Allopurinol-Induced DRESS Syndrome With a Histologic Pattern Consistent With Interstitial Granulomatous Drug Reaction

Abstract

To the Editor: We read the case reported by Suran and Christopher1 with great interest because we recently treated a similar case of drug rash with eosinophilia and systemic symptoms (DRESS syndrome) with a histologic pattern consistent with an interstitial granulomatous drug reaction (IGDR). A 45-year-old man was admitted to our department with a pruritic rash and facial edema present for 3 days. The medical history included hyperuricemia; the patient was treated with allopurinol for 2 months. The physical examination demonstrated marked generalized erythema with multiple overlying papules and plaques over the entire body and cervical lymphadenopathy (Figs. 1, 2). The patient had a fever for 2 weeks; the temperature was 39.5°C on admission. Laboratory studies showed a leukocytosis 14.9 (4.0–10.0 × 109/L) with an eosinophil count of 0.81 (0–0.5 × 109/L). The alanine aminotransferase 92 (5–40 IU/L), aspartate aminotransferase 74 (0–40 IU/L), and erythrocyte sedimentation rate 75 (0–10 mm/h) were also elevated. The kidney function testing showed significant abnormalities with a raised blood urea nitrogen 43.5 (7.8–22.0 mg/dL) and creatinine 3.5 (0.6–1.2 mg/dL). The kidney biopsy was consistent with an interstitial nephritis. The skin biopsy specimen taken from a papular lesion on the abdomen revealed a dense, diffuse interstitial, perivascular, and perifollicular infiltrate (Fig. 3A) composed of histiocytes, lymphocytes, eosinophils, and multinucleated giant cells (Figs. 3B, C). Piecemeal fragmentation of collagen and elastic fibers were revealed by Masson-trichrome and Verhoeff–van Gieson stains. There were few mucin deposits noted. Focal vacuolar interface dermatitis was also observed (Fig. 3B). The skin lesions subsided and the liver and kidney function returned to normal after withdrawal of the offending medication, hemodialysis, and steroid therapy.FIGURE 1: Facial edema and erythematous papules.FIGURE 2: Generalized, symmetrical erythema with overlying papules, and plaques on the whole body.FIGURE 3: Histologic findings. A, Dense, diffuse interstitial, perivascular, and perifollicular infiltrates (hematoxylin–eosin, ×12.5). B, Interface dermatitis with basal vacuolopathy (hematoxylin–eosin, ×100). C, Granulomatous infiltrate composed of histiocytes, lymphocytes, eosinophils, and multinucleated giant cells (hematoxylin–eosin, ×200).Allopurinol-induced DRESS syndrome is characterized by hematologic abnormalities, especially eosinophilia and atypical lymphocytosis, skin rash, fever, lymph node enlargement, and single or multiple organ involvement, which starts within 8 weeks after the start of treatment with the offending drug.2,3 Our patient was diagnosed with DRESS syndrome based on fever, lymphadenopathy, cutaneous eruption, eosinophila, and interstitial nephritis developing 8 weeks after starting allopurinol. Histologically, a dense lymphocytic infiltrate in the superficial dermis with eosinophils is frequently observed in patients with DRESS syndrome.2 Diffuse interstitial granulomatous infiltrates with DRESS syndrome, as seen in our patient, were reported by Suran and Christopher.1 IGDR is a rare drug associated entity, initially described in 1998.4 This reaction has been reported in response to calcium channel blockers, angiotensin-converting enzyme inhibitors, beta-blockers, lipid-lowering agents, antihistamines, anticonvulsants, antidepressants, diuretics, sennoside, herbal medications, strontium ranelate, ganciclovir, and anakinra.4–11 Most patients present with erythematous to violaceous plaques with a predilection for the skin fold areas. Lesions are usually caused by drug exposure over a long period of time, and resolve soon after discontinuation of the offending drug. Histopathologically, IGDR is characterized by diffuse interstitial infiltration of lymphocytes and histiocytes, with piecemeal fragmentation of collagen and elastic fibers. Interface dermatitis is usually noted, and affected hair follicles and acrosyringia have also been reported.4,10 Given the appearance of multiple erythematous papules and plaques in association with allopurinol treatment, the histology, and the resolution within 4 weeks after cessation of the drug, were consistent with the diagnosis of IGDR. Chen et al7 reported a case of IGDR that shared some of the features of DRESS, including erythroderma, eosinophilia, and abnormal lymphocytes. However, the patient did not have constitutional symptoms or internal organ involvement. Interestingly, our case and the case reported by Suran and Christopher1 were similar, both cases appeared to have DRESS syndrome and IGDR. Although the pathogenic mechanisms of allopurinol-induced DRESS syndrome have not been fully elucidated, immunologic, genetic, and other factors associated with drug and metabolite accumulation have been proposed to be correlated with the pathophysiology.12 In addition, the mechanisms underlying IGDR are unknown; however, type IV hypersensitivity has been postulated to play a role.7 Suran and Christopher1 proposed that herpes virus-stimulated T cells may cross-react to drug-derived hapten–protein conjugates. However, our patient did not show reactivation of herpes viruses. In conclusion, allopurinol is widely used for the treatment of hyperuricemia; some patients develop the allopurinol-induced DRESS syndrome. We report an extremely rare case of allopurinol-induced DRESS syndrome that was confirmed histologically to be present with IGDR.