Preprint: Detection of Antibodies Specific to H5 Avian Influenza Virus in a Sheep in Norway, June 2024

 

#18,840

Our view of avian influenza changed abruptly 17 months ago when HPAI H5N1 was detected in goats in the United States (see Minnesota BOAH Statement On HPAI H5N1 Infected Goat Kids), followed a few days later (March 25th) by the first HPAI detection in dairy cattle (see USDA Statement on HPAI In Dairy Cattle in Texas & Kansas Herds).

As we discussed at that time in A Brief History Of Influenza A In Cattle/Ruminants, while cattle had been experimentally infected with H5N1 in 2008, there had been little prior evidence of natural infection of ruminants.

Since then at least 1,078 cattle herds across 17 states have been infected, and we've seen scattered outbreaks in Alpacas and pigs in the United States, along with recent reports of sheep in both the UK and in Norway.

While most of the emphasis has been on U.S. dairy cattle, we've also seen reports of HPAI H5 in goats and sheep in Pakistan and horses in Mongolia, while in 2023, we saw a worrying spillover into pigs in Italy (Seroconversion of a Swine Herd in a Free-Range Rural Multi-Species Farm against HPAI H5N1 2.3.4.4b Clade Virus).

Testing of livestock around the globe remains limited, passive, and largely  voluntary, and we've seen studies (see Nature: A Mathematical Model of H5N1 Influenza Transmission in US Dairy Cattle) suggesting the we may only be seeing the tip of the iceberg.

Three months ago, in  First discovery of H5N1 in sheep in Norway, we looked at report on a retrospective seroprevalence study - conducted by the Norwegian Veterinary Institute - which turned up serological evidence of prior H5N1 infection in a sheep that had grazed in an area with high HPAI activity nearly a year earlier.

While only 1 sheep (out of 220) tested positive on all 3 antibody tests (ELISA, hemagglutination inhibition (HI), and microneutralization (MN)), 6 others showed partial evidence of prior infection. 

From the preprint: 

Detection of antibodies in one out of 220 sheep corresponds to a serological prevalence of approximately 0.5%. It is possible that this number underestimates the true rate of spillover infections, as the eleven-month interval between exposure and sampling could have decreased the sensitivity of our surveillance.

Six additional sheep showed partial serological evidence of H5 exposure, based on detection of antibodies against the H5 virus in the ELISA or the MN assay, despite testing negative in the comparatively less sensitive HI assay and for antibodies against type A influenza.

These findings should be interpreted with caution, considering the gaps in knowledge of antibody response kinetics to different viral proteins following H5 avian influenza virus infection in sheep and the limited validation of serological assays in this species.

The full report - uploaded to the bioRxiv on the 14th - only runs 8 pages and is well worth reading in its entirety (link below).  I'll have a bit more when you return. 

Detection of antibodies specific to H5 avian influenza virus in a sheep in Norway, June 2024, eleven months after an outbreak of  highly pathogenic avian influenza in a nearby seabird colony

Johanna Hol Fosse 1*, Grim Rømo 1*, Francesco Bonfante 2, Ida Kristin Myhrvold1, Kristin Stangeland Soetart1, Kristin Udjus1, Ragnhild Tønnessen 1.8*   

Abstract

A 2023 outbreak of highly pathogenic avian influenza in seabirds in Norway caused substantial environmental contamination of grazing areas frequented by local sheep. Eleven months later, 220 sheep were tested for antibodies to type A influenza and H5 subtype using ELISA, haemagglutination inhibition, and microneutralisation assays. One ewe (0.5%) tested positive by all methods, consistent with prior spillover infection. This underscores the importance of restricting livestock access to outbreak areas to mitigate cross-species transmission and zoonotic risk.

(SNIP)

HPAI in ruminants constitutes a zoonotic threat, with cattle identified as the likely source of 41 human cases during the ongoing U.S. outbreak (7). Our findings add to previous reports providing direct and indirect evidence of HPAI spillover from wild birds to small ruminants (12, 17).

From a One Health perspective, our findings underscore the need to prevent livestock contact with HPAI-contaminated grassland, diseased birds, and carcasses, and to include small ruminants in HPAI outbreak investigation and surveillance. 

        (Continue . . . ) 

For nearly a year following the announced discovery of HPAI H5N1 in dairy cows in the United States the USDA maintained it was the result of a single spillover from birds of a specific genotype (B3.13), and that all subsequent spread was likely due to the shipment of infected cattle to other states. 

They believed this was a `rare', one-off event, sparked by a single rogue genotype, and unlikely to be repeated.  A hope that was widely embraced by many other countries, comforted by the lack of spread of B3.13 outside of the United States. 

The May 2024 UK HAIRS Risk Statement On Avian Influenza (H5N1) In Livestock estimated that H5N1 genotype B3.13 presents ` at most, a very low risk' to the UK, citing a low likelihood of the virus being carried across the Atlantic to Europe. 

But less than a month later, in Germany: FLI Statement On Experimental Infection Of Dairy Cows With European H5N1 Virus, researchers reported `. . . not only the US isolate but also a recent H5N1 virus from a wild bird in Germany was able to multiply very well in the udder.'

In November of 2024 a different genotype (D1.2) was detected in two pigs on a farm in Oregon, but the big news came in February of 2025, when the USDA announced The Occurrence of Another Highly Pathogenic Avian Influenza (HPAI) Spillover from Wild Birds into Dairy Cattle.

