HPAI H5N5: A Variation On A Theme

HPAI H5N5 WAHIS Updates for 2024
 

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This week WOAH reported (see below) more detections of HPAI H5N5 (clade 2.3.4.4b) virus in raccoons from Nova Scotia and Prince Edward Island.  The virus had previously been detected in wild birds, but turned up in dead raccoons on Prince Edward Island a year ago (see CIDRAP Report Canada reports first H5N5 avian flu in a mammal).

EPIDEMIOLOGICAL COMMENTS

We report additional cases of highly pathogenic avian influenza Fully Eurasian H5N5 (2.3.4.4b) virus in raccoons from Nova Scotia and Prince Edward Island. Outbreaks are reported by province/territory. The geographical marker is on the capital. For detailed and current information on high pathogenicity avian influenza cases in wildlife, please consult : http://www.cwhc-rcsf.ca/avian_influenza.php.

While our biggest concern is currently HPAI H5N1, we've seen closely related H5N3, H5N4, H5N5, H5N6, and H5N8 viruses - the product of H5N1 reassorting with other LPAI viruses - infecting both birds and mammals around the globe. 

The H5N5 avian subtype first came to light in a 2011 report (see EID Journal: Novel H5N5 Avian Influenza Detected In China), which described the isolation of two novel reassortant HPAI H5N5 viruses from apparently healthy domestic ducks in Eastern China.

Several of the same authors wrote about additional isolates of the H5N5 virus in the journal Veterinary Microbiology (see Characterization of three H5N5 and one H5N8 highly pathogenic avian influenza viruses in China), that were isolated in China in 2009-10, suggesting that the first detection wasn’t a fluke.

Although we have looked at the the threat and evolution of HPAI H5N5 a number of times in the past (see here, here, and here), recent changes to clade 2.3.4.4b viruses probably make findings before 2021 less relevant. 

In June of 2022, in Norwegian Veterinary Institute : HPAI Detected In Arctic (Svalbard) For the First Time, both H5N1 and H5N5 were detected (see press release below).

Bird flu causes high mortality among wild birds in Norway

Published 21.06.2022 Modified 22.06.2022

In recent weeks, an abnormally high number of sick and dead birds has been observed in several places along the Norwegian coast. In May and June, the Veterinary Institute detected highly pathogenic avian influenza (HPAI) of subtype H5N5 in sea eagles, ravens, crows and several gull species in Troms and Finnmark. In the North Sea and along the coast in Rogaland, a high number of dead ospreys have been observed, and HPAI of the subtype H5N1 has been detected in several of these. In addition, HPAI has been detected in wild birds in Oslo, Bergen and several places in Trøndelag and Møre og Romsdal.

In the most recent ECDC/EFSA Quarterly Avian Influenza Overview Dec 2023 - Mar 2024, there were several mentions of HPAI H5N5, including:

• Subtype A(H5N5), genotype EA-2021-I, which has persistently been detected in Norway since the 2021–2022 epidemiological year, has since September 2023 spread to Iceland, the United Kingdom, Greenland and Germany, and – besides infecting wild birds – infected red foxes in Norway. A(H5N5) was also detected in Faroe Islands and Japan during the current epidemiological year.

• Unlike the mammalian infections reported in Europe during the summer months in 2023, mainly caused by the EA-2022-BB genotype, the recent A(H5) viruses identified in wild mammals belonged to different A(H5N1) and A(H5N5) genotypes. The detection of A(H5N5) virus in two red foxes from Norway represents the first detection of this subtype in mammals in Europe.

HPAI H5 is a highly promiscuous virus, capable of reassorting with a variety of other influenza A viruses.  It continually spins off new genotypes (including new subtypes) as it spreads, some potentially being more dangerous than others.

It is for this reason there is so much concern about HPAI H5 spilling over into pigs, which would give it access to a wide array of swine and human viruses. 

 

But other species, including humans, marine mammals, mink, and even dogs and cats could serve as an effective `mixing vessel'. 

Six years ago, HPAI H5N8 was the dominant H5 subtype, but was supplanted by H5N1 in 2020. It is entirely possible that we could seen another shift - from H5N1 to H5N5, or H5N6, or to some other n-type, in the months or years ahead.

And while clade 2.3.4.4b is currently in the driver's seat, we've seen a resurgence in clade 2.3.2.1c in Cambodia over the past year, and last week the FAO warned of a Reassortment Between H5N1 Clade 2.3.4.4b & Clade 2.3.2.1c Viruses In Mekong Delta Region.   

While we expect all influenza A viruses to change over time, HPAI H5 seems to be working overtime. 

Which is why we need to be prepared for more surprises. 

