#18,800
We've a remarkable study out of China this week which reads like a virologist's fever dream; it describes an aggressive, fatal, and NAI resistant novel influenza A infection (with neurological involvement) in a 7-year-old child from Yixing, China (southern Jiangsu province) in August of 2022, which was a recombinant of a swine H3N2 and human H7N9 virus.
This report ticks so many boxes, it is hard to know where to begin.
- First, this case occurred nearly 3 years ago (in the middle of COVID), but we are only just now learning about it. While Chinese studies are usually excellent, the are often only published after considerable delays.
- Second, as we've discussed numerous times, in recent years we've seen an increased level of concern over novel H3Nx viruses expressed by Chinese scientists (see here, here, here, and here).
- Third, this is another example of severe neurological manifestations from a novel flu infection (see last April's Vietnam: Ho Chi Minh DOH Reports A Rare H5N1 Encephalitis Case In a Child). A facet we've increasingly seen in H5 spillovers (see Cell: The Neuropathogenesis of HPAI H5Nx Viruses in Mammalian Species Including Humans).
- Fourth, the elephant in the room is the contribution of (circa 2013) internal H7N9 virus genes to this swine-origin H3N2 virus (dubbed YX805). The last human H7N9 case was reported in China in April of 2019, leaving many questions of how (and when) this reassortment occurred, and where this reassortant virus has been circulating ever since.
- Fifth, this YX805 virus is not only neuropathogenic, it sparked a severe cytokine storm, and it was highly resistant to NAI antivirals (oseltamivir/peramivir). It remained susceptible to Baloxavir, however.
Seemingly, the only pandemic trait this reassortant lacked was the ability to spread efficiently from human-to-human. Once again, we got lucky.
While many will want to read this report in its entirety, I've posted the abstract and discussion below. Follow the link to access the full report.
I'll have a bit more after the break.
Clinical features of a fatal case of acute encephalitis associated with a novel influenza H3N2 recombinant virus possessing human-origin H7N9 internal genes: a descriptive study
Wenlei Wang, Xuhua Mao, Ming Li, Kaituo Liu, Bo Peng, Qin Su, show all Article: 2528536 | Received 01 Apr 2025, Accepted 29 Jun 2025, Published online: 17 Jul 2025
ABSTRACT
Newly emerging or “re-emerging” influenza viruses have been regarded as a huge global threat to human public health. However, there are few reports of human deaths caused by newly emerging influenza viruses derived from pigs and poultry.
Here, we described the clinical and virological features of a fatal encephalitis caused by a novel H3N2 reassortant virus generated from swine H3N2 and human H7N9 viruses. A 7-year-old boy was diagnosed with acute encephalitis in Yixing, China, in August 2022. Chest computed tomography (CT) showed mild pneumonia. Brain CT indicated acute encephalitis companied brain parenchyma swelling. Haematological examinations revealed a markedly elevation of lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, creatine kinase and cytokines.
Pathogenic analysis confirmed that a novel H3N2 virus (A/Yixing/805/2022, YX805) was responsible for this case. Phylogenetic analysis showed that the surface protein-coding genes were originated from swine-origin H3N2 viruses, whereas the internal protein-coding genes were derived from human-origin H7N9 viruses.
This virus triggers stronger cytokines storm than these genetically related H7N9 viruses and has a natural resistance to neuraminidase inhibitors. The YX805 virus is highly pathogenic to mice. Our study highlights the urgent need to enhance epidemiological surveys for reassortment events between swine and avian influenza virus by full genome sequencing.
(SNIP)
Discussion
Here, we reported a critical case of acute AIE caused by a novel H3N2 virus. Phylogenetic analysis indicated that this YX805 virus is a novel reassortant between swine-origin H3N2 virus and human-origin H7N9 virus. Contrary to the low pathogenicity of H1N1 and these genetically related avian H7N9 viruses, the YX805 virus is highly pathogenicity to mice.
Moreover, our results showed the YX805 virus exhibited more pathogenicity in older mice or female mice than in young mice or male mice, suggesting that this virus may have a potentially high risk of mortality for female or older patients. Notably, the YZ805 virus has natural resistance to influenza neuraminidase inhibitors such as oseltamivir and peramivir, but it remains highly sensitive to viral polymerase inhibitors. Therefore, our results highlight the urgent need for continuous monitoring of this emerging virus.
IAE is a severe neurologic disease with high mortality [17,25]. Since the late 1990s, IAE occurred among children has been most frequently reported in Asia and become one of the leading causes of death among children since 2009 [16,25,26]. Similar to the previously reported IAE cases, this patient rapidly progressed to classical neurologic symptoms of acute encephalitis including fever, lethargy, limb weakness, seizures, limb and neck stiffness, and faecal incontinence. Within 36 h after ill onset, this patient further progressed to unconsciousness. Based on our previous successful experience in rescuing H5N6 viral encephalitis [18], a favourable prognosis for acute AIE is highly dependent on timely supportive care.
