Nipah virus encephalitis

Overview
Nipah virus was identified in 1999 when it caused an outbreak of neurological and respiratory disease on pig farms in peninsular Malaysia, resulting in 105 human deaths and the culling of one million pigs. In Singapore, 11 cases including one death occurred in abattoir workers exposed to pigs imported from the affected Malaysian farms. The Nipah virus has been classified by the CDC as a Category C agent (http://www.bt.cdc.gov/agent/agentlist-category.asp).

Symptoms of infection from the Malaysian outbreak were primarily encephalitic in humans and respiratory in pigs. Later outbreaks have caused respiratory illness in humans, increasing the likelihood of human-to-human transmission and indicating the existence of more dangerous strains of the virus.

Based on seroprevalence data and virus isolations, the primary reservoir for Nipah virus was identified as Pteropid fruit bats including Pteropus vampyrus (Malayan flying fox) and Pteropus hypomelanus (Island flying fox), both of which occur in Malaysia.

The transmission of Nipah virus from flying foxes to pigs is thought to be due to an increasing overlap between bat habitats and piggeries in peninsular Malaysia. At the index farm, fruit orchards were in close proximity to the piggery, allowing the spillage of urine, faeces and partially eaten fruit onto the pigs. Retrospective studies demonstrate that viral spillover into pigs may have been occurring in Malaysia since 1996 without detection. During 1998, viral spread was aided by the transfer of infected pigs to other farms where new outbreaks occurred.

History
Outbreaks

Seven more outbreaks of Nipah virus have occurred since 1998, all within Bangladesh and neighbouring parts of India. The outbreak sites lie within the range of Pteropus species (Pteropus giganteus). As with Hendra virus, the timing of the outbreaks indicates a seasonal effect.

Eleven isolated cases of Nipah virus encephalitis have also been documented in Bangladesh since 2001.
 * 2001 January 31 – February 23, Siliguri, India: 66 cases with a 74% mortality rate. 75% of patients were either hospital staff or had visited one of the other patients in hospital, indicating person-to-person transmission.
 * 2001 April – May, Meherpur district, Bangladesh: 13 cases with nine fatalities (69% mortality).
 * 2003 January, Naogaon district, Bangladesh: 12 cases with eight fatalities (67% mortality).
 * 2004 January – February, Manikganj and Rajbari provinces, Bangladesh: 42 cases with 14 fatalities (33% mortality).
 * 2004 19 February – 16 April, Faridpur district, Bangladesh: 36 cases with 27 fatalities (75% mortality). Epidemiological evidence strongly suggests that this outbreak involved person-to-person transmission of Nipah virus, which had not previously been confirmed. 92% of cases involved close contact with at least one other person infected with Nipah virus. Two cases involved a single short exposure to an ill patient, including a rickshaw driver who transported a patient to hospital. In addition, at least six cases involved acute respiratory distress syndrome which has not been reported previously for Nipah virus illness in humans. This symptom is likely to have assisted human-to-human transmission through large droplet dispersal.
 * 2005 January, Tangail district, Bangladesh: 12 cases with 11 fatalities (92% mortality). The virus was probably contracted from drinking date palm juice contaminated by fruit bat droppings or saliva.
 * 2007 February – May, Nadia District, India: up to 50 cases with five fatalities. The outbreak site borders the Bangladesh district of Kushtia where 50 suspected cases of Nipah virus encephalitis with six fatalities occurred during April 2007.

Nipah virus has been isolated from Lyle's flying fox (Pteropus lylei) in Cambodia and viral RNA found in urine and saliva from P. lylei and Horsfield's roundleaf bat (Hipposideros larvartus) in Thailand. Antibodies to henipaviruses have also been found in fruit bats (Pteropus rufus, Eidolon dupreanum) in Madagascar indicating a wide geographic distribution of the viruses. No infection of humans or other species have been observed in Cambodia, Thailand or Madagascar.

Hendra virus
Emergence

Hendra virus (originally Equine morbillivirus) was discovered in September 1994 when it caused the deaths of thirteen horses, and the prominent horse trainer Vic Rail at a training complex in Hendra, a suburb of Brisbane in Queensland, Australia.

The index case, a mare, was housed with 23 other horses after falling ill and died two days later. Subsequently, 19 of the remaining horses succumbed with 12 dying. Both the trainer and a stable hand were involved in nursing the index case and both fell ill within one week of the horse’s death with an influenza-like illness. The stable hand recovered while the trainer died of respiratory and renal failure. The source of virus was most likely frothy nasal discharge from the index case.