Nature Portfolio Preprint: Immune Imprinting Revealed by SARS-CoV-2 Omicron Infection Prior to vaccination

Credit NIAID

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The term Original Antigenic Sin (OAS) was first coined in 1960 by Thomas Francis, Jr. in his article On the Doctrine of Original Antigenic Sin, which postulated that when the body’s immune system is exposed to - and develops an immunological memory - to one virus, it may be less able to mount a defense against a subsequent exposure to a slightly different version of that virus.

We see the impact of OAS often with Dengue, which has 4 closely related serotypes.  Regardless of the serotype of one's first infection, that illness is generally mild or moderate.  Subsequent dengue infections (with different serotypes) often produce more severe illness, and sometimes death.

Why?  The body's immune system mistakenly recognizes the new infection as a repeat of the first, and sends cross reactive, but non-neutralizing (read: ineffective) antibodies to the field of battle.

And if mistakenly sending the wrong antibodies into the fray isn’t bad enough, sometimes non-neutralizing antibodies can actually enhance a virus’s ability to enter a host’s cells via a process called ADE or Antibody-dependent enhancement.

With influenza, it is increasingly being recognized that one's first exposure makes a significant, and lasting, impression on your immune system (see Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression).

Up until relatively recently, we thought of influenza viruses as being grouped primarily by HA subtype; H1, H3, H5, H7, etc. But, as the chart above shows, the 18 known subtypes are divided into two basic groups; Group 1 and Group 2.

And recent evidence suggests that the first HA group you are exposed to may determine your ability to fight infection by viruses from the other group.  A few past blogs include:

Science: Protection Against Novel Flu Subtypes Via Childhood HA Imprinting

PLoS Path.: Childhood Immune Imprinting to Influenza A

Nature Comms: Middle-Aged Individuals May Be in a Perpetual State of H3N2 Flu Virus Susceptibility

This childhood imprinting may help to explain why (HA Group 2) H7N9 cases in China skewed heavily to those > 50, while (HA Group 1) H5N1 cases generally affected those under the age of 40 (see chart below). 

The more diverse a family of viruses, the more problematic OAS becomes.  And when it comes to diversity, COVID is hard to beat. 

A little over two years ago (before Omicron swept the world), in Science: Heterologous Infection and Vaccination Shapes Immunity Against SARS-CoV-2 Variants, we looked at a lengthy study by researchers from Imperial College London and Queen Mary University of London, that looked at the long-term immune impacts of a person's 1st exposure (via infection or vaccination) to SARS-CoV-2.

From the Press release:

New research shows that the first SARS-CoV-2 spike protein a person encounters, be it by vaccination or infection, shapes their subsequent immune response against current and future variants. That is, it imparts different properties that have an impact on the immune system’s ability to protect against variants, and also affects the rate of decay of protection.

There are some studies that suggest that Repeated Omicron exposures override ancestral SARS-CoV-2 immune imprinting, but there are no guarantees we won't seen another seismic shift in the virus down the road.

Given the growing diversity of novel flu viruses, and the continued expansion of COVID variants, it is imperative that we get a better handle on the impact and mechanisms behind OAS, and find ways to mitigate its effect.

All of which brings us to a new preprint, which looks at the impact of OAS on Omicron infection, and finds it can occur either through vaccination or natural infection. I've reproduced the abstract below, but those up for a deeper diver will want to follow the link to read it in its entirety.

Immune imprinting revealed by SARS-CoV-2 Omicron infection prior to vaccination

Ravindra Gupta, Adam Abdullahi, James Onyemata, Sam Turner, Martin Edun, and 13 more
This is a preprint; it has not been peer reviewed by a journal.
https://doi.org/10.21203/rs.3.rs-4186317/v1

This work is licensed under a CC BY 4.0 License

Abstract

Immune imprinting or original antigenic sin (OAS) originally referred to a phenomenon of suboptimal immune response to a repeat exposure to a virus that was antigenically distinct from the original virus infection. OAS has been implicated in higher mortality in young people during the 2009-10 H1N1 pandemic where the elderly (H1N1 exposure in childhood) appeared relatively well protected compared to younger individuals whose first influenza infection was not H1N1.

Immune imprinting is part of a rapid recall system and is highly effective against a slowly evolving virus (drifting) but not antigenically shifting viruses such as influenza and SARS CoV-2. As predicted by OAS, suboptimal neutralization responses to the highly divergent SARS-COV-2 lineage Omicron have been observed in animal models and individuals previously vaccinated with primary course of ancestral (Wu-1) vaccine.

