Nipah Virus Outbreak

Introduction

An outbreak that occurred in farmers of Malaysia in 1998 originated in pigs, which were previously infected by bats. The causative agent was identified as Nipah (Nee-pa) virus. The disease can spread from human-to-human. Since 2001, Nipah virus infection is occurring annually in Bangladesh and twice in adjoining West Bengal, India. It made its appearance in Kerala in 2018 and four outbreaks happened since then. Deforestation and rapid urbanization in Kerala has created a situation in which people and animals such as bats that carry the virus have come in close contact.

Due to the widespread presence of the Pteropus bats which serves as the reservoir host and the detection of Nipah virus (NiV) in bats in different countries, the likelihood of outbreaks emerging in previously unaffected areas remains considerable. The World Health Organization (WHO) has recognized NiV as a significant epidemic risk and designated it as a prioritized pathogen for research and development.¹

Epidemiology

Malaysia

Cases of an unknown infection began to present in late September 1998 in villages around Ipoh, Perak, West Malaysia where pig farming formed a major industry. The cases continued to appear in that region till February 1999. Similar cases occurred in a second cluster between December 1998 and January 1999 in Negeri Semilan, near Sikamat in Seremban State in Malaysia. In the same state, a third and largest cluster of infection appeared in the city of Bukit Pelandok in December 1998.2 The infection was thought to be Japanese B encephalitis (JE) due to outbreaks in pig-farming region. Some patients even exhibited positive result for JE-specificimmunoglobulin and nucleic acids.

But the outbreak showed certain features that were not normally seen in JE, such as occurrence in adult males who had direct physical contact with pigs. Further, it was not a mosquito-borne disease. Another significant feature was clustering of one-third of symptomatic cases in the same household.^2,3 Pigs exhibited higher mortality with a severe barking cough.⁴ It was noteworthy that the condition was not seen in Malay villages. It was predominantly seen in Chinese farms. No human-to-human transmission was reported in Malaysia.

After identifying the outbreak's origin as a previously undiscovered virus linked to pigs, over one million pigs were euthanized within the affected regions over the following three months to contain the disease's spread. This step was deemed essential due to the belief that the infection was transmitted through the infected pigs and their bodily secretions.^5,6 The outbreak was totally controlled by May 1999. During the outbreak, there were 265 cases of Nipah encephalitis with 105 deaths making a case fatality of 40%. The condition has not recurred since then.

Singapore

There was spread of the outbreak to Singapore in late February 1999. They were importing pigs from farms located in Malaysia. Eleven persons, mostly abattoir workers exhibited features of Nipah infection including encephalitis. All patients were men with a median age of 44 years. One person died making the case fatality rate 9%. Intense screening of the abattoir workers was carried out and import of pigs, pork, and pork products was banned and subsequently the outbreak receded.⁷

It was soon identified that pteropodid fruit bats (flying fox) were the natural reservoirs and the area was infested with bats. Fruits incompletely eaten by bats were dropped or thrown into pigsties, and the pigs which ate them acquired the infection.⁸ The outbreak of Nipah infection made its disappearance by effective management in Malaysia and Singapore and there has not been any recurrence of the infection since then.

The virus has been named after the village Kampung Sungai Nipah (Nipah River Village) in Negeri Sembilan State, Malaysia where the antibodies were demonstrated in the cerebrospinal fluid against Hendra viral antigens in the first confirmed, fatal patient with features of encephalitis in 1999.⁹

Bangladesh

At the turn of the century in January-February 2001, Nipah virus infection was recognized in a geographically distant region in Bangladesh. The outbreak was quite different from that seen in Malaysia. It was more severe with a rapid progression, and increased mortality.

