Abstract

Nipah virus is an emerging paramyxovirus in the family Paramyxoviridae that infects humans as well as animals. It was first discovered in Malaysia in 1998 and has since spread across Southeast Asia. There are two strains of Nipah virus: the Malaysian strain (NiV-M) and the Bangladeshi strain (NiV-B) (NiV-B). NiV’s natural hosts are fruit bats of the genus Pteropus (“Flying bat”), which are the main risk factor for Nipah virus disease. Bats of the genus Pteropus are distributed across Asia's tropics and subtropics. Domesticated animals contract NiV after eating contaminated fruit, drinking polluted water or eating aborted bat fetuses or birth products. NiV is transmitted between bats and people through two main routes: intermediate hosts and food-borne transmission via date palm sap contaminated with fruit bat saliva or urine. The condition is extremely deadly, causing severe neurological and respiratory symptoms. A number of immunological and molecular diagnostic techniques have been developed for diagnosis and surveillance of disease. Diagnosis and management become more challenging when a new area is affected. The high mortality rate associated with infection, as well as the risk of infection spreading to other areas, has highlighted the significance of proper care and control of this life threatening zoonosis. For the time being, there is no treatment or vaccine available for Nipah virus infection. Preventing infection in livestock could be a valuable management method in places where they act as intermediate hosts. Humans can avoid contracting Nipah virus disease by avoiding direct contact with infected hosts (fruit bats and pigs) or their secretions.

1. Introduction

Emerging viral diseases have a large influence on communities around the world, generating significant mortality, morbidity, and economic losses. In order to infect humans, these viruses use a variety of tactics, either directly or through adaptation in the reservoir host species ¹. Nipah virus, like the severe acute respiratory syndrome corona virus that debuted in 2003, Ebola virus, and, most recently, SARS-CoV-2 that erupted in Wuhan, China, in late 2019, has been one of several emerging zoonotic virus risks to global health security ^{2, 3, 4, 5}.

Nipah (Nee-pa) virus disease is caused by Nipah virus (NiV), a RNA virus belonging to the family Paramyxoviridae of the genus Henipavirus that is spread by certain kinds of fruit bats, especially Pteropus species ⁶. Because of its considerable morbidity and mortality, as well as the possibility of rapid transmission in domestic animals and indications of zoonotic properties, the virus has been added to the World Organization for Animal Health's list of diseases relevant to international trade. As a result, NiV illness must be reported to the OIE ⁷. The World Health Organization has identified the Nipah virus as one of the most dangerous emerging viruses since 2015, owing to its ability to spread from person to person ⁸.

Nipah virus transmits through direct contact with infected bats, pigs, or other NiV-infected individuals. Nipah virus infection in humans manifests itself in a variety of ways, from asymptomatic infection to acute respiratory syndrome with deadly encephalitis ⁹. Nipah virus infection symptoms in pigs range from no symptoms to a high temperature, difficulty breathing, and neurological problems ¹⁰. There is limited clinical information available for other domestic animals. The case fatality rate in humans varies according on the geographic location of outbreaks, ranging from 40% to 75% ¹¹.

The disease is difficult to diagnose based on clinical signs alone, confirmation can be made through prescribed laboratory techniques. Guidelines for surveillance, diagnosis, case management, prevention and control of Nipah virus disease should be developed so that cases can be detected promptly and further human-to-human transmission can be prevented ¹². Thus, as NiV is one of the deadliest viruses known to infect humans, this review is intended to fill the gap on the current state of knowledge on Nipah virus disease and counter measures on prevention of this emerging zoonotic disease.

2. Nipah virus Disease

Nipah virus is an emerging zoonotic virus that can cause serious disease in both people and animals. It is a paramyxovirus (Henipavirus genus, Paramyxovirinae subfamily, Paramyxoviridae family) ¹³. NiV is a single-stranded RNA virus with an envelope ¹⁴. Nucleocapsid (N), phosphoprotein (P), matrix protein (M), fusion protein (F), glycoprotein (G), and RNA polymerase are the six structural proteins encoded by RNA (L). Along with the viral RNA, the N, P, and L form the ribonucleoprotein complex, an essential complex that regulates viral RNA transcription and synthesis. The attachment and admission into the host cell are controlled by the F and G proteins ¹⁵.

