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Randomized Controlled Multicenter Trial of Aerosolized Ribavirin for Respiratory Syncytial Virus Upper Respiratory Tract Infection in Hematopoietic Cell Transplant Recipients

  1. Michael Boeckh1,2,
  2. Janet Englund2,3,
  3. Yufeng Li4,
  4. Carole Miller5,a,
  5. Alan Cross6,
  6. Humberto Fernandez7,a,
  7. Jane Kuypers3,
  8. Hyung Kim1,
  9. John Gnann4,
  10. Richard Whitley4, and
  11. NIAID Collaborative Antiviral Study Group
  1. 1Fred Hutchinson Cancer Research Center, Seattle, Washington
  2. 2University of Washington, Seattle, Washington
  3. 3Children's Hospital and Regional Medical Center, Seattle, Washington
  4. 4University of Alabama at Birmingham, Alabama
  5. 5Johns Hopkins University, Baltimore, Maryland
  6. 6University of Maryland, Baltimore, Maryland
  7. 7ICN Pharmaceuticals, Costa Mesa, California
  1. Reprints or correspondence: Dr. Michael Boeckh, Fred Hutchinson Cancer Research Center, Program in Infectious Diseases, 1100 Fairview Ave. N., Seattle WA 98109 (mboeckh{at}FHCRC.org).

  • ↵Present affiliations: Cancer Center, St. Agnes Healthcare, Baltimore, Maryland (C.M.); Valeant Pharmaceuticals International, Costa Mesa, California (H.F.).

 
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Abstract

Background. Respiratory syncytial virus infection of the upper airways may progress to fatal pneumonia in hematopoietic cell transplant recipients. The safety and efficacy of aerosolized ribavirin in preventing disease progression is unknown.

Methods. In a multicenter prospective trial, hematopoietic cell transplant recipients with respiratory syncytial virus infection of the upper airways were randomized to receive ribavirin (2 g 3 times daily) or supportive care for 10 days. The primary end point was progression to radiographically proven pneumonia. Secondary end points included virologically proven respiratory syncytial virus pneumonia, viral load changes, and safety.

Results. Fourteen patients were randomized to 1 of 2 treatment arms. The trial was discontinued after 5 years because of slow accrual. Pneumonia at 1 month after randomization occurred in 1 of 9 patients who received ribavirin and in 2 of 5 patients who received supportive care (P = .51); virologically proven respiratory syncytial virus pneumonia occurred in 0 of 9 and 2 of 5 patients, respectively (P = .11). At 10 days after randomization, the average viral load decreased by 0.75 log10 copies/mL in ribavirin recipients, compared with a viral load increase of 1.26 log10 copies/mL in untreated patients (P = .07). No discontinuations of ribavirin therapy because of adverse effects occurred during 84 drug administrations. Rates of adverse events were similar in both groups.

Conclusions. Preemptive aerosolized ribavirin treatment appeared to be safe, and trends of decreasing viral load over time were observed. However, proof of efficacy remains elusive in hematopoietic cell transplant recipients.

Respiratory syncytial virus (RSV) can cause fatal pneumonia in hematopoietic cell transplant (HCT) recipients who are receiving myeloablative conditioning therapy [1, 2]. RSV pneumonia in HCT recipients is associated with fatality rates as high as 70%–80% if left untreated or when treatment is initiated at the stage of respiratory failure [3, 4]. Early treatment of RSV pneumonia with aerosolized ribavirin in combination with RSV-specific monoclonal antibodies or hyperimmune globulin appears to be more effective, but it is costly and requires hospitalization [1, 4–11]. Among survivors of RSV pneumonia, late airflow decline is common and is associated with significant morbidity and mortality [12]. Most immunocompromised patients with RSV pneumonia present to a health care facility with an upper respiratory tract infection ∼1 week prior to the onset of pneumonia [1]. Overall, 40%–50% of RSV upper respiratory tract infections in HCT recipients will progress to pneumonia [1]. Thus, preemptive antiviral therapy at the stage of upper respiratory tract infection could prevent progression to pneumonia. Uncontrolled studies suggest that treatment of RSV upper respiratory tract infection may prevent pneumonia [7, 9]. However, the issue is controversial, because aerosolized ribavirin is expensive, requires hospitalization, is considered to be potentially hazardous to health care workers, and proof of efficacy from randomized trials in these high-risk patients does not exist [13, 14]. The purpose of this study was to determine the efficacy and tolerability of aerosolized ribavirin for prevention of progression from an RSV upper respiratory tract infection to a lower respiratory tract infection.

