Toxic Epidermal Necrolysis After Exposure to ... - Wiley Online Library

Basic & Clinical Pharmacology & Toxicology, 2016, 118, 87–91

Doi: 10.1111/bcpt.12430

Case Report

Toxic Epidermal Necrolysis After Exposure to Dithiocarbamate Fungicide Mancozeb Sergey Zakharov1, Jan Csomor2, Petr Urbanek2 and Daniela Pelclova1 1

Toxicological Information Centre, Department of Occupational Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic and 2Department of Internal Medicine, First Faculty of Medicine, Charles University and Central Military Hospital, Prague, Czech Republic (Received 24 April 2015; Accepted 10 June 2015) Abstract: Toxic epidermal necrolysis (TEN) is a life-threatening mucocutaneous disease with high mortality. Dithiocarbamates (DTC) are organosulphur compounds widely used in agriculture, industry and households. We report a case of TEN after exposure to mancozeb in fungicide. A 48-year-old 75 kg b.w. man was admitted with fever and generalized skin/mucous lesions after application of fungicide in a home garden. The patient had necrotic desquamation of gastrointestinal/respiratory tract mucosa, ocular lesion and skin epidermolysis of 90% of body surface. The laboratory findings included elevation of inflammatory parameters, hyperglycaemia, increased urea, creatinine, liver enzymes, hypoalbuminemia and electrolyte disturbances. The treatment included supportive care, management of fluid/electrolyte requirements, analgesics and enteral nutrition. Skin lesions were treated with occlusive non-adhesive biological wound dressings. Due to the proof of Acinetobacter, Escherichia coli and Escherichia faecalis from skin swabs, a combination of meropenem with amikacin was administered. During the next 2 weeks, complete re-epithelialization of skin lesions occurred, mucosal lesions healed and the laboratory parameters returned to normal. The patient was discharged on day 42. TEN is a rare condition that is generally caused by medications. Nevertheless, high attention should be paid to the cases of occupational or household exposure to DTC fungicides widely used in agriculture and home gardens because of their ability to cause TEN after skin and inhalation exposure. Greater emphasis on the hazardous properties of these products is necessary to ensure non-professional users are aware of the necessity of protective clothing during mixing, loading, application and early re-entry into treated fields.

Toxic epidermal necrolysis (TEN), or Lyell’s syndrome, is an acute life-threatening mucocutaneous disease with an epidermal loss of more than 30% of the body surface area and the involvement of at least two mucosal surfaces comprising ocular, oral and genital [1,2]. It is a rare condition with an incidence of 0.4–1.2 cases per million persons per year, but with a high mortality rate of 30–50% [3–5]. The morbidity and mortality result not only from the extensive denuded skin areas but also from the visceral involvement – particularly in the gastrointestinal and respiratory systems – sepsis, and multiple organ failure [6]. The mechanism of TEN is not fully understood, but it appears to be the activation of autoimmune hypersensitivity reaction by the causative agents or their metabolites, as rechallenging an individual with the same agent can result in rapid recurrence of TEN [7,8]. The histopathology of skin lesions shows that keratinocyte apoptosis followed by necrosis is the pathogenic basis of the widespread epidermal detachment observed in TEN [9]. Author for correspondence: Sergey Zakharov, Toxicological Information Center, Department of Occupational Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital, Na Bojisti 1, 120 00 Prague 2, Czech Republic (e-mail [email protected]).

Medications are the most frequent triggers of TEN, and more than 100 drugs have been implicated, including antibacterial sulphonamides, aromatic anticonvulsants, allopurinol, oxicam nonsteroidal anti-inflammatory drugs, lamotrigine and others [10]. Data on the potential ability of other agents to cause TEN, especially of non-drug chemical substances and mixture products widely used in agriculture, industry and households, are very limited. Dithiocarbamates (DTC) are widely employed in agriculture as fungicides, in industry as slimicides in water-cooling systems, as scavengers in waste-water treatment, in sugar, pulp and paper manufacturing, and as vulcanization accelerators and antioxidants in rubber [11]. Among these organosulphur compounds, the group of ethylene-bis-dithiocarbamates (EBDCs) represented by maneb, zineb and mancozeb is widely used in pre-harvest agricultural applications under the trade names of Acrobat MZ, Dithane M-45, Manzate 200, GreenDaisen M and others. Ethylene-bis-dithiocarbamates react with, and inactivate, the sulfhydryl groups of amino acids and enzymes of fungal cells, resulting in the disruption of lipid metabolism, respiration and the production of adenosine triphosphate [12]. The acute toxicity of DTCs for human beings is relatively low, and cases of acute poisoning are rare. Nevertheless, in numerous studies,

