Delayed-type drug hypersensitivity reactions in a tertiary adult allergy clinic A 5-year cohort study
Main Article Content
Keywords
Beta-lactam, Drug Hypersensitivity, Severe Cutaneous Adverse Reaction
Abstract
Background and Objectives: Delayed-type drug hypersensitivity reactions (DHRs) range from maculopapular eruptions to severe cutaneous adverse reactions (SCARs). Provocation tests are unsafe in SCARs, so diagnosis depends on history, making regional data important for identifying high-risk drugs. This study aimed to retrospectively assess the clinical features and test results of patients with delayed-type DHRs in our clinic.
Materials and Methods: Adults ≥18 years with DHRs, evaluated at our clinic between 2019 and 2025, were included in this retrospective observational study. Patients with Types I–III reactions or incomplete records were excluded. Eligible cases were identified through retrospective review of medical records. Clinical data, laboratory findings, and patch and/or drug provocation test results were obtained from medical files.
Results: Thirty-three patients were included, of which 57.6% were females, and the median age was 40 years (19–70). The most common phenotype was maculopapular exanthem (n = 15, 45.5%), followed by fixed drug eruption (FDE) (n = 8, 24.2%). Seven patients (21.2%) had SCAR, including toxic epidermal necrolysis (TEN, n = 3), Stevens–Johnson syndrome (SJS, n = 1), SJS/ TEN overlap (n = 1), drug-related eosinophilia and systemic symptoms (n = 1), and generalized bullous FDE (n = 1). Six patients (18.2%) required hospitalization, four of whom were managed in an intensive care or burn unit. Seventeen patients (51.5%) had a single likely culprit drug, while the remaining patients were taking multiple medications. Antimicrobials (41.3%), particularly beta-lactam antibiotics, and nonsteroidal anti-inflammatory drugs (NSAIDs, 29.3%), were the most frequently implicated drug groups. Nine patients underwent diagnostic testing (patch testing n = 6, delayed intradermal testing n = 3), with four positive results.
Conclusions: Antibiotics, especially beta-lactam antibiotics and NSAIDs, were the leading culprit drugs. Polypharmacy complicates culprit identification, particularly in SCAR cases, underscoring the need for cautious prescribing and avoidance of unnecessary medications.
References
2. Lehloenya RJ, Peter JG, Copaescu A, Trubiano JA, Phillips EJ. Delabeling delayed drug hypersensitivity: How far can you safely go? J Allergy Clin Immunol Pract. 2020;8(9):2878–95.e6. https://doi.org/10.1016/j.jaip.2020.07.005. Erratum in: J Allergy Clin Immunol Pract. 2021;9(1):603. https://doi.org/10.1016/j.jaip.2020.10.024. Erratum in: J Allergy Clin Immunol Pract. 2022;10(2):651. https://doi.org/10.1016/j.jaip.2021.12.002
3. Gell PGH, Coombs RRA. Clinical aspects of immunology. Oxford: Blackwell Science; 1963.
4. Copaescu A, Gibson A, Li Y, Trubiano JA, Phillips EJ. An updated review of the diagnostic methods in delayed drug hypersensitivity. Front Pharmacol. 2021;11:573573. https://doi.org/10.3389/fphar.2020.573573
5. Tramontana M, Hansel K, Bianchi L, Sensini C, Malatesta N, Stingeni L. Advancing the understanding of allergic contact dermatitis: From pathophysiology to novel therapeutic approaches. Front Med (Lausanne). 2023;10:1184289. https://doi.org/10.3389/fmed.2023.1184289
6. Tanno LK, Calderon MA, Smith HE, Sanchez-Borges M, Sheikh A, Demoly P; Joint Allergy Academies. Dissemination of definitions and concepts of allergic and hypersensitivity conditions. World Allergy Organ J. 2016;9:24. https://doi.org/10.1186/s40413-016-0115-2
7. Riedl MA, Casillas AM. Adverse drug reactions: Types and treatment options. Am Fam Physician. 2003;68(9):1781–90.
8. Schuler AM, Smith EH, Chaudet KM, Bresler SC, Gudjonsson JE, Kroshinsky D, et al. Symmetric drug-related intertriginous and flexural exanthema: Clinicopathologic study of 19 cases and review of literature. J Cutan Pathol. 2021;48(12):1471–9. https://doi.org/10.1111/cup.14090
9. Durmaz MSB. Simetrik, ilaç ilişkili intertriginöz ve fleksural ekzantem. Turkiye Klinikleri Immunol Allergy-Special Topics. 2025;18(1):54–8.
