Nipah virus: Preventing the next outbreak

Abstract

Nipah is a deadly viral infection which has come to the news highlight recently, due to its fresh onslaught in Southern India. As the world continues to recover from coronavirus disease 2019, the World Health Organization has identified a list of high-priority pathogens with the potential to cause future pandemics. Among them is the Nipah virus (NiV), which poses a significant threat. Even a small outbreak could trigger widespread panic among the public. The emergence and re-emergence of NiV among other zoonotic infections is a stern reminder of the importance of One health concept.

Key Words: Encephalitis; Pandemic potential; Re-emergence; One health; Zoonosis

Core Tip: Nipah is a bat borne, zoonotic virus that is notorious to cause serious human outbreaks. The recent coronavirus disease 2019 (COVID-19) pandemic has shed light on the One Health approach and is a stark reminder of the indolent threat of emerging and re-emerging zoonotic infections. Lessons learned from the global COVID-19 pandemic can be applied to managing infections limited to regional outbreaks, such as Nipah, to help prevent recurrent re-emergences. Further studies on Nipah virus, disease development, diagnostic modalities, and treatment options, are need of the hour.

INTRODUCTION

Emerging and re-emerging zoonotic infections have been threatening human race since time immemorial[1]. Several of these outbreaks have high pandemic potentials. In 2014, the center of disease control (CDC) and prevention defined high-consequence pathogens as microorganisms which cause high mortality but have infrequent spillover from animals, and human to-human transmission is rare[2]. Common high-consequence pathogens like coronavirus, ebolaviruses, henipaviruses and monkeypox virus have challenged this understanding; re-emerged; spread rapidly and killed millions of people[3-5]. United States National Institutes of Health guidelines for managing risky pathogens categorized SARS and MERS in the risk 3 category group, while Nipah virus (NiV) is classified in the risk 4 group[6]. NiV has also been classified as a possible bio- and agroterrorism pathogen. Till date large NiV outbreaks has not been reported. This could probably be attributed to rapid containment initiatives or perhaps because of the virus’s intrinsic inability for mass transmission in a population[7,8]. Similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), NiV has also originated from bats, with cross-species transmission occurring via various intermediate hosts such as pangolins, rats, civets and camels[9,10]. While NiV may currently seem like a regionally confined infection with a low probability of becoming a global threat, the same was true of the coronavirus before it brought the world to a standstill, struggling to overcome its impact. The ability of NiV to spread to patient caregivers has raised concern that the virus might adapt to more efficient human-to-human transmission.

NiV: THE INCITANT

NiV is an RNA virus of genus Henipavirus, family Paramyxoviridae. It has a non-segmented negative-stranded RNA genome which consists of helical nucleocapsids enclosed inside an envelope. NiV like HEV has a genome larger than other paramyxoviruses. The RNA codes for 6 structural protein and 3 non-structural proteins. The structural proteins are nucleocapsid protein (N), phosphoprotein (P), the matrix protein (M), fusion protein (F), glycoprotein (G), large protein or RNA polymerase (L). The 3 non-structural proteins are C, V, W all of which are coded by the phosphoprotein gene. The genome has the arrangement of 3′-N-P-M-F-G-L-5′[5,11,12].

Two strains of NiV have been reported till now, namely, Bangladesh (NiV_B) and Malaysia (NiV_M). Compared to NiV_M, NiV_B strain shows human to human transmission as well as a higher mortality rate, thus making it more pathogenic[12].

Global warming and biodiversity loss over the years have led to emergence and re-emergence of infectious agents over the last two decades. Figure 1 illustrates deforestation, urbanization and the subsequent human invasion of natural animal habitat. The disturbed habitats favor opportunistic species to flourish, and transmission events occur.

Figure 1 Anthropogenic factors promoting zoonotic spillover. The menace of zoonotic spillover is result of consortium of factors which determine the interplay of ecological dynamics of infection in reservoir hosts, its’ transmission, and exposure among susceptible host. The geographical distribution of reservoir hosts, its propensity for human interaction, human behavior towards the reservoir and viral load carried by it are factors determining the possible site of attack. Host immunity and health status in conjunction with the viral load and virulence of the pathogen decide the probability and severity of infection.

Genetic factors also contribute to the zoonotic spillovers, as most of the causative viruses are RNA viruses, including SARS, NiV, influenza and SARS-CoV-2[11-13]. These RNA viruses have exceptionally short generation times without proof reading mechanism and faster mutation rates, which increases the probability of causing infection in new host species. Furthermore, since these viruses mutate so frequently, it is difficult to predict time of emergence of the next strain of NiV within the next 5 years or later[14,15].

