Posted by
Nancy Nurse on Wednesday, September 27, 2006 10:19:36 AM
HealthBird flu: A threat to humanity
By Mehdi Pervez
Sat, 23 Sep 2006, 10:07:00
Over
centuries natural calamities have hit this earth in many shapes.
Sometimes in the form of floods sometimes in the form of volcanic
eruptions and sometimes in the form of epidemic of deadly diseases.
Every instance has caused the lives of hundreds and thousands of human
lives. Even at the prime time of medical science an old disease is
re-emerging with its deadliest threats. We are thinking about none
other than bird flu. Bird flu is nothing new or uncommon. It first
pandemically occurred in 1918 immediately after World War I and killed
more than 40 million people. The later outbreaks were in 1957 and 1968.
All of the attacks from bird flu killed about 100 million people around
the world. Though this is not actually a human disease but its scourge
of killing 10 crore people in only 87 years is a fearful matter. For
more than a century, bird flu has circulated among birds, particularly
domesticated fowl, but recent attention has been called to avian
influenza since some strains infected humans. No longer is bird flu
relegated to pigs and birds, as the virus has strengthened and mutated,
resulting in a contagion that can move from bird to human. Human cases
of bird flu have caused infections and death across the globe as
scientists struggle to identify the dangerous strains and prevent a
fatal pandemic.
Now let us discuss some of the microbiological
aspects of Flu Virus. "Flu" is short for "influenza". The name goes
back hundreds of years when the disease was thought to be caused by
supernatural "influences". Many describe any nasty lung infection as
flu, but only specific lab tests can give a proper diagnosis. There are
several different viruses (and bacteria) which may infect the lung, but
true flu is caused by orthomyxoviruses, of which there are three types,
designated A, B, and C. An influenza virion has about 500 "spikes"
sticking out from its lipid envelope. About 80% of the spikes are a
glycoprotein peplomers-rod shaped viral protein called hemagglutinin
(or simply, HA) which are homotrimers of class I membrane
glycoprotein's. This was first identified by its ability to cause red
blood cells, which carry a molecule called "heme", to agglutinate
(stick together). We now know that HA is influenza's receptor-binding
protein. It plays the critical role of attaching the virus to the host
cell. The other 20% of the spikes are a mushroom shaped viral protein
called neuraminidase (NA), which is tetramer of a class II membrane
protein. This protein is an enzyme that destroys a host cell molecule
called neuraminic (or sialic) acid. NA might play a part in getting the
virus into the cell, but its most important function is that it helps
the newly made influenza virions to easily escape from the host cell so
they can infect others[1]. The virulent avian influenza H5N1 strains
differ from other avian strains in that, there lies a link between HA
cleavage and degree of virulence. In virulent strains the HAs contain
multiple basic amino acids at the cleavage site, which are cleaved
intracellularly by endogenous proteases. In contrast, in case of
avirulent avian strains as well as non-avian influenza A viruses, the
HAs lack the basic amino acid residues, hence not subjected to cleavage
by such proteases. Moreover, all types of influenza A viruses are
antigenically labile, well adapted to evade host defenses and lack
mechanisms for "proof reading"; hence constant, permanent and small
changes in antigenic composition are very common, which is known as
antigenic drift. Another important characteristic of great public
health concern is antigenic shift which results from reassortment of
genetic material from different species resulting in variability of HA
spikes, keeping the basic structure of the virus constant [2].
Influenza
viruses that infect birds are called avian influenza viruses. Only
influenza A viruses infect birds, and all known subtypes of influenza A
viruses can infect birds. However, there are substantial genetic
differences between the subtypes that typically infect both people and
birds. Within subtypes of avian influenza A viruses there also are
different strains. 13 different kinds of HA and 9 different kinds of NA
genes in type A influenza is known[3].
They evolve! Molecular
evolution (the evolution of molecules) is a fascinating area of
evolution and of prime concern to any scientist wanting to understand
viruses and how they spread. All genetic material can mutate, that is
change its nucleic acids. The mutations are random, but their selection
is not. "Selection" is another word for how well they survive and
reproduce. Selection ensures that the mutations that increase a virus'
ability to survive and reproduce will be represented in even greater
numbers in the next generation. Mutations are the "fuel" for evolution
because they provide the genetic variation on which selection acts.
