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Association Between Severe Acute Contact Dermatitis Due to Nigella sativa Oil and Epidermal Apoptosis
Olivier Gaudin, Feyrouz Toukal, Camille Hua, Nicolas Ortonne, Haudrey Assier, Arnaud Jannic, Elena Giménez-Arnau, Pierre Wolkenstein, Olivier
Chosidow, Saskia Ingen-Housz-Oro
To cite this version:
Olivier Gaudin, Feyrouz Toukal, Camille Hua, Nicolas Ortonne, Haudrey Assier, et al.. Associa- tion Between Severe Acute Contact Dermatitis Due to Nigella sativa Oil and Epidermal Apoptosis.
JAMA Dermatology, American Medical Association, 2018, 154 (9), pp.1062. �10.1001/jamaderma- tol.2018.2120�. �hal-02333665�
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Association Between Severe Acute Contact Dermatitis Due to Nigella sativa Oil and Epidermal Apoptosis
Olivier Gaudin, MD; Feyrouz Toukal, MD; Camille Hua, MD; Nicolas Ortonne, MD, PhD; Haudrey Assier, MD; Arnaud Jannic, MD; Elena Giménez-Arnau, PhD; Pierre Wolkenstein, MD, PhD; Olivier Chosidow, MD, PhD; Saskia Ingen-Housz-Oro, MD
1/ Dermatology department, AP-HP, Henri Mondor hospital, Créteil, France 2/ Pathology department, AP-HP, Henri Mondor hospital, Créteil, France 3/ Dermato-allergology, AP-HP, Henri Mondor hospital, Créteil, France 5/ University of Strasbourg-CNRS UMR 7177, Strasbourg, France 6/ University of Paris Est Créteil Val de marne, UPEC, Créteil, France 7/ Referral center for severe cutaneous adverse reactions, Créteil, France
8/ EA7379-EpiDermE (Epidémiologie en Dermatologie et Evaluation des Thérapeutiques), Créteil, France
Words count: 919 Corresponding Author:
Camille Hua
Address: 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France Telefon : 01 49 81 2512 ; Fax : 01 49 81 2508
Mail : [email protected]
No conflict of interest to disclosure
Key Points
Question: Severe acute contact dermatitis (ACD) to Nigella sativa oil (NSO) after topical use is misdiagnosed. Histological findings are poorly described.
Findings: We describe 6 patients who displayed clinical and histopathological features of epidermal necrolysis after NSO skin application. Analysis of the NSO showed thymoquinone and p-cymene as major components.
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Meaning: Acute epidermal apoptotic necrolysis may be triggered by topical agents such as NSO.
Abstract
Importance: Nigella sativa oil (NSO) is widely used. Acute contact dermatitis to NSO is poorly described and lack histological description.
Objective: To describe clinical and histological features of severe acute contact dermatitis (ACD) to NSO. To investigate the component(s) responsible for such eruption.
Design: Series of six cases admitted in the dermatology department between 2010 and 2016.
Setting: Monocenter, retrospective case series.
Participants: All patients referred in our department for ACD to NSO.
Main outcomes: We collected clinical and histological features of the cutaneous eruption, whether patients were hospitalized or not, treatment, length of stay, chemical analysis of NSO and results of patch tests when performed.
Results: Six patients (all female, median age 29 years) were included. None of them had oral intake of NSO. All patients had polymorphic skin lesions spreading over the area of
application: target and target-like lesions (n=6), patches with central blisters (n=5),
erythematous or purpuric plaques with positive Nikolsky sign (n=5) mimicking epidermal necrolysis, and pustules (n=3). Three patients had severe impairment with more than 15 % skin detachment and fever. Skin biopsies (n=4) showed vacuolar alteration of the basal layer, keratinocytes apoptosis and a moderate perivascular infiltrate of lymphocytes in the dermis.
Patch-tests using patient’s NSO were all positive. Gas chromatography combined to mass spectrometry (n=1) identified several constituent substances, mainly terpenes, thymoquinone, linoleic acid and fatty acids.