Due to the rapid scale up of vaccine before emergence of the antigenically distinct Omicron variant, it is unknown whether immunological imprinting for occurs in the context of SARS-COV-2 infection itself. We longitudinally assessed humoral responses to primary two dose Ad26.COV2.S Wu-hu-1 based vaccination in a Nigerian population following the global emergence of Omicron.

At study entry in Jan 2023, we found 93% and 58% of pre-vaccination participants previously exposed to ancestral Wu-1 and Omicron virus respectively by anti-N IgG and anti-receptor binding domain (RBD) IgG Wu-1 and Omicron -specific antibodies. In participants with no evidence of prior exposure to Omicron, neutralisation against Wu-1 was significantly higher than Omicron variants as expected. However, serum neutralisation titres in participants who were anti-RBD Omicron IgG positive were paradoxically 2-fold lower for Omicron BA.1 as compared to Wu-1.

This is clear evidence for imprinted immunity from the ancestral pre-omicron lineage viruses, and remarkably these old responses to Wu-1 were able to dominate over more recent, likely multiple, Omicron lineage infections. Furthermore, in these participants with prior exposure to Omicron and evidence of imprinting, we observed that further Omicron infection and Wu-1 based vaccine was associated with boosting of responses across variants with equalisation of neutralisation titres for Wu-1 and Omicron variants.

However, omicron responses did not surpass ancestral responses, suggesting persistence of imprinting and only partial mitigation. However, serum neutralisation titres in participants who were anti-RBD Omicron IgG positive were paradoxically 2-fold lower for Omicron BA.1 as compared to Wu-1.ion. Although neutralization responses at high titres were observed post dose 1 vaccination against ancestral and Omicron variants BA.1, BA.2, BA.4 in nearly all participants, neutralisation against the highly immune evasive XBB recombinant variant remained substantially lower, with a second vaccine dose providing very modest boosting. only partial mitigation

These data highlight immune imprinting against SARS-CoV-2 prior to vaccination and its persistence thereafter. In present day unvaccinated populations where serum neutralisation responses to pre-Omicron variants dominate, use of an omicron variant based vaccine should be used in preference to Wu-1 based vaccine to override imprinting and provide broader protection for vulnerable populations such as the elderly or those with compromised immunity.

Not surprisingly, this is all very complicated and only partially understood, but the development of a Pan-COV vaccine or a `Universal Flu Vaccine' likely hinges on our gaining a better understanding of immune imprinting and OAS.  

Microorganisms: Case Report On Symptomatic H5N1 Infection In A Dog - Poland, 2023

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While we await further developments surrounding the spread of HPAI H5N1 in American livestock, we have a follow up report from last summer's outbreak of H5N1 in Poland, which affected dozens of cats across multiple provinces (see Eurosurveillance: Two Papers On HPAI H5N1 clade 2.3.4.4b virus in cats, Poland, June to July 2023).

Although some cats were reportedly fed raw poultry, and others were allowed to roam outdoors, the source of the infection was never fully explained.  Many cats suffered severe neurological manifestations and organ damage, and genomic analysis of the virus revealed several mammalian mutations. 

While cats appear to be particularly susceptible to avian influenza viruses (see here, here, and here), dogs have occasionally been infected as well. 

Unlike with cats, dogs are thought more likely to carry the virus asymptomatically (see J. Virulence: HPAI H5N1 Virus Infection In Companion Animals).

There have been a few notable exceptions, including the following report from Canada's Food Inspection Agency last year:

Domestic dog tests positive for avian influenza in Canada

From: Canadian Food Inspection Agency

Statement

April 4, 2023 – Ottawa, Ontario

Today, the Canadian Food Inspection Agency and the Public Health Agency of Canada issued the following joint statement:

The Canadian Food Inspection Agency's (CFIA) National Centre for Foreign Animal Disease, confirmed on April 1, 2023, that a domestic dog in Oshawa, Ontario has tested positive for highly pathogenic avian influenza (HPAI).

The domestic dog was found to have been infected with avian influenza after chewing on a wild goose, and died after developing clinical signs. The necropsy was completed on April 3, 2023, and showed respiratory system involvement. Further testing is underway. It is the only case of its kind in Canada.

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Symptomatic H5 infection in dogs may be under-reported, however, since today's report points out ` . . .  in most European countries, dogs presenting with respiratory symptoms are not routinely tested for influenza'.  

As we've seen recently with HPAI in cattle, testing biases based on preconceived notions may be preventing us from seeing the bigger picture. It is axiomatic that the less diligently we look, the less evidence we'll find. 

First some excerpts from the case report, after which I'll return with a postscript.  Follow the link to read the report in its entirety. 

