# 8.5.7 Nipah and Hendra virus encephalitides 784 # 8.5.7 Nipah and Hendra virus encephalitides 784 784 section 8  Infectious diseases is assumed to be necessary if the virus is to be eradicated. Current vaccines do not meet these standards except when two doses have been given in national campaigns. New recombinant vaccines al- though successful in macaques have yet to be tried in humans; al- ternative routes of administration of the live vaccine given either as drops intranasally or by aerosol to the lung have proved less immunogenic than subcutaneous injection. The future programme to eradicate measles infection will face a more general challenge: should the number of doses of mea- sles vaccine and campaigns be reduced and should the vaccine be phased out once eradication has been reached? With the fear of bioterrorism, it is unlikely that all immunization will be stopped in the posteradication era; maybe an inactivated vaccine will be used instead of the live vaccine as is happing in the polio eradica- tion programme. But more important there is growing evidence, as recognized by WHO, that measles vaccine has beneficial non-​ specific effects in reducing lower respiratory infections in both low-​ and high-​income settings. Thus, there clearly is a risk that stopping live measles vaccination or reducing the number of doses administered in childhood would also reduce these bene- fits. Hence, eradication of measles infection and removal of the measles vaccine could lead to increases in morbidity and mor- tality with other pathogens. FURTHER READING Aaby P, et al. (1983). Measles mortality, state of nutrition, and family structure. A  community study from Guinea-​Bissau. J Infect Dis, 147, 693–​701. Aaby P, et al. (1995). Non-​specific beneficial effects of measles immun- ization:  analysis of mortality studies from developing countries. BMJ, 311, 481–​5. Aaby P, et al. (1996). No long-​term excess mortality after measles in- fection: a community study from Senegal. Am J Epidemiol, 143, 1035–​41. Aaby P, et al. (2003). Differences in female-​male mortality after high-​ titre measles vaccine and association with subsequent vaccination with diphtheria—​tetanus-​pertussis and inactivated poliovirus: re-​ analysis of West African studies. Lancet, 361, 2183–​88. Aaby P, et al. (2010). Non-​specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised con- trolled trial. BMJ, 341, c6495. de Quadros CA, et al. (1996). Measles elimination in the Americas. Evolving strategies. JAMA, 275, 224–​9. de Vries RD, et  al. (2015). Morbillivirus infections. Viruses, 7, 699–​706. Fenner F (1948). The pathogenesis of the acute exanthems: an inter- pretation based on experimental investigations with mouse-​pox (infectious ectromelia of mice). Lancet, 2, 915–​20. Fowlkes A, et al. (2011). Persistence of vaccine-​induced measles anti- body beyond age of 12 months: a comparison of response to one and two doses of Edmonston–​Zagreb measles vaccine among HIV-​infected and uninfected children in Malawi. J Infect Dis, 204, S149–​57. Garly ML, et al. (2006). Prophylactic antibiotics to prevent pneumonia and other complications after measles: community based random- ized double blind placebo controlled trial in Guinea-​Bissau. BMJ, 333, 1245–​50. Griffen DE (2010). Measles virus-​induced suppression of immune responses. Immunol Rev, 236, 176–​89. Jaye A, et al. (1998). Ex vivo analysis of cytotoxic T lymphocytes to measles antigens during infection and after vaccination in Gambian children. J Clin Invest, 102, 1969–​77. Laksono BM, et al. (2016). Measles virus host invasion and patho- genesis. Viruses, 8, 210–23. Mina MJ, et al. (2015). Long term measles-​induced immunomodu­ lation increases overall childhood infectious disease mortality. Science, 348, 694–​9. Morens DM, et  al. (2011). Global Rinderpest eradication:  les- sons learned and why humans should celebrate too. J Infect Dis, 201, 502–​5. Morley D (1969). Severe measles in the tropics. Br Med J, 1, 363–​5. Moss WJ (2017). Measles. Lancet, 390, 2490–502. Muscat M (2011). Who gets measles in Europe? J Infect Dis, 204, S353–​5. Samb B, et al. (1997). Decline in measles case fatality ratio after intro- duction of measles immunization in rural Senegal. Am J Epidemiol, 145, 51–​7. Strebel PM, et al. (2011). A world without measles. J Infect Dis, 204, S1–​3. Whittle HC, et al. (1979). Severe ulcerative herpes of mouth and eye following measles. Trans R Soc Trop Med Hyg, 73, 66–​9. Whittle HC, et al. (1999). Effect of sub-​clinical infection on maintaining immunity against measles in vaccinated children in West Africa. Lancet, 353, 98–​101. 8.5.7  Nipah and Hendra virus encephalitides C.T. Tan ESSENTIALS Nipah and Hendra are two related viruses of the Paramyxoviridae family that have their reservoir in large Pteropus fruit bats. Human disease manifests most often as acute encephalitis, which can be late-​onset or relapsing, or pneumonia, with high mortality. Transmission from bats to human includes direct spread from consumption of food contaminated by infected bat secretions, and contact with infected animals; human-​to-​human spread can also occur. Introduction Nipah and Hendra viruses are two new zoonotic viruses that have emerged in recent years. Both are Paramyxoviridae family sharing many similar characteristics. Because of their homology, a new genus called Henipavirus (Hendra + Nipah) was created for these two viruses. 