Pediatric Influenza-Associated Encephalopathy and Acute Necrotizing Encephalopathy — United States, 2024–25 Influenza Season

Abstract

Introduction

The 2024–25 influenza season was historically severe with the highest number of pediatric influenza-associated deaths reported during a seasonal influenza epidemic since U.S. surveillance for these deaths began in 2004 (excluding the 2009–10 influenza A(H1N1)pdm09 pandemic). No U.S. surveillance for neurologic complications of influenza exists. Influenza-associated encephalopathy (IAE), a recognized complication of influenza, refers to neurologic syndromes triggered by influenza virus infection of the respiratory tract, resulting in a dysregulated host inflammatory response and leading to varying degrees of brain dysfunction (1,2). One of the most severe forms of IAE is acute necrotizing encephalopathy (ANE), a condition that disproportionately affects children and is characterized by rapid neurologic decline and neuroimaging with evidence of necrosis or hemorrhage involving the thalami; ANE has a poor prognosis and can result in lasting neurologic sequelae or death (2,3).

In January 2025, CDC was alerted to several deaths of children with influenza-associated ANE (4). In response, CDC requested notification from clinicians and health departments of possible cases of pediatric IAE, including influenza-associated ANE, to better characterize these syndromes in the U.S. during the 2024–25 influenza season. This report describes cases reported in response to CDC’s request.

Methods

On February 28, 2025, CDC released a call for cases of IAE in persons aged <18 years via the Epidemic Information Exchange | Epi-X, asking clinicians and health departments to contact CDC if cases fulfilled CDC’s IAE surveillance criteria (Box) (4). Case report forms^† were completed by clinicians, public health practitioners, and partners from CDC-sponsored surveillance networks (i.e., FluSurv-NET | FluView, New Vaccine Surveillance Network | NVSN, and Influenza-Associated Pediatric Mortality | CDC) if surveillance criteria were met and electronic health record (EHR) data were available.

Case Categorization

Neuroimaging findings and discharge diagnoses underwent review by a physician to categorize cases as IAE or influenza-associated neurologic disease. IAE cases were subcategorized into ANE (those with compatible neuroimaging findings or an ANE discharge diagnosis) or other IAE. ANE cases were defined as probable if neuroimaging reports described bilateral thalamic inflammatory lesions and possible if the patient received a discharge diagnosis^§ of ANE without these neuroimaging findings. IAE cases that did not fulfill ANE criteria were categorized as other IAE if a discharge diagnosis of IAE was reported. All other submitted cases were categorized as influenza-associated neurologic disease and are described separately (Supplementary Table). Reports were excluded if co-detection of a neuroinvasive pathogen in addition to influenza was reported.

Demographics and clinical characteristics and outcomes were described overall and by case categorization. Deidentified data were collected and stored in a REDCap database (version 15.5.8; Vanderbilt University) hosted at CDC, and SAS software (version 9.4; SAS Institute) was used for all analyses. Missing responses were excluded from denominators. This activity was reviewed by CDC, deemed not research, and was conducted consistent with applicable federal law and CDC policy.^¶

Results

CDC received 192 reports that met surveillance criteria (Figure). Among those, 109 cases were categorized as IAE, 37 (34%) of which were subcategorized as ANE (Table). An additional 82 reports were categorized as influenza-associated neurologic disease, a category for those cases that did not meet the IAE case definition; demographics and clinical characteristics, influenza antiviral treatment, and illness severity of these cases were generally similar to those of IAE cases and are described separately (Supplementary Table). Percentages of characteristics were calculated among those patients with available information.

Characteristics of All Patients with Influenza-Associated Encephalopathy

Among the 109 IAE cases with available data, median patient age was 5 years (IQR = 3–10 years) (Table). Approximately one half of patients were female (46%) and non-Hispanic White (52%). Overall, 97 (89%) patients had influenza A virus infection; among the 59 (61%) cases with influenza A virus subtype available, 37 (63%) had A(H1N1)pdm09 and 22 (37%) had A(H3N2). Approximately one half (55%) of patients were previously healthy with no underlying medical conditions.** Signs and symptoms most commonly reported at initial assessment were altered mental status (88%), respiratory symptoms (87%), and fever (85%). Among patients with ANE, 87% had seizures at the time of admission; among the other IAE patients, seizures were noted in 45% of cases.

