Infection in Childhood Arterial Ischemic Stroke: Metagenomic Next-Generation Sequencing Results of the VIPS II Study

doi:10.1161/STROKEAHA.124.050548

Multicenter Study

. 2025 Aug;56(8):2110-2121.

doi: 10.1161/STROKEAHA.124.050548. Epub 2025 May 1.

Infection in Childhood Arterial Ischemic Stroke: Metagenomic Next-Generation Sequencing Results of the VIPS II Study

Mary C Karalius^{1

2}, Prashanth S Ramachandran^{1

3

4}, Annie Wapniarski¹, Mary Wang¹, Maham Zia¹, Nancy K Hills^{1

5}, Max Wintermark⁶, Charles Grose⁷, Michael M Dowling⁸, Jenny L Wilson^{9

10}, Sarah Lee¹¹, Melissa Chung¹², Megan Barry¹³, Huichun Xu¹⁴, Joseph L DeRisi¹⁵, Michael R Wilson¹, Heather J Fullerton^{1

2}; VIPS II Investigators

Collaborators, Affiliations

Collaborators

Affiliations

¹ Department of Neurology, Weill Institute for Neurosciences (M.C.K., P.S.R., A.W., M. Wang, M.Z., N.K.H., M.R.W., H.J.F.), University of California San Francisco.
² Department of Pediatrics (M.C.K., H.J.F.), University of California San Francisco.
³ The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia (P.S.R.).
⁴ Department of Neurology, The Royal Melbourne Hospital, Victoria, Australia (P.S.R.).
⁵ Department of Biostatistics and Epidemiology (N.K.H.), University of California San Francisco.
⁶ Department of Radiology, MD Anderson Cancer Center, Houston, TX (M. Wintermark).
⁷ Department of Pediatrics, University of Iowa (C.G.).
⁸ Departments of Pediatrics and Neurology, University of Texas Southwestern Medical Center, Dallas (M.M.D.).
⁹ Department of Biochemistry and Biophysics (J.L.D.), University of California San Francisco.
¹⁰ Division of Pediatric Neurology, Oregon Health & Science University, Portland (J.L.W.).
¹¹ Department of Neurology, Stanford University, Palo Alto, CA (S.L.).
¹² Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH (M.C.).
¹³ Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL (M.B.).
¹⁴ Department of Medicine, University of Maryland School of Medicine, Baltimore (H.X.).
¹⁵ Chan Zuckerberg Biohub SF, San Francisco, CA (J.L.D.).

PMID: 40308204
PMCID: PMC12303748 (available on 2026-05-01)
DOI: 10.1161/STROKEAHA.124.050548

Multicenter Study

Infection in Childhood Arterial Ischemic Stroke: Metagenomic Next-Generation Sequencing Results of the VIPS II Study

Mary C Karalius et al. Stroke. 2025 Aug.

. 2025 Aug;56(8):2110-2121.

doi: 10.1161/STROKEAHA.124.050548. Epub 2025 May 1.

Authors

Collaborators

Affiliations

¹ Department of Neurology, Weill Institute for Neurosciences (M.C.K., P.S.R., A.W., M. Wang, M.Z., N.K.H., M.R.W., H.J.F.), University of California San Francisco.
² Department of Pediatrics (M.C.K., H.J.F.), University of California San Francisco.
³ The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia (P.S.R.).
⁴ Department of Neurology, The Royal Melbourne Hospital, Victoria, Australia (P.S.R.).
⁵ Department of Biostatistics and Epidemiology (N.K.H.), University of California San Francisco.
⁶ Department of Radiology, MD Anderson Cancer Center, Houston, TX (M. Wintermark).
⁷ Department of Pediatrics, University of Iowa (C.G.).
⁸ Departments of Pediatrics and Neurology, University of Texas Southwestern Medical Center, Dallas (M.M.D.).
⁹ Department of Biochemistry and Biophysics (J.L.D.), University of California San Francisco.
¹⁰ Division of Pediatric Neurology, Oregon Health & Science University, Portland (J.L.W.).
¹¹ Department of Neurology, Stanford University, Palo Alto, CA (S.L.).
¹² Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH (M.C.).
¹³ Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL (M.B.).
¹⁴ Department of Medicine, University of Maryland School of Medicine, Baltimore (H.X.).
¹⁵ Chan Zuckerberg Biohub SF, San Francisco, CA (J.L.D.).

