JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

October 2023

P-V23

 

Signalment (JPC #627741): A six-month old colt.

 

HISTORY: This colt’s mother was immune to African horse sickness. This animal had been vaccinated once against African horse sickness at three months of age.

 

HISTOPATHOLOGIC DESCRIPTION: Lung: Over 90% of alveoli are filled with abundant pale, eosinophilic, homogenous to fibrillar material (edema and fibrin) admixed with low numbers of macrophages, lymphocytes, and minimal hemorrhage. Diffusely, alveolar septa are expanded up to 3 times normal diameter by fibrin, edema, markedly hypertrophied capillary endothelial cells, and few lymphocytes and macrophages. Diffusely, interlobular septa, perivascular and peribronchial adventitia, subpleural connective tissue, and bronchiole-associated lymphoid tissue are moderately to markedly expanded by edema, fibrin, and low numbers of lymphocytes, plasma cells, and macrophages. Endothelial cells within venules are swollen with vacuolated cytoplasm (degeneration) and large, reactive nuclei. Multifocally bronchi and bronchioles contain moderate amounts of hemorrhage, fibrin, and edema. In less affected areas, occasional alveolar lumina are confluent and lined by shortened alveolar septa with blunt, clubbed ends (emphysema).

 

MORPHOLOGIC DIAGNOSIS: Lung: Edema, subpleural, interlobular, interstitial and perivascular, acute, multifocal to coalescing, severe, with endothelial degeneration and mild interstitial pneumonia, breed unspecified, equine.

 

ETIOLOGIC DIAGNOSIS: Orbiviral pneumonia

 

CAUSE: African Horse Sickness virus (AHSV)

 

CONDITION: African Horse Sickness

 

GENERAL DISCUSSION: 

• African horse sickness virus: Genus Orbivirus, family Reoviridae (closely related to bluetongue virus), an infectious, non-contagious, arthropod-borne (arbovirus), peracute to subacute, often fatal disease of Equidae characterized by respiratory distress and/or cardiovascular failure
• AHS is the only OIE-notifiable equine disease: importance due to extreme lethal potential in susceptible horses and very wide distribution of the arthropod vector; concern due to recent spread of related Orbiviral disease (bluetongue virus)
• Horses, donkeys, and mules (solipeds); Horses are most susceptible; mortality rates reach 95% in horses, 80% in mules; South African donkey and zebra are resistant; zebras are likely the natural host and reservoir
• Nine major antigenic types which do not allow for solid immunity because so much diversity within types
• Endemic in Africa, the Middle East, India, and Spain; not found in the US 
• Seasonal occurrence because the arthropod vector (primarily Culicoides) thrives in hot, wet conditions; also, AHSV requires an ambient temperature of greater than 15 degrees C to replicate and be transmitted by the vector
• The disease is divided into four different forms based on clinical signs:  Pulmonary (peracute), cardiac (subacute), mixed (cardiopulmonary), and mild (African horse sickness fever, occurs in resistant species e.g. mules, donkeys, zebras and in horses with immunity to heterologous strains); same pathogenesis and gross findings

 

PATHOGENESIS:

• Bite of infected arthropod vector (Culicoides midges) à enter circulation or deposited in connective tissues à infects macrophages and lymphocytes or cell-free viremia à initial viral replication in regional lymph nodes à viremia (leukocyte trafficking or free) à infection of target organs (tropism for endothelial cells of lungs, heart, spleen, lymph nodes, liver, and kidney) and, to a lesser extent, dendritic, lymphoid, and monocyte-macrophage cells especially of spleen, lymph nodes, lung, and large intestine) à virally induced endothelial cell dysfunction, endothelial cell lysis, activation of infected macrophages with subsequent cytokine production (IL-1, IL-6, TNFα, IFN-β) à increased vascular permeability à edema, hemorrhage, microthrombosis
• Four different forms may be due to differences in viral tropism for different organs
• Virulence factors:

• Attachment proteins: 2 capsid structural proteins VP2 and VP5 that bind to glycosaminoglycans on target cell membranes and facilitate viral attachment and entry
• NS3, a protein inserted in the target cell membrane by the virus, may be cytotoxic (acting as a viroporin), involved in membrane damage and release of virus from infected cells

 

TYPICAL CLINICAL FINDINGS:

• Pulmonary (peracute) form: Most common; short duration fever followed by acute onset severe respiratory distress, rapid death (within a few hours) from pulmonary edema; 3-5 day incubation period
• Cardiac (subacute) form: Recurrent fever lasting 3-6 days, then as the fever subsides, subcutaneous and interfascial (cardiogenic) edema develops; mortality as high as 50%, with death due to cardiac failure and pulmonary edema; 7-14 day incubation
• Cardiopulmonary (mixed) form: Mixture of the cardiac and pulmonary form, most of the fatal cases of AHS can be considered of this form; initial mild pulmonary signs followed by characteristic swelling of the head and death due to cardiac failure, or cardiac form followed by marked dyspnea; 5-7 day incubation; death in 3-6 days
• Horse sickness fever (mild form): Fever; minimal clinical signs similar to equine influenza, often transient with full recovery, may go unnoticed in outbreaks, mortality rate is ~70%

 

TYPICAL GROSS FINDINGS:

