In vitro detection of drug-induced granzyme B, interferon-gamma, and interleukin-22 releasing cells in different phenotypes of severe cutaneous adverse reactions

The measurement of drug-induced interferon-gamma releasing cells is another option to identify the culprit drug in severe cutaneous adverse reactions (SCARs) since drug provocation is contraindicated. However, its sensitivity is rather limited since other cytokines also play a role in pathogenesis of drug hypersensitivity. Frequencies of drug-induced granzyme-B, interferon-gamma, and interleukin-22 releasing cells in patients diagnosed with SCARs were measured by stimulating peripheral blood mononuclear cells (PBMCs) with the culprit drugs and analyzed by using enzyme-linked immunospot assay. Twenty-five patients were recruited into this study (10 drug reaction with eosinophilia and systemic symptoms-DRESS, 8 Stevens-Johnson syndrome-SJS, and 7 acute generalized exanthematous pustulosis-AGEP). Drug-induced granzyme-B, interferon-gamma, and interleukin-22 releasing cells were measurable in 15, 9, and 10 SCAR subjects, respectively. The average frequencies of detectable drug-induced granzyme-B, interferon-gamma, and interleukin-22 releasing cells were 109.1±37.5, 117.8±76.0, and 46.4±9.6 spot-forming units (SFU)/million PBMCs. Drug-induced granzyme-B, interferon-gamma, and interleukin-22 releasing cells were mainly detectable in 60.0% (6/10) of DRESS, 50.0% (4/8) of SJS, and 57.1% (4/7) of AGEP, respectively. The combination of drug-induced granzyme-B, interferon-gamma, and interleukin-22 releasing cells could identify the culprit drug in 70.0% (7/10) of DRESS, 62.5% (5/8) of SJS, and 71.4% (5/7) of AGEP, respectively, based on the cut-off value at 20 SFU/ million PBMCs. Predominant cytokines in various SCAR phenotypes are different. The combination of drug-induced granzyme-B, interferon-gamma, and interleukin-22 releasing cell measurement could enhance in vitro sensitivity for culprit drug identification in different phenotypes of drug-induced SCARs.