BACKGROUND: Long-term sequelae are frequent and often disabling after epidermal necrolysis (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)). However, consensus on the modalities of management of these sequelae is lacking. OBJECTIVES: We conducted an international multicentric DELPHI exercise to establish a multidisciplinary expert consensus to standardize recommendations regarding management of SJS/TEN sequelae. METHODS: Participants were sent a survey via the online tool "Survey Monkey" consisting of 54 statements organized into 8 topics: general recommendations, professionals involved, skin, oral mucosa and teeth, eyes, genital area, mental health, and allergy workup. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). Results were analyzed according to the RAND/UCLA Appropriateness Method. RESULTS: Fifty-two healthcare professionals participated. After the first round, a consensus was obtained for 100% of 54 initially proposed statements (disagreement index < 1). Among them, 50 statements were agreed upon as 'appropriate'; four statements were considered 'uncertain', and ultimately finally discarded. CONCLUSIONS: Our DELPHI-based expert consensus should help guide physicians in conducting a prolonged multidisciplinary follow-up of sequelae in SJS-TEN.

1st Department of Dermatovenereology Masaryk University Faculty of Medicine St Ann's Faculty Hospital in Brno Brno Czech Republic

Academic Unit of Ophthalmology Birmingham and Midland Eye Centre Institute of Inflammation and Ageing University of Birmingham Birmingham UK

ADR AC GmbH Bern Switzerland

Allergy Unit IBIMA Regional University Hospital of Malaga UMA Málaga Spain

Burn Service Boston Shriners Hospital for Children Boston MA USA

Christine Kühne Center for Allergy Research and Education Davos Switzerland

Cornea and External Eye Disease Service Moorfields Eye Hospital London UK

Department of Adult and Pediatric Dermatology Bordeaux University Hospitals Bordeaux France

Department of Dermatology and Allergy Biederstein School of Medicine Technical University of Munich Munich Germany

Department of Dermatology and Allergy Center Odense Research Center for Anaphylaxis Odense University Hospital Odense Denmark

Department of Dermatology and Cutaneous Surgery University of South Florida Tampa FL USA

Department of Dermatology and Medicine Perelman School of Medicine University of Pennsylvania Philadelphia PA USA

Department of Dermatology AP HP Henri Mondor Hospital 1 Rue Gustave Eiffel 94000 Créteil France

Department of Dermatology Brigham and Women's Hospital Boston MA USA

Department of Dermatology Brigham and Women's Hospital Harvard Medical School Boston MA USA

Department of Dermatology CHU Edouard Herriot Lyon France

Department of Dermatology Coimbra University Hospital Center Faculty of Medicine University of Coimbra Coimbra Portugal

Department of Dermatology King's College Hospital NHS Foundation Trust London UK

Department of Dermatology National Taiwan University Hospital National Taiwan University College of Medicine No 7 Chung Shan South Road Taipei 10002 Taiwan

Department of Dermatology Northwestern University Feinberg School of Medicine Chicago IL USA

Department of Dermatology UC Davis Medical Center Sacramento CA USA

Department of Dermatology University Hospital Limerick Limerick Ireland

Department of Dermatology University Hospital Munich University of Ludwig Maximilian Munich Germany

Department of Dermatology University Hospital Zurich Zurich Switzerland

Department of Dermatology University Hospitals Birmingham NHS Foundation Trust Birmingham UK

Department of Dermatology University Medical Center Groningen University of Groningen Hanzeplein 1 9700 RB Groningen The Netherlands

Department of Dermatology University of California Davis Sacramento CA USA

Department of Dermatology University of Toronto Toronto ON Canada

Department of Immunology Sir Charles Gairdner Hospital Pathwest Laboratory Medicine Perth WA 6009 Australia

Department of Internal Medicine Centre Hospitalier Intercommunal de Créteil Créteil France

Department of Medicine University of Toronto Toronto Canada

Department of Medicine Vanderbilt University Medical Center Nashville TN USA

Department of Nursing and Midwifery University of Limerick Limerick Ireland

Department of Ophthalmology CHU Bichat Claude Bernard Paris France

Department of Ophthalmology CHU Charles Nicolle Rouen France

Department of Ophthalmology Kyoto Prefectural University of Medicine 465 Kajii Cho Hirokoji Agaru Kawaramach Dori Kamigyo Ku Kyoto 602 0841 Japan

Department of Oral Medicine Guy's and St Thomas' NHS Foundation Trust London UK

Department of Paediatric Dermatology Colentina Clinical Hospital Carol Davila University of Medicine and Pharmacy Bucharest Romania

