Avian Influenza

Prevention and Control of Influenza due to Avian Influenza Virus A (H5N1)

      Introduction

Influenza virus can infect both human beings and animals notably pigs and birds. Three types of influenza viruses viz A, B and C are known. Only influenza A viruses have been reported to cause natural infections of birds. Type A influenza viruses are further divided into subtypes based on the antigenic relationships in surface glycoproteins heamagglutinin (HA) and neuraminidase (NA). At present 15 HA subtypes (H1-H15) and nine neuraminidase subtypes (N1-N9) have been recognized. Each virus has one H and one N antigen, apparently in any combination.  The subtypes of influenza virus demonstrate species specificity and those, which infect animals, do not usually cause infection and disease in human beings.  Fifteen subtypes of influenza virus are known to infect birds; some of these are highly pathogenic.  To date, all outbreaks of the highly pathogenic form have been caused by influenza A viruses of subtypes H5 and H7. This “highly pathogenic avian influenza” is characterized in birds by sudden onset, severe illness, and rapid death, with a mortality that can approach 100%. Infections to human beings from poultry infected with H9 subtype have also been documented.

1.1  Spread of avian influenza

Migratory waterfowl – most notably wild ducks – are the natural reservoir of avian influenza viruses, and these are also the most resistant to infection. These birds excrete virus in their respiratory secretions and faeces. Spread of avian influenza virus is related chiefly to the excretion of high concentrations of virus in the faeces of the infected birds. Domestic poultry, including chickens and turkeys, are particularly susceptible to epidemics of rapidly fatal influenza.

Direct or indirect contact of domestic flocks with wild migratory waterfowl has been implicated as a frequent cause of epidemics. Epidemiological evidence of higher prevalence of infection in poultry on routes followed by migratory waterfowls supports this hypothesis which is further strengthened by the fact that most of the commercial poultry farms are concentrated in some countries on precisely the flyways of migratory waterfowls. The absence of poultry farms or poultry congregations on the flyways of the migratory birds may also explain the non-occurrence of avian influenza in some countries in spite of their geographical location.

Avian influenza outbreaks have been reported from Australia and the USA because of the presence of natural or artificial lakes or ponds near the poultry farms. The lakes always attract migratory waterfowls because of the availability of surface drinking water.

Influenza outbreaks also show a seasonal occurrence in high risk areas, which coincides with the migratory activity. In most documented specific outbreaks evidence has been obtained of probable waterfowl contact at the initial site.

Live bird markets may also played an important role in the spread of epidemics and so does the transport of infected chickens across borders, both legally as well as illegally. Man-driven movement of poultry within the country, mainly for commercial purposes, has the potential to cause secondary spread among poultry.

Avian influenza usually does not make wild birds sick, but can make domesticated birds very sick and kill them. Avian influenza A viruses do not usually infect humans; however, several instances of human infections and outbreaks have been reported since 1997. When such infections occur, public health authorities monitor the situation closely because of concerns about the potential for more widespread infection in the human population if the virus mutates and mixes with human-flu viruses, and suddenly starts spreading as swiftly and devastatingly among people as it has among chickens.

Avian Influenza Infections in Humans

The first documented infection of humans with an avian influenza virus occurred in Hong Kong in 1997, when the H5N1 strain caused severe respiratory disease in 18 humans, of whom 6 died. The infection of humans coincided with an epidemic of highly pathogenic avian influenza, caused by the same strain, in Hong Kong’s poultry population.

Extensive investigation of that outbreak determined that close contact with live infected poultry was the source of human infection. Studies at the genetic level further determined that the virus had jumped directly from birds to humans. Limited transmission to health care workers occurred, but did not cause severe disease.

Rapid destruction – within three days – of Hong Kong’s entire poultry population, estimated at around 1.5 million birds, reduced opportunities for further direct transmission to humans, and may have averted a pandemic.

The Hong Kong episode alarmed public health authorities, as it marked the first time that an avian influenza virus was transmitted directly to humans and caused severe illness with high mortality. Confirmed instances of avian influenza viruses infecting humans since 1997 have been summarized in Table 1. In all these cases close contact with poultry was incriminated.

