Workshops/Meetings : Emerging Diseases

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EMERGING INFECTIOUS DISEASES - A MALAYSIAN PERSPECTIVE

  • Aziz, A. J.1 , Nor Shahidah, K.2 , Chua, K. B.3 and Shamshad, S.1
  • 1 Veterinary Research Institute, 31400 Ipoh, Perak D.R., Malaysia.
  • 2 Institute for Medical Research, 50588 Jalan Pahang, Kuala Lumpur, Malaysia.
  • 3 International Medical University, 70300 Jalan Rasah, Seremban, Negeri Sembilan D.K., Malaysia

Introduction

The study by the Institute of Medicine in 1992 offers a working definition of emerging infections as clinically distinct conditions whose incidence in humans has increased over the past two decades or threatens to increase in the near future (CDC, 1992). Emergence may be due to the spread of a new agent, to the recognition of an infection that has been present in the population but has gone undetected, or to the realisation that an established disease has an infectious origin. Emergence may also be used to describe the reappearance (or "re-emergence") of a known infection after a decline in incidence. Habitat, climatic and anthropogenic changes including increased contact between wildlife and domestic animals all contribute to the uptake in animal and human illnesses. No nation, developed or under-developed, can any longer afford to ignore the potential threat of emerging infectious diseases.

The World Health Organization (WHO) statistics indicate that worldwide infectious diseases alone account for more than 17 million deaths annually (Lam, S.K., 1998). It has been estimated that at least 30 new infectious diseases have emerged within the last two decades. Up to half of the 5.8 billion people on earth are at risk for many endemic diseases, with the most overpopulated and economically depressed nations in South and South-East Asia at highest risk. Despite the fact that vaccines and antibiotics are available for many diseases, in 1995 alone, respiratory infections such as pneumonia killed 4.4 million people, 4 million of them were children. Diarrhoeal diseases like cholera, typhoid and dysentery killed 3.1 million, most of them children. Tuberculosis (TB) killed almost 3.1 million, malaria 2.1 million, hepatitis B and measles each more than one million.

Malaysia has a population of 22.3 million, with about 60% aged between 15-64 years, and approximately 51% living in urban areas. While demographic changes with rapid industrial and socio-economic development are likely to shift disease patterns towards an increasing importance of non-communicable disorders, it is nevertheless valid that communicable diseases are still of tremendous importance. A renewed effort must be made to invest in research that emphasises the control and prevention of such diseases.

National specific disease surveillance models in Malaysia

Prevention and control of animal diseases is an essential element in achieving species preservation, food security, economic development and public health. For farm animal surveillance, the greatest strength lies in the programme that has immediate economic benefits to participants. For instance, farms exporting products to Singapore are bound to lose their exporting rights if found not complying with the Republic's Public Health Regulations. However, there is a clear lack of appreciation by the general public on the importance of contamination of poultry products in the market; therefore a nationwide awareness campaign is imperative. There is the need to strengthen linkages and awareness between the veterinary and medical sectors in understanding zoonoses that require mutual involvement through a common surveillance. Specific funding for joint surveillance work on emerging or re-emerging diseases should readily be made available to both sectors. Since its inception in 1948, the Veterinary Research Institute (VRI) at Ipoh and the Regional Veterinary Laboratories (RVL) of the Department of Veterinary Services (DVS) have been entrusted with the mandate to carry out animal disease surveillance. Similarly, the Institute for Medical Research (IMR) of the Ministry of Health Malaysia has carried out many surveillance programmes for human diseases including zoonoses. Following the successful eradication of Nipah virus encephalitis in human and animals in 1999, a joint committee comprising representatives from five government ministries named Inter-Ministry Committee for Control of Zoonotic Diseases was formed to undertake responsibility in the control of zoonotic diseases in Malaysia.

Examples of emerging diseases of veterinary and medical importance in Malaysia

1) Highly pathogenic avian influenza (HPAI)

Highly pathogenic avian influenza (HPAI) or fowl plague is a highly infectious and contagious disease of poultry. The waterfowls harbour the viruses and are the main source of introduction of the disease into domestic poultry flocks. The disease syndrome varies from subclinical to mild respiratory disease, loss of egg production and high mortality rates.

