key: cord-0007217-50xvzmm4
authors: Foolad, Farnaz; Aitken, Samuel L; Shigle, Terri Lynn; Prayag, Amrita; Ghantoji, Shashank; Ariza-Heredia, Ella; Chemaly, Roy F
title: Oral Versus Aerosolized Ribavirin for the Treatment of Respiratory Syncytial Virus Infections in Hematopoietic Cell Transplant Recipients
date: 2019-05-15
journal: Clin Infect Dis
DOI: 10.1093/cid/ciy760
sha: a413760cebf82b6c766216a590fd5455ee49db61
doc_id: 7217
cord_uid: 50xvzmm4

BACKGROUND: The use of oral ribavirin (RBV) for respiratory syncytial virus (RSV) infections is not well studied. With the drastic increase in the cost of aerosolized RBV, we aimed to compare outcomes of hematopoietic cell transplant (HCT) recipients treated with oral or aerosolized RBV for RSV infections. METHODS: We reviewed the records of 124 HCT recipients with RSV infections treated with oral or aerosolized RBV from September 2014 through April 2017. An immunodeficiency scoring index (ISI) was used to classify patients as low, moderate, or high risk for progression to lower respiratory infection (LRI) or death. RESULTS: Seventy patients (56%) received aerosolized RBV and 54 (44%) oral RBV. Both groups had a 27% rate of progression to LRI (P = 1.00). Mortality rates did not significantly differ between groups (30-day: aerosolized 10%, oral 9%, P = 1.00; 90-day: aerosolized 23%, oral 11%, P = .10). Classification and regression tree analysis identified ISI ≥7 as an independent predictor of 30-day mortality. For patients with ISI ≥7, 30-day mortality was significantly increased overall, yet remained similar between the aerosolized and oral therapy groups (33% for both). After propensity score adjustment, Cox proportional hazards models showed similar mortality rates between oral and aerosolized therapy groups (30-day: hazard ratio [HR], 1.12 [95% confidence interval {CI}, .345–3.65, P = .845). CONCLUSIONS: HCT recipients with RSV infections had similar outcomes when treated with aerosolized or oral RBV. Oral ribavirin may be an effective alternative to aerosolized RBV, with potential significant cost savings.

Respiratory syncytial virus (RSV) is a single-stranded RNA virus of the Paramyxoviridae family and a common cause of seasonal respiratory viral infection [1] . Although RSV infection is frequently a self-limiting cause of upper respiratory infection (URI), it may progress to a more severe lower respiratory infection (LRI) in immunocompromised patients, including hematopoietic cell transplant (HCT) recipients. RSV infection in HCT recipients is associated with substantial morbidity and mortality [2] [3] [4] [5] , and often complicated by respiratory failure [6] . Several risk factors for progression to LRI and/or mortality include myelosuppression, preengraftment or early posttransplantation (ie, within 30 days), age, and mismatched or unrelated donor [6] [7] [8] .

Ribavirin (RBV), a guanosine analogue active against RNA and DNA viruses, is often used to treat RSV infections. Aerosolized RBV is approved for RSV LRI in pediatric patients, although it is frequently used off-label in other populations [2, 9] . Data on RBV to treat RSV infections in HCT recipients come from small, retrospective studies with heterogeneous treatment combinations. Nevertheless, treatment with RBV was shown to prevent poor outcomes [2] . In the largest evaluation of RBV therapy for RSV in HCT recipients, Shah et al showed that aerosolized RBV at the URI stage reduced progression to LRI (83%) and RSV-associated mortality (87%) compared with no treatment [6] . Most studies on RSV treatment have evaluated aerosolized RBV [2, 6, 10] ; information on other formulations is limited [2, 3, 9, 11, 12] .

Aerosolized RBV to treat RSV has remained controversial due to lack of randomized controlled trials, occupational exposure concerns, and the high drug cost. Thus, an immunodeficiency scoring index (ISI) was developed to identify patients who would most benefit from RBV based on risk for progression to LRI and RSV-associated mortality [13] . Patients with high ISI (≥7) were shown to have the highest rates of progression (48%) and death (29%), as well as the greatest benefit when aerosolized RBV was administered at the URI stage (6-and 8-fold reduction in progression and mortality, respectively) [13] .

A dramatic increase in the cost of aerosolized RBV in 2015 [14] limited its use at many institutions and necessitated the quest for alternative therapies, mainly via oral RBV. In addition to being inexpensive, oral RBV allows for outpatient therapy. Data on use of oral RBV to treat RSV in HCT recipients are scarce [15] . The purpose of this study was to compare progression to LRI and mortality in HCT recipients with RSV infections treated with either oral or aerosolized RBV.

