Sezione Medicina

from Leadership Medica n.8/2005


Walter PasiniThe presence of the bird flu virus in Europe is giving rise to some alarm in public opinion. It is the most extensive and severe bird flu we can recall. In the history of this disease, never in the past were so many countries struck at the same time, involving such a high animal mortality rate. The causal agent, the H5N1 virus, has proved to be particularly tenacious. Despite the destruction of 150 million birds, the virus is now considered endemic in many parts of Indonesia, Vietnam, parts of Cambodia, China, Thailand and Laos. From the close of 2003 to the spring of 2004 the disease has also been reported in Korea and Japan. The bird flu epidemic is a risk for human beings due to the fact that in a few cases this virus has proved that it can also infect man very aggressively with a high mortality rate, besides the virus could undergo changes and easily spread from person to person. The WHO has feared the risk of an influenza pandemic for at least ten years on the basis of data that influenza viruses periodically change all their antigenic features subsequently finding the human population partly or totally unprepared from an immune perspective. This possibility occurred thrice in the past century: in 1918-19 during the socalled “Spanish flu”, which counted 40-50 million dead, in 1957-58 and in 1968-69. The risk of the emergence of a virus pandemic depends on the possibility of human exposure and infections. This risk persists as long as the virus circulates in animals. The fight against the disease in poultry and other birds is hence the main measure to reduce the possibility of human infection and the outbreak of a viral pandemic. Interhuman transmission – which would start the pandemic – could occur through genetic reorganisation in case of a co-infection with a seasonal virus and the H5N1 virus. This could occur both in man and in pigs or through the H5N1 virus’ gradual adjustment to bind human cells in the respiratory system. The WHO’s strategic plan envisages
the following goals. The current pre-pandemic phase’s main goals are:
1 - reduce the opportunities of human infection, and
2 - strengthen the surveillance system to provide an early alert. During the next emergency phase of a viral pandemic the priority lies in restraining or delaying the spreading of the virus. During the declared pandemic phase efforts will focus on reducing morbidity, mortality and the subsequent social disruption.
Concerning Italy, our country has concretely taken steps to rapidly detect the infection’s hotbeds in birds and to book the purchase of 36 million vaccines and adequate supplies of antiviral drugs.
The world is facing the risk of an influenza pandemic. In a context of economic globalisation the health risks of a country or of an international region are quickly shared by other countries and continents. Concerning bird flu, the risk of the disease spreading among birds and hence the risk of a pandemic is created by another category of travellers: migratory birds. Faced with a global threat, all countries’ governments realise the importance of technical and scientific collaboration, health policies and collaboration with the pharmaceutical industry.

Bird Flu
Bird flu is a contagious animal disease, which is caused by viruses that normally infect only birds and less commonly pigs. Bird flu viruses are highly species-specific, but on rare occasions they cross species barriers and infect human beings. In domestic poultry the viral infection causes forms of disease that vary depending on the degree of virulence. The low pathogenic forms only cause mild symptoms and can even pass undetected. The highly pathogenic form is instead extremely serious. It spreads very quickly through poultry causing a disease, which involves many internal organs and whose mortality rate can reach 100% of the poultry in just 48 hours. The influenza A virus has 16 subtypes H and 9 subtypes N. We know that the virus’ subtypes H5 and H7 can cause highly pathogenic forms of the disease. However neither all H5 and H7 subtype viruses are highly pathogenic nor do all cause a severe disease in poultry. To judge by what we know the H5 ad H7 viruses are introduced in poultry in their low pathogenic form to then be transformed through mutations into their highly pathogenic form. This is why the presence of H5 or H7 viruses are a reason for concern even when the initial signs of infection are those typical of the low pathogenic form. The H5N1 infection in poultry is rapidly spreading in Europe too through migratory birds. Wild water fauna is considered the natural reserve of the influenza A virus. Probably they have spread flu viruses for centuries without causing any alarm for international public health till now. We know that they carry the H5 and H7 virus types’ low pathogenic form. Now instead it seems clear that certain types of migratory birds also carry these viruses’ highly pathogenic form. The current epidemic of highly pathogenic flu, which started in South East Asia in mid 2003, is the most extensive and severe one we recall. Never in the past were so many countries involved at the same time nor were so many infected birds counted. From mid December 2003 to early February 2004, the poultry epidemic caused by the H5N1 virus has been reported in Vietnam, Thailand, Cambodia, Laos, China, Indonesia, Korea and Japan. In August 2004 even Malaysia reported cases of infection. Russia reported the first poultry epidemics late in July 2005, followed by Mongolia and Kazakhstan. In October 2005, the H5N1 virus’ presence was confirmed in poultry also in Turkey and Romania. In countries like Vietnam, Cambodia, Indonesia, China and Thailand the epidemic is acquiring such endemic features as to make us think that the virus will circulate in those countries for still many years.

