Avian Infl

uenza A

(H 5N 1)
viruses am ong birds continues to

hum an

cause
disease w ith high
m ortality and to pose the threat ofa
pandem ic

Patients w ith conf r

im ed Inf u
l enza A
(H 5N 1) 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

Pandem ic
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

pandemic killed between

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 contributing

factor to epizootics.

Published online 6 january,2008

The Journal of Immunology

E-

pub (www.jimmunol.org)

Published online 6 January 200

Nature Biotechnology

 The outer surface of the

Inf u
l enza virus particl
es m ostl
y
particle
consists
of a lipid
spherical/ovoid, 80-120nm
diam
eter
envelope
-which
project two
types of

glycoprotein

spikes

haemagglutinin (HA), a

135 trimer
neuraminidase (NA), a 60
tetramer

The inner side of the

Paul Digard, Dept of Pathology,
University of Cambridge

envelope is lined by the

matrix protein.

H ost R ange
Genus
Influenza A virus

Most
dangerous

Host
Main Human
Pathogen but also
infects Horses,
pigs,ferrets, birds

Influenza B virus

Infects mammals only

Influenza C virus

Infects mammals only but

rarely causes diseases

Species barrier betw een birds

and hum an:
D eterm ined by diff
erentform s ofsialic acid present
on the virus glycoprotein-

H aem agglutinin protein

H um an viruses Avian viruses
H A 226 leu
H A 226 gln
Pig is a m ixing pot

R eplication

PB2, PB1
and PA

Ns-1

HemagglutininNeuraminidase M2

Hemagglutinin
Determine species
specificity for
avian 2,3 linked or
human 2,6 linked sialic
acid
Residues

Epidem iology of H um an 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
be 3-5 days or 8-9 days.

it could

Incidence and D em ographic Characteristics

Influenza A (H5N1) disease in

human is very rare.

Number of confirmed

cases of H5N1 virus infection is

Increases in human cases of H5N1 have been observed during

th

, 2007.

cooler months.

Infection rate and case fatality is more prevalent among younger individual (
compare to older individual

340 as of Dec 14

age 40 or below

( 50 yrs of age or older)

How age can be a factor for the ability of the virus to infect and cause fatality ?

W hether preexisting im m unity 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*

The Journal of Immunology, 2008, 180: 1758

1768.

Human immune system is nave 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 epitopesImmunological memory

Im m unologicalm em ory
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 provides lasting
protective immunity.

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-, TNF-, IL-5,IL-13.

H 5N 1 binds to

2,3-linked sialic acid

receptor on avian cells

Ta
ce rg
lls et

Lung

herkules.oulu.fi/.../html/equation11

H5N1 virus can acquire mutations that permit binding to both

2,3-linked sialic acid receptor and 2,6-linked sialic acid receptor

Changes in multiple viral genes are probably required to
generate a potentially pandemic Influenza A (H5N1) virus.

N ow the question arises how H 5N 1

can cause infection in hum an ?
A

switch in specificity of H5N1

hemagglutinin (HA) from avian like

(2-3-linked sialyated glycans

) to human- like (2-6 sialyated
glycans) receptors is believed to be
associated with their adaptation to
infect human

G lycan topology determ ines hum an adaptation of avian

H 5N 1 virus hem agglutinin :
NATURE BIOTECHNOLOGY VO LUM E 26 NUM BER 1 JANUARY 2008

a characteristic structural topologyand not the a2-6 linkage itselfenables 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.

W hy H 5N 1 viruses have not yet gained a

foothold in the hum an population?

biochemical,
analytical and data mining

An integrated

approach demonstrates that from the

human-adapted H1N1 and H3N2 viruses,
but not H5N1 (bird flu) viruses, specifically
bind to long 2-6 sialylated glycans with this
topology.

Clinical features

Severe pneumonia/
Acute respiratory distress syndrome
Other syndromes (listed in the paper
Laboratory diagnostic

Initial diagnosis by Real time

PCR ( from nasal swab, throat
swab)
Hemagglitination-inhibition
assay/microneutralization assay
labor intensive and require

Treatm ent
Antiviral agents

Oseltamivir
Zanamivir

Amantadine
Rimantadine

Synthetic sialic acid

analogues

Block membrane ion

channels

Combined Oseltamivir and amantadine

Other treatment

Corticosteroid

Immune suppression
-adverse effect of steroid

V iral laten cy
/O p p ortu n istic in fection

Prevention
AntiviralChem oprophylaxis
Im m unization

Increased V irus 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 Providence of China)