We reviewed the records of all HCT recipients who received RBV for RSV infections from 1 September 2014, through 30 April 2017, at The University of Texas MD Anderson Cancer Center. The BioFire FilmArray Respiratory Panel (BioFire Diagnostics, Salt Lake City, Utah) was used to diagnose RSV. Patients aged ≥18 years with a history of HCT were included if they received ≥1 dose of RBV for RSV infection, as an inpatient or outpatient. Patients were excluded if they were enrolled in a clinical trial for RSV, or received RBV for non-RSV indications. No formal restrictions/review of either formulation of RBV was in place at any time during this study.

Patients were identified by accessing pharmacy records for RBV orders/prescriptions. Only the first episode of RSV infection was considered for each patient. Patients were classified into the aerosolized or oral RBV group if they received that formulation for >48 hours at initiation of therapy. If the formulation was switched before 48 hours, they were classified as the formulation to which they were changed.

URI was defined as signs/symptoms of an RSV infection (rhinorrhea, nasal/sinus congestion, pharyngitis, cough) without chest radiographic imaging suggestive of pneumonia. LRI was defined as respiratory symptoms along with chest radiographic imaging suggestive of LRI (ie, ground glass opacities, interstitial infiltrates) with or without isolation of RSV from a lower respiratory sample. RSV was considered community-acquired if symptoms developed before hospitalization or within 5 days after admission and nosocomial if symptoms developed >5 days after admission.

The primary outcome was 30-day all-cause mortality. Secondary outcomes included progression to LRI for patients with URI upon treatment initiation, 90-day all-cause mortality, and need for intensive care unit (ICU) admission or mechanical ventilation. Risk for progression to LRI and RSV-associated death was stratified by ISI [13] (Table 1) .

The following information was collected for all patients: demographics, including age, sex, and race/ethnicity; malignancy; HCT and engraftment date; conditioning regimen; graft-vs-host disease (GVHD) status; immunosuppressive medications within 30 days prior to RSV diagnosis; formulation and duration of RBV therapy; creatinine clearance and hemoglobin; respiratory copathogens; radiographic imaging results; ICU admission and/or mechanical intubation, and date and cause of death. This study was approved by the MD Anderson Institutional Review Board and an informed consent waiver was granted.

Categorical and continuous variables were compared using Fisher exact test and the Wilcoxon-rank sum test, respectively. The primary outcome, 30-day mortality, was assessed visually using Kaplan-Meier curves and multivariate Cox proportional hazards. The final multivariate Cox proportional hazards model incorporated characteristics with a P value <.2 on bivariate analysis with administration of oral RBV forced into the model. The proportional hazards assumption was visually assessed using a plot of the scaled Schoenfeld residuals against time. A propensity score-based analysis was performed to also control for confounding. To create the propensity score, a nonparsimonious logistic regression model incorporating all measured baseline characteristics (sex, race, transplant type, ISI score, site of infection, time from transplantation, GVHD, steroid use, nosocomial infection status) was created to model the probability of oral RBV treatment. This propensity score was used to generate inverse probability of treatment weight (IPTW) and a subsequent IPTW Cox proportional hazards model [16] . Progression from URI to LRI was assessed among patients treated at the URI stage using a Fine-Gray competing risk model, treating death as a competing risk for progression to LRI [17] . A traditional multivariate model and IPTW competing risk model were constructed.

Progression to LRI and 30-and 90-day mortality were assessed with previously published ISI risk categories [13] . To identify a single group at highest risk, classification and regression tree (CART) analysis was used to identify the ISI score most predictive of 30-day mortality [18] . Progression to LRI and mortality were compared in CART-identified low-and high-risk patients.

Data were collected using REDCap electronic data capture tools [19] . Statistical analyses were performed using Stata The overall ISI is the sum of the weighted scores for the immunodeficiency criteria present at the time of RSV diagnosis. Patients with ISI 0-2 were classified as low risk, 3-6 as moderate risk, and 7-12 as high risk for progression to LRI and/or RSV-associated mortality.

Abbreviations: ALC, absolute lymphocyte count; ANC, absolute neutrophil count; GVHD, graft-vs-host disease; ISI, immunodeficiency virus scoring index; LRI, lower respiratory infection; RSV, respiratory syncytial virus; URI, upper respiratory infection. 

Hodgkin lymphoma 0 (0) 3 (6) 3 (2) Non-Hodgkin lymphoma 6 (9) 3 (6) 9 (7) Multiple myeloma 24 (34) (21) 14 (26) 29 (23) Matched unrelated 18 (26) 12 (22) 30 (24) Haploidentical 6 (9) 6 (11) 12 (10) .130

≤30 d from HCT to RSV infection 9 (13) 2 (4) 11 (9) .111 ≤90 d from HCT to RSV infection 15 (21) 6 (11) 21 (17) .153

Acute GVHD 9 (13) 6 (11) 15 (12) 1.000

Chronic GVHD 14 (20) 13 (24) 27 (22) .660

Corticosteroid use 37 (53) 29 (54) 66 (53) 1.000

Neutropenia a 5 (7) 6 (11) 11 (9) .531

Lymphopenia b 19 (27) 5 (9) 24 (19) .021

Hb, g/dL, at baseline, median (IQR) 9.6 (8.9-11.0) c 9.7 (8.6-11.7) 9.6 (8.7-11.3) .307

Nosocomial infection 11 (16) 4 (7) 15 (12) . 

