A mechanistic role for type III IFN-λ 1 in asthma exacerbations mediated by human rhinoviruses

E. Kathryn Miller, Johanna Zea Hernandez, Vera Wimmenauer, Bryan E. Shepherd, Diego Hijano, Romina Libster, M. Elina Serra, Niranjan Bhat, Juan P. Batalle, Yassir Mohamed, Andrea Reynaldi, Andrea Rodriguez, Monica Otello, Nestor Pisapia, Jimena Bugna, Miguel Bellabarba, David Kraft, Silvina Coviello, F. Martin Ferolla, Aaron ChenStephanie J. London, George K. Siberry, John V. Williams, Fernando P. Polack

Research output: Contribution to journalArticle

Abstract

Rationale: Human rhinoviruses (HRV) are the leading cause of upper respiratory infections and have been postulated to trigger asthma exacerbations. However, whether HRV are detected during crises because upper respiratory infections often accompany asthma attacks, or because they specifically elicit exacerbations, is unclear. Moreover, although several hypotheses have been advanced to explain virus-induced exacerbations, their mechanismremains unclear. Objectives: To determine the role of HRV in pediatric asthma exacerbations and the mechanisms mediating wheezing. Methods: We prospectively studied 409 children with asthma presenting with upper respiratory infection in the presence or absence of wheezing. Candidate viral and immune mediators of illness were compared among children with asthma with different degrees of severity of acute asthma. Measurements and Main Results: HRV infections specifically associated with asthma exacerbations, even after adjusting for relevant demographic and clinical variables defined a priori (odds ratio, 1.90; 95% confidence interval, 1.21-2.99; P = 0.005). No difference in virus titers, HRV species, and inflammatory or allergic molecules was observed between wheezing and nonwheezing children infected with HRV. Type III IFN-λ1 levels were higher in wheezing children infected with HRV compared with nonwheezing (P < 0.001) and increased with worsening symptoms(P < 0.001). Moreover, after adjusting for IFN-λ1, children with asthma infected withHRVwere no longer more likely to wheeze than those who were HRV-negative (odds ratio, 1.18; 95% confidence interval, 0.57-2.46; P = 0.66). Conclusions: Our findings suggest that HRV infections in children with asthma are specifically associated with acute wheezing, and that type III IFN-λ1 responses mediate exacerbations caused by HRV. Modulation of IFN- λ1 should be studied as a therapeutic target for exacerbations caused by HRV.

Original languageEnglish (US)
Pages (from-to)508-516
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Volume185
Issue number5
DOIs
StatePublished - Mar 1 2012

Keywords

  • Asthma
  • Asthma exacerbation
  • Children
  • Interferon-λ
  • Rhinovirus

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Miller, E. K., Hernandez, J. Z., Wimmenauer, V., Shepherd, B. E., Hijano, D., Libster, R., Serra, M. E., Bhat, N., Batalle, J. P., Mohamed, Y., Reynaldi, A., Rodriguez, A., Otello, M., Pisapia, N., Bugna, J., Bellabarba, M., Kraft, D., Coviello, S., Ferolla, F. M., ... Polack, F. P. (2012). A mechanistic role for type III IFN-λ 1 in asthma exacerbations mediated by human rhinoviruses. American journal of respiratory and critical care medicine, 185(5), 508-516. https://doi.org/10.1164/rccm.201108-1462OC