Pediatric Influenza-Related Acute Necrotizing Encephalopathy in the United States: A Multicenter Retrospective Analysis
Andrew Silverman1, Rachel Walsh2, Jonathan Santoro3, Katherine Thomas4, Elizabeth Ballinger5, Kristen Fisher5, Brian Appavu6, Michael Kruer6, Derek Neilson6, Jasmine Knoll6, April Sharp7, Hannah Edelman7, Scott Otallah8, Alexandra Morgan8, Aniela Grzezulkowska9, John Nguyen10, Lekha Rao10, Shaina Hecht11, Kristina Feja12, Jessica Wharton13, Hanna Retallack14, Craig Press14, Thomas LaRocca15, Keith P. Van Haren1, Molly Wilson-Murphy2
1Pediatric Neuroimmunology, Stanford Lucile Packard Children's Hospital, Stanford University, Palo Alto CA, 2Pediatric Neuroimmunology, Boston Children’s Hospital, Harvard University, Boston MA, 3Pediatric Neuroimmunology, Children's Hospital of Los Angeles, USC Keck School of Medicine, Los Angeles CA, 4Pediatric Rehabilitation Medicine, Santa Clara Valley Medical Center, Santa Clara CA, 5Pediatric Neurology, Texas Children’s Hospital, Baylor College of Medicine and Texas Children's Hospital, Houston TX, 6Pediatric Neuroimmunology and Neurogenetics, Neurocritical Care, Genetics and Metabolism, Barrow Neurological Institute at Phoenix Children's, University of Arizona School of Medicine, Phoenix AZ, 7Pediatric Neurology, Johns Hopkins Hospital, Johns Hopkins School of Medicine, Baltimore MD, 8Pediatric Neurology, Atrium Health Wake Forest Baptist, Wake Forest School of Medicine, Winston-Salem NC, 9Pediatric Neurology, Nemours Children’s Health, Sidney Kimmel Medical College, Wilmington DE, 10Pediatric Neurology, UCLA Mattel Children’s Hospital, David Geffen School of Medicine, Los Angeles CA, 11Pediatric Infectious Disease, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis IN, 12Pediatric Infectious Disease, Saint Peter’s University Hospital, Rutgers Robert Wood Johnson Medical School, New Brunswick NJ, 13Pediatric Neurology, Prisma Health, Greenville SC, 14Pediatric Neurology and Neurocritical Care, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia PA, 15Pediatric Critical Care, Stanford Lucile Packard Children's Hospital, Stanford University, Palo Alto and Madera CA
Objective:
To describe symptoms, interventions, and outcomes among US children diagnosed with influenza-related acute necrotizing encephalopathy (ANE).
Background:
The 2024/25 influenza season has been characterized by significant morbidity and mortality. ANE is a rare, but severe neurologic complication associated with influenza and other viral infections, for which epidemiologic and management data remain limited.
Design/Methods:
We conducted a retrospective case series of children diagnosed with ANE between October 1, 2023 and February 21, 2025 with inclusion criteria based on symptoms, influenza status, serum markers, and characteristic neuroimaging.
Results:
We identified 24 patients (14 female; median age 4.5) from 14 US hospitals. Most (75%) patients had no prior medical history. Among 23 patients with available vaccination history, only 4 (17%) had received age-appropriate seasonal influenza vaccination. Clinical presentation included fever and encephalopathy in nearly all patients, and seizures in 15 (62%). Eight of the 11 (73%) subtyped influenza strains were H1/2009; 3 were H3. Lab deviations included median AST 416U/L, ALT 216U/L, platelets 78k/µL, CSF protein 83mg/dL, and CSF WBC 4cells/µL. Among 16 patients with relevant genetic sequencing, 2 patients harbored RANBP2 pathogenic variants, and 2 had RANBP2 variants of uncertain significance. Treatments included intravenous methylprednisolone in 23 (96%) patients, IVIg in 14 (58%), tocilizumab in 12 (50%), oseltamivir in 16 (67%), plasmapheresis in 7 (29%), hypothermia in 3 (13%), anakinra in 2 (8%), and intrathecal corticosteroids in 1 (4%). Six (25%) patients died. Median length of stay in the ICU and hospital were 10 and 22 days, respectively, not including inpatient rehab.
Conclusions:
Despite aggressive multimodal therapy, influenza-associated ANE carried a high mortality in this series of predominantly young and previously healthy children. Low vaccination rates and H1/2009 strain predominance suggest prevention opportunities. Further research is needed to optimize treatment protocols and understand genetic susceptibility.
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