10. Barbaud A, Goncalo M, Mockenhaupt M, Copaescu A, Phillips EJ. Delayed skin testing for systemic medications: Helpful or not? J Allergy Clin Immunol Pract. 2024;12(9):2268–77. https://doi.org/10.1016/j.jaip.2024.06.047
11. Lee EY, Knox C, Phillips EJ. Worldwide prevalence of antibiotic-associated Stevens–Johnson syndrome and toxic epidermal necrolysis: A systematic review and meta-analysis. JAMA Dermatol. 2023;159(4):384–92. https://doi.org/10.1001/jamadermatol.2022.6378
12. Tempark T, John S, Rerknimitr P, Satapornpong P, Sukasem C. Drug-induced severe cutaneous adverse reactions: Insights into clinical presentation, immunopathogenesis, diagnostic methods, treatment, and pharmacogenomics. Front Pharmacol. 2022;13:832048. https://doi.org/10.3389/fphar.2022.832048
13. De A, Rajagopalan M, Sarda A, Das S, Biswas P. Drug reaction with eosinophilia and systemic symptoms: An update and review of recent literature. Indian J Dermatol. 2018;63(1):30–40. https://doi.org/10.4103/ijd.IJD_582_17
14. Mockenhaupt M. Introduction: Classification, terminology, epidemiology, and etiology of cutaneous adverse drug reactions. In: Shear NH, Dodiuk-Gad RP, editors. Advances in diagnosis and management of cutaneous adverse drug reactions: Current and future trends. Cham: Springer; 2019. pp. 3–20.
15. Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, et al. International consensus on drug allergy. Allergy. 2014;69(4):420–37. https://doi.org/10.1111/all.12350
16. Khan DA, Banerji A, Blumenthal KG, Phillips EJ, Solensky R, White AA, et al. Drug allergy: A 2022 practice parameter update. J Allergy Clin Immunol. 2022;150(6):1333–93. https://doi.org/10.1016/j.jaci.2022.08.028
17. Rive CM, Bourke J, Phillips EJ. Testing for drug hypersensitivity syndromes. Clin Biochem Rev. 2013;34(1):15–38.
18. 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(3):555–62. https://doi.org/10.1111/bjd.12125
19. Kardaun SH, Sidoroff A, Valeyrie-Allanore L, Halevy S, Davidovici BB, Mockenhaupt M, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: Does a DRESS syndrome really exist? Br J Dermatol. 2007;156(3):609–11. https://doi.org/10.1111/j.1365-2133.2006.07704.x
20. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens–Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129(1):92–6.
