EHV-5—Equine herpes virus 5
Equine Herpesvirus 5
Related terms:
Polymerase Chain Reaction
Equine Herpesvirus 3
Equine Herpesvirus 1
Equine Herpesvirus
Foals
Host Range
Proteins
DNA
Gammaherpesvirinae
Equus
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Disorders of the Respiratory System
Elizabeth Davis, in Equine Internal Medicine (Fourth Edition), 2018
Diagnosis
Diagnostic evaluation of suspect EHV-5 cases should include a complete evaluation of the respiratory tract. Physical examination followed by thoracic ultrasound will provide the clinician with evidence of primary pulmonary disease. Severity of ultrasonographic abnormalities will relate to chronicity of pulmonary disease demonstrated by pleural irregularity and thickening, peripheral nodules, and abscess that can often be visualized in non-acute cases (Fig. 8.15B). Subsequent respiratory system examination will often include thoracic radiographs, which reveal moderate to severe interstitial pulmonary nodules (Fig. 8.15C). Radiographic appearance of pulmonary nodules may resemble those resulting from metastatic neoplasia or fungal granulomas; therefore, additional diagnostic testing will be needed to definitively diagnose EMPF. Additional diagnostic testing includes BAL, which will allow the clinician to examine pulmonary cellularity of the lower airways. Characteristic findings include neutrophilic inflammation with marked mucous accumulation. In some instances, the cytologic characteristics may resemble RAO (heaves). Clinical distinction of the conditions is important. EMPF should be suspected in an equine patient diagnosed with RAO that does not respond to appropriate therapy and environmental management. In addition, EMPF-affected horses have chronic progressive disease, systemic inflammation, and a poor or incomplete response to corticosteroid therapy.
Postmortem examination of EMPF-affected horses reveals evidence of primary pulmonary disease characterized by enlarged lungs that fail to collapse, diffuse pleural thickening, and the presence of numerous fibrous nodules of variable size, in some cases up to 5 cm (or more) in diameter. Bronchial and mediastinal lymphadenopathy is commonly associated with the presence of pulmonary granulomas (Fig. 8.15D–E). There have been two types of pulmonary granulomas described in EMPF patients based on lesion size and distribution. The more common form is referred to as a disseminated nodular form in which multifocal, coalescing fibrotic nodules are present throughout all lung fields with lesions ranging from 1 to 5 cm. In this form of EMPF there is often minimal healthy pulmonary parenchyma present, and approximately 80% of the lungs are composed of fibrous granulomas. Alternatively, a discrete nodular form has been described in which large discreet nodules are separated by normal-appearing pulmonary parenchyma. The nodules in this form of disease are much larger, sometimes measuring 8 to 10 cm in diameter. Regardless of the form of disease on histologic examination, the lesions are characterized by marked interstitial fibrosis with type 2 pneumocyte hyperplasia. Alveoli are often filled with neutrophils, fewer alveolar macrophages, multinucleated giant cells, and eosinophilic proteinaceous material. Intranuclear inclusions, consistent with herpes viral infection, may be observed within macrophages and/or epithelial cells.302,307
Definitive diagnosis of EMPF is based on histopathologic evidence of pulmonary tissue obtained by lung biopsy or sample collection at postmortem. Diagnosis is often strongly suspected based on clinical history, ultrasonographic evaluation, thoracic radiographic findings, and pulmonary airway cytology, particularly if cells with intranuclear inclusions are identified. Additional supportive evidence for the diagnosis of EMPF is based on the presence of EHV-5 detected with molecular testing such as PCR and preferably with the qPCR method. Ideal samples for testing include BAL fluid and/or lung tissue. Additional samples that should be tested in parallel include peripheral blood (leukocytes) and nasal swab secretions (synthetic, nylon or Dacron swab). Testing should also include evaluation for additional viruses such as EHV-2 and AHV-5. Although they may not serve a primary role, their presence may potentiate disease development in affected horses.
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Diseases of the Hemolymphatic and Immune Systems
In Veterinary Medicine (Eleventh Edition), 2017
Etiology and Epidemiology.
Some equine lymphomas are associated with infection by equine herpesvirus-5 (EHV-5). Of 13 horses with lymphoma, 67% were positive on polymerase chain reaction (PCR) testing of tissue for EHV-5, whereas 14% of 21 clinically normal horses were positive. Neoplastic samples positive for EHV-5 were classified as T-cell-rich B-cell lymphoma (three samples), T-cell lymphoma (one), and nondifferentiated (one), and two were not examined.4 Although Koch's postulates have not been met and therefore a strict causal association demonstrated, there is circumstantial evidence, including response to antiviral therapy, that EHV-5 infection causes lymphoma in horses.2–5 Otherwise, lymphoma and lymphosarcoma in equids is idiopathic.
