Tuesday, March 26, 2024

A Brief History Of Influenza A In Cattle/Ruminants

The host range for all four types (IAV, IBV, ICV, and IDV) of influenza viruses.


The report yesterday that dairy cows in Texas, Kansas, (and likely) New Mexico have been infected with HPAI H5N1 - which followed the previous week's report of infected goat kids in Minnesota - is surprising, but not entirely without precedent.  

As noted previously, in 2008 researchers at Germany's FLI successfully infected four calves with an older clade of HPAI H5N1 (see EID Journal Experimental Infection of Cattle with HPAI H5N1), but reports of natural infection have been rare.

Admittedly, cattle are only rarely tested for HPAI, but a 2013 an H5N1 seroprevalence study in Egypt found that - while some horses, donkeys, and swine in the region showed evidence of past infection - cattle, sheep, goats and buffalo did not (see Sero-prevalence of Avian Influenza in Animals and Human in Egypt)

Although not influenza A - for the past dozen years we've been following research on the newly discovered Influenza D virus - which was first detected in swine, but is now believed to primarily infect cattle (see Viruses: Influenza D in Domestic and Wild Animals).

While we haven't seen any evidence that Influenza D can cause symptomatic illness in humans, in the summer of 2016 - in Serological Evidence Of Influenza D Among Persons With & Without Cattle Exposure - researchers reported finding a high prevalence of antibodies against Influenza D among people with cattle exposure. They wrote:
IDV poses a zoonotic risk to cattle-exposed workers, based on detection of high seroprevalence (94–97%). Whereas it is still unknown whether IDV causes disease in humans, our studies indicate that the virus may be an emerging pathogen among cattle-workers. 

Relatively little has appeared recently in the literature regarding influenza A infection in cattle and/or ruminants, but in 2019 the Journal Viruses carried a detailed review of the literature going back decades.  

While some of these reports are spotty, they cite a number of papers on both influenza and  influenza-like illnesses in cattle and goats. In some cases, viruses were identified, while in other cases they were not. 

This is a lengthy and detailed review, and I've only reproduced some excerpts below, so you'll want to  follow the link to read the report in its entirety.  I'll have a postscript after the break.

Viruses. 2019 Jun; 11(6): 561.
Published online 2019 Jun 17. doi: 10.3390/v11060561
PMCID: PMC6631717
PMID: 31213032

Influenza A in Bovine Species: A Narrative Literature Review

Chithra C. Sreenivasan,1 Milton Thomas,2 Radhey S. Kaushik,1 Dan Wang,1,3 and Feng Li1,3,*


It is quite intriguing that bovines were largely unaffected by influenza A, even though most of the domesticated and wild animals/birds at the human–animal interface succumbed to infection over the past few decades. Influenza A occurs on a very infrequent basis in bovine species and hence bovines were not considered to be susceptible hosts for influenza until the emergence of influenza D. 

This review describes a multifaceted chronological review of literature on influenza in cattle which comprises mainly of the natural infections/outbreaks, experimental studies, and pathological and seroepidemiological aspects of influenza A that have occurred in the past.
The review also sheds light on the bovine models used in vitro and in vivo for influenza-related studies over recent years. Despite a few natural cases in the mid-twentieth century and seroprevalence of human, swine, and avian influenza viruses in bovines, the evolution and host adaptation of influenza A virus (IAV) in this species suffered a serious hindrance until the novel influenza D virus (IDV) emerged recently in cattle across the world.

Supposedly, certain bovine host factors, particularly some serum components and secretory proteins, were reported to have anti-influenza properties, which could be an attributing factor for the resilient nature of bovines to IAV. Further studies are needed to identify the host-specific factors contributing to the differential pathogenetic mechanisms and disease progression of IAV in bovines compared to other susceptible mammalian hosts.

5. Natural Cases of Influenza A in Bovines

First recorded evidence of influenza in cattle occurred in 1949, where 160,000 cattle were infected in the western and middle part of Japan [76]. This incidence of cattle influenza ran for a short course with recovery in 2–3 days and the documented symptoms included high temperature (40–42 °C), blepharitis, nasal discharge, anorexia, tympanites, pneumonia, joint problems, and a decrease in lactation. 