Upper Respiratory Tract Disease in a Dog Infected by a Highly Pathogenic Avian A/H5N1 Virus
by
Olga Szaluś-Jordanow 1,*, Anna Golke 2, Tomasz Dzieciątkowski 3, Michał Czopowicz 4, Michał Kardas 5, Marcin Mickiewicz 4, Agata Moroz-Fik 4, Andrzej Łobaczewski 5, Iwona Markowska-Daniel 4 and Tadeusz Frymus 1

Abstract

In summer 2023, during an outbreak of highly pathogenic avian influenza (HPAI) in cats in Poland, a 16-year-old dog was presented to the veterinary clinic with persistent, debilitating, dry cough, submandibular lymphadenomegaly, mild serous nasal discharge, and left apical heart murmur. A preliminary diagnosis of kennel cough was made and the treatment with amoxicillin/clavulanic acid and dexamethasone was initiated.

Due to the lack of improvement within 2 days, a blood check-up, thoracic radiography and ultrasonography, and echocardiography were performed. Moreover, a rapid test for orthomyxovirus type A antigen in a throat swab was carried out and proved positive. The result was verified using RT-qPCR, which yielded a positive result for A/H5N1 influenza virus and negative results for A/H1N1, A/H3N2, type B influenza, and SARS-CoV-2.

This case indicates that HPAI should be considered as a differential diagnosis not only in cats, but also in dogs with upper respiratory tract disease, particularly in regions experiencing A/H5N1 avian influenza outbreaks.

(SNIP)

4. Discussion

Recent epizootics of HPAI in birds have also led to an increase in reported carnivore A/H5N1 infections over the last few years in Europe. Some examples are cases in cats in Poland and France [23,24,29], in foxes [30,31], in American minks, raccoon dogs on several fur farms in Finland [32], and in minks in Spain [33]. Generally, this infection has been much better characterized in domestic cats and wild felines than in other carnivores. 

However, in the literature, there is a growing body of evidence indicating that both domestic dogs and wild canids can also harbor this agent, with the potential for both asymptomatic shedding and clinical disease. The few experimental infections of dogs with A/H5N1 virus performed so far resulted only in subclinical replication of the agent or a transient fever and respiratory symptoms, which were rather mild [34,35]. 

However, it should be emphasized that the outcomes of natural infections can significantly differ from experimental infections, as evidenced by studies on foxes. A natural A/H5N1 infection has been recently confirmed in two deceased foxes in Italy [31]. The animals were found in an area experiencing mass HPAI mortalities among farmed pheasants, pointing toward a possible link between avian canid infections. Post-mortem examinations revealed in these foxes lung alterations and the presence of bloody fluid in the pleural cavity. 

Further insight into the virus’s impact on foxes was provided by an experimental study conducted by Reperant et al. [36]. The animals were divided into two groups: one received the A/H5N1 virus intratracheally, while the other was exposed through the consumption of infected bird carcasses. Foxes from the first group developed severe respiratory and systemic disease, including pneumonia, myocarditis, and encephalitis. In contrast, the group that consumed infected carcasses excreted the virus without manifesting severe illness, suggesting a potential asymptomatic shedding by foxes. The geographical scope of wild canid HPAI infections extends beyond Europe. In Asia, the A/H5N1 virus was confirmed in an Ezo red fox (Vulpes vulpes schrencki) and a tanuki (Nyctereutes procyonoides albus). The Ezo red fox was presented with viral meningoencephalitis and moderate virus replication in the upper respiratory tract [21].

In contrast to wild canids, reports about natural HPAI virus infections in domestic dogs have been scarce, thus far. There is only one published report of a natural A/H5N1 infection in a one-year-old dog from Thailand. This dog, which presented with severe respiratory symptoms, died in 2004 after ingesting a duck infected with the A/H5N1 virus. The virus was detected in multiple organs [2]. Controlled infection studies confirmed that dogs are susceptible to the A/H5N1 virus and can develop respiratory symptoms [34,35,37]. 

Our patient was a sick domestic dog, positive both in the influenza type A antigen test and in PCR for A/H5N1 sequences, presented to the clinic during a cluster of highly deadly cases in domestic cats caused by the A/H5N1 virus [23,24,25]. The dog showed symptoms that were initially suggestive of severe kennel cough, characterized by enlarged submandibular lymph nodes and a dry cough that persisted despite conventional treatment for an 18-day course. Unfortunately, information about the diet of this dog before the onset of the symptoms was not available.

The case described in our report confirms that on rare occasions the A/H5N1 virus can also induce a natural severe respiratory disease in dogs. While in some of them the infection remains asymptomatic, capable of shedding the virus [35], others exhibit mild symptoms such as transient fever [34], or even fatal disease [20].

