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RSV in HCT and hematologic malignancies
ease in HCT recipients and HM patients with RSV infec- tions.37,53,58 The protective benefits of ribavirin are dis- cussed further in the treatment section.
Long-term complications of respiratory syncytial virus infection
Certain long-term complications after RSV infection have been described in HCT recipients, with the most widely described long-term complication being a reduc- tion in pulmonary function.24,43,59-61 Delayed engraftment after RSV infection is less commonly described, with an uncertain association in small numbers of patients.45,46,62
A decrease in forced expiration in 1 second (FEV1) by more than 5% from baseline after HCT has been associat- ed with poor outcomes.63 In fact, previous studies have shown that a decrease in FEV1 of 10% or greater is associ- ated with the development of bronchiolitis obliterans.64 However, the relationship between respiratory viruses (RSV in particular) and changes in FEV1 or other markers of pulmonary function is not fully understood.
There are limited data on HCT recipients and pul- monary function (including changes in FEV1 and oxygen diffusion capacity) after an RSV infection. Avetisyan et al. showed that, compared to a control group, HCT recipi- ents with RSV infections were more likely to develop mild or marked changes in vital capacity or diffusion capacity during pulmonary function tests.24 Subsequently, Seo et al. described significant decreases in patients’ diffusion capacity 3 months after RSV infection, which persisted for a year.43 There were some indications that FEV1 and total lung capacity were also affected, but the sample size was too small to draw definite conclusions. Another study compared the effects of different viruses on pulmonary function in HCT recipients;60 RSV and parainfluenza were associated with FEV1 decreases of at least 10%. It was pos- tulated that subclinical shedding of these viruses may aug- ment airway inflammation, leading to airway restriction. In comparison, lung transplant recipients who are infected with respiratory viruses are at increased of risk of develop- ing bronchiolitis obliterans, with an associated mortality of up to 29%.65 Similarly, HCT recipients with prior respi- ratory viral infections were more likely to develop bron- chiolitis obliterans or changes in FEV1,59,66 with a higher mortality rate than that of patients without bronchiolitis obliterans (HR: 2.7).59
Delayed or failed engraftment of stem cells during or after acute RSV infection has been reported; however, it is an uncommon complication with a total of only seven patients having been described in a few case series.45,46,62 This association was first described in 1999 by McCarthy et al., who noted that four patients with graft failure had had an RSV infection in the pre-engraftment period,45 with no other identified infections. Furthermore, during an RSV outbreak in a hematologic unit in Australia, delayed neu- trophil and platelet engraftment occurred in two autolo- gous HCT recipients and graft failure occurred in one allo- geneic HCT recipient with an RSV infection.62 On the other hand, a study by Waghmare et al. showed no signif- icant changes in lymphocyte count dynamics in HCT recipients who experienced progression to RSV LRTI com- pared to patients who did not.46 Overall, there are very limited data supporting that RSV infection per se leads to graft failure or contributes to a delay in engraftment.
Mortality and associated risk factors
High mortality rates have been reported in HM patients and HCT recipients with RSV infection. RSV-attributable mortality rates in HCT recipients vary between 0% in outbreak situations,48,62,67 in which some patients received reduced-intensity conditioning regimens,62 and 43% in other circumstances.5,20,22,24,25,42-51 When HCT recipients develop RSV LRTI, the mortality rate can range from 21% to 83%4,31,42,43,45,46,48,68 Of note, when HCT recipients with RSV infections were classified into those with possible RSV LRTI (only radiological evidence of chest abnormali- ties and negative or no bronchoscopy data) or proven RSV LRTI (RSV detected in the lower respiratory tract),31 the mortality rate increased from 0% to 26%, respectively.31 Multiple other risk factors for mortality from RSV have been identified, most of which are host-related, including neutropenia and lymphopenia, time from transplant to infection, cell source, older age, steroid exposure, graft-ver- sus-host disease, hypoxia, and the use of myeloablative chemotherapy.25,42,43,46,47 The RSV-ISI has been validated to predict mortality risk in HCT recipients12,53,56 (Table 2). Based on the derivative cohort of allogeneic HCT recipi- ents with RSV infections, the predicted mortality for patients with high RSV-ISI was 29%53 and 50% in one of the validation cohorts.44 Interestingly, some studies showed that ribavirin may have a protective effect in HCT recipients and HM patients.37,42,44,53,58 This is discussed fur- ther in the treatment section.
Delaying transplant in patients diagnosed with RSV or other respiratory viruses prior to HCT was shown to improve survival.69 Campbell et al. reviewed 116 patients who had pre-transplant respiratory viral infections and found that, regardless of the virus, they had a higher 100- day mortality rate than did those without infections.70 At our institution, HCT is delayed for approximately 2 weeks when patients are diagnosed with RSV infections prior to transplantation.
Among HCT recipients with RSV infections, mortality was considerably lower in pediatric patients than in adults. Mortality varied from 0 to 5% among all pediatric HCT recipients with RSV infections39-41 and is higher in patients with LRTI (up to 15%).
The mortality rate amongst HM patients with RSV can be as high as 18%.4,50 The mortality rate in a small study conducted in the mid-1990s was 80% among leukemia patients with RSV LRTI who had recently undergone myelosuppressive chemotherapy.57 More recent studies of HM patients with RSV LRTI found mortality rates of 8% to 17%37,38,58 This better outlook could be explained in part by the improvement in supportive care over the years and the use of ribavirin for the treatment of RSV in this popu- lation of patients.37,58 Risk factors associated with mortality in RSV-infected leukemia patients include neutropenia (≤500 neutrophils/mL), lymphopenia (≤200 lympho- cytes/mL), and a high APACHE II score at diagnosis.37,58 These host factors reflect the patients’ immune status and its ability to curtail the impact of RSV infections. The severity and stage of the infection (URTI vs. LRTI) or the virulence of the RSV may also affect mortality. In HM patients with proven LRTI, the 30-day mortality rate was reported to be 36% compared to 14% in patients with possible LRTI.38 In a recent retrospective analysis, patients with HM, including HCT recipients, in whom respiratory viral infections were detected in the intensive care unit
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