Unfortunately, the patient’s arrival at the hospital was delayed too long. By the time of admission, his brain had already sustained severe damage, missing the optimal treatment for rescue. In addition, timely antiviral treatment is particularly crucial for this disease. After diagnosis, this patient was promptly treated with an antiviral drug (peramivir), but the disease progression was not reversed, which may be related to the natural resistance of this YX805 virus to neuraminidase inhibitors. Fortunately, BM remains highly effective and can provide complete protection. Therefore, it is very necessary to immediately evaluate the clinical efficacy of all anti-influenza virus drugs against this novel virus.
Although IAE is a severe central neurological complication with a poor prognosis, but the pathogenesis of acute IAE remains to be fully elucidated. Many clinical reports indicated that inflammatory responses that occurred in patients were significantly related with IAE [27,28]. Our findings revealed that all inflammatory cytokines levels in the YX805 virus-infected mice and patient were markedly elevated, implying the critical role of excessive inflammatory responses in this IAE case.
Additionally, previous studies also reported that elevated AST and ALT levels in patients were markedly associated with AIE [18,29,30]. Here, we also observed that the AST and ALT levels in the patient’s serum continued to elevate abnormally from the fifth day of illness onset. Therefore, we couldn’t rule out the role of elevated ALT and AST levels in this AIE case. In addition, although we didn’t collect cerebrospinal fluid from this patient to verify whether this H3N2 can invade CNS, no any neurological symptoms in all the YX805 virus-infected mice were observed, ruling out that the possibility of the YX805 virus directly invading the central nervous system.
Unfortunately, we didn’t know how the novel H3N2 virus spilled over this patient. However, this case occurred in Yixing city around Taihu Lake which is one epicentre of an avian influenza H7N9 virus in 2013. Therefore, it is possible that the infection source may be originated from local wildfowl or domestic poultry carrying H7N9 virus and then spread to pigs. Due to the rapid worsening of the patient’s condition, this patient was discharged. Therefore, we are unable to conduct further epidemiological investigations.
The patient’s family investigations revealed that they ran a small restaurant. Because of summer vacation, the patient stayed at this restaurant with his family and occasionally helped his parents with some miscellaneous work. It can be confirmed that the patient’s family has never previously interacted with live poultry and pigs, but it cannot be ruled out that the patient was directly exposed to contaminated fresh poultry and pork products in kitchen. Additionally, we also cannot rule out the possibility that the patient may have been infected by other potential patients who came to their restaurant. Besides, different from seasonal flu which mainly result in influenza-related respiratory symptoms, this novel H3N2 virus can cause severe influenza-associated encephalitis.
If it acquires the ability to transmit from person to person via airborne, it might become a serious risk to public health. Furthermore, it was worth noting that in most countries, routine clinical diagnosis only monitored the HA or NA subtypes of IAV, whereas rarely determined the internal protein-coding genes, making it easy to overlook the potential biosafety risks of novel reassortant IAVs.
Therefore, it is very urgent to strengthen the epidemiological surveillance of influenza A virus through full genome analysis, especially in areas where wild waterfowl migrate and establish a breeding and management policy that prohibits close contact between poultry and pigs.
Reassortment is the main superpower of influenza A viruses, and while most hybrid viruses end up as evolutionary failures, we've seen several pandemics - and a number of close calls - generated by this ability.
At least three times in my lifetime (1957, 1968 & 2009) a novel pandemic flu virus has emerged following (likely multiple) reassortment events.
- The first (1957) was H2N2, which according to the CDC `. . . was comprised of three different genes from an H2N2 virus that originated from an avian influenza A virus, including the H2 hemagglutinin and the N2 neuraminidase genes.'
- In 1968 an avian H3N2 virus emerged (a reassortment of 2 genes from a low path avian influenza H3 virus, and 6 genes from H2N2) which supplanted H2N2 - killed more than a million people during its first year - and continues to spark yearly epidemics more than 55 years later.
- In 2009, a triple-reassortant swine H1N1 virus emerged, sparking a relatively mild pandemic, that nonetheless heavily impacted younger adults and children.
Our current H5Nx threat is the result of hundreds of reassortments over the years, leaving us with scores of co-circulating HPAI H5 viruses with pandemic potential.
Unfortunately, surveillance and reporting from most of the world is minimal (sometimes nonexistent), and so much of what is happening in the wild occurs outside of our view.
The good news in today's report is that three years later, there are no overt signs that this reassortant H3N2/H7N9 virus continues to circulate widely in China.
The less comforting news is that surveillance, testing, and reporting so woefully inadequate in most of the world that our first clue that a new contender has emerged will likely only come weeks or months after it is a fait accompli.