Eosinophilic skin disease in dogs results from uncontrolled tissue damage following insults by parasites, allergens, infectious agents (fungi, bacteria, and viruses), or drugs. This clinical presentation includes eosinophilic furunculosis, canine acute eosinophilic dermatitis (CAEDE, Wells-like syndrome), eosinophilic granuloma, eosinophilic vasculitis, and necrotizing eosinophilic dermatitis (10). Canine eosinophilic granuloma (CEG) is an uncommon skin disease. Skin lesions are most frequently located in the oral cavity and infrequently involve other cutaneous sites, such as the nasal planum, ventral abdomen, thorax, metatarsus, prepuce, flank, digit, eyelid, external ear canal, and cheek region (6,9,13). The common clinical types of skin manifestations are papular, nodular, or plaque lesions. Lesions are typically firm, nonpruritic, erythematous, and ulcerated. Affected dogs are healthy without signs of systemic involvement. A marked breed predilection for Siberian husky dogs and cavalier King Charles spaniels suggests potential hereditary factors (13). Although the pathogenesis of CEG is unclear, immunological responses to antigenic exposure, including infectious and noninfectious allergens, are suspected (10). CEG is clinically managed with corticosteroid monotherapy (8). Treatment should be continued until the lesions have resolved completely to reduce the risk of recurrence. Prolonged use of high corticosteroid doses may have serious adverse effects, such as polyuria/polydipsia, diarrhea and vomiting, and hepatotoxicity. Therefore, some effective adjunctive immunosuppressive agents may be considered.

This case report describes the successful management of a case of CEG with prednisolone and azathioprine.

A two-year-old, intact male, 45 kg Doberman Pinscher presented with a seven-month history of dermal nodular lesions affecting the left hindlimb. The owner reported a partial reduction in the size of the lesions subsequent to the prednisolone (0.5 mg/kg/day) and antibiotics treatments (amoxicillin-clavulanate, cephalexin) for three months, but the granulomas recurred after withdrawing the drugs. The granulomas were removed by surgical excision. The referring veterinarian also used afoxolaner (NexGard spectra, Merial) to exclude an ectoparasites infestation. On the other hand, the lesions developed again within three weeks. Therefore, the dog was referred to the Chungnam National University Veterinary Teaching Hospital.

The clinical evaluation revealed two ulcerated nodular lesions that measured 25 mm and 5 mm on the left lateral thigh region (Fig. 1). The physical feature was no presence of palpably enlarged peripheral lymph nodes. Imprinting smear revealed eosinophilic inflammations, and occasionally macrophages and neutrophils containing intracellular cocci were seen. Hematological analysis showed no abnormalities. For a histopathological examination, two skin biopsy specimens were collected from the lesions using 6 mm and 4 mm biopsy punches.

Figure 1. Ulcerated nodules measuring 25 mm located in the lateral thigh region (left) and measuring 5 mm located in the metatarsal region (right).

The skin biopsy revealed moderate to severe infiltrates of eosinophils with fewer macrophages in the dermis (Fig. 2). Large clusters of eosinophils surrounded hyalinized dermal collagen fibers, and occasionally flame figures were observed. The diagnosis was an eosinophilic granuloma. Oral prednisolone (Solondo, Yuhan) was instituted at 1.5 mg/kg/day for the first week. In conjunction with prednisolone, azathioprine (Immuthera, Celltrion pharm) also was initiated at 2 mg/kg/day and oral cephalexin (20 mg/kg twice daily for 28 days). After one week, the lesion started to diminish dramatically, but the dog showed severe watery diarrhea. The prednisolone dose was reduced by 0.9 mg/kg/day, and dioctahedral smectite (Smecta, Daewoong pharm) was prescribed. The lesions and diarrhea improved markedly after one week. The prednisolone dose was tapered by 25% of the previous seven weeks’ dose every week to 0.2 mg/kg/day. Azathioprine therapy was also reduced to every other day (EOD). After nine weeks of combination treatment, the medications were withdrawn totally. On the other hand, a small area of erosion and erythema with purulent exudates developed again one week later. Azathioprine 2 mg/kg/EOD and cephalexin (Falexin, Dongwha pharm) 20 mg/kg twice daily were reintroduced for two weeks. The bacterial culture and antibiotics sensitivity test revealed Pseudomonas straminea (susceptible to doxycycline and cefovecin). Doxycycline (Kukje pharm) was prescribed at 10 mg/kg twice daily with azathioprine 1 mg/kg/EOD for two weeks. There was no relapse after all medications had been withdrawn over the two-month follow-up period (Fig. 3).

Figure 2. Photomicrograph of an eosinophilic granuloma. Focal granuloma is cuffed by large numbers of eosinophils with fewer macrophages (left). The dermis contains a moderate to severe infiltrate of degranulated eosinophils and degenerated collagen fibers, so-called “flame-figure” (right) (H&E, 400×).