Neurologic symptoms commenced a median 2 days after illness onset^†† (IQR = 1–3 days). Overall, neuroimaging was received by 94% of IAE patients; abnormal findings were reported for 97% of ANE patients and 49% of other IAE patients. Influenza antiviral treatment was administered to 84% of IAE patients, beginning a median of 3 days after illness onset, and among 90% of all IAE patients, antiviral treatment started on or after the date of hospital admission. Among all IAE patients, 74% were admitted to an intensive care unit (ICU), 54% received invasive mechanical ventilation, and 19% died. Among the 70 survivors with information on neurologic status at discharge, 47% had not returned to their neurologic baseline.^§§ Among 93 patients with information on seasonal influenza vaccination, 15 (16%) had received ≥1 dose of the 2024–25 seasonal influenza vaccine ≥14 days before illness onset.^¶¶

Characteristics of Patients with Acute Necrotizing Encephalopathy

Among the 37 IAE cases subcategorized as ANE with available data, the median patient age was 4 years (IQR = 1–7 years). Approximately one half (51%) of patients were previously healthy. Four (13%) of 30 ANE patients had received ≥1 dose of the 2024–25 seasonal influenza vaccine ≥14 days before illness onset. Among patients with data available on interventions provided, influenza antivirals were received by 94%, systemic corticosteroids by 88%, intravenous immunoglobulin by 67%, other immunomodulators (e.g., tocilizumab, baricitinib, or anakinra) by 56%, and plasma exchange by 44%. All patients with ANE were admitted to an ICU, and 89% received invasive mechanical ventilation. Fifteen (41%) patients with ANE died. Among 13 survivors with information about neurologic sequelae at discharge, only one had returned to neurologic baseline. The median hospital stay was 16 days (IQR = 4–31 days) for all ANE patients and 30 days (IQR = 18–38 days) among survivors. ANE patients who died were hospitalized for a median of 4 days (IQR = 3–7 days) before death.

Discussion

Since 2010, CDC and the Advisory Committee on Immunization Practices have recommended annual influenza vaccination for all persons aged ≥6 months (7). Influenza vaccination can prevent influenza illness and reduce the severity of influenza in children who do become ill, including reduction in occurrence of critical and life-threatening influenza (CDC | Benefits of the Flu Vaccine) (8). Influenza vaccination has also been found to reduce influenza-associated hospitalization and emergency department visits in children (9). Despite these known benefits, pediatric influenza vaccination coverage has declined in recent years*** and only 16% of vaccine-eligible IAE patients reported to CDC had received the 2024–25 influenza vaccine.

Preadmission oseltamivir treatment among IAE patients was low. Outpatients with suspected or confirmed influenza who are at high risk for influenza complications are recommended to start influenza antiviral treatment as soon as possible after symptom onset; antiviral treatment might also be considered for patients who are not at higher risk (CDC | Antiviral Medications). Whether influenza antiviral therapy affects the development or progression of IAE is unknown; however, one study demonstrated that oseltamivir treatment of influenza in outpatients aged 5–17 years was associated with a reduced risk for hospitalization with serious neuropsychiatric events, including neurologic events such as seizure, altered mental status, and encephalitis (10).

Limitations

The findings in this report are subject to at least three limitations. First, included cases are a convenience sample and might not be representative of all U.S. IAE cases during the 2024–25 influenza season. Second, categorization of IAE cases relied partially on discharge diagnoses, which likely underrepresent the true incidence of IAE, as IAE has no consensus standardized diagnostic criteria and might be underdiagnosed. Finally, deidentified data available for analysis were based on data abstracted from EHRs and reported on the surveillance case report form. Therefore, reported data did not necessarily include the complete clinical course and all clinical or laboratory data, neuroimaging reports, or primary neuroradiographic images.

Implications for Public Health Practice

IAE is a serious neurologic complication of influenza that can affect healthy children as well as those with underlying medical conditions. During influenza season, parents and caregivers of children with neurologic signs and symptoms (e.g., seizures, hallucinations, or altered level of consciousness) in conjunction with fever or respiratory symptoms should seek care urgently. Health care providers should consider IAE in children with recent or current febrile illness with encephalopathy, monitor these children for clinical deterioration, and initiate appropriate supportive care.

Annual influenza vaccination is recommended for all children aged ≥6 months to prevent influenza and associated complications, potentially including neurologic disease such as IAE and ANE. Early influenza antiviral treatment is recommended as soon as possible for all children with influenza who are hospitalized or at increased risk for influenza complications because of age or presence of comorbidities.

No consensus standardized diagnostic or surveillance case definitions for IAE currently exist. Additional measures are needed to develop and implement surveillance to improve understanding of the incidence, potential risk factors, severity, and public health impact of IAE in the United States.

CDC is integrating surveillance for IAE and ANE into existing CDC-sponsored surveillance systems for the 2025–26 influenza season to better understand these serious and potentially preventable complications of influenza.