A second outbreak occurred in August 1994 (chronologically preceding the first outbreak) in Mackay 1000km north of Brisbane resulting in the deaths of two horses and their owner. The owner assisted in autopsies of the horses and within three weeks was admitted to hospital suffering from meningitis. He recovered, but 14 months later developed neurologic signs and died. This outbreak was diagnosed retrospectively by the presence of Hendra virus in the brain of the patient.

A survey of wildlife in the outbreak areas was conducted and identified pteropid fruit bats as the most likely source of Hendra virus with a seroprevalence of 47%. All of the other 46 species sampled were negative. Virus isolations from the reproductive tract and urine of wild bats indicated that transmission to horses may have occurred via exposure to bat urine or birthing fluids.

Outbreaks

Four more incidents, in Cairns in January 1999 and October 2004, in Townsville in December 2004 and on the Sunshine Coast in June 2006 each resulted in the death of one horse. A vet involved in autopsy of the horse from the 2004 Townsville incident developed a Hendra-related illness soon after and recovered.

The distribution of black and spectacled flying foxes covers Townsville and Cairns, and the timing of incidents indicates a seasonal pattern of outbreaks possibly related to the seasonality of fruit bat birthing. As there is no evidence of transmission to humans directly from bats, it is thought that human infection only occurs via an intermediate host.

Infection/Transmission
Where are Hendra and Nipah viruses found?

The natural reservoir for Hendra virus is thought to be flying foxes (bats of the genus Pteropus) found in Australia. The natural reservoir for Nipah virus is still under investigation, but preliminary data suggest that bats of the genus Pteropus are also the reservoirs for Nipah virus in Malaysia.

Where are the diseases found?

Hendra virus caused disease in horses in Australia, and the human infections there were due to direct exposure to tissues and secretions from infected horses. Nipah virus caused a relatively mild disease in pigs in Malaysia and Singapore. Nipah virus was transmitted to humans, cats, and dogs through close contact with infected pigs.

Risk Factors
People who have contact with body fluids or excretions of horses infected with Hendra virus are at risk for Hendra virus disease. Nipah virus infection is associated with close contact with Nipah virus-infected pigs. Neither disease has spread from human to human.

Pathophysiology & Etiology
Hendra virus (formerly called equine morbillivirus) is a member of the family Paramyxoviridae.

Nipah virus, also a member of the family Paramyxoviridae, is related but not identical to Hendra virus.

Transmission

Australia, humans became ill after exposure to body fluids and excretions of horses infected with Hendra virus. In Malaysia and Singapore, humans were infected with Nipah virus through close contact with infected pigs.

Natural History
Hendra virus was first isolated in 1994 from specimens obtained during an outbreak of respiratory and neurologic disease in horses and humans in Hendra, a suburb of Brisbane, Australia.

Nipah virus was initially isolated in 1999 upon examining samples from an outbreak of encephalitis and respiratory illness among adult men in Malaysia and Singapore.

History and Symptoms

 * Only three human cases of Hendra virus disease have been recognized. Two of the three individuals known to be infected had a respiratory illness with severe flu-like signs and symptoms. Infection with Nipah virus was associated with an encephalitis (inflammation of the brain) characterized by fever and drowsiness and more serious central nervous system disease, such as coma, seizures, and inability to maintain breathing.


 * Illness with Nipah virus begins with 3-14 days of fever and headache. This is followed by drowsiness and disorientation characterized by mental confusion. These signs and symptoms can progress to coma within 24-48 hours. Some patients have had a respiratory illness during the early part of their infections.

Risk Stratification and Prognosis
One of the three Hendra virus infections was marked by a delayed onset of progressive encephalitis. Serious nervous disease with Nipah virus encephalitis has been marked by some sequelae, such as persistent convulsions and personality changes.

Two of the three human patients infected with Hendra virus died. During the Nipah virus disease outbreak in 1998-99, about 40% of the patients with serious nervous disease who entered hospitals died from the illness.

Treatment
What needs to be done to address the threat of Hendra and Nipah viruses?

The distribution of these agents in their natural reservoirs will eventually define the geographic range of the threat the viruses pose. However, these viruses are recent discoveries, and much work remains to be done on their geographic distribution and the reservoir species. The occurrence of the disease in humans has been associated only with infection of an intermediate species such as horses with Hendra and swine with Nipah virus. Early recognition of the disease in the intermediate animal host is probably the most crucial means of limiting future human cases.

Pharmacotherapy
The drug ribavirin has been shown to be effective against the viruses in vitro. However, controlled drug investigations have not been performed and the clinical usefulness of these drugs is uncertain.

Primary Prevention
These diseases can be prevented by avoiding animals that are known to be infected and using appropriate personal protective equipment devices when it is necessary to come into contact with potentially infected animals.

Acknowledgements
The content on this page was first contributed by: C. Michael Gibson, M.S., M.D.