Case and Research Letter
Usefulness of Immunohistochemial Staining With Antitrepenomal Antibodies in the Diagnosis of Syphilis
Utilidad de la inmunohistoquímica con anticuerpos antitreponema en el diagnóstico de la sífilis
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Imagen superior (tinción hematoxilina-eosina × 50) donde se aprecia un intenso infiltrado inflamatorio con predominio de células plasmáticas. En la parte inferior la misma biopsia con IHQ (× 400) donde se observa la infiltración de treponemas que aparecen como estructuras arrosariadas marronáceas.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "C. Hernández, R. Fúnez, B. Repiso, M. Frieyro" "autores" => array:4 [ 0 => array:2 [ "nombre" => "C." "apellidos" => "Hernández" ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Fúnez" ] 2 => array:2 [ "nombre" => "B." "apellidos" => "Repiso" ] 3 => array:2 [ "nombre" => "M." 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Hernández, R. Fúnez, B. Repiso, M. Frieyro" "autores" => array:4 [ 0 => array:4 [ "nombre" => "C." "apellidos" => "Hernández" "email" => array:1 [ 0 => "chernandez@aedv.es" ] "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" => "R." "apellidos" => "Fúnez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "B." "apellidos" => "Repiso" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "M." "apellidos" => "Frieyro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital Costa del Sol, Marbella, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicios de Anatomía Patológica, Hospital Costa del Sol, Marbella, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Utilidad de la inmunohistoquímica con anticuerpos antitreponema en el diagnóstico de la sífilis" ] ] "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" => 950 "Ancho" => 951 "Tamanyo" => 233516 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Biopsy of the lesion shown in Figure 1. Upper image: intense inflammatory infiltrate with a predominance of plasma cells (hematoxylin-eosin, original magnification × 50). Lower panel: IHC of the same biopsy (original magnification × 400) showing infiltration of treponemata, which appear as brownish bead-like structures.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Syphilis is a sexually transmitted infection (STI) caused by the spirochete <span class="elsevierStyleItalic">Treponema pallidum pallidum</span>. Recent years have seen a resurgence of syphilis. This is mainly due to an increased number of cases diagnosed in men who have sex with men (MSM).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Infection is associated with erratic condom use and a high number of sexual partners in the months before diagnosis.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In Spain the incidence of syphilis has tripled since the beginning of this century, increasing from 1.96 to 5.70 per 100 000 population between 1998 and 2008..<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Even with effective treatment, the disease remains a significant public health problem with high associated economic costs.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> Correct diagnosis is crucial in order to start antibiotic therapy as soon as possible and thus prevent new infections and stop the progression of the disease and associated sequelae.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Accordingly, new, more effective diagnostic techniques are required.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Traditionally the diagnosis of syphilis is based on a combination of clinical signs and symptoms, serological tests, and direct detection of the organism using dark field microscopy and silver impregnation techniques.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,5,6</span></a> A definitive diagnosis can be reached only by direct detection of the microorganism in infected tissues.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">These diagnostic methods can yield conflicting results in many clinical situations. Obtaining the clinical history of a patient with an STI can be difficult due to feelings of embarrassment or guilt.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Moreover, syphilis has a wide range of clinical manifestations, which has earned it the epigram <span class="elsevierStyleItalic">the great imitator</span>. It can present with very atypical clinical features and hence be mistaken for genital ulcers or other different types of rash.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–6,8</span></a> Clinical diagnosis thus depends on the experience of the physician and the presence of lesions.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Serology, using a combination of nontreponemal tests (Venereal Disease Research Laboratory and rapid plasma reagin) and treponemal tests (fluorescent treponemal antibody absorption and <span class="elsevierStyleItalic">Treponema pallidum</span> particle agglutination assay), has become the most commonly used means of indirect diagnosis, with proven benefits for the diagnosis and monitoring of patients after the initiation of treatment, although several acute and chronic infections can produce false positives in nontreponemal tests While treponemal tests are highly specific and sensitive (almost 100%) in cases of secondary syphilis, sensitivity and/or specificity are lower in the early stages of infection, in cases of congenital and tertiary syphilis, neurosyphilis with HIV coinfection, and in other immunosuppressive conditions.