—from Epidemiological Bulletin , Vol. 25 No. 1, march 2004—

Avian Influenza

Influenza experts agree that another influenza pandemic is unavoidable and perhaps even imminent (Figure 1). (3) An important challenge to control influenza is the magnitude of the animal reservoirs. It is not possible to prepare reagents and vaccines against all the strains of influenza found in animal reservoirs, and consequently, the viral subtypes for their preparation should be prioritized. Preliminary results of surveillance have identified subtypes H2, H5, H6, H7 and H9 of type A influenza as very probable to be transmitted to human beings. The type A influenza currently circulating in humans corresponds to subtypes H1 and H3, which continue to experiment antigenic changes.3

Characteristics of the virus and modes of transmission
There are three known types of RNA genome virus in the Orthomyxoviridae family: A, B, and C. The superficial antigens are of particular interest for immunity and epidemiology. These antigens, which reside in different protein subunits of the viral sheath, are hemagglutinin (H) and the neuraminidase (N). There are 15 known subtypes for the A type hemagglutinin antigens (H1 to H15) and nine subtypes for the neuraminidase antigens (N1 to N9).4

The variations of the principal H and N antigens are the cause for the changes in epidemiology and epizootiology of type A influenza (Kaplan, 1982).

This tendency of influenza viruses to experience frequent and permanent antigenic shifts makes it necessary to constantly monitor the global situation of influenza and to adjust the composition of vaccines against the disease annually. These two activities have been the cornerstone of WHO’s Global Influenza Program since its creation in 1947.

Influenza viruses present a second characteristic of great concern for public health: type A influenza viruses, including the subtypes of different species, can exchange genetic material and fuse. This exchange process, known as antigenic drift, results in a new subtype of the virus that is different from the two reproducing viruses. Since the populations lack immunity against the new subtype and there are no vaccines conferring immunological protection, antigenic drift have historically resulted in highly lethal pandemics. For that to happen, the new subtype should contain human influenza genes making it easily communicable from one person to another during a sufficient period of time.

Various subtypes of the type A virus have been found in birds, which is attributed to the great antigenic combination potential of the virus. Influenza viruses have been isolated from domestic birds (chickens, ducks, turkeys) and from wild birds such as sea swallows (Sterna hirundo), wedge-tailed shearwater (Puffinus pacificus), wild ducks and other species.4 A characteristic feature of these birds is that the influenza virus multiplies both in the respiratory system and in the intestines and, once eliminated through the feces, the agent contaminates the environment. Aquatic birds, especially domestic and wild ducks, have raised special concerns. The virus can be isolated from the cloaca of these birds and lakes where they swim.5

Recent research has demonstrated that after circulating in a bird population for a period of time – sometimes short, viruses with low pathogenicity can mutate to highly pathogenic and virulent viruses. During an epidemic in the United States, in 1983-1984, the H5N2 virus initially caused low mortality, but after 6 months, it became highly pathogenic, causing fatalities in 90 percent of the cases. Control of the outbreak required the destruction of over 17 million birds, with a cost of almost 65 million dollars. During an epidemic in Italy in 1999-2001, the virus H7N1, which was initially not highly pathogenic, mutated to a highly pathogenic strain in an interval of 9 months. More than 13 million birds died or were destroyed. 5


Figure 1: Timeline of human influenza over the past 100 years

The quarantine of infected poultry farms and the destruction of the infected or potentially exposed populations are standard control measures to prevent the dissemination to other farms and the eventual establishment of the virus in the poultry population. Aside from being highly contagious, avian influenza viruses are easily transmitted mechanically from farm to farm, for example through contaminated equipment, vehicles, food, cages or clothes. Highly pathogenic viruses can survive in the environment during long periods, especially at low temperatures. However, strict sanitary measures in farms can confer a certain degree of protection.

