Hendra virus

Authors: Mohamad Aljofan, Ph.D.

Monograph
Tables
What's New
Reviews
History

Virology

The Henipavirus genus represents a group of paramyxoviruses that are some of the deadliest of known human and animal pathogens. There are two known viruses within the Henipavirus genus, Hendra virus (HeV) and Nipah virus (NiV). However, a novel virus, cedar virus (CedPV), was isolated from Australian fruit bats during HeV surveillance activities and that genome characterization of cedar virus, identified a close like to Hendra virus and Nipah suggesting their inclusion as a third member of the genusHenipaviruses (8, 19). Henipaviruses are responsible for severe disease outbreaks in humans, pigs and horses, with an estimated human mortality rate between 50 and 100% making them one of the most deadly viruses known to infect humans (18).

Hendra Virus (HeV)

Hendra virus, previously referred to as equine morbillivirus, was first identified in an outbreak in September 1994 in Hendra, a suburb of Queensland, Australia, whichresulted in the deaths of 14 horses and 2 humans who had close contact with the infected horses (22). The naturally acquired symptomatic infection, characterized by a rapidly progressive illness involving the respiratory system and/or the central nervous system (CNS), has so far been recognized in horses, humans as well as domestic animals (40). However, there is potential for other species to be infected, with significant consequences for animal and human health. After its first emergence in Queensland, hendra virus continued to reemerge and spread to other areas in Queensland and neighboring state of New South Wales (1, 18).

Nipah Virus (NiV)

Nipah virus was first isolated in 1999 from cerebrospinal fluid (CSF) of an encephalitic patient from Sungai Nipah village (6). Molecular analyses indicated that the isolated virus was a paramyxovirus closely related, but not identical, to Hendra virus (29). The newly emerged virus was named Nipah virus after the village of the index case (7,36). Initially, the virus caused mild respiratory and neurological disease in swine and was associated with an acute febrile encephalitic and fetal disease in humans with estimated case fatality rates of approximately 35–75% in humans and approximately 5% in swine (29).

Epidemiology

Hendra Virus

The first Hendra virus outbreak occurred in a racing horse stable in 1994, where two people who worked at the stable were infected, along with 21 horses (23, 30). The second outbreak occurred in Mackay, approximately 1,000 kilometers north of Brisbane. A farmer who had assisted at the postmortem of two of his horses that had died at about the same time as the Hendra outbreak had also became infected (23, 24). In both outbreaks the mode of transmission was not clearly identified but the closeness of contact between human cases and horses in the Hendra stable and the postmortems in Mackay suggested that transmission by hands and/or inhalation were responsible (24). During a 17 year period, 1994-2011, there were a total of 14 known “spill over” events infecting 45 horses and seven humans, four of which were fatal (11). All seven recognized human cases of HeV infection have occurred in Queensland, Australia (32). The regular outbreaks of HeV-related disease that have occurred in Australia since 1994 have all been characterized by acute respiratory and neurological manifestations, with low morbidity but high case fatality rates infection (11). However, there has been an unprecedented rise in the number of Hendra virus outbreaks (Table 1), with 18 reported cases in 2011, more than 8 confirmed events in 2012 and about 7 events in 2013 (8).

Nipah Virus

The first Nipah virus outbreak in Malaysia resulted in 265 human cases including 105 fatal cases (7), and 11 cases and one death were reported among pig abattoir workers in Singapore. The Malaysian outbreak was controlled by the culling of over one million pigs and strict quarantine measures on pig movements (25).

Nipah virus was shown to be associated with high case fatality rates of approximately 35–75% in humans and roughly 5% in pigs (29). The prior knowledge of HeV outbreaks and the similarities between Hendra virus and Nipah virus facilitated the rapid identification of fruit bats as the reservoir hosts of Nipah virus (12). Furthermore, antibodies to henipaviruses have been detected in five different bat species from Australia, Malaysia, Bangladesh, India, Cambodia, Thailand, Indonesia and Madagascar (15, 26,42).

Clinical Manifestations

The clinical syndrome associated with Hendra virus infection in horses was predominantly associated with a rapid progress febrile illness culminating in fulminating respiratory disease (30), some of the early cases exhibited some mild neurological signs including muscle twitching and restlessness (28). However, in the later outbreaks such as the 2008 Redlands outbreak in Queensland, all of the five infected horses displayed various neurological signs; including ataxia, depression, disorientation, head tilt, facial nerve paralysis, circling, head pressing, stranguria and recumbent period (11). In contrast, young Nipah virus infected pigs presented with a febrile respiratory illness with epistaxis, dyspnea and coughing, while the older ones presented with neurological signs including agitation, muscle fasciculation, ataxia, paresis, and seizures (21).

