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JAMA
. 2025 Jul 30:e2511534.
doi: 10.1001/jama.2025.11534. Online ahead of print. Influenza-Associated Acute Necrotizing Encephalopathy in US Children
Influenza-Associated Acute Necrotizing Encephalopathy (IA-ANE) Working Group; Andrew Silverman 1 , Rachel Walsh 2 , Jonathan D Santoro 3 , Katherine Thomas 4 , Elizabeth Ballinger 5 , Kristen S Fisher 5 , Ajay X Thomas 5 , Brian Appavu 6 , Michael C Kruer 6 , Derek Neilson 6 , Jasmine Knoll 6 , April N Sharp 7 , Hannah E Edelman 7 , Scott Otallah 8 , Alexandra Morgan 8 , Aniela Grzezulkowska 9 , John Nguyen 10 , Lekha M Rao 10 , Shaina M Hecht 11 , Laura Catalano 12 , Hunter Daigle 12 , Catherine Kronfol 12 , Jessica Wharton 13 , David Adams 14 , Adam Z Kalawi 14 , Michael Kung 14 , Janetta L Arellano 14 , Lauren Smith 15 , Devorah Segal 15 , Kristina Feja 16 , Eileen Broomall 17 , Anuj Jayakar 18 , Sandra R Arnold 19 , Hanna Retallack 20 , Craig A Press 20 , Grace Gombolay 21 , Madeleine H McLaughlin 21 , Varun Kannan 21 , Kavita Thakkar 22 , Tasmia Rezwan 23 , Erin Hulfish 24 , Dalia Eid 24 , Jennifer Meylor 25 , Diane Peng 25 , Ryan Hurtado 26 , Taylor Nickerson 27 , Iris Mandell 27 , Abigail U Carbonell 28 , Mallory Kerner-Rossi 28 , Divya Jayaraman 28 , Mallory Davis 29 , Rosemary Olivero 29 , Neel Shah 30 , Christina M Osborne 31 , Bo Zhang 2 , Christopher Cortina 32 , Adrienne G Randolph 33 , Suchitra Rao 34 , Thomas LaRocca 35 , Keith P Van Haren 1 , Molly Wilson-Murphy 2
Affiliations
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.
. 2025 Jul 30:e2511534.
doi: 10.1001/jama.2025.11534. Online ahead of print. Influenza-Associated Acute Necrotizing Encephalopathy in US Children
Influenza-Associated Acute Necrotizing Encephalopathy (IA-ANE) Working Group; Andrew Silverman 1 , Rachel Walsh 2 , Jonathan D Santoro 3 , Katherine Thomas 4 , Elizabeth Ballinger 5 , Kristen S Fisher 5 , Ajay X Thomas 5 , Brian Appavu 6 , Michael C Kruer 6 , Derek Neilson 6 , Jasmine Knoll 6 , April N Sharp 7 , Hannah E Edelman 7 , Scott Otallah 8 , Alexandra Morgan 8 , Aniela Grzezulkowska 9 , John Nguyen 10 , Lekha M Rao 10 , Shaina M Hecht 11 , Laura Catalano 12 , Hunter Daigle 12 , Catherine Kronfol 12 , Jessica Wharton 13 , David Adams 14 , Adam Z Kalawi 14 , Michael Kung 14 , Janetta L Arellano 14 , Lauren Smith 15 , Devorah Segal 15 , Kristina Feja 16 , Eileen Broomall 17 , Anuj Jayakar 18 , Sandra R Arnold 19 , Hanna Retallack 20 , Craig A Press 20 , Grace Gombolay 21 , Madeleine H McLaughlin 21 , Varun Kannan 21 , Kavita Thakkar 22 , Tasmia Rezwan 23 , Erin Hulfish 24 , Dalia Eid 24 , Jennifer Meylor 25 , Diane Peng 25 , Ryan Hurtado 26 , Taylor Nickerson 27 , Iris Mandell 27 , Abigail U Carbonell 28 , Mallory Kerner-Rossi 28 , Divya Jayaraman 28 , Mallory Davis 29 , Rosemary Olivero 29 , Neel Shah 30 , Christina M Osborne 31 , Bo Zhang 2 , Christopher Cortina 32 , Adrienne G Randolph 33 , Suchitra Rao 34 , Thomas LaRocca 35 , Keith P Van Haren 1 , Molly Wilson-Murphy 2
Affiliations
- PMID: 40736730
- PMCID: PMC12311823 (available on 2026-01-30)
- DOI: 10.1001/jama.2025.11534
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.
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