This time, it was genotype D1.1, which has emerged the previous fall in wild and migratory birds, and had sparked numerous poultry outbreaks and roughly 2 dozen human infections, some serious (1 fatal). 

 Several weeks later a 3rd spillover into cattle was announced by the USDA (see APHIS Statement On HPAI Genotype D.1 In Arizona Dairy Cattle), where they reported:

Whole genome sequencing indicates that this detection is a separate wild-bird introduction of HPAI to dairy cattle, now the third identified spillover event into dairy cattle.

This finding may indicate an increased risk of HPAI introduction into dairies through wild bird exposure.

While reported spillover events are fairly rare, they obviously occur more often than originally assumed.  And their incidence appears to be on the ascendent. 

Scientists continue to call for better surveillance, more testing, and the timely sharing of data under a coordinated `One Health' strategy (see here, here, here, here, and here).

But we appear to be frozen in a holding pattern, unwilling to take decisive action. Whether we can shake ourselves free from this lethargy - before the virus does it for us - remains to be seen. 

Preprint: Incidence of Long COVID Following Reinfection with COVID-19

 

#18,839

For more than three years now,  many governments around the world - in an attempt to `move beyond the pandemic' - have minimized the ongoing impacts of COVID by ending surveillance and the reporting of numbers of associated hospitalizations or deaths.

As a result, most people now regard COVID as little more than a `bad cold'. COVID vaccine uptake has dropped precipitously, and mask wearing in public has all but disappeared.

At the same time, tens of millions of people have developed `Long COVID', which can range from mild to debilitating.  Since there is no standardized case definition for Long COVID (see JAMA Network) - we often see inconsistent data from studies - and many patients end up untreated. 

Based on limited data, however, the WHO estimates that 1 in 6 people who contract COVID will develop some type of `Long COVID'.  Globally, that suggests > 400 million people, and > 20 million in the United States.  

While many will see some improvement in their symptoms over time, others face chronic, and often debilitating, lifelong illness. Studies have suggested COVID sequelae could include increased cardiac risks, increased new onset hypertension, an increased risk of developing diabetes, strokes, and kidney disease/injury.

There may also be other, longer-range health impacts from COVID, that have yet to be elucidated (see BMC Neurology: Long-term Neurological and Cognitive Impact of COVID-19).

The WHO states:

Anyone who was infected with SARS-CoV-2 can develop post COVID-19 condition. Some people have higher risk. These include women, older adults, smokers, those who are overweight or obese or have pre-existing chronic health problems.

Repeated infections and severe COVID-19 needing hospitalization or ICU admission also increase the risk (4). We see higher numbers of post COVID-19 condition sufferers among people with disabilities, and where health disparity and access to health care is a problem (5).

 The CDC states:

Most people with Long COVID experience symptoms days after first learning they had COVID-19, but some people who later develop Long COVID do not know when they were infected. People can be reinfected with SARS-CoV-2 multiple times. Each time a person is infected with SARS-CoV-2, they have a risk of developing Long COVID. 12 Long COVID symptoms and conditions can emerge, persist, resolve, and reemerge over weeks and months. 345 These symptoms and conditions can range from mild to severe, may require comprehensive care, and can even result in a disability.

 
While each COVID infection is another opportunity for an individual to develop Long COVID there has been some debate over whether that risk increases with each bout of illness.  

In January of 2023, the AMA released a statement (see What doctors wish patients knew about COVID-19 reinfection) calling reinfection `problematic' and equating it to `. . . playing Russian roulette" with the virus.

A 2023 study - conducted after the emergence of Omicron (see Risk of New-Onset Long COVID Following Reinfection With Severe Acute Respiratory Syndrome Coronavirus 2) found:

The risk of new-onset long COVID after a second SARS-CoV-2 infection is lower than that after a first infection for persons aged ≥16 years, though there is no evidence of a difference in risk for those <16 years.

Earlier this year, CIDRAP reported a similar finding (see Data suggest COVID-19 reinfections less likely to cause long COVID), but with the caveat: 

The cumulative risk of long COVID increased with the number of reported COVID-19 infections, rising from 13.7% (95% confidence interval [CI], 13.1% to 14.4%) for a single infection to 37.0% (95% CI, 33.0% to 40.9%) for three infections in the online survey, and from 11.8% (a single infection) to 29.5% (≥3 infections) in the telephone survey, according to the authors.

Nebulous or inconsistent `Long COVID' case definitions, the abandonment of serious surveillance, testing, and reporting by most governments, and the resultant trivialization of COVID infection by society, are all obstacles to quantifying the risks. 

But today we have a preprint (yet to be peer-reviewed) which describes a large observational analysis using the data from National Clinical Cohort Collaborative (N3C)/RECOVER initiative, that finds that reinfection resulted in a 35% higher risk of Long COVID (compared to a single infection).

Due to its length, I've just posted the abstract and a small excerpt. Follow the link to read it in its entirety.   I'll have a postscript after you return. 