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Patients And Methods

Study design. This was a randomized, investigator-masked, controlled study of subjects with RSV infection in the upper respiratory tract as documented by detection of RSV antigen from a nasopharyngeal-throat specimen. All subjects received the standard care measures for immunocompromised patients with upper respiratory tract disease. At participating sites, subjects with upper respiratory symptoms underwent a nasal wash procedure. Subjects whose nasal wash fluid samples were positive for RSV by culture or rapid testing methods were eligible for inclusion. Eligible subjects were randomized to receive either high-dose, short-duration ribavirin aerosol (2 g at 60 mg/mL) 3 times daily for 10 days or supportive care only. To determine whether the primary outcome was met, all study patients were evaluated daily for progression to pneumonia by an investigator blinded to study group assignment. The primary end point was clinical pneumonia, defined as development of a new infiltrate on chest radiograph and new onset (since study entry) of signs and symptoms of lower respiratory tract infection. These signs and symptoms included an increase in respiratory rate to >150% of baseline, increasing cough, wheezing, sputum production, or pleuritic chest pain and oxygen saturation <90% on 2 consecutive measurements performed at 1-h intervals. If pneumonia was confirmed clinically, the patient then underwent a bronchoalveolar lavage at the discretion of the patient's primary physician. If analysis of the bronchoalveolar lavage fluid revealed RSV by any laboratory means (ELISA, direct fluorescent antibody test, PCR, or culture), the patient met criteria for RSV pneumonia—the secondary end point.

There was a 4-week postrandomization observation period. Patients were examined daily for the first 10 days and at 14 ± 2 and 28 ± 2 days thereafter for a physical examination, oximetry testing, and to obtain samples (throat swab or nasopharyngeal wash) for RSV PCR and clinical laboratory tests.

The study was reviewed by the National Institutes of Health and the US Food and Drug Administration and was approved by the institutional review boards of all participating sites. All patients gave informed consent.

Eligibility criteria. HCT recipients receiving myeloablative conditioning (age, >2 years) who developed an RSV upper respiratory tract infection between the start of conditioning and day 90 after HCT were eligible for inclusion. Between day 91 and day 180 after transplantation, only patients who had an unrelated or human leukocyte antigen (HLA) mismatch-related allogeneic HCT or those who had graft-versus-host disease and required systemically administered steroid therapy (dose, >1 mg/kg/day) that was expected to continue throughout the study period were eligible. All patients were required to have documentation of RSV infection by rapid antigen test (ELISA, direct fluorescent antibody test, or shell vial centrifugation culture), oxygen saturation of 92%–100% in room air, a baseline chest radiograph with no new abnormalities, and signs and/or symptoms of upper respiratory tract infection (i.e., rhinorrhea and/or low grade fever with or without evidence of a sore throat). Exclusion criteria were mechanical ventilation, previously known adverse reactions to ribavirin, known HIV infection, pregnancy, breast feeding, female patients unwilling to use a reliable method of birth control for the duration of the study, abnormal respiratory rate for age, and concomitant immunotherapy for RSV.

Study drug administration. Ribavirin inhalation solution (60 mg/mL, 2 g total) was administered for 2 consecutive h, 3 times each day for 10 days (every 8 h; minimum, ⩾4 h; maximum, 10 h). Medication was donated by ICN Pharmaceuticals (Costa Mesa, CA). Control subjects were not treated.

End point evaluation. Patients were examined once daily, at baseline assessment and throughout the 10-day treatment period, during a standardized time of day, by investigators masked to the treatment arm. Follow-up exams occurred on days 14 and 28 after randomization. Masking of the investigator was maintained by instructing the patient not to disclose the study arm assignment, asking standardized questions regarding signs and symptoms, and providing relevant clinical information in a shadow chart. Follow-up also included daily oximetry, serial chest radiographs (at baseline, days 5 and 10, and when clinically indicated) and performance of laboratory tests. Chest radiographs were interpreted by radiologists masked to the treatment arm. Adverse events were graded using an early edition of the Division of AIDS Toxicity Table [15].

Virologic testing. Virologic testing for study entry was performed at study sites using widely available rapid assays for RSV, including direct fluorescent antibody test, immunoassays, or shell vial centrifugation cultures. Nasal wash and throat samples were collected at study entry and on days 4, 6, and 10, and an aliquot of each was frozen at -70°C.

Testing of serial nasal wash samples by quantitative real-time RT-PCR assay was performed in Seattle from frozen samples. The assay detects both RSV-A and RSV-B subtypes using primers for a consensus region of the matrix protein gene [16]. An RNA control molecule (EXO) was added to each sample before RNA extraction to exclude false negative results caused by sample inhibition. The limit of detection was 1000 copies of RNA per mL.

