵⁹). Reactivation can occur in almost 5% of those receiving purine analogues and in 15% to 66% of those receiving alemtuzumab, with the highest risk period for the latter group being in the first 1 to 3 months after therapy (⁵⁹). Reactivation in the setting of alemtuzumab therapy, however, was significantly reduced (0% vs 35% in the control arm) with prophylaxis utilizing valganciclovir 450 mg orally twice per day when compared to 500 mg daily valacyclovir (⁶⁵).

In patients with HSCT, the highest-risk group is the CMV-seropositive recipient, regardless of donor serostatus, followed by the CMV-seronegative recipient with seropositive donor (⁵⁹). Nonmyeloablative regimens for HSCT patients have resulted in decreased risk of CMV reactivation, although cases have occurred later after transplant (⁶⁶). The period of highest risk is in the first 100 days after transplant, although prophylaxis and preemptive strategies have resulted in CMV infections after day 100 from transplantation (⁶⁷). Risk factors for late disease in HSCT patients include GVHD, CMV reactivation before day 100 posttransplant, steroid use, low CD4 count (<50), use of unmatched stem cells, cord blood, T-cell–depleted stem cells, and receipt of allograft-negative donors in CMV-positive recipients (^60,68). Also, CMV can be transmitted to HSCT recipients from seropositive donors and from blood products (⁵⁹). The utilization of CMV-seronegative blood for transfusions and leukoreduction of blood products has resulted in significantly reduced CMV infection (⁵⁹).

Diagnosis

Diagnosis of CMV depends on the site of infection. For detection of disseminated infection or reactivation, two types of tests are available and recommended for diagnosis of CMV: pp65 testing and detection of DNA (⁶⁰). Serologic testing is not useful, except for donor selection for transplant, because CMV antibodies demonstrate evidence of prior exposure, rather than active infection. For detection of end-organ disease such as in the liver and lungs, the recommended approach is biopsy with detection of viral inclusions on histopathology or by immunohistochemistry (Fig. 51-8), which has greater sensitivity. If available, in situ PCR and nucleic acid hybridization are also useful diagnostic tools for biopsy samples. Detection of CMV DNA is a widely available test in transplant centers, utilizing quantitative real-time polymerase chain reaction (RT-PCR) for CMV DNA detection (^59,60,69).

Therapy

Antiviral agents are used for prevention and treatment of CMV infection. Available agents are described in Tables 51-6 and 51-7. Strategies for utilization of these agents include treatment of established disease, preemptive therapy, or prophylaxis (⁵⁹). The last two strategies focus on disease prevention in high-risk HSCT patients. At MD Anderson Cancer Center, prophylaxis with ganciclovir or foscarnet used to be the strategy in high-risk HSCT patients; now, preemptive therapy is used in all HSCT patients at risk for reactivation.

A recent study compared daily oral 900 mg valganciclovir to placebo (paired with preemptive therapy) for prophylaxis against late CMV infection after allo-BMT. The study failed to show the impact of valganciclovir on reduction in mortality, CMV disease, or other invasive infections, although less CMV infection was detected (⁶⁷). Another multicenter study compared a novel anti-CMV agent, letermovir, targeted against the viral terminase complex, to placebo for prophylaxis for allo-BMT patients. In the modified intention-to-treat analysis, a dose-dependent reduction of 30% in CMV reactivation was noted in the letermovir group, without any noted adverse hematologic events (⁷⁰). A similar study in allo-BMT patients showed a 27% reduction in CMV events with CMX001, a lipid acyclic nucleoside phosphatase. Diarrhea was the most common adverse effect of the study medication (⁷¹).

Ganciclovir functions as a competitive inhibitor of viral DNA polymerase. Its major side effect is myelosuppression, limiting its use as a prophylactic agent and requiring frequent blood count monitoring (⁵⁹). Dosing for treatment is 5 mg/kg intravenously every 12 hours (⁵⁹). Valganciclovir, a prodrug of ganciclovir available in capsule form, is significantly better absorbed than its prodrug ganciclovir in oral form (⁵⁹). A common induction dose is 900 mg twice daily by mouth.

