Scientific Letter
Leukapheresis in the management of drug rash with eosinophilia and systemic symptoms syndrome
Leucoaféresis en el tratamiento del síndrome de drug rash with eosinophilia and systemic symptoms
I. Martínez de Lagrána,
, P. Marcosa, M. Batlleb, E. Alonsoc, A. Planad, T. Tomasaa
Corresponding author
a Medicina Intensiva, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
b Hematología Clínica, Instituto Catalán Oncológico, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
c Banco de Sangre y Tejidos, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
d Dermatología, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
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Martínez de Lagrán, P. Marcos, M. Batlle, E. Alonso, A. Plana, T. Tomasa" "autores" => array:6 [ 0 => array:4 [ "nombre" => "I." "apellidos" => "Martínez de Lagrán" "email" => array:1 [ 0 => "itziarmz@hotmail.com" ] "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" => "P." "apellidos" => "Marcos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "M." "apellidos" => "Batlle" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "E." 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"apellidos" => "Tomasa" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Medicina Intensiva, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Hematología Clínica, Instituto Catalán Oncológico, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Banco de Sangre y Tejidos, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Dermatología, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Leucoaféresis en el tratamiento del síndrome de <span class="elsevierStyleItalic">drug rash with eosinophilia and systemic symptoms</span>" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1162 "Ancho" => 500 "Tamanyo" => 51199 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Patient skin rash.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Drug rash with eosinophilia and systemic symptoms (DRESS) occurs in one out of every 1000–10,000 individuals exposed to drugs.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> The precise physiopathological mechanism involved is not clear, though two main theories have been proposed<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a>: (a) the development of an allergic hypersensitivity reaction in which the drug substance acts as a hapten or allergen; and (b) the absence of epoxide hydroxylase–an enzyme that mediates the detoxification of drugs that trigger the immune response. The disorder is often associated to reactivation of viruses belonging to the herpes family (HHV-6, HHV-7, Epstein–Barr and cytomegalovirus), though the relationship of this phenomenon to the etiopathogenesis of DRESS is not known.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The drugs most often associated to this syndrome are the aromatic antiepileptic agents (carbamazepine, phenobarbital) and allopurinol, though many others have also been implicated in DRESS, such as antibiotics, antituberculosis drugs<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> (especially rifampicin),<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> nonsteroidal antiinflammatory drugs (NSAIDs) and antivirals.</p><p id="par0015" class="elsevierStylePara elsevierViewall">A series of diagnostic criteria for DRESS have been developed over the last decade: the European Registry of Severe Cutaneous Adverse Reactions to Drugs (RegiSCAR)<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> and the Japanese Registry of Severe Cutaneous Adverse Reactions to Drugs (SCARJ)<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Symptoms onset occurs between 2 and 8 weeks after introduction of the drug.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">4,8</span></a> The initial manifestations comprise fever (90–100%), morbilliform rash (87–90%), erythroderma with mucosal membrane involvement (22%) and generalized adenopathies (75%). An erythematous maculopapular reaction subsequently develops affecting the skin of the face, trunk and extremities, together with facial edema (25%). The third phase is characterized by multisystem involvement–the most frequently affected organ being the liver (50–60%) in the form of hepatomegalia and serum transaminase elevation, followed by hematological disorders (23–50%) in the form of eosinophilia and atypical lymphocytosis, and interstitial nephritis (11%) that may result in acute renal failure. Less frequent manifestations are (interstitial pneumonitis 9%), carditis (pericarditis or myocarditis)<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> and even meningitis or encephalitis. The mortality rate associated to DRESS is 10%, and is mainly conditioned by the age of the patient and liver and kidney involvement.