Incidence of Long COVID Following Reinfection with COVID-19

M Daniel Brannock, Emily Hadley, Alexander Preiss, Megan L Fitzgerald, Nita Jain, Emily Taylor, Andrew Wylam, Yun J Yoo, Elaine Hill, Richard A Moffitt, N3C Consortium, RECOVER Consortium
doi: https://doi.org/10.1101/2025.08.12.25333155
This article is a preprint and has not been certified by peer review 

Preview PDF

Abstract

Background COVID-19 reinfections have emerged as a critical concern, particularly in relation to post-acute sequelae of SARS-CoV-2 infection, commonly known as long COVID. Long COVID is known to manifest diverse, debilitating symptoms across all demographics. Limited studies have investigated the causal relationship of COVID-19 reinfections and long COVID. 

Methods We leveraged demographically diverse electronic health records from the COVID-19 enclave of the National Clinical Cohort Collaborative, part of the RECOVER initiative, to create a matched cohort of reinfected and control adults. All participants had at least one documented COVID-19 infection. We used one-to-one coarsened exact matching on sex, race/ethnicity, age, healthcare utilization, existing comorbidities, site of care, and the timing and severity of first infection.

Index dates were assigned to each matched pair as the date of reinfection for the reinfected case. Long COVID was defined using a machine learning computable phenotype trained on clinically diagnosed long COVID cases. Cumulative incidence one year after index was calculated using an Aalen-Johansen estimator. Risk ratios were calculated by taking the ratio of long COVID incidence among reinfected and control cases. 

Results We found that reinfection resulted in a significantly higher risk of long COVID compared to not being reinfected (risk ratio, 1.35, 95% CI, 1.32-1.39; risk difference, 0.029, 95% CI, 0.027-0.031). This effect was consistent across most stratifications. 

Conclusions We found that COVID-19 reinfection resulted in a roughly 35% increase in the incidence of long COVID in a matched cohort using observational electronic health records.

        (SNIP)

In conclusion, we found that reinfections lead to a roughly 35% (95% CI, 32-39%) increase in the risk of long COVID as compared to not having a documented reinfection. The relative effect was consistent across most strata of most of our matching criteria, including sex and timing and severity of first infection. There were differences in relative risk across different age and CCI strata.

In a vaccination subanalysis, we found that those vaccinated between first infection and index date experienced a smaller increase in the relative risk of long COVID resulting from reinfection as compared to those vaccinated only prior to their first infection. 

       (Continue . . . )

While it is true most people will recover from acute COVID infection without sustaining long-term damage - it appears that the more times one tempts fate - the more likely they are to suffer real consequences. 

And that not only presents individual health challenges, but substantial societal burdens as well.  

Despite proven ways to reduce the risk of reinfection (COVID vaccines, wearing face mask in public, avoiding indoor crowds, etc.), few appear interested. Today - despite ample evidence to the contrary - many people are more inclined to blame the vaccine for their ills, than the virus. 

When it comes to prevention, everyone needs to make their own risk/reward analysis. I've made mine (staying current with the COVID vaccine, wearing a KN95 in crowded indoor venues, etc.). 

A few past studies that might be of interest to those who are still undecided, include:

Brain, Behavior & Immunity: COVID-19 may Enduringly Impact Cognitive Performance and Brain Haemodynamics in Undergraduate Students

ECDC Rapid Review: Does COVID-19 Vaccination Reduce the Risk and Duration of Post COVID-19 Condition?

Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks

Revisiting the Environmental Persistence and Airborne Spread of HPAI H5

#18,838

Not quite two weeks ago, in Preprint: Surveillance on California Dairy Farms Reveals Multiple Sources of H5N1 Transmission, we looked at a (yet-to-be-peer-reviewed) paper that found evidence of extensive environmental (air, water & milking equipment) contamination on HPAI H5 infected dairy farms.

That report - when combined with a recent study (see Dairy Cows Infected with Influenza A(H5N1) Reveals Low Infectious Dose and Transmission Barriers) - would seem to challenge the popular assumption that cow-to-cow transmission of HPAI was primarily due to contaminated milking machines.

Two days ago the Journal Nature took note of the California study:

NATURE BRIEFING
12 August 2025

Daily briefing: Bird flu is ‘everywhere’ on dairy farms

H5N1 avian influenza might be airborne, helping it to spread rapidly in dairy cows

Yesterday UNMC's Global Center for Health Security - which quoted Dr. Richard Webby as saying  “It’s a ridiculously contaminated environment” -  published:

Bird Flu on Dairy Farms May Be Airborne After All

These airborne concerns go far beyond just`exhaled' breath from infected cattle in milking parlors, or `milk spray', as contaminated milk and manure from infected cows must be safely handled and disposed of (along with farm wastewater); none of which are trivial tasks.  

While the USDA has issued biosecurity guidelines (link), the details (and enforcement) are left up to local officials and the producers. 

Any way you slice it, HPAI infected poultry and dairy farms must deal with extensive environmental contamination issues. A concern because we've seen environmental persistence studies showing that - under the right conditions - HPAI H5 can survive for days, weeks, or even months outside of a living host. 

• In 2012's EID Journal: Persistence Of H5N1 In Soil, we looked at several studies that found H5N1 could remain viable on various surfaces, and in different types of soil, for up to 13 days (depending upon temperature, relative humidity, and UV exposure).
• In 2017, researchers showed that - when refrigerated - H5N1 infected poultry could remain infectious for months (see Appl Environ Microbiol: Survival of HPAI H5N1 In Infected Poultry Tissues).