Lymphoma is a neoplasm arising from lymphoid tissue, which may be in the lymph nodes, spleen, or intestine. The disease is more accurately described as neoplasia of one of many lymphoid cell lines, and with increasing sophistication of immunohistochemical staining it is possible to differentiate lymphoma by the particular cell line that is affected. At least 14 subtypes of lymphoma are recognized in horses.17 Furthermore, molecular genetic techniques may soon permit use of PCR or chromosomal (genomic) analysis to better characterize the origins of tumors.18 Both immunohistochemistry of fixed tissue sections and fluorescent cell sorting of cells in body fluids have been used to determine the abnormal cell type. An additional advantage of advanced testing is that tumors of uncertain origin (lymphoid, myeloid) can sometimes be characterized.
The tumors in horses are most commonly of T-cell or B-cell lines. Of 203 horses with lymphoma, multicentric lymphoma was most common (83 horses, 41%), followed by disease in the skin (38 horses, 19%), gastrointestinal tract (24 horses, 12%), mediastinum (5%), lymph nodes (5%), eye or periorbital tissues (4%), spleen (3%), nasal cavity (2%), central nervous system (2%), oral cavity (2%), bone marrow (0.5%)m and heart (0.5%).17 Equine T-cell-rich, large B-cell lymphoma is the most common of the equine lymphomas (87 of 203 horses, 43%) followed by peripheral T-cell lymphoma (45 horses, 22%) and diffuse large B-cell lymphoma (11%).17 B-cell lymphomas that contain large numbers of T cells (which are not neoplastic) or peripheral T-cell lymphomas are characteristically tumors of the spleen and thoracic and mediastinal lymph nodes.17 B-cell tumors that contain large numbers of T cells (T-cell-rich B-cell lymphoma) account for approximately one-third of equine lymphoma. These latter are typically tumors of the skin and subcutis. T-cell lymphomas account for approximately 20% of equine lymphomas and typically cause disease involving the mediastinal lymph nodes. Approximately 50% of equine lymphomas have cells that express progesterone receptors, but none express the estrogen receptor, which might explain the regression of tumors in mares during pregnancy.
The disease occurs in all ages of horse, being reported from animals as young as 2 months to as old as 31 years. Median age of diagnosis is 10 years.17 There is no information on age-specific incidence. One study has reported cases in horses ranging from 4 months to 22 years of age, and the mean age of cases in this, and other case reviews, suggests that there is some increase in risk with increasing age. Limited slaughter surveys show a prevalence that varies from 0.7 to 3.2 cases per 100,000 animals. Thoroughbred horses are more likely to have cutaneous lymphosarcoma than are other breeds.19
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Herpesviruses of Horses
D.J. O'Callaghan, N. Osterrieder, in Encyclopedia of Virology (Third Edition), 2008
Defective Interfering Particles and Persistent Infection
EHV-1, EHV-2, and EHV-5 have been shown to mediate persistent infection. In the case of EHV-1, defective interfering particles (DIPs) have been shown to initiate and maintain this outcome. EHV-1 DIPs have been generated in vivo in the Syrian hamster model, and therefore may be relevant during EHV-1 infection of the natural host. DIPs are replication defective and require standard EHV-1 as a helper. The overwhelming majority of EHV-1 DNA sequences are absent from DIPs. The packaged DIP DNA molecule is a concatamer of EHV-1 sequences ranging in size from 5.9 to 7.3 kbp, repeated head to tail until it is approximately the size of the standard viral genome. DNA sequencing has revealed that sequences from three regions of the EHV-1 genome are conserved in DIPs: (1) the L terminus, including genes UL3, UL4 and the 3′ portion of UL5; (2) the junction between UL and the internal IR; and (3) the central portion of IR, including ORI and the 5′ portion of gene IR4. The UL3 and UL4 genes in DIP genomes are 100% identical to those of infectious virus, but their functions in virus replication remain to be elucidated. The DIP genome also contains a perfectly conserved cleavage/packaging signal. The sequences at the L terminus and IR are joined by a homologous recombination event mediated by a conserved 8 bp sequence present at both the L terminus and within the IR4 gene to generate a unique ORF present only in DIPs. This ORF is expressed as a 31 kDa 'hybrid protein' comprising the N-terminal 196 amino acid residues of the IR4 protein (the homolog of HSV-1 ICP22) linked in frame to the C-terminal 68 amino acids of the UL5 protein (the homolog of HSV-1 ICP27). Unique to EHV-1 persistently infected cells (not detected in EHV-1 cytolytic infection) is a 2.2 kbp transcript that maps to the UL/IR junction and is antisense to the IE mRNA. Interestingly, this transcript exhibits significant homology to the latency associated transcripts of HSV-1, which appear to be associated with HSV-1 reactivation rather than establishment of latency.
