JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

September 2023

P-T01

 

Signalment (JPC #1782717): 3-year-old Chianina bull

 

HISTORY: History of a cough.

 

HISTOPATHOLOGIC DESCRIPTION: Lung: Diffusely, 100% of the alveolar septa are characterized by one of the following changes: Type I pneumocytes are shrunken and hypereosinophilic with pyknotic nuclei (necrosis); discontinuous alveolar septa (septal necrosis) with resultant alveolar emphysema; type I pneumocytes are lost and replaced by deeply eosinophilic lamellations of polymerized fibrin and necrotic cellular debris (hyaline membranes); occasionally and multifocally, type I pneumocytes are replaced by cuboidal epithelium (type II pneumocyte hyperplasia); or alveolar septa are expanded up to 10x normal by pale eosinophilic beaded to fibrillar material (fibrin), increased clear space (edema), few macrophages, lymphocytes, neutrophils, and mild hemorrhage. Alveolar lumina are multifocally filled with varying amounts of exudate composed of fibrin, edema, hemorrhage, and increased numbers of macrophages and lymphocytes. Multifocally the interlobular septa, visceral pleura, and peribronchiolar and perivascular interstitium are expanded by are variable combinations and concentrations of viable and necrotic neutrophils, macrophages, lymphocytes, plasma cells, fibrin, edema, and hemorrhage. Multifocally lymphatics are markedly ectatic (edema).

 

MORPHOLOGIC DIAGNOSIS: Lung: Pneumonia, interstitial, fibrinonecrotic, diffuse, subacute, severe, with hyaline membranes, emphysema, and alveolar, interlobular, and pleural edema, Chianina, bovine.

 

ETIOLOGIC DIAGNOSIS: Toxic interstitial pneumonia

 

CAUSE: 3‑methylindole intoxication

 

CONDITION: Acute bovine pulmonary edema and emphysema (ABPEE)

 

SYNONYMS: Atypical interstitial pneumonia (AIP), "fog fever", cow asthma

 

GENERAL DISCUSSION: 

• Atypical interstitial pneumonia consists of separate syndromes (see Differential Diagnosis section), one of which is acute bovine pulmonary edema and emphysema (APBEE)
• APBEE is an acute pulmonary toxicosis caused by L-tryptophan (found in lush green grasses) which is converted to 3-methylindole in the rumen (or the large colon of non-ruminants)
• Usually occurs in adult cattle within 10 days after being moved from dry to lush, tryptophan‑rich pasture (especially rape, kale, and/or turnip tops)
  1. Young animals are resistant
  2. Often occurs in the autumn on new growth pasture following a recent cutting of hay
  3. Note: “Fog” refers to fog pastures (i.e., aftermath or foggage, regrowth after hay or silage has been cut).
• Experimental 3-MI toxicity in horses results in necrosis of club cells in bronchioles (not alveoli) due to species-dependent distribution of cytochrome P450

 

PATHOGENESIS:

• Animal consumes grasses with L‑tryptophan -> L‑tryptophan is converted to 3‑methylindole -> Hematogenous spread to lung -> 3-methylindole transformed by cytochrome P-450 of (e.g., of club cells) to 3-methyleneindolenine, a highly pneumotoxic compound that causes extensive and selective necrosis of bronchiolar cells and type I pneumonocytes 
  1. Leads to increased alveolar permeability, leading to edema, thickening of the alveolar interstitium, and alveolar and interstitial emphysemas 
  2. 3-Methylindole also interferes with the lipid metabolism of type II pneumonocytes
• Associated with “bronchopneumonia with interstitial pneumonia” (BIP) (Haydock, Vet Pathol 2023) 
  1. A proposed term in which chronic cranioventral bronchopneumonia precedes acute caudodorsal interstitial lung disease
  2. Supports a role of chronic inflammation (e.g., in cranioventral bronchopneumonia) in heightened sensitivity to 3-methylindole or another lung toxicants 

 

TYPICAL CLINICAL FINDINGS:

 

TYPICAL GROSS FINDINGS:

• Trachea is filled with foam
• Diffuse interstitial pneumonia with severe alveolar and interstitial edema and interlobular emphysema
  1. Heavy wet lungs that fail to collapse and are expanded, pale, and rubbery
• Interlobular or bullous emphysema is prominent in the caudal lobes in less fulminant cases