Conclusions and relevance: Our patients illustrate that epidermal necrolysis can be triggered by topics. They present features of hyperacute apoptotic injury of the epidermis, within the
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spectrum of Acute Syndrome of Apoptotic Pan-epidermolysis. Thymoquinone and p-cymene being the main constituents could be involved in the pathophysiology of this ACD to topical application of NSO. Clinicians should be aware of these severe cutaneous adverse events of NSO, and declare any severe cases to a pharmacovigilance center.
4 Introduction
Nigella sativa oil (NSO), extracted from the plant Nigella sativa found in South Europe,
North Africa and South-West Asia, is traditionally used for cosmetic and culinary properties.1 Its main components are thymoquinone and terpenes1, however, the exact composition of commercial NSO and proportion of its constituents are hardly predictable. NSO, and more generally essential oils, are known to be responsible for benign occupational contact dermatitis, but sometimes acute contact dermatitis (ACD).2
Acute Syndrome of Apoptotic Pan-epidermolysis (ASAP) phenomenon, characterized by a hyperacute apoptotic injury of the epidermis, has been described in various dermatoses.3 The main cause is epidermal necrolysis (EN) spectrum, including Stevens-Johnson (SJS) and toxic epidermal necrolysis (TEN), induced by systemic drugs in most cases.4 Other causes of ASAP include TEN-like acute graft versus host disease, TEN-like acute and subacute cutaneous lupus erythematous, severe eruptions associated with Mycoplasma pneumoniae infection.5 We report a series of 6 cases of severe ACD to NSO, showing polymorphic severe lesions mimicking erythema multiforme, bullous fixed drug eruption or EN, and, histologically, apoptotic epidermis, raising the hypothesis that ASAP could be topically-triggered by such essential oil.
Methods
We performed a retrospective monocenter study including consecutive patients referred to our Dermatology Department between 2010 and 2016 for dermatitis after NSO application. Cases were extracted from the database of our Department, which is a referral center for toxic bullous dermatoses.
For each case, the following parameters were collected from the charts: age, sex, previous application of NSO, oral take of NSO, duration and localization of the application, time
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between application and onset of cutaneous reaction, localization and extension of skin lesions, clinical aspect of skin lesions, mucous involvement, number of cutaneous flares, length of hospital stay, histologic analysis when skin biopsy was available, treatment and evolution, results of patch tests whenever performed. We investigated the composition of one of the patients’ NSO by gas chromatography (Chromatograph Trace GC Ultra) combined to mass spectrometry (Spectrometer Thermo Fisher TSQ Quantum).
Results
All cases were women with a median age of 29 years (range 20-47), who applied NSO in different parts of skin or scalp for cosmetic use only. None of them had oral intake of NSO (Table 1). Median time between application of NSO and onset of the disease was 1.5 days (range 1-2). Three patients had already used NSO before without cutaneous reaction. Clinical examination showed polymorphic skin lesions, spreading over the area of application (Fig.1):
target and atypical targets (n=6), patches with central blisters (n=5), erythematous and purpuric macules and plaques with Nikolsky’s sign (n=5), and pustules (n=3). Three patients had severe impairment with more than 15 % of the body surface area involved with Nikolsky sign, fever and hospital length of stay of more than 10 days. One patient had a second
cutaneous flare of the same lesions after washing her hair where she had initially applied NSO.
Histology of a skin biopsy was performed in 4 cases and revealed in all cases vacuolar alteration of the basal layer, keratinocytes apoptosis and a moderate perivascular infiltrate of lymphocytes in the dermis (Fig.2). Three patients healed with post inflammatory
hypopigmentation and hyperpigmentation.
Three patients underwent patch-tests using their own NSO diluted at 1 % and all were positive at 96 hours. Gas chromatography-mass spectrometry performed in NSO of patient n°6
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showed that the chemical composition of the oil was a complex mixture with p-cymene, thymoquinone, longofilene, linoleic acid and fatty acids as main components.
Discussion
We report 6 cases of severe and extensive ACD after topical use of NSO without oral intake, clinically mimicking erythema multiforme, bullous fixed drug eruption and EN, and
histologically showing apoptotic epidermis as previously described in erythema multiforme and EN.6 The severity of our cases suggests a systemic effect of NSO inducing an extension of the lesions away from the area of application.
