JPC SYSTEMIC PATHOLOGY
Signalment (JPC #2285063): 8-year-old female German shepherd dog
HISTORY: This dog had a productive cough and progressive weight loss. Radiographic examination revealed consolidation of the right middle, caudal and accessory lung lobes.
HISTOPATHOLOGIC DESCRIPTION: Lung: Effecting 60% of the section, effacing bronchioles and adjacent pulmonary parenchyma, there are multifocal to coalescing eosinophilic granulomas characterized by a central core of hypereosinophilic cellular and karyorrhectic debris (lytic necrosis) admixed with numerous degenerate eosinophils and fewer degenerate neutrophils. Eosinophils often surround irregular bands or radiating spicules of brightly eosinophilic, hyalinized collagen (suggestive of flame figures). Necrotic foci are surrounded by epithelioid macrophages, eosinophils, lymphocytes, and plasma cells, which are further surrounded by a thick rim of fibroblasts and abundant collagen (fibrosis). Eosinophilic granulomas are separated by numerous alveolar macrophages, eosinophils, lymphocytes, and plasma cells admixed with moderate amounts of fibrin and edema, and lesser amounts of cellular and karyorrhectic debris, which obscure pulmonary architecture and fill adjacent alveoli. Adjacent alveolar septa are thickened up to 4x normal by abundant fibrosis and low numbers of primarily macrophages and lymphocytes, with few plasma cells and eosinophils, and are occasionally lined by cuboidal pneumocytes (type II pneumocyte hyperplasia). Multifocally, the peribronchiolar and perivascular interstitia are expanded up to 5 times normal by dense fibrous connective tissue (fibrosis) and low numbers of previously described inflammatory cells. There is multifocal bronchiolar smooth muscle hypertrophy. Less affected alveoli contain increased numbers of foamy alveolar macrophages, while remaining bronchioles are often lined by hyperplastic epithelium and contain the previously described inflammatory exudate. The pleura is diffusely thickened, up to 1 mm in some areas, by fibrosis, ectatic lymphatic vessels, and low numbers of previously described inflammatory cells.
MORPHOLOGIC DIAGNOSIS: Lung: Eosinophilic granulomas, multifocal to coalescing, severe, with flame figures, marked fibrosis, and smooth muscle hypertrophy, German shepherd dog, canine
CONDITION: Eosinophilic pulmonary granulomatosis (EPG)
SYNONYMS: Pulmonary infiltrates with eosinophils, pulmonary eosinophilia (PE), eosinophilic pneumonia, and pulmonary hypersensitivity
- Eosinophilic bronchopneumopathy (EBP) (formerly pulmonary infiltrates with eosinophilia [PIE]), is an uncommon, usually steroid responsive condition of young dogs
- Causes chronic gagging, coughing, dsypnea
- Diagnosis of exclusion; the process is thought to be immune mediated, but following should be excluded:
- Tracheobronchial parasites: Crenosoma vulpis, Eucoleus aerophilus, Solerus osleri
- Lungworm: Angiostrongylus vasorum, Filaroides hirthi, occult Dirofilaria immitis
- Pulmonary carcinoma, histiocytic sarcoma, lymphoma
- Aspergillosis and drug reaction
- Eosinophilic pulmonary granulomatosis (EPG) is a severe form of EBP which tends to form distinct nodules or mass-like pulmonary lesions (as in this case); has a poorer prognosis
- May represent a progressive, uncontrollable form of EBP
- Generally a much higher and more consistent peripheral eosinophilia (>20,000/mL)
- Like in EBP, some (but not all) have occult dirofilariasis
- In both humans and dogs, hypersensitivity to aeroallergens is the suspected (but not confirmed) cause of EBP:
- Inciting allergen rarely identified
- Suspected causes: Fungi, molds, drugs, bacteria, parasites
- Dirofilariasis has been associated with EBP and EPG in dogs
- Th2 immune response is thought to dominate, as suggested by predominance of eosinophilic infiltration, selective increase in CD4+ T cells and selective decrease in CD8+ T cells in bronchoalveloar lavage (BAL) fluid, low expression of major histocompatibility complex (MHC) class II molecules by antigen presenting cells (APCs), increased number of dendritic cells, and low levels of APC activation