This is simply Darwin's old theory of evolution by means of natural
selection, but on a microscopic scale.
All influenza viruses
(all orthomyxoviruses) have RNA as their genetic material. When RNA is
replicated it tends to have more errors than when DNA is replicated.
These extra errors provide extra mutations upon which selection may
act. That means RNA viruses (not just influenza viruses but all RNA
viruses) have a high mutation rate and can evolve quickly - faster than
a DNA virus or even a DNA human! Over time these mutations accumulate
and eventually the virus evolves into a new strain. This progressive
accumulation of individual mutations is called antigenic drift, because
the shape of the antigen (the viral protein) slowly drifts into a
different shape with each generation of virus. Eventually they drift so
much that the original antibody can no longer bind to it.. All viruses
show antigenic drift, but RNA viruses mutate faster so they drift
faster. Antigenic drift is responsible for many of the localized
outbreaks of different strains of influenza, especially influenza B.
Importantly,
type A - but not B or C - undergo a kind of gene swapping or genetic
reassortment to give it its proper name. If a cell is simultaneously
infected by two different strains of type A influenza, the offspring
virions may contain mixtures of each parents' genes! This really
complicates things and makes it very easy for influenza A to quickly
evolve new combinations of HA and NA genes. To better understand what I
mean you need to learn a little bit about how we keep track of all this
reassortment. We know of 13 different kinds of HA and 9 different kinds
of NA genes in type A influenza. All these different kinds have evolved
by antigenic drift as described earlier. Any one virion can contain
only one HA and one NA. For example then an influenza A strain
designated H1N1 can be produced. (We drop the "A"s at the end to make
it clearer.) Along comes another virus with different kinds of HA and
NA genes, let's say it is H3N7. If these two different virions infect
the same cell at the same time they may produce offspring not only like
themselves (H1N1 and H3N7) but also with a mixed combination (H1N7 and
H3N1).
This is only a small sample of the many possible new
combinations that might be made. All eight segments may take part in
the reassortment. These newly created mixed genomes are very different
from their parents and (probably) have never been "seen" by your immune
system - or for that matter, anyone else's. This form of viral
evolution is called antigenic shift, to differentiate it from antigenic
drift (which occurs slowly and without a change in the gene
associations). These new combinations present us with such a unique
strain of virus that our immune system has to start all over to make
new antibodies to combat it[1].
Since now we have seen that
there are many strains of flu virus. But the strain that is mostly
infecting people since 1997 is the H5N1 strain. This strain, in many
ways, different and dangerous from other flu strains which we will try
to explain below.
A report by a World Health Organization (WHO)
committee says avian flu may have a longer incubation period and is
more likely to cause diarrhea than typical flu viruses are, among other
differences.
Published in the Sep 29 New England Journal of
Medicine, the review was written by experts from several countries,
including Vietnam, Cambodia, Thailand, the United States, the United
Kingdom, Hong Kong, and Myanmar. They reviewed 71 published studies and
reports, including details on 41 confirmed human cases from Vietnam,
Thailand, Cambodia, and Hong Kong.
Researchers from Hong Kong
report that lung cells growing in a laboratory responded much more
intensely to the H5N1 virus than to an ordinary flu virus, even though
the viruses reproduced at about the same rate, according to the report
published online by Respiratory Research.
The H5N1 viruses were
"more potent inducers" of cytokines and chemokines-chemical messengers
that trigger inflammation-than H1N1 viruses were, says the report by a
team led by J.S.M. Peiris of the University of Hong Kong. A flood of
inflammation-triggering chemicals released by the immune systems has
been referred to as a "cytokine storm."
They found that all the
H5N1 viruses caused cells to secrete significantly higher levels of
IP-10 (interferon-gamma-inducible protein 10), interferon beta, a type
of T cell known as RANTES, and interleukin-6 than the H1N1 virus did.
In addition, the 2004 versions of H5N1 caused cells to release more
IP-10 at 6 hours than the 1997 version did.