ASAP, a syndrome characterized by hyperacute apoptotic injury of the epidermis, comprises various severe dermatoses such as EN (most often induced by systemic drugs4),TEN-like acute graft versus host disease, TEN-like acute and subacute cutaneous lupus erythematous, severe eruptions associated with Mycoplasma pneumoniae infections.3,5 ASAP probably results from the expression of various effector activation leading to the same massive keratinocytes death.3
Our series illustrate that ASAP could also be triggered by topics such as NSO. In our cases, clinical and histological presentation mimics such ASAP phenomenon, but is topically-
triggered by NSO, maybe followed by a systemic diffusion that could explain the extension of the lesions. Such severe erythema multiform-like and TEN-like eruptions have already been described after contact with NSO7,8 and also with other essential oil9,10 (tea tree oil, iron wood trees, poison ivy…).
The market (often web-market) of these frequently not pure oils is not controlled and the component concentration is uncertain. The constituents of NSO were previously described showing the presence of thymoquinone and p-cymene as in our case.1,11 Thymoquinone is investigated for therapeutic uses in neurology and oncology thanks to its antioxidant, anti-
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inflammatory and supposed anti-neoplastic and pro-apoptotic properties. 12–15 p-Cymene is a monoterpene which acts as penetration enhancer by disrupting the stratum corneum lipid structure, thus facilitating the transport of drugs through the skin.16,17 NSO contains
thymoquinone and p-cymene in often unknown variable proportion. Synergy of p-cymene and thymoquinone might promote ASAP, by an additional effect of a toxic topical effect and systemic diffusion.
Conclusion
Clinicians and patients should be aware of the possibility of severe cutaneous adverse events of NSO. Components of NSO should be labeled and their proportions should be better
defined. The web-market needs to be better controlled. Severe cases should be declared to the pharmacovigilance.
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Figure 1: cutaneous eruption with large blisters (arrow), Nikolsky sign (star), atypical targets (arrow-head) and patches with central blisters (sharp).
*
*
#
#
#
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Figure 2: histological analysis of skin biopsy in HES staining: vacuolar alteration of the basal layer (arrow-head), keratinocytes apoptosis (arrow) and perivascular infiltrate of lymphocytes (star)
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Table 1: Characteristics of 6 patients seen in the Dermatology Department for a skin reaction following application of NSO
Patient Sexe
/ Age
NSO use
Time to onset (days)
Fever
Clinical aspects
Number of flare
Length of hospital stay
(days)
Allergologic investigation Area of
application
Previous use / reaction
Body surface
(%)
Area involved
Skin lesions
Extension over area
of applicaiton
Mucous
involvement Tested products Score*
1 F /
47
Left hand
Stomach None / - 2 Yes Unknown
Scalp Stomach Forearms Hands Thighs
Patches Blisters Atypical targets
Yes None 1 10 Patient's NSO 1
2 F /
22 Ear None / - 1 No 12
Face Torso Stomach
Thighs
Patches Blisters Typical targets Pustules
Yes None 1 3 NP -
3 F /
26
Hair and scalp
Unknown
/ - Unknown No 7
Forearms Hands Knees
Patches Typical targets
Yes Unknown 1 0 NP -
4 F/
20 Face Yes /
None 2 Yes 40
Face Torso Forearms
Blisters Atypical targets Pustules
Yes None 1 10
Patient's NSO limonene hydroperoxyde
linalool hydroperoxyde camomille extract achileamillefolium
Laurier essence
3 2 2
2 2 1
5 F /
29
Hair and scalp
Unknown
/ - Unknown No 18
Scalp Face Neck Back
Patches Blisters Typical targets
Yes None 1 0 NP -
6 F /
27
Hair and scalp
Yes /
None 1 Yes 30
Scalp Face Torso Stomach
Back Forearms
Hands Elbows
Pubis Thighs
Patches Blisters Atypical targets Pustules
Yes conjuntivitis 2 10 Patient’s NSO 1
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NSO: Nigella sativa oil; NP : not performed ; * : according to the International Contact Dermatitis Research Group Score for epicutaneous tests
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