A Randomized, Double-Blind, Placebo-Controlled Trial of Dexamethasone in Severe Respiratory Syncytial Virus (RSV) Infection: Effects on RSV Quantity and Clinical Outcome

1222 A Randomized, Double-Blind, Placebo-Controlled Trial of Dexamethasone in Severe Respiratory Syncytial Virus (RSV) Infection: Effects on RSV Quantity and Clinical Outcome Steven C. Buckingham,1,3,4,a Hasan S. Jafri,5,a Andrew J. Bush,2 Cecilia M. Carubelli,5,b Paul Sheeran,5 R. Doug Hardy,5 Martin G. Ottolini,6 Octavio Ramilo,5 and John P. DeVincenzo1,3 Departments of 1Pediatrics and 2Preventive Medicine, University of Tennessee Health Science Center, 3Children’s Foundation Research Center at Le Bonheur Children’s Medical Center, and 4Department of Infectious Disease, St. Jude Children’s Research Hospital, Memphis; 5Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas; 6Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants. Published data indicate that RSV infection results in the hospitalization of 73,400–126,300 infants annually in the United States [1]. At present, therapeutic options for the management of RSV lower respiratory tract illness are suboptimal. The pathogenesis of RSV lower respiratory infection is imperfectly understood, but pathology is likely to be mediated both by the direct effects of the virus and by the host’s inflammatory response. It is unclear whether corticosteroids can ameliorate the clinical course of RSV lower respiratory disease by altering the inflammatory response. A number of clinical trials [2–15] have addressed the potential utility of corticosteroids in bronchiolitis, the most frequent manifestation of RSV lower respiratory infection, with conflicting results. The effects of corticosteroids on viral replication and inflammation in infants with acute RSV lower respiratory infection, however, have not been studied. The present study was designed to evaluate the effects of corticosteroid therapy on RSV quantity and white blood cell (WBC) counts in respiratory secretions, serum antibody responses, and measures of clinical outcome in infants who required mechanical ventilation for severe RSV lower respiratory infection. Received 23 July 2001; revised 5 December 2001; electronically published 16 April 2002. Presented in part: Pediatric Academic Societies annual meeting, Boston, 12 May 2000 (abstract 1564). Informed consent was obtained from the parents or guardians of all subjects prior to enrollment, and human experimentation guidelines of the US Department of Health and Human Services were followed. The study was approved by the institutional review boards of the University of Tennessee Health Science Center and the University of Texas Southwestern Medical Center. Financial support: Methodist Hospitals Foundation (to J.P.D. and S.C.B.); Children’s Foundation Research Center (to J.P.D.); National Institutes of Health (RR-16187 to J.P.D.); American Lung Association (Career Investigator Award to O.R.). a S.C.B. and H.S.J. contributed equally to this project. b Present affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia. Reprints or correspondence: Dr. Steven C. Buckingham, Le Bonheur Children’s Medical Center, 50 N. Dunlap St., Rm. 301, Memphis, TN 38103 (sbuckingham@ utmem.edu). Methods The Journal of Infectious Diseases 2002;185:1222–8 q 2002 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2002/18509-0002$02.00 Study design. A randomized, double-blind, placebo-controlled trial comparing dexamethasone to saline placebo was conducted in 2 institutions (Le Bonheur Children’s Medical Center, Memphis, and Dallas Children’s Hospital) over the 1997– 1998 and 1998– 1999 winter seasons. Randomization was performed in blocks of 4 patients at each study site. Patients were randomized in a 1:1 ratio to receive dexamethasone sodium phosphate (0.5 mg/kg/dose) or an equal volume of identically appearing normal saline intravenously every 12 h for 4 days. Each patient’s attending physician, independent of the investigators, provided all other treatment. Patients. Children were eligible for enrollment in the study if they were ,24 months of age, had RSV detected in respiratory secretions within the preceding 48 h, and were intubated and required positive-pressure mechanical ventilation for , 36 h. Exclusion criteria included blood cultures positive for known bacterial pathogens (excluding skin flora) within 72 h before enrollment; diagnosed immunodeficiency; requirement for high-frequency oscillatory venti- Forty-one previously healthy children , 2 years of age who required mechanical ventilation for respiratory syncytial virus (RSV) infection were randomized to receive dexamethasone (0.5 mg/kg; n 5 22) or saline placebo (n 5 19) intravenously every 12 h for 4 days. RSV quantity was measured by quantitative plaque assay in fresh tracheal and nasal aspirates obtained at intervals of 24 6 3 h on days 0, 1, 2, 5, and 7 following entry. Analysis by linear mixed-effects modeling demonstrated a significantly greater decline in mean tracheal RSV quantity in the placebo group than in the dexamethasone group from day 0 to day 1 (0.82 vs. 0.21 log pfu/mL; P5 .01) and from day 0 to day 2 (1.45 vs. 0.53 log pfu/mL; P5 .03). No differences were found between groups in nasal RSV quantity, white blood cell counts in tracheal or nasal aspirates, serum neutralizing antibody titers during convalescence, or duration of mechanical ventilation, intensive care unit stay, or hospital stay. JID 2002;185 (1 May) Dexamethasone in Severe RSV Infection 10-fold serially in growth medium (Eagle MEM, 10% fetal bovine serum, penicillin, streptomycin, L -glutamine, and HEPES), and 100 mL of each dilution was inoculated in triplicate on 80% confluent HEp-2 cell monolayers in 12-well clusters. After incubation at 37
C in 5% CO2 for 1 h, inoculated monolayers were overlaid with growth medium supplemented with amphotericin B and 0.75% methylcellulose and were incubated at 37
C in 5% CO2 for 5 days. The monolayers were then fixed with buffered formalin phosphate and were stained with hematoxylin and eosin. Plaques were counted under an inverted microscope, and the RSV quantity was calculated for each specimen, as described elsewhere [16]. To ensure reproducibility and reliability, aliquots of an RSV (Long strain) standard of known quantity were cultured in parallel with all clinical specimens at both sites. WBC counts. WBC counts in tracheal and nasal aspirates were determined by pipetting 10 mL of fresh unspun specimen onto a hemacytometer (Neubauer) and counting WBCs under an inverted microscope. For the determination of differential counts, 10 mL of cytocentrifuged specimen was heat-fixed, and slides were stained with Wright-Giemsa stain. For each specimen, the percentage of segmented neutrophils, lymphocytes, monocytes, and eosinophils and the absolute neutrophil count per microliter (ANC) were calculated. Serum RSV antibod (...truncated)