Avian Influenza A (H5N1) viruses among birds continues

to cause human disease with high mortality and to pose the threat of a pandemic

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

Patients with confirmed Influenza A (H5N1) illness

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 pandemic killed between 20-40 million people

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 2008Nature 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 tetramer

The inner side of the envelope is lined by the matrix protein.

Paul Digard, Dept of Pathology,University of Cambridge

Host RangeGenus Host

Influenza A virus

Most dangerous

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 between birds and human:

Determined by different forms of sialic acid present on the virus glycoprotein-

Haemagglutinin protein

Human viruses Avian viruses HA226leu HA 226gln

Pig is a mixing pot

Replication

M2NeuraminidaseHemagglutinin

Ns-1

PB2, PB1 and PA

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 14th , 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 ?

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.

Most Probably Yes

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 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-γ, TNF-α, IL-5,IL-13.

H5N1 binds to α 2,3-linked sialic acid receptor on avian cells

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 Influenza A (H5N1) virus.

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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 :

NATURE BIOTECHNOLOGY VOLUME 26 NUMBER 1 JANUARY 2008

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 population?

An integrated biochemical, 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 topology.

Laboratory diagnosticInitial diagnosis by Real –time PCR ( from nasal swab, throat swab)

Hemagglitination-inhibition assay/microneutralization assay—labor –intensive and require BSL3 facility.

Clinical features

Severe pneumonia/ Acute respiratory distress syndromeOther syndromes (listed in the paper)

Treatment Antiviral agents

Oseltamivir Synthetic sialic acid Zanamivir analogues

Amantadine Block membrane ion Rimantadine

channels

Combined Oseltamivir and amantadine

Other treatment Corticosteroid

Viral latency /Opportunistic infection

Immune suppression -adverse effect of steroid

Prevention

Antiviral Chemoprophylaxis

Immunization

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 Providence of China)