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a 27-year-old man&#44; was transferred to our hospital from another center on suspicion of an acute lymphoproliferative syndrome&#46; The only relevant finding in his past history was that he had started treatment with sulfasalazine one month earlier for chondromalacia patellae&#46; At the time of admission he had fever of 40<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; a confluent maculopapular rash with a negative Nikolsky sign &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44; dyspepsia&#44; and biliary vomiting&#46; He also presented a 1-week history of pharyngoamygdalitis with a whitish exudate&#44; a purpuric rash on the soft palate &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; and loss of the lingual papillae for which he had received antibiotic treatment with cefuroxime and paracetamol&#44; with no improvement after a week of therapy&#46; Physical examination revealed hepatosplenomegaly&#44; jaundice &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#44; and distal purpuric edema of the upper and lower limbs&#44; associated with a painful lateral cervical and inguinal lymphadenopathy with mobile lymph nodes measuring 2 to 3<span class="elsevierStyleHsp" style=""></span>cm in diameter&#46; Laboratory test results showed leukocytosis of 34 700&#47;&#956;L with left shift &#40;neutrophils&#44; 14 650&#47;&#956;L&#59; lymphocytes&#44; 12 750&#47;&#956;L&#41;&#59; hemoglobin&#44; 12&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#44; platelets&#44; 384 x 10<span class="elsevierStyleSup">3</span>&#47;&#956;L&#59; prothrombin time&#44; 20&#46;1 s&#59; prothrombin index&#44; 58&#37;&#59; total proteins&#44; 4&#46;6<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#59; urea&#44; 90<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#59; creatinine 1&#46;55<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#59; sodium&#44; 126 mEq&#47;L&#59; potassium&#44; 5&#46;5<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#59; bilirubin&#44; 10&#46;1<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#59; aspartate aminotransferase&#44; 628<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#59; alanine aminotransferase&#44; 521<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#59; and lactate dehydrogenase&#44; 2219<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#46; There was no eosinophilia&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Thyroid function studies revealed a free thyroxine &#40;T4&#41; level of 1&#46;01<span class="elsevierStyleHsp" style=""></span>ng&#47;dL and a thyroid-stimulating hormone &#40;TSH&#41; concentration of 0&#46;066<span class="elsevierStyleHsp" style=""></span>mIU&#47;L&#46; Anti-TPO antibodies were detected at a level of 0&#46;3<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">There were no abnormalities in cytometry&#44; which suggested that the condition was reactive in origin&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">On skin biopsy&#44; there were occasional necrotic keratinocytes in the epidermis with vacuolar degeneration of the basal layer and a predominantly lymphoid inflammatory infiltrate in the superficial dermis&#44; findings consistent with toxicoderma&#46; Computed tomography of neck&#44; thorax&#44; abdomen&#44; and pelvis revealed multiple lymph nodes bilaterally&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Serology &#40;enzyme-linked immunosorbent assay&#41; for Epstein-Barr virus &#40;EBV&#41; &#40;viral capsid antigen &#91;VCA&#93;&#41;&#44; herpes simplex virus&#44; cytomegalovirus &#40;CMV&#41;&#44; hepatitis A&#44; B&#44; and C viruses&#44; parvovirus B19&#44; measles virus&#44; <span class="elsevierStyleItalic">Toxoplasma</span>&#44; <span class="elsevierStyleItalic">Chlamydia trachomatis</span>&#44; <span class="elsevierStyleItalic">Chlamydia pneumoniae</span>&#44; <span class="elsevierStyleItalic">Chlamydia psittaci</span>&#44; <span class="elsevierStyleItalic">Coxiella burnetti</span>&#44; <span class="elsevierStyleItalic">Legionella</span>&#44; <span class="elsevierStyleItalic">Mycoplasma pneumoniae</span>&#44; and human immunodeficiency virus&#44; was positive for CMV immunoglobulin &#40;Ig&#41; G&#44; EBV &#40;VCA&#41;&#44; and HHV-6 IgM and IgG&#46; In addition&#44; IgM anticardiolipin antibodies were later found to be positive&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">On the basis of these findings and the past history of treatment with sulfasalazine&#44; DIHS was diagnosed and treatment was started with intravenous methylprednisolone at a dose of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#46; This treatment produced a marked initial improvement&#44; but progressive tapering of the dose and withdrawal of the corticosteroid led to recurrence of the condition&#46; It was therefore decided to recommence therapy at the initial dose and taper more slowly&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Follow-up at 12 weeks found the patient to have marked hair loss on the scalp&#44; but he was otherwise asymptomatic&#46; Anticardiolipin IgG and IgM levels were within the normal ranges&#46; However&#44; thyroid