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1,2,5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The management of DRESS comprises suspension of the suspect drug and the administration of glucocorticoids at a dose of 1–2<span class="elsevierStyleHsp" style=""></span>mg/kg/day. If the condition persists despite such measures, 1<span class="elsevierStyleHsp" style=""></span>g/day pulses of methylprednisolone can be prescribed during three days. In cases that do not respond to the adopted treatments, there have been reports of a good outcome following the administration of systemic immunoglobulins or plasmapheresis.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1,2,5</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">We present the case of a 21-year-old male without known drug allergies who developed cough, fever and right-side pleural effusion. In addition to the pleural effusion, computed tomography revealed right pleural thickening and the presence of mediastinal adenopathies, with no lung lesions. Thoracocentesis yielded a lymphocytic exudate with adenosine deaminase (ADA) elevation. Ziehl-Neelsen staining and pleural fluid culture in Lowënstein medium proved negative, while interferon-gamma in response to <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> antigens was positive. The Mantoux intradermoreaction test proved positive. Pleural tuberculosis was diagnosed, and treatment was started with Rimstar<span class="elsevierStyleSup">®</span> (isoniazid, rifampicin, pyrazinamide and ethambutol).</p><p id="par0035" class="elsevierStylePara elsevierViewall">Three weeks later, the patient reported due to the appearance of a confluent maculopapular skin rash affecting 90% of the skin surface, including the soles and palms, but without mucosal membrane involvement (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), and accompanied by fever of up to 42<span class="elsevierStyleHsp" style=""></span>°C. The condition progressed to severe acute respiratory failure and distributive shock with lactate concentrations of up to 6<span class="elsevierStyleHsp" style=""></span>mmol/l. Admission to the Intensive Care Unit (ICU) was therefore decided. Intubation and mechanical ventilation proved necessary, as well as volume replacement and vasoactive amine drugs as shock resuscitation measures. A first echocardiographic evaluation revealed preserved ventricular function with mild pericardial effusion. Blood cultures, bronchial aspirate and urine culture were carried out, with negative results. Within 24<span class="elsevierStyleHsp" style=""></span>h the organ dysfunction worsened, with plasma transaminase elevation, coagulopathy, thrombocytopenia, eosinophilia and anuric acute renal failure requiring continuous renal replacement therapy. Abdominal ultrasound revealed important hepatosplenomegalia. The thoracic computed tomography scan showed a generalized bilateral ground-glass pattern. With the suspicion of DRESS, we suspended Rimstar<span class="elsevierStyleSup">®</span> and started glucocorticoid treatment (1.5<span class="elsevierStyleHsp" style=""></span>mg/kg/day). The skin biopsy revealed marked eosinophilic infiltration, which confirmed the diagnosis. Human herpes virus-6 serological testing was positive. The course proved unfavorable despite the treatment measures, with gradual intensification of the eosinophilia to 7.5<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span><span class="elsevierStyleHsp" style=""></span>cells/l and the appearance of myocardial dysfunction with global hypokinesis (left ventricular ejection fraction 45%) and a troponin I concentration of 4<span class="elsevierStyleHsp" style=""></span>ng/ml. Cardiac involvement secondary to eosinophilic infiltration was suspected. In view of the rapid progression of organ dysfunction, with no response to glucocorticoid therapy, and after 5 days of treatment, plasmapheresis was carried out, with poor hemodynamic tolerance. We therefore replaced plasmapheresis with a session of leukapheresis and granulocyte apheresis (the aim being to capture the granulocyte interphase, block the inflammatory response and eliminate the peripheral blood stem cells and avoid eosinophilic proliferation), followed by the administration of hydroxyurea in order to block bone marrow eosinophil proliferation. Following these treatment measures, the eosinophil count decreased rapidly and continuously, with a favorable clinical course allowing withdrawal of all the supportive measures and patient discharge from the ICU within 6 days.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Drug rash with eosinophilia and systemic symptoms (DRESS) is an often underdiagnosed and potentially fatal disorder, with a growing incidence. An early diagnostic suspicion is required in order to eliminate the causal agent as soon as possible and start first line treatment. In the absence of a response to glucocorticoids, second line therapy with immunoglobulins or plasmapheresis is considered. In our case leukapheresis was decided in view of the seriousness of the clinical condition and patient intolerance of plasmapheresis. Apheresis involves the removal of certain cellular components from blood–leukocytes being removed in the case of leukapheresis. This technique is indicated for the management of hyperleukocytosis (hematological malignancies with >100<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span><span class="elsevierStyleHsp" style=""></span>leukocytes/l) prior to chemotherapy, with the aim of obtaining CD34 progenitor cells for bone marrow transplantation, among other conditions.