Nipah Virus Outbreaks: Still Small but Extremely Lethal

(See the major Article by Arunkumar et al on pages 1867–78). In May 2018, 23 cases of Nipah virus (NiV) infection were identified in Kozhikode District, Kerala State, India. The case-fatality rate reached 91%, with 21 individuals dying and only 2 surviving. While the outbreak lasted for <1 month, it created fear and panic in the local community, as well as nationally and internationally, even overshadowing the concurrent Ebola virus outbreak in the Equateur Province of the Democratic Republic of the Congo in the global news [1]. Early diagnosis and application of infection prevention and control measures were the main factors that quickly brought the Kerala NiV outbreak under control. NiV is a single-stranded, negative-sense RNA virus belonging to the family Paramyxoviridae [2]. NiV was first detected in Malaysia, during 1998–1999, where it caused severe febrile encephalitis and was initially misidentified as Japanese encephalitis virus. During that initial outbreak, 283 human cases of acute encephalitis were diagnosed (mainly in farmers), with 109 deaths. Direct contact with pigs was a risk factor, as pigs were identified as the intermediate host of NiV [3]. Subsequent ecological studies showed that the pigs acquired the infection from fruit bats commonly referred to as flying foxes (Pteropus species), which turned out to be the natural reservoir of the virus [4]. Outbreak control in Malaysia focused on the mass culling of 2 million pigs, in an attempt to halt what was popularly named as the “Plague of the Orient.” Following these draconian measures, the number of reported human cases sharply decreased, and the outbreak was contained. Since that first outbreak, no other outbreaks of NiV disease have been detected in Malaysia. However, 2 years later, NiV was detected in both Bangladesh and India [5, 6]. Since 2001, sporadic outbreaks have occurred in Bangladesh almost every year, mainly detected retrospectively by the established countrywide encephalitis surveillance program. NiV encephalitis is still a rare disease, involving <5% of the total number of reported encephalitis cases investigated in Bangladesh [7]. Sequence analyses of the viral genomes from the Malaysian and Bangladesh/India outbreaks showed that NiV separates into 2 distinct lineages/genotypes: Nipah-Malaysia (NiV-M) and Nipah-Bangladesh (NiV-B) [8]. In addition to differences in genetics and geographic distribution, the viral lineages differ in several other important ways. First, while infected pigs acted as the intermediate host for NiV-M, no intermediate host has been identified for NiV-B. In contrast to NiV-M, the primary source of NiV-B human infections is the consumption of raw date palm sap contaminated by virus shed by infected fruit bats. Human-to-human transmission was not clearly observed during the NiV-M outbreak but was well documented in a number of NiV-B outbreaks. In addition, case-fatality rates for NiV-B outbreaks have been much higher (range, 60%–100%) than those caused by NiV-M (39%). However, differences in mortality rates may be attributable to differences in healthcare support in the different countries and the fact that Bangladeshi outbreaks are usually identified retrospectively [9]. Finally, in addition to the encephalitic symptoms seen during NiV-M infection, acute respiratory distress symptoms are also seen in cases of NiV-B infection. In this issue of The Journal of Infectious Diseases, Arunkumar et al report on the initial investigation of the NiV outbreak in Kerala, India. The article systematically details each step of the outbreak response, describing the case definition, disease symptoms, clinical management, early laboratory diagnosis of NiV, and complete NiV genome sequencing. It also reports on a well-documented line of human-to-human transmission of NiV-B. The index patient was responsible for the infection of 19 close contacts during his hospitalization; secondary transmission was reported only for 3 cases. Although the transmission was mainly nosocomial, only 2 infected individuals were healthcare workers, reflecting the common tradition in many Indian hospitals of close relatives, rather than healthcare personnel, providing immediate care for patients during their hospital stay. Based on extensive interviews and review of hospital closed-circuit television footage, the investigators concluded that the virus was transmitted via droplets generated by coughing. This is in contrast to previous reports, in which direct contact (eg, with dead bodies or bodily fluids) was reported to be sufficient for the transmission of the virus. Laboratory aspects of the investigation included rapid diagnosis, complete virus genome sequencing from clinical materials, and isolation of the virus, all of which were performed quickly. Analysis showed that the NiV causing the outbreak in Kerala was 97% identical to previous NiV-B isolates. These early results were critical for confirming the appropriate use of the existing NiV molecular diagnostic tools. Clinical features of NiV disease include acute respiratory distress and severe encephalitic symptoms, including seizures, convulsions, and coma. The onset of disease is very abrupt, and the course of the severe phase is very brief, as is very well documented by Arunkumar et al. These characteristics make treating patients very challenging. The high case-fatality rate for NiV-B had been attributed to the poor healthcare support in rural areas in comparison to the Malaysia outbreak. However, here Arunkumar et al raise concerns that the current NiV-B strain was highly lethal (case-fatality rate, 91%) despite a well-functioning healthcare system. The treatment of patients with NiV infection is dependent on supportive care. While promising experimental treatments exist for NiV infection, particularly the use of monoclonal antibody m102.4, the speed with which this outbreak was brought under control precluded the approval of such treatment for these patients [10]. Could NiV be the next Ebola virus? NiV is certainly a pathogen of concern, given its extreme lethality in humans and lack of therapeutic agents. However, NiV appears to be much less efficiently transmitted from human to human than Ebola virus. Not only are initial person-to-person NiV transmission events less common, but transmission chains are also much shorter (2–4 rounds of transmission). The capacity for NiV to sustain lengthy human-to-human transmission chains could change in the future, however, considering the respiratory mode of NiV-B transmission through droplets, suggested in this article, and the high mutation rate associated with the replication of RNA viruses in general. Is the presence of NiV infection in southern India worrisome? Two NiV outbreaks that had occurred in India earlier were confined to the area bordering Bangladesh. Thus, the geographic leap to Kerala is of concern. Fortunately, this outbreak occurred in an area in which the healthcare system is relatively sound, and the surveillance for encephalitis is strongly supported by outstanding academic and public health institutes. In addition, molecular and serological diagnostic tools for NiV were already in place, facilitating rapid identification and response. The Indian government and partners worldwide quickly came together to help contain the outbreak. Administration of a therapeutic intervention (monoclonal antibody m102.4) was considered but did not materialize because of the short time span of the outbreak itself. At a recent meeting in New Delhi, during 6–8 August 2018, partners from each country affected by NiV and experts from the international community came together to prioritize the needs in preparation for the next NiV outbreak, which could possibly arise this winter in Bangladesh. Issues that were discussed included active surveillance, the need for developing a point-of-care diagnostic assay, production of a substantial quantity of the therapeutic agent m102.4, and establishment of prepositioned clinical therapeutic protocols. The World Health Organization has identified NiV as one of the top 7 priority pathogens with outbreak potential. The Coalition for Epidemic Preparedness Innovation also included NiV, together with Lassa virus and Middle East respiratory syndrome virus, on its priority pathogens list and has recently awarded grants for NiV vaccine development. These proactive efforts, along with close collaboration with the international public health institutions and early dissemination of information, as seen in the response described by Arunkumar et al, will help us to be prepared for the next NiV outbreak wherever and whenever it may happen. Disclaimer. The views expressed in this article are those of the author and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Potential conflicts of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.