Research

JAMA Dermatology | Brief Report

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

Supplemental content
IMPORTANCE Nigella sativa oil (NSO) is widely used for cosmetic and culinary purposes. Cases
of severe acute contact dermatitis due to NSO are poorly described, with no histologic
description.

OBJECTIVES To describe the clinical and histologic features of severe acute contact dermatitis
due to NSO and investigate the components responsible for such eruptions.

DESIGN, SETTING, AND PARTICIPANTS A case series study of 3 patients with contact dermatitis
admitted to the dermatology department between August 21, 2009, and February 19, 2017,
was conducted. All patients had been referred to the dermatology department for acute
contact dermatitis due to NSO and had patch tests performed.

MAIN OUTCOMES AND MEASURES Clinical and histologic features of the cutaneous eruptions,
length of hospital stay, chemical analysis of NSO, and results of patch tests.

RESULTS Three patients (3 women; median age, 27 years [range, 20-47 years]) were included
in the case series. All patients had polymorphic skin lesions spreading beyond the area of NSO
application: typical and atypical targets, patches with central blisters, erythematous or
purpuric plaques with a positive Nikolsky sign mimicking Stevens-Johnson syndrome, or toxic
epidermal necrolysis. Two patients had pustules. They had severe impairment, with more
than 15% skin detachment and fever. The results of skin biopsies showed epidermal apoptosis
characterized by vacuolar alteration of the basal layer, keratinocyte apoptosis, and a
moderate perivascular infiltrate of lymphocytes in the dermis. The results of patch tests using
the patients’ NSO were all positive. The results of gas chromatography combined with mass
spectrometry performed on the NSO of 1 patient identified several constituent substances,
mainly terpenes, thymoquinone, linoleic acid, and fatty acids.

CONCLUSIONS AND RELEVANCE These cases suggest that acute contact dermatitis due to NSO
may induce topically triggered epidermal apoptosis, previously described as the concept of
acute syndrome of apoptotic pan epidermolysis. Thymoquinone and p-cymene may be the
main agents involved in the pathophysiologic characteristics of this acute contact dermatitis.
Clinicians should be aware of such severe reactions to NSO and report these cases to
pharmacovigilance authorities.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Camille Hua,
MD, Dermatology Department,
Assistance publique–Hôpitaux de
Paris, Henri Mondor Hospital, 51 Ave
du Maréchal de Lattre de Tassigny,
JAMA Dermatol. doi:10.1001/jamadermatol.2018.2120 94010 Créteil, France (camille.hua
Published online August 1, 2018. @aphp.fr).

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 Research Brief Report Association Between Severe Acute Contact Dermatitis Due to N sativa Oil and Epidermal Apoptosis

N
igella sativa oil (NSO), extracted from the seeds of N
sativa or black caraway (one of the plants also called
black cumin), found in Southern Europe, North Africa,
and Southwest Asia, is traditionally used for its cosmetic and
culinary properties.1 Its main components are thymoqui-
none and terpenes,1 but the exact composition of commer-
cial NSO and the proportion of its constituents are highly vari-
able. N sativa oil and essential oils, in general, are known to be
responsible for benign eczematous contact dermatitis, includ-
ing occupational contact dermatitis, but sometimes severe re-
actions, which have been poorly described, can occur.2,3 We re-
port 3 cases of severe acute contact dermatitis (ACD) due to NSO,
showing severe polymorphic lesions that mimicked erythema
multiforme, bullous fixed drug eruption, Stevens-Johnson syn-
drome, or toxic epidermal necrolysis (TEN) and histologically
showing epidermal apoptosis.
Methods
We performed a retrospective single-center study for consecu-
tive patients referred to our dermatology department between
August 21, 2009, and February 19, 2017, for dermatitis after NSO
application who had patch tests performed. Cases were ex-
tracted from the database of our department, which is a refer-
ence center for toxic bullous dermatoses. According to the Pub-
lic Health French Law (art L 1121-1-1, art L 1121-1-2), Institutional
Review Board approval and written consent are not required for
human noninterventional studies; oral consent was provided by
the patients.
Key Points
Question What are the histologic findings of severe acute contact
dermatitis due to Nigella sativa oil?
Findings This case series describes 3 patients who, after topical
use of N sativa oil, displayed extensive lesions mimicking
Stevens-Johnson syndrome or toxic epidermal necrolysis, bullous
fixed drug eruption, and/or erythema multiforme and histologic
features of epidermal apoptosis. Analysis of the N sativa oil
showed thymoquinone and p-cymene to be major components;
results of patch tests using the patients N sativa oil were positive.
Meaning Acute contact dermatitis due to N sativa oil is severe,
polymorphic, and histologically characterized by epidermal
apoptosis.
The following data were collected from the patients’ medi-
cal records: age, sex, nature of the NSO (essential or vegetable),
previous application of NSO, oral intake of NSO, duration and lo-
calization of the application, time between applications and on-
set of the lesions, localization and clinical aspect of skin le-
sions, mucous involvement, number of cutaneous flares, length
of hospital stay, histologic analysis, direct immunofluores-
cence, treatment and evolution, and results of patch tests.
All patients had patch tests performed with their own NSO
diluted at 1% in petrolatum and the European Baseline series with
2 readings at 48 and 96 hours, according to the International Con-
tact Dermatitis Research Group guidelines.4 N sativa oil diluted
in water, open tests (10% in petrolatum and water), or other es-
sential oils could be added. We investigated the composition of

