Nipah Virus and its Outbreaks in Tropical Areas

Shiv Kumar Kushawaha¹, Neelam Raj¹, Manish Sinha¹*, Puneet Kumar², Mahendra Singh Ashawat¹

¹Laureate Institute of Pharmacy, Kathog, Distt. Kangra, H.P. 176031.

²Department of Pharmaceutical Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda (India), 151001

*Corresponding Author E-mail: manish.pharm2000@gmail.com

ABSTRACT:

Nipah virus is an emerging zoonosis with the potential to cause significant morbidity and mortality in humans. This virus escaped obscurity as a nameless animal virus and assured a place for itself in the annals of history as most fatal virus by killing a large number of people and bringing down billion dollar swine industry in Malaysia within shorts span of time. Nipah virus is an enveloped negative-strand RNA paramyxovirus. The natural reservoir for this virus is ‘flying fox’ fruit bats. The virus caused an outbreak of severe febrile encephalitis in humans with a high mortality rate. Nipah virus provides one of the most striking examples of an emerging virus and illustrates many of the pathways leading from a wildlife reservoir to human infections. This review will provides the background of the emergence of Nipah virus, symptoms, pathogenesis &pathology, prevention, control, and treatment.

KEYWORDS: Nipah, Zoonosis, Flying Fox’, Encephalitis, Mortality Rate.

INTRODUCTION:

Nipah is a viral zoonotic disease of wide occurrence. The name Nipah virus was proposed because the first isolate was made from clinical material from a fatal human case from Kampung Sungai Nipah, a village in Negeri Sembilan.^[1] Today, the mortality rate of Nipah lies in between 40% to 100% for both humans and animals. Thus, NiV is one of the most deadly virus known to infect the humans and animal.^[2,3] The large percentage of casualty occurs in the tropical regions especially Asia, including the Indian subcontinent, Australia, Indonesia, Madagascar, and a number of remote oceanic islands in both the Indian and Pacific oceans where the absolute burden of these diseases is up to 130 times greater than in developed countries. Despite numerous control measures, it continues to be uninterrupted with high morbidity and mortality in these areas.^[4] 20 years of nipah infection and the death ratio has been summarized in figure 1. Recently, this fatal virus emerged in India.

India has a fast-growing human population which causing increased animal-human interactions, combined with changing environmental conditions and inadequate sanitation have made India one of the world’s top hotspots for livestock diseases. Due to loss of habitat and food availability, bats have driven toward human-populated areas. Similarly, encroachment by farmers into bat habitats creates exposure to these emerging pathogens. Bats have been recognized to be an important reservoir of zoonotic viruses, including Ebola, Marburg, SARS and Melaka viruses.^[5,6,7,8,9]

Figure 1: 20 Years of Nipah Virus and Human Interactions

Classification:

NiV is the second member of the genus Henipavirus in the family Paramyxoviridae. The prototype virus of the genus is the closely related Hendra virus (HeV), discovered during an investigation of the 1994 lethal disease outbreak in horses and humans in Australia.

While initially considered a potentially new member of the genus Morbillivirus, hence tentatively named Equine Morbilli virus (EMV)^[10] subsequent whole genome analysis revealed several major molecular signatures of HeV which were not shared by any of the known morbilli viruses. 

Further analysis of the NiV genome sequence consolidated the notion that HeV and NiV are novel paramyxoviruses that did not fit into any of the existing genera in the family and there was a need to generate a new genus to accommodate the classification of these novel viruses.^[11] In 2002, the International Committee for Virus Taxonmy (ICTV) approved the establishment of the new genus Henipavirus.  

The Malaysian strain of NiV (NiV-MY) is slightly different from that of Bangladesh (NiV-BD). The outbreak in the Philippines was most likely caused by a NiV-MY strain.

