Nipah, Hendra, and other henipaviruses

INTRODUCTION — Nipah and Hendra viruses are two related zoonotic pathogens that have emerged in the Asia-Pacific region. Both are RNA viruses belonging to the Paramyxoviridae family and grouped under the genus Henipavirus, since they share antigenic, serological, and ultrastructural characteristics and differ from other paramyxoviruses [1-4]. Another virus in the genus is the non-pathogenic Cedar virus [5]. A phylogenetically distinct henipavirus, named Langya henipavirus (LayV), was identified in 2019.

Nipah virus first caused an outbreak in pigs and humans in Malaysia and Singapore between 1998 and 1999 and has caused recurrent human outbreaks in Bangladesh and West Bengal, India since 2001 and in Kerala, India since 2018 [6-14]. Outbreaks have also occurred in the Philippines in 2014 and Kerala, India in 2018 [14,15]. Hendra virus infections affecting horses and humans have occurred in Australia since 1994 [16-19].

NIPAH VIRUS

Epidemiology of Nipah virus infection — Nipah virus was initially discovered when it caused an outbreak of viral encephalitis among pig farmers in Malaysia. The virus was named after a village in Malaysia, where the infected patient lived. Since then, there have been several outbreaks of acute Nipah encephalitis in various districts in Bangladesh, in the neighboring district of Siliguri in India, and in the Southern Philippines [13,15,20]. In May 2018, an outbreak was reported in India's Kerala state [14,21].

The outbreak in Malaysia was initially thought to be Japanese encephalitis (JE), which is endemic in Asia. However, certain features were not consistent with this diagnosis: the occurrence of encephalitis among adults rather than children, the clustering of cases in the same household, and a history of illness in pigs belonging to the affected farmers [7,9]. Furthermore, a high number of patients had been vaccinated against JE [7,9]. (See "Arthropod-borne encephalitides", section on 'Japanese encephalitis virus'.)

Animal reservoirs — The primary animal reservoirs of henipaviruses are bats of the genus Pteropus [22-27]. Antibodies against Nipah antigens were found in bats from Malaysia and Bangladesh, and the virus was isolated from urine of bats of the species Pteropus hypomelanus roosting in the East Coast of Malaysia [10,22,26]. In Bangladesh and India, the virus was found in Pteropus medius [28]. Serologic evidence of Nipah virus infection has been found in 23 species of bats from 10 genera in regions such as Yunan and Hainan Island in China, Cambodia, Thailand, India, Madagascar, and Ghana in West Africa [27]. Serologic evidence of henipa-like virus infection has also been found in bats in Brazil, suggesting potential host reservoirs in the western hemisphere [29].

Other animals can be intermediate hosts for the virus. As an example, in the Malaysian outbreak, these were pigs [7,9]. Unlike in JE, Nipah-infected pigs had clinical disease manifested by neurologic and respiratory symptoms [30,31]. The mode of transmission between pigs was probably through direct contact with infected fluids such as urine, saliva, pharyngeal and bronchial secretions. Domestic animals such as cats and dogs were also shown to have a positive serology for Nipah virus [9]. In the Philippines outbreak, horses were thought to be the intermediate hosts [15]. (See 'Individual outbreaks' below.)

Transmission to humans

Modes of transmission — Human infection results from spillover transmission from bats or through human-to-human transmission. Measures to prevent transmission are discussed below. (See 'Treatment and prevention of Nipah virus infection' below.)

Spillover transmission from bats can occur via two mechanisms, either through direct bat-to-human transmission (eg, contact with bats or their secretions, consumption of raw date palm sap [tari] contaminated by bat saliva) or through indirect transmission from bats through an intermediate animal host (see 'Animal reservoirs' above). The risk of spillover transmissions appears to be related to environmental factors (eg, transmission is more likely to occur in cooler years) [32].