PMID: 40308204
PMCID: PMC12303748 (available on 2026-05-01)
DOI: 10.1161/STROKEAHA.124.050548

Abstract

Background: Acute respiratory infection transiently increases risk for childhood arterial ischemic stroke (AIS). We hypothesize that this paradox of a common exposure linked to a rare outcome could be explained by either (1) the infection hypothesis: unusual or multiple pathogens or (2) the host response hypothesis: heterogeneity in the inflammatory response to infection. We leverage metagenomic next-generation sequencing (mNGS), a comprehensive microbial detection tool, to test the first hypothesis.

Methods: The VIPS II study (Vascular Effects of Infection in Pediatric Stroke II) prospectively enrolled children with AIS at 22 international sites over 5 years (December 2016 to January 2022). Sites measured prestroke clinical infection via standardized parental interviews and chart abstraction. To assess more broadly the background spectrum of pathogens, a central research laboratory performed mNGS on plasma and oropharyngeal swabs collected within 72 hours of stroke. mNGS was also performed on biological samples from stroke-free children (June 2017 to January 2022), both without (well) and with (ill) documentation of clinical infection.

Results: VIPS II enrolled 205 patients with AIS, 95 stroke-free well children, and 47 stroke-free ill children. Clinical infection, most commonly upper respiratory tract infection, was detected in 81 of 205 (40%) of patients. Both plasma and oropharyngeal swab mNGS data were available for 190 of 205 patients with AIS, 91 of 95 stroke-free well children, and 27 of 47 stroke-free ill children. mNGS detected viruses in 27 of 190 (14%) patients with AIS, 9 of 91 stroke-free well children (10%), and 9 of 27 (33%) stroke-free ill children. Most were common upper respiratory viruses. Coinfections were rare. Similar viruses were found in patients with AIS and stroke-free children.

Conclusions: mNGS detected a variety of common childhood viruses in both patients with AIS and stroke-free children, suggesting that the type of infection does not explain AIS susceptibility. Rather, the alternative hypothesis regarding an unusual host immune response to common infections in the pathogenicity of AIS should be further explored.

Keywords: child; ischemic stroke; respiratory tract infections; risk; viruses.

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Conflict of interest statement

Drs Wilson and DeRisi are cofounders of Delve Bio; Dr Wilson is on the Board of Directors and Dr DeRisi receives consulting fees. Dr DeRisi reports compensation from PHC Global for consultant services. Dr Wintermark reports compensation from Subtle Medical, Magnetic Insight, Icometrix for consultant services. Dr Xu reports grants from the National Institutes of Health and American Heart Association. H.J. Fullerton reports that the University of California receives compensation from Bayer HealthCare Pharmaceuticals Inc for her consultant services.

References

1. Fullerton HJ, Hills NK, Elkind MSV, Dowling MM, Wintermark M, Glaser CA, Tan M, Rivkin MJ, Titomanlio L, Barkovich AJ, et al. Infection, vaccination, and childhood arterial ischemic stroke: Results of the VIPS study. Neurology. 2015;85:1459–1466. doi: 10.1212/WNL.0000000000002065 - DOI - PMC - PubMed
1. Hills NK, Sidney S, Fullerton HJ. Timing and number of minor infections as risk factors for childhood arterial ischemic stroke. Neurology. 2014;83:890–897. doi: 10.1212/WNL.0000000000000752 - DOI - PMC - PubMed
1. Elkind MSV, Hills NK, Glaser CA, Lo WD, Amlie-Lefond C, Dlamini N, Kneen R, Hod EA, Wintermark M, deVeber GA, et al. Herpesvirus Infections and Childhood Arterial Ischemic Stroke: Results of the VIPS Study. Circulation. 2016;133:732–741. doi: 10.1161/CIRCULATIONAHA.115.018595 - DOI - PMC - PubMed
1. Fullerton HJ, Luna JM, Wintermark M, Hills NK, Tokarz R, Li Y, Glaser C, DeVeber GA, Lipkin WI, Elkind MSV. Parvovirus B19 Infection in Children with Arterial Ischemic Stroke. Stroke. 2017;48:2875–2877. doi: 10.1161/STROKEAHA.117.018272 - DOI - PMC - PubMed
1. Chiu CY, Miller SA. Clinical metagenomics. Nat Rev Genet. 2019;20:341–355. doi: 10.1038/s41576-019-0113-7 - DOI - PMC - PubMed