This report also mentioned about some major cattle influenza outbreaks occurred previously in the Fall of 1889 and 1893, and some minor outbreaks in 1914–1916 in Japan [76]. The same study also mentioned an experimental infection of 11 calves, using nasal discharge/defibrinated blood from diseased animals and the successful virus isolation in mice, characterized by few deaths and lung and liver lesions at the 20th serial passage.

The first report on influenza virus isolation from animals was documented by Romvary et al. [88] from Hungary in 1962, which described the isolation of IAV strains similar to human H2 HA glycoprotein from pigs and sheep during 1959–1960. Romvary et al. [46] also isolated porcine IAV strains bearing human H3 HA glycoprotein.
Lopez and Woods reviewed influenza viruses from cattle and the first cattle-origin influenza isolate was reported by Barb et al., 1962, cited in [47]. Furthermore, there were reports on cattle influenza from several countries primarily from the old Union of Soviet Socialist Republics (USSR), and the publications were mostly in the Russian language, with the rare occurrence of English abstract and keywords.

Among these, the earliest report was on the seroepidemiological study of influenza in domestic species of animals in 1969 [25]. During the period 1970–80, cattle isolates of influenza A have been reported from different parts of the world, post/around the time 1968 Hong Kong H3N2 pandemic occurred in humans.

In 1973, the isolation and identification of the A/Hong Kong/1/1968 (H3N2) virus from cattle suffering respiratory diseases were reported in Russia [45]. The earliest cattle influenza A strain studied under experimental conditions was A/calf/Duschambe/55/71 (H3N2) from Russia. This strain was derived from a natural case of respiratory illness in a terminally ailing calf and was isolated in embryonated chicken eggs [45].

Both H1N1 and H3N2 strains were isolated from cattle later. Few of these isolated strains reported include Sw/Shope (H1N1) from Hungary and several H3N2 strains from the USSR. The two viruses isolated from Hungary and the USSR possessed type 2 neuraminidase; however, HA glycoproteins were unidentified [47]. The H3N2 strains were similar to the prototypic human H3N2 strain A/Hong Kong/1/1968 (Schild G, C., World Influenza Center, London).


In 1997, an idiopathic condition manifested in dairy cows in Bristol, southwest England with a sporadic drop in milk production [95]. Brown et al. [96,97] also reported seroconversion against influenza A in cattle from Great Britain, which was markedly associated with reduced milk yield and respiratory disease. However, the virus isolation from these seroconverted animals was unsuccessful. Interestingly, these cattle seroconverted to influenza A virus alone, with no detectable antibodies against BVD, IBR, PI3, and BRSV, suggestive of the etiological role of influenza A in the reduction of milk yield.

Furthermore, in 1999, Gunning et al. [98] also reported that the natural cases of influenza in milking cows increased with an annual incidence rate of 10–20% in some herds of England with a sudden drop in milk yield, mild pyrexia, anorexia, occasional respiratory signs such as nasal discharge and increased respiratory rate. High levels of neutrophils and haptoglobin were present in the blood in most of these cases. Serological screening of paired sera collected from five cattle herds with the same clinical history against IBR, PI3, BRSV, adenovirus, M. bovis, H. somnus, C. psittaci, C. brunetti, P. hemolytica, P. trehalosi, treponemes revealed antibodies against BRSV and PI3 in all herds, while BVD and IBR were detected only in some herds. On the other hand, these cattle sera demonstrated significantly high antibody titer to two human IAVs: 60% for A/England/333/80 (H1N1) and 65% for A/England/427/88 (H3N2) and only 5% of the cows were seronegative against both viruses [98].

These observations clearly indicated the exposure and natural susceptibility of cattle to human influenza A viruses. 
Concurrently, Dr Ian Brown and his colleagues at Veterinary Laboratories Agency near Weybridge, United Kingdom reported the presence of influenza genes in cattle around the late 1990s (https://www.nature.com/news/1998/020107/full/news020107-4.html. accessed January 21, 2019). However, no related peer-reviewed records were available.