Human-to-human transmission appears to be impacted by the strain of virus and, as a result, the severity of disease manifestations [33,34]. As an example, the increased rate of human-to-human transmission demonstrated in Bangladesh may have occurred, in part, due to the increased severity of respiratory infection that was seen in those outbreaks [33,35,36]. In a study that evaluated 248 cases of Nipah virus infection in Bangladesh between 2001 and 2014, one-third were suspected to have acquired the infection via person-to-person transmission [36]. Twenty-two patients (9 percent) transmitted Nipah virus, and those who had difficulty breathing infected more contacts than those who did not (relative infectivity 23, 95% CI 4.1-130). Patients who were ≥45 years of age were also more likely to transmit infection. Among contacts, the risk of transmission increased with duration of exposure (adjusted odds ratio [AOR] for exposure >48 versus ≤1 hour, 13; 95% CI 2.6-62) and exposure to body fluids (AOR 4.3; 95% CI 1.6-11). A more detailed discussion of the individual outbreaks is found below. (See 'Individual outbreaks' below.)

Individual outbreaks — Several outbreaks of Nipah virus infection illustrate how infection occurs both via animal and person-to-person transmission. (See 'Modes of transmission' above.)

In the 1998 to 1999 Malaysian outbreak, human infection occurred through contact with respiratory secretions and urine from an intermediate animal host, infected pigs. Case-control studies showed that Nipah-infected persons were more likely than controls to have had direct contact with pigs [37,38]. Other affected patients were those who had occupational contact, including abattoir workers and pork sellers [37-40]. In a study of military personnel involved in pig culling during the outbreak, 6 of the 1412 personnel (0.4 percent) studied had detectable antibody against Nipah virus [40]. All six had IgM antibodies and one person also had IgG antibodies. Two of the six had clinical encephalitis. There was also evidence that Nipah virus may have been transmitted from person to person. As an example, a nurse in the Malaysian outbreak who had cared for Nipah virus-infected patients was found to be seropositive and have MRI findings typical of Nipah encephalitis, despite the fact that she had no exposure to infected animals [41].

In Bangladesh and India, Nipah virus infection resulted from bat-to-human transmission and, subsequently, human-to-human transmission. After an initial report of Nipah virus infection in 2001, recurrent outbreaks occurred almost annually [42,43]. Unlike the Malaysian outbreaks, no clusters of ill animals were reported, and a case-control study found that there was no increased risk of Nipah virus infection among individuals who had contact with a potential intermediate host (such as a pig) [10,12,44]. It was subsequently found that Nipah infection resulted from direct contact with bats or their secretions [44] or consumption of raw date palm sap (tari) contaminated by bat saliva [45], and human-to-human transmission [46,47]. In February of 2023, 10 of the 11 cases that occurred during an outbreak in Bangladesh were linked to date palm sap [48].

Human-to-human transmission was also important in the 2004 outbreak in Bangladesh, in which 33 of 36 reported cases had a history of close contact with another infected patient prior to the onset of illness [46]. Among patients with Nipah virus infection secondary to exposure from an infected patient, the median incubation period was nine days (range, 6 to 11 days) [20].

In the 2014 Philippine outbreak, there was evidence of horse-to-human and human-to-human transmission. Ten of 17 patients (59 percent) had either been involved in slaughtering horses or consuming infected horse meat, while most of the others, including two healthcare workers, helped care for patients [15].

In an outbreak that occurred in India's Kerala state from May to June 2018, 23 patients were infected [14]. The index case was infected in the community (presumably via a bat), and the remaining cases resulted from person-to-person nosocomial transmission, which occurred in the three different hospitals. This outbreak was subsequently followed by individual sporadic cases in 2019 and 2021 [49,50].

Pathology — In patients with Nipah virus encephalitis, the main pathology appears to be widespread ischemia and infarction caused by vasculitis-induced thrombosis, although direct neuronal invasion may also play a major role. Findings in the brains of patients with Nipah encephalitis have included necrotizing vasculitis and syncytial formation [19,51]. Eosinophilic cytoplasmic and nuclear viral inclusions were detected in many neurons adjacent to vasculitic vessels, a finding which may be present in infections caused by other paramyxoviruses.

In relapsed Nipah virus encephalitis, the pathology was confined to the central nervous system with extensive and confluent parenchymal necrosis, edema, and inflammation, but without vasculitis, endothelial syncytia, and thrombosis [51,52]. The presence of viral inclusions supported recurrent infection rather than a post-infectious encephalitis [51].

