JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

September 2023

P-T03

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Signalment (JPC #2941213): 6-year-old Rhodesian ridgeback

 

HISTORY: Dog presented with vomiting. Over the course of 6 days, the dog developed lingual ulcers, tachypnea, a cough, and excessive salivation. Fatigued easily and developed cyanosis after exercise.

 

HISTOPATHOLOGIC DESCRIPTION:  

Lung: Approximately 70% of the lung parenchyma is characterized by multifocal to coalescing areas of consolidation, atelectasis, and often abundant hemorrhage, fibrin, and edema. Diffusely, alveolar septa are expanded up to 25µm by fibrin, edema, hemorrhage, increased numbers of macrophages, lymphocytes, and neutrophils, and varying amounts of fibrous connective tissue (fibrosis). There is frequent necrosis and loss of type I pneumocytes with replacement by cuboidal type II pneumocytes (hyperplasia). Alveolar lumina are multifocally collapsed and/or contain abundant hemorrhage, fibrin, edema, increased numbers of alveolar macrophages, fewer neutrophils, and small amounts of necrotic debris. Multifocally, alveolar septa are discontinuous with blunt clubbed ends forming large confluent alveolar spaces (emphysema). Bronchiolar lumina often contain hemorrhage, fibrin, and edema, and bronchiolar epithelium is hyperplastic with goblet cell hyperplasia. Multifocally, perivascular and peribronchiolar connective tissue is expanded by hemorrhage, fibrin, edema, and scattered neutrophils. Diffusely, the pleura is expanded by hemorrhage, fibin, dilated lymphatics (edema), and scattered neutrophils, and lined by reactive, cuboidal mesothelium.

 

Kidney: There is multifocal mild to moderate interstitial hemorrhage that separates renal tubules. Multifocally within the cortex and medulla, renal tubular epithelium are either swollen with vacuolated cytoplasm (degeneration) often with yellow to light green, globular, cytoplasmic pigment (lipofuscin), or are shrunken with hypereosinophilic cytoplasm and a pyknotic nucleus (necrosis) with occasional sloughing into the lumen. Multifocally, tubular lumina contain eosinophilic cellular and karyorrhectic necrotic debris (granular cast). There is multifocal, mild lymphoplasmacytic interstitial nephritis. Multifocally, glomerular uriniferous spaces are expanded by refluxed necrotic tubular epithelial cells and eosinophilic homogenous material (protein).

 

MORPHOLOGIC DIAGNOSES:  

1.  Lung: Pneumonia, interstitial, necrohemorrhagic and fibrosing, chronic, diffuse, marked, with marked type II pneumocyte hyperplasia, Rhodesian ridgeback, canine.

2.  Kidney: Tubular degeneration and necrosis, subacute, multifocal, moderate, with multifocal interstitial lymphoplasmacytic inflammation and hemorrhage.

 

ETIOLOGIC DIAGNOSIS: Bipyridilium pneumonia and nephrosis

 

CAUSE: Bipyridilium (paraquat) toxicity

 

GENERAL DISCUSSION:  

• Paraquat and diquat are highly toxic broad-spectrum herbicides that cause acute alveolar damage and mortality in animals through malicious poisoning (oral) or accidental exposure (oral/dermal/inhalation)
• Acute lung injury and fatal interstitial pneumonia (pneumonitis) reported in cattle, sheep, pigs, dogs, cats, primates, and humans after ingestion of paraquat-contaminated foodstuffs
• Diffuse alveolar damage (DAD): Diffuse injury to type I pneumocytes or endothelial cells in the alveolar septa > pulmonary edema, hyaline membranes, proliferation of type II pneumocytes, and interstitial fibrosis 

• Most commonly identified form of interstitial disease

• Paraquat is used as an experimental model of oxidant-induced alveolar injury and fibrosis 
• Paraquat toxicosis and uremia are the two most notable noninfectious causes of canine respiratory disease 

 

PATHOGENESIS: 

