Case presentation
A 2-year-old girl presented with 2 weeks of fever and 1 week of progressive rash. Symptoms started 1 month after she was started on phenobarbital. On examination, temperature was 39.5°C (103.1°F), pulse 150 beats/minute, blood pressure 95/51 mmHg, respiratory rate 32 breaths/minute, and oxygen saturation of 98%. She was alert and in discomfort. Facial oedema, bilateral cervical adenopathy, and a desquamating erythematous rash were noted on the face, trunk, and extremities. Mucosal surfaces were erythematous with superficial erosions.
Laboratory values included white blood cell count 25,000/μl (30% neutrophils, 50% lymphocytes, 5% monocytes, 14% eosinophils, and 1% metamyelocytes), haemoglobin 10.5 g/dl, platelet count 239,000/μl, sodium 132 mmol/L, potassium 3.8 mmol/L, chloride 101 mmol/L, bicarbonate 19 mmol/L, blood urea nitrogen 3 mg/dl, creatinine 0.4 mg/dl, glucose 97 mg/dl, aspartate aminotransferase 446 U/L, alanine aminotransferase 456 U/L, alkaline phosphatase 193 U/L, total bilirubin 0.6 mg/dl, albumin 2.4 g/dl, and high-sensitivity C-reactive protein 56.5 mg/dl. Urinalysis revealed 100 mg/dl protein and 11–30 white blood cells per high-power field.
The patient was initially treated with two doses of intravenous immunoglobulin at 2 g/kg for presumed Kawasaki disease. Upon transfer to our hospital, she was diagnosed with drug rash with eosinophilia and systemic symptoms, also known as drug-induced hypersensitivity syndrome. She was treated with methylprednisolone 0.5 mg/kg/dose every 6 hours. Skin biopsy showed lymphocytic interface dermatitis with parakeratosis.
A week into her hospitalisation, she developed acute-onset hypotension, lactic acidosis, and acute kidney injury. Chest radiograph showed an enlarged cardiac silhouette, pulmonary oedema, and pleural effusions (Fig 1). Low-voltage QRS complexes were seen on electrocardiogram (Fig 2). Owing to concern for myocarditis, N-terminal pro-hormone of basic natriuretic peptide was obtained and found to be 55,060 pg/nl (normal range 0–125). An echocardiogram revealed global hypokinesis, left ventricular dilation, mild mitral and tricuspid regurgitation, and decreased contractility consistent with the diagnosis of myocarditis.
Figure 1 Chest radiograph shows an enlarged cardiac silhouette, pulmonary interstitial oedema, and pleural effusions.
Figure 2 EKG shows low-voltage QRS complexes consistent with the diagnosis of myocarditis. EKG=electrocardiogram.
Discussion
Drug rash with eosinophilia and systemic symptoms is drug hypersensitivity reaction that occurs 2–8 weeks after drug exposure.Reference Kardaun, Sekula and Valeyrie-Allanore 1 Reactivation of human herpesvirus 6 appears to play a role in the pathogenesis.Reference Shiohara, Inaoka and Kano 2 Most cases are due to anti-epileptics, allopurinol, and sulphonamides.Reference Kardaun, Sekula and Valeyrie-Allanore 1
Although both drug reaction with eosinophilia and systemic symptoms, Steven Johnson syndrome, and toxic epidermal necrolysis all have systemic involvement, the mucocutaneous features and time course help differentiate the conditions. Steven Johnson syndrome and toxic epidermal necrolysis are associated with deeper skin involvement, and onset is typically 1–2 weeks from drug exposure. In contrast, drug reaction with eosinophilia and systemic symptoms has a morbilliform appearance with facial swelling, later onset, and a protracted course. In addition, visceral involvement is more common (91%) and mucosal involvement is rare in drug rash with eosinophilia and systemic symptoms. The liver (75%) and kidney (37%) are the most common organs involved.Reference Kardaun, Sekula and Valeyrie-Allanore 1 Thyroiditis is also a well-recognised complication, often occurring 3 months or more after the onset of the disease. Myocarditis occurs in 13% of patients. Myocarditis has been described as late as 4 months after the diagnosis of drug rash with eosinophilia and systemic symptoms and may occur after the cutaneous findings have resolved.Reference Bourgeois, Cafardi, Groysman and Hughey 3 , Reference Bourgeois, Cafardi and Groysman 4
In a review of 22 patients with myocarditis associated with drug rash with eosinophilia and systemic symptoms, 12 patients died, 10 patients recovered, and 2 patients had residual cardiomyopathy. Several deaths occurred suddenly within hours of presentation: four patients died of a documented ventricular arrhythmia. Electrocardiogram changes include non-specific ST and T-wave changes, conduction delay, and sinus tachycardia. Given the high mortality rates, cardiac screening with troponin, electrocardiogram, and echocardiogram has been recommended in patients with drug rash with eosinophilia and systemic symptoms.Reference Bourgeois, Cafardi, Groysman and Hughey 3
Definitive diagnosis of myocarditis associated with drug rash with eosinophilia and systemic symptoms is made by endomyocardial biopsy. Histologic findings include a mixed eosinophilic and lymphocytic infiltrate. As the pattern of myocardial inflammation is patchy, sampling error may occur; therefore, biopsy should be reserved for patients with an unclear diagnosis or lack of response to corticosteroids and intravenous immunoglobulin.
