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Epizootic haemorrhagic disease

Preferred citation: Anipedia, www.anipedia.org: JAW Coetzer and P Oberem (Directors) In: Infectious Diseases of Livestock, JAW Coetzer, GR Thomson,
NJ Maclachlan and M-L Penrith (Editors). NJ Maclachlan , G Savini and BI Osburn, Epizootic haemorrhagic disease, 2018.
Epizootic haemorrhagic disease

Epizootic haemorrhagic disease

Previous authors: N J MACLACHLAN AND B I OSBURN

Current authors:
N J MACLACHLAN - Distinguished Professor Emeritus, BVSc, PhD, Dip ACVP, Department of Pathology, Microbiology and Immunology, VetMed 3A, School of Veterinary Medicine / Veterinary Tropical Diseases, Faculty of Veterinary Science, University of California / University of Pretoria, One Shields Ave, Davis, California, 95616, United States
G SAVINI - Head of the Animal Health Department and of the National and OIE Reference Laboratory for BT, DVM, PhD, Istituto Zooprofilatico Sperimentale dell'Abruzzo e Molise "G. Caporale" Via Campo Boario, Teramo, 64101, Italy
B I OSBURN - Emmeritus Proffessor, Faculty of Veterinary Science, University of California / University of Pretoria, One Shields Ave, Davis, California, 95616, United States

GENERAL INTRODUCTION: REOVIRIDAE

Introduction

Epizootic haemorrhagic disease (EHD) is a Culicoides-transmitted haemorrhagic viral disease of wild and domestic ruminants, particularly white-tailed deer (Odocoileus virginianus).38, 58, 63, 73 The causative agent, EHD virus (EHDV), is an orbivirus that is very closely related to bluetongue virus (BTV) and both EHDV and BTV cause a similar disease in susceptible ruminants.24, 30, 38, 41, 57, 58, 62, 68, 73

Epizootic haemorrhagic disease was first described in white-tailed deer in North America in 1955 and substantial epidemics have since been described among populations of white-tailed deer and, to a lesser extent, other wild ruminant species including pronghorn antelope (Antilocapra americana), and bighorn sheep (Ovis canadensis).16, 19, 24, 38, 52 Infection with EHDV has also been documented in many other regions of the world.9, 20, 21, 29, 33, 35, 46-48, 54, 55, 59, 71, 73 Epizootic haemorrhagic disease virus is generally not regarded as a pathogen of domestic ruminants,1, 10, 17, 32, 33, 70 a notable exception is Ibaraki virus, a specific  EHDV that caused an extensive outbreak of disease in cattle in Japan in the late summer and autumn of 1959 and 1960, and continues to cause disease amongst cattle in the Far East and perhaps elsewhere (see Ibaraki disease in cattle). Similarly, in recent years, EHDV has increasingly been identified as the cause of a disease syndrome of oral ulceration and coronitis in cattle in the Mediterranean Basin, Reunion Island, South Africa, South America and the USA.7, 13, 15, 18, 21, 28, 34-36, 39, 52, 63, 67, 72, 81 The increasing number of clinical cases reported in cattle has raised concerns amongst international authorities and in 2008, the disease was included in the OIE list of multispecies/ transboundary diseases.4

Aetiology

Epizootic haemorrhagic disease virus is a member of the family Reoviridae, subfamily Sedoreovirinae, genus Orbivirus.62  It is closely related to BTV, the prototype virus of the genus Orbivirus, and to African horse sickness virus.44 Viruses within the EHDV serogroup all share group-specific serologic cross-reactivity, and at least seven distinct serotypes are distinguished on the basis of neutralization tests with type-specific antisera and genetic and phylogenetic analyses.62 A novel additional serotype detected in an alpaca in South Africa has been proposed.80 The particles of EHDV are non-enveloped and include a genome of ten double-stranded RNA segments. The virion consists of two protein shells, with an inner ‘core’ that consists of viral proteins (VP) VP1, VP3, VP4, VP6 and VP7 and an outer shell of VP2 and VP5. Five nonstructural (NS) proteins (NS1, NS2, NS3/3A, NS4)14 also are produced in EHDV-infected cells. The coding assignments and functions of each protein are identical to those of BTV (see Bluetongue).

