key: cord-0003900-4fx18mlj
authors: Khawaja, Fareed; Chemaly, Roy F.
title: Respiratory syncytial virus in hematopoietic cell transplant recipients and patients with hematologic malignancies
date: 2019-07-03
journal: Haematologica
DOI: 10.3324/haematol.2018.215152
sha: 1f263aae1c1dcc053a85fc4444f0bc02a01e5b68
doc_id: 3900
cord_uid: 4fx18mlj

In the USA and other western nations, respiratory syncytial virus is one of the most commonly encountered respiratory viruses among patients who have been diagnosed with a hematologic malignancy or who have undergone a stem cell transplant. Multiple studies have been performed to evaluate the complications associated with respiratory syncytial virus infections. Other studies have evaluated therapeutic agents and strategies in which these agents can be used. There have also been numerous reports of outbreaks in bone marrow transplant units and oncology wards, where infection control measures have been invaluable in controlling the spread of disease. However, despite these novel approaches, respiratory syncytial virus continues to be potentially fatal in immunocompromised populations. In this review, we discuss the incidence of respiratory syncytial viral infections, risk factors associated with progression from upper respiratory tract infection to lower respiratory tract infection, other complications and outcomes (including mortality), management strategies, and prevention strategies in patients with a hematologic malignancy and in hematopoietic cell transplant recipients.

I n the USA and other western nations, respiratory syncytial virus is one of the most commonly encountered respiratory viruses among patients who have been diagnosed with a hematologic malignancy or who have undergone a stem cell transplant. Multiple studies have been performed to evaluate the complications associated with respiratory syncytial virus infections. Other studies have evaluated therapeutic agents and strategies in which these agents can be used. There have also been numerous reports of outbreaks in bone marrow transplant units and oncology wards, where infection control measures have been invaluable in controlling the spread of disease. However, despite these novel approaches, respiratory syncytial virus continues to be potentially fatal in immunocompromised populations. In this review, we discuss the incidence of respiratory syncytial viral infections, risk factors associated with progression from upper respiratory tract infection to lower respiratory tract infection, other complications and outcomes (including mortality), management strategies, and prevention strategies in patients with a hematologic malignancy and in hematopoietic cell transplant recipients.

Community respiratory viruses are a common cause of respiratory infections. [1] [2] [3] These viruses are perhaps best known for their seasonal variation. The outcomes of these infections vary on the basis of the patient population, with adverse outcomes having been described in hematopoietic cell transplant (HCT) recipients and patients with a hematologic malignancy (HM). [4] [5] [6] [7] [8] [9] One of the most common community respiratory viruses that may lead to the death of HCT recipients and HM patients is respiratory syncytial virus (RSV), 4-10 whose incidence is second only to that of influenza according to prior reports; 4, 5, 8, 11, 12 other viruses include parainfluenza virus, metapneumovirus, adenovirus, rhinovirus, and bocavirus. Different strategies have been used for the management of RSV infections in immunocompromised patients, and HCT recipients in particular, including ribavirin in its different formulations, intravenous immunoglobulins (IVIG), RSV immunoglobulins, and RSV monoclonal antibodies. 6 In addition, effective measures have been used to curtail outbreaks of RSV infection in numerous bone marrow transplantation units and oncology wards, with some success; [13] [14] [15] [16] [17] [18] [19] however, despite some advances over the past two decades in early detection and management of RSV infections in immunocompromised patients, the outcomes related to these infections remain poor.

In this review, we summarize the published data on RSV infections in adult HCT recipients and HM patients, focusing on recent findings. We highlight the incidence of RSV infections, risk factors associated with progression from upper respiratory tract infection (URTI) to lower respiratory tract infection (LRTI), other complications and outcomes (including mortality), management strategies including new agents under investigation, and prevention strategies. 30% to 37% of respiratory viral infections in this population, with approximately 19% to 36% of these infections resulting in LRTI. 4, 20 Determination of the true incidence of RSV infection among HCT recipients has been challenging, with a reported wide range of 5% to 49%, 5, 8, 18, [21] [22] [23] [24] [25] [26] [27] [28] as many studies included symptomatic patients diagnosed with different laboratory assays such as RSV antigen detection, identification of RSV by direct florescent antibody, viral cultures, and molecular assays in recent years (Table 1 ). In addition, the wide range of reported incidences of RSV infections could be due to the increased awareness of this virus over the years and its impact on immunocompromised patients. On the other hand, lower incidences of RSV infections were reported in studies in which molecular assays such as multiplex polymerase chain reaction were used to detect RSV, with the reported range in these cases being 8-30%. 8, 9, 29 This lower incidence could be explained by the increased rate of diagnosing other respiratory viruses, such as coronavirus, rhinovirus, and parainfluenza, with the use of molecular assays.

