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Bird Flu / Avian Influenza

There has been a lot of recent concern that "bird flu" [which can refer to a number of influenza viruses that occur in birds] could become causes of human disease in some situations. Avian influenza (AI) has been recognized as a highly lethal generalized viral disease of poultry since 1901. It has since been found that AI viruses cause a wide range of disease syndromes, ranging from severe to mild, in domestic poultry.

All influenza viruses have the potential to change. Many of the strains that circulate in wild birds are either non-pathogenic or mildly pathogenic for poultry. However, a virulent strain may emerge either by genetic mutation or by reassortment of less virulent strains.

It is possible that an avian influenza virus could change so that it could infect humans and could spread easily from person to person. The experience with the H5N1 virus in humans to date suggests that the virus is very different from a normal flu virus, which makes it difficult to predict exactly how it will behave if it gains the ability to transmit efficiently between humans. Because these viruses do not commonly infect humans, there is little or no immune protection against them in the human population. If an avian virus were able to infect people and gain the ability to spread easily from person to person, an influenza pandemic could begin. An influenza pandemic is a global outbreak of influenza and occurs when a new influenza virus emerges, spreads, and causes disease worldwide. Past influenza pandemics have led to high levels of illness, death, social disruption and economic loss.

Influenza A viruses infecting birds are usually at one of two extremes of virulence. Avian influenza is widespread in populations of wild birds, but typically has low lethality (so-called Low Pathogenic Avian Influenza - LPAI). Low pathogenic avian influenza viruses cause a localized infection with little or no disease unless exacerbated by other organisms or poor environmental conditions. Highly pathogenic avian influenza (HPAI) viruses cause a systemic disease in chickens and turkeys with rapid death, which often approaches 100% death rate. The H5N1 virus kills and kills quickly. The duration of symptomology in infected poultry was about 4 to 6 hours only. Signs noted in poultry are compatible with a massive cytokine disregulation.

The avian H5N1 virus is widespread and endemic in much of Asia with spread to Europe. Highly Pathogenic Avian Influenza of the form H5N1 seems to have originated in south-east Asia, but in recent years has spread to Kazahkstan, Romania, Turkey, Greece, Croatia and southern Russia. There is continuing concern that migrating wild birds may further spread HPAI.

Genetic studies confirm that H5N1, like other influenza viruses, is continuing to change and evolve. The avian H5N1 virus is becoming more deadly in a growing number of bird species and mammals. 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.

H5N1 appears to have expanded its host range, infecting and killing mammalian species previously considered resistant to infection with avian influenza viruses. Wild birds and domestic ducks may be infected asymptomatically, providing a reservoir for infection of other domestic poultry species. The virus is able to transmit directly from birds to some mammals and in some circumstances to people. There is sporadic spread directly from animals to humans with suspected human-to-human transmission in rare instances.

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).

While H5N1 is the greatest current pandemic threat, other avian influenza subtypes have also infected people in recent years. In 1999, H9N2 infections were identified in Hong Kong; in 2003, H7N7 infections occurred in the Netherlands; and in 2004, H7N3 infections occurred in Canada. Such outbreaks have the potential to give rise to the next pandemic, reinforcing the need for continued surveillance and ongoing vaccine development efforts against these strains.

Direct avian-to-human influenza transmission was unknown before 1997. Outbreaks of highly pathogenic avian influenza in poultry in East Asia (H5N1), Canada (H7N3), and the Netherlands (H7N7), and their subsequent transmission to humans, intensified concern over the emergence of a novel strain of influenza with pandemic potential. In 2003, highly pathogenic strains of avian influenza virus, including the H5N1 and H7N7 subtypes, again crossed from birds to humans and caused fatal disease.

Infected birds shed flu virus in their saliva, nasal secretions, and feces. Susceptible birds become infected when they have contact with contaminated excretions or surfaces that are contaminated with excretions. It is believed that most cases of bird flu infection in humans have resulted from contact with infected poultry or contaminated surfaces.

The incubation period of Avian Flu in birds is usually 3 to 7 days, depending upon the isolate, the dose of inoculum, the species, and age of the bird. The exact incubation period for bird flu in humans is unclear, though illness seems to develop within one to five days of exposure to the virus. People infected with the most virulent type of bird flu virus - (A) H5N1 - may develop life-threatening complications, particularly viral pneumonia and Acute Respiratory Distress Syndrome, the most common cause of bird flu-related deaths [as was the case with the 1918 Spanish Flu].

