Review

Nadia RAISON-PEYRON
Department of Dermatology, Allergy unit, Saint Eloi University Hospital, 80 avenue Augustin Fliche, 34295 Montpellier, France

Eur J Dermatol 2013; 23(4): 439-42

Cutaneous adverse drug reactions are not always drug-induced

Cutaneous adverse drug reactions present as many different clinical symptoms which may be induced by triggers other than drugs. This review focuses on the non-drug causes of xed drug eruptions, acute generalized erythematous pustulosis (AGEP), drug reactions with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (TEN), which may be induced by foods, xenobiotics, venoms etc... Key words: cutaneous adverse drug reaction

Reprints: N. Raison-Peyron <n-raison@chu-montpellier.fr>

Article accepted on 3/03/2013

utaneous adverse drug reactions (CADR) are cutaneous and mucous complications following systemic intake of drugs. An increasing number of skin reactions originally described as drug-induced can in fact be attributed to other factors, such as food, essential oils, food supplements, chemicals for professional use or venoms. The main reported clinical pictures are acute generalized exanthematous pustulosis (AGEP), xed drug eruptions (FDE), drug hypersensitivity syndrome or DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) and Stevens-Johnson syndrome/toxic epidermal necrolysis (TEN). This article will not include skin eruptions of infectious origin, particularly viral infections, which sometimes raise the problem of differential diagnosis with cutaneous adverse drug reactions, as the latter can be associated with viral reactivation. Similarly, we will not address a common cause of AGEP, mercury poisoning, nor contact dermatitis mimicking cutaneous drug adverse reactions, as in this case the substance is topically, and not systemically, administered.

was published by a French team [3]. For three years, a 57-year-old woman had been experiencing erythematous, oedematous sometimes bullous lesions on her lips, thumbs, wrists, right ear and hand, exclusively in the summer. It appears that in warm weather, she would drink zzy drinks and each time she drank Schweppes tonic water, she experienced a rash. Patch-testing was positive on affected skin with the incriminated soft drink.

Liquorice-induced FE [4]
A 22-year-old young woman presented with three typical FE attacks without taking any medication. Her medical history raised suspicions of the liquorice root sticks she chewed. Patch-testing with a decoction of roots diluted at 30% in petrolatum, applied on healthy skin and on the subsequent pigmented macules were negative at 48 and 72hrs. However, an oral challenge test conrmed the diagnosis.

FE and other food

Other cases of FE have been reported in relation to strawberries [1], cheese crisps [5], asparagus [6], cashew nuts [7] and lentils [8] but also to various types of sh [9, 10]. Patchtesting is sometimes positive on affected skin [6, 7, 10] but the oral challenge test often conrms the diagnosis [1, 7, 8]. Some of these reactions have histological specicities [10]. Indeed, a new entity called neutrophilic xed food eruption has been described, as its histological characteristics associate a neutrophilic perivascular inltrate to focal necrosis of suprabasal keratinocytes. Clinically it was a xed bullous eruption caused by ingestion of a great variety of sh species but also following skin contact. Patch-tests were negative on the back but positive on scarred lesions at 30 mins with a papular, erythematous aspect even a bullous aspect for some of them at 48hrs. Similarly, some of the prick-tests were positive at 1h and 24hrs. Such neutrophilic xed eruptions have already been reported with drugs, particularly with the amoxicillin-clavulanic acid combination and a non-steroid anti-inammatory, naproxen [11, 12].

Food-induced skin eruptions

Fixed eruption due to quinine contained in tonic water
Fixed eruptions are in most cases drug-related, that is why they are usually referred to as xed drug eruptions in English. The phrase xed food eruption was coined and then used by Kelso for the rst time in 1996 [1]. Three cases of xed eruptions due to tonic water containing quinine have been reported [2, 3]. In 2007, Muso et al. reported a 37-year-old man and a 24-year-old woman who presented with recurrent erythematous lesions, always on the same skin zone, after drinking cocktails [2]. Patch-testing was positive to quinine sulfate contained in the tonic water of the cocktails and oral challenge test was positive in both patients after drinking tonic water containing quinine. More recently, a similar case
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To cite this article: Raison-Peyron N. Cutaneous adverse drug reactions are not always drug-induced. Eur J Dermatol 2013; 23(4): 439-42 doi:10.1684/ejd.2013.2055

Eruptions induced by plants not for food use

Such plants are either used in herbal medicine, and are then considered as drugs, but they are often sold as food supplements. In this part, we report eruptions due to these two ways of using plants, although, strictly speaking, a skin reaction due to an ingested plant considered as a drug is indeed a cutaneous adverse drug reaction.

the systemic extension of the lesions was caused by the oral intake. These case reports have strong implications as nigella oil may be increasingly used since it has been discovered to have interesting properties in oncology and neurology. Besides, there is always a keen interest in organic products, particularly in cosmetic oils.

