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F. Khawaja et al.
had a higher intensive care unit mortality rate, with the association being strongest when influenza, parainfluenza or RSV was detected.10
Treatment options for respiratory syncytial virus infection in patients with hematologic malignancies and in hematopoietic cell transplant recipients
The current treatments for RSV infections in immuno- compromised adult patients are ribavirin, in different for- mulations [although it has not been approved by the Food and Drug Administration (FDA) for this purpose], and immuno-modulators, such as conventional IVIG or RSV monoclonal antibodies (palivizumab).
Ribavirin
Ribavirin is a nucleoside analog that is active against a broad spectrum of RNA viruses. It acts through intercala- tion into the RNA virus, enhancing its mutation rate. Ribavirin is available in aerosolized, oral, and intravenous formulations. Aerosolized ribavirin was approved by the FDA for the treatment of RSV LRTI in hospitalized infants and young children in 1985 and is the most studied formu- lation in HCT recipients.4,5,24,42,44,45,49,53,58,71-77 The conventional dosing regimen is 6 g delivered over 18 h through a small particle aerosol generator, with patients in a scavenger tent to decrease environmental contamination and expo- sure to healthcare workers (ribavirin is teratogenic). In an alternative regimen, the same total dose of ribavirin is given but is divided into three doses per day (2 g over 3 h, 3 times a day). This intermittent regimen was shown to be equivalent to the conventional continuous regimen in an adaptive randomized trial.78
Most of the studies on the use of ribavirin for RSV infec- tions in HCT recipients and HM patients are retrospective in nature, lacking a comparison or control group.26,45,73,74,79,80 Yet cumulative evidence, albeit not from clinical trials, suggests a better outcome when ribavirin is used in HCT recipients with early disease or URTI.4,46,71,78,81-83 A decrease in the rate of progression from RSV URTI to LRTI after aerosolized ribavirin therapy in HCT recipients with RSV infections was pronounced (from 59% to 20%) in one study.4 A randomized control trial that was halted before completing enrollment for different reasons, including slow accrual, showed a trend towards a lower rate of pro- gression to LRTI when aerosolized ribavirin was used.71 Of the nine patients who were treated with ribavirin, only one experienced progression compared to two of the five patients who were not treated.
A systemic review of the treatment of RSV infections in adult HCT recipients showed an overall reduction in the rate of progression to LRTI, from 45% to 16%, and a reduction in the rate of RSV-related mortality in patients with LRTI, from 70% to 35%, after early treatment with aerosolized ribavirin.84 In the largest retrospective study to date of the impact of aerosolized ribavirin therapy in HCT recipients (n=280) with RSV infections,42 early ribavirin therapy at the URTI stage reduced the risk of progression to LRTI. In addition, a lack of ribavirin therapy was asso- ciated with an increased mortality rate (odds ratio: 2.4).
Data on the use of ribavirin in HM patients with RSV infections are limited. Several retrospective studies demonstrated that early use of aerosolized ribavirin
reduced the mortality rate in leukemia patients with RSV infections.57,58 A large retrospective study of 181 HM patients showed better outcomes with aerosolized rib- avirin.37 On the other hand, Vakil et al. found that ribavirin use, at either the URTI or LRTI stage, did not reduce over- all mortality,38 but the objective of this study was to assess risk factors for mortality and not the role of ribavirin in HM patients. Although some of these studies showed a positive trend towards a benefit from therapy with rib- avirin, specific recommendations cannot be made at pres- ent.
Despite our experience with aerosolized ribavirin for the treatment of RSV infections in adult HCT recipients and its increase in popularity over the years, a major shift to the oral formulation occurred around 3 years ago, at least at our institution, when the cost of ribavirin increased drastically.85 Oral ribavirin has been used to treat RSV URTI or LRTI in both HCT recipients and HM patients.79,81,82,86-88 The dosing regimens vary between a weight-based regimen of 15 mg/kg to 60 mg/kg to a stan- dardized dosage of 600 mg-800 mg twice daily or 600 mg three times daily for a maximum of 1800 mg/day. Oral rib- avirin is more readily available than is aerosolized rib- avirin and is well tolerated, on the basis of data on its long- term use in patients with hepatitis C virus infections.89 In a retrospective analysis of our experience with aerosolized ribavirin and the recent switch to oral ribavirin, we found no significant differences in outcomes, including progres- sion to LRTI and day 30 or 60 all-cause mortality, in HCT recipients with RSV infections.90 On the basis of the results of a recent analysis, we propose the use of oral ribavirin as a viable alternative to aerosolized ribavirin (Figure 1). At our institution, we implemented a decision-making treat- ment algorithm as guidance for our clinical providers. HCT recipients are stratified on the basis of their RSV-ISI score and stage of RSV diagnosis (URTI vs. LRTI).
Side effects associated with oral and aerosolized rib- avirin have been reported in prior publications. One of the common side effects associated with aerosolized ribavirin is that patients often complained of feeling “lonely’ and seeing “hail” while they were in the scavenger tent.57 There have been a few reports of hepatotoxicity associat- ed with the use of aerosolized ribavirin.76,91 In a random- ized, placebo-controlled trial assessing the use of aerosolized ribavirin for the treatment of RSV in HCT recipients, the rates of hepatotoxicity were similar in the two groups, although the sample size was small;71 no other side effects were noted in the trial. Hepatotoxicity was reported in association with the use of oral ribavirin for the treatment of hepatitis C virus.92 However, the observed hepatotoxicity was probably due to the co- administration of interferon therapy.92 In a retrospective study assessing the use of oral ribavirin in immunocom- promised patients, including HCT recipients,79 only one of the 38 patients who received oral ribavirin developed hemolytic anemia and lactic acidosis. The latter was thought to be due to severe gastrointestinal graft-versus- host disease. In a recent retrospective analysis comparing outcomes of HCT recipients with RSV infections who received either aerosolized or oral ribavirin,90 two of 29 (6.9%) patients on oral ribavirin developed new-onset grade 3 or more anemia at day 14 compared to two of 41 (4.9%) patients who received the aerosolized formulation. These studies demonstrate that both aerosolized and oral ribavirin have similar safety profiles.
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haematologica | 2019; 104(7)