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EBDCs have been shown to be strong skin sensitizers, with evident irritant and allergic potential upon occupational exposure [13–17]. We here report a first documented clinical case of severe TEN, developed after exposure to mancozeb in Acrobat MZ WG fungicide by a home gardener who did not wear sufficient protective clothing during its application. In the United States, many home garden uses of EBDCs have been cancelled because the US Environmental Protection Agency (EPA) has assumed that home users of these pesticides do not wear sufficient protective clothing during application [18]. This case report is the first documented evidence strongly supporting this precautionary measure and raising the issue of the safety regarding the household application of DTC fungicides in EU countries. Case Description A 48-year-old 75 kg b.w. man was admitted to the emergency department of the hospital with fever and generalized skin and mucous lesions, which had developed gradually during the 3 days before admission. The patient reported that 5 days previously he had been spraying cucumbers in his garden with Acrobat MZ WG fungicide solution. It was the first time he had been in contact with EBDC fungicides. The total time of exposure had been approximately 30 min. during a hot sunny day; the patient had prepared the solution according to the instruction and sprayed the vegetables wearing long pants, Tshirt and gloves. No hat, safety glasses, respirator or other personal protective equipment were used. The patient had no allergy, comorbidity and denied any drug use. The patient had not been ill with infectious or non-infectious diseases and had not been vaccinated in the weeks prior to the exposure to the fungicide. The initial signs appeared on the third day after exposure, with weakness, a fever of 40°C, skin itching and pain, discomfort upon swallowing, then swelling of lips and tongue, with desquamation of buccal mucosa and spontaneous mucous bleeding (fig. 1). Further, the involvement of genital mucosa and cutaneous manifestations presented with erythema, erosions, macular eruptions and desquamation of skin, which rapidly progressed to the presternal region and sides of the trunk, face and extremities. The patient was examined by the general practitioner, who prescribed amoxicillin per os. The condition of the patient worsened until the skin lesions were generalized across most of the body surface, and the patient was transferred to the hospital by ambulance. On admission to hospital, the patient was lucid, with a Glasgow Coma Scale score of 15, eupneic, febrile with a temperature of 38.7°C, tachycardia 100, blood pressure 124/ 80 mmHg and symptoms of dehydration due to fluid loss by skin lesions. The patient had necrotic desquamation of oral, hypopharyngeal, laryngeal, epiglottal mucosa, ocular lesion and facial oedema. Ocular involvement included eyelid oedema and conjunctival erythema. Skin epidermolysis of palms, soles and genital region, flaccid blisters, bullous lesions with a tendency to rapid coalescence on the sides and

Fig. 1. Desquamation of oral mucosa and spontaneous mucous bleeding.

back of trunk, morbilliform exanthem of trunk, back and extremities were present. Later, large areas of epidermal detachment developed, with the extent of skin involvement being 90% of the body surface (fig. 2). The biochemical laboratory findings on admission included elevation of inflammatory parameters (C-reactive protein – 206 mg/ L, procalcitonine – 2.5 lg/L), hyperglycaemia – 8.6 mmol/L, increased serum urea – 8.5 mmol/L, creatinine – 111 lmol/L, and mild hypoalbuminemia (26.3 g/L), hypokalemia (3.7 mmol/L), hypocalcemia (1.82 mmol/L), hypophosphatemia (0.58 mmol/L). The liver enzymes were mildly elevated as well (AST – 0.75 ukat/L; GMT – 1.65 ukat/L), but coagulation parameters and amylase were normal. The blood tests revealed mild thrombocytopenia (86 9 109/L), lymphocytopenia (0.51 9 109/L) and neutrophilia (5.34 9 109/L). The patient was hospitalized in the intensive care unit (ICU) of the internal medicine department because of his severe condition and the score of 5 according to the validated SCORTEN disease severity-of-illness scoring system, which predicted mortality of 90% [19]. The treatment included supportive care, management of fluid and electrolyte requirements, three doses of corticosteroid during the first 3 days (solumedrol 250 mg, 125 mg, 80 mg i.v.) to prevent the progress of epiglottis oedema, antihistamines, antibiotics (aminopenicillins), eye drops with neomycin, polymyxin B and dexamethasone, opioid analgesics, antipyretics and enteral nutrition via a nasogastric tube. Antibiotics were stopped the first week after the normalization of inflammatory parameters. Skin lesions were treated conservatively; occlusive non-adhesive biological wound dressings were applied to prevent infectious complications and to promote re-epithelialization of skin lesions (fig. 3). No histology of skin lesions was obtained. The treatment was administered by ICU doctors in consultation with dermatologists and other specialists of Burns Center. In the second week of hospitalization, the state of the patient deteriorated with the recurrence of febrile states, re-elevation of inflammatory parameters (C-reactive protein – 246 mg/L, procalcitonine – 2.1 lg/L) and positive results from the cultivation of skin swabs with Acinetobacter, Escherichia coli and Escherichia faecalis. On day 12 of hospitalization, the patient was transferred to the ICU of specialized Burns Center On ultrasound examination, acute pyelonephritis of the