Table 1. Confirmed cases of avian influenza in human beings 1997-2003

The importance of H5N1 subtype of Influenza virus type A

Of the 15 avian influenza virus subtypes, H5N1 is of particular concern for several reasons. H5N1 mutates rapidly and has a documented propensity to acquire genes from viruses infecting other animal species. Its ability to cause severe disease in humans has now been documented on two occasions. In addition, laboratory studies have demonstrated that isolates from this virus have a high pathogenicity and can cause severe disease in humans. Birds that survive infection excrete virus for at least 10 days, orally and in faeces, thus facilitating further spread at live poultry markets and by migratory birds

      Genesis of Current Outbreak

The most recent cause for alarm occurred in January 2004, when laboratory tests confirmed the presence of H5N1 avian influenza virus in human cases of severe respiratory disease in the northern part of Viet Nam. The epidemic of highly pathogenic avian influenza caused by H5N1, is presumed to have begun in mid-December 2003 in the Republic of Korea and is now being seen in other Asian countries, is therefore of particular public health concern. H5N1 subtype has already demonstrated a capacity to directly infect humans in 1997, and have done so again in Viet Nam and Thailand  in January 2004. The spread of infection in birds increases the opportunities for direct infection of humans. If more humans become infected over time, the likelihood also increases that humans, if concurrently infected with human and avian influenza strains, could serve as the “mixing vessel” for the emergence of a novel subtype with sufficient human genes to be easily transmitted from person to person. Such an event would mark the start of an influenza pandemic.

Till date, WHO has reported 20 laboratory-confirmed cases of H5N1 avian influenza in Vietnam (15) and Thailand (5) of whom 16 (Five in Thailand and 11 in Vietnam) have died. Infection with this virus has been confirmed in poultry in Republic of Korea, Vietnam, Japan, Thailand, Cambodia, China, Laos and Indonesia. Infections in poultry in Delaware state of USA and in Pakistan due to H7 subtype of influenza A virus has also been reported recently.

Human to human transmission?

WHO has investigated a family in Vietnam for possible instance of limited human-to-human transmission of the H5N1 avian influenza strain. Virus genetic materials from two fatal cases in this cluster – sisters aged 23 and 30 years – have now been fully sequenced by the Government Virus Unit of Hong Kong’s Department of Health. Both viruses are of avian origin and contain no human influenza genes.

This finding, which indicates that the virus has not changed to a form easily transmitted from one person to another, is consistent with earlier findings from epidemiological investigations. No illness has been reported in other family members, in the local community, or in health workers involved in care of these patients.

      Epidemiology

Like SARS, epidemiology of avian influenza is complex and not fully understood. Influenza A viruses can infect human beings as well as many different animals, including ducks, chickens, pigs, whales, horses, and seals. Influenza B and C viruses circulate widely only among humans.

Wild birds are the primary natural reservoir for all subtypes of influenza A viruses and are thought to be the source of influenza A viruses in all other animals (not human beings). Most influenza viruses cause asymptomatic or mild infection in birds; however, the range of symptoms in birds varies greatly depending on the strain of virus. Infection with certain avian influenza A viruses (for example, some strains of H5 and H7 viruses) can cause widespread disease and death among some species of wild and especially domestic birds such as chickens and turkeys.

Pigs can be infected with both human and avian influenza viruses in addition to swine influenza viruses. Infected pigs get symptoms similar to humans, such as cough, fever, and runny nose. Because pigs are susceptible to avian, human and swine influenza viruses, they potentially may be infected with influenza viruses from different species (e.g., ducks and humans) at the same time. If this happens, it is possible for the genes of these viruses to mix and create a new virus. For example, if a pig were infected with a human influenza virus and an avian influenza virus at the same time, the viruses could mix (reassort) and produce a new virus that had most of the genes from the human virus, but a hemagglutinin and/or neuraminidase from the avian virus. The resulting new virus would likely be able to infect humans and spread from person to person, but it would have surface proteins (hemagglutinin and/or neuraminidase) not previously seen in influenza viruses that infect humans. This type of major change in the influenza A viruses is known as antigenic shift. Antigenic shift results when a new influenza A subtype to which most people have little or no immune protection infects humans. If this new virus causes illness in people and can be transmitted easily from person to person, an influenza pandemic can occur.

While it is unusual for people to get influenza infections directly from animals, sporadic human infections and outbreaks caused by certain avian influenza A viruses have been reported. The exact epidemiology of avian influenza and precise mechanisms of transmission of these viruses to human-beings need to be fully elucidated.

Once influenza virus is established in domestic poultry, it is a highly contagious disease and wild birds are no longer an essential ingredient for spread. Infected birds excrete virus in high concentration in their faeces and also in nasal and ocular discharges. Once introduced into a flock, the virus is spread from flock to flock by the usual methods involving the movement of infected birds, contaminated equipment, egg flats, feed trucks, and service crews, to mention a few. The disease generally spreads rapidly in a flock by direct contact, but on occasions spread is erratic.

In virulent (or highly pathogenic avian influenza) of the type traditionally associated with fowl plague, the disease appears suddenly in a flock and many birds die either without premonitory signs or with minimal signs of depression, inappetence, ruffled feathers and fever. Other birds show weakness and a staggering gait. Hens may at first lay soft-shelled eggs, but soon stop laying. Sick birds often sit or stand in a semi-comatose state with their heads touching the ground. Combs and wattles are cyanotic and oedematous, and may have petechial or ecchymotic haemorrhages at their tips. Profuse watery diarrhoea is frequently present and birds are excessively thirsty. Respiration may be laboured. Haemorrhages may occur on unfeathered areas of skin. The mortality rate varies from 50 to 100%.

