Letter to the Editor
Late onset dapsone hypersensitivity syndrome
Síndrome de hipersensibilidad a la dapsona de aparición tardía
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class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Cristina" "apellidos" => "Temiño Frade" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Pablo" "apellidos" => "Demelo-Rodríguez" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital General Universitario Gregorio Marañón, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Medicina Familiar y Comunitaria, Centro de Salud Buenos Aires, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndrome de hipersensibilidad a la dapsona de aparición tardía" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 509 "Ancho" => 750 "Tamanyo" => 53672 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Purpuric lesions on lower limbs (black arrow).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Dapsone is a sulfone that was synthesised for the first time in 1908, with bacteriostatic properties, as well as anti-inflammatory activity, used in multiple cutaneous inflammatory diseases.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">1,2</span></a> It is not currently marketed in Spain because of frequent adverse effects, especially haematological. Dapsone hypersensitivity syndrome (DHS) consists of a severe idiosyncratic reaction characterised by the triad of fever, rash and systemic involvement (usually hepatic and haematologic).<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">2,3</span></a> DHS resembles DRESS syndrome (drug reaction with eosinophilia and systemic symptoms).<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">A 88-year-old female patient with a history of arterial hypertension, iron deficiency anaemia and cicatricial pemphigoid with exclusively conjunctival involvement. She was receiving treatment with ophthalmic cyclosporine, lansoprazole, ferrous sulfate and dapsone, the latter prescribed by her dermatologist 11 months earlier and obtained through the Internet. She visited the emergency room because of a fever of 39<span class="elsevierStyleHsp" style=""></span>°<span class="elsevierStyleSmallCaps">C</span> of 48<span class="elsevierStyleHsp" style=""></span>h evolution with generalised cutaneous exanthema of abrupt appearance.</p><p id="par0015" class="elsevierStylePara elsevierViewall">On physical examination, she presented a non-confluent papular exanthema with involvement of the limbs, trunk and face. Purpuric lesions were observed on the lower limbs (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>); in the rest of the body the lesions bleached at vitro pressure. At the palms and soles, discreet erythema was observed. In the oral region there was a whitish plaque that detached when handled, as well as erosions in the palate.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Blood analysis results worth mentioning include: haemoglobin 11.2<span class="elsevierStyleHsp" style=""></span>g/dL, leucocyte 82,508.250/μL, platelets 187,000/μL, glucose 122<span class="elsevierStyleHsp" style=""></span>mg/dL, ALT 35<span class="elsevierStyleHsp" style=""></span>U/L, bilirubina 1.2<span class="elsevierStyleHsp" style=""></span>mg/dL, GGT 39<span class="elsevierStyleHsp" style=""></span>U/L, phosphatase alkaline 84<span class="elsevierStyleHsp" style=""></span>U/L, creatinine 0.82<span class="elsevierStyleHsp" style=""></span>mg/dL, sodio 132<span class="elsevierStyleHsp" style=""></span>mmol/L, and C-reactive protein 21.1<span class="elsevierStyleHsp" style=""></span>mg/dL. Serologies for HIV, parvovirus, <span class="elsevierStyleItalic">Rickettsia</span>, <span class="elsevierStyleItalic">Mycoplasma</span> and Epstein–Barr were negative.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The patient presented an analytical and functional deterioration during admission, and there was a gradual appearance of hypereosinophilia to up to 1200/μL, impaired renal function (up to 1.12<span class="elsevierStyleHsp" style=""></span>mg/dL), elevated cholestasis enzymes (GGT 82<span class="elsevierStyleHsp" style=""></span>U/L, alkaline phosphatase 162<span class="elsevierStyleHsp" style=""></span>U/L) and progressive anaemia until haemoglobin 8.1<span class="elsevierStyleHsp" style=""></span>g/dL without data of haemolysis, which required transfusion of two packed red blood cells. An abdominal ultrasound was normal. A skin biopsy of the lesions was performed, in which a lichenoid dermatitis pattern compatible with a clinical diagnosis of erythema exudative multiforme was observed.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Treatment with dapsone was suspended due to the suspicion of DHS, from which the patient showed a clear improvement both analytically and clinically, with disappearance of eosinophilia, recovery of renal function and stabilisation of anaemia, as well as disappearance of fever and resolution of skin lesions. The Naranjo algorithm score – used to evaluate the causation of a drug reaction – was 7/12 (possible).</p><p id="par0035" class="elsevierStylePara elsevierViewall">Dapsone is a sulfone with a high oral bioavailability that exceeds 85%, subsequently passing to the enterohepatic circulation. The metabolism is mainly hepatic, but also by activated polymorphonuclear leukocytes and mononuclear cells. One of its metabolic processes, which triggers dapsone hydroxylamine (DDS-NOH), is the process that is most involved in ensuring the efficacy of the drug and triggering adverse effects. It is believed that activated polymorphonuclear leukocytes are involved in this process. Dapsone accumulates in the skin, muscles, kidneys and liver, where it can be detected even three weeks after withdrawal of treatment. The excretion of the drug is mainly urinary.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">1</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Approximately 1.5% of patients taking dapsone develop a hypersensitivity syndrome, which manifests from two to six weeks after the start of treatment, although cases have also been described months after initiating treatment.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">3</span></a> Isolated cases of DHS have been described in Spain, with two cases published in the literature since 1991. DHS is initially characterised by a general malaise with fever, followed by alterations of the hepatic profile with skin rash. In some cases, haematological alterations such as eosinophilia and haemolytic anaemia also appear.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">3</span></a> A significant association between DHS and HLA-B*13:01<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">2</span></a> has been described. The main treatment for DHS is the withdrawal of the drug. Occasionally, corticosteroid treatment can be added.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">3</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Because dapsone is infrequently used in Spain, the development of complications or adverse reactions associated with its use is uncommon. However, its early detection and withdrawal of medication are very important because the end clinical profile may be fatal.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">3</span></a></p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Ordieres Ortega L, Temiño Frade C, Demelo-Rodríguez P. Síndrome de hipersensibilidad a la dapsona de aparición tardía. Med Clin (Barc). 2019;153:e23–e24.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 509 "Ancho" => 750 "Tamanyo" => 53672 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Purpuric lesions on lower limbs (black arrow).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:3 [ 0 => array:3 [ "identificador" => "bib0020" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dapsone in dermatology and beyond" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "G. Wozel" 1 => "C. 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Yu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1213096" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2013" "volumen" => "369" "paginaInicial" => "1620" "paginaFinal" => "1628" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24152261" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0030" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The dapsone hypersensitivity syndrome revisited: a potentially fatal multisystem disorder with prominent hepatopulmonary manifestations" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S.G. Kosselfi" 1 => "B. Guha" 2 => "D.N. Nassour" 3 => "D.S. Chi" 4 => "G. Krishnaswamy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1745-6673-1-9" "Revista" => array:5 [ "tituloSerie" => "J Occup Med Toxicol" "fecha" => "2006" "volumen" => "1" "paginaInicial" => "9" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16756657" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015300000005/v1_201909070744/S2387020619303614/v1_201909070744/en/main.assets" "Apartado" => array:4 [ "identificador" => "43309" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015300000005/v1_201909070744/S2387020619303614/v1_201909070744/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020619303614?idApp=UINPBA00004N" ]
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