• In 2020 we looked at a study from researchers at the USGS (see Proc. Royal Society B: Influenza A Viruses Remain Viable For Months In Northern Wetlands - USGS), which found long-term (up to 7 months) survival of influenza A viruses in wetlands in both Alaska and Minnesota.

How long avian flu viruses may remain viable, and how far they might be carried (by personnel, vehicles, peridomestic mammals, birds, flies, or even the wind), continues to be poorly understood.

As recently as last February - in Preprint: Genetic & Meteorological Data Supporting Windborne Transmission of HPAI H5N1 - we saw a study that strongly suggested that windborne spread of HPAI H5 virus particles may have spread the virus as far as 8 km between poultry farms in the Czech Republic.

Separation of Farms In Study

We can go back more than a dozen years to find other studies which came to similar conclusions, including. 

• In December of 2012 (see Barnstorming Avian Flu Viruses?) we looked at a study called Genetic data provide evidence for wind-mediated transmission of highly pathogenic avian influenza that found patterns that suggested farm-to-farm spread of the 2003 H7N7 in the Netherlands due to the prevailing wind.

• Another study of the same outbreak, Modelling the Wind-Borne Spread of Highly Pathogenic Avian Influenza Virus between Farms (PloS One 2012), found that windborne transmission could have accounted for up to 24% of the transmission over distances up to 25 km.

• In the spring of 2015 during the North American H5Nx epizootic, the idea of farm-to-farm spread via infected dust was openly discussed by the USDA (see Bird Flu’s Airborne `Division’).

• In 2018, in Frontiers: Two Studies On The Epidemiology of Avian Influenza Viruses, we looked at a study that detected airborne HPAI viruses during the 2016-17 H5N8 epizootic in France, which saw more than 400 farms affected.

• And in 2019, in Nature: Airborne Transmission May Have Played A Role In Spread Of U.S. 2015 HPAI Epizootic, we saw a study that looked at air movement trajectories and viral concentrations during the epizootic and the probability of airborne transmission for the 77 HPAI cases in Iowa. While not definitive, long-range airborne spread was considered plausible.

In 2022's Zoonoses & Public Health: Aerosol Exposure of Live Bird Market Workers to Viable Influenza A/H5N1 and A/H9N2 Viruses, Cambodia, researchers were able to extract viable avian flu viruses from the air in and around live bird markets in Cambodia.

And last January, in Osterholm Podcast: The Potential Environmental (Airborne) Spread of H5N1, Dr. Mike Osterholm discussed the real possibility that the H5N1 virus may be carried by contaminated `dust' from poultry farms, infecting other nearby farms, animals, and potentially even humans.

As we discussed yesterday, a big concern is the potential introduction of HPAI to swine (see Frontiers Vet. Sci (Review): Emerging Threats of HPAI H5N1 Clade 2.3.4.4b in Swine).  Airborne spread between farms is one plausible way that could happen.

Whether H5N1 has the ability to spark a pandemic remains to be seen - but even if it can't - it can still do tremendous damage to agricultural interests and to the economy.  

Which is why a fuller understanding of its abilities (both existing and evolving) is crucial if we hope to avoid a larger crisis. 

Frontiers Vet. Sci (Review): Emerging Threats of HPAI H5N1 Clade 2.3.4.4b in Swine

  

#18,837 

Less than two years ago - but before we first learned about the spillover of HPAI H5 into American Cattle - the big H5Nx livestock concern was its potential to infect and adapt to swine. 

While detections in swine have been limited, over the years we've scattered evidence that H5N1 can infect pigs, albeit usually asymptomatically. A few past reports include:

• WHO H5N1 detected in pigs in China (2004)

• EID Journal: Asymptomatic H5N1 In Pigs (2010)

• An Unusual Report Of H5N1 in Pigs (Indonesia 2016)

• Sci. Rpts.: Evidence Of H5N1 Exposure In Domestic Pigs - Nigeria (2018)

In May of 2023, in Netherlands: Zoonoses Experts Council (DB-Z) Risk Assessment & Warning of Swine As `Mixing Vessels' For Avian Flu, we looked at growing concerns in Europe that avian H5N1 could increase its pandemic threat by spreading (and evolving) in farmed swine.

A week later, a report out of Italy confirmed an H5N1 spillover event at a `mixed species' farm (poultry & swine) in Italy, and the subsequent seroconversion of the majority of the pigs tested on that farm (see Study: Seroconversion of a Swine Herd in a Free-Range Rural Multi-Species Farm against HPAI H5N1 2.3.4.4b Clade Virus).

Once again, swine showed mild or subclinical signs of infection - and little or no detectable virus replication in the nasal cavity.  While good news for the pig, it can make it challenging to identify spillover events without serological testing.

Last November, we saw two pigs infected with a new, recently emerged genotype (D1.2) in Oregon (see USDA Confirms 2nd Pig on Oregon Farm Tested Positive for H5N1).

While research studies have shown only limited susceptibility of swine to the H5N1 virus (see EID Journal: Low Susceptibility of Pigs against Experimental Infection with HPAI Virus H5N1 Clade 2.3.4.4b) only a handful of H5 variants (subclades and/or genotypes) have actually been tested. 

Until the emergence of H5 genotype B3.13 in late 2023, cattle were considered unlikely hosts for H5N1 as well. Since then, genotype D1.1 has also shown the ability to infect cattle. 

