JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

October 2023

P-V06

                                                                                            

Signalment (JPC #4066069): Tissue from an ox.

 

HISTORY: Unknown

 

HISTOPATHOLOGIC DESCRIPTION: Lung: Diffusely the lumina of all bronchi and bronchioles and to a lesser extent alveoli are expanded by an exudate composed of abundant viable and necrotic neutrophils, fewer alveolar macrophages, abundant sloughed epithelial cells, moderate numbers of viral syncytia, scattered eosinophilic cellular and karyorrhectic necrotic debris, and moderate fibrin, hemorrhage, and edema. The bronchiolar and bronchial epithelium is often either hyperplastic up to 8 cell layers thick, attenuated, and/or necrotic with numerous variably adherent or sloughed viral syncytial cells with up to 8 nuclei. The viral syncytia, and less often other respiratory epithelial cells, contain one to few, 3-6µm diameter, round to oval, eosinophilic intracytoplasmic viral inclusion bodies. The alveolar septa are expanded up to 3 times normal by moderate to abundant hemorrhage, fibrin, edema, congested capillaries, increased numbers of neutrophils and macrophages, and small amounts of cellular and karyorrhectic debris. Occasional alveolar septa are discontinuous or exhibit a loss of differential staining with retention of cellular architecture (septal necrosis). Alveolar septa are frequently lined by abundant type II pneumocyte hyperplasia which is often obscured by the inflammatory infiltrate, and occasionally lined by scattered viral syncytial cells. The interlobular septa, visceral pleura, and perivascular interstitium are moderately expanded by hemorrhage, fibrin, edema, and frequent markedly ectatic lymphatic vessels.

 

MORPHOLOGIC DIAGNOSIS: Lung: Pneumonia, bronchointerstitial, necrotizing and histiocytic, subacute, diffuse, marked, with bronchiolar and alveolar epithelial viral syncytial cells, epithelial intracytoplasmic viral inclusion bodies, and type II pneumocyte hyperplasia, breed unspecified, bovine.

 

ETIOLOGIC DIAGNOSIS: Paramyxoviral pneumonia

 

CAUSE: Bovine Respiratory Syncytial Virus (BRSV)

 

CONDITION: Enzootic pneumonia

 

SYNONYMS: Calf pneumonia, viral pneumonia

 

GENERAL DISCUSSION:

• Bovine respiratory disease complex is a multifactorial disease that often begins with a respiratory infection with BRSV, PI-3 virus, or other virus(es) (e.g. adenovirus, BoHV-1, reovirus, bovine respiratory coronavirus, rhinovirus) 
• BRSV, family pneumoviridae (formerly family paramyxoviridae), is a ssRNA, enveloped 80-450nm virus that is an important cause of acute outbreaks of respiratory disease and “enzootic pneumonia”
• Most often occurs in autumn and early winter, predisposes animals to secondary bacterial infections (e.g. Mannheimia haemolytica); BRSV is an essential component of fatal feedlot pneumonia in cattle; BRSV is also capable of independently producing primary respiratory disease 

 

PATHOGENESIS:

• Difficult to replicate natural disease, so understanding of pathogenesis is limited
• Mechanism of injury: Dysfunction and death of ciliated cells of the conductive system, and alveolar type II pneumocytes 
• Aerosolization and inhalation of viral antigen à deposition on mucous layer of the conductive system à penetration of mucous layer and entry to epithelial cells (unknown mechanism) à **replicates and infects all respiratory epithelial cells; however, ciliated cells are the main target (bronchiolar epithelum)** à virus attaches to ciliated cells via heparin binding domains on G glycoprotein (attachment protein) which mediates attachment of viral particles to the host cell and F glycoprotein (fusion protein)  which induces fusion of infected cells 
• Other encoded proteins include matrix proteins (M, M2, 22K), nucleocapsid protein (N), phosphoprotein (P), polymerase (L), small hydrophobic protein (SH), and non-structural proteins (NS1,2)
• Viral antigen most abundant in the bronchiolar epithelium of cranioventral lung lobes than compared to alveolar type II pneumocytes and macrophages 
• Virus impairs alveolar macrophage function, reduces mucociliary clearance, and may enhance proteolysis to facilitate bacterial invasion of the blood
• Virus may infect and replicate in lung dendritic cells and alveolar macrophages; TLR3 and TLR4 may initiate a cascade of events resulting in lung injury 

 

TYPICAL CLINICAL FINDINGS:

• Clinical signs in cows and calves are similar: high fever, coughing, tachypnea, nasal discharge, and conjunctivitis
• Severe cases may lead to pronounced dyspnea with open mouth breathing
• Can maintain appetite in face of severe respiratory distress, in comparison to those with bacterial pneumonia
• Biphasic course: Transient pyrexia and mild respiratory disease with temporary improvement for days-weeks; subsequent rapid onset of severe respiratory distress

 

TYPICAL GROSS FINDINGS:

• Cranioventral lung lobes: Consolidation and atelectasis; deep red or mottled and rubbery
• Caudodorsal lung lobes: Edematous, heavy and firm; fail to collapse
• Variation in the above two patterns occurs regularly
• +/- subpleural and interlobular emphysema with bullae formation
• +/- hypertrophy and edema of bronchial and mediastinal lymph nodes 

