NIPAH VIRUS

Clinical features of newly discovered paramyxovirus

Between September 1998 and June 1999, there was an outbreak of severe febrile encephalitis among pig farmers in Malaysia. Investigators from Malaysia working with the Centers for Disese Control and Prevention (CDC) identified the causative agent as a new paramyxovirus, now called the Nipah virus, that was directly transmitted to humans from pigs and their secretions. Mosquitos were not believed to be a vector for transmission. 
This report by Goh et al describes the clinical features of this novel viral disease. Ninety three percent of the 94 patients infected had had direct contact with pigs, usually within two weeks of the onset of illness. This suggests a short incubation period with direct transmission from the pigs to the humans. The main clinical presentations were fever, headache, dizziness, and vomiting. 55% had a reduced level of consciousness and prominent brain-stem dysfunction. Other distinctive clincal symptoms include areflexia and hypotonia, segmental myoclonus, hypertension, and tachycardia. Initial cerebrospinal fluid findings were abnormal in 75% of cases. Antibodies against Hendra virus were detected in 76% of 83 patients tested. 32% of patients died following rapid deterioration in their condition. An abnormal doll's-eye reflex and tachycardia were indicators of poor prognosis. 
Neurologic relapse occurred after initial mild disease in 3 patients and 15% had persistent neurologic defects. 53% of patients recovered fully. 
Thus, Nipah virus causes a severe, rapidly progressive encephalitis with a high mortality rate. Clinical features suggest brain stem involvement.

Story of the Outbreak 

In 1998-99, an outbreak of a previously unrecorded viral disease killed more than 100 people and thousands of pigs in Malaysia. Small numbers of other animals in Malaysia, including horses, cats, dogs, fruit bats (flying foxes), and goats were also shown to have been infected with the Nipah virus, as they had developed antibodies to the virus.
	
The Nipah virus was named after one of the villages affected by the outbreak: Sungai Nipah, in the Malaysian State of Negri Sembilan. Dr Chua Kaw Ping, from the Medical Microbiology Department (MMD) of the University Malaya, made the discovery of the new virus on 18 March 1999. 

How the outbreak unfolded
The first cases of the Nipah virus illness were believed to have been reported in 1997 in a number of pig-farm workers from near the city of Ipoh, one of whom died. These cases were at first diagnosed as Japanese encephalitis (JE), a viral disease unrelated to Nipah virus that causes similar clinical symptoms in humans. JE is endemic in Malaysia.
By the end of 1998, about 10 workers from Tambun, Ulu Piah and Ampang had died after being in a coma for from four days to a few weeks. A special Malaysian task force comprising medical and veterinary officers was formed to investigate the outbreak.
By mid-December 1998 the Nipah virus disease had reached Sikamat, about 60 km south of Kuala Lumpur, through movement of infected pigs.
The disease spread to the major pig producing area of Bukit Pelandok in the State of Negeri Sembilan by March 1999. From 1 - 10 March 1999 a total of 224 suspected human cases of viral encephalitis occurred in that State, with 80 fatalities.
Later that month, nine Singapore abattoir workers also became sick after slaughtering Malaysian pigs that were later shown to be infected with the disease. One worker died. There was no further spread of the disease within Singapore.
By June 1999, 101 people had died of the Nipah virus in Malaysia, with about 260 people suspected of having been infected.

A new virus
Nipah virus is a 'new' megamyxovirus - a genus within the paramyxovirus family of viruses. There are many types of paramyxoviruses, including rinderpest in cattle, distemper in dogs and measles in humans.
Nipah virus is related to but distinct from Hendra virus, the only other known megamyxovirus. Hendra virus (formerly known as equine morbillivirus) was first isolated in 1994 in Hendra, Brisbane, Australia. Hendra virus has only been found in the State of Queensland, where two humans and 16 horses died in three separate incidents.
Genetic characterisation has shown a variance between the two viruses of about 20 per cent. This is of similar magnitude to the difference between the measles and rinderpest viruses. The behaviour of the Nipah virus and Hendra virus is also different, in terms of the range of species they infect and the way in which the viruses appear to be transmitted.
Hendra virus does not transmit readily between animals other than in flying foxes. In contrast, the Nipah virus appears to be easily transmitted between pigs, and may be transmitted from pigs to other animals.
The Nipah virus cases in 1997 occurred at a farm in which fruit trees frequented by fruit bats were planted within metres of pig pens. It is believed the outbreak may have originated when infected fruit bats came into contact with the farmed pigs.