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,5,6,9</span></a> The increasingly common association of syphilis with HIV should be noted, given the confusion that can arise due to serological test results in these cases and the quite atypical clinical course.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">For direct detection of <span class="elsevierStyleItalic">T pallidum</span> dark field microscopy is sensitive but not specific, and requires trained personnel. Silver impregnation techniques are of low sensitivity (33% to 71%) and low specificity. Moreover, they give rise to numerous field artifacts and lack the necessary specificity to identify contaminant nontreponemal spirochetes (e.g., in oral mucosa).<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,6,9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Several recently published findings support the role of biopsy with immunohistochemistry (IHC) using antitreponemal antibodies for the diagnosis of syphilis. One study comparing IHC with silver impregnation techniques concluded that the former was more sensitive.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Indeed, the sensitivity of IHC is over 90% in most cases, although lower values (71%) have been reported in some studies.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Sensitivity and specificity are highest in early primary and secondary syphilis (when spirochetes are found in large quantities), but diminish in later stages due to decreases in the number of microorganisms in the lesions.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> IHC can distinguish syphilis lesions from other unrelated lesions, which may appear in patients with both true and false positive serology for <span class="elsevierStyleItalic">T pallidum.</span> Moreover, this technique permits the detection of spirochetes in the skin, although cross-reactivity with <span class="elsevierStyleItalic">Borrelia</span> species is possible.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Furthermore, IHC is a relatively rapid and inexpensive technique, with results available in about 48<span class="elsevierStyleHsp" style=""></span>h.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Here we present 5 clinical cases of patients treated in our STI outpatient clinic between January 2009 and January 2012 with a final diagnosis of syphilis (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>); in all cases IHC was crucial for accurate diagnosis. The selected cases are representative of those seen in everyday practice, in terms of their clinical manifestations and/or doubtful or even negative serology, and thus were difficult to diagnose. Case 1 was an HIV-positive patient with a negative treponemal test, a lesion suggestive of syphilitic chancre, and no lymph node enlargement. This test result may have been due to the window period, or may reflect a false negative influenced by HIV co-infection. In case 2, the patient had a lesion suggestive of syphilitic chancre, but a negative enzyme-linked immunosorbent assay (ELISA), which was also probably due to the window period. Similarly, the negative ELISA in case 3, despite lesions suggestive of secondary syphilis, was probably a rare case of a false negative using this technique. The patient in case 4 presented rarely seen clinical features with a faint macular rash without palmoplantar involvement. Finally, case 5 (<a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1 and 2</a>) is an example of atypical extragenital clinical manifestations.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">IHC offers increased sensitivity and specificity compared with conventional techniques for the detection of <span class="elsevierStyleItalic">T pallidum</span>.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3–6,8–10</span></a> Although this technique is not a widely used diagnostic method and we do not recommend its routine use, these 5 cases highlight its utility, especially in HIV patients or immunosuppressed patients in general, in those with secondary syphilis with negative and/or dubious serology, in cases with atypical clinical features (including cases of extragenital syphilis), and in the early stages of the disease.</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: Hernández C, Fúnez R, Repiso B, Frieyro M. Utilidad de la inmunohistoquímica con anticuerpos antitreponema en el diagnóstico de la sífilis. Actas Dermosifiliogr. 2013;104:926–928.</p>" ] ] "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" => 607 "Ancho" => 801 "Tamanyo" => 94772 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Case 5. Whitish papillary lesions on the lateral border of the tongue.