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October 27, 2015; 85 (17) Article

Infection, vaccination, and childhood arterial ischemic stroke

Results of the VIPS study

Heather J. Fullerton, Nancy K. Hills, Mitchell S.V. Elkind, Michael M. Dowling, Max Wintermark, Carol A. Glaser, Marilyn Tan, Michael J. Rivkin, Luigi Titomanlio, A. James Barkovich, Gabrielle A. deVeber
First published September 30, 2015, DOI: https://doi.org/10.1212/WNL.0000000000002065
Heather J. Fullerton
From the Departments of Neurology (H.J.F., N.K.H., A.J.B.), Pediatrics (H.J.F., C.A.G., A.J.B.), Biostatistics and Epidemiology (N.K.H.), and Radiology (A.J.B.), University of California San Francisco; the Departments of Neurology and Epidemiology (M.S.V.E.), Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY; the Departments of Pediatrics and Neurology and Neurotherapeutics (M.M.D.), UT Southwestern Medical Center, Dallas, TX; the Department of Radiology (M.W.), Stanford University, Palo Alto, CA; the Division of Communicable Disease Control (C.A.G.), Center for Infectious Diseases, California Department of Public Health, Richmond; the Departments of Pediatrics and Neurosciences (M.T.), University of the Philippines–Philippine General Hospital, Manila, Philippines; the Departments of Neurology, Psychiatry, and Radiology (M.J.R.), Boston Children's Hospital, MA; the Pediatric Emergency Department (L.T.), Robert Debré Hospital, Paris Diderot University, Paris, France; and the Department of Neurology (G.A.d.), Hospital for Sick Children, Toronto, Canada.
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Nancy K. Hills
From the Departments of Neurology (H.J.F., N.K.H., A.J.B.), Pediatrics (H.J.F., C.A.G., A.J.B.), Biostatistics and Epidemiology (N.K.H.), and Radiology (A.J.B.), University of California San Francisco; the Departments of Neurology and Epidemiology (M.S.V.E.), Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY; the Departments of Pediatrics and Neurology and Neurotherapeutics (M.M.D.), UT Southwestern Medical Center, Dallas, TX; the Department of Radiology (M.W.), Stanford University, Palo Alto, CA; the Division of Communicable Disease Control (C.A.G.), Center for Infectious Diseases, California Department of Public Health, Richmond; the Departments of Pediatrics and Neurosciences (M.T.), University of the Philippines–Philippine General Hospital, Manila, Philippines; the Departments of Neurology, Psychiatry, and Radiology (M.J.R.), Boston Children's Hospital, MA; the Pediatric Emergency Department (L.T.), Robert Debré Hospital, Paris Diderot University, Paris, France; and the Department of Neurology (G.A.d.), Hospital for Sick Children, Toronto, Canada.
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Mitchell S.V. Elkind
From the Departments of Neurology (H.J.F., N.K.H., A.J.B.), Pediatrics (H.J.F., C.A.G., A.J.B.), Biostatistics and Epidemiology (N.K.H.), and Radiology (A.J.B.), University of California San Francisco; the Departments of Neurology and Epidemiology (M.S.V.E.), Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY; the Departments of Pediatrics and Neurology and Neurotherapeutics (M.M.D.), UT Southwestern Medical Center, Dallas, TX; the Department of Radiology (M.W.), Stanford University, Palo Alto, CA; the Division of Communicable Disease Control (C.A.G.), Center for Infectious Diseases, California Department of Public Health, Richmond; the Departments of Pediatrics and Neurosciences (M.T.), University of the Philippines–Philippine General Hospital, Manila, Philippines; the Departments of Neurology, Psychiatry, and Radiology (M.J.R.), Boston Children's Hospital, MA; the Pediatric Emergency Department (L.T.), Robert Debré Hospital, Paris Diderot University, Paris, France; and the Department of Neurology (G.A.d.), Hospital for Sick Children, Toronto, Canada.
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Michael M. Dowling
From the Departments of Neurology (H.J.F., N.K.H., A.J.B.), Pediatrics (H.J.F., C.A.G., A.J.B.), Biostatistics and Epidemiology (N.K.H.), and Radiology (A.J.B.), University of California San Francisco; the Departments of Neurology and Epidemiology (M.S.V.E.), Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY; the Departments of Pediatrics and Neurology and Neurotherapeutics (M.M.D.), UT Southwestern Medical Center, Dallas, TX; the Department of Radiology (M.W.), Stanford University, Palo Alto, CA; the Division of Communicable Disease Control (C.A.G.), Center for Infectious Diseases, California Department of Public Health, Richmond; the Departments of Pediatrics and Neurosciences (M.T.), University of the Philippines–Philippine General Hospital, Manila, Philippines; the Departments of Neurology, Psychiatry, and Radiology (M.J.R.), Boston Children's Hospital, MA; the Pediatric Emergency Department (L.T.), Robert Debré Hospital, Paris Diderot University, Paris, France; and the Department of Neurology (G.A.d.), Hospital for Sick Children, Toronto, Canada.