Given that there are literally scores of genotypes circulating around the globe - and new ones continue to emerge - there are legitimate concerns that a more `swine-adapted' strain could eventually emerge. 

And since pigs are susceptible to a wide variety of (swine, human, avian, etc.) influenza A viruses - the worry is they could serve as a `mixing vessel' - and produce a more dangerous hybrid virus. 

Surveillance and testing of swine around the world is quite limited, and much of what happens with novel flu viruses in the wild typically flies under our radar.  

All of which brings us to a lengthy review article - published yesterday in Frontiers Vet. Sci. - which examines the emerging threat of HPAI H5N1 clade 2.3.4.4b in swine populations.

While you'll want to read this review in its entirety, I'll draw your attention to a couple of points.  First, the author's conclusion (excerpt below) that swine herd infection with HPAI is a `very likely event'. 

Considering the cumulative findings from both experimental and field studies, natural infection with HPAI H5N1 clade 2.3.4.4b genotypes B3.13 and D1.1 appears to be a very likely event. Once introduced into the swine population, these viruses may act as dead-end infections or exhibit limited transmission among pigs (48, 49, 52).

However, the epidemiological risk escalates depending on the virological context of the host population. In influenza-free herds, the virus could establish more readily due to the absence of immunity and competition, potentially increasing its adaptation and facilitating onward transmission (48). 

Conversely, if introduced into herds already endemic for swine IAV (swIAV), co-infection could lead to genetic reassortment, raising concern over the emergence of novel viruses with altered host range, pathogenicity, or transmissibility (15, 60). 

These scenarios highlight the critical need to evaluate the outcomes of HPAI H5N1 introduction under both naïve and swIAV-positive scenarios.

This review also identifies a number of critical knowledge gaps, including:

• A limited understanding of how HPAI H5N1 spreads between pigs in commercial farming operations

• Whether current tests for swine influenza virus surveillance have adequate  sensitivity or specificity for detecting HPAI H5N1 infections

• Uncertainty about whether existing swine influenza vaccines provide cross-protection against HPAI H5N1

There is obviously much more.  I've posted the abstract, and some excerpts below.  I'll have a postscript after the break. 

Front. Vet. Sci., 12 August 2025

Sec. Veterinary Infectious Diseases

Volume 12 - 2025 | https://doi.org/10.3389/fvets.2025.1648878

Emerging threats of HPAI H5N1 clade 2.3.4.4b in swine: knowledge gaps and the imperative for a One Health approach

Juan Mena-Vasquez , Ana Marco-Fuertes. Marie Culhane, Montserrat Torremorell 

Abstract

 Highly pathogenic avian influenza (HPAI) H5N1 represents a significant threat to wildlife, livestock, and public health. The recent detection of HPAI H5N1 clade 2.3.4.4b genotypes B3.13 and D1.1 in dairy cows, poultry, wild birds, wild mammals, and humans, along with the recent detection of D1.2 genotype in outdoor pigs, reflects an accelerated shift in the ecological and transmission dynamics of the virus. Given the pigs’ role in influenza ecology, these shifts present a serious threat to the swine industry and public health, accentuating the urgency for a coordinated One Health response.

However, the current understanding of swine influenza, particularly in preventing and preparing for potential HPAI H5N1 incursions, has not been fully discussed. Furthermore, the consequences of such incursions on the swine industry and consequently on public health have not been explored extensively. This review addresses the knowledge gaps related to HPAI H5N1 clade 2.3.4.4b infections in pigs. Assessing the risks of HPAI H5N1 in pigs and the consequences for cross-species transmission is crucial. Preventing the introduction of HPAI into pigs and minimizing spillover risks through evidence-based strategies is vital to ensuring food security, maintaining a safe food supply, sustaining animal production systems, and preventing human infections, including potential pandemics.

(SNIP)

Conclusion

The expanding host range and ongoing evolution of HPAI H5N1 clade 2.3.4.4b highlight the urgent need for comprehensive surveillance, preparedness strategies, and support for scientific investigations. While experimental and field data so far suggest limited replication and transmission of HPAI H5N1 in pigs, the emergence of mammalian-adaptive mutations, even at low frequencies, demonstrates the potential for further viral evolution in this host and highlights the need for close monitoring of this virus in swine populations. As pigs serve as key hosts in the influenza virus ecosystem, they remain a critical species for the generation of reassortant viruses with pandemic potential.

Current swine influenza control strategies, including vaccination, biosecurity, and surveillance, offer a valuable foundation. However, they must be evaluated and potentially adapted to address the distinct risks posed by HPAI H5N1. In particular, cross-species transmission, mammalian adaptation, and the risk of zoonotic spillovers underscore the importance of integrating virological, epidemiological, and immunological monitoring.

In addition, vaccine development strategies should explore the feasibility and efficacy of homologous and broadly protective HPAI H5N1 vaccines for use in pigs. Understanding the HPAI H5N1 immune responses in swine following natural infection or vaccination will be critical for shaping effective control programs.

Finally, mitigating the public health threat posed by HPAI H5N1 in pigs will require a One Health approach that includes coordinated efforts across veterinary, human health, and wildlife sectors to assess occupational risks, preexisting immunity in exposed populations, and to implement mitigation strategies that consider both animal and public health. The current panzootic reinforces the importance of proactive, science-based policies to prevent the emergence of the next pandemic.