Figure 3. Skin lesions of the lateral thigh region (left) and the metatarsal region (right) after eight weeks of prednisolone and azathioprine treatment.

CEG is an unusual skin disease with an uncertain etiology. Type I cell-mediated hypersensitivity reaction appears to play a role in the pathogenesis (13). This theory is supported by the predominance of eosinophils in these lesions and their positive response to glucocorticoid therapy (7). The triggers for such hypersensitivity reactions may be inhaled or ingested allergens, including seasonal allergens (pollens and molds), insects (mosquitoes), food, or exposure to irritants (fungi and bacteria) (7). No evidence of any of these possible causes was obtained in this case. On the other hand, the granuloma was located superficial to the deep dermis, and the nodules were found in the lateral thigh, suggesting a possible reaction to contact with an irritant.

Eosinophilic skin diseases in dogs include eosinophilic furunculosis, eosinophilic vasculitis, acute eosinophilic dermatitis (Wells-like syndrome), necrotizing eosinophilic dermatitis, and eosinophilic granuloma (2). This dog’s histopathologic presentation differed from the other eosinophilic diseases. Eosinophilic furunculosis was excluded due to a lack of folliculocentric eosinophilic inflammation (4). The blood vessels were intact in the skin biopsies, and there was no histopathological evidence of vascular damage ruling out eosinophilic vasculitis (3).

Eosinophilic granulomas have similar clinical lesions to Wells-like syndrome and necrotizing eosinophilic dermatitis, including erythematous papules, plaques, and nodules with yellow exudate and ulceration (2,3,13). In contrast to eosinophilic granuloma, Wells-like syndrome is frequently encountered with marked erythroderma of the ventrum, hypoalbuminemia, and gastrointestinal signs before the development of skin lesions. In addition, it has eosinophilic infiltration without degranulation (2). Necrotizing eosinophilic dermatitis typically shows significant areas of necrosis and features of vasculitis on histopathology (1). The dog fulfilled the conditions for distinct granulomas with marked central eosinophilic degranulation and multifocal areas of collagen degeneration, referred to as “flame figures” (2,5,13).

Most CEG cases in dogs have been treated based on the clinical presentation. Conventional therapy consists of symptomatic treatment and control of the suspected causes, such as parasitic, infectious, or allergenic agents. Therapeutic drugs may include glucocorticoids, antihistamines, or other hyposensitization therapies (7). Other treatments yielding various results include CO₂ laser therapy and surgical incision (6). In this case, several treatments were conducted with anti-inflammatory therapy and surgical removal before referral. Because these treatments could not control the disease, immunosuppressive therapy was initiated as an alternative.

Several choices to control CEG have been reported, including glucocorticoid with prednisolone sparing drugs, particularly for chlorambucil and azathioprine (7,11,12). Chlorambucil is a cell cycle nonspecific alkylating antineoplastic and immunosuppressive agent (6). It targets B-cells and is considered a slow-acting agent that may require two weeks to reach therapeutic efficacy (14). The drug has previously been shown to be an effective steroid-sparing agent in a case of CEG of the digits (6). Azathioprine is an immunosuppressant used in both human and veterinary medicine (15). Azathioprine is a purine analog. A metabolite of azathioprine, 6-thioguanin nucleotides (6-TGNs), competes with endogenous purines for DNA and RNA synthesis and inhibits proliferation and T-cell-dependent antibody synthesis (14). On the other hand, the use of azathioprine is limited by the risk of hepato-toxicosis and bone marrow suppression. The hepatotoxic effect has been attributed to the accumulation of another metabolite, 6-methyl mercaptopurine (6-MMP). Bone marrow suppression, including neutropenia, thrombocytopenia, or both, is a commonly listed adverse effect of azathioprine. On the other hand, no prevalence studies have been reported in dogs (15). Hepatotoxicosis is defined by increases in alanine aminotransferase (ALT) activity more than two times the upper limit of the reference range. The clinical signs include vomiting, lethargy, and jaundice. In a retrospective study, hepatotoxicosis was observed in five out of 34 dogs (15%) treated with azathioprine within a median onset of 14 days (15). Therefore, it is recommended to monitor the serum liver enzymes on one or more occasions between one and four weeks after starting azathioprine in dogs (15). In the present case, the dog was monitored to obtain biochemical evidence of hepatotoxicosis, but no specific findings were identified, even with a combination of prednisolone.

The dog experienced the successful management of eosinophilic granuloma with oral glucocorticoid and azathioprine. The use of azathioprine may be an effective adjunctive immunosuppressive agent, and may be considered a well-tolerated prednisolone-sparing agent for the treatment of CEG. Nevertheless, the underlying etiology remains obscure. Therefore, further research will be needed to allow more effective treatment recommendations.

This work was supported by research fund of Chungnam National University.

The authors have no conflicting interests.