Toxic epidermal necrolysis and St Johns wort [17]

St Johns wort (Hypericum perforatum) is a medicinal plant used for the treatment of mood disorders (anxiety, depression). In France, it is registered as a medication in the herbal medicine category but is also available as a food supplement, in which case its concentration should not exceed 2%. The active principle is hyperhicin. In 2008, the Belgian pharmacovigilance bulletin reported a case of toxic epidermal necrolysis in a 56-year-old female patient who, approximately 10 days after starting St Johns wort (contained in Zibrine , a food supplement) and an iron-based supplement (Bio Fer ), presented with a generalised rash involving the mucous membranes and with major skin detachment, associated with a u-like syndrome. She was hospitalised due to a worsening condition. The diagnosis of toxic epidermal necrolysis (or Lyell syndrome) was made on clinical features and skin biopsy. The causality link between St Johns wort ingestion and Lyell syndrome was deemed probable, as Lyell syndrome developed shortly after starting St Johns wort. Directions for the use of products containing St Johns wort state possible allergic and photosensitisation reactions but not Lyell syndrome.

AGEP following Ginkgo biloba ingestion [13]

The patient had started oral Ginkgo biloba treatment for tinnitus 48 hours before the rash developed. The clinical and biological pictures were evocative of AGEP, as histology conrmed. The rash cleared within ten days after withdrawal of Ginkgo biloba. The patient refused follow-up patch tests and was lost. Ginkgo biloba leaves are the part of the plant used in herbal medicine and ginkgolic acids are thought to be the main allergens.

AGEP induced by Boldoorine herbal tea [14]

Boldoorine herbal tea has laxative and stimulating properties. In a female patient with typical AGEP, patch tests were positive at 48 hrs for three of the twelve ingredients supplied by the laboratory: elecampane (Inula helenium), buckthorn bark (Rhannus frangula) and senna leaves (Cassia angustifolia). The other two chronologically suspect drugs, lactitol (Importal ) and alverin-simethicone combination (Meteospasmyl ), were resumed by the patient without further incident.

Eruptions induced by food supplements except plants

AGEP following chromium picolinate ingestion [18]
According to the laboratories that manufacture chromium picolinate, it is said to have a positive effect on cholesterol and blood sugar levels, to strengthen muscle tone and reduce fat in people practising weight training. There is a case report of a 32-year-old man with no particular history of disease. The patient practised weight training and developed an eruption consisting of widespread non-follicular pustules 4 days after ingesting a food supplement containing chromium picolinate (1mg per day). The histologic features were most consistent with AGEP. Symptoms resolved within one week of treatment with oral corticosteroids and discontinuation of chromium picolinate. Patch tests performed with various concentrations of chromium picolinate in petrolatum and potassium dichromate remained negative at delayed reading. The patient was not re-challenged because of the severity of the eruption. The authors mention that there was no recurrence of the eruption in follow-up for 15 months

Stevens-Johnson/TEN-like bullous eruption to nigella oil

Nigella is a plant genus of the family ranunculaceae, sometimes also called black cumin. However, this name is also sometimes used for other families of plants, which is a source of confusion. Nigella oil is cold pressed from nigella seeds and is rich in thymoquinone and monoterpenes. It is used to treat various diseases, among which are allergic diseases such as allergic rhinitis and eczema. A 53-year-old woman was hospitalised for a fever and an erythematous, vesicular and bullous rash on about 15% of her body, which had appeared a week before [15]. Two weeks before she was admitted to the hospital, she had purchased nigella oil in a market. The seller himself had bought the oil on the internet. The patient had ingested the oil and also massaged it onto the affected areas. Skin biopsy showed detachment of the epidermis and necrosis of the epidermal roof compatible with lesions of the erythema multiforme-toxic epidermal necrolysis spectrum. Evolution was favourable with persistent pigmented lesions after 3 months. Patch tests to nigella oil were strongly positive. Another similar French case had been reported shortly before [16]. In this case as well, the female patient had applied nigella oil on her skin (in the auditory canal) and had also ingested it. The authors hypothesised that the patient had been sensitised through the cutaneous route and that