Table. Characteristics of 3 Patients With Acute Contact Dermatitis Following the Application of NSO

NSO Use Clinical Aspects

Time Extension Length
to Body Beyond of Patch-Tested
Patient Area of Previous Onset, surface, Area Skin Area of Mucous No. of Hospital Product
No. Sex/Age Application Use/Reaction d Fever % Involved Lesions Application Involvement Flares Stay, d (Result)a
1 F/40s Left hand No previous 2 Yes ND Scalp, Patches, Yes None 1 10 Patient’s NSO
and use stomach, blisters, (++)
stomach forearms, and
hands, atypical
and targets
thighs
2 F/20s Face Yes/none 2 Yes 40 Face, Blisters, Yes None 1 10 Patient’s NSO
torso, atypical (+++);
and targets, limonene
forearms and hydroperoxide
pustules (++); linalool
hydroperoxide
(++);
Chamomilla
recutita extract
(++); Achillea
millefolium
extract (++);
laurel leaf oil
(+)
3 F/20s Hair and Yes/none 1 Yes 30 Scalp, Patches, Yes Conjunctivitis 2 10 Patient’s NSO
scalp face, blisters, (++)
trunk, atypical
forearms, targets,
hands, and
elbows, pustules
and
pubis
a
Abbreviations: ND, not determined; NSO, Nigella sativa oil; +, weak positive According to the International Contact Dermatitis Research Group Score for
reaction; ++, strong positive reaction; +++, extreme positive reaction. epicutaneous tests.

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 Association Between Severe Acute Contact Dermatitis Due to N sativa Oil and Epidermal Apoptosis
Figure 1. Clinical Findings
Well-delineated patches with central vesicles and blisters on the trunk of
patient 3.
the NSO of 1 patient using gas chromatography (Trace GC Ultra
Chromatograph; Thermo Fisher Scientific) combined with mass
spectrometry (TSQ Quantum Spectrometer; Thermo Fisher).
Results
During the study period, 7 patients were hospitalized in our der-
matology department for ACD due to NSO, but 4 of the
7 patients did not have patch tests performed. Three patients who
met the inclusion criteria were thus included (3 women; me-
dian age, 27 years [range, 20-47 years]) (Table). They all had used
vegetable oil extracted from N sativa seeds, which they applied
to various areas of the skin or scalp for cosmetic purposes. The
median time between application of NSO and the onset of dis-
ease was 2 days (range, 1-2 days). Two patients had previously
used NSO, with no cutaneous reaction. The results of clinical ex-
amination showed polymorphic skin lesions spreading over the
area of application: typical and atypical targets (3 patients),
patches with central vesicles and blisters (3 patients) (Figure 1),
erythematous and purpuric macules and plaques with the Nikol-
sky sign (3 patients), and pustules (2 patients). All 3 patients had
severe impairment with more than 15% of the body surface area
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Brief Report Research
Figure 2. Histologic Analysis of Skin Biopsy
Vacuolar alteration of the basal layer (asterisk) and dispersed or confluent nests
of apoptotic keratinocytes with subepidermal detachment (arrowheads) in
patient 3 (hematoxylin-eosin saffron, original magnification ×400).
involved, with Nikolsky sign and fever, and had a hospital length
of stay of more than 10 days. One patient had a second cutane-
ous flare of the same lesions during her hospital stay, after wash-
ing her hair where she had initially applied NSO.
Histologic examination of a skin biopsy was performed in
all cases and revealed epidermal apoptosis characterized by con-
fluent nests of apoptotic keratinocytes, with subepidermal de-
tachment or epidermal regenerative changes, and a slight to mod-
erate perivascular infiltrate of lymphocytes in the superficial
dermis (Figure 2). All patients had negative results from direct
immunofluorescence.
The patients were successfully treated with clobetasol pro-
pionate 0.05% cream and white petroleum jelly. Their lesions
healed, but their skin exhibited postinflammatory hypopigmen-
tation or hyperpigmentation.
Results of patch tests were positive at 48 and 96 hours in the
3 cases. Gas chromatography and mass spectrometry per-
formed on the NSO of patient 3 showed the chemical composi-
tion of the oil to be a complex mixture including p-cymene, thy-
moquinone, longifolene, linoleic acid, and fatty acids as the main
components (eFigure in the Supplement).
Discussion
We report 3 cases of severe and extensive ACD after topical use
of NSO clinically mimicking erythema multiforme, bullous fixed
drug eruption, Stevens-Johnson syndrome, or TEN and histo-
logically showing epidermal apoptosis, as previously de-
scribed in erythema multiforme and TEN.5 The severity of these
cases suggests a systemic effect of NSO, inducing an extension
of the lesions away from the area of application, even after topi-
cal use alone. Furthermore, in the third case, a second flare dur-
ing the hospital stay suggested a remanence phenomenon from
the hair where NSO had been initially applied. Such severe erup-
tions, which are similar to erythema multiforme and TEN
eruptions, have been described after contact with NSO,6,7 as well
as with other essential oils (tea tree oil, iron wood trees, and poi-
son ivy).8
(Reprinted) JAMA Dermatology Published online August 1, 2018 E3
 Research Brief Report Association Between Severe Acute Contact Dermatitis Due to N sativa Oil and Epidermal Apoptosis