</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" => 950 "Ancho" => 951 "Tamanyo" => 233516 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Biopsy of the lesion shown in Figure 1. Upper image: intense inflammatory infiltrate with a predominance of plasma cells (hematoxylin-eosin, original magnification × 50). Lower panel: IHC of the same biopsy (original magnification × 400) showing infiltration of treponemata, which appear as brownish bead-like structures.</p>" ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Abbreviations: ELISA, enzyme-linked immunosorbent assay; F, female; HIV, human immunodeficiency virus; IHC, immunohistochemistry; M, male; NP, not performed; RPR, rapid plasma regain; TPHA, <span class="elsevierStyleItalic">Treponema pallidum</span> haemagglutination test.</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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Clinical Cases \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Sex \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Clinical Features \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">HIV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">ELISA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">RPR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">TPHA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Case Details \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">IHC \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><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">Case 1 \t\t\t\t\t\t\n \t\t\t\t</td><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"><span class="elsevierStyleSmallCaps">M</span> \t\t\t\t\t\t\n \t\t\t\t</td><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">42 \t\t\t\t\t\t\n \t\t\t\t</td><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">Painful genital ulcer Swollen lymph nodes \t\t\t\t\t\t\n \t\t\t\t</td><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">+ \t\t\t\t\t\t\n \t\t\t\t</td><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">+ \t\t\t\t\t\t\n \t\t\t\t</td><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">1/4 \t\t\t\t\t\t\n \t\t\t\t</td><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">− \t\t\t\t\t\t\n \t\t\t\t</td><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">TPHA \t\t\t\t\t\t\n \t\t\t\t</td><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">+ \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">Case 2 \t\t\t\t\t\t\n \t\t\t\t</td><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"><span class="elsevierStyleSmallCaps">M</span> \t\t\t\t\t\t\n \t\t\t\t</td><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">54 \t\t\t\t\t\t\n \t\t\t\t</td><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">Two painful genital ulcers Swollen lymph nodes \t\t\t\t\t\t\n \t\t\t\t</td><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">− \t\t\t\t\t\t\n \t\t\t\t</td><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">− \t\t\t\t\t\t\n \t\t\t\t</td><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">NP \t\t\t\t\t\t\n \t\t\t\t</td><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">NP \t\t\t\t\t\t\n \t\t\t\t</td><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">ELISA with typical clinical features \t\t\t\t\t\t\n \t\t\t\t</td><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">+ \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">Case 3 \t\t\t\t\t\t\n \t\t\t\t</td><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"><span class="elsevierStyleSmallCaps">M</span> \t\t\t\t\t\t\n \t\t\t\t</td><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">37 \t\t\t\t\t\t\n \t\t\t\t</td><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">Plaques with depressed center and multiple non-painful ulcers in the pubic area \t\t\t\t\t\t\n \t\t\t\t</td><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"><span class="elsevierStyleBold">−</span> \t\t\t\t\t\t\n \t\t\t\t</td><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"><span class="elsevierStyleBold">−</span> \t\t\t\t\t\t\n \t\t\t\t</td><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">NP \t\t\t\t\t\t\n \t\t\t\t</td><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">NP \t\t\t\t\t\t\n \t\t\t\t</td><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">ELISA with typical clinical features \t\t\t\t\t\t\n \t\t\t\t</td><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">+ \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">Case 4 \t\t\t\t\t\t\n \t\t\t\t</td><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"><span class="elsevierStyleSmallCaps">M</span> \t\t\t\t\t\t\n \t\t\t\t</td><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">47 \t\t\t\t\t\t\n \t\t\t\t</td><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">Faint macular rash without palmoplantar involvement \t\t\t\t\t\t\n \t\t\t\t</td><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"><span class="elsevierStyleBold">−</span> \t\t\t\t\t\t\n \t\t\t\t</td><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">+ \t\t\t\t\t\t\n \t\t\t\t</td><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">1/64 \t\t\t\t\t\t\n \t\t\t\t</td><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">1/2560 \t\t\t\t\t\t\n \t\t\t\t</td><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">Atypical clinical features \t\t\t\t\t\t\n \t\t\t\t</td><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">+ \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">Case 5 \t\t\t\t\t\t\n \t\t\t\t</td><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">F \t\t\t\t\t\t\n \t\t\t\t</td><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">55 \t\t\t\t\t\t\n \t\t\t\t</td><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">Whitish papillary lesions on the lateral border of the tongue \t\t\t\t\t\t\n \t\t\t\t</td><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"><span class="elsevierStyleBold">−</span> \t\t\t\t\t\t\n \t\t\t\t</td><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">NP \t\t\t\t\t\t\n \t\t\t\t</td><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">1/128 \t\t\t\t\t\t\n \t\t\t\t</td><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">1/2560 \t\t\t\t\t\t\n \t\t\t\t</td><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">Atypical clinical features \t\t\t\t\t\t\n \t\t\t\t</td><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">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab430513.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Clinical and Serological Features of the 5 Clinical Cases.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 17 | 7 | 24 |
| 2024 October | 108 | 40 | 148 |
| 2024 September | 123 | 19 | 142 |
| 2024 August | 132 | 52 | 184 |
| 2024 July | 124 | 38 | 162 |
| 2024 June | 148 | 58 | 206 |
| 2024 May | 101 | 35 | 136 |
| 2024 April | 111 | 19 | 130 |
| 2024 March | 113 | 27 | 140 |
| 2024 February | 104 | 37 | 141 |
| 2024 January | 88 | 26 | 114 |
| 2023 December | 75 | 24 | 99 |
| 2023 November | 80 | 40 | 120 |
| 2023 October | 86 | 36 | 122 |
| 2023 September | 88 | 32 | 120 |
| 2023 August | 73 | 27 | 100 |
| 2023 July | 73 | 28 | 101 |
| 2023 June | 57 | 20 | 77 |
| 2023 May | 76 | 24 | 100 |
| 2023 April | 78 | 30 | 108 |
| 2023 March | 60 | 20 | 80 |
| 2023 February | 65 | 25 | 90 |
| 2023 January | 75 | 23 | 98 |
| 2022 December | 76 | 40 | 116 |
| 2022 November | 23 | 21 | 44 |
| 2022 October | 27 | 30 | 57 |
| 2022 September | 29 | 46 | 75 |
| 2022 August | 23 | 32 | 55 |
| 2022 July | 45 | 41 | 86 |
| 2022 June | 21 | 25 | 46 |
| 2022 May | 59 | 44 | 103 |
| 2022 April | 73 | 53 | 126 |
| 2022 March | 137 | 57 | 194 |
| 2022 February | 85 | 28 | 113 |
| 2022 January | 79 | 37 | 116 |
| 2021 December | 47 | 27 | 74 |
| 2021 November | 70 | 52 | 122 |
| 2021 October | 84 | 51 | 135 |
| 2021 September | 54 | 46 | 100 |
| 2021 August | 42 | 22 | 64 |
| 2021 July | 44 | 40 | 84 |
| 2021 June | 65 | 29 | 94 |
| 2021 May | 47 | 37 | 84 |
| 2021 April | 142 | 42 | 184 |
| 2021 March | 111 | 27 | 138 |
| 2021 February | 69 | 27 | 96 |
| 2021 January | 56 | 20 | 76 |
| 2020 December | 50 | 23 | 73 |
| 2020 November | 40 | 13 | 53 |
| 2020 October | 41 | 17 | 58 |
| 2020 September | 34 | 14 | 48 |
| 2020 August | 26 | 24 | 50 |
| 2020 July | 40 | 13 | 53 |
| 2020 June | 37 | 24 | 61 |
| 2020 May | 24 | 15 | 39 |
| 2020 April | 34 | 17 | 51 |
| 2020 March | 31 | 17 | 48 |
| 2020 February | 4 | 6 | 10 |
| 2020 January | 4 | 6 | 10 |
| 2019 December | 8 | 0 | 8 |
| 2019 November | 4 | 1 | 5 |
| 2019 October | 0 | 1 | 1 |
| 2019 September | 8 | 2 | 10 |
| 2019 August | 3 | 3 | 6 |
| 2019 July | 4 | 5 | 9 |
| 2019 June | 6 | 14 | 20 |
| 2019 May | 4 | 15 | 19 |
| 2019 April | 2 | 14 | 16 |
| 2019 March | 2 | 8 | 10 |
| 2019 February | 4 | 4 | 8 |
| 2019 January | 1 | 1 | 2 |
| 2018 December | 0 | 7 | 7 |
| 2018 November | 2 | 0 | 2 |
| 2018 October | 3 | 0 | 3 |
| 2018 September | 4 | 0 | 4 |
| 2018 March | 14 | 0 | 14 |
| 2018 February | 61 | 6 | 67 |
| 2018 January | 75 | 4 | 79 |
| 2017 December | 77 | 4 | 81 |
| 2017 November | 72 | 6 | 78 |
| 2017 October | 67 | 8 | 75 |
| 2017 September | 74 | 4 | 78 |
| 2017 August | 74 | 8 | 82 |
| 2017 July | 65 | 9 | 74 |
| 2017 June | 68 | 9 | 77 |
| 2017 May | 84 | 8 | 92 |
| 2017 April | 70 | 4 | 74 |
| 2017 March | 60 | 5 | 65 |
| 2017 February | 59 | 11 | 70 |
| 2017 January | 60 | 7 | 67 |
| 2016 December | 71 | 6 | 77 |
| 2016 November | 87 | 5 | 92 |
| 2016 October | 103 | 8 | 111 |
| 2016 September | 146 | 11 | 157 |
| 2016 August | 82 | 5 | 87 |
| 2016 July | 50 | 7 | 57 |
| 2016 June | 7 | 10 | 17 |
| 2016 May | 5 | 2 | 7 |
| 2016 April | 4 | 4 | 8 |
| 2016 March | 12 | 0 | 12 |
| 2016 February | 8 | 2 | 10 |
| 2016 January | 5 | 1 | 6 |
| 2015 December | 5 | 0 | 5 |
| 2015 November | 10 | 2 | 12 |
| 2015 October | 4 | 1 | 5 |
| 2015 September | 2 | 1 | 3 |
| 2015 August | 4 | 3 | 7 |
| 2015 July | 57 | 3 | 60 |
| 2015 June | 37 | 6 | 43 |
| 2015 May | 51 | 12 | 63 |
| 2015 April | 37 | 7 | 44 |
| 2015 March | 67 | 4 | 71 |
| 2015 February | 47 | 1 | 48 |
| 2015 January | 36 | 4 | 40 |
| 2014 December | 42 | 3 | 45 |
| 2014 November | 24 | 2 | 26 |
| 2014 October | 37 | 5 | 42 |
| 2014 September | 37 | 0 | 37 |
| 2014 August | 27 | 6 | 33 |
| 2014 July | 18 | 6 | 24 |
| 2014 June | 45 | 5 | 50 |
| 2014 May | 37 | 6 | 43 |
| 2014 April | 26 | 4 | 30 |
| 2014 March | 32 | 4 | 36 |
| 2014 February | 28 | 3 | 31 |
| 2014 January | 25 | 5 | 30 |
| 2013 December | 30 | 6 | 36 |
| 2013 November | 0 | 1 | 1 |
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