Recently, five seropositive healthy dogs were found on a farm in Italy during an outbreak of clade 2.3.4.4b HPAI A/H5N1 infection in poultry. The virus isolated from birds had in the PB2 gene the T271A mutation, which is a marker of virus adaptation to mammals [38]. Studies by Maas et al. [35] using labeled A/H5N1 virus highlighted the agents’ ability to adhere to tissues in both the upper and lower respiratory tracts of dogs. This suggests a potential role of dogs as intermediate hosts in transmitting HPAI from birds to humans, as discussed by Chen et al. [37].

In Poland, as in most European countries, dogs presenting with respiratory symptoms are not routinely tested for influenza. The presented case confirms that in Europe dogs can develop a natural disease induced by the A/H5N1 virus, since HPAI outbreaks have become common in Europe during the last several years. Thus, in areas with endemic HPAI in birds, this infection should be considered in the differential diagnostics not only in cats but also in dogs, especially in patients with respiratory disease.

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While the risk that your pet will be infected with H5N1 is still believed quite low, given what we've seen over the past couple of years, it does appear to be increasing over time.  

Things that were once considered highly unlikely - like HPAI in cattle, or mass mortality events in marine mammals - are increasingly common, and we need to learn how to adjust to this `new normal'. 

To that end the CDC has offered some advice to pet owners, to help keep their pets (and by extension, themselves) safe from HPAI.  

Pet Owners

If your domestic animals (e.g., cats or dogs) go outside and could potentially eat or be exposed to sick or dead birds infected with bird flu viruses, or an environment contaminated with bird flu virus, they could become infected with bird flu. While it’s unlikely that you would get sick with bird flu through direct contact with your infected pet, it is possible. For example, in 2016, the spread of bird flu from a cat to a person was reported in NYC. The person who was infected [2.29 MB, 4 pages] was a veterinarian who had mild flu symptoms after prolonged exposure to sick cats without using personal protective equipment.

If your pet is showing signs of illness compatible with bird flu virus infection and has been exposed to infected (sick or dead) wild birds/poultry, you should monitor your health for signs of fever or infection.

Take precautions to prevent the spread of bird flu.

As a general precaution, people should avoid direct contact with wild birds and observe wild birds only from a distance, whenever possible. People should also avoid contact between their pets (e.g., pet birds, dogs and cats) with wild birds. Don’t touch sick or dead birds, their feces or litter, or any surface or water source (e.g., ponds, waterers, buckets, pans, troughs) that might be contaminated with their saliva, feces, or any other bodily fluids without wearing personal protective equipment (PPE).

More information about specific precautions to take for preventing the spread of bird flu viruses between animals and people is available at Prevention and Antiviral Treatment of Bird Flu Viruses in People. Additional information about the appropriate PPE to wear is available at Backyard Flock Owners: Take Steps to Protect Yourself from Avian Influenza.

 

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Whether people will actually heed this advice - and for how long - is another matter. 

JAVMA: HPAI in Wildlife: A Changing Disease Dynamic

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Although HPAI H5 has been a pandemic concern for most of the past 2 decades, it is safe to say that the abrupt changes in the virus's behavior over the past 2-3 years have raised the stakes significantly.  

Since 2021 we've see increased spillover into mammalian species (see graphic above), with many displaying severe neurological symptoms. 

Travel Med. & Inf. Dis.: Pacific and Atlantic Sea Lion Mortality Caused by HPAI A(H5N1) in South America

J. Virulence: HPAI H5N1 Virus Infection In Companion Animals

EID Journal: HPAI A(H5N1) Virus Clade 2.3.4.4b Infections in Wild Terrestrial Mammals, United States, 2022

Cell: The Neuropathogenesis of HPAI H5Nx Viruses in Mammalian Species Including Humans

In addition to poultry and wildlife, farmed animals - including mink, foxes, pigs and most recently goats and dairy cows - have all been affected by the virus.  How widespread these spillovers really are is unknown, but they are likely far more common than has been reported. 

Surveillance and testing is limited, even in places like the United States and Europe, while in many regions of the world, surveillance is practically non-existent.  Some countries - for economic or political reasons - may know of outbreaks, but may be reluctant to share that information (see Flying Blind In The Viral Storm).

But even with the limited dataset we have, it is pretty obvious that the behavior of HPAI has changed over the past 3 years.  Where, exactly, all of this will lead is unknown.  But we need to be prepared for more - potentially unpleasant - surprises in the future. 

Assumptions about how this virus behaves, and the threat it poses going forward, may need to be adjusted.  As may many of our current health and safety practices (see examples below). 