As for BTV, there is a strong correlation between EHDV genome-sequences and the geographic origin of the strains (topotypes)5-7 but no relationship exists between serotype and virulence. Like other orbiviruses, EHDV has a segmented genome and can undergo genetic reassortment. Individual genes also undergo genetic drift thus there is considerable genetic variation amongst the strains of EHDV that circulate within endemic regions. As an example, at least 3 different serotypes of EHDV currently circulate in North America, one of which (EHDV serotype 6) is a relatively recently introduced serotype that spread into the southeastern United States from the adjacent Caribbean ecosystem. Interestingly, however, only strains of EHDV serotype 6 that include reassorted genes from the historically endemic EHDV serotypes 1 and 2 were apparently able to expand their range beyond the southeastern United States.3, 75, 78

The original Ibaraki virus that was first described in Japan in 1959 is serologically related to the prototype strain of EHDV serotype 2 that was originally isolated in Alberta in 1964 (see Ibaraki disease in cattle). The serotype-specific L2 gene of this Ibaraki virus shares only partial homology (72 per cent) with isolates of EHDV serotype 2 from the USA,56  whereas the sequence of genes encoding core proteins (VP3, VP7) of Ibaraki virus are more conserved and very similar to those of Australian strains of EHDV.43 The similarity of the core protein genes of Australian strains of EHDV and Ibaraki virus suggests that they are included in an Asian ‘topotype’ of EHDV. Interestingly, recent outbreaks of Ibaraki-like disease among cattle in Japan were caused by EHDV serotypes 6 and 7, not EHDV 2.46, 64 These same EHDV serotypes have also been recently associated with outbreaks of EHD in cattle elsewhere in the world suggesting that the distinction between Ibaraki disease in Asia and EHD of cattle elsewhere in the world is increasingly less clear.

Epidemiology

Epizootic haemorrhagic disease virus infection occurs throughout extensive portions of North America, South America, Africa, the Middle East, Australia and Asia.52, 63 Its distribution is probably similar to that of BTV and includes tropical and temperate regions throughout the world between latitudes of approximately 50 °N and 35 °S.2, 9, 20, 25, 29, 33, 38, 55, 58, 73

The infection in ruminants is not contagious; the virus is transmitted between susceptible ruminants by haematophagous midges of the genus Culicoides that serve as biological vectors of the virus.38 The specific vector species differ throughout the world; Culicoides imicola is a vector of EHDV in Africa, Culicoides brevitarsis in Australia, and Culicoides sonorensis (previously designated as C. variipennis) in the USA.73

Serological evidence of EHDV infection has been reported in many ruminant species, both wild and domestic, including sheep, cattle, various species of Asian and North American deer, elk (Cervus canadensis), moose (Alces alces), pronghorn antelope, bighorn sheep, black (Diceros bicornis) and white (Ceratotherium simum) African rhinoceros, American black bears (Ursus americanus), yaks (Bos grunniens), camelids and Florida panthers (Felis concolor) among others.2, 24, 25, 28, 31, 36, 37, 44, 56, 58, 61, 73, 79 In temperate regions infection is most common in the late summer and autumn when vector populations peak, whereas infection occurs year-round in tropical regions of the world.

Female Culicoides midges become persistently infected with EHDV and can transmit the virus to susceptible ruminants after an external extrinsic period of approximately 10 to 14 days. As in BTV infection, viraemia can be prolonged beyond 50 days in EHDV-infected ruminants because of a novel association of the virus with ruminant erythrocytes.60, 65  Truly persistent infection of ruminants has not been documented in   EHDV infected ruminants, although cattle probably serve as temporary reservoir hosts of the virus.1, 10, 17, 33, 70 The cycle of infection is completed when uninfected female Culicoides midges feed on viraemic ruminants.

