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Time Line on H5N1 Bird Flu Pandemic Move to Phase 6

Recombinomics Commentary
June 20, 2005

Since the 2005 flu pandemic is entering the final phase 6, a review of the H5N1 pandemic timeline is useful.  H5N1 progressed in Asia from a bird flu in 1996 to a human pandemic in 2005.

H5N1 was first detected in Asia in 1996 in a duck from Guangdong Province, which moved the pandemic to phase 2.

The following year there were 18 human cases of H5N1 in Hong Kong, including 6 deaths.  This moved the pandemic into phase 3 defined by human infections.  The H5N1 was similar to the 1996 goose isolate in H and N.  The H had a poly-basic cleavage site and the N had a 19 amino acid deletion.  However, the new strain was a reassortant, with several internal genes that matched genes from H9N2 and H6N1 isolates.  In addition there was evidence for recombination, with polymorphisms normally found in mammalian isolates.  The acquisition of these polymorphisms was called "humanization".

The pandemic moved into early phase 4 when antibodies to H5N1 were found in health care workers.  These health care workers did not show signs of illness, indicating the virus could transmit to humans, but very inefficiently.  All poultry in Hong Kong was culled, eliminating this particular constellation of genes.

Between 1997 and 2003 H5N1 did considerable evolution via recombination and some reassortment and in 2003 it re-emerged in humans.  The human cases were a Hong Kong family vacationing in Fujian province.  The daughter died in China, but the father and son returned to Hong Kong.  The father died, but H5N1 was isolated from both.  The H5N1 was similar to the 1997 version in H, but there was no deletion in N and the constellation of genes was designated as the Z+ genotype.  In addition, the M2 had an amantadine resistant change at position 31 in the M2 gene.  However, this gene was more closely related to M2 from amantadine resistant swine isolates. The human cases were limited to the family, keeping the pandemic at early phase 4.

In 2004 H5N1 exploded across Asia.  There were reported bird infections in China, Japan, South Korea, Vietnam, Thailand, and Indonesia (as well as several additional countries in the area where no virus was isolated and sequenced).  In addition, there were human cases in Vietnam and Thailand.  The various isolates were similar to 2003, but had a 20 amino acid deletion in NA.  This deletion overlapped the 19 amino acid deletion seen in 1997, but was slightly further downstream. 

This constellation of genes was designated as the Z genotype.  Although all of the genes were similar, there were regional differences in all of the isolates.  A very small number had the amantadine resistant marker at position 31, but were more distant from the earlier swine isolates.  In contrast, all isolates from Vietnam and Thailand were amantadine resistant at position 31 and they had a second marker at position 26.  The second marker was not found in any isolates outside of Vietnam and Thailand.  In addition, these isolates from Vietnam and Thailand had a number of polymorphisms not seen in the other H5N1 isolates.  These markers were found in mammalian isolates.  The only reported human H5N1 cases in 2004 were in Vietnam and Thailand.

In 2004 the pandemic phase moved solidly into phase 4 with human-to-human transmission resulting in death.  There were several small familial clusters of 2-4 family members.  All of these clusters were bimodal.  Additional family members would develop symptoms 5-10 days after the index case.  One of the largest clusters was in Thai Binh in January 2004, involving a groom and his two sisters.  All three died.  The two sisters had cared for their brother.  The most well documented transmission was in Thailand last summer.  The pattern was the same, but the index case was living with her aunt and the mother was several hundred miles away in a Bangkok office.  The mother developed symptoms after she visited her daughter in the hospital.  The aunt also became infected.  Only the aunt survived.  Thus, human-to-human transmission of a fatal H5N1 was well established in 2004.  The case fatality rate in 2004 was approximately 70% in Vietnam and Thailand, at the beginning and middle of 2004.

The pandemic moved to phase 5 at the beginning of 2005.  There were reported outbreaks in birds in Vietnam, Thailand, Cambodia, and Indonesia.  The reported human cases were limited to Vietnam and Cambodia.  However, the demographics began to change within Vietnam.  The southern cases had a case fatality rate approaching 100%, while the fatality rate in northern Vietnam fell to 10-20%.  The cases in the north also covered a wider age range and the clusters grew larger. Transmission extended to health care workers and five members of a single family tested positive for H5N1, but all recovered. 

This change in demographics and size of clusters was accompanied by genetic recombination which created a version in the north with an HA cleavage site found in China and Japan in 2003 and 2004.  This newer version of H5N1 was found in northern Vietnam and Thailand, although Thailand did not report human cases in 2005.  A second version of H5N1 was found in southern Vietnam and Cambodia, where the case fatality rate was close to 100%, but clusters were smaller and less frequent.

This month there has been a new outbreak in northern and central Vietnam.  The cases are again milder, but now the number of cases has jumped markedly, with 28 cases admitted this month.  Many of most have no history of exposure to dead poultry, and most of the poultry is raised in the south, where there are also new cases of H5N1 in chickens.  The large increase of mild cases in at least 6 provinces in northern and central Vietnam may represent a small percentage of the H5N1 infection because these patients have a milder disease, and more non-hospitalized H5N1 infections are likely.  Thus, although the increased admissions may signal phase 6, the fatality rate is markedly below the rate in the south or the rate in 2004.

In addition to the new outbreaks in Vietnam, there have been two significant outbreaks in western China.  The first outbreak was discovered in early May at Qinghai Lake Nature Reserve.  Initially the deaths were limited to 180 bar headed geese, but quickly rose to over 1000 dead birds representing at least 5 species of migratory birds.  This outbreak was unusual in size and the fact that the H5N1 confirmed infection was lethal in geese.  The outbreak in Qinghai was followed by an outbreak of domestic geese in Tacheng near the Kazakhstan border in Xinjiang, China.  This H5N1 confirmed outbreak again involved lethal infections in geese.

The two outbreaks in western China were accompanied by third party reports on infections in humans.  In Qinghai there were reports of deaths of 6 tourists and 121 residents in 18 communities.  The reports of human cases have been denied by China, but new fever clinics were established.  Another third party report described a pneumonia outbreak involving patients and health care workers in Tacheng.  China again denied human cases.  WHO requested permission to visit Qinghai, but there have been no reports of that request being granted.

The large number of reported human cases in Qinghai and the isolation of health care workers in Tacheng would signal phase 6, if confirmed.  It is likely that the H5N1 would be carried to Kazakhstan and Russia by the migrating birds, although there have not been reports of H5N1 in the neighboring countries.

Thus, at this time it looks like H5N1 is moving from phase 5 to phase 6 in northern Vietnam, and may be doing the same in western China, if reports of human fatalities are accurate.

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