JPC SYSTEMIC PATHOLOGY
Signalment (JPC #1761490): Equine fetus
HISTORY: This 5-day-old male Quarterhorse became depressed, weak, and stopped nursing by 36 hours of age. His condition progressively worsened and he presented to the veterinarian at 48 hours of age. Bloodwork revealed severe leukopenia, azotemia, hypoproteinemia, severe dehydration, hypoxemia, hypercapnia, and acidosis, then he developed thrombocytopenia. His condition continued to worsen despite medical therapy, he broke with severe diarrhea, and then died.
HISTOPATHOLOGIC DESCRIPTION: Lung: The pleura and interlobular septa are multifocally and moderately expanded by acute hemorrhage and edema. Within these areas, and scattered throughout the remainder of the section, small vessel walls are expanded mildly by extravasated protein, erythrocytes, and small amounts of cellular debris (vasculitis). Multifocally, endothelial nuclei rarely are expanded by a single, 2-4um, eosinophilic viral inclusion that peripheralizes the chromatin. Diffusely, alveolar septa are expanded by congestion, edema, hypertrophic endothelium, few macrophages, few degenerate neutrophils, and occasional cellular debris (necrosis). Alveolar lumina contain low numbers of alveolar macrophages, degenerate neutrophils, and small to moderate amounts of fibrin. Bronchiolar epithelium is autolytic, sloughed into the lumen in sheets.
Liver: Multifocally, there are random small foci of hepatocellular necrosis and loss that are infiltrated by low numbers of histiocytes and admixed with moderate hemorrhage replacing disrupted hepatic sinusoids. Within these areas, hepatocytes are shrunken and fragmented with hypereosinophilic cytoplasm and karyorrhexis (necrosis). Rarely, there are multinucleated hepatocytes (viral syncytia). Within and at the periphery of necrotic, hepatocytes occasionally contain a single, 2-4um, eosinophilic, intranuclear viral inclusion that peripheralizes the chromatin. There are low numbers of periportal lymphocytes. There is mild periportal and capsular edema.
Adrenal gland: Within the cortex, predominantly within the zona reticularis and zona fasciculata, there are multifocal to coalescing areas of lytic necrosis characterized by loss of architecture with replacement by cellular and karyorrhectic debris admixed with abundant hemorrhage, fibrin, edema, and low numbers of degenerate neutrophils. In these foci, cortical cells are shrunken with hypereosinophilic cytoplasm and pyknotic or karyorrhectic nuclei. Scattered throughout and at the periphery of necrotic foci, cortical cells contain a single intranuclear, 2-4um, eosinophilic viral inclusion that peripheralizes the chromatin. There are rare multinucleated viral syncytia with intranuclear viral inclusions as previously described.
- Adrenal gland, cortex: Adrenalitis, necrohemorrhagic, multifocal to coalescing, severe, with intranuclear viral inclusion bodies, Quarterhorse, equine.
- Liver: Hepatitis, necrotizing, multifocal and random, marked, with intranuclear viral inclusion bodies.
- Lung: Pneumonia, interstitial, necrotizing, diffuse, mild, with mild vasculitis and rare intranuclear viral inclusion bodies.