The VRI has embarked on a national surveillance programme which includes sampling of blood (for detection of HPAI antibodies) or faecal materials (for virus isolation) from ducks raised under (open) pond system, poultry and exotic birds found in pet shops, parks and sanctuaries of migratory birds. An R&D programme to develop and establish an early warning immunological and molecular based detection system for HPAI is ongoing. In this programme, an ELISA system for antibody detection was developed and comparisons with AGID and FA test made (Hassan, J., 2001; Sohayati, A.R. 2001). Field surveys for avian influenza is presently ongoing for exotic birds and poultry and pathogenicity tests on field isolates obtained.

2) Avian salmonellosis (S. enteritidis/S.typhimurium/S. pullorum/S. gallinarum)

Salmonellosis is a disease due to Salmonella bacteria that cause infection and illness in both animals and human. Salmonellosis is more common in intensively managed farms where many animals are crowded into a relatively small area. S. enteritidis is associated primarily with poultry and eggs.

The national surveillance programme for avian salmonellosis was launched by the DVS in 2000 with the objective of reducing the prevalence and control of S. enteritidis, S. typhimurium, S. pullorum and S. gallinarum in poultry. The programme is targeted at breeders, layers, hatcheries, broilers including both domestic and export farms. The programme aims to reduce losses in poultry production, reduce losses in market value from suspension of exports, ensure poultry products are safe and wholesome, and meet export requirements.

The VRI and all RVLs conduct serological tests based on agreed protocol before accrediting a farm's free-status. Response from private sector is encouraging. In future the tests shall be decentralised to ensure rapid testing and generation of results with wider coverage. To further expand the efficiency of the programme, development of a private testing laboratory was encouraged with accreditation and guidance from the DVS. In 2002, the department has targeted 78 breeder farms and 270 layer farms to be free of Salmonella in an initiative to establish a disease free zone.

3) Multi-resistant organisms

Multidrug-resistant organisms are bacteria and other microorganisms that have developed resistance to multiple antimicrobial drugs. Common examples of these organisms include:

  • Methicillin/oxacillin-resistant Staphylococcus aureus (MRSA);
  • Vancomycin-resistant enterococci (VRE);
  • Extended-spectrum beta-lactamases (which are resistant to cephalosporins and monobactams) (ESBLs);
  • Penicillin-resistant Streptococcus pneumoniae (PRSP);
  • Multi-drug resistant tuberculosis (MDR-TB); and
  • S. typhimurium - DT104 (resistant to five antibiotics namely ampicillin, chloramphenicol, streptomycin, sufonamides and tetracycline).

A nationwide VRE surveillance is currently being planned to be made mandatory to all poultry broiler farms exporting chickens to Singapore. Subsequently the plan will include all other remaining broiler and breeder farms. The DVS has targeted at least 100 broiler farms to be free of VRE by 2005.

The WHO estimates that 10 million people are dying of infectious diseases related to antibiotic resistance. What is more disturbing is that many of the diseases are curable, including acute respiratory infections, diarrhoea, malaria and TB. The list is growing according to WHO. Many cases, such as acute respiratory infections and diarrhoea, can be treated without the use of antibiotics.

Sources from the Ministry of Health Malaysia indicate that the number of TB cases in Malaysia has risen from about 11,000 in 1990 to about 15,000 in 1999. Fortunately TB is not a significant problem in our domestic animals because of the practice of rigorous testing and culling of positive reactors in our dairy cattle herds. However, the disease occasionally afflicts imported deer in the country. While the situation is still under control, Malaysia is at high risk of TB emergence as the country is surrounded by many other countries with a high TB burden like Indonesia, Thailand, Philippines, Bangladesh and India where many foreign workers originated. Hence, rigorous screening of foreign labour is inevitable and the use of antibiotics must be strictly regulated and monitored.

