Correspondence

Toxic epidermal necrolysis and natural remedies DOI: 10.1111/bjd.13161 DEAR EDITOR, Toxic epidermal necrolysis (TEN) is a rare disease with a high mortality,1 and drugs are implicated in 70% of TEN cases.2 Twenty-five per cent of hospitalized patients have

consumed undisclosed herbal or dietary supplements.3 Adverse reactions are described for many herbal preparations and may be induced by phytochemicals or undeclared contaminants.4 An association of TEN as a severe adverse reaction to herbal remedies has yet to be established. Three patients with TEN were admitted to our unit over 1 year; they developed TEN within 4–5 days following the ingestion of herbal remedy preparations (Fig. 1).

Fig 1. Timeline of toxic epidermal necrolysis (TEN) disease course and medication in days. Black arrows indicate clinical symptoms of the patients during the time course. Green arrows show the time point of admission to our unit. Hospital periods are underlined in green. © 2014 British Association of Dermatologists

British Journal of Dermatology (2014)

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Case 1, an 83-year-old woman, was admitted with epidermolysis of nearly 100% of her total body surface area (TBSA), including multiple oral and vaginal erosions. Histopathological analysis of skin biopsies established the diagnosis of TEN. The severity of illness measure Score of Toxic Epidermal Necrolysis (SCORTEN) was > 5, predicting a mortality of 90%. She had chronic renal failure and hypertension treated with torasemide, enalapril, amlodipine and hydrochlorothiazide/metoprolol, and gout treated with allopurinol; she was also an insulin-dependent type two diabetic. Seven weeks prior to admission she had been treated with 7 days of ciprofloxacin for cystitis. Following this she started to take St John’s wort and hop and valerian capsules for depression. Four days later she developed flu-like symptoms and trunk erythema. Urinary tract infection (UTI) was suspected and empirically treated with piperacillin/tazobactam over 1 week, changed to ciprofloxacin to treat a then proven Escherichia coli UTI. Flu-like symptoms progressed to generalized blistering and sloughing of the skin within 5 days. She had suffered from no prior hypersensitivity reactions. The patient died from severe septicaemia 9 days after her admission (Fig. 1). Case 2, a 64-year-old woman, was admitted with flu-like symptoms, erythema of the face, neck, trunk and palms and blistering of the inner lower lip. Penicillin and prednisolone were initiated but erythema progressed to detachment of epidermis from > 85% of the TBSA, and multiple oral and vaginal mucosa ulcerations (Fig. 2a–c). The SCORTEN of three predicted a mortality of 36%. TEN diagnosis was histopathologically established with skin biopsies (Fig. 2d). She had been taking tamoxifen and pantoprazole since breast cancer surgery in 2009. One week prior to symptom onset, she began taking the following natural remedies: (i) a mix containing seaweed, mussels and glucosamine; (ii) methylsulfonylmethane (MSM) capsules; (iii) self-tanning capsules containing vitamin D, liquorice, zinc, kiwi fruit, white British Journal of Dermatology (2014)

Fig 2. Photographs of skin manifestations in patient 2 following wound debridement, showing (a) the patient’s back and (b) a lower leg with multiple macules, papules, blisters and erythematous and epidermolytic areas, typical of toxic epidermal necrolysis (TEN). (c) Involvement of the inner lip mucosa in this patient. (d) Haematoxylin and eosin-stained sections of a skin biopsy specimen of patient 2, with typical epidermolysis and leucocyte infiltrate of TEN.