Statistical design and analysis. It was assumed that inhaled ribavirin would reduce the proportion of patients who progressed to pneumonia from 50% to 20%. On the basis of a comparison of the 2 proportions, with a 5% significance level and at 80% power in a 2-sided test, 45 patients were needed in each study arm. Patients were stratified for engraftment status (pre- or postengraftment, defined as absolute neutrophil count >500/mm3 for 3 consecutive days) and for donor type (unrelated or related-mismatched vs. all others). Fisher's exact test was used to test the difference of the proportion of patients who progress to pneumonia in the 2 study arms. Nonparametric methods with the Wilcoxon rank test was used to test the median difference for continuous variables in the 2 study arms—such as viral loads—and the slopes of the regression lines were compared using the Wilxocon test.

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Results

Patient characteristics. Fourteen HCT patients were enrolled at 3 clinical sites over 5 years. Patient characteristics are shown in table 1. More patients in the ribavirin group than the control group were severely lymphopenic at the time of randomization, but this difference was not statistically significant. All other baseline characteristics were well balanced.

Table 1
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Table 1

Patient characteristics at baseline.

Clinical efficacy. The primary end point of the trial was progression to clinical pneumonia, as determined by chest radiograph and by the blinded evaluator. Blinding was maintained in 138 (93.9%) of 147 exams. On a per-patient basis, blinding was maintained in 9 (64.3%) of 14 patients throughout the study period. In 3 of 14 patients, the investigator suspected the study arm and in 2 of 14 patients the identity of the study arm was disclosed on at least 1 occasion. Because blinded investigators were rotating in most cases, suspected and definite knowledge of the code at a particular time point resulted in permanent disclosure of the study arm assignment for all subsequent evaluations in only 2 patients.

Clinical pneumonia after randomization occurred in 1 (11.1%) of 9 ribavirin recipients and 2 (40%) of 5 control patients (table 2). The patient who developed clinical pneumonia while receiving ribavirin did so after 4 days. A bronchoalveolar lavage was not performed. The 2 patients in the control patient group developed pneumonia after 7 and 14 days, respectively. All patients were treated with aerosolized ribavirin and RSV Ig and recovered from pneumonia. All patients survived the 28-day observation period. Patients in the control group had higher median respiratory rates (P = .03), higher body temperatures (P = .002), and lower pulse oximeter levels (P = .01; data not shown). There were no differences in the physical examination findings by blinded investigators between the groups (data not shown).

Table 2
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Table 2

Efficacy end points.

Virologic analysis. RSV load was determined in serial nasal wash samples by quantitative real-time PCR in 6 ribavirin recipients and 4 control patients. At 10 days after randomization, the average viral load decreased by 0.75 log10 copies/mL in ribavirin recipients, compared with an increase of 1.26 log10 copies/mL in untreated patients (P = .07; figure 1). A comparison of the slope of the regression line showed a difference between ribavirin and untreated controls (-0.088 log10 and 0.09 log10 decrease in RSV load per day; P = .17).

Figure 1
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Figure 1

Mean RSV load (± SE) in serial nasal wash samples following randomization. Ribavirin was administered for 10 days. Panel A shows absolute changes; panel B shows relative changes from baseline.

Toxicity and adverse events. Rates and severity of clinical and laboratory tests (blood chemistry tests, including alanine transaminase, aspartate transaminase, lactate dehydrogenase, alkaline phosphatase, uric acid, bilirubin, and hemaglobin levels, hematocrit, white blood counts, and platelet counts) and adverse events were similar in both groups (data not shown). No discontinuations of ribavirin aerosol because of adverse effects occurred during 84 drug admininistrations.

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Discussion

This study was designed to test whether preemptive aerosolized ribavirin is effective and safe for preventing the progression of RSV upper respiratory tract infection to clinical pneumonia in HCT recipients. The study was terminated prematurely because of slow accrual of study patients. The study results show less clinically and virologically proven RSV pneumonia, as well as a decrease in RSV load, but these results did not reach statistical significance.

To our knowledge, this is the first attempt to study RSV management strategies for HCT recipients in a randomized fashion. Despite adequate financial and logistical support by a large clinical trial group, we were unable to complete the trial after 5 years because of slow patient accrual. There were 2 factors that are likely to be responsible for this. First, we observed a decline in RSV incidence in all participating centers after initiation of the trial. We attribute this to increased awareness and infection control practices when the protocol was activated at study sites. The use of infection control practices to decrease the incidence of RSV infection in the hospital setting has been previously documented [17]. The other factor likely related to poor study accrual was the complexity of the study design, which included hospitalization for patients randomized to ribavirin and the daily masked clinical evaluation, which required intense investigator involvement and major logistical effort. An interesting finding of this study was that masked evaluation appeared to work well in maintaining the blind with regard to the study arm. In >90% of individual visits, the investigators indicated that they were unaware of the patient's study group assignment. This is consistent with earlier reports [18].