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Max Wintermark
From the Departments of Neurology (H.J.F., N.K.H., A.J.B.), Pediatrics (H.J.F., C.A.G., A.J.B.), Biostatistics and Epidemiology (N.K.H.), and Radiology (A.J.B.), University of California San Francisco; the Departments of Neurology and Epidemiology (M.S.V.E.), Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY; the Departments of Pediatrics and Neurology and Neurotherapeutics (M.M.D.), UT Southwestern Medical Center, Dallas, TX; the Department of Radiology (M.W.), Stanford University, Palo Alto, CA; the Division of Communicable Disease Control (C.A.G.), Center for Infectious Diseases, California Department of Public Health, Richmond; the Departments of Pediatrics and Neurosciences (M.T.), University of the Philippines–Philippine General Hospital, Manila, Philippines; the Departments of Neurology, Psychiatry, and Radiology (M.J.R.), Boston Children's Hospital, MA; the Pediatric Emergency Department (L.T.), Robert Debré Hospital, Paris Diderot University, Paris, France; and the Department of Neurology (G.A.d.), Hospital for Sick Children, Toronto, Canada.
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Carol A. Glaser
From the Departments of Neurology (H.J.F., N.K.H., A.J.B.), Pediatrics (H.J.F., C.A.G., A.J.B.), Biostatistics and Epidemiology (N.K.H.), and Radiology (A.J.B.), University of California San Francisco; the Departments of Neurology and Epidemiology (M.S.V.E.), Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY; the Departments of Pediatrics and Neurology and Neurotherapeutics (M.M.D.), UT Southwestern Medical Center, Dallas, TX; the Department of Radiology (M.W.), Stanford University, Palo Alto, CA; the Division of Communicable Disease Control (C.A.G.), Center for Infectious Diseases, California Department of Public Health, Richmond; the Departments of Pediatrics and Neurosciences (M.T.), University of the Philippines–Philippine General Hospital, Manila, Philippines; the Departments of Neurology, Psychiatry, and Radiology (M.J.R.), Boston Children's Hospital, MA; the Pediatric Emergency Department (L.T.), Robert Debré Hospital, Paris Diderot University, Paris, France; and the Department of Neurology (G.A.d.), Hospital for Sick Children, Toronto, Canada.
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Marilyn Tan
From the Departments of Neurology (H.J.F., N.K.H., A.J.B.), Pediatrics (H.J.F., C.A.G., A.J.B.), Biostatistics and Epidemiology (N.K.H.), and Radiology (A.J.B.), University of California San Francisco; the Departments of Neurology and Epidemiology (M.S.V.E.), Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY; the Departments of Pediatrics and Neurology and Neurotherapeutics (M.M.D.), UT Southwestern Medical Center, Dallas, TX; the Department of Radiology (M.W.), Stanford University, Palo Alto, CA; the Division of Communicable Disease Control (C.A.G.), Center for Infectious Diseases, California Department of Public Health, Richmond; the Departments of Pediatrics and Neurosciences (M.T.), University of the Philippines–Philippine General Hospital, Manila, Philippines; the Departments of Neurology, Psychiatry, and Radiology (M.J.R.), Boston Children's Hospital, MA; the Pediatric Emergency Department (L.T.), Robert Debré Hospital, Paris Diderot University, Paris, France; and the Department of Neurology (G.A.d.), Hospital for Sick Children, Toronto, Canada.
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Michael J. Rivkin