Lastly, in EHV-1 persistently infected cells, transcription of certain viral genes appears delayed compared with cytolytically infected cells. Recent findings reveal that expression of the 31 kDa IR4/UL5 hybrid protein downregulates expression of specific EHV-1 promoters. Moreover, altered forms of the EHV-1 IE polypeptides have been observed only in persistently infected cells. Taken together, these studies indicate that altered or aberrant viral regulatory mechanisms may be involved in establishing or maintaining persistent infection. Ongoing studies with recombinant forms of the DIP genome indicate that the hybrid gene is not essential for DIP replication, but is important in the ability of EHV-1 DIPs to establish persistent infection.
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Equine Herpesviruses
Gisela Soboll Hussey, ... Walid Azab, in Reference Module in Life Sciences, 2019
Classification
EHV-1, EHV-2, EHV-3, EHV-4, EHV-5, and EHV-9 are all members of the Herpesviridae but belong to two different subfamilies (Alpha- and Gammaherpesvirinae) in this large virus family. EHV-6, 7 and 8 are also referred to as asinine herpesviruses 1, 2, and 3, respectively (AsHV-1 to AsHV-3), and will not be discussed in this article. The morphology of all six members is typical of the herpesviruses in that they are enveloped, contain an icosahedral capsid, and have a proteinaceous layer, the so-called tegument, which surrounds the nucleocapsid. Equine herpesviruses are composed of six distinct species: (1) EHV-1 is the major equine pathogen causing abortions, respiratory illness, neurological disease and ocular disease; (2) EHV-2 establishes asymptomatic long-term persistent infection and might be associated with keratoconjunctivitis; (3) EHV-3 is the causative agent of mild progenital exanthema; (4) EHV-4 is a major respiratory pathogen that differs significantly from EHV-1 at the DNA level, and is associated occasionally with equine abortions; (5) EHV-5 may be associated with equine multinodular pulmonary fibrosis; (6) EHV-9 can cause subclinical encephalitides in horses under experimental conditions. Experimental and accidental natural infections of non-equid species are mostly lethal due to severe neurological disorders. In this latter respect, EHV-9 possesses biological properties very akin to the alphaherpesvirus of pigs, pseudorabies virus.
EHV-1, 3, 4, and 9 are Alphaherpesvirinae members and belong to the genus Varicellovirus. EHV-2 and EHV-5 are members of the Gammaherpesvirinae and are classified into the genus Percavirus.
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Other epithelial neoplasms
Derek C. Knottenbelt OBE BVM&S DVM&S Dip ECEIM MRCVS, ... Katie L. Snalune BSc MA VetMB Cert EM (Int.Med.) Cert ES (Soft Tissue) MRCVS, in Clinical Equine Oncology, 2015
Differential diagnoses
These are listed in Box 14.9.