ETIOLOGIC DIAGNOSIS: Herpesviral pneumonia, hepatitis, and adrenalitis
CAUSE: Equine Herpesvirus-1 (EHV-1)
CONDITION: Equine Viral Abortion
- Equine herpesvirus-1 (EHV-1), an alphaherpesvirus, genus Varicellovirus, is a worldwide important cause of abortions in horses and generalized perinatal foal infections and death; this virus less frequently causes neurological and respiratory disease (see P-V10) in horses
- The virus is very common, and most horses are exposed by 1 year of age
- Two recognized subtypes based on restriction endonuclease cleavage of viral DNA; both cause respiratory disease, abortion, and neonatal disease;
- Subtype 1 is less common but more severe and more associated with abortion, and probably the only one associated with neurologic disease
- Subtype 2 is more common, causes mild respiratory disease, and is infrequently associated with abortion
- Secondary bacterial pulmonary infection, e.g. Streptococcus zooepidemicus or other streptococci, is common
- A point mutation has been identified to differentiate between neuropathogenic from non-neuropathogenic strains of EHV-1, but horses infected with non-neuropathogenic strains can also develop neurologic disease, suggesting other unidentified factors also contribute
- Equine herpesvirus-4 is less common, sporadic, and causes a similar disease to EHV-1; one reference states that equine herpesvirus-3 (equine coital exanthema) can also rarely cause a similar disease
- Alphaherpesviruses are enveloped, icosahedral, 150 nm diameter, dsDNA viruses with intranuclear replication
- Despite high frequency of exposure, the level of immunity is generally low (like other herpesviruses)
- Fetal death does not occur until the onset of abortion
- Fetal stress à lymphoid necrosis
- Time from virus exposure (recrudescence of latent infection or reinfection) to abortion ranges from 9 days to several months
- Inhalation, ingestion of infective nasal discharge or aborted fetal material, or via fomites à virus proliferates rapidly in nasal, pharyngeal, and tonsillar mucosa à infects mononuclear leukocytes (primarily T-lymphocytes) à viremia à endothelial infection in numerous sites including lungs, uterus, and CNS àvasculitis, thrombosis, ischemia, necrosis
- Abortion occurs after endometrial arteriolar endothelial necrosis à thrombosis, edema, hemorrhage, infarction à separation of maternal and fetal layers of the placenta à virus from endometrium allowed into the placenta then to the fetus à fetal infection (fetal endothelium and cells of most organs)
TYPICAL CLINICAL FINDINGS:
- 95% of EHV-1 abortions occur in the last 3 months of gestation and has not produced abortion before 5 months of gestation
- No premonitory signs noted in mare (typically no respiratory signs in mares that abort), abortion is usually rapid and uncomplicated; fetus is aborted fresh or foal is born alive at or near term, and many die within the first few days of life from severe interstitial pneumonia and secondary bacteremia
- Respiratory disease:
- Mares: Inapparent or mild upper respiratory tract infection
- Neonatal foals: Dyspnea, increased respiratory rate, fever, congestion of mucous membranes, serous to mucopurulent nasal discharge, +/- coughing
TYPICAL GROSS FINDINGS:
- Aborted fetus may have characteristic and diagnostic lesions:
- Aborted in fresh state
- Severe pulmonary edema is the most consistent gross lesion; heavy, rubbery lungs with rib impressions, pitting response to pressure, interlobular septal edema, and may have foci of necrosis; may have fibrin casts in the bronchi and rarely the trachea
- Few to numerous foci of random hepatic necrosis in 50% of aborted fetuses, classic lesion as with most herpesviruses
- Edema of subcutis and fascia, body cavity effusion
- Slight icterus
- Meconium staining of the eponychia and amnion
- Petechial hemorrhage especially in upper respiratory mucosa
- Thymus may be small with edema
- +/- Renal cortex multifocal necrosis
- The placenta is normal
- Foals born alive with early death
- Multifocal hepatic necrosis is not present
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Eosinophilic intranuclear viral inclusions in bronchiolar and alveolar epithelium, hepatocytes, and lymphoid reticular cells
- Aborted fetus:
- Lungs: Pulmonary and septal edema with mononuclear inflammation (diffuse pneumonia); fibrinous alveolar exudate; hemorrhage; multifocal epithelial necrosis with intranuclear viral inclusion bodies in bronchial and alveolar epithelium (specific) and syncytial cells
- Liver: Foci of necrosis (less common than lung lesions, may be extremely small); low numbers of hepatocellular eosinophilic intranuclear inclusions (inconsistent finding); edema, leukocytes in necrotic foci and portal triads; less commonly diffuse hepatitis without focal necrosis
- Lymphoid tissues (splenic follicles, thymus, lymph nodes): Germinal center/lymphoid necrosis, focal hemorrhage; loss of distinction between cortex and medulla in thymic lobules due to cortical cell loss; eosinophilic intranuclear viral inclusions may be present in these foci including thymic medullary epithelium
- Multiorgan microscopic foci of necrosis +/- syncytial cells
- The placenta is normal
- Foals born alive with early death: Liver lesions are not present, but focal necrosis of intestinal crypt epithelium with hemorrhage is sometimes present
- Enveloped, 150 nm diameter virions with a 100 nm icosahedral nucelocapsid
ADDITIONAL DIAGNOSTIC TESTS:
- Immunofluorescent antibody, virus isolation
- ELISA (differentiates EHV-1 from EHV-4)
- PCR used to differentiate between subtype 1 and 2
- Serology is of limited use; nearly 100% of horses have seroconverted to both EHV-1 and EHV-4
- Equine viral arteritis (Arterivirus): 5-10 months gestation; fetal autolysis, occasionally myocardial arteritis
- Most common: Streptococcus , Escherichia coli, Pseudomondas sp., Klebsiella sp., and Staphylococcus sp.
