1. AVIAN INFLUENZA

2. Influenza: A devastating disease!
“Flu spreads across the world and ages.”
412 BC: Epidemic reported by
Hippocrates
1580: First pandemic
1781 & 1830: Epidemics Asia -> Russia
1918: Spanish Flu killed 20-40M
people
1933: First human influenza virus
isolated
1957: Asian Flu
1968: HongKong Flu
1977: Russian Flu

3. Influenza:
“The World Health Organization (WHO) estimates that seasonal influenza epidemics result in 3 to 5 million cases of severe illness and lead to 250,000 to 500,000 deaths each year worldwide.”
“Influenza affects all ages.”
DOH - Technical Working Group on Influenza, Nov. 20, 2003

4. TEN LEADING CAUSES OF MORBIDITY (No
TEN LEADING CAUSES OF MORBIDITY (No. & Rate/100,000 Population)           PHILIPPINES, 2001
CAUSE NO. RATE
1. Diarrheas
2. Bronchitis/Bronchiolitis 694,
3. Pneumonias 652,
4. Influenza 499,
5. Hypertension 318,
6. TB Respiratory 110,
7. Diseases of the Heart 47,
8. Malaria 40,
9. Measles 24,
10. Chickenpox 24,  

5. INFLUENZA: BY AGE GROUP (No
INFLUENZA: BY AGE GROUP (No. & Rate/100,000 Population)           PHILIPPINES, 2001

6. Classification RNA virus Family: Genus: Types: Man Animal Specificity:
ORTHOMYXOVIRIDAE
Genus:
Influenza virus
Influenza C virus
slide: 7
Classification
- The Influenza viruses are members of the Orthomyxoviridae, a family of RNA viruses.
- The genus, Influenza virus, includes viruses of type A and type B, and has been most closely studied since it is the most important cause of morbidity and mortality.
- In recognition of the distinctive properties of the influenza C viruses, the International Congress for Viral Taxonomy has recently placed them in a separate genus.
- Influenza A virus exists in several different species or subtypes, some of which can infect humans and animals.
- B and C viruses are mainly human pathogens and type C are thought to be relatively unimportant in causing disease in humans.
Vaccination programmes are, therefore, targeted at preventing influenza A and B.
[4] [5]
Complementary information:
As the term myxo (from the Greek myxa, meaning mucus) attests, the Orthomyxoviridae have special affinities for mucopolysaccharides and glycoproteins (in particular, for sialic acid-containing receptors on cell surfaces)
The divisions in three types are based on the antigenic differences between their nucleoprotein (NP) and matrix (M) protein antigens. (see slide 8)
Types:
Type A
Type B
Type C
Man
Animal
Specificity:
Man
Man
Kingsbury D. W., Virology, IInd edition, New York, 1990, 7

7. Structure: segmented and enveloped viruses
Nucleocapsid:
Nucleoprotein (NP) -RNA (7 or 8 segments)
Matrix protein (M)
Lipid bilayer
Haemaglutinin (HA)
Neuraminidase (NA)
Internal
antigens
Surface
antigens
slide: 8
Structure: segmented and envelopped viruses
- The virions are spherical particles 80 to 120 nm in diameter.
- The antigenic structures of influenza viruses are of two kinds:
- Internal antigens wich are components of the nucleocapsid (RNA and NP) and the protein M. They possess a type specific antigenicity.
- The RNA genome is segmented into 8 fragments corresponding to 8 different genes for type A and B (7 fragments for influenza C virus). Each fragment is closely associated with the nucleoprotein (NP) and polymerases (PA, PB1, PB2). Together with the genome, these proteins make up the nucleocapsid.
- The M protein form the inner layer of the lipidic envelope (double layer made up of lipids of cellular origin), derived from the plasma membrane of the host cell. This enveloppe gives resistance to the virus.
This segmented structure explains the aptitude of the influenza viruses for genomic reconstruction (see slide 15).
- Surface antigens (or external antigens) are the glycoproteins: haemagglutinin and neuraminidase. Both are subtype and strain specific antigens. They form the spicules which project out from the surface of the virion.
- the Hemagglutinin (HA) spicule: distributed evenly on the surface of virions. It is one of the major antigens of the influenza virus. The HA spike is the site for the attachment (see slide 20) of the virus to host cells to initiate infection. HA induces antibody that directly neutralizes viral infectivity by preventing attachment of the virus to host cells.
- the Neuraminidase (NA) spicule may play a role in the attachment of the virus to the cell and in the release of newly produced virus particles from infected cells. Proportion is 1 NA for 4 HA.
The HA and NA proteins are important for viral infectivity and host immunity. [3] [5]
80 to 120 nm
Kingsbury D. W., Virology, IInd edition, New York, 1990, 8