An alternative agent, foscarnet, functions as a noncompetitive inhibitor of the pyrophosphate-binding site of CMV DNA polymerase, which does not require phosphorylation to become active (⁵⁹). Foscarnet is typically used when resistance to ganciclovir is suspected or bone marrow suppression is excessive with ganciclovir. It is also useful in patients with delayed engraftment (⁶⁹). Side effects of foscarnet include nephrotoxicity, azotemia, and electrolyte abnormalities.

Cidofovir, a nucleotide analogue, has been approved for treatment of CMV retinitis in patients with HIV. It works as a competitive inhibitor of the CMV DNA polymerase. Its role in treatment or prophylaxis of CMV in immunocompromised patients, however, is limited due to nephrotoxicity. The long half-life not only makes once-weekly administration possible, but also results in a lasting impact of adverse effects (⁶⁹). Modalities used to reduce risk of nephrotoxicity include hydration and probenicid.

Human Herpesvirus 6

Human herpesvirus 6 is a beta-herpesvirus with two subtypes (A and B). Primary infection with HHV-6 is common in children. Exanthem subitum, the most common cause of fever and hospitalization of infants less than 1 year of age, is caused by HHV-6 subtype B (^58,59). In addition to fever, children present with mild upper respiratory symptoms and a classic diffuse maculopapular exanthem. It is unclear whether HHV-6 subtype A causes any primary infection. In immunosuppressed individuals, typically patients with AIDS and transplant recipients, HHV-6 may cause opportunistic viral infections. As this infection is common early in life, positive titers are found in more than 95% of adults. In immunosuppressed individuals, especially HSCT recipients, this virus occasionally may cause interstitial pneumonia, fever, encephalitis, hepatitis, and delayed engraftment (⁶⁰). Up to 40% to 60% of HSCT patients may demonstrate viremia by PCR, but the significance of this finding is unclear, so routine surveillance is not currently recommended (^58,59,60).

Therapy

Both ganciclovir and foscarnet are used to treat HHV-6 infections, but this is based on in vitro studies only because clinical experience is minimal. Both ganciclovir and foscarnet have been reported to be effective against HHV-6 meningoencephalitis after HSCT in a small number of patients (⁵⁸).

Epstein-Barr Virus

Epstein-Barr virus infection is common in the adult population. It is the cause of infectious mononucleosis and has also been linked to several geographically defined cancers. Posttransplant lymphoproliferative disorder (PTLD) associated with EBV is an important cause of morbidity and mortality in HSCT and solid-organ transplant recipients. Posttransplant lymphoproliferative disorder is reported in 0.45% to 29% of HSCT patients, depending on the source of hematopoietic cells (cord blood with the higher risk), manipulation of those cells, and immunosuppressive regimen (⁷²). Although variable in incidence, PTLD can be fulminant and lethal. The disease results from suppression of cytotoxic T-cell function.

The first step in the management of PTLD is to reduce the dose of any immunosuppressive therapy if possible. Another therapeutic approach using the anti-CD20 monoclonal antibody (rituximab) has been tested for therapy for EBV-induced PTLD. It has been successful for the treatment or prevention of PTLD in solid-organ transplant and HSCT recipients as well as those with proven EBV lymphomas (^58,59). Another approach is utilization of EBV-cytotoxic T lymphocytes (CTL), typically derived from EBV-positive stem cell donors or from third-party donors (⁷²). There is no apparent role for antivirals in treatment of EBV-associated PTLD. Treatment with rituximab and EBV-targeted CTLs has resulted in over 85% survival, compared with less than 20% before these modalities were available (⁷²).

