1 2 3 ALLERGIC CONTACT DERMATITIS TO NIGELLA OIL EXPRESSING AS ERYTHEMA MULTIFORME 4 Nguyen Thi Mai Huong1,2,3 5 6 1: Hanoi Medical University, Hanoi, Vietnam 7 2: Department of Dermatology, Saint Louis Hospital, Paris, France 8 3: National Hospital of dermatology et venereology, Hanoi, Vietnam 9 10 Background 11 Nigella oil, extracted from the seeds of black cumin, is traditionally used for its cosmetic 12 and culinary properties. Modern-day laboratory studies have shown its varying 13 composition according to geographical origin and its various pharmacological 14 properties(1). This oil and essential oils in general, are known to be responsible for 15 eczematous contact dermatitis, sometimes severe reactions, which have been poorly 16 described, can occur. Herein we report a case of severe acute contact dermatitis due 17 to Nigella oil, clinically showing polymorphic lesions that mimicked erythema 18 multiforme. 19 Observation 20 A previously healthy 29-year-old woman was admitted to the dermatology department 21 for suspicion of drug eruption. 10 days before admission, she had a pilonidal sinus in 22 the cleft at the top of her buttocks. She self- treated at home with application of 23 betadine and Nigella oil. 4 days after, the lesion worsened with large erythematous 24 macule and formation of an abscess. She went to the hospital. The abcess was then 25 drained and she was prescrit Augmentin 3g per days for 7 days. She continued to 26 apply Nigella oil to te buttock and her back. The abscess regressed after 5 days of 27 antibiotic therapy but skin eruption gradually spread to the thighs, legs, chest, hands, 28 arms amd face, associated with moderate prurit. She reported no fever, no 29 gastrointestinal and respiratory signs. She was referred to dermatology service for 30 suspicion of drug-induced erythema multiforme by Augmentin. Initial clinical 31 examination found typical and atypical target-like lesions, compatible with an erythema 32 multiforme, without Nikolski’s sign, nor mucosal involvement. Detailed health history 33 found repetation use of Augmentin before without any reaction. 34 Biology examinations (blood count, plasma urea, creatinine and ionogram, liver test) 35 were also normal. The EBV, CMV, HIV, HHV6 and HHV8 serologies were negative. 36 A diagnosis of severe acute contact dermatitis showing severe polymorphic lesion that 37 mimicked erythema multiforme due to Nigella oil was made. With cessation of Nigella 38 sativa oil and topical corticosteroid, lesions healed within 1 month, but her skin 39 exhibited post-inflammatory hyperpigmentation. Patch tests, performed 2 months after 40 resolution, revealed positivity at 72 hours with Nigella oil and stayed negative with 41 betadine. Allergy testing with an oral amoxicillin 250mg challenge was negative. 42 Discussion 43 Nigella sativa oil extracted from the seeds of N. sativa or black cumin, found in 44 Southern Europe, North Africa, Mideast, Bangladesh, India is traditionally used for its 45 cosmetic and culinary properties. Its main active components are thymoquinone and 46 terpenes, but the exact composition of commercial oil and the proportion of its 47 constituents are highly variable(1). Many studies have shown the positive effects of 48 Nigella oil for the treatment and prevention of a variety of diseases and conditions that 49 include eczema, asthma, hypertension, diabetes, inflammation disorders(1) and more 50 recently for neurology(2) and oncology diseases(3). 51 However, skin reactions after topical use of Nigella oil have been reported in medical 52 literature, with a variaty of clinical magnifestation, from eczema(4,5), erythema 53 multiforme(6) to Stevens Johnson-like syndrome(7). In our case, the diagnosis of 54 erythema multiforme due to Nigella oil was made before the erythemas present mostly 55 on the contact areas with the present of typical and atypical target lesions. It was then 56 confirmed by the positivity of patch test. Otherwise, the extension of the lesions away 57 from the area of application, even after topical use alone suggests a systemic effect of 58 Nigella oil, this phenomenon was observed in other case reports(6,7). In our patient, 59 the onset of skin lesions is difficult to determined exactly because she had an erythema 60 of the pilonidal sinus before application of Nigella oil. In other reports, the time between 61 application of oil and the onset of disease varied from 1 day to 4 months (4–8). All the 62 cases reported had a complete regression after treatment of topical or short-term 63 systemic corticoid. Our patient was succesfully treated with the use of very strong 64 topical corticosteroids (clobetasol propionate). 