Mortality reduction with influenza vaccine in patients with pneumonia outside "Flu" season - Pleiotropic benefits or residual confounding?

Rationale: Observational studies suggest a 50% mortality reduction for older patients receiving influenza vaccination; some deem this magnitude of benefit implausible and invoke confounding by the "healthy user effect" as an alternate explanation. Objectives: To evaluate unrecognized confounding by hypothesizing the presence of a 50% mortality reduction with vaccination for patients with pneumonia outside of influenza season. Methods: Clinical, laboratory, and functional data were prospectively collected on 1,813 adults with community-acquired pneumonia admitted to six hospitals outside of influenza season in the Capital Health region (AB, Canada). Vaccination status was ascertained by interview and chart review. Outcome was in-hospital mortality. Influenza-vaccinated patients were matched to a nonvaccinated control using propensity scores, and then multivariable regression was used to determine the independent association between vaccination and mortality. Measurements and Main Results: The cohort consisted of 352 vaccine recipients and 352 matched control subjects. Most (85%) patients were 65 years or older, 29% had severe pneumonia, and 12% died. Influenza vaccination was associated with a 51% mortality reduction (28 of 352 [8%] died vs. 53 of 352 [15%] control subjects; unadjusted odds ratio [OR], 0.49; 95% confidence interval [CI], 0.30-0.79; P = 0.004) outside influenza season. Adjustment for age, sex, and comorbidities did not alter these findings (adjusted OR, 0.45; 95% CI, 0.27-0.76). More complete adjustment for confounding (e.g., functional and socioeconomic status) markedly attenuated these benefits and their statistical significance (adjusted OR, 0.81; 95% CI, 0.35-1.85; P = 0.61). Conclusions: The 51% reduction in mortality with vaccination initially observed in patients with pneumonia who did not have influenza was most likely a result of confounding. Previous observational studies may have overestimated mortality benefits of influenza vaccination.