PATHOGENESIS

NiV enters the human body through the oro-nasal route. There are various speculations about its early replication site, as most of the investigations on human tissues have been done only in the later stage of the disease. Although, high antigen load in lymphoid and pulmonary tissues makes them likely site of early replication. NiV glycoprotein G interacts with the receptor Ephrin-B2 or Ephrin-B3, highly expressed on the endothelium and smooth muscle cells of the brain, placenta, lungs, prostate and arteries in other organs as shown in Figure 2. Ephrin-B2 has a significant role in the migration of neuron precursors during embryogenesis explaining the clinical and pathological aspects of NiV infection[16]. The receptor Ephrin B2 shows about 96% similarities between bats and pigs. This extensive distribution among various animal species corroborates the wide host range of NiV[17]. The central nervous system may be either infected by NiV through hematogenous route or direct invasion via olfactory nerves. The high fatality rate of NiV is because it evades the innate immune response[18].

Figure 2 Pathogenesis of Nipah virus. The Nipah virus (1) may enter the human body through oral or nasal route (2). From these sites it reaches the blood stream (3) and gets carried away to brain either by crossing the blood brain barrier or through the olfactory nerve. While in the blood stream it may cause generalized septicemia (4). So the secondary infections (5) can occour in organs with epinephrin b2/b3 receptors i.e. brain, blood vessels and smooth muscles. Inflammatory cytokine come into play like IL-6, IL-8, TNF-α. BBB: Blood brain barrier; IL: Interleukin; TNF-α: Tumor necrosis factor-alpha; G-CSF: Granulocyte colony-stimulating factor.

NiV survives up to three days in fruits and around seven days in artificial date palm sap. The main reservoir host of NiV are fruit bats or flying foxes of genus Pteropus, family Pteropodidae. Virus spillover is based on various factors related to disease ecology from infective stages in the reservoir host, genetic constitution of the virus to population dynamics of the affected host. It has been observed that a bat shedding NiV infects only one or a few people, the amplification and divergent spread is initiated by infected individuals who spread the virus through person-to-person transmission leading to outbreaks[19-22]. The interventions required to curtail NiV infection include preventing farm animals from eating fruit contaminated by bats. Farm designs to minimize overcrowding to control the infection from spreading at rapid rate between animals. Culling of infected animals followed by disposal by deep burial with quick lime, along with other control measures has been found to stop the chain of transmission[23].

THE OUTBREAK SERIES

NiV infection was first reported in Kampung Sungai Nipah, Malaysia, in 1998. The Malaysian government in collaboration with the CDC reported around 258 cases with a case fatality rate of almost 40%. Mass culling of more than a million pigs in the outbreak areas, led to control of the epidemic and finally the ordeal was over in May 1999. The next blow came very shortly in Bangladesh (2001), and also in Siliguri, West Bengal, India. Around 65 people were infected, out of which 45 patients died. The origin of infection was pigs in Malaysia and presumptively bats, in India[24,25]. From thereupon there has been no stopping for NiV, frequent fatal outbreaks have been documented mostly form South and South-East Asia.

In India, after the first outbreak in Siliguri, second occurred in Nadia district of West Bengal which was a minor one with 5 cases in 2007 but the case fatality was 100%. Both these districts are at the border of the Nipah belt in Bangladesh. However, the outbreak of 2018 occurred in Kerala (Kozhikode and Malappuram) which is a southern state on the west coast, geographically distant to previously affected areas and date palm sap intake is not widespread there. Since then, Kerala has become an endemic site with the latest outbreak in Kozhikode district (2023) being the sixth incident in the state. The outbreak was contained with vigorous public health measures with 6 cases and 2 fatalities[26-28].

The index case in the 2001 outbreak remained undetected in Siliguri but it infected 11 patients, 25 employees and eight visitors. In 2007, the index case started with a person consuming date palm-derived alcohol later infecting a healthcare professional caring for him. In 2018 epidemic, there was a case of NiV in a 12-year-old boy in Kerala, which was hypothesized to have eaten infected tropical fruit, rambutan. In the same episode, healthcare practitioners got infected with the virus while caring for the boy[26,27].

