Why COX inhibitors may help patients with influenza A/H5N1 virus infections

Abstract

The mortality of patients suffering from pneumonia and multiorgan involvement caused by influenza A/H5N1 virus (H5N1) varies between 45% and 81%. Despite the use of oseltamivir, the mortality associated with this virus has not been reduced. This unsatisfactory outcome was attributed to the induction of a severe, uncontrolled virus-induced cytokine storm. Attempts to use anti-inflammatory doses of corticosteroids to control excessive inflammation were associated with severe side effects without any improvement in survival. In our studies, we challenged BALB/c mice with 1000 LD50 of influenza A/Vietnam/1194/04. Survival, body weight, histopathology, inflammatory markers, viral loads, T lymphocyte counts, and neutralizing antibody response were documented in infected mice treated individually or in combination with zanamivir (viral neuraminidase inhibitor), celecoxib (cyclooxygenase-2 inhibitor), mesalazine (inhibitor of inflammation widely used for treatment of inflammatory bowel disease) and gemfibrozil. To imitate the real-life scenario, treatment was initiated 48 h after viral challenge. There were significant improvements in survival rate (P = 0.02), survival time (P < 0.02), and inflammatory markers (P < 0.01) in the group treated with a triple combination of zanamivir, celecoxib and mesalazine when compared with zanamivir alone. Zanamivir with or without immunomodulators reduced viral load to a similar extent. Zanamivir alone reduced viral load but not inflammation and mortality. Insignificant prolongation of survival was observed when individual agents were used alone. Significantly higher levels of CD4+ and CD8+ T lymphocytes and less pulmonary inflammation were also found in the group receiving zanamivir, celecoxib and mesalazine. The survival benefits of adding celecoxib and mesalazine to zanamivir could be caused by their synergistic effects in reducing cytokine dysfunction and preventing