function remained abnormal as follows&#58; free T4&#44; 0&#46;41<span class="elsevierStyleHsp" style=""></span>ng&#47;dL&#59; TSH&#44; 144&#46;952<span class="elsevierStyleHsp" style=""></span>mU&#47;L&#59; and anti-TPO antibody levels of 57&#46;36<span class="elsevierStyleHsp" style=""></span>U&#47;mL&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0060" class="elsevierStylePara elsevierViewall">We present a case of DIHS&#44; an uncommon but severe toxicoderma whose etiology&#44; pathogenesis&#44; and prognosis are related to HHV-6 reactivation&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In some patients it can lead to the transient induction of anticardiolipin antibodies or an antiphospholipid syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The appearance of autoimmune disorders after an asymptomatic period is also relatively common&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Symptom severity is related to the duration of exposure to the drug after onset of the condition &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Recently&#44; HHV-6 reactivation has also been included as a diagnostic criterion &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> and has been linked to more severe disease because&#44; in some series&#44; it was associated with prolongation of the febrile state due to the severity of the hepatitis or renal failure&#59; viral reactivation is a common finding in the cases with a fatal outcome&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> In addition&#44; in our case we observed papular erythematous lesions on the soft palate and base of the uvula&#44; known as Nagayama spots &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#59; these are seen in up to 65&#37; of patients with HHV-6 infection&#46; Although many pediatricians use this sign as an early marker of infection&#44; its specificity and predictive value continue to be a subject of discussion&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">It has also been suggested that HHV-6 may play a possible pathogenic role in the induction of an antiphospholipid syndrome&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;11</span></a> In many cases&#44; as in the one we present&#44; the presence of anticardiolipin antibodies is transient and the patient becomes antibody-negative after 2 to 3 months&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> In our patient&#44; despite the absence of signs of thrombosis consistent with antiphospholipid syndrome&#44; anticardiolipin antibodies were detected at the onset of the disorder&#46; We therefore recommend requesting laboratory studies for anticardiolipin antibodies&#44; antinuclear antigen&#44; and extractable nuclear antigen&#44; in addition to markers of hemostasis&#44; to monitor the clinical course of this dermatosis&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">It is important to draw attention to the relative frequency with which autoimmune diseases can develop after resolution of the acute disorder&#59; their pathogenesis is associated with suppressor T-cell dysfunction&#44; cytotoxic T-cell activation and proliferation&#44; and the appearance of autoantibodies&#44; especially if preceded by viral reactivation&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In particular&#44; thyroid function must be monitored for many months after resolution of the condition&#44; as hypothyroidism tends to be asymptomatic initially&#44; but there is early induction of anti-TPO antibodies and a progressive rise in TSH concentrations and fall in free T4 levels&#44; indicative of severe hypothyroidism&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The treatment of choice&#44; in addition to withdrawal of the culprit drug&#44; consists of systemic corticosteroid therapy&#46; However&#44; DIHS carries a mortality of up to 20&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Despite the controversy concerning the use of corticosteroids in the context of a possible viral infection&#44; the cases described in the literature have presented a favorable clinical course after starting this treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;13</span></a> It should also be emphasized that the dose of corticosteroid should be tapered slowly in order to avoid potential recurrences<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a>&#59; this was done in our case&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">In conclusion&#44; when DIHS is suspected&#44; the drug considered to be the cause must be withdrawn as early as possible&#46; It should be noted that the causative drug may have been introduced up to 3 months before the onset of the condition&#46; It is also important to screen for HHV-6 reactivation as not only is this one of the diagnostic criteria&#44; but it also has prognostic value&#46; Furthermore&#44; treatment with systemic corticosteroids rather than being contraindicated is actually the treatment of choice&#44; and it should be withdrawn slowly to prevent recurrence&#46; In patients who develop thrombocytopenia&#44; alterations of hemostasis&#44; or associated thrombotic disorders&#44; the presence of antiphospholipid antibodies should also be investigated&#46; Finally&#44; the possibility of the patient developing autoimmune disease as a sequela of the condition must also be considered&#59; this requires medium-to-long-term monitoring and follow-up even after complete resolution of the syndrome&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of Interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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        0 => array:2 [