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Alveolar and interstitial edema and emphysema with formation of hyaline membranes, and necrosis of type I pneumocytes 
• Alveolar septa are distended by edema, and may contain eosinophils and/or neutrophil
• More variable lesions include: Bronchiolitis obliterans, infiltration of neutrophils and eosinophils, and patchy alveolar hemorrhages from emphysematous rupture of alveolar septa
• With more chronic cases, there is type II pneumocyte hyperplasia, accumulations of alveolar histiocytes, and interstitial fibrosis (diffuse alveolar damage)

 

DIFFERENTIAL DIAGNOSIS:

• Other causes of AIP in cattle (edema, emphysema, hyaline membranes and type II pneumocyte hyperplasia):
  1. NOTE: Recent access to lush pasture favors ABPEE
  2. Other toxins with the same clinical and pathologic picture
     • 4‑ipomeanol (from Fusarium solani in moldy sweet potatoes)
     • Paraquat toxicity (P-T03): Toxic herbicide that causes acute diffuse alveolar damage
     • Purple mint (Perilla frutescens), stinkwood (Zieria arborescens), rapeseed and kale (Brassica species)
  3. Post-patent forms of Dictyocaulus viviparus infection (P-P12)
  4. Acute infection with Ascaris suum or Dictyocaulus larvae, generally in younger calves and have many eosinophils with at least a few histologically visible larvae
  5. Viral pneumonia (late stages of Bovine Respiratory Syncytial Virus) (P-V06): Unless there are syncytia or inclusion bodies, may require laboratory testing to differentiate
  6. Anaphylaxis: Causes pulmonary edema, congestion, emphysema, and rare eosinophil infiltrate; NOT hyaline membranes
  7. Extrinsic allergic alveolitis: Type III hypersensitivity reaction to inhaled organic antigens resulting in lymphocytes and granulomas form beside bronchioles and within alveolar septa; often from chronic inhalation of fungal spore or the spores of thermophilic actinomycetes such as of Saccharopolyspora rectivirgula found in moldy hay
• Other causes of diffuse necrosis of bronchiolar cells and type I pneumocytes:
  1. O₂ toxicity (P-T02)
  2. Smoke inhalation
  3. Toxic gases (NO₂, H₂S and NH₃)

 

COMPARATIVE PATHOLOGY:

• 3-methylindole toxicity has also been associated with 
  1. Horses:
     • A possible causative agent or contributing factor for bronchointerstitial pneumonia in 1- to 4-month-old foals
     • A contributing factor for Equine Asthma Syndrome, a collective term to include chronic inflammatory diseases of the lower airways including recurrent airway obstruction (RAO, previously referred to as COPD, or heaves), summer pasture-associated recurrent airway obstruction, and inflammatory airway disease (IAD)
  2. Necrosis of nasal respiratory or olfactory epithelium due to cytochrome P450-dependent biotransformation activity of the nasal mucosa in a variety of species
• Other toxic causes of interstitial lung disease
  1. Similar pulmonary lesions can be found in horses, pigs, sheep, and cattle with pyrrolizidine alkaloid intoxication from a variety of plants (Crotalaria, Trichodesma, and Senecio spp.)
  2. Horses: Crofton weed (Eupatorium adenophorum) causes a chronic interstitial pneumonia with prominent proliferation and metaplasia of alveolar epithelial cells and fibroplasia
  3. Pigs: Fumonisin B1 a mycotoxin associated with moldy corn; causes massive interlobular pulmonary edema and hydrothorax with pancreatic necrosis
  4. α-Naphthylthiourea (ANTU): rodenticide that causes respiratory distress from pulmonary edema and pleural effusion
  5. Dogs: Paraquat ingestion induces acute interstitial pneumonia with edema and hemorrhage
  6. Lambs: Selenium-accumulator plants cause mainly myocardial necrosis but also pulmonary edema and hemorrhage due to vasculitis of the alveolar septae

 

REFERENCES:

1. Caswell JL, Williams KJ. The respiratory system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's Pathology of Domestic Animals. 6th ed. Vol 2. Philadelphia, PA: Elsevier Saunders; 2016:479, 513-514, 519-520.
2. Haydock LAJ, Fenton RK, et al. Bronchopneumonia with interstitial pneumonia in beef feedlot cattle: Characterization and laboratory investigation. Vet Pathol. 2023;60(2):214-225. 
3. Haydock LAJ, Fenton RK, Smerek D, Renaud DL, Caswell JL. Bronchopneumonia with interstitial pneumonia in feedlot cattle: Epidemiologic characteristics of affected animals. Vet Pathol. 2023;60(2):226-234.
4. 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; 2022:600, 615-616.

 

 

 

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