Evidence of Varicella Zoster Virus Reactivation in Children With Arterial Ischemic Stroke: Results of the VIPS II Study

BACKGROUND: Varicella zoster virus (VZV) has historically been associated with focal cerebral arteriopathy and arterial ischemic stroke (AIS) in children, and risk of AIS and myocardial infarction in adults. The VIPS (Vascular Effects of Infection in Pediatric Stroke) II study aimed to determine whether VZV remains a pediatric stroke trigger in an era of routine VZV vaccination. METHODS: This 22-center prospective cohort study enrolled 205 patients (28 days to 18 years; median, 11.6 years) with spontaneous AIS (December 2016 to January 2022) in North America and Australia, performed parental interviews, and collected baseline (hyperacute [≤72 hours; n=194] and acute [4–6 days; n=181]) and convalescent (1–6 weeks; n=74) serum samples. A virology research laboratory measured VZV IgM and IgG titers by an in-house ELISA in patients with AIS and 95 unmatched well control children. RESULTS: Baseline serologies indicated prior VZV exposure in 198 patients (97%). Parents recalled prior VZV vaccination in 160 (78%) and remote chickenpox in 3 (1.4%). Twenty patients (9.8%) had serologic evidence of recent VZV reactivation at the time of their stroke; all were asymptomatic. All had remote VZV exposure with VZV vaccination (median) 6.1 years prior. We observed recent VZV reactivation in patients with focal cerebral arteriopathy (4/32 [12.5%]) but not with arterial dissection or moyamoya. All 95 controls had serologic evidence of prior VZV exposure and 3 (3.1%) had recent VZV reactivation. CONCLUSIONS: One in 10 patients with childhood AIS had recent, asymptomatic VZV reactivation. In a vaccinated population, VZV may continue to play a modest role in childhood stroke pathogenesis.