Community respiratory viruses (CRVs) have been recognized as a potential cause of pneumonia and death among hematopoietic stem cell transplantation (HSCT) recipients and patients with hematologic malignancies. We reviewed the Microbiology Laboratory records dated from July 1, 2000, to June 30, 2002, to identify patients who had respiratory specimens positive for influenza, parainfluenza, respiratory syncytial virus, or picornavirus. We identified 343 infections among patients with underlying hematologic malignancies and HSCT. We collected data on type of disease, age, sex, type of infection, neutrophil and lymphocyte counts, therapy, and outcome. Influenza, parainfluenza, and respiratory syncytial virus accounted for most cases and were approximately equal in frequency. Most infections occurred predominantly among recipients of allogeneic transplants. Infection progressed to pneumonia in 119 patients (35%) and occurred with similar frequency for the 3 viruses. Patients at greatest risk for developing pneumonia included those with leukemia, those aged more than 65 years, and those with severe neutropenia or lymphopenia. Lack of respiratory syncytial virus-directed antiviral therapy (p = 0.025) and age (p = 0.042) were associated with development of respiratory syncytial virus pneumonia, and an absolute lymphocyte count ≤200 cells/mL (p = 0.049) was associated with development of influenza pneumonia. The overall mortality rate for CRV pneumonia was 15%. The only independent predictor of fatal outcome was an absolute lymphocyte count ≤200 cells/mL (p = 0.03) in patients with influenza pneumonia. HSCT recipients and patients with hematologic malignancies who develop upper respiratory infection due to CRVs should be considered for antiviral therapy of proven efficacy to reduce the risk of pneumonia and death.

Despite advances in preventive strategies, cytomegalovirus (CMV) infection remains a major complication in solid organ and hematopoietic cell transplant recipients. CMV infection may fail to respond to commercially available antiviral therapies, with or without demonstrating genotypic mutation(s) known to be associated with resistance to these therapies. This lack of response has been termed “resistant/refractory CMV” and is a key focus of clinical trials of some investigational antiviral agents. To provide consistent criteria for future clinical trials and outcomes research, the CMV Resistance Working Group of the CMV Drug Development Forum (consisting of scientists, clinicians, regulatory officials, and industry representatives from the United States, Canada, and Europe) has undertaken establishing standardized consensus definitions of “resistant” and “refractory” CMV. These definitions have emerged from the Working Group’s review of the available virologic and clinical literature and will be subject to reassessment and modification based on results of future studies.

Despite preventive strategies and increased awareness, a high incidence of respiratory viral infections still occur in patients with hematologic malignancies (HMs) and in recipients of hematopoietic cell transplant (HCT). Progression of these viral infections to lower respiratory tract may prove fatal, especially in HCT recipients. Increasing evidence on the successful use of ribavirin (alone or in combination with immunomodulators) for the treatment of respiratory syncytial virus infections in HM patients and HCT recipients is available from retrospective studies; however, prospective clinical trials are necessary to establish its efficacy with confidence. The impact on progression to pneumonitis and/or mortality of treating parainfluenza virus infections with available (ribavirin) or investigational (DAS181) antiviral agents still needs to be determined. Influenza infections have been successfully treated with neuraminidase inhibitors (oseltamivir or zanamivir); however, the efficacy of these agents for influenza pneumonia has not been established, and immunocompromised patients are highly susceptible to emergence of antiviral drug resistance, most probably due to prolonged viral shedding. Infection control measures and an appreciation of the complications following respiratory viral infections in immunocompromised patients remain crucial for reducing transmission. Future studies should focus on strategies to identify patients at high risk for increased morbidity and mortality from these infections and to determine the efficacy of novel or available antiviral drugs.

