History

A 12-year-old 493-kg Andalusian gelding was evaluated because of recurrent colic and a potential abdominal mass. The gelding had been relocated from Connecticut to Texas 6 months prior to presentation and had 3 episodes of colic within the 5 weeks prior to presentation.

Clinical and Gross Findings

On admission, the gelding was bright, alert, and responsive and had pink and moist mucous membranes, a capillary refill time of < 2 seconds, and vital signs, borborygmi, and digital pulses within reference limits. A doughy impaction in the pelvic flexure and a soft, moveable mass-like structure to the right of the pelvic flexure were identified on transrectal palpation. Abdominal ultrasonography demonstrated a poorly defined mass-like structure near the pelvic flexure but no other abnormalities. A CBC revealed mild eosinophilia, and serum biochemical analyses findings were unremarkable. Abdominocentesis was performed, and the results of abdominal fluid analysis included a total nucleated cell count of 1,565/µL (reference limit, < 5,000 cells/µL), composed of approximately 42% large mononuclear cells, 40% nondegenerate neutrophils, 12% eosinophils, and 6% small lymphocytes. The total protein concentration was 3.7 g/dL (reference limit, < 2.5 g/dL), consistent with a modified transudate (Figure 1).

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Antemortem photomicrograph of the cytospin preparation of an abdominal fluid sample obtained by abdominocentesis at the time of admission (A) and postmortem image of the mucosal surface of the pelvic flexure of the colon (B) of a 12-year-old 493-kg Andalusian gelding evaluated because of recurrent colic episodes and a potential mass in the right ventral region of the abdomen. A—Eosinophils (red arrows), neutrophils (black arrows), and mononuclear cells (arrowheads) are evident. Modified Wright stain; bar = 20 µm. B—There is a raised, firm, tan nodule (5 X 5 X 10 mm; asterisk), and the surrounding mucosa is mildly edematous. Scale bar = 1 cm.

Citation: Journal of the American Veterinary Medical Association 260, 6; 10.2460/javma.20.09.0502

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The gelding underwent exploratory laparotomy. The pelvic flexure was bright red and thick, and there was an irregular, black, raised plaque (approx 0.3 X 7 X 21 cm) on the serosal surface of the distal portion of the ileum (hemomelasma ilei); a firm, irregular, smooth, dark brown to red, intramural mass (approx 3 X 2.8 X 1.5 cm) at the apex of the cecum; and several enlarged lymph nodes (up to 4 X 2.5 X 2 cm) peripheral to the ileum, cecum, and colon. Biopsy specimens of the cecal mass, enlarged lymph nodes, and colon were submitted. The horse recovered from anesthesia uneventfully but developed severe diarrhea and pyrexia that minimally responded to treatment. Due to the gelding’s clinical condition, and ultimate pathology results, the owners elected euthanasia. On necropsy, the gelding had a firm, poorly demarcated, dark red to tan area (1 X 1.2 X 1.5 cm) in the caudodorsal aspect of the right lung lobe; an enlarged cecal lymph node (2 X 3 X 5 cm), mild thickening and dark red small intestine with hemorrhagic contents; mild thickening and edema of the cecum and large colon; and a tan, firm, raised mucosal nodule (5 X 5 X 10 mm) in the pelvic flexure (Figure 1).

Histopathologic Findings

In sections of the cecal mass from the surgical biopsy specimen, the mucosa, submucosa, and tunica muscularis were disrupted and effaced by multifocal to coalescing, eosinophilic granulomas (up to 1 X 0.5 cm; Figure 2). These granulomas had a central core of degranulated, degenerate, and necrotic eosinophils surrounded by epithelioid macrophages, foreign body type multinucleated giant cells, and fibrous connective tissue with occasional aggregates of lymphocytes and plasma cells. Additionally, the mucosal surface was diffusely ulcerated and necrotic with moderate to large numbers of eosinophils dissecting transmurally from the mucosa to the serosa. These inflammatory infiltrates surrounded but did not invade large vessels. Evidence of edema included transmural separation of tissue structures and accumulation of protein around serosal vessels. The biopsy specimens from the colon and cecal lymph node were similarly affected, and the ileal lymph node and large colon lymph node were diffusely infiltrated by eosinophils, had multiple eosinophilic granulomas, and had marked lymphoid hyperplasia. Grocott methenamine silver staining to identify potential intralesional fungal organisms was performed on tissue sections of the cecal mass, colon, cecal lymph node, ileal mass, and large colon. No organisms were appreciated.

