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Complete Summary of H5N1 Bird Flu.
Current Update 26th December 2005
Blue = points of uncertainty that needs to be rechecked
DISCLAIMER FOR OUTSIDE READERS
All material included in the Complete Summary on H5N1 Bird Flu is for
informational purposes only and may not reflect the most current or complete
information. The material contained herein is not offered as medical or any other
advice on any particular matter relating to H5N1 Avian Influenza, including
medical diagnosis or treatment. I expressly disclaim any liability or responsibility
in respect to action taken or not taken based on any or all the information
contained herein. Any representation or warranty that might be otherwise implied
is expressly disclaimed.
INTRODUCTION TO BIRD FLU
“Bird flu” is due to several types of type A influenza virus including H5N1, H9N2, H7N7, H5N2
and H7N1. It was first recognized in Italy over 100 years ago. In poultry H7 can be either of high
or low pathogenicity. In poultry the H9 serotype is always of low pathogenicity. In humans H7 and
H9 are almost always mild. H9N2 bird flu caused a mild self-limiting respiratory infection in
children in 1999 and again in 2003. H7N7 bird flu caused an outbreak in poultry in the
Netherlands in 2003 and 83 humans involved in culling developed viral conjunctivitis whilst 5 had
an influenza like illness. There was evidence of human-to-human transmission of H7N7 bird flu in
the Netherlands in 2003 and a vet died of it, showing that H7N7 is not always a mild disease in
humans. An outbreak of H7N3 conjunctivitis occurred in poultry workers in Canada in 2005.
This discussion relates to both seasonal (“ordinary”) influenza and to H5N1 influenza. H5N1 is but
one cause of bird flu. It is also known as “highly pathogenic avian influenza” (HPAI) because it
normally kills all poultry it infects. It can be transmitted from birds to human where it generally
causes a severe illness. In the last two years there have been hundreds of outbreaks of H5N1 in
poultry in Asia. There have been a few outbreaks in Europe. At least 141 humans have been
affected with a death rate of over 50%. Authorities are concerned that H5N1 has pandemic
potential and that millions of people would die should that potential be realized.
This summary of both seasonal (“ordinary”) influenza and H5N1 avian influenza is a “work-inprogress” and as new knowledge emerges it will be updated at regular intervals.
I hope it will serve as a tool for people to educate themselves on all the various aspects of these
illnesses and, most importantly, on how to protect themselves, and their families, should a
pandemic emerge.
John Simon
CONTENTS
1. Definitions
2. Epidemiology of H5N1 in birds
 Outbreaks
 Bird species affected by H5N1
 Control of H5N1 in birds
 Poultry vaccine
 Surveillance of bird flu in birds
3. Epidemiology of H5N1 in humans
 Human cases of H5N1
 Clusters
 Case fatality rate (CFR)
 Transmission from birds to humans
 Human infection from the environment
 Human-to-human transmission
4. Influenza viruses and Pandemics
 Influenza viruses
 Past pandemic viruses
 H5N1 virus
 H5N1 mutations capable of causing human-to-human transmission
 Potential for a pandemic
5. Clinical aspects
 Distinction of influenza form a cold or allergy
 Recognition of fever
 Incubation period
 Infectious period
 Asymptomatic or mild infection
 Hospitalization
 Initial clinical manifestations
 Clinical course
 Radiological appearances
 Laboratory findings
 When to test for H5N1?
 Diagnosis
 Histopathology
 Pathogenesis
6. General conclusions for prophylaxis and treatment
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6.1 Treatment
Adamantane derivatives: amantadine and rimantadine
Neuraminidase inhibitors
Mechanism of action of neuraminidase inhibitors
Resistance of seasonal influenza to neuraminidase inhibitors
Resistance of H5N1 to neuraminidase inhibitors
Treatment of influenza with “Tamiflu”
Treatment of influenza with “Relenza”
Other treatments for H5N1

“Tamiflu” availability in Asia
7. Prevention
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7.1 Prevention: General Hygiene Measures
General
Building resistance
Hand washing and hand hygiene
Direct contacts with other people
Coughing and sneezing precautions
Masks
Living and working areas


7.2 Prevention: Specific Additional Hygiene Measures to Prevent H5N1.
Contacts of cases
Food precautions
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7.3 Prevention: Travel Concerns
General travel concerns
Travel kit
During travel
After travel
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7.4 Prevention: Vaccination
Vaccination against seasonal influenza
Vaccination against H5N1
Vaccination against Streptococcus pneumoniae
7.5 Prevention: Antiviral Prophylaxis
8. Pandemics
 Pandemic indicators
 Number of deaths in a pandemic
 Economic and social effects of a pandemic
 Economic impact of an avian flu pandemic in Asia
 Psychological aspects of a pandemic
 Ethical guide to pandemic planning
 Preventing a pandemic
 Quarantine
 Security aspects
 Pandemic business check list
 WHO pandemic classification
 WHO actions and documents
 WHO and government stockpiling of antivirals
 Government pandemic planning
9. Corporate
 Corporate
 Asia/Pacific
10. H5N1 Web Sites
1. DEFINITIONS
Domestic fowl
Birds reared for their flesh, eggs or feathers and are kept in a yard or similar enclosure. They
include chickens, ducks, geese, turkeys and guinea-fowl.
Endemic
A disease/s constantly present in a particular locality or maintained within a population.
Epidemic
An epidemic is defined as a local or regional outbreak of an infectious disease. Epidemics of
“ordinary” (“seasonal”) influenza occur every year.
Pandemic
A pandemic is defined as a global epidemic of an infectious disease OR disease/s impacting an
extensive geographic area and affecting a large portion of the population. Pandemics may be
catastrophic. Two examples include the Black Death 1345-1350 and the Spanish Flu 1918-1919.
It has recently been shown that the 1918 Spanish flu pandemic was due to a bird flu virus that
jumped directly to man. The World Health Organization (WHO) expects 3-4 flu pandemics each
century.
2. EPIDEMIOLOGY H5N1 IN BIRDS
2.1. Outbreaks
H5N1 in Birds
Pre-1997
H5N1 bird flu was first detected in a chicken in Aberdeen in Scotland in 1959 and was called
A/chicken/Scotland/1959. It was next isolated from an outbreak in wild terns in South Africa in
1961. Little was then heard about it until 1997.
1997
It caused a large outbreak in poultry in Hong Kong in 1997, solved by culling (killing) all the
poultry in Hong Kong. It was detected again in Hong Kong in a single peregrine falcon in January
2004, in a single grey heron in December 2004 and in a single Chinese pond heron in January
2005.
2003
After several years of anonymity it rose again to cause several large outbreaks in poultry in
several countries in SE Asia and in China. In 2003 there was an outbreak in South Korea.
2004
In 2004 there were outbreaks in Japan (confined to a single farm in Yamaguchi province) and
outbreaks in Vietnam, Thailand, Cambodia, Indonesia, Laos, Pakistan, Malaysia, South Korea
and Southern China.
2005
China
In April 2005 it was found to be the cause of death in many migratory birds in Qinghai Province.
Probably over 2000 birds died. This is of particular epidemiological importance because Qinghai
Lake is a major stopover for migratory birds on their way North or South. In particular bar-headed
geese fly over the Himalayas to India in September and return to Qinghai in April. Thus it is
possible that H5N1 could be introduced into India. Birds from Qinghai also take migratory flyways
to Europe. In June it was found in Xinjiang province, in August in Tibet. In October there were
outbreaks in Inner Mongolia, Anhui and Hunan provinces. Several new outbreaks in poultry in
China have occurred since end October 2005, most notably in Liaoning province including the
cities of Jinzhou and Fuxin. Over 370,000 birds have been culled in Liaoning. In November there
were outbreaks in Hunan province, Inner Mongolia (including a new one 25th November in
Zalantun City), Anhui province, Shanxi province, Ningxia prvonice, Yunan province, Hubei
province and Xinjiang Uygur Autonomous Region and an outbreak in Turpan in the far west of
Xinjiang 24th November. A new outbreak in Xinyuan county in the far northwest of Xinjiang
province was confirmed 1st December. Several authorities including Dr Guan Yi of Hong Kong
University Microbiology Department suspect that there have been many more outbreaks in China
than the numbers reported. Such underreporting could be due to several factors including lack of
surveillance, lack of diagnostic facilities and lack of will on the part of local authorities to report
outbreaks. Beijing wants to improve this situation and has ordered local authorities in China to
report outbreaks to national authorities within 4 hours
Indonesia
A new outbreak of H5N1 in Aceh Province in Indonesia was reported 24th November.
Mongolia
There was an H5N1 in Mongolia in August 2005
Philippines
There was an H5 outbreak in the Philippines in July 2005 but it was not confirmed as H5N1.
Thailand
H5N1 outbreaks in poultry have been reported monthly in Thailand since the beginning of 2005.
Vietnam
H5N1 is widespread in Vietnam where 70-80% of ducks in the Mekong Delta are infected. An
outbreak in Quang Nam province in central Vietnam reported 11th November killed 300 ducks. In
Vietnam outbreaks were reported in 17 of the 64 provinces. In December outbreaks occurred in
the northern provinces of Pho Tho, Thai Binh and Hoa Binh Yen Bai and Ha Giang.
Former Soviet Republics and Russia
H5N1 was reported in Kazakhstan and Russia, including Siberia and Chelybinsk in the Urals.
New outbreaks were reported in Russia in Tambov, Omsk and Kurgan from 1st November
onwards. The Crimean region of Ukraine confirmed an outbreak of H5 on 9th December.
Europe & Middle East
It caused poultry outbreaks in Romania, Turkey, Greece and Croatia starting early October 2005.
Four chickens found dead in Caraorman in Romania’s Danube Delta on 16th November were
found to carry H5N1. It was found in a turkey in a remote village 70km from the Danube Delta,
Scarlatesti, in Bralia county, Romania on 27th November. Three new outbreaks in Bralia were
reported 2nd December and another on 22nd December. An outbreak in Stelnica, 140k east of
Bucharest was reported 24th December 2005. On 11th November Kuwait reported a dead
flamingo found on the beach infected with H5N1. Several hundred dead pigeons in Somali region
of Ethiopia were tested for H5N1.
Avian influenza outbreaks NOT due to H5N1
1. Japan reported an outbreak on 9th November 2005 at a chicken farm in Ibaraki prefecture –
resulting in the culling of 170,000 birds. This outbreak was due to H5N2 and not to H5N1.
There were 4 outbreaks in Japan in the period June - December 2005 due to H5N2
2. Canada reported a low pathogenic H5N2 strain in birds in Manitoba and British Columbia on
19th November 2005. Canada had an outbreak due to H7N3 in 2004
3. Taipei had an outbreak due to H5N2 in 2004
4. USA had outbreaks due to H2N2, H5N2 and H7N2 in 2004
5. South Africa had an outbreak due to H5N2 in 2004
6. North Korea had an outbreak due to H7 in April 2005.
7. An H5N2 outbreak in ostriches in Matabeleland, Zimbabwe was reported on 10th December
2005
2.2. Bird Species Affected by H5N1
H5N1 has been found in poultry including chickens and turkeys, sea birds, shore birds, wild duck,
wild geese, wildfowl, herons, peregrine falcons, pigeons, quail and in domestic ducks and geese.
Domestic ducks are usually not affected, excrete large amounts of virus and act as asymptomatic
carriers. They are silent reservoirs of the disease.
H5N1 was found in dead birds in Qinghai Lake in April 2005. Prior to this H5N1 was thought to
cause only asymptomatic disease in wild birds. Over 2000 birds died, the vast majority being barheaded geese, brown-headed gulls and great black-headed gulls. A few great cormorants were
also affected. All of these birds had the same H5N1 virus, namely A/chicken/Shantou/810/2005
also known as the ‘Z’ genotype. This finding was of great importance as it implied that wild birds
are active in spreading the disease. Prior to this it had been found in wild birds only in the vicinity
of poultry farms. (Nature 436;191-192 Chen et al 14th July 2005). H5N1 can thus be spread from
country to country by migrating wild waterfowl, especially by wild ducks.
In early October Indonesia reported healthy chickens that tested positive for H5N1. If confirmed
this is very worrying as there would be a possibility that asymptomatic chickens could spread the
disease.
2.3. Control of H5N1 in Birds
Preventative measures in birds include vaccination, culling, disinfection and other biosecurity
measures, quarantining infected farms and isolating unaffected farms. Bird flu may be passed
from farm-to-farm by imperfect biosecurity. Thus vehicles, equipment and cages must all be
properly disinfected. Feed taken from farm-to-farm may also be contaminated. It is possible that a
worker at a commercial poultry farm may get his/her clothes/shoes contaminated at home from
his/her “backyard flock” and infect the commercial farm. The UN Food & Agriculture Organization
estimated that over 100 million domestic fowl died or were culled because of H5N1 between late
2003 and 2004. The UN has urged countries not to cull wild birds as this is unlikely to make any
significant difference.
Such standard measures are likely to be only temporarily successful in halting the spread of the
disease since the major reservoir of the disease is in wild waterfowl whose movements cannot be
controlled.
In rural areas of Asia where most households maintain free-ranging poultry and depend upon
them for income and food the disease seems entrenched and difficult to control. Even in a
developed country like Hong Kong about 1850 households keep 3600 ducks and 9200 chickens
as well as an estimated 3000 food and racing pigeons. The same is true to a lesser extent in
Singapore. Such backyard flocks lack biosecurity. In Hong Kong a license is needed for anyone
keeping more than 20 birds.
