Berneburg, Mark

Drexler, Konstantin

Karrer, Sigrid

Koschitzki, Kevin

Niebel, Dennis

University of Regensburg Publication Server

Received: 30 November 2022 Accepted: 16 January 2024DOI: 10.1111/ddg.15381CL IN ICAL LET TERRare case of itraconazole induced SDRIFE (symmetricaldrug-related intertriginous and flexural exanthema)Kevin Koschitzki Sigrid Karrer Mark Berneburg Dennis NiebelKonstantin DrexlerDepartment of Dermatology, University Hospital Regensburg, Regensburg, GermanyCorrespondenceKonstantin Drexler, MD, Department of Dermatology, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.Email: konstantin.drexler@ukr.deKEYWORDSdrug eruption, exanthema, itraconazole, SDRIFEDear Editors,A 53-year-old male patient had been suffering fromperianal dermatitis for 6 months with recent mycoticsuperinfection (Candida albicans), which had been treatedwith topical antimycotics (nystatin) in combination withzinc ointments as well as topical glucocorticosteroids(Figure 1). As the dermatitis showed no remission, itra-conazole 100 mg once daily was added to the therapeuticregimen for 9 days. The patient then started to notice anexacerbation and progressive weeping of the perianal rashas well as new lesions in the inguinal and axillar region.Upon examination, the patient showed symmetricalbilateral erythemas of the inguinal and axillar regionsas well as macerations and erosions, particularly on thebuttocks and in the inguinal folds (Figure 1). Mucous mem-branes were unremarkable. The patient showed normalvital signs and did not show any symptoms of systemicinvolvement.Two punch biopsies were taken from axillary and gluteallesions on the day of hospitalization. The biopsy taken fromthe axillary region showed hyperkeratosis and acanthopa-pillomatosis. A marked spongiosis as well as vacuolar inter-face dermatitis was visible. In addition, individual paraker-atotic cones were detectable. The upper corium showedmarked edema with increased eosinophilic granulocytes(Figure 2a). Overall, the findings were consistent with adrug reaction. The biopsy taken from the gluteal regionshowed orthokeratosis, an acanthotic epidermis with spon-This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.© 2024 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by Wiley-VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.giosis. Moreover, the upper corium showed increased neu-trophilic granulocytes (Figure 2b). The findingswere consis-tent with hematogenous contact dermatitis. Periodic acid-Schiff (PAS) staining was unremarkable. Differential bloodcount showed only slight leukocytosis and no elevation ofeosinophiles.Upon oral treatment with prednisolone 1 mg/kg/ body-weight (BW) per day and topical treatment with diflucor-tolone valerate 0.1%, the patient improved within 2 days.Adjunctive therapy consisted of disinfecting agents (poly-hexanide and phenol-methanal uric acid bathing) aswell asanalgesic treatment with metamizole.The exanthema had severely abated at day six of treat-ment. The dose of prednisolone could be tapered quickly,and after 17 days the patient showed complete remissionof itraconazole-induced symmetrical drug-related intertrig-inous and flexural exanthema (SDRIFE).Symmetrical drug-related intertriginous and flexuralexanthema is characterized by the eruption of a benigndermatitis, particularly in the intertriginous, inguinal, andgluteal areas. This particular macular rash is commonlycaused by systemic drugs such as antibiotics, for instanceamoxicillin and clindamycin, antimycotics, as well as certaincytostatics, urostatics, contrast agents and anticoagulants.The rash develops without any previous sensitization andusually starts within hours up to 2 days after the first drugadministration.1,2 Typical antimycotics reported to causeSDRIFE include terbinafine, nystatin, and fluconazole.3–5JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2024;22:833–836. wileyonlinelibrary.com/journal/ddg 833834 CLINICAL LETTERF IGURE 1 Clinical Picture. (a) Perianaldermatitis and candida superinfection. (b)Symmetrical gluteal erythema with erosions. (c)Typical symmetrical erythema of the inguinalregion.Only very few cases in the literature have hitherto sug-gested that itraconazole may cause SDRIFE.4,6 In their caseseries of twelve patients from eastern India, Hassanandaniet al. proposed a correlation