Factsheet on A(H5N1)

factsheet

Highly pathogenic avian influenza virus A(H5N1)

Avian influenza viruses can cause infection in birds and humans. By definition, ‘highly pathogenic’ avian influenza viruses cause high mortality in poultry, while ‘low pathogenic’ viruses result in mild disease. The classification of avian influenza viruses as ‘low pathogenic’ or ‘highly pathogenic’  is defined either by the composition of the cleavage site in the haemagglutinin (HA) gene or by the intravenous pathogenicity index in six-week old chickens in accordance with the criteria listed in Council Directive 2005/94/EC and the OIE International Health Standards.

Highly pathogenic avian influenza (HPAI) virus A(H5N1) is highly infectious for a number of bird species, including most species of domestic poultry [1]. Unlike most other avian influenza viruses, this virus has also infected mammals, including cats, pigs and tigers, and is potentially infectious for humans. However, the virus remains poorly adapted to humans, and transmission from birds to humans is infrequent [2]. Since the first detection of zoonotic transmission of HPAI A(H5N1), limited clusters of human cases have been observed but showed no sustained human-to-human transmission. Zoonotic transmission to humans from infected birds occurs either directly or through environmental contamination. Hence, almost all human infections have been related to close contact with infected or sick birds or their faecal products in domestic settings, e.g. in ‘wet markets’ in Asia or in backyard farming [3]. The circulation of HPAI A(H5N1) in bird populations in different regions of the world has contributed to the emergence of different virus clades [4].

Case definition

All novel influenza strains are notifiable diseases in the EU under EU legislation and the International Health Regulations (IHR) through the Early Warning and Response System (EWRS) and IHR, respectively. Human infections with A(H5N1) are notifiable according to EU Decisions 2012/506/EU and 1082/2013/EU.

EU legislation for surveillance and control of highly pathogenic avian influenza viruses in birds and poultry is detailed in2005/94/EC and 2010/367/EU. Official notifications have to be reported by the Terrestrial Animal Health Code of the World Organisation for Animal Health (OIE). 

Case definition: Avian influenza A(H5) OR A(H5N1) in humans

Clinical criteria
Any person with one of the following two:
— Fever AND signs and symptoms of acute respiratory infection
— Death from an unexplained acute respiratory illness

Laboratory criteria
At least one of the following three:
— Isolation of influenza A(H5N1) from a clinical specimen
— Detection of influenza A(H5) nucleic acid in a clinical specimen
— Influenza A(H5) specific antibody response (fourfold or greater rise or single high titre)

Epidemiological criteria
At least one of the following four:
— Human-to-human transmission by having been in close contact (within one metre) to a person reported as probable or confirmed case
— Laboratory exposure: where there is a potential exposure to influenza A(H5N1)
— Close contact (within one metre) with an animal with confirmed A(H5N1) infection other than poultry or wild birds
(e.g. cat or pig)
— Reside in or have visited an area where influenza A(H5N1) is currently suspected or confirmed* AND at least one of the following two:
-- Having been in close contact (within one metre) with sick or dead domestic poultry or wild birds** in the affected area
-- Having been in a home or a farm where sick or dead domestic poultry have been reported in the previous month in the affected area

Case classification
A. Possible case
Any person meeting the clinical and the epidemiological criteria

B. Probable case
Any person with a positive test for influenza A(H5) or A(H5N1) performed by a laboratory which is not a National Reference Laboratory participating in the EU Community Network of Reference Laboratories for human influenza (CNRL)

C. Nationally confirmed case
Any person with a positive test for influenza A(H5) or A(H5N1) performed by a National Reference Laboratory participating in the EU Community Network of Reference Laboratories for human influenza (CNRL)

D. WHO confirmed case
Any person with a laboratory confirmation by a WHO Collaborating Centre for A(H5)

* See World Organisation for Animal Health (OIE) and the European Commission’s Animal Disease Notification System (ADNS), available from: http://www.oie.int/eng/en_index.htm and http://ec.europa.eu/food/animal/diseases/adns/index_en.htm
** This does not include seemingly well birds that have been killed, for example by hunting.