Despite some of the variations, the general clinical manifestations of henipavirus infections in humans and other animals appear to be similar. After a short incubation period, an acute illness manifesting as acute encephalitis or pulmonary disease with a high mortality may occur. In some patients relapsing encephalitis or late onset of encephalitis could complicate initial recovery from the acute illness months or years later (40).

Laboratory Diagnosis

There are currently no diagnostic tests to detect early animal responses to henipavirus infection in use (37). Further elucidation of the excretion of Hendra virus during the course of Hendra virus infections in horses has shown that Hendra virus can be detected in nasal excretions even in the preclinical phase (18), while early studies of Nipah virus infections in pteropid bats showed that detection of virus even in known infected animals could be problematic (20). However, there are a number of diagnostic approaches to Hendra virus and Nipah virus testing with different degrees of strength and shortcomings.

Molecular diagnosis include conventional polymerase chain reaction (PCR), which can be used for detection of viral genetic materials in different types of specimens, including fixed, or fresh tissue, various swabs, cerebrospinal fluid or urine samples (9). Real-Time PCR or quantitative PCR (qPCR) has been used for the development of sensitive and specific molecular tests for henipaviruses. The most commonly used form is the TaqMan test which utilizes a specific 30-minor groove binder-DNA probe targeting a short sequence between the two priming sites (14).

Virus isolation remains an important primary diagnostic approach for henipavirus infections (9). For confirmation of new cases or outbreaks or identification of new host(s) for henipavirus, virus isolation method is highly desirable. However, due to their classification as dangerous zoonotic agents it is absolutely essential that isolation of virus from suspected henipavirus infections should only be conducted where laboratory biosafety can be guaranteed (37)

Immunohistochemistryis one of the most useful tests for Hendra virus and Nipah virus detection, especially where formalin-fixed tissues are presented as the main form of specimen for diagnosis. The initial immunohistochemical investigation of Hendra virus-infected tissue used a convalescent human serum, but a range of polyclonal and monoclonal antisera is now available (13, 34, 38, 39).

Serological tests are highly important for investigation of infection status in the natural reservoir, bats, and in the identification of new animal hosts which may or may not present acute symptoms following henipavirus infection. This is best illustrated by the recent diagnosis of a sero-positive dog in a property where lethal infection of horses byHendra virus was confirmed as part of the 2011 Hendra virus outbreak investigations jointly conducted by Biosecurity Queensland and the Australian Animal Health Laboratory (AAHL) (27). The other serological method is enzyme linked immunosorbent assay (ELISA), which is the most affordable serological test for diagnosis of henipavirus infection. The most used indirect ELISA for detection of IgG antibodies to HeV is based on inactivated HeV-infected Vero cell lysate (9).

Pathogenesis

Histopathological findings from Nipah virus infected animals and guinea pigs, revealed evidence of endothelial and/or epithelial syncytial cells as well as mural lymphohistiocytic vasculitis with fibrinoid vascular change (35). The autopsy results of the first Hendra virus human victim revealed lesions of congestion in his lungs, haemorrhage and oedema associated with histological chronic alveolitis with syncytia (22). In humans, henipavirus infections can also result in a clinically calm period following an apparent recovery from an acute infection, which can later recrudesce as encephalitis. Clinically, severe henipavirus infection in humans will present as a severe respiratory disease, encephalitis or a combination of both, include neurological symptoms (e.g. headaches, drowsiness, disorientation, myoclonus, motor, and sensory loss), respiratory disorders (observed in Hendra virus-infected horses, Nipah virus infected pigs, and 25–40 % of Nipah virus-infected humans), unstable blood pressure, and, in one case, vision loss (6, 16,17). Totally 40–92 % of Nipah virus-infected humans succumb to acute encephalitis with an average time of 10 days from fever onset to death, while 3–7 % of infected patients exhibit a late onset or relapsed encephalitis months to years after the initial infection (6, 31).

SUSCEPTIBILITY IN VITRO AND IN VIVO

There are variable differences in virus replication and giant cell (syncytia) formation amongst different cell lines and that Nipah virus was noticed to replicate to a higher titre compared to Hendra virus (2). While, the mechanism behind the observed difference is still unclear, it may be valid to speculate that the rapid in vitro replication of Nipah virusis related to its high fatality rate; and that significant differences between the two viruses make one virus generate more viral particles than the other.