- Streptococcus zooepidemicus: Any gestational stage; fibrinonecrotic placentitis around cervical star; fetal autolysis; variable degrees of inflammation in fetal tissues
- Leptospira (L. pomona most common): 3.5-11 months gestation; fetal interstitial nephritis
- Nocardioform actinomycete: Late gestation abortion, still birth, and premature birth; focally extensive, well-demarcated, necrotizing placentitis involving base of horns; brown mucoid exudate; filamentous bacteria along chorionic surface; also implicated in cystic adenomatous hyperplasia of the allantois (see R-N11)
- Salmonella (S. Typhimurium most common; S. Abortus-equi rarely): Late gestation; maternal septicemia; fibrinonecrotic placentitis; variable degrees of inflammation in fetal tissues
Fungal: Late gestation
- Aspergillus fumigatus & Mucor: Chronic necrotizing placentitis especially around cervical star
- Candida: Diffuse necrotizing and proliferative placentitis
- Histoplasma capsulatum: Multifocal granulomatous placentitis
- Twinning: Most common non-infectious cause of abortion; mid-gestation
- Torsion of umbilical cord: Excessively long, allowing torsion in utero
- Premature placental separation ("Red Bag")
- Uterine body pregnancy
- Fetal congenital abnormalities
- Mare Reproductive Loss Syndrome: Early and late gestation; often premature placental separation; associated with presence of eastern tent caterpillars (ETC) in the spring, fibrinous pericarditis, and severe unilateral uveitis
- Two theories for reproductive loss: 1: an unidentified toxin related to the ETC; 2: mechanical trauma from the ETC setae allow secondary bacterial infection
Neonatal Equine Pneumonia:
- Streptococcus zooepidemicus: Most common cause of bacterial pneumonia in foals and a common cause of pleuropneumonia in older horses; fibrinous bronchopneumonia
- Rhodococcus equi: Pyogranulomatous pneumonia
- Embolic pneumonia: Streptococcus equi, Actinobacillus equuli, Pasteurella multocida, Bordatella bronchiseptica, E. coli, Bacteroides , Salmonella sp., and Chlamydia psittaci
- Equine influenza virus (Orthomyxovirus): Mild self-limiting bronchointerstitial pneumonia
- Rhinovirus (Picornavirus): Typically affects upper respiratory system not lungs
- Equine adenovirus: Necrotizing pneumonia; smudgy basophilic intranuclear inclusions in bronchial, bronchiolar, and alveolar epithelial cells; usually in SCID Arabian foals
- Equine Viral Arteritis (Arterivirus): Interstitial pneumonia with arteritis and edema
- Pneumocystis carinii: Interstitial pneumonia, usually in immunocompromised foals; presence of carinii in silver stained sections
- Zebra-born EHV-1: Isolated from a Grevy’s zebra fetus, a Persian onager fetus, Thomson’s gazelles, polar bears, black bears, guinea pigs, and an Indian rhinoceros in association with neurologic disease and abortion; recent report of meningoencephalitis in a Thomson’s gazelle (Sakaguchi 2017)
- EHV-9: The most recently recognized alphaherpesvirus, zebras are considered the natural host, characteristic lesion is fatal encephalitis; associated with an outbreak of epizootic encephalitis in Thomson’s gazelles; recent report of fatal infection in a Grant’s zebra (Moeller 2018); recent study on the effect of mouse strain on EHV-9 infection concluded that C3H, C57BL, DBA, BALB/c-nu/nu, and ICR were the most susceptible while BALB/c was less susceptible (El-Nahass 2017)
