Friday, March 10, 2023

Emerging Microbes & Infections: Triple-reassortant Influenza C virus With Household-associated Infection, China, 2022

3 D Influenza C Virus - Credit NIH


When we discuss human influenza viruses, Influenza A and Influenza B pretty much capture all of the headlines. Less well known are Influenza C viruses and Influenza D viruses, both of which can occur in swine and cattle, but appear to have limited abilities to infect humans. 

The CDC describes theses viruses as:

There are four types of influenza viruses: A, B, C, and D. Influenza A and B viruses cause seasonal epidemics of disease in people (known as flu season) almost every winter in the United States. Influenza A viruses are the only influenza viruses known to cause flu pandemics (i.e., global epidemics of flu disease). A pandemic can occur when a new and different influenza A virus emerges that infects people, has the ability to spread efficiently among people, and against which people have little or no immunity. 

Influenza C virus infections generally cause mild illness and are not thought to cause human epidemics. Influenza D viruses primarily affect cattle and are not known to infect or cause illness in people. 

The rub is, we routinely test for Influenza A & B viruses, but only rarely do so for Influenza C & D.  Which means our understanding of their spread and impact in humans is limited.  

In 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.

Last November, in Zoonoses & Pub. Health: Influenza D Virus Exposure Among US Cattle Workers: A Call for Surveillance, we saw additional concerns over its zoonotic potential raised.  

Our knowledge of Influenza C is somewhat better, but still incomplete.  This excerpt from the Encyclopedia of Virology. 

Influenza C virus (ICV) was first isolated in 1947 from a human patient having mild respiratory symptoms. Since the virus showed no cross-reactivity with antisera against influenza A or B viruses, it was classified as a new genus of the Orthomyxoviridae (influenza C virus). The virus has a worldwide distribution and the majority of humans develop antibodies against ICV early in life. Humans are the main reservoir of ICV, but occasionally the virus may also infect dogs and pigs.

In recent years we have seen some evidence to suggest that influenza C may not be quite as benign as previously advertised. A study published in Clinical Infectious Diseases (2017) found:

Detection of Influenza C Viruses Among Outpatients and Patients Hospitalized for Severe Acute Respiratory Infection, Minnesota, 2013-2016.
Thielen BK1,2, Friedlander H3, Bistodeau S3, Shu B4, Lynch B4, Martin K3, Bye E3, Como-Sabetti K3, Boxrud D3, Strain AK3, Chaves SS4, Steffens A4, Fowlkes AL4, Lindstrom S4, Lynfield R3.
Conclusion: We found seasonal circulation of influenza C with year-to-year variability. Detection was most frequent among young children but occurred in all ages. Some cases that were positive for influenza C, particularly those with comorbid conditions, had severe disease, suggesting a need for further study of the role of influenza C virus in the pathogenesis of respiratory disease.

A Research Letter published in the CDC's EID Journal in 2019, detailed 3 serious Influenza C infections detected in children in Cameroon. I've only posted some excerpts, so follow the link to read it in its entirety.

Volume 25, Number 3—March 2019
Research Letter
Detection of Influenza C Virus Infection among Hospitalized Patients, Cameroon
Richard Njouom , Gwladys Chavely Monamele, Burcu Ermetal, Serge Tchatchouang, Sylvie Moyo-Tetang, John W. McCauley, and Rodney S. Daniels

We report 3 cases of influenza C virus in children hospitalized with severe acute respiratory infection in Cameroon. Two of these case-patients had grave clinical manifestations, but all 3 recovered. The lack of specific antiviral drugs for influenza C virus highlights the need to identify and describe cases involving this virus.
Also in December of 2019 (just before COVID emerged), we looked at a report out of Hong Kong: A Severe Pediatric Case Of Influenza C.

All of which brings us to a new study, published this week in Emerging Microbes and Infections, that describes the detection last summer of a triple reassortant influenza C virus at a kindergarten in Guangzhou, China. 

