AVIAN AND PANDEMIC INFLUENZA
The world is currently experiencing an outbreak of highly pathogenic avian influenza (HPAI) of unprecedented proportions. Although this has dire consequences for poultry farmers and communities relying on poultry as their main protein source and for those few humans unlucky enough to become infected, it is not (yet) a major human health hazard. However, the H5N1 virus has the potential to develop into a novel human pathogen that might cause the next influenza pandemic.
Influenza viruses have been known for decades to cause human illness in two ways:
Firstly, through seasonal epidemics caused by influenza A and B virus strains circulating in the population, that undergo relatively minor antigenic changes ("antigenic drift") enabling them to infect those who have partial immunity due to previous infection with (or immunisation against) influenza viruses.
Secondly, and more dramatically through influenza pandemics. These are caused by "new" virus strains that emerge through "antigenic shift", i.e. major antigenic changes. These strains encounter no population immunity at all, and if they are highly pathogenic and virulent for humans as well as efficiently transmitted from human to human, a devastating worldwide outbreak can occur like in 1918. Such viruses originate from animals, with wild aquatic birds harbouring the greatest variety of influenza virus strains. Avian influenza or "bird flu" is an animal disease that in its malignant form can bring devastation to the poultry industry. Its public health importance stems from the fact that such a virus may evolve to become the ancestor of a pandemic virus strain. The current situation is cause for alarm: We are witnessing an unprecedented outbreak of a very pathogenic avian influenza virus across continents, which increases the chance for changes occurring in the causative H5N1 virus which will confer on it the properties necessary to cause the next pandemic. So far, however, the world remains in the pandemic alert period, more accurately in phase 3 thereof: Human infections with a new influenza virus subtype are occurring, but there is no human-to-human spread, or at most rare instances of spread to close contacts.
Influenza - not to be confused with the "common cold" - is an illness caused by influenza viruses, members of the family Orthomyxoviridae. Three influenza viruses are currently circulating in humans: two members of the genus influenza virus A, namely subtype A(H3N2) and subtype A(H1N1), as well as an influenza B virus.
Figure 1 illustrates some important features of influenza A viruses: The negative-sense, single-stranded RNA genome which is divided into eight segments; and the envelope surrounding the virus particle with two types of "spikes" consisting of functionally and immunologically important surface proteins: the haemagglutinin which attaches to the host cell, and the neuraminidase which plays a role in the release of newly formed virus particles.
Human influenza viruses mainly infect the cells lining the upper respiratory tract, causing an acute illness characterised by sudden onset of high fever, myalgia, headache and severe malaise, non-productive cough, sore throat, and rhinitis. Whilst most individuals recover within one to two weeks without specific treatment, elderly people and those with chronic illnesses may develop severe, sometimes life-threatening disease.
In order to understand the challenges posed by the spreading epizootic of avian influenza and its implications for human health, it is vital to distinguish between three different, yet closely connected entities: human seasonal influenza, human pandemic influenza and avian influenza.
Seasonal influenza (in humans) occurs during the winter in temperate climatic zones (i.e. between May and August in the Southern hemisphere and between November and February in the Northern hemisphere) and are caused by the "human" influenza A and B viruses. Seasonal influenza outbreaks vary greatly in intensity and affect between 2 and 30% of the population, resulting in a variable degree of morbidity and mortality. It is estimated that every year, around 10,000 South Africans succumb to seasonal influenza.
Seasonal influenza is caused by a mechanism called "antigenic drift": Being easily transmitted from human to human and spreading through large parts of the population, the viruses are faced with a considerable degree of pre-existing population immunity due to previous infections (or immunisations). This favours the selection of mutant viruses that are less well neutralised by the immune system, leading to gradual changes in the genetic make-up of circulating virus strains over time.
To ensure the closest possible match between the influenza vaccine and the circulating influenza viruses, the World Health Organisation WHO since 1948 organises the Global Influenza Surveillance Network. Based on numerous influenza patient virus isolates that are genetically and antigenically analysed to monitor these permanent antigenic changes, WHO every year issues recommendations for the composition of influenza virus vaccines.
Vaccines to be used in the 2006 season (southern hemisphere winter) for instance should contain the following components:
· an A/New Caledonia/20/99(H1N1)-like virus;
· an A/California/7/2004(H3N2)-like virus;
· a B/Malaysia/2506/2004-like virus.