From the Departments of Neurology (H.J.F., N.K.H., A.J.B.), Pediatrics (H.J.F., C.A.G., A.J.B.), Biostatistics and Epidemiology (N.K.H.), and Radiology (A.J.B.), University of California San Francisco; the Departments of Neurology and Epidemiology (M.S.V.E.), Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY; the Departments of Pediatrics and Neurology and Neurotherapeutics (M.M.D.), UT Southwestern Medical Center, Dallas, TX; the Department of Radiology (M.W.), Stanford University, Palo Alto, CA; the Division of Communicable Disease Control (C.A.G.), Center for Infectious Diseases, California Department of Public Health, Richmond; the Departments of Pediatrics and Neurosciences (M.T.), University of the Philippines–Philippine General Hospital, Manila, Philippines; the Departments of Neurology, Psychiatry, and Radiology (M.J.R.), Boston Children's Hospital, MA; the Pediatric Emergency Department (L.T.), Robert Debré Hospital, Paris Diderot University, Paris, France; and the Department of Neurology (G.A.d.), Hospital for Sick Children, Toronto, Canada.
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Luigi Titomanlio
From the Departments of Neurology (H.J.F., N.K.H., A.J.B.), Pediatrics (H.J.F., C.A.G., A.J.B.), Biostatistics and Epidemiology (N.K.H.), and Radiology (A.J.B.), University of California San Francisco; the Departments of Neurology and Epidemiology (M.S.V.E.), Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY; the Departments of Pediatrics and Neurology and Neurotherapeutics (M.M.D.), UT Southwestern Medical Center, Dallas, TX; the Department of Radiology (M.W.), Stanford University, Palo Alto, CA; the Division of Communicable Disease Control (C.A.G.), Center for Infectious Diseases, California Department of Public Health, Richmond; the Departments of Pediatrics and Neurosciences (M.T.), University of the Philippines–Philippine General Hospital, Manila, Philippines; the Departments of Neurology, Psychiatry, and Radiology (M.J.R.), Boston Children's Hospital, MA; the Pediatric Emergency Department (L.T.), Robert Debré Hospital, Paris Diderot University, Paris, France; and the Department of Neurology (G.A.d.), Hospital for Sick Children, Toronto, Canada.
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A. James Barkovich
From the Departments of Neurology (H.J.F., N.K.H., A.J.B.), Pediatrics (H.J.F., C.A.G., A.J.B.), Biostatistics and Epidemiology (N.K.H.), and Radiology (A.J.B.), University of California San Francisco; the Departments of Neurology and Epidemiology (M.S.V.E.), Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY; the Departments of Pediatrics and Neurology and Neurotherapeutics (M.M.D.), UT Southwestern Medical Center, Dallas, TX; the Department of Radiology (M.W.), Stanford University, Palo Alto, CA; the Division of Communicable Disease Control (C.A.G.), Center for Infectious Diseases, California Department of Public Health, Richmond; the Departments of Pediatrics and Neurosciences (M.T.), University of the Philippines–Philippine General Hospital, Manila, Philippines; the Departments of Neurology, Psychiatry, and Radiology (M.J.R.), Boston Children's Hospital, MA; the Pediatric Emergency Department (L.T.), Robert Debré Hospital, Paris Diderot University, Paris, France; and the Department of Neurology (G.A.d.), Hospital for Sick Children, Toronto, Canada.
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Gabrielle A. deVeber
From the Departments of Neurology (H.J.F., N.K.H., A.J.B.), Pediatrics (H.J.F., C.A.G., A.J.B.), Biostatistics and Epidemiology (N.K.H.), and Radiology (A.J.B.), University of California San Francisco; the Departments of Neurology and Epidemiology (M.S.V.E.), Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY; the Departments of Pediatrics and Neurology and Neurotherapeutics (M.M.D.), UT Southwestern Medical Center, Dallas, TX; the Department of Radiology (M.W.), Stanford University, Palo Alto, CA; the Division of Communicable Disease Control (C.A.G.), Center for Infectious Diseases, California Department of Public Health, Richmond; the Departments of Pediatrics and Neurosciences (M.T.), University of the Philippines–Philippine General Hospital, Manila, Philippines; the Departments of Neurology, Psychiatry, and Radiology (M.J.R.), Boston Children's Hospital, MA; the Pediatric Emergency Department (L.T.), Robert Debré Hospital, Paris Diderot University, Paris, France; and the Department of Neurology (G.A.d.), Hospital for Sick Children, Toronto, Canada.
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Citation
Infection, vaccination, and childhood arterial ischemic stroke
Results of the VIPS study
Heather J. Fullerton, Nancy K. Hills, Mitchell S.V. Elkind, Michael M. Dowling, Max Wintermark, Carol A. Glaser, Marilyn Tan, Michael J. Rivkin, Luigi Titomanlio, A. James Barkovich, Gabrielle A. deVeber
Neurology Oct 2015, 85 (17) 1459-1466; DOI: 10.1212/WNL.0000000000002065

