Factsheet on A(H7N9)

factsheet

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. Wild birds serve as a reservoir and the virus has 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 have tested positive for influenza A(H7N9). Direct contact with birds or visiting live bird markets has been associated with infection. The vast majority of human cases are reported from Mainland China, including a few travel-related cases in patients who had visited Mainland China. The clinical picture can range from mild disease to severe disease leading to hospitalisation. A high proportion of patients die. More men 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. Small family clusters have been reported, but there is no convincing evidence of sustained person-to-person transmission.

Case definition

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 novel influenza strains are notifiable diseases in the EU according to commission decisionsCommission 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), and also all H5 and H7 AIV, irrespective of virulence, are reported to animal health authorities as notifiable avian influenza according to EU legislation (Council Directive 2005/94/EC and Commission Decision 2010/367/EU).

The pathogen

The novel influenza A(H7N9) virus is the first low- pathogenic avian influenza virus (LPAI) that has been documented to have caused severe human disease. An avian influenza strain is called 'low-pathogenic' or ‘highly pathogenic’ based on its capacity to cause severe disease and death in birds*. One crucial difference between the already circulating highly pathogenic avian influenza A(H5N1) and the low- pathogenic influenza A(H7N9) strain is that birds infected with A(H7N9) do not show signs of disease, but both viruses are able to transmit to humans causing severe respiratory disease, with a high case fatality rate.

A(H7N9) is 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 [1]. 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. 

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 has been affecting 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 [2]. Experimental data have shown that susceptibility and transmission, as well as shedding of the virus in birds, is dependent on the bird species [3]. Evolution of A(H7N9) viruses in the poultry population since 2013 has resulted in a genetic heterogeneity across different regions in China [4]. 

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. 

This gene constellation makes this strain different from previously isolated avian influenza A(H7N9) viruses, including those reported in birds in Europe. The recently circulating influenza A(H7N9) in China has so far 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

Epidemiology

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 detected in chickens, in particular in the yellow and silkie chicken breeds, ducks, pigeons, a goose and a tree sparrow, but not in pigs. Judging from surveillance results, chickens appear to be the poultry species most affected [5]. Samples from the environment, particularly from live poultry markets but also some backyard farms, kitchen and slaughterhouses, have tested positive for influenza A(H7N9) [6]. While wild birds are the reservoir for H7 and N9 genes of influenza viruses, live bird markets seem to serve 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 is likely to be 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. The first wave in 2013 (week 07/2013 to week 40/2013) included 135 cases, the second wave 319 cases between week 41/2013 and week 40/2014. The third wave started in October 2014 (week 41/2015) and included 226 cases according to the EMPRES-I database. The second wave, in 2014, had significantly larger amplitude, both in terms of number of cases and geographical spead, suggesting that the virus became more widespread in its domestic bird reservoir, providing increased opportunity for individuals to be exposed. A fourth wave with human cases has been ongoing since October 2015.

Clinical features

The incubation period for LPAI might vary between different strains, for A(H7N9) the median incubation period has been estimated to be 6 days (range of 1-10 days) [9]. Fever and cough have been the most common symptoms, with vomiting and diarrhoea appearing in a smaller proportion of cases [10]. Conjunctivitis, a common finding with previous human infections with avian H7 viruses [11], 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 [9]. 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 [12]. Paediatric A(H7N9) patients seem to present with clinically milder disease [13].

Transmission

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 infection with influenza A(H7N9) for humans is likely to be 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. For example, 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 are 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 is no indication of sustained human-to-human transmission [9]. Studies have identified seroconversion in up to 10% of asymptomatic close contacts of symptomatic A(H7N9) cases [18]. Genetic sequence analysis suggests that the virus has not changed in its transmissibility or infectivity for humans since its first identification.

Diagnostics

People in the EU presenting with severe respiratory or influenza-like infection and a history of travel to the affected areas in China with potential exposure to poultry or birds will require careful investigation, management and infection control. Adequate samples for influenza tests should be rapidly taken and processed from patients with relevant exposure history. To assist European laboratories in verifying and ensuring their diagnostic capabilities with regard to 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.