Pathogen

Since 1996, when HPAI A(H5N1) virus was first observed in China, detections in wild birds and poultry have been reported world-wide and recorded in a WHO timeline. The Global Animal Disease Information System (EMPRES-i) of the Food and Agriculture Organization of the United Nations (FAO) also maintains a list of avian influenza outbreaks. Since the first detection, HPAI A(H5N1) has evolved, resulting in multiple genetic lineages (clades) across the world [4]. For example, viruses currently circulating in Egypt have diversified from the strains found in Asia and described in the November 2015 WHO document Antigenic and genetic characteristics of zoonotic influenza viruses and development of candidate vaccine viruses for pandemic preparedness.

Various influenza A(H5) subtypes, such as influenza A(H5N1), A(H5N2), A(H5N3), A(H5N6) and A(H5N8) have been detected in birds in Europe, North America and Asia, according to reports received by OIE. Although these influenza A(H5) viruses might have the potential to cause disease in humans, so far no human cases of infection have been reported by WHO, with the exception of the human infections with influenza A(H5N1) and A(H5N6) viruses.

Epidemiology

Detections of HPAI A(H5N1) in poultry and wild birds have been reported initially in the Far East and later in parts of Europe, the Middle East, Africa and the United States (as listed by WHO).

In 1997, Hong Kong identified the first human infections. In 2003, the first confirmed human cases were notified by WHO, and since then more human cases and fatalities have been reported by WHO (see detailed timeline).

Between 2005 and 2008, Indonesia reported the highest number of cases each year, but since 2009, Egypt has been the country most-affected by A(H5N1) (Table 1). In 2015, Egypt reported the highest number of human cases and became the country with the overall highest number of cases. No human cases have been reported in Europe, where cats and mustelids were the only mammals found to be infected.

Globally, the population groups that are most affected by A(H5N1) are children and housewives due to their frequent direct contact with infected poultry.

Table 1. Distribution of A(H5N1) cases by reporting country and year, February 2003 to 13 November 2015

 

Reporting country

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015*

Total

Azerbaijan

     

8

                 

8

Bangladesh

         

1

   

2

3

1

   

7

Cambodia

   

4

2

1

1

1

1

8

3

26

9

 

56

Canada

                   

1

   

1

China

1

 

8

13

5

4

7

2

1

2

2

2

5

52

Djibouti

     

1

                 

1

Egypt

     

18

25

8

39

29

39

11

4

37

136

346

Indonesia

   

20

55

42

24

21

9

12

9

3

2

2

199

Iraq

     

3

                 

3

Laos

       

2

               

2

Myanmar

       

1

               

1

Nigeria

       

1

               

1

Pakistan

       

3

               

3

Thailand

 

17

5

3

                 

25

Turkey

     

12

                 

12

Vietnam

3

29

61

 

8

6

5

7

 

4

2

2

 

127

Total

4

46

98

115

88

44

73

48

62

32

39

52

143

844

Source: WHO/GIP * 2015 data incomplete

Clinical features

The clinical course of human cases of A(H5N1) is characterised by initial fever and cough, with rapid progression to lower respiratory disease. Upper respiratory tract symptoms of rhinorrhoea and sore throat might not be common in all patients, but the disease can progress to respiratory failure, acute respiratory distress syndrome (ARDS) and multi-organ failure [5].

The overall case–fatality ratio (CFR) is 55%, although this appears to differ from country to country. The CFR has been lower in Egypt, which may be due to a lower virulence of the virus clade and the early detection as well as better treatment of human cases. Indonesia has reported the highest number of fatal cases overall, with a CFR of 84%.

Transmission

The incubation period for A(H5N1) infection has been estimated to be up to seven days, although it is usually 2–5 days after the last known exposure to sick or dead poultry. Longer periods have, however, been suggested [5].

A subset of avian influenza viruses may infect humans; whenever such viruses are circulating in poultry, sporadic infections or small clusters of human cases are possible in people exposed to infected poultry or contaminated environments, especially in households. Human infections remain rare, and influenza A(H5N1) viruses do not appear to transmit easily between people. WHO reports that the risk of community-level spread of these viruses remains low.

