Vascular effects of Infection in Pediatric Stroke (VIPS) Study I

Principal Investigators: Heather J. Fullerton and Gabrielle A. DeVeber

STATUS: Data Analysis, Immunology Study, Manuscript Writing
FUNDING: NIH-NINDS, R01 and Marc and Lynne Benioff Pediatric Stroke Research Fund

The VIPS study began in August 2009 and ended August 2016. VIPS I successfully enrolled and fully characterized 355 children with arterial ischemic stroke and 354 stroke-free controls from 37 centers on 5 continents.  It has already led to 10 original manuscripts (8 published, 2 under review), representing the most scientifically rigorous body of work in the field of childhood stroke. We worked with  Stanford University neuroradiologist, Dr. Max Wintermark, to establish novel and rigorous methods for prospectively diagnosing and classifying childhood arteriopathies using a combination of clinical and radiographic data (Wintermark, Stroke 2014).  We confirmed the importance of arteriopathies as a predictor of recurrent stroke (Fullerton, Stroke 2016).   We confirmed minor clinical infection as a transient risk factor for childhood (Fullerton, Neurology 2015), and found that herpes viral infections (not only varicella, but also herpes simplex) might play a particular role in childhood stroke (Elkind, Circulation 2016).  We also found that serum inflammatory markers differ by stroke sub-type, and predict recurrent stroke risk (Fullerton, Stroke 2017). 

VIPS data led to the paradox of a common exposure (infection) and rare outcome (childhood stroke).  We hypothesize that this paradox is explained by (1) unusual strains or combinations of pathogens and/or (2) unusual host immune responses to infection.  NIH-NINDS just approved the R01 funding  for VIPS II study (PI Fullerton) which will use next-generation sequencing as an unbiased measure of exposure to infectious organisms to determine which specific agents contribute to childhood stroke (in collaboration with Dr. Joe DeRisi); it will also further assess the role of the host immune response in stroke pathogenesis.  The merits of the VIPS research program were also recognized by Marc and Lynne Benioff, benefactors to UCSF Benioff Children's Hospitals, who awarded us a large programmatic gift to continue this line of work. 

PUBLICATIONS:

  1. Fullerton HJ, Elkind MS, Barkovich AJ, Glaser C, Glidden D, Hills NK, Leiva-Salinas C, Wintermark M, Deveber GA. The vascular effects of infection in Pediatric Stroke (VIPS) Study. J Child Neurol. 2011 Sep; 26(9):1101-10. PMID: 21616922

  2. Wintermark M, Hills NK, deVeber GA, Barkovich AJ, Elkind MS, Sear K, Zhu G, Leiva-Salinas C, Hou Q, Dowling MM, Bernard TJ, Friedman NR, Ichord RN, Fullerton HJ. Arteriopathy diagnosis in childhood arterial ischemic stroke: results of the vascular effects of infection in pediatric stroke study. Stroke. 2014 Dec; 45(12):3597-605. PMID: 25388419

  3. Fullerton HJ, Hills NK, Elkind MS, Dowling MM, Wintermark M, Glaser CA, Tan M, Rivkin MJ, Titomanlio L, Barkovich AJ, deVeber GA. Infection, vaccination, and childhood arterial ischemic stroke: Results of the VIPS study. Neurology. 2015 Oct 27; 85(17):1459-66. PMID: 26423434

  4. Editorial : Fullerton HJ, Hills NK, Elkind MS, Dowling MM, Wintermark M, Glaser CA, Tan M, Rivkin MJ, Titomanlio L, Barkovich AJ, deVeber GA. Infection, vaccination, and childhood arterial ischemic stroke: Results of the VIPS study. Neurology. 2015 Oct 27; 85(17):1459-66. PMID: 26423434

  5. Fullerton HJ, Wintermark M, Hills NK, Dowling MM, Tan M, Rafay MF, Elkind MS, Barkovich AJ, deVeber GA. Risk of Recurrent Arterial Ischemic Stroke in Childhood: A Prospective International Study. Stroke. 2016 Jan; 47(1):53-9. PMID: 26556824

  6. Elkind MS, Hills NK, Glaser CA, Lo WD, Amlie-Lefond C, Dlamini N, Kneen R, Hod EA, Wintermark M, deVeber GA, Fullerton HJ. Herpesvirus Infections and Childhood Arterial Ischemic Stroke: Results of the VIPS Study. Circulation. 2016 Feb 23; 133(8):732-41. PMID: 26813104

  7. Wei F, Diedrich KT, Fullerton HJ, deVeber G, Wintermark M, Hodge J, Kirton A. Arterial Tortuosity: An Imaging Biomarker of Childhood Stroke Pathogenesis? Stroke. 2016 May; 47(5):1265-70. PMID: 27006453

  8. Wintermark M, Hills NK, DeVeber GA, Barkovich AJ, Bernard TJ, Friedman NR, Mackay MT, Kirton A, Zhu G, Leiva-Salinas C, Hou Q, Fullerton HJ, and the VIPS Investigators.Clinical and Imaging Characteristics of Arteriopathy Subtypes in Children with Arterial Ischemic Stroke: Result of the VIPS Study. American Journal of Neuradiology. 2017 Oct 5. doi: 10.3174/ajnr. A5376. PMID: 28982784

  9. Fullerton HJ, Luna JM, Wintermark M, Hills NK, Tokarz R, Li Y, Glaser C, De Veber GA, Lipkin WI, Ekind, MS and the VIPS Investigators. Parvovirus B19 Infection in Children with Arterial Ischemic Stroke. Stroke. 2017 Oct; 48 (10):2875-2877.doi 10.1161/STROKEAHA.117.018272. PMID: 28864597.

  10. Jordan LC, Hills NK, Fox CF, Ichord RN, Pergami P, deVeber GA, Fullerton HJ, Lo W, and the VIPS Investigators. Socioeconomic Determinants of Outcome after Childhood Arterial Ischemic Stroke. Neurology. April 2018. In press, waiting for ePub.

  11. Fullerton HJ, Stence N, Hills NK, Jiang B, Amlie-Lefond C, Bernard TJ, Friedman N, Ichord RN, Mackay M, Rafay M, Chabrier S, Steinlin M, Elkind M, deVeber GA, Wintermark W, and the VIPS Investigators. Focal Cerebral Arteriopathy of Childhood: Novel Severity Score and Natural History. Stroke. April 2018. Ongoing revision.