          "identificador" => "xres95331"
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        1 => array:2 [
          "identificador" => "xpalclavsec82491"
          "titulo" => "Keywords"
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        2 => array:2 [
          "identificador" => "xres95332"
          "titulo" => "Resumen"
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          "identificador" => "xpalclavsec82492"
          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Case Description"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Discussion"
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        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Conflicts of Interest"
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        8 => array:1 [
          "titulo" => "References"
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      ]
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2010-08-04"
    "fechaAceptado" => "2010-12-17"
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      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec82491"
          "palabras" => array:5 [
            0 => "Drug-induced hypersensitivity"
            1 => "Human herpesvirus 6"
            2 => "Antiphospholipid syndrome"
            3 => "Hypothyroidism"
            4 => "Anti-thyroid peroxidase antibodies"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec82492"
          "palabras" => array:5 [
            0 => "Hipersensibilidad inducida por f&#225;rmacos"
            1 => "Virus herpes humano-6"
            2 => "S&#237;ndrome antifosfol&#237;pido"
            3 => "Hipotiroidismo"
            4 => "Anticuerpos Anti-TPO"
          ]
        ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Drug-induced hypersensitivity syndrome is a toxicoderma with systemic involvement&#46; Suspicion of this disorder obliges rapid withdrawal of the suspected drug&#44; which may have been introduced up to 3 months earlier&#46; Screening for human herpesvirus &#40;HHV&#41; 6 reactivation is important both for its diagnostic value and for its association with a poor prognosis&#46; Reactivation of this virus is not a contraindication for systemic corticosteroid treatment&#44; which should be tapered slowly in order to avoid recurrence&#46; The possible appearance of antiphospholipid antibodies must also be considered in those cases associated with thrombocytopenia&#44; altered hemostasis&#44; or thrombotic events&#46; Autoimmune disorders may also develop as a sequela of the condition&#46; Medium-to-long-term follow-up is required even after complete resolution of the condition&#46; We describe a new case of sulfasalazine-induced hypersensitivity syndrome associated with HHV-6 reactivation and the induction of anticardiolipin and anti-thyroid peroxidase antibodies&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El s&#237;ndrome de hipersensibilidad inducido por f&#225;rmacos &#40;DIHS&#41; se engloba dentro de los cuadros toxicod&#233;rmicos con afectaci&#243;n sist&#233;mica&#44; cuya sospecha obliga a la retirada lo m&#225;s precoz posible del f&#225;rmaco que consideremos pueda estar implicado&#44; que puede haber sido introducido hasta tres meses antes&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Es importante el despistaje de la reactivaci&#243;n del virus herpes humano &#40;VHH&#41; 6&#44; tanto por su valor diagn&#243;stico como por el pron&#243;stico de gravedad que supone&#46; Por otro lado&#44; esta reactivaci&#243;n no contraindica que el tratamiento pueda llevarse a cabo con corticoides sist&#233;micos&#44; que adem&#225;s&#44; deber&#225;n retirarse lentamente para evitar reca&#237;das&#46; Deber&#237;a pensarse asimismo en la posibilidad de la presencia de anticuerpos antifofolip&#237;dicos en los casos en que apareciera trombopenia&#44; alteraci&#243;n en la hemostasia o cuadros tromb&#243;ticos asociados&#44; como tambi&#233;n tener en cuenta el desarrollo de procesos autoinmunes como secuela del cuadro&#44; que requiere de monitorizaci&#243;n y seguimiento a medio-largo plazo&#44; a pesar de la resoluci&#243;n completa del cuadro&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Describimos un nuevo caso donde se muestra la reactivaci&#243;n del VHH-6&#44; la activaci&#243;n de anticuerpos anticardiolipina y la inducci&#243;n de anticuerpos anti-tiroperoxidasa &#40;anti-TPO&#41;&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Tung Y&#44; et al&#46; S&#237;ndrome de hipersensibilidad inducido por sulfasalazina asociado a reactivaci&#243;n de VHH-6 e inducci&#243;n de s&#237;ndrome antifosfol&#237;pido&#46; Actas Dermosifiliogr&#46; 2011&#59;102&#58;537-540&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Confluent maculopapular rash on the trunk&#44; with a negative Nikolsky sign&#46;</p>"
