Case Report
Autoimmune Response in Children With Dengue. Case Reports
Respuesta autoinmune en niños con dengue. Reporte de casos
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Case Reports" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "257" "paginaFinal" => "259" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Zoilo Morel, Andrea Ramírez" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Zoilo" "apellidos" => "Morel" "email" => array:1 [ 0 => "zoiloma@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" => "Andrea" "apellidos" => "Ramírez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Pediatría, Reumatología Pediátrica, Hospital Central del Instituto de Previsión Social, Asunción, Paraguay" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Pediatría, Hospital Central del Instituto de Previsión Social, Asunción, Paraguay" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Respuesta autoinmune en niños con dengue. Reporte de casos" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Dengue is an infectious disease caused by the DV, which can progress to dengue hemorrhagic fever and dengue shock syndrome (DSS).<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> Viral infection can also cause abnormal immune responses. Autoimmunity is characterized by autoantibody production and activation of autoreactive lymphocytes, which have been demonstrated to be associated to a number of viral pathogens. Previous studies indicate that the onset of the autoimmune response in dengue is a part of the pathogenesis of the disease; this can affect different organs and systems.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">We report 3 pediatric cases with autoimmune responses related to DV infection.</p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Case 1</span><p id="par0015" class="elsevierStylePara elsevierViewall">An 8-year-old male, with fever for 8 days, abdominal pain of 4 days of evolution in the epigastrium and right upper quadrant, which is accompanied by bloating, joint pain and general malaise. Physical examination: tachycardia, tachypnea, bilateral pleural effusion, globular abdomen, with collateral circulation, liver 8<span class="elsevierStyleHsp" style=""></span>cm below the right costal ridge and spleen 12<span class="elsevierStyleHsp" style=""></span>cm the left of the rib margin. The fever persisted after 14 days, with retroperitoneal lymphadenopathy. Lymph node biopsy was negative for malignancy. Serology for hepatitis, and Widal and Hudlesson reactions monotest, IgM isotype antibodies against toxoplasmosis, rK39 and IgM isotype antibodies vs CMV were all negative, IgG and IgM antibody isotypes for DV were positive. The cultures were negative. He also had proteinuria with hypoalbuminemia, bicytopenia (2500/ml leukocytes, platelets 80<span class="elsevierStyleHsp" style=""></span>000/mm<span class="elsevierStyleSup">3</span>) and hypocomplementemia. Lupus anticoagulant was negative, IgM isotype anticardiolipin antibodies were positive, C3 and C4 were normal, antinuclear antibodies (ANA) and anti-DNA were negative. Subsequently he presented improvement without treatment, and was discharged in good condition.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Case 2</span><p id="par0020" class="elsevierStylePara elsevierViewall">Male patient, 3 years old, with fever of 7 days, skin lesions for 7 days, predominantly on the trunk and upper limbs, erythematous macules, and petechiae of universal distribution. He also had abdominal pain of 2 days duration. Physical examination: tachycardia, tachypnea, petechiae. Bilateral breath sounds were rough, decreased in the right base. Abdomen globose, liver 3<span class="elsevierStyleHsp" style=""></span>cm below the right costal margin and spleen 2<span class="elsevierStyleHsp" style=""></span>cm below the left costal margin. Chest X ray showed condensation on the right base. By means of echocardiography, a minimal pericardial effusion was detected. Abdominal ultrasound found hepatosplenomegaly and free fluid in the abdomen. The dengue NS1 antigen was positive. The patient had persistent fever for 3 weeks with hepatomegaly 9<span class="elsevierStyleHsp" style=""></span>cm below the right costal ridge and spleen 3<span class="elsevierStyleHsp" style=""></span>cm below the left rib margin, with jaundice. Serology for hepatitis and the IgM isotype antibodies against CMV, Epstein–Barr virus, toxoplasmosis and HIV were all negative. Febrile antigens, ANA, anti-DNA and rheumatoid factor (RF) were also negative. The bone marrow aspirate was normal. Macrophage activation syndrome was diagnosed due to fever, leucopenia with neutropenia (3000/ml leukocytes, neutrophils 900/ml), anemia (hemoglobin 8.2<span class="elsevierStyleHsp" style=""></span>g/dl), hepatosplenomegaly, triglycerides 470<span class="elsevierStyleHsp" style=""></span>mg/dl and 1150 hyperferritinemia mg/dl. Boluses of methylprednisolone were initiated, which led to an improvement of the clinical status and the jaundice disappeared, as did the enlarged organs and the fever. He was discharged later.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Case 3</span><p id="par0025" class="elsevierStylePara elsevierViewall">Male infant, 3 months of age with fever for 4 days of evolution, in addition to vomiting and diarrhea 2 days earlier. Physical examination: globose abdomen, liver 3<span class="elsevierStyleHsp" style=""></span>cm below the right rib margin. An abdominal ultrasound showed hepatosplenomegaly, thickened gallbladder wall and free fluid in the abdomen. The dengue NS1 antigen was positive. He had anemia (hemoglobin 8.0<span class="elsevierStyleHsp" style=""></span>g/dl) which increase progressively with increasing hepatomegaly, up to 6<span class="elsevierStyleHsp" style=""></span>cm below the right costal margin. Serology for hepatitis and IgM isotype antibodies against CMV, Epstein–Barr virus, toxoplasmosis and HIV were negative. Febrile antigens, ANA, anti-DNA and RF were negative. The marrow aspirate was normal. A diagnosis of macrophage activation syndrome was made due to fever, hepatosplenomegaly, leucopenia, neutropenia (3500/ml leukocytes, neutrophils 1100/ml), anemia (hemoglobin 8.0<span class="elsevierStyleHsp" style=""></span>g/dl), hypertriglyceridemia 383<span class="elsevierStyleHsp" style=""></span>mg/dl and hyperferritinemia 3828<span class="elsevierStyleHsp" style=""></span>mg/dl. Boluses of methylprednisolone were started, with improvement of clinical status, decreased visceromegalies and hematologic improvement. He was subsequently discharged.