Avian/Bird Flu Virus: Poultry Pathogen Having Zoonotic and Pandemic Threats: A Review
Shyma K. Latheef,
Mohd Yaqoob Wani
Avian/Bird flu, caused by Avian Influenza Virus (AIV) belonging to Orthomyxoviridae family, is the most fearful viral disease of birds. H5N1 subtype of AIV is of major concern for poultry as well as for humans due to its high economical impacts and zoonotic concerns. During the past ten years, the Highly Pathogenic Avian Influenza (HPAI) H5N1 subtype alone has affected more than 60 countries of the world. Domestic poultry is mostly affected by the disease episodes and outbreaks. Wild and migratory birds are the AIV reservoirs wherein H5N1 is found to be lethal. Major antigenic changes in Haemagglutinin (HA) or Neuraminidase (NA) result in periodic pandemics. Pigs can act as mixing vessel. The bird flu virus if gets the capability of transmitting from human to human can trigger a pandemic claiming millions of lives. A wide variety of serological tests and molecular tools have greatly aided in the diagnosis of avian flu. Disease management for the prevention of bird flu outbreaks including mass awareness and pandemic preparedness following World Health Organization (WHO) guidelines is of utmost importance. Interesting approaches of HPAI control are development of universal influenza virus vaccines and universal antibodies-based flu therapies. Vaccination using inactivated and recombinant vaccines is the common strategy adopted in different parts of the globe. Development of new generation vaccines is quiet noteworthy. Tamiflu is the drug of choice. Herbal therapy is gaining much attention to control disease in humans. All these aspects of the bird flu virus have been discussed vividly in the present review.
Received: March 26, 2013;
Accepted: April 19, 2013;
Published: June 13, 2013
Bird flu, also known as avian influenza/fowl plague/fowl pest/avian flu/chicken
ebola, is the most fearful viral disease of birds and particularly affects domesticated
birds with very high flock mortality (upto 100%). The disease is of great economical
significance along with having zoonotic potentials and probable pandemic threats.
Its etiological agent Avian Influenza Virus (AIV) causes infections from subclinical
to highly virulent disease in poultry birds. The virus was first detected in
1878 in poultry flocks in Italy and thereafter disease outbreaks in poultry
have been reported worldwide (Sims et al., 2005).
Important reservoirs of AIV are free flying migratory/wild birds, ducks and
geese, where infection is mostly inapparent/subclinical and clinical disease
is generally not observed (Singh et al., 2003).
On the basis of pathogenicity the disease is categorized into Highly Pathogenic
Avian Influenza (HPAI) and Low Pathogenicity Avian Influenza (LPAI). HPAI is
an extremely contagious, multi-organ systemic disease and is a listed disease
of World Organization for Animal Health (OIE) and there is risk of spread of
the disease beyond the national boundaries. Control is difficult due to extreme
genetic alteration. Earlier the AIV H5N1 subtype was restricted to poultry but
now involves migratory birds also and has emerged in mammals and among human
population too. Recent reports have indicated H5N1 subtype to be lethal in reservoir
birds (migratory/wild) too (Dhama et al., 2005;
Munster et al., 2007; Reperant
et al., 2011; Cappelle et al., 2012).
Thus, the virus is continuously evolving and becoming more and more lethal.
During the past ten years, many countries have confirmed the AIV H5N1 subtype
outbreaks in poultry populations resulting in tremendous monitory losses (Millions
of chickens and other birds have died or been slaughtered to contain the infection).
These recent waves of HPAI have highlighted the global impact of this transboundary
animal disease (Swayne and Suarez, 2000; Chen
et al., 2005; Dhama et al., 2005;
Thomas and Noppenberger, 2007; Tiwari
and Dhama, 2012).
The AI virus has yet to acquire the ability of rapid spread from human to human,
as has been observed recently for the swine flu virus (H1N1 subtype) (Dhama
et al., 2005, 2012a; Pawaiya
et al., 2009). This kind of human to human transmission of bird flu
virus can trigger a human pandemic claiming millions of lives like that happened
during the spanish flu of 1918 in which human influenza virus of
H1N1 subtype got evolved causing more than 40 million deaths globally (Liu
et al., 2009). If bird flu pandemic happens then this deadly avian
pathogen could cause serious socio-economic and public health consequences (Dhama
et al., 2013a). In preventing disease in fowls, judicious and strict
biosecurity and disease surveillance measures along with proper culling and
vaccination strategies are of utmost importance; thereby further helping to
limit epidemic and human pandemic threats. Vaccine for human influenza does
not prevent avian influenza infection in people. To protect both birds and humans
against H5N1 effective vaccination is required (Mathew et
al., 2006; Tiwari and Dhama, 2012).
Avian/bird flu is caused by Avian Influenza Virus (AIV), a Type A influenza
virus [Genus: Influenzavirus A, Family Orthomyxoviridae]. AIV is a negative
sense single stranded (ss) RNA virus, 80-120 nm diameter. It is an enveloped
virus with 10-12 nm long spikes or projections [rod
shaped Hemagglutinin (HA) and mushroom shaped Neuraminidase (NA) glycoproteins].
