Dapsone-induced DRESS after infliximab-induced vasculitis: a case of cerebral infarction in the context of multiple drug reactions

Background

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially severe clinical entity occurring in between 1 in 1000 and 1 in 10 000 drug exposures but carrying mortality rates as high as 10%.1 2 Symptoms usually arise between 2 and 6 weeks after initial exposure but persist despite withdrawal of the culprit agent. Many drugs have been associated with DRESS including anticonvulsants such as phenytoin or carbamazepine, allopurinol and sulfur-containing drugs including sulfa agents and dapsone.1 2 Although the pathophysiology behind DRESS has not been fully elucidated, there appears to be an association between certain medications, polymorphisms in HLA genes and severe drug reactions including DRESS. In particular, HLA polymorphisms more common in certain ethnic populations may place those populations at higher risk for DRESS triggered by specific medications.1–3 Herpesvirus infection and/or reactivation, particularly with human herpesvirus 6 (HHV-6), has also been associated with DRESS.1 2 4

The typical clinical features of DRESS include a morbilliform rash, leucocytosis with profound eosinophilia or atypical lymphocytosis, fever, lymphadenopathy and the laboratory and clinical manifestations of multi-organ damage, most frequently hepatic injury.1 Although any organ may be involved, DRESS-associated central nervous system (CNS) vasculitis is an exceedingly rare phenomenon, with only a handful of cases reported in the literature.5 Despite the paucity of cases, early recognition of CNS vasculitis is crucial because of the potential for focal motor deficits and lasting neurological sequelae. We present a case of a patient presenting with DRESS and focal neurological deficits who was subsequently found to have multiple ischaemic foci on neuroimaging suggesting a CNS vasculitis.

Case presentation

A 31-year-old woman of Vietnamese descent with a medical history remarkable for Crohn’s disease controlled on infliximab and a documented allergy to trimethoprim–sulfamethoxazole was brought to the emergency department by family with hypersomnolence and a diffuse morbilliform rash. Initial history revealed that she had been started on dapsone 4 weeks earlier for biopsy-proven leucocytoclastic vasculitis thought to be secondary to her infliximab despite a prior reaction to sulfa medications. Two weeks after starting dapsone, she developed malaise and a diffuse, pruritic, morbilliform rash prompting an emergency department visit at an outside hospital and discontinuation of dapsone. Her symptoms persisted prompting admission to the same outside hospital 1 week later at which point she was diagnosed with DRESS, started on intravenous corticosteroids, and discharged 3 days later with an 8-day prednisone taper. Two days after discharge, she became increasingly somnolent with worsening rash prompting presentation to our institution.

On initial vital signs, she was afebrile but had a blood pressure of 92/63 mm Hg and a heart rate of 122 beats per minute. On physical examination, the patient was lethargic and disoriented to place and situation. Skin examination was notable for erythematous facial patches and a morbilliform rash covering the torso, buttocks, arms, legs, palms and soles without evidence of mucosal involvement (figure 1). Anterior cervical, axillary and inguinal lymphadenopathy were also noted. Neurological examination demonstrated bilateral patellar hyperreflexia and multiple beats of ankle clonus, right greater than left. Initial laboratory studies included a complete blood count remarkable for a leucocytosis to 54×10⁹ cells /L with absolute eosinophilia (8640/µL) and anaemia with a haemoglobin of 93 g/L. A liver function panel was remarkable for elevated liver enzymes with an alanine aminotransferase (ALT) of 108 U/L and an aspartate aminotransferase (AST) of 76 U/L. An ECG demonstrated T wave inversions, and subsequent laboratory studies disclosed a troponin T of 0.81 ng/mL. The patient was admitted to the medical intensive care unit for further evaluation and initiation of corticosteroid therapy for presumed drug reaction.

Investigations

A brain MRI revealed multiple foci of restricted diffusion in the bilateral frontal, parietal and occipital lobes largely, but not entirely, in vascular watershed areas, indicative of acute infarction (figure 2). Also observed were areas of pathological enhancement in a similar vascular distribution. Accompanying MR angiogram demonstrated vessel irregularity in the distal middle cerebral artery and anterior cerebral artery distributions but no evidence of frank vascular thrombosis. The imaging findings were read as suggestive of a vasculitic process. A transcranial doppler study demonstrated no evidence for a cardioembolic source. Subsequent vasculitis work-up was remarkable for low C3 (83.4 mg/dL) and C4 (5.4 mg/dL) but negative for anti-neutrophil cytoplasmic antibodies (ANCA), anti-nuclear antibodies (ANA) and anti-double stranded DNA (ds-DNA) antibodies, a negative rapid plasma reagin and negative serologies and PCR for Epstein-Barr virus, cytomegalovirus, HIV and chronic viral hepatitides. Flow cytometry of peripheral blood was also performed and negative for a lymphoproliferative process, and total IgG values were within normal limits.

The patient’s troponin T initially downtrended to 0.40 ng/mL on hospital day 2, but then remained persistently elevated at that level raising concern for eosinophilic myocarditis. Subsequent cardiac MRI demonstrated numerous foci of subendocardial late gadolinium enhancement (figure 3) suggesting subendocardial fibrosis with no evidence of intracardiac thrombus and a normal left ventricular ejection fraction of 56%. Eosinophilic endomyocarditis secondary to DRESS was strongly suspected based on these findings.

Treatment

The patient was started on intravenous methylprednisolone at a dose of 1000 mg every 24 hours. The patient’s rash and eosinophilia improved rapidly following initiation of steroid therapy, with a decrease in absolute eosinophil count to 283/µL 2 days after admission. Her methylprednisolone dose was tapered starting on hospital day 6, and she was successfully transitioned to oral prednisone at a dose of 80 mg two times per day starting on hospital day 13. HHV-6 DNA testing ordered on admission returned positive on hospital week 2 further suggesting a diagnosis of DRESS. Her anaemia initially worsened to a nadir of 8.1 g/dL with an elevated lactate dehydrogenase to 896 U/L and a low haptoglobin to <10 mg/dL suggestive of haemolysis, presumably secondary to prior dapsone use. Her haemoglobin subsequently recovered gradually without intervention to 9.8 g/dL on discharge. Her transaminitis increased to an ALT and AST of 2727 and 1457 U/L, respectively, on hospital day 7 with an associated hyperbilirubinemia to 2.5 mg/dL (direct 1.6 mg/dL) before improving prior to discharge. Her mental status improved throughout her hospital stay, but she continued to have brisk reflexes and mild generalised weakness. She was discharged to an acute rehab facility on hospital day 15 for continued rehabilitation after cerebrovascular accident.

Outcome and follow-up

High-dose steroids were continued on discharge with 80 mg of oral prednisone daily and tapered gradually over time before complete discontinuation 3 months after admission. Laboratory monitoring at outpatient follow-up demonstrated improvement in haemoglobin to 131 g/L and in her ALT and AST to 55 and 27 U/L, respectively, with resolution of hyperbilirubinemia. Repeat cardiac MRI 3 months after her admission showed near-complete resolution of late gadolinium enhancement. At clinical follow-up 5 months after discharge, her neurological deficits had resolved with the exception of subtle right-hand weakness, and she had returned to full-time office work.