Implications for Human Health
Such an extensive spreading of the virus and its persistence in bird populations gives rise to certain risks for human health. The first, which causes a serious disease, is the transition of the virus directly from poultry to man. In rare cases when there was a species leap and hence the direct transition from poultry to man, the H5N1 virus caused serious forms of disease involving the death of over sixty people on a total of about 150 cases. Unlike the normal seasonal miflu, when the infection only causes moderate respiratory symptoms in most people, the disease caused by the H5N1 virus has a serious clinical progress and a high mortality rate due to primary viral pneumonia and the involvement of many systems. Most cases so far have involved children and adults who are in good health. It is currently believed that the route of infection for human beings is direct contact with infected poultry or surfaces or objects that are contaminated by animal faeces. Currently most cases have occurred in rural or periurban areas where there are farmyard animals and the poultry moves freely even entering houses and sharing the same spaces where children play. Since birds expel large quantities of virus in their faeces, the possibilities of contact with poultry faeces or with the environment that is contaminated by the virus are many. Besides since most family budgets depend on poultry, they sell or destroy them, thus eating infected birds. Even the destruction of poultry flocks or their slaughtering are considered as high risk operations for the contagion of man. A second risk, which is far more important, is that the virus can change into a highly contagious form for human beings and that it can spread from person to person. This situation can mark the start of an international epidemic, an influenza pandemic.

The Risk of a Pandemic
A pandemic can start when there emerges a new subtype of virus, when it infects human beings causing a serious disease and when it spreads easily and in a lasting manner among human beings. The H5N1 virus is a new virus for human beings, which has never circulated before among the population. It has infected over one hundred people with a very high mortality rate. Nobody would certainly be immune if the H5N1 virus emerged in the international population. The prerequisite, which is lacking to start a human pandemic, is the established, efficient and lasting interhuman transmission of the virus. The risk that this situation may occur depends on the opportunities given to the virus to change. The lasting circulation of the virus in the population and the extension of the same to such a large number of countries are favourable conditions in this sense. The virus can improve its transmissibility through a genetic reorganisation process during which genetic material is exchanged between human viruses and bird viruses during an infection either in a human being or in a pig. In this case the pandemic seems to have had an explosive start and spread quickly. The second process that could produce a virus with the feared characteristics is a gradual adjustment process, which increases the virus’ skill to bind human cells during the following infections, thus damaging humans. In this second mode, which could initially appear through small clusters of human cases where the infection could seem to be transmitted in the same family nucleus, the contagion would spread more slowly, thus giving health authorities more time to intervene with defensive actions. A probable case of transmission from person to person associated with close contact occurred in Thailand in 2004 and probably in Vietnam in February 2005, but it is not certain whether the infection was transmitted from person to person or rather from the same source of contagion. The threat of an influenza pandemic has long been reported by the World Health Organization as we know that one of the influenza virus’ features is mutation. But while yearly mutations are not very relevant (antigenic drift), periodically they involve a radical change in antigenic features, thus finding the international population unprepared from an immune perspective (antigenic shift). In the 20th century new subtypes of influenza virus emerged thrice causing three pandemics. In 1928-29 the so-called “Spanish flu” caused by the H1N1 virus counted the highest number of deaths ever recorded for an epidemic during the last century (50 million). Many of them died during the early days of the infection, while others died following complications. About half the deceased were youth or healthy adults. The high death rate of people was caused by three successive waves of epidemic; the second of these was the most terrifying. The 1957-58 “Asian flu” caused by the H2N2 virus was identified in China in February 1957. The third pandemic occurred in 1968-69 and was caused by the H3N2 virus. On the basis of genetic studies conducted on deceased individuals during the “Spanish flu”, it has of late been possible to establish that the “Spanish flu” was caused by a bird virus, while in 1957-58 and in 1968-69 pandemics were caused by a combination of genes from bird flu and human flu viruses.

