Discussion
Drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DiHS) is a severe adverse idiosyncratic type IV hypersensitivity drug reaction characterized by an extensive skin rash and systemic organ involvement, lymphadenopathy, eosinophilia, and atypical lymphocytosis [1,2]. The combination of certain genetic predispositions and drug-virus interactions has been hypothesized to be the underlying pathogenesis of DRESS [2,3]. Certain Human leukocyte antigens (HLA) alleles have been associated with an increased risk of developing drug-specific DRESS in certain population groups [3]. Common drugs causing DRESS include aromatic antiepileptics, allopurinol, and sulfonamide drugs [2-4]. Two main theories describing the pathophysiology of DRESS involve drug-specific T-cell reactions and viral reactivation [1,2]. Firstly, an immune response against the drug reactivates viral infection. Secondly, concomitant immune response to viral reactivation is responsible for clinical manifestations of DRESS syndrome [1,4,5]. Human herpesvirus including cytomegalovirus (CMV), Ebstein-Barr virus (EBV), human herpes virus-6 (HHV-6), and human herpes virus-7 (HHV-7) is often associated with DRESS syndrome [2,3]. Quantitative PCR of viral DNA is the method of choice to determine active viral infection, primary or reactivation [6]. HHV-6 and EBV appear to be detected earlier in the course of the disease, followed by HHV-7 and CMV. This sequential viral reactivation suggests that it is related to the clinical phase of DRESS [2].
Clinical manifestations usually appear between 2 to 8 weeks after the introduction of the triggering drug [1,2]. With re-exposure, the time to onset is shorter with a more severe presentation [2,3]. The cutaneous eruptions usually begin with morbilliform eruption and later become edematous with follicular attenuation and can, less commonly, present with urticaria, erythroderma, vesicles, bullae, and pustules. Facial and neck edema is a hallmark, while mucosal involvement is rare and mild [2,3]. The systemic manifestations that commonly present and are part of the diagnostic criteria comprise fever, hematological abnormalities (leukocytosis, eosinophilia, and/or positive atypical lymphocytes), lymphadenopathy, and elevated liver function tests. Other possible internal organ involvements include kidneys (interstitial nephritis), lungs (pneumonitis), pancreas (pancreatitis), thyroid (thyroiditis), and heart (myocarditis, pericarditis). These organ involvements are the major causes of morbidity and mortality, which range from 2-10% [2-4] The most severe and life-threatening complication is fulminant liver failure [3,4]. Because of the systemic involvement features, DRESS is commonly mistaken for sepsis; a careful investigation must be undertaken to exclude sepsis as a cause of the patient’s clinical manifestations. Other severe cutaneous adverse reactions (SCAR) syndrome like Steven-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) or AGEP should also be considered in the differential diagnosis. However, the onset of eruption—shorter in SJS/TEN and AGEP– can help distinguish DRESS from the rest [2].
Diagnostic criteria commonly utilized are the RegiSCAR criteria for hospitalized patients with DRESS syndrome and a Japanese group’s criteria for diagnosis of DRESS/DIHS; the main difference is the inclusion of HHV-6 reactivation in the latter [3,4]. Patients who do not initially fulfill the diagnostic criteria on admission may evolve and eventually fulfill the criteria [2]. However, the diagnostic gold standard remains drug re-challenge, which is not practical due to life-threatening consequences [2,4]. An alternative is a patch test of the offending drug, which is positive in approximately 60% of the cases [7]. Previous data showed that around 10% of patients diagnosed with DRESS syndrome had normal eosinophilic count, and 30-50% had no lymphadenopathies, making the diagnosis more challenging. Proper clinical history and temporal relation with drug exposure can increase the accuracy of diagnosis and improve the overall prognosis [8].
Regardless of the proposed pathogenic mechanisms of DRESS syndrome, there is no difference in management [1]. Early cessation of the offending drug and all unnecessary drugs is essential for improved prognosis and shorter duration [1,2]. Supportive therapies such as intravenous fluids and antipyretics may be required to maintain hemodynamics [2,3]. Corticosteroids are the first line of treatment, either topical to relieve itchiness or systemic [2-4]. However, most of the cases require systemic corticosteroid therapy. If oral therapy fails or intravenous therapy is required, pulse therapy with methylprednisolone is indicated [2]. Steroid tapering dose varies from 1 to 3 months based on the clinical course [2,3,5]. In steroid-refractory cases, immunosuppressive therapies such as ciclosporin, cyclophosphamide, rituximab, or intravenous immunoglobulin (IVIG) can be used [1,2]. Cutaneous and systemic involvement can persist for several weeks to months after drug withdrawal or following systemic corticosteroid tapering [2,3]. Follow-up is required as patients can develop autoimmune phenomena or thyroid dysfunction following DRESS syndrome.
Conclusion
The severity of cutaneous manifestations of DRESS syndrome varies, but systemic involvement is the main cause of morbidity and mortality and requires close monitoring during hospitalization. The disease course can continue to progress even when the triggering drug is discontinued. Some patients may not respond to oral corticosteroids and require high-dose intravenous corticosteroid therapy, with disease flares that can also occur during the steroid dose tapering. Future administration of the drug-induced DRESS is contraindicated due to the potential risk of recurrence and complications.