</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Discussion</span><p id="par0030" class="elsevierStylePara elsevierViewall">It is currently considered that there are several mechanisms that could explain the association of autoimmunity and viral infection, including molecular mimicry, cell activation and viral persistence. Previous studies showed that the DV infection leads to the production of autoantibodies against human cells. DV is an important infectious disease in tropical and subtropical regions of the world.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–4</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The pathogenic mechanisms of dengue hemorrhagic fever (DHF) and DSS caused by DV infection remain unresolved. Patients with DV/DSS are characterized by various manifestations including severe thrombocytopenia, vascular leakage and hepatomegaly. Besides the effects of the viral load and the variation of the virus, abnormal host immune responses after DV infection may also account for the progression of DHF/DSS. Actually, autoimmunity is implicated in the pathogenesis of many viral infections such as HIV, hepatitis C, CMV, herpes simplex virus, Epstein–Barr and DV. Antibodies directed against the DV 1 nonstructural protein (NS1) show cross-reactivity with human platelets and endothelial cells, which leads to damage to the endothelial cells and platelets, as well as inflammation. These results, as well as the hypothesis that the anti-DV NS1 is involved in the pathogenesis of dengue and DHF/DSS can lead to important information on the development of a vaccine against dengue.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5–8</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">A wide variety of factors have been associated with macrophage activation syndrome. These include infections (Epstein–Barr, varicella, Coxsackie, parvovirus B19, hepatitis A, Salmonella, Pneumocystis jiroveci, enterococci, leishmaniasis, etc.), drugs (aspirin, NSAIDs, methotrexate, etanercept, anakinra, gold salts, sulfasalazine and morniflumate) and autoimmune diseases (systemic lupus erythematosus, juvenile idiopathic arthritis of systemic-onset).<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9–13</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Hemophagocytic lymphohistiocytosis (HLH), which has many genetic causes, is characterized by multisystem inflammation. HLH is a reactive process resulting from prolonged and excessive activation of antigen presenting cells (macrophages, histiocytes) and CD8+T cells. Hemophagocytosis, which is mediated through CD163, is a characteristic of activated macrophages and histiocytes, giving the disease its name. The predominant clinical features of HLH are fever (often persistent), cytopenias, hepatitis and splenomegaly. The diagnostic protocol classification of HLH (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) is used. Because of the involvement by the disease and life-threatening manifestations, treatment should be started as soon as possible with anti-inflammatory therapy, consisting of glucocorticoids, cyclosporine, etoposide or anti-thymocyte globulin (ATG). Secondary MAS is associated with autoimmune diseases or viral infections, with a significant mortality rate.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,14</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Our patients clinically presented an autoimmune response developed due to DV infection, which in the first case was self-limiting. The other 2 cases presented as secondary MAS and showed a good response to glucocorticoids. It is noteworthy that the last 2 cases showed no bone marrow hemophagocytosis, but met other criteria for the diagnosis in question.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Our country currently has cases of endemic dengue with hyperimmune responses. Therefore, the treating physician should consider this possibility in the presence of uncommon conditions.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Ethical Responsibilities</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Protection of human and animal subjects</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors declare that no experiments have been performed on humans or animals.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Confidentiality of data</span><p id="par0065" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their workplace on the publication of data from patients and all patients included in the study have received sufficient information and gave written informed consent to participate in the study.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Right to privacy and informed consent</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors have obtained informed consent from patients and/or subjects referred to in the article. This document is in the possession of the corresponding author.