Department of Psychology University of Limerick Limerick Ireland

Department of Rheumatology Allergy and Immunology Tan Tock Seng Hospital Singapore Singapore

Department of Surgery Harvard Medical School Boston MA USA

Dermatology Department Emek Medical Center Bruce Rappaport Faculty of Medicine Technion Institute of Technology Haifa Israel

Division of Allergology and Clinical Immunology Department of Pneumology Inselspital Bern University Hospital University of Bern Bern Switzerland

Division of Burns Massachusetts General Hospital Boston 02114 USA

Division of Burns Massachusetts General Hospital Boston MA USA

Division of Dermatology Niigata University Graduate School of Medical and Dental Sciences Niigata Japan

Dr Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Miami FL USA

EpiDermE Université Paris Est Créteil Créteil France

Faculty of Medicine University of Zurich Zurich Switzerland

Fondation Ophtalmologique Adolphe de Rothschild Paris France

Institute for Immunology and Infectious Diseases Murdoch University Murdoch WA Australia

Medical School University of Western Australia Perth WA 6009 Australia

MICORALIS Laboratory Department of Periodontology Faculty of Dentistry Côte d'Azur University Saint Roch Hospital Nice France

Moorfields Eye Hospital NHS Foundation Trust The UCL Institute of Ophthalmology London UK

Nd Department of Dermatology Colentina Clinical Hospital Carol Davila University of Medicine and Pharmacy Bucharest Romania

Oasi Research Institute IRCCS Troina Italy

Ophthalmology Bon Secours Hospital Cork Ireland

Rare Disease Unit 1 Dermatology Division Istituto Dermopatico Dell'Immacolata IRCCS Rome Italy

Reference Center for Toxic Bullous Dermatoses and Severe Drug Reactions TOXIBUL Créteil France

St John's Institute of Dermatology Guy's and St Thomas' Hospital London UK

Sunnybrook Health Sciences Centre Toronto ON Canada

The Ohio State University Wexner Medical Center Division of Dermatology Upper Arlington OH USA

ToxiTEN Group European Reference Network for Rare Skin Diseases Paris France

University Hospital Basel Basel Switzerland

Zobrazit více v PubMed

Duong TA, Valeyrie-Allanore L, Wolkenstein P, Chosidow O. Severe cutaneous adverse reactions to drugs. Lancet. 2017;390:1996–2011. doi: 10.1016/S0140-6736(16)30378-6. PubMed DOI

Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. 2008;128:35–44. doi: 10.1038/sj.jid.5701033. PubMed DOI

Monnet P, Rodriguez C, Gaudin O, Cirotteau P, Papouin B, Dereure O, et al. Towards a better understanding of adult idiopathic epidermal necrolysis: a retrospective study of 19 cases. J Eur Acad Dermatol Venereol. 2021;35:1569–1576. doi: 10.1111/jdv.17274. PubMed DOI

Kuijper EC, French LE, Tensen CP, Vermeer MH, Bouwes Bavinck JN. Clinical and pathogenic aspects of the severe cutaneous adverse reaction epidermal necrolysis (EN) J Eur Acad Dermatol Venereol. 2020;34(9):1957–1971. doi: 10.1111/jdv.16339. PubMed DOI PMC

Lalevée S, Contassot E, Ortonne N, Gaudin O, Ben Said B, Vocanson M, et al. Advances in understanding of the pathophysiology of epidermal necrolysis (Stevens-Johnson syndrome and toxic epidermal necrolysis) Ann Dermatol Venereol. 2020;147:475–81. doi: 10.1016/j.annder.2020.02.010. PubMed DOI

Chaby G, Maldini C, Haddad C, Lebrun-Vignes B, Hemery F, Ingen-Housz-Oro S, et al. Incidence of and mortality from epidermal necrolysis (Stevens-Johnson syndrome/toxic epidermal necrolysis) in France during 2003–16: a four-source capture-recapture estimate. Br J Dermatol. 2020;182:618–624. doi: 10.1111/bjd.18424. PubMed DOI

Bettuzzi T, Penso L, de Prost N, Hemery F, Hua C, Colin A, et al. Trends in mortality rates for Stevens-Johnson syndrome and toxic epidermal necrolysis: experience of a single centre in France between 1997 and 2017. Br J Dermatol. 2020;182:247–248. PubMed

Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol. 2000;115:149–153. doi: 10.1046/j.1523-1747.2000.00061.x. PubMed DOI

Sekula P, Dunant A, Mockenhaupt M, Naldi L, Bouwes Bavinck JN, Halevy S, et al. Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Invest Dermatol. 2013;133:1197–1204. doi: 10.1038/jid.2012.510. PubMed DOI