between itraconazole andSDRIFE due to the prevalent use of the drug in light of risingincidence of dermatophytoses in the region.Clinically, the symmetrical erythema is often describedto be associated with oozing and sometimes with papulescausing itch, pain, and discomfort, while bullae are rare.SDRIFE neither affects palmoplantar surfaces nor theface.7,8 Diagnostic criteria suggested by Häusermann et al.include exposure to a systemic drug, erythema of thegluteal or perianal area, V-shaped erythema of the inguinalarea, involvement of at least one other intertriginous bodysite, symmetry of the affected areas, and absence of sys-temic toxicity.5 Even though guidelines for epicutaneouspatch tests suggest this diagnostic tool in SDRIFE, theOxford Centre for Evidence-Based Medicine only providesmechanism-based reasoning for this disease, with no sys-tematic reviews or clinical studies proving the benefit ofan allergological work-up. Since a prior sensitization is notessential in SDRIFE, we decided not to perform an epicu-taneous patch test with our patient who presented char-acteristic clinical findings.9 Differential blood count shouldexclude leukocytosis which can be seen with “acute gener-alized exanthematous pustulosis” (AGEP) and eosinophilia,present in “drug rash with eosinophilia and systemic symp-toms” (DRESS). Histologic features of SDRIFE include super-ficial perivascular lymphocytic infiltrate, sometimes withneutrophils and lymphocytes, although these findings arenot specific.5 Fever, abrupt onset of non-follicular pustules,and edema of the face and hands suggest systemic involve-ment and point towards initial stages of “severe cutaneousadverse reactions”(SCAR) suchasAGEPorDRESS.Otherder-matoses with a predilection for intertriginous areas shouldbe ruled out. While satellite lesions and odor may indicatecutaneous infections or Morbus Hailey Hailey, a history ofpreviously applied topical agents may indicate a contactallergy.10 Other differential diagnoses of SDRIFE includemoisture-associated-skin damage, intertrigo, tinea, psori-asis inversa, eccrine squamous syringometaplasia, neu-trophilic eccrine hidradenitis and staphylococcal scaldedskin syndrome.10Symmetrical drug-related intertriginous and flexuralexanthema was formerly considered as fixed drug erup-tion. The location-specific rash known as “baboon syn-drome” was associated not only with systemic drugs butalso with hematogenous contact eczema. This association 16100387, 2024, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ddg.15381 by Universitaet Regensburg, Wiley Online Library on [19/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseCLINICAL LETTER 835F IGURE 2 Histology. (a) Axillary Biopsy showing hyperkeratosis,acanthopapillomatosis, marked spongiosis and vacuolar interfacedermatitis consistent with SDRIFE. (b) Gluteal biopsy showingorthokeratosis, acanthotic epidermis with spongiosis and aninflammatory infiltrate consistent with SDRIFE (hematoxylin-eosin stain,scale bar: 200 μm).resulted in an unreasonable classification and undefinedpathomechanism of the disease. In 2004, Häusermann et al.proposed the term SDRIFE to replace the broad and polit-ically incorrect catchword “baboon syndrome”. The termSDRIFE helps to differentiate this benign skin conditionfrom drug eruptions such as AGEP, from drug rash witheosinophilia and systemic symptoms (DRESS), and fromfixed drug eruptions.5 The pathogenesis of SDRIFE is notyet completely understood. A delayed localized T-cell reac-tion has been suggested to trigger drug-induced allergicand toxic skin reactions. The fact that SDRIFE is caused bydrugs without any existing sensitization clearly separatesthis condition fromhematogenous contact dermatitis. SuchT-cell activation, known as a “pharmacology interactions ofdrugs with immune receptors”, however, may be related tothe concentration or the dose of a drug. Yet, the reasonwhy these reactions are site-specific remains unclear.11,12The areas of distribution are prone to mechanical friction,heat, and sweat. However, apocrine sweat glands are exclu-sively found in those exact areas. Those glands gain theirfunction only after the introduction of sex hormones inpuberty. The fact that there have not yet been any reportedcases of SDRIFE in children might indicate that apocrinesweat glands are involved in the