Bird Flu in Humans

Of all viruses in the avian flu pool, H5N1 is of particular concern for human health for two reasons. First, H5N1, though strictly an avian pathogen, has a documented ability to pass directly from birds to humans. Second, once in humans, H5N1 causes severe disease with very high mortality. These two features combine to make H5N1 of concern for a third and greater reason: its potential to ignite an especially severe pandemic.

The main route of human infection is direct contact with infected poultry or surfaces and objects contaminated with their feces or blood. It is not understood why some people but not others become infected with similar exposures. To date, most human cases have occurred in rural and periurban areas where households keep small poultry flocks that roam freely, often entering homes and sharing children's outdoor play areas. Large quantities of the virus are excreted in the feces of infected poultry. In countries where poultry is relied upon for income and food, families slaughter and consume birds that are ill. Exposure occurs during slaughtering, defeathering, butchering and preparation of poultry for cooking.

Infection in humans occurs with consumption of inadequately cooked poultry or raw poultry products such as duck's blood. There is no evidence that properly cooked poultry or eggs are a source of infection. Most strains of avian influenza virus are found only in the respiratory and gastrointestinal tracts of infected birds, and not in meat. Available studies indicate that highly pathogenic viruses, including the H5N1 virus, spread to virtually all parts of an infected bird, including meat. For this reason, proper handling of poultry and poultry products during food preparation and proper cooking are extremely important in areas experiencing outbreaks of H5N1 avian influenza in poultry. The H5N1 avian influenza virus is not transmitted to humans through properly cooked food. The virus is sensitive to heat. Normal temperatures used for cooking (so that food reaches 70oC in all parts) will kill the virus. To date, no evidence indicates that any person has become infected with the H5N1 virus following the consumption of properly cooked poultry or poultry products, even in cases where the food item contained the virus prior to cooking. In countries with outbreaks, thorough cooking is imperative. 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" yolkes).

As of October 2005 there had been only 116 confirmed cases of this strain of flu being transmitted from infected birds to people, all of them in Asia. But 60 of those people have died -- a death rate greater than 50 percent, making it one of the most virulent strains ever seen. The estimated case fatality rate in known human cases vastly exceeds the 1% experienced with the other two pandemics in 1957 and 1968. The experience in poultry, the other non-reservoir susceptible species, is that both the exposed flock attack rate and case fatality rate are very high, close to 100%. If the speed and pathogenic mechanism is similar in humans, the US health care system may be unable to keep a fatality rate near a 1% level, even with an adequate (quality and quantity) surge capacity in the US. While significant improvements have been made in medical care over the last 90 years, health care providers and volunteers may again be afraid and reluctant to aid the ill, and as the capacity to safely handle the ill becomes overtaxed, care centers will be avoided by the general public.

The primary viral infection is rarely the direct cause of mortality. Instead, infected persons die of cardiac disease (usually patients with pre-existing co-morbidities) or succumb to secondary bacterial pneumonia. Around 25% of all mortality during a typical influenza season is due secondary bacterial infections. During pandemic influenza, around 70% of influenza cases are complicated by bacterial co-infections. Despite this association being appreciated since 1803 and being the focus of the majority of research following the 1918 pandemic, little is known about the pathogenesis of either cardiac death or secondary bacterial infections following influenza.

A striking feature of the 1997 Hong Kong H5N1 outbreak was the presence of primary viral pneumonia in severe cases. When pneumonia occurs in influenza patients, it is usually a complication caused by a secondary bacterial infection. In the H5N1 cases, pneumonia was directly caused by the virus, did not respond to antibiotics, and was frequently rapidly fatal. Many other cases, too mild to be detected, were almost certainly occurring, thus expanding opportunities for coinfections.

H5N1 has become progressively more pathogenic in poultry and in the mammalian mouse model, and is now hardier than in the past, surviving several days longer in the environment. It is not known with certainty why H5N1 causes such severe disease in children and young adults, with death frequently following multi-organ failure in addition to severe respiratory disease. Similarities between H5N1 and the 1918 virus include the severity of disease, its concentration in the young and healthy, and the occurrence of primary viral pneumonia in the absence of secondary bacterial infection. The present high lethality of H5N1 would probably not be retained in an H5N1-like pandemic virus, as an avian influenza virus is expected to lose pathogenicity when it acquires the improved transmissibility needed to ignite a pandemic.

The newly formed International Partnership on Avian and Pandemic Influenza, announced by President Bush at the United Nations General Assembly on September 14, 2005, was created to improve international surveillance, transparency, timeliness, and response capabilities. Over 200 delegates from 88 countries and nine international organizations attended the first Senior Officials meeting on October 7, 2005. This initiative will strive for complete transparency, rapid response capabilities, and cooperative surveillance, and will facilitate the sharing of epidemiological data and samples among nations and with the World Health Organization.

