Mortality reduction with influenza vaccine in patients with pneumonia outside "flu" season: pleiotropic benefits or residual confounding?

Abstract

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. To evaluate unrecognized confounding by hypothesizing the presence of a 50% mortality reduction with vaccination for patients with pneumonia outside of influenza season. 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. 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). 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.