Garcia-Doval I, LeCleach L, Bocquet H, Otero XL, Roujeau JC. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol. 2000;136:323–327. doi: 10.1001/archderm.136.3.323. PubMed DOI

Traikia C, Hua C, Le Cleach L, de Prost N, Hemery F, Bettuzzi T, et al. Individual- and hospital-level factors associated with epidermal necrolysis mortality: a nationwide multilevel study, France, 2012–2016. Br J Dermatol. 2020;182:900–906. doi: 10.1111/bjd.18294. PubMed DOI

Creamer D, Walsh SA, Dziewulski P, Exton LS, Lee HY, Dart JKG, et al. U.K. guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol. 2016;174:1194–227. doi: 10.1111/bjd.14530. PubMed DOI

Ingen-Housz-Oro S, Duong TA, Bensaid B, Bellon N, de Prost N, Lu D, et al. Epidermal necrolysis French national diagnosis and care protocol (PNDS; protocole national de diagnostic et de soins) Orphanet J Rare Dis. 2018;13:56. doi: 10.1186/s13023-018-0793-7. PubMed DOI PMC

Seminario-Vidal L, Kroshinsky D, Malachowski SJ, Sun J, Markova A, Beachkofsky TM, et al. Society of Dermatology Hospitalists supportive care guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults. J Am Acad Dermatol. 2020;82:1553–1567. doi: 10.1016/j.jaad.2020.02.066. PubMed DOI

Brüggen MC, Le ST, Walsh S, Toussi A, de Prost N, Ranki A, et al. Supportive care in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi-based consensus. Br J Dermatol. 2021;185:616–626. doi: 10.1111/bjd.19893. PubMed DOI

Lee HY, Walsh SA, Creamer D. Long-term complications of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN): the spectrum of chronic problems in patients who survive an episode of SJS/TEN necessitates multidisciplinary follow-up. Br J Dermatol. 2017;177:924–935. doi: 10.1111/bjd.15360. PubMed DOI

Ingen-Housz-Oro S, Alves A, Colin A, Ouedraogo R, Layese R, Canoui-Poitrine F, et al. Health-related quality of life and long-term sequelae in survivors of epidermal necrolysis: an observational study of 57 patients. Br J Dermatol. 2020;182:916–926. doi: 10.1111/bjd.18387. PubMed DOI

Hajj C, Ezzedine K, Thorel D, Delcampe A, Royer G, Hua C, et al. Disabling ocular sequelae of epidermal necrolysis: risk factors during the acute phase and associated sequelae. Br J Dermatol. 2019;181:421–422. doi: 10.1111/bjd.18023. PubMed DOI

Hefez L, Zaghbib K, Sbidian E, Valeyrie-Allanore L, Allain M, Duong TA, et al. Post-traumatic stress disorder in Stevens-Johnson syndrome and toxic epidermal necrolysis: prevalence and risk factors. A prospective study of 31 patients. Br J Dermatol. 2019;180:1206–13. doi: 10.1111/bjd.17267. PubMed DOI

Dodiuk-Gad RP, Olteanu C, Feinstein A, Hashimoto R, Alhusayen R, Whyte-Croasdaile S, et al. Major psychological complications and decreased health-related quality of life among survivors of Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 2016;175:422–424. doi: 10.1111/bjd.14799. PubMed DOI

Yang CW, Cho YT, Chen KL, Chen YC, Song HL, Chu CY. Long-term sequelae of Stevens-Johnson syndrome/toxic epidermal necrolysis. Acta Derm Venereol. 2016;96:525–529. doi: 10.2340/00015555-2295. PubMed DOI

Fitch K, Bernstein S, Aguilar MD, Burnand B, LaCalle JR, Lazaro P, van het Loo M, McDonnell J, Vader JP, Kahan JP. The RAND/UCLA appropriateness method user's manual. Santa Monica: RAND Corporation; 2001.

Isvy-Joubert A, Ingen-Housz-Oro S, Vincent R, Haddad C, Valeyrie-Allanore L, Chosidow O, et al. Severe cutaneous adverse reactions to drugs: from patients to the national office for compensation of medical accidents. Dermatology (Basel) 2014;228:338–343. doi: 10.1159/000358295. PubMed DOI

Lian SB, Oh CC, Yeo YW, Lee HY. Spectrum of nail sequelae in Stevens-Johnson syndrome and toxic epidermal necrolysis. JAMA Dermatol. 2021;157:117–119. doi: 10.1001/jamadermatol.2020.4664. PubMed DOI PMC

