A randomized placebo controlled trial of ibuprofen as an immunomodulator in a bovine model of respiratory syncytial virus bronchiolitis

Background: Respiratory syncytial virus (RSV) bronchiolitis is a major cause of morbidity in infants as is bovine RSV (bRSV) in calves. The severity of RSV bronchiolitis increases with increasing Th2 bias. Th2 behavior is thought to be increased increased by prostaglandin E2. Fever decreases interferon‐c a Th1 cytokine. Objectives: To compare the effect of ibuprofen and placebo on the clinical severity, immunological response, and histological findings in a bovine model of RSV bronchiolitis. Methods: We performed a randomized controlled trial in bovine calves with bRSV bronchiolitis using 10 mg/kg ibuprofen three times daily and identical‐appearing placebo. Calves were excluded for existing RSV infection, proximity to an infected animal, morbidity, or high maternal antibody titers. We observed calves for 3‐4 days prior to infecting them with nebulized bRSV. Calves were randomized using minimization based on weight and maternal RSV antibody titers. First drug administration was within 4 hours of infection. We examined the calves daily and calculated a clinical score. We performed quantitative polymerase chain reaction (PCR) for bRSV for each day. We performed respiratory exams and measured temperatures three times a day. The calves were weighed, euthanized and necropsied on day 10 post infection. Bronchial lymph nodes were tested for interferon‐c, IL4, IL13 and IL7 RNA expression using PCR. Results: We screened 45 calves and enrolled 16, 8 in each group. All calves developed clinical bronchiolitis at day 4 post infection. One calf in the ibuprofen group was euthanized on day 8 for respiratory distress. Overall, calves in the ibuprofen group had lower mean Collie scores, lower temperatures, and lower respiratory rates than those in the placebo group (p<0.01). At necropsy the mean weight gain in the ibuprofen group was 4kg greater than in the placebo group (p=NS). There was non‐significantly increased bacterial consolidation in the lungs of the ibuprofen group. Overall histology was similar between groups. There was significantly increased bRSV viral RNA shedding in the ibuprofen group (p<0.001). This may represent increased killing of infected epithelial cells rather than intact virus shedding. Alternatively, other benefits of antipyresis could have masked increased virus reproduction. We found minimal effect on Il4 expression but large changes in IL17 and IL13 for given interferon‐c and Il4 levels. (See Figure 56.) (Figure presented) Conclusion: Ibuprofen decreased clinical illness as evidenced by clinical scores and respiratory rate. bRSV RNA shedding was increased in the ibuprofen group. Lung histology was similar for placebo and ibuprofen groups. Ibuprofen had a substantial immunodulatory effect.