• JKP: Paraquat is absorbed by type I pneumocytes > reduction-oxidation (redox) cycling depletes the cells of NADPH and glutathione > uncontrolled generation of superoxide anion > oxidant injury and alveolar damage
• PBVD: Paraquat is metabolized by Club cells > production of toxic metabolite > local release of free radicals > lipid peroxidation of type I and II pneumocytes and alveolar endothelial cells > extensive damage to Club cells and the blood-air barrier
• Malicious poisoning (high dose toxicosis) > fulminant pulmonary edema and hemorrhage; survival 2-3 days
• Accidental poisonings (low dose toxicosis) > early exudative changes followed by compensatory type II pneumocyte hyperplasia and fibrosis

 

TYPICAL CLINICAL FINDINGS:   

• Oral ingestion results in stomatitis, esophageal necrosis, vomiting, and nausea
• Additional signs include lethargy, dyspnea, hyperpnea, tachycardia, adipsia, diarrhea, ataxia, hyperexcitability, convulsions, and death
• Primates: Cyanosis, tachycardia, and severe arterial hypoxemia that is not responsive to oxygen therapy 

 

TYPICAL GROSS FINDINGS:  

• Acute: Heavy, edematous, rubbery, and hemorrhagic lungs
• Chronic: Pale lungs with interstitial emphysema, bullous emphysema, +/ pneumomediastinum; fail to collapse 

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

Pulmonary lesions:

• Acute: Extensive necrosis of epithelial cells (especially type I pneumocytes) and endothelial cells in the alveolar wall; interstitial and alveolar edema; intraalveolar hemorrhage; hyaline membrane formation in alveolar ducts; fluid in the hilar connective tissue
• Subacute: Type II pneumocyte hyperplasia 
• Chronic (4-8 weeks post toxic insult): Profuse fibroplasia

Extrapulmonary lesions:

• Kidney: Renal tubular epithelial degeneration and necrosis
• Oral cavity: Severe erosive stomatitis in dogs
• Adrenal gland: Patchy necrosis of adrenal zona glomerulosa

 

DIFFERENTIAL DIAGNOSIS:  

• Uremic pneumonitis: Mineral, especially in vessels, may be difficult to appreciate
• Oxygen toxicosis (P-T02) causes diffuse alveolar damage (see other causes of diffuse alveolar damage in the Comparative Pathology section below)
• Induced/acquired coagulopathies such as those caused by warfarin, ionizing radiation and neoplasia  

 

COMPARATIVE PATHOLOGY:

 

Other causes of DAD (JKP vol. 2, 6^th ed., Box 5-6):

• Pulmonary infections: Many viruses, Toxoplasma gondii (P-P01), FIP virus (P-V15), ascarid larval migration
• Gastric aspiration of sterile vomitus in monogastric animals
• Toxic gases: Nitrogen dioxide, sulfur dioxide, chlorine, 100% oxygen (P-T02), ammonia, phosgene, ozone
• Ingested toxin: Paraquat, kerosene, 3-methlyindole (P-T01), ipomeanol, perilla mint, Brassica, Crofton weed
• Septicemia and endotoxemia, DIC, shock
• Massive trauma, strangulation, near drowning, pulmonary contusion
• Ischemic lung injury: Lung lobe torsion, reperfusion injury
• Chronic left heart failure
• Burns: Inhalation of steam or smoke during fire
• Pancreatitis, uremia, parvoviral enteritis, irradiation
• Surfactant dysfunction: Prematurity (hyaline membrane disease), inherited defects in surfactant proteins B or C
• Ventilator-induced lung injury
• Adverse drug reactions
• Acute hypersensitivity reactions

 

REFERENCES:

1. Abee CR, Mansfield K, Tardif S, Morris T. Respiratory system diseases of nonhuman primates. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2^nd ed. San Diego, CA: Elsevier; 2012:442.
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 Inc; 2016:485, 509-511, 519.
3. 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; 2022:638.
4. Uzal FA, Plattner BL, Hostetter JM. Alimentary System. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:13. 

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