Brain Trauma Stroke race/ethnicity to 474 population-based controls.43 Elevated
C. pneumoniae immunoglobulin A (IgA) titres were significantly associated with risk of ischaemic stroke after adjusting for other stroke risk factors (adjusted odds ratio [OR] 1.5, 95% confidence interval [CI] 1–2.2). IgG titres were not significantly associated with stroke risk (adjusted OR 1.2, 95% CI 0.8–1.8).43
responses, are most likely to have advanced atherosclerosis and be at the greatest risk of vascular events.
There was also a
statistically significant interaction between sex and C. pneumoniae antibody status, with an increased risk associated with IgA titres among women (p=0.04). The fact that IgA titres were more consistently associated with risk of stroke than IgG titres in this and other studies may reflect the possibility that IgA antibodies, which last only three to five days in the circulation, are a marker of persistent, chronic infection, while IgG antibodies, which remain elevated for several years after infection, are a marker of remote, completed infection.44
Evidence from studies of IgA in other
chlamydial diseases supports this hypothesis, although there is no consensus on this matter.45
Prospective studies have also not
confirmed an association of C. pneumoniae antibody titres and stroke risk.
Clinical studies of herpesviruses have found evidence that herpesvirus infection may also be associated with risk of stroke. For example, in one case–control study 59 subjects with acute ischaemic stroke at early age onset (mean age 50.4 years) and 52 hospital controls were assessed.46
Only positivity to CMV IgG (adjusted OR
2.94, 95% CI 1.27–6.81) and HSV1 IgA (adjusted OR 4.65, 95% CI 1.34–16.16) demonstrated associations with ischaemic stroke.
Similarly, some evidence supports an association between H. pylori and ischaemic stroke. In a case–control study in which 80 ischaemic stroke patients were age- and sex-matched to 320 blood donors, H. pylori serologies were significantly associated with acute ischaemic stroke. H. pylori has also been implicated in ischaemic heart disease.47
Interestingly, a large-scale cohort study of 10,938 normotensive patients in Sweden found stomach ulcers to be significantly associated with a first stroke (adjusted relative risk [RR] 2.21, 95% CI 1.03–4.71), after adjusting for risk factors. Although H. pylori was not investigated in this study, it is considered an important cause of stomach ulcers.
Chronic Infection – Associations of Multiple Pathogens with Stroke – ’Infectious Burden’ Construct
The lack of consistency among studies attempting to link exposure to infectious pathogens and stroke risk provides empirical evidence that a single pathogen is likely not responsible for stroke. Pathogens elicit a complex and multifactorial response from the host immune system that occurs in the presence of other vascular risk factors. In fact, the role of chronic infection in atherosclerosis may be complementary in terms of existing risk factors that elicit atherosclerotic effects. Restructuring the measurement construct of ‘infectious exposure’ as ‘pathogen burden’ or IB aligns with our understanding that the totality of pro-inflammatory agents can contribute to atherosclerosis. For example, the role of low-density lipoprotein (LDL) in ischaemic stroke would be difficult to elucidate by measuring only recent exposure to cheeseburgers. Instead, the cumulative life-course exposure to dietary fat intake is of consequence to atheromatous plaque progression. Analogously, those individuals with the greatest IB, defined as cumulative life- course exposure to infectious agents eliciting strong inflammatory
36
Several studies have incorporated IB measures in their study design and have found significant associations with vascular disease. Zhu et al. considered total pathogen burden as an independent predictor of vascular disease.2
This study primarily selected from a
population of individuals with complaints of chest pain or suspected MI, and the outcome was defined as coronary artery disease (CAD) with angiographically confirmed atherosclerosis. The infectious pathogen measure (IgG antibodies to C. pneumoniae, CMV, HAV, HSV1 and HSV2) was categorically partitioned as nought to two, three to four or five positive serologies. Within this study, 68% of individuals had CAD and 75% of the subjects had exposure to at leat three pathogens. Positivity for five infectious agents compared with those with positivity for fewer than two was associated with an increased risk of disease (adjusted OR 6.08; p
Another study of 504 randomly selected participants of the AtheroGene cohort measured IB (IgG and IgA antibodies for HSV1, HSV2, CMV, Epstein-Barr virus (EBV), Haemophilus influenzae, C. pneumoniae, Mycoplasma pneumoniae and H. pylori) and carotid atherosclerosis progression.49
IB was partitioned into
categories of nought to three, four to five or six to eight positive serologies, and progression was confirmed by Doppler ultra- sonography over 2.5 years of follow-up. Those with six to eight serologies were significantly more likely to have progression of carotid IMT than those with nought to three positive serologies (adjusted OR 3.8, 95% CI 1.6–8.8). These results were adjusted for risk factors and a dose-response was observed. A second cohort study by the same group among 572 subjects found advanced atherosclerosis, as measured by angiography, Doppler and ankle–arm indices, to be significantly higher in those individuals with six to eight serologies.50
Only 6% of this population was observed to have six to nine positive serologies.
Vascular outcome end-points have also been found to be associated with IB measures. A second study by Zhu et al. in a cohort of 890 subjects with angiographically confirmed CAD who were followed for three years found an association between MI and IB.51
At least six positive infectious serologies compared with nought to one positive serologies was significantly associated with MI (adjusted RR 3.18, 95% CI 1.32–7.66) after adjusting for traditional risk factors. Although the reference group sample size was small, the test for trend was significant (p=0.0006) and showed increasing risk for each additional positive serology. Stroke was not evaluated in this study. Among 1,018 patients,52
Rupprecht
et al. assessed IgG or IgA antibodies to CMV, EBV, HSV1, HSV2, H. influenzae, C. pneumoniae, M. pneumoniae and H. pylori, and separated participants into nought to three, four to five or six to eight positive serologies. Those with six to eight positive serologies comprised 22% of the study population and were at increased risk of death from cardiovascular disease (CVD) (adjusted RR 5.1, 95% CI 1.4–18.3). The association was mainly driven by herpesviridae (p
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