{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:36:48Z","timestamp":1790692608661,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2017,8,10]],"date-time":"2017-08-10T00:00:00Z","timestamp":1502323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Severe cutaneous adverse drug reactions (SCARs) represent life-threatening medical conditions and an appropriate causative diagnosis of these conditions is of the highest importance. Existing in vivo diagnostic methods are risky or are just contraindicated in these patients. Therefore, in vitro tests take on greater significance. In this survey, the studies on in vitro assays in SCARs were identified with a defined searching strategy and strict eligibility criteria. Different methods in the particular clinical manifestations and the groups of drugs were compared in respect to the diagnostic parameters obtained. The lymphocyte transformation test and IFNg-ELISpot (Interferon \u03b3-Enzyme-linked immunospot assay) appeared to have the best evidence currently available. Further diagnostic assays, which are based mostly on distinct mechanisms of SCARs, may outdo previous assays but they still need confirmation in a larger group of patients and in more research centers. Data from pediatric populations and acute generalized exanthematous pustulosis (AGEP) patients are scarce. Some technical issues, limitations, and modifications of routine laboratory methods are also discussed.<\/jats:p>","DOI":"10.3390\/ijms18081737","type":"journal-article","created":{"date-parts":[[2017,8,10]],"date-time":"2017-08-10T10:34:35Z","timestamp":1502361275000},"page":"1737","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["In Vitro Assays in Severe Cutaneous Adverse Drug Reactions: Are They Still Research Tools or Diagnostic Tests Already?"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6146-0188","authenticated-orcid":false,"given":"Grzegorz","family":"Porebski","sequence":"first","affiliation":[{"name":"Department of Clinical and Environmental Allergology, Jagiellonian University Medical College, Sniadeckich 10, 31-531 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1111\/all.12350","article-title":"International consensus on drug allergy","volume":"69","author":"Demoly","year":"2014","journal-title":"Allergy"},{"key":"ref_2","unstructured":"Davies, D.M. (1977). Pathogenesis of Adverse Drug Reactions, Oxford University Press. Textbook of Adverse Drug Reactions."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1111\/j.1365-2222.2011.03701.x","article-title":"In vitro diagnosis of T cell-mediated drug allergy","volume":"41","author":"Porebski","year":"2011","journal-title":"Clin. Exp. Allergy"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1111\/bcp.12505","article-title":"In vitro testing for diagnosis of idiosyncratic adverse drug reactions: Implications for pathophysiology","volume":"80","author":"Elzagallaai","year":"2015","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_5","unstructured":"Gell, P.G. (1976). Classification of Allergic Reactions Responsible for Clinical Hypersensitivity and Disease, Oxford University Press. Clinical Aspects of Immunology."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"683","DOI":"10.7326\/0003-4819-139-8-200310210-00012","article-title":"Delayed drug hypersensitivity reactions","volume":"139","author":"Pichler","year":"2003","journal-title":"Ann. Intern. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1159\/000453265","article-title":"Classification of drug hypersensitivity into allergic, p-i, and Pseudo-Allergic forms","volume":"171","author":"Pichler","year":"2016","journal-title":"Int. Arch. Allergy. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"200","DOI":"10.4049\/jimmunol.1100647","article-title":"Mass spectrometric characterization of circulating and functional antigens derived from piperacillin in patients with cystic fibrosis","volume":"187","author":"Whitaker","year":"2011","journal-title":"J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0300-483X(02)00255-X","article-title":"The danger hypothesis\u2014Potential role in idiosyncratic drug reactions","volume":"181\u2013182","author":"Pirmohamed","year":"2002","journal-title":"Toxicology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1097\/00130832-200208000-00003","article-title":"Pharmacological interaction of drugs with antigen-specific immune receptors: The p-i concept","volume":"2","author":"Pichler","year":"2002","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1159\/000441280","article-title":"Drug hypersensitivity: How drugs stimulate T cells via pharmacological interaction with immune receptors","volume":"168","author":"Pichler","year":"2015","journal-title":"Int. Arch. Allergy Clin. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9959","DOI":"10.1073\/pnas.1207934109","article-title":"Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire","volume":"109","author":"Ostrov","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/clpt.2011.155","article-title":"In vitro testing for hypersensitivity-mediated adverse drug reactions: Challenges and future directions","volume":"90","author":"Elzagallaai","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1111\/bjd.12125","article-title":"A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions","volume":"168","author":"Barbaud","year":"2013","journal-title":"Br. J. