Hemodynamic Instability and Systemic Biomarkers in Influenza-associated Acute Necrotizing Encephalopathy: Lessons From Global Cohorts

To the Editors: We read with great interest the study by Al-Rashdi et al.,1 which offers valuable insights into influenza-associated neurologic complications (IANC) in children in Oman. The authors reported a 5.6% incidence of IANC, underscoring the substantial burden of this condition. Among these complications, acute necrotizing encephalopathy (ANE) is distinguished as the most severe form, where the interaction between systemic inflammation and neurologic damage is most apparent. While Al-Rashdi et al. focus on the clinical and radiologic spectrum of IANC, data from other recent global cohorts suggest that the systemic hemodynamic state of these patients is a critical yet often underdiscussed determinant of survival. A recent large-scale United States study (IA-ANE Working Group, 2025) demonstrated that 51% of pediatric patients with influenza-associated ANE necessitated the use of inotropic or vasopressor support.2 This substantial incidence of hemodynamic instability indicates that ANE should be addressed primarily as a multisystemic cytokine storm rather than as an isolated neurologic event. The early identification of patients at risk for progression to ANE is of utmost importance. Zhang et al.3 identified blood lactate levels exceeding 2.87 mmol/L as an independent risk factor for the progression from standard encephalopathy to ANE. This metabolic marker presumably indicates the initial stages of systemic hypoperfusion that antecede irreversible brain injury. The prognostic significance of systemic markers is further corroborated by Wang et al.,4 who determined that elevated D-dimer levels upon admission are indicative of unfavorable outcomes in pediatric patients. This likely signifies systemic endothelial dysfunction and vasoplegic shock. Since mortality in ANE is often connected to cerebral herniation, it is important to explore whether this herniation worsens due to the loss of cerebral autoregulation during systemic hypotension episodes.2,5 As we improve immunomodulatory treatments—such as high-dose steroids and tocilizumab to control the cytokine storm—we should also prioritize aggressive hemodynamic resuscitation and monitor systemic markers like lactate and D-dimer.3 We thank Al-Rashdi et al. for their contribution to the global understanding of IANC and suggest that integrating hemodynamic monitoring into early management protocols may further improve outcomes for the most severe cases.