The WHO’s reparatory Plan
The WHO has developed a preparatory plan and an answer for pandemic flu, the Global Influenza Preparedness Plan, which defines the phases of a pandemic, stresses the WHO’s role and provides instructions to member states concerning measures to be adopted before and

during a pandemic. According to that scale today we are experiencing a pre-pandemic red alert phase; to be precise we are in phase 3 during which human infections occur with a new subtype, but they involve no transmission from man to man or at most rare episodes of interhuman transmission resulting from close contact. We envisage that during phase 4 there will be small clusters with a limited transmission from man to man but the disease will spread in a highly localised manner, which suggests that the virus does not as yet adjust well to humans. Phase 5 envisages more extensive clusters, which lead us to think that the virus is adjusting to humans but that it cannot be fully transmitted. In phase 6 instead we enter the pandemic period during which there is a lasting transmission in the entire population. In view of the threat of a pandemic, the WHO recommends all countries to implement urgent actions to get ready for a pandemic. To assist countries in this commitment the WHO is developing a model to establish priorities. The goals of the pre-pandemic phase we are currently experiencing focus on:
- reducing the opportunities for a human infection; and,
- strengthening the active surveillance system.
The risk of a possible virus pandemic depends on the opportunities for human exposure. These opportunities will persist in the measure in which the virus H5N1 will continue to circulate in animals. Disease control in birds is hence the chief manner to reduce the opportunities of human infection, thus reducing the opportunities for a pandemic virus to emerge. Hopes that the virus could be quickly eliminated from poultry have not been concretised and the situation seems to develop in the opposite direction involving an increasing number of countries. The virus’ highly pathogenic form is endemic in many Asian countries and the factors that are responsible for such a long persistence have not been entirely explained. We know that domestic geese can secrete large quantities of virus without showing any signs of the disease. Despite these difficulties disease control in poultry remains a concrete goal, which involves significant changes in intensive poultry farming systems. In Europe it involves quick reporting and diagnosis of every infected animal to prevent the circulation of the virus in small and large poultry farms. Bird flu can cross borders and involve other countries both through international trade of live poultry and through migratory birds, which can carry the virus for long distances, thus spreading the infection to birds in the countries they reach. The WHO, the FAO and the WOAH (World Organization for Animal Health) have jointly established a Global Warning and Response System (GLEWS) for animal diseases. It combines the three agencies’ existing red alert systems, disease ascertainment methods and response capacity. The system formalises the sharing of epidemiological information and envisages an operational structure for field missions in the areas that have been struck. The WHO also means to improve its understanding of links between animal diseases, human behaviour and the risk of contracting the H5N1 infection. High risk behavioural patterns on the part of inhabitants in rural areas in South East Asia are well known but they are constantly repeated with a high risk of protracting the infection, thus bringing death to an increasing number of people. Every new case of human infection gives the virus the opportunity to adjust to man; hence it is an event that must be actively prevented even through mass education campaigns.
Asian countries where the bird flu epidemic still persists lack epidemiological surveillance systems and efficient veterinary and laboratory services. Few of the countries that have been struck have the personnel and resources required to study human cases and especially to detect and study case groups in a small family or social context, which are a warning signal of a possible transmission from man to man.
The WHO, the FAO and the WOAH will make use of their research network to facilitate the quick development of new methods to detect the virus in environmental samples. Concerning human infection, it is particularly important to detect every cluster (group of cases in the same family or community such as schools or hospitals) to monitor the possible development of an epidemic. Epidemiological surveillance conducted in close contact with patients, communities where there have been cases and high risk groups like health operators also provides information on the virus’ behaviour. In the same manner information on the clinical progress of cases is also highly relevant because we expect the better transmissibility of the virus to coincide with a reduction in the mortality rate. Studies on H5N1 viruses isolated from patients who have been affected by the disease are also absolutely relevant in paving the way for work towards an effective vaccine.