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      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
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        "figura" => array:1 [
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Nagayama spots&#46; Purpuric rash on the soft palate and base of the uvula&#44; characteristic of human herpesvirus 6 infection&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Maculopapular rash&#44; jaundice&#44; and desquamation of the lesions&#46;</p>"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Adapted from Shiohara T et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46; Erythematous morbilliform rash 3 weeks after starting a new medication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46; Persistence of symptoms at least 2 weeks after withdrawal of the medication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46; Fever &#62;38<span class="elsevierStyleHsp" style=""></span>&#176;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46; Dysfunction of the liver &#40;alanine aminotransferase &#62; 100 U&#47;L&#41;&#44; kidney&#44; or lungs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46; Alterations of white cell populations&#58; leukocytosis &#62;11 000&#47;mm<span class="elsevierStyleSup">3</span>&#44; atypical lymphocytosis &#62;5&#37;&#44; and&#47;or eosinophilia &#62;1500&#47;mm<span class="elsevierStyleSup">3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46; Lymphadenopathies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46; Human herpesvirus 6 reactivation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              "nota" => "<p class="elsevierStyleNotepara">The diagnosis is confirmed by the presence of these 7 criteria &#40;typical drug-induced hypersensitivity syndrome&#41; or of the first 5 &#40;atypical drug-induced hypersensitivity syndrome&#41;&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Diagnostic Criteria for Drug-Induced Hypersensitivity Syndrome&#46;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></p>"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Adapted from Eshki M et al&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Ben m&#8217;rad M et al&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> and Ang CC et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Anticonvulsants</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Carbamazepine&#44; phenytoin&#44; phenobarbital&#44; lamotrigine&#44; zonisamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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Case report
Sulfasalazine-Induced Hypersensitivity Syndrome Associated With Human Herpesvirus 6 Reactivation and Induction of Antiphospholipid Syndrome
Síndrome de hipersensibilidad inducido por sulfasalazina asociado a reactivación de VHH-6 e inducción de síndrome antifosfolípido
Y. Tunga,
Autor para correspondencia
yale.tung@comv.es

Corresponding author.
, B. Escutiab, M. Blanesc, M. Navarrob, C. Pujolb
a Servicio de Medicina Interna, Hospital Universitario La Fe, Valencia, Spain
b Servicio de Dermatología, Hospital Universitario La Fe, Valencia, Spain
c Unidad de Enfermedades Infecciosas, Hospital Universitario La Fe, Valencia, Spain
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        "titulo" => "S&#237;ndrome de hipersensibilidad inducido por sulfasalazina asociado a reactivaci&#243;n de VHH-6 e inducci&#243;n de s&#237;ndrome antifosfol&#237;pido"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Nagayama spots&#46; Purpuric rash on the soft palate and base of the uvula&#44; characteristic of human herpesvirus 6 infection&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Drug-induced hypersensitivity syndrome &#40;DIHS&#41;&#44; also known as drug reaction with eosinophilia and systemic symptoms<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> or drug-induced delayed multiorgan hypersensitivity syndrome&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> is a drug hypersensitivity disorder and must be suspected in any patient who develops fever&#44; a rash&#44; hepatitis&#44; lymphadenopathy&#44; and leukocytosis &#40;with or without eosinophilia&#41; between 2 weeks and 3 months after starting treatment with certain drugs &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">The involvement of human herpesvirus &#40;HHV&#41; 6<span class="elsevierStyleHsp" style=""></span>has been reported by a number of study groups and has even been considered a risk factor for severity&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The relationship between HHV-6 reactivation and the severity of DIHS has led to such reactivation being considered a diagnostic criterion&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Activation of antiphospholipid antibodies<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and anti-thyroid peroxidase &#40;anti-TPO&#41; antibodies<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> in these syndromes has also been reported&#44; although how this may affect the severity of the disorder is unknown&#46; The presence of such antibodies is not