Nipah virus comes in two strains: Malaysian strain (NiV-M) and Bangladeshi strain (NiV-B). The N and G gene sequences are the difference between the two strains ¹⁶. In Bangladesh and Indian epidemics, the virus was confirmed to be NiV-B, whereas outbreaks in Malaysia were proved to be NiV-M ¹⁷. Several variations between the strains have been discovered in clinical reports. In the Malaysian strain, transmission occurs through an intermediary amplifying host (pigs). Pig handling is the most common cause of outbreaks, and cases have shown increased neurological symptoms. Direct transmission by bat-infected sap, increased human-to-human transmission, and respiratory symptoms are more common in the Bangladeshi strain ¹⁶.

Nipah virus can persist for up to 3 days in some fruit juices or mango fruit, and for at least 7 days in artificial date palm sap stored at 22 ⁰C. The virus has an 18-hour half-life in fruit bat urine. NiV is relatively stable in the environment, and it can survive for 1 hour at 70°C. It can be entirely deactivated by heating for more than 15 minutes at 100°C ¹⁸. Soaps, detergents, and many disinfectants, like other paramyxoviruses, quickly inactivate Nipah virus ¹⁹.

Nipah virus was discovered in Malaysia in 1998 following a 9-month outbreak of infectious respiratory and neurologic infection in commercially farmed pigs, possibly transmitted by Malaysian flying foxes. Pigs have been infected with Nipah virus, which has spread swiftly throughout pig herds causing respiratory symptoms in particular. Acute febrile encephalitis was caused by pig-to-human transfer in adult males who worked in the pig industry ²⁰. In total, 276 cases with 106 deaths were reported ²¹. More than one million pigs were killed during NiV disease outbreaks, resulting in an economic loss of between $350 and $400 million ¹³. The epidemic expanded to Singapore after contaminated pigs were exported there ²².

In April 2001, In Bangladesh, a village in the Meherpur district registered the first Nipah virus disease outbreak ¹³. Since the first Meherpur NiV diagnosis in 2001, Bangladesh has had multiple Nipah virus epidemics in humans practically every year ⁹. Ingestion of raw date palm sap contaminated with NiV was the predominant mode of transmission ²³. A total of 261 confirmed cases and 199 deaths were reported, with a 76.2 percent fatality rate ¹.

The first NiV outbreak was recorded in India in 2001 in the area of Siliguri, West Bengal. There were no reports of animals being involved in the spread because it was mostly nosocomial. This outbreak claimed the lives of 45 people out of a total of 66 confirmed victims. In 2007, another Nadia district incident occurred, with all five NiV positive patients dying within ten days of infection ¹³. In 2018, the state of Kerala saw its third NiV outbreak, with 23 NiV positive patients and a 91 percent case fatality rate ²⁴. Fruit bats have been recognized as the source of this outbreak ²⁵. In the Kerala district of Ernakulum, one patient tested positive for NiV in 2019. The Kerala state government's foresight helped to contain the outbreak in 2019 ²⁶.

NiV-specific antibodies were discovered in Cambodian Pteropus lylei (Lyle's flying foxes). Antibodies to NiV were also found by ELISA in serum taken from Pteropus vampyrus bats in Indonesia ¹. The presence of NiV RNA in bat saliva and urine, as well as immunoglobulin G in the serum was discovered in Thailand, showing long-term NiV persistence ²⁷. Serological evidence or molecular detection of the virus in the native reservoir (Pteropus bats species) and several other bat species has been found in China, Ghana, Madagascar, Papua New Guinea, Philippines, and Taiwan. These bats can be found from the east coast of Africa to the Philippines, Pacific islands, and Australia, as well as in South and Southeast Asia. As a human infection, Nipah virus can appear anywhere in these distribution zones ¹².