Influenza viruses are classified into subtypes based on haemagglutinin (H1-17)
and neuraminidase (N1-10) antigens. All the 16 H and 9 N in all possible combinations
have been isolated from birds. Recently, H10 and N10 have been also discovered
(Dhama et al., 2012b). Highly fatal infections
are associated with the H5 and H7 subtypes which posses multiple basic amino
acids at the cleave site of H protein (Dhama et al.,
2005; OIE, 2012). HA glycoprotein is responsible
for hemagglutinating activity and virus attachment to host cells and producing
protective antibodies in host after infection (Kumari et
al., 2007). NA glycoprotein aids in the release and spread of new virus
from the infected cell. The virus is unstable in the environment and heat, high
or low pH and dryness can inactivate the virus and is susceptible to a variety
of detergents and disinfectants. Long term storage of viruses should be done
at -70°C or following lyophilization. Avian influenza virus is killed at
a temperature of 56°C for 3 h, 60°C for 30 min, 70°C for 3 min and
80°C for 1 min (Dhama et al., 2005; Hampson
and Mackenzie, 2006).
Genomic/antigenic variation: Influenza viruses undergo genetic/antigenic
variations by antigenic drift (point mutation) and genetic reassortment (antigenic
shift). Evolution of new strains (belonging to same subtype) occurs due to accumulation
of point mutation. These minor antigenic changes in HA or NA, results in frequent
epidemics (Dhiman et al., 2010). A completely
new subtype or a novel strain is evolved by genetic reassortment. Viral genome
has eight segments and during mixed infection these are capable of re-assorting
with segments from other influenza viruses (human, avian, swine). In a mixed
infection with two strains there is a possibility of generation of 256 (28)
genetically different progeny viruses. Periodic pandemics are the outcomes of
mutation in HA or NA. Genetic reassortment occurs as pigs can act as mixing
vessels as well as intermediate host for evolution of influenza viruses having
pandemic potential (Olsen, 2004). 17 H subtypes (H1-H16)
and 10 N subtypes (N1-N9) can rise to 170 possible combinations (designated
as H1N1, H1N2, H5N1, H7N2, H7N3, H7N7, H17N10 etc.) (Dhama
et al., 2005, 2012a; Forrest
and Webster, 2012; Gamblin and Skehel, 2010). Interest
regarding the origin and evolution of influenza viruses has been raised by the
H17N10 virus genome even though the H17 HA shares considerable amino acid sequence
identity with the other 16 HA subtypes. The N10 genes of this virus (from little
yellow-shouldered bats) code for the NA-like (NAL) protein and shows extensive
divergence from known influenza NAs (Tong et al.,
2012). H5N1 is of particular concern having the ability to mutate rapidly.
Presently, the circulating H5N1 subtypes have gained the ability to cross/jump
the species barrier and to affect animals (pigs and carnivores such as tigers,
cats and leopards) as well as human beings besides causing high mortality in
birds (Kuiken et al., 2011). Gene swapping between
influenza viruses can occur in pigs between avian, swine and human viruses.
AIV can escape infection as well as vaccination induced immunity, thus helping
more pathogenic biovars to evolve thereby causing more outbreaks and epidemics
(WHO/OIE/FAO H5N1 Evolution Working Group, 2012). Even
though only H5 and H7 subtypes cause HPAI, most of these subtypes are of low
virulence. But mutation can help converting viruses having low pathogenecity
to those having high pathogenecity after short duration circulation (Webster
et al., 1992; Dhama et al., 2005;
Caron et al., 2008).
Globally, AIV has caused chaos in poultry industry leading to enormous economic
losses worldwide (Alexander, 2000, 2007;
Dhama et al., 2005; Kataria
et al., 2005a; Adams and Sandrock, 2010).
Particularly, the H5N1 subtype affected more than 60 countries with losses of
more than 300 million birds and 368 human lives, indicating the flu virus is
becoming more and more dangerous. Following countries have reported most number
of AIV H5N1 disease outbreaks in poultry (from end of 2003 to 12th March, 2013):
Vietnam (2681), Thailand (1141), Egypt (1084), Bangladesh (546), Romania (273),
Indonesia (261), Turkey (219), Russia (149), Myanmar (115), Korea (Rep. of)
(112), China (Peoples Rep. of) (105), India (93), Nigeria (65), Pakistan
(51). In the year 2013 (till 12th March, 2013), countries reporting bird flu
are Bangladesh, Bhutan, Cambodia, Hong Kong (SAR-PRC), India and Nepal (Adams
and Sandrock, 2010; WHO, 2011; WHO/OIE/FAO
H5N1 Evolution Working Group, 2012).
Host range, transmission and spread: Virus can naturally infect a wide
variety of avian species and is primarily a disease of domesticated poultry
such as fowl and turkeys. Turkeys followed by chickens are the most susceptible
species. Quails, guinea fowls, pheasants, partridges, geese and ducks (Mallards
and Muscovy) are also susceptible. Ostriches, passerine birds and pheasants
can also be infected (Alexander, 2000; Dhama
et al., 2005, 2008a). Virus is highly contagious
and can spread very fast and easily could cross the continents. AIV is usually
introduced into one country through wild fauna and subsequently spreads to the
domestic flocks directly via wild and domestic birds or indirectly through contaminated
fomites (Munster et al., 2007; Feare,
2007). Virus is transmitted by direct contact between infected and susceptible
birds or indirect contact through air borne droplets or exposure to contaminated
feed and fomites, secretions, aerosols, faeces, water, equipments and clothings.
Faeco-oral is the major route of transmission. One gram of infected bird feces
is capable of infecting one million (10 Lakh) susceptible birds. Wild/migratory/free
flying birds, ducks and geese, are important reservoirs of influenza viruses,
these birds constantly shed virus through their respiratory secretions and droppings
which helps virus to persist in environment (Brown and
Stallknecht, 2008; Dhama et al., 2008a).
