The emergence of Nipah virus in Malaysia
The economic and social impacts of the outbreak
The putative natural host
Diseases that are rapidly increasing in incidence or distribution are said to be emerging. The definition encompasses not only diseases associated with previously unknown (or novel) agents, but also those known diseases that are re-emerging spatially or temporally. What triggers disease emergence? Modern epidemiological principles contend that disease is multi-factorial - that in addition to the presence of the infectious agent, additional factors are generally necessary for infection and disease to occur. Such factors may relate to the agent, to the host, or to the environment. Putative contributing factors to disease emergence include ecological changes, changes in human demographics and behaviour, increased international travel and commerce, advances in technology and industry, microbial adaptation or change, and breakdown of public health measures (Morse 1995).
Many emerging infections are zoonoses. The introduction of a new zoonotic infection into a human or domestic animal population can follow the incursion of humans (accompanied by their domestic animals, livestock, and crops) into previously remote natural habitats where unknown disease agents exist in harmony with wild reservoir hosts. Upon contact with new and naive species, an agent may jump species and establish in a new species which has no natural immunity or evolved resistance (unlike the natural host which may have evolved with the agent over time). The maintenance of monocultures of genetically similar or identical individuals may further promote susceptibility to infection. Further, artificially maintained high population densities may facilitate the rapid spread of pathogens throughout livestock populations. Zoonotic infections may be passed directly to humans from the natural reservoir, or they may be transmitted to humans via an intermediate, amplifying host.
Approximately 1.1 million pigs were culled to contain a major outbreak of disease in pigs and humans in Peninsular Malaysia between September 1998 and May 1999. Of 257 reported and attributed human cases in Malaysia, 105 were fatal. The disease in pigs was highly contagious, and characterized by acute fever with respiratory involvement and sometimes nervous signs in all age classes. Sows and boars sometimes died peracutely (Nor et al. 2000). The predominant clinical syndrome in humans was encephalitic rather than respiratory, with clinical signs including fever, headache, myalgia, drowsiness, and disorientation sometimes proceeding to coma within 48 hours (Chua et al. 1999; Goh et al. 2000). In total, at least 115 people died as a result of the outbreak. In addition to the 105 fatal cases in Malaysia, two farm workers who returned home to Indonesia (Dr Mohd Taha Arif, Ministry of Health, Kuala Lumpur: personal communication) and one abattoir worker in Singapore (Paton et al. 1999) died. In Malaysia, numerous others infected during the outbreak died subsequently, and many of the surviving encephalitis cases suffer nervous sequel. The majority of human cases were employed in the pig industry and had a history of direct contact with live pigs (Parashar et al. 2000).
Preliminary characterization of an isolate from a human case at the Centers for Disease Control and Prevention (CDC) in Fort Collins and Atlanta, USA, showed the primary causative agent in the outbreak to be a previously undescribed virus of the family Paramyxoviridae (CDC 1999), (Chua et al. 1999). This and later investigations showed the new virus, named Nipah virus, to be more closely related to Hendra virus than to other paramyxoviruses (Chua et al. 2000; Harcourt et al. 2000; Wang et al. 2000). Hendra virus is a recently emerged and zoonotic virus first described in horses and humans in Australia in 1994 (Murray et al. 1995). Nipah virus has subsequently been isolated from pigs and dogs on infected pig farms (Chua et al. 2000), and experimental infections of pigs and cats have confirmed the susceptibility of these species to infection and disease (Middleton et al. 2001).
Epidemiological evidence suggested that during the outbreak, the primary means of spread between farms and between regions was the movement of pigs. The primary mode of transmission on pig farms was believed to be via the oro-nasal route. The epidemic is believed to have started in the northern Malaysian State of Perak, from where fire sales (panic selling in the face of a disease outbreak) dispersed pigs across the country. Secondary modes of transmission between farms within localized farming communities may have included roaming infected dogs and cats, and sharing of boar semen (although at present, virus has not been identified in porcine semen). Lorries transporting pigs may also have introduced the virus onto farms.
The early epidemiology of the disease in Perak, and the spillover mechanism that first introduced the infection to pigs remains undetermined. However, retrospective investigations suggest that Nipah virus has been responsible for sporadic disease in pigs in Peninsular Malaysia since late 1996, but was not recognized as a new syndrome because the clinical signs were not markedly different from those of several endemic pig diseases, and because morbidity and mortality were not remarkable (Aziz et al. 1999; Bunning et al. 2000).