We recommend obtaining N-terminal pro-hormone of basic natriuretic peptide levels in all patients with drug rash with eosinophilia and systemic symptoms. In our patient, obtaining N-terminal pro-hormone of basic natriuretic peptide may have allowed us to recognise myocarditis before her clinical decompensation. Values should be interpreted with caution as normal reference intervals vary by age, gender, puberty, and body habitus.Reference Nir, Lindinger and Rauh 5
N-terminal pro-hormone of basic natriuretic peptide may also play a role in assessing long-term morbidity. In one study (n=23), elevated levels of N-terminal pro-hormone of basic natriuretic peptide were found to be associated with left ventricular dysfunction in children with myocarditis.Reference Nasser, Perles, Rein and Nir 6 Conversely, normal values of N-terminal pro-hormone of basic natriuretic peptide are associated with echocardiographic recovery.Reference Nasser, Perles, Rein and Nir 6 In another report of 10 patients with myocarditis, children with elevated N-terminal pro-hormone of basic natriuretic peptide 6 or 12 months after diagnosis were more likely to receive a cardiac transplant.Reference Mlczoch, Darbandi-Mesri, Luckner and Salzer-Muhar 7
Treatment of drug reaction with eosinophilia and systemic symptoms includes discontinuation of the offending agent, high-dose corticosteroids, and supportive care. Intravenous immunoglobulin is not routinely recommended;Reference Joly, Janela and Tetart 8 however, for patients with myocarditis, intravenous immunoglobulin should be considered.Reference Bourgeois, Cafardi, Groysman and Hughey 3 , Reference Singer, Wanat and Rosenbach 9 Relapse is common with tapering or discontinuation of steroids; therefore, steroids are continued for months to years before tapering.Reference Chopra, Levell, Conley and Gilkes 10 Steroid-sparing immunosuppressive agents such as mycophenolate mofetil should be considered for patients with frequent relapses during steroid tapering.Reference Bourgeois, Cafardi, Groysman and Hughey 3
Our patient was initially treated with two doses of intravenous immunoglobulin (2 g/kg) by the transferring hospital followed by methylprednisolone 0.5 mg/kg/dose every 6 hours at our hospital. After 2 weeks, N-terminal pro-hormone of basic natriuretic peptide was 416 pg/ml and echocardiogram showed normal cardiac contractility. Serial measurements of N-terminal pro-hormone of basic natriuretic peptide were 55,060 pg/nl (initial), 15,763 pg/ml (4 days), 416 pg/ml (14 days), and 51 pg/ml (45 days). She was discharged after a 3-week hospitalisation with prednisone 2 mg/kg/day for 4 months followed by tapering. During her steroid tapering, she developed relapse of her rash and she was treated with high-dose intravenous methylprednisolone. After a duration of 7 months, she was again admitted for relapse after another attempted tapering and treated with intravenous immunoglobulin 2 g/kg and maintained on 0.5 mg/kg/day of prednisone. Echocardiogram showed normal cardiac function.
Myocarditis is a potentially fatal complication of drug reaction with eosinophilia and systemic symptoms. Early recognition and treatment with high-dose corticosteroids and intravenous immunoglobulin may improve clinical outcomes. As the time course of onset is variable and the clinical manifestations may be subtle, we recommend obtaining N-terminal pro-hormone of basic natriuretic peptide values in all patients with drug reaction with eosinophilia and systemic symptoms. We also recommend serial measurements for the first 6 months after diagnosis as myocarditis can present later in the disease course, after cutaneous manifestations have resolved.
Acknowledgements
None.
Financial Support
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflicts of Interest
None.