AGEP following zinc ingestion [19]

This case report was presented as a poster at the GERDA conference in Montpellier in 2011. A 76-year-old female
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patient presented with a typical clinical picture of AGEP with histologic conrmation. She had taken no suspect medication and no toxic cause was found, including mercury intoxication. In fact, for a month the patient had been taking a food supplement containing zinc, selenium, magnesium, lemon balm extract, rosemary, vitamin B1 as well as wild sh oils. After treatment discontinuation, evolution was positive. Patch tests carried out some time later were positive to zinc and elicited an erythematous pustular reaction but were negative to the nished product. The authors hypothesised that it was a false negative due to a too low zinc concentration, poor skin penetration or failure to metabolise the product. Since zinc, like mercury, is a heavy metal, it might induce erythematous and pustular eruptions similar to the toxic AGEP observed with mercury erythema.

Stevens-Johnson syndrome [26-28]

Liver involvement occurs in almost all cases and the mortality rate is estimated at 13% [26]. In an article describing ve cases, the liver was involved in all and in 3 it was serious. One death was reported [27]. Tetrachlorethylene, another solvent, was also incriminated [28].

DRESS
Such cases have been reported more recently [26, 2932]. The onset of the reaction is approximately 1 month after trichlorethylene or drug exposure. Liver involvement ranges from 46 to 94%, there was fever in 75% of cases and eosinophilia was less frequent than in hypersensitivity syndrome caused by drugs [29]. A Japanese male patient presented with DRESS symptoms with HHV-6 and CMV reactivation, as can be seen in DRESS [31]. Patch testing was positive for the metabolites of trichlorethylene (trichlorethanol, trichloracetic acid and chloral hydrate) but not for trichlorethylene itself. Allele HLA-B*1301 was present in the patient. Indeed, allele HLA-B*1301 is strongly associated with trichlorethylene-induced DRESS among exposed Asian workers and might be used as a biomarker to predict high risk individuals [32]. To conclude, when confronted with symptoms resembling cutaneous adverse drug reactions with no medication involved, it has to be borne in mind that the cause may not be drug-related.
This review article is part of a series of papers published by experts from GERDA, the French study and research group on contact dermatitis

Eruptions induced by spider bites [20-25]

Many cases of AGEP following spider bites have been published in the literature: three cases in Tunisia [20], three in Israel [21], one in Greece [22], one in Turkey [23], one in Great Britain [24] and one in a child, in the USA [25]. The most commonly involved spider belongs to the loxosceles genus. Its bite causes necrotic skin lesions and visceral lesions. In these viscerocutaneous forms of loxoscelism, hematologic disorders such as complementmediated hemolysis have been reported. In two cases of AGEP there was associated hemolytic anemia [20, 25], including a case in a child [25]. Complex mechanisms are involved in loxosceles envenomation (sphingomyelinase D causes necrotic lesions and activates complement components, platelets and neutrophils). The arguments in favour of a spider bite are the presence of a lesion indicating a bite, timing of events with a 24 to 48-hours delay between the bite and the eruption and the absence of a traditional cause of AGEP.

Trichlorethylene-induced eruptions
A fairly recent article provides an update on severe skin reactions with systemic involvement due to occupational exposure to trichlorethylene, a degreasing solvent widely used up to the mid-1980s [26]. As it was a potential carcinogen, it was replaced by chlorouorocarbons and trichlorethane. Both of these were prohibited in 1996 as they are ozone depleting substances. Thus there has been a renewal of interest in trichlorethylene in industrialised countries. The cases published are from the USA, Spain, and, since the mid-1990s, mostly from Asia [26-32]. Half of them are cases of Stevens-Johnson syndrome/TEN and the other half are drug-induced hypersensitivity syndromes (over a hundred cases have been reported for each syndrome). In both cases, the incidence ranges from below 1% to 13% of the exposed workers. The mean interval between exposure and onset of the reaction ranges from 2 to 5 weeks.
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Disclosure. Financial support: none. Conict of interest: none.

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