Year: 2025
Type: article
Study design: Observational Study
Abstract: Importance: Acute necrotizing encephalopathy (ANE) is a rare, but severe, neurologic condition for which epidemiologic and management data remain limited. During the 2024-2025 US influenza season, clinicians at large pediatric centers anecdotally reported an increased number of children with influenza-associated ANE, prompting this national investigation. Objective: To understand the clinical presentation, interventions, and outcomes among US children diagnosed with influenza-associated ANE. Design, Setting, and Participants: This study was a multicenter case series of children diagnosed with ANE with longitudinal follow-up. A call for cases was issued via academic societies, public health agencies, and by directly contacting pediatric specialists at 76 US academic centers, requesting cases between October 1, 2023, and May 30, 2025. Inclusion criteria required acute encephalopathy with radiologic evidence of acute thalamic injury and laboratory confirmation of influenza infection in individuals aged 21 years or younger. Exposure: Influenza-associated ANE. Main Outcomes and Measures: Presenting symptoms, vaccination history, laboratory and genetic findings, interventions, and clinical outcomes, including modified Rankin Scale score (0: no symptoms; 1-2: mild disability; 3-5: moderate to severe disability; 6: death), length of stay, and functional outcomes. Results: Of 58 submitted cases, 41 cases (23 females; median age, 5 years [IQR, 2-8]) from 23 US hospitals met inclusion criteria. Thirty-one cases (76%) had no significant medical history; 5 (12%) were medically complex. Clinical presentation included fever in 38 patients (93%), encephalopathy in 41 (100%), and seizures in 28 (68%). Thirty-nine patients (95%) had influenza A (14 with A/H1pdm/2009, 7 with A/H3N2, and 18 with no subtype) and 2 had influenza B. Laboratory deviations included elevated liver enzymes (78%), thrombocytopenia (63%), and elevated cerebrospinal fluid protein (63%). Among 32 patients (78%) with genetic testing, 15 (47%) had genetic risk alleles potentially related to risk of ANE including 11 (34%) with RANBP2 variants. Among 38 patients with available vaccination history, only 6 (16%) had received age-appropriate seasonal influenza vaccination. Most patients received multiple immunomodulatory treatments, including methylprednisolone (95%), intravenous immunoglobulin (66%), tocilizumab (51%), plasmapheresis (32%), anakinra (5%), and intrathecal methylprednisolone (5%). Median intensive care unit and hospital lengths of stay were 11 days (IQR, 4-19) and 22 days (IQR, 7-36), respectively. Eleven patients (27%) died a median of 3 days (IQR, 2-4) from symptom onset, primarily from cerebral herniation (91%). Among the 27 survivors with 90-day follow-up, 63% had at least moderate disability (modified Rankin Scale score ≥3). Conclusions and Relevance: In this case series of children with influenza-associated ANE from the 2 most recent influenza seasons in the US, the condition was associated with high morbidity and mortality in this cohort of predominantly young and previously healthy children. The findings emphasize the need for prevention, early recognition, intensive treatment, and standardized management protocols.
Source: JAMA
Authors: Influenza-Associated Acute Necrotizing Encephalopathy (IA-ANE) Working Group, Andrew Silverman, Rachel Walsh, Jonathan D. Santoro, Katherine Thomas, Elizabeth Ballinger, Kristen S. Fisher, Ajay X. Thomas, Brian Appavu, Michael C. Kruer, Derek Neilson, Jasmine Knoll, April N. Sharp, Hannah E. Edelman, Scott Otallah, Alexandra Morgan, Aniela Grzezulkowska, John Nguyen, Lekha M. Rao, Shaina M. Hecht, Laura Catalano, Hunter Daigle, Catherine Kronfol, Jessica Wharton, David Adams, Adam Z. Kalawi, Michael Kung, Janetta L. Arellano, Lauren Smith, Devorah Segal, Kristina Feja, Eileen Broomall, Anuj Jayakar, Sandra R. Arnold, Hanna Retallack, Craig A. Press, Grace Gombolay, Madeleine H. McLaughlin, Varun Kannan, Kavita Thakkar, Tasmia Rezwan, Erin Hulfish, Dalia Eid, Jennifer Meylor, Diane Peng, Ryan Hurtado, Taylor Nickerson, Iris Mandell, Abigail U. Carbonell, Mallory Kerner-Rossi, Divya Jayaraman, Mallory Davis, Rosemary Olivero, Neel Shah, Christina M. Osborne, Bo Zhang, Christopher Cortina, Adrienne G. Randolph, Suchitra Rao, Thomas LaRocca, Keith P. Van Haren, Molly Wilson-Murphy
Institutions: Lucile Packard Children's Hospital, Stanford University, Boston Children's Hospital, Harvard University, University of Southern California, Children's Hospital of Los Angeles, Santa Clara Valley Medical Center, Baylor College of Medicine, Texas Children's Hospital, Barrow Neurological Institute, University of Arizona, University of Arizona College of Medicine- Phoenix, Johns Hopkins University, Johns Hopkins Medicine, Johns Hopkins Children's Center, Atrium Health Wake Forest Baptist, Wake Forest University Health Sciences, University of California, Los Angeles, Mattel Children's Hospital, Riley Hospital for Children, Indiana University School of Medicine, Dell Children's Medical Center of Central Texas, The University of Texas at Austin, Prisma Health, University of South Carolina, Children's Hospital of Orange County, University of California, Irvine, NYU Langone Health, New York University, Rutgers, The State University of New Jersey, Saint Peter's University Hospital, Cincinnati Children's Hospital Medical Center, Miami Children's Hospital, University of Tennessee Health Science Center, Le Bonheur Children's Hospital, Children's Hospital of Philadelphia, University of Pennsylvania, Emory University, Children's Healthcare of Atlanta, Northwestern University, Lurie Children's Hospital, Good Samaritan University Hospital, Stony Brook University Hospital, Medical College of Wisconsin, Children's Hospital of Illinois, Northwell Health, Cohen Children's Medical Center, Columbia University Irving Medical Center, Helen DeVos Children's Hospital, Corewell Health, St. Louis Children's Hospital, Washington University in St. Louis, University of Colorado Anschutz
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
Award: G7773741480
OpenAlex ID: W4412738583