CDC Updated Advice On Bird Flu in Pets and Other Animals

UK Guidance for the Public: Minimize Contact with Wild Birds

Two days ago, in AJVR: The Virus is Out of the Barn: The Emergence of HPAI, we looked at a cautionary report from the American Journal of Veterinary Research, which goes into the history of HPAI (and LPAI) viruses, and examines the risks posed by increasing spillovers into mammalian species (including pigs).

Today we've a report from another prestigious veterinary journal (JAVMA - Journal of the American Veterinary Medical Association), that describes the evolution - and unprecedented changes in behavior - of HPAI over the past 3 years. 

This is a lengthy, and highly informative, review and is well worth reading in its entirety.   I'll have a brief postscript after the break. 

High-pathogenicity avian influenza in wildlife: a changing disease dynamic that is expanding in wild birds and having an increasing impact on a growing number of mammals

Wendy B. Puryear PhD and Jonathan A. Runstadler

DVM, PhD jonathan.runstadler@tufts.eduView More
DOI: https://doi.org/10.2460/javma.24.01.0053
Volume/Issue: Online Early
Online Publication Date: 10 Apr 2024

Abstract

While diverse strains of low-pathogenicity avian influenza have circulated in wild birds for a long period of time, there has previously been little pathology in wild birds, ducks have been the primary and largely asymptomatic wild reservoir, and spillover into mammals has been limited and rare.

In recent years, a high-pathogenicity avian influenza (HPAI) virus has emerged on the global scene and shifted the previously established dogmas for influenza infection. High-pathogenicity avian influenza has expanded into wildlife in unprecedented numbers and species diversity, with unmatched disease severity for influenza in wildlife. 

As the disease ecology of influenza has shifted with this new variant, significant efforts are underway to understand disease course, pathology, and species susceptibility. Here we focus primarily on the impact that HPAI has had in wild mammals while framing these novel spillovers within the context of significantly expanding disease in avian species and geography. The clinical and pathology presentations of HPAI in these atypical hosts are discussed, as well as prognosis and risk for continued spillover.

The companion Currents in One Health by Runstadler and Puryear, AJVR, May 2024, provides further context on viral reservoirs and possible routes of direct or environmental transmission and risk assessment of viral variants that are emerging within wildlife.

          (SNIP)

Conclusions

After the initial incursion of Eurasian-origin H5N1 2.3.4.4 virus into North America from trans-Atlantic migratory birds,46 there have continued to be additional incursions of new lineages.25,47,48 These have occurred primarily from Europe,47 across Iceland,49 and onto the North Atlantic seaboard.25 Incursions of HPAI have also been observed from the Pacific.25 In addition to an ongoing influx of new lineages, HPAI continues to reassort and evolve.38,48 The spillover into mink in Spain was associated with an H5N1 reassortment with a gull-associated LPAI H13 variant.23 A gull-adapted reassortment termed the BB genotype has become common in Europe and is responsible for the fur farm outbreaks in Finland43 but is as yet undetected in North America. The HPAI reassortment H5N5 has recently been detected in North America, entering along the trans-Atlantic route, and associated with mortality in raccoon, red fox, and striped skunk in Canada.15

The current HPAI outbreak is unique in global expansion and in the wildlife species diversity that it is impacting and the range of wild mammals in which it is being detected. In March of 2024, infection of several dairy herds in multiple states was diagnosed, with possible transmission to a second human case in the US.50–52

Though the risk to humans remains low, this unexpected outbreak well illustrates the continued need for vigilance and further study. As the range of HPAI expands and the frequency of mammalian infections increase, the risk of zoonotic transmission continues to increase. This is why it is critical that robust surveillance occurs and appropriate biosafety caution is exercised, particularly in novel and atypical hosts, so that evidence for mammalian adaptation and mammal-to-mammal spread can be captured as early as possible. This then allows for variants to undergo pandemic risk assessment and to help inform vaccine preparedness efforts, as detailed further in the companion Currents in One Health article by Runstadler and Puryear, AJVR, May 2024.

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Although it remains to be seen whether HPAI H5 has what it takes to spark a pandemic, there is almost certainly another pandemic in our future.  While an influenza virus is the most likely culprit, another coronavirus, or perhaps something far afield (aka `Disease X') is always possible.

Many scientists believe the frequency of pandemics and epidemics will only increase in the future  (see BMJ Global: Historical Trends Demonstrate a Pattern of Increasingly Frequent & Severe Zoonotic Spillover Events).

Given the risks - and our bitter experience with COVID - it makes sense to be preparing with some urgency for whatever comes down the pike next.  The following quote is 18 years old, but it is just as true today as it was in 2006:

“Everything you say in advance of a pandemic seems alarmist.  Anything you’ve done after it starts is inadequate." - Michael Leavitt,  Former Secretary of HHS

Michigan: MDARD Reports Dairy Herds In 3 More Counties Test Positive For HPAI

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It is disappointing that after more than two weeks - and nearly 30 confirmed infections across 8 states - we still don't have a better understanding on how the HPAI virus is spreading.  I'm sure there are multiple epidemiological investigations underway, but so far I haven't seen anything definitive. 