I've only posted some excerpts, so follow the link to read the report in its entirety.  I'll have a brief postscript when you return. 

Emerging triple-reassortant influenza C virus with household-associated infection during an influenza A(H3N2) outbreak, China, 2022

Lan Cao,Ying Lu,Chaojun Xie,Yiyun Chen,Lijun Liang,Tengfei Zhou, show all
Article: 2175593 | Received 15 Nov 2022, Accepted 26 Jan 2023, Published online: 07 Mar 2023


Recent research have shown that influenza C virus (ICV) has a possible higher clinical impact than previously thought. But knowledge about ICV is limited compared with influenza A and B viruses, due to poor systematic surveillance and inability to propagate. Herein, a case infected with triple reassortant ICV was identified during an influenza A(H3N2) outbreak, which was the first report of ICV infection in mainland China. 

Phylogenetic analysis showed that this ICV was triple reassortant. Serological evidence revealed that the index case might be related to family-clustering infection. Therefore, it is essential to heighten surveillance for the prevalence and variation of ICV in China, during the COVID-19 pandemic.


During the COVID-19 pandemic, the influenza epidemic increased in China and caused the influenza outbreak in 2021–2022 [Citation2]. Since May 2022, influenza A(H3N2) viruses continued to prevail in China. On 14 June, 2022, there was an abnormal increase in influenza-like illness in a kindergarten in Guangzhou, involving 68 children aged from 3 to 4. Oropharyngeal swabs were sampled on the next day. Viral RNAs were extracted by QIAamp Viral RNA Mini Kit (Qiagen, Dusseldorf, Germany). Influenza A, B, and C viruses were detected using qRT-PCR kits (BioGerm, Shanghai, China). Results showed that four samples tested positive for the influenza A(H3N2) virus and one tested positive for the influenza C virus (Cycle of threshold: 33).

The index case infected with ICV was a 4-year-old girl, with no injection of influenza vaccine, who had symptoms, including runny nose, stuffy nose, slight cough, pharyngeal congestion, breathing sound aggravated, and conjunctival congestion, no vomiting and diarrhoea. She got fever for 6 days intermittently, with the highest temperature of 38.7°C on June 14. She was diagnosed with acute upper respiratory tract infection and conjunctivitis in Community Hospital Center. The girl took Paracetamol Pseudoephedrine Hydrochloride and Chlorphenamine Maleate Tablets, Levofloxacin, and oseltamivir during treatment and got well soon.


The long-term surveillance of ICV infections revealed that biennial epidemic waves occurred both in Hong Kong [Citation13] and Japan [Citation7], with the detection rate of 0.22% being associated with outbreaks in the winters in Hong Kong [Citation6]. Research have pointed out that ICV could also cause lower respiratory infections, such as bronchitis and pneumonia, which might have significant clinical impacts in human [Citation14]. However, the prevalence baseline of ICV was still unknown in mainland China. Thus it was necessary to carry out epidemiological surveillance of influenza C during the influenza season.

With the continuous evolution of SARS-Cov-2, the proportion of mild and asymptomatic COVID-19 cases is relatively high, with similar symptoms as influenza C infection, so it is difficult to distinguish clinically. Experts have presented that the superposition effect of influenza and COVID-19 co-epidemic should be alert in this winter of 2022. We suggest that the epidemic impact of influenza C should be monitored during the COVID-19 pandemic in China.

          (Continue . . . )

While influenza C is still viewed as having little in the way of epidemic potential, there remains a lot we don't know about this type of virus.  

Not so very long ago, Influenza B viruses were regarded as `lesser' threats to human health, but today we know they can be every bit as severe as Influenza A infections (see Influenza B: A Virus Not To Be Underestimated).

Twenty years ago, no one would have bet on a coronavirus sparking a pandemic.  Which is why influenza C and influenza D deserve more study.