Avian influenza, human (148): pathogenesis

International Society for Infectious Diseases
<http://www.isid.org>

Source: Reuters Foundation AlertNet [edited]
< http://www.alertnet.org/thenews/newsdesk/SP54405.htm>


Research Suggests H5N1 Virus Replicates More Strongly Than Common Flu
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The H5N1 bird flu virus replicates far more aggressively in people
than common human flu viruses, a study of patients in Viet Nam has
found, offering further insight as to why the virus is so deadly. The
study, in the latest issue of Nature Medicine [see below], also found
that the virus had gotten into the blood stream of many of the human
victims it killed, which means the virus could have spread to other
parts of the body.

Menno de Jong, a key researcher in the study, explained that the
unusually high viral loads triggered intense "cytokine" responses; an
immune system overreaction that can be fatal. Cytokines are proteins
in the immune system that fight off intruders such as bacteria and
viruses. "During H5N1 virus infection, the (cytokine) response seems
to be very, very intense. Cytokines want to get rid of this intruder,
but if you have very high levels of cytokines, it can also damage the
body ... it can be directed against your own cells and organs," de
Jong told Reuters in an interview.

The study involved 18 people infected with H5N1 and 8 with human flu
in 2004 and 2005 in Viet Nam. Scientists found far higher viral loads
in the nose and throats of those infected with bird flu than human
flu. 13 of those infected with H5N1 died, and the virus was found in
the blood of at least 9 of them, implying it could have been
transported out of the respiratory tract. The virus was also found in
the rectums of most of those with H5N1, suggesting it could have
spread through the blood stream into the gastrointestinal tract.
Those with common flu had no virus in their blood or rectum. No one
died in that group.

"The fatal outcome of H5N1 infections seems to be associated with
high levels of replication of the virus and also the detection of the
virus in the blood," said de Jong, of the Oxford University Clinical
Research Unit at the Hospital for Tropical Diseases in Ho Chi Minh
City in southern Viet Nam.

The team was able to draw a connection between those who were most
ill and the level of cytokines found in them. "We found that levels
of cytokines were much higher in H5N1 patients than in the human flu
cases. Again, the highest levels of cytokines were found in those who
died of H5N1," he said. "The high levels of the virus triggered an
overwhelming inflammatory response that contributed to lung
dysfunction and eventual death."

De Jong highlighted the need to stop the virus replicating. "What's
important is to stop the replication as soon as possible, so you
prevent damage to the lungs and prevent the inflammatory response to
the virus," he said. But he conceded that early diagnosis was a
challenge, especially in remote places where health services were not
readily available.

The paper referred to above was published ahead of print on Sun 10
Sep 2006 in Nature Medicine online. The authors are Menno D de Jong
and 17 others at the Oxford University Clinical Research Unit, 190
Ben Ham Tu, Ho Chi Minh City, Viet Nam.

The paper is entitled: Fatal outcome of human influenza A (H5N1) is
associated with high viral load and hypercytokinemia.

The Abstract reads as follows:
"Avian influenza A (H5N1) viruses cause severe disease in humans, but
the basis for their virulence remains unclear. In vitro and animal
studies indicate that high and disseminated viral replication is
important for disease pathogenesis. Laboratory experiments suggest
that virus-induced cytokine dysregulation may contribute to disease
severity. To assess the relevance of these findings for human
disease, we performed virological and immunological studies in 18
individuals with H5N1 and 8 individuals infected with human influenza
virus subtypes. Influenza H5N1 infection in humans is characterized
by high pharyngeal virus loads and frequent detection of viral RNA in
rectum and blood. Viral RNA in blood was present only in fatal H5N1
cases and was associated with higher pharyngeal viral loads. We
observed low peripheral blood T-lymphocyte counts and high chemokine
and cytokine levels in H5N1-infected individuals, particularly in
those who died, and these correlated with pharyngeal viral loads.
Genetic characterization of H5N1 viruses revealed mutations in the
viral polymerase complex associated with mammalian adaptation and
virulence. Our observations indicate that high viral load, and the
resulting intense inflammatory responses, are central to influenza
H5N1 pathogenesis. The focus of clinical management should be on
preventing this intense cytokine response by early diagnosis and
effective antiviral treatment."

The authors conclude that their observations point to a central role
for high viral burden in the pathogenesis of human H5N1 disease and
suggest that timely suppression of viral replication should remain
the mainstay for treatment of H5N1 influenza. This is the most
unequivocal outcome of their investigation.

Detection of virus RNA in blood and gastrointestinal canal are other
interesting features of their data. Also their genetic
characterization of virus isolated from their patients are consistent
with other data demonstrating the importance of the viral polymerase
complex in determining H5N1 influenza virus virulence in mammals
(see: Salomon R., et al., The polymerase complex genes contribute to
the high virulence of the human H5N1 influenza virus isolate A/Viet
Nam/1203/04. J.Exp. 203, 689-697, 2006).

To what extent, however, their observations are specific for H5N1
influenza is debatable. Their 2 groups of patients were not precisely
comparable, the seasonal influenza patients being hospitalized at an
earlier stage in the disease process and possibly from urban rather
than rural communities. Of greater relevance may be the genetic
constitution of their patients, since most humans are vulnerable to
seasonal influenza, whereas few contract avian influenza.
Furthermore, detrimental chemokine and cytokine cascades can be an
accompaniment of other respiratory virus infections, such as severe
respiratory syncytial virus (RSV) infections in infancy.