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Avian Influenza A (H5N1)

viruses among birds continues to


cause human disease with
high mortality and to pose the
threat of a pandemic
Patients with confirmed Influenza A
(H5N1) illness

Writing Committee of the Second World Health Organization Consultation on Clinical Aspects
of Human Infection with Avian Influenza A (H5N1) Virus. N Engl J Med 2008;358:261-273
Pandemic
 According to the
World Health Organization (WHO), a
pandemic can start when three
conditions have been met:

 the emergence of a disease new to the population.


 the agent infects humans, causing serious illness.
 the agent spreads easily and sustainably among
humans.

 The Influenza of 1918


Epizootic

 In epizoology, an epizootic (from


Greek epi- upon + zoion animal) is a
disease that appears as;

new cases in a given animal


population, during a given period, at
a rate that substantially exceeds
what is "expected" based on recent
experience (i.e. a sharp elevation in
the incidence rate).

 High population density is a major


Published online 6 january, 2008


The Journal of Immunology
 E-
pub (www.jimmunol.org)

Published online 6
January 2008
Nature Biotechnology
Influenza virus particles mostly
spherical/ovoid, 80-120nm diameter

 The outer surface of the


particle consists of a lipid
envelope-which project two
types of
 glycoprotein
spikes :

 haemagglutinin (HA), a
135Å trimer
 neuraminidase (NA), a 60Å
Paul Digard, Dept of
tetramer
Pathology,
University of Cambridge
Host Range
Species barrier between birds
and human:
Replication
PB2, PB1
and PA

Ns-
1

Hemaggluti Neuraminid M
nin ase 2
Hemagglutinin

Determine species
specificity for
avian α 2,3 –linked or
human α 2,6 –linked sialic
acid
Residues
Epidemiology of Human
Infections

 Incidence and Demographic


Characteristics

 Transmission
 Handling of dead and sick poultry during the
week before the onset of illness –

 Consuming raw or uncooked poultry

 Incubation Period
2-5 days

If happened human –to -human transmission


it could be 3-5 days or 8-9 days.
Incidence and Demographic
Characteristics

 Influenza A (H5N1) disease in


human is very rare.
 Number of confirmed cases of H5N1 virus infection is 340 as of Dec 14
th , 2007.

 Increases in human cases of H5N1 have been observed during cooler months.

Infection rate and case fatality is more prevalent among younger individual ( age 40 or below )

compare to older individual ( 50 yrs of age or older)

How age can be a factor for the ability of


the virus to infect and cause fatality ?
Whether preexisting immunity and
exposure could contribute ?

Most
Probably Yes
 Healthy Human Subjects Have CD4 T
Cells Directed Against
 H5N1 Influenza Virus

Michelle Roti,* Junbao Yang,* DeAnna Berger,* Laurie


Huston,* Eddie A. James,*and William W. Kwok2*†
Human immune system is naïve to the
newly emerged H5N1 virus

Most adults immune system are


acquainted with H1N1 and H3N2 viruses
through vaccination or infection

Adult born before 1968 have likely been


exposed to H2N2 virus

CD4+T cells generated in response to


H1N1, H3N2 and H2N2 influenza A
viruses also recognize H5N1 epitopes-

Immunological memory
Immunological memory
- After infection
(antigen) is cleared
majority of effector
cells die by apoptosis
(programmed cell death).
- However, a significant
number persist as
memory cells –
immunological
memory.
- Immunological
memory ensures
rapid response on a
second encounter
with a pathogen, and
thereby usually
Pathogenesis
Viral Factors

Viral Replication
•Bronchiolar and alveolar cells, upper and
lower respiratory track
•Viral RNA persists in the respiratory track
upto 3 months
Pathological Findings
•Diffuse alveolar damage, inflammatory cells
and apoptosis in alveolar cells
Host Responses
•Increased level of imflammatory
cytokines IFN-γ, TNF-α, IL-5,IL-13.
H5N1 binds to α2,3-linked sialic acid
receptor on avian cells

L
ung
lls et
ce rg

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herkules.oulu.fi/.../html/equa
tion11

H5N1 virus can acquire mutations that permit


binding to both α 2,3-linked sialic acid receptor
and α2,6-linked sialic acid receptor
Changes in multiple viral genes are probably
required to generate a potentially pandemic
Now the question arises how H5N1
can cause infection in human ?

 A switch in specificity of H5N1


hemagglutinin (HA) from avian like
(α2-3-linked sialyated glycans
) to human- like (α2-6 sialyated
glycans) receptors is believed to be
associated with their adaptation to
infect human
Glycan topology determines human
adaptation of avian H5N1 virus
hemagglutinin :

 a characteristic structural topology—and


not the a2-6 linkage itself—enables
specific binding of HA to a2-6 sialylated
glycans

 recognition of this topology may be


critical for adaptation of HA to bind
glycans in the upper respiratory tract of
humans.
Why H5N1 viruses have not yet
gained a foothold in the human

biochemical,
 An integrated
analytical and data
mining approach demonstrates
that from the human-adapted H1N1
and H3N2 viruses, but not H5N1 (bird
flu) viruses, specifically bind to long
α2-6 sialylated glycans with this
Clinical
features Severe pneumonia/
Acute respiratory distress
syndrome
Other syndromes (listed in the
Laboratory diagnostic

• Initial diagnosis by Real –time PCR


( from nasal swab, throat swab)
• Hemagglitination-inhibition
assay/microneutralization assay—
labor –intensive and require BSL3
facility.
Treatment
 Antiviral agents
 Oseltamivir Synthetic sialic acid
 Zanamivir analogues

 Amantadine Block membrane


ion
 Rimantadine
channels

 Combined Oseltamivir and


amantadine
Immune suppression
-adverse effect of steroid

VIRAL LATENCY
/OPPORTUNISTIC
INFECTION
Prevention
Increased Virus threat

 increasing open trade in food


/ animal products / pets
 faster human transportation
in the shrinking world
 species jump
Viruses listed as threat

Human deficiency virus (from Africa)


From chimpanzee or other non human
primates

West Nile Virus (WNV) (from the middle


east)
From birds via mosquitoes

H5N1 avian influenza virus (from east Asia


)
From birds directly

• SARS( Severe acute respiratory


syndrome virus )(from Guangdong