Factsheet on A(H7N9)
The information contained in this fact sheet is intended for the purpose of general information and should not be used as a substitute for the individual expertise and judgement of healthcare professionals.
Avian influenza A(H7N9) viruses
On 31 March 2013, Chinese authorities reported the identification of a novel zoonotic avian influenza A(H7N9) virus transmitted to humans causing severe disease. The virus had been detected in different bird species, with chickens being the poultry species most affected. Samples from the environment, particularly from live poultry markets but also some backyard farms tested positive for influenza A(H7N9). The low pathogenic A(H7N9) virus mutated into a form highly pathogenic (for chickens) in late 2016 (https://empres-i.review.fao.org/#/, https://www.ecdc.europa.eu/en/publications-data/surveillance-report-avian-influenza-overview-october-2016-august-2017, https://pubmed.ncbi.nlm.nih.gov/30269969/). Direct contact with birds or visiting live bird markets has been associated with human infection. The vast majority of human cases were reported from Mainland China, including a few travel-related cases in patients who had visited Mainland China. The majority of cases were reported between 2013 to 2017 with 28 human cases reported with the highly pathogenic form of the virus. Since the introduction of a large vaccination programme against A(H7N9) in poultry in China, both the number of outbreaks and detections in poultry or environmental settings, as well as the number of human cases dropped significantly (https://pubmed.ncbi.nlm.nih.gov/30414008/, https://pubmed.ncbi.nlm.nih.gov/30903740/). Since 2018, only a very few sporadic human cases have been reported with A(H7N9) infection. The clinical picture can range from mild disease to very severe disease requiring hospitalisation. A high proportion (~1/3) of patients die. More men (~2/3) than women have been affected and the mean age of the cases is 55 years. The outbreak shows a seasonal pattern with a peak during November-March and sporadic cases during the summer, except for 2017, where cases were also reported throughout the summer months until September (https://www.ecdc.europa.eu/en/publications-data/surveillance-report-avian-influenza-overview-november-2017-february-2018, https://www.ecdc.europa.eu/en/publications-data/zoonotic-influenza-annual-epidemiological-report-2017). Small family clusters have been reported, but there is no convincing evidence of sustained person-to-person transmission.
Commission Decision 2008/426/EC lays down case definitions for reporting communicable diseases in the EU: 2008/426/EC: Commission Decision of 28 April 2008 amending Decision 2002/253/EC laying down case definitions for reporting communicable diseases to the Community network under Decision No 2119/98/EC of the European Parliament and of the Council.
All human cases infected with novel influenza strains are notifiable in the EU according to Commission Decisions and the International Health Regulations (IHR), through the Early Warning and Response System and IHR, respectively. ECDC has developed an interim case-finding algorithm and a case definition for disease surveillance and the reporting of patients infected by the avian influenza A(H7N9) virus in EU/EEA Member States.
All infections in poultry caused by avian influenza virus (AIV) of any subtype fulfilling the in vivo criteria for high virulence laid down in the Terrestrial Animal Health Code of the World Organisation for Animal Health (OIE), The detection and control of avian influenza in the EU/EEA is laid down in the Animal Health Law adopted in the Regulation (EU) 2016/429.
The novel influenza A(H7N9) virus is the first low- pathogenic avian influenza virus (LPAI) documented to have caused severe human disease and which evolved in a highly pathogenic form (https://pubmed.ncbi.nlm.nih.gov/30269969/). An avian influenza strain is called 'low-pathogenic' or ‘highly pathogenic’ based on its capacity to cause severe disease and death in chickens and/or carry a multi-basic amino acid cleavage site*.
A combination of active surveillance, screening of virus archives, and evolutionary analyses has shown that the A(H7) viruses probably transferred from domestic duck to chicken populations in China and then reassorted with poultry influenza A(H9N2) to generate the influenza A(H7N9) strain that affected humans. The reservoir for this novel virus remains unknown, although a continuous co-circulation of multiple A(H9N2) genotypes in farmed poultry over a longer time might be responsible for antigenic changes and adaptation to chickens . Experimental data have shown that susceptibility and transmission, as well as shedding of the virus in birds is dependent on the bird species . Evolution of A(H7N9) viruses in the poultry population since 2013 has resulted in a genetic heterogeneity across different regions in China and the emergence of a highly pathogenic form (https://pubmed.ncbi.nlm.nih.gov/30269969/, https://pubmed.ncbi.nlm.nih.gov/29070694/) .