2.4. Poultry Vaccine
Poultry vaccines can be made quickly as safety requirements are of little concern. In Harbin
China the National China Bird Flu reference Laboratory has developed H5N1 vaccines and over
2.68 billion birds were vaccinated between February 2004 – January 2005. China plans to
vaccinate all 14 billion poultry in the country. The efficacy of these vaccines is uncertain. Hong
Kong is vaccinating all poultry (except sentinel birds) against H5N1. There are still concerns that,
despite vaccination decreasing viral excretion, if vaccinated birds become infected the decrease
in viral excretion might not be to non-infectious doses. Such birds might therefore be a significant
hazard.
2.5. Surveillance of Bird Flu in Birds
The United Nations is setting up a bird-flu early-warning system. This will alert countries of
incoming migratory birds that could be carrying H5N1. This system will take two years to become
operational. It will provide precise details of wild birds, arrival times and destinations – giving
countries enough time to prepare.
3. EPIDEMIOLOGY H5N1 IN HUMANS
3.1. Human Cases of H5N1
The first reported human cases of H5N1 occurred in 1997 in Hong Kong. There were 18 cases
with 6 deaths. In early 2003 there were 2 more cases in Hong Kong in a family who had visited
Southern China. There were then no further reports of disease in humans until early January
2004 when cases of human infection due to H5N1 started to occur in SE Asia. This outbreak has
occurred in 3 waves and the WHO reports the following laboratory confirmed case numbers: (1)
January – March 2004 12 cases in Thailand and 23 in Vietnam with a case fatality rate (CFR) of
69%. (2) July – October 2004: 6 cases in Thailand and 4 in Vietnam with a CFR of 89%. (3)
December 2004 – present time: 4 cases in Cambodia, 66 cases in Vietnam, 16 in Indonesia, 4 in
Thailand and 6 in China. Cases from Indonesia were first reported in July 2005. The total number
of cases since January 2004 is 141 with 22 in Thailand, 4 in Cambodia, 93 in Vietnam, 16 in
Indonesia and 6 in China. The male/female ratio is approximately 1:1. Cases have ranged in age
from 4 months to 69 years. The average age is 24 and the median age 19. At least 80% of cases
have a history of poultry exposure.
Cases in China were confirmed in Heishan county in Liaoning province, Xiangtang county in
Hunan province, Anhui province (23rd November), Guangxi (8th December) , Liaoning province
(10th December), and Suichuan county in the east of Jiangxi province (17th December). The WHO
has confirmed all six cases.
The WHO reports only laboratory confirmed cases and it is likely that the true number of cases
might be much higher. In China there may have been significant numbers of undiagnosed or/and
unreported cases and/or deaths. Thus Dr Masato Tashiro, a WHO consultant who visited Hunan
province, stated that he believed that China has had 300 human deaths from avian influenza.
WHO stated that Dr Tashiro was not part of the recent WHO mission and that WHO had no
information to suggest that there are unreported human H5N1 cases or deaths in China. The
Chinese Ministry of Health refuted similar rumors. Dr Tashiro has now retracted his claims. I-OnAsia, an investigation company, has made over 300 visits to farms, wet farms and hospitals in
China and have found NO evidence of human cases April – October 2005.
There have also been reports of several more unconfirmed cases in Indonesia. Some of these
involved people who worked in, or visited, the Jakarta Ragunan Zoo. Israel also investigated a
man with suspected H5N1 who feeds birds on a nature reserve in Galilee
3.2. Clusters
An increasing number of clusters, either in time or space, will be the first evidence of improved
transmissibility of H5N1 human-to-human. There have been several clusters of cases. The
largest of these occurred in Haiphong in Vietnam in April 2005 involving father, mother and three
daughters. There have been three clusters involving mother and daughter but in only one of these
(August 2005 in Thailand. NEJM 2005;352:333-340)) was it thought likely that there was humanto-human transmission. The Indonesian case was a man whose two daughters also died –
however H5N1 was proven only in the father. A Thai health official said that the two latest cases
in Thailand might be human-to-human transmission. Both had mild symptoms and neither had
physical contact with chickens or birds.
3.3. Case Fatality Rate (CFR)
The final percentage of those infected who die from avian influenza is called the case fatality rate
(CFR). The gross attack rate (GAR) (infection rate) is the percentage of the population that is
likely to become clinically ill. Typically influenza pandemics have a gross attack rate of 20-40%.
The mortality rate = CFR x GAR.
The overall CFR, so far, is 51.7% This compares to the 33% CFR in Hong Kong in 1997). In
Vietnam 42 out of 93 cases have died. In Thailand 14 out of 22 cases have died. In Cambodia all
4 cases died. In Indonesia 11 out of 16 cases have died and in China 2 out of 6 cases have died.
In the last 11 months the CFR has dropped to 40.7%. There is a high death rate in infants, young
children and in young people up to the age of 39 after which the CFR appears to decrease
significantly. The CFR in Thailand is 89% in those aged <15. Death occurs on average 9-10 days
after onset (range 6-30). Most patients die of progressive respiratory failure.
3.4. Transmission from birds to humans
H5N1 is transmitted to humans by direct contact with infected birds or with surfaces contaminated
by bird excretions. The virus is excreted in the nasal and salivary secretions of birds and in their
feces. Most patients have a history of direct contact with birds and have been involved in
activities such as plucking or preparing diseased birds, handling fighting cocks, playing with
poultry (especially asymptomatic infected ducks) and consumption of ducks’ blood. Infected birds
that become ill but survive infection will excrete the virus for over 10 days. Some bird species
may be asymptomatic carriers and excrete the virus for long periods of time. Humans may also
acquire the disease through inhalation of dried out bird feces (“fomites”). Chickens remain
viraemic for 12 hours and if eaten undercooked (not cooked to a uniform temperature of at least
70C/158F) during this period could infect humans. Eating contaminated eggs may theoretically
lead to infection. Eggs, like poultry, must be cooked to a uniform temperature of 70C/158F.
Tigers and leopards in zoos have contracted the disease after eating raw infected chickens.
The H5N1 virus can survive for long periods in tissues and feces especially when the temperature
is low. Thus it can survive in frozen tissues indefinitely and has been found in frozen duck meat.
3.5. Human infection from the environment
The virus can survive for long periods of time in the environment. It is therefore possible that
humans could get infected in several other ways: (a). by oral ingestion of contaminated water
during swimming (b). by contamination of the eyes (conjunctival inoculation) by infected water (c).
by contamination of the hands by infected fomites (d). by contamination from untreated poultry
feces used as fertilized.
3.6. Human-to-human transmission
Although there have been several clusters of cases (see 3.2) there have been only two probable
case of human-to-human transmission: (1) a case of child-to-mother transmission that involved
intimate contact. (2) a nurse exposed to an infected patient in Vietnam. So far no case of humanto-human transmission by small particle aerosols has been identified.
4. INFLUENZA VIRUSES AND PANDEMICS
4.1 Influenza viruses
The family Orthomyxoviridae includes three genera of Influenza viruses: A, B and C. Influenza A
viruses contain a single-stranded negative sense RNA segmented genome divided into 8
segments. Each segment codes for a specific product. The 8 genes comprise three avian
ploymerase genes (PB) named ‘PA’, ‘PB1’ and ‘PB2’. There is one ‘NP’ gene, one ‘M’ gene and
one ‘NS’ gene. The last 2 genes are the haemagglutinin (HA) and neuraminidase (NA). These
produce the surface proteins found on the envelope of the virus. There are 16 HA and 9 NA types
and individual viral strains may have any combination of HA and NA types. H5N1 is one example.
Influenza viruses can rapidly undergo antigenic changes at the HA or NA antigens. Such changes
may be relatively minor and are due to genetic mutation and are called “antigenic drift”. Major
changes are due to a reassortment of the RNA fragments and are called “antigenic shift”. Such
major changes might cause the emergence of a pandemic virus .
4.2 Past pandemic viruses
The segmented genome allows an influenza A virus to exchange material with other influenza A
viruses. The 1918 Spanish flu H1N1 virus has been sequenced (Taubenberger et al Nature 2004;
437:889-93) and recovered by reverse genetic engineering (Tumpey et al Science 2005; 310:7780). The 1918 virus was unique in two ways (1) it could replicate in tissue culture in the absence
of the protein trypsin. Trypsin is normally needed by flu viruses to activate HA to initiate infection
of tissue culture (2) It was 100x as lethal in mice as other flu viruses and releases cytokines
resulting in the rapid onset of lung disease and death. The 1918 virus can be used to study
various compounds that have a blocking action on the effects of specific cytokines.
It is found that all 8 genes in the 1918 H1N1 virus came from birds. This virus arose via a direct
adaptation to humans and there was no reassortment with genes from any human virus. The
1957 H2N2 pandemic virus however contained 5 genetic RNA segments from the H1N1 virus and
3 from the avian H2N2 virus, namely: HA, NA and PB1. This virus therefore arose by a
reassortment. This probably happened in humans or in pigs. The same is true of the 1968 H3N2
pandemic virus. This contained 5 genetic segments from the 1918 H1N1, 1 segment from the
1957 H2N2 (the NA), and 2 new segments from the avian H3N2 virus, namely HA and PB1.
Again this virus arose via a reassortment. The role of PB1 is critical in the pandemic viruses of
1957 and 1968 since it was transferred along with HA. This is well covered by Belshe R (NEJM
351; 21. 24th November 2005).
4.3. H5N1 virus
Since the 1997 Hong Kong outbreak the H5N1 virus has changed by “antigenic drift”. It is now
able to infect more species of birds. It can now infect cats and tigers and causes a more severe
illness in mice and ferrets. It has become increasingly stable in the environment. It has done this
by changing its genetic structure. Several strains of H5N1 have been named thus: (a) 1997:
A/HK/156/97 and A/HK/148/97 (b) 2003: A/HK/213/03 (c) 2004 from Vietnam: A/VN/1203/04 and
A/VN/1194/04 (d) 2004 Thailand: A/Thai/16/04. The Z genotype has become dominant and there
are two distinct types (clades) of this. The first is in Cambodia, Laos, Malaysia, Thailand and
Vietnam. The second is in China, Indonesia, Japan and South Korea. Recently a new type has
been found in Northern Vietnam and Thailand. There are several other genotypes / variants viz:
17B in Hunan, R12 in Xinjiang, 19A in Shantou and RK7 in Qinghai (a subvariant of the “Z”). In
summary the virus is continually changing.
4.4. H5N1 mutations capable of causing human-to-human transmission
An H5N1 mutation capable of causing human-to-human mutation might arise in one of two ways:
(1) By a gradual change in the genes of the avian virus, with a direct jump to humans. In this case
the mutant virus will contain pure avian virus genes. This happened in the 1918 Spanish flu
pandemic. Such a mutant, containing only avian flu virus genes is expected to cause severe
disease in humans. Mutations have already occurred and the dominant strain (genotype) now
circulating is called the “Z” strain.
(2) By a genetic reassortment wherein human flu genes are mixed with H5N1 avian flu genes.
The H3N2 human flu virus has infected pigs since 1998 and pigs act as a large reservoir of
H3N2. Pig trachea contains receptors for both avian and human influenza viruses. It is possible
that pigs may act as a “mixing vessel” allowing a genetic reassortment between H5N1 and H3N2.
A mutant virus may thus emerge capable of causing human-to-human transmission. Such a
mutant is expected to cause less severe disease than a mutant containing only avian flu genes.
There is a third possibility that most people have neglected – the possibility of H3 acquiring H5N1
genes – if this happens we will get a pandemic of H3. Surveillance in birds in Vietnam has
recently found H3N4 and H4N5 circulating in birds,
4.5. Potential for a pandemic
All previous pandemics were caused by influenza A with haemagglutinin subtypes H1, H2 and
H3. There is reason however to believe that the next pandemic may be due to H5N1. H5N1
currently has a low potential for human-to-human spread and requires close and prolonged
contact with a case. However experts are concerned that mutation might occur and that the
mutant virus might allow efficient human-to-human spread and give rise to a pandemic
(worldwide epidemic). The chance of a mutant virus with pandemic potential emerging is
increasing because H5N1 is (a) becoming increasingly widespread in more species of birds (b).
expanding its mammalian host range (it was found in diseased pigs in Southern China in 2003,
domestic cats in Thailand in 2004 and tigers and leopards in Thai zoos in 2005. Cats in Liaoning
province in China have died after eating dead chickens) (c) surviving for longer in the
environment and (d) increasing in its poultry-human interface due to increasing outbreaks in Asia
and Europe.
Avian flu viruses do not normally infect species other than birds and pigs. Many experts consider
avian flu to be the single greatest threat the world faces. Some, however, such as Paul Ewald, an
evolutionary biologist from the University of Louisville believes that that an H5N1 pandemic will
not happen. He says that a pandemic due to both a virulent and highly transmissible virus is
unlikely. He says that conditions were ripe for this in the environment on the Western Front in
WWI – but not now. Nature depends upon natural selection and this overrides a random
mutation. He believes that by vaccinating those working with chickens we can prevent a
pandemic.
