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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 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 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 7.3 Prevention: Travel Concerns General travel concerns Travel kit During travel After travel 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 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 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 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: 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