Risk of Myocardial Infarction and Stroke after Acute Infection or Vaccination
Liam Smeeth, Ph.D.,
Sara L. Thomas, Ph.D., Andrew J. Hall, Ph.D., Richard Hubbard, D.M., Paddy Farrington,
Ph.D., and Patrick Vallance, M.D.
ABSTRACT
Background There is evidence that chronic
inflammation may promoteatherosclerotic disease. We tested the hypothesis that
acuteinfection and vaccination increase the short-term risk of vascularevents.
Methods We undertook within-person
comparisons, using the case-seriesmethod, to study the risks of myocardial
infarction and strokeafter common vaccinations and naturally occurring
infections.The study was based on the United Kingdom General Practice ResearchDatabase, which contains computerized medical records of morethan 5
million patients.
Results A total of 20,486 persons with a
first myocardial infarctionand 19,063 persons with a first stroke who received
influenzavaccine were included in the analysis. There was no increasein
the risk of myocardial infarction or stroke in the periodafter influenza,
tetanus, or pneumococcal vaccination. However,the risks of both events were
substantially higher after a diagnosisof systemic respiratory tract infection
and were highest duringthe first three days (incidence ratio for myocardial
infarction,4.95; 95 percent confidence interval, 4.43 to 5.53; incidenceratio
for stroke, 3.19; 95 percent confidence interval, 2.81to 3.62). The risks then
gradually fell during the followingweeks. The risks were raised significantly
but to a lesser degreeafter a diagnosis of urinary tract infection. The
findings forrecurrent myocardial infarctions and stroke were similar tothose
for first events.
Conclusions Our findings provide support for
the concept thatacute infections are associated with a transient increase inthe risk of vascular events. By contrast, influenza, tetanus,and
pneumococcal vaccinations do not produce a detectable increasein the risk of
vascular events.
Systemic inflammation and infections
accelerate atherogenesisin animals,1 and
circulating markers of inflammation, such asC-reactive protein, predict the
risk of vascular events in humans.2,3However,
systemic inflammation is not a constant but variesin response to infections or
to other proinflammatory stimuli.Such intermittent changes may be linked to an
increase in therisk of vascular events. Indeed, inflammatory markers predictthe outcome in acute vascular events4,5; an increased
leukocytecount may herald a short period of increased risk of stroke6;and
several small studies have suggested that there may be atransient increase in
the risk of a myocardial infarction afterinfection.7,8,9,10,11,12
The mechanisms by which acute inflammation may
affect the riskof vascular events are uncertain but may include endothelialdysfunction. Such dysfunction is a feature of the increasedrisk induced
by conventional risk factors,13,14 and in an
experimentalmodel, the vaccination of healthy volunteers induced a short-livedinflammation that was associated with profound suppression ofendothelium-dependent
relaxation.15 If the
likelihood of a vascularevent is related to variations in the underlying
inflammatorystate and endothelial function, many naturally occurring commoninfections or even vaccination could be associated with a short-livedincrease
in the event rate. To test this hypothesis, we studiedthe incidence of
myocardial infarction and stroke after influenzaand other vaccinations or
after naturally occurring infections,using the United Kingdom General Practice
Research Database(GPRD) and the self-controlled case-series method.16
Methods
Database
The GPRD has been described in detail elsewhere.17 It is
thelargest source of continuous data on illness and prescribinghabits
in the United Kingdom.17 The
database is representativeof all practices in England and Wales in terms of
geographicdistribution and size, and the age and sex distributions ofthe
population included in it are similar to those of the wholepopulation of the
United Kingdom.18 The
information obtainedfor the database is anonymous. We obtained approval for
ourstudy from the scientific and ethics advisory group of the GPRD.
Participants
The source population was all patients who were
registered forat least one year with a general practice that contributed tothe GPRD between 1987 and 2001 (i.e., a total of 5,767,499 peoplefrom
687 general practices). The patients had received one ortwo new diagnoses of
myocardial infarction or stroke duringthe period of at least six months after
the start of their follow-upin the GPRD. The events documented during the
first six monthswere excluded because of the possibility that they had
occurredbefore the patient joined the GPRD and had been recorded
retrospectively.We did not differentiate between ischemic and hemorrhagic
stroke,because such differentiation has been shown to be unreliablewith
the use of the GPRD.19 Patients
were excluded if they wereyounger than 18 years of age at the time of a first
myocardialinfarction or stroke recorded in the GPRD or if the data intheir
medical records indicated that the vascular event waslikely to have been
recorded retrospectively. Examples of retrospectivelyrecorded data include the
date of a myocardial infarction orstroke that was the same as the recorded
date of other medicalevents on the date of a new-patient or well-person visit,
dischargefrom the hospital, or a postmortem report or cremation certificate.