5. CLINICAL ASPECTS
5.1. Distinction of influenza from a cold or allergy
Before we consider an illness as being influenza due to H5N1 we need to first diagnose that the
illness is due to influenza. The following table will give the lay person guidance in distinguishing
influenza from colds and other upper respiratory tract infections or simply a seasonal respiratory
allergy:
Symptoms
Fever
Airborne allergy
Never
Cold
Rare
Flu
Usual. High (100102F)( 37.8-38.9C)
sometimes higher
(especially in young
children); last 3-5
days
Common
Usual; often severe
Headache
General aches &
pains
Fatigue, weakness
Rare
Never
Rare
Slight
Sometimes
Sometimes
Extreme exhaustion
Never
Never
Stuffy or ‘runny’ nose
Sneezing
Sore throat
Cough
Common
Usual
Sometimes
Sometimes. Dry (nonproductive)
Common
Usual
Common
Common, hacking,
often productive
Chest discomfort
Rare
Mild to moderate
Usual, can last up to 3
weeks
Usual, at the
beginning of the
illness
Sometimes
Sometimes
Sometimes
Common, can
become severe.
Usually nonproductive
Common
There are some additional clues that may help distinguish the three:
Symptom
Onset
Duration
“Red eye”
Airborne allergy
May be sudden
Over a week
Possible
Cold
Gradual
3-5 days
Uncommon
Flu
Acute & sudden
Over 5 days
May be prominent
5.2. Recognition of Fever
People with high fever (temperature) might have hot and cold spells or even chills or rigors where
their teeth chatter and their body might shake. People with low-grade fevers might not even know
they have a fever. The best way of determining whether or not you have a fever is to take your
temperature with a thermometer. The gold-standard thermometer is a mercury under-the-tongue
thermometer but this is not suitable for travel and an electronic under-the-tongue thermometer or
an ear-reading thermometer is almost as accurate. Taking the temperature under the armpit
(axilla) is not as accurate.
In the USA the Fahrenheit (F) scale whilst in Europe the Centigrade (C) scale is used.
A normal person’s temperature is 37C (98.6F) but may as low as 36C (96.8F) and on occasions
even lower. Occasionally normal people may have temperatures as high as 37.5C (99.5F). The
body temperature might also increase to 38-38.5C (100.4-101.3F) with exercise, hot weather and
overdressing.
To convert Fahrenheit to Centigrade use the following formula: C=(F-32) x 0.5555
To convert Centigrade to Fahrenheit use the following formula: F= (Cx1.8) +32
Table showing equivalent Centigrade Fahrenheit values
Centigrade
36
36.5
37
37.5
Fahrenheit
96.8
97.7
98.6
99.5
Fahrenheit
99
99.5
100
100.5
Centigrade
37.2
37.5
37.8
38.1
38
38.5
39
39.5
40
40.5
41
100.4
101.3
102.2
103.1
104
104.9
105.8
101
101.5
102
102.5
103
103.5
104
38.3
38.6
38.9
39.2
39.4
39.7
40
5.3. Incubation period
The incubation period (time between infection and the development of first symptoms) of H5N1 in
humans is not known but is thought to be up to 8 days. This may be longer than seasonal
(“ordinary”) influenza where the incubation period is 1-4 days. Although in the 1997
H5N1outbreak most cases occurred within 2-4 days after exposure 2004 cases range up to 8
days incubation. In a few household clusters incubation period has been 8-17 days but this may
be due to unrecognized environmental or animal exposure. The median incubation in a series of
59 cases was 5 days.
5.4 Infectious period
It is important to note that people with “ordinary” flu are infectious for one day before they become
ill. If a mutant H5N1 strain capable of causing easy human-to-human spread develops and if, as
appears likely, people with this strain are infectious to others one day before they become ill this
will cause huge problems in controlling the spread of the disease.
People with seasonal influenza show persistent viral shedding and are infectious to others for 5
days following the onset of symptoms. Viral replication and shedding appears to be prolonged in
H5N1 compared to seasonal influenza. Additionally there is less nasopharyngeal replication than
in human influenza. Viral RNA has also been found in fecal samples including, in one case,
infectious virus suggesting replication in the gastrointestinal system.
5.5. Asymptomatic or mild infections
In the 1997 outbreak in Hong Kong several cullers and market workers developed antibodies to
H5N1 without developing the disease suggesting that infection could occur asymptomatically or
could possibly cause a mild disease. Serological surveys in recent cases in Thailand and Vietnam
have not confirmed this. However recently RT-PCR assay in contacts of patients in Northern
Vietnam has detected mild cases, more cases in older adults and an increasing number of
clusters. This suggests local virus strains may be adapting to humans.
5.6. Hospitalization
All with suspected H5N1 should ideally be isolated in hospital. Of course this will not be possible
in a pandemic due to an overwhelming number of cases. In a pandemic hospitalization will be
determined largely by a triaging process. Nebulizers and high-air flow oxygen masks should be
used only with strict airborne precautions. If discharged early patient and family need educating
on infection control and personal hygiene measures.
5.7. Initial clinical manifestations
H5N1 in humans starts like any other flu as an influenza-like illness (ILI). An ILI is defined as a
clinically unexplained elevated temperature of 37.8C or higher, and systemic symptoms such as
muscle aches (myalgia) and fatigue (with or without chills or headache), or respiratory symptoms
such as cough (with or without a runny nose (rhinorrhoea) or sore throat). During the peak flu
season the combination of fever, cough, fatigue and myalgia has a sensitivity of 30% and a
specificity of 80% in diagnosing influenza.
An analysis of H5N1 patients shows: fever >38C (100%), cough (94-100%) and this is productive
of sputum in 30-76%, muscle aches (11-50%), headache (10-100%). Sore throat although
reported in 33% of 1997 cases and 71% of Thailand cases has not been reported in Vietnam
cases. Runny nose (coryza or rhinorrhoea) was reported in 58% of 1997 cases and 53% of
Thailand cases but has not been reported in Vietnam cases. Diarrhoea appears to be an
important initial manifestation of H5N1 in humans and although occurring in only 17% of 1997
cases now occurs in 41-70% of recent cases. It is watery and without blood and may precede
respiratory manifestations by up to one week. One report described 2 patients presenting with
brain symptoms (encephalopathy) and diarrhoea without respiratory symptoms (NEJM 2005;352:
686-691). Vomiting occurs in 10-33% and abdominal pain in 17-50%. Conjunctivitis (“red eye”) is
rare, unlike avian flu due to H7. In many cases usual flu like symptoms are bypassed and the
patient will go from a non-specific high persistent fever to a pneumonic illness with organ failure.
5.8. Clinical course
In many cases H5N1 progresses to cause a community-acquired pneumonia characterized by
difficulty in breathing (dyspnoea). This develops, on average, 5 days after the onset of illness
(range 1-16 days). Examination may show fast shallow breathing (tachypnoea) and inspiratory
crackles when listening with the stethoscope. Sputum may be bloody. This may progress to a
respiratory distress syndrome. Some will get kidney or liver failure or DIC (disseminated
intravascular coagulation). Some get enlargement of the heart (cardiac dilatation) and
abnormalities of rhythm of the heart (arrythmias) such as SVT. These serious manifestations are
due to a “cytokine storm” and parallel cases seen in the 1918 Spanish flu pandemic. Other
complications include ventilator-associated pneumonia, pulmonary haemorrhage, pneumothorax,
pancytopenia, and sepsis syndrome without bacteraemia. Secondary bacterial pneumonia in
seasonal influenza is a common cause of death and the most common bacteria are
Streptococcus pneumoniae and Staphylococcus aureus (including MRSA). It is likely that these
same bacteria will be the cause of most cases of secondary bacterial pneumonia in H5N1.
Children should not be given aspirin as they might develop Reye’s syndrome. It is noted that the
1997 cases were exclusively pneumonic. The virus has changed since 1997 and both viral
shedding is higher and the amount of virus needed to cause disease in humans is less. The
current virus is more virulent than the 1997 one. The disease is now a systemic one. Despite this
mortality remains approximately the same as in 1997.
5.9. Radiological appearances
X-ray changes show pneumonia in most patients with breathing difficulty and occur, on average,
7 days after onset of fever (range 3-17 days). Changes include diffuse, multifocal or patchy
infiltrates, interstitial infiltrates and segmental or lobular consolidation with air bronchograms.
These changes are rapidly progressive. In most cases at least two zones are involved. Pleural
effusions are uncommon. Microbiological studies show these changes to be due to a primary viral
pneumonia and there is usually no bacterial superinfection. This may progress to respiratory
failure wherein X-rays show diffuse, bilateral, ground glass infiltrates. The features are those of
Acute Respiratory Distress Syndrome (ARDS). The time from onset of illness to ARDS is 6 days
(range 4-13).
5.10. Laboratory findings
Leucopenia (low white cell count) is common. A lymphopenia (low lymphocte count) occurs in 5080%. The degree of leucopenia / lymphopenia may be a predictor of severity. A low platelet count
(thrombocytopenia) occurs in 33-80%. A slight to moderate increase in liver enzymes
(aminotransferases) is common and occurs in 61-83%. High blood sugar (hyperglycaemia) may
also occur but might be due to the use of steroids. Increased creatinine levels may occur
indicating abnormal kidney function.
5.11. When to test for H5N1?
1. Testing for H5N1 is indicated for hospitalized persons with:
 Radiographically confirmed pneumonia, ARDS or other severe respiratory illness for which an
alternative diagnosis has not been established
AND
 History of travel within 10 days of symptoms onset to a country with documented H5N1
infections in poultry and/or humans
2. Testing should be considered on a case-by-case basis in consultation with health authorities
for hospitalized or ambulatory persons with:
 Documented temperature of >38C (>100.4F)
AND
 One or more of the following: cough, sore throat or shortness of breath
AND
 History of contact with poultry (e.g. visited a poultry farm, a household raising poultry, a bird
market) or with a known or suspected human case of H5N1 in an H5N1-affected country
within 10 days prior to onset of symptoms.
5.12. Diagnosis
Laboratory diagnosis of H5N1 is made by
(a).a positive viral culture, which takes 2-10 days or
(b) RT-PCR on a throat (pharyngeal swab) or on nasopharyngeal aspirate (NPA) or
(c) a positive immunofluorescence test for antigen with the use of monoclonal antibody against
H5 AND at least a four-fold rise in H5 specific antibody titers in serological specimens taken on
days 1 and 14.
(d) antigen detection on pharyngeal sample or NPA by e.g. NASBA (nucleic acid sequence based
amplification) The results of the last test can be known within 4-6 hours.
In H5N1, unlike “ordinary flu”, at 4-8 days after the onset of the illness there is
(a) a higher amount of virus in the pharynx than in NPA and
(b) at least 10 times as much virus as in “ordinary flu”. Thus virus detection is best made from a
pharyngeal swab rather than from an NPA sample
It should be noted that, as in seasonal flu, a diagnostic test depending upon culture or antigen
detection is only useful if performed during the time of active viral shedding. Such tests give best
results when viral shedding is at its highest.
Newer tests are being developed which hopefully will give results within 15-30 minutes. Clearly
the more rapid the detection method the more useful the test. Rapid and early detection of cases
is essential for effective and rapid epidemiological control. Dr Kathy Rowlen of the University of
Colorado has developed a quick diagnostic “chip” test that can test for 11 different influenza
strains including H5N1. It is said to be >90% accurate in identifying H5N1. There are commercial
rapid antigen tests already available but these will detect only Influenza A and are not specific for
H5N1. They are also rather insensitive (the 12 rapid tests available in the US for detection of
influenza A have an overall sensitivity of only 70%) and will not detect many cases of Influenza A
including H5N1. The specificity of rapid diagnostic tests for influenza A is however high at 9099%. We need newer, more sensitive and rapid tests that are specific for H5N1. Current tests
may be giving a certain number of false negative results due to mismatching of PCR primers. In
H5N1 viral replication is prolonged and can be detected in NPA at a median of 6.5 days after
onset (range 3-16). Most fecal samples tested have been positive for viral RNA suggesting
replication within the gastrointestinal tract. Urine has been negative. In humans 6 of 7 serum
samples were positive for viral RNA 4-9 days after onset. Virus has also been detected in the
cerebrospinal fluid (CSF).
Current testing can determine new strains of H5N1 within one week.
5.13. Histopathology
The lungs show diffuse alveolar damage including alveolar space filling with fibrinous exudates
and red cells, hyaline membrane formation, vascular congestion, lymphocyte infiltration into
interstitial areas and proliferation of reactive fibroblast. The spleen and lymphoid tissue may show
lymphoid depletion and atypical lymphocytes. The liver may show centrilobular hepatic necrosis.
The kidneys may show acute tubular necrosis. It is not known whether these effects on extrapulmonary organs are due to a direct effect of the virus or due to profound cytokine release.
5.14. Pathogenesis
The H5N1 virus causes human macrophages to release chemicals called cytokines. These
include TNF-alfa (tumor necrosis factor), interleukin-6, interferon-gamma and interleukin-8. These
cytokines include inflammatory mediators and are responsible for much of the severe tissue
damage. In fact the term “cytokine storm” has been given to the process wherein massive
amounts of these chemicals are released and cause potentially irreversible tissue damage. Some
humans are probably more susceptible to the release of cytokines than others by H5N1 –
possibly because of genetic factors – but this is not well understood. It is possible that the
relatively higher case fatality rate seen in younger people is due to a stronger immune response
leading to a higher release of cytokines.