The proportion of RSV infections causing LRTI in HCT recipients ranges from 30% to 60% with higher rates reported in earlier years (in the early 1990s), 5, 21, 22 whereas in more recent studies, since year 2000, lower rates of LRTI (24-44%) have been observed. 4, 11, [23] [24] [25] 29, 30 This could possibly be explained by the increased use of ribavirin at earlier stages of RSV infection to prevent the infection from progressing to the lower respiratory tract, as well as the use of molecular assays for the detection not only of RSV but also other respiratory viruses. Recent studies from the Fred Hutchinson Cancer Research Center on respiratory viral infections in HCT patients applied specific definitions to better delineate the types of LRTI associated with respiratory viral infections. 31 Patients with proven or probable LRTI were defined as patients with microbiological detection of respiratory viruses in the lower respiratory tract with or without radiological evidence of disease in the lungs, respectively. Patients with possible LRTI were defined as patients with microbiological detection of respiratory viruses in the upper respiratory tract only and with radiological evidence of disease in the lungs. 31 In one of the studies, the proportions of patients with proven/probable or possible RSV LRTI were 48% and 52%, respectively. 31 Interestingly, the authors showed that patients with proven or probable LRTI had a higher need for supplemental oxygen use and for mechanical ventilation compared to those with possible LRTI. These definitions were also applied in studies on coronavirus, 32 parainfluenza virus 33 and rhinovirus. 34 Data on RSV infections in HM patients are scarce. Some studies have reported the rate of RSV infections in these patients. 4, 28, 29, [35] [36] [37] In an early study, the incidence of RSV was 31% among all symptomatic HM patients, including HCT recipients. A large proportion of these infections were diagnosed as LRTI (36%). 29 Similar studies reported a range of 3% to 37%, but the sample sizes were relative- ly small. 28, 35, 36 In a recent study, 181 HM patients with RSV infections were identified over 13 years. 37 Of these, 65% and 35% presented with URTI and LRTI, respectively. Among the HM patients with URTI, 13% progressed to develop a LRTI (73% were patients with leukemia, 27% with multiple myeloma, and none with lymphoma). 37 In a recent study from our institution focusing on RSV LRTI in HM patients who had or had not undergone HCT, we found that most HM patients who had not undergone HCT were defined as having possible RSV LRTI as bronchoscopy had not been performed in most of these patients at the time of diagnosis. 38 Few data are available with regards to RSV infections in pediatric HCT recipients. The estimated incidence of RSV infections among this population is 3% to 7%, 39, 40 with 22%-37% 39,41 developing LRTI.

The most significant complication of RSV infection in HM patients and HCT recipients is progression to LRTI, which is associated with a higher mortality rate. 5, 20, 22, 24, 25, [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] Many risk factors for progression have been identified in the hopes that target populations that could benefit from early therapy could be identified. These risk factors primarily consist of host factors, as previous studies on RSV serotypes A and B found no differences in outcomes. 35, 52 To assist with the identification of HCT recipients who are at risk of progression to LRTI and a fatal outcome, an Immunodeficiency Scoring Index (ISI) for RSV was developed based on a combination of multiple host risk factors, 53 which means it is applicable to other respiratory viruses. Six factors were included in the scoring index: neutropenia of less than 500 neutrophils/mL, lymphopenia of less than 200 lymphocytes/mL, age greater than 40 years, graft-versus-host disease, steroid use, myeloablative chemotherapy, and time from HCT. 53 On the basis of the total score, the ISI stratifies HCT recipients with RSV URTI into low-risk (score of 0-2), medium-risk (score of 3-6), and high-risk (score of 7-12) categories. 53 Other risk factors that were identified in other studies and were not included in the ISI were smoking status, 54 hypoxia, 28 nosocomial infection, 28,37 matched unrelated donor/mismatched donor status, 25, 42, 55 prior autologous HCT, and stem cell source 25, 28 (Table 2 ). The ISI for RSV has been validated by other authors 12, 56 (Table 3) . Wang et al. found that allogenic HCT recipients with high ISI scores experienced progression to pneumonia after being diagnosed with RSV, influenza, coronavirus, or adenovirus. 12 There is currently no predictive scoring index for the progression of respiratory viruses in patients with leukemia, lymphoma, or multiple myeloma. On the other hand, there are well-described risk factors that are associated with progression to LRTI in HM patients; these include lymphopenia and neutropenia, 4, 28, 37, 54, 55, 57 which are generally defined as ≤200 lymphocytes/mL 37, 54, 57 and ≤500 neutrophils/mL, respectively .In multiple retrospective analyses of HCT recipients, lymphocytopenia 4,37,54,57 and neutropenia 4, 37, 54, 57 at the time of the diagnosis of RSV were independent predictors of progression to LRTI.