4) Brucellosis

Brucellosis is caused by a bacterium, Brucella abortus in cattle, Brucella suis in swine, Brucella melintensis or Brucella ovis in sheep and any one of these organisms can infect humans. In bulls, rams, and boars it causes sterility or epididymitis. In humans it causes undulant fever, arthritis and orchi-epididymitis. Brucella species have a high probability for use in biologic terrorism.

To prevent this disease in domestic animals, vaccination would generally be used or slaughter of all animals in an area found to be infected with the disease (formation of a brucellosis-free zone). In Malaysia, the national surveillance programme for Brucellosis is ongoing since 1978 and statistics showed a declining national prevalence from 3.4% in 1998 to 2.4% in 2001. However, there is a resurgence of Brucella melintensis of late due to importation of sheep and goats. Brucellosis has become an important disease to control in cattle production under livestock-tree crop integration system. RB51, a new live B. abortus vaccine, has been recently introduced and the development of a serologic test to detect infection is under study (Palanisamy, K. 1999). Vaccination, culling and compensation are the strategy adopted by the DVS to control this disease. Vaccination of workers in the high-risk group may be recommended as a short-term measure.

5) Rabies

Rabies in domestic and wild animal represents a significant threat to public health and can cause considerable economic losses amongst livestock. It is caused by a virus that attacks the nervous system. Once symptoms of rabies develop it is 100% fatal. Sporadic cases were reported in 1992 and 1995 in the northern states of Peninsular Malaysia (Perlis and Kedah) that share the border with Thailand. More recently, in 1996 and 1999 the disease emerged in Terengganu, a state outside the immune belt that shares no land borders with Thailand. So far, no rabies has been reported in East Malaysia although they share a common land border with Kalimantan where rabies was prevalent especially in the east coastal region. The principal vector of the disease in Malaysia is the canine species.

The disease transmission remains mainly within the canine species though cases of rabies in humans and other domestic animals through dog bites have been reported. There appears to be no documented evidence of a wildlife cycle of the disease in Malaysia. The VRI has embarked on a dynamic surveillance and stringent control system of rabies since 1997 and the national anti-rabies campaign is expected to end in 2005.

6) Dengue fever

Arthropod-borne viruses or arboviruses are yet another group of viruses synonymous with countries in the region and cause considerable sickness and death. Dengue fever (DF) is by far the most important arbovirus infection in South-East Asia. WHO has reported dengue in over 100 nations worldwide, which poses a threat to about 2 billion people. Dengue is an acute viral infection characterised by abrupt onset of fever, severe headache, and pain behind the eyes, muscle and joint pains and rash. The Housing and Local Government Ministry reported that the number of dengue cases increased by 42% in 1998 over the previous year despite a massive campaign against the disease.

Statistics revealed there were 19,225 dengue cases with 47 deaths in 1997 compared to 27,370 cases with 58 deaths in 1998 in Malaysia (Lam, S.K., 1998). Local authorities and state governments had stepped up surveillance on aedes mosquitoes. The haemorrhagic form of dengue fever (DHF), was recognised as a new disease in the Philippines in 1953 and has been reported in India, Singapore, Indonesia, Vietnam, Cambodia and Sri Lanka including Malaysia. The rise of dengue in tropical and subtropical regions of the world is explained by factors such as rapid population growth, expanding urbanisation, inadequate municipal water supplies and difficulties in proper refuse disposal. These then lead to an abundance of new breeding sites for the mosquitoes while human migration patterns help to disperse vectors and viruses into new areas.

The World Health Organization recently announced that this year, DF has reached epidemic proportions in Asia and Latin America. The Ministry of Health Malaysia reported that the number of notified cases of DF/DHF up to June 2002 has totalled 13,992 cases compared to 8,946 cases reported for the whole of last year. The four dengue virus serotypes cocirculate endemically with predominant serotype switch expected every 4-5 years. This change in predominant serotype will subsequent in a more severe season. Serotypic surveillance carried out by the Ministry of Health using molecular methods has successfully predicted this severe season as evidenced by the increased detection of Dengue 3 virus over the previous dominance of Dengue 2 virus.