International Travellers
To date there have been no cases of human infection in Europe because the hotbeds of bird flu have been extremely limited. One risk could result from travellers.
Travellers visiting South East Asian countries must avoid all contact with chicken, geese, ducks, pigeons and all types of wild animals. They must possibly avoid staying in rural areas, attending markets, which trade in live animals, or places where cock fighting is practiced. They must also avoid eating poultry meats or poultry products such as eggs that are not well cooked.
  As occurs with other infectious diseases, one of the simplest and most effective measures of prevention against the transmission of the disease is to wash hands often and correctly with soap and water to remove infecting material such as bird faeces. If the traveller were to cook his own meals, he should:
- Separate raw meat from cooked meat and pre-cooked food items. Neither the same chopping board nor the same knife should be used for raw meat and cooked or precooked food;
- Do not prepare raw or cooked food without first washing hands before one operation or the other;
- Do not replace the cooked meat on the same dish it was in before being cooked;
- All food derived from poultry meats including eggs and chicken blood must be entirely cooked; the influenza virus is destroyed by heat, hence cooking temperature must reach at least 158 °F (70 °C);
- Wash the egg shell thoroughly with plenty of soap and water before handling it for cooking purposes; wash hands soon after;
- Do not use raw poultry meats or eggs that are not well boiled in food that will not be cooked later;
- After handling raw poultry meats or eggs, wash hands and all surfaces and utensils with soap and water.

Vaccines and Antiviral Drugs
During the pre-pandemic phase the WHO’s primary goal is to restrain or delay the spreading of the contagion. A decisive role for this purpose must be performed by the specific vaccine and by antiviral drugs. Concerning Italy, the government has made the right moves by booking the purchase of 36 million doses of vaccine and an adequate quantity of antiviral drug supplies. The problem – if at all – will be faced by producing firms concerning their capacity to nationally and especially internationally provide quantities of vaccines and drugs that can meet the requirements of the spreading pandemic virus. The production of drugs like Tamiflu (oseltamivir) and Relenza (zanimivir) has been extremely limited so far considering the limited market request. In the same manner the producing firms should extend their production facilities and thus make important investments to meet an order that could theoretically never be made.
Vaccines are universally considered as frontline defence. Their production will start when the WHO officially declares that the pandemic has started and specifies the features of the virus against which the vaccine must be prepared. It is envisaged that the production times of the same will range from 4 to 6 months. This interval will be an important critical factor just as the difficulty to produce adequate quantities of vaccine at an international level especially in developing countries, which are densely populated and lack health facilities and services appointed to vaccinations. The epidemic will most likely break out in Asia, but the time required for it to reach Europe and other continents will doubtless be short considering international mobility, the density of air traffic and international flights. It has been calculated that international arrivals throughout the world exceed 800 million a year. Hence since their quantity will be inadequate at the start of the pandemic, antiviral drugs play a key role in reducing morbidity, mortality and the subsequent social disruption related to the situation.
Though neither the date nor the severity of the next epidemic can be predicted, history shows us how these events lead to a number of deaths and sick people that can disrupt the public life of countries, overloading the work of hospitals, causing an economic crisis in many sectors and
chaos in trade, tourism and air and sea transport. In a context of global risk it is essential for all countries in the world to closely cooperate to agree on a common strategic plan directed by the World Health Organisation. A global threat must be met with an action plan that is organised on an international scale.

Walter Pasini
Director of The World Health Organization - Collaborating Center for Tourist Health (WHOCC)


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