AIV H5N1, H5N2, H5N3, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2, H10N7 and also
H1N2, H2N2, H6N1 and H3 subtypes have been reported in poultry (Dhama
et al., 2005, Alexander, 2007; Weber
and Stilianakis, 2007; Pawaiya et al., 2009;
Tiwari and Dhama, 2012).
Role of migratory birds in the spread of bird flu: It is indicative
that H5N1 viruses are now being transmitted between migratory birds (Dhama
et al., 2005; Reperant et al., 2011;
Cappelle et al., 2012; Tiwari
and Dhama, 2012) and may pose a threat to humans (Sakoda
et al., 2012). Spread of pandemic human strains of bird flu virus
through wild birds however remains debated (Reid and Taubenberger,
2003). The most recent pandemic strain (H1N1) contains several segments
that most likely originate in migratory birds. Intimate linkage is thus there
among wild birds (migratory) and mammals (including human) that governs dynamics
of influenza infections (Vandegrift et al., 2010).
More than one factor increases the risk of introduction or spread as well as
maintenance of AIV via wild birds. These include: the species of susceptible
animal; number and age of target individuals; characteristics of the geographical
area of origin and destination; local (seasonal) abundance of that species and
the gregariousness of the species during the breeding and migration and non-breeding
seasons (Artois et al., 2009). In a specific
geographical area, probability of spread of infection through contact with domestic
avian species increases due to congregations of migratory wild bird population
which are natural as well as principal reservoirs for most of the AIV subtypes
(H1-H16 and N1-N9) (Dhama et al., 2005; Sengupta
et al., 2007; Lee et al., 2008, Musa
et al., 2009). Avian flu H5N1 virus outbreak in migratory waterfowl
such as bar-headed geese, brown-headed gulls and great black-headed gulls in
western China, killed nearly 1,500 migratory birds in 2005. In the United States,
shore birds and great black-headed gulls are found to be reservoirs of subtypes
H1-H13 and N1-N9 (Olsen et al., 2006; Krauss
et al., 2007). However, majority of the AIVs that are circulating
in migratory birds belong to Low Pathogenicity Avian Influenza (LPAI) viruses
(Gonzalez-Reiche et al., 2012; Henaux
et al., 2012).
DISEASE IN BIRDS (AVIAN/BIRD FLU)
The disease syndrome in birds ranges from asymptomatic/subclinical to mild
upper respiratory illness and loss of egg production to a highly contagious
and rapidly fatal systemic disease resulting in severe epidemics, with very
high morbidity and mortality in the affected poultry flocks. Incubation period
of the virus is few hours to 3 days (Alexander, 2000;
Dhama et al., 2005; Capua
and Alexander, 2007, 2009).
Highly pathogenic avian influenza (HPAI): HPAI is an acute, generalized,
highly infectious and dynamically evolving disease of birds causing huge morbidity
and mortality leading to very high economical losses. Infections with HPAI H5
and H7 subtypes can occur in poultry including other types of birds and result
into the clinical picture of bird flu. These subtypes can replicate throughout
the birds body (pantropism), resulting in disease with a very high mortality
rate. HPAI have multiple basic amino acids at the cleavage site, are cleavable
by ubiquitous proteases and causes extensive damage to all systems and vital
organs (Dhama et al., 2005; Eagles
et al., 2009).
Clinical signs: In domestic poultry (chickens and turkeys primarily),
there is sudden onset of severe illness, rapid death, high mortality and morbidity
which may reach to 100% within few days. It is a fatal systemic disease affecting
most organ systems including the nervous and cardiovascular systems. In peracute
cases, birds are seen dead prior to observance of any clinical signs. Signs
include severe respiratory distress/sounds, depression, coughing, sneezing,
watery eyes and sinuses with excessive eye discharges, cyanosis of head, combs,
wattles and shanks, edema/swelling of head, face and sinuses, ruffled feathers
and diarrhoea (initially bright green, later white) and nervous signs. Drops
in egg production occur in breeders and layers with typical declines including
total cessation of egg production within six days (Alexander,
2000; Dhama et al., 2005; Gowthaman
et al., 2009).
Lesions: Petechial hemorrhages of whole viscera and peritoneum with
generalized congestion and periorbital edema are the most commonly observed
lesions. In visceral organs, there are serosal or mucosal surface hemorrhages
and necrotic foci within parenchyma. Especially prominent are the petechial
hemorrhages on the epicardial fat, in pectoral muscles and in mucosa and around
the ducts of proventricular glands. Death is usually by mutiple visceral organ
failure (Alexander, 2000; Dhama
et al., 2005; Mathew et al., 2006;
Korteweg and Gu, 2008).
PUBLIC HEALTH SIGNIFICANCE
Influenza A viruses infects a variety of animal species including humans,
pigs, horses, marine mammals and birds. The virus has expanded its host range
and has infected dogs and other mammals. Only HPAI viruses have been reported
to have zoonotic importance. Zoonotic potential of AIV was first observed in
1997, wherein six persons died out of eighteen affected following infection
with HPAI (H5N1) in Hong Kong. Zoonotic alarm of bird flu virus mounted again
in 2003 with human deaths in Vietnam (3) and China (2) with subsequently increasing
number of human casualties till date, as reported in Thailand, Azerbaijan, Cambodia,
China, Indonesia, Cambodia, Egypt, Iraq, Turkey, Nigeria, Pakistan, Laos and
Bangladesh (Peiris et al., 2004; Dhama
et al., 2005; Tiwari and Dhama, 2012). Till
date (March 15, 2013), the bird flu virus has caused 368 human deaths out of
a total of 622 confirmed human cases (nearly 60% Mortality Rate). Highest number
of human casualties has been reported from Indonesia (160), Vietnam (61), Egypt
(61), China (29), Combodia (25) and Thailand (17) (WHO, 2008).
