‘Infectious Burden’ – New Insights into Stroke Prevention
clinical trial among 3,168 patients with 4.5 years of follow-up. They assessed IgG and IgA antibodies for H. pylori, C. pneumoniae, CMV and HAV and evaluated a combination of CV outcomes (MI, stroke or CV death).53
Those subjects with an IB score of four (17% of the study group) had a modest increased risk of vascular events (adjusted RR 1.41, 95% CI 1.02–1.96) compared with those with a score of nought to one. The authors note that antibody titres may be consistent with several underlying phenomena, including re-infection, persistence or non-specific immune stimulation. Stroke alone was not found to be associated with this IB score.
A few studies of the association of IB and stroke alone have been performed. In a case–control study of 91 acute strokes or transient ischaemic attacks (TIAs) and 87 hospital controls, the authors measured IB with three pathogens (C. pneumoniae, M. pneumoniae and Legionella pneumophila). Those with three positive serologies were at higher risk of stroke compared with those with one positive serology. The analysis was adjusted for traditional risk factors. Grau et al., in a case–control study of 370 ischaemic or haemorrhagic strokes and TIA matched to 370 population controls, observed that more than two non-specific flu-like infections per year was associated with increased stroke risk (adjusted OR 3.68, 95% CI 1.52–8.27) compared with those with fewer than two events per year.54
However, not all studies have found an association between IB measures and cardiovascular risk.55
In an analysis of 1,056 subjects
selected from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, there was no association between IB and IMT or coronary artery calcification.56
However, there are several limitations to the existing studies. The assessment of IB across these studies fails to distinguish the effects of different pathogens and assumes an equal contribution to disease. Also, the threshold for determination of a positive serology differs among studies and in some cases was established post hoc. Furthermore, the prevalence of risk factors and infectious pathogens varies across study samples.
To address some of these concerns of heterogeneity of the IB measurement construct and other potential limitations, NOMAS constructed a novel measure of IB that allows for variable impacts of different pathogens by applying weights for the magnitude of association with stroke, specific to the population under study.57
The
NOMAS cohort is an urban, population-based prospective study in a tri-ethnic population. The IB index comprised weights derived from univariate Cox model parameter estimates of associations between individual infectious serologies (antibodies to C. pneumoniae, H. pylori, CMV, HSV1 and HSV2) and stroke, using baseline serum samples from 1,625 participants. The mean IB index was significantly (p
These findings EUROPEAN NEUROLOGICAL REVIEW
support the methodological approach of deriving IB measures based on the observed weights of individual pathogens associations for a given population. Although promising, these results need to be validated in other study populations.
Acute Infection as a Precipitant to Ischaemic Stroke
Acute infections may play a specific role in triggering acute vascular events. Thrombotic complications arise when the site of an atherosclerotic plaque becomes destabilised and exposes the underlying pro-coagulant surface.59
Although macrophage activity
has been shown to play a role in fibrous plaque destabilisation,60 the precipitants of ischaemic events remain largely unknown. Empirical evidence across multiple studies and populations suggests acute infections may play a role. The magnitude of association between preceding infections and vascular events appears to increase with increasing proximity in timing. In a case–control study, an increasing association of stroke and respiratory infection was found as the period between infection and stroke decreased: adjusted OR 1.09 at 29–91 days before stroke, OR 1.76 at eight to 28 days before stroke and OR 1.92 at one to seven days before stroke.61
Ischaemic coronary
and cerebrovascular events have been associated with recent respiratory infection and influenza-like illness,62–64 infections,65
community-acquired pneumonia66 and gastroenteritis.67
Many studies have focused on the role of influenza in precipitating vascular events.68,69
Prevention Strategies and Interventions The accumulated evidence implicating IB in atherogenesis and stroke supports the a priori hypothesis that intervening with antimicrobials or vaccination strategies may reduce the risk of vascular events. Observational studies provided early evidence that vaccination strategies may be effective in preventing vascular events in high-risk populations. Influenza vaccination has been associated with a decreased risk of stroke, for example, even after adjusting for risk factors, education and health-seeking behaviour. Vaccine effects were significant in individuals with characteristics consistent with high-risk groups such as age >65 years and previous history of vascular disease. In a large observational study among 286,383 Oxford Health Plan members, influenza vaccination status, as measured by insurance databases, was associated with a 16% reduction (p
Based on these
and other data, recommendations from professional organisations advise influenza vaccination for secondary prevention of CVD.71
On the other hand, numerous randomised trials of antibiotic therapy for vascular risk reduction, primarily focused on treatment of C. pneumoniae, have provided mixed results.72–84
A meta-analysis
of 12 of these trials found no significant association between antibiotic treatment and risk of vascular disease or death (OR 0.84, 95% CI 0.67–1.05), although the direction of the effect was protective.85
However, these studies were not primarily focused on patients with cerebrovascular disease and it remains possible that effects in stroke prevention may differ from those in heart disease. Moreover, despite overall null findings, antibiotic regimens may be effective in subpopulations of patients. Furthermore, most antibiotics in these trials were not expected to be active against latent or hidden forms of infection. Some studies suggest that some antibiotic
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