Individual-level Association of Influenza Infection With Subsequent Pneumonia: A Case-control and Prospective Cohort Study

Abstract

BACKGROUND: Pneumonia is a leading cause of mortality worldwide. Influenza may result in primary pneumonia or be associated with secondary bacterial pneumonia. While the association with secondary pneumonia has been established ecologically, individual-level evidence remains sparse and the risk period for pneumonia following influenza poorly defined. METHODS: We conducted a matched case-control study and a prospective cohort study among Nicaraguan children aged 0-14 years from 2011 through 2018. Physicians diagnosed pneumonia cases based on Integrated Management for Childhood Illness guidelines. Cases were matched with up to 4 controls on age (months) and study week. We fit conditional logistic regression models to assess the association between influenza subtype and subsequent pneumonia development, and a Bayesian nonlinear survival model to estimate pneumonia hazard following influenza. RESULTS: Participants with influenza had greater risk of developing pneumonia in the 30 days following onset compared to those without influenza (matched odds ratio [mOR], 2.7 [95% confidence interval {CI}, 1.9-3.9]). Odds of developing pneumonia were highest for participants following A(H1N1)pdm09 illness (mOR, 3.7 [95% CI, 2.0-6.9]), followed by influenza B and A(H3N2). Participants' odds of pneumonia following influenza were not constant, showing distinct peaks 0-6 days (mOR, 8.3 [95% CI, 4.8-14.5] days) and 14-20 (mOR, 2.5 [95% CI, 1.1-5.5] days) after influenza infection. CONCLUSIONS: Influenza is a significant driver of both primary and secondary pneumonia among children. The presence of distinct periods of elevated pneumonia risk in the 30 days following influenza supports multiple etiological pathways.