Risk of Acute Necrotizing Encephalopathy (ANEC) with Ibuprofen Use in Pediatric Influenza
There is no established causal relationship between ibuprofen (NSAID) use and acute necrotizing encephalopathy (ANEC) in children with influenza. The primary concern with NSAIDs in influenza relates to ibuprofen potentially antagonizing aspirin's antiplatelet effects when used concurrently, not to ANEC risk 1.
Understanding ANEC in Influenza Context
ANEC is a rare but devastating complication of influenza itself, not a medication-induced condition:
- ANEC occurs predominantly in Japan where it was first described in 1995, with an estimated 100 deaths annually related to CNS complications of influenza, suggesting either genetic predisposition or strain variation 1
- Clinical presentation includes high fever, convulsions, and coma with bilateral symmetric brain lesions primarily involving the thalami 1, 2
- Mortality and morbidity are severe: Among 202 Japanese children with influenza-associated encephalopathy (1997-2001), death occurred in 31%, residual neurological deficit in 26%, and full recovery in only 43% 1
Recent US Data Confirms High Risk Independent of NSAID Use
The most recent and highest quality evidence comes from a 2025 multicenter US case series:
- 41 children with influenza-associated ANEC from 23 hospitals (2023-2025 seasons) showed 27% mortality and 63% of survivors had at least moderate disability at 90 days 3
- Only 16% had received age-appropriate influenza vaccination, highlighting prevention as the critical intervention 3
- Genetic susceptibility is significant: 47% of tested patients had genetic risk alleles (including 34% with RANBP2 variants) 3
- The condition is associated with influenza infection itself, not antipyretic choice 3
The Real NSAID Concern: Aspirin and Reye's Syndrome
The established medication-related encephalopathy risk in pediatric influenza is Reye's syndrome with aspirin, not ANEC with ibuprofen:
- Aspirin has a clear association with Reye's syndrome in children with viral illnesses, particularly influenza B 1
- Dramatic fall in Reye's syndrome incidence followed warnings about aspirin use in children 1
- Ibuprofen should generally be avoided only when children are taking aspirin (for conditions like Kawasaki disease) because it may antagonize aspirin's antiplatelet effect, not due to encephalopathy risk 1
Clinical Recommendations for NSAID Use
Ibuprofen is safe for fever management in pediatric influenza with the following caveats:
- Avoid aspirin entirely in children <16 years with influenza-like illness due to Reye's syndrome risk 4
- Use paracetamol or ibuprofen for symptomatic management of fever, myalgias, and headache 4
- Avoid ibuprofen only if the child is on aspirin therapy (e.g., for Kawasaki disease) to prevent antagonism of antiplatelet effects 1
Focus on Prevention and Early Recognition
Rather than avoiding ibuprofen, clinicians should prioritize:
- Annual influenza vaccination for all eligible children, especially those with prior neurological complications from respiratory illness 5, 3
- Early antiviral treatment (oseltamivir) when influenza is suspected, particularly in high-risk children or those with severe illness 1, 3
- High index of suspicion for ANEC in children presenting with fever, altered consciousness, and seizures during influenza season—this requires urgent neuroimaging 2, 6
- Genetic testing consideration for RANBP2 mutations in ANE survivors and their siblings, as familial cases occur 5, 3
Critical Pitfall to Avoid
Do not withhold appropriate antipyretic therapy (ibuprofen or paracetamol) due to unfounded concerns about ANEC risk. The evidence clearly shows ANEC is a complication of influenza infection itself, with genetic predisposition playing a significant role, not a medication-induced condition 1, 5, 3. The only antipyretic to avoid is aspirin due to Reye's syndrome risk 1, 4.