Research Letter
Severe dermatitis caused by diltiazem
J.C. Mirallesa,
, A. Carbonella, I. Sánchez-Guerrerob, F. Pastorc, A. Escuderoa, C. Brufaud, F. López-Andreue
Corresponding author
a Allergology Section, Hospital General Universitario Reina Sofía, Murcia, Spain
b Allergology Section, Hospital General Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain
c Pathology Department, Hospital General Universitario Reina Sofía, Murcia, Spain
d Dermatology Department, Hospital General Universitario Reina Sofía, Murcia, Spain
e Internal Medicine Department, Hospital General Universitario Reina Sofía, Murcia, Spain
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"apellidos" => "Miralles" "email" => array:1 [ 0 => "jucarmir@telefonica.net" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "A." "apellidos" => "Carbonell" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "I." "apellidos" => "Sánchez-Guerrero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "F." "apellidos" => "Pastor" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "A." "apellidos" => "Escudero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "C." "apellidos" => "Brufau" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 6 => array:3 [ "nombre" => "F." "apellidos" => "López-Andreu" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Allergology Section, Hospital General Universitario Reina Sofía, Murcia, Spain" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Allergology Section, Hospital General Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Pathology Department, Hospital General Universitario Reina Sofía, Murcia, Spain" "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Dermatology Department, Hospital General Universitario Reina Sofía, Murcia, Spain" "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Internal Medicine Department, Hospital General Universitario Reina Sofía, Murcia, Spain" "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1126 "Ancho" => 1500 "Tamanyo" => 289242 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Areas of skin detachment in the arm.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Skin rash which caused by drugs shows a high polymorphism, which is determined, on the one hand, by the large amount of drugs used, and on the other hand, by the presence of polymedication, particularly in seriously-ill elderly patients, that increases the possibility for interaction among them, with the attendant risk of morphological expression of medicinal rash.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The spectrum of these reactions ranges from mild rash to the most severe forms, which are Stevens-Johnson's syndrome and epidermal toxic necrolysis. The term epidermal necrolysis is a neologism proposed by Lyell<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> to indicate necrosis and separation of epidermis. Blisters are merely exudates accumulating under the necrotic epidermis. The necrolysis phenomenon results from massive apoptosis of the epidermal cells, together with the degradation of the adhesion molecules between the basal cells and the basal membrane of the epidermis.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Stevens-Johnson's syndrome and epidermal toxic necrolysis are considered to be variants of the same disease, based on their similar condition (epidermal necrolysis), similar risk factors, causes and frequent progression from Stevens-Johnson's syndrome to toxic epidermal necrolysis. The main difference between these two conditions resides in the extension of the skin lesions: classified as Stevens-Johnson's syndrome when necrolysis affects less than 10% of the body surface; as superposition of both when it affects from 10 to 30%; and as toxic epidermal necrolysis when it affects over 30% of the body surface.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We here present the case of a 66-year-old woman, with a history of depressive syndrome treated with mirtazapine and previous cholecystectomy, who in the past year reported dyspnoea on moderate effort. Fifteen days before admission, she started to suffer cough and expectoration, and subsequently fever of 39<span class="elsevierStyleHsp" style=""></span>°C and increased dyspnoea. She also reported palpitations starting a few days before admission.</p><p id="par0020" class="elsevierStylePara elsevierViewall">On admission the patient had a temperature of 39<span class="elsevierStyleHsp" style=""></span>°C, 140 beats per minute, arrhythmia, BP 120/60, 88% oxygen saturation, normal cardiac auscultation and pulmonary auscultation with hypoventilation and bilateral wheezing. The rest of the physical examination was normal.