Staphylococcus aureus a-toxin response distinguishes respiratory virus-methicillin-resistant s. aureus coinfection in children

Background. Development of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia after a respiratory viral infection is frequently fatal in children. In mice, S. aureus a-toxin directly injures pneumocytes and increases mortality, whereas a-toxin blockade mitigates disease. The role of a-toxin in pediatric staphylococcal-viral coinfection is unclear. Methods. We enrolled children across 34 North American pediatric intensive care units with acute respiratory failure and suspected influenza virus infection. Serial serum anti-a-toxin antibody titers and functional a-toxin neutralization capacity were compared across children coinfected with MRSA or methicillin-susceptible S. aureus (MSSA) and control children infected with influenza virus only. MRSA isolates were tested for a-toxin production and lethality in a murine pneumonia model. Results. Influenza virus was identified in 22 of 25 children with MRSA coinfection (9 died) and 22 patients with MSSA coinfection (all survived). Initial a-toxin-specific antibody titers were similar, compared with those in the 13 controls. In patients with serial samples, only MRSA-coinfected patients showed time-dependent increases in anti-a-toxin titer and functional neutralization capacity. MRSA a-toxin production from patient isolates correlated with initial serologic titers and with mortality in murine pneumonia. Conclusions. These data implicate a-toxin as a relevant antigen in severe pediatric MRSA pneumonia associated with respiratory viral infection, supporting a potential role for toxin-neutralizing therapy.