JPC SYSTEMIC PATHOLOGY
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. It fatigued easily and developed cyanosis after exercise.
- Lung: There are multifocal to coalescing areas of consolidation and atalectasis multifocally throughout the section that often contain abundant hemorrhage. Alveoli coalesce to form multifocal areas of alveolar emphysema. Bronchiole lumina often contain hemorrhage and bronchiolar epithelium is hyperplastic. Diffusely, the alveolar septa are expanded up to 25um by fibrin, edema, hemorrhage and increased numbers of macrophages and lymphocytes. There is necrosis and loss of type I pneumocytes which have been replaced by cuboidal type II pneumocytes (hyperplasia), fibrin and varying amounts of fibrous connective tissue (fibrosis). 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 spaces (emphysema). 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 plump cubodial mesothelium (reactive mesothelium); there is subpleural fibrosis.
- Kidney: Rental tubules are separated by mild to moderate hemorrhage which expands the interstitium. Multifocally within the cortex and medulla, renal tubular epithelium are swollen with bright eosinophilic, granular cytoplasm (degeneration) or contain one discrete, round cytoplasmic vacuole (lipid degeneration) often with yellow to light green globular pigment (lipofuscin), or have a shrunken, pyknotic nucleus (necrosis). Multifocally, tubular lumina contain eosinophilic cellular and karyorrhectic debris (necrosis). Multifocally, glomerular uriniferous spaces are expanded by refluxed tubular epithelial cells and an eosinophilic homogenous material (protein). Multifocally, the interstitium is expanded by aggregates of lymphocytes and plasma cells and there is mild interstitial and periglomerular fibrosis and mineralization
- Lung: Pneumonia, interstitial, chronic, diffuse, marked, with loss of type I pneumocytes, type II pneumocyte hyperplasia, alveolar hemorrhage, emphysema and fibrosis, Rhodesian ridgeback, canine.
- Kidney: Tubular degeneration and necrosis and interstitial hemorrhage subacute, multifocal, moderate.
ETIOLOGIC DIAGNOSIS: Bipyridilium pneumonia and nephrosis
CAUSE: Bipyridilium (paraquat) toxicity
- Paraquat and diquat are highly toxic bipyridilium broad-spectrum herbicides that cause mortality in animals through malicious poisoning (oral) or accidental exposure (oral/dermal/inhalation)
- The LD50 is 22-262 mg/kg and is species dependent
- Often cause fatal interstitial pneumonia (pneumonitis) in cattle, sheep, dogs, cats, humans, other species
- Causes acute diffuse alveolar damage if inhaled or ingested, and taken up by type 1 pneumocyte
- Large oral doses cause fulminating pulmonary edema, hemorrhage, interstitial pneumonia, acute renal tubular necrosis and death
- Lower oral doses cause fatal progressive pulmonary fibrosis in 5-10 days
- Unlike paraquat, the target organs of diquat include the gastrointestinal tract, liver and kidneys
- Paraquat is rapidly, but incompletely absorbed from the gastrointestinal tract; pulmonary specificity occurs via accumulation in alveolar pneumocytes through active uptake by diamine and polyamine transport systems; also taken up into the brain via the neural amino acid transporter
- Paraquat undergoes redox cycling (alternate reduction followed by re-oxidation) in cells, which results in oxidation and depletion of NADPH via NADPH-cytochrome P450 reductase, and depletion of glutathione in Club cells in the lung
- Resulting reactive oxygen species (ROS) damage the blood air barrier
- Type I pneumocytes are target cells in acute and chronic poisoning
- Type II pneumocytes are less affected and proliferate to replace defects left by necrosis of type I pneumocytes
- Endothelial cell damage contributes to the acute edema and hemorrhage
- Alveolar macrophages release both fibronectin and growth factors for fibroblasts, which cause the marked fibrosis in chronic intoxication
- Paraquat is excreted in the urine and feces; transport mechanism for the renal proximal tubular cells is not well understood; two membrane proteins have been found in rats (organic cation transporter 1(OCT1) and organic cation transporter 2 (OCT2))