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1111\/bjd.14492","article-title":"Diagnostic patch testing following tuberculosis-associated cutaneous adverse drug reactions induces systemic reactions in HIV-infected persons","volume":"175","author":"Lehloenya","year":"2016","journal-title":"Br. J. Dermatol."},{"key":"ref_16","first-page":"272","article-title":"Lymphocyte-stimulation tests and patch tests to carbamazepine hypersensitivity","volume":"29","author":"Houwerzijl","year":"1977","journal-title":"Clin. Exp. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1023\/A:1018850805536","article-title":"Flow cytometric method to detect lymphocyte transformation in drug-allergic hepatic injury","volume":"43","author":"Ikeda","year":"1998","journal-title":"Dig. Dis. Sci."},{"key":"ref_18","first-page":"425","article-title":"Piperacillin-induced DRESS: Distinguishing features observed in a clinical and allergy study of 8 patients","volume":"24","author":"Calderon","year":"2014","journal-title":"J. Investig. Allergol. Clin. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"227","DOI":"10.2174\/187152812800392751","article-title":"Detection of abacavir hypersensitivity by ELISpot method","volume":"11","author":"Esser","year":"2012","journal-title":"Inflamm. Allergy Drug Targets"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1111\/cea.12145","article-title":"In vitro drug causality assessment in Stevens-Johnson syndrome\u2014Alternatives for lymphocyte transformation test","volume":"43","author":"Porebski","year":"2013","journal-title":"Clin. Exp. Allergy"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1159\/000233856","article-title":"Lymphocyte transformation test in drug-induced toxic epidermal necrolysis","volume":"78","author":"Roujeau","year":"1985","journal-title":"Int. Arch. Allergy Appl. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1038\/jid.2015.165","article-title":"Oxypurinol-specific T cells possess preferential TCR clonotypes and express granulysin in allopurinol-induced severe cutaneous adverse reactions","volume":"135","author":"Chung","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1111\/bjd.14701","article-title":"In vitro test to confirm diagnosis of allopurinol-induced severe cutaneous adverse reactions","volume":"175","author":"Klaewsongkram","year":"2016","journal-title":"Br. J. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"O1","DOI":"10.1186\/2045-7022-4-S3-O1","article-title":"Mechanisms that limit proliferative potential of drugspecific LTT in drug-induced severe cutaneous adverse reaction patients","volume":"4","author":"Mockenhaupt","year":"2014","journal-title":"Clin. Transl. Allergy"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1067\/mai.2003.1507","article-title":"Characterization of drug-specific T cells in lamotrigine hypersensitivity","volume":"111","author":"Naisbitt","year":"2003","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.anai.2016.04.017","article-title":"In vitro rapid diagnostic tests for severe drug hypersensitivity reactions in children","volume":"117","author":"Haw","year":"2016","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1159\/000448284","article-title":"Evaluation of lymphocyte transformation test results in patients with delayed hypersensitivity reactions following the use of anticonvulsant drugs","volume":"170","author":"Karami","year":"2016","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.jaad.2004.05.006","article-title":"Clinical implications of in vitro drug-induced interferon \u03b3 release from peripheral blood lymphocytes in cutaneous adverse drug reactions","volume":"52","author":"Halevy","year":"2005","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1046\/j.1365-2222.2002.01382.x","article-title":"Determination of interleukin-5 secretion from drugspecific activated ex vivo peripheral blood mononuclear cells as a test system for the in vitro detection of drug sensitization","volume":"32","author":"Sachs","year":"2002","journal-title":"Clin. Exp. Allergy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1111\/bjd.14839","article-title":"Drug-specific CD4+ T-cell immune responses are responsible for antituberculosis drug-induced maculopapular exanthema and drug reaction with eosinophilia and systemic symptoms syndrome","volume":"176","author":"Ye","year":"2017","journal-title":"Br. J. Dermatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/j.1398-9995.2009.02143.x","article-title":"In vitro detection and characterization of drug hypersensitivity using flow cytometry","volume":"65","author":"Martin","year":"2010","journal-title":"Allergy"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.jdermsci.2017.03.007","article-title":"Novel interferon-\u03b3 enzyme-linked immunoSpot assay using activated cells for identifying hypersensitivity-inducing drug culprits","volume":"86","author":"Kato","year":"2017","journal-title":"J. Dermatol. Sci."},{"key":"ref_33","first-page":"1089","article-title":"Lymphocyte transformation studies in drug hypersensitivity","volume":"120","author":"Warrington","year":"1979","journal-title":"Can. Med. Assoc. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1159\/000358491","article-title":"Enhancement of Drug-Specific Lymphocyte proliferation using CD25-depleted CD3 effector cells","volume":"163","author":"Srinoulprasert","year":"2014","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.jaci.2005.10.030","article-title":"Long-lasting reactivity and high frequency of drug-specific T cells after severe systemic drug hypersensitivity reactions","volume":"117","author":"Beeler","year":"2006","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Fu, M., Gao, Y., Pan, Y., Li, W., Liao, W., Wang, G., Li, C., Li, C., Gao, T., and Liu, Y. (2012). Recovered patients with Stevens-Johson syndrome and toxic epidermal necrolysis maintain long-lived IFN-\u03b3 and sFasL memory response. