‘Infectious Burden’—New Insights into Stroke Prevention serum levels were not specified.39 Polymorphisms in the TLR4 gene have
been demonstrated to increase risk for MI in the presence of infection as well.40
Chronic Infection—Single Pathogen Associations with Stroke
Several case–control and cross-sectional studies have found a positive association between C. pneumoniae antibody titers and stroke risk.41,42 For example, in data from the Northern Manhattan Study (NOMAS), 246 stroke cases were matched by age, sex, and race/ethnicity to 474 population-based controls.43
Elevated C. pneumoniae immunoglobulin
A (IgA) titers were significantly associated with risk for ischemic stroke after adjusting for other stroke risk factors (adjusted odds ratio [OR] 1.5, 95% confidence interval [CI] 1–2.2). IgG titers were not significantly associated with stroke risk (adjusted OR 1.2, 95% CI 0.8–1.8).43
There
was also a statistically significant interaction between sex and C. pneumoniae antibody status, with an increased risk associated with IgA titers among women (p=0.04). The fact that IgA titers were more consistently associated with risk for stroke than IgG titers in this and other studies may reflect the possibility that IgA antibodies, which remain for 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 support this hypothesis, although there is no consensus on this matter.45
association of C. pneumoniae antibody titers and stroke risk.
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 ischemic stroke.
Clinical studies of herpesviruses have found evidence that herpesvirus infection may also be associated with risk for stroke. For example, in one case–control study 59 subjects with acute ischemic stroke at early age onset (mean age 50.4 years) and 52 hospital controls were assessed.46
Prospective studies have also not confirmed an
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 ischemic 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 responses, are most likely to have advanced atherosclerosis and be at the greatest risk for vascular events.
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 angiographic-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 subjects had exposure to at least three pathogens. Positivity for five infectious agents compared with those with positivity for fewer than two was associated with an increased risk for disease (adjusted OR 6.08; p
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
Similarly, some evidence supports an association between H. pylori and ischemic stroke. In a case–control study in which 80 ischemic stroke patients were age- and sex-matched to 320 blood donors, H. pylori serologies were significantly associated with acute ischemic stroke. H. pylori has also been implicated in ischemic 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 to be 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 empiric 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
US NEUROLOGY
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 population was observed to have six to nine positive serologies.
Only 6% of this
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%
47
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