Global spread of H5N1
The global spread of H5N1 influenza in birds is considered a significant pandemic threat. While other H5N1 influenza strains are known, they are significantly different on a genetic level from a recent, highly pathogenic, emergent strain of H5N1, which was able to achieve hitherto unprecedented global spread in 2008. The H5N1 strain is a fast-mutating, highly pathogenic avian influenza virus (HPAI) found in multiple bird species. It is both epizootic (an epidemic in non-humans) and panzootic (a disease affecting animals of many species especially over a wide area). Unless otherwise indicated, "H5N1" in this  timeline refers to the recent highly pathogenic strain of H5N1. Tens of millions of birds have died of H5N1 influenza and hundreds of millions of birds have been slaughtered and disposed of, to limit the spread of H5N1. Countries that have reported one or more major highly pathogenic H5N1 outbreaks in birds (causing at least thousands but in some cases millions of dead birds) are (in order of first outbreak occurrence): South Korea, Vietnam, Japan, Thailand, Cambodia, Laos, Indonesia, China, Malaysia, Russia, Kazakhstan, Mongolia, Turkey, Romania, Croatia, Ukraine, Cyprus, Iraq, Nigeria, Egypt, India, France, Niger, Bosnia, Azerbaijan, Albania, Cameroon, Myanmar , Afghanistan, Israel, Pakistan, Jordan, Burkina Faso, Germany, Sudan, Ivory Coast, Djibouti, Hungary, United Kingdom, Kuwait, Bangladesh, Saudi Arabia, Ghana, Czech Republic, Togo, Nepal, and Bhutan. Highly pathogenic H5N1 has been found in birds in the wild in numerous other countries: Austria, Bulgaria, Denmark, Greece, Iran, Italy, Poland, Serbia and Montenegro, Slovakia, Slovenia, Spain, Sweden, and Switzerland. Surveillance of H5N1 in humans, poultry, wild birds, cats and other animals remains very weak in many parts of Asia and Africa. Much remains unknown about the exact extent of its spread. H5N1 has low pathogenic varieties endemic in birds in North America. H5N1  has a highly pathogenic variety that is endemic in dozens of species of birds throughout south Asia and parts of Africa. So far, it is very difficult for humans to become infected with H5N1. The presence of highly pathogenic (deadly) H5N1 around the world in both birds in the wild (swans, magpies, ducks, geese, pigeons, eagles, etc.) and in chickens and turkeys on farms has been demonstrated in millions of cases with the virus isolate actually sequenced in hundreds of cases yielding definitive proof of the evolution of this strain of this subtype of the species Influenzavirus A (bird flu  virus). According to Robert G. Webster: On July 25, 2008, the Food and Agriculture Organization (FAO) released an Avian Influenza Disease Emergency Situation Update, reporting that H5N1 pathogenicity was continuing to gradually rise in endemic areas but the avian influenza disease situation in farmed birds was being held in check by vaccination. Eleven outbreaks of H5N1 were reported worldwide in June 2008 in five countries (China, Egypt, Indonesia, Pakistan and Vietnam) compared to 65 outbreaks in June 2006 and 55 in June 2007. Timeline. 2004. In January 2004 a major new outbreak of H5N1 surfaced in Vietnam and Thailand's  poultry industry, and within weeks spread to ten countries and regions in Asia, including Indonesia, South Korea, Japan and China. In October 2004 researchers discovered H5N1 is far more dangerous than previously believed because waterfowl, especially ducks, were directly spreading the highly pathogenic strain of H5N1 to chickens, crows, pigeons, and other birds and that it was increasing its ability to infect mammals as well. From this point on, avian influenza experts increasingly refer to containment as a strategy that can delay but not prevent a future avian flu pandemic. 2005. In January 2005 an outbreak of avian influenza affected  thirty three out of sixty four cities and provinces in Vietnam, leading to the forced killing of nearly 1.2 million poultry. Up to 140 million birds are believed to have died or been killed because of the outbreak. In April 2005 there begins an unprecedented die-off of over 6,000 migratory birds at Qinghai Lake in central China over three months. This strain of H5N1 is the same strain as is spread west by migratory birds over at least the next ten months. In August 2005 H5N1 spread to Kazakhstan, Mongolia and Russia. On September 29, 2005, David Nabarro, the  newly appointed Senior United Nations System Coordinator for Avian and Human Influenza, warned the world that an outbreak of avian influenza could kill 5 to 150 million people. David Nabarro later stated that as the virus had spread to migratory birds, an outbreak could start in Africa or the Middle East. Later in 2005 H5N1 spread to Turkey, Romania, Croatia and Kuwait. 2007. In January, Japan, Hungary, Russia, and the United Kingdom joined the list of nations seeing a resurgence of bird deaths due to H5N1. In February, Pakistan, Turkey, Afghanistan, and Myanmar joined the list and Kuwait saw its  first major outbreak of H5N1 avian influenza. In March Bangladesh and Saudi Arabia each saw their first major outbreak of H5N1 avian influenza and Ghana in May. As H5N1 continued killing many birds and a few people throughout the spring in countries where it is now endemic, in June Malaysia and Germany saw a resurgence of bird deaths due to H5N1, while the Czech Republic and Togo experienced their first major outbreak of H5N1 avian influenza. In July France and India also saw a resurgence of bird deaths due to H5N1. 