Diagnostic Challenges of Old Diseases in the COVID-19 Era: A Report of Two Cases of Carbamazepine-Induced DRESS Syndrome

Since early December 2019, the COVID-19 pandemic has been a major public health issue affecting individuals worldwide. Although the disease seems to have a milder clinical course in the pediatric population, and can even be classified as asymptomatic, there is increasing recognition of MIS-C temporally associated with COVID-19.^1,2 Drug reaction with eosinophilia and systemic symptoms syndrome is a potentially life-threatening cutaneous and systemic drug reaction characterized by rash, fever, lymphadenopathy, hematologic abnormalities (eosinophilia and/or atypical lymphocytosis), and multiple internal organ involvement. It has also been associated with reactivation of herpes viruses.³ The authors report 2 cases of pediatric patients who presented with MIS-C suspicion but were diagnosed with carbamazepine-induced DRESS syndrome.

Case 1

A 10-year-old boy was admitted to the emergency department with concerns of generalized erythematous rash, abdominal pain, and fever lasting 3 days. The patient’s condition had progressed within the past 2 days. There was a history of epilepsy treated with twice-daily carbamazepine at a dose of 400 mg/day for approximately 2 months. In addition, 5 weeks before the onset of symptoms, the patient had been in close contact with family members who were positive for COVID-19. On admission, the patient appeared unwell and had an elevated body temperature (39°C). Physical examination showed facial edema; disseminated maculopapular eruption on the trunk, face, and extremities; mild liver enlargement; and right cervical lymphadenopathy (Figure 1).

Laboratory testing was remarkable for eosinophilia and showed elevated liver enzymes. A complete blood count revealed leukocytosis and eosinophilia with a count of 17 000/mm³ and 900/mm³, respectively. Aspartate aminotransferase, ALT, and lactate dehydrogenase were elevated, with levels of 64 IU/L (range, 10–37 IU/L), 187 IU/L (range, 10–40 IU/L), and 485 IU/L (range, 0–248 IU/L), respectively. The following tests were negative: COVID-19 PCR, IgM, and IgG for suspected MIS-C. Parvovirus B19 IgM was positive. Diagnosis of MIS-C was ruled out, and the patient was diagnosed with carbamazepine-induced DRESS syndrome possibly triggered by parvovirus B19 infection. Carbamazepine treatment was discontinued. Systemic methylprednisolone was given in addition to oral antihistamine treatment. The patient’s clinical and laboratory findings improved after 4 days of treatment.

Case 2

A 15-year-old boy was admitted to the emergency department with concerns of generalized pruritic erythematous rash and fever starting 4 weeks after the initiation of twice-daily carbamazepine treatment at a dose of 800 mg/day treatment for epilepsy. The eruption began on the trunk and was disseminated on the body. Three weeks before the onset of symptoms, the patient had a definite diagnosis of COVID-19. On physical examination, the patient was restless and febrile (39°C). The patient had bilateral cervical lymphadenopathy, facial edema, and widespread maculopapular rash that tended to be confluent (Figure 2).

Laboratory findings revealed a leucocyte count of 16 000/mm³ with 700/mm³ eosinophils, AST of 56 IU/L, and ALT of 145 IU/L. Other laboratory values and viral serological tests were normal. The COVID-19 PCR was negative. Diagnosis of MIS-C was excluded, and the patient was diagnosed with carbamazepine-induced DRESS syndrome. Carbamazepine treatment was discontinued. Systemic methylprednisolone at a dose of 2 mg/kg for 5 days and oral antihistamine at a dose of 5 mg/kg per day in equally divided doses administered every 6 hours as needed were started. Lesions resolved gradually, and 2 weeks after treatment the laboratory findings for eosinophil, AST, and ALT levels showed normal values (300/mm³, 34 IU/L, 36 IU/L, respectively).

Previous studies have demonstrated that the number of pediatric patients with COVID-19 was lower and that pediatric patients presented with milder clinical characteristics, disease progression, and outcomes compared with adult patients. However, there have been increasing reports describing children and adolescents with COVID-19–associated systemic inflammatory response developing after the acute stage of infection.⁴ Drug reaction with eosinophilia and systemic symptoms syndrome presents with fever, disseminated cutaneous eruption, multiorgan involvement, lymphadenopathy, and hematologic abnormalities including eosinophilia and/or atypical lymphocytosis.⁵ There are different mechanisms in the pathogenesis of this syndrome, including immune-mediated type III hypersensitivity response, a direct cytotoxic effect of the drug or its metabolites, a genetic susceptibility, and reactivation of viral infections, especially human herpes viruses.⁶

Anticonvulsant drugs such as phenytoin, phenobarbital, and carbamazepine are the most common triggers of DRESS syndrome. In the current report, both patients’ medical histories were notable for epilepsy treated with carbamazepine for at least 1 month. Ganeva et al⁷ reported on 4 cases of DRESS syndrome with clinical features appearing 3 to 4 weeks after the administration of carbamazepine. Severe DRESS syndrome has also been reported with viral reactivation of herpes viruses, including human herpesvirus 6, cytomegalovirus, Epstein-Barr virus, and parvovirus B19.⁸ Parvovirus B19 infection was also identified in the first case reported herein.

Diagnosis of DRESS syndrome is difficult, and a high index of suspicion should be maintained for this condition because of the variability in clinical features and broad differential diagnosis. Both current patients were admitted with suspicion of MIS-C, but that condition was ruled out. Drug-related extensive skin eruption and all other findings (fever, lymphadenopathy, eosinophilia, lymphocytosis, and involvement of at least one internal organ) were consistent with the diagnostic criteria of DRESS syndrome. Besli et al⁹ reported a case of oxcarbazepine-induced DRESS syndrome that included hematologic malignancy in the differential diagnosis.

The mainstay of management for DRESS syndrome is withdrawal of the causative medication and the use of systemic corticosteroids. In the current report, carbamazepine treatment was immediately discontinued, and an oral antihistamine and methylprednisolone were started. The patients' clinical condition and laboratory findings improved, and they were discharged without any sequelae.

The current study’s major limitations consist of its small sample size (2 cases) and single-center design.

Although DRESS syndrome may seem very similar to other systemic disorders, it is severe, progressive, and potentially life-threatening if not diagnosed in a timely manner. Health care practitioners should be aware of DRESS syndrome to ensure early diagnosis and medical intervention of this challenging disease.