Exposure
Data were extracted on vaccinations against
influenza, tetanus,and pneumococcus. Some patients had multiple records withina few days of one another for the same vaccination, indicatingthat the
recorded date of the vaccination was inaccurate. Therefore,for our study,
vaccinated persons were restricted to those forwhom an influenza vaccination
was recorded on a single day withinthe vaccination season (September 1 to
March 31), tetanus vaccinationswere received at least three months apart, or a
single pneumococcalvaccination was recorded. Data were also extracted on acuteurinary tract infections and acute systemic respiratory tractinfections
such as pneumonia, acute bronchitis, "chest infections,"and
influenza.
Case-Series Method
Because vaccinated and unvaccinated persons and
those with diagnosedinfection and those without it differ in ways that are
difficultto measure and control for, we undertook within-person comparisonsusing the case-series method16,20 in a
population of personswho had the outcome of interest. We derived measures of
therelative incidence of events within defined intervals afteran
exposure as compared with all other observed time periodsfor each person.21 The null
hypothesis was that vascular-eventrates remain constant from day to day and
are not affected byan acute exposure to vaccination or infection. The period
ofexposure was defined as extending up to 91 days after the inflammatoryexposure
and was subdivided into periods of 1 through 3 days,4 through 7 days, 8
through 14 days, 15 through 28 days, and29 through 91 days after the exposure.
All other observationtime was taken as the baseline period (i.e., without
exposure).
Vascular events recorded on the same day as a
vaccination oran infection were excluded from the baseline period, becausethese events may have been recorded retrospectively, when thepatient
attended the general practice for another reason, asshown in a previous study.22 For
participants who were exposedto a vaccine or an infection more than once
during the observationperiod, each exposure was followed by a 91-day period in
whichthe participants were at risk. This method and the time intervalsused
are illustrated in Figure 1. Incidence
ratios were calculatedfor events occurring within each stratum of the period
of exposureas compared with the baseline periods.
Outcome Measures
We performed separate analyses for the type of event
(myocardialinfarction or stroke), whether the event was the first of itstype
or a subsequent event, and the type of inflammatory exposure.A recurrent event
was defined as either the first occurrenceof the event during the observation
period for a participantwho had had the same type of event before the start of
the observationperiod or the second of two events that both occurred withinthe observation period for a participant with no history ofsuch an
event. The baseline risk of myocardial infarction orstroke is higher among
persons who have had a vascular event.Therefore, the observation period for a
recurrent event wasrestricted to the time after the first event had occurred
—either beginning six months after the start of observation ofthe
participant in the GPRD (for the first occurrence of anevent during the
observation period for a participant who hadhad the same type of event before
the start of the observationperiod) or beginning with the date of the first
event withinthe observation period (for the second of two events that occurredwithin the observation period).
The exception to these starting dates was influenza
vaccination.One of the indications for administration of this vaccine ispreexisting
cardiovascular disease, so that the probabilityof receiving influenza
vaccination is itself associated withthe risk of vascular events. To ensure
that during the observationperiod there was minimal variation in the
opportunity to bevaccinated, the observation period used in the analysis withregard to influenza vaccination did not include the time beforea
participant's first influenza vaccination.
Age, Time, and Secondary Analyses
Age was controlled for in five-year age groups, and
the analysiswas repeated with the use of two-year age groups to assess whetherfiner stratification affected the results. In a case-seriesanalysis,
participants who are not exposed to a stimulus atany time during the
observation period do not contribute tothe estimate of the association between
exposure and outcome,but the inclusion of such participants can improve
control forconfounding by age. Our primary analysis was restricted to
participantswho were exposed to inflammatory stimuli at least once duringthe follow-up period, but the analysis was repeated to includeall cases
in order to ensure that the estimates did not vary.Because the chance of
receiving a vaccination during the periodimmediately after a vascular event
may have been different fromthat during the remainder of the observation
period, we repeatedthe analysis by excluding from the baseline period the
threemonths before each vaccination.
Deaths from cardiovascular disease are more common
in winterthan in summer.23
Respiratory infections occur more commonlyin the winter months, and influenza
vaccine is usually administeredin the early winter. Therefore, a temporal
association betweenvascular events and respiratory infections or influenza
vaccinationcould be observed even in the absence of a causal role. To
investigatethis possibility, we analyzed separately the effect of respiratorytract infections acquired in warm months (April through September)and in
cool months (October through March).
We estimated that the analysis of the risk of
myocardial infarctionor stroke after influenza vaccination could include
around 20,000participants who had been exposed, a sample size sufficientto
provide more than 90 percent power at the 5 percent levelof significance to
detect a rate ratio of 1.3 during the firstthree days after exposure.
