Influenza-associated acute necrotizing encephalopathy in US children

Influenza-Associated Acute Necrotizing Encephalopathy (IA-ANE) Working Group; Silverman A, Walsh R, Santoro JD, Thomas K, Ballinger E, Fisher KS, Thomas AX, Appavu B, Kruer MC, Neilson D, Knoll J, Sharp AN, Edelman HE, Otallah S, Morgan A, Grzezulkowska A, Nguyen J, Rao LM, Hecht SM, Catalano L, Daigle H, Kronfol C, Wharton J, Adams D, Kalawi AZ, Kung M, Arellano JL, Smith L, Segal D, Feja K, Broomall E, Jayakar A, Arnold SR, Retallack H, Press CA, Gombolay G, McLaughlin MH, Kannan V, Thakkar K, Rezwan T, Hulfish E, Eid D, Meylor J, Peng D, Hurtado R, Nickerson T, Mandell I, Carbonell AU, Kerner-Rossi M, Jayaraman D, Davis M, Olivero R, Shah N, Osborne CM, Zhang B, Cortina C, Randolph AG, Rao S, LaRocca T, Van Haren KP, Wilson-Murphy M. Influenza-Associated Acute Necrotizing Encephalopathy in US Children. JAMA. 2025 Jul 30. doi: 10.1001/jama.2025.11534. Epub ahead of print. PMID: 40736730.

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.

Uyeki TM. Pediatric Influenza-Associated Acute Necrotizing Encephalopathy-Gaps Need to Be Addressed. JAMA. 2025 Jul 30. doi: 10.1001/jama.2025.13003. Epub ahead of print. PMID: 40737115.

Influenza is associated with a wide spectrum of respiratory and nonrespiratory complications, including neurologic manifestations, of variable disease severity. Influenza-associated encephalopathy (IAE) encompasses several clinical syndromes in which impaired consciousness and/or altered mental status and brain dysfunction may range from brief, mild, and self-limited to rapid progression to coma and death. The most severe clinical syndrome of IAE is acute necrotizing encephalopathy (ANE). Although thought to be rare, ANE has been associated with high mortality and high frequency of neurologic sequelae in survivors. Recently, consensus case definitions for ANE were proposed that include acute neurologic deterioration with neuroimaging findings of bilateral symmetric thalamic lesions and may also involve other areas of the brain such as the brainstem, cerebellum, and cerebral white matter. ANE can be triggered by multiple pathogens and has been described since the late 1970s in Japan, with some ANE cases identified during influenza epidemics. In the United States, pediatric deaths with IAE, and influenza-associated ANE (IANE) cases, have been reported, but no national surveillance exists for IAE or IANE.