Fruit bats of the species Pteropus (“Flying bat”) are NiV's natural hosts, and infected bats shed virus in their excretion and secretions, such as saliva, urine, sperm, and excreta, but they are asymptomatic carriers ²⁸. During their seasonal migration, many bat species fly considerable distances. Fruit bats' long-distance flight capability plays an important role in the virus's propagation. When pigs forage in the fruit bat distribution region, they have a high possibility of consuming residues and seeds, and the danger of NiV infection is significant ²⁹.

Ingestion of contaminated fruit, water, or aborted bat fetuses or birth products (e.g., by pigs) is suspected as a method of transmission of NiV to domesticated animals. After consuming saliva-contaminated fruits or fruit buds, pigs become infected with NiV ³⁰. Pigs spread the Nipah virus through aerosols and direct contact because they shed the virus in their respiratory secretions and saliva ¹². Vertical transmission across the placenta, by iatrogenic means and in semen has been suggested but not confirmed ¹⁴.

Epidemiological investigations of NiV epidemics in Malaysia, Singapore, Bangladesh, the Philippines, and India revealed that a variety of factors play a critical role in NiV transmission to humans. Close contact with NiV-infected animals, reservoir animals, and contaminated food consumption are the main causes of NiV transmission ³¹. Hospital workers and those caring for those infected with the virus face a high risk of infection. In Malaysia and Singapore, Nipah virus disease was found in people who had close contact with infected pigs. In Bangladesh and India, the disease has been associated with consumption of contaminated raw date palm sap ³².

Nipah virus is transmitted to humans through two main routes: intermediate hosts and food-borne transmission via date palm sap contaminated with fruit bat saliva or urine ³³. Pigs transmit NiV to humans by sputum, splashing urine, and huge respiratory droplets, which are aided by an infected pig's characteristic barking cough ³⁴. Nipah virus can be shed in respiratory secretions, saliva, and urine, and respiratory secretions are assumed to be the main route of transmission. Direct contact with an infected patient results in human-to-human transmission ³⁵.

Fruit bats, often known as flying foxes, are the principal reservoir hosts, belonging to the genus Pteropus, family Pteropodidae, and order Chiroptera ³⁶. Henipaviruses are found in a wide spectrum of frugivorous and insectivorous bats, not just those belonging to the genus Pteropus ³⁷.

The virus does not appear to induce clinical disease in bats, whether they are infected naturally or artificially ³⁶. Bats of the genus Pteropus can be found all over the world. They can be found in Asia's tropics and subtropics, including the Indian subcontinent, Australia, Indonesia, Madagascar, and some distant oceanic islands in both the Indian and Pacific Oceans ¹⁴.

Pigs serve as amplifiers host. The symptoms of the disease are similar to those of other pig diseases. If the Nipah virus infection in pigs had not happened at the same time as a human disease outbreak, it could have gone undiscovered ³⁸. It has been proven that human encephalitis outbreaks in Malaysia and Singapore, with a 40% case fatality rate, were caused by contact with sick swine. The outbreak in Singapore ceased when the importation of pigs from Malaysia was forbidden, and the outbreak in Malaysia ended when over 1 million pigs (45 percent of all pigs in Malaysia) were culled from the outbreak area and neighboring areas ¹³.

Many domesticated mammals appear to be susceptible to Nipah virus ³⁹. Naturally infected dogs, cats, horses, and goats are not thought to be capable of spreading the virus to humans or other animals ⁴⁰. Nipah virus appears to have affected horses in the Philippines in 2014, based on clinical indications and epidemiological linkages to human patients. However, no tissues from the horses were available for confirmation. Infected cats shed NiV through the nasopharynx and urine during the viremic phase ⁴¹. Guinea pigs, hamsters, ferrets, squirrel monkeys, and African green monkeys have all been infected with NiV experimentally ⁴².