used for diagnostic purposes&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">We present the case of a patient diagnosed with DIHS in whom we were able to demonstrate HHV-6 reactivation and the presence of antiphospholipid antibodies&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Case Description</span><p id="par0025" class="elsevierStylePara elsevierViewall">The patient&#44; a 27-year-old man&#44; was transferred to our hospital from another center on suspicion of an acute lymphoproliferative syndrome&#46; The only relevant finding in his past history was that he had started treatment with sulfasalazine one month earlier for chondromalacia patellae&#46; At the time of admission he had fever of 40<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; a confluent maculopapular rash with a negative Nikolsky sign &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44; dyspepsia&#44; and biliary vomiting&#46; He also presented a 1-week history of pharyngoamygdalitis with a whitish exudate&#44; a purpuric rash on the soft palate &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; and loss of the lingual papillae for which he had received antibiotic treatment with cefuroxime and paracetamol&#44; with no improvement after a week of therapy&#46; Physical examination revealed hepatosplenomegaly&#44; jaundice &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#44; and distal purpuric edema of the upper and lower limbs&#44; associated with a painful lateral cervical and inguinal lymphadenopathy with mobile lymph nodes measuring 2 to 3<span class="elsevierStyleHsp" style=""></span>cm in diameter&#46; Laboratory test results showed leukocytosis of 34 700&#47;&#956;L with left shift &#40;neutrophils&#44; 14 650&#47;&#956;L&#59; lymphocytes&#44; 12 750&#47;&#956;L&#41;&#59; hemoglobin&#44; 12&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#44; platelets&#44; 384 x 10<span class="elsevierStyleSup">3</span>&#47;&#956;L&#59; prothrombin time&#44; 20&#46;1 s&#59; prothrombin index&#44; 58&#37;&#59; total proteins&#44; 4&#46;6<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#59; urea&#44; 90<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#59; creatinine 1&#46;55<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#59; sodium&#44; 126 mEq&#47;L&#59; potassium&#44; 5&#46;5<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#59; bilirubin&#44; 10&#46;1<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#59; aspartate aminotransferase&#44; 628<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#59; alanine aminotransferase&#44; 521<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#59; and lactate dehydrogenase&#44; 2219<span class="elsevierStyleHsp" style=""></span>IU&#47;L&#46; There was no eosinophilia&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Thyroid function studies revealed a free thyroxine &#40;T4&#41; level of 1&#46;01<span class="elsevierStyleHsp" style=""></span>ng&#47;dL and a thyroid-stimulating hormone &#40;TSH&#41; concentration of 0&#46;066<span class="elsevierStyleHsp" style=""></span>mIU&#47;L&#46; Anti-TPO antibodies were detected at a level of 0&#46;3<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">There were no abnormalities in cytometry&#44; which suggested that the condition was reactive in origin&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">On skin biopsy&#44; there were occasional necrotic keratinocytes in the epidermis with vacuolar degeneration of the basal layer and a predominantly lymphoid inflammatory infiltrate in the superficial dermis&#44; findings consistent with toxicoderma&#46; Computed tomography of neck&#44; thorax&#44; abdomen&#44; and pelvis revealed multiple lymph nodes bilaterally&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Serology &#40;enzyme-linked immunosorbent assay&#41; for Epstein-Barr virus &#40;EBV&#41; &#40;viral capsid antigen &#91;VCA&#93;&#41;&#44; herpes simplex virus&#44; cytomegalovirus &#40;CMV&#41;&#44; hepatitis A&#44; B&#44; and C viruses&#44; parvovirus B19&#44; measles virus&#44; <span class="elsevierStyleItalic">Toxoplasma</span>&#44; <span class="elsevierStyleItalic">Chlamydia trachomatis</span>&#44; <span class="elsevierStyleItalic">Chlamydia pneumoniae</span>&#44; <span class="elsevierStyleItalic">Chlamydia psittaci</span>&#44; <span class="elsevierStyleItalic">Coxiella burnetti</span>&#44; <span class="elsevierStyleItalic">Legionella</span>&#44; <span class="elsevierStyleItalic">Mycoplasma pneumoniae</span>&#44; and human immunodeficiency virus&#44; was positive for CMV immunoglobulin &#40;Ig&#41; G&#44; EBV &#40;VCA&#41;&#44; and HHV-6 IgM and IgG&#46; In addition&#44; IgM anticardiolipin antibodies were later found to be positive&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">On the basis of these findings and the past history of treatment with sulfasalazine&#44; DIHS was diagnosed and treatment was started with intravenous methylprednisolone at a dose of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#46; This treatment produced a marked initial improvement&#44; but progressive tapering of the dose and withdrawal of the corticosteroid led to recurrence of the condition&#46; It was therefore