8.5.7  Nipah and Hendra virus encephalitides 785 Hendra virus infection Hendra virus was first isolated in an outbreak of acute respiratory illness involving horses in Queensland, Australia in 1994. A horse trainer and stable hand were also infected, manifesting with respira- tory illness from which the horse trainer died. A second human death occurred in 1995, when a farmer who had contact with ill horses about a year earlier died from encephalitis. Another two deaths involving veterinary workers occurred in the Hendra virus outbreaks in July 2008 and July 2009, also in Australia. Since then, more than 50 spillover events of Hendra virus infection have oc- curred in Queensland and New South Wales in Australia, all involving horses. Five of these involved subsequent horse-​to-​human transmission, with four deaths among a total of seven human cases. To date all cases have been in Australia. Thus, Hendra virus can cause respiratory and encephalitic illness in humans who have close contact with infected horses. There could be considerable delay before the manifestations of the encephalitic illness. The reservoir of Hendra virus is the Pteropus genus of fruit bats (see Chapter 8.5.10, Fig. 8.5.10.16) which also harbour Nipah, Menangle, Tioman, and Australian bat lyssaviruses. Treatment and prevention Treatment is primarily supportive and although ribavirin has been used in several human cases, there is no evidence of its efficacy. A vaccine for horses is now available to prevent Hendra virus infec- tion. It is hoped that this will prevent the infection among veterinary healthcare workers. Nipah virus infection In late 1998 to early 1999, there was an outbreak of viral enceph- alitis in several pig-​farming villages in peninsular Malaysia which subsequently involved abattoir workers in Singapore. More than 300 patients were affected. Isolation of virus from cerebrospinal fluid specimens of several patients indicated that this was due to the previously unknown Nipah virus. Epidemiology Human Nipah virus infection was transmitted by close contact with infected pigs. Human-​to-​human transmission was thought to be rare, although the virus could be readily isolated from patients’ respiratory secretions and urine. The bat as reservoir host As for Hendra virus, the reservoir of Nipah virus is fruit bats of the Pteropus species. Half-​eaten fruits dropped by bats near pig farms may have infected an animal that subsequently ingested them. Pigs were the amplifying hosts for the virus. There was pig-​to-​pig trans- mission which subsequently spread to humans. Pathology and pathogenesis Vasculitis of the medium-​sized to small blood vessels in brain, causing thrombosis, and vascular occlusion with areas of necrosis and ischaemia, were the major findings (Fig. 8.5.7.1). There were also viral inclusions indicating direct viral involvement of the neurons. Vasculitis was also seen in lung and kidney. Clinical manifestations During the outbreak, more than half of the patients had affected family members, suggesting a high infection rate. Some of the household members had seroconversion without clinical dis- ease, indicating subclinical infection at a ratio of asymptomatic vs. symptomatic infection of 1 to 3. The infection involved all age groups. The incubation period was less than 2 weeks in most patients. The clinical manifestations were those of an acute encephalitis with fever, headache, vomiting, and reduced level of conscious- ness. Distinctive clinical features were areflexia, hypotonia, and prominent autonomic changes such as tachycardia and hyperten- sion. Segmental myoclonus found in about one-​third of patients was characterized by focal, rhythmic jerking of muscles, com- monly involving the diaphragm and anterior muscles of the neck. Respiratory tract involvement with cough was seen at presentation in 14% of patients. There were some patients who had non​enceph- alitic infection with seroconversion and systemic symptoms but no evidence of encephalitis. The overall mortality of acute Nipah encephalitis was 40%. Severe brainstem involvement was associated with poor prognosis. Laboratory investigations Cerebrospinal fluid examination was abnormal in 75% of patients with elevated protein levels or elevated white cell counts. Glucose levels were within normal limits. These features are non​specific. IgM and IgG antibody detection in serum and cerebrospinal fluid were critical to the diagnosis of Nipah virus infection. The antibody test utilized an enzyme-​linked immunosorbent assay (ELISA) test. The rate of positive IgM was 100% by day 12 of illness. For IgG, it was 100% by 4 weeks of illness. Brain MRI in acute encephalitis showed multiple, disseminated, small discrete hyperintense lesions best seen in the fluid attenuation inversion recovery (FLAIR) sequence, particularly in the subcortical Fig. 8.5.7.1  Nipah virus encepahalitis: vasculitis of a medium-​sized cerebral blood vessel, showing thrombosis and vascular occlusion with areas of necrosis and ischaemia. 