Clinical features of Nipah virus infection

Signs and symptoms — Nipah virus primarily causes an encephalitic and/or respiratory syndrome with a high mortality rate. The mortality rate was approximately 30 to 40 percent in Malaysia [9] and greater than 70 percent in Bangladesh [20]. During the outbreak in Kerala, India in 2018, 23 cases were identified, and only two patients survived (case fatality rate of 91 percent) [14]. However, a few patients may remain asymptomatic [37].

The incubation period ranges from 7 to 40 days. The initial presentation is nonspecific, characterized by the sudden onset of fever, headache, myalgia, nausea and vomiting. Meningismus is seen in approximately one-third of patients, but marked nuchal rigidity and photophobia are uncommon. Respiratory symptoms including cough and dyspnea and abnormal chest radiographs were also seen in patients in the Kerala and Bangladesh outbreaks [10-12,14,21,53]. In Kerala, myocardial involvement (as evidenced by electrocardiogram changes), left ventricular hypokinesia, and elevated troponin I levels were also reported [21].

In approximately 60 percent of patients, the disease rapidly progresses, with deterioration in consciousness leading to coma within five to seven days. Generalized seizures occur in approximately 20 percent of patients. Other neurologic findings associated with Nipah encephalitis include: segmental myoclonus (involving predominantly the diaphragm, upper limb and neck musculature), cerebellar dysfunction, tremors, and areflexia. Brainstem involvement, characterized by pinpoint, unreactive pupils, abnormal Doll's eye reflex, tachycardia and hypertension, occurs in the more severe cases and portends a poorer prognosis [9].

Some patients had relapsing encephalitis presenting as recurrent episodes of neurological dysfunction. In addition, a few patients who were initially asymptomatic, or who had mild non-encephalitic illness initially, developed late onset neurological disease [52]. These patients presented with fever, headache, seizures and focal neurological signs. Mortality was 18 percent. MRI scans showed large patchy, confluent lesions that differed from the initial findings [52,54]. There was some similarity to a fatal case of Hendra viral encephalitis (see below) [18].

Long-term follow-up of survivors showed that persistent fatigue and daytime somnolence were common disabling symptoms [55,56]. Functional neurologic impairment was also common.

Laboratory findings — The laboratory abnormalities in Nipah encephalitis are also nonspecific. Leukocyte counts are usually normal but moderate thrombocytopenia can occur. The liver transaminases were elevated in the mild-to-moderate range, but clinical jaundice was not a feature of the illness.

Abnormalities of the cerebrospinal fluid (CSF) were observed in the majority of cases. Most had an increased white blood cell count (range 10 to 800 cells/mm3), with lymphocyte predominance, and an elevated protein concentration (range 50 to 250 mg/dL). The CSF glucose concentration was normal, and red blood cells were not usually present. These findings are in keeping with the CSF abnormalities seen in most other viral encephalitides. (See "Viral encephalitis in adults".)

Neuroimaging — Magnetic resonance imaging (MRI) is a useful tool in the diagnosis of Nipah encephalitis [54,57] although it does not distinguish this form of encephalitis from other viral encephalitides. The characteristic MRI abnormalities are multiple, small (less than 5 mm), asymmetric focal lesions in the subcortical and deep white matter without surrounding edema. These lesions most probably represent areas of micro-infarction that have also been observed on histopathology. There is no correlation between MRI findings and focal neurological signs.

Electroencephalogram — The electroencephalogram (EEG) shows continuous diffuse slow waves with or without periodic bitemporal independent sharp wave discharges.

Diagnosis of Nipah virus infection — A definitive diagnosis of Nipah virus infection involves demonstrating the presence of virus in body fluids (eg, throat and nasal swabs, tissue samples, urine, blood and cerebrospinal fluid). However, virus isolation is not routinely done since Nipah virus is classified as a biosafety level 4 agent. Thus, other methods, such as polymerase chain reaction (PCR) or serology are more commonly employed.