Small clusters with the same exposure prior to disease onset have been observed often, yet no sustained human-to-human transmission has been identified. Human cases have reported direct exposure to apparently healthy looking or sick poultry, mostly backyard poultry before onset of disease. The most commonly identified risk factors associated with A(H5N1) virus infection include contact with infected blood/organs or bodily fluids of infected poultry through food preparation practices; touching and caring for infected poultry; exposure to A(H5N1) by swimming or bathing in potentially virus-laden ponds, exposure to A(H5N1) at live bird markets in Asia and via backyard poultry in Egypt [3].

Diagnostics

EU legislation for surveillance and control of highly pathogenic avian influenza viruses is in place in Directive 2005/94/EC and Commission Decision 2010/367/EU. This legislation specifies in detail the detection and diagnosis of H5 viruses in birds.

No EU legislation for human cases in Europe exists. Risk management is managed under the authority of the Member States.

WHO published recommendations and laboratory procedures for the detection of A(H5N1) in 2007.

Case management and treatment

WHO has published guidance on the clinical management of human infection with A(H5N1) as well as rapid advice guidelines on pharmacological management of humans infected with avian influenza A (H5N1) virus, which contains a chapter on ‘chemoprophylaxis of H5N1 infection’.

Four licensed influenza antiviral agents are available in the EU/EEA: amantadine, rimantadine, zanamivir and oseltamivir. However, current circulating seasonal influenza A viruses are resistant (>99%) to the adamantanes (amantadine and rimantadine). Isolates of influenza A(H5) strains are also widely resistant to the adamantanes [6]. Zanamivir and oseltamivir are included in a class of drugs known as influenza neuraminidase inhibitors and are active against both influenza A and B viruses.

The oral inhalation powder zanamivir (‘Relenza’) has been authorised since 1999 through the mutual recognition procedure in all EU/EEA Member States except Cyprus. Zanamivir is an intravenous infusion formulation and has been approved under an early access to medicines scheme (‘compassionate use’) in the EU since 2010 [7].

Oral oseltamivir (‘Tamiflu’) has been centrally authorised by the European Commission since 2002 and is available in all EU Member States. The first generic oseltamivir (‘Ebilfumin’) was approved in 2014 via the centralised EU procedure.

HPAI A(H5N1) viruses have so far been reported to be sensitive to neuraminidase inhibitors, even though a few viruses of the Egyptian clade showed resistance.

Public health control measures

Given the potential zoonotic risk, contingency plans for the control of avian influenza in poultry and birds should be considered. Public health and occupational health authorities need to make sure that persons at risk are sufficiently protected from infection.

In Europe, persons directly exposed to the virus or close contacts of confirmed cases returning from affected regions should be considered for follow-up by the local health service to identify human-to-human transmission events.

Evidence of the effectiveness of contact tracing of airplane passengers in reducing the spread of the infection is limited and should only be considered after conducting a risk assessment on a case-by-case basis as outlined in the ECDC publication Risk assessment guidelines for infectious diseases transmitted on aircraft.

The risk that migratory birds introduce HPAI A(H5N1) to Europe was assessed as low. However, the increase in the number of outbreaks and the higher level of virus circulation in the poultry population in Asian and African countries might increase the likelihood of HPAI A(H5N1) introduction through migratory birds or contaminated goods. Migratory waterfowl in particular are known to be potential vectors for the introduction of A(H5N1) to virus-free areas. The veterinary sector should remain vigilant and continue to rely on established surveillance systems for early disease detection to monitor for new introductions.

The animal health control mechanisms to control outbreaks of HPAI are laid down in Directive 2005/94/EC and Commission Decision 2010/367/EU. Main measures are the culling of birds in the affected holdings and the establishment of control and monitoring areas.

Infection control, personal protection and prevention

Appropriate personal protective equipment, including respiratory protection, should be made available and used during outbreaks. All protective equipment should meet national guidelines and regulations.