786 section 8  Infectious diseases and deep white matter (Fig. 8.5.7.2). The lesions were likely to cor- respond to the microinfarctions noted in postmortem tissues. Similar imaging changes were also seen in asymptomatic patients with Nipah virus infection. Treatment and prevention Treatment is mainly supportive with mechanical ventilatory sup- port for seriously ill patients. Ribavirin, a broad-​spectrum antiviral agent, appeared to reduce the mortality rate. Relapse and late-​onset Nipah encephalitis Close to 10% of patients suffered a second or even a third neuro- logical episode months or years after recovery from acute enceph- alitis. About 5%, who were either asymptomatic or only had mild non​encephalitic illness initially, also developed similar neurologic episodes (late-​onset Nipah encephalitis) for the first time after a de- layed period. Clinical, radiologic, and pathologic findings indicate that relapse and late-​onset Nipah encephalitis was the same disease process, which was distinct from acute Nipah virus encephalitis. The common clinical features were fever, headache, seizures, and focal neurological signs. There was an 18% mortality. MRI showed patchy areas of confluent cortical lesions. Necropsy showed focal confluent encephalitis due to a recurrent infection. Nipah encephalitis in Bangladesh, India, and Philippines Almost yearly outbreaks of Nipah encephalitis have been reported in Bangladesh from 2001 onwards. Two other outbreaks were reported from north-​eastern India, in Siliguri district in 2001, Nadia district in 2007, and Kerala in 2018. As in Malaysia, Nipah virus caused a fatal encephalitic illness in humans in Bangladesh and India. However, the Bangladeshi and Indian outbreaks showed prominent human-​to-​human spread of infection with physicians who cared for the patients also affected. There was florid pulmonary involvement in some patients. Brain MRI in some patients showed confluent high signal lesions involving both grey and white matter, which is unlike the acute Nipah enceph- alitis in the Malaysian outbreak, suggesting some differences in the pathology from the Malaysian patients. The RNA of Nipah virus in Bangladesh and India was close to, but not identical with, that causing the outbreak in Malaysia. Pteropus bats were also the reser- voir of Nipah virus in Bangladesh. There might be a variety of modes of transmission from bats to humans in the Bangladesh and Indian outbreaks. Consumption of raw date-​palm juice and half-​eaten fruits contaminated by secretions from bats are suggested modes of transmission. In 2014, an outbreak of Nipah virus infection occurred in Mindanao, Southern Philippines, involving 17 patients, with 82% mortality among those with encephalitis. The outbreak involved two villages where there were deaths of horses, and consumption of the horse meat by the villages. The spread of infection was thought to be from bats to horse, horse to human, and human to human. The virus was found to have 99% homology to the Malaysian virus. Pteropus bats are widespread in large parts of Asia, Africa, and Australia. Nipah virus has been isolated in urine of Pteropus bats in Cambodia, and Nipah viral antigen has been found in saliva of Pteropus bats in Thailand. Serological evidence of Henipavirus infection has been reported in fruit bats from Papua New Guinea to Ghana, Africa from east to west, and Yunnan, China to Australia from north to south, indicating potential human Nipah virus infection elsewhere. In fact, a recent study in Cameroon, West Africa showed serological evidence of spill over of human Henipavirus infection, all involving individuals who butchered bats for bushmeat. Menangle and Tioman viruses These are two other newly identified paramyxoviruses harboured by Pteropis fruit bats. Menangle causes disease in pigs but neither has been implicated in human infections. FURTHER READING Chadha MS, et  al. (2006). Nipah virus-​associated encephalitis out- break, Siliguri, India. Emerg Infect Dis, 12, 235–​40. Ching PKG, et  al. (2015). Outbreak of Henipah virus infection, Philippines, 2014. Emerg Infect Dis, 21, 328–​31. Chong HT, Jahangir Hossain M, Tan CT (2008). Differences in epi- demiologic and clinical features of Nipah virus encephalitis between the Malaysian and Bangladesh outbreaks. Neurol Asia, 13, 23–​6. Chua KB, et al. (1999). Fatal encephalitis due to Nipah virus among pig-​farmers in Malaysia. Lancet, 354, 1257–​9. Goh KJ, et  al. (2000). Clinical features of Nipah virus encephalitis among pig farmers in Malaysia. N Engl J Med, 342, 1229–​35. Hsu VP, et  al. (2004). Nipah virus encephalitis reemergence, Bangladesh. Emerg Infect Dis, 10, 2082–​7. Pernet O, et al. (2014). Evidence for Henipavirus spillover into human populations in Africa. Nat Commun, 5, 5324. Playford EG, et al. (2010). Human Hendra virus encephalitis associ- ated with equine outbreak, Australia, 2008. Emerg Infect Dis, 16, 219–​23. Tan CT, et al. (2002). Relapse and late-​onset Nipah encephalitis. Ann Neurol, 51, 703–​8. Fig. 8.5.7.2  Nipah virus encepahalitis: MRI FLAIR showing disseminated, small discrete hyperintense lesions.