Community Respiratory Viral Infections

Infections caused by community respiratory viruses (CRVs) were not considered to be a significant problem for patients with cancer until the early 1990s. Since then, it has been recognized that they represent a threat to patients undergoing chemotherapy for acute leukemia and to HSCT recipients, especially recipients of allogeneic transplants (⁷³). Early surveys indicated that about 30% of respiratory illnesses occurring during the winter and spring among these patient populations were due to CRVs. Recent studies have reported CRVs as the cause of as few as 5% to as many as 48% of respiratory infections (⁷³). Although many patients acquire only upper respiratory infections (URIs), some develop pneumonias, which may be fatal. In a retrospective study conducted at our institution, progression from URI to pneumonia was noted in 35% of patients with HSCT and hematologic malignancy (⁷³). Many of these pneumonias may be due to bacterial or fungal pathogens and not attributed to the virus. For example, it has been recognized for many years that influenza can predispose to bacterial pneumonia.

Epidemics of CRV have occurred on leukemia and transplant units, where the virus may be transmitted by patients, visitors, and hospital personnel. Clinics may serve as an important starting point for epidemics. Also, epidemics may occur among these susceptible patients in the absence of a recognized epidemic in the community. An additional problem is that these immunocompromised patients may have prolonged viral shedding (in some cases >100 days) after resolution of symptoms (^59,74). Shedding of influenza virus continued despite antiviral therapy, halting only when lymphopenia resolved (^59,74).

The most commonly reported viruses causing infection are influenza A and B (predominantly influenza A), RSV, and parainfluenza virus (almost entirely type 3) (⁵). Rhinoviruses are the most common cause of community respiratory illnesses but are identified infrequently in most surveys of patients with cancer, suggesting that they are underdiagnosed. Rhinoviruses have been associated with pneumonia in HSCT patients, but commonly are accompanied by bacterial coinfection (⁷⁵). Influenza, RSV, and parainfluenza types 1 and 2 occur during the winter and spring, whereas parainfluenza 3 infection occurs throughout the year. Some patients may be infected by multiple viruses simultaneously or have multiple episodes of the same viral infection separated by only a few weeks. There is considerable variability in the relative frequency of the three major viruses in different geographical areas and in different years, most likely reflecting the relative prevalence of the infections within the community.

A study of parainfluenza virus pneumonia in HSCT patients pointed to high oxygen requirement, low monocyte counts, and high-dose steroids as predisposing to mortality, ranging from 13% to 55% (⁷⁶). A retrospective study conducted at our center emphasized relapsed or refractory malignancy, high APACHE (Acute Physiology and Chronic Health Evaluation) II score, and high-dose steroids as predictors of mortality in a mixed population of patients with leukemia and HSCT (⁷⁷). Human metapneumovirus is a paramyxovirus similar to RSV that was first described in children but has now been described in immunocompetent and immunocompromised adults (^78,79). Fatal cases in HSCT patients were reported from Seattle, Washington, with mortality rates as high as 43% (⁸⁰), but HSCT patients from France demonstrated a low mortality rate, even with lower respiratory tract infection (⁸¹). One of the continuing challenges in comparison of mortality between studies is the degree to which individual investigators consider viral infection the cause or major contributor to death, particularly when considering the significant underlying disease in the oncology populations studied to date (⁸¹).

Finally, influenza virus infection is associated with different presentation and natural course of disease in severely immunocompromised hosts. In a recent study at the US National Institutes of Health, immunocompromised hosts exhibited less prominent symptoms, such as cough, chills, myalgias, or dyspnea than hosts who were not immunocompromised (⁷⁴). Physical exam findings demonstrating pulmonary compromise were also more common in nonimmunocompromised hosts, but radiographic abnormalities on chest imaging were more common in immunocompromised hosts (⁷⁴). Finally, immunocompromised patients exhibited more severe disease, despite similar cytokine profiles, with prolonged viral shedding and higher risk of developing drug-resistant influenza virus (⁷⁴).

Predisposing Factors

Several important predisposing factors for these infections have been identified in HSCT recipients and patients with hematologic malignancies. These include age more than 65 years, severe neutropenia, severe lymphopenia, allogeneic transplantation, transplant conditioning regimen, GVHD, and adrenal corticosteroid therapy (over 1 mg/kg body weight) (^58,73,79,82). Recipients of HSCT are at greatest risk within the first 100 days posttransplant, although nonmyeloablative transplant has resulted in an increase in disease occurring after this initial period (^58,82). Neutropenia, lymphopenia, marrow or cord blood as source of transplant, age over 65 years, GVHD, smoking history, and allogeneic HSCT were risk factors for progression from RSV URI to pneumonia (^5,73).

