Timing and number of minor infections as risk factors for childhood arterial ischemic stroke

Abstract

Objective: In a population-based case-control study, we examined whether the timing and number of minor infections increased risk of childhood arterial ischemic stroke (AIS).Methods: Among 102 children with AIS and 306 age-matched controls identified from a cohort of 2.5 million children in a large integrated health care plan (1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007), we abstracted data on all medical visits for minor infection within the 2 years prior to AIS or index date for pairwise agematched controls. We excluded cases of AIS with severe infection (e.g., sepsis, meningitis). Using conditional logistic regression, we examined the effect of timing and total number of minor infections on stroke risk. Results:After adjusting for known pediatric stroke risk factors, the strongest association between infection and AIS was observed for infectious visits #3 days prior to stroke (odds ratio [OR] 12.1, 95% confidence interval [CI] 2.5, 57, p 5 0.002). Respiratory infections represented 80% of case infections in that time period. Cases had more infectious visits, but not significantly so, for all time periods $4 days prior to the stroke. A greater cumulative number of infectious visits over 2 years did not increase risk of AIS.Conclusions: Minor infections appear to have a strong but short-lived effect on pediatric stroke risk, while cumulative burden of infection had no effect. Proposed mechanisms for the link between minor infection and stroke in adults include an inflammatory-mediated prothrombotic state and chronic endothelial injury. The transient effect of infection in children may suggest a greater role for a prothrombotic mechanism. Neurology ® 2014;83:890-897 GLOSSARY AIS 5 arterial ischemic stroke; CI 5 confidence interval; ICD-9 5 International Classification of Diseases, 9th revision; KPNC 5 Kaiser Permanente Northern California; KPSS 5 Kaiser Pediatric Stroke Study; OR 5 odds ratio.A minority of children with established stroke risk factors (e.g., congenital heart disease) ever has an arterial ischemic stroke (AIS), 1 suggesting that childhood AIS is multifactorial and potentially affected by environmental risk factors. Exposure to minor infection is both pervasive throughout childhood and linked to AIS in adults. 2-8Minor infection may affect stroke risk either through systemic effects of inflammatory mediators causing a prothrombotic state or by direct or indirect effects on arteries through various mechanisms.3 Several studies suggest that minor acute infection can trigger stroke in adults, particularly young adults. 6,[8][9][10][11][12][13] Infectious burden, the cumulative exposure to multiple infections over time as measured by laboratory assays, exacerbates atherosclerosis [14][15][16][17][18][19] and increases stroke risk in adults. 20,21 Children have negligible atherosclerosis and less time to accumulate chronic effects of infection, but are commonly exposed to minor acute infections. We hypothesized that minor infection can trigger child...

Infection, vaccination, and childhood arterial ischemic stroke

“…20 In the only prior association study, set in the population of children receiving care from Kaiser Permanente Northern California, 33% of 126 cases (vs 13% of controls) had a medical encounter for infection in the prior 4 weeks, 21 and 14% of cases (1.7% of controls) in the prior 7 days. 15 The study reported an adjusted OR of 15 (95% CI 3.3-68) for minor infection #3 days prior to stroke, and OR 4.0 (0.9-17.9) for infection 4-7 days prior. 15 This Kaiser study was geographically narrow, based purely on retrospective chart review, and unable to review imaging to either confirm or classify the AIS.…”

“…15 The study reported an adjusted OR of 15 (95% CI 3.3-68) for minor infection #3 days prior to stroke, and OR 4.0 (0.9-17.9) for infection 4-7 days prior. 15 This Kaiser study was geographically narrow, based purely on retrospective chart review, and unable to review imaging to either confirm or classify the AIS. VIPS improves upon the Kaiser study with its large sample size, broad geographic representation, prospective enrollment, and central imaging review for case confirmation and stroke classification.…”

“…Furthermore, our prior study in the Kaiser population, although retrospective, had a measure of infection (documented medical encounter) resistant to either selection or recall bias, and similarly demonstrated an association between acute infection and childhood AIS. 15 Other limitations are our inability to measure subclinical infections and that our cases and controls were not matched geographically.…”

“…[6][7][8][9][10][11][12][13][14] In a retrospective case-control study set in Northern California, we found that a medical encounter for minor infection transiently increased AIS risk 15-fold (p , 0.0001) over a 3-day period, and that this risk factor was present in 10% of childhood AIS cases. 15 This suggests a potential opportunity for primary stroke prevention through improved hygiene and vaccination, and potential avenues for secondary stroke prevention by expanding our understanding of stroke pathogenesis in children. The study was limited by its narrow geographic region, retrospective data, inability to measure infections not resulting in a medical encounter (or exposure to vasoactive cold medications), and poor characterization of stroke subtypes because imaging studies were not available for review.…”

Prevalence of Excess Sodium Intake in the United States — NHANES, 2009–2012

“…218 The effect of infection on pediatric stroke risk is short-lived, lasting for days; 80% of infections preceding childhood stroke are respiratory. 219 …”