ANTIVIRAL THERAPY

There are no clinically available antivirals for the treatment of henipaviruses. The only antiviral compound with demonstrated clinical efficacy against henipaviruses is ribavirin, a broad spectrum antiviral often used to treat Hepatitis C infection (32). A limited non-randomized clinical trial of ribavirin during the initial Nipah virus outbreak in Malaysia indicated a reduction in mortality of acute Nipah virus encephalitis (5). An in vitro study of ribavirin showed a more than 50 fold reduction in Hendra virus infection (41). Although, these two studies have shown that ribavirin is effective both in vitro and in a clinical trial, there are a number of studies indicating that ribavirin is also associated with a range of side effects such as haemolytic anaemia (10). This might result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions (31).

A potentially effective post-exposure therapy is the human monoclonal antibody (mAb) known as m102.4. This antibody has been used in humans, and in Queensland, Australia they have a limited license to use in high risk exposures. Bossart et al. (2011), illustrated that the use of this neutralizing human monoclonal antibody in African green monkeys challenged with a lethal dose of Hendra virus provided 100% survival rate. While, the animal subjects displayed some neurological signs of the disease, they have all survived the infection by day 16 (3, 4).

ADJUNCTIVE THERAPY

There are no adjunctive therapies available. However, a number of research laboratories are currently, working at evaluating potential adjunctive therapies to enhance the monoclonal antibody m102.4, which has already been shown (in non-human primates) to suppress severe Hendra virus infection when administered during the incubation period.

ENDPOINTS FOR MONITORING THERAPY

No therapeutic endpoints have been established.

VACCINES

As part of finding a potential treatment against the lethal infections, several vaccine candidates have been tested for potential protection. Nevertheless, the only effective therapy against Hendra or Nipah virus infection is a recently discovered Hendra virus vaccine, commercially known as Equivac HeV®, which is a soluble form of the G glycoprotein (4). The vaccine however, is licensed for equine uses only.

PREVENTION OR INFECTION CONTROL MEASURES

The exact route of infection is unknown, however, horses may contract Hendra virus infection whenever, they have close contact with infected bats (e.g. bites or urine) or body fluids of an infected horse. Virus may be present in the infected horse's body fluids, particularly nasal secretions.

All humans confirmed with HeV infections had contact with Hendra virus infected horses. The absence of human cases among healthcare workers and among family members suggests that Hendra virus is not easily transmissible from person-to-person. However, all of the confirmed human cases became infected following high level exposures to respiratory secretions and/or blood of Hendra virus infected horses, for instance, assisting with post mortem examination, performing certain veterinary procedures or having extensive exposure to respiratory secretions. The virus was shown to be killed by drying, heat or cleaning with detergent.

REFERENCES

1. Aljofan M. Hendra and Nipah infection: Emerging paramyxoviruses. Virus Res. 2013;177:119-26. [PubMed]

2. Aljofan M, Saubern S, Meyer AG, Marsh G, Meers J, Mungall BA. Characteristics of Nipah virus and Hendra virus replication in different cell lines and their suitability for antiviral screening. Virus Res. 2009:142 (1–2):92–99. [PubMed]

3. Bossart KN, Rockx B, Feldmann F, Brining D, Scott D, LaCasse R, Geisbert JB, Feng YR, Chan YP, Hickey AC, Broder CC, Feldmann H, Geisbert TW. A Hendra virus G glycoprotein subunit vaccine protects African green monkeys from Nipah virus challenge. Sci. Transl. Med. 4 2012. [PubMed]

4. Broder CC. Passive immunization and active vaccination against Hendra and Nipah viruses. Dev. Biol. 2013:135:125–138. [PubMed]

5. Chong HT, Kamarulzaman A, Tan CT, Goh KJ, Thayaparan T, Kunjapan SR, Chew NK, Chua KB, Lam SK. Treatment of acute Nipah encephalitis with ribavirin. Ann. Neurol. 2001:49: 810–813. [PubMed]

6. Chua KB, Goh KJ, Wong KT, Kamarulzaman A, Tan PS, Ksiazek TG, Zaki SR, Paul G, Lam SK, Tan CT. Fatal encephalitis due to Nipah virus among pig-farmers in Malaysia. Lancet. 1999: 354:1257–1259. [PubMed]

7. Chua KB, Bellini WJ, Rota PA, Harcourt BH, Tamin A, Lam SK, Ksiazek TG, Rollin PE, Zaki SR, Shieh W, Goldsmith CS, Gubler DJ, Roehrig JT, Eaton B, Gould AR, Olson J, Field H,Daniels P, Ling AE, Peters CJ, Anderson LJ, Mahy BW. Nipah virus: a recently emergent deadly paramyxovirus. Science. 2000: 288:1432–1435. [PubMed]

