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Emerging Infections in Asia and the Pacific Region

OVERVIEW

The trend toward globalization of the economy is most evident across Asia, Australia, and the Pacific region. Common political interests are among the driving forces bringing together countries in Asia, along with the United States, and other countries in the Pacific region. However, obstacles to globalization exist in the region. Among these are public health problems, which are often at the heart of the political and economic challenges to globalization. For example, a number of important global diseases, such as influenza, dengue, Japanese encephalitis, tuberculosis, and pneumonia, are endemic to the region, as are the newly emerging Hendra and Nipah viruses.

Although the emerging infectious disease problems facing countries in the Asia-Pacific region are as great as those facing countries elsewhere, the potential for the prevention and mitigation of disease outbreaks in the region is noteworthy, as evidenced by several recent epidemic threats. The region is fortunate to have access to advances in electronic communications, infectious disease epidemiology, and laboratory techniques, together with resources for training and for maintenance and enhancement of the public health infrastructure.



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EMERGING INFECTIOUS DISEASES FROM THE GLOBAL TO THE LOCAL PERSPECTIVE: A Summary of a Workshop of the Forum on Emerging Infections 4 Emerging Infections in Asia and the Pacific Region OVERVIEW The trend toward globalization of the economy is most evident across Asia, Australia, and the Pacific region. Common political interests are among the driving forces bringing together countries in Asia, along with the United States, and other countries in the Pacific region. However, obstacles to globalization exist in the region. Among these are public health problems, which are often at the heart of the political and economic challenges to globalization. For example, a number of important global diseases, such as influenza, dengue, Japanese encephalitis, tuberculosis, and pneumonia, are endemic to the region, as are the newly emerging Hendra and Nipah viruses. Although the emerging infectious disease problems facing countries in the Asia-Pacific region are as great as those facing countries elsewhere, the potential for the prevention and mitigation of disease outbreaks in the region is noteworthy, as evidenced by several recent epidemic threats. The region is fortunate to have access to advances in electronic communications, infectious disease epidemiology, and laboratory techniques, together with resources for training and for maintenance and enhancement of the public health infrastructure.

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EMERGING INFECTIOUS DISEASES FROM THE GLOBAL TO THE LOCAL PERSPECTIVE: A Summary of a Workshop of the Forum on Emerging Infections EMERGING INFECTIOUS DISEASES IN HONG KONG AND THEIR PUBLIC HEALTH SIGNIFICANCE Kwok Hang Mak, M.B., M.Sc. Consultant, Community Medicine, Department of Health Hong Kong Special Administrative Region, People's Republic of China In recent years, the Hong Kong Special Administrative Region of the People's Republic of China has witnessed, like other parts of the world, the emergence and reemergence of various infectious diseases, in particular influenza, cholera, and enterovirus infections. This region is particularly vulnerable to infectious diseases because it is densely populated (6.68 million people in 1998), is in the crossroads between the East and the West, encounters a heavy volume of international travel, and has live poultry markets in close proximity to residential areas. Influenza A Virus (H5N1) In 1997, a total of 18 cases of human infection with influenza A virus sub-type H5N1, which was previously known to infect birds only, occurred in Hong Kong. The first case appeared in May 1997; the remaining cases occurred in November and December 1997. They involved 8 males and 10 females ages 1 to 60 years. Half of the cases occurred among children at or under age 12. All of the patients presented with a high temperature and a sore throat; the majority also developed a cough. Six individuals died as a result of viral pneumonia and multiorgan failure. Genetic sequencing confirmed the avian origins of the viruses isolated from patients. Results of an investigation indicated that the main mode of transmission was from bird to human. Human-to-human transmission was documented but was found to be relatively inefficient and uncommon. Epidemiological studies showed that the major risk factor was visiting poultry stalls in a market the week before the onset of illness. In view of the evidence that the H5N1 virus affected chickens in the local community, a slaughtering exercise was launched on December 29, 1997; a total of 1.5 million poultry were killed. This measure effectively brought the outbreak to an end. A whole host of measures was introduced to ensure that the poultry sold in local markets were safe. They included quarantine and testing of imported chickens, segregation of chickens from ducks and geese, and improvement of hygienic conditions in the markets. Close attention to surveillance of humans and animals for evidence of influenza was maintained while preparation of pandemic plans and the development of vaccine and antiviral agents continued. This outbreak illustrates the importance of a robust public health infrastructure for disease surveillance and the need for international efforts and multidisciplinary collaboration to address the threat of influenza. Apart from disease prevention and control, due consideration should also be given to the economic