In seasonal influenza some people develop severe disease. In some cases this may be due to
secondary bacterial disease e.g. 24% of pediatric deaths in the US in the 2003-2004 season were
associated with bacterial infection. In other cases severe disease may be associated with the
particular serotype. Thus H3N2 is associated with severe disease more than H1N1. Severe cases
of seasonal influenza are often associated with the induction of proinflammatory cytokines cf type
1 interferons, TNF, interleukin-6 and interleukin-8. This parallels H5N1. It is important to
determine whether therapy directed against host responses (e.g. cytokine release) is of benefit in
both H5N1 and severe seasonal influenza.
6. GENERAL CONCLUSIONS FOR PROPHYLAXIS AND TREATMENT
1. The adamantanes, when used for treatment, induce clinically significant resistance. The
resistant virus is as pathogenic and transmissible as the parent virus. Their use should be
reserved for prophylaxis, provided the pandemic strain is sensitive.
2. Both neuraminidase (NA) inhibitors and adamantanes are equally effective for prophylaxis in
influenza A and the adamantanes are preferable because they are much less expensive
provided the pandemic strain is susceptible.
3. Currently only a few strains of H5N1 appear to be sensitive to the adamantanes.
4. Neuraminidase inhibitors reduce pneumonia and other lower respiratory tract complications
and are the preferred choice of treatment.
5. Any antiviral used for treatment should be given within the first 24 hours of the onset of
symptoms and may not be so effective if given after 48 hours. The exceptions to this might be
in the immunosuppressed or in H5N1. In both there is a prolonged period of active viral
replication. .
6. Early treatment may also reduce viral shedding, thereby minimizing infectivity & transmission.
7. The public should be educated to seek early treatment. Rapid diagnostic tests (at least for
influenza A and preferably for H5N1) should be available. If these are not available treatment
should be started on the basis of clinical symptoms.
8. During a pandemic the virus will circulate in any given community around 6-8 weeks and if
long-term prophylaxis is given it should be given for at least 8 weeks.
9. Short-term prophylaxis for 10-14 days should be given to those exposed to a case.
10. If there is only a limited supply of antiviral drugs treatment only is a more efficient strategy to
reduce health impacts than a prophylaxis strategy.
11. If a person is vaccinated whilst receiving prophylaxis the antiviral can be stopped 14 days
after vaccination. If two vaccine doses are needed to achieve protection then antivirals can
be stopped 14 days after the second dose. Prophylaxis should not be used in conjunction
with live-virus vaccination.
12. If there is a shortage of antiviral drugs target their use to priority groups. The groups that
many countries define as high priority are health care workers, public safety services, key
decision makers and those at high risk for severe complication (in seasonal flu this group
includes those with chronic disease e.g. heart, kidney, lung, diabetes etc. In a pandemic the
high-risk group may change to young persons, as was the case in the 1918 pandemic). Most
country plans give different priority to the above.
13. Communications plans must be clear to describe the rationale for defining certain groups as
higher priority for prophylaxis (and possibly treatment if there is a severe antiviral shortage).
14. In a pandemic ongoing monitoring for resistance and new adverse effects is essential.
15. All of this assumes H5N1 will be sensitive to at least the neuraminidase drugs.
6.1 TREATMENT
6.1.1 Adamantane derivatives: Amantadine and Rimantadine
The adamantane derivatives comprise amantadine and rimantadine and act as M2 ion-channel
inhibitors. Amantadine (“Symmetrel”) manufactured by Novartis is also used to treat Parkinson’s
disease. It is approved for treatment in the US in those aged >1 year. It is active against Influenza
A viruses. It must not be used in pregnancy and caution should be used in the following
conditions: glaucoma, prostatic enlargement, history of peptic ulcer, congestive heart failure,
orthostatic hypotension, cardiovascular disease, hepatic impairment, renal impairment, eczema,
the elderly, epilepsy, psychiatric illness, children <5 years old and lactation. Adverse effects
include gastrointestinal upset, nervous excitement, increased drive, concentration difficulties,
insomnia, dizziness, anticholinergic effects, peripheral oedema and livedo reticularis.
Neurological adverse effects may be severe and suicide attempts and fits have followed its use.
It is supplied as 100mg capsules with a shelf life of 5 years. The dose is 200mg daily or 100mg
twice daily for 5 days. The dose should be reduced in those with renal failure (creatinine
clearance <80mls/minute). There are several generic manufacturers.
Rimantadine is approved for treatment of influenza A in adults in the US. The dose is 100mg
twice daily for 5 days. It has a similar spectrum of adverse effects as amantadine but has fewer
neurological side effects.
If started within 48 hours of symptoms both drugs reduce the duration of symptoms in influenza A
by one day. No trials document reduction in complications.
Like the neuraminhidase inhibitors there is little, if any, therapeutic benefit to be gained from
starting the adamantanes later than 48 hours after the onset of symptoms and they should be
started as early as possible and preferably within the first 24 hours.
Influenza A viruses readily develop resistance and such resistant viruses demonstrate similar
transmissibility and virulence to non-resistant viruses. In some situations resistance has been
found in >30% treated. Resistance to amantadine implies resistance to rimantadine and vice
versa. The prevalence of adamantane resistance in influenza A is 14.5% in the US and 70% in
SE Asia.
Most H5N1 strains are resistant to amantadine and rimantadine and it may appear that these
drugs have little role in the treatment of H5N1. However it appears that a small number of strains
in Vietnam and Thailand may be sensitive.
6.1.2 Neuraminidase inhibitors.
These include oseltamivir (“Tamiflu®”) developed by Gilead Sciences and licensed to Roche, and
zanamavir (“Relenza®”) manufactured by GlaxoSmithKline. The fruit, star anise, is the starting
material for Tamiflu and is grown mainly in China. It is noted that star anise itself is of NO use in
preventing or treating avian influenza and some star anise teas can make people seriously ill. A
third, peramivir, for intravenous use, is manufactured by Biocryst Pharmaceuticals and is under
investigation. These drugs are effective in all cases of type A influenza. They reduce the
symptoms of seasonal influenza by 1-2 days. In seasonal influenza oseltamivir reduced
pneumonia by 55% in one trial and in another trial zanamivir reduced pneumonia by 40%. The
impact on reduction of mortality has not been assessed. They are theoretically useful in both
treating H5N1 and in preventing (prophylaxis of) it.
If they are as effective in H5N1 as in seasonal influenza they will be expected to shorten the
illness by one day, to reduce severity and the need for hospitalization. Theoretically they should
(a) reduce the transmission of the virus but there is no proof of this, and (b) reduce mortality in
cases of severe disease, but again there is no proof of this. Mice given oseltamivir before and
after injection with a lethal strain of H5N1 (H5N1 A/Vietnam/1203/04) were protected against its
lethal effects (JID 2005;192). It has recently been shown that the neuraminidase inhibitors are
effective against the virus that caused the 1918 pandemic. Dr Nguyen Tuong Van, who runs the
ICU at the Centre for Tropical Diseases in Hanoi, has treated 41 H5N1 cases. She stated that
Tamiflu had no effect. However (a) she gave no indication of the time after symptom onset at
which Tamiflu was given. It is noted that the earlier it is given the better the results and that it is
less likely to be of use if given after 48 hours. (b) she did not indicate the dose that was given
and it is noted that the correct dose is probably 150mg 12 hourly. (c) there was no control group
to her patients.
6.1.3. Mechanism of action of neuraminidase Inhibitors
All influenza viruses, including H5N1, have two surface glycoproteins, a hemagglutinin (HA) and a
neuraminidase (NA). The hemagglutinin binds sialic acid receptors on cell surfaces and allows
entry of the virus into cells. Virus then multiplies within cells. The new viruses then attach to sialic
acid receptors within cells and the neuraminidase breaks them thus causing a hole in the cell wall
and allowing the virus to exit the cell. The neuraminidase inhibitors act by binding to the active
site of the influenza virus neuraminidase thus preventing the virus attaching to the sialic acid
receptors of the cell. They therefore interfere with the release of influenza virus from human host
cells. This will halt the infection. The active site of the NA has to change its shape to a pocket to
accommodate the bulky molecule of oseltamivir but zanamivir fits nicely into this active NA site
and the site does not need to change its shape to accommodate zanamivir. Since replication of
influenza virus in the respiratory tract reaches its peak between 24 – 72 hours after the onset of
infection these drugs must be given as early as possible, and preferably within the first 24 hours.
There is probably little therapeutic benefit in giving these drugs later than 48 hours after the onset
of symptoms.
6.1.4. Resistance of seasonal influenza to neuraminidase Inhibitors
In Influenza A resistance can occur by neuraminidase (NA) mutations or haemagglutinin (HA)
mutations. Whilst HA mutations confer cross-resistance to all neuraminidase inhibitors NA
mutations appear to be drug specific. This relates to the molecular shape of the particular
neuraminidase inhibitor and whether or not it can fit into the active site of the NA. Mutations in the
NA may occur which prevent oseltamivir fitting into the active site. Such mutations do NOT
however prevent the NA binding to the cell’s sialic acid receptors and allowing cell cleavage and
viral release. Such mutated viruses still allow zanamivir to bind to the active NA site. Thus
mutations to oseltamivir occur with both seasonal flu and with H5N1 whilst NO mutation
preventing the action of zanamivir has been found.
In a study of “seasonal flu” 0.4% of adults treated with oseltamivir had resistant viruses at the end
of treatment. However in children treated for “seasonal flu” resistant viruses emerge more often.
In one study on seasonal influenza 4% of children treated with oseltamivir transiently carried a
virus of reduced neuraminidase susceptibility. In a 2000-2001 Japanese study 16% of children
showed high level resistance of an H1N1 virus to oseltamivir at the end of treatment. In a 2004
Japanese study 18% of children had a resistant H3N2 virus to oseltamivir at the end of treatment.
This surprisingly high rate of emerging resistance in these Japanese studies may have been due
to the use of insufficient doses. Thus these children were given 2mg/kg. In a US trial where
similar aged children were given higher doses none shed resistant viruses.
It is therefore worrying that insufficient doses, or inadequate courses, of oseltamivir may lead to
viral resistance. This is particularly true with seasonal flu where children have higher viral loads
and excrete the virus for longer than adults. This is because children have no degree of preexisting immunity due to past infection with similar flu viruses. The habit of stopping treatment
prematurely could also lead to suboptimal treatment of influenza and promote drug resistance. In
an editorial Anne Moscona notes that personal stockpiling may promote this tendency to misuse
oseltamivir and promote resistance (NEJM 353:25 22nd December 2005).
The question then arises as to whether or not such oseltamivir resistant viruses could spread?
Clinical data suggests that neuraminidase inhibitor resistance might reduce the fitness of
influenza strains and decrease their transmissibility. Thus infectivity and pathogenicity in mice
were not compromised by HA mutations but NA mutants were less infectious and pathogenic in
mice and ferrets. Indeed there was previously NO documented primary resistance to oseltamivir
in seasonal influenza. However recent reports from Japan isolated oseltamivir resistant virus in 3
out of 1200 isolates from ill patients with seasonal influenza showing that these resistant viruses
are transmitted, at least at a low level, in humans.
In studies on prophylaxis of seasonal influenza using oseltamivir there was no evidence of
emergence of drug resistance.
6.1.5. Resistance of H5N1 to neuraminidase Inhibitors
There is evidence that some strains of H5N1 are partly resistant to oseltamivir. Thus studies on
mice using a strain isolated in 2004 show that to achieve similar survival rates and viral clearance
one needs to use higher doses for longer viz. 10-14 days. It is therefore reasonable to consider
using oseltamivir in doses of 150mg twice daily for 10-14 days to treat H5N1. This dose has been
shown to be as tolerable as 75mg twice daily. Indeed as discussed below treatment with the
currently recommended doses may select for resistant H5N1 viruses. Similarly double the normal
dose of zanamivir is as tolerable as the normal dose.
Partial resistance to Tamiflu was described in a Vietnamese patient with H5N1 whilst on
prophylaxis. This patient subsequently received a therapeutic twice daily doses and survived (Le
QM et al. Nature 2005;437:1108). This strain is less infectious than the susceptible parent virus
but is still transmissible to ferrets. Recently (NEJM 353:25 22 nd December 2005) de Jong et al
described two Vietnamese patients with high-level oseltamivir resistance. In one of these patients
the resistance developed during treatment. In the other case it is not known whether the
resistance was present at the beginning of treatment or developed during treatment. Both
patients died. One patient started treatment on the second day of illness i.e. within the first 48
hours. The other patient started treatment on day 6. The resistant virus in both cases showed the
H274Y mutation in the neuraminidase site (and the mechanism of resistance is the same as
described in the section on resistance of seasonal influenza to neuraminidase inhibitors). The
question remains whether such resistant H5N1 strains could be transmissible from person-toperson.
Despite these cases of resistance de Jong’s paper also notes 4 patients who survived. In these
patients oseltamivir treatment was associated with a rapid decline of viral RNA to undetectable
levels. Treatment initiated later in the illness than 48 hours also appeared to be beneficial
suggesting that treatment may be beneficial as long as there is viral replication. In the two
patients who died there was incomplete suppression of viral replication. This suggests that using
higher doses for longer and the use of combination therapy may be needed for (a) optimal
treatment and (b) to prevent the emergence of resistance.
In seasonal influenza children have higher viral loads compared to adults and excrete the virus
for longer than adults. In H5N1 because neither adults nor children have pre-existing immunity
viral loads and length of excretion are likely to be the same in both. This, together with a longer
incubation period than seasonal flu, will increase the potential for transmission and promote the
development of resistance if oseltamivir is misused.