"We have found that
infection with H5N1 viruses led to the production of 10 times higher
levels of cytokines from human cells than normal human flu viruses,"
said Peiris, as quoted Nov 12 in The Standard, a Chinese business
newspaper.
The most alarming news about this H5N1 virus is that,
Scientists reported findings which may help explain what made the 1918
pandemic influenza virus so deadly and that reveal similarities between
that virus and the H5N1 avian influenza virus now circulating in Asia.
The 1918 flu pandemic, regarded as the worst in history, killed as many
as 100 million people
"The new studies could have an immediate
impact by helping scientists focus on detecting changes in the evolving
H5N1 virus that might make widespread transmission among humans more
likely," the statement said[4].
Avian influenza viruses
circulate among birds worldwide. Certain birds, particularly water
birds, act as hosts for influenza viruses by carrying the virus in
their intestines and shedding it. Infected birds shed virus in saliva,
nasal secretions, and feces. Susceptible birds can become infected with
avian influenza virus when they have contact with contaminated nasal,
respiratory, or fecal material from infected birds. Fecal-to-oral
transmission is the most common mode of spread between birds.
Most
often, the wild birds that are host to the virus do not get sick, but
they can spread influenza to other birds. Infection with certain avian
influenza A viruses (for example, some H5 and H7 strains) can cause
widespread disease and death among some species of domesticated
birds[3].Domesticated birds may become infected with avian
influenza virus through direct contact with infected waterfowl or other
infected poultry, or through contact with surfaces (such as dirt or
cages) or materials (such as water or feed) that have been contaminated
with virus[3]. Avian influenza A viruses may be transmitted from
animals to humans in two main ways:Ø Directly from birds or
from avian virus-contaminated environments to people. Almost all these
casualties were directly exposed to infected fowl, making contact with
the virus through the birds' saliva, nasal secretions and feces, which
become dry, pulverized and are then inhaled.Ø Through an intermediate host, such as a pig[3].A
new study indicates that H5N1 avian influenza viruses are becoming less
deadly to ducks, permitting them to carry the viruses for days or weeks
and spread them to more susceptible birds and potentially to humans.The
findings "suggest that the duck has become the 'Trojan horse' of Asian
H5N1 influenza viruses," says the report by an international team led
by researchers from St. Jude Children's Research Hospital in Memphis.
"The ducks that are unaffected by infection with these viruses continue
to circulate these viruses, presenting a pandemic threat."The
researchers experimentally infected ducks with various H5N1 viruses,
most of them dating to 2003 and 2004. About half of the infected ducks
survived while shedding the virus for as long as 17 days, according to
the report, published online today by the Proceedings of the National
Academy of Sciences[4].Avian influenza virus lacks the ability
to 'hop' easily between people, which have probably helped to contain
the problem. However, in the future, it is possible that the process of
genetic reassortment could occur in a human who is co-infected with
avian influenza A virus and a human strain of influenza A virus. The
genetic information in these viruses could reassort to create a new
virus with a hemagglutinin from the avian virus and other genes from
the human virus. Theoretically, influenza A viruses with a
hemagglutinin against which humans have little or no immunity that have
reassorted with a human influenza virus are more likely to result in
sustained human-to-human transmission and pandemic influenza.