decided to recommence therapy at the initial dose and taper more slowly&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Follow-up at 12 weeks found the patient to have marked hair loss on the scalp&#44; but he was otherwise asymptomatic&#46; Anticardiolipin IgG and IgM levels were within the normal ranges&#46; However&#44; thyroid function remained abnormal as follows&#58; free T4&#44; 0&#46;41<span class="elsevierStyleHsp" style=""></span>ng&#47;dL&#59; TSH&#44; 144&#46;952<span class="elsevierStyleHsp" style=""></span>mU&#47;L&#59; and anti-TPO antibody levels of 57&#46;36<span class="elsevierStyleHsp" style=""></span>U&#47;mL&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0060" class="elsevierStylePara elsevierViewall">We present a case of DIHS&#44; an uncommon but severe toxicoderma whose etiology&#44; pathogenesis&#44; and prognosis are related to HHV-6 reactivation&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In some patients it can lead to the transient induction of anticardiolipin antibodies or an antiphospholipid syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The appearance of autoimmune disorders after an asymptomatic period is also relatively common&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Symptom severity is related to the duration of exposure to the drug after onset of the condition &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Recently&#44; HHV-6 reactivation has also been included as a diagnostic criterion &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> and has been linked to more severe disease because&#44; in some series&#44; it was associated with prolongation of the febrile state due to the severity of the hepatitis or renal failure&#59; viral reactivation is a common finding in the cases with a fatal outcome&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> In addition&#44; in our case we observed papular erythematous lesions on the soft palate and base of the uvula&#44; known as Nagayama spots &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#59; these are seen in up to 65&#37; of patients with HHV-6 infection&#46; Although many pediatricians use this sign as an early marker of infection&#44; its specificity and predictive value continue to be a subject of discussion&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">It has also been suggested that HHV-6 may play a possible pathogenic role in the induction of an antiphospholipid syndrome&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;11</span></a> In many cases&#44; as in the one we present&#44; the presence of anticardiolipin antibodies is transient and the patient becomes antibody-negative after 2 to 3 months&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> In our patient&#44; despite the absence of signs of thrombosis consistent with antiphospholipid syndrome&#44; anticardiolipin antibodies were detected at the onset of the disorder&#46; We therefore recommend requesting laboratory studies for anticardiolipin antibodies&#44; antinuclear antigen&#44; and extractable nuclear antigen&#44; in addition to markers of hemostasis&#44; to monitor the clinical course of this dermatosis&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">It is important to draw attention to the relative frequency with which autoimmune diseases can develop after resolution of the acute disorder&#59; their pathogenesis is associated with suppressor T-cell dysfunction&#44; cytotoxic T-cell activation and proliferation&#44; and the appearance of autoantibodies&#44; especially if preceded by viral reactivation&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In particular&#44; thyroid function must be monitored for many months after resolution of the condition&#44; as hypothyroidism tends to be asymptomatic initially&#44; but there is early induction of anti-TPO antibodies and a progressive rise in TSH concentrations and fall in free T4 levels&#44; indicative of severe hypothyroidism&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The treatment of choice&#44; in addition to withdrawal of the culprit drug&#44; consists of systemic corticosteroid therapy&#46; However&#44; DIHS carries a mortality of up to 20&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Despite the controversy concerning the use of corticosteroids in the context of a possible viral infection&#44; the cases described in the literature have presented a favorable clinical course after starting this treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;13</span></a> It should also be emphasized that the dose of corticosteroid should be tapered slowly in order to avoid potential recurrences<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a>&#59; this was done in our case&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">In conclusion&#44; when DIHS is suspected&#44; the drug considered to be the cause must be withdrawn as early as possible&#46; It should be noted that the causative drug may have been introduced up to 3 months before the onset of the condition&#46; It is also important to screen for HHV-6 reactivation as not only is this one of the diagnostic criteria&#44; but it also has prognostic value&#46; Furthermore&#44; treatment