Both the primary end point (progression to clinical and radiographic pneumonia) and secondary RSV-specific end points (e.g., bronchoalveolar lavage-proven RSV pneumonia and serial viral load in nasal wash samples) were affected in the direction that we hypothesized. The finding that viral load, as detected by PCR, decreased with ribavirin therapy is novel and may serve as a model for future evaluations of antiviral drugs against RSV. It is notable that the viral load in the “no treatment” group actually slightly increased over the 10-day observation period. The use of RSV load measurements as a sensitive marker of antiviral activity, at least in the immunocompromised host, holds promise for future evaluation of anti-RSV compounds.

Ribavirin inhalations were well tolerated. The study included prospective and comprehensive evaluation of possible adverse effects of aerosolized ribavirin. None of the patients discontinued treatment, and the overall adverse event rate and severity was similar between the study groups. This is consistent with the safety profile reported in the literature [3, 6, 7, 10, 19, 20].

In conclusion, this study attempted to examine the efficacy of aerosolized ribavirin on the progression from RSV upper respiratory tract infection to RSV lower respiratory tract infection to pneumonia in HCT recipients. The study showed trends toward reduced pneumonia and viral load among ribavirin recipients but proof remains elusive. Drugs with anti-RSV activity that are easier to administer and do not require hospitalization are needed.

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acknowledgments

We thank the following individuals for their contributions to the study: Laura Riser, Pam Walls, and the study staff of the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. The study was active at the following sites: University of Alabama at Birmingham (principal investigator, Dr. Donna Salzman; study coordinator, Nancy Grady); Johns Hopkins University, Baltimore, MD (principal investigator, Dr. Carole Miller; study coordinator, Julie Yerian); University of Florida, Gainesville (principal investigator, Dr. Paulette Mehta; study coordinator, Carol Delaney); University of Chicago, Chicago, IL (principal investigator, Dr. Janet Englund; study coordinator, Brent Buhr); State University of New York-Syracuse (principal investigator, Dr. Leonard Weiner; study coordinator, Lisa Susko); Dana Farber Cancer Institute, Boston, MA (principal investigator, Dr. Robert W. Finberg); City of Hope National Medical Center, Duarte, CA (principal investigator, Dr. Robert Sweetman; study coordinator, Carol Brubaker); Riley Hospital, Indianapolis, IN (principal investigator, Dr. Franklin Smith; study coordinator, Patricia Smith); Fred Hutchinson Cancer Center, Seattle, WA (principal investigator, Dr. Michael Boeckh; study coordinators, Gina McBrayer, Molly McKillop, Maggie Hoyle, Mary Grabowsky, Steve Wroblewsky, and Terri Cunningham; lab analysis, Terry Stevens-Ayers; masked investigators, Garrett Nichols, Adam Geballe, Kieren Marr, Uma Malhotra, Anna Wald, Daniel Weiss, Julie McElrath, Marnia Elizaga, Morgan Hakki, Tobias Kollman, and Michael Myint); University of California, San Francisco (principal investigator, Dr. Morton Cowan); University of Maryland, College Park (principal investigator, Dr. Alan Cross; study coordinator, Kathy Newman); Northside Hospital Atlanta, GA (principal investigator, Dr. Lawrence Morris; study coordinator, Stephanie McMillan); Princess Margaret Hospital, Toronto, Canada (principal investigator, Dr. Jeff Upton; study coordinator, Mary-Anne Miles); St. Luke's Hospital, Kansas City, MO (principal investigator, Dr. Joseph McGuirk; study coordinator, Jami L. Niehus); University of Arkansas, Fayetteville (principal investigator, Dr. Elias Anaissie); and University of Minnesota, Minneapolis (principal investigator, Dr. Jo Anne Van Burik; study coordinator, Gerri Anderson).

Financial support. Supported by a contract from the National Institute of Allergy and Infectious Diseases (NO1-AI-30025, NO1-AI -65306, NO1-AI -15113, and NO1-AI-62554), the Division of Research resources for General Clinical Research Centers (RR-032); and CA 18029 (for parts of the statistical analysis), all of the National Institutes of Health.

Potential conflicts of interest. M.B. is a consultant for Arrow Therapeutics and Novartis and has received speaker's honoraria from ICN Pharmaceuticals and MedImmune. J.E. is a consultant for Arrow Therapeutics Limited and has received speaker's honoraria from ICN Pharmaceuticals and MedImmune. R.W. is on the speaker's bureaus for GlaxoSmithKlein and Novartis. J.G. has received research support, honoraria, or consultant fees from Merck, GlaxoSmithKline, Astellas, and Novartis. All other authors: no conflicts.

  • Received August 7, 2006.
  • Accepted September 11, 2006.
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