title: Herpesvirus Infections and Childhood Arterial Ischemic Stroke: Results of the VIPS Study.
abstract: BACKGROUND
  Epidemiological studies demonstrate that childhood infections, including varicella zoster virus, are associated with an increased risk of arterial ischemic stroke (AIS). Other herpesviruses have been linked to childhood AIS in case reports. We sought to determine whether herpesvirus infections, which are potentially treatable, increase the risk of childhood AIS.
  
  
  RESULTS
  We enrolled 326 centrally confirmed cases of AIS and 115 stroke-free controls with trauma (29 days to 18 years of age) with acute blood samples (≤3 weeks after stroke/trauma); cases had convalescent samples (7-28 days later) when feasible. Samples were tested by commercial enzyme-linked immunosorbent assay kits for immunoglobulin M/immunoglobulin G antibodies to herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus, and varicella zoster virus. An algorithm developed a priori classified serological evidence of past and acute herpesvirus infection as dichotomous variables. The median (quartiles) age was 7.7 (3.1-14.3) years for cases and 10.7 (6.9-13.2) years for controls (P=0.03). Serological evidence of past infection did not differ between cases and controls. However, serological evidence of acute herpesvirus infection doubled the odds of childhood AIS, even after adjusting for age, race, and socioeconomic status (odds ratio, 2.2; 95% confidence interval, 1.2-4.0; P=0.007). Among 187 cases with acute and convalescent blood samples, 85 (45%) showed evidence of acute herpesvirus infection; herpes simplex virus 1 was found most often. Most infections were asymptomatic.
  
  
  CONCLUSIONS
  Herpesviruses may act as a trigger for childhood AIS, even if the infection is subclinical. Antivirals like acyclovir might have a role in the prevention of recurrent stroke if further studies confirm a causal relationship.
authors.affiliation: From Department of Neurology Columbia University, New York, NY (M.S.V.E.); Department of Epidemiology, Mailman School of Public Health, New York, NY (M.S.V.E.); Departments of Neurology (N.K.H., H.J.F.), Biostatistics & Epidemiology (N.K.H.), and Pediatrics (C.A.G., H.J.F.), University of California San Francisco, San Francisco, CA; Department of Pediatrics (Infectious Disease), Kaiser Permanente, Oakland, CA (C.A.G.); Departments of Pediatrics and Neurology, Ohio State University, Columbus OH (W.D.L.); Department of Neurology, University of Washington, Seattle, WA (C.A.-L,); Department of Neurology, Hospital for Sick Children, Toronto, Canada (N.D., G.A.deV.); Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, England (R.K.); Department of Pathology, Columbia University, New York, NY (E.A.H.); and Department of Radiology, Stanford University, Palo Alto, CA (M.W.).
authors.forename: Mitchell S V
authors.initials: MS
authors.lastname: Elkind
authors.affiliation: From Department of Neurology Columbia University, New York, NY (M.S.V.E.); Department of Epidemiology, Mailman School of Public Health, New York, NY (M.S.V.E.); Departments of Neurology (N.K.H., H.J.F.), Biostatistics & Epidemiology (N.K.H.), and Pediatrics (C.A.G., H.J.F.), University of California San Francisco, San Francisco, CA; Department of Pediatrics (Infectious Disease), Kaiser Permanente, Oakland, CA (C.A.G.); Departments of Pediatrics and Neurology, Ohio State University, Columbus OH (W.D.L.); Department of Neurology, University of Washington, Seattle, WA (C.A.-L,); Department of Neurology, Hospital for Sick Children, Toronto, Canada (N.D., G.A.deV.); Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, England (R.K.); Department of Pathology, Columbia University, New York, NY (E.A.H.); and Department of Radiology, Stanford University, Palo Alto, CA (M.W.).
