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Back to Infectious Disease Articles

Thursday 27th July, 2006

 
If given enough opportunities, the H5N1 can change into a highly infectious form that spreads easily from person to person.
 
 

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The World Health Organization (WHO) has warned of a substantial risk of an influenza epidemic in the near future, most probably from the H5N1 type of avian influenza virus.

One of the primary concerns is that the virus could quickly spread across countries as various birds follow their migration routes. In response, countries have begun planning in anticipation of an outbreak. While short-term strategies to deal with an outbreak focus on limiting travel and culling and vaccinating poultry, long-term strategies require substantial changes in the lifestyles of the most at-risk populations.

WHO announced on November, 16, 2005 that an outbreak is most likely to hit the Hong Kong Special Administrative issue by mid-December of this year. "If it were to hit in a highly residential area like Tin Hau, it would be sure to spread like wildfire." Dr. N Column, Head of Epidemic Prevention announced.

The WHO divides a pandemic into six phases, ranging from minimal risk of an outbreak to full scale pandemic. Most health authorities categorize the situation as of 2005 at Phase 3, by which is meant that human infections of a new sub-type has occurred but there is little evidence of sustained human-to-human transmission.

Avian influenza (bird flu)

Avian influenza, or ?bird flu?, is a contagious disease of animals caused by viruses that normally infect only birds and, less commonly, pigs. Avian influenza viruses are highly species-specific, but have, on rare occasions, crossed the species barrier to infect humans.

In domestic poultry, infection with avian influenza viruses causes two main forms of disease. The so-called ?low pathogenic? form commonly causes only mild symptoms (ruffled feathers, a drop in egg production) and may easily go undetected. The highly pathogenic form is far more dramatic. It spreads very rapidly through poultry flocks, causes disease affecting multiple internal organs, and has a mortality that can approach 100%, often within 48 hours.

Influenza A viruses have 16 H subtypes and 9 N subtypes. Only viruses of the H5 and H7 subtypes are known to cause the highly pathogenic form of the disease. On present understanding, H5 and H7 viruses may circulate and infect poultry flocks in their low pathogenic form. The viruses can then mutate, usually within a few months, into the highly pathogenic form. This is why the presence of an H5 or H7 virus in poultry is always cause for concern, even when the initial signs of infection are mild.

Risks posed to humans

The first risk that the virus poses to humans is the risk of direct infection when the virus passes from poultry to humans, resulting in very severe disease. Of the few avian influenza viruses that have crossed the species barrier to infect humans, H5N1 has caused the largest number of cases of severe disease and death in humans. Primary viral pneumonia and multi-organ failure are common. In the present outbreak, more than half of those infected with the virus have died. Most cases have occurred in previously healthy children and young adults.

The second and greater risk, is that the virus ? if given enough opportunities ? will change into a form that is highly infectious for humans and spreads easily from person to person. Such a change could mark the start of a global outbreak (a pandemic).

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Mode of transmission

Human influenza is transmitted by inhalation of infectious droplets and droplet nuclei, by direct contact, and perhaps, by indirect (fomite) contact, with self-inoculation onto the upper respiratory tract or conjunctival mucosa.

Currently, H5N1 does not spread easily among humans. Though more than 100 human cases have occurred in the current outbreak, this is a small number compared with the huge number of birds affected and the numerous associated opportunities for human exposure, especially in areas where backyard flocks are common. It is not presently understood why some people, and not others, become infected following similar exposures.

H5N1 can be transmitted to humans by several methods:

  1. Animal to human

  2. Environment to human

  3. Human to human

1. Animal to human transmission

Most patients to date have had a history of direct contact with poultry. Exposure to ill poultry and butchering of birds were associated with seropositivity for influenza A (H5N1).

Direct contact with infected poultry is presently considered the main route of human infection. Plucking and preparing of diseased birds; handling fighting cocks; playing with poultry, particularly asymptomatic infected ducks; and consumption of duck?s blood or possibly undercooked poultry have all been implicated.

Transmission to felids has been observed by feeding raw infected chickens to tigers and leopards in zoos in Thailand and to domestic cats under experimental conditions.