The outbreak had a devastating impact on the pig industry in Malaysia. Most of the 257 human encephalitis cases and the 105 fatalities were pig industry people, and their loss is keenly felt by all associated with the industry. Major economic costs have been incurred in controlling the outbreak, in lost domestic and export markets, and in allied businesses.
The government paid US$35 million in compensation for the 1.1 million pigs destroyed at an average price of US$32 per pig. An estimated cost of US$136 million was spent in the control programme from the Department of Veterinary Services. Tax revenue estimated at US$105 million was lost from the pig industry. Approximately 618 homes and 111 shops, as well as schools and banks, were evacuated in bringing the outbreak under control, causing great financial loss to the families and business involved. In addition, the pig industry in Malaysia also provided employment to farm workers and primary supporting services like drug and vaccine sales, feed and transport. It was estimated that 36 000 people from this group had suffered from the loss of employment due to closure of farms (Nor & Ong 2000b).
Prior to the outbreak, Malaysia had a standing pig population of 2.4 million. During the stamping out operation an estimated 901 228 pigs from 896 farms were destroyed in the infected areas between 28 February to 26 April 1999. A further 50 farms were culled under the national testing and surveillance programme. In total, approximately 1.1 million pigs were destroyed which cost about US$97 million, assuming that the average price per pig was US$95. Also, prior to the epidemic, Malaysia had been exporting pigs to Singapore and Hong Kong. The loss of this export trade meant a loss of about US$120 million in 1999, assuming average price per pig of US$120. In addition, local pork consumption during the peak of the outbreak dropped by 80 percent and farmers supplying this market suffered financial loss estimated to be about US$124 million during the outbreak period alone.
The episode caused a drastic change in the direction of the future of the pig industry in Malaysia. Pig farming is now allowed only in identified pig farming areas, with farmers in other areas encouraged to undertake other agricultural and livestock activities.
Fruit bats of the genus Pteropus have been identified as a natural reservoir host of Nipah virus (Johara et al. 2001). Surveillance of wildlife species for evidence of the origin of the virus was an integral part of the outbreak investigation, and when laboratory evidence indicated that Nipah and Hendra viruses were closely related, Malaysian bat species were targeted for surveillance. In common with most countries in the region, Malaysia has a great diversity of bat species. Of 324 bats from 14 species surveyed, neutralizing antibodies to Nipah virus were found in 21 bats from five species (four species of fruit bats, including two flying fox species, and one insectivorous species), although only two flying fox species showed a substantial seroprevalence. Cross neutralization of Nipah antigen by antibodies to Hendra virus was excluded as the cause of the reactivity. Subsequently, Nipah virus was isolated from the urine of a free living colony of Pteropus hyomelanus in Malaysia (Chua et al. 2001). Experimental infections of an Australian species, Pteropus poliocephalus, showed that this species supported a permissive cycle of infection with a human isolate of Nipah virus (Deborah Middleton et al., Australian Animal Health Laboratory, Geelong, Australia: unpublished data).
Flying foxes occur across South-east Asia. The world distribution of flying foxes (genus Pteropus) extends from the west Indian Ocean islands of Mauritius, Madagascar and Comoro, along the sub-Himalayan region of Pakistan and India, through South-east Asia, the Philippines, Indonesia, New Guinea, the South-west Pacific Islands (to the Cook Islands), and Australia (Figure 1). There are about 60 species of flying foxes in total. Flying foxes range in body weight from 300 g to over 1 kg, and in wingspan from 600 mm to 1.7 m. They are the largest bats in the world, do not echolocate but navigate at night by eyesight and their keen sense of smell. Females usually have only one young a year, after a six-month pregnancy. The young are independent after about three months. All flying fox species eat fruits, flowers or pollen, and roost communally in trees (Hall & Richards 2000). Flying foxes are nomadic, known to travel over considerable distances. Radiotracking studies in eastern Australia have shown individuals to undertake periodic movements of up to 600 km (Eby 1991). Where the distributions of different species overlap, roosts are shared. Thus the potential exists for interaction between flying fox populations across the region.
In the course of investigating the origins of Nipah virus, ubiquitous peridomestic species were also extensively surveyed. The uniformly negative serology results from surveyed peridomestic rodents, insectivores, and birds in Malaysia (Asiah et al., unpublished data) indicate that these animals did not play a role as secondary reservoirs for Nipah virus. While evidence suggests that dogs readily acquired infection following close association with infected pigs, targeted surveillance indicated that Nipah virus did not spread horizontally within dog populations.
Figure 1: World distribution of flying foxes (genus Pteropus) (adapted from Hall & Richards 2000)