An immunodeficiency scoring system developed at MD Anderson has been useful in estimating outcomes and appropriate focus of expensive therapy for RSV infection (⁸³). Factors given the most weight are neutropenia, lymphopenia, and age 40 years or older, followed by other factors such as GVHD, corticosteroid use, myeloablative conditioning regimen, and preengraftment or within 30 days of engraftment (⁸³). Without therapy, those patients in the highest-risk category all progressed to pneumonia, compared to 15% of those who received antiviral therapy. The subsequent mortality in untreated high-risk patients who progressed to pneumonia was 100%, compared to 50% for those who received antiviral therapy (⁸³).

Pneumonia

There is great variability in the frequency of viral pneumonia in different studies, ranging from 15% to over 70%, but most surveys have reported only small patient populations. Fatality rates from viral pneumonia vary widely in different reports, but most include only small numbers of cases. In our institution, mortality in patients with hematologic malignancies was 15%, although reports in HSCT patients range as high as 50% to 70% (⁷³). The same factors that predispose for pneumonia may predispose to fatal outcome.

Diagnosis

The diagnosis of CRV infection is established from nasopharyngeal wash, sputum, swab, or bronchoalveolar lavage specimens (⁷³). Rapid antigen detection tests are available for influenza and RSV, whereas tissue cell cultures are used for detecting parainfluenza and rhinoviruses. Modern tools for diagnosis include available multiplex PCR platforms that are capable of detecting multiple respiratory viruses simultaneously with improved sensitivity compared to cell culture or direct fluorescent antibody (⁸⁴).

Therapy

Therapy for these infections has been limited (see Tables 51-6 and 51-7). At present, there is no demonstrably effective therapy for parainfluenza infection, with DAS-181, a fusion protein inhibitor, under evaluation (⁵). Neuraminidase inhibitors, inhaled zanamavir, oral oseltamavir, and intravenous peramavir are currently approved antivirals against influenza (^85,86). In the pandemic 2009 H1N1 influenza A outbreak, early therapy was shown to be critical in improving mortality in patients with cancer (⁵). Viral resistance to these agents developed in some patients during therapy, particularly among those with lymphopenia, who may shed the viruses for weeks to months (⁷⁴). Given the predisposition to prolonged shedding in immunocompromised hosts, innovative approaches to treatment are required to prevent poor outcomes and antiviral resistance (^74,86). Considerations have included immunomodulatory medications from statins to naproxen to mTOR inhibitors (⁸⁶). Steroids should be used with caution because they may prolong the duration of shedding, leading to emerging resistance. Steroids are also associated with increased risk of secondary fungal and bacterial infections (⁸⁶).

Ribavirin is available for therapy for RSV infection (Fig. 51-9). Ribavirin is administered by aerosolization 2 to 3 hours every 8 hours or continuously over 18 hours, requiring the patient to be confined in a tent (⁸⁷). In patients with leukemia, lack of aerosolized ribavirin and high APACHE II scores were independent predictors of developing pneumonia in this population (⁸³). Use of aerosolized ribavirin was suggested to be the key predictor of progression to pneumonia and mortality in allo-HSCT recipients in a study conducted at our center (⁸⁸). Ribavirin may also be combined with immunoglobulin (Ig) therapy when the infection progresses to the lower tract (⁵). Palivizumab, a humanized monoclonal antibody directed against the F glycoprotein of RSV, is currently available and approved for prophylaxis of RSV infection in high-risk pediatric patients (⁵). Most patients with RSV pneumonia are being treated with combination therapy, but the limited numbers of patients and lack of clinical trial data reported make interpretation of results difficult.

