JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

October 2023

P-V10

 

Signalment (JPC #N93-1 10): 1-day-old thoroughbred foal

 

HISTORY: This foal was weak from birth and showed an elevated respiratory rate and effort. Mucous membranes were hyperemic and icteric. Supportive care and treatment, including positive pressure ventilation, were pursued without success. The foal developed pulmonary hemorrhage and edema terminally and died within one day of its birth.

 

HISTOPATHOLOGIC DESCRIPTION:  

Lung: Diffusely, bronchial and bronchiolar epithelium is either sloughed or necrotic with shrunken, hypereosinophilic cytoplasm and pyknotic nuclei, or is degenerate with swollen cytoplasm and loss of cilia. There are frequent multinucleated viral syncytial cells of the bronchial and bronchiolar epithelium. Epithelial and syncytial cells multifocally contain 4µm, eosinophilic, intranuclear inclusion bodies that marginate the chromatin. The bronchiolar submucosa is expanded by necrotic debris, viable and necrotic neutrophils, macrophages, fibrin, hemorrhage, and edema. Multifocally, alveolar septa are replaced by eosinophilic cellular debris (septal necrosis) or expanded by neutrophils and macrophages. Alveolar epithelial cells are covered by a brightly eosinophilic, 7µm thick layer of polymerized fibrin (hyaline membrane). Alveolar spaces frequently contain a variable amount of fibrin, hemorrhage, edema, scattered necrotic cellular debris, and neutrophils. Diffusely, the subpleural space, intralobular septa, perivascular, peribronchial, and peribronchiolar areas are markedly expanded up to 500µm by abundant hemorrhage, fibrin, edema, and few macrophages, neutrophils, and lymphocytes.

 

MORPHOLOGIC DIAGNOSIS: Lung: Pneumonia, bronchointerstitial, fibrinonecrotic, acute, diffuse, marked, with hemorrhage, alveolar hyaline membranes, epithelial syncytial cells, and epithelial intranuclear viral inclusion bodies, Thoroughbred, equine.  

 

ETIOLOGIC DIAGNOSIS: Equine herpesviral pneumonia (in utero infection)

 

CAUSE: Equine herpesvirus-1 (EHV-1) 

 

CONDITION: Equine viral rhinopneumonitis

 

GENERAL DISCUSSION: 

• Equid herpesvirus 1 (EHV-1), family Herpesviridae, subfamily Alphahepesvirinae, genus Varicellovirus
  1. Subtype 1 and subtype 2; separated based on restriction endonuclease cleavage of the viral DNA
  2. Subtype 1 causes more severe respiratory disease and is more frequently isolated from aborted foals and foals with neonatal EHV-1 related disease; suspected to be the only subtype to cause neurologic disease
  3. Subtype 2 is commonly isolated from mild upper respiratory disease; infrequently the cause of abortions
• EHV-4 may cause similar disease; less common and sporadic 
• Worldwide distribution; differing disease patterns by region likely due to the differing mixtures of subtypes 1 and 2 
• Respiratory, neurologic, systemic neonatal disease, abortion, and chorioretinopathy (Hussey, Vet Pathol 2019)

 

PATHOGENESIS: 

• Pulmonary (EHV-1 and EHV-4): Virus infects nasal respiratory epithelial cells > virus replication in the nasopharynx > local epithelial necrosis and inflammation > rhinitis, nasal discharge > virus shed 2-10 days post infection during pyrexia (virus shedding can last up to 3 weeks) >latency established in neuronal cells (ex. trigeminal ganglion), lymphocytes, and lung epithelial cells (EHV-4 only)
  1. Rarely extends to the trachea
  2. Viremia dependent on the strain of the virus and prior exposure of the host
• Systemic (EHV-1 only): Virus infects nasal respiratory epithelial cells > virus replication in the nasopharynx and associated lymphoid tissue (within 24-48 hours) > cell-associated viremia between 4-10 dpi  > virus transported to sites of secondary infection > endothelial cell infection, inflammation, thrombosis, and tissue necrosis (Hussey, Vet Pathol 2019)
• Seroconversion is common; nearly 100% of horses have EHV-4 seroconversion 
• S. zooepidemicus and other streptococci are common respiratory co-isolates
• Classic low-level immunity; common with herpesviruses
• EHV-1 single nucleotide polymorphism (SNP) coding change D₇₅₂/G₂₂₅₄ is strongly associated with neuropathogenicity and high levels of viremia; SNP from aspargine (N₇₅₂) to aspartate (D₇₅₂) (Lechmann, J Vet Diagn Invest.  2019)
• Glycoprotein D (gD) is an important viral determinant for cellular entry; differences between EHV-1 and EHV-4 gD may be responsible for the systemic infections of EHV-1 vs respiratory specific infections of EHV-4 (Hussey, Vet Pathol 2019)
• Abortion: See R-V01 – Equine Viral Abortion for detailed pathogenesis of EHV-1 abortions
  1. Mares that abort generally do not experience respiratory disease