Habre M, Ortonne N, Colin A, Meningaud JP, Chosidow O, Wolkenstein P, et al. Facial scars following toxic epidermal necrolysis: role of adnexal involvement? Dermatology (Basel) 2016;232:220–223. doi: 10.1159/000443164. PubMed DOI

Lefaucheur JP, Valeyrie-Allanore L, Ng Wing Tin S, Abgrall G, Colin A, Hajj C, et al. Chronic pain: a long-term sequela of epidermal necrolysis (Stevens-Johnson syndrome/toxic epidermal necrolysis) - prevalence, clinical characteristics and risk factors. J Eur Acad Dermatol Venereol. 2021;35:188–94. doi: 10.1111/jdv.16891. PubMed DOI

Gaultier F, Rochefort J, Landru MM, Allanore L, Naveau A, Roujeau JC, et al. Severe and unrecognized dental abnormalities after drug-induced epidermal necrolysis. Arch Dermatol. 2009;145:1332–1333. doi: 10.1001/archdermatol.2009.233. PubMed DOI

Villa A, Connell CL, Abati S. Diagnosis and management of xerostomia and hyposalivation. Ther Clin Risk Manag. 2015;11:45–51. PubMed PMC

Gueudry J, Roujeau JC, Binaghi M, Soubrane G, Muraine M. Risk factors for the development of ocular complications of Stevens-Johnson syndrome and toxic epidermal necrolysis. Arch Dermatol. 2009;145:157–162. PubMed

Prabhasawat P, Tesavibul N, Karnchanachetanee C, Kasemson S. Efficacy of cyclosporine 0.05% eye drops in Stevens Johnson syndrome with chronic dry eye. J Ocul Pharmacol Ther. 2013;29:372–7. doi: 10.1089/jop.2012.0009. PubMed DOI

Wan KH, Chen LJ, Young AL. Efficacy and safety of topical 0.05% cyclosporine eye drops in the treatment of dry eye syndrome: a systematic review and meta-analysis. Ocul Surf. 2015;13:213–25. doi: 10.1016/j.jtos.2014.12.006. PubMed DOI

Lee YJ, Kim SW, Seo KY. Application for tacrolimus ointment in treating refractory inflammatory ocular surface diseases. Am J Ophthalmol. 2013;155:804–813. doi: 10.1016/j.ajo.2012.12.009. PubMed DOI

Sotozono C, Ueta M, Yokoi N. Severe dry eye with combined mechanisms is involved in the ocular sequelae of SJS/TEN at the chronic stage. Invest Ophthalmol Vis Sci. 2018;59:DES80–6. doi: 10.1167/iovs.18-24019. PubMed DOI

Tougeron-Brousseau B, Delcampe A, Gueudry J, Vera L, Doan S, Hoang-Xuan T, et al. Vision-related function after scleral lens fitting in ocular complications of Stevens-Johnson syndrome and toxic epidermal necrolysis. Am J Ophthalmol. 2009;148:852–859.e2. doi: 10.1016/j.ajo.2009.07.006. PubMed DOI

Sotozono C, Yamauchi N, Maeda S, Kinoshita S. Tear exchangeable limbal rigid contact lens for ocular sequelae resulting from Stevens-Johnson syndrome or toxic epidermal necrolysis. Am J Ophthalmol. 2014;158:983–993. doi: 10.1016/j.ajo.2014.07.012. PubMed DOI

Tugal-Tutkun I, Akova YA, Foster CS. Penetrating keratoplasty in cicatrizing conjunctival diseases. Ophthalmology. 1995;102:576–585. doi: 10.1016/S0161-6420(95)30980-3. PubMed DOI

Kaser DJ, Reichman DE, Laufer MR. Prevention of vulvovaginal sequelae in stevens-johnson syndrome and toxic epidermal necrolysis. Rev Obstet Gynecol. 2011;4:81–85. PubMed PMC

Holtz M, Grimstad F, Higgins J, Denny G, Strickland J, Dowlut-McElroy T. Vulvovaginal involvement in pediatric Stevens-Johnson syndrome: a case series. J Pediatr Adolesc Gynecol. 2021;34:745–748. doi: 10.1016/j.jpag.2021.03.011. PubMed DOI PMC

Van Batavia JP, Chu DI, Long CJ, Jen M, Canning DA, Weiss DA. Genitourinary involvement and management in children with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Pediatr Urol. 2017;13:490.e1–490.e7. doi: 10.1016/j.jpurol.2017.01.018. PubMed DOI

Boyraz G, Basaran D, Salman MC, Ozgul N, Yuce K. Vaginal reconstruction for vaginal obliteration secondary to stevens johnson syndrome: a case report and review of literature. Oman Med J. 2017;32:436–439. doi: 10.5001/omj.2017.82. PubMed DOI PMC

Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67:361–370. doi: 10.1111/j.1600-0447.1983.tb09716.x. PubMed DOI

Harorani M, Davodabady F, Masmouei B, Barati N. The effect of progressive muscle relaxation on anxiety and sleep quality in burn patients: a randomized clinical trial. Burns. 2020;46:1107–1113. doi: 10.1016/j.burns.2019.11.021. PubMed DOI

Hornsby N, Blom L, Sengoelge M. Psychosocial interventions targeting recovery in child and adolescent burns: a systematic review. J Pediatr Psychol. 2020;45:15–33. PubMed

Duong TA, de Prost N, Ingen-Housz-Oro S, Carrié AS, Zerah F, Valeyrie-Allanore L, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: follow-up of pulmonary function after remission. Br J Dermatol. 2015;172:400–405. doi: 10.1111/bjd.13505. PubMed DOI

Seccombe EL, Ardern-Jones M, Walker W, Austin S, Taibjee S, Williams S, et al. Bronchiolitis obliterans as a long-term sequela of Stevens-Johnson syndrome and toxic epidermal necrolysis in children. Clin Exp Dermatol. 2019;44:897–902. doi: 10.1111/ced.13969. PubMed DOI

Wolkenstein P, Chosidow O, Fléchet ML, Robbiola O, Paul M, Dumé L, et al. Patch testing in severe cutaneous adverse drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Contact Derm. 1996;35:234–236. doi: 10.1111/j.1600-0536.1996.tb02364.x. PubMed DOI

Barbaud A, Collet E, Milpied B, Assier H, Staumont D, Avenel-Audran M, et al. A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions. Br J Dermatol. 2013;168:555–562. doi: 10.1111/bjd.12125. PubMed DOI

Lin YT, Chang YC, Hui RCY, Yang CH, Ho HC, Hung SI, et al. A patch testing and cross-sensitivity study of carbamazepine-induced severe cutaneous adverse drug reactions. J Eur Acad Dermatol Venereol. 2013;27:356–364. doi: 10.1111/j.1468-3083.2011.04418.x. PubMed DOI

Barbaud A, Collet E, Milpied B, Assier H, Staumont D, Avenel-Audran M, et al. A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions. Br J Dermatol. 2013;168:555–562. doi: 10.1111/bjd.12125. PubMed DOI

Kano Y, Hirahara K, Mitsuyama Y, Takahashi R, Shiohara T. Utility of the lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its timing and the type of drug eruption. Allergy. 2007;62:1439–1444. doi: 10.1111/j.1398-9995.2007.01553.x. PubMed DOI

Phillips EJ, Bigliardi P, Bircher AJ, Broyles A, Chang YS, Chung WH, et al. Controversies in drug allergy: testing for delayed reactions. J Allergy Clin Immunol. 2019;143:66–73. doi: 10.1016/j.jaci.2018.10.030. PubMed DOI PMC

Barbaud A, Castagna J, Soria A. Skin tests in the work-up of cutaneous adverse drug reactions: a review and update. Contact Dermat. 2022;86:344–356. doi: 10.1111/cod.14063. PubMed DOI

Bergmann MM, Caubet JC. Role of in vivo and in vitro tests in the Diagnosis of severe cutaneous adverse reactions (SCAR) to drug. Curr Pharm Des. 2019;25:3872–3880. doi: 10.2174/1381612825666191107104126. PubMed DOI

Bellón T, Rodríguez-Martín S, Cabañas R, Ramírez E, Lerma V, González-Herrada C, et al. Assessment of drug causality in Stevens-Johnson syndrome/toxic epidermal necrolysis: concordance between lymphocyte transformation test and ALDEN. Allergy. 2020;75:956–959. doi: 10.1111/all.14062. PubMed DOI

Kumkamthornkul P, Udnaen S, Tansit T, Tuchinda P, Srinoulprasert Y. Evaluation of a lymphocyte transformation test and cytokine detection assay to identify phenytoin and carbamazepine provoked DRESS or SJS/TEN in epilepsy patients. Int Immunopharmacol. 2018;63:204–210. doi: 10.1016/j.intimp.2018.08.010. PubMed DOI

Trubiano JA, Strautins K, Redwood AJ, Pavlos R, Konvinse KC, Aung AK, et al. The combined utility of ex vivo IFN-γ release enzyme-linked immunospot assay and in vivo skin testing in patients with antibiotic-associated severe cutaneous adverse reactions. J Allergy Clin Immunol Pract. 2018;6:1287–1296.e1. doi: 10.1016/j.jaip.2017.09.004. PubMed DOI PMC