Monday, June 10, 2024

Viruses: Natural Infection With HPAI H5N1 In Pet Ferrets - Poland, 2023



While this year infected cattle are the big H5N1 story, last summer we were following an unprecedented outbreak of H5N1 in cats in Poland (and later in South Korea), and a massive outbreak of H5N1 on numerous mink and fur farms in in Finland

Of the three, the South Korean outbreak was the smallest (affecting just 2 animal shelters), and was resolved the quickest (see South Korea: MAFRA Statement On Detection Of H5 Contaminated Cat Feed). 

Finland's outbreak was the largest, involving > 70 fur farms, and hundreds of thousands of animals.  Given its size, and the obvious opportunities for study, thus far we've seen disappointingly few studies published on this event. 

Reports from the Finnish Food Safety Authority (Ruokavirasto) tailed off late last year, with no new fur farm outbreaks reported in 2024. 

After a flurry of reports of dozens of cats dying across the country in June of last year, official statements from Poland's Chief Veterinary Officer (GLW) dried up in early July, with the last reference posted on 7/17/23.  

Despite drawing considerable attention from the WHO, the ECDC and the CDC, we never really saw a satisfactory resolution as to how these indoor and outdoor cats came to be infected.
While infected poultry was suspected, officials seemed primarily concerned with reassuring on the safety of their products (see Poland : Ministry of Agriculture Statement On H5N1 & Food Safety).

Since then we've seen only a few independent reports (mostly from veterinarians) on previously unreported cases of H5N1 infection in the region, including last April's Microorganisms: Case Report On Symptomatic H5N1 Infection In A Dog - Poland, 2023.

Today we've another of these reports, this time on H5N1 infected pet ferrets (n=5), which fell ill in late June of last year in Southern Poland. While the 2 adult ferrets were asymptomatic, the 3 juvenile ferrets were severely affected, with one fatality. 

First some excerpts from the report (which I very much recommend reading in its entirety), after which I'll have a bit more. 

Natural Infection with Highly Pathogenic Avian Influenza A/H5N1 Virus in Pet Ferrets
Anna Golke 1, Dawid Jańczak 2, Olga Szaluś-Jordanow 3,*, Tomasz Dzieciątkowski 4, Rafał Sapierzyński 5, Agata Moroz-Fik 6, Marcin Mickiewicz 6 and Tadeusz Frymus 3


The study involved five ferrets from one household in Poland, comprising three sick 9-week-old juveniles, their healthy mother, and another clinically normal adult, admitted to the veterinary clinic in June 2023. The juvenile ferrets displayed significant lethargy and a pronounced unwillingness to move with accompanying pulmonary distress. Prompted by concurrent outbreaks of A/H5N1 influenza virus infections in Polish cats, point-of-care tests were conducted that revealed type A influenza antigens in the throat swabs of all five ferrets.
Despite treatment, one juvenile ferret exhibited dyspnea and neurological symptoms and eventually died. The two remaining ferrets recovered fully, including one severely affected showing persistent dyspnea and incoordination without fever that recovered after 11 days of treatment. In the RT-qPCR, the throat swabs collected from all surviving ferrets as well as the samples of lungs, trachea, heart, brain, pancreas, liver, and intestine of the succumbed ferret were found positive for A/H5N1 virus RNA.
To our best knowledge, this is the first documented natural A/H5N1 avian influenza in domestic ferrets kept as pets. In addition, this outbreak suggests the possibility of asymptomatic A/H5N1 virus shedding by ferrets, highlighting their zoonotic potential and the advisability of excluding fresh or frozen poultry from their diet to reduce the A/H5N1 virus transmission risks.
Ferrets, due to their high susceptibility to influenza virus infections, serve worldwide as an established research model for exploring the pathogenesis of influenza [8,9,10,11]. Also, HPAI A/H5N1 virus infection has been extensively studied on experimental ferrets which have developed respiratory and neurological symptoms, severe lethargy, fever, weight loss, transient lymphopenia, and occasionally, digestive problems [8,17,18]. The clinical symptoms seen in the three clinically ill ferrets in our outbreak were concordant with the clinical picture after experimental infections, and in one of these ferrets, the disease was lethal. However, the natural outbreak of HPAI A/H5N1 virus infection in ferrets described in this paper brings to light several novel concerns.