TYPICAL CLINICAL FINDINGS:
- Transgenic mice lacking Cu/Zn SOD (superoxide dismutase) show markedly increased sensitivity
- Oily substance on hair with skin irritation
- Oral ingestion results in stomatitis, esophageal necrosis, vomiting and nausea
- Additional signs include lethargy, dyspnea, hyperpnea, tachycardia, adipsia, diarrhea, ataxia, hyperexcitability, convulsions and death
- Renal failure
TYPICAL GROSS FINDINGS:
Heavy, edematous and hemorrhagic lungs
Pale lungs with interstitial emphysema, bullous emphysema +/-pneumomediastinum
Fail to collapse
TYPICAL LIGHT MICROSCOPIC FINDINGS:
Necrosis of type I pneumocytes
Intestitial and alveolar edema
Proliferation of type II pneumocytes
Interstitial and intraalveolar fibrosis
Type II pneumocyte hyperplasia
- Kidney: Renal tubular epithelial degeneration and necrosis
- Liver: Centrilobular hepatic necrosis and bile duct epithelial necrosis with portal hepatitis
- Oral cavity: Severe erosive stomatitis in dogs
- Adrenal gland: Patchy necrosis of adrenal zona glomerulosa
- Oxygen toxicosis
- Induced/acquired coagulopathies such as those caused by warfarin, ionizing radiation and neoplasia
- ANTU (alpha-naphthyl thiourea) causes pulmonary edema without necrosis or later epithelial hyperplasia and fibroplasia
- Uremic pneumonitis: Mineral, especially in vessels (may be difficult to see)
Other causes of diffuse alveolar damage (DAD):
- Pulmonary Infections:
- Many viruses, toxoplasma gondii, FIP virus, ascarid larval migration
- Gastric aspiration of sterile vomitus in monogastric animal
- Toxic gases: nitrogen dioxide, sulfur dioxide,chlorine, 100% oxygen, ammonia, phosgene, ozone
- Ingested toxin: paraquat, kerosene, 3-methlyindole, 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
- Idiopathic: Dalmations with familial acute respiratory distress syndrome (ARDS)
- Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer"s Pathology of Domestic Animals. Vol. 2 6th ed. Philadelphia, PA: Elsevier; 2017:519.
- Costa LG. Bipyridine. In: Klaassen CD, ed. Casarett and Doull"s Toxicology: The Basic Science of Poisons. 8th ed. New York, NY: McGraw-Hill; 2013:961-962.
- Gupta RC. Toxicity of herbicides. In: Gupta RC, ed. Veterinary Toxicology: Basic and Clinical Principles. New York, NY: Academic Press; 2007:567-576.
- Herfst S, van den Brand JM, Schrauwen EJ, et al. Pandemic 2009 H1N1 Influenza Virus Causes Diffuse Alveolar Damage in Cynomolgus Macaques. Vet Pathol. 2010;47(6):1040-1047.
- Husain AL. The Lung. In: Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia, PA: Saunder Elsevier; 2010:680-682.
- Kehrer JP. Systemic Pulmonary Toxicity. In: Ballantyne B, Marrs TC, Syversen T, eds. General and Applied Toxicology. Vol 2. 2nd ed. London, UK: Macmillan Reference Ltd; 2000:723-724.
- Lopez A, Martinson SA. Respiratory System, Mediastinum and Pleurae. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 6th St. Louis, MO: Elsevier; 2016:549.
- Nagata T, Kono I, Masaoka T, Akahori F. Subacute Toxicity of Paraquat in Beagle Dogs: Clinicopathology and Pathologic examinations. Vet Hum Toxicol. 1992;34(1):15-20.
- Pickrell JA. Respiratory toxicity. In: Gupta RC, ed. Veterinary Toxicology: Basic and Clinical Principles. New York, NY: Academic Press; 2007:185-187.
- Syrja P, Saari S, Rajamaki M, Saario E, Jarvinen AK. Pulmonary Histopathology in Dalmatians with Familial Acute Respiratory Distress Syndrome (ARDS). J Comp Pathol. 2009;141(4):254-259.
- Uzal FA, Plattner BL, Hostetter JM, Alimentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer"s Pathology of Domestic Animals. Vol. 2 6th ed. Philadelphia, PA: Elsevier; 2017:13.Witschi HR, Last JA. Toxic Responses of the Respiratory System. In: Klaassen CD, ed. Casarett and Doull"s Toxicology: The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill; 2001:529.
- Van Riel D, Rimmelzwann GF, van Amerongen G, Osterhaus AD, Kuiken T. Highly Pathogenic Avian Influenza Virus H7N7 Isolated From a Fatal Human Case Causes Respiratory Disease in Cats but Does Not Spread Systemically. Am J Pathol. 2010;177(5):2185-2190.