Fatal H5N1 Avian Influenza Pneumonia Associated with Autoantibodies Neutralizing Type I Interferons

Highly pathogenic avian influenza A (H5N1) remains a major zoonotic threat, yet human infections continue to display striking heterogeneity in clinical severity. We report a fatal case of H5N1 pneumonia in an adult patient from Louisiana, highlighting the intersection between critical illness and impaired type I interferon (IFN) immunity. A previously independent adult male presented with one week of dyspnea, fever, and confusion. He was hypoxemic on arrival and rapidly progressed to severe respiratory failure and moderate renal failure requiring intubation within 24 hours. Imaging revealed multifocal pneumonia, and repeat respiratory testing detected influenza A, later subtyped as H5. Clinical deterioration occurred despite guideline-directed antiviral therapy. History revealed multiple recently deceased pet and wild bird contacts. The patient’s course was marked by refractory hypoxemia, right ventricular dysfunction with intracardiac shunting responsive to inhaled nitric oxide, and multiorgan failure. He required venovenous extracorporeal membrane oxygenation (ECMO), therapeutic plasma exchange, continuous renal replacement therapy, and adjunctive Seraph-100 blood purification. Despite maximal support, he developed recurrent vasoplegic shock and progressive respiratory failure and died following transition to comfort care. Immunologic investigation demonstrated the presence of high-titer autoantibodies neutralizing type I IFNs (AAN-I-IFNs), including all 12 IFN-α subtypes and IFN-ω, at concentrations known to abolish antiviral signaling. Functional assays confirmed that the patient’s serum blocked IFN-mediated restriction of influenza replication in vitro. These findings align with emerging evidence that AAN-I-IFNs underlie a proportion of severe viral pneumonias, including seasonal influenza, SARS-CoV-2, West Nile virus, and others. Their prevalence rises with age and may serve as a key determinant of susceptibility to severe disease. In this case, the coexistence of a zoonotic H5N1 infection with high-potency AAN-I-IFNs provides a biologically plausible mechanism for unchecked viral replication, fulminant respiratory failure, and poor response to antiviral therapies. This case reinforces that impaired type I IFN immunity, whether genetic or acquired, should be considered in severe or atypical presentations of viral pneumonia, including emerging zoonoses. Early recognition may inform use of alternative IFN-β–based therapies, guide prognostication, and enhance understanding of host factors that shape viral pathogenesis and pandemic potential. Figure 1.