Equine multinodular pulmonary fibrosis (EMPF) is a progressive fibrotic lung disease that has been associated with equine herpesvirus-5 (EHV-5) infection.130–132 There may be co-infection with EHV-2 in some horses, this being a closely related gammaherpesvirus.130,132 This disease occurs in adult horses (age range 4–28 years); affected animals tend to be older, with mean ages of 13 and 14.5 years in two studies.130,131 There is no apparent breed or gender predilection. In most cases, there are numerous coalescing nodules of fibrotic tissue that measure <1–5 cm in diameter, but in some horses, the nodules are larger (up to 10 cm diameter) with grossly normal regions of lung tissue between them; the latter form is particularly difficult to differentiate clinically from a neoplastic process and might progress to diffuse involvement.130,131 The nodules are pale, tan or tan-white, firm, bulge slightly from surrounding tissue and, on sectioned surfaces, have a homogeneous appearance. Other intrathoracic tissues/organs are not involved and pleural effusion is not common, but the lymph nodes may be grossly enlarged due to reactive lymphoid hyperplasia. Histologically, the well-demarcated nodular lesions are found in the alveolar parenchyma. They are composed of (generally) mature collagenous tissue containing 'alveolar-like' structures lined by cuboidal epithelial cells and containing intraluminal neutrophils and macrophages; mixed inflammatory cell infiltrates are noted within the stroma, that may include multinucleate giant cells.130,131 Eosinophilic intranuclear viral inclusion bodies have been noted in enlarged macrophages in these lesions.130–132 Polymerase chain reaction (PCR) can be used to detect EHV-5 DNA in lung tissue, bronchoalveolar lavage fluid, or both, for confirmation of the diagnosis.130,131 Asinine herpesvirus type 5 (AHV-5) was also detected by PCR in one case. Hypertrophic pulmonary osteopathy was reported in one horse.133,134
Horses may present with multiple eosinophilic granulomas in the lungs as part of multisystemic eosinophilic epitheliotropic disease (MEED) or as an idiopathic condition confined to pulmonary tissue.135
Pulmonary hamartomas have been diagnosed (congenital polyalveolar lobes) in foals only (n = 3).136 These tumour-like masses involved the entire right lung. They were spongy, pink to dark red and lobulated, and histologically were composed of normal alveoli, bronchioli and blood vessels.136
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Coccidioidomycosis
In Clinical Veterinary Advisor: The Horse, 2012
Diagnosis
Differential Diagnosis
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Respiratory infection
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Bacterial pneumonia, pleuropneumonia
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Other fungal pneumonias
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Pulmonary abscess
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Interstitial pneumonia
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Pulmonary nodular fibrosis (equine herpesvirus-5)
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Systemic infection
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Abdominal abscess
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Strangles (Streptococcus equi subsp. equi)
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Pigeon fever (Corynebacterium pseudotuberculosis)
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Other bacterial or fungal forms of osteomyelitis
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Abortion secondary to bacterial or fungal endometritis, nocardioform infection, leptospirosis
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Cutaneous infection
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Subcutaneous bacterial or fungal abscesses
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Sporotrichosis
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Corynebacterium pseudotuberculosis
Initial Database
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Mild to moderate anemia
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Leukocytosis caused by mature neutrophilia
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Hyperfibrinogenemia
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Hyperglobulinemia
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Monocytosis
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Thrombocytosis
Advanced or Confirmatory Testing
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Imaging such as radiography or ultrasonography depending on the site of suspected infection
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Direct demonstration of organism in tracheobronchial aspirates, exudates, or tissues
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Culture of appropriate tissues, exudates, or tracheobronchial aspirates
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Serum antibody testing by immunodiffusion or enzyme immunoassay. Higher titers are seen in horses with disseminated disease or pneumonia with thoracic effusion compared with horses with abortion, bone involvement only, or cutaneous infection.
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Pulmonary Fibrosis, Multinodular
In Clinical Veterinary Advisor: The Horse, 2012
Basic Information
Definition
Multinodular pulmonary fibrosis (MPF) is a respiratory disease of adult horses that is characterized by interstitial and nodular pulmonary infiltrates of collagen and inflammatory cells. It has been associated with equine herpesvirus-5 (EHV-5).
Epidemiology
Species, Age, Sex
Affects adults
Contagion and Zoonosis
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Despite the association with EHV-5, there have been no clusters of MPF reported, suggesting that it is minimally to noncontagious.
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EHV-5 is not known to be zoonotic.
Clinical Presentation
History, Chief Complaint
Horses with MPF typically have a history of respiratory distress, tachypnea, cough, increased rectal temperature, and chronic weight loss with hyporexia.
Physical Exam Findings
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Affected animals are usually thin and have an increased respiratory rate (20–30 breaths/min), mild to moderate tachycardia, and rectal temperatures up to 105° F.
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Thoracic auscultation may reveal either loud bronchovesicular sounds or widely dispersed crackles and wheezes.
Etiology and Pathophysiology
The cause of MPF has not been fully elucidated. However, EHV-5 was obtained from the bronchoalveolar (BAL) fluid or biopsies of all cases included in a recently published series and is found only rarely in unaffected horses. Despite this strong association, a causative relationship has not yet been established.
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Herpesvirus
In Clinical Veterinary Advisor: The Horse, 2012
Definition
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Equine herpesviruses (EHVs) are ubiquitous enveloped DNA viruses that have a major economic and welfare impact on the horse industry worldwide.
