Program Schedule

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Evidence for Staphylococcus aureus α-toxin as a Dominant Antigen in Severe Pediatric Influenza-staphylococcal Co-infection — Implications for Therapy

Session: Oral Abstract Session: Bacterial Pathogenesis
Thursday, October 9, 2014: 9:30 AM
Room: The Pennsylvania Convention Center: 109-AB
Background: Staphylococcus aureus superinfection contributed to high morbidity during the 2009 H1N1 influenza epidemic. In this setting, co-infection with methicillin-resistant S. aureus (MRSA) is specifically associated with increased mortality in pediatric patients. The molecular pathogenesis of co-infection is poorly understood, precluding the development of preventive or therapeutic interventions. S. aureus α-toxin (Hla) is a key virulence factor in acute lung injury and a focus of anti-staphylococcal clinical trials. Whereas past studies suggest that humans develop Hla-specific antibody after invasive infection, data is lacking for the current MRSA epidemic in the context of influenza co-infection.

Methods: Quantitative in vitro assays measuring anti-Hla IgG and Hla-neutralizing activity were developed.  In collaboration with the Pediatric Acute Lung Injury and Sepsis Investigators, sera from 57 severely-ill influenza patients admitted to pediatric intensive care units were prospectively collected and analyzed. Serial specimens were available for 34 children.

Results: Day 0 sera (indicating pre- or early disease exposure) displayed anti-Hla activity that spanned 1–2 orders of magnitude, with no difference in serologic activity in patients mono-infected with influenza versus those co-infected with either methicillin-sensitive (MS-) or MRSA.  However, Hla-antibody significantly increased in those with MRSA co-infection (median 16-fold increase from baseline, < 0.001 v. MSSA or influenza only).  In some children, anti-Hla IgG and neutralization activity increased over 100-fold in 2 weeks.

Conclusion: Hla is a potent immunogen in influenza-S. aureus co-infection, consistent with toxin production early in disease. The observation of elevated anti-toxin titers in influenza-MRSA co-infected children suggests that toxin-mediated lung injury may exacerbate disease in this population, highlighting potential benefit from Hla-neutralization therapy in early influenza infection. These data provide impetus for ongoing studies to understand pathogen synergy, the role of Hla, and targeted disease interventions.

Project support is from the Depts. of Microbiology and Pediatrics (University of Chicago), the NIH (AI084011) and the CDC.

Karl Yu, MD, PhD, Department of Pediatrics (Infectious Diseases), Comer Children's Hospital / University of Chicago, Chicago, IL, Adrienne Randolph, MD, MSc, Department of Anesthesia, Perioperative and Pain Medicine and Division of Critical Care, Boston Children's Hospital, Boston, MA and Juliane Bubeck Wardenburg, MD, PhD, Department of Microbiology and Department of Pediatrics (Critical Care), University of Chicago, Chicago, IL

Disclosures:

K. Yu, None

A. Randolph, None

J. Bubeck Wardenburg, Novartis Vaccines and Diagnostics: (see comment), JBW has the potential to receive royalties from Novartis Vaccines and Diagnostics in relation to patents owned by the University of Chicago.

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