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Fig. 2. Areas of epidermal detachment with the extent of skin involvement of 90%.

present. The most serious sequelae were the recurrent complete bilateral nasolacrimal duct obstructions, requiring periodical surgical interventions to restore the passage of fluid. Discussion

Fig. 3. Covering of skin lesions with occlusive non-adhesive biological wound dressings.

left kidney was diagnosed, and the urine cultivation was positive with E. coli. In accordance with the results of sensitivity tests, the combination of meropenem and amikacin was administered. The wound management included occlusive non-adhesive biological wound covering, antibacterial and antifungal medication, and pantothenic acid preparations to support regeneration. During the next 2 weeks, the condition of the patient was stabilized, the complete re-epithelialization of skin lesions occurred, mucosal lesions healed, and the laboratory biochemical parameters returned to normal. The patient was discharged from the hospital on day 42 without sequelae. The follow-up interview and examination 2 years after the discharge showed that the patient’s skin lesions had completely healed without scars in the areas of hypo- and hyperpigmentation, but the fingernail abnormalities, with pathological nail plates and very slow growth, were still

Mancozeb is widely available fungicide for both professional and non-professional consumers marketed as Acrobat MZ, Dithane M-45, Manzate 200, Green-Daisen M and other products. It can be purchased in any gardening store or through the internet. To the best of our knowledge, we present the first documented clinical case of severe TEN after exposure to DTC mancozeb in Acrobat MZ WG fungicide. This product is a combined fungicide with systemic and contact effect used worldwide for the pre-harvest protection of potatoes, tomatoes, cucumbers, lettuce, onion, grapes and other plants. It contains morpholine fungicide dimethomorph and EBDC mancozeb. Dimethomorph has low acute oral, dermal and inhalational toxicity, is a slight eye irritant, but is not irritating and sensitizing to the skin. Mancozeb is the predominant active ingredient by weight, and it is a combination of two other chemicals of this class, maneb and zineb [20]. It is a skin irritant and sensitizer, and a mild-to-moderate eye irritant in rabbits [21]. Agricultural workers handling crops treated with mancozeb have developed sensitization rashes [22]. Cases of diffuse erythema and eczematoid epidermatitis of the eyelids and inguinal regions were observed among agricultural workers in contact with zineb or maneb [23–27]. Copeman [28] described in 1968 a case of TEN caused by monosulfiram, the alkyl DTC, to which EBDCs have rather a close chemical affinity. The major routes of exposure to mancozeb are through the skin or from inhalation [29]. Symptoms of acute exposure to mancozeb and other EBDCs include itching, scratchy throat, sneezing, coughing, inflammation of the nose or throat and