• All forms: Vascular (endothelial) injury à edema, active hyperemia, petechial and ecchymotic hemorrhages, hydrothorax, hydropericardium, ascites, and rhabdomyocyte necrosis
• Pulmonary form:  

• Lung: Copious fluid and froth in the airways, pulmonary edema (especially ventral lungs), lungs fail to collapse, hydrothorax
• Other organs: Periaortic and peritracheal edema, diffuse or patchy hyperemia of the glandular fundus of the stomach, hyperemia and petechial hemorrhages of the mucosa and serosa of the small and large intestines, subcapsular hemorrhages in the spleen, renal cortex congestion, lymph node enlargement and edema, variable hydropericardium, petechial hemorrhages of the pericardium

• Cardiac form: 

• Heart: Massive hydropericardium (often >2L fluid); epicardial and endocardial ecchymoses 

• Other tissues: Edema of the subcutaneous, subfascial, subserous, and intermuscular tissues of the head and neck (especially palpebral and supraorbital tissues, nuchal ligament) +/- lower neck, brisket, shoulders; lungs typically normal to slightly engorged; diffuse gastrointestinal submucosal edema; terminally, petechial hemorrhages usually occur on the conjunctiva and ventral surface of the tongue

• Mixed form: Any combination of the above lesions
• Mild form: No significant gross lesions

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Endothelial swelling (degeneration) and lytic necrosis, edema, +/- hemorrhage, +/- vascular thrombosis/infarction
• Lung: Interstitial, alveolar, subpleural, and perivascular edema; alveolar exudate composed of fibrin, protein rich fluid, and few mixed inflammatory cells; venule endothelial cells swollen with vacuolated cytoplasm and large reactive nuclei (direct viral cytotoxicity); fibrinous microthrombi; capillary congestion
• Heart: Myocardial, epicardial, and endocardial hemorrhage; myocardial edema; multifocal myocardial necrosis with inflammation
• Subcutis, intramuscular tissue, lymph nodes, gastrointestinal tract: Edema

 

ULTRASTRUCTURE:

• Icosahedral; approximately 60-80nm in diameter; paracrystalline arrays
• Vascular endothelium: hypertrophy, alterations in intercellular junctions, subendothelial deposition of cellular debris/fibrin, or loss

 

ADDITIONAL DIAGNOSTIC TESTS:

 

DIFFERENTIAL DIAGNOSIS:

• Hydrothorax:

• Cattle: Right-sided heart failure
• Dogs and cats: Congestive heart failure, chronic hepatic disease, or congestive heart failure, nephrotic syndrome
• Pigs: Mulberry heart disease

• Equine viral arteritis (Arterivirus): Fibrinoid vasculitis, interstitial pneumonia, ventral and lower limb edema, serous nasal discharge, widespread hemorrhage, pulmonary edema, hydrothorax, and hydroperitoneum 
• Hendra virus (P-V26, Paramyxoviridae): Alveolar edema, vasculitis, endothelial syncytial cells; pulmonary and visceral edema
• Equine infectious anemia (H-V10, Lentivirus): Immune mediated (C3 complement) hemolysis, edema, petechia, hepatosplenomegaly, erythroid hyperplasia
• Purpura hemorrhagica (post streptococcal leukocytoclastic vasculitis): severe widespread hemorrhage and edema (face and limbs)
• Babesia caballi, B. equi (Equine Babesiosis/Piroplasmosis): Fever, anemia, supraorbital edema; intraerythrocytic protozoa evident during acute phase
• Equine viral rhinopneumonitis (P-V10, Herpesvirus, EHV-1): Bronchointerstitial pneumonia with interlobular septal edema, eosinophilic intranuclear inclusions in bronchial and alveolar epithelium
• Equine encephalosis virus (Orbivirus):F swelling, CNS signs especially loss of control or incoordination of hindquarters
• Surra (Trypanosoma evansi), other trypanosomes (T. congolense, T. vivax, T. brucei brucei): Fatal in horses, camel, and dogs, transmitted by tsetse and other flies, results in intermittent fever, anemia, and weight loss
• Anthrax (H-B01, Bacillus anthracis): Diffuse hemorrhage, edema, large intravascular bacilli

 

COMPARATIVE PATHOLOGY:

• Dogs: The pulmonary form of infection (severe respiratory distress, high mortality) can occur following ingestion of infected horseflesh; infective viral dose is very high
• Zebras are the natural host and reservoir, rarely exhibit clinical signs.
• AHS has been experimentally induced in goats, guinea pigs, mice, ferrets, and rats
• AHS is reported in elephants, camels, and other wildlife in sub-Saharan Africa

 

Other Selected Orbiviruses: Vasculitis-induced lesions

• Equine: Equine encephalosis virus (facial swelling, pelvic limb incoordination)
• Ruminants: Bluetongue virus
• Cattle: Ibaraki virus
• Deer: Epizootic hemorrhagic disease virus

            

 

 

REFERENCES:

1. 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; 2022:596, 604.
2. Gal A, Castillo-Alcala F. Cardiovascular System, Pericardial Cavity, and Lymphatic Vessels. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:659, 685.
3. Robinson WF, Robinson NA. Cardiovascular system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier; 2016:72-74.
4. Stanton JB, Zachary JF. Mechanisms of Microbial Infections. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:258-259.

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