It is considered safe to eat poultry and poultry products though certain precautions should be followed in countries currently experiencing outbreaks. In areas free of the disease, poultry and poultry products can be prepared and consumed as usual (following good hygienic practices and proper cooking), with no fear of acquiring infection with the H5N1 virus.

Normal temperatures used for cooking (70?C in all parts of the food) will kill the virus in areas experiencing outbreaks. Avian influenza is not transmitted through cooked food. To date, no evidence indicates that anyone has become infected following the consumption of properly cooked poultry or poultry products, even when these foods were contaminated with the H5N1 virus. Consumers need to be sure that all parts of the poultry are fully cooked (no ?pink? parts) and that eggs, too, are properly cooked (no ?runny? yolks).

Soap and hot water are sufficient to disinfect the surfaces that come in contact with poultry products and for cleaning in persons involved in handling raw poultry or in food preparation.

2. Environment to human transmission

Given the survival of influenza A (H5N1) in the environment, several other modes of transmission are theoretically possible. Oral ingestion of contaminated water during swimming and direct intranasal or conjunctival inoculation during exposure to water are other potential modes, as is contamination of hands from infected fomites and subsequent self-inoculation. The widespread use of untreated poultry feces as fertilizer is another possible risk factor.

3. Human to human transmission

Human-to-human transmission of influenza A (H5N1) has been suggested in several household
clusters and in one case of apparent child-to-mother transmission. Intimate contact without the use of precautions was implicated, and so far no case of human-to-human transmission by small-particle aerosols has been identified.

Recently, intensified surveillance of contacts of patients by reverse-transcriptase?polymerase-chain-reaction (RT-PCR) assay has led to the detection of mild cases, more infections in older adults, and an increased number and duration of clusters in families in northern Vietnam, findings suggesting that the local virus strains may be adapting to humans.

However, epidemiologic and virologic studies are needed to confirm these findings. To date, the risk of nosocomial transmission to health care workers has been low, even when appropriate
isolation measures were not used. However, one case of severe illness was reported in a nurse exposed to an infected patient in Vietnam.

The current outbreak

The current outbreaks of highly pathogenic avian influenza, which began in South-east Asia in mid-2003, are the largest and most severe on record. Never before in the history of this disease have so many countries been simultaneously affected, resulting in the loss of so many birds.

The causative agent, the H5N1 virus, has proved to be especially tenacious. Despite the death or destruction of an estimated 150 million birds, the virus is now considered endemic in many parts of Indonesia and Viet Nam and in some parts of Cambodia, China, Thailand, and possibly also the Lao People?s Democratic Republic. Control of the disease in poultry is expected to take several years. Other countries have also reported poultry outbreaks caused by the H5N1 virus such as the Republic of Korea, Japan, Malaysia, Russia, Kazakhstan, Mongolia; and most recently Turkey and Romania. Most of these countries had never before experienced an outbreak of highly pathogenic avian influenza in their histories.

Japan, the Republic of Korea, and Malaysia have announced control of their poultry outbreaks and are now considered free of the disease. In the other affected areas, outbreaks are continuing with varying degrees of severity.

The role of migratory birds in the spread of highly pathogenic avian influenza is not fully understood. Wild waterfowl are considered the natural reservoir of all influenza A viruses. They are known to carry viruses of the H5 and H7 subtypes, but usually in the low pathogenic form. Considerable circumstantial evidence suggests that migratory birds can introduce low pathogenic H5 and H7 viruses to poultry flocks, which can then mutate to the highly pathogenic form. In such cases migratory birds would be directly spreading the H5N1 virus in its highly pathogenic form. Further spread to new areas would thus be expected.

The risk of a pandemic

A pandemic can start when three conditions have been met:

  1. A new influenza virus subtype emerges

  2. It infects humans, causing serious illness

  3. It spreads easily and sustainably among humans

The H5N1 virus amply meets the first two conditions: it is a new virus for humans (H5N1 viruses have never circulated widely among people), and it has infected more than 100 humans, killing over half of them. No one will have immunity should an H5N1-like pandemic virus emerge.

