A Case of Vancomycin-Induced Drug Reaction with Eosinophilia, Systemic Symptoms and Multiorgan Involvement Proven Using Lymphocyte Transformation Test

Abstract

Drug-induced hypersensitivity syndrome (DiHS), also referred to as drug reaction with eosinophilia and systemic symptoms (DRESS), is a rare but potentially life-threatening condition induced by drug hypersensitivity that leads to significant morbidity and mortality and often occurs in patients undergoing combination antibiotic therapy. Due to a recent increase in the incidence of methicillin-resistant Staphylococcus aureus infections, the occurrence of vancomycin-induced DiHS/DRESS has increased rapidly. However, because of insufficient pharmacogenetic data on vancomycin-induced drug eruptions in Asians coupled with the risk of re-eliciting the symptoms by provocation tests, confirmation of the culprit drug in vancomycin-induced DiHS/DRESS is often challenging. Here, we report a case of vancomycin-induced DiHS/DRESS, where the causal relationship was confirmed using a lymphocyte transformation test (LTT). A 51-year-old woman was treated with combination antibiotics, including vancomycin, for infective pericarditis. The patient subsequently developed fever, facial edema, generalized rash followed by multiple internal organ involvement, including the kidney, lung, liver, and heart. Thus, based on the International Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria, the case was diagnosed as 'definite' DiHS/DRESS, although the culprit drug was obscured by combination antibiotic therapy. The LTT confirmed that vancomycin, but not other glycopeptide antibiotics, specifically induced T-cell proliferation in this case. Collectively, our case suggests that clinicians can utilize LTT to identify the causative medication of DiHS/DRESS when the clinical information is limited to defining the culprit drug.

Keywords: Drug eruptions; Drug hypersensitivity; Drug hypersensitivity syndrome; Lymphocyte activation; Vancomycin.

Fig. 1. Clinical presentation of the patient with facial edema (A) and generalized morbilliform eruption (B~E) following desquamation (F, G). We received the patient’s consent form about publishing all photographic materials.

Fig. 2. Lymphadenopathy and pulmonary involvement based on chest computed tomography. (A) Increased size of multiple lymph nodes (arrows) in the retroperitoneum, both iliac chains, and inguinal area. (B) Diffuse body wall edema and skin thickening of both breasts (arrows) with pulmonary edema and bilateral pleural effusion (arrowheads). (C) Multiple enlarged lymph nodes (arrow) in the axillae.

Fig. 3. Lymphocyte transformation test confirmed a causative medication of DiHS/DRESS. Peripheral blood mononuclear monocytes (PBMCs) were isolated from freshly isolated whole blood using a Ficoll-Paque gradient method. Carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled PBMCs were cultured with or without 0, 5, and 50 µg/ml of vancomycin or 20 µg/ml of teicoplanin for 7 days. Zombie-aqua^–CD3⁺CD4⁺ T cells were gated using flow cytometry. (A) Representative flow cytometry plots and (B) quantified results of CFSE-diluted fraction as a measure of cell proliferation with or without vancomycin or teicoplanin (the percentage of CFSE-diluted cells among Zombie-aqua^–CD3⁺CD4⁺ cells, n=3, a representative data from more than two independent experiments with similar results). Statistics based on multiple comparison to healthy volunteer (0 µg/ml) and DiHS/DRESS (0 µg/ml) by one-way ANOVA, ^****p<0.001, post-hoc comparison between the negative control and 50 µg/ml vancomycin. DiHS: drug-induced hypersensitivity syndrome, DRESS: drug reaction with eosinophilia and systemic symptoms.