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Effect of influenza vaccination on excess deaths occurring during periods of high circulation of influenza: cohort study in elderly people
http://www.100md.com 《英国医生杂志》
     1 London School of Hygiene and Tropical Medicine, London WC1E 7HT

    Correspondence to: B G Armstrong ben.armstrong@lshtm.ac.uk

    Abstract

    A randomised trial showed the effectiveness of vaccination against laboratory confirmed clinical influenza to be 58%,1 but mortality is too rare an end point for reduction in mortality to be clearly established. Observational studies, mostly on people aged 65 and over, have estimated effects on mortality but are subject to confounding.2-7 Confounding "by indication," whereby sicker people may be selected for vaccination, biases estimates of effectiveness downwards.6-9 However, people vaccinated may be healthier than those not vaccinated, potentially biasing estimates upwards.8 9 Problems also exist in identifying deaths due to influenza. Deaths certified with influenza as underlying cause are known to be a small fraction of deaths due to influenza,10 leading researchers to prefer all deaths during influenza epidemics and due to respiratory or cardiovascular disease as an outcome measure. However, these deaths include many not caused by influenza, and this lack of specificity reduces estimates of the clinical effectiveness of vaccination, particularly as cold related deaths and other non-influenzal infections such as respiratory syncytial virus often occur in temperate climates at the same time of the year as influenza.11

    We sought to overcome these problems by measuring vaccine effectiveness as the extent to which increases in mortality during periods of high circulating influenza are diminished in vaccinated people, rather than by direct comparison of mortality in vaccinated and unvaccinated people.

    Methods

    In the vaccinated cohort compared with the unvaccinated cohort, the tendency of mortality to rise in periods of high influenza infection rates was clearly reduced. This is not easily explicable by chance or confounding. We have substantially reduced vulnerability to confounding by avoiding direct comparison of mortality in vaccinated and unvaccinated groups in favour of comparing vulnerability within each group to increasing mortality associated with high circulation of influenza. It is hard to envisage confounding that would cause spurious patterns of sharply reduced mortality in vaccinated people specifically during the high influenza periods.

    This approach also improves specificity of outcome. By estimating deaths attributable to influenza statistically, we avoided a choice between reliance on information from death certificates or settling for a non-specific outcome. A somewhat similar idea has been used in the study of malaria.16 The robustness and improved outcome specificity of our indirect approach is at the cost of low precision. Only for all cause mortality and respiratory mortality was the protection by vaccination statistically significant at conventional benchmarks. Estimation of vaccine effectiveness, still more demanding of information under this approach, was even less precise. Furthermore, the approach is not immune to information bias. Errors in the index of circulating influenza would have reduced associations of circulating influenza with mortality in both vaccinated and unvaccinated people. Misclassification of vaccination status would have blurred differences between the groups.17

    Several recent conventional observational studies have reported vaccine effectiveness against all cause mortality in the influenza season. A UK study of people aged 55 and over in 1989-90 reported a vaccine effectiveness of 75% (95% confidence interval 21% to 92%).3 Among studies of vaccine effectiveness against all cause mortality in people aged 65 and over, vaccine effectiveness was 57% (55% to 60%) in a Swedish cohort study in 1998-2000,8 24% (3% to 40%) in 1996-7 in the Netherlands,7 and 50% in the United States in 1998-2000.6 A meta-analysis of 20 earlier observational studies found mean vaccine effectiveness for all cause mortality of 68% (56% to 76%).4

    These estimates were all lower than our estimate of 83%. However, these fractions were of all deaths in the influenza season, rather than of the excess associated with high influenza periods measured by the more specific estimate of vaccine effectiveness we used in our study. Furthermore, because no comparison was made with a non-influenza season, estimates were more vulnerable to confounding and may have been overestimated owing to vaccine recipients being healthier than non-recipients. Control for confounding is possible in conventional studies, but only for the limited variables measured. One study noted a 12% (8% to 16%) protective effect against acute respiratory mortality averaged over a several influenza seasons (1989-90 to 1998-9). Mortality outside the influenza season, during which vaccination had no effect on respiratory mortality, was also investigated. An apparent protective effect against all cause mortality was seen.9 The authors concluded that the estimate of vaccine effectiveness against all cause mortality during influenza seasons was probably upwardly biased due to the "healthy vaccinee" effect. Our study also shows the presence of the healthy vaccinee effect (second column of table), but we controlled for this by comparing effects of influenza rather than mortality in vaccinated and unvaccinated people, as described earlier.

    What is already known on this topic

    Randomised trials have shown effectiveness of vaccination against influenza, but mortality is too rare an end point for a reduction to be clearly established

    Observational studies have estimated effects on mortality but are subject to confounding and to problems in identifying deaths due to influenza

    What this study adds

    Mortality in periods of high circulating influenza was clearly increased in unvaccinated people but not in vaccinated people, strongly suggesting a protective effect of vaccination

    By avoiding direct comparisons of mortality in vaccinated and unvaccinated people in favour of comparisons of responses to circulating influenza, we avoided most confounding

    The difference in the point estimates of vaccine effectiveness between the results in the literature and our estimate could thus be due to differences in methods as discussed above or to chance, given our wide confidence intervals. In particular, the greater specificity of outcome from the examination of mortality during periods of high influenza activity and adjustment for cold weather may account for the higher effectiveness seen here. In conclusion, this research adds to evidence that influenza vaccination protects against mortality from influenza, although estimates of vaccine effectiveness are imprecise. The novel method we adopted offers improved control of confounding at the cost of some precision and is applicable to most studies of effects of episodic infections on mortality.

    Details of statistical methods are on bmj.com

    We thank the respiratory division of CDSC, Public Health Laboratory Service (since April 2003 the Health Protection Agency) for access to laboratory reports of influenza. AMcM now works at the National Centre for Epidemiology and Population Health, Australian National University, Canberra.

    Contributors: BGA was involved in study design, statistical analysis, and preparation of the manuscript. PM was involved in collection of data on vaccination and influenza and preparation of the manuscript. AF was involved in study design and was principal investigator for this study and the parent study. SK was involved in collection of data on vaccination, influenza, and weather. AMcM and PW were involved in study design. SP was involved in statistical analysis. All contributors commented on manuscript drafts and participated in study progress meetings. BGA is the guarantor of the paper. He accepts full responsibility for the conduct of the study, had access to the data and controlled the decision to publish in consultation with the other authors.

    Funding: This study was supported by the UK Medical Research Council. PM was funded by the Wellcome Foundation (grant number 051637) during this work. PW is supported by a public health career scientist award (NHS Executive, CCB/BS/PHCS031).

    Competing interests: None declared.

    Ethical approval: The study was approved by the relevant local research ethics committees.

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