Impact of influenza vaccination on mortality
risk among the elderly
R.H.H. Groenwold*, A.W. Hoes* and E. Hak*,#
nonrandomised studies and therefore are potentially confounded. The aim of the current study
was to estimate influenza vaccine effectiveness in preventing mortality among the elderly, taking
both measured and unmeasured confounding into account.
Information on patients aged o65 yrs from the computerised Utrecht General Practitioner
database on eight influenza epidemic periods and summer periods was pooled to estimate
influenza vaccine effectiveness in preventing mortality. Summer periods (during which no effect
of vaccination was expected) were used as a reference to control for unmeasured confounding in
After adjustment for measured confounders using multivariable regression analysis, propensity
score matching and propensity score regression analysis, influenza vaccination reduced mortality
risk (odds ratios (ORs) 0.58 (95% confidence interval (CI) 0.46–0.72), 0.56 (95% CI 0.44–0.71) and
0.56 (95% CI 0.45–0.69), respectively). After additional adjustment for unmeasured confounding
(as observed during summer periods), the association between influenza vaccination and
mortality risk decreased (OR 0.69 (95% CI 0.52–0.92)).
We conclude that after state-of-the-art adjustment for typical confounders such as age, sex and
comorbidity status, unmeasured confounding still biased estimates of influenza vaccine
effectiveness. After taking unmeasured confounding into account, influenza vaccination is still
associated with substantial reduction in mortality risk.
Estimates of influenza vaccine effectiveness have mostly been derived from
introduction of influenza vaccines, only one
randomised double-blind trial has been con-
ducted among (younger) elderly persons, and
influenza infection was halved in the vaccine
group compared with the placebo group .
Large-scale trials evaluating more serious out-
comes such as mortality are not available, in part
because of the large sample size needed, and also
due to ethical constraints. Instead, several non-
randomised observational studies have set out to
estimate the effects of influenza vaccination on
serious outcomes among elderly persons [4, 5]. In
2007, results were published of a 10-yr United
States Health Maintenance Organisation data-
pooling project, including more observations
than available in all meta-analyses, and findings
of substantial mortality reduction of the same
magnitude as in previous studies were observed
. However, recently there has been a debate
regarding the validity of findings from such
nnually, influenza epidemics are asso-
ciated with high mortality rates, notably
among elderly persons [1, 2]. Since the
nonrandomised studies [7, 8]. The main concern
is that selection of patients for influenza vaccina-
tion in daily practice has resulted in incompar-
able groups of vaccinated and unvaccinated
subjects, which may have led to considerable
confounding bias [9, 10].
Several methods have been proposed in order to
adjust for measured confounders, but unmea-
sured confounders are likely to result in residual
bias. For example, functional health status, which
is not routinely collected in medical databases, is
an important potential confounder [11, 12].
NICHOL et al.  quantified the potential effect
of such an unmeasured confounder using sensi-
tivity analysis and showed that only in unlikely
confounder scenarios was influenza vaccination
not associated with mortality reduction.
Alternatively, the use of reference periods has
also been proposed to quantify unmeasured
confounding, since vaccine effectiveness can be
considered known during these periods . For
example, in pre-influenza [7, 13, 14], or summer
*Julius Center for Health Sciences
and Primary Care, University Medical
Center Utrecht, Utrecht, and
#Dept of Epidemiology, University
Medical Center Groningen,
Groningen, The Netherlands.
Julius Center for Health Sciences and
University Medical Center Utrecht
P.O. Box 85500
Dec 16 2008
Accepted after revision:
Jan 19 2009
First published online:
Feb 12 2009
European Respiratory Journal
Print ISSN 0903-1936
Online ISSN 1399-3003
VOLUME 34 NUMBER 1
EUROPEAN RESPIRATORY JOURNAL
Eur Respir J 2009; 34: 56–62
Copyright?ERS Journals Ltd 2009
unmeasured confounding into account. After adjusting for both
measured and unmeasured confounding, influenza vaccination
was associated with a 30% reduction in all-cause mortality
during influenza epidemics among elderly persons and efforts
should continue to vaccinate these high-risk persons.
What is already known on this topic
Since most evidence for influenza vaccine effectiveness in
terms of reduction of mortality among the elderly has been
derived from nonrandomised studies, selection of patients for
influenza vaccination may have induced confounding bias
and, hence, vaccine effects might have been overestimated.
Summer periods have been used as a reference period to
quantify unmeasured confounding.
What this study adds
In the present study, in which data on eight influenza epidemic
periods were pooled, unmeasured confounding was taken into
account by estimating influenza vaccine effectiveness during a
summer reference period. After adjustment for both measured
and unmeasured confounding, influenza vaccination was still
associated with substantial mortality risk reduction.
This study is part of a personal grant of E. Hak, to study confounding
in observational intervention studies, from the Netherlands Scientific
Organization (The Hague; NWO-VENI no. 916.56.109).
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EUROPEAN RESPIRATORY JOURNAL