No 9 - 2014

Avian influenza in humans

About avian influenza

Avian influenza (bird flu) is an infectious disease in birds caused by influenza A virus. Humans only rarely become infected with avian influenza and the majority of the detected cases of avian influenza in humans have occurred in persons with previous, close contact with birds or poultry.

Influenza A virus belongs to the Orthomyxoviridae family and is divided into subtypes based on haemagglutinin and neuraminidase antigens found on the surface of the virus. Presently, a total of 18 H antigens (H1-H18) and 11 N antigens (N1-N10) have been found that can form various combinations. The majority of the subtypes have been found in birds (H1-H16 and N1-N9).

The seasonal influenza viruses that typically affect humans are of subtypes H1, H2 and H3. Wild birds, aquatic birds in particular, are an influenza A reservoir. Avian influenza is divided according to its pathogenic properties in hens into either low-pathogenic (no or only mild symptoms) or high-pathogenic (severe symptoms and up to 100% mortality).

High-pathogenic avian influenza virus causes a systemic infection and not simply a local respiratory infection as seen in low-pathogenic virus. So far, only the subtypes H5 and H7 have caused high-pathogenic avian influenza in birds. The development of high-pathogenic virus has been observed in connection with the introduction of low-pathogenic H5 or H7 into poultry flocks where the virus has mutated into high-pathogenic virus. The pathogenicity of avian influenza in birds does not correspond to its pathogenicity in humans.

Avian influenza is mainly excreted from the droppings of infected birds and from secretions from the trachea and airways of birds. Other animals can become infected through direct or indirect contact to infected birds or their environment. Avian influenza can also be transmitted to mammals including pigs, cats and dogs, but inter-mammalian transmission is typically ineffective.

In the EU, including Denmark, outbreaks of low-pathogenic avian influenza with H5 and H7 are occasionally seen in poultry flocks. Outbreaks of high-pathogenic avian influenza with H5 or H7 in EU poultry flocks are rarer. Flocks are destroyed both in high-pathogenic and low-pathogenic avian influenza outbreaks, and production areas are cleaned and disinfected.

In Denmark, surveillance includes living as well as dead wild birds. Surveillance results show that the low-pathogenic forms of avian influenza are found naturally among Danish water birds, particularly swimming ducks. The Danish Veterinary and Food Administration is interested in being notified when citizens find dead water birds, birds of prey or magpies (www.fvst.dk)

Humans are rarely infected with avian influenza, and the symptoms and severity of infection depend on the subtype. Symptoms vary from eye infections (H6N1, H7N2, H7N3, H7N7 and H10N7) and mild airway infections (H7N2, H7N3, H7N7, H9N2 and H10N7) to more serious lower airway infections that are associated with a high mortality (H5N1, H7N9 and most recently H10N8). In Denmark, examples of human infection with high- or low-pathogenic avian influenza have never been recorded.

In the following, we describe the current outbreaks of avian influenza which have caused severe disease in humans.

Influenza A (H5N1)

1997 saw the first human cases of avian influenza A (H5N1) infection in connection with an outbreak among poultry in Hong Kong. Influenza A (H5N1) is high-pathogenic in birds. In humans, the mortality following infection with influenza A (H5N1) virus is approx. 60%, and since 2003 a total of nearly 400 deaths have been reported worldwide. Avian influenza A (H5N1) occurs enzootically in birds in Asia and endemically in humans in Asia where Indonesia, Vietnam and China account for the majority of the reported cases. Additionally, (H5N1) occurs endemically in Egypt. There is considerable seasonal variation in the occurrence with more cases being observed in the winter months.

In 2005, influenza A (H5N1) spread from Asia to Europe, presumably in migratory birds, and in 2006 influenza A (H5N1) was detected in several dead wild birds and in the stock of a minor hobby poultry keeper in Denmark. No human cases of influenza A (H5N1) have been reported in any EU country.

The majority of the reported human influenza A (H5N1) cases occurred in persons who had come into close contact with sick birds. A limited number of person-to-person infections have been observed, mainly within families in connection with nursing of severely ill persons. Influenza A (H5N1) outbreaks can be contained by destroying the flocks where sick birds were found and by avoiding contact to sick birds.

In January 2014, a young Canadian man tested positive for A H5N1 after travelling to Beijing. The man had no underlying condition and died as a result of the infection. This was unusual as he had only stayed in urban areas and had not come into contact with poultry or poultry markets. It therefore remains unknown how he became infected, but this is considered a unique case.

Influenza A (H7N9)

In March 2013, the Chinese health authorities informed of the first cases of infections and deaths caused by a new genetic variant of influenza A (H7N9), which had not previously been seen in either animals or humans. As per 24 February 2014, a total of 365 laboratory-verified cases including 116 fatalities had been reported, corresponding to a mortality of approx. 32%.

Nearly all cases were reported from China's Eastern Provinces, but individual cases have also been reported from Taiwan, Hong Kong and Malaysia among persons who had previously travelled to China. The majority of the reported cases had come into direct contact with poultry or markets with live birds and poultry.