In a cohort of 237 allogeneic HCT recipients with RSV infection, the hazard ratio (HR) of experiencing progression from RSV URTI to LRTI was 4.1 for an absolute neutrophil count of <500 cells/mL and 2.6 for an absolute lymphocyte count of <200 cells/mL, 53 making them the most predictive factors for progression. 53 Among leukemia patients, post-induction chemotherapy neutropenia and leukopenia have also been shown to increase the risk of progression to LRTI. 22, 24 In a recent retrospective study, neutropenia and lymphopenia were not independently associated with progression of disease in HM patients, but the combination of the two factors was associated with a higher risk of progression. 37 However, time from last chemotherapy was not shown to play a role in progression to LRTI in HM patients. 37 On the other hand, lack of ribavirin therapy was associated with progression of dishaematologica | 2019; 104(7) 37, 53, 58 The protective benefits of ribavirin are discussed further in the treatment section.

Certain long-term complications after RSV infection have been described in HCT recipients, with the most widely described long-term complication being a reduction in pulmonary function. 24, 43, [59] [60] [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 (FEV 1 ) by more than 5% from baseline after HCT has been associated with poor outcomes. 63 In fact, previous studies have shown that a decrease in FEV 1 of 10% or greater is associated with the development of bronchiolitis obliterans. 64 However, the relationship between respiratory viruses (RSV in particular) and changes in FEV 1 or other markers of pulmonary function is not fully understood.

There are limited data on HCT recipients and pulmonary function (including changes in FEV 1 and oxygen diffusion capacity) after an RSV infection. Avetisyan et al. showed that, compared to a control group, HCT recipients 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 FEV 1 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 FEV 1 decreases of at least 10%. It was postulated that subclinical shedding of these viruses may augment airway inflammation, leading to airway restriction. In comparison, lung transplant recipients who are infected with respiratory viruses are at increased of risk of developing bronchiolitis obliterans, with an associated mortality of up to 29%. 65 Similarly, HCT recipients with prior respiratory viral infections were more likely to develop bronchiolitis obliterans or changes in FEV 1 , 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 neutrophil and platelet engraftment occurred in two autologous HCT recipients and graft failure occurred in one allogeneic HCT recipient with an RSV infection. 62 On the other hand, a study by Waghmare et al. showed no significant changes in lymphocyte count dynamics in HCT recipients who experienced progression to RSV LRTI compared 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.

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] [43] [44] [45] [46] [47] [48] [49] [50] [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 abnormalities 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-versus-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 recipients 12, 53, 56 (Table 2) . Based on the derivative cohort of allogeneic HCT recipients 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 further 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 100day 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 infections [39] [40] [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 population of patients. 37, 58 Risk factors associated with mortality in RSV-infected leukemia patients include neutropenia (≤500 neutrophils/mL), lymphopenia (≤200 lymphocytes/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 had a higher intensive care unit mortality rate, with the association being strongest when influenza, parainfluenza or RSV was detected. 10

The current treatments for RSV infections in immunocompromised adult patients are ribavirin, in different formulations [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 is a nucleoside analog that is active against a broad spectrum of RNA viruses. It acts through intercalation 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 formulation in HCT recipients. 4, 5, 24, 42, 44, 45, 49, 53, 58, [71] [72] [73] [74] [75] [76] [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 exposure 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 infections 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] [82] [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 progression 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 associated 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 ribavirin. 37 On the other hand, Vakil et al. found that ribavirin use, at either the URTI or LRTI stage, did not reduce overall 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 ribavirin, specific recommendations cannot be made at present.

