Principal Investigator: Heather J. Fullerton

STATUS: Enrolling, Active
FUNDING: NIH-NINDS: R56, R01 and Marc and Lynne Benioff Pediatric Stroke Research Fund 
SITES and CORE LABS

The Vascular effects of Infection in Pediatric Stroke (VIPS I) study established a network of 37 sites on 5 continents, enrolled 355 children with arterial ischemic stroke (AIS) and 354 stroke-free controls, and generated a wealth of new knowledge on the relationship between infection and childhood AIS.  We discovered that clinical infection acts as a stroke trigger, the upper respiratory tract is the most common location of preceding infection, and routine childhood vaccines protect against stroke.  Serologic assays for herpesviruses revealed that acute herpesvirus infections increase risk of childhood AIS and are present in almost half our cases, mostly as subclinical and primary infections (i.e., first-time infections in seronegative children).  The full spectrum of pathogens that contribute to childhood stroke risk remains unknown.

VIPS findings were generalizable across childhood AIS subtypes—cardioembolic, arteriopathic, idiopathic—suggesting that infection plays a role in different mechanistic pathways to AIS in children.    These findings also present an unresolved paradox:  childhood infection is common, yet childhood AIS is rare.  Possible explanations are (1) the “infection hypothesis”: heterogeneity in pathogens (unusual strains or combinations of pathogens) drives susceptibility to AIS; and (2) the “host response hypothesis”: heterogeneity in the inflammatory response to infection determines susceptibility to AIS.  To explore the former, we performed a pilot study using MassTag PCR as a broader measure of infectious exposure, and found other viruses in almost 10% of the cases tested, often in combination with a herpesvirus.  To explore the latter, we measured serum levels of four immune mediators and found significantly different levels between the different AIS subtypes.  Potential pathways by which differences in the inflammatory response may contribute to stroke risk include hypercoagulability, endothelial injury, and leukocyte activation. 

With readily available therapies for both infections and downstream inflammatory effects, infection should be further pursued as a modifiable stroke risk factor.  New analyses of VIPS follow-up data demonstrate the urgent need for better strategies for secondary stroke prevention in children:  1-year recurrence rates were 4.5% after idiopathic AIS, 8.1% after cardioembolic AIS, and 21% after arteriopathic AIS, which is the most common stroke type in a previously healthy child.  Determining the specific pathogens and inflammatory processes underlying childhood arteriopathy is the most promising avenue for reducing recurrent stroke in children.  

VIPS II will extend our initial work, taking advantage of state of the art techniques to address the exposure paradox and test the overall hypothesis:  different pathogens, pathogen strains, pathogen combinations, and host inflammatory responses underlie different childhood stroke subtypes (arteriopathic, cardioembolic, idiopathic). Our specific aims are:

1.  To identify known and novel pathogens in children with AIS, and determine whether different pathogens (including unusual strains or combinations of pathogens) are associated with arteriopathic versus cardioembolic or idiopathic stroke.   We will use next generation sequencing (NGS) of nucleic acids for the efficient, highly sensitive and unbiased detection of microbes, including novel pathogens.  Since samples needed for NGS were not collected in VIPS I, we will enroll an additional 200 AIS cases in VIPS II.

2. To determine whether children with arteriopathic AIS have a distinct analyte signature consistent with an alternative pathway of inflammation compared to children with cardioembolic or idiopathic stroke.  

In samples obtained from our well-characterized VIPS I  derivation cohort, we will use high sensitivity multiplex bead arrays to measure a custom panel of soluble immune mediators and related analytes that have been implicated in other forms of vascular disease.  We will confirm the resulting associations in the VIPS II validation cohort.

3.  To obtain and analyze the childhood stroke transcriptome, and identify molecular correlates of stroke heterogeneity.  In cases and controls enrolled in VIPS II, we will generate genome-wide transcriptional profiles from the peripheral blood to determine which genes and pathways are dysregulated after AIS, and how they correlate with stroke subtype (arteriopathic, cardioembolic, idiopathic).