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Nine EHVs have been characterized. Five (EHV-1 to EHV-5) infect domestic horses, and two (EHV-6 and EHV-9) are associated with infections in wild Equids, including asses and zebra.
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EHV-1 through EHV-5 may be further classified into viral subfamilies on the basis of their genetic sequence:
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α-Herpesviridae: EHV-1, EHV-3, and EHV-4
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γ-Herpesviridae: EHV-2 and EHV-5
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In domestic horses, EHV-1 is associated with respiratory disease, abortion, and neurologic disease.
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EHV-2 has not been convincingly associated with pathology in horses as a primary etiologic agent, but some evidence suggests that it may be associated with keratoconjunctivitis in young horses and superficial keratopathies in adult horses.
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EHV-3 causes coital exanthema, a venereal disease of stallions and mares (see "Venereal Diseases in the Stallion: Viruses," in this section).
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EHV-4 is associated primarily with respiratory tract disease in horses.
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EHV-5 is epidemiologically associated with pulmonary nodular fibrosis in adult horses.
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Equine Herpesviruses
Josh Slater, in Equine Infectious Diseases (Second Edition), 2014
Latency
Latency and reactivation are key features of the epidemiology of EHV-1 and EHV-4 infections and are responsible for the ubiquitous distribution of these viruses in the horse population. The large majority of recovered horses carry latent EHV infections for extended periods, possibly for life.61,62 Latency almost certainly also plays a key role in the biology of EHV-2 and EHV-5, since the majority of adult horses and almost all foals harbor latent infection in circulating lymphocytes. EHV-1 and EHV-4 enter into a latent state in the lymphoreticular system, in circulating and lymph node CD8+ T lymphocytes, and in neurons within the trigeminal ganglia.40 EHV-2 and EHV-5 establish functional latency in circulating lymphocytes and trigeminal ganglia, from which virus can be reactivated in vitro.122,123 Viral DNA can also be detected in other locations,124 including the trigeminal ganglia,45 but it is not clear whether virus is capable of undergoing reactivation from these other sites. These latently infected cells form, by means of periodic reactivations that result in shedding of infectious virus from the host, a transmissible reservoir of infection that maintains all the EHVs in the horse population.
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Disorders of the Neurologic System
Monica Aleman, ... Stephen M. Reed, in Equine Internal Medicine (Fourth Edition), 2018
Virologic Findings
Of the five distinct herpesviruses that are known to infect horses, three are typical α-herpesviruses with a double-stranded DNA genome and are designated EHV-1 (equine abortion virus, formerly known as EHV-1, subtype 1), EHV-4 (equine rhinopneumonitis virus, formerly known as EHV-1, subtype 2), and EHV-3 (equine coital exanthema virus), and two are γ-herpesviruses, designated EHV-2 (formerly called equine cytomegalovirus) and EHV-5 (which has recently been associated with interstitial pulmonary disease).375,376,389-391 In addition, three asinine α-herpesviruses (AHV1, AHV2, and AHV3) have been isolated from donkeys. Of these, AHV3 has been shown by many criteria to be related closely to EHV-1. Indeed, EHV-1 and AHV3 are related more closely to each other than either is to EHV-4.375,391-393 Phylogenetic analysis and epidemiologic evidence suggest that EHV-1 recently has been derived from AHV3 and that donkeys may remain an alternate host for EHV-1, serving as a reservoir to infect horses.389,391
EHV-1 and EHV-4 are distinguishable from EHV-2, EHV-3, and EHV-5 by biologic properties and virus neutralization tests (and distinguishable from each other by restriction endonuclease fingerprinting of DNA, DNA sequences, and several immunologic tests based on monoclonal antibodies to each virus).374-376,389,390,394 EHV-1 and EHV-4 produce eosinophilic intranuclear inclusion bodies in infected cells in vivo and in vitro. Several strains have been identified within EHV-4 and EHV-1, although the epidemiologic, immunologic, and pathogenic significance of this finding is not known. The 1-p and 1-b subtypes of EHV-1 likely are capable of inducing neurologic disease. Apart from differences in endotheliotropism, genetic and antigenic fingerprinting and experiments in baby mice have not yielded clear markers distinguishing EHV-1 strains that induce neurologic disease or abortion (or both).389,395-399 However, a recent analysis of EHV-1 isolates from neurologic and nonneurologic disease outbreaks revealed a point mutation within the DNA polymerase gene that was strongly associated with neuropathogenic disease.400,401 A hamster model has been described showing some potential for discrimination between abortigenic and neuropathogenic EHV-1 strains.402