7) Chikungunya virus

Chikungunya virus was fairly common in South and South-East Asia in the 1960s. However in 1999, 100 cases of high fever, arthralgia and arthritis were reported by Ministry of Health Malaysia in a squatter settlement in Peninsular Malaysia. They were diagnosed as suffering from Chikungunya, a rare viral disease, transmitted by mosquito and is not previously known in the medical history of Malaysia but prevalent in neighbouring countries. Here again, it is speculated that the virus was introduced by migrant workers. There is no specific treatment for Chikungunya but it is a self-eliminating disease and patients usually recover within days to weeks.

Viruses with the propensity to cause emerging infections may already exist in this region and may have been missed because of the lack of surveillance and appropriate diagnostic capabilities. An example of this is Hantavirus infection which has been documented serologically among rodents in Malaysia and in 4 of 119 patients with chronic renal failure.

8) Enterovirus 71 (EV71) infection

Enteroviruses are frequently associated with the hot and humid climate of tropical countries in South-East Asia. Coxsackie A16 and Enterovirus 71 infection is common in many countries in this region. In the recent outbreak of hand, foot, and mouth disease (HFMD) in Malaysia, a new clinical entity of encephalomyelitis emerged, which resulted in several deaths among children. Thirty-four deaths occurred in Sarawak, 4 deaths were reported in Kuala Lumpur and 3 in Japan. The first epidemic occurred in 1997 in Sarawak with subsequent spread to Peninsula Malaysia. Of the 34 deaths were children from Sarawak ranging from ages 5 months to 7 years who died of cardiac and central nervous system involvement. Enterovirus 71 was isolated from brain stem in four fatal cases (Lam et al, 1998).

Although the children of Sarawak died as a result of rapidly progressive pulmonary oedema similar to that observed elsewhere, a clinical diagnosis of acute myocarditis was made in many cases. In addition, both EV71 and a novel group B adenovirus were isolated from specimens from sterile sites (including brain and heart) and nonsterile sites taken both before and after patients' deaths. It is suggested that the adenovirus might have played a causative role in these fatal cases either as the primary pathogen or by interacting with EV71 (Cardosa, J., 2000).

In 1998 the largest recorded epidemic of EV71-associated HFMD occurred in Taiwan where 130,000 cases were reported. A total of 405 cases were of severe neurological disease and 78 cases of fatal neurogenic pulmonary oedema. At the same time Hong Kong reported a small outbreak. I n addition, 29 cases of severe neurologic disease were diagnosed in Perth, Australia back in 1999. Molecular genetic studies of EV71 isolates have indicated that several distinct viral genotypes circulated in Sarawak, Peninsular Malaysia, Japan, Taiwan and Western Australia between 1997 and 2000.

9) Nipah virus

An outbreak of Nipah virus in Malaysia and Singapore from October 1998 to 1999 underscore the epidemiological significance of movements of animals from their natural habitats. Nipah virus takes its name from a village in Peninsular Malaysia where the virus was first isolated from a human victim. A close relative, Hendra virus causing mortality in horses and human in Australia in 1994 was found to be not identical to Nipah virus (Chua et al, 2000). The virus persists in low numbers in the island flying fox Pteropus hypomelanus (Johara, M.Y., 1999; Johara et al, 2001; Chua, K.B., 2001), a type of fruit bat and Malayan flying fox, Pteropus vampyrus. In pig, the virus replicates explosively where it causes respiratory and/or neurological syndromes followed with death (Aziz., J. 1999a, 1999b; Mohd Nor et al, 1999; Middleton, D. et al 2000). In human victim the virus caused severe encephalitis (Mohd Taha, 1999). Of the 269 human cases of viral encephalitis associated with Nipah virus infection reported in Malaysia in 1999, 108 were fatal (Ministry of Health Malaysia, 2001).