A(H7N9) from 2013 was a reassortant avian influenza A virus in which the six RNA segments encoding the internal proteins are closely related to avian A(H9N2) viruses isolated from poultry in China . The segment encoding haemagglutinin (HA) belongs to the Eurasian A(H7) avian influenza virus lineage, and the segment for neuraminidase (NA) is most similar to avian A(H11N9) and A(H7N9) viruses. However, the nearest matches found for the HA and NA are considerably less closely related than for the six internal-gene RNA segments.
The genetic characteristics of A(H7N9) virus are of concern because of their pandemic potential, e.g. their potential to recognise human and avian influenza virus receptors which affects the ability to cause sustained human-to-human transmission, or the ability to replicate in the human host.
The influenza A(H7N9) in China had not been detected in Europe, neither in wild birds, domestic poultry nor in travellers returning from an affected area.
*According to Council Directive 2005/94/EC: ‘highly pathogenic avian influenza (HPAI)’ means an infection of poultry or other captive birds caused by:
(a) avian influenza viruses of the subtypes H5 or H7 with genome sequences codifying for multiple basic amino acids at the cleavage site of the haemagglutinin molecule similar to that observed for other HPAI viruses, indicating that the haemagglutinin molecule can be cleaved by a host ubiquitous protease; or
(b) avian influenza viruses with an intravenous pathogenicity index in six-week old chickens greater than 1.2
On 31 March 2013, Chinese authorities reported the identification of a novel reassortant influenza A(H7N9) virus. This event also marked the identification of the first fatal human infections caused by a low- pathogenic virus of avian origin. Influenza A(H7N9) has been detected in animal and environmental samples in China. Specifically, the virus has been mostly detected in chickens, and other bird species, but not in pigs. Samples from the environment, particularly from live poultry markets but also some backyard settings, kitchen and slaughterhouses, have tested positive for influenza A(H7N9) . While wild birds are the reservoir for H7 and N9 genes of influenza viruses, live bird markets had served as amplifiers [7,8]. Considering the spread of other avian influenza viruses over national and geographic borders in and outside Asia, it is noteworthy that neighbouring Asian countries have not reported cases of influenza A(H7N9). The major source of infection with influenza A(H7N9) for humans was mostly poultry or birds handled in live bird markets or slaughtered at home.
A time-series analysis of the human A(H7N9) cases can be accessed from: http://gis.ecdc.europa.eu/influenza/H7N9/
The vast majority of cases have been reported from China by the China National Health and Family Planning Commission, a few cases by the Taipei Centers for Disease Control (Taipei CDC) and by the Centre for Health Protection, China, Hong Kong SAR. Travel-related cases have been reported from Malaysia and Canada. The notification of human cases of influenza A(H7N9) in China follow a seasonal pattern peaking in the winter months and a few sporadic cases during the summer with most of the cases between 2013 and 2017.
The incubation period for LPAI might vary between different strains, for A(H7N9) the median incubation period has been estimated to be six days (range of one to ten days) . Fever and cough have been the most common symptoms, with vomiting and diarrhoea appearing in a smaller proportion of cases . Conjunctivitis, a common finding with previous human infections with avian H7 viruses , was not a reported feature of the A(H7N9) infections in China. Pneumonia and respiratory failure were reported in the majority of cases identified in China, resulting in high rates of hospitalisation, admission to intensive care units and fatal cases. High frequency of underlying medical comorbidities were noted . Some mild cases have also been identified through expanded testing of outpatients with influenza-like illness, suggesting that A(H7N9) presents with a wide clinical spectrum . Paediatric A(H7N9) patients seem to present with clinically milder disease .
Information to date suggests that these viruses do not transmit easily from human-to-human and does not support sustained human-to-human transmission.