With regards to serologic testing, the diagnosis of Nipah virus infection can be established by enzyme-linked immunoassay (ELISA). An IgM capture ELISA and an indirect IgG ELISA have high specificity for the diagnosis [58]. Typically, the IgM ELISA is the first line serological diagnostic test, which is then followed by confirmatory testing via detection of serum neutralizing antibodies against Nipah virus in the patient’s serum [58]. The use of neutralizing antibodies requires biosafety level 4 laboratory containment facilities; however, the use of neutralization assays based on noninfectious pseudotyped viruses bearing Nipah virus glycoproteins may be a way to avoid the need for live viruses [15,59,60].

Treatment and prevention of Nipah virus infection — Supportive care is the mainstay of treatment, and infected patients may require intensive care monitoring. Mechanical ventilation for airway protection should be initiated with the onset of neurologic deterioration.

No antiviral therapies have been proven to be effective for Nipah virus infection. There has been some interest in the nucleoside analogue ribavirin. Although ribavirin was found to be ineffective in animal models [61,62], small studies in humans suggest there may be some benefit. In one report, 140 patients treated with ribavirin during the Malaysian outbreak were compared with 54 patients who did not receive ribavirin, and fewer treated patients died (32 versus 54 percent) [63]. In a case series of 12 patients from Kerala, two of the six patients who received ribavirin survived, whereas the six untreated patients all had fatal outcomes, although this difference was not statistically significant [21]. Until more data are available, the role of ribavirin for the treatment of Nipah virus infection remains unclear.

Prevention efforts include educating at-risk populations about transmission of infection [64]. As examples:

●To reduce the risk of bat-to-human transmission, individuals should be advised to avoid raw palm sap that could be contaminated, although this can be difficult and requires sensitivity to local customs and beliefs [65].

●Individuals should wear gloves and other protective clothing while handling sick animals or their tissues and avoiding close unprotected physical contact with patients who have Nipah virus infection.

●Health care workers who care for patients with suspected or confirmed infection, or handle their specimens, should implement standard infection control precautions, as well as contact and droplet precautions. (See "Infection prevention: Precautions for preventing transmission of infection".)

Investigational approaches to preventing Nipah virus infection include vaccination and the use of monoclonal antibodies. A phase 1 dose-escalation study of an mRNA-1215 Nipah virus vaccine is underway to evaluate its safety, tolerability, and ability to generate an immune response in 40 healthy adults ages 18 to 60 years [66]. In a phase 1 clinical trial of the human monoclonal antibody (m102.4) no significant adverse side-effects were reported [67]. This agent was also administered as a compassionate-use therapy in 14 patients who had a high-risk henipavirus exposure, and none of the patients developed treatment-related adverse events or disease [67-69].

HENDRA VIRUS — In September of 1994, an outbreak of acute, severe respiratory illness resulting in the death of 14 of 21 affected horses occurred in Queensland, Australia. Two humans, a trainer and a stable hand with close contact to these sick horses became ill and the trainer died [16,17]. The virus isolated from the horses' infected tissues was named Hendra after the Brisbane suburb where the outbreak occurred. Most of the equine cases have been reported in Queensland and Northern New South Wales. One equine case was reported in the Hunter Valley of New South Wales, but no human cases were reported [70].

Epidemiology of Hendra virus infection — Hendra virus primarily infects horses. Human infection results from direct contact with infected horses. Animal–to-animal transmission has been demonstrated in dogs who had close contact with infected horses [71,72]. No human-to-human transmission has been documented [73].

Similar to Nipah virus, the natural host of Hendra virus is believed to be fruit bats of the Pteropus species, four of which have been demonstrated to have serologic evidence of infection with this virus [74]. The virus has also been isolated from fetal tissue and uterine fluids of these bats [75]. Although the virus appears to be widespread in the bat population, there is no clinical evidence of infection or seroconversion among bat caregivers, despite close contact with these mammals [76]. The mode of transmission of the virus from the natural hosts to the infected horses in the outbreak is unclear and the focus of reducing future henipavirus infections is to identify factors that will trigger a spillover infection from bats to livestock and humans [77].

Clinical features of Hendra virus infection — Since Hendra virus was recognized, there have been about 100 infections in horses, and seven human infections with four fatalities [77,78]. The initial two patients had an acute influenza-like illness with fever and respiratory symptoms [16]. The third patient had a mild meningoencephalitis after nursing two ill horses that subsequently died [18]. After apparent full recovery, the farmer developed seizures, coma and died. Both the patient and the horses' tissues were seropositive for Hendra. MRI brain imaging showed focal high signal cortical lesions on T2 weighted sequences while the EEG showed persistent periodic epileptiform discharges [18].