Some states, but not all, suggest the virus was imported from Texas by infected dairy cows, but it isn't clear if all affected states received livestock. Or how the virus is spreading within herds after the virus is introduced. 

Today Michigan's Department of Agriculture and Rural Development (MDARD) announced diary cows from 3 more counties are affected by the virus. Two (Ionia & Isabella) are adjacent to the first county (Montcalm) that reported infection, while Ottawa county is a bit of an outlier. 

MDARD Director Tim Boring states in today's update:

"What is happening with HPAI in Michigan, mirrors what is happening in states across the country. This virus does not stop at county or state lines, which is why we must all be on high alert. This news is unfortunate and upsetting for our poultry and dairy farming families and communities . . . "

The full statement from MDARD follows:

Highly Pathogenic Avian Influenza Detected in Three New Michigan Dairy Herds

April 12, 2024

LANSING, MI – Today, Michigan Department of Agriculture and Rural Development (MDARD) Director Tim Boring announced the detection of highly pathogenic avian influenza (HPAI) in dairy herds in three additional counties—Ionia, Isabella, and Ottawa—bringing the total number of affected herds to four. On March 29, MDARD announced the state’s first HPAI-positive dairy herd located in Montcalm County. The U.S. Department of Agriculture’s (USDA) National Veterinary Services Laboratory confirmed these detections late in the evening on April 11.

"What is happening with HPAI in Michigan, mirrors what is happening in states across the country. This virus does not stop at county or state lines, which is why we must all be on high alert. This news is unfortunate and upsetting for our poultry and dairy farming families and communities," said Boring.

"Experts from across the nation continue to assess this situation and provide insights into the role of HPAI in the affected livestock as they become aware. MDARD continues working with our federal, state, and local partners to respond robustly to this disease. Thanks to recent budget investments, MDARD is well poised to properly engage in this response. If you believe your livestock are showing clinical signs, contact your veterinarian immediately. We're all on the same team as we combat HPAI."

According to the USDA, the Food and Drug Administration, and Centers for Disease and Prevention, the commercial milk supply remains safe due to federal animal health requirements and pasteurization. Federal experts continue to stress there is no concern about the safety of the commercial milk supply or that this circumstance poses any increased risk to consumer health. Analysis of the virus from this case and the other cases of affected cattle has not shown any significant new adaptation to make the virus more transmissible between mammals. Therefore, the public health risk associated with HPAI remains low.

In Michigan, state law requires pasteurization for any milk sold in stores. Pasteurization has continually proven to inactivate bacteria and viruses, like influenza, in milk.

“HPAI doesn’t affect dairy cows the same way as it does with poultry. With proper veterinary care, cows are recovering. Biosecurity is the best line of defense. Still, we want to stress working with your veterinarian is fundamental for the recovery of affected dairy cows,” said State Veterinarian Dr. Nora Wineland, DVM, MS, DACVPM. “It continues to be vitally important for producers to work with their veterinarian, minimize the number of visitors to their farms, prevent contact between their animals and wildlife, and continue to monitor the health of animals vigilantly.”

Dairies continue to be strongly encouraged to implement enhanced biosecurity measures to help prevent the spread of disease. It is recommended to limit persons coming onto dairies to employees and essential personnel only and to follow best management practices, including washing hands often. Additional biosecurity resources are available through Secure Milk Supply.

HPAI is a highly contagious virus in birds and poultry that can be spread directly by infected wild birds or animals or indirectly through any item that has been exposed to the virus, such as equipment, feed, or the clothing and shoes of caretakers. The virus has been detected in various species of mammals, presumably after the animals come into contact with infected birds. The affected premises voluntarily stopped movement to limit the spread of the disease.

Producers who have concerns about their animals' health and/or questions regarding how to improve the measures they take to protect animal health on their farm should contact their veterinarian.

If anyone suspects the presence of HPAI or any other reportable animal disease in their domestic animals, contact MDARD immediately at 800-292-3939 (daytime) or 517-373-0440 (after-hours).

For more information on the detections of HPAI in cattle, please visit the U.S. Department of Agriculture’s website.

For more information on HPAI, visit www.michigan.gov/birdflu.

Nature Portfolio: Preprint Case Report On China's 3rd H10N3 Case (Yunnan Province)

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With so much attention currently focused on HPAI H5N1 clade 2.3.4.4b, it is easy to forget that it is just one of many avian influenza viruses (e.g. H5N6, H7N9, H9N2, H3N8, etc.) with zoonotic potential.

