CASE NOTES

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An update on Hendra virus (HeV), HeV-like illnesses and horses as sentinels for emerging infectious disease

Edward Annand¹, Peter Reid², Ina Smith³, Ibrahim Diallo⁵, Stacey Lynch⁶, Richard Weir⁷, Lorna Melville⁷, Cristy Secombe⁸, Philip N. Britton⁹, James Gilkerson⁴, Cheryl Jones¹⁰, and Navneet Dhand¹

1. University of Sydney, School of Veterinary Science and Marie Bashir Institute for Infectious Diseases and Biosecurity
2. Private Equine Veterinarian and The Australian Veterinary Association
3. CSIRO, Australian Animal Health Laboratory (AAHL)
4. University of Melbourne, Faculty of Veterinary Science, Centre for Equine Infectious Disease
5. Biosecurity Sciences Laboratory, Biosecurity Queensland, QDAF
6. AgriBio, Victorian Arbovirus control program, Agriculture Victoria, DEDJTR
7. Berrimah Veterinary Laboratory, NT DPI&F
8. College of Veterinary Medicine, Murdoch University
9. University of Sydney, Faculty of Medicine and Marie Bashir Institute for Infectious Diseases and Biosecurity
10. University of Melbourne, Department of Paediatrics and Murdoch Children's Research Institute

Posted Flock & Herd September 2018

Abstract

Hendra virus (HeV) causes a usually fatal acute disease in horses mediated by an endothelial vasculitis. It also has a high case fatality rate in humans who may become infected via exposure to an infected horse.

We are conducting a project that aims to identify infectious causes of severe acute equine illness presentations other than HeV and evaluate the respective zoonotic potential of any pathogens identified.

This will provide much needed additional knowledge for health professionals and the public and will clarify the potential human health risk associated with contact with unwell horses.

Key words

Hendra virus, Australian bat lyssavirus, Horse, Zoonoses, Emerging Infectious Disease.

Hendra virus (HeV) causes a usually fatal acute disease in horses mediated by an endothelial vasculitis.

Following its initial diagnosis, and based on the 1994 cases attended by Dr Peter Reid, HeV was originally thought of as an acute equine respiratory syndrome featuring marked pyrexia1 which resulted in death predominantly from pulmonary oedema and hypoxia. Most cases had featured terminal, frothy, clear or bloody nasal discharge with interstitial pneumonia and pulmonary haemorrhage. Neurological signs, while present, were not the major clinical features. This emergence of a fatal zoonotic disease in horses has changed the veterinary approach to the investigation of sick horses in Australia to more carefully consider zoonotic risk.

In 2008, the cases at Redlands in Queensland were interpreted and described with more emphasis on neurological signs and other nonspecific signs that included dull demeanor and mild colic with less emphasis on respiratory signs. A review of these cases published in the Emerging Infectious Diseases prompted veterinarians and horse owners to consider HeV infection in any horse exhibiting acute-onset febrile illness, regardless of clinical manifestations, and to implement appropriate risk assessment and management strategies in sick horses and in horses in the pre-clinical stage of infection.² Subsequently, experimental live virus challenge studies at the Australian Animal Health Laboratory (AAHL) using the Redlands isolate demonstrated pulmonary pathology and respiratory signs in all horses consistent with that shown previously in 1994.³

Clinical presentations of naturally infected acute field cases since 1994 have shown either or both of these signs. Consequently, an appropriate 'typical presentation for HeV' might be considered an 'acute severe and often rapidly progressing fatal illness usually featuring pyrexia, with respiratory and/or neurological signs.'

A recent, retrospective clinical review of 11 New South Wales cases of HeV between 2006 and 2012 described 5 cases as being found dead or dying along a fence line. This suggested neurological dysfunction likely featured in the unobserved clinical deterioration. In most cases, disease was an acute illness leading to death within 48 hours. The cases further highlight that HeV should be considered in cases of acute unexplained equine fatality. Full autopsies were not conducted so therefore pulmonary involvement was not able to be described. When signs of disease were observed, neurological signs predominated.4

A review of the emergence of both HeV and another emergent virus in the same family, Nipah virus (NiV), has been recently published in Vaccine by Broder, Weir and Reid.⁵ The review discusses virus tissue tropism and cellular entry, replication strategies, pathogenesis, clinical features of human and animal infection, and the development of an effective, safe vaccine and post exposure prophylaxis.

Vets are reminded of the appropriate samples to collect from suspect animals for HeV testing as described in the Queensland (QLD) Department of Agriculture and Fisheries 'Guidelines for veterinarians handling potential HeV infection in horses'.⁶ The samples include nasal, oral, rectal mucosal, vaginal and possibly urine swabs into viral transport medium (obtainable from your government laboratory) or 1ml of saline (in a serum blood tube), as well as blood collected into EDTA and serum clot tubes.