Results
A total of 61,556 adults with a first or subsequent
myocardialinfarction were identified in the GPRD, of whom 1495 were excludedbecause the date of the myocardial infarction was uncertain.Of the
remaining 60,061 patients, 53,709 had had a first myocardialinfarction (median
age at myocardial infarction, 72.3 years;interquartile range, 62.9 to 80.5;
male sex, 59.1 percent; meanduration of observation, 5.6 years), and 12,134
had had a recurrentmyocardial infarction (median age, 71.8 years;
interquartilerange, 63.3 to 79.1; male sex, 68.8 percent; mean duration ofobservation, 4.1 years). There were 5782 persons with no historyof
myocardial infarction before the observation period who hadtwo myocardial
infarctions within the observation period andwere included in both groups of
participants. Of a total of56,018 adults with a first or subsequent stroke who
were identifiedin the GPRD, 861 were excluded because of an unlikely date ofstroke. Of the remaining 55,157 patients, 50,766 had had a firststroke
(median age at stroke, 78.3 years; interquartile range,70.2 to 85.0; male sex,
43.8 percent; mean duration of observation,5.3 years), and 12,804 had had a
subsequent stroke (median age,78.8 years, interquartile range, 71.2 to 85.0;
male sex, 46.6percent; mean duration of observation, 3.5 years). Subsequently,13,099 patients with myocardial infarction and 12,572 with strokewere
excluded from one or more of the vaccine analyses becauseof uncertain
vaccination dates.
Only persons who were exposed to either vaccine or
infectionwere included in the primary analysis (Table 1 and Table 2).The
proportion of participants with a first myocardial infarctionor stroke who
were exposed to the stimuli of interest rangedfrom 9 percent (those with
stroke who were exposed to pneumococcalvaccine) to 44 percent (those with
stroke who were exposed toa systemic respiratory tract infection). The numbers
of patientsexposed who had a first myocardial infarction or a first strokeand the age-adjusted incidence ratios of a first myocardialinfarction or
stroke after vaccination and acute infection areshown in Table 1.
There was no increase in the rate
of a first myocardial infarctionor stroke in the periods after vaccination.
However, the ratesof both myocardial infarction and stroke were substantiallyhigher after a diagnosis of an acute respiratory tract infection.The
rates were highest during the first three days after exposure(i.e., an
increase by a factor of nearly five for myocardialinfarction and a factor of
slightly more than three for stroke)and then fell during the following weeks.
The rates also increasedafter a diagnosis of urinary tract infection.
For second myocardial infarctions or second strokes,
again,there was no increase in the rate of events after vaccination(Table 2). The rate of
second events after a diagnosis of respiratorytract infection or urinary tract
infection followed patternssimilar to those observed for first events,
although the effectestimates were slightly lower.
Secondary Analyses
Controlling for age in two-year age groups,
including participantswho had not been exposed, and excluding the three months
beforeeach vaccination made no material difference to the effect estimates(data not shown). There were slightly more participants witha first
myocardial infarction (21,957) or stroke (20,023) inwinter than in summer
(20,154 participants with a first myocardialinfarction, and 19,148 with a
first stroke). However, the significantgraded effect of respiratory tract
infection remained when theanalysis was restricted to events occurring in the
summer.
Discussion
This study shows that acute lower respiratory tract
infectionsand urinary tract infections are associated with a transientincrease
in the risk of a vascular event. The effect is seenfor a first or a subsequent
myocardial infarction or strokeand is most marked in the few days after
infection. These findings,based on a very large set of data, support the link
betweenacute infection and the risk of a vascular event, identify themagnitude
of the association and its resolution over time, andoffer insight into the
factors that may determine the timingof acute vascular events. No increase in
the event rate wasdetected after influenza, tetanus, and pneumococcal
vaccines.
In a study of the risk of vascular events after
inflammatorystimuli, the potential for confounding is great, because
participantswho are vaccinated or in whom infections develop may differfrom
those who are not vaccinated or do not have infections.The advantage of the
case-series method is that the influenceof factors that vary among the
participants, such as the baselinecardiovascular risk, is removed, because
within-person comparisonsare performed. The null hypothesis was that the event
ratesstay relatively constant with time and are not influenced bydiscrete
external stimuli such as acute infections. Our findingof a substantial but
short-lived increase in the incidence ofvascular events after acute infection
shows that the risk ofa cardiovascular event fluctuates, and it is highly
suggestiveof a causal role for acute infections in triggering cardiovascularevents.