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[1] Fullerton HJ, Hills NK, Elkind MSV, Dowling MM, Wintermark M, Glaser CA, Tan M, Rivkin MJ, Titomanlio L, Barkovich AJ, et al. Infection, vaccination, and childhood arterial ischemic stroke: Results of the VIPS study. Neurology. 2015;85:1459–1466. doi: 10.1212/WNL.0000000000002065 - DOI - PMC - PubMed

[2] Fullerton HJ, Hills NK, Elkind MSV, Dowling MM, Wintermark M, Glaser CA, Tan M, Rivkin MJ, Titomanlio L, Barkovich AJ, et al. Infection, vaccination, and childhood arterial ischemic stroke: Results of the VIPS study. Neurology. 2015;85:1459–1466. doi: 10.1212/WNL.0000000000002065 - DOI - PMC - PubMed

[3] Hills NK, Sidney S, Fullerton HJ. Timing and number of minor infections as risk factors for childhood arterial ischemic stroke. Neurology. 2014;83:890–897. doi: 10.1212/WNL.0000000000000752 - DOI - PMC - PubMed

[4] Hills NK, Sidney S, Fullerton HJ. Timing and number of minor infections as risk factors for childhood arterial ischemic stroke. Neurology. 2014;83:890–897. doi: 10.1212/WNL.0000000000000752 - DOI - PMC - PubMed

[5] Elkind MSV, Hills NK, Glaser CA, Lo WD, Amlie-Lefond C, Dlamini N, Kneen R, Hod EA, Wintermark M, deVeber GA, et al. Herpesvirus Infections and Childhood Arterial Ischemic Stroke: Results of the VIPS Study. Circulation. 2016;133:732–741. doi: 10.1161/CIRCULATIONAHA.115.018595 - DOI - PMC - PubMed

[6] Elkind MSV, Hills NK, Glaser CA, Lo WD, Amlie-Lefond C, Dlamini N, Kneen R, Hod EA, Wintermark M, deVeber GA, et al. Herpesvirus Infections and Childhood Arterial Ischemic Stroke: Results of the VIPS Study. Circulation. 2016;133:732–741. doi: 10.1161/CIRCULATIONAHA.115.018595 - DOI - PMC - PubMed

[7] Fullerton HJ, Luna JM, Wintermark M, Hills NK, Tokarz R, Li Y, Glaser C, DeVeber GA, Lipkin WI, Elkind MSV. Parvovirus B19 Infection in Children with Arterial Ischemic Stroke. Stroke. 2017;48:2875–2877. doi: 10.1161/STROKEAHA.117.018272 - DOI - PMC - PubMed

[8] Fullerton HJ, Luna JM, Wintermark M, Hills NK, Tokarz R, Li Y, Glaser C, DeVeber GA, Lipkin WI, Elkind MSV. Parvovirus B19 Infection in Children with Arterial Ischemic Stroke. Stroke. 2017;48:2875–2877. doi: 10.1161/STROKEAHA.117.018272 - DOI - PMC - PubMed

[9] Chiu CY, Miller SA. Clinical metagenomics. Nat Rev Genet. 2019;20:341–355. doi: 10.1038/s41576-019-0113-7 - DOI - PMC - PubMed

[10] Chiu CY, Miller SA. Clinical metagenomics. Nat Rev Genet. 2019;20:341–355. doi: 10.1038/s41576-019-0113-7 - DOI - PMC - PubMed

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Infection in Childhood Arterial Ischemic Stroke: Metagenomic Next-Generation Sequencing Results of the VIPS II Study

Collaborators

Affiliations

Infection in Childhood Arterial Ischemic Stroke: Metagenomic Next-Generation Sequencing Results of the VIPS II Study

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

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Abstract

Conflict of interest statement

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