Influenza Increases Risk of Invasive Pneumococcal Disease: A Multi-Country Study

Background: Streptococcus pneumoniae is the most commonly identified cause of bacterial pneumonia, and invasive pneumococcal disease (IPD) has a high case fatality rate. The wintertime co-seasonality of influenza and IPD in temperate countries has suggested that pathogen-pathogen interaction or environmental conditions contribute to IPD risk. We evaluated the contribution of influenza and environmental conditions, using standardized methodology, across multiple geographical regions. Methods: Case data for 25,292 cases from jurisdictions in Canada, the United States and Australia were available. Associations between influenza, temperature, absolute humidity and ultraviolet radiation and IPD were evaluated using a case-crossover design. Identical models were used in all jurisdictions; heterogeneity of effects was explored using meta-analytic methods. Findings: In adjusted models, elevated influenza activity at a 2-week lag was associated with increases in IPD risk (adjusted OR (aOR) per standard deviation increase 1.07, 95% CI: 1.01-1.13). Increased humidity decreased IPD risk at a 1-week lag (aOR per gram.m-3 of water 0.98, 95% CI 0.96-1.00). Other effects were heterogeneous; meta-regression suggested that combinations of environmental factors might represent unique local "risk signatures". Interpretation: Influenza drives IPD risk in temperate countries. This association is not explained by co-seasonality or case characteristics and appears generalizable. Absolute humidity attenuates IPD risk in the same jurisdictions. The generalizable nature of these associations has important implications for influenza control and advances the understanding of seasonality of this important disease. Funding Statement: Supported by Canadian Institutes for Health Research Operating Grants (#222287 and #337516) and by the Canadian Immunization Research Network. Declaration of Interests: The authors state: "None." Ethics Approval Statement: Ethical approval for this study was obtained by the University of Toronto Research Ethics Board.