Symptoms
In humans, Nipah virus has caused mild to severe clinical signs, including fever and headaches, and occasionally drowsiness and disorientation, sometimes resulting in coma. The majority of those patients in a coma subsequently died.
In pigs, the virus appears to cause a high rate of infection, but a low rate of sickness and death. Clinical signs include mild to severe coughing, laboured breathing, convulsions and death.
In a sick dog that was examined, both brain and lung were affected.

Control and eradication
A program for eradication was developed by the Malaysian Cabinet taskforce, together with international experts. From 28 February 1999 to 26 April 1999, more than 900,000 pigs from affected areas were culled. At the end of the eradication period, the number of new human cases had slowed dramatically.
International assistance effort
The Australian assistance effort was coordinated by Australia's Chief Veterinary Officer, Dr Gardner Murray, through the National Office of Animal and Plant Health in the Department of Agriculture, Forestry and Fisheries-Australia (NOAPH - AFFA) and the Australian Quarantine and Inspection Service (AQIS).
The Australian Task Force also comprised representatives from the Commonwealth Department of Health and Aged Care, CSIRO Australian Animal Health Laboratory (AAHL), and the World Health Organization Reference Laboratory. In addition, the Malaysian authorities requested the assistance of the Queensland Department of Primary Industries (QDPI).
CSIRO AAHL's Dr Peter Daniels and Dr John White, together with Dr Hume Field from the QDPI, travelled to Malaysia in March 1999, where they joined a team from the US Centers for Disease Control and Prevention in investigating and controlling the outbreak.
Dr Peter Daniels is a veterinarian and project leader of CSIRO AAHL's Diagnosis and Epidemiology section. He worked with the Malaysian Department of Veterinary Services in conducting animal post mortems and collecting blood samples from pigs and other animals for testing at AAHL in Geelong.
Dr John White is a CSIRO AAHL research scientist with experience in developing diagnostic tests for viral diseases. Dr White worked with staff from the Veterinary Research Institute in Ipoh, Malaysia to develop a blood test to show if pigs and other animals had been exposed to the virus.
The test is now being used in Malaysia to screen at least 30,000 pig blood samples from more than 800 pig farms nationwide as part of the surveillance strategy for the Nipah virus. Pigs are also being randomly sampled at Malaysian abattoirs to ensure potentially diseased animals are not being submitted for human consumption.
AAHL scientists also undertook transmission experiments with pigs to determine how they may be passing the virus to other pigs, and to people. The scientific team used techniques such as electron microscopy, histology, and genetic sequencing to research the virus. The unique biocontainment facilities at AAHL make it one of the few places in the world where testing and research of infectious diseases that affect animals and humans can be safely carried out.
Scientists from AAHL also helped the Malaysian Veterinary Services Department design the national surveillance and eradication program for the disease in livestock, based on the detection and culling of infected pigs.
Dr Hume Field, a veterinary research scientist and wildlife expert from QDPI, also worked in Malaysia, focussing on wildlife investigation studies. He collected animal samples for testing to determine the natural 'host' of the virus. Dr Field is part of the QDPI team that discovered the role of flying foxes as natural hosts of Hendra virus.

Current and future focus
The Malaysian Veterinary Services Department has conducted a national testing program to detect any pig farms where the disease has been present. Nearly 900 farms were tested, with approximately 50 farms found to have evidence of infection. All such farms were culled. At the end of the three-month program in July 1999, all farms were tested twice. There will be further random testing of pigs at abattoirs to ensure the virus does not become active again.
If research confirms fruit bats are the natural host of the virus, design of pig farms in Malaysia will have to be modified to ensure pigs are not again exposed to possible infections from that source.