Indications for Routine
Flu Vaccine: (best =April, ok’ til August) Adults and children with
medical conditions at high risk of complications: Chronic renal
diseases, disorders, and Diabetes mellitus and similar metabolic diseases
Chronic pulmonary and cardiac disease and Immunosuppression (incl. HIV CD4
> 200 Residents
of old-age homes, chronic care/ rehabilitation institutions; Children
on long-term aspirin therapy; Medical
and nursing staff caring for high-risk cases; Adults
and children who are family contacts of high-risk cases; All
persons over the age of 65 years; Pregnant women
in 2nd or 3rd trimester in the flu season or with
medical conditions above at any stage of pregnancy; Any
persons wishing to protect themselves from the risk of
contracting influenza, especially in industrial settings, where
large-scale absenteeism could cause significant economic loss People involved in avian influenza surveillance or
research, (and in stage 4 in the handling or culling infected
birds) to prevent possible re-assortment and reduce the number of
flu-like illnesses, unnecessary investigation and diagnostic confusion in
Indications for Routine Flu Vaccine: (best =April, ok’ til August)
Adults and children with medical conditions at high risk of complications: Chronic renal diseases, disorders, and Diabetes mellitus and similar metabolic diseases Chronic pulmonary and cardiac disease and Immunosuppression (incl. HIV CD4 > 200
Residents of old-age homes, chronic care/ rehabilitation institutions;
Children on long-term aspirin therapy;
Medical and nursing staff caring for high-risk cases;
Adults and children who are family contacts of high-risk cases;
All persons over the age of 65 years;
Pregnant women in 2nd or 3rd trimester in the flu season or with medical conditions above at any stage of pregnancy;
Any persons wishing to protect themselves from the risk of contracting influenza, especially in industrial settings, where large-scale absenteeism could cause significant economic loss
People involved in avian influenza surveillance or research, (and in stage 4 in the handling or culling infected birds) to prevent possible re-assortment and reduce the number of flu-like illnesses, unnecessary investigation and diagnostic confusion in such individuals.
Pandemic influenza is caused by a new influenza virus subtype entering the human population. A pandemic occurs when influenza A viruses that did not previously circulate amongst human beings are transmitted across the species barrier. Because the new virus does not encounter any degree of population immunity and can therefore spread unhindered. Pandemic have been documented 31 times since being first accurately described in 1580, the last three in the 20th century: the ‘Spanish’ flu in 1918, the ‘Asian’ flu in 1957 and the ‘Hong Kong’ flu in 1969. Millions of people died during these pandemics.
Such new human viruses are the result of “antigenic shift or “reassortment" of two different influenza A viruses infecting the same individual (and cell); and during viral replication, some of their gene segments may be swapped, resulting in a progeny virus that combines some genes from its "animal" with some from its "human" predecessor, as illustrated in Figure 2. If such a novel strain acquires an "animal" haemagglutinin and/or neuraminidase on its surface, it will not be faced with any pre-existing immunity in the human population; and if it also has a high pathogenicity and virulence for humans plus is easily transmitted from human to human, it will cause a pandemic. In the present situation, a pandemic might be caused by an influenza virus with a haemagglutinin other than H1 or H3 and/or a neuraminidase other than N1 or N2; in practice, it is likely that it will be an H5 or an H7 virus as these contain strains with highly pathogenic characteristics.
Pigs used to be thought of as the crucial "mixing vessel" for "human" and "animal" influenza viruses, being susceptible for both due to their biochemical characteristics. However, human beings themselves might also act as "mixing vessels", which is why seasonal influenza immunisation is recommended for all those exposed to the current epizootic H5N1 strain, e.g. when culling and handling infected birds: To protect them not against H5N1 infection, but from dual infection with H5N1 plus a human influenza A virus which might then lead to reassortment.
Avian influenza Avian flu is diagnosed in birds, causing illness primarily in birds and potentially leading to severe losses in the poultry industry, its direct human health implications are comparatively minor. However, it may serve as the origin of a new "human" influenza virus subtype which might then be rapidly transmitted between people and cause a human influenza pandemic.
(AI), or “bird flu”, is caused by various influenza A virus strains. While all 15 haemagglutinin and all nine neuraminidase subtypes have been found in wild water birds, these appear to be the natural reservoir of these viruses and typically do not develop overt disease. However, some of these viruses can cause disease in other bird species, particularly domestic poultry. Normally, avian influenza viruses do not affect non-avian species, and "bird flu" is a concern mainly for poultry farmers and communities relying on poultry as their main protein source.
In domestic poultry, infection with AI viruses may cause two forms of disease: So-called low pathogenic avian influenza (LPAI) viruses cause only mild disease which easily goes undetected. In contrast, highly pathogenic avian influenza (HPAI) viruses cause severe disease affecting not only the respiratory tract but invading multiple organs and tissues, with a mortality rate of up to 100 % within two days. HPAI, or "fowl plague", was first identified in Italy in 1878. All HPAI viruses belong to the H5 and H7 haemagglutinin subtypes; on the other hand, not all viruses with those subtypes are highly pathogenic but, due to the potentially devastating consequences of HPAI for the poultry industry, their occurrence still has to be notified to the Office International des Epizooties (OIE, World Organisation for Animal Health) which can impose trade restrictions and other measures.