In pigs, the incubation period ranges from four to fourteen days. Signs of NiV in pigs can range from no symptoms to a high temperature, difficult breathing, and neurological symptoms ¹⁰. Sucking piglets can show leg weakness, muscle tremors, and neurological twitches. NiV infection in growing pigs might be asymptomatic or induce a febrile illness with respiratory and CNS symptoms (muscle fasciculation, leg weakness, ataxia, and spastic paresis). A “barking” cough is characteristic respiratory symptom in infected pigs, albeit it may just be laborious to open-mouth breathing ⁴³. In adults, tongue drooping, frothy salivation, head pushing, anxiety, tetanic spasms and convulsions, and pharyngeal muscular paralysis are common neurological indications. A bloody nasal discharge may be seen in dead pigs. Abortions have also been reported during the first trimester of pregnancy ⁴⁴.

In naturally infected goats, unproductive cough, poor growth, severe respiratory signs, febrile neurological syndrome, and deaths were reported. The disease resembled canine distemper in dogs, with fever, respiratory distress, conjunctivitis, and mucopurulent nasal and conjunctival discharges among the clinical signs ⁴¹. Horses suspected of being infected with the Nipah virus in the Philippines either died suddenly with no evident signs or had rapidly showed acute lethal neurological symptoms ⁴⁵. Severe depression, serous nasal discharge, cough, dyspnea, tremors, and hind limb paresis were observed in experimentally infected ferrets. Some experimentally infected hamsters have also shown neurological and/or respiratory symptoms that can be severe ⁴².

The morbidity rate in pigs is estimated to be 70-100% ⁴¹. Mortality is uncommon in NiV-infected sows or boars, though they may die unexpectedly without symptoms or within 24 hours of development of symptoms ¹². Young piglets have the highest mortality rate (up to 40%). In general, mortality in growing pigs is minimal (5%) ³⁴. NiV-M infection resulted in 50% mortality in African green monkeys, but NiV-B infection resulted in 100% mortality in all experimental individuals ⁴⁶.

Nipah virus is a newly discovered zoonotic and very lethal virus that poses a pandemic risk, causing severe febrile infection and significant fatality rates in infected people ⁴⁷. Because humans are already susceptible, there are strains capable of limited person-to-person transmission, NiV has an exceptionally high mutation rate as an RNA virus, and if a human-adapted strain infects communities in South Asia, high population densities and global interconnectedness would quickly spread the disease, the risk of it becoming a global pandemic increases ³².

Nipah virus infection in humans manifests itself in a variety of ways, from asymptomatic infection to acute respiratory illness (mild or severe) and deadly encephalitis ⁸. During the Malaysian outbreak, the incubation period (time between infection and development of symptoms) ranged from 2 to 4 months, whereas it was 10 days in Bangladesh ¹³. In Kerala, the incubation period ranged from 6 to 14 days, with a median of 9.5 days ⁴⁸. Late onset encephalitis can occur months or years after a mild or subclinical infection ⁴⁹.

The signs and symptoms in people are flu-like initially, with fever, headache, sore throat, and myalgia. It is also possible to see nausea, vomiting, and coughing. Drowsiness, disorientation, signs of brainstem dysfunction, convulsions, coma, and other symptoms may accompany encephalitis ⁴¹. Aseptic meningitis, widespread encephalitis, and localized brainstem involvement were among the neurological manifestations. Cerebellar symptoms were fairly common ⁴⁰. In NiV disease, respiratory symptoms are the second most frequent after neurological symptoms. Cough, cold, and dyspnea were the most prevalent respiratory symptoms ¹. Septicemia can develop in conjunction with renal system dysfunction and gastrointestinal hemorrhage ¹⁴.

