- 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 H5N1in
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
- The pandemic moved into early phase 4 when antibodies
to H5N1 were found in health care works. 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
- 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 slight 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
- 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 cluster s 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 quick 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 Qingahi was followed by an outbreak of
domestic geese in Tacheng near the Kasakhstan 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 Kasakhstan 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.
- Patricia A. Doyle, PhD
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