Cytomegalovirus (CMV) infection is a significant complication in hematopoietic cell transplantation (HCT) recipients. Four antiviral drugs are used for preventing or treating CMV: ganciclovir, valganciclovir, foscarnet, and cidofovir. With prolonged and repeated use of these drugs, CMV can become resistant to standard therapy, resulting in increased morbidity and mortality, especially in HCT recipients. Antiviral drug resistance should be suspected when CMV viremia (DNAemia or antigenemia) fails to improve or continue to increase after 2 weeks of appropriately dosed and delivered antiviral therapy. CMV resistance is diagnosed by detecting specific genetic mutations. UL97 mutations confer resistance to ganciclovir and valganciclovir, and a UL54 mutation confers multidrug resistance. Risk factors for resistance include prolonged or previous anti-CMV drug exposure or inadequate dosing, absorption, or bioavailability. Host risk factors include type of HCT and degree of immunosuppression. Depending on the genotyping results, multiple strategies can be adopted to treat resistant CMV infections, albeit no randomized clinical trials exist so far, after reducing immunosuppression (if possible): ganciclovir dose escalation, ganciclovir and foscarnet combination, and adjunct therapy such as CMV-specific cytotoxic T-lymphocyte infusions. Novel therapies such as maribavir, brincidofovir, and letermovir should be further studied for treatment of resistant CMV.

Adenovirus infection in immunocompromised patients contributes to significant morbidity and mortality, especially after allogeneic hematopoietic cell transplantation (HCT). Brincidofovir (BCV, CMX001) is an orally bioavailable lipid conjugate of cidofovir that has in vitro activity against adenoviruses and other double-stranded DNA viruses. This randomized placebo-controlled phase II trial evaluated pre-emptive treatment with BCV for the prevention of adenovirus disease in pediatric and adult allogeneic HCT recipients with asymptomatic adenovirus viremia. Allogeneic HCT recipients with adenovirus viremia were randomized 1:1:1 to receive oral BCV 100 mg (2 mg/kg if <50 kg) twice weekly (BIW), BCV 200 mg (4 mg/kg if <50 kg) once weekly (QW), or placebo for 6 to 12 weeks, followed by 4 weeks of post-treatment follow-up. For randomization, subjects were stratified by screening absolute lymphocyte count (<300 cells/mm3 versus ≥300 cells/mm3). Assignment to BCV or placebo was double blinded; dose frequency was unblinded. The primary endpoint was the proportion of subjects experiencing treatment failure, defined as either progression to probable or definitive adenovirus disease or confirmed increasing adenovirus viremia (≥1 log10 copies/mL) during randomized therapy. Between June 2011 and December 2012, 48 subjects were randomized to the BCV BIW (n = 14), BCV QW (n = 16), or placebo (n = 18) groups. The proportion of subjects with treatment failure in the BCV BIW group was 21% (odds ratio, .53; 95% confidence interval [CI], .11 to 2.71; P = .45), 38% (odds ratio, 1.23; 95% CI, .30 to 5.05, P = .779) in the BCV QW group, and 33% in the placebo group. All-cause mortality was lower in the BCV BIW (14%) and BCV QW groups (31%) relative to the placebo group (39%), but these differences were not statistically significant. After 1 week of therapy, 8 of 12 subjects (67%) randomized to BCV BIW had undetectable adenovirus viremia (<100 copies/mL), compared with 4 of 14 subjects (29%) randomized to BCV QW and 5 of 15 subjects (33%) randomized to placebo. In a post hoc analysis of subjects with viremia ≥1000 copies/mL at baseline, 6 of 7 BCV BIW subjects (86%) achieved undetectable viremia compared with 2 of 8 placebo subjects (25%; P = .04). Early treatment discontinuation because of adverse events was more common in subjects treated with BCV than with placebo. Diarrhea was the most common event in all groups (57% BCV BIW, 38% BCV QW, 28% placebo), but it led to treatment discontinuation in only 1 subject receiving BCV QW. Events diagnosed as acute graft-versus-host disease, primarily of the gastrointestinal tract, were more frequent in the BCV BIW group (50%) than in the BCV QW (25%) and placebo (17%) groups. There was no evidence of myelotoxicity or nephrotoxicity in BCV-treated subjects. The results of this trial confirm the antiviral activity of BCV against adenoviruses. Further investigation is ongoing to define the optimal treatment strategy for HCT recipients with serious adenovirus infection and disease.

Key Points: An immunodeficiency scoring index for RSV-infected hematopoietic cell transplant recipients predicts the risk of pneumonia and death. This scoring index would assist in the decision-making for initiating antiviral therapy in patients at high risk for poor outcomes.