The close proximity of birds to humans increases the risk of transmission to
humans. Strains jumping to humans are limited to 4 HA types: H5, H7, H9 and
H10 (AIV subtypes H7N2, H7N3, H7N7, H9N2 and H10N7). The exact conditions for
human infection are not clear, but it would appear that these mostly occur in
situations of high exposure to virus and oro-nasal route, affects predominantly
the respiratory tract (breathing passages) and is acquired by virus inhalation
(Beigel et al., 2005; Perdue
and Swayne, 2005). Infected birds or egg/meat when handled possess more
risk of transmitting bird flu than edible poultry products but well cooked food
hardly transmits the disease (Beato et al., 2009;
Taubenberger and Morens, 2010; Tiwari
and Dhama, 2012).
Bird flu virus still has not attained the capability to undergo human to human
transmission in a rapid/pandemic manner as during 1918 spanish flu
(H1N1 killed 40-50 million persons globally in 2 years). A completely new subtype
could be generated when avian and human influenza viruses exchange genes during
a co-infection of a person with both viruses. Newly evolving virus if contains
sufficient human genes, spread directly from one person to another can occur,
in a rapid, easy and vicious manner and human flu could acquire the deadly virulence
of the avian flu-the start of a new influenza pandemic could begin therein.
A change in viral receptor specificity from avian type (α-2, 3 sialic acid
receptor) to human type (α-2, 6 sialic receptor) could make a probable
deadly pandemic. The disease spreads explosively due to the world population
being immunologically naive (Dhama et al.,
2005; Sellwood et al., 2007; Iwami
et al., 2008; Taubenberger and Kash, 2010;
Tiwari and Dhama, 2012).
Vaccination of persons at high risk of exposure to infected poultry, using
existing vaccines effective against currently circulating human influenza strains,
could reduce the likelihood of co-infection of humans with avian and human influenza
strains. Influenza epicenter is the region where birds, other animals and humans
live closely together. Ducks/chickens with pigs sharing ponds into which they
discharge household wastewater, including human and pig excreta and the birds
faeces, the significant carriers of viruses, can very well contribute to the
development of a reassortant virus (World Health Organization
Global Influenza Program Surveillance Network, 2005). In generating reassortants
of novel flu virus, role of birds become evident due to past pandemics; and
in last 40 years the first global pandemic is recorded caused by H1N1 triple
human/avian/swine reassortant virus (of human) resulting in substantial illness,
hospitalizations of millions of peoples and thousands of deaths throughout the
world (Beveridge, 1991; Dhama
et al., 2005, 2008a; Vijaykrishna
et al., 2008; Pawaiya et al., 2009;
Centers for Disease Control and Prevention, 2010; Tiwari
and Dhama, 2012).
CLINICAL FEATURES OF BIRD FLU IN HUMANS
The incubation period for AIV in humans is probably between 3-7 days. A rapid
onset of severe viral pneumonia with a high fatality rate is seen in humans
affected with bird flu. Typical influenza-like symptoms are observed: Fever,
sore throat, cough, breathing problems (acute respiratory distress), chest pain,
acute respiratory distress, muscle aches, malaise, fatigue and lethargy. Eye
infections (conjunctivitis), severe bilateral pneumonia, myocarditis (inflammation
of the heart muscle) and other severe and life-threatening complications can
occur (Dhama et al., 2005; Malik
Peiris, 2009; Riquelme et al., 2009; Tiwari
and Dhama, 2012).
Tentatively diagnosis is based on the clinical signs and very high flock mortality.
Confirmatory diagnosis requires isolation, identification and characterization
of the virus from suspected samples (tracheal/cloacal swabs, feces, tissue samples
including trachea, lungs, etc.). Definitive diagnosis requires direct detection
of AI viral antigen/nucleic acid in affected tissues, swabs, clinical samples
and inoculated cell cultures or embryonating chicken eggs (Babiuk
et al., 2003; Dhama et al., 2005;
Kataria et al., 2005a, b;
Schmitt and Henderson, 2005; Brown,
2006; Suarez et al., 2007). Hemagglutination
(HA) test done with the infected chicken embryo allantoic fluid during virus
isolation indicates towards the hemagglutinating nature of the virus. Hemagglutination
Inhibition (HI) assays using reference AIV antiserum, confirms the virus infection.
For demonstration of viral antigen in the suspected clinical samples, the techniques
employed are Agar Gel Immunodiffusion (AGID), Immunofluorescence Test (IFT),
Immunoperoxidase Test (IPT) and Enzyme-linked Immunosorbent Assays (ELISA).