Influenza A (H7N9) virus is low-pathogenic in poultry, and the poultry may therefore excrete virus while being symptom-free. Despite massive testing activity at Chinese markets, the virus has only been isolated from a relatively limited number of pigeons, hens, ducks and geese. Some of the genes of this virus are very similar to the genes identified in the H9N2 virus detected in birds and also in pigs in China in recent years.

Brief closure of markets with live poultry in Eastern China in the spring of 2013 probably helped curb the outbreak and only few individual cases were observed in the autumn of 2013. In recent months, a marked increase has once again been observed in the occurrence, and the majority of these cases therefore now belong to this second wave. This increase may have been fuelled by seasonal variation in the Chinese population's intake of poultry and visits to poultry markets around the Chinese New Year on 31 January 2013 and by seasonal variation in influenza transmission.

Contacttracing has been performed among several thousands of contacts to the confirmed cases, and even though individual examples of infection have been observed within families and involving hospital staff members, there are no signs of effective person-to-person transmission, i.e. inter-personal infection is very rare.

Influenza A (H10N8)

Since Mid-December 2013, a total of three cases of a new type of avian influenza of the subtype H10N8 have been reported in the Jiangxi Province of China, including two fatalities. All cases had come into contact with poultry or poultry markets, and at least one of the cases had underlying chronic disease. No secondary cases have been observed. Influenza A (H10N8) is low-pathogenic in birds, which complicatessurveillance as is the case for influenza A (H7N9) virus.

Infection risk and prevention

The risk of spreading of influenza A (H5N1), (H7N9) and (H10N8) to Europa is considered to be small.
Travellers to the affected areas (currently China, Vietnam, Cambodia, Bangladesh, Indonesia and Egypt) should avoid contact to poultry and poultry excretions, e.g. at markets and the like. Frequent hand-washing using hot water and soap or alcohol-based disinfectants is recommended, particularly before and after cooking and after contact to animals. No risk is associated with eating prepared poultry or other types of meat, as the virus is destroyed by heating. The meat should therefore be cooked thoroughly/boiled. This also applies to eggs.

We do not recommend bringing medicines for influenza self-medication as influenza-like symptoms during stays abroad may be caused by a wide range of infections. However, persons who experience symptoms should see a doctor. Currently, no vaccine is marketed against either influenza A (H5N1) or influenza A (H7N9) in Denmark.

Diagnostics

Patients should be tested for influenza if they suffer from severe lower airway infections (pneumonia detected by x-ray and acute respiratory distress syndrome (ARDS) and have stayed in countries where avian influenza is in circulation within ten days from symptom onset. Samples that test positive to influenza A or samples that test negative to influenza A, but for which clinical presentation points towards influenza infection shall be forwarded to the SSI along with information on travel history. The National Influenza Centre at the SSI can rapidly distinguish A (H5N1) from A(H7N9) and seasonal influenza.

Suspicion of avian influenza in humans shall be notified by phone to the Public Health Medical Officers and on Form 1515 to the Public Health Medical Officers and to the Department of Infectious Disease Epidemiology at Statens Serum Institut.

Commentary

The described avian influenza outbreaks are subject to considerable attention at the WHO and with other international authorities. This is so because infection of humans can cause severe disease that carries a high mortality. As the relevant subtypes are new, the population has no community immunity, and this raises the question if these avian influenzas carry a pandemic potential.

For all of the described viruses, no signs have presently been observed to substantiate effective person-to-person transmission, which is a prerequisite to endemic spreading. Both influenza A (H5N1) and (H7N9) are capable of binding effectively to cells in the lower airways in humans, but they are unable to bind effectively to cells in the upper airways. This is in contrast to seasonal influenza which binds to cells in the upper airways, why seasonal influenza can easily cause infection through coughing and sneezing, for instance.

There is concern that the virus might change, acquiring the properties that make inter-personal transmission possible. This could, among others, occur through genetic exchange of the virus genome of a host, human or animal, concurrently infected with several influenza viruses. The major second wave of the influenza A (H7N9) outbreak in China coincides with the season for normal seasonal influenza, and at the same time influenza A (H9N2) is in circulation in poultry. This risk, then, seems to be real.

The new influenza A (H7N9) virus is a low-pathogenic avian influenza virus that does not cause serious symptoms in poultry or wild birds. Therefore, outbreaks are harder to detect and contain than e.g. outbreaks of high-pathogenic avian influenza A (H5N1), which is associated with a very high mortality in poultry and which is therefore almost exclusively seen in humans who have come into close contact with infected poultry. Influenza A (H7N9) has only been detected in relatively few samples from poultry and poultry markets, and not all human cases have had known contact to poultry or poultry markets. This might indicate that the virus transmits more readily from birds and poultry to humans than e.g. avian influenza (H5N1) virus, or that another reservoir exists.

The most recent outbreaks of avian influenza may also be associated with the fact that surveillance is now better than ever before. Additionally, in pursuance of the 2012 implementation of the WHO's International Health Regulations, all countries are obliged to inform the WHO of any new influenza A findings of a new subtype.
(T. G. Krause, Department of Infectious Disease Epidemiology, R. Trebbien, T.K. Fischer, Virology Surveillance and Research, B.B.) Jørgensen, Danish Veterinary and Food Administration)

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26 February 2014