        (Continue . . . )

As we've seen with other recent reviews (see here, here, and here), the authors of this report offer a number of crucial steps we should be taking to help mitigate the HPAI H5 threat. 

But whether producers and regulatory agencies are listening - or are inclined to adopt them in a meaningful way - remains to be seen. 

The USDA's surveillance program for Influenza A in swine (IAV-S) is strictly voluntary and relies on passive sample submission. The latest USDA summary report (below) illustrates some of the limitations of current surveillance. 

As the USDA notes:  

Due to the voluntary nature of this surveillance, the information in this report cannot be used to determine regional and/or national incidence, prevalence, or other epidemiological measures, but it may help identify IAV-S trends.

Somewhat unnervingly, we are probably testing more than a great many other nations around the globe.  

The good news is - with this level of global surveillance - when the next pandemic finally does emerge, governments can honestly state:

They `never saw it coming'. 

JAMA Neuro: Influenza With and Without Oseltamivir Treatment and Neuropsychiatric Events Among Children and Adolescents

 

#18,836

For twenty years the influenza antiviral Tamiflu (oseltamivir) has carried a `black box warning' regarding potential neuropsychiatric events in children and adolescents; including confusion, delirium, abnormal behavior, self-harm, and even suicidal behavior.

These warnings were largely based on anecdotal reports from Japan in the mid-2000s - which were widely repeated by the tabloid press, and amplified online - and not based on real studies. 

While a lot of people remember (and continue to repeat) those press reports, few bother to cite the 2008 study which found no link between the drug and those events (see Japan: No Link Between Tamiflu And Abnormal Behavior).

Or the 2010 a review in the journal Eurosurveillance: Adverse Effects of Oseltamivir in Children which, looked at the antiviral treatment of a number of students at a primary school in Sheffield, UK during the 2009 pandemic which found none of the side effects reported were life-threatening.

Again in 2012, in Study: Adverse Events Associated With Oseltamivir Outpatient Treatment, researchers writing in the journal Pharmacoepidemiology and Drug Safety, found `no evidence was identified for an increased risk of neuropsychiatric or other AEs following oseltamivir treatment.’

Still, social media rumors and press reports have continued to cast doubt on the drug's safety - particularly when administered to children and adolescents.

In 2018, we revisited this story (see Study Finds No Relationship Between Suicide & Oseltamivir In Pediatric Patients), where a study published in the Annals of Family Medicine, once again found no credible link between the use of oseltamivir and neuropsychiatric events in pediatric patients.

What was becoming increasingly apparent, however, was that influenza itself (both seasonal and novel) could produce significant neurological manifestations, particularly in children and adolescents.

In 2018's Neuroinfluenza: A Review Of Recently Published Studies, we looked at a CDC COCA Call - and a number of recent studies - illustrating the threat.

Since then Neuroinfluenza has gotten a great deal more attention, but the stigma attached to oseltamivir has remained. 

Today we've yet another study, published in JAMA, which finds the exact opposite; that oseltamivir reduces the risk of serious neuropsychiatric events in children and adolescents with influenza. 

I've only posted the abstract - along with a link to a press release -  so follow the link(s) to read it in its entirety.  I'll have a bit more after the break. 

Influenza With and Without Oseltamivir Treatment and Neuropsychiatric Events Among Children and Adolescents

James W. Antoon, MD, PhD, MPH1; Derek J. Williams, MD, MPH1; Jean Bruce, BS2; et al

Published Online: August 4, 2025

doi: 10.1001/jamaneurol.2025.1995

Key Points

Question  Is the use of the influenza antiviral oseltamivir associated with serious neuropsychiatric events?

Findings  In this cohort study, the risk of serious neuropsychiatric events was lowest during periods without influenza. During influenza periods, treatment with oseltamivir was associated with a reduced risk of serious neuropsychiatric events compared with influenza periods without oseltamivir treatment.

Meaning  Oseltamivir use was associated with a reduced risk of serious neuropsychiatric events when used for influenza treatment; findings from this study should inform both caregivers and clinicians on the safety of oseltamivir and its role in preventing influenza-associated complications.

Abstract

Importance  Reports of pediatric neuropsychiatric events during influenza treatment with oseltamivir have prompted public concerns. However, whether oseltamivir or influenza infection is associated with increased risk of neuropsychiatric events remains unclear.

Objective  To determine the association between influenza, oseltamivir, and serious neuropsychiatric events.

Design, Setting, and Participants  This retrospective cohort study was conducted in a population-based ambulatory setting during the 2016 to 2017 and 2019 to 2020 influenza seasons. Follow-up began on the first day of the influenza season and continued through the earliest occurrence of an outcome event, loss of enrollment, death, age 18 years, or end of the season or study. Children aged 5 to 17 years enrolled in Tennessee Medicaid were for eligible for inclusion. Data analysis was completed from July 2023 to March 2025.

Exposures  Each person-day of follow-up was assigned to 1 of the following 5 mutually exclusive exposure groups: (1) untreated influenza; (2) treated influenza; (3) posttreatment period (period between oseltamivir completion and end of influenza period); (4) influenza prophylaxis; and (5) no exposure.

Main Outcomes and Measures  The primary outcome was a neuropsychiatric event requiring hospitalization, and events were identified using a validated algorithm. Poisson regression estimated incidence rate ratios (IRRs) while accounting for relevant covariates measured on each person-day. Sensitivity analyses examined robustness of findings to alternate exposure and outcome definitions, time-varying outcome risk, negative control outcome, and unmeasured confounding.

