Influenza and Acute Necrotizing Encephalopathy in Children
September 1, 2025
By Philip R. Fischer, MD, DTM&H
Synopsis: Of 41 U.S. pediatric patients with influenza-associated acute necrotizing encephalitis, 56% were female, the median age was 5 years, and 12% had underlying complex medical conditions. Influenza A accounted for 95% of cases. Despite the use of a variety of immunomodulating agents, 27% of these children died, and 63% of the survivors were left with at least moderate disability.
Source: Influenza-Associated Acute Necrotizing Encephalopathy (IA-ANE) Working Group; Silverman A, Walsh R, Santoro JD, et al. Influenza-associated acute necrotizing encephalopathy in US children. JAMA. 2025; Jul 30. doi: 10.1001/jama.2025.11534. [Online ahead of print].
Acute necrotizing encephalopathy is rare. When it occurs, it usually is caused by viruses, often influenza, but it also can occur with infection by SARS-CoV-2, human herpesvirus-6, and some other infectious agents. Acute necrotizing encephalopathy is the most severe form of encephalopathy seen with influenza and is characterized by fulminant cerebral injury with edema, inflammation, or necrosis. Affected patients, most often children, have an initial viral prodrome followed by rapid deterioration and associated thalamic lesions. Patients sometimes have an underlying genetic predisposition to acute necrotizing encephalopathy, but the actual pathogenesis and best treatments are not well understood.
The 2024-2025 influenza season was particularly severe, as compared to previous years, and the Centers for Disease Control and Prevention (CDC) became aware of four fatal cases of acute necrotizing encephalopathy. In an effort to better understand and manage this condition, a collaborative group gathered data about patients with acute necrotizing encephalopathy from across the United States.
Children diagnosed with acute necrotizing encephalopathy between October 2023 and May 2025 were identified by contacting 76 pediatric neurology programs, members of professional societies, and public health groups. Suspected cases were defined as: having a recent or persisting influenza-like illness, being hospitalized during the months of the study, having a test result that was positive for influenza, and having a suspected diagnosis of acute necrotizing encephalopathy. From those suspected cases, confirmed diagnoses were based on having: acute encephalopathy or seizure, and having a computed tomography or magnetic resonance imaging study showing multifocal lesions in the brain with prominent involvement of the thalamus. Patients were excluded if they had one of several other concurrent diagnoses (hemophagocytic lymphohistiocytosis, mitochondrial encephalopathy, acute disseminated encephalomyelitis, Reye syndrome, venous or arterial infarction, toxic-metabolic encephalopathy, and infectious encephalitis due to something other than influenza virus).
Completed data forms were submitted for a total of 58 suspected cases from 32 centers. After applying inclusion and exclusion criteria, 41 patients from 23 hospitals were included in the study.
The median age of patients was 5 years. There were 18 males (44%) and 23 females. Five patients (12%) were considered to be medically complex (having a chronic health problem and functional limitation associated with high levels of healthcare need and use). During the season of sickness, 16% had received age-appropriate influenza vaccination, and 78% were unvaccinated (with three children not having confirmation of vaccination status).
At presentation, fever was present in 93% of patients (median 39.7°C). Altered mental status was noted a median of two days after the onset of seemingly viral respiratory and/or gastrointestinal symptoms. Two-thirds of patients had seizures on presentation, and the median Glasgow Coma Scale score was 6 (with the scaled score ranging from deep coma at 3 to fully alert at 15).
On initial laboratory testing, liver enzymes were, overall, about two to three times the upper limit of the normal range. Platelet counts were mildly decreased (median 123,000 per microliter). Spinal fluid, when tested, had elevated protein levels and a median of 3 white blood cells per microliter (interquartile range 2-8). Influenza A was identified in 39 (95%) of the children (half of whom underwent strain testing; two-thirds of the tested children had the 2009 H1 strain) and influenza B was identified in the other two children.
Of these children, 32% underwent genetic testing, and 48% of those tested had a genetic variant thought to confer risk of acute necrotizing encephalopathy. Eleven patients had a heterozygous variant in RANBP2. (This gene encodes for a nuclear pore complex protein that is involved in intracellular transport. Pathogenic variants of RANBP2 are associated with an increased susceptibility to acute necrotizing encephalopathy, most often in patients with familial or recurrent disease with which bouts sometimes are triggered by viral infections.)
Typical magnetic resonance imaging (MRI) findings included signal intensity changes on T2-weighted imaging, most predominant in the thalamus, basal ganglia, subcortical white matter, cerebellum, and brainstem. Trilaminar thalamic necrosis was seen in about half of patients. Those patients who only had computed tomography (CT) imaging showed bilateral thalamic hypodensity.
Antiviral agents were used (oseltamivir in 76% of patients) along with immunomodulatory agents (intravenous methylprednisolone in 95% of patients, intravenous immunoglobulin in two-thirds, and tocilizumab in half).
Patients were very ill. They were intubated and ventilated for a median of seven days and stayed in intensive care units for a median of 11 days. One patient required extracorporeal membrane oxygenation, and one required renal replacement therapy. Twenty-seven patients (66%) died, almost always due to cerebral herniation, a median of three days after hospitalization. Three months after hospitalization, 63% of survivors had at least moderate neurologic disability (modified Rankin Scale score of 3 to 5 on a scale where 0 is none and 6 is death) and only 53% were able to stand independently.