Although most people who survive acute encephalitis recover completely, survivors have been recognized as having long-term neurological issues. Approximately 20% of individuals experience persistent neurological effects, such as seizure disorder and personality abnormalities ⁸. Late onset or relapse encephalitis, which was deadly in some cases, has been reported anywhere from 4 months and 11 years after the first Nipah virus exposure ⁴⁹.

Human case fatality rates are said to be greater, with rates of around 40% in Malaysia/Singapore and 75% in Bangladesh and India ⁵⁰. During an outbreak of disease in India in the year 2007, a case-fatality rate of 100% was reported ¹³. This rate can vary by epidemic depending on the virus strain, local epidemiological surveillance and clinical care capabilities ⁸.

Nipah virus is diagnosed in enhanced BSL4 facilities in the laboratory. Molecular and serological assays, immune-histochemistry, histopathology, viral isolation, and neutralization are diagnostic tests for the diagnosis of Nipah virus ⁵¹.

Nipah antigens, as well as IgM and IgG antibodies produced against NiV antigens, can be detected directly using serological tests ⁵². Anti-NiV IgM detection in serum peaks after 9 days of sickness (based on hospital admission) and can last up to 3 months. IgG tests are mostly utilized for epidemiological investigations and surveillance because IgG can continue long after convalescence; detection of anti-NiV IgG peaks after 17 days of sickness and can last for more than 8 months. Gold-standard sero-neutralisation assays using live NiV are typically used to confirm NiV infection, which necessitates a high-containment BSL-4 facility ⁵³.

The most sensitive approach for diagnosing active NiV infection is polymerase chain reaction (PCR) ⁸. Nipah virus reverse transcriptase polymerase chain reaction (RT-PCR) experiments have focused on the conserved N, M, and P genomic segments. There have been several types of PCR assays developed for NiV, including conventional RT-PCR, nested RT-PCR, and real-time RT-PCR (also known as quantitative PCR or qPCR). Real-time PCR has been proved to be 1000 times more sensitive than traditional PCR, and it is currently virtually exclusively utilized in research ³⁶. In fatal cases, histopathology (immune histochemistry) is performed to confirm NiV diagnosis after death ⁵¹.

There is currently no treatment for Nipah virus infection. In humans, the primary treatment is on symptom management, such as fever and neurological symptoms, by giving intense supportive care ³². Supportive therapy, including as hydration and ventilator support, are critical components of NiV case care ¹⁷. Because physical human-to-human contact is the largest risk factor for infection transmission, greater vigilance is required in the treatment of these patients ⁵⁴.

Although no licensed therapeutic interventions for NiV disease exist, antiviral treatment appears to be the obvious choice. Ribavirin and acyclovir were two drugs used during earlier NiV outbreaks in Malaysia and Singapore ⁵⁵. Ribavirin, which is effective against other paramyxoviruses, has mixed results when used to treat infected patients in Malaysia ⁵⁶. In the absence of a successful antiviral, the CDC recommends the use of oral or parenteral Ribavirin for all confirmed cases ⁵⁷. Favipiravir, a medication registered in Japan for the treatment of influenza, was proven to be effective in a hamster model ⁵⁸.

In preclinical investigations, monoclonal antibodies were employed to treat patients ⁴². An in vivo investigation using completely humanized monoclonal antibody m102.4 against NiV in a nonhuman monkey model revealed that a possible medicine for NiV disease treatment is available in the future ⁵⁹. In 2018, the World Health Organization added Nipah virus infections to its list of priority diseases for investment in diagnostics, prevention, and therapies ⁸.

In areas where livestock act as intermediate hosts, preventing infection in livestock could be a useful technique. It entails maintaining fruit trees and bat roosting trees away from livestock farms and grazing pastures that are vulnerable to virus contamination. In certain areas, such as Malaysia, such initiatives have already shown to be quite effective. Wire screens can help to avoid bat contact when pigs are reared in open-sided pig sheds. Nipah virus sickness can be averted by avoiding contact with sick pigs and bats in endemic areas. Early detection of infected pigs can help in the protection of other animals as well as people. Mass culling of seropositive animals may be necessary because of high contagious nature of the virus in swine populations ⁴².

