To describe symptoms, interventions, and outcomes among US children diagnosed with influenza-related acute necrotizing encephalopathy (ANE).

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.  

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. 

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. 

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.