Pathogenesis

The pathogenesis of EHDV infection of ruminants is probably very similar or identical to that caused by BTV (see Bluetongue), and has been most comprehensively described in white-tailed deer.30, 38, 40-42, 60, 65, 69 After infection has occurred by the feeding of infected Culicoides, the virus first replicates in lymph nodes draining the site of its inoculation. It is then disseminated to secondary sites of replication such as the lungs and spleen. Many of the clinical manifestations are a reflection of widespread vascular injury and subsequent disseminated intravascular coagulation that leads to haemorrhage, oedema, and tissue necrosis (infarction).38, 41, 69 Microvascular endothelial injury is characteristic of fulminant EHD of white-tailed deer, and both BTV and EHDV clearly replicate in the endothelium of infected ruminants.42, 62, 69 A prolonged cell-associated viraemia (50 days or longer) can occur in both BTV- and EHDV-infected ruminants that survive acute infection, the viraemia persisting despite the presence of neutralizing antibody.38, 60, 65 The intimate association of virus particles with erythrocytes is probably responsible for this prolonged viraemia, which provides a ready source of virus for the haematophagous vectors.65

Clinical signs

Epizootic haemorrhagic disease manifests as a haemorrhagic disease in deer, whereas EHDV infection typically is asymptomatic in domestic ruminants. The high seroprevalence of EHDV infection among domestic ruminants in endemic areas indicates that many animals survive infection or experience only subclinical infections.2, 25, 26, 29, 32, 33, 45, 57, 58 Although experimental infection of cattle with strains of EHDV isolated in the USA and Southeast Asia consistently has failed to induce clinical disease,1, 10, 17, 70 the virus increasingly  has been incriminated as a cause of outbreaks of  a distinctive disease syndrome among cattle in different areas of the world.13, 15, 18, 21, 34-36, 39, 52, 63, 67 Features of this disease include low morbidity and mortality, with signs in affected animals of excessive lachrymation and salivation, difficulty in swallowing, congestion and oedema of the conjunctivae, lips and tongue, linear to circular oral ulcers (Figures 1 and 2), and a stiff gait associated with visible hyperaemia at the coronary band and, occasionally, sloughing of the hoof.

Acute EHD in deer is manifested by fever, weakness, inappetance, excessive salivation, facial oedema, hyperaemia of the conjunctivae and the mucous membranes of the oral cavity, coronitis, and stomatitis with excessive salivation.30, 38 Oral ulcers may occur on the dental pad, hard palate and tongue in prolonged cases, and severe necrotizing glossitis occurs sporadically. The fulminant disease is characterized by excessive bleeding (haemorrhagic diathesis), which may manifest as bloody diarrhoea and/or haematuria, dehydration, diarrhoea, and death.

Figure 1 Severe necrotising stomatitis (Courtesy of the Department of Veterinary Tropical diseases, Faculty of Veterinary Science, University of Pretoria, South Africa)

Figure 2 Multifocal ulcerative stomatitis (Courtesy by Drs J Mediger, C Chase and R Daly, The Department of Veterinary and Biomedical Sciences, Animal Research and Diagnostic Laboratory, South Dakota State University, Brooking, SD57007, USA)

Pathology

Affected animals exhibit increasing perturbations in blood coagulation with progressive thrombocytopenia and prolongation of clotting assays such as the activated partial thromboplastin time and prothrombin time.