Detection of antibodies to AI virus by AGID and HI tests are of significant
value. Virus Neutralization Test (VNT), IFT, IPT and ELISA are important diagnostic
tools (He et al., 2007; Alexander,
2008; Dhama and Mahendran, 2008). Subtyping of
AIVs can be done by using mono-specific antisera prepared against antigens of
each of the 17 HA and 10 NA can be used in AGID. Haemagglutination and neuraminidase
inhibition (HI/NI) tests against a battery of polyclonal antisera are also useful
in this direction. By Reverse Transcription-polymerase Chain Reaction (RT-PCR),
real time -PCR, PCR-ELISA and other molecular tools also subtyping can be achieved
(Alexander, 2008; Cattoli and
Terregino, 2008; Dahlhausen, 2010; Tiwari
and Dhama, 2012).
Molecular tools for AIV detection: The virus can be identified by employing
RT-PCR using a set of primers specific to the Nucleoprotein (NP) gene or matrix
gene. RT-PCR has been used for identification and HA-subtyping which can be
further confirmed by sequence analysis (Dhama et al.,
2005, 2008b; Alexander, 2008).
Subtypes H5 and H7 can be detected by H5 and H7 primers covering the cleavage
site of the HA gene, by the presence or absence of multiple basic amino acids
determined by sequencing of PCR product (Sidoti et al.,
2010). In situ hybridization assay is also available for detection
of AIV. An H9-based RT-PCR-ELISA has been found highly sensitive when compared
to virus isolation method in detecting H9N2 AIV. RT-PCR Heteroduplex Mobility
Assay (HMA), M gene RT-PCR, can be used to detect and partially characterize
influenza A viruses from different species (human, avian and swine influenza
A viruses) and offers a rapid and sensitive means for screening for novel or
unusual influenza viruses. Multiplex-PCR (m-PCR) including two or more primer
pairs specific for target sequences of different viral pathogens has been developed
for detecting H5 and H7 AIVs (Rashid et al., 2009).
Nucleic acid sequence-based amplification (NASBA) s a rapid and sensitive method
of detection as well as identification of pathogenic influenza viruses, can
detect a portion of the HA gene of AIV subtypes H5 and H7 (Cavanagh,
2001; Kataria et al., 2005b). NASBA/ECL (electrochemiluminescent
detection) is an isothermal technique especially suitable for amplifying RNA,
from a diverse range of sources.
RRT-PCR (Real time-RT-PCR), a real-time detection has eliminated need for post-PCR
screening by electrophoresis allowing definitive confirmation of a virus within
minutes and is highly useful for AIV surveillance and monitoring programs. LUX
(Light Upon eXtension) real-time RT-PCR utilizes lux (light upon extension)
fluorogenic primer for rapid detection of AIVs in real-time PCR assays. Sequencing
and phylogenetic analysis helps in tracing the origin of virus and gemomic relatedness/lineages
(Kim et al., 2008; Munster
et al., 2008; Takekawa et al., 2010).
Loop-mediated Isothermal Amplification (LAMP) and Real-time RT-LAMP assay for
AIV H5 and H7 strains holds some promise for routine veterinary diagnostic purposes
(Capua and Alexander, 2004; Postel
et al., 2010). Sensitivity and specificity odf real time RT-PCR assays
are more and at the same time it is cost effective and can rapidly detect and
screen H5 and H7 isolates (alternative to isolation of virus) during outbreaks
due to influenza A virus. To understand in a better manner the involvement of
wild birds in HPAI H5N1 transmission and to tally the results of surveillance
portable real-time RT-PCR (with lyophilized reagents) is helpful. DNA micro-arrays
are also being developed (Peeters, 2008). Recently,
a rapid H5N1 bird flu test kit (real-time RT-PCR assay based), detecting all
known strains of H5N1 virus with a single test and with almost 100% accuracy,
has been reported to be developed for diagnosing bird flu within a few hours
in humans (Tiwari and Dhama, 2012).
Proper collection and dispatch procedures need to be followed for clinical
samples of bird flu, also care should be taken to prevent leakage and the spoilage
during transport. Samples must be sent at earliest and appropriately preferably
by special messenger to the referral laboratory. Diagnosis of avian flu requires
referral laboratories equipped with trained scientific manpower and minimum
level 3 biosecurity (BSL-3) measures. Suitable samples are required to be sent
worldwide in designated referral laboratories in order to diagnose the disease
timely and precisely (Dhama et al., 2005; Tiwari
and Dhama, 2012).
Differential diagnosis of avian influenza should be done from Newcastle disease
virus, avian pneumovirus and other parmayxoviruses, infectious laryngotracheitis,
infectious bronchitis, Chlamydia, Mycoplasma and fowl cholera
(Dhama et al., 2005; Kataria
et al., 2005b; Centers for Disease Control and
Prevention, 2007; George, 2012).
No specific drug therapy is practiced in birds. To reduce the secondary bacterial
infections, antibiotics and supportive therapy have been recommended. Anti-Flu
drugs (Amantadine, Rimantadine, Zanamivir/Relenza and Oseltamivir/Tamiflu) may
be used both to prevent people from catching bird flu and to treat those who
have it. They work best if given within 2 days of becoming ill, but may be given
later if illness is severe or for those at a high risk for complications. They
can turn the illness into a milder form and help in preventing serious complications.
