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

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.