While they have received far less attention than H5 or H7, H10Nx viruses have also shown a proclivity for spilling over into mammals (see Avian H10N7 Linked To Dead European Seals), and occasionally, infecting humans.  

A few past blogs include:

CHINA NHC Reports 1st Human H10N3 Avian Flu Infection - Jiangsu Province

HK CHP: A Cryptic Report of A 2nd H10N3 Case On the Mainland

Cell Host & MIcrobe: Avian H10N7 Adaptation In Harbor Seals

Jiangxi Province Reports 3rd H10N8 Case

Today the ECDC's weekly CDTR carried a synopsis of a preprint - published a few days ago in Nature Portflio - that describes the third known human infection with H10N3, which was detected in early March in Yunnan province.  Their risk assessment follows:

ECDC assessment 

Sporadic human cases of avian influenza A(H10N3) have been observed, but no human-to-human transmission has been documented. The risk to human health in the EU/EEA is considered very low. Direct contact with infected birds or contaminated environments is the most likely source of human infection with avian influenza. The use of personal protective measures for people exposed to sick or dead birds and their droppings will reduce the associated risk of infection.

The first two reported cases were in East-Central China (Jiangsu & Zhejiang Provinces). This is the first case in Southwest China. First, some excerpts from the preprint, which reports potentially significant mutations. 

Follow the link to read it in its entirety. 

First human case of avian influenza A (H10N3) in Southwest China

Guiming Liu, Jingyi Dai, Jun Zhao, Jiawei Xia, Pei Zhang, Yadi Ding, and 5 more

This is a preprint; it has not been peer reviewed by a journal.
https://doi.org/10.21203/rs.3.rs-4181286/v1

This work is licensed under a CC BY 4.0 License

. . . . a previously healthy 51-year-old male, presented with recurrent fever peaking at 39℃, accompanied by symptoms such as cough, expectoration, chest tightness, and shortness of breath. Diagnosis revealed severe pneumonia, type I respiratory failure, and infection with avian influenza virus H10N3. Additionally, the patient experienced complications from Candida albicans and Staphylococcus epidermidis infections. Following treatment with appropriate antiviral drugs and antibiotics, the patient's condition improved. Molecular analysis of the viral strain identified four mutations potentially hazardous to human health. This underscores the importance of continuous and vigilant monitoring of the dynamics surrounding the H10N3 subtype of avian influenza virus.

          (SNIP)

On March 6, 2024 the patient went to Kunming Third People's Hospital for treatment due to continuous fever for many days, and was diagnosed with severe pneumonia, type I respiratory failure and infection by avian influenza virus. After the diagnosis of avian influenza virus infection, the patient investigated by using questionnaires, including demographic information, poultry contact history, basic diseases, etc.

          (SNIP)

The symptoms observed in the patient infected with H10N3 in this case closely resemble those documented in the two previously known cases of H10N3 infection. Notably, all cases resulted in severe pneumonia in the affected patients8,9. In light of our findings, the identification of HA-Q226L, PB2-D701N, PA-S409N, and M2-S31N mutations in the protein of the Yunnan H10N3 virus strain underscores the potential for increased harm posed by H10N3 in humans. Therefore, it is imperative to closely monitor the dynamics of this subtype.

The case of human infection with H10N3 avian influenza virus highlighted in this study involved close contact with live birds, particularly through the handling and slaughtering of dead birds. This contact ultimately led to the patient contracting avian influenza and experiencing severe illness. This underscores the importance of paying special attention to instances of unexpected bird deaths and promptly reporting such cases. 

Moreover, it emphasizes the necessity of establishing a comprehensive avian influenza surveillance system, not only within Yunnan but also globally, to continuously and vigilantly monitor the H10N3 virus strain and its potential impact on human health.

         (Continue . . . )

A little over 2 months ago, we looked at a study in The Lancet Microbe: Novel H10N3 Avian Influenza Viruses - a Potential Threat to Public Health, on the zoonotic potential of H10N3 viruses in China.

They report finding at least 15 genotypes - all with internal genes derived from the H9N2 virus - multiple AA mammalian adaptations - and a high binding affinity to α2,6 receptor cells, which are abundant in the human upper respiratory system.

Although the number of reported H10 infected humans remains small - possibly due to a lack of surveillance and testing - in 2014's BMC: H10N8 Antibodies In Animal Workers – Guangdong Province, China, we saw evidence that some people may have been infected with the H10N8 virus in China long before the first case was recognized.

A reminder that nature's laboratory is open 24/7, and while we focus on one threat, there may be others in the queue.