These must strictly be prescribed by a medical doctor only. Antipyretic medications
and suitable anti-inflammatory drugs are also prescribed. Relenza and Tamiflu
are neuraminidase inhibitors which check the flu viruses from multiplying within
the host cell and are found to be most effective. Tamiflu is the drug of choice
(Dhama et al., 2005; Hsu
et al., 2012; Jarhult, 2012). Ayurveda plays
a substantial role in promoting immunity of the host. Various herbs for boosting
immunity include: basil (Ocimum basilicum); Ginger (Zingiber officinalis);
garlic (Allium sativum); Gooseberry (Embelica officinalis); Aloevera
(Aloe barbadensis); Camphor (Cinnamomum camphora) and Eucalyptus
oil; Ginkgo (Ginkgo biloba) leaf extract; Red Sea grass (Thallasodendron
ciliatum); flavanoids of various plants and acidic polysaccharides from
green algae (Coccomyxa gloeobotrydiformi) (Parmar
et al., 2011; Costa et al., 2012;
Haruyama and Nagata, 2012; Ibrahim
et al., 2012; Komatsu et al., 2013).
PREVENTION AND CONTROL
Pre-requisites for effective control programs aimed at eradication of AI virus
infection in poultry include disease awareness, early detection, culling and
stamping out, proper disposal of affected birds, timely notification, strict
biosecurity measures, isolation, zoning and quarantine, control of live bird
market and judicious vaccination strategy. Continuous global surveillance of
influenza is a key factor (Dhama et al., 2005;
Graham et al., 2008; Tiwari
and Dhama, 2012). The best way to check HPAI from spreading is to prevent
exposure of flocks and rapid elimination/culling of the virus infected birds
which are essential for preventing a major outbreak (Chen
et al., 2006). Adapt the key principles of biosecurity i.e., isolation,
traffic control and sanitation. Follow strict cleanliness, good sanitation and
hygienic practices, along with suitable decontamination and disinfection procedures
on the farm. Virus spreads via movement of birds, crates or vehicles/trucks
to other farms and/or market, therefore necessary precautions need to be adapted.
Vehicles coming from other poultry farms or poultry market should be sanitized
before and after arrival.
Prevention of the exposure of poultry flocks is the best measure to eliminate
the virus infected birds. Human traffic need to be checked and visitors are
to be avoided. Employees and crews should wear clean clothing supplied at the
farm each day. Disinfectant boot dips should be placed to reduce the probability
of introducing and spreading the infection. Contact of poultry with migratory/wild/free
flying birds and waterfowls should be avoided (Dhama
et al., 2005, 2008a; Munster
et al., 2007; Krauss and Webster, 2010).
The accumulation of standing and stagnant water should be prevented as it is
a great source of attraction to migrating waterfowl and shorebirds. Employees
of the poultry farm house need to be educated about the dangers of live birds
markets which are potent source of AIV infection. Sick or dying and dead birds
should be appropriately and immediately submitted to recognized laboratories
for a timely diagnosis. All the infected or exposed poultry flocks should be
culled and slaughtered (stamping out) following the prescribed procedures appropriately
and timely. Dead birds should be properly disposed off following burial or incineration
methods. Cleanliness and sanitation/hygienic measures should be upgraded at
the farm level with follow up of washing of hands and feet frequently with soap
and water and suitable disinfectants after handling affected birds or contaminated
materials. Surveillance and monitoring of Avian influenza virus should be followed
regularly to know the disease status (Kataria et al.,
2005b; Tiwari and Dhama, 2012). Epidemiological
investigations with strict biosecurity measures are followed to prevent further
spread. Stamping out of all domestic poultry is applied in an approximately
3-km-radius zone around the outbreak, with an exhaustive supervision and monitoring
campaign in a 10 km radius zone. Prohibition needs to be imposed on sale and
transportation of poultry products and closure of poultry markets in the infected
zone. Disinfection of premises after culling of birds is an important aspect.
Restocking is advised in accordance with a specified protocol and period (Kataria
et al., 2005a; Bunn et al., 2011).
Disease management for preventing the bird flu outbreaks:
Bird flu being a Notifiable disease therefore, any suspected disease
condition or an outbreak should be immediately reported to the regulatory authorities
and officials and leave handling of the poultry to experienced personnels (veterinarians,
cullers, clean-up personnel etc.). Only trained veterinarians and professionals
wearing protective gloves, masks etc., as biosafety measures should handle suspected
birds. Affected poultry birds should not be necropsied in the field. In case,
bird flu is detected in any country all the movements of birds from area where
disease has appeared should be strictly restricted. AIV infected or exposed
poultry flocks should be culled and slaughtered (stamping out). Field veterinarians
should be trained for collection and dispatch of appropriate samples and the
suspected/clinical samples should be immediately processed for timely diagnosis
(Dhama et al., 2005; Kalthoff
et al., 2010). While handling dead or sick poultry follow appropriate
safety measures such as wearing protective clothing, gloves, face masks (nano
masks), goggles, gown, rubber boots etc (MacMahon et
al., 2008). Confine live birds being submitted to laboratory in boxes
that will not return to farm. Dead bird should be put in a leak proof plastic
bag, double packed, sealed and transported under chilled conditions immediately
to the investigation laboratory. Assistance from local animal husbandry authorities
should be sought on how to bury dead birds safely and appropriately. Local authorities
should keep under close monitoring persons having exposure to bird flu virus
infected chickens and suspicious farms. Liaison with neighboring countries for
international trade should be monitored to check the influx of avian influenza
(Koh et al., 2008). Cross border trades with
affected countries should be strictly regulated or banned completely. Strict
surveillance and vigilance for bird flu virus are required at international
airports as well as in railways and land transport (Gowthaman
et al., 2010; Dhama et al., 2013b).
Mass media should take part in providing public awareness widely in order to
prevent and control spread of bird flu to humans. Along with it education and
training programmes should be organized for veterinary para-professionals, farmers,
marketers, poultry transport contractors, egg collectors and concerned professionals.