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] [87] [88] The dosing regimens vary between a weight-based regimen of 15 mg/kg to 60 mg/kg to a standardized dosage of 600 mg-800 mg twice daily or 600 mg three times daily for a maximum of 1800 mg/day. Oral ribavirin is more readily available than is aerosolized ribavirin and is well tolerated, on the basis of data on its longterm 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 progression 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 treatment 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 ribavirin 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 associated with the use of aerosolized ribavirin. 76, 91 In a randomized, 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 coadministration of interferon therapy. 92 In a retrospective study assessing the use of oral ribavirin in immunocompromised 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-versushost 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.

Intravenous ribavirin has been used to treat RSV infection in HCT recipients. 24, 45, 49, 80 The most common regimen used is a single 33 mg/kg loading dose, followed by 16 mg/kg four times a day for 4 days with a maintenance dose of 8 mg/kg three times a day until symptoms resolve. The intravenous formulation of ribavirin is not readily available in the USA due to the lack of FDA approval; however, it can be acquired through the FDA for emergency or compassionate use.

Many immunomodulators have been used as adjunctive therapy for RSV infections in adult HM patients and HCT recipients. There have been no randomized control trials comparing the benefits of adding IVIG to ribavirin therapy. Many retrospective analyses have reported variable results for this combination. 22, 42, 45, 46, 49, 53, 85, 93, 94 Shah et al. suggested a minimal benefit in HCT recipients with RSV infections; 42 all 51 HCT patients who were treated with combination therapy survived, and only one of 61 patients treated with ribavirin alone died. This was not evaluated in multivariate analysis. Another study showed no clinical benefit in HCT recipients who received weekly or highdose IVIG as adjunctive therapy for RSV infections. 46 It was hypothesized that humanized IVIG lacks sufficient specific antibodies to RSV, which would explain the mixed results seen in retrospective studies.

RSV-specific monoclonal antibodies, such as palivizumab, have also been evaluated for the treatment of RSV infections in HCT recipients and HM patients. Originally, palivizumab was approved for the prevention of RSV infections in neonates and children. Experience with palivizumab as treatment in HCT recipients with RSV is very limited. Several studies showed no survival benefit when comparing palivizumab as adjunctive therapy to ribavirin as monotherapy for RSV infections in adult HCT recipients. 42, 46, 83, 95, 96 In a recent retrospective study of a mixed population of adult HCT recipients and patients with HM, 97 those treated with palivizumab for RSV infections showed a trend towards better 90-day survival compared to the control group, with mortality rates of 11% compared to 17%, respectively. 97 However, this difference was not statistically significant and recommendations for the routine use of palivizumab in this population of patients cannot be made.

As previously discussed, there are limited therapeutic options for RSV infections and new therapies are desperately needed. Presatovir is an oral RSV fusion inhibitor with selective anti-RSV activity in vitro. In a phase I, firstin-human, single-and multiple-ascending dose study, 98 presatovir had an excellent safety profile, despite having an extended half-life. The oral bioavailability was also good, regardless of prandial state. 98 Although clinical trials on RSV infections in transplant recipients have been challenging due to low recruitment, 71 two phase II trials on presatovir in HCT recipients with RSV infections were recently completed 99, 100 (ClinicalTrials.gov number NCT02254408). To overcome potential low recruitment, 189 HCT recipients with RSV infections limited to the upper respiratory tract were recruited from a total of 43 centers in nine countries over 2.5 years. 99, 100 Preliminary data showed that presatovir was not effective at reducing nasal RSV viral load over time or at reducing the incidence of lower respiratory tract complications. However, in an exploratory analysis, presatovir did reduce the rate of progression to lower respiratory tract complications in patients with lymphopenia relative to the rate in placebotreated patients. Furthermore, presatovir was not effective at reducing nasal RSV viral load, supplemental oxygen use or all-cause mortality in another phase II trial in HCT recipients with RSV LRTI. 99, 100 Several lessons were learned from the two trials. HCT recipients with one or more risk factors (i.e. lymphopenia, neutropenia, or infected within a year from transplant) for poorer outcomes from RSV infections may benefit the most from an effective antiviral therapy. On the other hand, time from symptom onset and time before the development of lower respiratory tract complications are probably critical factors in determining the effectiveness of fusion inhibitors.

