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 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.
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.
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.
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).
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.
Table 51-6Antiviral Compounds ||Download (.pdf) Table 51-6 Antiviral Compounds
|Antiviral ||Dosage ||Mechanism of Action ||Active Against |
|Acyclovir ||5-10 mg/kg IV every 8 h ||Inhibits DNA polymerase ||HSV, VZV |
|Famciclovir ||500 mg by mouth every 8 h ||Inhibits DNA polymerase ||HSV, VZV |
|Valacyclovir ||0.5-1 g every 8-12 h ||Inhibits DNA polymerase ||HSV, VZV |
|Ganciclovir ||5 mg/kg every 12 h ||Inhibits DNA polymerase ||CMV |
|Foscarnet ||60 mg/kg IV every 8 h ||Inhibits DNA polymerase ||CMV, HSV, VZV, HHV-6 |
|Cidofovira ||5 mg/kg IV once a week ||Inhibits DNA polymerase ||CMV, ADV, HSV, VZV, BK |
|Ribavirin ||Oral or aerosolized ||Inhibits viral replication ||HCV, RSV |
|Amantadine ||100 mg by mouth every 12 h or 200 mg by mouth daily ||Inhibits M2 protein ||Influenza A only |
|Ramantadine ||100 mg by mouth every 12 h ||Inhibits M2 protein ||Influenza A only |
|Oseltamivir ||75 mg by mouth every 12 h ||Neuraminidase inhibitor ||Influenza A and B |
|Peramavir ||600 mg IV daily ||Neuraminidase inhibitor ||Influenza A and B |
|Zanamivir ||2 inhalations every 12 h (IV formulation available, clinical trial) ||Neuraminidase inhibitor ||Influenza A and B |
Table 51-7Common and Serious Toxicities of Antivirals ||Download (.pdf) Table 51-7 Common and Serious Toxicities of Antivirals
|Acyclovir ||Transient renal insufficiency (IV), nausea, vomiting, agitation, confusion, TTP (rare) |
|Famciclovir ||Headache, somnolence, nausea, diarrhea |
|Valacyclovir ||Headache, nausea, vomiting, TTP (rare) |
|Ganciclovir ||Anemia, neutropenia (more common), thrombocytopenia, fever, phlebitis, anorexia |
|Foscarnet ||Nephrotoxicity (major toxicity), electrolyte disturbances (hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, hypokalemia), diarrhea, nausea, vomiting |
|Cidofovir ||Headache, rash, severe nephrotoxicity, metabolic acidosis, decreased intraocular pressure, neutropenia |
|Ribavirin ||Fatigue, headache, nausea, rash, pruritus, conjunctivitis (risk of toxicity to healthcare workers during administration), hemolytic anemia (cardiac and pulmonary events have occurred), worsening respiratory status, including death (inhalation) |
|Oseltamivir ||Insomnia, vertigo, nausea, vomiting (most common), bronchitis |
|Zanamivir ||Headache, nausea, diarrhea, cough, bronchospasm, decline in lung function (some fatal outcomes) |
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).
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).
Hemorrhagic vesicular lesions of herpes zoster.
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.
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).
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).
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).
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 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).
Typical cytomegalovirus inclusions in the lung parenchyma of a patient with lymphoma with pneumonia.
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 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).
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 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).
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).
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.
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 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.
Management of RSV infection after hematopoietic stem cell transplantation. ID, infectious disease; IVIG, intravenous immunoglobulin; RSV, respiratory syncytial virus SPAG, small particle aerosol generator; BAL, bronchoalveolar lavage.
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 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).
Management of hepatitis C viral infection. IFN, pegylated IFN; RBV, ribavirin; DAA, direct-acting antivirals.
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.
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.
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.
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 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
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).
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.