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Hills
authors.affiliation: From Department of Neurology Columbia University, New York, NY (M.S.V.E.); Department of Epidemiology, Mailman School of Public Health, New York, NY (M.S.V.E.); Departments of Neurology (N.K.H., H.J.F.), Biostatistics & Epidemiology (N.K.H.), and Pediatrics (C.A.G., H.J.F.), University of California San Francisco, San Francisco, CA; Department of Pediatrics (Infectious Disease), Kaiser Permanente, Oakland, CA (C.A.G.); Departments of Pediatrics and Neurology, Ohio State University, Columbus OH (W.D.L.); Department of Neurology, University of Washington, Seattle, WA (C.A.-L,); Department of Neurology, Hospital for Sick Children, Toronto, Canada (N.D., G.A.deV.); Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, England (R.K.); Department of Pathology, Columbia University, New York, NY (E.A.H.); and Department of Radiology, Stanford University, Palo Alto, CA (M.W.).
authors.forename: Carol A
authors.initials: CA
authors.lastname: Glaser
authors.affiliation: From Department of Neurology Columbia University, New York, NY (M.S.V.E.); Department of Epidemiology, Mailman School of Public Health, New York, NY (M.S.V.E.); Departments of Neurology (N.K.H., H.J.F.), Biostatistics & Epidemiology (N.K.H.), and Pediatrics (C.A.G., H.J.F.), University of California San Francisco, San Francisco, CA; Department of Pediatrics (Infectious Disease), Kaiser Permanente, Oakland, CA (C.A.G.); Departments of Pediatrics and Neurology, Ohio State University, Columbus OH (W.D.L.); Department of Neurology, University of Washington, Seattle, WA (C.A.-L,); Department of Neurology, Hospital for Sick Children, Toronto, Canada (N.D., G.A.deV.); Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, England (R.K.); Department of Pathology, Columbia University, New York, NY (E.A.H.); and Department of Radiology, Stanford University, Palo Alto, CA (M.W.).
authors.forename: Warren D
authors.initials: WD
authors.lastname: Lo
authors.affiliation: From Department of Neurology Columbia University, New York, NY (M.S.V.E.); Department of Epidemiology, Mailman School of Public Health, New York, NY (M.S.V.E.); Departments of Neurology (N.K.H., H.J.F.), Biostatistics & Epidemiology (N.K.H.), and Pediatrics (C.A.G., H.J.F.), University of California San Francisco, San Francisco, CA; Department of Pediatrics (Infectious Disease), Kaiser Permanente, Oakland, CA (C.A.G.); Departments of Pediatrics and Neurology, Ohio State University, Columbus OH (W.D.L.); Department of Neurology, University of Washington, Seattle, WA (C.A.-L,); Department of Neurology, Hospital for Sick Children, Toronto, Canada (N.D., G.A.deV.); Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, England (R.K.); Department of Pathology, Columbia University, New York, NY (E.A.H.); and Department of Radiology, Stanford University, Palo Alto, CA (M.W.).
authors.forename: Catherine
authors.initials: C
authors.lastname: Amlie-Lefond
authors.affiliation: From Department of Neurology Columbia University, New York, NY (M.S.V.E.); Department of Epidemiology, Mailman School of Public Health, New York, NY (M.S.V.E.); Departments of Neurology (N.K.H., H.J.F.), Biostatistics & Epidemiology (N.K.H.), and Pediatrics (C.A.G., H.J.F.), University of California San Francisco, San Francisco, CA; Department of Pediatrics (Infectious Disease), Kaiser Permanente, Oakland, CA (C.A.G.); Departments of Pediatrics and Neurology, Ohio State University, Columbus OH (W.D.L.); Department of Neurology, University of Washington, Seattle, WA (C.A.-L,); Department of Neurology, Hospital for Sick Children, Toronto, Canada (N.D., G.A.deV.); Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, England (R.K.); Department of Pathology, Columbia University, New York, NY (E.A.H.); and Department of Radiology, Stanford University, Palo Alto, CA (M.W.).
authors.forename: Nomazulu
authors.initials: N
authors.lastname: Dlamini
authors.affiliation: From Department of Neurology Columbia University, New York, NY (M.S.V.E.); Department of Epidemiology, Mailman School of Public Health, New York, NY (M.S.V.E.); Departments of Neurology (N.K.H., H.J.F.), Biostatistics & Epidemiology (N.K.H.), and Pediatrics (C.A.G., H.J.F.), University of California San Francisco, San Francisco, CA; Department of Pediatrics (Infectious Disease), Kaiser Permanente, Oakland, CA (C.A.G.); Departments of Pediatrics and Neurology, Ohio State University, Columbus OH (W.D.L.); Department of Neurology, University of Washington, Seattle, WA (C.A.-L,); Department of Neurology, Hospital for Sick Children, Toronto, Canada (N.D., G.A.deV.); Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, England (R.K.); Department of Pathology, Columbia University, New York, NY (E.A.H.); and Department of Radiology, Stanford University, Palo Alto, CA (M.W.).