- EHV-5: gammaherpesvirus, causes multinodular pulmonary fibrosis in horses, there was no evidence of herpesviral infection in West Highland White Terriers with similar lesions in a recent report (Roels 2016)
Other Significant Alphaherpesviruses:
- Gallid herpesvirus 1 – Avian infectious laryngotracheitis
- Gallid herpesvirus 2 – Marek's disease (used to be a gamma, lymphoproliferative)
- Anatid herpesvirus 1 – Duck virus enteritis/duck plague
- Psittacid herpesvirus – Pacheco’s disease
- Bovine herpesvirus 1 – Infectious bovine rhinotracheitis & infectious pustular vulvovaginitis
- May also cause abortion (less common)
- Bovine herpesvirus 2 – Bovine mammillitis/pseudo-lumpy skin disease
- Bovine herpesvirus 5 – Bovine herpes encephalitis
- Porcine herpesvirus 1 – Pseudorabies/Aujeszky’s Disease
- May also cause inflammation in the adrenal gland with necrosis in intranuclear inclusion bodies
- May also cause abortion, stillbirth, reduced fertility; in cases of abortion may see chorionic villar necrosis and necrosis in the liver, adrenal gland and spleen of fetus with possible intranuclear inclusion bodies
- Equid herpesvirus 3 – Equine coital exanthema
- Equid herpesvirus 4 – Equine rhinopneumonitis
- Equid herpesvirus 9 – Gazelle herpesvirus (original name)
- Asinine herpesvirus 3 & 4 – Donkey pneumonia
- Canine herpesvirus 1
- May also cause abortions
- Feline herpesvirus 1 – Feline viral rhinotracheitis
- Cercopithecine herpesvirus 1 – B virus of macaques; lethal in humans
- Saimirine herpesvirus 1 – Herpes tamarinus/Herpes T of squirrel monkeys; lethal in owl monkeys
- Human herpesvirus 1 & 2 – Herpes simplex; lethal in owl monkeys
- Caswell JL, Williams KJ. The respiratory system. In: Maxie MG, ed. Jubb, Kennedy, and Palmers Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Saunders Elsevier; 2016:568.
- El-Nahass E, El-Habashi N, El-Dakhly KM, Tsuchiya Y, Yanai T. Effect of mouse strain on equine herpesvirus-9 infection. Jour Comp Pathol. 2017;157(1):67-74.
- Foster RA. Female reproductive system and mammae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2016: 1175, 1177.
- Moeller RB Jr, Crossley B, Pipkin A, Li Y, Balasuriya UBR. Systemic equid alphaherpesvirus 9 in a Grant’s zebra. Jour Vet Diagn Invest. 2018;30(4):580-583.
- Roels E, Dourcy M, Holopainen S, et. al. No evidence of herpesvirus infection in West Highland white terriers with canine idiopathic pulmonary fibrosis. Vet Pathol. 2016;53(6):1210-1212.
- Rosol TJ, Gröne A. Endocrine glands. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016:340.
- Sakaguchi K, Kim K, Langohr I, et. al. Zebra-born neurotropic equid herpesvirus 1 meningoencephalitis in a Thomson’s gazelle (Eudorcas thomsonii). J Vet Diagn Invest. 2017;29(4):548-556.
- Schlafer DH, Foster RA. Female genital system. In: Maxie MG, ed. Jubb Kennedy and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:399, 432, 435-437.
- Valli VEO, Kiupel M, Bienzle D. Hematopoietic system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:145-146, 182-183.