Laboratory resistance to Tamiflu can be determined within 1-2 days.
6.1.6. Treatment of influenza with “Tamiflu”
Treatment of H5N1 is with Tamiflu or Relenza. Tamiflu is taken orally and is readily absorbed
from the gastrointestinal tract. Liver enzymes convert it to the active form, oseltamivir carboxylate.
It has an advantage over Relenza in that it achieves high levels in the blood and thus has actions
both within and without the respiratory tract. Relenza has an advantage over Tamiflu in that it
achieves very high concentrations in the lungs.
The dose of Tamiflu age >13 is one 75mg capsule twice daily for 5 days. This dose needs to be
reduced to 75mg daily for those in kidney failure with a creatinine clearance between 1030mls/minute. No dose adjustment is needed for liver problems. Some experts now believe we
should treat H5N1 with a dose of 150mg twice daily for 14 days (until neutralizing antibodies
appear) and even consider adding Relenza. Whether or not the addition of an immunomodulator
might help in treatment remains to be demonstrated. The expiry date of Tamiflu is 4 years from
the date of manufacture. Tamiflu should be stored at a temperature <30C.
There is an oral suspension that needs to be reconstituted with water to treat those aged >1 year
to <13 years. The dose is 30mg twice daily for weight <15kg, 45mg twice daily for weight >15kg –
23kg, 60mg twice daily for weight >23kg – 40kg and the adult dose of 75mg twice daily for weight
>40kg. The oral suspension contains sorbitol and it is not indicated for those with hereditary
fructose intolerance.
Tamiflu is not indicated for use in those aged <1 year because there is concern that the immature
blood-brain barrier allows considerable quantities of Tamiflu to accumulate in the brain. High dose
oseltamivir in infant rats resulted in a significant number of deaths.
Adverse effects include nausea (11% on treatment and 7% on prophylaxis) and vomiting (8% in
treatment and 2% on prophylaxis), diarrhoea and abdominal pain. These can be decreased if
Tamiflu is taken with food. Other minor adverse effects include insomnia, vertigo, headache and
fatigue. Very rarely people may have severe allergic reactions to Tamiflu including erythema
multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis and anaphylaxis. Other rare
but serious adverse effects include aggravation of diabetes, cardiac arrythmia, confusion,
hepatitis, pseudomembranous colitis, fever, fits, rash and unstable angina. There have been
reports of neurotoxicity due to Tamiflu from Japan. Apparently 12 children who took Tamiflu in
Japan died. These cases included one suicide, 4 cases of sudden death, 4 cases of cardiac
arrest, 1 case of pancreatitis, 1 case of pneumonia and 1 case of asphyxiation. Apparently 32
children who took Tamiflu developed hallucinations and abnormal behavior. All but one of these
reports is from Japan. The US FDA has investigated this and declared Tamiflu safe and found no
direct links between the drug and the deaths of the Japanese children. Roche have stated that
“there is no increase in deaths and neuropsychiatric events in patients on Tamiflu versus
influenza patients in general”.
Because of the potential of adverse effects Tamiflu should only be taken when prescribed by
physicians,
Although it is not known whether Tamiflu can harm the fetus or newborn it is advised that it
should be used in pregnancy or lactation only if it is judged that potential benefit outweighs any
potential risk to the fetus or baby.
In studies on “seasonal flu” Tamiflu reduced the duration by 30% and the severity of the illness by
40%. Patients also had less secondary complications. In another study on “ordinary flu” if
treatment was started within the first 12 hours the illness was shortened by 3 days. It appears to
be just as effective in the elderly aged >65 and in children aged 1-12. In one study of “seasonal
flu” in children the incidence of otitis media, a frequent complication, was reduced by 44%.
6.1.6. Treatment of influenza with “Relenza”
Relenza is as effective as Tamiflu, and possibly more effective (Lancet 13th August 2005:
366;533-534). It is recommended for those aged >5 years old. It is not approved for those aged
<7 years old in the US. Some experts believe that Tamiflu is better than Relenza for treatment as
we need to treat a systemic viral disease and Relenza achieves only low serum and tissue levels.
Relenza is concentrated in the respiratory tract where concentrations are 1000 times as high as
those needed to inhibit 50% of H5N1. The inhibitory effects start within 10 seconds.
It needs however to be taken by inhalation – making it more difficult and less convenient to use. If
the patient also takes bronchodilators these should be given before Relenza. The dose is 10mg
(two 5mg inhalations) twice daily for 5 days. It is approved for use in children aged >7 years old
by the FDA.
Adverse effects are uncommon but include headache, nausea, diarrhoea, vomiting, bronchitis,
cough and sinusitis all in about 2% of cases. Serious adverse effects include bronchospasm,
cardiac arrythmia, rash, fits, urticaria, anaphylaxis and syncope (fainting). It should be used with
caution, and is generally not recommended, in those with severe asthma or chronic obstructive
pulmonary disease. It is not recommended in pregnancy or lactation.
6.1.7. Other treatments of H5N1
The role of steroids is uncertain. Ribavirin and Interferon-alfa are under investigation. Interferonalfa possesses both antiviral and immunomodulatory activity. If Ribavirin is given it should be by
aerosol to avoid the haemolytic effects. Ribavirin is active against H5N1 in vitro.
Recently it is reported that Ampligen (R) , a dsRNA immunomodulator manufactured by
Hemispherx Biopharm, enhances the effect of Tamiflu.
Glutathione (GSH) has been proposed as an adjunct to therapy with antiviral drugs. Oral Nacetylcysteine increases GSH levels. It has been shown to attenuate influenza symptoms (De
Flora et al Eur respir J 1997; 10:1535-1541).
Angiotensin II is a key cytokine for T-cell mediated immune disease. Angiotensin converting
enzyme (ACE) leads to the production of Angiotensin II. The use of an ACE inhibitor will decrease
the levels of Angiotensin II. Similarly the use of an Angiotensin II receptor blocker (ARB) will
prevent the action of Angiotensin II. It is possible that the rapid response in macrophages in
mouse lungs seen after infection with H5N1 may be inhibited by the use of ACE inhibitors or
ARB, and the immune response therefore “toned down”. Their use has been successful in the
treatment of West Nile Virus according to Dr David Moskowitz of GenoMed. www.genomed.com ,
[email protected] . Both classes of drugs are readily available and are used to treat
hypertension. One example is “Cozaar”.
It is possible that these drugs could have a use in both prophylaxis and treatment of H5N1.
6.1.8. “Tamiflu” Availability in Asia
Tamiflu has become almost completely sold out in most countries in Asia/Pacific. It is not
available in India and Pakistan. Roche has registered Tamiflu in Indonesia. The cost in
Asia/Pacific varies from US$28 – US$60 per course of 10 capsules. Several Asian countries are
exploring the possibility of manufacturing their own generic form of Tamiflu. The Thai government
pharmaceutical company states they will make enough to treat 100,000 patients by February
2006. Vietnam has reached an agreement with Roche to produce a generic version starting early
2006. Chinese government scientists are attempting to develop their own generic version. Taiwan
has stated it will make its own generic version. Ranbax Laboratories in India is in talks with Roche
about producing a generic version. Roche is also talking to Teva Pharmaceuticals, Mylun
laboratories and Barr Pharmaceuticals about making Tamiflu. Unilab, a Philippines based drug
firm, has been granted a license to manufacture Oseltamivir.
There is now such a high demand for Tamiflu that FAKE Tamiflu is appearing on the market. US
custom agents have already seized shipments of fake Tamiflu.
7. PREVENTION
7.1 PREVENTION: General Hygienic Measures
7.1.1.General
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All measures described below apply equally to seasonal flu, other respiratory viruses and to a
possible person-to-person H5N1 pandemic.
Readers may consider buying several weeks supply of masks and alcohol hand-rub
Readers should buy a thermometer, liquid soap and antipyretics (to lower fever) such as
acetaminophen (Panadol® or Tylenol®). Aspirin should not be used in children.
Readers are advised to get vaccinated against “seasonal” influenza
The environment should be well-ventilated.
7.1.2. Building resistance
Resistance to most infections is increased by regular exercise, getting enough rest, eating a
balanced diet and not smoking.
7.1.3. Hand washing and hand hygiene
Good hand hygiene is the single most important measure in preventing the spread of many
viruses including SARS and any type of influenza. Hands should be washed (a) before touching
eyes, mouth or nose (b) when hands are contaminated by respiratory secretion e.g. after
coughing or sneezing (c) after touching public installations e.g. escalator handrails, elevator
control panels or door knobs. People with hands contaminated by flu virus will unwittingly touch
their mouth or eyes and contract the disease. People should avoid touching their eyes, nose and
mouth as far as possible.
Proper hand washing technique is described:
1. Consider the sink, including the faucet controls (taps), as contaminated.
2. Avoid touching the sink.
3. Turn water on using a paper towel and then wet your hands and wrists. If possible use warm
water.
4. Work soap into a lather
5. Vigorously rub together all surfaces of the lathered hands for 15 seconds. Friction helps
remove dirt and microorganisms. Wash around and under rings, around cuticles and under
fingernails.
6. Rinse hands thoroughly under a stream of water. Running water carries away dirt and debris.
Point fingers down so water and contamination won’t drip towards elbows.
7. Dry hands completely with a clean dry paper towel or under a hand dryer.
8. Use a dry paper towel to turn faucet (tap) off
9. To keep soap from becoming a breeding ground for microorganisms thoroughly clean soap
dispensers before refilling with fresh soap.
10. When hand-washing facilities are not available at a remote work site, use an appropriate
antiseptic hand cleaner or antiseptic towelettes (“wipes”)
An Australian study showed that long term alcohol-based hand rub causes very few cutaneous
(skin) reactions and the authors estimated that there would be one cutaneous adverse reaction
for every 72 years of health care worker exposure (Antimicrob Agents Chemother 2005;49:44044405)
7.1.4. Direct contacts with other people
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During a pandemic you should avoid shaking hands with and kissing other people.
Even in the absence of a pandemic if you have a cold, cough or seasonal flu you should avoid
shaking hands with, or kissing, other people
Exercise judgment about time spent in crowded areas especially when the concentration of
influenza cases in your local area is high.
7.1.5. Coughing and sneezing precautions
Cover your mouth when you cough and sneeze into a tissue. Dispose of the tissue into the wastepaper (trash) basket. If a tissue is not handy cough or sneeze into your upper sleeve rather than
onto your hands. Wash or disinfect your hands immediately afterwards so that you do not spread
your germs to others.
7.1.6. Masks
N95 masks are more efficient than surgical masks but are very unpleasant and difficult to wear for
prolonged periods of time. Hand contact whilst adjusting the masks with subsequent
contamination of the eyes may negate the benefit of N95 masks. Aerosol spread of influenza
virus occurs rarely. Surgical masks, if worn properly, are effective in preventing the spread of
droplet infections. The spread of influenza viruses is mainly by droplet infection. Surgical masks
are therefore regarded as adequate for most situations. Three-ply surgical masks are probably
better than two-ply. Two-ply masks are better than one-ply.
The proper way of wearing a surgical mask is described:
 Wash hands before wearing the mask and after taking it off.
 The mask should fit snugly over the face.
 The colored side of the mask should face outwards with the metallic strip uppermost.
 The strings or elastic bands should be properly positioned to keep the mask in place.
 The metallic strip moulds to the bridge of the nose.
 Try not to touch the mask once it is secured as frequent handling reduces protection. If you
must touch the mask wash your hands before and after touching it.
 When taking off the mask avoid touching the outside of the mask.
 After taking off the mask put it into a plastic or paper bag & then put it into a rubbish (trash)
bin with a lid.
 Then wash your hands
 A surgical mask should be changed at least daily. If it is damaged or soiled replace it
immediately.
7.1.7 Living and work areas
Living and work areas should be kept clean. Surfaces at home should be kept clean with
household detergents and sanitized with disinfectant, alcohol or bleach solution prepared
according to instructions on the label. In the office wipe down your phone, keyboard and other
surfaces every evening as you leave work with a disinfectant that will not harm office equipment
or surfaces.
7.2. PREVENTION: Specific additional hygiene measures to prevent H5N1
7.2.1 Contacts of cases
Household contacts of a case of H5N1 should receive post-exposure Tamiflu prophylaxis. They
should monitor their temperature. They should self-quarantine themselves for one week after the
last exposure.
7.2.2. Food precautions
We advise that people (a). cook chickens to a uniform temperature of at least 70C (158F) (b). use
designated chopping board for chickens and wash it with disinfectant between each chicken (c).
wash hands thoroughly after chicken preparation (d). preferably buy frozen chickens and properly
defrost and cook them (e). wash eggs in disinfectant and cook them well and avoid runny
scrambled eggs. Only eat hard-boiled eggs if they are cooked in their shell. (f) avoid touching any
live birds or bird droppings including birds kept at home as pets. (g) avoid contact with ducks and
avoid eating ducks in Vietnam unless very well cooked. (h) should not drink ducks’ blood: at least
2 cases in Vietnam were due to the consumption of uncooked ducks’ blood and (i) involved in
culling birds should wear personal protective equipment and should receive prophylactic
oseltamivir.
7.2.3. Health care workers
Health care workers should;
 Pay careful attention to hand hygiene before and after all patient contact
 Use gloves and gown for all patient contact
 Wear eye protection when within 3 feet (1 metre) of the patient. In most situations a faceshield or safety glasses is regarded as adequate. In situations where aerosol might be
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generated, or where there may be heavy exposure to respiratory secretions ( e.g. taking a
pharyngeal swab or nasopharyngeal aspiration, bronchoscopy etc) then wear goggles.