8. Croser EL, Marsh GA. The changing face of the henipaviruses. Vet Micro. 2013:6:151–158. [PubMed]

9. Daniels P, Ksiazek T, Eaton BT. Laboratory diagnosis of Nipah and Hendra virus infections. Microbes Infect 2001:3:289–295. [PubMed]

10. De Franceschi L, Fattovich G, Turrini F, Ayi K, Brugnara C, Manzato F, Noventa F, Stanzial AM, Solero P, Corrocher R. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 2000:31:997–1004. [PubMed]

11. Field H. Human Hendra virus encephalitis associated with equine outbreak, Australia. Emerg Infect Dis 2010:16:219–223. [PubMed]

12. Field H, Young P, Yob JM, Mills J, Hall L, Mackenzie J. The atural history of Hendra and Nipah viruses. Microbes Infect. 2001;3:307–314. [PubMed]

13. Imada T, Abdul Rahman MA, Kashiwazaki Y, Tanimura N, Syed Hassan S, Jamaluddin A. Production and characterization of monoclonal antibodies against formalin-inactivated Nipah virus isolated from the lungs of a pig. J Vet Med Sci 2004:66:81–83. [PubMed]

14. Kutyavin IV, Afonina IA, Mills A, Gorn VV, Lukhtanov EA, Belousov ES, Singer MJ, Walburger DK, Lokhov SG, Gall AA, Dempcy R, Reed MW, Meyer RB, Hedgpeth J. 30-minor groove binder-DNA probes increase sequence specificity at PCR extension temperatures. Nucleic Acids Res 2000:28:655–661. [PubMed]

15. Iehlé C, Razafitrimo G, Razainirina J, Andriaholinirina N, Goodman SM, Faure C, Georges-Courbot MC, Rousset D, Reynes JM. Henipavirus and Tioman virus antibodies in pteropid bats, Madagascar. Emerg Infect Dis 2007;13:159–161. [PubMed]

16. Lim CC, Sitoh YY, Lee KE, Kurup A, Hui F. Meningoencephalitis caused by a novel Paramyxovirus: an advanced MRI case report in an emerging disease. Singap Med J 1999;40:356–358. [PubMed]

17. Lim CCT, Lee WL, Leo YS, Lee KE, Chan KP, Ling AE, Oh H, Auchus AP, Paton NI, Hui F, Tambyah PA. Late clinical and magnetic resonance imaging follow up of Nipah virus infection. J Neurol Neurosurg Psychiatr 2003: 74:131–133. [PubMed]

18. Marsh GA, Wang LF. Hendra and Nipah viruses: why are they so deadly? Curr Opin Virol. 2012;2:242-7. [PubMed]

19. Marsh GA, Barr JA, Tachedjian M, Smith C, Middleton D, Yu M, Todd S, Foord AJ, Haring V, Payne J, Robinson R, Broz I, Crameri G, Field HE, Wang LF. Cedar virus: a novel Henipavirus isolated from Australian bats. PLoS pathogens, 2012. 8(8): p. e1002836. [PubMed]

20. Middleton DJ, Morrissy CJ, van der Heide BM, Russell GM, Braun MA, Westbury HA, Halpin K, Daniels PW. Experimental Nipah virus infection in pteropid bats (Pteropus poliocephalus). J Comp Pathol 2000;136:266–272. [PubMed]

21. Mohd Nor MN, Gan CH, Ong BL. Nipah virus infection of pigs in peninsular Malaysia. Rev Sci Tech Off Int Epiz 2000;19:160–165. [PubMed]

22. Murray K, Selleck P, Hooper P, Hyatt A, Gould A, Gleeson L, Westbury H, Hiley L, Selvey L, Rodwell B, et al. A morbillivirus that caused fatal disease in horses and humans.Science. 1995;268(5207):94-7 [PubMed]

23. O’Sullivan JD, Allworth AM, Paterson DL, Snow TM, Boots R, Gleeson LJ, Gould AR, Hyatt AD, Bradfield J. Fatal encephalitis due to novel paramyxovirus transmitted from horses. Lancet 1997;349:93-5. [PubMed]

24. Paterson DL, Murray PK, McCormack JG. Zoonotic disease in Australia caused by a novel member of the paramyxoviridiae. Clinical Infectious Diseases 1998;27:112-8. [PubMed]

25. Patton JT, Jones MT, Kalbach AN, He YW, Xiaobo J. Rotavirus RNA polymerase requires the core shell protein to synthesize the doublestranded RNA genome. J. Virol. 1997;71: 9618–9626. [PubMed]