pathophysiology of thedisease. More clinical studies will be necessary to help usunderstand the mechanisms behind this particular drugeruption.It is still unclear how COVID-19 infections are connectedtoSDRIFE, but thenumberof SDRIFE caseshasbeen increas-ing since the start of the pandemic in 2020.12,13 Whetherthe virus itself, the broad immune response, or multimodaltreatments including new antiviral agents have causedthe rise in case numbers of SDRIFE or SDRIFE-like lesionsremains unknown.14,15ACKNOWLEDGMENTOpen access funding enabled and organized by ProjektDEAL.CONFL ICT OF INTEREST STATEMENTNone.ORC IDKevin Koschitzki https://orcid.org/0000-0001-5659-124XDennisNiebel https://orcid.org/0000-0003-2069-0486REFERENCES1. Megna M, Camela E, Ocampo Garza SS, et al. Ciprofloxacin-inducedsymmetrical drug related intertriginous and flexural exanthema(SDRIFE) in a psoriasis patient. Contact Dermatitis. 2021;85(4):467-469.2. Hassanandani T, Panda M, Agarwal A, Das A. Rising trends of sym-metrical drug related intertriginous and flexural exanthem due toItraconazole in patients with superficial dermatophytosis: A caseseries of 12 patients from eastern part of India. Dermatol Ther.2020;33(6):e13911.3. Yadav N, Kar S, Verma V, et al. Symmetrical drug related intertrig-inous and flexural exanthema after ranitidine therapy: A probablecausal association in an 18-year-old girl. Indian J Drugs Dermatol.2018;4(1):34.4. Mohapatra M, Panda M, Kar BR, et al. Symmetric drug-related intert-riginous and flexural exanthema due to itraconazole: An uncommonside effect of a commonly used drug. Indian Dermatology Online J.2017;8(6):501-503.5. Häusermann P, Harr T, Bircher AJ. Baboon syndrome resultingfrom systemic drugs: is there strife between SDRIFE and allergiccontact dermatitis syndrome? Contact Dermatitis. 2004;51(5-6):297-310.6. Kalita BJ, Das S, Dutta B. Itraconazole-induced symmetrical drug-related intertriginous and flexural exanthema (SDRIFE): A rare occur-rence. Int J Dermatol. 2020;59(11):e419-e421.7. Blackmur JP, Lammy S, Baring DEC. Baboon syndrome:an unusual complication arising from antibiotic treatmentof tonsillitis and review of the literature. BMJ Case Rep.2013;Nov282013:bcr2013201977.8. Cabrera Hernandez V, Gonzalez Afonso M, Callero Viera A, Martin-Fernandez L. Symmetrical drug-related intertriginous and flexuralexanthema due to clindamycin. BMJ Case Rep. 2019;12(8):e230077.9. Mahler V, Nast A, Bauer A, et al. S3-Leitlinie: Durchführung des Epiku-tantests mit Kontaktallergenen und Arzneimitteln – Kurzfassung Teil2. J Dtsch Dermatol Ges. 2019;17(10):1075-1093.10. WinnickiM, Shear NH. A systematic approach to systemic contact der-matitis and symmetric drug-related intertriginous and flexural exan-thema (SDRIFE): a closer look at these conditions and an approach tointertriginous eruptions. Am J Clin Dermatol. 2011;12:171-180.11. Niebel D, Wenzel J. Immunpathologie von kutanen Medikamenten-nebenwirkungen. Pathologe. 2018;6(39):563-570. 16100387, 2024, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ddg.15381 by Universitaet Regensburg, Wiley Online Library on [19/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License836 CLINICAL LETTER12. Athira R, Hamsa L, Thomas N, Zacharias R. SDRIFE-Like Rash WithCOVID-19. Indian Pediatr. 2022;59(2):168.13. Chicharro P, Rodríguez-Jiménez P, Muñoz-Aceituno E, et al.SDRIFE-like rash associated with COVID-19, clinicopatho-logical correlation. Australas Journal Dermatol. 2021;62(1):88.14. Lim PN, Wylie G. Symmetrical drug-related intertriginous and flexuralexanthema like eruption associated with COVID-19 vaccination. ClinExp Dermatol. 2022;47(1):175-176.15. Hai J, Shawa H, Kim-Lim P, et al. Systemic drug-related intertriginousand flexural exanthema induced by the Pfizer-BioNTech COVID-19vaccine: A report of 2 cases. JAAD Case Rep. 2021;18:57-60. 16100387, 2024, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ddg.15381 by Universitaet Regensburg, Wiley Online Library on [19/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Rare case of itraconazole induced SDRIFE (symmetrical drug‐related intertriginous and flexural exanthema)

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Rare case of itraconazole induced SDRIFE (symmetrical drug‐related intertriginous and flexural exanthema)

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