Wear a fit tested N95 mask if in a clinic or hospital assessing patients in a pandemic situation
or in any situation where the patient is suspected to have H5N1. In routine situations a
surgical mask is regarded as adequate.
Take a prophylactic antiviral especially if they have been exposed to aerosols or secretions.
Monitor temperature twice daily and see a doctor if they have a fever.
Ensure patient wears a surgical mask when outside the room for x-rays etc
Ensure patient is in an airborne isolation room (i.e. monitored negative air pressure in relation
to the surrounding areas with 6-12 air changes hourly). The door should be kept closed.
Visitors should be limited.
7.3. PREVENTION: Travel concerns
7.3.1. General travel concerns
Travelers to areas affected with H5N1 should be educated before they leave home.
They should be immunized against seasonal influenza.
Many countries are now enforcing temperature screening at its borders. Those people with fever
will be questioned and possibly quarantined. During a pandemic those with fever will certainly be
quarantined. Travelers are advised not to travel to or from H5N1 areas if they have fever.
Many countries will certainly close borders during a pandemic. Some countries will close their
border the moment human-to-human transmission occurs. It is therefore likely that if human-tohuman transmission starts in China then China will close its borders for both entry and exit. This
will certainly cause problems for travelers who may be confined to a hotel for many weeks. It will
also cause problems for expatriates.
At present there is no or at most very inefficient human-to-human transmission and there is no
need to restrict travel even to a country with many outbreaks in poultry and several human cases.
Travelers are however advised to check for any travel restrictions before and during travel.
7.3.2. Travel kit
Travelers are advised to carry a medical travel kit and this should include:
 A non-mercury oral thermometer
 Alcohol hand-rub, wipes or hand-sanitizer
 Surgical masks
Whether or not travelers to affected countries should carry an antiviral with them is controversial.
Currently they are at no risk provided they do not visit poultry farms or markets. However if
human-to-human transmission occurs whilst they are in that country they may be stuck there
without access to antivirals. This would be most unfortunate if they contracted H5N1. Moreover
knowing that you have Tamiflu in your travel kit is psychologically reassuring. We therefore
advise that travelers to affected countries carry an antiviral drug. There are, however, concerns
that travelers may use their antivirals inappropriately and some authorities do not recommend
putting Tamiflu in the travel kit. It is clear that if an antiviral is given to a traveler then the traveler
must be well educated on its use.
7.3.3. During travel
Whilst traveling in affected countries people should not (a) visit chicken farms (b) visit markets
where there are live chickens (c) purchase live chickens. People should only buy chickens with
the entrails (intestines) removed. People should take measures as listed in “Prevention: general
hygienic measures” and “Prevention: additional hygiene measures”. They should change seats in
aeroplanes to avoid those with respiratory symptoms. They should seek early medical
consultation for any fever or influenza like illness.
7.3.4. After travel
Travelers should monitor their health for 10 days. If they get ill with fever, cough or breathing
difficulty they should seek medical help.
7.4.
PREVENTION: Vaccination
7.4.1. Vaccination against Seasonal Influenza
Many health departments advocate influenza vaccination for the following groups of people: (a).
elderly people living in residential care homes (b) long-stay residents of institutions for the
disabled (c). elderly persons aged 65 or more (d) persons with chronic illness (e) health care
workers (f). poultry workers (g). children aged 6-23 months (h). pregnant women in the 2nd & 3rd
trimesters .
We, however, advise that ALL people (aged >6 months) who have no contraindication to
vaccination against flu , such as allergy to egg, undergo vaccination with the currently
recommended influenza vaccine for the 2005-2006. Whilst this will in no way prevent H5N1, nor
mitigate its effects, it will at least lessen the chances of the vaccinated person getting a disease
which could easily be mistaken for H5N1. This would be of great importance should a pandemic
emerge because such people would immediately be isolated.
After vaccination it takes about 2 weeks for protective antibodies to form. The vaccine does not
give 100% protection and protection declines with time so that although the chances of getting flu
are reduced people may still get influenza.
Those who are allergic to eggs, neomycin or a previous dose of influenza vaccine should NOT
receive influenza vaccination. People with bleeding disorders or those who are taking warfarin
(coumadin) may take the vaccination by deep subcutaneous injection. People with an acute fever
should only take the influenza vaccine after they recover. People who have none of these
conditions often refuse to have the flu vaccine because they are concerned about side-effects.
Flu vaccines can cause local reactions (such as redness, swelling and discomfort) at the site of
the injection and may also cause fever. Sometimes people may get an immediate allergic
reaction. Modern flu vaccines vary rarely cause serious adverse effects. A case recently reported
in Hong Kong was of a nurse who developed meningo-encephalitis. However both CDC and
WHO do not regard flu vaccine as a cause of meningo-encephalitis. However the media tend
to make much of such cases and this is unfortunate because it may detract people from
accepting the vaccine.
Influenza itself causes many more serious problems and deaths in people than flu vaccine. For
example influenza may be very serious in young children and the US Advisory Committee on
Immunization Practice (ACIP) advises annual immunization vaccination for ALL children between
the ages of 6 months and 23 months. Influenza vaccination is now recommended for pregnant
women. On the risk-benefit equation vaccination wins every time. The FDA approved in June
2003 a trivalent intranasal live attenuated influenza (LAIV) for use in people aged 5-49 years old.
As of August 2005 2,500,000 people had been given this vaccine with 760 adverse events
reported. It should probably not be used in asthmatics as it can cause an exacerbation of asthma.
In short there are no unexpected adverse events associated with the use of this vaccine.
Secondary transmission of the vaccine virus merits further investigation. It is possible that an
H5N1 intranasal vaccine may be developed. It is noted that NO influenza vaccine is approved
for infants under the age of six months, the most vulnerable group in terms of serious disease. A
study involving 8000 children aged 6-36 months in the 2004-2005 season will hopefully produce
results suggesting the LAIV vaccine is safe for children in this age group.
7.4.2 Vaccination against H5N1
An H5N1 vaccine has been made by Sanofi-Pasteur. Chiron is also developing a vaccine.
GlaxoSmithKline announced that they would be able to make millions of doses within 4 months
from the start of a pandemic. The GSK prototype vaccine will use an adjuvant and allow for lower
doses to be used thus making more vaccine available. Various countries are also considering
manufacturing bird flu vaccine e.g. Cuba! Hungary will license an avian influenza vaccine in
March 2006 and India, Indonesia, Russia and the Philippines are interested in buying it. CSL
(Commonwealth Serum Laboratories) said on 24th November that it could develop an effective
vaccine within 2 years. China has developed a human H5N1 vaccine called “Panflu”
manufactured by Sinovac Biotech and this is undergoing clinical trials. Dr Anthony Fauci of the
National Institute of Allergy and Infectious Diseases (NIAID) announced successful trials in the
USA on 6th August 2005 of the Sanofi-Pasteur vaccine. Protective antibodies occur after two
shots 4 weeks apart. Unfortunately it has several drawbacks (a) each dose needs 90 micrograms
of antigen compared to 15 micrograms in conventional flu vaccine (antigen is that part of a
vaccine that elicits an immune response). The total amount of antigen is therefore 12 times that
for a normal flu vaccine (b) it needs to be grown on chicken eggs, a very slow production method
due partly to the fact that the virus destroys chicken eggs.. All this means that vaccine production
will be a very slow process.
Newer technologies are needed to (a) speed up vaccine production (b) increase vaccine
effectiveness whilst using smaller amounts of antigen. One such technique is to use cell-culture
based vaccines. These are being developed by Baxter, Chiron, GSK and Solvay and virus is
grown in a serum and protein free medium producing a high yield of antigen. Another
development is to use reverse genetics to create a well-matched non-pathogenic H5N1 virus that
has a high capacity to grow in eggs.
Another technique involves the use of adjuvants. Thus Alum is being studied as an adjuvant
whilst Chiron is studying the use of MF59 as an adjuvant. It is noted that Ampligen (R ), a dsRNA
immunomodulator made by Hemispherx Biopharm, is said to increase vaccine effectiveness
significantly.
The other drawback is that H5N1 keeps changing and there is no guarantee that the current
vaccine will be effective against a pandemic strain of H5N1. A strain specific vaccine would be
the most efficient weapon during a pandemic but cannot of course be developed until after an
outbreak starts. Currently WHO states that there is no need to change the recommended vaccine
prototype strains (A/Vietnam/1194/04, A/Vietnam/1203/04, A/Hong Kong/213/03).
In summary the current vaccine availability is only enough to cover a very small fraction of the
global population and even if effective most persons will go unvaccinated.
WHO documents strategies for expediting the development of a pandemic vaccine:
1. Shorten the time between the emergence of a pandemic virus and the start of commercial
production:
 Develop global standards for quality, safety and efficacy
 Resolve outstanding laboratory and safety issues. This includes specifications for accelerated
safety testing of candidate vaccines
 Harmonize regulatory pathways for licensure of pandemic influenza vaccines
 Address safety issues associated with vaccine use
 Support production strategies that economize on the use of antigen.
2. Increase the supply of influenza vaccines:
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Find ways to bridge the gap between current vaccine production capacity and the expected
demand during a pandemic.
Involve vaccine manufacturers from all countries
Support efforts in developing countries, including technology transfer, for vaccine
development and production
Enhance utilization of seasonal influenza vaccines in high-risk groups, in line with WHO
targets (50% coverage in 2006 and 75% IN 2010).
7.4.3. Vaccination against Streptococcus pneumoniae
Secondary pneumococcal pneumonia is sufficiently common in seasonal influenza to suggest
that it may also occur in H5N1. Some authorities are recommending that health care workers also
receive immunization with a Pneumococcal vaccine.
7.5. PREVENTION : Antiviral prophylaxis
If used for prophylaxis the dose of Tamiflu is one capsule daily for those aged >13. Prophylaxis is
indicated for (a) contacts of known cases (b) those visiting farms where there is known to be
H5N1 (c) those involved in culling.
In pandemic situations prophylaxis will be one method of control. In such situations I can
envisage taking it for as long as the pandemic lasts or until an effective vaccine has produced
protective antibodies.
In studies on “ordinary flu” both Tamiflu and Relenza were 70 – 90% effective when used for
prophylaxis either before or after exposure. In a study in residential homes, where most were
vaccinated, oseltamivir prophylaxis led to a 92% reduction in influenza. When Tamiflu is used for
prophylaxis the following adverse effects are more commonly reported than when used for
treatment: headache (20%), fatigue (8%), cough (6%) and diarrhoea (3%). Some experts believe
that Relenza is a better drug than Tamiflu for prophylaxis as it achieves very high levels in
respiratory secretions. Relenza is not approved for prophylaxis in the US. The prophylactic dose
of Relenza is two inhalations (2x5mg) once daily for up to 28 days.
Amantadine may possibly be used as a prophylaxis against H5N1 as some strains are sensitive
to it. In the US it is approved for prophylaxis of seasonal influenza in persons aged one year or
older. The prophylactic dose is 100mg daily for children aged 5-9 and for adults >65 years old.
The dose for those aged 10-65 is 100mg twice daily. Prophylaxis should start immediately after
exposure and continue for at least 10 days. In a pandemic prolonged prophylaxis throughout the
pandemic may be indicated. The dose needs to be decreased in renal failure. Rimantadine is
approved for prophylaxis in those aged one year or older in the US. Prophylactic efficacy is
around 70-90% although in some trials it is lower.
It is important to note that in human challenge studies on seasonal influenza most individuals who
took antiviral prophylaxis did NOT develop immunity to influenza and remained fully
SUSCEPTIBLE to infection when the drug was discontinued. The same is likely to be true with
H5N1.
N-acetylcysteine (NAC) 600mg daily will increase glutathione (GSH) levels in the blood.
Prophylactic GSH has been shown to decrease mortality in a model influenza infection in mice
(Int J Immunopathol Pharmacol. 2000 Sep,13(3):123-128).
8. PANDEMICS
8.1 Pandemic indicators
The earliest indicators of efficient human-to-human transmission will be reports of an increase in
size and number of clusters. Such reports are at first likely to be in the form of rumors.
Employees, friends and news media in the affected area may contribute to these rumors.
Financial markets are likely to over-react. Other early indicators might be a rise in hospital
admissions or emergency government meetings. Authoritative sources include web-based
organizations such as ProMed whilst the most authoritative sources would be the WHO or the
CDC. It is likely that there will be a lag period of 2-10 days between the earliest reports and WHO
confirmation.
8.2 Number of deaths in a pandemic
A normal seasonal flu epidemic causes 250,000 – 500,000 deaths worldwide. WHO estimates
that an H5N1 pandemic will kill 2 – 50 million people worldwide. CDC projects that a pandemic is
likely to cause 2 to 7.4 million deaths. Other experts are more pessimistic and project figures of
up to 150 million deaths. In the 1918 Spanish flu pandemic it is estimated that 40-100 million
people died, with a case fatality rate of around 3%.
8.3 Economic and social effects of a pandemic
If a pandemic emerges it is certain that there will be enormous disruption of travel and business.
Many international borders will be closed. Despite this worldwide spread is likely to occur within
2-3 months. Schools, cinemas, public recreational facilities and shopping malls will be closed.