Hepatitis Viruses

Hepatitis B

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are common in many countries. There is a global epidemic of HBV infections, affecting more than 350 million people worldwide. Chronic HBV or HCV infections lead to progressive liver disease, cirrhosis, and hepatocellular cancer. Hepatitis can be a serious problem in patients with cancer for various reasons. Chemotherapy-induced immunosuppression may lead to reactivation and fulminant infection in patients with chronic HBV infection. Furthermore, the presence of hepatitis may require substantial delays in the administration of antineoplastic therapy. In HSCT patients, reactivation is more likely in those who have received high-dose steroids, fludarabine, rituximab, or alemtuzumab (⁶⁰).

Hepatitis C

Hepatitis C is the most common chronic blood-borne infection. In the United States, 4 million individuals (1.6% of the population) have been infected (⁸⁹). It is the leading indication for liver transplantation. Transmission of HCV occurs primarily through exposure to infected blood. It can be acquired from intravenous drug abuse, blood transfusion before 1992, solid-organ transplantation from infected donors, unsafe medical practices, occupational exposure to infected blood, birth to an infected mother, sexual contact with an infected person, and possibly via intranasal cocaine use (⁵⁸).

Antibody testing should be used first to assess exposure to HCV, but in cases of persistent liver disease with immunocompromised status that may prevent adequate response, HCV RNA testing should be undertaken (⁸⁹). Patients who are seropositive for HCV should be tested for HCV RNA to determine if virus is circulating (⁸⁹). If virus is circulating, then the MD Anderson algorithm (Fig. 51-10), can be used for further management (⁸⁹). The combination of pegylated INF-α plus ribavirin produced sustained virologic responses (SVRs) in only 4% of genotype 1 infections (⁸⁹). Notably, even treated patients without SVR exhibited slower progression to cirrhosis and portal hypertension (⁸⁹). The authors also cited an important link between HCV infection and various cancers, including hepatocellular carcinoma, lymphomas, and esophageal, prostate, and thyroid cancers (⁸⁹).

This intriguing suggestion points to an expanded role for testing and treatment of HCV infection in prevention or treatment of malignancy. The treatment of HCV is also being revolutionized by new directly acting antivirals (DAAs) that are being rapidly introduced and promise to reduce the complications associated with HCV infection as well as improve outcomes. Treatment is uniformly recommended for HCV-infected HSCT recipients, although timing should be at least 2 years after transplant with no evidence of GVHD and off immunosuppression (⁶⁰). At present, no active or passive immunizations are available for HCV.

Adenovirus

Adenoviruses are a common cause of self-limited respiratory and GI infections in normal individuals. Transmission occurs by aerosolized droplets or the oral-fecal route. Adenovirus infections have been recognized in patients undergoing intensive chemotherapy for hematologic and occasionally other malignancies, but they are especially prevalent among HSCT recipients (⁵⁸). The frequency of infection among HSCT recipients has varied from 3% to 21%, and it is more prevalent among children than adults. There is no seasonal variation, and the onset of infection from time of transplantation can be variable, although the median interval is about 50 days (⁵⁸).

Important risk factors have been identified for adenovirus infection, including childhood, allogeneic transplantation (particularly umbilical cord blood), GVHD, total-body irradiation (in children), T-cell–depleting conditioning regimens, alemtuzumab, corticosteroid therapy, and lymphopenia (⁵⁸).

Immunocompromised patients may have asymptomatic infection, single-organ disease, or disseminated disease (⁵⁸). The most common disease is gastroenteritis, presenting as fever and diarrhea, which may become bloody. Infections of the respiratory tract may vary from mild URI to severe pneumonitis with respiratory failure. Adenovirus may cause nephritis, and as many as 50% of patients with positive urine cultures develop hemorrhagic cystitis. Hepatitis may lead to liver failure and death. Other types of infection include encephalitis, pancreatitis, and disseminated infection with multiple- organ failure.