The lesions of EHD (see also clinical signs) have been described most comprehensively in white-tailed deer, and are characterized by extensive oral ulceration and widespread haemorrhage and oedema.30, 38 Haemorrhages vary considerably in extent (ranging from petechiae to ecchymoses) and distribution, and are often present in the skin and subcutis, mucosa and submucosa of the oral cavity, walls of the abomasum, forestomachs and urinary bladder, salivary glands, lymph nodes, serosal surfaces of the pleural and peritoneal cavities, endocardium, myocardium, and in the wall of the pulmonary artery and aorta. Hydropericardium and pulmonary oedema can be severe in acutely affected animals. Histologically, the lesions of EHD are characterized by haemorrhage and necrosis, with accompanying thrombosis of capillaries and small vessels in affected tissues. Tongue, salivary glands, walls of the forestomachs and aorta, and myocardium especially that of the papillary muscle of the left ventricle, are commonly affected.

Diagnosis

The diagnosis of EHD is accomplished by either virus detection or serology, or both. The optimal tissues for isolation of the virus include anticoagulated blood, spleen, lungs, and lymph nodes. It can be isolated by inoculation of embryonated hens’ eggs or insect (e.g. Kc and C6/36, cells derived from Culicoides sonorensis and Aedes albopictus, respectively) and/or mammal cells. The Kc cells are generally considered the most sensitive means of virus isolation,27 although Australian strains of EHDV are isolated in embryonated hens’ eggs and Aedes albopictus cell cultures just as well.33 Polymerase chain reaction (PCR)-based methods are increasingly used  for detection of EHDV nucleic acid,9, 49, 51, 52, 72, 74, 76 however interpretation of these assays is complicated by the fact that EHDV nucleic acid may persist in the blood of infected ruminants far longer than does infectious virus.  Both serogroup (that detect all serotypes of EHDV) targeting conserved genome segments 5, 6, 7, 9 and 10 and segment 2 directed serotype-specific RT-PCR assays are now available for rapid identification of field strains of the virus.8, 11, 12, 19, 22, 49, 50, 66, 72, 76, 77

Serological methods for detection of EHDV group-specific antibodies in the serum of ruminants include agar gel immunodiffusion test and competitive enzyme-linked immunosorbent assay (c-ELISA) that incorporates a monoclonal antibody to the EHDV group-specific antigen.31, 52, 82 While the former was widely used in the past, the more sensitive and specific c-ELISA is currently the recommended serological test for animal trade. Serotype-specific antibodies are detected by serum neutralization assay and is still the gold standard for their identification and quantification.62

Differential diagnosis

Epizootic haemorrhagic disease virus is the cause of a disease of deer and other wild ruminants that is indistinguishable from bluetongue.30, 38, 41, 42, 68 The lesions of EHD can also resemble some of those that occur in bovine virus diarrhoea/mucosal disease, vesicular stomatitis, and malignant catarrhal fever. Its diagnosis is complicated by the fact that both EHDV and BTV infections can be very common in endemic areas; thus animals in such areas are often seropositive to, or asymptomatically infected with the virus.32, 33, 57 The mere presence of either antibody or EHDV (or nucleic acid) in the blood of a ruminant is not proof of disease causality.

Serological cross-reactions with BTV further complicate the serological diagnosis of EHDV infection.17, 23 Thus, the presence of group-specific antibodies to either BTV or EHDV should always be confirmed to confirm the identity of the infecting virus. Furthermore, animals infected with more than one serotype of EHDV can produce cross-reacting antibodies that can lead to mis-identification when tested with virus-specific serum neutralization assays.

Control

With the notable exception of Ibaraki disease (see Ibaraki disease in cattle), methods to control EHDV infection are not widely available.52, 53 Vaccines are not commercially available, although they could be developed. Any efficacious vaccination strategy would involve the use of vaccines against all serotypes of EHDV endemic in a given area as humoral immunity is serotype-specific. Control of the Culicoides insect vectors theoretically might be achieved through use of insecticides and/or larvacides, the use of insect repellents on susceptible ruminants, and water management to minimize the breeding areas of those Culicoides spp. that breed in standing water.

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