8. Antigenic drift Affects Influenza A and B viruses
Occurs every year or every few years within an influenza subtype
Mutations affecting RNA amino acids
Does not result in new subtype
Can result in significant epidemics

9. Antigenic shift: emergence of a "new" virus worldwide
affects only Influenza A virus
major and sudden genetic variations in HA and/or NA
no immunity in population
intervals between previous pandemics - 11 to 42 years
last pandemic in 1968/69
slide: 15
Genetic shift: emergence of a "new" virus worldwide
The major and sudden antigenic shifts that herald pandemic influenza presumably result from a different mechanism than the one which produces the drifts.
- The antigenic shift affects only human and animal Influenza A viruses.
- These viruses are "new" viruses to which the population has no immunity. There is very little or no serologic relationship between the HA and/or NA antigens of the "old" and "new" virus; hence, in nomenclature, each receives a different designation. In this century, three "new" HA and two "new" NA have appeared in human
- Pandemics have occured every 10 to 40 years
- The mechanism of antigenic shift is explained by the migration and genomic reconstruction of RNA segments, coding for one of the two glycoproteins. The introduction of a "new" segment of RNA resulting in a new surface glycoprotein has been shown to be most easily explained by genetic reassortment.
Complementary information:
Suppose two different strains of the influenza A virus , for example a human strain and an avian strain simultaneously infect the same host cell. During the virus replication process, it is possible that a new hybrid virus contains a mixture of genes from both human and avian viruses. If the genes which code for HA or NA in the new strain are derived from avian material, they will code for surface antigens which are not recognised by existing antibodies in the human population. The new strain therefore has a great evolutionary advantage over old strains and, provided it possesses other properties such as virulence and transmissibility, people of all ages will be susceptible to it and a worlwide outbreak of influenza, a pandemic, can occur. In theory, a very large number of new strains could be produced by reassortment between human and animal influenza A viruses. [3] [8] [9] 15

10. What is Bird Flu?
An infectious disease of birds ranging from mild to severe form of illness.
All birds susceptible to avian influenza, though some species are more resistant to infection than others.
Some forms of bird flu infections can cause illness to humans.

11. What causes bird flu?
Bird flu is caused by15 subtypes of influenza A virus subtype of avian influenza .
Viruses of low pathogenicity can, after circulation for sometimes short periods in a poultry population, mutate into highly pathogenic viruses.

12. Host distribution of influenza A subtypes
HA subtypes
NA subtypes
Man
Swine
Horse
Seal
Turkey
Duck + H1 + H2 + H3 + H4 + N1 + N2 + H7 + N7 + N8 + N5 + H5 + H6 + H9 +
H10 + N3 + N4 + H8 +
H15 + N6 + N9
slide: 9
Host distribution of influenza A subtypes
The maintenance of the virus in nature probably depends on a chain of serial transmission in species in which congregation occurs. This attribute characterizes all the species in which propagated interspecific infections have been demonstrated.
The striking points made by this tabulation are :
-the wide representation of HA and NA antigenic subtypes in avian species, especially in ducks,*
-conversely, the limited number of subtypes recovered from outbreaks in mammals, including man,
-and the lack of restriction of any HA or NA subtype antigen to human or other mammalian species.
Of these, only H1N1, H2N2, and H3N2 viruses have been isolated from human infections and H2N2 virus disappeared in So viruses of H1N1 subtype continue to cocirculate with H3N2 strains at this writing.
Although the HAs of B viruses also show extensive variation in antigenicity, subtypes of neither B- nor C-type viruses have been distinguished.
[5] [6][7] [8]
complementary information:
* To date, fifteen distinct HA subtypes and nine NA subtypes have been identified in human, swine, equine, and avian influenza A viruses. Some antigenic cross reactivity is sporadically demonstrable among them. All the influenza viruses of mammalian sources originated from the avian gene pool.
Two partly overlapping reservoirs of influenza A viruses exist in migrating waterfowl and shorebirds throughout the world. These species harbor influenza viruses of all known HA and NA subtypes.
To date, all outbreaks of the highly pathogenic form have been caused by influenza A viruses of subtypes H5.
Kilbourne E. D., Influenza, New York, plenum 1987:229-51 9

13. Avian Flu in 1997
A/ QUAIL/HONG KONG /G1/97 VIRUS
1997 – H5N1 – Hongkong, 18 human cases, 6 died (30% mortality)
Birds - actual source of human infection
No person –to- person transmission.
This occurrence highlighted the potential of new and lethal pathogens to emerge unexpectedly.

