#18,931
Since we've already seen serological evidence suggesting asymptomatic (or exceedingly mild) HPAI H5N1 infection in humans (see MMWR: Serologic Evidence of Recent Infection with HPAI A(H5) Virus Among Dairy Workers), one might reasonably wonder why a particularly strict scoping review published this week in JAMA Open is getting so much press.
While important investigational tools, serological testing (hemagglutination inhibition (HI) assays & microneutralization (MN) assays) are not foolproof, and can sometimes yield false positives.
Both are susceptible to potential cross-reactivity with seasonal influenza antibodies, have often used non-standardized antigens or varying cutoff titers, and may occasionally detect low, non-specific reactions.
Even PCR tests - the `gold standard' - can be fooled by environmental contamination (e.g. poultry `dust' in nares) or lab contamination, and yield a false positive. It appears to be rare, but it can happen (see CDC Report).
Which is why this report only considers a narrow, and highly restrictive, data set,
Inclusion Criteria
We included any study published through August 25, 2025, that reported a confirmed A(H5N1) virus infection that met primary or secondary outcome definitions and had a full-text report available in English. We excluded articles that reported results from A(H5N1) serologic testing in humans without molecular testing. We also excluded serosurveys and other immunologic studies,11 some of which have been interpreted as evidence of asymptomatic infection.
This sets the bar incredibly high, and likely ignores many other legitimate cases. But in its favor, their findings are far more difficult to dismiss. Even with these restrictions, they identified 10 reports which describe 18 asymptomatic human H5N1 infections over the past 20+ years.
Of those, 2 were confirmed via molecular and serologic confirmation (MSC) and 16 with molecular confirmation alone (MC).
First the link, and abstract, from the report (follow the link to read it in its entirety), after which I'll have a bit more.
Asymptomatic Human Infections With Avian Influenza A(H5N1) Virus Confirmed by Molecular and Serologic TestingA Scoping Review
Fatimah S. Dawood, MD1; Shikha Garg, MD, MPH1; Pragna Patel, MD, MPH1
et al
JAMA Netw Open
Published Online: October 29, 2025
2025;8;(10):e2540249. doi:10.1001/jamanetworkopen.2025.40249
Key Points
Question Have asymptomatic infections with highly pathogenic avian influenza A(H5N1) virus been reported in humans?
Findings This scoping review of published reports through August 25, 2025, identified 10 reports of 18 cases of asymptomatic infection with A(H5N1) virus, including 2 cases with molecular and serologic confirmation and 16 cases with molecular confirmation alone. Symptom ascertainment methods varied among reported cases.
Meaning Asymptomatic human avian influenza A(H5N1) virus infections have been infrequently reported, with most lacking serologic confirmation; prospective surveillance studies with serial respiratory and serum sampling and detailed symptom monitoring for persons with high-risk exposures could provide data to inform future public health responses.
Abstract
Importance Since 1997, more than 1000 infections with highly pathogenic avian influenza A(H5N1) virus among humans have been reported globally. Given ongoing A(H5N1) outbreaks in animals, understanding the frequency of A(H5N1) virus infections among asymptomatic persons can inform public health risk assessments and infection prevention guidance.
Objective To identify and characterize reported cases of asymptomatic A(H5N1) virus infection among humans with confirmation by both molecular testing of 1 or more respiratory specimens and 1 or more serum specimens meeting World Health Organization criteria (molecularly and serologically confirmed [MSC]) or molecular confirmation (MC) alone.
Evidence Review MEDLINE, Embase, Global Health, Cochrane, Scopus, Virtual Health Library, and Europe PubMed Central were searched for publication through August 25, 2025. Articles for full-text screening were evaluated by 2 investigators. Studies published through August 25, 2025, were included if they reported a confirmed A(H5N1) virus infection that met MSC or MC criteria and had a full-text report in English. Articles were excluded if they reported results from A(H5N1) serologic testing alone, serosurveys, or other immunologic studies.
Findings Of 1567 unique reports that underwent title or abstract screening, 42 were selected for full-text screening, of which 10 met inclusion criteria (3 reports about 2 MSC cases and 7 reports about 16 MC cases). The 2 MSC cases occurred among adults in Pakistan and Vietnam who were identified by investigations of household contacts of index A(H5N1) case patients; 1 case patient also had exposure to A(H5N1) virus–infected chickens as the possible infection source and 1 is thought to have been infected through human-to-human transmission. Neither MSC case patient used personal protective equipment. Of 16 reported MC cases (14 adults, 2 children), 11 were identified by enhanced surveillance of persons exposed to A(H5N1) virus–infected poultry (8 in Bangladesh, 2 in Spain, and 1 in the UK) and the remaining 5 MC cases (3 in Vietnam, 2 in Cambodia) were identified by investigations of household contacts of index A(H5N1) case patients.
Conclusions and Relevance Asymptomatic human infections with A(H5N1) virus have been infrequently reported, with most cases identified through enhanced surveillance or household contact investigations of persons with known exposure. Robust data collection is needed from persons with possible asymptomatic A(H5N1) virus infection to inform future public health responses.
(SNIP)
Conclusions
Prospective surveillance studies with serial respiratory and serum sampling and detailed symptom monitoring in persons with high-risk exposures to infected animals or close contact with humans with confirmed A(H5N1) virus infection could elucidate the true fractions of human A(H5N1) virus infections that are asymptomatic with and without seroconversion and the duration of viral shedding with asymptomatic infection. Careful attention to the timing of initiation of influenza antiviral postexposure prophylaxis and antiviral treatment would be needed when interpreting results.
Such studies could provide information to guide risk assessment, infection control guidance, and population immunity projections but are resource intensive and may be unacceptable in some populations. Whether persons with asymptomatic A(H5N1) virus infections are a transmission risk to their close contacts is an additional critical knowledge gap.
This review highlights the need for robust data collection from persons with possible asymptomatic A(H5N1) virus infection to inform future public health responses.
Although this study finds only a reassuringly small handful of cases that meet their criteria, it provides compelling evidence they do exist.
The reality is, asymptomatic cases have only rarely been tested for H5N1, and even mildly or moderately symptomatic individuals are unlikely to be identified, unless they are sick enough to be hospitalized.
Once again, their primary recommendation, and the one thing that nearly every study calls for (see here, here, here, here, and here); enhanced surveillance and testing for HPAI H5N1, seems to be the last thing that governments want to do.
As long as confirmed cases are low and there is `no evidence of sustained or efficient human transmission of H5N1', they don't have to make the hard political and economic decisions on how to contain it.
But as Dr. Carl Sagan pointed out years ago, `Absence of evidence is not evidence of absence'. While our current reluctance to aggressively test for this virus may provide short-term bliss, it risks our sleepwalking into the next pandemic.