Agreed protocols for clinical investigations have been prepared by the International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC). WHO published technical guidance protocols for the serological analysis and detection of A(H7N9) using real-time RT-PCR assays. Applied PCR methods always need to be checked to see that they match with the most recent sequences of the current circulating viruses.

Case management and treatment

Studies of A(H7N9) viruses isolated from humans suggest that they are 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 [22]. 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 [23].

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 A(H7N9), 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 two neuraminidase inhibitors available in the EU/EEA are:

  • Oral inhalation powder zanamivir (Relenza) authorised through the mutual recognition procedure since 1999 in all EU/EEA Member States except Cyprus. Zanamivir as an intravenous infusion solution formulation is also approved for compassionate use in the EU since 2010 by EMA [24].
  • Oral oseltamivir (Tamiflu) is centrally authorised by the European Commission since 2002 and available in all EU Member States. Further, the first generic oseltamivir (Ebilfumin) was approved in 2014 via the centralised procedure.

WHO recommends antiviral treatment with a neuraminidase inhibitor as soon as possible for patients with suspected or confirmed A(H7N9) infection in the publication Avian influenza A(H7N9) virus: Post-exposure antiviral chemoprophylaxis of close contacts of a patient with confirmed H7N9 virus infection and/or high risk poultry/environmental exposures. The US CDC has also published an Interim Guidance on Influenza Antiviral Chemoprophylaxis of Persons Exposed to Birds with Avian Influenza A Viruses Associated with Severe Human Disease or with the Potential to Cause Severe Human Disease.

Public health control measures

While wild birds are the reservoir for H7 and N9 genes of influenza viruses, live bird markets seem to serve as amplifiers [7]. So far, implemented ‘stamping-out’ control measures in poultry markets and temporary closure of markets were the most effective way 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 [8].

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 EU Council Directive 2005/94/EC. Moreover, vaccination of poultry has been successful in controlling poultry outbreaks of subtype H7 influenza [25].

In Europe, persons directly exposed to the virus or close contacts of a confirmed case returning from China should be followed -up by the local health service to identify possible human-to-human transmission.

Moreover, infectious disease protocols for case investigations are available from the Consortium for the Standardization of Influenza Seroepidemiology (CONSISE) and national authorities.

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 is almost entirely confined to people who have close direct contact with diseased chickens, their carcasses or droppings. This group should maintain vigilance and take precautions.

At present, the most immediate threat to EU citizens is to those living or visiting influenza A(H7N9)- affected areas in China and having direct contact with birds or bird products. In order to decrease their risk of infection, EU citizens travelling to or living in affected areas in China are advised to minimise their exposure to live poultry markets, avoid 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. Especially during the period December to March when a marked increase in human cases is generally recorded in China, travellers should avoid bird contact including visiting live bird markets. Travellers developing severe respiratory or flu-like symptoms within ten days after travel to affected areas and with exposure to poultry or untreated poultry products in China should be rapidly managed and appropriately sampled for influenza testing. Travel-related cases in Europe might be possible, as seen previously in Malaysia and Canada.

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. In May 2013, WHO published its first summary of development and release of candidate vaccine viruses for clinical trials, as well as a provisional recommendation on A(H7N9) vaccine virus in September 2013. Subsequently, nine candidate vaccine viruses have passed relevant safety testing and two-way haemagglutinin inhibition (HI) tests that allow them to be handled under BSL-2 enhanced containment [26].

Advice to travellers

In order to decrease the risk of infection, EU citizens travelling or living in China are advisced to minimise their exposure to live poultry markets, avoid contact with live or dead poultry or their products, and practice good hand hygiene when visiting recreation farms or sites with wild birds, particularly during the cold months December to March when human cases of A(H7N9) are reported. Travellers developing severe respiratory or flu-like symptoms within ten days after travel to affected areas and exposure to poultry or untreated poultry products in China are asked to inform their local general practictioner, be rapidly managed, and appropriately sampled for influenza testing.

WHO has not issued any travel restriction to the affected areas.

References

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