Avian Flu Human-to-Human Transmission

With the H5N1 strain now endemic in birds in large parts of Asia, the probability that this potential for a pandemic will be realized has increased. The world has never before seen outbreaks of avian influenza on the scale of those that have swept through large parts of Asia, including densely populated China.

A pandemic may occur when three conditions have been met: a new influenza virus subtype emerges; it infects humans causing serious illness; and it spreads easily and sustainably among humans. The H5N1 virus meets the first two conditions. The risk that it will acquire the ability to have efficient and sustained human-to-human transmission is present as long as opportunities for human infections occur. These opportunities will persist as long as the virus continues to circulate in domestic birds, perhaps for years to come.

The relatively low frequencies of influenza A (H5N1) illness in humans despite widespread exposure to infected poultry indicate that the species barrier to acquisition of this avian virus is substantial.

  1. The avian viruses thrives in the gut of birds, where the temperature is 37 degrees Celsius. The human respiratory has a temperature of 33 degrees to 34 degrees Celsius, below the permissive temperature that is optimal for viral reproduction. Nasopharyngeal replication is less than in human influenza. In human cases, the majority of fecal samples tested have been positive for viral RNA, whereas urine samples were negative. The high frequency of diarrhea among affected patients and the detection of viral RNA in fecal samples, including infectious virus in one case, suggest that the virus replicates in the gastrointestinal tract in humans. In the late 1960s and early 1970s, a large collection of influenza virus temperature-sensitive (ts) mutants, derived from differing strains, was generated in several laboratories worldwide. Such ts mutants were selected for growth at a permissive temperature (usually between 31C and 36C, depending on the study), but were significantly inhibited for replication at a higher nonpermissive temperature (usually between 38C and 42C).
  2. Influenza viruses enter the airway epithelium through specific target cells. In this respect there are striking differences between human and avian viruses. Human viruses preferentially infect nonciliated cells, whereas avian viruses mainly infect ciliated cells. This pattern correlated with the predominant localization of receptors for human viruses (2-6-linked sialic acids) on nonciliated cells and of receptors for avian viruses (2-3-linked sialic acids) on ciliated cells. Although avian influenza viruses can infect human airway epithelium, their replication may be limited by a nonoptimal cellular tropism.
  3. The hemagglutinin (HA) protein enables the virus to bind to and enter cells. The protein covers the surface of the influenza virus and acts as a sort of spike that first attaches to the host cell. The protein also helps the virus membrane fuse with the cell membrane, so that the virus can enter the cell being attacked. The avian virus is presently unable to attach itself effectively to certain types of human cells. The host range of influenza A viruses is associated with differences in the specificity of HA for attachment to sialic acid-containing receptors on susceptible cells, reflecting the preponderance of these terminal sugar moieties in the different hosts. Changes in preference for moieties have been observed to accompany establishment of avian viruses in human and porcine hosts. Only 2 amino acid changes in the receptor-binding pocket of H5 lead to a virus that efficiently recognizes receptors on human cells. By 2005 viruses isolated from healthy ducks in southern China since 1999 had progressively acquired the ability to replicate and cause disease in mice -- a single amino acid substitution enabled the virus to infect and become lethal for mice. The 1918 virus had a lot of features of avian viruses. But the shape of its binding site allows it to bind to human cells. When that happened, there wasn't anything stopping it from infecting human cells. A number of studies have concluded that avian influenza viruses can acquire the ability to recognize and bind to human cells while they are in the respiratory tract of pigs. The findings support the notion that pigs act as mixing vessels that alter avian virus strains so that they can cause an influenza pandemic.

By 2005 intensified surveillance of contacts of patients by reverse -transcriptase -polymerase -chain -reaction (RT-PCR) assay 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.

Some epidemiological features of human H5N1 infections occurred in northern Viet Nam during January through April 2005 appeared to differ in some respects from those seen in 2004 in other parts of Asia, and in the concurrent period in southern Viet Nam. These included an increase in the number of case clusters in the north compared with the south, a prolonged interval between the first and last cases in clusters, detection of sub-clinical infections, an expanded age range of cases and fewer fatal cases. Investigators were not able to prove that human-to-human transmission had occurred. However the pattern of disease appeared to have changed in a manner consistent with this possibility. These differences suggest that the epidemiology of H5N1 infections may be evolving in Asia. The changes in epidemiological patterns are consistent with the possibility that recently emerging H5N1 viruses may be more infectious for humans.