Results  Among 692 975 eligible children, a total of 692 295 children (median [IQR] age, 11 [7-14] years; 50.3% female) experienced 1230 serious neuropsychiatric events (898 neurologic and 332 psychiatric) during 19 688 320 person-weeks of follow-up. Among the 151 401 influenza episodes, 66.7% (95% CI, 66.5%-67.0%) were dispensed oseltamivir (60.1% [95% CI, 59.6%-60.6%] among those at high risk for influenza complications). The most common events overall were mood disorders (36.3%) and suicidal or self-harm behaviors (34.2%).

Compared with untreated influenza, event rates were lower during oseltamivir-treated influenza periods (IRR, 0.53; 95% CI, 0.33-0.88) and posttreatment periods (IRR, 0.42; 95% CI, 0.24-0.74). Subanalyses suggest that this finding is driven more by a reduction in neurologic events (IRR, 0.45; 95% CI, 0.25-0.82) than psychiatric events (IRR, 0.80; 95% CI, 0.34-1.88). Sensitivity analyses suggest misclassification or unmeasured confounding would not explain these findings.

Conclusions and Relevance  In this cohort study, oseltamivir treatment during influenza episodes was associated with a reduced risk of serious neuropsychiatric events. These findings support oseltamivir use for prevention of these influenza-related complications.

A press release from Vanderbilt University Medical Center on this study can be read at:

Researchers debunk long-standing concern about flu treatment in children 

Admittedly, this is an observational study - albeit a fairly large one - and not a randomized control trial. While RCTs in children might better confirm these findings, withholding treatment from infected cohorts presents obvious ethical problems.

None of this is to suggest that oseltamivir is 100% benign in 100% of patients, but side effects are generally mild, with nausea and vomiting being the most commonly reported.  

Whether this study will change many minds remains to be seen.  Negative views, once baked into the social consciousness, are notoriously difficult to change. 

Sadly, if there is one truism for life the 2020s, it's that: 

One negative meme gets more views than a dozen scientific studies. 

JAVMA: Companion Animals and H5N1 Highly Pathogenic Avian Influenza: Cause for Concern?

Cats As Potential Vectors/Mixing Vessels for Novel Flu

#18,835

While we enjoy the relative lull in HPAI reports during the summer months, the annual southbound migration of birds from their high latitude roosting sites has already begun, and with it may soon arrive new genotypes, subtypes, and variants of HPAI H5. 

In North America alone, more than 100 genotypes have been identified over the past 3+ years, with more expected to emerge over time. Over the past 16 months we've seen 4 new genotypes of note emerge in the United States.

• B3.13 aka the `bovine' strain affecting dairy cattle in at least 17 states and mildly infecting dozens of humans, along with > 100 cats.
• D1.1  a wild bird/poultry strain which has spilled over into > a dozen people in Washington State, severely infected a teenager in British Columbia, and produced a fatal infection in Louisiana. 
• D1.2  a wild bird/poultry strain which recently detected in poultry and 2 pigs in Oregon
• D1.3  a recently detected wild bird/poultry strain which has been infection poultry and at least 1 human

Globally, that number is much larger, although given the limits of surveillance and reporting, we aren't aware of all of them.  

In Cambodia we've seen a reassorted clade 2.3.2.1e virus infect > 30 people since 2023, while a new triple-reassortant H5N1 clade  2.3.2.1a virus in India has reportedly infected both humans and cats. 

Other HPAI H5 genotypes/subtypes have infected cats, dogs, (and other mammals) in Europe and Asia (see here, here, here, and here), and North America.  The USDA lists at least 144 domestic cats infected, along with dozens of other felines.

The take-away here is that HPAI H5 has diversified into numerous new subclades, subtypes, and genotypes; with many of them demonstrating an affinity for infecting both terrestrial and marine mammals. 

While not unheard of before 2020 (see 2015's HPAI H5: Catch As Cats Can), we've seen a significant increase in the number of HPAI spillovers into mammals, and cats appear to be particularly susceptible.

These trends (and more) have led veterinarians to worry that companion animals (particularly cats, but also including dogs, ferrets, mice, etc.) could serve as a potential `mixing vessel' for reassortment, or as a bridge to infecting humans.  

A few past blogs include:

CDC MMWR: HPAI H5N1 Virus Infection of Indoor Domestic Cats Within Dairy Industry Worker Households — Michigan, May 2024

California: San Mateo County Warns Residents After Stray Cat Found With H5N1

Emerg. Microbes & Inf.: Marked Neurotropism and Potential Adaptation of H5N1 Clade 2.3.4.4.b Virus in Naturally Infected Domestic Cats

Oregon Recalls Raw Pet Foods After Domestic Cat Death - California DPH Warns On Raw Pet Food

CAHSS/Animal Health Canada: HPAI H5N1 in Cats

All of which brings us to a new open access article published in the Journal of American Veterinary Association last week, which looks at the concerns over the role of companion animals in the evolution and spread of HPAI H5. 

Due to its length I've only posted the abstract and some extended excerpts.  You'll want to follow the link to read it in its entirety.  

I'll have a brief postscript after you return. 

Companion animals and H5N1 highly pathogenic avian influenza: cause for concern?

