News of the WeekEpidemiology

New Virus Fingered in Malaysian Epidemic

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Science  16 Apr 1999:
Vol. 284, Issue 5413, pp. 407-410
DOI: 10.1126/science.284.5413.407

Scientists have unmasked a killer responsible for the deaths of at least 95 people in Malaysia in the last 6 months, most of them pig farm workers. The culprit, named the Nipah virus for the small town from whence the strain was first identified, is a previously unknown virus that replicates in pigs and seems to be easily transmitted to humans. It is closely related to another notorious agent, the Hendra virus, which surfaced in Australia in 1994 and killed two people and more than a dozen horses. But the new virus spreads much more rapidly, making it “an emerging virus of grave concern,” says John Mackenzie, head of the department of microbiology and parasitology at the University of Queensland in Brisbane, Australia.

The country's health authorities initially assumed they were dealing with an outbreak of Japanese encephalitis (JE), which causes similar symptoms, and some critics have accused the Malaysian government of being slow to consider alternative causes. Indeed, even now authorities insist that the country is battling a “dual epidemic” of JE and the new disease. But last week the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta said that the Nipah virus is the main culprit, and that the JE virus has played at best a marginal role in the continuing tragedy. The epidemic peaked around the middle of March and seems to be waning now. Early this week, the Malaysian Ministry of Health put the total number of cases at 251. Since early March, Malaysian health authorities have killed over 800,000 pigs to halt the spread of the virus.

The first cases of the disease occurred in late September near the city of Ipoh, in the northern state of Perak. The victims, all of whom worked in the pig industry, came down with high fever and encephalitis (an inflammation of the brain), and some died. Officials concluded that they had succumbed to JE, which is transmitted by Culex mosquitoes and known to replicate in pigs.

Circumstantial evidence supported that theory. A few dozen people contract JE in Malaysia yearly, and the numbers usually rise at the end of the year. In addition, tests at the University of Malaya in Kuala Lumpur and the Institute of Tropical Medicine in Nagasaki, Japan, confirmed that blood and cerebrospinal fluid of some patients contained antibodies against JE. To contain the outbreak, Malaysian authorities fogged thousands of pig farms and nearby houses with insecticide and inoculated tens of thousands of people at risk with a vaccine for JE.

But the disease kept spreading. By late December, when several dozen cases had been reported, it reached the southern state of Negeri Sembilan. Scientists also began to notice that the outbreak wasn't behaving like JE. For one, it was killing pigs, which are carriers of JE but rarely its victims. For another, it was felling adults, whereas JE mostly kills children. Third, it seemed to affect only those who had been in close contact with pigs while their family members stayed healthy, which didn't fit the pattern of a mosquito-borne disease. Furthermore, some people contracted the disease after being vaccinated for JE. And finally, scientists were unable to isolate live virus from any of the patients whose blood contained JE antibodies.

At the time, the investigations were still handled by the country's Institute for Medical Research, a part of the Ministry of Health, which stood by its initial diagnosis. But when all prevention measures failed and the epidemic spread, the government sought help from Lam Kai Sit, head of the University of Malaya's department of medical microbiology. Five days after they obtained the first patient blood and cerebrospinal fluid samples on 1 March, Lam and his colleague Chua Kaw Bing had isolated a virus that, judging by its appearance, belonged to the Paramyxoviridae, a family that doesn't include the JE virus. They noticed that the virus caused cells to clump together in giant multinucleate cells or “syncytia.” Mackenzie then suggested that the Malaysian samples be tested for Hendra, which also produces syncytia and causes encephalitis in humans, and for Menangle-virus, a paramyxovirus that was recently isolated from Australian pigs.

Chua took the samples to the CDC in Atlanta, and tests showed that Mackenzie's hunch was correct. The new virus reacted with antibodies to the Hendra virus, indicating a similarity between the two. The CDC then sequenced the viral genome and showed the new virus to be about 20% different from the Hendra virus, says Brian Mahy, director of CDC's Division of Viral and Rickettsial Diseases. The Nipah virus was found not only in the tissues of patients, but also in sick pigs and in 11 abattoir workers from Singapore who had fallen sick in March after contact with Malaysian pigs.

Although there have been no cases of human-to-human transmission, the CDC classified the new virus as a P4-pathogen. That meant samples can be collected and handled only by researchers clad in space suits and examined only in high-level safety labs. As for the virus's mode of transmission, one theory is that it is present in pig lungs and urine and that humans can get infected by inhaling aerosols. What is particularly worrying, says Mahy, is that one of the Australian victims of the Hendra virus died 14 months after he was infected. If the new virus has a similar lag time, he says, the current fatalities may only be the beginning.

Another riddle is how the virus entered the Malaysian pig population. Scientists have shown that four species of Australian fruit bats normally harbor the Hendra virus, and they suspect horses could become infected if they ingest bat urine or part of a bat placenta, both of which contain the virus.

As for any link to JE, most researchers now think that a few cases of JE may have occurred simultaneously when the outbreak began but that JE didn't cause the widespread epidemic. The presence of antibodies in some patients, they say, is not surprising given JE's prevalence in Malaysia, and because many people—especially pig industry workers—may have been exposed to JE without getting sick. “I don't think the JE virus has been involved in any significant way in this current epidemic,” says Mahy.

But Malaysian health authorities remain convinced that JE is involved. Lam says he alerted the ministry immediately after the CDC informed him on 18 March about the new virus. But 5 days later, a press release by the ministry's director-general summed up the arguments behind the initial diagnosis and repeated that “the present outbreak is confirmed as JE.” The release briefly mentioned the discovery of the Hendra-like virus but said “we are not sure if the virus is a pathogen.”

This week, Mohamad Taha Arif, director of the Disease Control Division of the Malaysian Ministry of Health, said that “currently the [Nipah] outbreak is more prominent,” but insists there is a dual epidemic and that measures to prevent the spread of JE need to remain in place. He says there wasn't enough proof on 18 March to say that the new virus had caused the epidemic.

Some Malaysian scientists say they are not surprised at the government's rigidity. Jane Cardosa, a virologist at the Institute for Health and Community Medicine at the University of Malaysia in Sarawak, says she called the health ministry in November and again in January, urging officials to look for alternative infectious agents. She also expressed her doubts in a January message to ProMED, an electronic forum for emerging-disease researchers. The government's response, she says, was an e-mail reprimanding her for questioning the official theory. “The ministry made an early presumptive diagnosis, and they have difficulty admitting it was a mistake,” she says. When costly fogging and vaccination campaigns failed to halt the disease, she adds, “it became even more difficult to admit there was an error.” Lam, too, says “it was quite obvious to us right from the beginning that not all the cases were due to Japanese encephalitis.” But not being involved in the official investigation, he didn't look for other possible culprits.

David Quek, editor of the journal of the Malaysian Medical Association, says the episode reminds him of a heart infection outbreak in Sarawak in 1997, in which more than 20 children died. Health authorities blamed that epidemic on the Coxsackie virus—and kept doing so long after scientists had ruled it out as the culprit. This time, says Quek, “we hope that the authorities can be a bit more enlightened. Sometimes it's all right to admit an error.”

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