21. Sidoroff A, Halevy S, Bavinck JN, Vaillant L, Roujeau JC. Acute generalized exanthematous pustulosis (AGEP)—A clinical reaction pattern. J Cutan Pathol. 2001;28(3):113–9. https://doi.org/10.1034/j.1600-0560.2001.028003113.x
22. 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(2):149–53. https://doi.org/10.1046/j.1523-1747.2000.00061.x
23. Brockow K, Garvey LH, Aberer W, Atanaskovic-Markovic M, Barbaud A, Bilo MB, et al. Skin test concentrations for systemically administered drugs: An ENDA/EAACI Drug Allergy Interest Group position paper. Allergy. 2013;68(6):702–12. https://doi.org/10.1111/all.12142
24. Barbaud A, Gonçalo M, Bruynzeel D, Bircher A; European Society of Contact Dermatitis. Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug reactions. Contact Dermatitis. 2001;45(6):321–8. https://doi.org/10.1034/j.1600-0536.2001.450601.x
25. Johansen JD, Aalto-Korte K, Agner T, Andersen KE, Bircher A, Bruze M, et al. European Society of Contact Dermatitis guideline for diagnostic patch testing: Recommendations on best practice. Contact Dermatitis. 2015;73(4):195–221. https://doi.org/10.1111/cod.12432
26. Fonacier L, Bernstein DI, Pacheco K, Holness DL, Blessing-Moore J, Khan D, et al. Contact dermatitis: A practice parameter update 2015. J Allergy Clin Immunol Pract. 2015;3(3 Suppl):S1–39. https://doi.org/10.1016/j.jaip.2015.02.009
27. Aberer W, Bircher A, Romano A, Blanca M, Campi P, Fernandez J, et al. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: General considerations. Allergy. 2003;58(9):854–63. https://doi.org/10.1034/j.1398-9995.2003.00279.x
28. Farshchian M, Ansar A, Zamanian A, Rahmatpour-Rokni G, Kimyai-Asadi A, Farshchian M. Drug-induced skin reactions: A 2-year study. Clin Cosmet Investig Dermatol. 2015;8:53–56. https://doi.org/10.2147/CCID.S75849
29. Peter JG, Lehloenya R, Dlamini S, Risma K, White KD, Konvinse KC, Phillips EJ. Severe delayed cutaneous and systemic reactions to drugs: A global perspective on the science and art of current practice. J Allergy Clin Immunol Pract. 2017;5(3):547–63. https://doi.org/10.1016/j.jaip.2017.01.025
30. Huang HY, Luo XQ, Chan LS, Cao ZH, Sun XF, Xu JH. Cutaneous adverse drug reactions in a hospital-based Chinese population. Clin Exp Dermatol. 2011;36(2):135–41. https://doi.org/10.1111/j.1365-2230.2010.03922.x
31. Mockenhaupt M. Epidemiology of cutaneous adverse drug reactions. Chem Immunol Allergy. 2012;97:1–17. https://doi.org/10.1159/000335612
32. Al-Ahmad M, Edin J, Musa F, Rodriguez-Bouza T. Drug allergy profile from a national drug allergy registry. Front Pharmacol. 2021;11:555666. https://doi.org/10.3389/fphar.2020.555666
33. Hernández-Salazar A, Rosales SP, Rangel-Frausto S, Criollo E, Archer-Dubon C, Orozco-Topete R. Epidemiology of adverse cutaneous drug reactions: A prospective study in hospitalized patients. Arch Med Res. 2006;37(7):899-902. https://doi.org/10.1016/j.arcmed.2006.03.010
34. Souissi A, Fenniche S, Benmously R, Ben Jannet S, Marrak H, Mokhtar I. Study of the cutaneous drug reactions in a teaching hospital in Tunis. Tunis Med. 2007;85(12):1011–5.
35. Patel RM, Marfatia YS. Clinical study of cutaneous drug eruptions in 200 patients. Indian J Dermatol Venereol Leprol. 2008;74(4):430. https://doi.org/10.4103/0378-6323.42883
36. Guzman AI, Paliza AC. Epidemiology of severe cutaneous adverse drug reactions in a university hospital: A five-year review. J Med Univ Santo Tomas. 2018;2(1):171–84. https://doi.org/10.35460/2546-1621.2017-0031
37. Badar Uddin U, Zeenat Un N. Cutaneous adverse drug reactions to antibiotics: How much is the extent of the problem? JOJ Dermatol Cosmet. 2023;5(4):555666. https://doi.org/10.19080/JOJDC.2023.05.555666
38. Stirton H, Shear NH, Dodiuk-Gad RP. Drug reaction with eosinophilia and systemic symptoms (DReSS)/drug-induced hypersensitivity syndrome (DiHS)—Readdressing the DReSS. Biomedicines. 2022;10(5):999. https://doi.org/10.3390/biomedicines10050999
39. 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 Dermatitis. 1996;35(4):234–6. https://doi.org/10.1111/j.1600-0536.1996.tb02364.x