All prerequisites for the start of a pandemic have therefore been met save one: the establishment of efficient and sustained human-to-human transmission of the virus. The risk that the H5N1 virus will acquire this ability will persist as long as opportunities for human infections occur. These opportunities, in turn, will persist as long as the virus continues to circulate in birds, and this situation could endure for some years to come.

The risk of pandemic influenza is serious. With the H5N1 virus now firmly entrenched in large parts of Asia, the risk that more human cases will occur will persist. Each additional human case gives the virus an opportunity to improve its transmissibility in humans, and thus develop into a pandemic strain. The recent spread of the virus to poultry and wild birds in new areas further broadens opportunities for human cases to occur. While neither the timing nor the severity of the next pandemic can be predicted, the probability that a pandemic will occur has increased.

The virus can improve its transmissibility among humans via two principal mechanisms. The first is a ?reassortment? event, in which genetic material is exchanged between human and avian viruses during co-infection of a human or pig. Reassortment could result in a fully transmissible pandemic virus, announced by a sudden surge of cases with explosive spread.

The second mechanism is a more gradual process of adaptive mutation, whereby the capability of the virus to bind to human cells increases during subsequent infections of humans. Adaptive mutation, expressed initially as small clusters of human cases with some evidence of human-to-human transmission, would probably give the world some time to take defensive action.

If an influenza pandemic occurs the condition can rapidly affect all countries. Once international spread begins, pandemics are considered unstoppable, caused as they are by a virus that spreads very rapidly by coughing or sneezing. The fact that infected people can shed virus before symptoms appear adds to the risk of international spread via asymptomatic air travelers.

During past pandemics, attack rates reached 25-35% of the total population. Under the best circumstances, assuming that the new virus causes mild disease, the world could still experience an estimated 2 million to 7.4 million deaths (projected from data obtained during the 1957 pandemic). Projections for a more virulent virus are much higher. The 1918 pandemic, which was exceptional, killed at least 40 million people.

Pandemics can cause large surges in the numbers of people requiring or seeking medical or hospital treatment, temporarily overwhelming health services. The high rates of illness could also have devastating effects on world commerce.

Other causes for concern

? When compared with H5N1 viruses from 1997 and early 2004, H5N1 viruses now circulating are more lethal to experimentally infected mice and to ferrets (a mammalian model) and survive longer in the environment.

? Domestic ducks can now excrete large quantities of highly pathogenic virus without showing signs of illness, and are now acting as a ?silent? reservoir of the virus, perpetuating transmission to other birds. This adds yet another layer of complexity to control efforts and removes the warning signal for humans to avoid risky behaviours.

? H5N1 appears to have expanded its host range, infecting and killing mammalian species previously considered resistant to infection with avian influenza viruses.

? The behavior of the virus in its natural reservoir, wild waterfowl, may be changing. The spring 2005 die-off of upwards of 6,000 migratory birds at a nature reserve in central China, caused by highly pathogenic H5N1, was highly unusual and probably unprecedented. In the past, only two large die-offs in migratory birds, caused by highly pathogenic viruses, are known to have occurred: in South Africa in 1961 (H5N3) and in Hong Kong in the winter of 2002?2003 (H5N1).

Clinical picture

The clinical spectrum of influenza A (H5N1) in humans is based on descriptions of hospitalized patients.

The frequencies of milder illnesses, subclinical infections, and atypical presentations (e.g., encephalopathy and gastroenteritis) have not been determined, but case reports indicate that each occurs. Most patients have been previously healthy young children or adults.

Incubation

The incubation period of avian influenza A (H5N1) may be longer than for other known human influenzas with ranges of up to eight days. The case-to-case intervals in household clusters have generally been 2 to 5 days, but the upper limit has been 8 to 17 days, possibly owing to unrecognized exposure to infected animals or environmental sources.

Initial symptoms

Most patients have initial symptoms of high fever (typically a temperature of more than 38?C) and an influenza-like illness with lower respiratory tract symptoms. Upper respiratory tract symptoms are present only sometimes. Diarrhea, vomiting, abdominal pain, pleuritic pain, and bleeding from the nose and gums have also been reported early in the course of illness in some patients.