Diagnosis of Hendra virus infection — The diagnosis can be confirmed by ELISA or serum neutralization tests [17]. Specific, reliable polymerase chain reaction methods are also available [79,80].

Post mortem examination of one patient described above with respiratory illness showed severe interstitial pneumonia. In the fatal case with neurologic involvement, there were areas of focal necrosis with multinucleated endothelial cells. Viral antigen were demonstrated on immunohistochemistry [16,18].

Treatment and prevention of Hendra virus infection — Supportive care is the mainstay of treatment and infected patients may require intensive care monitoring. Similar to Nipah virus, ribavirin has not been found to be effective in animal models of Hendra virus [81]. (See 'Treatment and prevention of Nipah virus infection' above.)

A vaccine based on the G glycoprotein of Hendra virus for horses has been approved for use in Australia [82,83]. Since its introduction in 2012, more than 120,000 horses have been vaccinated without any confirmed infections [68].

LANGYA HENIPAVIRUS — A phylogenetically distinct henipavirus, named Langya henipavirus (LayV), was identified in China in 2019. One report identified 35 patients with acute LayV infection between 2019 to 2021 [84]. In this report, patients presented with fever, fatigue, cough, anorexia, myalgia, nausea, headache, and vomiting. Laboratory abnormalities included thrombocytopenia, leukopenia, and abnormal liver and kidney function. Infection was felt to occur through animal exposure; among wild animals, this virus was predominantly detected in shrews. There was no evidence of human-to-human transmission.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infectious encephalitis".)

SUMMARY AND RECOMMENDATIONS

●Virology – Nipah and Hendra viruses are two related zoonotic pathogens that have emerged in the Asia-Pacific region. Both are RNA viruses that belong to the Paramyxoviridae family. A phylogenetically distinct henipavirus, named Langya henipavirus (LayV), was identified in China in 2019. (See 'Introduction' above.)

●Epidemiology

•Nipah virus – Human infection from Nipah virus results from spillover transmission from bats or through human-to-human transmission. Transmission from bats can occur either through direct bat-to-human transmission or through indirect transmission from bats through an intermediate animal host (eg, pigs or horses). (See 'Epidemiology of Nipah virus infection' above.)

•Epidemiology of Hendra virus – Human infection with Hendra virus results from direct contact with infected horses. Patients have presented with fever and influenza-like illnesses or with meningoencephalitis. (See 'Epidemiology of Hendra virus infection' above and 'Clinical features of Hendra virus infection' above.)

●Clinical features – Nipah virus primarily causes an encephalitic syndrome with a high mortality rate. The characteristic MRI abnormalities are multiple, small (less than 5 mm), asymmetric focal lesions in the subcortical and deep white matter without surrounding edema. Respiratory symptoms and abnormal chest radiographs can also be seen. (See 'Clinical features of Nipah virus infection' above.)

Patients with Hendra virus have presented with an acute influenza-like illness with fever and respiratory symptoms, as well as mild meningoencephalitis. Those with Langya henipavirus generally present with fever, fatigue, cough, anorexia, myalgia, nausea, headache, and vomiting. (See 'Clinical features of Hendra virus infection' above and 'Langya henipavirus' above.)

●Diagnosis – The diagnosis of Nipah and Hendra virus is generally established using methods such as polymerase chain reaction (PCR) testing or serologic testing using an enzyme-linked immunoassay (ELISA). (See 'Diagnosis of Nipah virus infection' above and 'Diagnosis of Hendra virus infection' above.)

●Treatment and prevention – For patients with henipavirus infection, supportive care is the mainstay of treatment; in addition, some patients may require intensive care monitoring.

For Nipah virus, prevention efforts include educating at-risk populations about ways to reduce transmission of infection, mRNA vaccines and monoclonal antibodies are also being evaluated. An effective Hendra vaccine is available for horses. (See 'Treatment and prevention of Nipah virus infection' above and 'Treatment and prevention of Hendra virus infection' above.)