Diagnosis

The virus may be identified from nasopharyngeal washings, throat swabs, lower respiratory specimens, urine, stool, blood, and infected tissues. The diagnosis can be established by culture or more rapidly by the use of commercially available tests for antigen detection. Positive cultures are most often obtained from stool or urine specimens. Polymerase chain reaction is a useful diagnostic tool, particularly in screening those HSCT recipients at highest risk (⁵⁸). Unfortunately, however, there is no threshold for viral load that definitively correlate with clinically relevant infection.

Outcome

The mortality rate from symptomatic infection is about 25%, but it is 60% to 75% in patients with disseminated disease (⁹⁰). Death is mainly due to pneumonitis, hepatitis, or multiorgan failure. Many patients who die have other concomitant infections. There is no established therapy for these infections. In one series of 45 patients, intravenous cidofovir produced successful results in 69% and was as effective in asymptomatic patients as in those with definite disease (⁹¹). Lipid esters of cidofovir have been developed to improve bioavailability and reduce toxicity associated with this compound (⁹²) and are currently under evaluation in immunocompromised patients with either localized or disseminated infection. Immunotherapy with adenovirus-specific cytotoxic T-lymphocyte infusions is a promising future approach (⁵⁸).

Parvovirus B19 Infection

Parvovirus B19 causes erythema infectiosum in children. It has been associated with aplastic crises in diseases in which the life span or production of red blood cells is reduced (⁹³). Anti-B19 IgG has been found to be more prevalent among patients with cancer undergoing chemotherapy than among the general population. In this study, 63% of the seropositive patients with cancer had unexplained anemia (⁹⁴). Prolonged erythroid aplasia in childhood acute lymphocytic leukemia was associated with detection of B19 DNA in the bone marrow. Several patients with CLL have developed severe parvovirus B19 infection, manifested by a flulike illness followed by anemia owing to pure red cell aplasia in the bone marrow. The infection may be followed by an incapacitating polyarthritis. Intravenous Ig is a treatment available for this infection, but with significant risk of relapse (⁹⁵). A concern is the potential risk posed for infection or reactivation with parvovirus B19 for patients on dasatinib (a tyrosine kinase inhibitor) (⁹⁶).

Polyoma Viruses Infection

BK Virus

Polyoma hominis, or BK virus, infects 80% of the general population without causing clinical manifestations (⁵⁸). It persists in the genitourinary tract and is a major cause of hemorrhagic cystitis among HSCT recipients. About 60% to 80% of these patients have persistent viruria, and 5% to 15% develop hemorrhagic cystitis (⁵⁸). Risk is higher in allo-HSCT recipients (⁵⁸). Patients with hemorrhagic cystitis have higher viral loads in the urine, as detected by PCR (⁶⁰). The disease may vary from asymptomatic microscopic hematuria to severe dysuria, frequency, and passage of clots, which may cause outflow obstruction and renal failure. Symptomatic therapy includes red blood cell and platelet transfusions, saline bladder irrigations, and cauterization. The use of quinolones is of unclear benefit. Intravenous cidofovir has been utilized, and successful treatment of refractory cystitis with hyperbaric oxygen therapy was reported (⁹⁷), but no specific therapy is currently recommended (⁵⁸).

JC Virus

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the brain caused by the JC virus, a polyomavirus that is related to BK virus (⁹⁸). The disease results from reactivation of latent infection. About 80% of normal adults demonstrate JC virus antibodies by middle age. Progressive multifocal leukoencephalopathy was first described in patients with CLL and Hodgkin’s disease. Subsequent reports centered on patients with HIV, who currently account for 80% of new PML cases (⁹⁸). Symptoms include visual disturbances, speech defects, and mental deterioration leading to dementia and coma. The mortality rate is 80% at 1 year, and the mean time from diagnosis to death is 4 months. An association has been reported with steroid use, fludarabine, cyclophosphamide, methotrexate, mycophenolate, and, more recently, monoclonal antibodies, including rituximab (^98,99). Therapeutic choices are limited, with individual and combination therapy attempted with cytarabine, cidofovir, IL-2, IFN-α, Ig, zidovudine, ganciclovir, donor lymphocyte infusion, and if possible, discontinuation of GVHD prophylaxis (¹⁰⁰). No consistently effective therapy is available.