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Abstract

Objectives: Minor infection can trigger adult arterial ischemic stroke (AIS) and is common in childhood. We tested the hypotheses that infection transiently increases risk of AIS in children, regardless of stroke subtype, while vaccination against infection is protective.

Methods: The Vascular Effects of Infection in Pediatric Stroke study is an international case-control study that prospectively enrolled 355 centrally confirmed cases of AIS (29 days–18 years old) and 354 stroke-free controls. To determine prior exposure to infections and vaccines, we conducted parental interviews and chart review.

Results: Median (interquartile range) age was 7.6 years for cases and 9.3 for controls (p = 0.44). Infection in the week prior to stroke, or interview date for controls, was reported in 18% of cases, vs 3% of controls, conferring a 6.3-fold increased risk of AIS (p < 0.0001); upper respiratory infections were most common. Prevalence of preceding infection was similar across stroke subtypes: arteriopathic, cardioembolic, and idiopathic. Use of vasoactive cold medications was similarly low in both groups. Children with some/few/no routine vaccinations were at higher stroke risk than those receiving all or most (odds ratio [OR] 7.3, p = 0.0002). In an age-adjusted multivariate logistic regression model, independent risk factors for AIS included infection in the prior week (OR 6.3, p < 0.0001), undervaccination (OR 8.2, p = 0.0004), black race (compared to white; OR 1.9, p = 0.009), and rural residence (compared to urban; OR 3.0, p = 0.0003).

Conclusions: Infection may act as a trigger for childhood AIS, while routine vaccinations appear protective. Hence, efforts to reduce the spread of common infections might help prevent stroke in children.

GLOSSARY

AIS=
arterial ischemic stroke;
CI=
confidence interval;
IQR=
interquartile range;
OR=
odds ratio;
PFO=
patent foramen ovale;
SES=
socioeconomic status;
VIPS=
Vascular Effects of Infection in Pediatric Stroke

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Coinvestigators are listed on the Neurology® Web site at Neurology.org.

  • Supplemental data at Neurology.org

  • Editorial, page 1438

  • Received February 26, 2015.
  • Accepted in final form June 15, 2015.
  • © 2015 American Academy of Neurology
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