13-year-old femaleThoroughbred horse (Equus caballus)This horse was presented for exercise intolerance. The radiographic appearance of the lungs was
consistent with equine multinodular pulmonary fibrosis. The horse was euthanized, and necropsy was performed by
the referring veterinarian, who submitted lung, liver and spleen for histologic examination and microbiologic tests.
Irregularly shaped, but well-demarcated, coalescing nodules (2 to >10 cm in diameter) of firm,
pale tan tissue were distributed through all lobes of the lung (Fig. 1).
Lung: The pulmonary nodules are well-demarcated from unaffected lung and are the
result of interstitial fibrosis. Within the nodules, -alveolar septa are thickened up to 100 μm or more by fibrous
tissue composed of birefringent, orderly collagen fibers with low to moderate cellularity (well-differentiated
fibroblasts) and light infiltration by lymphocytes, plasma cells and fewer neutrophils. Alveolar spaces are lined by
cuboidal epithelial cells with pale vacuolated cytoplasm, and are partially filled with macrophages, neutrophils,
exfoliated epithelial cells, and debris. Intranuclear eosinophilic to amphophilic inclusion bodies are easiest to find in
alveolar macrophages. Bronchi and bronchioles within the nodules are filled with similar exudate and surrounded
by increased fibrous tissue.
Fibrosing alveolitis with eosinophilic intranuclear inclusions in
Equine herpesvirus 5 was identified antemortem in bronchoalveolar lavage fluid by PCR.
Herpesvirus was isolated from the lung postmortem and also identified as equine herpesvirus 5 by PCR.
Equine Multinodular Pulmonary Fibrosis (EMPF)
Histologic findings resemble those described in equine multinodular pulmonary fibrosis,
attributed to infection with equine herpesvirus 5 (EHV-5). Infection with this gammaherpesvirus is reportedly fairly
common in Europe, parts of South America, Australia and New Zealand, but association of EHV-5 infection with
multinodular pulmonary fibrosis was first described in the United States in 2007(1) and then again in 2008.(2)
Twenty-four adult horses with multinodular pulmonary fibrosis, 4-28 years of age (mean, 14.5 yr) and with nearly
equal gender distribution, were evaluated in the first article.(1) Sixteen of the horses were Thoroughbreds. Salient
gross lesions were restricted to the lungs and bronchial lymph nodes, and usually appeared as numerous coalescing
fibrotic nodules that involved most of the lung. A less common macroscopic presentation was as multiple discrete
and larger fibrotic nodules, separated by unaffected pulmonary parenchyma.
Histologically, well-organized, mature fibrous tissue expand the interalveolar septa with preservation of alveolar architecture.(1) Lymphocytes infiltrate the fibrotic interstitium. Alveolar spaces are lined by cuboidal cells, and contain neutrophils and macrophages. A few of the alveolar macrophages have eosinophilic intranuclear inclusions.
Multinodular pulmonary fibrosis is histologically distinct from the pulmonary interstitial fibrosis of silicate pneumoconiosis, which is associated with granulomatous inflammation, and from idiopathic pulmonary fibrosis, which more commonly affects foals than adults and is attributed to diffuse alveolar damage. In the second report, equine multinodular pulmonary fibrosis was tentatively diagnosed antemortem, as in this case, on the basis of clinical presentation and radiologic findings (nodular pulmonary interstitial pattern) with supportive PCR detection of EHV-5 from bronchoalveolar lavage specimens. Inappetance, weight loss, fever, cough, and respiratory distress were common to all 5 cases in that study.(2)
To date, Kochs postulates have not been fulfilled to establish EHV-5 as the definitive cause of equine multinodular pulmonary fibrosis. However, the virus is consistently associated with this unique pulmonary lesion, so pathologic findings of nodular pulmonary fibrosis with herpetiform inclusions and supportive PCR analysis should prompt consideration of EMPF in adult horses with respiratory distress and nodular interstitial pneumonia.
Lung: Pneumonia, interstitial, fibrosing, focally extensive, severe, with marked type II pneumocyte
hyperplasia, neutrophilic and histiocytic alveolitis, and rare intrahistiocytic eosinophilic intranuclear inclusions.
It is worth noting, that EMPF presents grossly in two distinct manifestations: the more
common diffuse to coalescing form with little unaffected lung parenchyma, and a discrete nodular form in which
fibrotic nodules are separated by grossly unaffected lung. Marked lymphadenomegaly of the bronchial lymph nodes
resulting from lymphoid hyperplasia with sinus histiocytosis.
An interstitial pneumonia of donkeys has been reported which is associated with asinine herpesvirus.(1) This disease differs from EMPF in that it is a diffuse inflammatory disease with syncytial cell formation without viral inclusions; interstitial fibrosis is considered a secondary component.
Conference participants noted that pleural arteries were often hypertrophied and surrounded by abundant collagen. This is likely due to increased intrapulmonary blood pressure due to the diffuse fibrosis, which inhibits adequate blood flow through large portions of the affected lung.
Conference participants also discussed a differential diagnosis that included that paraquat and diquat toxicosis, which causes fulminant pulmonary fibrosis, although due to the dwindling availability of these compounds, this differential is becoming exceedingly rare. Another possibility is exercise-induced pulmonary hemorrhage, which also has large areas of pulmonary fibrosis, but is characterized by numerous hemosiderophages, and lacks intranuclear inclusion bodies.
Alveolitis, a term commonly used in human respiratory pathology, was used in our morphologic diagnosis because of the striking inflammation centered on alveolar lumens as separate from the fibrosing interstitial pneumonia, which is characteristic of EMPF. This histologic finding is expected with interstitial pneumonias in which there is abundant protein exudation, as well as viral-induced leukocyte chemotaxis. A common feature of EMPF is the preservation of an alveolar-like architecture(2), which are often filled with neutrophils and macrophages; hence the designation of alveolitis in addition to fibrosing interstitial pneumonia.
1. Kleiboeker SB, Schommer SK, Johnson PJ, Ehlers B, Turnquist SE, Boucher M, Kreeger
JMKleiboeker SB, Schommer SK, Johnson PJ, Ehlers B, Turnquist SE, Boucher M, Kreeger JM.
Association of two newly recognized herpesviruses with interstitial pneumonia in donkeys (Equus
asinus). J Vet Diagn Invest 2002; 14:273280.
2. Williams KJ, Maes R, Del Piero F, Lim A, Wise A, Bolin DC, Caswell J, Jackson C, Robinson NE, Derksen F, Scott MA, Uhal BD, Li X, Youssef SA, Bolin SR: Equine multinodular pulmonary fibrosis: a newly recognized herpesvirus-associated fibrotic lung disease. Vet Pathol 44:849-862, 2007
3. Wong DM, Belgrave RL, Williams KJ, Del Piero F, Alcott CJ, Bolin SR, Marr CM, Nolen-Walston R, Myers RK, Wilkins PA: Multinodular pulmonary fibrosis in five horses. J Am Vet Med Assoc 232:898-905, 2008