It is believed that the enabling environment for the genetic changes involves humans that live in proximity with domestic fowl and pigs. Since pigs are susceptible to infection both by the avian and mammal virus, including the human strains, they can behave as a “melting pot” in which the breeding materials from the human and avian viruses combine, resulting in a new subtype of the virus. However, recent events have identified a second possible mechanism, through direct contact of humans with birds. This subtype mutates rapidly and has a documented tendency to acquire genes from virus that infect other animal specials. Its capacity to cause severe disease in humans has been documented on two occasions. Further, laboratory studies have shown that the isolated viruses are highly pathogenic and may cause severe disease in humans. Birds that survive the infection excrete the virus for at least 10 days, both orally and fecally, which facilitates even further its dissemination in live bird markets and through migratory birds.

Background
Avian influenza viruses normally do not infect species other than birds and pigs. The first case of human infection by an avian influenza virus was documented in Hong Kong in 1997, when the H5N1 strain caused severe respiratory disease in 18 humans, six of which died. The infection of humans coincided with an epidemic of highly pathogenic avian influenza in the poultry population of Hong Kong, produced by the same strain.

There was another alert in February 2003 in Hong Kong, when an outbreak of H5N1 avian influenza caused two cases and a death in a family that had recently traveled to the south of China. Another member of the family, who was a minor in age, died during such visit but the cause of death is unknown. Recently, two additional avian influenza viruses have caused disease in humans. In Hong Kong in 1999, there were two mild cases of H9N2 avian influenza in children and another case in mid-December 2003. The H9N2 subtype is not highly pathogenic in birds. An outbreak of highly pathogenic H9N2 avian influenza, which started in the Netherlands in February 2003, caused the death of a veterinarian and mild disease in 83 additional people two months later.

The most recent cause for alarm occurred in January 2004 in Viet Nam and Thailand, where the presence of avian H5N1 influenza virus was confirmed and 8 countries reported epizootics in birds.

Based on the historical patterns, it is to be expected that influenza pandemics occur 3 to 4 times every century on average, when new subtypes of the virus appear that are easily transmitted from one person to another. However, it is not possible to predict an influenza pandemic. During the 20th century, the pandemics of 1957-1958 and 1968-1969 followed the great 1918-1919 influenza pandemic, which caused 50 million deaths around the world.

Experts agree that another influenza pandemic is unavoidable and possibly imminent. The majority of influenza experts also agree that the immediate sacrifice of the entire poultry population of Hong Kong in 1997 probably prevented a pandemic.

The existing information on the clinical course of the human infection by H5N1 avian influenza virus is limited to case studies of the outbreak of 1997 in Hong Kong. In this outbreak, the patients developed symptoms such as fever, angina, cough and, in several of the fatal cases, severe difficult breathing secondary to viral pneumonia. Those affected were previously healthy adults and children, and some people with chronic medical conditions.

As of 24 February 2004, a total of 32 human cases of type A (H5N1) influenza have been confirmed in laboratory in Viet Nam and Thailand. Of those, 22 (69%) have died. The H5N1 viruses identified in Asia in 2004 are antigenically and genetically different from the 1997 viruses and seem to be associated with fatal infections in domestic fowl and in a variety of wild bird species, which is unusual. The report published in the WHO’s Weekly Epidemiological Record (13 February 2004) provides a preliminary clinical description of five laboratory-confirmed cases in Thailand. Four of those were in boys between 6 and 7 years of age, all previously healthy. Four patients notified deaths in the domestic fowl of their family and two of them reported having touched a sick chicken. One had sick chickens in his neighborhood and reported having played near a cage. The patients were taken to the hospital 2 to 6 days after the onset of fever and cough. Other first symptoms included sore throat, rhinorrhea and myalgia. Dyspnea was reported in all the patients 1 to 5 days after the appearance of symptoms. Radiological changes were present in all the patients, with irregular infiltrates in four and interstitial infiltrates in one of them.1

The diagnostic tests for all strains of animal and human influenza are fast and reliable. Many laboratories of WHO’s global influenza network have safe areas and the appropriate reagents, in addition to considerable experience, to carry out these tests. Fast clinical tests for the diagnosis of influenza also exist, but they are not as precise as the laboratory tests that are currently necessary for achieving a complete understanding of the most recent cases and to determine if the human infection is spreading, either directly from the birds or from one person to another.

