More Evidence for Flu Shot Mortality Benefit in Older Adults, but Debate Continues

MINNEAPOLIS, Oct. 3 -- Influenza vaccination reduces older adults' risk of hospitalization and mortality, researchers affirmed, despite lingering questions.

Even in the most extreme sensitivity analysis, vaccination was associated with a statistically significant 7% decrease in risk of hospitalization and a 33% reduction in all-cause mortality risk, reported Kristin L. Nichol, M.D., M.P.H., M.B.A., of the VA Medical Center here, and colleagues, in the Oct. 4 issue of the New England Journal of Medicine.

Their large retrospective cohort study attempted to address some of the limitations and confounding in previous studies that has led to criticism such as that leveled in a review article in the October issue of The Lancet Infectious Diseases.

That review suggested that cohort studies have found an impossibly high mortality benefit because of selection bias as less-frail individuals are more likely to get their annual flu shot. (See: Flu Shots May Have Little Mortality Benefit in Older Adults)

The new study provides "additional support for the current strategy to vaccinate elderly adults," but questions as to the true magnitude of benefit remain, commented John D. Treanor, M.D., of the University of Rochester Medical Center in Rochester, N.Y., and a member of the CDC Advisory Committee on Immunization Practices, in an accompanying editorial.

Because most studies assessing the effectiveness of flu shots in the elderly have included only a few influenza seasons, the researchers studied 18 cohorts of community-dwelling adults 65 and older across 10 flu seasons from 1990-1991 through 1999-2000.

The cohorts were members of three health maintenance organizations -- HealthPartners in Minnesota and Wisconsin; Kaiser Permanente Northwest in the Portland, Oregon, and Vancouver, Washington, area; and Oxford Health Plans in New York City and surrounding counties -- for a total of 713,872 person-seasons.

Over the study period, there were 4,599 hospitalizations for pneumonia or influenza and 8,796 deaths. Hospitalization rates were 0.7% per season for unvaccinated enrollees and 0.6% for those who were vaccinated, with death rates of 1.6% and 1.0% per season, respectively.

On average, vaccination was associated with a 27% reduction in risk of hospitalization for pneumonia or influenza (adjusted odds ratio, 0.73, 95% confidence interval 0.68 to 0.77) and a 48% reduction in likelihood of death (adjusted OR 0.52, 95% CI 0.50 to 0.55).

In a sensitivity analysis, the researchers modeled the effect of a hypothetical unmeasured confounder that might that would have resulted in their overestimation of vaccine effectiveness. Vaccination was still associated with a statistically significant 7% decrease in risk of hospitalization and a 33% reduction in all-cause mortality risk.

In the 1992-93 and 1997-98 seasons, when there was a poor match between vaccine and circulating virus strains, vaccine effectiveness dropped to 37% for reducing death (adjusted OR 0.63, 95% CI, 0.57 to 0.69), although it was not less effective for reducing hospitalization.

"Reductions in risk associated with vaccination were observed during multiple influenza seasons, including seasons dominated by influenza H3, H1, or B viruses, and were similar among the three participating HMOs," Dr. Treanor said. "These results convincingly dispel concerns that the previous studies were artifacts of a specific influenza season or unique population."

The study did show an interaction between vaccination status and high risk for hospitalization (P=0.004) as well as between vaccination and gender for risk of death (P=0.03) and vaccination and outpatient visits at baseline for risk of death (P=0.03).

So, the researchers tested for selection bias by comparing hospitalization rates for vaccinated and for unvaccinated persons outside the flu season, in June through September of 1999 and 2000.

They found no difference in summertime hospitalization risk by vaccination status in 1999 (adjusted OR 1.0, 95% CI 0.78 to 1.28) or in 2000 (adjusted OR 0.94, 95% CI 0.74 to 1.19).

The researchers cautioned that their findings may not be applicable to older adults not enrolled in HMOs or the "frailest elderly" in nursing homes, who may have impaired immune responses attenuating the effectiveness of influenza vaccination.

"The methodologic issues are important to debate, and doubt about the precise magnitude of the benefit of vaccination in this age group remains," Dr. Treanor said.

Although he concluded that flu shots are beneficial and should be widely used, he also said "it is clear that inactivated influenza vaccine is not a perfect solution to the problem."

He suggested that a key to improving influenza control in older adults may be reducing their exposure by increasing vaccination of health care workers and children.

Dr. Nichol reported serving as a consultant to or as a member of medical advisory boards of Sanofi Pasteur, MedImmune, GlaxoSmithKline, and Novartis and receiving grant support from Sanofi Pasteur and GlaxoSmithKline. A coauthor reported receiving grant support from Sanofi Pasteur and the CDC.

Dr. Treanor reported receiving consulting fees from Alpha Vax, Dynavax, GlaxoSmithKline, and Powdermed and grant support from ID Biomedical/GSK, Merck, Protein Sciences, Wyeth, and Sanofi Pasteur. He is a member of the CDC Advisory Committee on Immunization Practices.