The role of in vivo and ex vivo diagnostic tools in severe delayed immune-mediated adverse antibiotic drug reactions.

Abstract

The use of in vivo and ex vivo diagnostic tools for delayed immune-mediated adverse drug reactions (IM-ADR) is currently ill defined. To determine if the combination of skin testing and/or interferon-γ (IFN-γ) enzyme-linked immunoSpot assay (ELISpot) can aid diagnosis of these allergy phenotypes. Patients with antibiotic-associated severe delayed IM-ADR hypersensitivity, including SJS and TEN, DRESS, AGEP, GBFDE and severe MPE, were prospectively recruited. In vivo testing was completed to the implicated drug(s) and ex vivo testing was performed with the patient's PBMC stimulated with the relevant antibiotic concentrations for IFN-γ release ELISpot measurement. Eighty-one patients met the inclusion with DRESS (42; 51.9%) accounting for the majority of cases. Among the 63 (78%) who had an ELISpot assay performed, 34 (54%) were positive to at least one implicated antibiotic (median spot forming units/ million cells, 99.5; [IQR], 68-187) with glycopeptide being a strong predictor of positivity (aOR 6.11 95% CI 1.74, 21.42). In combination (in vivo and ex vivo), 51 (63%) of those tested were positive to an implicated antibiotic. For DRESS and severe MPE associated with penicillins and cephalosporins, this combination confirmed the culprit agent in 11/12 of the cases and in 6/7 for DRESS associated with glycopeptides. This study demonstrates that using in vivo in combination with ex vivo testing can enhance the diagnostic approach in these severe phenotypes by assisting with the identification of possible culprit antibiotics.