Acute syndrome of apoptotic panepidermolysis (ASAP), a
syndrome characterized by hyperacute apoptotic injury of the
epidermis, comprises various severe dermatoses, such as TEN,9
TEN-like acute graft-vs-host disease, TEN-like cutaneous lu-
pus erythematous, and severe eruptions associated with
Mycoplasma pneumoniae infections.10,11 Histologically, ASAP is
characterized by epidermal apoptosis. Acute syndrome of apop-
totic panepidermolysis probably results from the expression of
various activation effectors, leading to the massive death of
keratinocytes.10 Our series suggests that ASAP can also be trig-
gered by topical medications, such as NSO, possibly followed
by systemic diffusion, explaining the extension of the lesions.
The market (often via online sales) of these oils is not con-
trolled. They are often impure, and the concentration of their
components is uncertain. The constituents of NSO have been pre-
viously described, showing the presence of thymoquinone and
p-cymene.1,12 Gas chromatography performed on the NSO be-
longing to 1 of the patients confirms this chemical composi-
tion. Thymoquinone is investigated for therapeutic uses in neu-
rology and oncology owing to its antioxidant, anti-inflammatory,
and supposed antineoplastic and proapoptotic properties.13,14
p-Cymene is a monoterpene that acts as a penetration en-
hancer by disrupting the stratum corneum lipid structure, thus
facilitating the transport of drugs through the skin.15 N sativa oil
contains thymoquinone and p-cymene in often variable un-
known proportions. The pathophysiologic characteristics of ACD
from NSO remain poorly understood. Synergy of p-cymene and
thymoquinone may promote epidermal apoptosis by combin-
ing a topical toxic effect with systemic diffusion and/or a
hypersensitivity.
Limitations
The limitations of this study are its retrospective nature and the
small number of patients included. More patients could have
been included if patch tests had been performed every time. Fur-
thermore, thymoquinone and p-cymene should be tested sepa-
rately and together to better understand the pathophysiologic
characteristics of this ACD.
Conclusions
Clinicians and patients should be aware of the possibility of se-
vere cutaneous adverse reactions to topical NSO. The compo-
nents of NSO should be labeled and their proportions better de-
fined. Sales of NSO online need to be better regulated. Severe
cases of ACD due to NSO should be reported to the pharma-
covigilance authorities.

ARTICLE INFORMATION
Accepted for Publication: May 19, 2018.
Published Online: August 1, 2018.
doi:10.1001/jamadermatol.2018.2120
Author Affiliations: Dermatology Department,
Assistance publique–Hôpitaux de Paris, Henri Mondor
Hospital, Créteil, France (Gaudin, Toukal, Hua, Assier,
Jannic, Wolkenstein, Chosidow, Ingen-Housz-Oro);
Pathology Department, Assistance publique–
Hôpitaux de Paris, Henri Mondor Hospital, Créteil,
France (Ortonne); National Center for Research,
Mixed Research Unit 7177, University of Strasbourg,
Strasbourg, France (Giménez-Arnau); University of
Paris Est Créteil Val de Marne, Université Paris-Est
Créteil, Créteil, France (Wolkenstein, Chosidow);
Reference Center for Severe Cutaneous Adverse
Reactions, Créteil, France (Wolkenstein, Chosidow,
Ingen-Housz-Oro); Equipe d'Accueil 7379,
Epidémiologie en Dermatologie et Evaluation des
Thérapeutiques, Créteil, France (Wolkenstein,
Chosidow, Ingen-Housz-Oro).
Author Contributions: Drs Gaudin and Hua had full
access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis. Drs Gaudin, Toukal,
Chosidow, and Ingen-Housz-Oro contributed equally.
Concept and design: Gaudin, Ortonne, Wolkenstein,
Chosidow, Ingen-Housz-Oro.
Acquisition, analysis, or interpretation of data:
Gaudin, Toukal, Hua, Ortonne, Assier, Jannic,
Giménez-Arnau, Chosidow, Ingen-Housz-Oro.
Drafting of the manuscript: Gaudin, Toukal, Hua,
Jannic, Ingen-Housz-Oro.
Critical revision of the manuscript for important
intellectual content: Ortonne, Assier,
Giménez-Arnau, Wolkenstein, Chosidow,
Ingen-Housz-Oro.
Statistical analysis: Gaudin, Toukal.
Obtained funding: Toukal, Hua.
Administrative, technical, or material support:
Gaudin, Hua, Ortonne, Assier, Giménez-Arnau.
Supervision: Hua, Chosidow, Ingen-Housz-Oro.
Conflict of Interest Disclosures: None reported.
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