The development of another novel agent, ALX-0171, was recently stopped and the drug may not enter clinical trials on RSV infections in HCT recipients. This inhaled agent is a trivalent nanobody that inhibits RSV replication by binding the F-protein on the surface of the virus and thereby neutralizes RSV by blocking virus uptake into cells. A recent phase 1 trial in infants with RSV infections was prematurely terminated due to lack of efficacy (ClinicalTrials.gov identifier: NCT03418571).

The prevention of RSV in HM patients and HCT recipients is limited to infection control measures and interventions. There are many reports of outbreaks in these popu-lations of patients, [13] [14] [15] [16] [17] [18] 101, 102 and the emphasis has been on multifaceted interventions, including compliance with hand hygiene, contact precautions with gowns and the use of gloves, screening visitors and healthcare workers for respiratory symptoms and restricting visitors and healthcare workers if they are symptomatic, grouping RSV-infected patients together, and sometimes screening asymptomatic patients in the same treatment areas. These interventions have been shown to be effective in mixed adult and pediatric patients. 19, 103, 104 At our institution, we place all patients diagnosed with respiratory viral infections on contact and droplet precautions. 105 Interestingly, the use of chemoprophylaxis with palivizumab was described during an outbreak 15 in patients who were at high risk of acquiring RSV infections in a bone marrow transplant ward. Sixteen asymptomatic patients were given one prophylactic dose of palivizumab during the outbreak, and none developed an RSV infection. These results warrant further investigation into the use of palivizumab in an outbreak; however, no definite recommendation can be made at this time. Finally, an RSV vaccine for children or adults is not available at present. Multiple trials in children and healthy adults are in progress (www: ClinicalTrials.gov). Whether immunization for RSV would be beneficial in immunocompromised patients is uncertain.

RSV is a common respiratory viral infection in adult HM patients and HCT recipients. Its incidence is affected by its seasonality and geography and the diagnostic method used. The mortality rate associated with RSV can be high in severely immunocompromised patients with LRTI. The use of an ISI is helpful to stratify HCT recipients into risk categories; a similar scoring system is needed for HM patients. Ribavirin, with or without IVIG, may mitigate the impact of RSV infections in this population of patients. The further development of new antiviral agents or other treatment modalities is of the utmost importance to have a greater impact on rates of progression to LTRI and mortality in adult HM patients and HCT recipients.

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Respiratory syncytial virus pneumonia in hospitalized adult patients with leukemia

Characteristics and outcome of respiratory syncytial virus infection in patients with leukemia

Pulmonary function decline after respiratory viral infection predicts mortality after hematopoietic stem cell transplantation

Airflow decline after myeloablative allogeneic hematopoietic cell transplantation: the role of community respiratory viruses

Symptomatic respiratory virus infection and chronic lung allograft dysfunction

An outbreak of respiratory syncytial virus infection in a bone marrow transplant unit: effect on engraftment and outcome of pneumonia without specific antiviral treatment

Airflow obstruction after myeloablative allogeneic hematopoietic stem cell transplantation

Predictive value of bronchiolitis obliterans syndrome stage 0p in chronic graft-versushost disease of the lung

Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death

Strong association between respiratory viral infection early after hematopoietic stem cell transplantation and the development of lifethreatening acute and chronic alloimmune lung syndromes

Virus infection facilitates the development of severe pneumonia in transplant patients with hematologic malignancies

Respiratory syncytial virus pneumonitis in immunocompromised adults: clinical features and outcome

Pretransplantation respiratory syncytial virus infection: impact of a strategy to delay transplantation

Clinical outcomes associated with respiratory virus detection before allogeneic hematopoietic stem cell transplant

Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients

Severe respiratory syncytial virus pneumonia complicating fludarabine and cyclophosphamide treatment of chronic lymphocytic leukemia

