Case 2: A 13-year-old boy with fever and rash

A 13-year-old boy presented to the emergency department with a three-week history of daily fever. This was associated with a two-week history of a pruritic rash, which started on his torso and subsequently spread to his face and limbs, sparing his palms and soles.

His medical history was significant for seizures following a closed head injury two months before presentation, for which he had been started on phenytoin. His family physician recommended discontinuation of phenytoin; however, the rash and fever persisted.

Physical examination revealed a febrile (38.1°C), ill-appearing adolescent. He was tachycardic (heart rate 132 beats/min) and slightly hypotensive (blood pressure 91/55 mmHg). He exhibited significant facial swelling and a diffuse, erythematous, blanchable maculopapular rash. There was no lymphadenopathy. The remainder of his examination was unremarkable. He was started on broad-spectrum antibiotics given an initial concern for sepsis.

Investigations showed leukocytosis (white blood cell count 27.2×10⁹/L), with neutrophilia (20.41×10⁹/L) and eosinophilia (1.07×10⁹/L). His creatinine level was elevated (90 μmol/L). Liver enzymes were elevated (aspartate aminotransferase level 109 U/L, alanine aminotransferase level 128 U/L). Rheumatological investigations, including antinuclear antibody, rheumatoid factor, and C3 and C4 levels, were normal. Erythrocyte sedimentation rate (11 mm/h) and C-reactive protein level (58.4 mg/L) were elevated. A monospot test, throat and blood cultures were negative. An echocardiogram was normal.

A skin biopsy confirmed the diagnosis.

CASE 2 DIAGNOSIS: DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS SYNDROME

A skin biopsy revealed focal upper dermal perivascular lymphocytic infiltrate with eosinophils suggestive of drug reaction with eosinophilia and systemic symptoms (DRESS).

This syndrome describes a severe skin eruption, fever, hematological abnormalities (eosinophilia or atypical lymphocytosis), lymphadenopathy and internal organ involvement (1). Features typically occur two to six weeks after the initiation of drug therapy and may persist or even worsen despite its discontinuation. This latency period is longer than in most drug eruptions. Antiepileptic agents (eg, carbamazepine, lamotrigine, phenytoin, phenobarbital) and allopurinol are the most frequently reported inciting agents (2). Sulfa derivatives, antidepressants, nonsteroidal anti-inflammatory drugs and antimicrobials have also been implicated (2).

The skin eruption is typically observed on the trunk and extremities initially as a morbilliform rash, which can advance to an exfoliative dermatitis. Histopatholgical examination will reveal spongiosis, a lymphocytic infiltrate in the superficial dermis, with eosinophils and dermal edema. This finding is not specific to DRESS but supports the diagnosis of a drug hypersensitivity reaction. Organ involvement occurs in up to 90% of patients and most frequently involves the liver, kidneys and lungs (1).

The pathogenesis of DRESS is not well understood. Three potential causative factors have been identified: a defect in drug metabolism resulting in the failure to eliminate toxic intermediates; reactivation of certain viruses (human herpesvirus 6, human herpesvirus 7, Epstein-Barr virus, cytomegalovirus) which may serve as a trigger for the reaction; and a genetic predisposition that alters immune responses (2).

The definite diagnosis of DRESS was made in our patient according to a scoring system for classifying DRESS composed by Kardaun et al (1), wherein his final score was 7. Differential diagnoses, such as viral infection, Kawasaki disease and toxic shock syndrome, were ruled out due to negative serology and failure to meet diagnostic criteria.

The management of DRESS involves prompt withdrawal of the offending agent and treatment with corticosteroids until clinical improvement and normalization of laboratory parameters (3). Corticosteroids should then be tapered slowly over eight to 12 weeks to avoid the risk of relapse. Our patient was started on intravenous solumedrol (1 mg/kg) daily for three days followed by oral prednisone 40 mg daily to complete seven days. On the fifth day of his admission, he developed type 1 second-degree atrioventricular block. This was considered to be an incidental finding because he was asymptomatic. Concern for the development of DRESS-associated myocarditis led to additional investigations; cardiac enzymes and an echocardiogram were both normal. This self-resolved after three days and an explanation for this brief conduction defect was not found.

On completion of seven days of oral prednisone, given the improvement of his rash and liver enzyme levels, he was discharged home to taper his steroids slowly. However, three days into the newly tapered dose of 35 mg daily, he experienced recurrence of his fever and rash with worsening of his liver enzyme levels, requiring readmission and resumption of intravenous solumedrol at 1 mg/kg every 8 h for three days. He was subsequently switched to prednisone 50 mg daily and weaned slowly over 11 weeks, with no recurrence of symptoms. His rash had completely resolved and liver enzyme levels normalized after two and 11 weeks, respectively.

Worsening of DRESS with tapering has been reported (3). Retrospectively, a higher dose of steroids coupled with gradual tapering may have prevented this scenario in our patient. Myocarditis, interstitial nephritis, pneumonitis and thyroiditis are other complications of DRESS that require long-term monitoring.

The incidence of DRESS following anticonvulsant therapy varies from one in 1000 to one in 100,000 exposures. The mortality rate is 10% to 20%, with most fatalities occurring as a result of liver failure (2). DRESS most commonly affects adults, and is relatively infrequently reported in children. It is a potentially fatal hypersensitivity reaction and its high mortality rate commands a high level of awareness among pediatricians.

CLINICAL PEARLS

• DRESS is a potentially life-threatening syndrome including severe skin eruption, fever, hypereosinophilia and internal organ involvement.

• Antiepileptic drugs are the most frequently reported causes.

• The mainstay of treatment of DRESS is identification and prompt withdrawal of the offending drug and the use of corticosteroids, with strict avoidance of the offending drug in the future.