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EMERGING INFECTIOUS DISEASES FROM THE GLOBAL TO THE LOCAL PERSPECTIVE: A Summary of a Workshop of the Forum on Emerging Infections and political impacts of such an outbreak, as well as to the communication strategies used during a disease outbreak. Avian H9N2 Viruses In April 1999, avian subtype H9N2 viruses were isolated from two young girls ages 1 and 4, but only the older girl had a history of exposure to chickens. Both girls recovered completely from influenza-like illnesses. Investigation results also suggested that the main mode of transmission was from bird to human, although the possibility of human-to-human transmission remained open. In view of the low prevalence of antibodies among various study groups, the satisfactory outcomes of the cases, and the fact that the virus—although commonly found in poultry—usually caused mild symptoms, there was ample evidence to conclude that the discovery of this H9N2 virus in humans did not appear to pose an imminent threat to public health. Swine Influenza A Virus (H3N2) Another discovery new to Hong Kong in the arena of influenza occurred in October 1999. An influenza A virus subtype H3N2 isolated from a 10-month-old girl was proved by overseas reference laboratories to have originated in swine. The patient had a mild influenza-like illness and made a full recovery. Investigations did not reveal any history of exposure to pigs or poultry by the patient or her family members. Initial blood tests also showed that the family members were not exposed to this swine flu virus. Although this reflects the sensitivity of the local influenza surveillance system, it further reinforces the importance of veterinary surveillance in animals, including pigs and birds. Conclusion The discovery of avian and swine influenza virus infections among humans in Hong Kong has driven home a strong message that vigilance in public health surveillance of human and animal populations is indispensable. Many emerging infectious diseases, like influenza, are zoonotic problems, and their control requires a close and effective collaboration between public health and veterinary workers. As surveillance increases, it is likely that more avian influenza virus isolates will be identified, linking research issues to public policy. It is the concerted efforts of individuals across different disciplines and boundaries that provide the winning edge.

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EMERGING INFECTIOUS DISEASES FROM THE GLOBAL TO THE LOCAL PERSPECTIVE: A Summary of a Workshop of the Forum on Emerging Infections EMERGING DISEASES IN THE AUSTRALASIAN REGION John S. Mackenzie, Ph.D. Professor and Head, Department of Microbiology and Parasitology, The University of Queensland, Brisbane, Australia Emerging diseases in Australia are, with a few important exceptions, not dissimilar in their identity, occurrence, and patterns of incidence to those described in developed countries elsewhere. Most of the exceptions are either vector-borne or zoonotic viral diseases, and they fall into two patterns: known diseases that are increasing in incidence or geographical spread and novel diseases that had not previously been recognized. The former include mosquito-borne virus diseases, such as disease caused by Japanese encephalitis (JE) virus, dengue viruses, and Barmah Forest virus, whereas the latter are zoonotic diseases, such as those caused by Hendra virus, Menangle virus, and Australian bat lyssavirus (ABL). Japanese Encephalitis Virus Of the mosquito-borne viral diseases, the greatest threat to Australia and nearby Pacific islands is undoubtedly that caused by JE virus. To date there have been five clinical cases of JE: four on Badu Island in the Torres Strait and one in Cape York on the Australian mainland. The first three cases occurred on Badu Island in 1995, whereas the fourth case occurred on Badu Island and the fifth case occurred on the Australian mainland in 1998. There have been almost 60 virus isolations from mosquitoes and pigs. All but one of the mosquito isolates was from Culex annulirostris mosquitoes. The first outbreak, in 1995, was driven by the close proximity to human habitation of mosquitoes and their breeding habitats and by the widespread practice of keeping pigs in backyards. The second outbreak, in 1998, was believed to have been associated with an extensive drought in Papua New Guinea (PNG), which led to increased mosquito breeding as rivers began to dry into stagnant pools. Australia has suitable vertebrate hosts (feral pigs and ardeid birds) and vectors (Cx. annulirostris) by which JE becomes enzootic. Of some concern is that fruit bats might be potential vertebrate hosts in both rural and urban settings. The virus is now widespread in PNG and is threatening to move farther east, toward the Solomon Islands. The first four clinical cases of JE in PNG were recognized in 1997 and 1998, and two mosquito isolates were obtained. Molecular epidemiological studies showed that the Australian and PNG virus isolates were almost identical, indicating that the source of the Australian outbreaks was PNG. After the 1995 outbreak, the JE vaccine (Biken) was offered to inhabitants of the central and northern islands of the Torres Strait. Approximately 9,000