Therefore, careful evaluation of influenza viruses recovered from
humans who are infected with avian influenza is very important to
identify reassortment if it occurs[3].Symptoms of Avian InfluenzaInfected
bird will get fever with rigor; diarrhea, paralysis then the bird will
be unable to stand and keep the head up and ultimately die in 1-2
days[5].The reported symptoms of avian influenza in humans have ranged from typical influenza-like symptoms:1. fever (usually high)2. headache3. extreme tiredness4. dry cough5. sore throat6. runny or stuffy nose7. muscle aches8. Stomach symptoms, such as nausea, vomiting, and diarrhea, also can occur but are more common in children than adults9. Conjunctivitis is seen in some patientsLife
threatening complications like viral pneumonia, respiratory distress
syndrome, worsening of chronic medical conditions, such as congestive
heart failure, asthma, or diabetes and multi organ failure may result
in the death of the patient[3].Laboratory Testing ProceduresRapid
antigen detection by immunofluorescence assay and enzyme immunoassay,
virus isolation by culture in HeP-2, RD cells or MDCK cell lines and
identification by immunofluorescence assay using specific monoclonal
antibody and haemagglutination inhibition assay have been used for
diagnosis. Detection of influenza- specific RNA by reverse
transcriptase-polymerase chain reaction, by using primer sets specific
for HA sequence of influenza A/H5 and of N1 are some of the other tests
that have been developed. Serological identification by measuring the
specific antibodies by haemagglutination inhibition test, enzyme immuno
assay and the virus neutralisation test, more specifically the micro
neutralisation test, have also been developed. Following kits are
presently available:1. Immunoflourescence assay- WHO influenza
reagent kit for the identification of Influenza A/H5 virus (1997-1998,
2003 or 2004 version) which includes influenza type A/H5- specific
monoclonal antibody pool along with influenza B, A/H1 and A/H3 subtype
specific monoclonal antibodies.2. Virus culture - Madin-Darby Canine Kidney cells (MDCK). ATCC CCL34.· Inactivated virus, goat serum to A/Term/South Africa/61/H5, and chicken pooled serum to A/Goose/Hong Kong/437-4/99.· WHO influenza reagent kit: reference antigens and reference antisera.· Receptor destroying enzyme (RDE)[3].Highly
pathogenic avian influenza A (H5N1) is classified as a select agent,
and culturing of clinical specimens for influenza A (H5N1) virus must
be conducted under laboratory conditions that meet the requirements for
Biosafety Level (BSL) 3 with enhancements. These enhancements include
controlled access double-door entry with change room and shower, use of
respirators, decontamination of all wastes, and showering out of all
personnel. Laboratories working on these viruses must be certified by
the U.S. Department of Agriculture. 4 recommends that virus isolation
studies be conducted on respiratory specimens from patients who meet
the above criteria only if requirements for BSL 3 with enhancements can
be met[3].3. Polymerase chain reaction - Gene primers from Hong Kong, Government Virus Unit.All
laboratory results for influenza A/H5N1 should be confirmed by a WHO
collaborating center for influenza or by another WHO- recommended
reference laboratory. The WHO reference laboratories are as below:1. Queen Mary Hospital, University of Hong Kong.2. National Influenza Center, Kowloon, Hong Kong.3. National Institute of Infectious disease, Tokyo, Japan.4. National Institute of Medical Research, UK.5. Department of Infectious disease, Memphis, USA.6. Centers for Disease Control and Prevention, Atlanta, USA[2].Clinical
specimens from suspect influenza A (H5N1) cases may be tested by PCR
assays under standard BSL 2 conditions in a Class II biological safety
cabinet. In addition, commercial antigen detection testing can be
conducted under standard BSL 2 conditions used to test for influenza[3].The
range of antiviral drugs is small, but especially so when it comes to
bird flu. Four different influenza antiviral drugs (amantadine,
rimantadine, oseltamivir, and zanamivir) are approved by the U.S. Food
and Drug Administration (FDA) for the treatment of influenza; three are
approved for prophylaxis. All four have activity against influenza A
viruses. (4). Two of them, amantadine and rimantadine, are ineffective
against H5N1. The other two are zanamavir (commercialized as Relenza)
and the widely-stockpiled oseltamivir, commercialized as Tamiflu. These
medications are called neuraminidase inhibitors, which block the virus
from replicating. If taken within a couple of days of the onset of
illness, they can ease the severity of some symptoms and reduce the
duration of sickness[6].No definitive vaccine against the viral
threat is available, because no-one knows the precise shape that it
will take after mutating to the feared highly contagious form. Several
prototypes are being explored, but the risk is that they could be only
partially effective or even useless because the virus' genetic shape
will have changed and will not be recognized by antibodies. If a
pandemic does occur, one worry is about manufacturing capacity and
distribution: making enough of the vaccine and getting it on time and
to the right people, without causing panic or a black market or leaving
poor countries helpless[6].