Carbamazepine‐induced DRESS syndrome with recurrent fever and exanthema
Authors: Valencak Julia , Ortiz‐Urda Susana , Heere‐Ress Elisabeth , Kunstfeld Rainer , Base Wolfgang 
Published: December 2003

A 43‐year‐old woman was admitted to hospital with a history of recurrent attacks of vertigo, which had been treated with carbamazepine for 4 weeks. The patient presented with fever, cold chills, lymphadenopathy, and erythematous and highly infiltrated skin. The Nikolski phenomenon was negative and there was no pruritus. Symptoms had begun 5 days earlier, with a diffuse maculopapular exanthema, first localized on the breast and trunk, with consecutive generalization, and accompanied by a severe enteritis. The exanthema worsened to a state of generalized erythroderma (Fig. 1).The patient's left arm and right hand showing infiltrated, edematous, and erythematous skin with a hemorrhagic aspectimageThe patient's performance status was 2, according to the World Health Organization (WHO). Laboratory findings showed a white blood cell count of 22.4 × 109/L [normal, (4.0–10.0) × 109/L] with 32% eosinophils (normal, up to 4% of total circulating leukocytes), an aspartate aminotransferase (ASAT) level of 63 U/L (normal, 0–15 U/L), an alanine aminotransferase (ALAT) level of 95 U/L (normal, 0–19 U/L), a γ‐glutamyl transpeptidase (γ‐GT) level of 176 U/L (normal, 4–18 U/L), and an alkaline phosphatase (AP) level of 305 U/L (normal, 60–170 U/L). The C‐reactive protein (CRP) level was 8.9 mg/dL (normal, < 1 mg/dL). Renal function, chest radiography, and abdominal sonography were completely normal. Serologic tests for viral infections, including cytomegalovirus, Epstein–Barr virus, parvovirus, Coxsackievirus, human immunodeficiency virus, and hepatitis A, B, and C virus, were negative. Stool cultures and serology were negative for bacteria, protozoa, or helminthic eggs. Blood cultures and nasal–throat swabs were repeatedly negative. Carbamazepine was discontinued from day 1 of hospitalization. From day 1–5 of admission, the patient received intravenous therapy with 1000 mg/day prednisolone‐ 21‐hydrogensuccinate‐sodium and diphenhydramine (60 mg twice daily), and antimicrobial therapy with clindamycin (900 mg three times daily) and fosfomycin (8000 mg twice daily), a therapy with good efficacy against Gram‐positive cocci (Bergan T. Pharmacokinetic comparison between fosfomycin and other phosphonic acid derivatives. Chemotherapy 1990; 36 (Suppl. 1): 10–18), was given for a total of 7 days. Fever persisted, however, and the physical status deteriorated within the first 3 days of hospitalization. The creatine kinase (CK) level increased to 108 U/L (normal, 0–70 U/L), with a CK‐muscle‐brain (MB) fraction of 33.6% (normal, 0–6%). The patient was monitored. Electrocardiography (ECG) showed tachycardia with frequent ventricular extrasystoles and tachypnea, but regular blood pressure and adequate oxygen saturation.After 1 week of hospitalization, the patient's status improved, the number of eosinophils was reduced to 6%, and an acute onset of rheumatic disease was ruled out by negative blood samples for antinuclear antibodies, antineutrophil cytoplasmic antibodies, and complement system. After two more weeks in hospital, the cardiac symptoms had resolved, most laboratory parameters had returned to normal values, and the skin had markedly improved. The patient was discharged with local therapy consisting of 30% betamethasone cream.Seven days later, the patient was re‐admitted. She presented with a new, bright red urticarial exanthema over the entire body with pruritus. She had a return of fever, up to 38.2 °C, and a white blood cell count of 2.4 × 109/L with 11% eosinophils; CRP was 2.38 mg/dL, γ‐GT was elevated at 106 U/L, but liver transaminases, CK, and CK‐MB fraction were normal. Fever was recurrent, with spikes up to 37.8 °C.The diagnosis of a recurrent carbamazepine‐induced DRESS (drug rash with eosinophilia and systemic symptoms) syndrome was made, and further therapy with a low‐dose oral glucocorticosteroid was considered. The patient refused further medication, and therefore a watch and wait strategy was planned. Again, 7 days after re‐admission, the skin returned to normal and the patient was discharged. At an outpatient visit after 1 week, the patient noted a modest recurrent temperature increase of 37.8 °C, which she treated with nonsteroidal antiphlogistics, but the skin and laboratory values were completely normal.Two weeks later, i.e. 6 weeks after the acute onset of DRESS syndrome, she again showed new, sharply limited, livid‐reddish macular skin lesions with central scaling and hyperkeratotic areas, localized on the ventral trunk, the legs, and the soles. The new skin lesion was treated with topical ointment consisting of 3% salicylate, 10% urea, and propyleneglycol in a neutral base. At the control visit, 2 weeks later, the lesions had markedly improved. The neurologic medication for vertigo had been changed to lamotrigine 3 weeks before, which was well tolerated. Follow‐up visits were conducted at 3‐week intervals for two more months, but the skin symptoms and fever did not recur. Taken together, complete resolution of all symptoms was achieved 9 weeks after the discontinuation of treatment with carbamazepine.