Since 2009 testing for HeV has increased throughout Qld,⁷ likely in part, due to increased awareness of the disease. Many practicing and government veterinarians have been all too aware of a considerable number of cases that have concerning HeV-like clinical signs involving acute respiratory and or neurological presentation, which are often fatal. Strikingly, the majority of these cases return negative results for HeV testing and yet many are suggestive of an infectious cause. In 2013, two such cases that underwent additional testing were found to have died from Australian bat lyssavirus (ABLV), which causes a disease indistinguishable in clinical presentation and outcome to rabies in mammals including in humans.⁸ Could more of these cases featuring HeV-like clinical signs, yet testing negative for HeV be posing further zoonotic disease threats? The authors are conducting a project aiming to answer this question and identify other known and unknown pathogens that may be causing such equine illnesses.

The differential diagnoses for acute severe illness in horses includes a long list of both infectious and non-infectious aetilologies (See Box 1).

Box 1. Examples of differential diagnoses that could be considered for acute severe illness in horses by category
Infectious: Bacterial meningitis / abscessation; Bacterial pneumonia; Bacterial systemic toxaemia; Anthrax; Viral infection (encephalitis / meningitis, vasculitis, severe respiratory)##; Mycotic infection - particularly Cryptococcus (pneumonia / encephalitis); Equine protozoal myeloencephalitis*/ Amoebic encephalitis*; Trypanosomiasis* #
* Not known to occur in Australia.
# Surra (Trypanosoma evansi) is not found in Australia but is endemic in our close neighbours. Native trypanosome species are of unknown presence or clinical significance in horses.
## See tables for lists of viruses potentially involved in acute equine illness.
Colic due to acute abdominal conditions (examples include strangulating intestinal or infarctive lesions)
Toxicity: Snake envenomation - brown, tiger, taipan; Tick paralysis - Ixodes holocyclus; Tetanus; Botulism; Metaldehyde; Ergot alkaloidosis,
Plant toxicities: Avocado; Pyrrolizidine alkaloids (in the NT Crotolaria spp. especially C. crispate); Annual ryegrass toxicity; Cardiac Glycosides Eg. Indigofera.
Poisons: 1080; Paraquat; Monensin; Lead
Trauma: Traumatic encephalopathy
Neoplastic: Acute clinical signs due to progression (Rare in horse - examples include:Cholesterol granuloma; Adenocarcinoma; Lymphoma; Pituitary adenoma)
Iatrogenic: Air embolism; Intracarotid injection; Drug overdoses (Moxidectin, Metronidazole, Trimethoprim sulphonamide, Lignocaine)
Other: Cardiac - ruptured chordae tendinae; aortic root rupture Metabolic derangement (Hypocalcemia; Hyponatremia; Hypoglycemia); Hypo-/hyperosmolality disorders; Hyperammonemia, severe haemorrhage into a body cavity, hepatotoxic encephalopathy.

Case features or symptoms that may increase the suspicion of infectious causes in the differential diagnosis include pyrexia, respiratory and or neurological signs as well as multiple cases occurring in apparent epidemiological relationship. In such cases, and where HeV testing is negative, the following viruses already detected in Australia could be involved (Table 1) , many of which would pose direct or indirect (arthropod vector) human health threats. The viruses in Table 2 are known to cause similar disease in horses internationally.

In addition to these viruses those in Table 3 have been recently identified in Australian bats¹⁰ and potentially may follow a similar 'spill-over' pathway to horses as HeV with unknown clinical significance.¹¹

Table 1

Virus	Genus / Family	Reservoir	Insect vector	Confirmed infection in:
				Horses	Humans
Australian bat lyssavirus(ABLV)	Lyssavirus / Rhabdoviridae	All bats	None	Yes	Yes
Menangle (MenPV)	Rubulavirus / Paramyxoviridae	Flying foxes	None	No#	Yes
Elsey ELSV (PHSV)	Orbivirus / Reoviridae	Unknown	Mosquito / Culicoides	Yes	No
Murray valley encephalitis virus (MVEV)	Flavivirus / Flaviviridae	Birds / mosquitoes	Mosquitoes	Yes	Yes
West Nile virus WNV (Kunjin) (KUNV)	Flavivirus / Flaviviridae	Birds / mosquitoes	Mosquitoes	Yes	Yes
Japanese Encephalitis (JEV)	Flavivirus / Flaviviridae	Birds / mosquitoes	Mosquitoes	Yes	Yes
Ross River Virus (RRV)	Alphavirus / Togaviridae	Macropods	Mosquitoes	Yes	Yes
Equine Herpes viruses1 (EHV-1)	Varicellovirus / Alphaherpesvirus	Horse	None	Yes	No

# Equine seropositivity for this or a very closely related virus has recently been identified as part of this research. Further testing is currently underway.