willow, carotene and L-phenylalanine; (iv) incense capsules and (v) curcumar extract. Except for pantoprazole and heparin all medication was discontinued, and piritramide was added for pain control. The patient recovered and was discharged after a 4-week inpatient stay (Fig. 1). Case 3, an 81-year-old man, was admitted with erythema and blisters of the trunk, which had developed after he had consumed eucalyptus oil capsules taken for a cold. His prescription medication consisted of tamsulosin for prostate hypertrophy. Suspected community-acquired pneumonia was treated with azithromycin and amoxicillin. Erythema and blisters of the upper body progressed to skin sloughing of 60% of TBSA, and multiple mucosal ulcers of the bronchial system were present. TEN was histopathologically diagnosed in skin biopsies. Two years before, he had been treated with corticosteroids for unclear severe allergic skin symptoms and respiratory compromise. All medication except pantoprazole and heparin was stopped, and piritramide was administered. Epidermolysis continued and the patient died after 4 weeks secondary to Pseudomonas aeruginosa pneumonia and septicaemia. For many drugs, the risk of TEN is greatest in the first weeks of use,1 mostly within 1–3 weeks of initiation.5 None of the cases presented here had been taking medications commonly associated with TEN within this timeframe. In case 1, ciprofloxacin cross-sensitization to natural remedies, contaminants or metabolites may have been a possible pathomechanism. Allopurinol is commonly associated with TEN; however, the patient had been taking it for many years with no indication of recent overdosing or drug accumulation. Anecdotal reports of St John’s wort and severe sunburn-like skin changes in cattle suggest a dermatopathological side-effect of this herb.6 Likewise, hop and valerian herbal preparations have been described as inducing hypersensitivity reactions in single cases.7 Case 2, with no history of newly administered drugs, had taken MSM, a chemically inert primitive plant ingredient © 2014 British Association of Dermatologists

Correspondence 3

containing sulfur groups, which may play a role in sulfadrug-associated TEN. Cross reactivity of MSM to sulfa drugs such as allopurinol or ciprofloxacin may have contributed to TEN in this case. In case 3, eucalyptus capsules were the only newly administered reagent in association with TEN onset. Topical use of eucalyptus oil has been reported to induce allergic skin reactions.8 There is no evidence of severe skin reactions to oral eucalyptus in the current literature, but phytochemical–drug interactions cannot be excluded. Finally, all three patients were taking herbal preparations in capsules, an imaginable common denominator of TEN development. A single or multiplier effect by idiosyncratic, dose-related or drug-interactive reactions of phytochemicals or contaminants might be involved in the development of TEN in these patients. The objective evaluation by the Naranjo adverse drug reaction (ADR) probability scale9 calculated a possible ADR by the herbal remedy in cases 1 and 3 and a probable cause in case 2. In all cases, the TEN-specific algorithm for epidermal necrolysis (ALDEN) confirmed a possible cause of herbal remedies in TEN developement.10 1

Department of Plastic, Hand and Reconstructive Surgery and 3Interdisciplinary Emergency and Disaster Medicine, Hannover Medical School, Hannover, Lower Saxony 30625, Germany 2 Department of Plastic Surgery, Frenchay Hospital, Bristol, U.K. E-mail: [email protected]

A. LIMBOURG1 A. STEIERT1 A. JOKUSZIES1 K. YOUNG2 H.-A. ADAMS3 P.M. VOGT1

References 1 Roujeau JC, Kelly JP, Naldi L et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995; 333:1600–7. 2 Guillaume JC, Roujeau JC, Revuz J et al. The culprit drugs in 87 cases of toxic epidermal necrolysis (Lyell’s syndrome). Arch Dermatol 1987; 123:1166–70. 3 Goldstein LH, Elias M, Ron-Avraham G et al. Consumption of herbal remedies and dietary supplements amongst patients hospitalized in medical wards. Br J Clin Pharmacol 2007; 64:373–80. 4 Newmaster SG, Ragupathy S, Dhivya S et al. Genomic valorization of the fine scale classification of small millet landraces in southern India. Genome 2013; 56:123–7. 5 Revuz J, Penso D, Roujeau JC et al. Toxic epidermal necrolysis. Clinical findings and prognosis factors in 87 patients. Arch Dermatol 1987; 123:1160–5. 6 Araya OS, Ford EJ. An investigation of the type of photosensitization caused by the ingestion of St John’s Wort (Hypericum perforatum) by calves. J Comp Pathol 1981; 91:135–41. 7 Estrada JL, Gozalo F, Cecchini C, Casquete E. Contact urticaria from hops (Humulus lupulus) in a patient with previous urticaria-angioedema from peanut, chestnut and banana. Contact Dermatitis 2002; 46:127. 8 Ernst E. Adverse effects of herbal drugs in dermatology. Br J Dermatol 2000; 143:923–9. 9 Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30:239–45. 10 Sassolas B, Haddad C, Mockenhaupt M et al. ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson syndrome and toxic epidermal necrolysis: comparison with case–control analysis. Clin Pharmacol Ther 2010; 88:60–8. Funding sources: none. Conflicts of interest: none declared.

© 2014 British Association of Dermatologists

British Journal of Dermatology (2014)

Toxic epidermal necrolysis and natural remedies.

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