Research Summary

Residual Confounding Tempers Influenza Vaccine Findings in COPD

Edited by:
Anthony Calabro, MA

Key Highlights

  • Influenza vaccination was associated with a lower risk of hospitalized influenza during epidemic periods among patients with COPD.
  • The hazard of hospitalized influenza was 39% lower among vaccinated patients than matched unvaccinated patients.
  • Vaccination was also associated with an unexpectedly lower risk of urinary tract infection, a negative control outcome.
  • The authors cautioned that this finding indicated important residual confounding despite efforts to address immortal time bias.

Influenza vaccination was associated with a lower risk of hospitalized influenza among patients with chronic obstructive pulmonary disease (COPD), although a negative control analysis suggested that residual confounding influenced the findings. Results from the cohort study emulating a randomized trial were published in Clinical Microbiology and Infection.

The researchers conducted the study using data from primary care practices contributing to England’s Clinical Practice Research Datalink. The base cohort included patients aged ≥40 years who had COPD and were initiating an inhaled treatment.

Patients vaccinated between September 2014 and March 2020 were matched 1:1 with unvaccinated patients according to the week of vaccination and a time-conditional propensity score. The primary outcome was hospitalized influenza during epidemic periods. The secondary outcome was a composite of acute COPD exacerbations, pneumonia, and hospitalized influenza.

To evaluate potential residual confounding, the researchers examined urinary tract infections during influenza epidemic periods as a negative control outcome. They also assessed the composite secondary outcome outside influenza seasons, defined as May through August.

Study Findings

The emulated trial included 56,652 matched pairs of vaccinated and unvaccinated patients with COPD. During influenza epidemic periods, vaccination was associated with a 39% lower hazard of hospitalized influenza compared with no vaccination (hazard ratio [HR], 0.61; 95% CI, 0.48-0.77).

For the composite of acute COPD exacerbations, pneumonia, and hospitalized influenza, the HR was 0.89 (95% CI, 0.87-0.92) during epidemic periods. Outside influenza seasons, however, the HR for this composite outcome was 0.99 (95% CI, 0.94-1.04).

Influenza vaccination was also associated with a lower risk of urinary tract infection during epidemic periods (HR, 0.83; 95% CI, 0.77-0.90). Results remained consistent across several sensitivity analyses, including an analysis that excluded patients who sought care for reasons that may have precluded vaccination.

Clinical Implications

According to the authors, influenza vaccination was associated with a reduced risk of hospitalized influenza among patients with COPD. However, the association between vaccination and a lower risk of urinary tract infection—an outcome that vaccination would not be expected to prevent—suggested that important residual confounding remained.

Although the trial-emulation design addressed immortal time bias, the authors stated that further methodological improvements are needed to control residual confounding in observational influenza vaccine studies. They recommended evaluating negative control outcomes during influenza epidemics to improve the detection of residual confounding.

Expert Commentary

“Methodological improvements are needed to better address residual confounding in cohort studies of the influenza vaccine,” the researchers concluded.

Reference
Galmiche S, Dell’Aniello S, Lévesque L, Suissa S. Influenza vaccine effectiveness in patients with chronic obstructive pulmonary disease: a cohort study emulating a randomized trial. Clin Microbiol Infect. Published online September 12, 2026. doi:10.1016/j.cmi.2026.09.006