Restaurants and other public places will be avoided. Transport systems may be affected due to
staff sickness. There will be shortages of food and other commodities. Hospitals will be unable to
cope, and there will be a severe shortage of mechanical ventilators. The Australian Health
Minister declared on 22nd November that a pandemic would cause major shortages of food, fuel
and labor causing some companies to shut down entirely. The Lowy Institute for International
Policy said a pandemic would cause instability and lead to a sell-off in bonds and equities and a
flight into cash and gold. The Australian Homeland Security Research Center has listed practical
actions that should be incorporated into each company’s business continuity and emergency
management plans.
8.4 Economic impact of an avian flu pandemic in Asia
A report by the Asian Development Bank (ADB) in November 2005 is summarized: The economic
impact of SARS, a disease with a relatively small health impact, was $18 billion. The economic
impact of SARS was on the demand side reflecting decreased consumption of services due to the
psychological impact and to the need to limit contact to prevent infection. The demand side is
affected by consumer confidence, and by investor confidence, and it is noted that markets have a
tendency to overreact. In an avian flu pandemic the supply side will also be impacted as
members of the labor force get sick or die. This will reduce the region’s long term economic
growth potential. One model envisaged a scenario of a relatively mild pandemic with an attack
rate of 20% and a case fatality rate of 0.5%. About 3 million people would die in Asia. If the
psychological impact is severe the supply shock will be greater due to absenteeism of otherwise
healthy workers. In a sub-scenario where the pandemic is short lived and only affects demand for
6 months the cost of the demand shock will be $99 billion and the supply shock will cost $14.2
billion. This equates to 2.6% of GDP. If the pandemic lasts longer and affects demand for one
year with another one year of smaller shock the economic impact may force the world into
recession. The cost of the supply shock will remain the same at $14.2 billion but the demand cost
will be $283. Growth in Asia will stop. Global trade in goods and services will contract 14%. Even
5 years after the pandemic the GDP growth will be lower by 3.6%. The pandemic may impact the
region in other ways e.g. could shake confidence in the region’s growth potential. Many
businesses will be forced to close and many households will be pushed below the poverty line.
The psychological impact is huge. Governments should act transparently and disseminate
accurate and timely information. The public and markets often panic in the face of uncertainty and
governments should not contribute unnecessarily to panic. The international community needs to
provide financing and critical commodities to the poorest countries. Countries should increase
their support to the health sector. An avian flu pandemic will be the most serious crisis to the
region since the 1997 financial crisis. Nobody can predict the consequences – there are too many
unknowns. The consequences will be significantly worse if the outbreak lasts longer or is more
virulent. However people adapt and life continues!
8.5 Psychological aspects of a pandemic
An editorial in the Lancet (366: 1751 November 19 2005) states that anxiety will lead to inevitable
civil unrest. Even before a pandemic emerges panic is a danger. The recent increase in
momentum for action against avian influenza is paralleled by a rise in anxiety. These fears are
perpetuated by politicians’ misplaced instincts to withhold information instead of talking openly.
Widespread fear can lead to social and economic consequences as serious as the disease itself.
Thailand and China report damaged poultry sales. Cambodia says a psychosis has gripped its
population. Such fears are minor compared to the anxieties at the beginning of a pandemic when
people will avoid travel, avoid hospitals or even start riots in the streets. Patients will be
stigmatized and confidence in governments damaged or lost. Governments should now win the
public’s trust by admitting to uncertainty, acting transparently, issuing guidance on disease
protection and making sure new information is disseminated to the public. WHO have stated, not
referring specifically to avian influenza, that “information may be the only source of protection
during a public health emergency”. During a pandemic the psychological aspects of quarantine
and social isolation must be considered (see section on “Quarantine”).
At a corporate level companies must ensure that accurate information is disseminated to
employees, and this must be done frequently. An EAP (employee assistance program) must start
writing and answering questions now referring to the psychological aspects of a potential
pandemic or a pandemic itself.
8.6 Ethical guide for pandemic planning
The University of Toronto Bio-ethics Center has developed a guide for pandemic planning:
1. There should be an ethical component to plans
2. Medical & nursing bodies and bodies for other Health Care Workers (HCW) should provide
clear guidance of expectations & obligations to its members.
3. Health care professionals should be protected at all times and they should receive disability
and death benefits.
4. There should be strategies to ensure equitable distribution of risk to HCW
5. Government plans for restrictive measures must be transparent. Liberty should be balanced
against the need to protect the public from harm. A ‘right of appeal’ safeguard should be built
in.
6. The public must be aware of the rationale for compliance, benefits of compliance and
consequences of non-compliance.
7. People should be protected against stigmatization and the privacy of those affected by
quarantine should be safeguarded.
8. Plans need to guarantee provisions and support for those affected by restrictions (e.g.
quarantine) and to state in advance what back-up support there will be.
9. The rationale for priority of provision of antiviral drugs and vaccine to HCW and those in
emergency services must be clearly stated.
10. There must be a clear rationale & criteria for resource allocation e.g. ventilator access.
11. There should be a mechanism to appeal against or to raise concern about allocation
decisions.
12. The WHO must be transparent and equitable about travel recommendations.
13. The developed world should invest in surveillance of developing countries and improve their
health infrastructure.
8.7 Preventing a pandemic
Is it possible to prevent a pandemic once an H5N1 mutant strain with effective human-to-human
transmission has emerged? To answer this we must first understand the concept of Ro. Ro, or
the basic reproductive number, is defined as the average number of secondary cases generated
by a typical primary case in an entirely susceptible population. If Ro is >1 a disease can spread. If
Ro is <1 transmission dies out. Several studies using mathematical disease modeling assuming
Ro’s between 1.5 – 4 have been published e.g. Nature 3rd August 2005. In summary it appears
that a pandemic can be halted at source provided (a) the first viruses able to sustain human-tohuman transmission are not highly contagious (i.e. they have a low Ro). (b) emergence is limited
to a small geographical area. (c) the first clusters are rapidly detected and reported. (d) antiviral
drugs, i.e. Tamiflu, are rapidly mobilized from a stockpile and given to sufficiently large numbers
of people (e) movement of people in and out of affected areas is effectively restricted (f) social
isolation measures are enacted such as quarantine, banning public gatherings etc. Such
measures aim at decreasing the Ro to <1.
In one study it was estimated that if an outbreak occurred in a 3,500 square mile area in rural
Thailand we would have up to 2-3 weeks to intervene with antivirals and quarantine. This plan
depends upon an efficient bureaucracy. Whether it is achievable or not is doubtful. WHO, as part
of its pandemic planning, has adopted this scenario and plans to move a large amount of Tamiflu
from a central stockpile to the first affected area. Once the virus has become fully contagious its
spread to all parts of the world is considered unstoppable – however it could be slowed down by
such measures.
8.8 Quarantine
In the last 3 pandemics in any country there has been a bell shaped (Gaussian) distribution with a
peak around 6 weeks and the epidemic over at 12 weeks. Modeling studies suggest that
quarantine procedures will cause an epidemic to last 16-20 weeks – the curve is again Gaussian
but the total area under the curve is decreased i.e. the total number of cases is lower.
Quarantine will only work if the population is convinced of such measures. Thus at the beginning
of the SARS epidemic in Hong Kong 90% of people followed quarantine guidelines – by the end
of the epidemic this figure was down to 70%, and even this figure is regarded as excellent. In a
pandemic situation it is thought that it will be impossible to police quarantine regulations.
Quarantine, either voluntary or forced, is likely to be an effective measure in an avian flu
pandemic. It is however controversial. There will be psychosocial stigma and a fear of prejudice.
It creates social isolation and may impair an individual’s ability to meet home and work
responsibilities. The person quarantined may lose wages.
8.9 Security aspects
During a pandemic there will be many security concerns e.g.
1. Personal security due to looting for scarce commodities and a reduced police force
2. Factory security. Many items made by certain companies may be an attractive target.
Security guards may need back-ups and procedures may need to be upgraded.
3. Corporate security of stockpiled antiviral drugs. There are fears that governments may
expropriate such supplies. Some companies have negated this possibility by not maintaining
any central stockpile but have instead distributed small amounts of antiviral drugs to several
locations and in some cases directly to its employees.
8.10 Pandemic business check list
CDC posted on its web site www.cdc.gov/business on 7th December 2005 a preparedness &
response check-list for businesses. This is reproduced below with one or two small changes.
Thus this author has added ‘masks’ and ‘antiviral’ in the Allocating resources section and this is
represented in green. The US government has also issued a pandemic flu business letter
encouraging businesses to support preparedness. President Bush outlined a coordinated
government strategy. In this he notes that seasonal flu in the US results in over 200,000
hospitalizations a year and costs the economy over 10 billion US$ a year. He states that this
figure would be dwarfed by a pandemic. He notes that influenza viruses “are not constrained by
geographic borders” and that a pandemic is likely to come in waves, each lasting months. He
says individual citizens should be prepared and educated, and that effective risk communication
must be ensured by timely, clear, coordinated messages. He says individuals & families should
take precautions to prevent the spread of infection to others, be prepared to follow public health
guidance and keep supplies of materials at home as recommended by authorities.
Complete
In
Progress
Not
Started
Plan impact of a pandemic on your business
Identify pandemic coordinator & team. Define roles &
responsibilities for preparedness & response planning.
Process should include labor representatives input.
Identify essential employees & other critical inputs (e.g.
raw materials, suppliers, contractors, logistics) to
maintain operations by location & function
Train & prepare ancillary workforce (e.g. contractors,
retirees, employees doing other jobs)
Develop scenarios likely to result in increase or
decrease in demand for products and/or services (e.g.
need for hygiene supplies, mass gatherings)
Determine impact on financials using multiple scenarios
affecting different product lines or production sites
Determine impact on domestic & international travel
(e.g. quarantines, border closures)
Find up-to-date reliable pandemic information
Establish emergency communications plan & revise
periodically. Plan includes identification of key contacts
(with back-ups), chain of communications (including
suppliers & customers), and processes for tracking &
communicating business & employee status.
Implement an exercise to test plan & revise periodically
Plan for the impact of a pandemic on your
employees & customers
Forecast & allow for employee absence due to illness
(personal or family), community containment measures,
quarantine, school closure, public transport closure
Implement guidelines to modify frequency & type of
face-to-face contact (e.g. hand-shaking, seating at
meetings, shared workstations) among employees and
customers
Encourage and track influenza vaccination annually
Evaluate employee access to health care services and
improve services as needed
Evaluate employee access to & availability of mental
health & social services including community & faithbased services & improve as needed.
Identify employees & key customers with special needs
& incorporate requirements into preparedness plans.
Establish policies to be implemented in a pandemic
For employee compensation & sick leave absence
unique to a pandemic (e.g. non-punitive, liberal leave),
including when an ill person is no longer infectious and
can return to work
For flexible work site (e.g. telecommuting) & flexible
work hours (staggered shifts)
For preventing influenza at the work place (e.g.
promoting respiratory hygiene, cough etiquette, prompt
exclusion of those with flu symptoms
For employees who have been exposed to influenza,
are suspected of being ill, or become ill at the work site
(e.g. infection control, immediate mandatory sick leave)
For restricting travel to affected areas (domestic &
international), evacuating employees in or near an
affected area when an outbreak begins, & guidance for
employees returning from affected areas
Set up authorities, triggers & procedures for activating
& terminating the company response plan, altering
business operations (e.g. closing down a plant) &
transferring business knowledge to key employees
Allocate resources to protect your employees &
customers during a pandemic
Provide sufficient & accessible infection control
supplies (e.g. hand-hygiene, tissues, receptacles for
disposal, paper towels) in all locations
Provide sufficient masks
Consider providing antiviral drugs & their equitable
distribution
Enhance communications & IT infrastructures to
support telecommuting & remote customer access
Ensure availability of medical consultation & advice for
emergency response.
Communicate to and educate your employees
Develop & disseminate programs & materials covering
pandemic fundamentals (e.g. symptoms of flu, modes
of transmission), personal & family protection &
response strategies (e.g. hand hygiene,
coughing/sneezing etiquette, contingency plans)
Anticipate employee fear & anxiety, rumors &
misinformation & plan communications accordingly
Disseminate information to employees about your
pandemic preparedness & response plan
Provide information for the at-home care of ill
employees and family members
Develop platforms (e.g. hotlines, dedicated web sites)
for communicating pandemic status & actions to
employees, vendors, suppliers & customers inside &
outside the work place in a consistent & timely way,
including redundancies in emergency contact systems.
Identify sources for accurate & up-to-date pandemic
information (domestic & international) & resources for
obtaining vaccines & antivirals
Coordinate with external organizations and help
your community
Collaborate with insurers, health plans, & major local
healthcare facilities to share your pandemic plans &
understand their capabilities & plans
Collaborate with local public health authorities &
emergency responders to participate in their planning
process, share your pandemic plans, & understand
their capabilities and plans
Communicate with local public health agencies and/or
emergency responders about the assets and services
your business could contribute to the community
Share best practices with other businesses, chambers
of commerce to improve community response efforts.
8.11 WHO pandemic classification
The World Health Organization (WHO) classify a potential influenza pandemic into six phases.
Phase 1: no new influenza subtypes detected. An influenza virus subtype that has infected
humans may be present in animals. If present in animals the risk of human infection is considered
low
Phase 2: no new influenza virus subtypes have been detected in humans. A circulating animal
virus subtype poses substantial risk of human disease.