This is a classic example of a new viral disease emerging as a result of species jumping (Hume et al, 2002). To make it worst, a large number of pigs moved south of the peninsular, so too did the human disease. The 11 cases in Singapore involving abattoir workers were traced to the importation of pigs from Peninsular Malaysia. Between March and September 1999 a follow-up screening of abattoir workers in Singapore found another three infected people amongst 635 tested. Then in 2000, routine surveillance of pig blood in Singapore revealed infection again, and four of 160 workers were found to harbour the virus (Anonymous, 1999; Chua et al, 2000).

A Nipah virus National Swine Surveillance (NSS) programme was set up in the VRI that involved active serological surveillance for pig farms and abattoirs. There is control of movement of pigs which is restricted with permits only to abattoirs. In the abattoir random sampling was carried out so that positive cases could be traced back to each individual farm. Farm to farm movement is also under control, with only stock that was tested and approved free from Nipah virus infection by the DVS was allowed movement.

Of great concern is the fact that changing geographic distribution of fruit bats means the possibility of spreading new human diseases. Common with most countries in South-East Asia, Peninsular Malaysia has a great diversity of bat species. At least 13 species of fruit bat (suborder Megachiroptera), including two flying fox species and at least 60 species of insectivorous bats (suborder Microchiroptera) are known. The inability to readily isolate and detect Nipah virus from bats during the outbreak may suggest that there are other wildlife reservoirs that might play a bigger role in the transmission of the virus such as mammals either arboreal or terrestrial (Aziz, A.J., 2002), the sample size is too small, or virus excretion is periodical.

Ongoing genetic studies to discern Nipah virus characteristics indicated that the bat and human viruses showed little variation (Chua, K.B. 2002 - personal communication). An immunological study on the Nipah virus infection in laboratory animals was undertaken with the help of locally produced Mab for the development of rapid and sensitive determination of infection in animals (Sharifah Syed Hassan - personal communication). Currently, work is progressing in the VRI and other collaborating centres, towards the expression of the full length G-protein in bacullovirus system and truncation forms of the G-protein in both E. coli and bacullovirus system.

10) Menangle and Tioman viruses

A previously unknown virus, Menangle virus, was isolated from stillborn piglets with deformities at a large commercial piggery in New South Wales. The virus was responsible for reduced farrowing rate and for causing stillbirths with deformities. The search for the natural host of Nipah virus in our country led to the discovery of new members of the Paramyxoviridae family, Tioman virus, isolated from urine of flying fox found on Tioman Island off the eastern coast of the Malaysian Peninsular. Tioman virus failed to react with antibodies against a number of known paramyxoviruses but did cross react in immunofluorescence tests with antisera to Menangle virus. However, antiserum to Menangle virus failed to neutralise Tioman virus. Phylogenetic analysis indicated that Tioman and Menangle viruses are closely related members of the Rubulavirus genus. Sequences of the nucleocapsid protein gene of the two viruses are approximately 70% identical at the nucleotide level and approximately 85% identical at the amino acid level (K.B. Chua et al, 2000). The potential of Tioman virus to cause disease in both animals and humans is unknown.

11) Oya virus

In April 2000, an unidentified virus was isolated from Vero cell culture of lung tissue sampled from a pig suspected of Nipah virus infection (Ali, M. et al, 2000). Upon characterisation, the unidentified virus was named Oya virus, after a village in which it was isolated. The sequence data of the product revealed that the partial gene of Oya virus S-RNA segment had 65%-70% homology with published cDNA sequences of Simbu serogroup viruses. Serological surveys revealed that the virus distributed widely and densely in Malaysia. Simbu serogroup is known to cause febrile illness in human (LeDuc, J.W. 1986) and the pathogenicity of Oya virus in animals is not known. Studies are ongoing to determine its pathogenicity in pigs.

12) Other diseases

Rapid transportation has been partly attributed to the spread of diseases, and this is especially true in countries in this region. Tourism is an important industry in South-East Asia, and a series of conferences on travel medicine has highlighted the problems, particularly in emerging infectious diseases. Another important factor, the exodus of people between countries in this region is migrant workers. In Malaysia, estimated 1.7 million workers are migrants, of which only 1.2 million came in legally (Lam, S.K., 1998). Most of the migrant workers are from Indonesia, Philippines, Myanmar, Bangladesh, India, Nepal and Pakistan and they usually are employed in the agricultural sector as well as in construction and domestic services.