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">9,10</span></a> Its use in successfully treating hypereosinophilia has not been reported to date. We therefore decided to describe this potential indication of apheresis, which caused no complications and proved very successful in the context of a patient with extremely serious multiorgan dysfunction.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Financial support</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors have received no financial support for carrying out this study.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of interest</span><p id="par0050" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Financial support" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflicts of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Martínez de Lagrán I, Marcos P, Batlle M, Alonso E, Plana A, Tomasa T. Leucoaféresis en el tratamiento del síndrome de <span class="elsevierStyleItalic">drug rash with eosinophilia and systemic symptoms</span>. Med Intensiva. 2017;41:191–193.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1162 "Ancho" => 500 "Tamanyo" => 51199 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Patient skin rash.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">SCARJ: all 7 criteria are to be met for establishing the diagnosis; RegiSCAR: 3 of the 4 criteria marked by an asterisk (*) are required to establish the diagnosis.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">RegiSCAR \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SCARJ \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">– Acute skin rash \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– Maculopapular rash developing<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>3<span class="elsevierStyleHsp" style=""></span>weeks after start of drug \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">– Suspected drug reaction \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– Persistence of symptoms<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>weeks after drug suspension \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">– Fever<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>38<span class="elsevierStyleHsp" style=""></span>°C* \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– Fever<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>38<span class="elsevierStyleHsp" style=""></span>°C \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">– Blood count anomalies: eosinophilia, leukopenia or lymphocytosis, thrombocytopenia* \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– Leukocyte anomalies: atypical lymphocytosis (>5%); leukocytosis (>11<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>/l); eosinophilia (>1.5<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>/l) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">– Adenopathies<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>2 sites* \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– Adenopathies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">– Involvement of at least one internal organ* \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– Liver alterations (ALT<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>IU) or involvement of other organs \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">– Hospitalization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– HHV-6 reactivation \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1391734.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Diagnostic criteria of DRESS.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Reacción por drogas con eosinofilia y síntomas sistémicos (síndrome de DRESS). 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| Year/Month | Html | Total | |
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| 2020 April | 42 | 18 | 60 |
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| 2020 February | 49 | 33 | 82 |
| 2020 January | 36 | 30 | 66 |
| 2019 December | 52 | 26 | 78 |
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| 2019 October | 51 | 15 | 66 |
| 2019 September | 43 | 20 | 63 |
| 2019 August | 69 | 25 | 94 |
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| 2018 December | 70 | 34 | 104 |
| 2018 November | 102 | 47 | 149 |
| 2018 October | 95 | 24 | 119 |
| 2018 September | 52 | 9 | 61 |
| 2018 August | 48 | 5 | 53 |
| 2018 July | 32 | 9 | 41 |
| 2018 June | 31 | 9 | 40 |
| 2018 May | 31 | 8 | 39 |
| 2018 April | 46 | 11 | 57 |
| 2018 March | 54 | 7 | 61 |
| 2018 February | 70 | 7 | 77 |
| 2018 January | 68 | 20 | 88 |
| 2017 December | 80 | 4 | 84 |
| 2017 November | 28 | 8 | 36 |
| 2017 October | 36 | 10 | 46 |
| 2017 September | 36 | 13 | 49 |
| 2017 August | 23 | 13 | 36 |
| 2017 July | 7 | 3 | 10 |
| 2017 May | 1 | 0 | 1 |
| 2017 April | 0 | 1 | 1 |
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