There was an outbreak of encephalitis in 2001 in the villages of Meherpur, Bangladesh. In 2003, in Naogaon District, 150 km from Meherpur, there was a cluster of febrile cases with neurological manifestations. The manifestations exhibited by patients in Meherpur and Naogaon were similar. The cause of the febrile illness was investigated with the help of Centre for Disease Control and Prevention (CDC) and it established that Nipah virus was responsible for encephalitis.¹⁰

The study further revealed the condition did not involve pigs as intermediate host. The condition is acquired through an entirely different route. People are in the habit of consuming sap obtained from the date palm tree either as a fresh juice or after fermentation into an alcoholic drink (popularly known as toddy, kallu, tuak and tuba). The sap that oozes from the shaven date palm tree overnight is collected in mud pots attached to the trees. This is frequently consumed by fruit bats belonging to the family of Pteropus. While doing so, the sap is often contaminated by saliva, urine and excreta of the bats. Bangladesh outbreak proved the transmission of infection by bat-to-human route.¹¹

In following years, outbreaks have occurred almost annually, particularly in the winter months, in many parts of Bangladesh where the infection spread by human-to-human transmission. It was exemplified in the outbreak of infection that involved five generations affecting 14 members of a family in Faridpur.¹² In a period of a decade (2001-2012), a total of 208 patients were seen in Bangladesh, of whom 161 patients died, taking the case fatality rate to 77%.¹³

West Bengal, India

An outbreak of febrile illness exhibiting features of encephalitis occurred in January-February 2001 in Siliguri, West Bengal, adjoining NiV belt in Bangladesh. The condition was characterized by fever in association with altered sensorium. The cause of the illness was proved to be due to Nipah virus.¹⁴ There was no disease in pigs. The contaminated sap from the date palm tree was considered as the source of infection. The virus can remain stable for at least a week at 22^oC in date palm sap. The infection spreads from human-to-human and by nosocomial way. A single patient admitted to a private hospital infected 33 hospital staff and visitors.¹⁴ From 2001 to 2003, there were 66 infected cases, of which 45 died making a case fatality of 68%. Another outbreak occurred in Nadia district, West Bengal in 2007 where 30 cases of fever with acute respiratory distress and/or neurological manifestations were encountered and five infected persons died. All five fatal cases were positive for NiV by reverse transcriptase-polymer chain reaction (RT-PCR) test, thus making a case fatality of 100%.¹³

Kerala, India

In May-June 2018, there was an outbreak of Nipah viral infection in Kozhikode district, located in Northern Kerala. The primary features of this outbreak included acute respiratory syndrome and encephalitis, and it was determined that fruit bats were the source of the outbreak.¹⁵ Deaths occurred in the infected patients as well as in the healthcare workers who took care of the patients. There were four deaths on May 2018. Within a short period of time, there were 10 deaths from Kozhikode district and three from adjoining Malappuram district. About 21 of 23 infected persons succumbed to the infection making mortality rate of 94%. These cases were proved by RT-PCR testing. Genetic testing confirmed NiV as the cause and the strain showed resemblance to the BD strain of NiV.¹⁶ The infection appeared to follow human-to-human transmission as most people who exhibited infection were either members of the family of the infected individuals or caregivers.¹⁷ The outbreak showed that the risk of person-to-person spread is very high. During the outbreak, the condition affected many health care workers even causing death.^18,19

There was a second outbreak in Kerala in June 2019, where an isolated single case of NiV was reported in Ernakulum district. The patient made full recovery.

In 2021, there was a third outbreak in September 2021 in Kozhikode district. A 12-year old boy died of seizure from the NiV infection. Contact tracing did not reveal any positive case.

The fourth outbreak occurred in August-September 2023 in Kozhikode district, and six proven cases have been recognized. Of them two male persons aged 47 years and 39 years succumbed to this infection. Of the six cases, five had contacted the virus from the index case, a 47-year old male. It included a 9-year-old child of the diseased index case. The mortality rate was 33% against the usual case fatality of 70%. The reasons ascribed for successful recovery of the patients were the fast diagnosis and isolation of all included on the contact list of the index patient, and use of antiviral drugs at the correct time. Of 323 samples tested for Nipah, 317 appeared to be negative. The virus strain was a Bangladesh variant that spread from human-to-human with high mortality, but less infectious potential. There is a greater chance for the people living in forest areas to get infected.²⁰

Fruit eating bats are the important source of the infection. They live on trees in close proximity to markets, places of worship, schools and tourist spots. The fruits contaminated with bat saliva can spread the disease.