14. Recent cases of human infection caused by avian influenza viruses (New Influenza Virus Subtypes)
H5N1 - Hongkong, 18 cases, 6 human deaths
1999 – H9N2 - Hongkong, I human case, mild infection
2003 – H5N1 – Hongkong – 2 human cases, 1 death
H7N7 – The Netherlands, hundreds with
conjunctivitis, ILI , 86 confirmed,
3 cases w/ human-to-human
transmission, 1 human death (a
veterinarian)
H9N2 – Hongkong – 1 human case, mild infection
H5N1 - South Korea, Japan – death of chickens,
no human case
H5N human cases and death in Vietnam and
Thailand.

15. How is bird flu transmitted to chickens and other birds?
Direct contact with discharges from infected birds, especially feces and respiratory secretions
Contaminated feed, water, cages equipment, vehicles and clothing
Clinically normal waterfowl and sea birds my introduce the virus into flocks
Broken contaminated eggs may infect chicks in the incubator

17. How is bird flu transmitted in chickens and other birds?
Birds that survive infection excrete virus for at least 10 days, orally and in feces
Highly pathogenic viruses can survive for long periods in tissues, water and the environment, especially when temperatures are low.

18. How is bird flu transmitted to humans?
Direct or indirect contact with infected wild ducks and chickens through infected aerosols, discharges and surfaces.
Based on present knowledge, there appears to be no risk of transmission of the H5N1 virus to humans from raw, chilled or frozen poultry foods.
Since the virus is easily inactivated by heat, one does not get bird flu from thoroughly cooked chicken meat.
No evidence of human-to- human transmission.

19. Why are we concerned with bird flu?
With its capacity to cause severe disease (high pathogenicity ) and epidemics, it causes severe epidemics and mass death of chickens
The poultry industry and food security feared to be greatly affected
High mortality to humans

20. Why are we concerned with bird flu?
Influenza A viruses have the capacity and propensity to mutate and recombine with another subtype of influenza virus in humans resulting into a totally new influenza A virus subtype.
This new subtype having the characteristic of human influenza virus of being capable to spread from one person to another.
The absence of immunity to the totally new virus through previous infection and no existing vaccines can confer protection make the human population vulnerable, leading to high number of cases and deaths worldwide (pandemic).

22. Hypothesis concerning pandemics occurence
Direct transfer of viruses between animals and humans
New subtypes are reassortants of human and waterfowl Influenza virus
Pig or humans - "mixing vessel" of human and avian influenza virus
South China: Pandemics starting-point?
Wild
aquatic birds
Humans or
Swine
Human
slide: 16
Hypothesis concerning pandemics occurence
- New pandemic influenza A strains seem to be created by reassortment between avian and the prevailing human strain
- Aquatic birds are the source of all influenza viruses in other species.
- Since human influenza viruses do not spread in birds and vice versa we have to assume that this reassortment occurs in a species which is rather tolerant in accepting viruses from the human as well as the avian reservoir.
- Since pigs exhibit a quite low species barrier towards avian as well as human strains, they are regarded to function as "mixing vessels" by becoming doubly infected with human and avian influenza A viruses relatively easily.
- Subtypes new to man arise from hybridation between human and animal Influenza A viruses.
Complementary information:
- It is well-known fact that all influenza pandemics in this century have started in the region of South China. In this area pigs mainly live with the farmers under the same roof, andthey are chased into rice fields after the harvest, where they meet ducks, which often are infected with influenza viruses. Thus in this region the probability of double infection of pigs with human and avian influenza strains is highest, and may explain why pandemics always seem to originate from this region.
[8][12] [13]
Kawaoka Y., Bean W. J., Gorman O.T., et al. In : Elsevier Science Publishers B.V. 1992:
Scholtissek C, Shultz U, Ludwig S, Fitch WM. In : Elsevier Science Publishers B.V. 1992: 16