Currently, a huge HPAI epizootic caused by an influenza A(H5N1) virus is spreading across much of the globe. The present virus is related to the "bird flu" virus first isolated during an outbreak in Hong Kong in 1997, which at the time was controlled through culling of all the poultry in Hong Kong! However, beginning in 2003, an H5N1 epizootic has emerged in the Far East and from there spread to numerous countries in Asia, Europe and recently also Africa.
It kills affected flocks within days and spreads rapidly; both the direct effects and the measures to control it (trade restrictions, culling etc.) have brought hardship to poultry farmers in the affected countries. Despite all efforts the H5N1 virus must now be regarded as firmly established in several countries, including Thailand, Vietnam, Indonesia, and China.
The HN1 virus has on comparatively rare occasions crossed the species barrier to infect cats and other carnivores that fed on infected bird carcasses, but it can also infect humans (like other avian influenza viruses, too: see Figure 3). As of 21 March 2006, a total of 185 human H5N1 infections with 104 deaths have been notified to WHO from eight countries: Thailand, Vietnam, Cambodia, China, Indonesia, Turkey, Iraq, Azerbaijan; and Egypt. This is, given the massive outbreaks in domestic poultry in so many countries, is not a large number. So far the overwhelming majority of these human cases seem to have stemmed from direct, close contact with diseased domestic birds.
Whilst the high death rate (> 50 %) amongst affected human beings is clearly cause for concern, the low transmissibility of this virus to humans and the absence of easy human-to-human transmission mean it is not a major public health threat at present. However, avian H5N1 is a strain with pandemic potential (see below), since it might ultimately adapt into a strain that is highly contagious between human beings. Once this adaptation occurs, it will no longer be a bird virus but a human influenza virus that may potentially cause an influenza pandemic.
It is very important to understand the fundamental differences between human seasonal influenza, avian influenza and human pandemic influenza. Even as far as seasonal influenza goes, the situation is far from being "under control": Despite effective vaccines being available and relatively affordable, it is estimated that approximately 10,000 South Africans die from influenza-related illness every year. Avian influenza is obviously a natural phenomenon, clearly aggravated by man-made factors such as intensive poultry production to satisfy increasing demand, feeding and rearing practices, "wet markets" where live birds are sold, the international movement of poultry and poultry products often intensified when there is talk of culling in an area Avian flu is a huge problem for those whose livelihoods depend on poultry, and for those few humans unlucky enough to become infected through close contact with diseased birds. However, it has not yet developed into a public health catastrophe - which it may, however, become once the virus acquires the properties that will allow it to be efficiently transmitted between human beings whilst at the same time retaining its high pathogenicity. If such a situation arises (whether due to the currently circulating H5N1 or another animal influenza virus), the world will be faced with an influenza pandemic which will undoubtedly have major consequences: All countries will be affected, widespread illness will occur, medical supplies will be inadequate, large numbers of deaths will occur, and economic and social disruption will be great. Neither the timing nor the severity of this pandemic can be predicted with any certainty, but most experts agree that it will happen at some stage, and that the world is closer to it than at any time since the last one in 1968.
It is therefore an urgent necessity for all countries to prepare for such a pandemic. Key issues for pandemic preparedness are early warning systems, health facility preparedness, stockpiling of essential items (not only antiviral drugs but also face masks etc.), intersectoral coordination and communication. South Africa is developing a detailed response plan very much in line with the WHO generic plans which can be found at http://www.who.int/csr/disease/influenza/pandemic/en/index.html.
The South African national plan should in future be available on the Department of Health website: www.doh.gov.za.
For the time being the world remains at Phase 3 of the WHO alert scale:
Phase 1: No new influenza virus subtypes found in humans
Phase 2: Circulating animal influenza virus subtype poses a substantial risk of human disease
Pandemic alert period
Phase 3: Human infection(s) with a influenza virus new subtype, but no human-to-human spread, or at most rare instances of spread to close contacts
Phase 4: Small cluster(s) of cases with limited human-to-human transmission but spread highly localized (i.e. virus not well adapted to humans)
Phase 5: Larger cluster(s) of cases but human-to-human spread still localized (i.e. virus becoming increasingly better adapted to humans)
Phase 6: Influenza pandemic: increased and sustained transmission of novel human influenza virus in the general population
Figure 3: (Source: WHO)
Prof W Preiser
Department of Medical Virology, University of Stellenbosch
1. Influenza Report 2006. This is a medical textbook that provides a comprehensive overview of epidemic and pandemic influenza. Access to the online version is free at: http://www.influenzareport.com/
2. Science and Development Network (SciDev.Net): http://www.scidev.net/ms/bird_flu
3. World Health Organization (WHO), Epidemic and Pandemic Alert and Response (EPR):
4. Influenza: http://www.who.int/csr/disease/influenza/en/index.html
5. Avian influenza: http://www.who.int/csr/disease/avian_influenza/en/index.html
© StellMed Updates,Faculty of Health Sciences,Stellenbosch University. All Articles are Peer Reviewed.