Aetiology

Nipah virus is a large, pleomorphic, thread-like enveloped paramyxovirus with a non-segmented RNA genome having a helical symmetry. It has a size of 40-1900 nm, and contains a single layer of surface protrusion. It infects host cells via two glycoproteins named G and F proteins. The glycoprotein (G) facilitates the binding to receptors on the host cell surface, while the fusion (F) protein is responsible for merging the virus and cell membranes to enable viral entry into the host cell.⁶

Being a member of the genus Henipavirus, Nipah virus (NiV) has structural similarity with Hendra virus (HeV). There is presence of significant cross reactivity on serological tests between NiV and HeV. But they are not identical and differ in their pathogenenicity and transmissibility.¹⁵ The virus gains entry into the cells by fusing with the cell membrane located on the plasma membrane.

Immunofluorescence antibody assays have not shown any reaction between Nipah virus and other paramyxoviruses such as measles virus, respiratory syncitial virus, parainfluenza viruses, herpes virus, and enteroviruses. The NiV virus can be categorized into two primary clades, each distinguished by their N and G gene sequences. The NiV isolates from Malaysia, Singapore, and Cambodia have formed a distinct group known as the NiV-MY clade. Meanwhile, the isolates from Bangladesh and India have collectively grouped together in the NiV-BD clade.²¹ There is slight difference between the Malaysian and Bangladesh strains.

Transmission

Nipah virus lives among fruit bats belonging to Pteropodidae family and spreads to humans or animals through fruits, food or sap contaminated with bat droppings. CDC stated that transmission of the virus occurs in three ways, such as direct contact with infected animals or their body fluids, consumption of contaminated food products and close contact with infected persons of their fluids.²² Persons infected with Nipah infection appear to be more infectious when they are presenting with symptoms. The spread from person-to-person occurs through respiratory secretions or from cough and sneezes.²³

Caregivers in close proximity, including family members and occasionally healthcare workers face the greatest risk of infection, primarily through contact with the patient's infectious respiratory secretions. The transmission route of the virus from bats to humans in Kerala remains unverified. It is perplexing why Kerala experienced three Nipah virus outbreaks, all concentrated in the Kozhikode district, and one in Ernakulum in 2019.

Pathogenesis

The pathogenesis of Nipah infection is poorly understood. Disease makes a rapid progression affecting the brain and respiratory system. The brain's pathological abnormalities manifest as widespread micro-infarctions caused by a combination of vasculitisinduced thrombosis and direct neuronal impact. These effects are multifocal, with areas of merged lesions found in both the cortex and white matter.²⁴ The clinical manifestations are due to release of cytokines and chemokines that cause vascular damage.

Clinical Features

The clinical features appear after an incubation period of four days to 21 days. The patients present symptoms in the form of acute respiratory infection such as fever, sore throat, muscle ache, fatigue, headache, vomiting and severe sore throat. These symptoms may progress rapidly to encephalitis with features like dizziness, drowsiness or altered consciousness which may progress into severe encephalitis. Respiratory involvement may lead to pneumonia and acute respiratory failure which may progress to acute respiratory distress syndrome (ARDS) in some patients.

In Singapore, two out of eleven patients displayed respiratory symptoms exclusively, while the rest exhibited encephalitis. In India, there is a higher incidence of respiratory involvement, attributed to variations in the viral strains.

In the first outbreak of Nipah in Siliguri, 97% of patients presented with fever followed by development of altered sensorium in next 3 to 4 days. Around 34% of patients demonstrated convulsions. 54% of patients showed respiratory manifestations in the later stages of the disease.²⁵

Sequelae

Majority of patients who survive do not exhibit any sequelae. However, some patients may exhibit neurological deficits, and neuropsychiatric sequelae. They may present with gait or movement abnormalities, and sometimes their encephalitis may be relapsing.