Respiratory syncytial virus upper respiratory tract illnesses in adult blood and marrow transplant recipients: combination therapy with aerosolized ribavirin and intravenous immunoglobulin

Respiratory syncytial virus infection in adult BMT recipients: effective therapy with short duration nebulised ribavirin

Treatment of respiratory syncytial virus infection in adult patients with hematologic malignancies based on an institution-specific guideline

Ribavirin therapy in bone marrow transplant recipients with viral respiratory tract infections

Successful therapy with ribavirin of late onset respiratory syncytial virus pneumonitis complicating allogeneic bone transplantation

An adaptive randomized trial of an intermittent dosing schedule of aerosolized ribavirin in patients with cancer and respiratory syncytial virus infection

Transplant Infectious Diseases Services. Oral ribavirin therapy for respiratory syncytial virus infections in moderately to severely immunocompromised patients

Intravenous ribavirin for eradication of respiratory syncytial virus (RSV) and adenovirus isolates from the respiratory and/or gastrointestinal tract in recipients of allogeneic hematopoietic stem cell transplants

Oral ribavirin for treatment of respiratory syncitial virus and parainfluenza 3 virus infections post allogeneic haematopoietic stem cell transplantation

Successful systemic high-dose ribavirin treatment of respiratory syncytial virusinduced infections occurring pre-engraftment in allogeneic hematopoietic stem cell transplant recipients

Phase I study of intravenous ribavirin treatment of respiratory syncytial virus pneumonia after marrow transplantation

Management of RSV infections in adult recipients of hematopoietic stem cell transplantation

Aerosolized ribavirin: the most expensive drug for pneumonia

Preemptive oral ribavirin therapy of paramyxovirus infections after haematopoietic stem cell transplantation: a pilot study

Effective use of oral ribavirin for respiratory syncytial viral infections in allogeneic haematopoietic stem cell transplant recipients

Oral ribavirin therapy for lower respiratory tract infection of respiratory syncytial virus complicating bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation

Pharmacokinetics and safety of single-dose ribavirin in patients with chronic renal impairment

Oral versus aerosolized ribavirin for the treatment of respiratory syncytial virus infections in hematopoietic cell transplantation recipients

Aerosolized ribavirininduced reversible hepatotoxicity in a hematopoietic stem cell transplant recipient with Hodgkin lymphoma

Therapy of hepatitis C: patients with normal aminotransferase levels

Compassionate use experience with high-titer respiratory syncytical virus (RSV) immunoglobulin in RSV-infected immunocompromised persons

Respiratory syncytial virus pneumonitis-induced diffuse alveolar damage in an autologous bone marrow transplant recipient

Palivizumab treatment of respiratory syncytial virus infection after allogeneic hematopoietic stem cell transplantation

Treatment of respiratory syncytial virus infection in haemopoietic stem cell transplant recipients with aerosolized ribavirin and the humanized monoclonal antibody palivizumab: a single centre experience

Clinical characteristics and treatment outcomes among respiratory syncytial virus (RSV)-infected hematologic malignancy and hematopoietic stem cell transplant recipients receiving palivizumab

Phase 1 first-in-human, single-and multiple-ascending dose, and food effect studies to assess the safety, tolerability, and pharmacokinetics of presatovir for the treatment of respiratory syncytial virus infection

A phase 2b, randomized, double-blind, èlacebo-controlled trial of presatovir (GS-5806) for the treatment of respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in hematopoietic-cell transplantation (HCT) recipients. BMT Tandem Meeting

A phase 2b, randomized, double-blind, placebo-controlled trial of presatovir(GS-5806), an oral fusion inhibitor for the treatment of respiratory syncytial virus (RSV) upper respiratory tract infection (URTI) in hematopoietic-cell transplant (HCT) recipients

Molecular investigations of an outbreak of parainfluenza virus type 3 and respiratory syncytial virus infections in a hematology unit

Risk factors and containment of respiratory syncytial virus outbreak in a hematology and transplant unit

The use of eye-nose goggles to control nosocomial respiratory syncytial virus infection

Screening for respiratory syncytial virus and assignment to a cohort at admission to reduce nosocomial transmission

Update on infection control practices in cancer hospitals