In Northern Ireland, a seroepidemiological study conducted on 84 paired acute and convalescent cattle sera collected from 17 outbreaks, against A/England/333/80 (HIN1) and A/England/427/88 (H3N2) during 1998–1999, with clinical manifestations of respiratory disease, diarrhea, and milk drop syndrome demonstrated seroconversion in 56.5 and 58.8% of the convalescent sera against H1N1 and H3N2 respectively. While H3N2 antibody titers were higher compared to H1N1 in general, this study also revealed a higher rate of seropositivity against human H3N2 over porcine H3N2 strains. However, virus isolation in specific pathogen-free chicken embryos was unsuccessful from 142 cattle with similar clinical manifestations [99].

The association of human influenza A viruses with milk drop in cows was prevalent in the early 2000s. In 2008, Crawshaw et al. [100] demonstrated rising antibody titers against same human influenza viruses, A/England/333/80 (H1N1) and A/England/427/88 (H3N2) from a Holstein Friesian herd suffering from acute fall in milk production and tested seronegative against BRSV, BVD, IBR, and PI3 viruses.


11. Summary

Here, we conducted a comprehensive review of the literature available on the past influenza cases/studies occurring globally in ruminant (bovine, caprine, ovine) population, and have summarized the overall influenza A prevalence in bovines. In this review, we have discussed the host range of the four types of influenza, emphasizing the susceptibility/utility of bovine in vivo and in vitro models to influenza A studies over recent years.
Even though natural cases of influenza occurred in bovines causing influenza-like respiratory disease with bronchopneumonia, epizootic cough, nasal discharge, lacrimation, or other extrapulmonary signs such as milk drop, only a few cases culminated in successful virus isolation.
Cattle-origin IAV strains were isolated during the early 1970s, around the time when Hongkong/1968 human IAV strains (H3N2) were prevalent. Although the relatedness of HA glycoprotein of these cattle IAV strains to human H2 and H3 prototypes was reported, sufficient data/characterization studies were lacking to support the extent of genetic relatedness.
Pigs, which were domesticated by humans 1500 years after cattle, are naturally susceptible to all four influenza types and are excellent mixing vessels of influenza. Hence, the refractory nature of bovines against influenza A could be due to species-specific host-associated interference as discussed before. Compared to IAV and IBV (eight segmented genomes), bovines are naturally susceptible to IDV, and lately to ICV (seven segmented genomes) as indicated by the seroprevalence studies and isolation of complete viral genomes, thus contributing significantly to the bovine respiratory disease along with other bacterial/viral pathogens.
The transboundary occurrence of influenza D in bovines, compounded with its extraordinary thermal and pH stability [236] compared to other influenza types, demands further studies to study the pathobiological aspects of this virus and its predisposition in bovine species. The fact that bovines harbor some natural predisposing factors, amenable for the tissue tropism and pathogenesis of ICV and IDV, while detrimental to IAV and IBV, would make them a suitable model to delineate influenza type-specific host–pathogen interactions, and further studies are needed to address this differential disease pathogenesis at the cellular and molecular level.

          (Continue . . . )


Exactly why HPAI H5N1 is suddenly turning up in ruminants after 20 years is unknown. Some of it may be due to testing bias; since cattle have long been assumed to be poor hosts for influenza A, they are less likely to be tested, which only helps perpetuate the belief. 

But we've also seen a dramatic shift in HPAI H5N1's ability to infect mammals around the globe over the past 2 or 3 years.  It does appear to be expanding its host range.  A genomic analysis of the viruses isolated from these ruminants will hopefully yield some valuable clues.

An obvious concern now is, if H5N1 has adapted well enough to spillover into cattle and goats, are swine next?  A year ago, the ECDC/EFSA Avian Influenza Overview December 2022 – March 2023 warned:

The additional reports of transmission events to and potentially between mammals, e.g. mink, sea lion, seals, foxes and other carnivores as well as seroepidemiological evidence of transmission to wild boar and domestic pigs, associated with evolutionary processes including mammalian adaptation are of concern and need to be closely followed up.

While we've seen scattered reports of H5N1 in pigs (see here , here, and here), the virus has yet to gain a foothold (see EID Journal: Low Susceptibility of Pigs against Experimental Infection with HPAI Virus H5N1 Clade

In swine, HPAI would potentially have access to a plethora of other influenza A viruses, which could greatly increase the risk of viral reassortment. 

This is obviously a developing story, with investigations underway in several states.  Right now, we have more questions than answers.

Stay tuned.