Jane E. Sykes BVSc, PhD, MPH, MBA, DACVIM jesykes@ucdavis.edu 
Open access

Published online August 8, 2025 

doi.org/10.2460/javma.25.06.0388

Download PDF   

Abstract

The first known human infection with a highly pathogenic H5N1 influenza A virus appeared in China in 1997. Between 2003 and 2017, the WHO documented an additional 862 human cases, mainly from southeast Asia and Egypt, with a mean annual case fatality rate of 56%. By 2006, the susceptibility of cats to severe respiratory and neurologic disease became apparent. 

Scientists raised concerns regarding the potential for domestic cats to transmit novel pathogenic strains to humans. But after 2006, reports of new H5N1 infections in companion animals dwindled, and human cases fell after 2016. 

In 2021, H5N1 clade 2.3.4.4b viruses suddenly appeared in Europe and spread rapidly to the Americas, wreaking havoc on wildlife and crippling the poultry and dairy industries. Between 2022 and 2025, dozens of domestic cats died, most often following raw food consumption. Unease regarding the transmission potential of pets resurfaced. 

Although most human infections in the Americas were mild and associated with poultry or dairy contact, the recent detection of genotype D1.1 in association with severe illness or death is cause for concern. Genotype D1.1 has now also been detected in dairy cattle and domestic cats. Reports of H5N1 clade 2.3.2.1a viruses in India suggest a new potential threat.

Successful control of H5N1 infections is strongly dependent on a One Health approach. Small animal veterinarians play a key role in this approach through recognition of cases and education of pet owners, thus preserving the human-animal bond.

       (SNIP)

Risk of Human Infection from Domestic Cat Exposure

At the time of publication, the risk of severe human infection because of pet exposure is considered low. However, the ability of H5N1 clade 2.3.4.4b strains to replicate in such a broad array of avian and mammalian host species—together with the frequency of reassortment events—creates a recipe for emergence of strains with greater pathogenicity for humans.

Factors that support the ability of cats to act as vessels for reassortment of mammalian and avian influenza virus subtypes include (1) widespread tissue distribution of both α-2,3-Gal and α-2,6-Gal sialic acid receptors in cats,97 (2) co-localization of H5N1 antigen with these receptors,15 and (3) recovery of viruses from infected cats that have mutations associated with adaptation for replication in mammals.61

The widespread distribution of pet cats, their close proximity with humans, their predatory behavior and outdoor roaming activity, and the popularity of raw food diets add to the potential for infection and spillback.

Further, although clade 2.3.4.4b viruses have predominated worldwide, other clade 2 H5N1 viruses have caused severe human infections in south Asia (Bangladesh and India, clade 2.3.2.1a) and southeast Asia (clade 2.3.2.1c) since 2022.98 In March 2024, an H5N1 clade 2.3.2.1a virus was detected in a severely ill child returning home to Australia from India.98 In January 2025, a closely related H5N1 clade 2.3.2.1a virus was detected in 2 cats that died in India.99

        (SNIP)

Conclusion

The emergence of H5N1 clade 2.3.4.4b strains in 2021 represented a more significant threat than previous reports of fatal H5N1 AIV infections in cats from Europe, the Middle East, and Asia.

Compared to previous H5N1 variants, clade 2.3.4.4b strains have demonstrated more rapid global dissemination, more frequent reassortment with LPAIVs, a greater ability to replicate in an enormous variety of mammalian species, and a wider array of transmission pathways to domestic cats.

The recent detections of genotype D1.1 in 3 humans with severe or fatal illness from Canada, the US, and Mexico and in a cat from the US in early 2025 are worrisome new developments. Concurrently, the recognition of highly related clade 2.3.2.1a viruses in humans and cats from India demonstrates how multiple pathways for reassortment could evolve simultaneously.

Veterinarians play important roles in educating owners regarding ways to prevent infections in pets. More studies of the prevalence of persistent subclinical infections in dogs and cats are needed, as these also represent a threat to human and animal health. In light of the general availability of safer vaccines for cats, interdisciplinary conversations are warranted regarding the feasibility, impact, and value of immunizing cats against H5N1 infections.

       (Continue . . . )

The HPAI H5 threat of today is far different from what it was 20, 10, or even 5 years ago.  There is far greater viral diversity (subclades, genotypes, subtypes) circulating today than we've ever seen before.

While it is possible that H5Nx faces some insurmountable species barrier (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?), it continues to expand its (avian & mammalian) host range around the globe.

Our understanding of the ecology of H5 - in the wild, on the farm, and in companion animals - remains limited, and we see the continued introduction of new genotypes and variants every year. 

Yet most people seem oblivious to the threat (see Two Surveys (UK & U.S.) Illustrating The Public's Lack of Concern Over Avian Flu), and many governments are content to do little and say even less. 

We humans like to believe that tomorrow will be pretty much like today, or yesterday (aka `Normalcy Bias '). We tend to discount bad things happening in the future in favor of enjoying more immediate rewards.

So we blithely build cities on known fault lines or in the shadow of a volcano, or subdivisions and schools on toxic waste sites, and hope for the best. Similarly, we seem to be waiting for HPAI to `burn itself out' in cattle, or in wild birds; because it is easier than actually addressing the threat.  

These laissez-faire style strategies can often work well for years, sometimes even decades.  

But when they fail, they have a habit of doing so spectacularly.