Over 3 consecutive RSV seasons, 127 adult HCT recipients with microbiologically documented RSV infections received RBV therapy. Three patients were excluded because their transplantation was done at outside institutions, and transplantation date and/or the conditioning regimen was unknown. Of the remaining 124 patients, 70 (56%) received aerosolized and 54 (44%) received oral RBV (Table 2) . Only 3 patients (2 oral, 1 aerosolized RBV) received the alternate formulation for <48 hours and were classified as the regimen to which they were switched. Both groups had similar baseline demographics. The median age at RSV diagnosis was 59 years (range, 21-80 years), and multiple myeloma (33%) and AML (27%) were the most common underlying malignancies. Median time from HCT to RSV infection was 466 days (range, -1 to 7090 days). Malignancy relapse at time of RSV infection was similar between groups (aerosolized: 24%, oral: 30%, P = .543). Lymphopenia at RSV diagnosis was more common in the aerosolized (27%) than oral RBV group (9%) (P = .021), which was the only significant difference between groups. The number/types of respiratory copathogens were similar between both groups (Supplementary Table 1 ). Fifty-six patients had URI at RSV presentation (45%), and 68 (55%) presented with LRI.

CART analysis identified ISI ≥7 as the most significant predictor of 30-day mortality (sensitivity 50%, specificity 89%, area under the receiver operating curve 0.70). We found that among patients treated with aerosolized and oral RBV, patients with ISI <7 had similar rates of progression to LRI (24% vs 29%), 30-day mortality (5% vs 6%), and 90-day mortality (16% vs 8%) ( Table 3 and Supplementary Tables 2 and 3 ). Patients with ISI ≥7 had higher 30-day and 90-day mortality rates than those with ISI <7, but rates remained similar between groups (30-day mortality: aerosolized 33%, oral 33%; 90-day mortality: aerosolized 58%, oral 33%).

Patient demographic and clinical characteristics stratified by 30-day mortality are presented in Table 4 and outcomes are shown in Tables 5 and 6 . Patients who died within 30 days were more likely to receive corticosteroids than survivors (83% vs 50%; P = .034) and to have lymphopenia (50% vs 16%; P = .012), nosocomial infection (50% vs 8%; P = .001), and a high-risk ISI score (50% vs 11%; P = .002). No differences were noted in percentage of patients receiving oral RBV as their initial treatment between survivors (44%) and nonsurvivors (42%) (P = 1.000). (Figure 1 and Supplementary Figures 1 and 2) . Complete results of univariate and multivariate Cox proportional hazards models are depicted in 

The ICU transfer rate and need for mechanical ventilation in oral vs aerosolized RBV patients was similar (ICU transfer: 7% vs 10%, P = .76; mechanical ventilation: 6% vs 10%, P = .511). 

Hemoglobin levels were similar between aerosolized and oral groups at baseline, day 7, and day 14, as was new-onset grade 3 anemia classified by the Common Terminology Criteria for Adverse Events (Supplementary Table 7 ).

In this study, HCT recipients with RSV infections had similar mortality and progression to LRI when treated with aerosolized or oral RBV. Despite the use of multiple statistical methods including propensity score-based modeling, no signals of increased efficacy of aerosolized RBV were observed. Moreover, oral RBV was not associated with increased rates of grade 3 or greater anemia. These findings suggest that oral RBV may be a safe and effective alternative to aerosolized RBV for the treatment of RSV in HCT recipients and have important implications for HCT programs given the significant aerosolized RBV costs. Treatment options for RSV infection in HCT recipients are limited. RBV is the only commonly used pharmaceutical agent and is marketed in 3 formulations: aerosolized, oral, and intravenous. The intravenous formulation is not approved by the US Food and Drug Administration (FDA) and is not routinely available for clinical use [20] . Although aerosolized RBV is only FDA-approved for the treatment of RSV in children, several retrospective studies suggest that treatment with aerosolized RBV is associated with reduced mortality in HCT recipients and is thus broadly used for this indication [13, [21] [22] [23] . Due to teratogenicity, aerosolized RBV must be administered while inpatient via a scavenging tent, and the 6-to 18-hour daily administration time is challenging for patients and providers [9] .