First of all, the course of the infection differed significantly between adult and young animals. The two adults showed no clinical symptoms despite significant viral loads in the throat (Table 1). In contrast, nine-week-old ferrets showed primarily severe respiratory distress, accompanied by neurological symptoms. A similar situation occurred during the outbreak caused by the HPAI A/H5N1 virus on fur farms in Finland in July 2023, when mainly young blue and silver foxes, raccoon dogs and American minks were affected [13]

These differences could probably be partially explained by different immunological experiences and the degree of development of the immune system in juveniles and adults. However, in the outbreak described in the present paper, young ferrets were fed with poultry meat from a different batch than the adults. 

Hunting infected birds and eating raw contaminated poultry products are typical reasons for HPAI cases in cats and other carnivores [19]. Infection through contaminated poultry meat was also suspected in feline cases in Poland 2023 [3], and the ferret outbreak occurred at the same time. Though other routs cannot be excluded, for example, the owners’ shoes contaminated with faeces of infected birds, the alimental infection is much more probable, as the affected ferrets were kept strictly indoors, and fed raw poultry meat. 

Therefore, the questions arise whether (1) young ferrets were infected after consuming poultry meat and then infected the adults, or (2) all ferrets were infected consuming poultry meat? 
Although the mammal-to-mammal transmission of A/H5N1 virus has not yet been strictly proven, several instances suggest the possibility of such an event. Recently, in experimental conditions, co-housing of infected and non-infected ferrets promoted the transmission of the virus between these two groups [18]. Moreover, transmission between mammals was suggested during an A/H5N1 influenza outbreak on a mink farm in Spain and on multiple fur farms in Finland [12,13]. Similarly, during an outbreak of A/H5N1 HPAI in Thailand, horizontal transmission among tigers was suspected in a zoo [20]. Also, the scale of the mass mortality in South American sea lions raised speculations about the transmission of the A/H5N1 virus infection between the sea lions themselves [21,22]. 

Therefore, in the described five co-housed ferrets, the first proposed transmission scenario, though unverified, warrants consideration, especially since it is also known that the course of the A/H5N1 virus infection in ferrets depends not only on the immune status of the animals, but also on the route of infection [17].

Another concerning aspect is the high susceptibility of ferrets to various influenza A virus subtypes, potentially allowing for co-infection with multiple subtypes. Such scenarios could lead to the emergence of new influenza virus reassortants with enhanced human cell affinity and maintained high pathogenicity. Given the growing popularity of ferrets as pets globally, and their close contact with humans, this could contribute to an adaptation of this virus to humans.

Cases like these highlight the imperative need for vigilant HPAI surveillance also in ferrets and a deeper understanding of the pathogenesis, transmission dynamics, and cross-species infectivity potential of the A/H5N1 virus. Two of the five infected ferrets remained clinically healthy while RT-qPCR confirmed A/H5N1 RNA in their throat swabs (Table 1). 

Subclinical HPAI A/H5N1 virus infections are possible also in birds, especially wild ones, but were documented also in cats [23]. Asymptomatic infections documented in two adult ferrets mean that clinically healthy animals, maintaining close contact with their owners without raising any suspect, could be shedders of the virus. This point is especially significant given the zoonotic potential of the A/H5N1 virus. Human infections are extremely rare, but can be very severe, and the case fatality rate is over 50% [24].
          (Continue . . . )

Although ferrets - which are highly susceptible to a wide range of influenza viruses - are often used for influenza research, this appears to be a rare report of a natural infection.  Ferrets belong to the same general family as minks, otters, and weaselsMustelidae - all of which are susceptible to influenza A infection.

In 2019, in Nature: Semiaquatic Mammals As Intermediate Hosts For Avian Influenza, we looked at concerns over captive and wild members of this family serving as `mixing vessels' for influenza reassortment 

Last year in PNAS: Mink Farming Poses Risks for Future Viral Pandemics, we looked at an opinion piece by Professor Wendy Barclay & Tom Peacock on why fur farms - and mink farms in particular - are high risk venues for flu.

A reminder that while we watch obvious hosts like cattle, pigs, and poultry, the H5N1 virus has plenty of other - less obvious - evolutionary pathways it could follow.