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While there are no signs that avian influenza is spreading in an efficient or sustained manner between humans, there are concerns that some spillover infections are going unrecognized, and each instance provides with virus with another opportunity to adapt to a human host.
Retrospective antibody testing has shown that some infections are either mild, or subclinical (see JAMA Open: Asymptomatic Human Infections With Avian Influenza A(H5N1) Virus Confirmed by Molecular and Serologic Testing).
We've also seen reports of atypical presentation (both mild and severe) with avian influenza, along with difficulties in testing some patients, even in a modern hospital setting.
Because of this, we've seen many instances where patients have been hospitalized for days or even weeks before their avian flu infection was finally confirmed. A few examples:
- In the fall of 2024, a Missouri man was hospitalized for a week - then released - only to be notified that he had tested positive for H5N1
- In June of 2025, we saw a Statement on a Fatal H5N2 Infection In Mexico City, which we would eventually learn, was only detected 2 weeks after the patient had died.
- Last April, in Eurosurveillance, we looked at an imported fever/cough case in Italy who initially tested negative for influenza A/B, RSV & COVID, but after a more invasive BAL (Bronchoalveolar lavage), was identified as having H9N2 on the 6th day of his hospitalization.
- And 3 weeks ago, the MMWR report on the fatal H5N5 case in Washington State last year repeatedly tested negative for influenza/COVID during the first 6 days of his hospitalization.
As noted by infectious experts, this is a rare case in which the A/H5N1 avian influenza virus damages the central nervous system and does not attack the respiratory tract.
The opportunities for spillover into humans have increased markedly over the past few years, which makes its important for clinicians to raise their index of suspicion - particularly during times of known outbreaks - even when dealing with atypical presentations or negative test results.
Avian Influenza in Humans: Virology, Transmission, and Clinical PrioritiesNitin Gupta , Anna Smielewska , Jan Felix Drexler , Casandra Bulescu , Marta Mora-Rillo , Aleksandra Barac , Pikka Jokelainen , François-Xavier Lescure , Martin P Grobusch , Sotirios Tsiodras ... Show more
QJM: An International Journal of Medicine, hcag138, https://doi.org/10.1093/qjmed/hcag138
Published:29 May 2026 Article history
Abstract
Avian influenza continues to evolve as a zoonotic threat with important implications for clinical practice and global health preparedness. Sustained circulation in wild birds, repeated spillover into poultry, and an increasing number of infections across diverse mammalian hosts have reshaped exposure pathways and broadened the risk landscape for human infection. For clinicians, this evolving ecology translates into atypical presentations and increased diagnostic uncertainty. Recent global activity has been characterised by widespread animal outbreaks and the emergence of new transmission interfaces, including occupational exposures and livestock-associated events. Human infections remain largely zoonotic and geographically heterogeneous, with patterns influenced by surveillance intensity, exposure context, and healthcare access.
We synthesise current evidence on the virology, transmission, global epidemiology, clinical manifestations, diagnosis, treatment, and prevention of avian influenza in humans. We highlight evolving mammalian adaptation and changing risk interfaces that complicate risk assessment. Improved clinician awareness, early diagnosis, and integrated One Health surveillance remain central to strengthening preparedness for future influenza threats.
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Clinical Presentation and Diagnosis of Avian Influenza in Humans
Human infection with avian influenza viruses spans a broad clinical spectrum, ranging from asymptomatic infection to severe, rapidly progressive multisystem disease (Table 1) [2,56]. Asymptomatic or subclinical infection has increasingly been recognised through serosurveys and occupational surveillance programmes, indicating that mild infections are likely underdetected outside targeted screening settings [57,58].
In a serosurvey of bovine veterinary practitioners in the United States during the 2024 H5 outbreak in dairy cattle, antibodies indicating recent infection were detected in 3 of 150 participants (2%), none of whom reported respiratory or influenza-like symptoms [58]. Similar findings from studies among poultry workers have demonstrated measurable seropositivity in individuals without recognised illness [57].
These observations indicate that reliance on clinically apparent cases may underestimate the true burden of zoonotic infections and lead to overestimation of case fatality rates based solely on detected severe cases.
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Neurological complications, including encephalopathy, encephalitis, seizures, convulsions, and altered consciousness, have been reported in severe H5N1 infection and may occasionally dominate the clinical picture, even in the absence of prominent respiratory disease [69,70].
Human case reports describe acute encephalitis with detectable H5N1 RNA in cerebrospinal fluid, including a child with minimal respiratory symptoms who developed encephalitis complicated by obstructive hydrocephalus, supporting direct central nervous system involvement [71]. Other reported manifestations include diffuse encephalitis, coma, and rapidly progressive neurological deterioration in the setting of severe systemic infection.
Neuropathological and postmortem studies have demonstrated viral antigen and RNA in neurons and glial cells across multiple brain regions, supporting direct neuroinvasion rather than solely secondary inflammatory injury [69]. Experimental studies in ferrets further support this neurotropic potential, showing that H5N1 can invade the brain, often via the olfactory pathway, and may be associated with encephalitis, vasculitis, hemorrhagic lesions, and even subclinical but persistent brain injury [72].
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Conclusion
Avian influenza is ecologically entrenched, globally mobile, and increasingly multi-host. The expansion of H5Nx viruses into previously unafflicted regions, diverse mammalian species, combined with persistent circulation in wild birds and poultry, underscores that the conditions for emergence are continuously present. Apparent epidemiological lulls may reflect surveillance artefacts rather than reduced risk.
In a world where birds migrate, viruses reassort, and agricultural systems are intensified, preparedness, not prediction, remains the most reliable defence. Strengthening One Health surveillance, ensuring rapid clinical recognition, and maintaining flexible medical countermeasures are essential to prevent avian influenza from becoming the next global pandemic. For clinicians worldwide, recognising avian influenza as an evolving zoonotic interface rather than a rare exotic infection will be central to early detection and response.