Airborne transmission may occur if birds are in close proximity and with appropriate air movement. Birds are readily infected via instillation of virus into the conjunctival sac, nares, or the trachea. Preliminary field and laboratory evidence indicates that virus can be recovered from the yolk and albumen of eggs laid by hens at the height of the disease. The possibility of vertical transmission is unresolved; however, it is unlikely infected embryos could survive and hatch. Attempts to hatch eggs in disease isolation cabinets from a broiler breeder flock at the height of disease failed to result in any avian influenza -infected chickens. This does not mean that broken contaminated eggs could not be the source of virus to infect chicks after they hatch in the same incubator. The hatching of eggs from a diseased flock would likely be associated with considerable risk.  

      Aetiology

Influenza viruses are members of the family Orthomyxoviridae. These are classified into types A, B or C based on differences between their nucleoprotein and matrix protein antigens. Influenza viruses are further categorised into subtypes according to the antigens of the haemagglutinin (H) and neuraminidase (N) projections on their surfaces. There are 15 haemagglutinin subtypes and 9 neuraminidase subtypes of influenza A viruses. While all subtypes can be found in birds, only 3 subtypes of HA (H1, H2 and H3) and two subtypes of NA (N1 and N2) are known to have circulated widely in humans.

Influenza A, B, and C viruses

Influenza types A or B viruses cause epidemics of disease in human beings almost every winter. Influenza type C infections cause a mild respiratory illness and are not thought to cause epidemics. Influenza type A viruses are divided into subtypes based on two proteins on the surface of the virus. These proteins are called hemagglutinin (H) and neuraminidase (N). The current subtypes of influenza A viruses found in people are A(H1N1) and A(H3N2). Influenza B and C viruses are not divided into subtypes. Influenza A(H1N1), A(H3N2), and influenza B strains are included in each year's influenza vaccine.

      Provisional Case Definitions for Avian Influenza

For clinical management and reporting within a country or territory, case definitions with a hierarchy of case categories will need to be developed according to the epidemiological situation. The case-definition being followed in Vietnam is reproduced below. However, the countries may need to adapt these to match their epidemiological situation. In general, countries with reported highly pathogenic avian influenza  (HPAI) in animal populations need to adopt more sensitive case definitions to initiate laboratory testing than countries without reported outbreaks of avian influenza.

Patient under investigation

Any individual presenting with fever (temperature >38°C)

AND one or more of the following symptoms:

cough;
sore throat;
shortness of breath;

who is under clinical observation and laboratory investigations are under way.

Possible influenza A/H5 case

I.       Any individual presenting with fever (temperature >38°C)
AND one or more of the following symptoms:

cough;
sore throat;
shortness of breath;

AND one or more of the following:

a        laboratory evidence for influenza A by a test that does not sub-type the   virus;

b        having been in contact during the 7 days prior to the onset of symptoms with a confirmed case of Influenza A/H5 while this case was infectious*;

c        having been in contact during the 7 days prior to the onset of symptoms with birds, including chickens, that have died of an illness;

d        having worked in a laboratory during the 7 days prior to the onset of symptoms where there is processing of samples from persons or animals that are suspected of having highly pathogenic avian influenza (HPAI) infection.

OR

II.     Death from an unexplained acute respiratory illness
AND one or more of the following

a.    residing in area where HPAI is suspected or confirmed;

b.     having been in contact during the 7 days prior to the onset of symptoms with a confirmed case of Influenza A/H5 while this case was infectious*.

Probable influenza A/H5 case

Any individual presenting with fever (temperature >38°C)
AND one or more of the following symptoms:

cough;
sore throat;
shortness of breath;

AND limited laboratory evidence for Influenza A/H5 (H5 specific antibodies detected in a single serum specimen).

Confirmed influenza A/H5 case

An individual§ for whom laboratory testing demonstrates one or more of the following

a.    positive viral culture for Influenza A/H5;

b.    positive PCR for Influenza A/H5;

c.     immunofluorescence antibody (IFA) test positive with A/H5 monoclonal antibodies;

d.    4-fold rise in Influenza A/H5 specific antibody titre in paired serum samples.

* Individuals infected with Influenza A/H5 virus are considered to be infectious starting from one day before the onset of symptoms up to 7 days after onset of symptoms.

§ Laboratory investigations for Influenza A/H5 may also be undertaken on deceased individuals and in the context of targeted epidemiological studies.  Laboratory confirmed cases identified under these circumstances should also be reported.