Surveillance of severe influenza-associated encephalopathy and related complications in US children

STATEMENT OF WORK Title: Surveillance of severe influenza-associated encephalopathy and related complications in US children Short title: Severe IAE Performance period: Base period: August 1, 2026 – July 31, 2027 Option period 1: August 1, 2027 – July 31, 2028 Option period 2: August 1, 2028 – July 31, 2029 Option period 3: August 1, 2029 – July 31, 2030 Option period 4: August 1, 2030 – July 31, 2031 C.1 – Background and Need Influenza-associated encephalopathy (IAE) is a rare and serious neurologic complication of influenza virus infection. One of the most severe forms of IAE is acute necrotizing encephalopathy (ANE), a condition that disproportionately affects children, has a poor prognosis, and can result in lasting neurologic sequelae or death. In January 2025, CDC received anecdotal reports of critically ill children with IAE, including deaths with ANE in the United States. In response, CDC requested notification of U.S. IAE cases from health departments and clinicians. Among 192 reports of suspected IAE submitted to CDC, 109 were categorized as IAE, roughly one-third of which were subcategorized as ANE. IAE cases were notable for a high frequency of severe disease, including intensive care unit admission (74% of all IAE cases) and death (19% of all IAE cases and 41% of acute necrotizing encephalopathy cases); over half of cases occurred in previously healthy children. Given the severity of this complication observed in the 2025 investigation and the lack of existing national surveillance, in October of the same year, CDC’s Influenza Division introduced IAE surveillance to two CDC influenza surveillance systems, the Influenza-Associated Pediatric Mortality Surveillance System and the Influenza Hospitalization Surveillance Network (FluSurv-NET). However, these surveillance systems do not comprehensively capture data on critically ill children in the United States especially given the rarity of IAE; pediatric mortality surveillance only captures influenza-related deaths, while FluSurv-NET includes approximately 10% of the US population and does not cover many major pediatric referral hospitals. Significant gaps exist in our understanding of IAE that cannot be completely address by these two surveillance systems. There are no diagnostic criteria or treatment protocols for IAE, and while several forms of IAE have been described, they have not been validated with real-world data. Additional critical gaps in our understanding of IAE include the spectrum of disease, disease course, risk factors for severe disease, and the impact/effectiveness of influenza vaccination and influenza antiviral treatment. One major gap is the lack of consensus definitions for infection-triggered encephalopathy syndromes associated with influenza; efforts at defining this with neuroimaging patterns have been made, but require real-world validation. No consensus standardized diagnostic criteria exist for IAE and the role of neuroimaging in guiding diagnosis and clinical management is unclear. Obtaining and validating neuroimaging to fit into previously described infection-triggered encephalopathy neuroimaging patterns, or recognizing novel neuroimaging patterns associated with IAE, will significantly contribute to the development of diagnostic definitions for IAE and can potentially guide clinical management. While IAE has been described during influenza A(H1N1) predominant seasons, data generally support that encephalopathy is a complication of influenza unrelated to virus type or subtype. Evaluation of influenza virus subtype to assess for associations of disease frequency or severity with influenza subtype will contribute to the evidence base. Other viruses, such as SARS-CoV-2 and HHV-6, are also associated with infection-triggered encephalopathy syndromes such as ANE. Research testing for additional viruses allows for better understanding of contributors to disease. Additionally, characterization and description of pre- and post-treatment cytokine and other inflammatory markers for IAE is limited in the data; this information could guide the development of diagnostic and therapeutic parameters. Children with ANE can have lasting neurologic sequelae. Long-term follow-up studies on outcomes for severe IAE are limited. This follow-up can help understand the implications of severe IAE on neurologic, cognitive, and educational outcomes and overall quality of life. Other respiratory viral pathogens, like COVID-19, can cause similar neurologic disease (and other non-neurologic complications) as influenza, and some are also implicated in the pathogenesis of ANE. The ability to study other respiratory viruses and their clinical complications, such as respiratory failure and multisystem inflammatory syndrome in children (MIS-C), improves our understanding of how respiratory viruses cause severe disease in children, and is critical for developing preventive strategies. C.2 – Project Objective The purpose of this contract is to conduct surveillance for severe IAE among critically ill hospitalized children and improve understanding of the spectrum of disease, disease course, risk factors for severe disease, optimal management, and the impact of influenza vaccination and influenza antiviral treatment on disease course. Detailed clinical data will be collected for children with IAE admitted to participating ICUs, estimated to be less than 200 cases during a given non-pandemic influenza season. This active surveillance effort will allow for improved understanding of IAE in U.S. children and the public health impact of this severe complication of influenza. C.3 – Scope of Work The specific goals of this project are to: Perform surveillance for severe IAE in hospitalized children with laboratory-confirmed influenza using standardized case definitions. Collect clinical information on identified IAE cases to assess risk factors for severe disease, describe the disease course and spectrum of disease…