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0045516"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1172\/JCI12118","article-title":"T-cell involvement in drug-induced acute generalized exanthematous pustulosis","volume":"107","author":"Britschgi","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1111\/j.1398-9995.2009.02180.x","article-title":"In vitro detection of cytotoxic T and NK cells in peripheral blood of patients with various drug-induced skin diseases","volume":"65","author":"Zawodniak","year":"2010","journal-title":"Allergy"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1111\/j.1398-9995.2007.01516.x","article-title":"CD69 Upregulation on T cells as an in vitro marker for delayed-type drug hypersensitivity","volume":"63","author":"Beeler","year":"2008","journal-title":"Allergy"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1111\/j.1398-9995.2009.01985.x","article-title":"Drug-specific in vitro release of IL-2, IL-5, IL-13 and IFN-\u03b3 in patients with delayed-type drug hypersensitivity","volume":"64","author":"Lochmatter","year":"2009","journal-title":"Allergy"},{"key":"ref_41","first-page":"429","article-title":"Case report blast transformation in vivo and in vitro carbamazepin hypersensitivity","volume":"9","author":"Virolainen","year":"1971","journal-title":"Clin. Exp. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1111\/bjd.12109","article-title":"In vitro diagnostic assays are effective during the acute phase of delayed-type drug hypersensitivity reactions","volume":"168","author":"Polak","year":"2013","journal-title":"Br. J. Dermatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/j.1365-2222.1997.tb00690.x","article-title":"The lymphocyte transformation test for the diagnosis of drug allergy: Sensitivity and specificity","volume":"27","author":"Nyfeler","year":"1997","journal-title":"Clin. Exp. Allergy"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1111\/j.1468-3083.2011.04418.x","article-title":"A patch testing and cross-sensitivity study of carbamazepine-induced severe cutaneous adverse drug reactions","volume":"27","author":"Lin","year":"2013","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1111\/j.1398-9995.2007.01553.x","article-title":"Utility of the lymphocyte transformation test in the diagnosis of drug sensitivity: Dependence on its timing and the type of drug eruption","volume":"62","author":"Kano","year":"2007","journal-title":"Allergy"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.jaci.2004.09.012","article-title":"T cell-mediated reactions to iodinated contrast media: Evaluation by skin and lymphocyte activation tests","volume":"115","author":"Kanny","year":"2005","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_47","first-page":"865","article-title":"Multiple drug allergy in patients with cutaneous adverse drug reactions diagnosed by in vitro drug-induced interferon-\u03b3 release","volume":"10","author":"Halevy","year":"2008","journal-title":"Isr. Med. Assoc. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1023\/A:1006682413834","article-title":"Il-4 and IFN-\u03b3 mRNA induction in human peripheral lymphocytes specific for \u03b2-lactam antibiotics in immediate or delayed hypersensitivity reactions","volume":"20","author":"Gaspard","year":"2000","journal-title":"J. Clin. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/j.1365-2222.2006.02402.x","article-title":"T cell-mediated hypersensitivity to quinolones: Mechanisms and cross-reactivity","volume":"36","author":"Schmid","year":"2006","journal-title":"Clin. Exp. Allergy"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1111\/cea.12184","article-title":"Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response","volume":"43","author":"Yun","year":"2013","journal-title":"Clin. Exp. Allergy"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.jdermsci.2011.12.002","article-title":"The predominant drug-specific T-cell population may switch from cytotoxic T cells to regulatory T cells during the course of anticonvulsant-induced hypersensitivity","volume":"65","author":"Hanafusa","year":"2012","journal-title":"J. Dermatol. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1046\/j.1365-2222.2001.01164.x","article-title":"T cell involvement in cutaneous drug eruptions","volume":"31","author":"Hari","year":"2001","journal-title":"Clin. Exp. Allergy"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1111\/j.1398-9995.2008.01674.x","article-title":"Detection and quantification of drugspecific T cells in penicillin allergy","volume":"64","author":"Rozieres","year":"2009","journal-title":"Allergy"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/8\/1737\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:42:03Z","timestamp":1760208123000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/8\/1737"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,10]]},"references-count":53,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2017,8]]}},"alternative-id":["ijms18081737"],"URL":"https:\/\/doi.org\/10.3390\/ijms18081737","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,10]]}}}