Diseases associated with migrant workers are chloramphenicol-resistant typhoid, multidrug resistant TB, leprosy, malaria, HIV/AIDS, and filariasis. Back in 1993, the first case of Kala-azar caused by Leishmania donovani was reported in a Bangladeshi migrant worker in Malaysia and since then four other cases were identified, all of them in Bangladeshi workers. Prior to this epidemic, Malaysia was free of the disease. The incidence of hepatitis B in Malaysia which had shown a downward trend since 1988 from 56.78 per 100,000 population (1,151 cases) to 1.42 in 1997 (307 cases) recorded an increase to 22.59 (5,010 cases) in 1998 as a result of mandatory screening of foreign workers (Ministry of Health Malaysia, 2001).

The recent emergence of a new strain (H5N1) of influenza A virus, the avian flu, in Hong Kong underscore the importance of South-East Asia as an epicentre for other microbial agents. In late 1992, Vibrio cholerae 0139 appeared in the Indian subcontinent and within a few months, it spread to China, Nepal, Pakistan, Malaysia and Russia. Cholera has been re-introduced into countries and continents where it had previously disappeared and where it can spread because water and sanitation systems have deteriorated and food safety measures are not adequate. The influx of Africans to Malaysia, most of them through illegal entry may bring in exotic diseases like Ebola, Rift Valley fever, Meningococcal Meningitis or yellow fever to name a few.

International Solutions to Emerging Infectious Diseases

The global nature of the threat posed by new and re-emerging infectious diseases will require international cooperation in identifying, controlling and preventing these diseases. Therefore the following activities need to be given importance:

  • Strengthen international surveillance networks to issue early warning, detect, control, and reduce emerging infectious diseases.
  • Improve international public health infrastructure (e.g. laboratories, research facilities, technology and communication links).
  • Improve international capabilities to respond to disease outbreaks with adequate medical and veterinary resources and expertise.
  • Strengthen international research efforts on emerging infectious diseases, giving priority to antibiotic-resistant strains of diseases.
  • Focus attention and resources on training and developing medical and veterinary capability.
  • Encourage national governments to improve their public health care systems, devote resources to eliminating or controlling causes of emerging infectious diseases and coordinate public health activities with WHO, OIE and other international communities.
  • Develop better international standards, guidelines and recommendations.

WHO has gone a step ahead to revise the International Health Regulations which may help to facilitate international cooperation in achieving a global response against emerging infectious diseases. The need for global cooperation increases the importance of international law in the public health arena.

Conclusion

The above-mentioned problems underline the need to strengthen epidemiological surveillance and concentrate on public health activities in South-East Asia, the epicentre of many emerging diseases. An outbreak management team has to be multi-disciplinary with specific expertise focussed on emerging infectious diseases. The blueprint for outbreak management means a flexible, non-political hierarchy that is unburdened by bureaucracy and can swiftly call on skills and intelligence across all disciplines and fields.

The emergence of zoonoses is likely to persist owing to factors such as increased human to animal interaction, increased production and manufacture of animal-derived products, encroachment of human populations into feral animal habitat causing pathogen pollution as well as increased global trade and transportation of animals and animal products over wider area in shorter time.

Zoonotic outbreaks emphasise the importance of a robust public health infrastructure for disease surveillance and the need for national efforts and multidisciplinary collaboration to address public health threats. Apart from human and animal health welfare, zoonotic disease outbreaks may also have profound economic and political implications.

Most emerging infectious diseases in the Asia-Pacific region are due to either novel zoonotic viruses or to an increased incidence or geographic spread of known viruses. The importance of the emergence of novel zoonotic diseases arising from wildlife should not be underestimated. Currently, very few countries anywhere have active wildlife disease surveillance, but it is hoped that such surveillance activities will eventually increase. Some of the new agents detected in the last two decades are now genuine public health problems on a local, regional and global scale.

References:

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