- Eosinophil and mononuclear cell recruitment: Driven by increased monocyte chemoattractant protein (MCP)-3, eotaxin-2, and eotaxin-3
- Destruction and remodeling: Up-regulation of collagenolysis and proteolysis
- Increased production by macrophages and epithelial cells (but not eosinophils) of matrix metalloproteinases (MMPs) 8, 9, and 13, which degrade epithelial laminins
- Dogs with EBP (but also healthy growing dogs) have increased levels of serum and bronchoalveolar procollagen type III amino terminal propeptide (PIIINP), a marker of extracellular matrix turnover
TYPICAL CLINICAL FINDINGS:
- Highly variable: Often include productive, corticosteroid-responsive cough; gagging; retching; exercise intolerance, dyspnea, and green nasal discharge; bronchoconstriction typically not a major feature
- Most common cause of bronchiectasis in dogs
TYPICAL GROSS FINDINGS:
- Lung lobes may be firm, consolidated, and fail to collapse
- Multifocal to regionally extensive, greenish-tan, discrete, nodules
- Nodules may also be found in the intrathoracic lymph nodes (hilar lymphadenopathy may be severe), liver, spleen, abdominal lymph nodes, small intestine, and kidneys
- Adult heartworms may be present
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Highly variable, owing to diverse clinical picture and likely variety of causes
- Acute: Alveoli flooded with eosinophils, lymphocytes, and histiocytes; later - type II pneumocyte hyperplasia, epithelial ulceration, microhemorrhage
- Chronic: Chronic eosinophilic bronchitis with epithelial hyperplasia, ulceration, or squamous metaplasia
- Lung parenchyma: Diffuse eosinophilic and granulomatous infiltrates, focal eosinophilic granuloma centered on necrotic tissue and densely eosinophilic material and large areas of necrosis and fibrosis
- Perivascular infiltration with lymphocytes and eosinophils is inconsistent
- Interstitial pneumonia with granulomas that obliterate normal architecture
- Granulomas contain dense aggregates of epithelioid cells, macrophages, eosinophils, fewer plasma cells, lymphocytes, and mast cells with occasional areas of necrosis
- Bronchial smooth muscle hypertrophy prominent in granulomatous areas
- Possible infiltration of eosinophils or eosinophilic granulomas throughout the body (e.g., intrathoracic lymph nodes, liver, spleen, trachea, peripheral or abdominal lymph nodes, small intestine and kidney)
ADDITIONAL DIAGNOSTIC TESTS:
- CBC and differential: Eosinophilia and basophilia are the most common abnormalities; however, eosinophilia may be absent in spite of marked pulmonary involvement; variable neutrophilia
- Cytology: TTW/BAL fluid, and thoracic aspirates may have increased cell counts (cells/uL) with elevated percentages of eosinophils and neutrophils
- Rule out other causes of eosinophilic pulmonary disease:
- Heartworm tests – microfilaria-concentrating and antigen tests
- Fecal samples (multiple) – fecal flotation and Baermann examination to check for lungworm infection
- Serology for endemic mycotic diseases
- Endothelin 1 (ET 1) was used to differentiate EBP from idiopathic pulmonary fibrosis in one study; ET 1 not elevated in dogs with EBP
- C reactive protein (CRP) was used to differentiate EBP from bacterial pneumonia in one study; CRP not elevated in dogs with EBP
- For eosinophilic lung disease:
- Hypersensitivity - pulmonary parasites, immitis, drugs, or aeroallergens
- Infection – parasitic, fungal, bacteria
- Gross Ddx for pulmonary nodules +/- hilar lymphadenopathy:
- Systemic mycoses
- Primary and metastatic pulmonary neoplasia
- Lymphoid granulomatosis
- Brown Norway rats – Eosinophilic granulomatous pneumonia:
- Used to study asthma pathogenesis
- May develop spontaneous eosinophil-rich granulomatous pneumonia in absence of experimental procedure
- Gross: Multifocal tan to gray 1-3 mm foci throughout lungs
- Histologic: Multifocal to diffuse granulomatous pneumonitis with a cellular infiltrate of epithelioid cells with occasional multinucleated giant cells
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