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bronchitis [20]. It is stated that protective clothing, including long pants, long-sleeved shirt, gloves, hat and boots should be worn during mixing, loading, application and early re-entry into treated fields [18,29]. The lipophilic nature of mancozeb and other DTC enables it to pass across the skin cell membrane. Studies have shown DTC induce the activation of T cells, natural killer cells and increase immunoglobulin secretion by B cells [30]. DTCs can act as haptens, which on conjugating to proteins may induce allergic hypersensitivity [31]. These mechanisms can be responsible for systemic autoimmune disorder leading to the severe mucosal and cutaneous reactions. In this patient, TEN after exposure to Acrobat MZ WG fungicide had a typical clinical course with initial fever, sore throat, itching skin, followed by mucosal lesions involving oral and genital mucosa, cutaneous manifestations progressing to flaccid blisters and generalized epidermolysis, high C-reactive protein level and hepatic dysfunction [32]. The patient was treated with systemic corticosteroids, three decreasing doses to prevent the oedema of the epiglottis. Steroid therapy for TEN is reported as controversial and is no longer recommended [3,6,10]. Clinical studies on the use of intravenous immunoglobulin for patients with TEN have shown mixed results. Other medications that have been studied and been found beneficial include IV infliximab, cyclosporine and intravenous N-acetylcysteine [33]. For severe cases involving loss of epidermis, wound management goals are to prevent fluid loss, prevent infection and facilitate re-epithelialization [10]. Different occlusive non-adhesive wound coverings that prevent fluid loss and minimize pain with dressing changes have been recommended for wound management [34]. These biological dressings create a physiological interface between the wound surface and the environment that is impermeable to bacteria, thus helping to prevent local wound infection [35]. In addition, the collagen sheets are non-inflammatory, facilitate fibroblast migration to the wound site, assist in extracellular matrix synthesis, are non-toxic and minimize scarring [34]. This approach to wound management was successfully applied in the present case. Conclusion Human exposure to EBDCs is not insignificant, and fungicide compounds like Acrobat MZ WG can affect not only workers in specific industries, but also the ordinary public applying it in their home gardens. It is therefore important to study and estimate the risks incurred by such exposures, particularly in the light of possible lower adherence by non-professionals to the principles of safe handling and self-protection, as well as the protection of other persons, during its application. Toxic epidermal necrolysis is a rare, acute life-threatening condition that is generally caused by medications. Nevertheless, high attention should be paid to the cases of occupational or household exposure to DTC fungicides widely used in agriculture and home gardens because of its sensitizing properties and ability to cause TEN after single skin and inhalation exposure, with a high risk of mortality and serious

long-term health sequelae, such as nasolacrimal duct obstruction. Greater emphasis on the hazardous properties of these products is necessary to ensure that non-professional users are aware of the necessity of protective clothing, including long pants, long-sleeved shirt, gloves, respirators, hat and boots during mixing, loading, application and early re-entry into treated fields. Acknowledgements The authors acknowledge the financial support of the Projects of the Charles University in Prague PRVOUK – P25/ 1LF/2, P26/1LF/2 and P28/1LF/6, and EU Project ‘Material – technical Research Base for the Diagnostics and Treatment of Environmentally-caused and Oncological Disorders and their Risks, in the General University Hospital in Prague’ (reg. No. CZ.2.16/3.1.00/24.12). Conflict of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the manuscript. References 1 Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol 2011;7:803–15. 2 French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding. Allergol Int 2006;55:9–16. 3 Ellender RP, Peters CW, Albritton HL, Garcia AJ, Kaye AD. Clinical considerations for epidermal necrolysis. Oschner J 2014; 14:413–7. 4 French LE, Prins C. Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis. In: Bolognia JL, Jorizzo JL, Rapini RP (eds). Dermatology, 2nd edn. Elsevier, Philadelphia, PA, 2008;287–300. 5 Letko G, Papaliodis DN, Papaliodis GN, Daoud YJ, Ahmed AR, Foster CS. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol 2005;94:419–36. 6 Pozzo-Magana BR, Lazo-Langner A, Carleton B, Castro-Pastrana LI, Rieder MJ. A systematic review of the treatment of druginduced Stevens-Johnson syndrome and toxic epidermal necrolysis in children. J Popul Ther Clin Pharmacol 2011;18:e121–33. 7 Halevi A, Ben-Amitai D, Garty BZ. Toxic epidermal necrolysis associated with acetaminophen ingestion. Ann Pharmacother 2000;34:32–4. 8 Schmidt D, Kluge W. Fatal toxic epidermal necrolysis following reexposure to phenytoin: a case report. Epilepsia 1983;24:440–3. 9 Harr T, French LE. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis 2010;5:39. 10 Hamm RL. Drug-hypersensitivity syndrome: diagnosis and treatment. J Am Col Certif Wound Spec 2012;3:77–81. 11 Houeto P, Bindoula G, Hoffman JR. Ethylenebisdithiocarbamates and ethylenethiourea: possible human health hazards. Environ Health Perspect 1995;103:568–73. 12 Tomlin, Clive DS (ed), British Crop Protection Council and Tomlin, Clive The pesticide manual : a world compendium (13th edn. editor, C.D.S. Tomlin). British Crop Protection Council, Alton, 2003. 13 Burry JN. Contact dermatitis from agricultural fungicide in South Australia. Contact Dermatitis 1976;2:289. 14 Nater JP, Terpstra H, Bleuminik E. Allergic contact sensitization to the fungicide maneb. Contact Dermatitis 1979;5:24–6. 15 Kleibl K, Rackova M. Cutaneous allergic reactions to dithiocarbamate. Contact Dermatitis 1980;6:348–9.


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