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EMERGING INFECTIOUS DISEASES FROM THE GLOBAL TO THE LOCAL PERSPECTIVE: A Summary of a Workshop of the Forum on Emerging Infections doses of vaccine were distributed. In addition, sentinel pigs were established on several islands in the Torres Strait and on the Australian mainland near Bamega. There was widespread seroconversion in these pigs during the 1998 outbreak. Surveillance of humans and pigs has continued to the present. The spread of JE to the Australian zoogeographic region may have occurred by a number of means, including natural spread through eastern Indonesia by means of mosquito-pig or mosquito-bird transmission cycles, human travel and transmigration, and airlifts of pigs to indigenous people. Dengue All four types of dengue virus have been introduced into the dengue-receptive areas of northeastern Australia over the past decade, and epidemics caused by three serotypes of dengue virus have occurred. Humans are the only vertebrate hosts; when an epidemic subsides, the virus disappears and must be reintroduced, probably via viremic travelers returning to Australia or through the movement of people across the Torres Strait. The only vector in Australia is Aedes aegypti, whose range extends over most of northern Queensland, Australia. The management plan for control includes rapid reporting of cases and subsequent vector control. In a 4-year period (1995 to 1998), 31 reports of dengue came from general practitioners, public hospitals doctors, private laboratories, or Queensland Health Scientific Services. It was determined that the countries of origin included PNG, Indonesia, Thailand, the Philippines, and Vietnam. Other Emerging Diseases Barmah Forest virus is an alphavirus only found in Australia. It has been recognized as a human pathogen for about 13 years, but it has recently been shown to have spread into new areas of Australia. Its vertebrate hosts are believed to be marsupials, especially small species. It was first isolated from mosquitoes captured in southeast Australia in 1974. The Barmah Forest virus causes a disease syndrome similar to that caused by another Australian alphavirus, the Ross River virus, which is found throughout Australia. The Ross River virus has been referred to such a virus in some reports, but it does not fully fall into the definition of as an emerging virus. Although the incidence of Ross River virus infection has indeed increased slightly in recent years, this may largely be due to population increases and changes in demography. Of the novel zoonotic diseases, Hendra virus was the first to be recognized during an outbreak in race horses in Brisbane in 1994. This was shown to be a natural virus of fruit bats, and to be widely distributed in northern and eastern Australia, as well as PNG. Hendra virus has been classified as the first member of a new genus in the family Paramyxoviridae. Studies of Hendra virus led to the discovery of ABL, a rabies virus-like virus, in both fruit bats and at least one

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EMERGING INFECTIOUS DISEASES FROM THE GLOBAL TO THE LOCAL PERSPECTIVE: A Summary of a Workshop of the Forum on Emerging Infections species of insectivorous bat. ABL belongs to antigenic group 1 of the lyssaviruses, which is the same group to which classical rabies virus belongs, but ABL and rabies virus can be differentiated on genetic grounds. The virus most recently detected in Australia, Menangle virus, was recognized as the cause of an increased incidence of fetal death in a commercial piggery and as a possible cause of an influenza-like illness in humans. It also appears to be a virus of fruit bats and is a member of the Rubalavirus genus in the family Paramyxoviridae. The discovery of three new zoonotic viruses from fruit bats in Australia is of wider interest, as fruit bat populations overlap from the Pacific islands through Australia, southern Asia, and possibly into the Middle East and Africa. Thus, for any virus found in Australia, related viruses will probably exist throughout the range of similar bats. The first of these may be Nipah virus, which was recently discovered in Malaysia. There have been other examples of emerging diseases in Australia, such as the occurrence of waterborne epidemics due to Cryptosporidium parvum in eastern Australia, and an increased incidence of enterohemorrhagic Escherichia coli belonging to serotype O111:H, which is associated with hemolytic-uremic syndrome. Australia has also had a recent emerging problem with community-acquired strains of methicillin-resistant Staphylococcus aureus (cMRSA). These strains of MRSA appear to have arisen in two distinct areas. One strain appears to have initially developed and spread in northern, western, and southern Australia, whereas a strain known to be a Western Samoan strain, which appears to have developed in the South Pacific, then became a problem in New Zealand and is now found in eastern Australia. The significance is that the standard antibiotics that are given for therapy (e.g., flucloxacillin) are ineffective and it takes 48 hours for a laboratory to confirm that the isolate is resistant. Hence, patients with serious infections may be receiving ineffective antibiotics for 48 hours. MRSA is still relatively infrequent (less than 1 percent of S. aureus isolates in eastern Australia). However in certain areas of Auckland, New Zealand, more than 10 percent of community-acquired S. aureus infections are now caused by cMRSA. The importance of epizootics in wildlife is of growing concern because of their possible zoonotic potential. Indeed, in recent years most novel emerging diseases have been zoonotic diseases. Thus, there is a recognition of the necessity for improved infectious disease surveillance in humans. However, there is also a need to undertake surveillance of infectious diseases in wild and domestic animals and a need for public education and awareness of the possibility of transmission of diseases from wildlife to humans. Finally, the experiences gained with emerging infectious diseases in Australia have clearly indicated that disease surveillance should be undertaken as a regional, multinational activity.