There has been one previous case–control study
of an associationbetween acute respiratory tract infection and myocardial
infarctionthat was based on the GPRD.24 The
study included 475 personswho had a respiratory tract infection within the 12
months precedinga myocardial infarction and found that the risk of respiratoryinfection was increased by approximately a factor of three duringthe 10
days before the myocardial infarction but found no significantassociation with
urinary tract infection. We confirmed thisfinding in a much larger group (more
than 20,000 participantsexposed to respiratory tract infections), using a
differentstudy design. In our study, the effect was similar for stroke,for
both first and subsequent events, and, unlike the earliersmaller study, our
study showed an increased risk after urinarytract infection. This finding is
important, because it suggeststhat the effect of infections on cardiovascular
risk may begeneric and is not linked to specific types of infection.
Furthermore,although certain cardiac presentations might be misdiagnosedas
respiratory tract infection, this seems highly unlikely tobe the case for
urinary tract infection.
Our study was based on routine clinical data, and a
potentialweakness may be related to the quality of the data. However,the
diagnosis of myocardial infarction in the GPRD has beenexamined in a subgroup
of patients on the basis of electrocardiographicfindings, elevated levels of
cardiac enzymes, features of thehistory, or the receipt of fibrinolytic
therapy, and the diagnosiswas confirmed in more than 90 percent of the
recorded cases.25,26A diagnosis
of stroke in the GPRD was checked by a review ofhospital records and confirmed
in 89 percent (78 of 88) of cases,and the incidence rates for stroke are
similar to estimatesobtained from other sources.19 The
vaccination data recordedin the GPRD are likely to be of high quality, because
thereis close agreement between the prescribing data in this databaseand
national data from the Prescription Pricing Authority; moreover,general
practitioners have a financial incentive to record vaccinesgiven.27
The incidence rates of myocardial infarction or
stroke did notreturn fully to the baseline level within the three-month riskperiod after infection, a result that might be due to a greaterlikelihood
that a diagnosis was recorded, but the magnitudeof the residual increase was
small (incidence ratio, 1.2 to1.4) and even after taking this increase into
account, the greatlyincreased rates seen in the period soon after infection
remainedsignificantly elevated. The effects of infection were not explainedby seasonal patterns of exposure and vascular events.
One limitation of the study is that we did not know
preciselythe date of onset of infections but, rather, used the date ofdiagnosis.
However, the majority of patients, even those withupper respiratory tract
infections, visit their general practitionerwithin three days after the onset
of symptoms,28 so that
weare unlikely to have underestimated the duration of the increasein
the risk of vascular events by more than a few days. An advantageof looking at
vaccination as a stimulus is that we knew thedate of exposure, but we saw no
effect of vaccination on risk,probably because both the magnitude and the
duration of theinflammation induced by vaccination are small,15 as
comparedwith naturally occurring infection.29 The
small protective effectseen after vaccination may have been due to the
administrationof vaccination when people were in periods of relatively goodhealth.
The finding that two very different infectious
processes indifferent organ systems are associated with a large but transientincrease in the risk of cardiovascular events lends strong supportto the
concept that systemic inflammation itself alters theprobability of the
occurrence of a vascular event. The alternativeexplanation that there is some
common acute precipitant of infectionand vascular events seems less likely. We
do not know whetherthe transient increase in risk is due to a short-term
alterationof endothelial function or to other mechanisms, such as changesin plaque composition, white-cell activation, dehydration, orbed rest.
Clearly, however, it will now be important to establishthe mechanisms of and
implications for prevention.
Our observations offer insight into the factors that
may determinethe timing of the onset of a vascular event in persons who havehad a fairly stable degree of atherosclerosis for many years.The mild
transient inflammation and associated suppression ofendothelium-dependent
relaxation induced by vaccination15 doesnot appear to translate into a detectable increase in the riskof
vascular events.
Supported by a grant from the
British Heart Foundation; a MedicalResearch Council Clinician Scientist
Fellowship (to Dr. Smeeth);and a Wellcome Trust Advanced Fellowship (to Dr.
Hubbard).
We are indebted to Chris Smith and
Helena Viljoen for help withdata processing.
Source Information
From the Departments of Epidemiology and
Population Health (L.S.) and Infectious and Tropical Diseases (S.L.T., A.J.H.), London
School of Hygiene and Tropical Medicine, London; the Division of Respiratory Medicine,
University of Nottingham, Nottingham (R.H.); the Division of Statistics, Open University,
Milton Keynes (P.F.); and the Centre for Clinical Pharmacology, British Heart Foundation
Laboratories, Division of Medicine, University College London (P.V.) — all in the
United Kingdom.
Address reprint requests to Dr. Smeeth at
the Department of Epidemiology and Population Health, London School of Hygiene and
Tropical Medicine, Keppel St., London WC1E 7HT, United Kingdom, or at liam.smeeth@lshtm.ac.uk.
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