26. Peel AJ, Baker KS, Crameri G, Barr JA, Hayman DT, Wright E, Broder CC, Fernández-Loras A, Fooks AR, Wang LF, Cunningham AA, Wood JL. Henipavirus neutralising antibodies in an isolated island population of African fruit bats. PLOS One 2012;7(1):e30346 [PubMed]

27. Promed 20110525.1589 (2011) Hendra virus—Australia. Vaccine 06.

28. Rogers RJ, Douglas IC, Baldock FC, Glanville RJ, Seppanen KT, Gleeson LJ, Selleck PN, Dunn KJ. Investigation of a second focus of equine morbillivirus infection in coastal Queensland. Aust Vet J 1996:74:243–244. [PubMed]

29. Sawatsky B, Grolla A, Kuzenko N, Weingartl, H., Czub, M. Inhibition of henipavirus infection by Nipah virus attachment glycoprotein occurs without cell-surface downregulation of ephrin-B2 or ephrin-B3. J Gen Virol. 2007:88 (Pt 2), 582–591. [PubMed]

30. Selvey LA, Wells RM, McCormack JG, Ansford AJ, Murray K, Rogers RJ, Lavercombe PS, Selleck P, Sheridan JW. Infections of humans and horses by a newly described morbillivirus. Medical Journal of Australia 1995;162:642-5. [PubMed]

31. Shakil AO, McGuire B, Crippin J, Teperman L, Demetris AJ, Conjeevaram H, Gish R, Kwo P, Balan V, Wright TL, Brass C, Rakela J. A pilot study of interferon alfa and ribavirin combination in liver transplant recipients with recurrent hepatitis C. Hepatology 2002;36:1253–1258. [PubMed]

32. Siebert U, Sroczynski G. Antiviral combination therapy with interferon/ peginterferon plus ribavirin for patients with chronic hepatitis C in Germany: a health technology assessment commissioned by the German Agency for Health Technology Assessment. Ger. Med. Sci. 2003:1:07.

33. Luby SP, Gurley ES. Epidemiology of Henipavirus Disease in Humans. Curr Top Microbiol Immunol. 2012;359:25-40. [PubMed]

34. Tanimura N, Imada T, Kashiwazaki Y, Shamusudin S, Syed Hassan S, Jamaluddin A, Russell G, White J. Reactivity of anti-Nipah virus monoclonal antibodies to formalin-fixed, paraffin-embedded lung tissues from experimental Nipah and Hendra virus infections. J Vet Med Sci 2004:66:1263–1266. [PubMed]

35. Torres-Velez FJ, Shieh WJ, Rollin PE, Morken T, Brown C, Ksiazek TG, Zaki SR. Histopathologic and immunohistochemical characterization of Nipah virus infection in the guinea pig. Vet. Pathol. 2008;45:576–585. [PubMed]

36. Wang L, Harcourt BH, Yu M, Tamin A, Rota PA, Bellini WJ, Eaton BT. Molecular biology of Hendra and Nipah viruses. Microbes Infect. 2001: 3;279–287. [PubMed]

37. Wang LF, Daniels P. Diagnosis of henipavirus infection: current capabilities and future directions. Current topics in microbiology and immunology, 2012;359:179-96. [PubMed]

38. Wang LF, Michalski WP, Yu M, Pritchard LI, Crameri G, Shiell B, Eaton BT. A novel P/V/C gene in a new member of the Paramyxoviridae family, which causes lethal infection in humans, horses, and other animals. J Virol 1998:72:1482–1490. [PubMed]

39. White JR, Boyd V, Crameri GS, Duch CJ, van Laar RK, Wang LF, Eaton BT. Location of, immunogenicity of and relationships between neutralization epitopes on the attachment protein (G) of Hendra virus. J Gen Virol 2005:86:2839–2848. [PubMed]

40. Wong KT, Ong KC. Pathology of acute henipavirus infection in humans and animals. Pathol Res Int 2011:1–12. [PubMed]

41. Wright PJ, Crameri G, Eaton BT. RNA synthesis during infection by Hendra virus: an examination by quantitative real-time PCR of RNA accumulation, the effect of ribavirin and the attenuation of transcription. Arch. Virol. 2005;150:521–532. [PubMed]

42. Young PL, Halpin K, Selleck PW, Field H, Gravel JL, Kelly MA, Mackenzie JS. Serologic evidence for the presence in Pteropus bats of aramyxovirus. Emerg Infect Dis. 1996; 2(3): 239–240. [PubMed]