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EMERGING INFECTIOUS DISEASES FROM THE GLOBAL TO THE LOCAL PERSPECTIVE: A Summary of a Workshop of the Forum on Emerging Infections INTERNATIONAL SMART PARTNERSHIP IN EMERGING DISEASES: SENSE AND SENSITIVITY Sai-Kit Lam, M.Sc., Ph.D. Professor and Head, Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia Introduction The World Health Organization (WHO) estimates that infectious diseases account for more than 17 million deaths per year worldwide and that at least 30 new infectious diseases have emerged within the last two decades. The world's 6 billion people are at risk for many endemic diseases, with the most populated and economically depressed countries in Southeast Asia at highest risk (Lam, 1998). There are inadequate funds, personnel, resources, and political commitment in developing countries to adopt the WHO Resolution of 1995, urging member countries to commit to an international program for the worldwide monitoring and control of infectious diseases. Emerging infections can arise in countries in Asia and the Pacific. The emergence of the avian influenza A virus serves as an example of the need for strengthened surveillance of emerging diseases in this part of the world. Other viruses that should be placed on the “watch list” include yellow fever—because of the presence of its vector in the region—and the African hemorrhagic fevers, because of increased trade and traffic among countries of these regions. Many viruses responsible for emerging infections already may exist in Southeast Asian countries, but because of the lack of surveillance and diagnostic capabilities, their existence may have gone unnoticed. Hantaviruses in Malaysia provide an example: Since the 1980s, there have been only three publications providing evidence of the existence of hantavirus in humans and rodents. Interest in hantaviruses recently was revived when, with the help of South Korea, we obtained serological evidence of hantavirus infections in 4 of 119 patients with chronic renal failure. Additional serological evidence in rodents indicated that there might be more than one member of the hantavirus family lurking in Malaysia. Virus isolation from lungs and other tissues of seropositive rodents is underway. Emerging infections pose a serious problem in Malaysia, as evidenced by three outbreaks of unknown viral etiology in the relatively short period of two years. International assistance was sought and the help rendered was greatly appreciated. Many lessons were learned in the handling of these outbreaks and the unexpected problems that occurred. It is hoped that by sharing our experiences, we can obtain a greater understanding of investigations and, with hope, establish a better international “smart partnership” in future.

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EMERGING INFECTIOUS DISEASES FROM THE GLOBAL TO THE LOCAL PERSPECTIVE: A Summary of a Workshop of the Forum on Emerging Infections Emerging Infections in Malaysia The first outbreak took place in 1997 in Sarawak, East Malaysia, and subsequently spread to peninsular Malaysia. The outbreak in Sarawak was investigated by local scientists and by the U.S. Centers for Disease Control and Prevention (CDC). Thirty-four children between the ages of 5 months and 7 years died with cardiac and central nervous system involvement. The early diagnosis announced by the Ministry of Health was Coxsackie B myocarditis. When similar cases were seen and investigated in Peninsular Malaysia, enterovirus 71 (EV71) was isolated from the brain stem in 4 fatal cases (Lam et al., 1998). This finding was supported by immunohistochemical staining (Wong et al., 1999). Outbreaks of EV71 in Taiwan (Huang et al., 1999) and Australia subsequently provided further evidence of the neurovirulence of this enterovirus strain. However, a recent paper from Sarawak disputed the finding of EV71 as the cause of the Malaysian outbreak, claiming that the deaths were due to viral myocarditis and caused by subgenus B adenovirus (Cardosa et al., 1999). The second outbreak took place in early 1999. Over 100 cases of fever, arthralgia, and arthritis were reported by the local press in a squatter settlement where sanitation was poor and there was an abundance of Aedes aegypti. Dengue and other known viral infections were excluded. With the help of Australia, the cause of the outbreak was found to be due to chikungunya virus, a virus hitherto unknown locally, but prevalent in neighboring countries. It is speculated that the virus was introduced into the country through migrant workers. Since Malaysia is heavily dependent on a migrant workforce, it is anticipated that other emerging infections will be introduced into the country. The third outbreak also was of viral encephalitis and thought to be Japanese encephalitis (JE), an endemic, seasonal disease. For five months it was treated as a JE outbreak and control measures included vector control and vaccination against JE Despite these efforts the disease spread to several states in Malaysia as well as to Singapore. Of the 265 clinical cases reported among pig farm workers, 105 died and there were neurological sequelae and relapses in a few who recovered. A new paramyxovirus related to the Australian Hendra virus was isolated, and with the help of CDC it was confirmed to be a new virus (Chua et al., 1999). It was named Nipah virus after the village from which the patient came. Because of the earlier misdiagnosis of JE, the whole issue was politicized and played up by the press and public media, creating a difficult situation for the investigators. Lessons Learned In developing countries, there are seldom enough funds, personnel, or resources to conduct outbreak investigation. Thus, there is reliance on international agencies for assistance. Such assistance, which is usually on a govern-