65 The pathogenesis of acute contact dermatitis by Nigella oil is not well understood. 66 Thymoquinone and terpenes are the main pharmacologically active compounds(1) 67 Thymoquinone is shown to induce apoptosis, regulates the levels of pro- and anti- 68 apoptotic in several cancers (9), but its role in epidermal apotosis is unclear. p-cymene 69 is a monoterpene contained in Nigella oil that acts as a penetration enhancer by 70 disrupting the stratum corneum lipid structure, thus facilitating the transport of drugs 71 through the skin(10). These elements may promote epidermal apoptosis by topical 72 toxic and/or a hypersensitivity. 73 Finally, it is interesting to note the great number of non-scientist websites and tutorial 74 talking in Vietnamese about Nigella oil and how to use it. While the black cumin is not 75 cultivated in Vietnam, the key word black cumin oil in Vietnamese (“dầu hạt thì là đen”) 76 find 7 320 000 results on Google search. These sources demonstrate the great interest 77 of non-medical population in Vietnam about this product. Conversely, to our 78 knowledge, there isn’t any scientist article in Vietnam talking about skin reaction after 79 application of this oil. 80 Conclusion 81 In conclusion, Nigella oil can be a cause of erythema multiforme. A careful interrogation 82 and patch test should be done before cases of erythema multiforme with undetermined 83 causes. In term of treatment, the use of systemic corticoid is not obligatory because in 84 certain cases, topical corticosteroids are sufficient. a b c Figure 1. Erythematous macules in the zone of application of Nigella oil ( a and b) Typical and atypical target lesions away from the area of application (c) Figure 2: Patch test positive with Nigella oil 85 86 Referrences 87 88 1. Ali BH, Blunden G. Pharmacological and toxicological properties of Nigella sativa. Phytother Res. 2003;17(4):299–305. 89 90 91 2. Isaev NK, Chetverikov NS, Stelmashook EV, Genrikhs EE, Khaspekov LG, Illarioshkin SN. Thymoquinone as a Potential Neuroprotector in Acute and Chronic Forms of Cerebral Pathology. Biochem Biokhimiia. 2020 Feb;85(2):167–76. 92 93 94 3. Majdalawieh AF, Fayyad MW, Nasrallah GK. Anti-cancer properties and mechanisms of action of thymoquinone, the major active ingredient of Nigella sativa. Crit Rev Food Sci Nutr. 2017 Dec 12;57(18):3911–28. 95 96 4. Zedlitz S, Kaufmann R, Boehncke WH. Allergic contact dermatitis from black cumin (Nigella sativa) oil-containing ointment. Contact Dermatitis. 2002;46(3):188 97 98 99 5. Steinmann A, Schätzle M, Agathos M, Breit R. Allergic contact dermatitis from black cumin (Nigella sativa) oil after topical use. Contact Dermatitis. 1997;36(5):268–269. 100 101 102 6. Gelot P, Bara-Passot C, Gimenez-Arnau E, Beneton N, Maillard H, Celerier P. Éruption bulleuse à l'huile de nigelle [Bullous drug eruption with Nigella sativa oil]. Ann Dermatol Venereol. 2012;139(4):287–291 103 104 105 7. Gaudin O, Toukal F, Hua C, et al. Association Between Severe Acute Contact Dermatitis Due to Nigella sativa Oil and Epidermal Apoptosis. JAMA Dermatol. 2018;154(9):1062–1065. 106 107 108 8. Dehavay F, Kolivras A, Scheers C. Local and systemic adverse skin reactions following the use of herbal products believed to contain Nigella sativa seeds and oil. Contact Dermatitis. 2019;80(3):176–177 109 110 111 9. Imran M, Rauf A, Khan IA, Shahbaz M, Qaisrani TB, Fatmawati S, et al. Thymoquinone: A novel strategy to combat cancer: A review. Biomed Pharmacother Biomedecine Pharmacother. 2018 Oct;106:390–402. 112 113 10. 114 Ramadan MF, Mörsel J-T. Characterization of phospholipid composition of black cumin (Nigella sativa L.) seed oil. Nahr. 2002 Aug;46(4):240–4.