Morphology:

Similar to other paramyxovirus, NiV particles are pleomorphic, varying from spherical to filamentous ranging in size from 40-1,900 nm.  They contain a single layer of surface projections with an average length of 17±1 nm. [12]

Genetic diversity:

Among the NiV known to cause disease in humans, there are two major genetic lineages, i.e., NiV Malaysia (NiV-MY) and NiV Bangladesh (NiV-BD).   

Epidemiology:

Nipah virus is an enveloped negative-strand RNA paramyxovirus (genus, Henipavirus; family, paramyxovirus) It is first appeared in Malaysia and Singapore in1998–1999 when it caused disease in humans andpigs.^[13] More than 250 people were affected with more than 100 deaths.^[14] The subsequent outbreaks in Bangladesh from 2001 to 2004,^[15] and neighboring West Bengal, in India (2001) showed that the virus is spreading very fast.

Species Susceptible to NiV:

Most of the species such as humans, pigs, bats, dogs, cats, goats, and horses are sensible to NiV infection.^[16,17] NiV infection has been reported also in sheep.^[18]

Natural Host:

The natural reservoir for Nipah virus is ‘flying fox’fruit bats (genus Pteropus).^[19] Specially the Indian Flying Fox (Pteropusgiganteus, wingspan 1.5 m and up to 1.2 kg) and the relatively smaller Greater short-nosed fruit bat or Short-nosed Indian fruit bat (Cynopterus sphinx, wingspan 48 cm) are the common species in South Asia that have been identified as the main natural reservoir.^[20]

Outbreaks:

Focal outbreaks of Nipah virus are of common occurrence mainly in forest-fringed villages. Nipah virus was first recognized in 1998 during an outbreak among pig farmers in Malaysia. Since then, there are many outbreaks in all over the South Asian region. The chronology of outbreaks due to Nipah virus is given in (Table 1).^[21,22] The Nipah virus infection has become endemic in Bangladesh, causing regularly outbreaks, especially in districts where date palm are cultivated. Thus, Bangladesh is a known asa hyper-endemic area.

Table1: Chronology of outbreaks due to Nipah virus (1998-2018)

Year	Country	State/ District	Cases	Death	Case fatality
1998-1999	Malaysia	Perak, Selangor, Negeri Sembilan states	265	105	40%
1999	Singapore	Singapore	11	1	9%
2001	India	Siliguri district, West Bengal	66	49	74%
2001	Bangladesh	Meherpur district	13	9	69%
2003	Bangladesh	Naogaon district	12	8	67%
2004	Bangladesh	Faridpur and Rajbari districts	67	50	75%
2005	Bangladesh	Tangaildstrict	12	11	92%
2007	Bangladesh	Thakurgaon, Naoga and Kushtia districts	18	9	50%
2007	India	Nadia district, West Bengal	5	5	100%
2008	Bangladesh	Manikgonj, Rajbari and Faridpur district	11	9	82%
2009	Bangladesh	Rajbari, Gaibandha, Rangpur and Nilphamari districts	4	1	25%
2010	Bangladesh	Faridpur, Rajbari, Gopalganj and Madaripur districts	16	14	88%
2011	Bangladesh	Lalmonirhat, Dinajpur, Comilla, Nilphamari and Rangpur districts	44	40	91%
2012	Bangladesh	Joypurhat Rajshahi, Natore, Rajbari and Gopalganj districts	12	10	83%
2013	Bangladesh	Gaibandha, Jhinaidaha, Kurigram, Kushtia, Magura, Manikgonj, Mymenshingh, Naogaon, Natore, Nilphamari, Pabna, Rajbari and Rajshahi districts	24	21	87%
Jan-Feb 2015	Bangladesh	Nilphamari, Ponchoghor, Faridpur, Magura, Naugaon, Rajbari	9	6	67%
2018	India	Kozhikode, Mallapuram, Kerala	14	12	86%

Virus emergence:

It is impossible to ascertain retrospectively the definitive vents and factors that lead to its emergence, especially when the outbreak due to this novel virus was only realized nearly a year after its initial introduction into the swine population. However, available data and evidence suggest that a complex interplay of multiple factors lead to the spillage of the virus from its natural reservoir host into the domestic pig population with subsequent spread to humans.^[23]

When the flying fox habitat is destroyed by over human activity the bats get stressed due to unavailbility of foodthis leads to physiologicalalteration andtheir immune system gets weaker. This results in an increase in their viralload resulted invirus spillage in urine and saliva.^[24] Similar fluctuation of virus shedding may be associated with seasons.