2008. July. As of the July 25, 2008 FAO  Avian Influenza Disease Emergency Situation Update, H5N1 pathogenicity is continuing to gradually rise in wild birds in endemic areas but the avian influenza disease situation in farmed birds is being held in check by vaccination. Eleven outbreaks of H5N1 were reported worldwide in June 2008 in five countries (China, Egypt, Indonesia, Pakistan and Vietnam) compared to 65 outbreaks in June 2006 and 55 in June 2007. The "global HPAI situation can be said to have improved markedly in the first half of 2008 [but] cases of HPAI are still underestimated and underreported in many countries because of limitations in country  disease surveillance systems". Section::::"Suidae" (Pigs). Avian influenza virus H3N2 is endemic in pigs ("swine flu") in China and has been detected in pigs in Vietnam, increasing fears of the emergence of new variant strains. Health experts say pigs can carry human influenza viruses, which can combine (i.e. exchange homologous genome sub-units by genetic reassortment) with H5N1, passing genes and mutating into a form which can pass easily among humans. H3N2 evolved from H2N2 by antigenic shift and caused the Hong Kong Flu pandemic of 1968 and 1969 that killed up to 750,000 humans. The dominant strain of annual flu  in humans in January 2006 is H3N2. Measured resistance to the standard antiviral drugs amantadine and rimantadine in H3N2 in humans has increased to 91% in 2005. A combination of these two subtypes of the species known as the avian influenza virus in a country like China is a worst-case scenario. In August 2004, researchers in China found H5N1 in pigs. In 2005, it was discovered that H5N1 "could be infecting up to half of the pig population in some areas of Indonesia, but without causing symptoms [...] Chairul Nidom, a virologist at Airlangga University's tropical disease center in  Surabaya, Java, was conducting independent research earlier this year. He tested the blood of 10 apparently healthy pigs housed near poultry farms in western Java where avian flu had broken out, "Nature" reported. Five of the pig samples contained the H5N1 virus. The Indonesian government has since found similar results in the same region, Nature reported. Additional tests of 150 pigs outside the area were negative." Section::::"Felidae" (cats). "In Bangkok, Thailand, all the cats in one household are known to have died of H5N1 in 2004. Tigers and leopards in Thai zoos also died, while in 2007 two cats near  an outbreak in poultry and people in Iraq were confirmed to have died of H5N1, as were three German cats that ate wild birds. In Austria, cats were infected but remained healthy". Cats in Indonesia were also found to have been infected with H5N1. The spread to more and more types and populations of birds and the ability of felidae (cats) to catch H5N1 from eating this natural prey means the creation of a reservoir for H5N1 in cats where the virus can adapt to mammals is one of the many possible pathways to a pandemic. October 2004. Variants have  been found in a number of domestic cats, leopards, and tigers in Thailand, with high lethality. "The Thailand Zoo tiger outbreak killed more than 140 tigers, causing health officials to make the decision to cull all the sick tigers in an effort to stop the zoo from becoming a reservoir for H5N1 influenza. A study of domestic cats showed H5N1 virus infection by ingestion of infected poultry and also by contact with other infected cats (Kuiken et al., 2004)." The initial OIE report reads: "the clinical manifestations began on 11 October 2004 with weakness, lethargy, respiratory distress, and high fever  (about 41-42 degrees Celsius). There was no response to any antibiotic treatment. Death occurred within three days following the onset of clinical signs with severe pulmonary lesions." February 28, 2006. A dead cat infected with the H5N1 bird flu virus was found in Germany. March 6, 2006. Hans Seitinger, the top agriculture official in the southern state of Styria, Austria announced that several still living cats in Styria have tested positive for H5N1: August 2006. It was announced in the August 2006 CDC EID journal that while literature describing HPAI H5N1 infection in cats had been limited to a  subset of clade I viruses; a Qinghai-like virus (they are genetically distinct from other clade II viruses) killed up to five cats and 51 chickens from February 3 to 5, 2006 in Grd Jotyar (~10 km north of Erbil City, Iraq). Two of the cats were available for examination. January 24, 2007. "Chairul Anwar Nidom of Airlangga University in Surabaya, Indonesia, told journalists last week that he had taken blood samples from 500 stray cats near poultry markets in four areas of Java, including the capital, Jakarta, and one area in Sumatra, all of which have recently had outbreaks  of H5N1 in poultry and people. Of these cats, 20% carried antibodies to H5N1. This does not mean that they were still carrying the virus, only that they had been infected - probably through eating birds that had H5N1. Many other cats that were infected are likely to have died from the resulting illness, so many more than 20% of the original cat populations may have acquired H5N1." Mammals in general. H5N1 has been transmitted in laboratories to many species including mice and ferrets to study its effects. A purposely mutated strain in ferrets has engendered a notable international policy debate  regarding the openness of scientific research, the mandates of public health, and the potential for bioterrorism. H5N1 was transmitted in the wild to three civet cats in Vietnam in August 2005 and a stone marten in Germany in March 2006. The BBC reported that a stray dog in Azerbaijan died from the disease on March 15, 2006. People living in areas where the A(H5N1) virus has infected birds are advised to keep their cats indoors. "Cats can be infected through the respiratory tract. Cats can also be infected when they ingest the virus, which is a novel route for influenza  transmission in mammals. But cats excrete only one-thousandth the amount of virus that chickens do [...] The concern is that if large numbers of felines and other carnivores become infected, the virus might mutate in a series of events that could lead to an epidemic among humans. Dogs, foxes, seals, and other carnivores may be vulnerable to A(H5N1) virus infection, Dr. Osterhaus said. Tests in Thailand have shown that the virus has infected dogs without causing apparent symptoms." H5N1 has the potential to infect cattle. Asymptomatic shedding of H5N1 by infected calves and subsequent seroconversion is possible. Bird-to-calf  transmission resulting in seroconversion is probable. While the incidence of clinical infections of cattle with H5N1 in H5N1 endemic regions should be low, "serum from bovine species would be a valuable source of additional information about transmission events, especially in regions like Asia and Egypt, where HPAIV (H5N1) is endemic and probability of contact between poultry and cattle is high."