Sporadic human infections with avian influenza A viruses have caused a wide spectrum of illness. As these novel influenza A viruses pose pandemic potential, timely detection and characterization of such human infections are important for global public health.
In October 2025, a 75-year-old woman with Waldenstr?m macroglobulinemia presented to a local hospital with fever and diarrhea?(illness day 1).?She had had lymphopenia for several years and had received treatment with rituximab and bendamustine 7 months before presentation (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). She had not received the 2025–2026 influenza vaccine. Real-time reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay of a nasal swab was negative for influenza A virus, and her chest radiograph was unremarkable. She was discharged home with instructions for supportive care, with no scheduled follow-up.
Cough, pharyngitis, and progressive dyspnea subsequently developed, and the patient returned to the hospital 9 days after she had been discharged; she was admitted for acute hypoxemic respiratory failure. Computed tomography of the chest revealed bilateral ground-glass and consolidative opacities in her lungs?(Fig. S1 in the Supplementary Appendix),?and her trachea was intubated on illness day 11. Repeat nasal swabs were again negative for influenza A virus on days 10 and 13. Despite treatment with broad-spectrum antimicrobials and glucocorticoids, her hypoxemia worsened, and severe acute respiratory distress syndrome developed. She was transferred twice for escalating levels of care, and she ultimately arrived at a tertiary center in Seattle, Washington, on day 15?(Table S1).
In Seattle, influenza A virus was detected by RT-PCR in both nasal-swab and bronchoalveolar-lavage specimens (cycle-threshold values, 34.6 and 23.8, respectively) (Figure 1A and Table S1). Both specimens subsequently tested positive for influenza A(H5).1 An extended respiratory viral PCR panel was otherwise negative. Oseltamivir therapy was started on illness day 16, along with baloxavir and amantadine on day 19 (Table S2) and tocilizumab on day 22? (Fig. S2). Pneumocystis jirovecii DNA was also detected by PCR in a bronchoalveolar-lavage specimen, although a direct fluorescent antibody test was negative. This finding was thought to represent colonization or a false positive result; however, the patient received trimethoprim–sulfamethoxazole owing to the severity of her respiratory failure. Despite antimicrobial therapy, lung-protective ventilation, prone positioning, neuromuscular blockade, and inhaled epoprostenol, she remained critically ill. Her hypoxemia worsened, and she died on illness day 28, after she had been transitioned to comfort-focused care.