In a nutshell, over the last two decades, the forest habitat of these fruitbats (flying-foxes) in Southeast Asia has been substantially reduced by deforestation for pulpwood and industrial plantation.^[25] In 1997/1998, slash-and-burn deforestation leads to the formation of a severe smog that covered much of Southeast Asia. The simultaneous outbreak of Nipah virus in this region may correlates these two incidents.^[26] This series of events lead to an acute reduction in the availability of flowering and fruiting forest trees for foraging by flying-foxes in their already shrinking wildlife habitat.^[27] This culminated in an unprecedented encroachment of flying-foxes into cultivated fruit orchards in the initial outbreak area in the suburb of Ipoh.

The disease outbreak is also linked with the domestic animals, in literature, it is reported that anthropogenic event is coupled with the location of piggeries in orchards. Further, the design of pigsties in the index farms allowed transmission of a novel paramyxovirus from its reservoir host to the domestic pig and ultimately to the human population and other domestic animals.^[28]

Sources of Virus:

Literature shows that Nipah virus has been present in urine and uterine fluids of wild pteropid bats and experimentally it is isolated from urine, kidney, and uterus of infected bats.^[28] When bat feeds on fruit the virus survives long enough in the fruit and its juice (e.g. unpasteurized date palm sap) to infect contacted humans. Further, more the contaminated drinking water and aborted bat fetuses or other body fluids or tissues of parturition are the other source of infection. Infected pigs shed Nipah virus in respiratory secretions, saliva, and urine. Role of other animals as a source of virus in outbreaks is less clear though the virus has been isolated from feline respiratory secretions, urine, placenta and embryonic fluids.^[28]

The mode of transmission:

The NiV is highly contagious among pigs, spread by coughing. Infected bats shed the virus in their secretion and excretion such as saliva, urine, semen, and excreta but they are symptomless carriers. Literature reports say that direct contact with infected pigs was identified as the predominant mode of transmission in humans when it was first recognized in a large outbreak in Malaysia in 1999.^[29] Ninety percent of the infected people in the 1998 & 1999 outbreaks were pig farmers, or had contact with pigs. Figure 2 is showing the mode of virus transmission.

There were focal outbreaks of NiV in India and Bangladesh in 2001 during winter. Drinking of fresh date palm sap, possibly contaminated by fruit bats (P. giganteus) and indirect transmission of Nipah virus to humans may have been responsible during the winter season.^[30]

It is evidenced that the human-to-human transmission occurs in India in 2001 during the outbreak in Siliguri. There were 33 health workers and hospital visitors fell ill after exposure to patients hospitalized with Nipah virus which is indicating towards nosocomial infection.^[31]

During the Bangladesh outbreak, the virus was transmitted either directly or indirectly from infected bats to humans. Strong evidence indicative of human-to-human transmission of NiV in Bangladesh in 2004.^[32]

Figure 2. Mode of virus transmission

Signs and Symptoms:

The illness begins with following symptoms and sign (Table 2) after an incubation period in Human: 4 to 18 days.^[33-37]

Table 2. Symptoms and Signs of Nipah Infection

Symptoms	Signs
Fever	Reduced consciousness
Drowsiness	Seizure, Cranial nerve palsy, Meningitis, Encephalitis
Headache	Nystagmus
Disorientation/confusion	Gastrointestinal Bleeding
Giddiness	Renal Impairment Hypertension
Myalgia	Tachycardia
Cough/ Respiratory symptoms	Irregular slow wave
Convulsion	Thrombocytopenia and Leucopenia.
Vomiting	Coma