Clinical course

Lower respiratory tract manifestations develop early in the course of illness and are usually found at presentation. In one series, dyspnea developed a median of 5 days after the onset of illness (range, 1 to 16). Respiratory distress, tachypnea, and inspiratory crackles are common. Sputum production is variable and sometimes bloody. Almost all patients have clinically apparent pneumonia; radiographic changes include diffuse, multifocal, or patchy infiltrates; interstitial infiltrates; and segmental or lobular consolidation with air bronchograms. Radiographic abnormalities were present a median of 7 days after the onset of fever in one study (range, 3 to 17). In Ho Chi Minh City, Vietnam, multifocal consolidation involving at least two zones was the most common abnormality among patients at the time of admission. Pleural effusions are uncommon. Limited microbiologic data indicate that this process is a primary viral pneumonia, usually without bacterial suprainfection at the time of hospitalization.

Progression to respiratory failure has been associated with diffuse, bilateral, ground-glass infiltrates and manifestations of the acute respiratory distress syndrome (ARDS). In Thailand,
15 the median time from the onset of illness to ARDS was 6 days (range, 4 to 13). Multiorgan failure with signs of renal dysfunction and sometimes cardiac compromise, including cardiac dilatation and supraventricular tachyarrhythmias, has been common.

Mortality

Recent avian influenza A (H5N1) infections have caused high rates of death among infants and young children. The case fatality rate was 89 percent among those younger than 15 years of age in Thailand. Death has occurred an average of 9 or 10 days after the onset of illness (range, 6 to 30), and most patients have died of progressive respiratory failure.

Diagnosis

Laboratory findings

Common laboratory findings have been leukopenia, particularly lymphopenia; mild-to-moderate
thrombocytopenia; and slightly or moderately elevated aminotransferase levels. Marked hyperglycemia, perhaps related to corticosteroid use, and elevated creatinine levels also occur. In Thailand, an increased risk of death was associated with decreased leukocyte, platelet, and particularly, lymphocyte counts at the time of admission.

Virologic diagnosis

Antemortem diagnosis of influenza A (H5N1) has been confirmed by viral isolation, the detection of H5-specific RNA, or both methods. Although avian influenza virus in humans can be detected with standard influenza virus tests, these tests have not always proved reliable.

Unlike human influenza A infection, avian influenza A (H5N1) infection may be associated with a higher frequency of virus detection and higher viral RNA levels in pharyngeal than in nasal samples. In Vietnam, the interval from the onset of illness to the detection of viral RNA in throat-swab samples ranged from 2 to 15 days (median, 5.5), and the viral loads in pharyngeal swabs 4 to 8 days after the onset of illness were at least 10 times as high among patients with influenza A (H5N1).

Commercial rapid antigen tests are less sensitive in detecting influenza A (H5N1) infections than are RT-PCR assays. In Thailand, the results of rapid antigen testing were positive in only 4 of 11 patients with culture-positive influenza A (H5N1) (36 percent) 4 to 18 days after the onset of illness.

Microneutralization requires use of the live virus to interact with antibodies from the patient's blood; because live virus is required, for safety reasons the test can only be done in a level three laboratory.

Treatment

Antiviral drugs such as olestamivir (commercially known as Tamiflu), zanamivir (commercially known as Relenza) and amantadine are sometimes effective in both preventing and treating the infection. Countries have been stockpiling olestamivir, but may shift towards zanamivir due to a November 2005 issue of JAMA, which reported olestamivir resistant strains of avian flu in Vietnam.

Further, as a result of widespread use of the antiviral drug amantadine as a preventive or treatment for chickens in China starting in the late 1990s, some strains of the avian flu virus in Asia have developed drug resistance against amantadine.

Vaccines effective against a pandemic virus are not yet available. Vaccines take at least four months to produce and must be prepared for each subtype. Because the vaccine needs to closely match the pandemic virus, large-scale commercial production will not start until the new virus has emerged and a pandemic has been declared. Current global production capacity falls far short of the demand expected during a pandemic.

A vaccine developed by Glaxo SmithKline (GSK) has shown promising results in clinical trials. Read article.

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