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The chest X-ray carried out was normal and the ECG showed atrial fibrillation at 140 beats per minute. Blood count showed 14200 WBCs with normal formula, normal RBCs and platelets. Biochemistry showed glucose 125, GPT 44, with other normal parameters.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The admission treatment was levofloxacin, furosemide, diltiazem, digoxin, sintrom (coumarin), cloperastine, N-acetyl cysteine, and bromazepam, continuing treatment with mirtazapine. Twelve days later, the patient started to suffer from a maculopapular rash, first erythematous and then purple in colour, which started on her head, neck, and upper chest and then descended to affect all of her skin. Despite discontinuing all of the drugs, some pustular lesions (on her back), large blister lesions and areas of skin detachment appeared, affecting the trunk, the arms and the legs (<a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1 and 2</a>). Pathological studies can be observed in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>. The patient also had ulcer lesions in the oral mucosa. The day after the condition started, imipenem had been added to the treatment.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Treatment was instituted with chlorphenamine and methylprednisolone intravenously at doses of 120<span class="elsevierStyleHsp" style=""></span>mg/day, despite which progressive evolution of the skin lesions continued. After the blister lesions and skin detachment occurred, and for fear of an evolution to a highly severe condition such as Stevens-Johnson's syndrome or toxic epidermal necrolysis, it was decided to add cyclosporine 300<span class="elsevierStyleHsp" style=""></span>mg/day, intravenously for the first three days and orally from then on. Twenty-four hours after starting treatment with cyclosporine, the progression of the skin rash stopped, with progressive improvement of the lesions and complete healing in about two weeks. The doses of both the cyclosporine and the steroids were decreased to discontinuation in two weeks.</p><p id="par0040" class="elsevierStylePara elsevierViewall">One week after the skin condition had disappeared, concomitantly with a febrile condition, the patient had a new generalised, mild macular rash, while she has being treated with ampicillin, mirtazapine, fraxiparine, digoxin, spironolactone, verapamil, ranitidine, acetaminophen, nistatin, risperidone and lorazepam, which subsided after drug discontinuation and adding antihistamines to the treatment.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Given the large number of drugs involved, some of which could be necessary for the patient in a later date, it was decided to perform drug allergy tests. It was considered that levofloxacin and furosemide were the drugs most likely to have caused the skin condition, and so it was decided to exclude these two drugs from the study.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Prick and intradermal test were performed with PPL (penicilloyl-polylysine), MMD (mixture of minor determinants) (Diater, Valencia, Spain), penicillin, imipenem and ampicillin with a negative result. Patch tests were carried out with the other drugs with negative results.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Oral challenges were performed with ampicillin, mirtazapine, digoxin, spironolactone, verapamil, ranitidine, acetaminophen, nistatin, risperidone, lorazepam, sintrom, cloperastine, N-acetyl cysteine, and bromazepam, with negative results. Intramuscular challenge was performed with imipenem and subcutaneous challenge with fraxiparine with negative results.</p><p id="par0060" class="elsevierStylePara elsevierViewall">One day after the oral challenge with 30<span class="elsevierStyleHsp" style=""></span>mg of diltiazem, the patient started to suffer from a generalised maculopapular rash (of the same characteristics as that leading to the initial severe condition), and therefore it was decided to start treatment with methylprednisolone 60<span class="elsevierStyleHsp" style=""></span>mg/day and cyclosporine 200<span class="elsevierStyleHsp" style=""></span>mg/day, which were maintained for seven days with steadily decreasing doses. The skin rash subsided completely, with no other more severe lesions occurring.