Thorough cleanliness and heightened sanitation and hygiene measure should be
adapted; specifically hands should be washed with a soap/detergent every time
after handling any contaminated items (Kataria et al.,
2005a; World Health Organization Global Influenza Program
Surveillance Network, 2005; WHO, 2005; Bunn
et al., 2011; Tiwari and Dhama, 2012).
Pandemic preparedness: The persons to be included for bird flu pandemic
preparedness include: virologists and epidemiologists experts from human and
animal health professionals; military and paramilitary forces; representatives
of NGOs; press and media persons and administration (Dhama
et al., 2005; Rebmann et al., 2012;
Tiwari and Dhama, 2012). Extension works and strategies
must be employed in order to fill the gaps in knowledge about the pandemic and
vaccine particularly in underdeveloped nations where there is evidence of substantial
disparities in education and media access (Kouassi et
al., 2012; Cantey et al., 2013). There
is a need for developing simple and easy to use tests for the characterization
of emerging influenza strains as the bird flu virus is a very dynamically evolving
and changing virus (Mak et al., 2012). Safe
international trade in the least trade restrictive manner controls the international
movement of birds and products which should be based on OIE recommendations.
Measures may be modified in the light of specific risk assessments and agreements
between trading partners. In order to develop disease control and prevention
strategies Veterinary authorities must consider the cross-boundary leakages.
There is need to implement measures to prevent wild bird populations from infecting
domestic poultry (WHO, 2004; Dhama
et al., 2005, 2008a). It is essential to
thoroughly understand the factors that contribute to the willingness of health
care professionals to work during an influenza outbreak and is critical in planning
for pandemic preparedness (Devnani, 2012; Godderis
and Rossiter, 2013). It is also important to have overall tight coordination
along with communication as well as integration and alignment in any management
structure (Fieldston et al., 2012). Any country
faces an extra burden on resources to control the disease during a pandemic
but this situation may help in understanding of the disease and effect of preventive
measures in order to contribute to global knowledge. The research directions
needed may include virus transmission; antigenic and molecular characterization
of virus strain; antiviral drug resistance and vaccine efficacy along with socioeconomic
impact of the pandemic (Dhama et al., 2005; Fouchier
et al., 2012; Van Gageldonk-Lafeber et al.,
2012). By virtue of the differences in the poultry sector infrastructures,
restructuring the poultry sector may be an important strategy to guard against
the damaging effects of HPAI and requires different approaches at different
levels of poultry sector in different countries. The general principles to be
undertaken in this regard include: well-defined socio-economic impact analysis;
government commitment with stakeholders full support as well as collaboration
between private and public sectors and above all public awareness. For enforcing
measures to control animal diseases and to support trade both within regions
and globally, the need to strengthen regulatory policies is recognised by many
countries that are directly affected or are at risk. Realigning the veterinary
regulations and policies to meet world trade organization (WHO)/OIE standards
is the need of hour for this reason. These mechanisms include: quality and evaluation
of Veterinary Services along with animal quarantine and institutional reforms;
introduction of OIE standards, guidelines and recommendations for international
as well as domestic trades; certification for exports and designation of disease
free zones and compartments. For creating necessary cordial environments, long-term
national or regional HPAI control or prevention interventions should be supported
strengthened (Dhama et al., 2005; Pawaiya
et al., 2009).
Salient precautionary measures for general public: Appropriate sanitation,
hygiene and safety measures need to be followed during bird flu outbreaks to
avoid AIV infection. During a disease epidemic, avoid going to poultry farms
and markets where birds are sold and make sure to keep children away from dead
or sick poultry/birds. During laying, egg shells may be contaminated with birds
faeces that contains sufficient amount of virus, thus the live bird as well
as poultry products including eggs, egg products, chicken and duck meat and
objects contaminated with faeces from infected birds can carry disease spreading
virus. Proper cooking procedures destroy the virus in poultry meat and eggs,
therefore good kitchen hygiene practices and eating properly cooked eggs and
poultry meat/products need to be encouraged (Dhama et
al., 2005; Chmielewski and Swayne, 2011; Tiwari
and Dhama, 2012). Thorough and frequent hand washing using suitable disinfectants
need to be practiced especially by food handlers at home and in restaurants
which should become a routine practice to help avoid infection. All persons
exposed to AIV infected chickens or to farms under bird flu suspicion should
be under close monitoring by local health authorities (Kataria
et al., 2005a; MacMahon et al., 2008).
Vaccination: Inactivated AIV vaccines are the commonly used vaccines
throughout the world at present. Live conventional influenza vaccines against
any subtype are not recommended in birds. Inactivated homologous (same field
strain), heterologous (same H but different N-marker vaccine) and
oil emulsion vaccines have been developed for use in avian species. Inactivated
monovalent and polyvalent viral vaccines, with adjuvants, are capable of inducing
antibody (Dhama et al., 2005; Kataria
et al., 2005b). Haemagglutinin (HA) based vaccines protect against
a broad array of homologous HA subtype viruses, but provide poor protection
against a heterologous HA virus. It is not practical to use preventive vaccination
against all possible AIV subtypes. For stopping the spread of disease and for
improving chances of eradication, vaccination combined with selective culling
is effective. Widespread use of vaccine against HPAI is being used with increasing
frequency in countries experiencing large disease outbreaks of H5N1. Routine
use of AI vaccine in poultry production system is rare (Dhama
et al., 2005; Kataria et al., 2005b).