Clearly, influenza-associated acute necrotizing encephalopathy can be devastating. The uncommonness of appropriate influenza immunization in affected children suggests that, while imperfect, annual childhood influenza vaccination could be beneficial. The association of a genetic variation in some patients points to the complex interplay of virus-host interactions in the pathogenesis of this condition.
Commentary
The CDC provides helpful (and concerning) data about influenza immunization in U.S. children. There has been a steady drop in coverage from 62% at the end of the 2019-2020 influenza season to 49% at the end of the 2024-2025 influenza season.1 With only 16% of children in the new influenza-associated acute necrotizing encephalopathy study having documentation of vaccination, it seems that influenza vaccine could have prevented some or even most of the cases in the new study. Sharing the story of the unfortunate outcomes of patients in this study might help more families to pursue vaccination.
The CDC reviewed influenza-associated deaths and acute necrotizing encephalopathy from the 2010-2011 influenza season through the years of the COVID-19 pandemic (with many fewer deaths during the 2020-2021 and 2021-2022 seasons when aggressive measures were instituted to prevent respiratory infections) and to the mid-point of the 2024-2025 season.2 Influenza death rates increased from 133/year during the 10 years prior to the COVID-19 pandemic to 146/year following the two years of COVID-related prevention measures.2 Deaths resulting from acute necrotizing encephalopathy in patients with influenza increased from 11/year pre-pandemic to 15/year post-pandemic.2 Related to declining vaccination rates and, likely, other factors, the incidence of influenza-associated acute necrotizing encephalopathy with and without death is rising.
From May 2022 through April 2023, 23 children with influenza-associated encephalopathy were treated at a single hospital in China.3 Of these children, 78% had influenza A, and 22% had influenza B. Only about half had elevated levels of liver enzymes, and those with elevated liver enzyme levels were more likely to die.3 Although perhaps with some methodologic differences, patients in this study were less likely to die (only 26% vs. 66% in the new U.S. study) and more likely to fully recover (52%).3
Pulse steroids are used for children with influenza-associated encephalopathy in Japan, as in the United States.4 However, longitudinal data in Japan suggest that the prognosis is improving over time, leading researchers to speculate that the addition of a “mitochondrial cocktail” and aggressive temperature control might be behind the improvement in outcomes.4
Variations in the RANBP2 gene were identified in almost half of the children who underwent genetic testing in the study reviewed here. Similarly, a recent study in China identified variations in this gene in six of 16 patients with acute necrotizing encephalopathy (although not all these patients were children, and not all had influenza as the triggering infection).5 The Chinese study also found genetic variations affecting complement pathways that might be relevant in increasing the risk of developing acute necrotizing encephalopathy.5
A study of micro ribonucleic acid (RNA) sequencing analysis recently reported from elsewhere in China identified two genes, hsa-miR-4657 and hsa-miR-342-3p, that were significantly downregulated in patients with influenza-associated acute necrotizing encephalopathy as compared to influenza-infected patients without severe neurologic disease.6 Since there still is no consensus on best-practice medical management of children with acute necrotizing encephalopathy, perhaps ongoing studies will yield better understanding of the pathophysiology of influenza-associated acute necrotizing encephalopathy and more effectively targeted treatments.7
Philip R. Fischer, MD, DTM&H, is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.
References
1. Centers for Disease Control and Prevention. Influenza Vaccination Coverage, Children 6 months through 17 years, United States. May 7, 2025. https://www.cdc.gov/fluvaxview/dashboard/children-vaccination-coverage.html
2. Fazal A, Reinhart K, Huang S, et al. Reports of encephalopathy among children with influenza-associated mortality — United States, 2010-11 through 2024-25 influenza seasons. MMWR Morb Mortal Wkly Rep. 2025;74(6):91-95.
3. Wang D, Guo H, Wu CF, et al. [Clinical features and prognosis of children with influenza-associated encephalopathy: An analysis of 23 cases]. Zhongguo Dang Dai Er Ke Za Zhi. 2025;27(7):829-833. [Article in Chinese]. (Note: Comments discussed earlier are based on the English abstract; the full article is only available in Chinese.)
4. Omata T, Sakuma H, Nagase H, et al. National study on pediatric acute encephalopathy in Japan (April 2020 to October 2023): Insights from the third study. Brain Dev. 2025;47(4):104387.
5. Geng C, Ju Y, Wang J, et al. The genetic landscape of acute necrotizing encephalopathy: Insights into the possible pathogenesis. J Clin Neurol. 2025;21(4):340-347.
6. Wang W, Chen J, Bao Y, et al. MicroRNA sequencing analysis in pediatric patients with influenza-associated acute necrotizing encephalopathy: Potential biomarkers for early diagnosis and therapy. Infect Genet Evol. 2025;130:105734.
7. Uyeki TM. Pediatric influenza-associated acute necrotizing encephalopathy — gaps need to be addressed. JAMA. 2025; Jul 30. doi: 10.1001/jama.2025.13003. [Online ahead of print].
Of 41 U.S. pediatric patients with influenza-associated acute necrotizing encephalitis, 56% were female, the median age was 5 years, and 12% had underlying complex medical conditions. Influenza A accounted for 95% of cases. Despite the use of a variety of immunomodulating agents, 27% of these children died, and 63% of the survivors were left with at least moderate disability.
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