EPIDEMIOLOGY OF NIV AS COMPARED TO CORONAVIRUS DISEASE 2019

NiV, being less widespread as compared to coronavirus disease 2019 (COVID-19), still poses a significant threat to cause a pandemic due to its high mortality rate, infrequently sprouting outbreaks, and practically no treatment or vaccines as depicted in Table 1. When compared to SARS-CoV-2, NiV infection has a high fatality rate, which ranges from 40% to 75%, depending upon the level of outbreak and the robustness of healthcare system of the affected areas. The severity of the infection and its clinical complications including severe respiratory and neurological symptoms are far worse for NiV. Like COVID-19, NiV is also a zoonotic infection, meaning it can be transmitted from animals to humans. Fruit bats are the main reservoir of NiV, like the speculated theory for zoonotic spill of COVID-19. NiV can also be transmitted from person to person, especially in healthcare setting or through close contact with infected people. Unlike COVID-19, which is highly transmissible through respiratory droplets, the transmission of NiV among humans is less efficient but still is a significant risk, especially during outbreaks. Currently, there are no approved vaccines or specific antiviral treatments for the NiV infection. While supportive care can manage symptoms, there is an urgent need for the development of vaccines and antiviral drugs to combat NiV. Although there are quite a few COVID vaccines, time will tell whether they actually worked, or they were detrimental to human health in long term scenario. Various treatment strategies were tried during the pandemic some of which added to the complication and mortality. Lastly, NiV outbreaks have occurred sporadically in several countries, including Malaysia, Bangladesh, India, and Singapore. The potential for outbreaks, combined with globalization and increased travel, is concerning for the global spread of the virus. NiV infections can be devastating for global public health, economies, and healthcare systems.

Table 1 Comparative analysis of Nipah and coronavirus disease 2019.

Features	Nipah virus disease	COVID-19
Agent	Nipah virus	SARS-CoV-2
Transmission	Fruit bats to humans, eating contaminated fruit or juice, date palm, fluids from infected animals like pigs, dogs, horses, cats. Few cases of person-to-person transmission	Origin speculated to be from bats or pangolins. Further transmission through respiratory droplets or airborne
Human-to-human transmission	Limited, but can occur through close contact with an infected person	Efficient
Incubation period	4 to 14 days	2 to 14 days
Symptoms	Fever, headache, muscle aches, sore throat, dizziness, nausea, vomiting, acute respiratory syndrome, encephalitis and in severe cases, coma, or death	Fever, dry cough, fatigue, shortness of breath, body aches, loss of taste or smell, sore throat, headache, chills, congestion or runny nose, nausea or vomiting, diarrhea
Severity	Variable, ranging from asymptomatic or mild illness to severe respiratory or neurological symptoms	Variable, ranging from asymptomatic or mild illness to severe pneumonia and acute respiratory distress syndrome
Case fatality rate	40% to 75%	Generally lower, estimated around 1%-3%
Vaccination	No specific vaccine available	Vaccines available
Treatment	Supportive care to relieve symptoms and prevent complications; no specific antiviral drugs available	Supportive care, oxygen therapy, antiviral drugs like Remdesivir, and in severe cases, corticosteroids and immunomodulators
Preventive measures	Avoiding exposure to sick pigs or bats, avoiding consuming raw date palm sap, culling of infected animals and decontamination of their remains, standard precautions	Vaccination, standard precautions, quarantine, and isolation measures
Global impact	Outbreaks, mainly in Southeast Asia	Recent pandemic

COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.

In 2019, a conference of researchers conducted in Singapore analysed the outbreaks and the recent epidemiologic data, vaccines and management strategies for NiV[5]. The deliberations also pondered upon the fact that NiV could become an agent responsible for the next pandemic while in the backdrop COVID-19 pandemic still brewing. Many previous studies have also indicated that NiV has the potential to cause a pandemic or epidemic[13,28]. In a recent publication, Moore et al highlighted the significant global threat posed by the Nipah virus and other henipaviruses. The authors emphasized the urgency of addressing this issue and supported the World Health Organization’s advanced draft proposal for developing medical countermeasures against the Nipah virus. They underscored the critical need for an internationally coordinated effort to accelerate the development of rapid point-of-care diagnostic tests, as well as affordable vaccines and therapeutics, to combat Nipah virus and related pathogens[29].

CONCLUSION

NiV outbreaks have mostly been confined to Indo-Bangladesh region till now but the chronicles of emerging infectious diseases have shown such infections to find newer hotspots as part of their evolution. The origins of such infections are substantially associated with socio-economic and geographical factors with increased global travel being the driving force of further dissemination. The NiV outbreaks in India shifting from western parts to the southern India is an austere reminder of the possibility of spill over episodes to sites where risk variables were hitherto unknown. The strategies of prevention and management apprehended from the global COVID disaster should become the rule book to follow for further such infections. One Health approach is required for comprehending the transmission risk and preventing NiV from becoming the next disease of global concern.