Pathogenesis:

When human comes in contact with respiratory secretion from pig or human, bat excreta, contaminated date juice the virus invades the primary immune system and the virus resided in the endothelial cells or in neuronal cells. The endothelial cells and neurons had anamazingly high viral load, which is evidenced by immune staining of Nipah virus antigens. The histopathological study revealsthat endothelial and neuronal cells are consistent sites for the virus replication.^[38,39] Widespread vasculitis is the crucial event in the pathogenesis of Nipah virus infection, seems to be a consequence of infection of the vascular endothelial and smooth muscle cells (Fig. 3). Overall, the frequency of vasculitis seemed to be proportional to necrosis and necrotic plaques, particularly in the CNS and lung. The necrotic plaques and the acute encephalitis syndrome may stem from both direct neuronal infection and ischemic injury. This sequence of pathological events is supported by the concomitant increase in the frequency of syncytia, vasculitis, thrombosis, necrotic plaques, and viral antigen in the CNS.^40-43

Figure 3. Systematic progression of virus in various tissues

Laboratory diagnosis:

Nipah virus infections in humans and animals are confirmed by virus isolation, nucleic acid amplification tests. Serology, Histopathology, PCR and Virus Isolation are the main test for the diagnostic process.^[44]

Nipah virus infection can be diagnosed by a number of different tests. Since Nipah is kept in the category of a bio-safety level 4 (BSL4) agents. So during the handling of Nipah samples, we need to take some special precaution for the collection, submission, and processing of these samples in the laboratory.^[44] Various strategies have been developed to reduce the risk of contamination in the laboratory, which includes gamma-irradiation sera or sera dilution and heat-inactivation. Henipavirus antigens derived from tissue culture for use in ELISA can be irradiated with 6-kilo Greys prior to use, with negligible effect on antigen titer.^[45]

Serum neutralization (SN) test is designated as the reference standard for anti-henipavirus antibody detection.^[45] Cultures are read at 3 days, and those sera that completely block development of CPE are designated as positive. An immune plaque assay is an option in case of cytotoxicity. Indirect or capture enzyme-linked immune-sorbent assay (ELISA) can be applied on for detection of IgG and IgM, respectively. Due to false-positives related to the specificity of ELISA, positive reactions have to be confirmed by SN.^[45] Real-time RT-PCR and Duplex nested RT-PCR which can be confirmed by sequencing of amplified products.^[46,47]

Bio-safety Issues of Nipah Virus:

For those who have to work in the field or on farms where Nipah infection is suspected, personal protection, such as masks, goggles, gloves, gowns, and boots, is advocated together with  hand-washing and disinfection of equipment.^[48,49]  With its high virulence, animal–to- human, and human- to –human spread, significant morbidity and mortality, resultant fear and panic and tremendous economic losses caused, it fulfils some criteria to be considered a potential agent for bioterrorism.^[50,51] and is thus listed as a  Category C  agent on a list of Bioterrorism Agents by Centres of Disease Control^[52]  and any  handling has to be done in BSL-4 facilities. 

Prevention and control:

Nipah Virus can be prevented by taking the following measures:

· Avoid close (unprotected) physical contact with infected people

· Wear NH95-grade and higher masks

· Wash hands regularly with soap

· Avoid consuming partly eaten fruits or unpasteurized fruit juices

· Avoid being around animal pens

· Boil freshly collected date palm juice before consuming

· Thoroughly wash and peel fruits before consuming

· Maintain your and children's personal hygiene

· Cover your household properly

Treatment:

There are no approved or licensed therapeutics for treating Nipah virus infection or disease in people, and antiviral approaches against the Nipah virus that have been tested in animal models are few.^[53] Figure 4 is showing the target sites of drugs used at different levels of pathogenesis of disease. Ribavirin may alleviate the symptoms of nausea, vomiting, and convulsions. Ribavirin exhibits antiviral activity against a wide variety of both RNA and some DNA viruses^[54] and is an accepted or approved treatment for several viral infections including respiratory syncytial virus and arenaviral hemorrhagic-fevers.^[55] In vitro studies have shown that ribavirin is effective against Nipah virus replication.^[56] In literature reported that cholorquine was shown to inhibit Nipah virus infection in cell culture.^[57] Intensive supportive care with treatment of symptoms is the main approach to managing the infection in people. Airway protection should be initiated with the onset of neurologic decline. Severely ill individuals need to be hospitalized and may require the use of a ventilator. Antithrombotic agents have been used based on pathologic findings of ischemia and infarction.

Figure 4. The target sites of drugs used at different levels of pathogenesis of disease.

A passive immunotherapy for people:

In contrast, passive immunotherapy with polyclonal or monoclonal antibody specific for the viral envelope glycoproteins has proved successful from initial proof-of-concept findings from several studies carried out in hamsters ^[58,59].

Presently, the only reported and effective post-exposure therapy against Hendra or Nipah virus infection and one that could likely be approved in the near future for use in people has been a human monoclonal antibody (mAb) known as m102.4 which was isolated from a recombinant naïve human phage-displayed Fab library ^[60].

The m102.4 mAb has exceptionally potent neutralizing activity against both Nipah and Hendra viruses and its epitope maps to the ephrin receptor binding site. Testing of m102.4 has confirmed its neutralization activity against several isolates; NiV Malaysia, HeV-1994, HeV-Redlands, NiV-Bangladesh^[61]. Effective post-exposure efficacy with m102.4 has now been demonstrated in both ferrets and nonhuman primates (African green monkey (AGM)) infected with either Hendra virus or Nipah virus.

Vaccination:

Initial immunization strategies using the Nipah virus G or F viral glycoproteins were first evaluated using recombinant vaccinia viruses providing evidence that complete protection from disease was achievable by eliciting an immune response to the Nipah virus envelope glycoproteins.^[62]

Some of the studies shown that recombinant canarypox-based vaccine candidates for potential use in pigs is under study.^[63]

HeV-sG subunit immunogen as a successful vaccine against lethal Nipah virus challenge on cat^[64,65] and ferret ^[66] is also under the study.

Experimentally, the therapeutic use of a neutralizing human monoclonal antibody, which recognizes the receptor binding domain of the NiV G glycoproteins, appeared promising in a ferret animal model.^[67]

CONCLUSION:

The other zoonotic infections, good surveillance and culling the infected animal population may be the most cost-effective and rapid measure for controlling the spread of the disease. In addition, with a better understanding of wild animal reservoirs and reasons for its spilling over to domestic animals and subsequently to human hosts, necessary measures can be taken to prevent the re-emergence of the virus. A simpler, more sensitive and specific laboratory test for rapid diagnosis will support the surveillance. Moreover the molecular mechanisms that how the virus is passed from one species to other species are still fairly unknown and a hurdle for the development of proper therapeutic agents. This RNA virus has a high mutation rate which enables it to escape from both host immune systems and to develop a vaccines. Until the development of proper therapeutic break through, the main strategy should be to prevent NiV in humans is by establishing appropriate surveillance. Fortunately, a new international coalition of governments and pharmaceutical companies called the Coalition for Epidemic Preparedness Innovations (CEPI) was formed in January 2017 to develop safe, effective and affordable vaccines for diseases with pandemic potential, such as NiV.

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Received on 11.05.2019           Modified on 10.06.2019

Accepted on 09.08.2019         © RJPT All right reserved

Research J. Pharm. and Tech. 2020; 13(1): 491-497.

DOI: 10.5958/0974-360X.2020.00095.5