Table 2

Virus	Genus / Family	Reservoir	Confirmed infection in:
			Horses	Humans
Nipah (NiPV)	Henipavirus / Paramyxoviridae	Flying foxes	Yes*	Yes
Rabies virus (RABV)	Lyssavirus/ Rhabdoviridae	Terrestrial carnivores and bats	Yes	Yes
African horse sickness virus (AHS)	Orbivirus/ Reoviridae	Culicoides, mosquitoes and ticks	Yes	No
Equine Encephalosis virus (EEV)	Orbivirus/ Reoviridae	Culicoides	Yes	No
Peruvian horse sickness (PHSV)**	Orbivirus/ Reoviridae	Mosquitoes	Yes	Yes
Eastern equine encephalitis virus (EEEV)	Alphavirus/ Togaviridae	Mosquitoes	Yes	Yes
Getah virus (GETV)	Alphavirus/ Togaviridae	Mosquitoes	Yes	Yes
Shuni virus (SHUV)	Orthobunyavirus / Bunyaviridae	Culicoides, mosquitoes	Yes	No
Borna disease virus (BDV)	Bornavirus / Bornaviriadae	Rodents suspected	Yes	Yes
St. Louise encephalitis virus (SLEV)	Flavivirus/ Flaviviridae	Birds / Mosquitoes	Yes	Yes

*Confirmed in 1998 / 1999 Malaysia / Singapore outbreak. Also a henipavirus outbreak occurred in 2014 in the Philippines that caused fatalities in horses, humans, dogs and a cat and featured human to human transmission - it is thought to have been very closely related to HeV and NiV9
**This virus is considered practically identical to ELSV

Table 3

Virus	Genus / Family	Reservoir	Confirmed infection in:
			Horses	Humans
Cedar virus (CedPV)	Henipavirus/ Paramyxoviridae	Flying foxes	No#	No
Hervey virus (HerPV)	Rubulavirus / Paramyxoviridae	Flying foxes	No	No
Grove virus (GroPV)	Rubulavirus / Paramyxoviridae	Flying foxes	No	No
Teviot virus (TevPV)	Rubulavirus / Paramyxoviridae	Flying foxes	No#	No
Yepoon virus (YepPV)	Rubulavirus / Paramyxoviridae	Flying foxes	No	No

# Equine seropositivity for this or a very closely related virus has recently been identified as part of this research. Further testing is currently underway.

Our project aims to investigate the possibility of infectious causes of severe acute equine illness presentations other than HeV and evaluate the respective zoonotic potential of any pathogens identified.

This will provide much needed additional knowledge for health professionals and the public and will clarify the potential human health risk associated with contact with unwell horses. It is also expected to improve treatment and outcome for horses which may be compromised by uncertainty surrounding these presentations.

Horses, monitored closely for individual illness, that are often heavily exposed to biting insects and featuring a proven spill-over risk for bat borne viruses (HeV and ABLV) are a highly suitable sentinel species for early detection of emerging infectious diseases of potential human and livestock significance.

For vets attending suitable cases please mark submissions for forwarding to AAHL following timely HeV +/- ABLV testing at the EMAI, for inclusion in this additional research testing. Please don't hesitate to contact Dr Ed Annand for further information or to discuss case suitability.

References

1. Muray, K. et al. A Morbillivirus That Caused Fatal Disease in Horses and Humans. Science 268, 94-97 (1995)
2. Field, H. et al. Hendra Virus Outbreak with Novel Clinical Features, Australia Emerging Infectious Diseases 16, 338-340 (2010)
3. Marsh, G. et al. Experimental Infection of Horses with Hendra Virus/Australia/Horse/2008/Redlands. Emerging Infectious Diseases 17, 2232-2238 (2011)
4. Ball, M., Dewberry, T., Freeman, P., Kemsley, P. & Poe, I. Clinical review of Hendra virus infection in 11 horses in New South Wales, Australia. The Australian Veterinary Journal 92, 213-218 (2014)
5. Broder, C., Weir, D. & Reid, P. Hendra virus and Nipah virus animal vaccines. Vaccine 34, 3525-3534 (2016)
6. Queensland Government, Department of Agriculture and Fisheries. Guidelines for veterinarians handling potential Hendra virus infection in horses. Version 5.1 www.daf.qld.gov.au"
7. Smith, C. et al. Twenty years of Hendra virus: laboratory submission trends and risk factors for infection in horses. Epidemiology and Infection 144, 3176-3183 (2016)
8. Annand, E. & Reid, P. Clinical review of two fatal equine cases of infection with the insectivorous bat strain of Australian bat lyssavirus. Australian Veterinary Journal 92, 324-332 (2014)
9. Ching, P. et al. Outbreak of Henipavirus Infection, Philippines, 2014. Emerging Infectious Diseases 21, 328-331 (2015)
10. Barr, J. et al. Isolation of multiple novel paramyxoviruses from pteropid bat urine. Journal of General Virology 96, 24-29 (2015)
11. Plowright, R. et al. Ecological dynamics of emerging bat virus spillover. Proceedings of The Royal Society B 282 (2015)