Investigations

The routine investigations demonstrate leucopenia, thrombocytopenia, raised levels of liver enzymes and hyponatremia. Cerebrospinal fluid (CSF) analysis shows raised protein and normal glucose levels, and lymphocytic pleocytosis. MRI study of the brain reveals 2-7 mm multifocal discrete high-signal intensity lesions due to micro-infarction in the subcortical and deep white matter of the cerebral hemispheres. IgM antibodies against NiV may be identified in sera or CSF. Enzyme-linked immunosorbent assay (ELISA test) is useful to detect the presence of antibodies in later stage of the disease and after recovery. During the early stages of infection, virus isolation and reverse transcriptase polymerase chain reaction (RT-PCR) assay from body secretions obtained from throat and nasal swabs, CSF, urine and blood is NiV specific to confirm the diagnosis.

Isolation and propagation of NiV from respiratory secretions may be carried out in Biosafety laboratory (BSL)-4. However, rules have been relaxed allowing hospitals with BSE L-2 level laboratories to perform such tests.

Management

There is no specific therapy and supportive care is sheet anchor in the management. The patients are advised bed rest and hydration. Syndromic management of acute encephalitis syndrome and respiratory failure must be undertaken.²⁶

Ribavirin has been used in the management of Nipah virus infection, though there is no strong evidence of proven therapeutic value. However, the dose is not well established. It is advised to prescribe 2000 mg as loading dose, followed by 1000 mg six-hourly for four days, to be followed by 500 mg six-hourly for six days. When it is given intravenously, the loading dose is 30 mg/kg. It is to be followed by administration of 15 mg/kg every six hours for four days. Then the dose is reduced and 7.5 mg/kg is administered every six hours for another six days.²⁷ The agent is able to cross the blood-brain barrier following oral administration.

The viral RNA-dependent RNA polymerase inhibitor Favipiravir is shown to be effective against Nipah infection.

Monoclonal antibody (M.102.4) has shown to target the receptor binding domain of the Henipavirus G envelope glycoprotein and possess potent cross-reactive neutralizing agent to suppress the virus. These antibodies were used in Australia for Hendra virus infection. Two doses were administered for a patient. These antibodies were administered on compassionate grounds. No one in the country had received it. These laboratory made proteins that mimic the behavior of antibodies produced by the immune systems can be used to protect against disease. They are to be given at an early stage of infection. Monoclonal antibodies are specifically engineered and generated to target a disease.²⁸ These antibodies must be administered before the onset of clinical features. They are unlikely to be useful for treating symptomatic patients, and could probably be beneficial for post-exposure prophylaxis in potentially exposed individuals.²⁹ Ribavirin was successfully used in patients during recent Kerala outbreak.

Prevention

There is currently no vaccine available for disease prevention. The management of Nipah infection primarily hinges on prevention. Key strategies involve implementing measures to safeguard farm animals from contracting NiV by avoiding the consumption of fruits contaminated by bats and refraining from consuming contaminated sap. A suspected Nipah case should be immediately isolated and infection control precautions must be instituted. There is need to contain the infection, and efforts are to be made for contact tracing and to trace the contacts of index patients for isolation. This was effectively carried out during the fourth outbreak of NiV infection which effectively contained the infection from spreading.

Prevention of human-to-human transmission occurs through infection prevention measures. It is important to avoid close, unprotected physical contact with NiV-infected persons. They should avoid contact with the bodily fluids or blood of infected individuals.²⁸ The individuals should regularly wash their hands with soap and water after caring or visiting diseased persons.³⁰ Animal-to-human infections are prevented by avoiding fruits contaminated by fruit bats. Most of the Covid precautions like wearing a mask, washing hands, maintaining proper hygiene, and avoiding contact with an infected person should be followed.

Conflict of interest

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Financial assistance

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