Antiviral drugs, some of which can be used both for preventive treatment, are clinically effective against the A strains of the influenza virus in healthy adults and children, but have some limitations. Furthermore, some of these drugs are expensive and in limited supplies. Until the vaccines can be prepared, a world influenza strategy would require the storage of antiviral influenza drugs for use in the case of a pandemic. However, it has been shown that few countries have this stock. Nevertheless, others have begun to collect antiviral drugs.3

There is also considerable experience in producing influenza vaccines, particularly to adjust the composition of the vaccine every year to the variations due to the antigenic drift of the circulating virus. However, at least four months would be required to produce a new vaccine in significant quantities and able to confer protection against a new subtype of virus.

The highly pathogenic avian influenza caused by H5N1 that began in mid-December 2003 in the Republic of Korea and is currently being reported in other countries of Asia is, as a result, of special importance to public health. In 1997, the variants of H5N1 demonstrated an ability to infect humans directly and have done it again in January 2004 in Viet Nam and Thailand. The spread of the infection among the birds increases the timeliness of direct infection to humans. If more people acquire the infection, as time passes the risk also increases that humans, if jointly infected by avian and human influenza strains, could also serve as “melting pots” for the appearance of a new subtype with sufficient human genes to be transmitted easily from one person to another. This would constitute the onset of an influenza pandemic.

There are several measures available to minimize the risks for global public health that could arise as a consequence of major outbreaks of H5N1 avian influenza in birds. An immediate priority is to stop the additional spread of epidemics among the bird populations. This strategy is effective in reducing the opportunities for human exposure to the virus. The vaccination of people at high risk of exposure to infected birds with the existing effective vaccines against the influenza virus strains in circulation can currently reduce the probability of human co-infection by strains of avian and human influenza and thus reduce the risk that genetic exchange occurs. The workers involved in the slaughter of bird flocks should be protected from the infection with adequate clothing and equipment. These workers should also receive antiviral drugs as a prophylactic measure.

While these activities can reduce the possibility of an emergency for a pandemic strain, it is not possible to determine with certainty if another influenza pandemic can be prevented.

WHO emphasizes three strategic goals: to prevent an influenza pandemic, to control the current human outbreaks and prevent the additional spread, in addition to the realization of necessary research for better preparation and response, including the fast development of an H5N1 vaccine for humans. Additional information, including the progress of the epidemic and technical standards is available on WHO’s avian influenza web site: http://www.who.int/csr/disease/avian_influenza/en/

In light of the threat that the next influenza pandemic may include a virus with the capacity to spread between humans, the most urgent needs are:
1) Sufficient supplies of drugs in order to reduce the severity and spread of the infection.
2) A vaccine for the subtype of the strain of the emerging influenza pandemic that has gone through clinical trials and that manufacturers are prepared for “increasing” production. Such a vaccine would not probably coincide antigenically with the emerging strain and would not prevent the infection, but could reduce the severity of the disease until a specific vaccine is made. The production of such vaccines has been pending for 20 years. None is available but specific plans to produce it are currently being formulated.
3) Improve the world capacity for the manufacture of influenza vaccines for the inter-pandemic periods. Without special efforts, the currently inadequate capacity will not be increased rapidly.

The conclusion of this analysis is unavoidable: The world will be in serious difficulties if the imminent influenza pandemic hits this week, this month or even this year. It is time to advance toward the preparation of contingency plans for a pandemic and take action for the production of the recommended vaccines.3

References:
(1) WHO. Weekly epidemiological record, 13 February 2004, 79th year. No. 7, 2004. http://www.who.int/wer
(2) Karl G. Nicholson, John M. Wood, Maria Zambon. Influenza. The Lancet. Vol 363. November 22, 2003
(3) Richard J. Webby and Robert G. Webster. SCIENCE. Vol 302. 28 November 2003
(4) Pedro N. Acha y Boris Szyfres. Zoonosis y enfermedades transmisibles comunes al hombre y a los animales. Tercera edición. Publicación Científica y técnica No. 580 2003 Pág. 329
(5) OMS- Influenza Aviar- Ficha descriptiva- 15 de enero del 204
(6) WHO- confirmed human cases of Avian Influenza A(H5N1).
http://who.int/crs/disease/avian_influenza/country/cases_tables_2004_02_23/en/

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Epidemiological Bulletin , Vol. 25 No. 1, march 2004