Review
Mortality benefits of influenza vaccination in elderly people: an ongoing controversy

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Summary

Influenza vaccination policy in most high-income countries attempts to reduce the mortality burden of influenza by targeting people aged at least 65 years for vaccination. However, the effectiveness of this strategy is under debate. Although placebo-controlled randomised trials show influenza vaccine is effective in younger adults, few trials have included elderly people, and especially those aged at least 70 years, the age-group that accounts for three-quarters of all influenza-related deaths. Recent excess mortality studies were unable to confirm a decline in influenza-related mortality since 1980, even as vaccination coverage increased from 15% to 65%. Paradoxically, whereas those studies attribute about 5% of all winter deaths to influenza, many cohort studies report a 50% reduction in the total risk of death in winter—a benefit ten times greater than the estimated influenza mortality burden. New studies, however, have shown substantial unadjusted selection bias in previous cohort studies. We propose an analytical framework for detecting such residual bias. We conclude that frailty selection bias and use of non-specific endpoints such as all-cause mortality have led cohort studies to greatly exaggerate vaccine benefits. The remaining evidence base is currently insufficient to indicate the magnitude of the mortality benefit, if any, that elderly people derive from the vaccination programme.

Introduction

Influenza epidemics occur almost every winter in the USA. These epidemics cause illness in about 5–20% of the US population,1, 2 and lead to approximately 300 000 influenza-related hospital admissions and 36 000 influenza-related deaths annually.3, 4 Except during pandemic seasons, about 90% of all influenza-related deaths occur among people aged at least 65 years.5, 6

Influenza vaccines have convincingly been shown to be effective in preventing influenza infection in healthy adults.7 In 1960, US health authorities adopted a policy of targeting influenza vaccination efforts to those at high risk for severe outcomes, including people with chronic conditions and elderly people.8, 9, 10 Similar policies have been adopted in most other high-income countries and have been endorsed by WHO.11 Vaccination coverage of US elderly people has risen substantially in recent decades, from approximately 15% in 1980 to approximately 65% by the mid-1990s.12

Although current policy emphasises vaccination of elderly people, the evidence that this strategy effectively reduces influenza-related mortality in that age-group is weak. Placebo-controlled randomised clinical trial (RCT) data indicate that vaccination effectively prevents influenza illness in younger, healthy elderly people, but no RCT data conclusively show a similar benefit in those aged 70 years or more, the age-group that accounts for nearly all influenza-related deaths.

In the absence of so-called gold-standard RCT data, the evidence base consists mainly of observational studies that compare mortality risks in self-selected groups of vaccinated and unvaccinated elderly people. Many of these studies have concluded that vaccination reduces winter-season mortality from any cause by approximately 50% in community-dwelling elderly people,13 and even more in nursing-home populations.14 However, such astonishing mortality benefits are simply not consistent with estimates of the influenza-related mortality burden among elderly people, as derived from national vital statistics data.6, 15

In this Review, we examine the major findings of, and inconsistencies between, the various kinds of evidence regarding mortality benefits of influenza vaccination of elderly people. We argue that unrecognised selection bias has led cohort studies to greatly overestimate mortality benefits. The remaining evidence is not sufficient to show that vaccination substantially reduces the risk of influenza-related mortality among elderly people. We propose a framework for identifying residual bias in cohort studies, which should help to provide a clearer picture of what vaccine mortality benefits can and cannot reasonably be expected. Our objective is to move towards a better evidence base for the setting of priorities for influenza vaccination and to identify areas where further research is needed.

Section snippets

National excess mortality studies and assessment of influenza-related mortality

Assessment of the number of influenza-related deaths in elderly people is a difficult task, for many reasons. What is diagnosed as an influenza-like illness is often caused by a respiratory virus other than influenza. Moreover, influenza is often a precipitating factor that brings about death from secondary bacterial pneumonia or underlying chronic disorders,16, 17 which are usually identified as the cause of death.

Influenza-related mortality is therefore traditionally assessed by use of an

Randomised placebo-controlled clinical trials

Few placebo-controlled RCTs of influenza vaccine efficacy in elderly people have been done, and none have been powered to study severe outcomes, including mortality. However, because of the importance of this gold-standard type of evidence, we do include RCTs with morbidity endpoints in this Review. With the exception of one small trial,25 placebo-controlled trials comprised healthy, relatively young, elderly people.26, 27, 28 This fact severely limits what such RCTs can tell us about vaccine

Cohort studies of influenza vaccine benefits

Cohort studies of influenza vaccine effectiveness can be divided into two distinct types. Before 1990, cohort studies were usually prospective and done in nursing homes, had laboratory-confirmed primary endpoints, and used laboratory surveillance data to define the influenza season. Additionally, these earlier cohort studies often reported on less specific outcomes, such as death from any cause, even though the number of deaths among study participants tended to be small. A quantitative review

Towards a stronger evidence base

We have argued that cohort studies asserting that influenza vaccination can reduce winter mortality by approximately 50% cannot possibly be correct. This problem was also highlighted in a recent Cochrane review and an editorial.36, 44 We suggest two factors have caused this substantial mismeasurement.

The first of these is frailty selection. We hypothesise that a small subset of under-vaccinated and very frail elderly people contributed a substantial proportion of the total winter deaths

Conclusions

Between the paucity of RCT data and the problematic cohort studies done to date, the evidence base for mortality benefits of influenza vaccination in older elderly people is slim and not particularly encouraging with regard to the degree to which influenza vaccination protects elderly people against severe influenza outcomes. Govaert and colleagues27 suggested that vaccine effectiveness declines sharply after age 70 years. Data from a study by Falsey and colleagues54 suggested a vaccine

Search strategy and selection criteria

Data for this Review included all available clinical studies addressing vaccine effectiveness against influenza-related mortality in elderly people. We also relied on the compilation of studies identified in a recent Cochrane review of clinical trials and observational studies in elderly people, and several meta-analyses of observational studies done in recent decades in community-living elderly people and nursing-home populations. Because no clinical trials studied mortality outcomes, we

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