Herpesvirus Infection and Childhood Stroke

Study Questions:

Is serologic evidence of acute herpesvirus infection (VZV, HSV1, HSV2, EBV, CMV) associated with an increased risk of acute ischemic stroke in children?

Methods:

This work was part of the VIPS (Vascular Effects of Infection in Pediatric Stroke) study, which prospectively enrolled children (29 days to 18 years old) at 37 sites in nine countries. Stroke cases were enrolled within 3 weeks of the ictus and had brain imaging. Stroke cases were confirmed by central review. The study used trauma patients as controls. For cases and controls, the study team used structured interviews to screen for a history of infection in the past 6 months, vaccination history, and markers of socioeconomic status. Blood samples were drawn and serology assays for HSV1, HSV2, VZZ, CMV, and EBV were performed using enzyme-linked immunosorbent assay (ELISA). When possible, convalescent samples were drawn. Criteria for serologic evidence of a herpesvirus infection were defined a priori. As not all subjects (and no controls) had convalescent samples, herpesvirus infection was defined by the acute sample. Baseline characteristics of cases and controls were compared. Logistic regression was used to create models to predict the relationship between herpesvirus infection and acute ischemic stroke.

Results:

There were 326 children with acute ischemic stroke analyzed, and of these, 187 had an acute and convalescent blood sample. The study enrolled 115 trauma patients as controls. The stroke patients were younger and had lower socioeconomic status than the controls. Past herpesvirus infection was not more common in cases than controls (odds ratio [OR], 0.83; 95% confidence interval [CI], 0.46-3.31). Acute herpesvirus infection (positive immunoglobulin M) was more common in stroke cases (31.1%) than controls (18.3%) (OR, 1.91; 95% CI, 1.14-3.31). When individual viruses were evaluated, HSV1 and VZV were significantly more likely to be present in acute cases. There was no difference in the stroke subtype between cases with and without a herpesvirus infection. For the patients with a clinical history of infection in the preceding month, 46% had positive herpesvirus serologies. In the multivariable model that included various predictors of stroke, acute herpesvirus was an independent risk for acute ischemic stroke (OR, 1.9; 95% CI, 1.1-3.6). In the analysis of the subgroup of cases with paired acute and convalescent samples, the findings from a single sample had a sensitivity of 46% for the diagnosis of an acute herpesvirus infection.

Conclusions:

Acute herpesvirus infection seems to be associated with acute ischemic stroke in children.

Perspective:

This international case-control study found that acute herpesvirus infection was associated with an increased risk of acute ischemic stroke in children. HSV and VZV were the most common viruses and most infectious were a subclinical initial infection. A single serologic analysis (as opposed to an acute and convalescent sample) was unable to rule out infection. The mechanism by which herpesvirus increases the risk of ischemic stroke is unclear, but it may cause a vasculopathy or lead to increased cytokine production. While additional research is needed, because herpesvirus infections are potentially treatable, the findings from this study have the potential to change how we think about secondary stroke prevention in children.

Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Prevention, CHD & Pediatrics and Arrhythmias

Keywords: Child, Herpesviridae Infections, Herpesvirus 4, Human, Immunoglobulin M, Infection, Ischemia, Neuroimaging, Pediatrics, Secondary Prevention, Social Class, Stroke, Vascular Diseases


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