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Subsequently, given that the challenge with diltiazem was positive, oral challenges were then performed with levofloxacin and furosemide, with negative results.</p><p id="par0070" class="elsevierStylePara elsevierViewall">The first drug challenges performed were with those that the patient was taking when she had the second mild macular rash, that, as she tolerated all the drugs possibly involved, was attributed to a rash associated to the febrile condition that the patient then had.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Subsequently, thinking that the severe skin disease could be secondary to levofloxacin or furosemide, it was decided to perform challenges with the other drugs taken by the patient at the start of the condition, although retrospectively, diltiazem should have also been included in this group, and thus prohibited as well.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Given that when the patient had the skin disease, treatment with methylprednisolone at doses of 120<span class="elsevierStyleHsp" style=""></span>mg/day could not reverse the condition, and it was required to add cyclosporine, when the patient started with the maculopapular rash the day after oral challenge with 30<span class="elsevierStyleHsp" style=""></span>mg of diltiazem<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> (of the same characteristics as that leading to the initial severe condition), it was decided to add treatment with steroids and cyclosporine, which were maintained for one week, and the skin condition disappeared completely, with no more severe lesions occurring.</p><p id="par0085" class="elsevierStylePara elsevierViewall">This case could illustrate the value of adding cyclosporine in patients with a severe skin allergy, results consistent with those of other authors.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,6</span></a> Although there are no large series of cases published on the treatment with cyclosporine in severe cases of skin allergy, such as Lyell syndrome, the results are generally favourable to treatment with this drug.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In our case the drug could reverse the skin disease, which had not been achieved with steroids at doses of 120<span class="elsevierStyleHsp" style=""></span>mg/day of methylprednisolone. In addition, it must be noted that after the oral challenge with diltiazem, treatment with cyclosporine and steroids could prevent the development of a new severe skin disease in the patient, who only had a maculopapular skin rash, and this subsequently subsided without progressing to a more severe form.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Although this is only one isolated case, and more studies are necessary, we consider that it could be beneficial to add cyclosporine<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> at an early stage of treatment in the case of severe skin reactions to drugs.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 999 "Ancho" => 750 "Tamanyo" => 163479 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Skin rash with some pustular lesions and areas of skin detachment.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1126 "Ancho" => 1500 "Tamanyo" => 289242 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Areas of skin detachment in the arm.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 511 "Ancho" => 1000 "Tamanyo" => 113799 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">(Left) An epidermis with hyperkeratosis and acanthosis, with a widening of the interpapillary crests and fusion, associated with dense inflammatory infiltrate in a superficial band is seen. H&E 50×. (Right) A detailed image of the above lesion which shows the dermis-epidermis junction with the presence of multiple apoptotic Civatte bodies. H&E 200×.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:8 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Toxic epidermal necrolysis: an eruption resembling scalding of the skin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A. 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Bahna" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1081-1206(10)60789-2" "Revista" => array:6 [ "tituloSerie" => "Ann Allergy Asthma Immunol" "fecha" => "2006" "volumen" => "97" "paginaInicial" => "272" "paginaFinal" => "281" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17042130" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Early cyclosporine treatment of incipient toxic epidermal necrolysis induced by concomitant use of lamotrigine and sodium valproate" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "N. Hashim" 1 => "D. Bandara" 2 => "E. Tan" 3 => "A. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 38 | 2 | 40 |