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Photomicrographs of the surgical biopsy specimen of the cecal mass (A), an eosinophilic granuloma in the cecal mass (B), muscularis layers of the cecum (C), and cecal lymph node (D) of the horse described in Figure 1. A—There is extensive ulceration of the mucosa, and the submucosa is expanded by dense eosinophilic nodules that are surrounded by fibrous connective tissue (eosinophilic granulomas; short black arrow). H&E stain; bar = 500 µm. B—The center of an eosinophilic granuloma in the cecal mass is composed of degenerate (short red arrows) and nondegenerate (long red arrows) eosinophils and is surrounded by abundant epithelioid macrophages (long black arrows) and a thick rim of plump fibroblasts (arrowheads). H&E stain; bar = 20 µm. C—There are intersecting bands of inflammatory cells (dashed outline and in inset) effacing large portions of the tunica muscularis. H&E stain; bar = 500 µm. Inset—The inflammatory cell population is composed almost entirely of eosinophils. H&E stain; bar = 20 µm. D—Multifocally throughout the lymph node are dense eosinophilic nodules surrounded by fibrous connective tissue (eosinophilic granulomas; dashed outline and in inset). Lymphoid follicles are markedly hyperplastic with prominent germinal centers. H&E stain; bar = 500 µm. Inset—The eosinophilic granuloma is composed of a center of degenerate eosinophils surrounded by a rim of epithelioid macrophages, collagen, and fibroblasts. Surrounding the node is a large number of nondegenerate eosinophils. H&E stain; bar = 20 µm.

Citation: Journal of the American Veterinary Medical Association 260, 6; 10.2460/javma.20.09.0502

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Histopathology of the pelvic flexure nodule, colon, and colonic, cecal, and mesenteric lymph node specimens obtained at the time of necropsy displayed similar changes. Results for the abnormal section of lung indicated focal eosinophilic granuloma and marked eosinophilic pneumonia. The ileum was transmurally infiltrated by a mild number of eosinophils, and the liver displayed a mild, multifocal portal to random eosinophilic and necrotizing hepatitis. Grocott methenamine silver staining was performed on sections from the lung and pelvic flexure nodule; no organisms were appreciated.

Morphologic Diagnosis and Case Summary

Morphologic diagnosis: moderate to marked, multifocal, chronic eosinophilic and granulomatous typhlocolitis, lymphadenitis, hepatitis, and pneumonia.

Case summary: presumptive diagnosis of multisystemic eosinophilic epitheliotropic disease (MEED) in an Andalusian gelding.

Comments

A presumptive diagnosis of MEED (historically also known as eosinophilic gastroenteritis, eosinophilic granulomatosis, hypereosinophilia syndrome, and exfoliative eosinophilic dermatitis and stomatitis¹) was made given the multifocal eosinophilic granulomas and eosinophilic inflammation throughout several organs, including the large and small intestines, lymph nodes, lung, and liver. The diagnosis was supported by absence of fungi, and lack of evidence for parasitic infestation or a neoplastic process. Salmonella spp PCR assay and testing for Clostridium difficile toxins A and B and Clostridium perfringens enterotoxin were performed due to the history of postoperative diarrhea. Results were positive for the Salmonella spp PCR assay. Although salmonellosis may have compounded the horse’s illness and was likely the primary cause of hemorrhagic enteritis noted at necropsy, it was considered unrelated to the underlying eosinophilic disease.