 

TYPICAL CLINICAL FINDINGS:

• Juvenile and adult horses 
  1. Usually uncomplicated rhinitis; febrile; mucopurulent nasal discharge 
  2. Cough if the infection extends to trachea
  3. Rarely fatal unless complicated by secondary bacterial infection 
  4. Late term abortion
• Young horses: Rare; biphasic fever, depression, anorexia, coughing and nasal and ocular discharge; may lead to secondary bacterial infection lasting 2-3 weeks (Hussey, Vet Pathol 2019)

 

TYPICAL GROSS FINDINGS: 

• Aborted fetus: 
  1. Consistent severe pulmonary edema; lungs are heavy and rubbery with impressions of the ribs and pitting under pressure; edema of interlobular septa; lungs may be darker or lighter than normal with multiple 2-4 mm tan to white foci of necrosis and petechial hemorrhages; casts of fibrin and sloughed epithelial cells in bronchi and trachea
  2. Petechia and ecchymoses throughout body, but most common in the upper respiratory mucosae
  3. Edema of subcutis and fascia; amber fluid in body cavities
  4. Slight icteric discoloration and meconium staining of the eponychia and amnion
  5. 50% of aborted fetuses have minute to 5 mm, gray to white foci of necrosis in the liver
  6. Occasional hemorrhagic necrosis of renal cortices
• Neonatal foals
  1. Lungs are heavy with a diffuse rubbery-firm texture; multifocal areas of inconspicuous focal necrosis
• Yearlings or adult horses
  1. Rare systemic disease
  2. Pulmonary or systemic necrotizing vasculitis; pulmonary edema and hemorrhage; lymphoid necrosis; encephalomyelitis with vasculitis 
• Foals may be born alive, but it is unknown whether any survive

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Aborted fetus
  1. Pulmonary interlobular septa are edematous and contain mononuclear inflammation; edema, hemorrhage, and necrosis throughout lung; fibrinous alveolar exudation and necrosis of bronchial and alveolar epithelial cells 
  2. Acidophilic intranuclear inclusion bodies in the bronchial and alveolar epithelial cells are pathognomonic
  3. Liver lesions are minute and may be overlooked; inconsistently there are few intranuclear acidophilic inclusion bodies in hepatic parenchymal cells; focal necrosis; edema; leukocytes admixed with necrosis and within portal regions
  4. Rarely, diffuse hepatitis without focal necrosis 
  5. Necrosis of germinal centers in splenic follicles, thymus and other lymphoid tissues; focal splenic hemorrhage; rare inclusions
  6. Placenta is normal   
• Neonatal foal
  1. Severe bronchointerstitial pneumonia; multifocal necrosis in liver, spleen, adrenal gland, and other tissues; prominent intranuclear inclusion bodies; rare syncytia 
• CNS: Characteristic lesion is nonsuppurative necrotizing vasculitis and thrombosis

 

ULTRASTRUCTURE:

• Enveloped, 150 nm diameter virions with a 100 nm icosahedral nucelocapsid
• Capsid surrounded by "tegument" enclosed by a lipoprotein envelope
• Envelope covered by small glycoprotein peplomers (heparan sulfate proteoglycan)

 

ADDITIONAL DIAGNOSTIC TESTS:

• Virus-specific PCR or virus isolation on nasal swabs material 
  1. PCR combined with sequencing is effective at discriminating between neuropathogenic and non-neuropathogenic EHV-1 strains (Lechmann, J Vet Diagn Invest.  2019)
• Serology is not useful due to widespread exposure 

 

DIFFERENTIAL DIAGNOSIS:

Viral respiratory infections in foals:

• Equine arteritis virus (Arterivirus, Arteriviridae) - Rapidly progressive bronchointerstitial pneumonia and intestinal necrosis in foals and yearlings; no inclusions
• Equine adenovirus (Mastadenovirus, Adenoviridae) in SCID foals - Bronchiolitis and pneumonia, pancreatic and salivary gland necrosis; basophilic INIB
• EHV-2 (Equine Cytomegalovirus, Gammaherpesvirus) - Purulent nasal discharge and lymphadenopathy
• EHV-3 (Equine coital exanthema, Alphaherpesvirus) - Subclinical respiratory infection in yearling horses
• EHV-4 (Equine rhinopneumonitis, Alphaherpesvirus) - Acute respiratory disease in foals > 2 months, weanlings and yearlings; less common and sporadic
• EHV-5 (P-V27) (Equine multinodular pulmonary fibrosis, Gammaherpesvirus) – Multinodular pulmonary fibrosis
• Equine paramyxoviral pneumonia (P-V26) (Hendra virus; family Paramyxoviridae, genus Henipavirus) - Marked pulmonary edema with gelatinous sub-pleural lymphangiectasia; diffuse alveolar edema with vasculitis, capillary thrombosis, ectatic lymphatics, fibrinous exudate, hemorrhage, and syncytial cells within vessels
• African horse sickness (Orbivirus; family Reoviridae) – Massive pulmonary edema

 

COMPARATIVE PATHOLOGY:

Herpesviral Respiratory Diseases:

• Canine Herpesvirus (U-V03) (Canine Herpesvirus 1, Alphaherpesvirus)
• Feline Herpesvirus (P-V09) (Feline Herpesvirus 1, Alphaherpesvirus)
• Infectious Bovine Rhinotracheitis (Bovine Herpesvirus 1, Alphaherpesvirus)
• Malignant Catarrhal Fever (D-V15, S-V01, U-V02) (Alcelaphine Herpesvirus 1 or Ovine Herpesvirus 2, Gammaherpesviruses)
• Bovine Herpesvirus (Bovine Herpesvirus 4)
• Caprine Herpesvirus (Caprine Herpesvirus 1, Alphaherpesvirus)
• Pseudorabies (N-V07) (Suid Herpesvirus 1, Alphaherpesvirus)
• Porcine Cytomegalovirus (P-V13) (Porcine Herpesvirus 2, Betaherpesvirus)
• Avian Infectious laryngotracheitis (P-V11) (Gallid Herpesvirus 1, Alphaherpesvirus)
• OWM & NWM NHP and Apes (Cytomegaloviruses, Betaherpesviruses)
• Apes:  Human Herpesvirus (Human Herpesvirus 1 & 2, Alphaherpesviruses)
• Elephant Endotheliotropic Herpes Virus (EEHV) Disease (C-V05) (EEHV 1-7, Betaherpesvirus)
• Rabbits (Leporid Herpesvirus 3, Gammaherpesvirus)

 

REFERENCES:

1. Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol. 1. 6th ed. St. Louis, MO: Elsevier; 2016:383-384.
2. Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol. 2. 6th ed. St. Louis, MO: Elsevier; 2016:537, 568. 
3. Delaney MA, Treuting PM, Rothenburger JL. Lagomorpha. In:  Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, Cambridge, MA Academic Press; 2018:490.
4. Durham AC, Boes KM. Bone Marrow, Blood Cells, and the Lymphoid/Lymphatic System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:881.
5. Hussey GS. Key determinants in the pathogenesis of equine herpesvirus 1 and 4 infections. Vet Pathol. 2019;56(5):656-659.
6. Landolfi JA, Terrell SP. Proboscidae. In:  Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, Cambridge, MA Academic Press; 2018: 419-421.
7. Lechmann J, Schoster A, Ernstberger M, Fouche N, Fraefel C, Bachofen C. A nove PCR protocol for detection and differentiation of neuropathogenic and non-neuropathogenic equid alphaherpesvirus 1. J Vet Diagn Invest. 2019;31(5):696-703.
8. Lopez A, Martinson SA. Respiratory System, Thoracic Cavities, Mediastinum, and Pleurae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:602. 
9. Lowenstine LJ, McManamon R, Terio KA. Apes. In:  Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, Cambridge, MA Academic Press; 2018:383-385.
10. Matz-Rensing M, Lowenstine LJ. New world and old world monkeys. In:   Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals, Cambridge, MA Academic Press; 2018:350-351.
11. Miller AD, Porter, BF. Nervous System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:861-962.
12. Minato E, Aoshima K, Kobayashi A, Ohnishi N, Sasaki N, Kimura T. Exogenous Expression of Equine MHC Class I Molecules in Mice Increases Susceptibility to Equine Herpesvirus 1 Pulmonary Infection. Vet Pathol. 2019;56(5):703-710.
13. Schlafer DH, Foster RA. Female genital system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol. 3. 6th ed. St. Louis, MO: Elsevier; 2016:435-437.

 

 

 

 

 

 

 

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