Outbreaks with LPAI A(H7) viruses have generally been associated with limited transmission. Persons at risk are mainly people with occupational exposure and direct contact/handling diseased chickens or their carcasses, e.g. farmers, veterinarians and workers involved in the culling.
The major source of influenza A(H7N9) infection in humans was poultry or birds handled in live bird markets or slaughtered at home. Direct exposure to infected birds has been identified as a risk factor for transmission (https://pubmed.ncbi.nlm.nih.gov/28703705/). Serological studies in China have found poultry workers seropositive for antibodies against A(H7N9) [14,15]. Transmission from infected birds to humans is a rare event and contacts of A(H7N9) cases need to be monitored to identify case clustering and potential human-to-human transmission. A few small family clusters have been detected, showing high genomic sequence similarities and reported common exposure to risk sources (live bird market or dead poultry) prior to onset of symptoms [13,16,17]. While probable human-to-human transmission of A(H7N9) in clusters of reported cases has been documented in a few instances, there was no indication of sustained human-to-human transmission . Studies have identified seroconversion in up to 10% of asymptomatic close contacts of symptomatic A(H7N9) cases .
To assist European laboratories in verifying and ensuring their diagnostic capabilities regarding avian influenza A(H7N9) virus, ECDC, ERLI-Net and the WHO Regional Office for Europe have released a technical briefing note on diagnostic preparedness in Europe for detection of avian influenza A(H7N9) viruses.
With routine diagnostic laboratory assays e.g. NAT testing or rapid tests, A(H7) viruses might be detected as positive for influenza A virus, and negative for influenza B, A(H1), A(H1)pdm09, A(H3) and A(H5) viruses. Hence, influenza A(H7) viruses are expected to be classified as un-subtypeable influenza A if no specific A(H7) diagnostic test is performed. It is standard procedure in diagnostic laboratories to send influenza A virus isolates or clinical samples that cannot be subtyped to the national reference laboratory (National Influenza Centres; NICs), and further to a WHO Collaborating Centre for characterisation.
Case management and treatment
Studies of A(H7N9) viruses isolated from humans suggested that they were resistant to adamantane antiviral agents but susceptible to neuraminidase inhibitors oseltamivir and zanamivir [19-21]. However, Arg292Lys substitutions in the viral neuraminidase associated with reduced susceptibility to neuraminidase inhibitors have been documented in several cases after the start of oseltamivir treatment . A study describing a family cluster with probable human-to-human transmission, detected one amino acid substitution in the PB2 gene, two new mutations in the NA and six in the PB2 gene, which were not present in isolates from the first wave in 2013. These new isolates showed drug resistance to oseltamivir but were sensitive to peramivir .
Considering the severity of the disease, the fact that limited human-to-human transmission cannot be excluded in some clusters, that no vaccine is available against avian influenza viruses, and the favourable safety profile of the anti-viral drugs of choice, it is likely that the benefits of post-exposure chemoprophylaxis of close contacts with neuraminidase inhibitors outweigh the risks. Evidence of benefits and effectiveness of treatment, remain very limited. Early or presumptive treatment with neuraminidase inhibitors could be considered by the local health authorities for suspected or confirmed cases and post-exposure prophylaxis could be considered for contacts of confirmed cases according to national policies.
The three antiviral therapeutics authorised in the EU/EEA are oseltamivir (Tamiflu), baloxavir marboxil (Xofluza) and zanamivir (Relenza).
Public health control measures
While wild birds are the reservoir for H7 and N9 genes of influenza viruses, live bird markets were amplifiers, and closures of such markets contributed to reducing the number of human cases, but at the same time led to the spread of the infection across regions (https://pubmed.ncbi.nlm.nih.gov/30540847/, https://pubmed.ncbi.nlm.nih.gov/31848585/). So far, implemented ‘stamping-out’ control measures in poultry markets and temporary closure of markets was able to reduce the risk for A(H7N9) infection in humans as these closures were associated with a decrease in the number of human cases of A(H7N9) in those localities . The most effective way to significantly impact the incidence in the source population was the implementation of large vaccination campaigns for poultry in China, which at the same time prevent transmission to humans (https://pubmed.ncbi.nlm.nih.gov/30414008/). Since the vaccination efforts with a vaccine against H5 and H7 viruses, only very few sporadic human cases related to A(H7N9) and A(H5) have been reported (https://pubmed.ncbi.nlm.nih.gov/32065513/).