People exposed to infected birds should be monitored for ten days in order to document possible related symptoms. Local health authorities may consider ways to actively monitor these groups and administer antiviral prophylaxis dependent on the local risk assessment (i.e. intensity of exposure).

Unvaccinated persons who were exposed to avian influenza viruses as a result of their occupation should be offered vaccination against seasonal influenza in accordance with national guidelines.

On 26 February 2015, WHO published a proposal for Antigenic and genetic characteristics of zoonotic influenza viruses and development of candidate vaccine viruses for pandemic preparedness.

There are three influenza A(H5N1)-containing vaccines which are centrally authorised and produced by vaccine producers in the EU/EEA: a) Adjupanrix, produced by GSK, containing 3.75 μg of the influenza A/Vietnam/1194/2004 (H5N1)-like strain (NIBRG-14) [8]; b) prepandemic influenza vaccine (H5N1), produced by GSK Vaccines and Diagnostics, containing 7.5 μg of the influenza A/Vietnam/1194/2004 (H5N1)-like strain (NIBRG-14) [9]; and c) pandemic influenza vaccine A(H5N1) by Baxter, containing influenza A/Vietnam/1203/2004 (H5N1) [10]. In addition, the Hungarian vaccine producer Omninvest has authorised an influenza A(H5N1)-containing vaccine in Hungary. These vaccines are only intended for pandemic situations and are currently not available for use during avian influenza outbreaks.

The public health impact of A(H5) vaccination programmes in poultry has been limited, because the vaccination fails to prevent shedding and human exposure to the virus. It does, however, decrease the severity of clinical signs and reduces mortality of the vaccinated poultry.

Advice to travellers

The risk for travellers from the EU of becoming infected with A(H5N1) is extremely low, given the fact that poultry transmission mostly occurs in rural areas and that visitors from the EU overwhelmingly stay in tourist areas. In 2014, one travel-associated case was detected in Canada, but no cases of A(H5N1) among EU travellers have been reported. Travellers should be advised to avoid direct contact with poultry or poultry products in affected countries.

References

1. Kelly TR, Hawkins MG, Sandrock CE, Boyce WM. A review of highly pathogenic avian influenza in birds, with an emphasis on Asian H5N1 and recommendations for prevention and control. J Avian Med Surg. 2008 Mar;22(1):1-16.

2. Malik Peiris JS. Avian influenza viruses in humans. Rev Sci Tech. 2009 Apr;28(1):161-73.

3. Van Kerkhove MD, Mumford E, Mounts AW, Bresee J, Ly S, Bridges CB, et al. Highly pathogenic avian influenza (H5N1): pathways of exposure at the animal-human interface, a systematic review. PLoS One. 2011;6(1):e14582.

4. World Health Organization/World Organisation for Animal HF, Agriculture Organization HNEWG. Revised and updated nomenclature for highly pathogenic avian influenza A (H5N1) viruses. Influenza Other Respir Viruses. 2014 May;8(3):384-8.

5. Uyeki TM. Human infection with highly pathogenic avian influenza A (H5N1) virus: review of clinical issues. Clinical Infectious Diseases. 2009 Jul 15;49(2):279-90.

6. Dong G, Peng C, Luo J, Wang C, Han L, Wu B, et al. Adamantane-resistant influenza a viruses in the world (1902-2013): frequency and distribution of M2 gene mutations. PLoS One. 2015;10(3):e0119115.

7. European Medicines Agency. CHMP scientific opinion 2010. London: EMA; 2010.

8. European Medicines Agency. Adjupanrix (previously Pandemic influenza vaccine (H5N1) (split virion, inactivated, adjuvanted) GlaxoSmithKline Biologicals) 2013 [cited 2015 26 August]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001206/human_med_001214.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124.

9. European Medicines Agency. Prepandemic influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) Novartis Vaccines and Diagnostics 2011 [cited 2015 26 August]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002269/human_med_001397.jsp&mid=WC0b01ac058001d124.

10. European Medicines Agency. Pandemic Influenza Vaccine H5N1 Baxter AG 2014 [cited 2015 26 August]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001200/human_med_001215.jsp&mid=WC0b01ac058001d124.​