| 2024 October | 195 | 18 | 213 |
| 2024 September | 120 | 20 | 140 |
| 2024 August | 148 | 23 | 171 |
| 2024 July | 203 | 22 | 225 |
| 2024 June | 107 | 12 | 119 |
| 2024 May | 101 | 14 | 115 |
| 2024 April | 104 | 9 | 113 |
| 2024 March | 131 | 19 | 150 |
| 2024 February | 185 | 31 | 216 |
| 2024 January | 122 | 27 | 149 |
| 2023 December | 147 | 35 | 182 |
| 2023 November | 179 | 31 | 210 |
| 2023 October | 184 | 38 | 222 |
| 2023 September | 92 | 17 | 109 |
| 2023 August | 97 | 9 | 106 |
| 2023 July | 119 | 23 | 142 |
| 2023 June | 106 | 27 | 133 |
| 2023 May | 100 | 28 | 128 |
| 2023 April | 88 | 17 | 105 |
| 2023 March | 101 | 13 | 114 |
| 2023 February | 83 | 14 | 97 |
| 2023 January | 92 | 7 | 99 |
| 2022 December | 66 | 25 | 91 |
| 2022 November | 73 | 11 | 84 |
| 2022 October | 63 | 13 | 76 |
| 2022 September | 81 | 24 | 105 |
| 2022 August | 73 | 23 | 96 |
| 2022 July | 50 | 12 | 62 |
| 2022 June | 46 | 12 | 58 |
| 2022 May | 54 | 11 | 65 |
| 2022 April | 33 | 21 | 54 |
| 2022 March | 34 | 27 | 61 |
| 2022 February | 15 | 20 | 35 |
| 2022 January | 14 | 34 | 48 |
| 2021 December | 10 | 20 | 30 |
| 2021 November | 25 | 30 | 55 |
| 2021 October | 12 | 26 | 38 |
| 2021 September | 10 | 24 | 34 |
| 2021 August | 16 | 10 | 26 |
| 2021 July | 7 | 16 | 23 |
| 2021 June | 11 | 9 | 20 |
| 2021 May | 14 | 12 | 26 |
| 2021 April | 16 | 11 | 27 |
| 2021 March | 11 | 4 | 15 |
| 2021 February | 9 | 10 | 19 |
| 2021 January | 4 | 9 | 13 |
| 2020 November | 0 | 3 | 3 |
| 2020 September | 0 | 2 | 2 |
| 2020 August | 0 | 3 | 3 |
| 2020 July | 0 | 1 | 1 |
| 2020 May | 0 | 2 | 2 |
| 2020 April | 0 | 2 | 2 |
| 2020 March | 0 | 1 | 1 |
| 2020 February | 0 | 1 | 1 |
| 2019 December | 0 | 1 | 1 |
| 2019 November | 0 | 1 | 1 |
| 2019 October | 0 | 1 | 1 |
| 2019 September | 0 | 2 | 2 |
| 2019 July | 0 | 4 | 4 |
| 2019 June | 0 | 25 | 25 |
| 2019 May | 0 | 42 | 42 |
| 2019 April | 0 | 13 | 13 |
| 2019 March | 0 | 2 | 2 |
| 2019 February | 0 | 3 | 3 |
| 2019 January | 0 | 2 | 2 |
| 2018 December | 0 | 6 | 6 |
| 2018 November | 0 | 1 | 1 |
| 2018 October | 0 | 7 | 7 |
| 2018 August | 0 | 1 | 1 |
| 2018 February | 17 | 36 | 53 |
| 2018 January | 16 | 25 | 41 |
| 2017 December | 21 | 20 | 41 |
| 2017 November | 7 | 17 | 24 |
| 2017 October | 29 | 24 | 53 |
| 2017 September | 9 | 19 | 28 |
| 2017 August | 21 | 32 | 53 |
| 2017 July | 12 | 17 | 29 |
| 2017 June | 20 | 27 | 47 |
| 2017 May | 19 | 20 | 39 |
| 2017 April | 17 | 6 | 23 |
| 2017 March | 16 | 74 | 90 |
| 2017 February | 90 | 15 | 105 |
| 2017 January | 20 | 4 | 24 |
| 2016 December | 27 | 9 | 36 |
| 2016 November | 31 | 6 | 37 |
| 2016 October | 34 | 5 | 39 |
| 2016 September | 21 | 9 | 30 |
| 2016 August | 27 | 2 | 29 |
| 2016 July | 11 | 2 | 13 |
| 2016 June | 37 | 13 | 50 |
| 2016 May | 21 | 5 | 26 |
| 2016 April | 26 | 20 | 46 |
| 2016 March | 44 | 13 | 57 |
| 2016 February | 25 | 20 | 45 |
| 2016 January | 28 | 17 | 45 |
| 2015 December | 19 | 17 | 36 |
| 2015 November | 18 | 12 | 30 |
| 2015 October | 33 | 14 | 47 |
| 2015 September | 15 | 7 | 22 |
| 2015 August | 47 | 4 | 51 |
| 2015 July | 100 | 5 | 105 |
| 2015 June | 44 | 3 | 47 |
| 2015 May | 61 | 1 | 62 |
| 2015 April | 57 | 10 | 67 |
| 2015 March | 63 | 11 | 74 |
| 2015 February | 17 | 17 | 34 |
| 2015 January | 15 | 3 | 18 |
| 2014 December | 13 | 2 | 15 |
| 2014 November | 11 | 6 | 17 |
| 2014 October | 20 | 6 | 26 |
| 2014 September | 27 | 5 | 32 |
| 2014 August | 10 | 0 | 10 |
| 2014 July | 16 | 2 | 18 |
| 2014 June | 10 | 1 | 11 |
| 2014 May | 17 | 2 | 19 |
| 2014 April | 13 | 4 | 17 |
| 2014 March | 83 | 8 | 91 |
| 2014 February | 85 | 9 | 94 |
| 2014 January | 98 | 3 | 101 |
| 2013 December | 70 | 11 | 81 |
| 2013 November | 91 | 9 | 100 |
| 2013 October | 71 | 9 | 80 |
| 2013 September | 62 | 8 | 70 |
| 2013 August | 90 | 10 | 100 |
| 2013 July | 61 | 9 | 70 |
| 2013 June | 54 | 4 | 58 |
| 2013 May | 72 | 8 | 80 |
| 2013 April | 47 | 7 | 54 |
| 2013 March | 33 | 9 | 42 |
| 2013 February | 10 | 8 | 18 |
| 2013 January | 2 | 1 | 3 |
| 2012 December | 6 | 3 | 9 |
| 2012 November | 0 | 2 | 2 |
| 2012 October | 2 | 2 | 4 |
| 2012 January | 290 | 0 | 290 |
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