authors.forename: Rachel
authors.initials: R
authors.lastname: Kneen
authors.affiliation: From Department of Neurology Columbia University, New York, NY (M.S.V.E.); Department of Epidemiology, Mailman School of Public Health, New York, NY (M.S.V.E.); Departments of Neurology (N.K.H., H.J.F.), Biostatistics & Epidemiology (N.K.H.), and Pediatrics (C.A.G., H.J.F.), University of California San Francisco, San Francisco, CA; Department of Pediatrics (Infectious Disease), Kaiser Permanente, Oakland, CA (C.A.G.); Departments of Pediatrics and Neurology, Ohio State University, Columbus OH (W.D.L.); Department of Neurology, University of Washington, Seattle, WA (C.A.-L,); Department of Neurology, Hospital for Sick Children, Toronto, Canada (N.D., G.A.deV.); Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, England (R.K.); Department of Pathology, Columbia University, New York, NY (E.A.H.); and Department of Radiology, Stanford University, Palo Alto, CA (M.W.).
authors.forename: Eldad A
authors.initials: EA
authors.lastname: Hod
authors.affiliation: From Department of Neurology Columbia University, New York, NY (M.S.V.E.); Department of Epidemiology, Mailman School of Public Health, New York, NY (M.S.V.E.); Departments of Neurology (N.K.H., H.J.F.), Biostatistics & Epidemiology (N.K.H.), and Pediatrics (C.A.G., H.J.F.), University of California San Francisco, San Francisco, CA; Department of Pediatrics (Infectious Disease), Kaiser Permanente, Oakland, CA (C.A.G.); Departments of Pediatrics and Neurology, Ohio State University, Columbus OH (W.D.L.); Department of Neurology, University of Washington, Seattle, WA (C.A.-L,); Department of Neurology, Hospital for Sick Children, Toronto, Canada (N.D., G.A.deV.); Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, England (R.K.); Department of Pathology, Columbia University, New York, NY (E.A.H.); and Department of Radiology, Stanford University, Palo Alto, CA (M.W.).
authors.forename: Max
authors.initials: M
authors.lastname: Wintermark
authors.affiliation: From Department of Neurology Columbia University, New York, NY (M.S.V.E.); Department of Epidemiology, Mailman School of Public Health, New York, NY (M.S.V.E.); Departments of Neurology (N.K.H., H.J.F.), Biostatistics & Epidemiology (N.K.H.), and Pediatrics (C.A.G., H.J.F.), University of California San Francisco, San Francisco, CA; Department of Pediatrics (Infectious Disease), Kaiser Permanente, Oakland, CA (C.A.G.); Departments of Pediatrics and Neurology, Ohio State University, Columbus OH (W.D.L.); Department of Neurology, University of Washington, Seattle, WA (C.A.-L,); Department of Neurology, Hospital for Sick Children, Toronto, Canada (N.D., G.A.deV.); Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, England (R.K.); Department of Pathology, Columbia University, New York, NY (E.A.H.); and Department of Radiology, Stanford University, Palo Alto, CA (M.W.).
authors.forename: Gabrielle A
authors.initials: GA
authors.lastname: deVeber
authors.affiliation: From Department of Neurology Columbia University, New York, NY (M.S.V.E.); Department of Epidemiology, Mailman School of Public Health, New York, NY (M.S.V.E.); Departments of Neurology (N.K.H., H.J.F.), Biostatistics & Epidemiology (N.K.H.), and Pediatrics (C.A.G., H.J.F.), University of California San Francisco, San Francisco, CA; Department of Pediatrics (Infectious Disease), Kaiser Permanente, Oakland, CA (C.A.G.); Departments of Pediatrics and Neurology, Ohio State University, Columbus OH (W.D.L.); Department of Neurology, University of Washington, Seattle, WA (C.A.-L,); Department of Neurology, Hospital for Sick Children, Toronto, Canada (N.D., G.A.deV.); Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, England (R.K.); Department of Pathology, Columbia University, New York, NY (E.A.H.); and Department of Radiology, Stanford University, Palo Alto, CA (M.W.). Heather.Fullerton@ucsf.edu.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Fullerton
mesh_terms: D000293:Adolescent; D002545:Brain Ischemia / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D006566:Herpesviridae Infections / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D038622:Internationality; D008297:Male; D011446:Prospective Studies; D020521:Stroke / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology*
keywords: child; herpesviridae infections; infection; pediatrics; stroke
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