Comparison of Corticosteroids for Treatment of Respiratory Syncytial Virus Bronchiolitis and Pneumonia in Cotton Rats

Abstract

Triamcinolone acetonide, methylprednisolone, and dexamethasone were each evaluated in combination with palivizumab (Synagis) for the therapy of established respiratory syncytial virus infection in the cotton rat. Triamcinolone and methylprednisolone proved to be more effective than dexamethasone in reducing lung pathology. No recurrence of viral replication or pulmonary pathology followed the cessation of therapy.The cotton rat model of respiratory syncytial virus (RSV) infection has been used for over 20 years to study the pathogenesis and potential therapy of RSV (7). This animal model was invaluable in proving the protective efficacy of anti-RSV antibody (6) and led to the development of RSV immunoglobulin (RespiGam; Medimmune, Inc., Gaithersburg, Md.) and palivizumab (Synagis; Medimmune) for the prevention of severe RSV infection of the lower respiratory tract (1, 2, 5). These preparations have been less effective when used therapeutically (9, 10). Recent experiments with cotton rats demonstrated that combined systemic therapy with palivizumab and triamcinolone acetonide, a potent glucocorticoid, greatly reduced inflammatory changes and viral replication in animals infected with RSV but that palivizumab alone reduced viral titers without altering the degree of inflammation (8). Systemic triamcinolone acetonide is rarely used in the treatment of pediatric respiratory disease, and therefore we examined the comparative efficacies of triamcinolone acetonide, methylprednisolone, and dexamethasone when each was used in combination with palivizumab in the treatment of experimental RSV infection.( Virus. A pool of the prototypic Long strain of RSV (American Type Culture Collection, Manassas, Va.) which contained 10 7.5 PFU/ml was used for all experiments. Pulmonary virus titers were determined by plaque assay as described previously (7).Monoclonal antibody and glucocorticoids. Palivizumab was provided by Medimmune, Inc. Triamcinolone acetonide (Steris Laboratories, Phoenix, Ariz.) was administered as a single daily intramuscular (i.m.) dose of 16 mg/kg of body weight, a dose previously found to be highly effective in reducing pulmonary pathology (8). Dexamethasone (Elkins-Sinn, Cherry Hill, N.J.) was administered in a single daily intraperitoneal (i.p.) dose of 0.6 or 1.2 mg/kg. Methylprednisolone (SoluMedrol; Phamacia and Upjohn, Kalamazoo, Mich.) was administered in a total daily dose of 4 or 8 mg/kg divided into four equal i.p. injections.Histopathology. Lungs were inflated to their normal volume with 10% formalin. Hematoxylin-and eosin-stained slides were prepared from coronal paraffin-embedded sections and scored for peribronchiolitis (inflammatory cells around small airways), interstitial pneumonitis (inflammatory cell infiltration and thickening of alveolar walls), and alveolitis (inflammatory cells within the alveolar spaces). Slides were scored in a blind manner by three investigators using a scale ranging from 0 (no inflammatory changes) to 100 (maximum inflammation).Statistical analysis. A viral titer was...

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