with systemic corticosteroids rather than being contraindicated is actually the treatment of choice&#44; and it should be withdrawn slowly to prevent recurrence&#46; In patients who develop thrombocytopenia&#44; alterations of hemostasis&#44; or associated thrombotic disorders&#44; the presence of antiphospholipid antibodies should also be investigated&#46; Finally&#44; the possibility of the patient developing autoimmune disease as a sequela of the condition must also be considered&#59; this requires medium-to-long-term monitoring and follow-up even after complete resolution of the syndrome&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of Interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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            1 => "Virus herpes humano-6"
            2 => "S&#237;ndrome antifosfol&#237;pido"
            3 => "Hipotiroidismo"
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        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Drug-induced hypersensitivity syndrome is a toxicoderma with systemic involvement&#46; Suspicion of this disorder obliges rapid withdrawal of the suspected drug&#44; which may have been introduced up to 3 months earlier&#46; Screening for human herpesvirus &#40;HHV&#41; 6 reactivation is important both for its diagnostic value and for its association with a poor prognosis&#46; Reactivation of this virus is not a contraindication for systemic corticosteroid treatment&#44; which should be tapered slowly in order to avoid recurrence&#46; The possible appearance of antiphospholipid antibodies must also be considered in those cases associated with thrombocytopenia&#44; altered hemostasis&#44; or thrombotic events&#46; Autoimmune disorders may also develop as a sequela of the condition&#46; Medium-to-long-term follow-up is required even after complete resolution of the condition&#46; We describe a new case of sulfasalazine-induced hypersensitivity syndrome associated with HHV-6 reactivation and the induction of anticardiolipin and anti-thyroid peroxidase antibodies&#46;</p>"
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        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El s&#237;ndrome de hipersensibilidad inducido por f&#225;rmacos &#40;DIHS&#41; se engloba dentro de los cuadros toxicod&#233;rmicos con afectaci&#243;n sist&#233;mica&#44; cuya sospecha obliga a la retirada lo m&#225;s precoz posible del f&#225;rmaco que consideremos pueda estar implicado&#44; que puede haber sido introducido hasta tres meses antes&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Es importante el despistaje de la reactivaci&#243;n del virus herpes humano &#40;VHH&#41; 6&#44; tanto por su valor diagn&#243;stico como por el pron&#243;stico de gravedad que supone&#46; Por otro lado&#44; esta reactivaci&#243;n no contraindica que el tratamiento pueda llevarse a cabo con corticoides sist&#233;micos&#44; que adem&#225;s&#44; deber&#225;n retirarse lentamente para evitar reca&#237;das&#46; Deber&#237;a pensarse asimismo en la posibilidad de la presencia de anticuerpos antifofolip&#237;dicos en los casos en que apareciera trombopenia&#44; alteraci&#243;n en la hemostasia o cuadros tromb&#243;ticos asociados&#44; como tambi&#233;n tener en cuenta el desarrollo de procesos autoinmunes como secuela del cuadro&#44; que requiere de monitorizaci&#243;n y seguimiento a medio-largo plazo&#44; a pesar de la resoluci&#243;n completa del cuadro&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Describimos un nuevo caso donde se muestra la reactivaci&#243;n del VHH-6&#44; la activaci&#243;n de anticuerpos anticardiolipina y la inducci&#243;n de anticuerpos anti-tiroperoxidasa &#40;anti-TPO&#41;&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Tung Y&#44; et al&#46; S&#237;ndrome de hipersensibilidad inducido por sulfasalazina asociado a reactivaci&#243;n de VHH-6 e inducci&#243;n de s&#237;ndrome antifosfol&#237;pido&#46; Actas Dermosifiliogr&#46; 2011&#59;102&#58;537-540&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Confluent maculopapular rash on the trunk&#44; with a negative Nikolsky sign&#46;</p>"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Adapted from Shiohara T et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p>"
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46; Fever &#62;38<span class="elsevierStyleHsp" style=""></span>&#176;C&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46; Dysfunction of the liver &#40;alanine aminotransferase &#62; 100 U&#47;L&#41;&#44; kidney&#44; or lungs&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">5&#46; Alterations of white cell populations&#58; leukocytosis &#62;11 000&#47;mm<span class="elsevierStyleSup">3</span>&#44; atypical lymphocytosis &#62;5&#37;&#44; and&#47;or eosinophilia &#62;1500&#47;mm<span class="elsevierStyleSup">3</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46; Lymphadenopathies&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46; Human herpesvirus 6 reactivation&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Diagnostic Criteria for Drug-Induced Hypersensitivity Syndrome&#46;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></p>"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Adapted from Eshki M et al&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Ben m&#8217;rad M et al&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> and Ang CC et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p>"