Humans can avoid Nipah virus disease by avoiding direct contact with infected host organisms (fruit bats and pigs) or their secretions, as well as avoiding intake of tainted food contaminated by saliva or bat dropping. Fruits and other items from trees that host fruit bats should be thoroughly checked and cleansed before consumption ¹. During the year 2012-2014, the main strategy for preventing the disease in Bangladesh was to raise public knowledge about the dangers of drinking raw sap and to keep sap collection pots clean ⁶⁰.

Disease control practices, such as isolation of patients, frequent hand washing, 70 percent ethanol sanitization, and avoidance of direct contact with body fluids like urine, saliva, and blood should be practiced as standard operating procedures in order to prevent person-to-person transmission ¹. Contacts found through contact tracing are tested and monitored until they come back negative ³⁵.

All proposed NiV vaccines are now at the pre-clinical stage, with animal models being used to assess their efficacy ⁶¹. Despite encouraging findings and the ongoing threat posed by NiV, no vaccine candidate for pigs or humans has made it to the market ⁶². The new Coalition for Epidemic Preparedness Innovations (CEPI) has identified Nipah virus as one of three viruses (together with Lassa virus and Middle East respiratory syndrome corona virus (MERS-CoV)) that will be prioritized for vaccine development in 2017 ⁶³.

Nipah virus looks to be the most hazardous agent, and its spread into non-endemic areas is still a possibility, especially given the presence of NiV-susceptible animal species ⁴⁷. It is not impossible that the virus may be introduced and spread by insectivorous bats, domestic pigs, or other wild animals like wild boars or mustelids, and then spread across the human population via person-to-person transmission ¹⁴. Monitoring the epidemiology of a dangerous pathogen such as Nipah virus is an important element to be able to rapidly adapt control plans in the case that it might become a new public health priority ¹².

3. Conclusion and Reccomendations

Nipah Virus (NiV) disease and its current state as a potential pandemic infection of humans worldwide are the subjects of this review study. Before twenty years, NiV disease had emerged as a lethal zoonotic disease. Bats are the virus's natural reservoir host. Despite numerous warnings over the last two decades, NiV outbreaks have resulted in numerous deaths and morbidities in humans and animals. The disease is difficult to identify due to its acute nature and the dearth of readily available low-cost diagnostic procedures and facilities prepared to handle viral samples. There is no effective treatment or prophylaxis available. The avoidance of this disease is crucial due to its pandemic potential, and this condition may be exacerbated by virus mutation as infection spreads and progresses in the human population. Early discovery of the outbreak and the implementation of preventive measures as soon as feasible are critical to managing the outbreak and lowering fatalities. To completely understand how and when bats excrete the virus, strong inter-institutional and international coordination among human-animal virologists, as well as virologists and ecologists, is required. Simultaneously there is also a need for educating the common people about personal and food hygiene. Based on the above conclusion, the following recommendations are forwarded;

• The disease's knowledge and awareness should be improved and disseminated to health care professionals, veterinarians, farmers, and consumers.

• It is critical to create effective treatment and prophylaxis for both humans and animals.

• Strengthening the current and developing new capacities among health stakeholders in all nations is required so that they can better comprehend the human, animal, and environmental health aspects of zoonotic and other diseases.

• More research on the molecular epidemiology, mechanisms of transmission, and potential prevention and control techniques, as well as a greater understanding of bat ecology, is needed.

Acknowledgements

The authors are very thankful to Prof. Dr. R.K. Narayan for his suggestions during the preparation of manuscript and Anubha Priyabandhu for computer help. This paper is dedicated to the scientists who made important contribution in the field of viral zoonoses.

Contribution of Authors

All the authors contributed equally. They read the final version, and approved it for the publication.

Conflict of Interest

The authors declare that they do not have conflict of interest.

Source of Financial Grant

There was no financial support for this manuscript.

References