Phase 3: Human infection(s) with a new subtype but no human-to-human spread to a close
contact.
Phase 4: Small cluster(s) with limited human-to-human spread. Spread is highly localized
suggesting the virus is not well adapted to humans
Phase 5: Large cluster(s) but human-to-human spread still localized. Virus becoming better
adapted to human host but not yet optimal transmission efficacy.
Phase 6: Efficient and sustained transmission to the general population.
In respect to H5N1 we are at the least at phase III: “human infection(s) with a new subtype but no
human-to-human spread to a close contact”. WHO announced on 5th November that we are in
Phase 3 of pandemic alert.
8.12 WHO actions and documents
The WHO recommends that all countries take urgent action to prepare for a pandemic. Advice is
given in the WHO global influenza preparedness plan
http://whqlibdoc.who.int/hq/2005/WHO_CDS_CSR_GIP_2005.5.pdf
And in the WHO checklist for influenza preparedness planning
http://whqlibdoc.who.int/hq/2005/WHO_CDS_CSR_GIP_2005.4.pdf
Strategies for improving national preparedness:
 Assist developing countries planning to manufacture their own vaccines
 Support national pandemic preparedness planning. Currently there is no regional or global
tool for evaluating the actual status of preparedness in individual countries and pinpointing
weaknesses. WHO is preparing template pandemic plans.
 Develop model pandemic response table-top exercises.
Strategies for expediting the development of a pandemic vaccine:
(see paragraph on Vaccination)
WHO point out that the world has been warned in advance. They note that 23 countries have
ordered antiviral drugs for national stockpiles. They note that a strengthened early warning
system and international collaboration are essential. In their situation assessment they point out:
1. The risk of a pandemic is great
2. The risk will persist
3. Evolution of the threat cannot be predicted.
4. The early warning system is weak and a sensitive system is needed. (This is hampered by
inability to compensate farmers for culled poultry discouraging reporting, by rural poverty
perpetuating high-risk behaviors, by weak laboratory diagnosis in many affected countries)
5. Preventive intervention is possible but untested
6. Inadequate medical supplies will impede the reduction of morbidity and mortality during a
pandemic.
WHO in the document “Responding to the avian influenza pandemic threat state that there are 3
opportunities to intervene and describe strategic actions to capitalize on the opportunity to
intervene:
(a) Phase: PRE-PANDEMIC
---------------------Intervention is aimed at reducing the risk that a pandemic virus will emerge
1. Reduce opportunities for human infection.
{WHO think that complete eradication of H5N1 is probably precluded by its presence in wild bird
population. Control in poultry is however feasible and of high priority. The Food and Agriculture
Organization (FAO) and the World Organization for Animal health (OIE) have issued detailed
technical recommendations. These include significant changes in traditional farming systems}.
Strategic actions recommended are:
 Support the FAO/OIE control strategy: The initial focus should be on Vietnam, Thailand,
Cambodia and Indonesia. Recommend poultry vaccination in some epidemiological
situations. Strict bio-security. Compulsory international notification of outbreaks. Food-safety
of poultry products
 Intensify collaboration between the animal and public health sectors (WHO note that most
cases have been due to exposure to small rural flocks and no case has occurred in workers
in the commercial poultry sector. Priority needs to be given to the backyard rural farming
system and in wet-markets where live poultry are sold in crowded & unsanitary conditions.
WHO, FAO and OIE have established a Global Early Warning and Response System
(GLEWS) for cross-boundary animal diseases.
 Strengthen risk communication to rural residents
 Improve approaches to environmental detection of the virus
2. Strengthen the early warning system
WHO notes (a) some countries lack epidemiological and laboratory capacity. This is important
because detection of changes in the behavior of the virus will trigger activities in pandemic
response plans. (b) serological surveys in close contacts also provide early alerts to viral
behavioral change. (c) the clinical course of cases is a vital sign as milder disease with lower
fatality is expected to coincide with improved transmissibility. Strategic actions recommended are:
 Improve the detection of human cases. Specially equipped staff & laboratories are needed.
 Combine detection of new outbreaks in animals with active searches for human cases.
Human cases may have been missed e.g All 4 Cambodian cases were only diagnosed after
seeking treatment in Vietnam. Likely several cases in Cambodia who did not go to Vietnam.
 Support epidemiological investigation. Guidelines are being developed to investigate clusters.
 Co-ordinate clinical research in Asia. Hospital networks engaged in clinical research &
treatment
 Strengthen risk assessment. Ministries of Health to be more fully engaged in the collection
and verification of data.
 Strengthen existing national influenza centers throughout the risk-prone region.
 Give risk-prone countries an incentive to collaborate internationally.
(b) Phase: EMERGENCE OF A VIRUS WITH IMPROVED TRANSMISSIBILITY
----------------------------------------------------------Intervention is aimed to change the early history of a pandemic
3. Contain or delay spread at the source
Mathematical modeling shows that to prevent a pandemic an international stockpile of antiviral
drugs for use at the site of an emerging pandemic virus must be used within 3 weeks of symptom
onset in the first people infected and blanket prophylaxis must reach 80%. Success depends
upon several assumptions: (a). the first viruses are not yet highly transmissible (b). the
emergence must be geographically circumscribed (c). the first clusters must be rapidly detected
and reported and the viruses rapidly detected and identified (d). antiviral drugs will be rapidly
mobilized and administered (e). movement of people in and out of the area will be effectively
restricted. Even if these actions are not successful they might gain time to put emergency
measures in place and augment vaccine supply.
Strategic actions recommended are:
 Establish an international stockpile of drugs
 Develop mass delivery mechanisms for antiviral drugs
 Conduct surveillance of antiviral susceptibility. A mechanism must be in place to monitor
any development of drug resistance.
(c ) Phase: PANDEMIC DECLARED AND SPREADING INTERNATIONALLY
-----------------------------------------------------------Intervention is aimed at modifying the pandemic
4. Reduce morbidity, mortality and social disruption
Vaccine supply will be inadequate. A pandemic will paralyze public services and economic
productivity. Absenteeism will increase. A pandemic will NOT affect all countries or all parts of a
country at the same time. Countries should ensure legislation is in place to enforce extraordinary
measures.
Strategic recommended actions:
 Monitor the evolving pandemic in real time. A virtual network of experts is needed to
determine in real time age groups at risk, infectivity, severity, establish whether deaths due to
primary viral pneumonia or secondary bacterial pneumonia
 Introduce non-pharmaceutical interventions: quarantine, ban mass gatherings
 Use antiviral drugs to protect priority groups e.g. frontline workers
 Augment vaccine supplies
 Ensure equitable access to vaccines
 Communicate risks to the public. Process must be continuous.
5. Conduct research to guide response measures
 Assess the epidemiological characteristics of an emerging pandemic
 Monitor the effectiveness of health non-pharmaceutical interventions

Evaluate the medical and economic consequences.
8.13 WHO and Government Stockpiling of Antivirals
In order to build an international stockpile WHO has been given 3 million courses (30 million
capsules) of Tamiflu by Roche. The first million doses will be delivered in early 2006 and the
other 2 million by mid-2006. WHO has recommended that countries obtain enough Tamiflu to
treat 25% of their population. There is not enough Tamiflu available to fulfil this recommendation
and if a pandemic occurs Tamiflu will be available to only a fraction of the global population. An
Israeli study on the “Cost Benefit of Stockpiling Drug for an Influenza Pandemic” showed that
stockpiling Tamiflu resulted in cost saving to the economy. There was also direct cost saving to
the health care system even if its use was limited to treating high-risk patients. Such cost saving
to the economy remained as long as the estimated pandemic risk was >1 pandemic every 80
years. In the last 400 years there have been 31 pandemics recorded. The study concluded:
“regardless of recent events in SE Asia stockpiling will yield a return of investment of 3.8 to 1.
Some countries have acquired, or are ordering, Tamiflu. These include: New Zealand (800,000
courses to cover 20% of the population). France (13 million courses to cover 20% of the
population). UK (14.6 million courses to cover 20%), Canada (4 million courses to cover 13% of
the population), USA (20 million courses to cover 7% of the population) and Hong Kong (enough
to cover 5% of the population). Australia has ordered enough antiviral to treat 28% of their
population. Finland, Norway, Iceland, Ireland, Luxembourg, Netherlands and Switzerland have
ordered enough to cover 20-40% of the population. Thailand, a country where it is most likely to
be initially needed, has ordered enough to treat 22,000 people. Malaysia has ordered enough to
treat 60,000 people. A SE Asian stockpile is being considered by a group of companies. Some
experts believe that such stockpiling will result in a shortage of Tamiflu where it is most needed:
in SE Asia where human-to-human transmission is most likely to emerge. We may therefore be
denied a chance to halt the pandemic simply because of a shortage of Tamiflu.
8.14 Government Pandemic Planning
In addition to stockpiling antiviral drugs many governments are developing plans to deal with a
pandemic. Europe and Hong Kong have already run pandemic simulation exercises.
The governments of Australia, UK, US and Hong Kong have published lengthy documents
detailing their draft pandemic plans. Morocco and Algeria have drawn up plans. Thus e.g. the
Hong Kong government’s preparedness plan has three levels of response. (1) Alert Level
activated when: HPAI confirmed in poultry outside HK or cases of HPAI in HK in imported birds,
wild birds, pet chops or human cases outside HK. Aim: to prevent disease entering HK and to
promptly survey local cases (2) Serious Level activated when: confirmed outbreaks in poultry in
retail or wholesale markets or farms in HK or human case(s) in HK without evidence of human-tohuman transmission. Aim: to control spread of disease, to identify the source and contain the
virus. (3) Emergency Level activated when: efficient human-to-human transmission overseas or in
HK or WHO declares a pandemic. Aim: to slow down progression of epidemic & minimize loss of
life to buy time for vaccine production. The HK government has published a booklet entitled
“Influenza pandemic preparedness kit” that it gives to all incoming travelers. This may be found
on the Center for Health Protection web site (see web sites).
9. CORPORATE
9.1 Corporate
Many companies are working on pandemic contingency planning and are studying coordination,
communications, crisis preparedness, continuity planning, tracking cases as well as medical
policy and actions. The corporate core team may be a subset of the Corporate Crisis
Management team and includes medical & psychological support programs, sourcing, public
affairs, HR, security, safety, operations, finance, legal, an epidemiologist, a government affairs
representative and regional representation...
9.2 Asia/Pacific Branch Offices
Asia/Pacific should draw up contingency plans that are aligned with corporate and which
recognize the different potential scenarios such as (a) a large outbreak that might be the
harbinger of a pandemic (b) a case involving an employee or family member (c) a pandemic.
Needless to say in the event of a pandemic it is most likely that national government and
international agencies will become the principal means of addressing the crisis, whilst a
company’s own contingency plans will relate to advice concerning employee and family
protection, work place protocols and business continuity.
Currently in Asia/Pacific I do not feel that there is any need to restrict business travel to an
affected country. This is in line with the World Health Organization who state that in Phase 3 of
Pandemic alert there is NO need to restrict travel, nor any need for screening at borders as the
risk that the virus will be carried by international travelers is considered negligible. Nonetheless
the DH in Hong Kong has reinstituted temperature screening at Lo Wu and Lok Ma Chau and
other borders.
I have advised that in affected countries employees do not (a) visit chicken farms (b) visit markets
where live chickens or purchase live chickens. I have also given advice on poultry and egg food
hygiene (see Prevention: Hygienic measures section)
Companies are advised to offer vaccination with the currently recommended influenza vaccine for
the 2005-2006 season to its employees, and consider offering this at company expense.
In Asia/Pacific I advise that employees consider purchasing, at their own expense, 1-3 courses
(10-30 capsules) of Tamiflu for each family member. Unfortunately it is not available in Indonesia,
India and Pakistan and availability may be limited elsewhere as governments stockpile supplies.
Companies should advise employees, including travelers, to ONLY take a therapeutic course of
Tamiflu if they have been advised by a doctor to take it. They should advise that once prescribed
a course of Tamiflu they MUST complete the course. They should advise employees NOT take it
for prophylactic use unless (a) there is definite evidence that they have been exposed to a
person with H5N1 or (b) they have been exposed to birds with H5N1.
Companies may consider keeping an emergency supply of Tamiflu in every country in
Asia/Pacific.
I also advise that all factories and offices obtain an adequate supply of masks, alcohol hand-rub
and thermometers now. These will be unobtainable should a pandemic occur.
I also advised that travelers to or from countries where there has been an outbreak of avian flu in
birds should be supplied with Tamiflu (or Relenza) in their travel kit as well as a supply of masks,
alcohol hand-rub.
10. H5N1 WEBSITES
Those interested in learning more about H5N1 are referred to the following websites:
http://www.cdc.gov/flu/avian/index.htm
http://www.who.int/csr/disease/avian_influenza/en/
http://www.who.int/csr/disease/avian_influenza/pandemic/en/index.html
http://www.wpro.who.int/avian/
http://www.info.gov.hk/dh/diseases/influenza/influenza.htm
http://www.oie.int/eng/en_index.htm (updates on avian flu in animals)
http://www.chp.gov.hk
http://www.travelhealth.gov.hk
http://www.ds-osac.org/Reports/report.cfm?contentID=38077 (this report from the Overseas
Security Advisory Council has links to several other useful sites)
http://www.cdc.gov/business
http://www.pandemicflu.gov
http://gilligan.mc.duke.edu/pandemic/ (links to many other sites)
John Simon
26th December 2005