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                  \t\t\t\t"><span class="elsevierStyleItalic">Epoetin alfa</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Bupropion</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Biological therapy&#58;</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Imatinib&#44; efalizumab&nbsp;\t\t\t\t\t\t\n
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      "titulo" => "References"
      "seccion" => array:1 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Drug-induced pseudolymphoma and drug hypersensitivity syndrome &#40;Drug Rash With Eosinophilia and Systemic Symptoms&#58; DRESS&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46; Boquet"
                            1 => "M&#46; Bagot"
                            2 => "J&#46;C&#46; Roujeau"
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                        ]
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                    ]
                  ]
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                    0 => array:1 [
                      "Revista" => array:6 [
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                        "volumen" => "15"
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                        "link" => array:1 [
                          0 => array:2 [
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                            "web" => "Medline"
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              "etiqueta" => "2"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "DIDMOHS&#58; A proposed consensus nomenclature for the drug-induced delayed multiorgan hypersensitivity syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46;D&#46; Sontheimer"
                            1 => "K&#46;R&#46; Houpt"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Dermatol"
                        "fecha" => "1998"
                        "volumen" => "134"
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                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9681358"
                            "web" => "Medline"
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                      ]
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              "etiqueta" => "3"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Human herpesvirus 6 infection as a risk factor for the development of severe drug induced hypersensitivity syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Y&#46; Suzuki"
                            1 => "R&#46; Inagi"
                            2 => "T&#46; Aono"
                            3 => "K&#46; Yamanishi"
                            4 => "T&#46; Shiohara"
                          ]
                        ]
                      ]
                    ]
                  ]
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                      "titulo" => "Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "K&#46; Hashimoto"
                            2 => "M&#46; Yasukawa"
                            3 => "H&#46; Kimura"
                            4 => "T&#46; Horikawa"
                            5 => "K&#46; Nakajima"
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                  ]
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                    0 => array:2 [
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                            0 => "M&#46; Toyoshima"
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                            2 => "K&#46; Yotsumata"
                            3 => "S&#46; Takei"
                            4 => "Y&#46; Kawano"
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                          "autores" => array:6 [
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                            1 => "M&#46;C&#46; Eggo"
                            2 => "J&#46;P&#46; Uetrecht"
                            3 => "A&#46;E&#46; Cribb"
                            4 => "D&#46; Daneman"
                            5 => "M&#46;J&#46; Rieder"
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                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Pharmacol Ther"
                        "fecha" => "1992"
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                        "paginaInicial" => "56"
                        "paginaFinal" => "67"
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                      "titulo" => "Viral connection between drug rashes and autoimmune diseases&#58; How autoimmune responses are generated after resolution of drug rashes"
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                          "autores" => array:2 [
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                      "doi" => "10.1016/j.autrev.2009.02.029"
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