23. Subtype emergence and recirculation
20th century pandemics
Extent of antigenic change in
indicated surface protein
Severity of
pandemic
Year
Designation
1918
1957
1968
1977
"Spanish flu" H1N1
"Asian flu" H2N2
"Hong Kong flu" H3N2
"Russian flu" H1N1
HA/NA: major change
HA: moderate change
recirculation
Severe
Moderate
Mild
slide: 17
Subtype emergence and recirculation
- Pandemics occur less frequently than epidemics, however four have been recorded in this century:
- Swinelike influenza virus (H1N1) is believe to have caused the catastrophic pandemic in The seroepidemiological information suggested that human strains recirculate, and the reapearance of the H1N1 strain in 1977 gives credence to this belief. Until the first human influenza virus was isolated in 1933, it was impossible to tell with certainty which pandemics were caused by influenza virus.
- Since 1933, major antigenic shifts occured in 1957 when the H2N2 subtype (Asian influenza) replaced the H1N1 subtype, in 1968 when the Hong-Kong (H3N2) virus appeared. In 1977 the H1N1 virus reappeared. The most severe pandemics have resulted when major alterations occured in both of the major surface antigens [9].
- Since 1977, H1N1 and H3N2 co-exists; this is a unique situation.
Although a pandemic is responsible for higher morbidity and mortality than an epidemic because it infects a larger part of the population, the interpandemic burden of influenza deaths and severe illness is cumulatively greater than that of pandemics.
Complementary information:
The severe pandemics affected in 2 successive waves 80 to 100% of the world's population.[10]
When H1N1 reappeared, it mostly caused illness in children and young adults because healthy older population had residual immunity to this subtype. Today H1N1 remains important and can affect, people of any age all over the world. [14].
Betts FR, Douglas RG, Mandell G.L., Douglas R. G., Bennett J.E., Principles and practice of infectious diseases, 3rd ed., 1990;39: 17

24. What are the signs of bird flu in chickens?
Sudden onset, severe illness
Severe depression, inappetence
Drastic decline in egg production
Facial edema with swollen and cyanotic combs and
wattles
Petechial hemorrhages on internal membrane
surfaces
Sudden deaths (mortality that can reach 100%)
Virus isolation needed for definitive diagnosis

25. What are the signs and symptoms of bird flu in humans?
A (H5N1) infection very similar to other influenza viruses, most will be self-limiting
Initial symptoms are fever, malaise, myalgia, sore throat and cough.
Conjunctivitis in some patients
Persistently high fever
X-ray of the chest is useful in detecting early viral pneumonia.
Complications and death due to severe pneumonia, respiratory distress syndrome and multi-organ failure.

26. 8. Since there are so many cases of influenza, pneumonia or any other respiratory illness, when does one suspect that the patient is a case of bird flu?
If the patient has had direct or indirect contact through handling or having taken care or getting near sick chickens or other birds.
A laboratory confirmation of the bird flu infection and epidemiologic link with unusual death or epidemics of chickens will support the diagnosis of bird flu.

27. What is the treatment of bird flu?
One should not wait for the laboratory diagnosis of H5N1, infection before treatment is started.
Treatment for HSN, infection is essentially the same as for other influenza viruses.
Antiviral drugs for both treatment and prevention, but have some limitations.

28. How do we prevent bird flu?
The ban on importation of live chickens and other poultry products from countries affected with bird flu is a critical step to prevent the entry of bird flu into the country.

29. How do we prevent bird flu?
For poultry caretakers and handlers of chickens and other birds:
Avoid contact of poultry with wild birds, in particular waterfowl
Do not import/ avoid introduction of birds of unknown health condition into flock
Control human traffic into poultries
Practice proper hand washing and cleaning and disinfection procedures in poultries
Report to authorities any unusual death or illness of chickens and other birds
Report to authorities any illness among the workers in poultry farms

30. How do we prevent bird flu?
For consumers and the general public:
Thoroughly wash hands with soap and water before and after handling chicken meat
Clean kitchen surfaces and utensils before and after use
Cook chicken well by seeing to it that the boiling temperature is reached
Go only to places where there are no wild waterfowl
Report to authorities any unusual death or illness of chickens and other birds
Report to authorities any case of respiratory illness with history of exposure to sick or dead chickens and other birds

31. How do we prevent bird flu?
♦ Everyone should consider getting a vaccine for influenza.
Priority should be given to those who are directly exposed
to birds.

32. Is it safe to travel to countries affected with bird flu?
Bird flu is not transmitted from one person to another.
Individuals at risk are those who are directly or indirectly exposed to sick chickens and other fowl.
The government thereby advises travelers to countries affected with bird flu not to go to bird parks (aviaries) and poultry farms.

33. Summary
Avian influenza viruses can infect and have infected people through close, unprotected direct contact with infected poultry.
Human infection with high path avian influenza viruses has resulted in mild to severe illness.
There is no current evidence of sustained person to person transmission.
However, these viruses are continuing to evolve and have the potential for genetic resentment to evolve into a virus that may be more easily transmissible among humans which can result to a pandemic .