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EMERGING INFECTIOUS DISEASES FROM THE GLOBAL TO THE LOCAL PERSPECTIVE: A Summary of a Workshop of the Forum on Emerging Infections ment-to-government basis, is much appreciated. In the Nipah outbreak international assistance came from many countries, including the United States, Australia, Japan, Taiwan, and Germany. However, unexpected problems can arise due to failure to recognize and appreciate cultural, religious, and political sensitivities. Because of the tragic loss of lives and livelihoods during the Nipah outbreak, there was considerable pressure brought to bear by political parties on both local and international experts. It is imperative that investigators not get caught in the quagmire of intrigue and become political pawns. One area that was poorly handled was publicity. The Nipah outbreak created international interest, some unfortunately sensationalistic. There were also some biased comments and reporting by critics not involved in the investigation. Foreign press releases caused embarrassment to the local government because of contradicting data and viewpoints. It is important to release accurate information during the outbreak, preferably from a single source. Misleading statements can lead to confusion, anguish, and fear in an already tense situation. The electronic media have an important role to play in the fight against emerging infections. During the EV71 and Nipah outbreaks, offers of help came in quickly, a true advantage. However, rapid communication also can be abused, as was all too evident in the Nipah outbreak when the issue was politicized and used to cast aspersions on those handling the outbreak. After the Nipah outbreak an international meeting was held to discuss areas of future research. There was some pressure to include Nipah virus as a strict P4 agent, which effectively would prevent any further work with the virus in Malaysia. This was a sensitive issue, but fortunately good sense prevailed and a compromise was reached. The final recommendation was to allow this highly pathogenic virus to be handled at the highest level of biosafety possible, with responsible national authorities developing appropriate policies and guidelines for laboratory procedures. Two years after the Sarawak outbreak there remains a difference of opinion about the cause of death and the etiologic agent responsible. The findings have yet to be released by those called in to assist in the investigation, thus prolonging the confusion. Rapid response is an important component in the fight against emerging infections. Many countries are ill prepared for rapid response. Recent events in Malaysia have highlighted the need to strengthen this aspect of public health. The Ministry of Health has formed a permanent committee to identify weaknesses in the system and proposals for change. In addition, a new Infectious Disease Center has been established and will be equipped with adequate facilities to handle future emerging diseases outbreaks. Transfer of appropriate technology to developing countries from foreign experts is most important. In the Nipah outbreak, CDC and the Australian Animal Health Laboratory were instrumental in helping set up diagnostic capabilities and generously provided the necessary reagents.

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EMERGING INFECTIOUS DISEASES FROM THE GLOBAL TO THE LOCAL PERSPECTIVE: A Summary of a Workshop of the Forum on Emerging Infections Following the outbreak, there is usually much interest in continued research and data analyses on the materials gathered. Research priorities should be developed by giving equal consideration to all of the international partners to avoid dissension over proprietary rights to clinical materials and authorship of publications. “Smart partnership” requires total trust and transparency in all aspects of the investigation; there should be no hidden agendas. Open communication should be established and misunderstandings ironed out to prevent frustration and unwarranted accusation. In summary, emerging infection is something we have to live with for years to come. Developing countries usually serve as the epicenter, and yet they are not equipped to handle outbreak investigation without international assistance. Such investigations must be conducted in a “smart partnership” agreement to promote cooperation to achieve public health.