In 2015, the cost of aerosolized RBV increased by 400% to roughly $30 000 per day, placing the cost of a 5-day treatment course at a staggering $150 000 [14] . As a result, aerosolized RBV is no longer viable for many institutions, leaving oral RBV (~$25/day) as the only available treatment [14, 15] . At our institution, aerosolized RBV remained unrestricted, but given the widespread publicity over the increased cost of therapy and ease of oral administration, a shift in use toward oral RBV occurred naturally over the last 3 RSV seasons. However, the paucity of data on oral RBV for RSV in HCT recipients has limited its widespread acceptability as an equivalent alternative to aerosolized RBV.

Prior studies of oral RBV in HCT patients provide limited, mixed results [3, 9, 11, 12, 24, 25] . To our knowledge, ours is the largest study to date that compared outcomes of oral and aerosolized RBV for RSV in HCT recipients. Thirty-day mortality rates were similar between groups, while 90-day mortality was significantly lower in recipients of oral RBV in the Transfer to ICU b 7 (10) 4 (7) 11 (9) .755

Mechanical ventilation b 7 (10) 3 (6) 10 (8) . multivariate Cox proportional hazards model. As several other significant predictors of 90-day mortality reflect underlying high-risk transplants and relapse of the underlying malignancy, it is more likely that this reflects a degree of residual selection bias rather than a true efficacy signal. Although the number of patients at high risk (ISI ≥7) was relatively low, no indicators of increased mortality were observed in patients treated with oral RBV. Additionally, 30-and 90-day mortality was the same with oral or aerosolized RBV for patients with LRI, suggesting that the oral formulation is as effective as aerosolized therapy for lower respiratory disease. Patients with URI had a similar progression rates to LRI regardless of treatment with oral or aerosolized RBV (both 27%). This finding was robust in both a standard Fine-Gray competing risk model and a propensity score-based analysis. As with mortality, patients at high risk for progression did not appear to be at any additional risk if treated with oral RBV. These findings contrast with those of Casey et al, who evaluated 13 patients treated with oral RBV for RSV infection after allogeneic HCT (7 URI) [11] . In that cohort, URI progression was documented in every case and 3 patients (23%) died from respiratory failure. However, those patients were treated a median of 14 days following transplantation, so were high risk for progression regardless of treatment, whereas our cohort included the entire posttransplantation spectrum.

Our study did not include a comparator group that did not receive RBV and there are limited data comparing oral RBV to no therapy. Fifty-six patients at the University of Heidelberg were treated with oral RBV during an RSV outbreak, 32 of whom were HCT recipients and received oral RBV [25] . Multivariable analysis identified that treatment with RBV was a protective factor against fatal outcomes (P = .02). Marcelin [9] . At our institution, aerosolized RBV is most commonly dosed intermittently at 2 g over 3 hours 3 times per day. Two common dosing strategies for oral RBV are used: (1) a fixed dose of 600 mg every 8 hours or (2) a loading dose of 10 mg/kg followed by 20 mg/kg/day divided into 3 doses, both with adjustments for renal dysfunction [26] [27] [28] . Both of the doses used are based on those reported in the literature; however, the optimal dosing of RBV for RSV has not been established [7, 15] . Similarly, the optimal duration of therapy is unknown and substantial heterogeneity in practice is reported [3, 7, 9, 11, 12, 14, 24, 25] . Assessment of the optimal dose and duration of oral RBV is an area of ongoing research for our group.

Strengths of our study include comparisons of outcomes by both RBV formulation and disease severity after controlling for many cofounders. Additionally, the size of our institution and inclusion of 3 consecutive RSV seasons allowed for the inclusion of a large number of patients with different HCT types and risk strata, including relapsed disease. However, our study has some limitations. This was a single-center study that evaluated only HCT recipients; therefore, generalizability to nontransplant recipients and other institutions may be limited. Our study included low-risk HCT patients (ISI = 0-2) that may not require treatment with RBV; however, this group comprised a small portion (10%) of our cohort. Similarly, the number of patients in the high-risk group (ISI = 7-12) was low (15% of the cohort); thus, the impact of oral RBV in these high-risk patients needs further study. Last, our study was retrospective in nature and there were significantly more patients with lymphopenia in the aerosolized group, although this was not found to be independently associated with mortality on the multivariate analysis (Table 7) .

In summary, our study provides evidence supporting the use of oral RBV in place of aerosolized RBV for the treatment of RSV infection in HCT recipients, including patients at high risk for progression and mortality. These findings still require validation, preferably via prospective trial. As many institutions have already adopted this practice, our findings may address some of the remaining concerns over the use of oral instead of aerosolized RBV in HCT patients.

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

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We acknowledge Erica Goodoff of the Department of Scientific Publications at MD Anderson for assistance with this manuscript.Potential conflicts of interest. R. F. C. has received personal fees from Ablynx, JNJ, ADMA Biologics, and grants from Gilead. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.