Early detection of avian influenza viruses, and restriction and control measures, including culling of birds and disinfection of affected holdings, are public health measures aimed at preventing the spread of the disease. Restriction and surveillance zones are further activities laid down in the Animal Health Law. Moreover, vaccination of poultry has been successful in controlling poultry outbreaks of subtype H7 influenza .
In Europe, persons directly exposed to the virus or close contacts of a confirmed case should be followed -up by the local health service to identify possible human-to-human transmission.
The evidence in support of contact tracing after possible exposure on board an aircraft is limited and it should only be considered upon a risk assessment on a case-by-case basis as stated in the risk assessment guidelines for infectious diseases transmitted on aircraft (RAGIDA).
Infection control, personal protection and prevention
The risk of infection with LPAIs and also with HPAIs is almost entirely confined to people who have close direct and unprotected contact with diseased chickens, their carcasses or droppings. This group should maintain vigilance and take precautions.
People should avoid direct contact with live or dead poultry or their products, and practice good hand hygiene when visiting recreation farms or sites with wild birds or their droppings. Small clusters of human-to-human transmission have been observed. Therefore, healthcare workers caring for those suspected or confirmed to have A(H7N9) infection need to apply appropriate infection prevention and control measures (standard precautions). Consistent application in all healthcare settings at all times in accordance with national guidelines is vital, and the health status of healthcare workers needs to be closely monitored. WHO has produced guidance on infection control in healthcare facilities and laboratory biorisk management. These guidelines are broadly applicable to management of all human cases of avian influenza and related samples in the EU.
ECDC and the European Food Safety Authority (EFSA) have performed multiple independent risk assessments in the past regarding avian influenza that also cover pathways for avian influenza A(H7N9). Strict regulatory measures are in place in the European Union to protect commercial poultry and to prevent infected birds entering the food chain.
The most important intervention in preparing for the pandemic potential of influenza A(H7N9) is the development and use of human vaccines. WHO reviews and updates the list of candidate vaccine viruses for pandemic preparedness twice a year during their Vaccine Composition Meetings.
1. Liu D, Shi W, Shi Y, Wang D, Xiao H, Li W, et al. Origin and diversity of novel avian influenza A H7N9 viruses causing human infection: phylogenetic, structural, and coalescent analyses. Lancet. 2013 Jun 1;381(9881):1926-32.
2. Pu J, Wang S, Yin Y, Zhang G, Carter RA, Wang J, et al. Evolution of the H9N2 influenza genotype that facilitated the genesis of the novel H7N9 virus. Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):548-53.
3. Pantin-Jackwood MJ, Miller PJ, Spackman E, Swayne DE, Susta L, Costa-Hurtado M, et al. Role of poultry in the spread of novel H7N9 influenza virus in China. J Virol. 2014 May;88(10):5381-90.
4. Cui L, Liu D, Shi W, Pan J, Qi X, Li X, et al. Dynamic reassortments and genetic heterogeneity of the human-infecting influenza A (H7N9) virus. Nat Commun. 2014;5:3142.
5. FAO. Qualitative risk assessment update. Addressing avian influenza A(H7N9). Rome: 2014.
6. Feng Y, Mao H, Xu C, Jiang J, Chen Y, Yan J, et al. Origin and characteristics of internal genes affect infectivity of the novel avian-origin influenza A (H7N9) virus. PLoS One. 2013;8(11):e81136.
7. Wang C, Wang J, Su W, Gao S, Luo J, Zhang M, et al. Relationship Between Domestic and Wild Birds in Live Poultry Market and a Novel Human H7N9 Virus in China. Journal of Infectious Diseases. 2014 January 1, 2014;209(1):34-7.
8. Yu H, Wu JT, Cowling BJ, Liao Q, Fang VJ, Zhou S, et al. Effect of closure of live poultry markets on poultry-to-person transmission of avian influenza A H7N9 virus: an ecological study. Lancet. 2013 Oct 30.