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• HALLMARKS: Bronchointerstitial pneumonia characterized by necrotizing bronchiolitis, formation of bronchiolar and alveolar epithelial syncytia, and exudative and proliferative alveolitis
• Acute lesions: 1-8 days post infection
  • Bronchioles lined by flattened epithelium; lumina contain necrotic epithelial cells, neutrophils, and lymphocytes
  • Alveoli contain moderate numbers of neutrophils and macrophages
  • Alveolar septa thickened with mononuclear cells
  • Infrequent hyaline membranes
  • Bronchiolar syncytia
  • Intracytoplasmic eosinophilic inclusion bodies in syncytial cells and rarely in bronchiolar and alveolar epithelium
• Subacute lesions: > 8 days post infection
  • Represents early repair of the above lesions
  • Bronchiolar epithelium becomes hyperplastic and there is disappearance of syncytial cells as viral antigen is cleared
  • Type II pneumocyte hyperplasia
  • Lymphocytes and plasma cell surround bronchioles and thicken alveolar septa (as early as 10 days post infection)
  • Bronchiolitis obliterans (P-M02, as early as 10 days post infection)
  • +/- medial hypertrophy of pulmonary arterioles (which may develop secondary to pulmonary hypertension and bronchiolitis obliterans)

 

ULTRASTRUCTURAL FINDINGS:

 

ADDITIONAL DIAGNOSTIC TESTS:

• Immunhistochemistry and ELISA 
• PCR may be more effective for subacute or chronic cases- RT-PCR can be positive following vaccination
• Virus isolation not recommended (immune response interferes and virus is easily inactivated by transport)
• Affected cranioventral lung lobes most profitable sites for viral detection

 

DIFFERENTIAL DIAGNOSIS:

• Parainfluenza type 3 (PI-3) (paramyxovirus, respirovirus): Very similar histologically with syncytial cells and ICIB
• Fibrinous bacterial bronchopneumonia: Commonly results in formation of alveolar multinucleated macrophages; presence of bronchiolar multinucleated syncytial cells in BRSV will help differentiate
• Infectious bovine rhinotracheitis (Bovine herpesvirus-1): INIB; not ICIB
• Atypical interstitial pneumonia (P-T01, fog fever): No inclusions, differentiate multinucleated giant cells from syncytial cells at the level of the bronchioles and alveoli

 

COMPARATIVE PATHOLOGY:

• Bighorn sheep: Susceptible to BRSV as a component of epizootic bronchopneumonia of bighorn sheep
• Mice: Pneumonia virus of mice (PMV); Sendai (respirovirus) viral pneumonia 
• Chimpanzees: Respiratory syncytial virus (RSV) a reverse zoonosis from humans; sneezing, rhinorrhea, catarrh and cough; variable severity and often concurrent streptococcal pneumonia
  1. Gross lesions: Reddening of nasopharyngeal mucosa, enlarged tonsils and cervical and tracheobronchial lymph nodes, pulmonary edema consolidation and fibrosis in fatal cases
  2. Histology: Bronchointerstitial pattern with epithelial necrosis, syncytia and IC inclusions
• Human RSV can cause respiratory disease in calves, but there is no evidence that BRSV causes disease in humans

 

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley Blackwell; 2016:32-33.
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 limited; 2016:539-541.   
3. Chien RC, Sorensen NJ, Payton ME, Confer AW. Comparative Histopathology of Bovine Acute Interstitial Pneumonia and Bovine Respiratory Syncytial Virus-Associated Interstitial Pneumonia. J Comp Pathol. 2022;192:23-32.
4. Ferella A, Streitenberger N, Pérez Aguirreburualde MS, et al. Bovine respiratory syncytial virus infection in feedlot cattle cases in Argentina. J Vet Diagn Invest. 2023;35(5):535-542.
5. Headley SA, Okano W, Balbo LC, et. al. Molecular survey of infectious agents associated with bovine respiratory disease in a beef cattle feedlot in southern Brazil. J Vet Diagn Invest. 2018;30(2):249-51.
6. Jones MEB, Gasper DJ, Mitchell E. Bovidae, Antilocapridae, Giraffidae, Tragulidae, Hippopotamidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:135. 
7. Kumagai A, Kawauchi K, Andoh K, Hatama S. Sequence and unique phylogeny of G genes of bovine respiratory syncytial viruses circulating in Japan. J Vet Diagn Invest. 2021;33(1):162-166.
8. Lowenstine LJ, McManamon R, Terio KA. Apes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:386-387. 
9. Lowenstine LJ, Obborn KG. Respiratory system diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2nd ed. San Diego, CA: Elsevier; 2012:46-47. 
10. Mehinagic K, Pilo P, Vidondo B, et. al. Coinfection of Swiss cattle with bovine parainfluenza virus 3 and Mycoplasma bovis at acute and chronic stages of bovine respiratory disease complex. J Vet Diagn Invest. 2019;31(5):674-80.
11. Stanton JB, Zachary JF. Mechanisms of microbial infections. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 7th ed. St Louis, MO: Elsevier; 2022:254.
12. Wachtman L, Mansfield K. Viral diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2nd ed. San Diego, CA: Elsevier; 2012:46-47.

 

Click the slide to view.

---