Multisystemic eosinophilic epitheliotropic disease is an uncommon disease of unknown etiology, with suggested pathogeneses involving environmental triggers, parasite migration inducing a type I hypersensitivity reaction, or potentially secondary to a T-cell lymphoma.^1–4 Virus isolation and bacteriologic assessments on affected tissues have failed.¹ Multisystemic eosinophilic epitheliotropic disease is currently considered to be a subtype of inflammatory bowel disease, which also include granulomatous enteritis, idiopathic eosinophilic enterocolitis, and lymphocytic-plasmacytic enterocolitis in horses.¹ Differentiation is primarily based on histopathologic evidence: MEED involves eosinophilic granulomas and eosinophilic infiltration within multiple organ systems, whereas granulomatous enteritis is characterized by sheets of macrophages and defined granulomas in the mucosa or submucosa in the absence of other inflammatory cells, idiopathic eosinophilic enterocolitis is characterized by eosinophil-rich pleocellular infiltrates confined to the intestinal tract, and lymphocytic-plasmacytic enterocolitis is characterized by infiltration of the mucosa and submucosa by lymphocytes and plasma cells.^1,5 Although eosinophilic infiltration can have many causes, eosinophilic granulomas with vasculitis and fibrinoid vascular necrosis in the absence of infectious organisms is considered diagnostic for MEED.¹ Importantly, the most common causes of eosinophilic granulomas in horses should be ruled out prior to making a diagnosis of MEED. Habronemiasis, pythiosis, equine eosinophilic granuloma complex, and mast cell tumors can cause individualized eosinophilic granulomas, with equine eosinophilic granuloma complex resulting in eosinophilic granulomas restricted to the dermis of affected horses. In contrast, multiple organ system involvement, a history of chronic weight loss, diarrhea, or both; the presence of skin lesions; and clinicopathologic data can be helpful in the diagnosis of MEED. Although fibrinoid vascular necrosis was absent in this case, the other histologic criteria were met, and other causes of eosinophilic granulomas were ruled out, allowing a presumptive, though not definitive, diagnosis of MEED.

The most common presenting clinical sign in MEED is chronic refractory weight loss but it can also include diarrhea, respiratory signs, coronitis, and recurrent colic,^1,5 as was appreciated in this case. Standardbreds are believed to be predisposed, but the condition has been reported in Thoroughbreds, Arabians, Quarter Horses, American Paso Finos, Paint Horses, and Welsh Ponies.^2,4,6,7 To our knowledge, this was the first report of the condition in an Andalusian. Affected horses are typically less than 4 years old. There is no reported sex predilection.¹ Multisystemic eosinophilic epitheliotropic disease is classically associated with eosinophilic gastroenteritis, eosinophilic pancreatitis, or eosinophilic dermatitis, alone or in combination, and involvement of the liver, common bile duct, upper and lower respiratory tracts, and urinary tract has also been reported.^1–12 Dermatologic abnormalities are frequently, though not consistently, as demonstrated by the lack of them in this case, a prominent component, ranging from a multifocal scaling dermatitis to a widespread exfoliative dermatitis, with or without pruritis.^4,6,11 The diagnosis of MEED typically carries a grave prognosis.^1,4,5,7

Hematologic findings can be unremarkable in horses with MEED. Liver enzyme activities, particularly alkaline phosphatase and γ-glutamyl transferase, are often elevated when the biliary tree is involved.¹ Although not present in this case, hypoalbuminemia often occurs secondary to protein loss through the intestines, with variable contribution from chronic inappetence or hepatic dysfunction if the liver is severely affected.⁷ Eosinophilia is an unreliable indicator, with only 5 of 46 affected horses reported to have had eosinophilia.¹ Nonetheless, MEED should be considered for those with eosinophilia, chronic weight loss, or dermatologic abnormalities, especially when eosinophilic infiltrates and eosinophilic granulomas are present throughout multiple organ systems.