The pathogenicity of influenza viruses is a polygenic trait. Although the virulence of avian influenza virus is polygenic, the hemagglutinin (HA) surface glycoprotein plays a pivotal role. It initiates infection by mediating virus binding to cell receptors and by promoting release of the viral RNP through membrane fusion. The HA glycoprotein is also clearly a major determinant of host range restriction, primarily because of its role in host cell recognition.

The argument that a highly lethal virus will not become easily transmissible assumes that the highly lethal virus incapacitates its victim before the victim can infect potential new hosts. But H5N1, like other flu viruses, has a few days of asymptomatic viral shedding before the patient victim is incapacitated. Bird flu cases in Vietnam exhibited a latency period of 2 to 4 days, and an average of 3 days. This is possibly longer than that of ordinary seasonal flu. There is thus no apparent selective pressure toward a milder H5N1. Indeed, the worst strains of H5N1 have been growing deadlier over the last several years.

It is possible that infections of humans by avian influenza viruses have been ongoing for decades, and it is only the reporting that has improved in recent years. In this case, the present concern about the hazards of an imminent pandemic outbreak of bird flu would be unjustified. No can know how the pandemic virus that emerges will behave. It is possible that it will be less deadly than the current H5N1, or less transmissible than typical flu, or more so on both counts. Past pandemics hit populations like a flash flood: starting abruptly and explosively, they swept through populations, and left great damage in their wake. Those infected with influenza are contagious both before they become symptomatic and after they feel well again, making it extremely difficult, if not impossible, to stop the spread of the virus across the globe. The unpredictability of these pandemics, their rapid spread and high attack rates mean it is impossible to be totally reassuring.

New Avian Influenza Strains in Humans

1986 (H1N1)

The Netherlands. Swine virus derived from avian source One adult with severe pneumonia

1993 (H3N2)

The Netherlands. Swine reassortant between old human H3N2 (1973/75-like) and avian H1N1 Two children with mild disease. Fathers suspected to have transmitted the virus to the children after having been infected by pigs.

1995 (H7N7)

United Kingdom Duck virus One adult with conjunctivitis

1997 H5N1 Chicken flu

The first time an influenza virus was found to be transmitted directly from birds to people, with infections linked to exposure to poultry markets. Eighteen people in Hong Kong were hospitalized, six of whom died.

1999 H9N2

Appeared for the first time in humans. It caused illness in two children in Hong Kong, with poultry being the probable source.

2002 H7N2

Evidence of infection is found in one person in Virginia following a poultry outbreak.

2003 H5N1

Caused two Hong Kong family members to be hospitalized after a visit to China, killing one of them, a 33-year-old man. (A third family member died while in China of an undiagnosed respiratory illness.)

2003 H7N7

In the first reported cases of this strain in humans, 89 people in the Netherlands, most of whom were poultry workers, became ill with eye infections or flu-like symptoms. A veterinarian who visited one of the affected poultry farms died.

2003 H7N2

Caused a person to be hospitalized in New York.

2003 H9N2

Caused illness in one child in Hong Kong.

2004 H5N1

Caused illness in 47 people in Thailand and Vietnam, 34 of whom died. Researchers are especially concerned because this flu strain, which is quite deadly, is becoming endemic in Asia.

2004 H7N3

Is reported for the first time in humans. The strain caused illness in two poultry workers in Canada.

2004 H10N7

Is reported for the first time in humans. It caused illness in two infants in Egypt. One child's father is a poultry merchant.

2005 H5N1

The first case of human infection with H5N1 arises in Cambodia in February. By May, WHO reports 4 Cambodian cases, all fatal. Indonesia reports its first case, which is fatal, in July. Over the next three months, 7 cases of laboratory-confirmed H5N1 infection in Indonesia, and 4 deaths, occur. On December 30, WHO reports a cumulative total of 142 laboratory-confirmed cases of H5N1 infection worldwide, all in Asia, with 74 deaths. Asian countries in which human infection with H5N1 has been detected: Thailand, Vietnam, Cambodia, Indonesia and China.

2006 H5N1

In early January, two human cases of H5N1 infection, both fatal, are reported in rural areas of Eastern Turkey. Also in January, China reports new cases of H5N1 infection. As of January 25, China reports a total of 10 cases, with 7 deaths. On January 30, Iraq reports its first case of human H5N1 infection, which was fatal, to the WHO. WHO confirmed human cases of avian influenza A (H5N1)



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