Tuesday, June 28, 2022

Preprint: Human infection With a Novel Reassortment Avian Influenza A H3N8 Virus: An Epidemiological Investigation Study

Two H3N8 cases in Henan Province roughly 400 miles apart


Two months ago (Apr 26th), we saw the first confirmed human infection by avian H3N8 reported by Chinese officials in Henan Province (see China: NHC Confirms Human Avian H3N8 Infection In Henan Province). The patient - described as a 4 year-old boy from Zhumadian City - fell ill in early April - and at the time was reported to be in critical condition with respiratory failure.

A month later (May 26th), I wrote about a 2nd case - also in Henan Province - which was eventually  confirmed by Hong Kong's CHP (see Hong Kong CHP Finally Notified Of 2nd H3N8 case).

H3N8 is of particular concern because it remains a plausible cause of a flu pandemic that spread out of Russia in the late 1800s, and because we've seen it jump successfully from birds to other species (equines, canines, and aquatic mammals) in recent decades (see overview in FAO/OIE/WHO Joint Rapid Risk Assessment Human infection with Influenza A(H3N8)).

Last fall, in CCDC Weekly: Epidemiological and Genetic Characteristics of the H3 Subtype Avian Influenza Viruses in China, we looked at a rare, detailed, and highly informative overview of avian H3 viruses detected in wild birds and poultry across China. One which highlighted both H3N2 and H3N8 as growing threats.

More recently, in Adaptation of Two Wild Bird-Origin H3N8 Avian Influenza Viruses to Mammalian Hosts, we looked at a study investigating the transmissibility and pathogenicity of two H3N8 LPAI viruses (GZA1 & XJ47) isolated from wild birds in China.

Both strains were subjected to a serial passage experiment, and both developed much higher virulence, and picked up known mammalian adaptations (PA T97I and D701N in PB2).

So far, the details on these two human H3N8 cases have been relatively sparse.  But today we have a preprint describing the epidemiological investigation into the first case.  Perhaps most notably, the family dog and cat both tested positive for H3N8, and a full-length HA sequencing revealed the HA to be identical to the boy's. 

It isn't possible to ascertain who infected who.  The child could have contracted the virus from an avian exposure, and passed it on to these companion animals.  Or, or one of these animals could have contracted it, and passed it on to the child. 

First the link, abstract, and an abstract from the preprint.  Most will want to read the report in its entirety.  I'll have a bit more after the break.  

Human infection with a novel reassortment avian influenza A H3N8 virus: an epidemiological investigation study

Pengtao Bao, Yang Liu, Xiao-Ai Zhang, Hang Fan, Jie Zhao, Mi Mu, and 16 more
This is a preprint; it has not been peer reviewed by a journal.

This work is licensed under a CC BY 4.0 License


A four-year-old boy developed recurrent fever and severe pneumonia in April, 2022. High-throughput sequencing on his bronchoalveolar lavage fluid revealed a novel reassortant avian influenza A-H3N8 virus (A/Henan/ZMD-22-2/2022(H3N8). Both HA and NA genes of the virus were of avian origin, with the HA gene most closely related to H3N2 and H3N8 viruses detected in ducks in Guangdong Province, and NA gene most closely related to wild bird H3N8 influenza viruses detected in the USA and Japan.

The six internal genes were acquired from Eurasian lineage H9N2 viruses. Molecular substitutions analysis revealed the haemagglutin retained avian-like receptor binding specificity but PB2 genes possessed sequence changes (E627K) associated with increased virulence and transmissibility in mammalian animal models. 

The patient developed respiratory failure, liver, renal, coagulation dysfunction and sepsis. Endotracheal intubation and extracorporeal membrane oxygenation were administered. 

Positive detection of the novel A(H3N8) RNA was obtained from nasopharyngeal swab of a dog, anal swab of a cat, and environmental samples collected in the patient’s house. The full-length HA sequence from the dog and cat was identical to sequence from the patient

No influenza like illness developed and no H3N8-RNA was identified from the family members. Serological test revealed neutralizing antibody induced against ZMD-22-2 virus in the patient and three of his family members.

 Our results suggest a novel triple reassortant H3N8 caused severe human disease. There is some evidence of mammalian adaptation, possible via an intermediary mammalian species, but no evidence of person to person transmission. The potential threat from avian influenzas viruses warrants continuous evaluation and mitigation.




It’s notable that H3N8 virus was also detected from the domesticated cat and dog that were in close contact with the patient. Both dogs and cats are known to be susceptible to human influenza and avian influenza strains. Dogs are particularly susceptible to influenza A viruses, including H3N2, H3N8, H5N1, and H6N1. In Asia, respiratory disease caused by influenza virus H3N2 was documented in dogs, and fatal infection with the highly pathogenic avian influenza virus (HPAIV) H5N1 has also been reported29. 

A number of single cases of H5N1 HPAI infections in cats have also been reported in different parts of the world, mainly associated with recent avian outbreaks30. Here we observed the H3N8 infected dog developed mild clinical signs, moreover, laboratory abnormality of elevated LDH was observed, possibly indicating a systematic infection. The infected dog excreted virus not only via the respiratory tract but also possibly via the digestive tract as evidenced by positive detection of H3N8 specific RNA in the drinking water. Therefore, both the respiratory and gastrointestinal routes of infection may cause horizontal transmission among dog, cat and the human being. 

However, it is not possible to infer the direction of transmission, since both dogs and cats are naturally susceptible to influenza virus strains from other hosts, including birds and mammals. Under current situation, both cat and dog are semidomesticated and may highly likely come in contact with wild birds, ducks in the nearby pond, on the other hand, frequently exposed to human and poultry. Spillover of H3N8 virus into dog and cat further to human, or the otherwise manner can both occur, and it’s impossible to determine mamallian adaptation happened first in dog, cat or human.

 The potential ability of cat and dog to be a “mixing vessel” of diverse origin influenza strains into novel reassortant might be indicated. Unfortunately, the lack of poultry specimens from the household of the patient, and the unsuccessful sampling of the duck in the neighboring pond means we cannot firmly establish the original zoonotic source of infection nor determine the genetic sequence of the original virus.

It will be interesting to see if any similar details emerge on the 2nd case, reported in May. 

In the meantime, we've looked at the potential for dogs and cats to serve as `mixing vessels' for influenza many times in the past, including:
Pathogens: Emergence and Characterization of a Novel Reassortant Canine Influenza Virus Isolated from Cats

J. Clin. Microb: Serological Screening Of Dogs & Cats For Influenza A - Europe

China: Avian-Origin Canine H3N2 Prevalence In Farmed Dogs

Seroprevalence Of Influenza Viruses In Cats - China

Study: Dogs As Potential `Mixing Vessels’ For Influenza

J. Virology: Zoonotic Risk, Pathogenesis, and Transmission of Canine H3N2

Access Microbiology: Inter-Species Transmission of Avian Influenza Virus to Dogs
Perhaps the biggest wake up call came in late 2016 when we saw an avian H7N2 virus sweep through hundreds of cats housed at multiple New York Animal shelters - while also infecting at least two people - demonstrating that that cats can become efficient transmitters of a novel flu virus as well.

While spillover events such as these two H3N8 infections are rare, this is a reminder that nature never stops tinkering, and has as much time as it needs to create the next global health crisis.