Virus infection can not be prevented completely by the use of commercial AIV
vaccines but certainly multiple goals can be achieved if vaccines are used properly.
Newer vaccines include recombinant vaccines, DNA vaccines, reverse genetics
based vaccines, vector vaccines, or subunit vaccines and DIVA (differentiating
infected from vaccinated animals) strategy (Dhama et
al., 2005, 2008b; Peeters,
2008; Tiwari and Dhama, 2012; Yang
et al., 2012). Gene-deleted mutants allow the use of live bird flu
vaccines (Swayne, 2004). During the use of such vaccines
it should be kept always in mind that there are inherent dangers for gene reassortment
with field viruses in the generation of disease-causing strains. A different
Neuraminidase (NA) is used in the vaccine to differentiate with the field virus
infection by looking for specific antibodies against the NA of circulating field
virus in the vaccinated birds in order to allow the differentiation of infected
from vaccinated flocks (Capua et al., 2003).
DIVA strategy using these kinds of marker vaccines with a heterologous strain
differing in NA from the circulating field virus during the outbreaks of H7N1
is useful (Marangon et al., 2003). This strategy
can help countries to escape from trade restrictions. Field strain
(similar H subtype but different N subtype) is incorporated in vaccines for
DIVA strategy (Capua and Marangon, 2003; Bano
et al., 2003; Capua et al., 2004).
In the recent past, there have been development of vectored bird flu vaccines
using Fowl Pox Virus (FPV) and Infectious Laryngotracheitis Virus (ILTV), baculovirus;
vaccinia virus and new castle disease virus (NDV) expressing H5, H7 of bird
flu virus hemagglutinin gene insert (Swayne et al.,
2000a; Veits et al., 2003; Dhama
et al., 2005; Cornelissen et al., 2012).
These vaccines however replicate poorly in birds that have had field exposure
(Swayne et al., 2000b). A single dose of plasmids
expressing H5 and H7 hemagglutinins can protect the birds from infection by
either subtype (Kodihalli et al., 2000). For
the development of candidate vaccine viruses against the HPAI viruses including
H5N1 subtype virus the reverse genetics techniques have been exploited (Nicolson
et al., 2005; Tian et al., 2005).
The reassortant viruses generated using this technology, containing the same
H5 and H7 hemagglutinin gene as the challenge virus, but a heterologous neuraminidase
gene, can help in differentiating the infected and vaccinated birds (DIVA strategy)
(Lee et al., 2004). To control the spread of
avian influenza and ND alike recombinant NDV expressing HA of AIV/H5N1 generated
through reverse genetics can be useful (Ge et al.,
2007). India has not adapted vaccination for controlling AIV and followed
culling and containing the virus in affected areas and preventing further spread
(Meeusen et al., 2007; Murugkar
et al., 2008; Tiwari and Dhama, 2012).
Disease outbreaks of bird flu, its public health impacts with probable potential
of a deadly human pandemic have created an alarming situation worldwide. Continuous
global efforts are on the way so as to better understand about the basic knowledge
of the virus focusing on its pathogenesis, genetic versatility, zoonosis, pandemic
potential, therapy and control possibilities. AIV has caused havoc in poultry
industry recently leading to enormous economic losses worldwide and in last
ten years only the H5N1 subtype has affected more than 60 countries with losses
of more than 300 million birds and 360 human lives. This is indicative of the
fact that flu virus is becoming more and more dangerous, especially in south-eastern
Asian countries. Prevention and control strategies focus on strict biosecurity,
adequate disease surveillance, timely diagnosis, appropriate culling measures
and judicious vaccination practices along with adequate public health and biosafety
measures. Even though commercial antiviral drugs such as Zanamivir and Oseltamivir
are available for treatment of the human flu, effective vaccination strategies
together with careful and far-sighted disease prevention and control measures
is the need of the hour. This may help to wipe down the bird flu virus before
it re-emerges with a changed genetic make-up (reassortant or mutant virus) with
much more lethal virulence or killing ability and acquire human to human transmission
abilities that too in a rapid way to cause a devastating pandemic. Such kind
of a probable pandemic if happens practically then the situation could be much
dangerous for human life and the existence of mankind. The avian flu virus is
posing a great challenge due to its high mutational abilities, various combinations
and many subtypes, interspecies transmissions which are all the impeding factors
for developing an effective prophylactic strategy. Being a global problem and
a huge challenge, the solutions for bird flu requires international and coordinated
efforts, collaborative projects and integrated approaches. Since the appearance
of this disease is unpredictable, these responses must be prompt and timely,
well planned and complete. For tackling bird flu, multidisciplinary approach,
effective co-operation and networking among scientists, veterinary/medical and
public health officials, wildlife specialists, avian disease experts, life science
researchers and the regulatory authorities is required. These measures adapted
on priority would help in preventing and eradicating the bird flu and restricting
its zoonotic impact. Now-a-days, advancements in biotechnology and molecular
biology have provided rapid and confirmatory diagnostics for this deadly disease.
The recent advances in vaccinology and biotechnology are being exploited for
developing effective and safer vaccines for protecting birds as well as the
humans against the AIV H5N1 subtype. Formulation and adaptation of effective
and sound strategies for preventing and controlling bird flu would alleviate
the economic losses to the poultry industry as well as save the precious lives
of millions of people living under a possible and deadly pandemic threat.
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