9. Li Q, Zhou L, Zhou M, Chen Z, Li F, Wu H, et al. Epidemiology of human infections with avian influenza A(H7N9) virus in China. N Engl J Med. 2014 Feb 6;370(6):520-32.
10. Gao H-N, Lu H-Z, Cao B, Du B, Shang H, Gan J-H, et al. Clinical Findings in 111 Cases of Influenza A (H7N9) Virus Infection. N Engl J Med. 2013;368(24):2277-85.
11. Wong SS, Yuen KY. Avian influenza virus infections in humans. Chest. 2006 Jan;129(1):156-68.
12. Xu C, Havers F, Wang L, Chen T, Shi J, Wang D, et al. Monitoring avian influenza A(H7N9) virus through national influenza-like illness surveillance, China. Emerg Infect Dis. 2013 Aug;19(8):1289-92.
13. Yi L, Guan D, Kang M, Wu J, Zeng X, Lu J, et al. Family Clusters of Avian Influenza A H7N9 Virus Infection in Guangdong Province, China. J Clin Microbiol. 2015 Jan;53(1):22-8.
14. Yang S, Chen Y, Cui D, Yao H, Lou J, Huo Z, et al. Avian-origin H7N9 virus infection in H7N9-affected areas of China: a serological study. Journal of Infectious Diseases. 2013 August 9, 2013.
15. Wang X, Fang S, Lu X, Xu C, Cowling BJ, Tang X, et al. Seroprevalence to avian influenza A(H7N9) virus among poultry workers and the general population in southern China: a longitudinal study. Clinical Infectious Diseases. 2014 Sep 15;59(6):e76-83.
16. Ding H, Chen Y, Yu Z, Horby PW, Wang F, Hu J, et al. A family cluster of three confirmed cases infected with avian influenza A (H7N9) virus in Zhejiang Province of China. BMC Infect Dis. 2014 Dec 31;14(1):3846.
17. Mao H, Guo B, Wang F, Sun Y, Lou X, Chen Y, et al. A study of family clustering in two young girls with novel avian influenza A (H7N9) in Dongyang, Zhejiang Province, in 2014. J Clin Virol. 2015 Feb;63:18-24.
18. Mai-Juan M, Guang-Yuan M, Xiao-Xian Y, Shan-Hui C, Gregory CG, Teng Z, et al. Avian Influenza A(H7N9) Virus Antibodies in Close Contacts of Infected Persons, China, 2013–2014. Emerging Infectious Disease journal. 2015;21(4).
19. Gao R, Cao B, Hu Y, Feng Z, Wang D, Hu W, et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med. 2013 May 16;368(20):1888-97.
20. Watanabe T, Kiso M, Fukuyama S, Nakajima N, Imai M, Yamada S, et al. Characterization of H7N9 influenza A viruses isolated from humans. Nature. 2013 Sep 26;501(7468):551-5.
21. Zhou J, Wang D, Gao R, Zhao B, Song J, Qi X, et al. Biological features of novel avian influenza A (H7N9) virus. Nature. 2013 Jul 25;499(7459):500-3.
22. Hu Y, Lu S, Song Z, Wang W, Hao P, Li J, et al. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. The Lancet. //29;381(9885):2273-9.
23. Gao HN, Yao HP, Liang WF, Wu XX, Wu HB, Wu NP, et al. Viral genome and antiviral drug sensitivity analysis of two patients from a family cluster caused by the influenza A(H7N9) virus in Zhejiang, China, 2013. Int J Infect Dis. 2014 Dec;29:254-8.
24. EMA. CHMP scientific opinion 2010. 2010.
25. Capua I, Marangon S. The use of vaccination to combat multiple introductions of Notifiable Avian Influenza viruses of the H5 and H7 subtypes between 2000 and 2006 in Italy. Vaccine. 2007 Jun 28;25(27):4987-95.
26. World Health Organisation. Summary of status of development and availability of avian influenza A(H7N9) candidate vaccine viruses and potency testing reagents. 2014.