</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of Interest</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:2 [ "identificador" => "xres348915" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec330609" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres348916" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec330608" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Introduction" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Case 1" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Case 2" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "Case 3" ] ] ] 5 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "Ethical Responsibilities" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Right to privacy and informed consent" ] ] ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflicts of Interest" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-12-23" "fechaAceptado" => "2013-07-03" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec330609" "palabras" => array:4 [ 0 => "Dengue" 1 => "Autoinmune response" 2 => "Hemophagocytic syndrome" 3 => "Macrophage activation syndrome" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec330608" "palabras" => array:4 [ 0 => "Dengue" 1 => "Respuesta autoinmune" 2 => "Síndrome hemofagocítico" 3 => "Síndrome de activación de macrófagos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Dengue is an infectious disease caused by the dengue virus (DV), which can progress to dengue hemorrhagic fever and dengue shock syndrome. DV causes the production of auto-antibodies against human cells. A variety of factors have been associated with macrophage activation syndrome, including infections, drugs and autoimmune pathologies (systemic lupus erythematosus, systemic onset juvenile idiopathic arthritis). We present three cases of patients that clinically developed an autoimmune response related to a DV infection. Our country currently has endemic cases of dengue, with hyperimmune responses. Therefore, the physician should consider this possibility in the presence of unusual conditions.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El dengue es una enfermedad infecciosa producida por el virus del dengue (VD), que puede evolucionar hacia fiebre hemorrágica dengue y síndrome de choque por dengue. El VD es causante de la producción de autoanticuerpos contra células humanas. Una amplia variedad de factores han sido asociados al síndrome de activación de macrófagos, incluyendo infecciones, fármacos y enfermedades autoinmunes de base (lupus eritematoso sistémico, artritis idiomática juvenil de inicio sistémico). Presentamos 3 casos de pacientes que desarrollaron clínicamente una respuesta autoinmune relacionada con una infección por VD. Nuestro país actualmente presenta casos de dengue en forma endémica, con respuestas hiperinmunes. Por lo tanto, el médico tratante debe pensar en esta posibilidad ante la presencia de afecciones no comunes.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Morel Z, Ramírez A. Respuesta autoinmune en niños con dengue. Reporte de casos. Reumatol Clin. 2014;10:257–259.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Dapena Diaz et al.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>" "tabla" => array:2 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">HLH diagnosis can be performed with one or both criteria described in the table.</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=""><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"><span class="elsevierStyleBold">1. Molecular diagnosis consistent with HLH</span> \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"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">2. Diagnostic criteria for HLH fulfilled (5 or more of the 8 criteria below)</span> \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"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>(a) Fever \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"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>(b) Splenomegaly \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"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>(c) Cytopenias (affecting 2 of 3 lineages in the peripheral blood): hemoglobin <9.0<span class="elsevierStyleHsp" style=""></span>g/l (in infants less than 4 weeks: hemoglobin <10.0<span class="elsevierStyleHsp" style=""></span>g/l), platelets <100<span class="elsevierStyleHsp" style=""></span>000/mm<span class="elsevierStyleSup">3</span> three neutrophil count <1000/mm<span class="elsevierStyleSup">3</span> \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"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>(d) Hypertriglyceridemia and/or hypofibrinogenemia: triglycerides ≥265<span class="elsevierStyleHsp" style=""></span>mg/dl, fibrinogen ≤1.5<span class="elsevierStyleHsp" style=""></span>g/l \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"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>(e) Hemophagocytosis in bone marrow, spleen, lymph nodes, or cerebrospinal fluid: no evidence of malignancy \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"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>(f) Low or no activity of “natural killer” cells (according to the reference laboratory) \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"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>(g) elevated serum ferritin (≥500<span class="elsevierStyleHsp" style=""></span>mg/l) \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"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>(h) soluble CD25 over the normal range for age \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab520493.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Guidelines for the Diagnosis of Hemophagocytic Lymphohistiocytosis: HLH 2004 Protocol.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:14 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "Dengue: Guidelines for diagnosis, treatment, prevention and control. 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Saad" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Braz J Infect Dis" "fecha" => "2012" "volumen" => "16" "paginaInicial" => "92" "paginaFinal" => "95" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22358365" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune pathogenesis in dengue virus infection" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "C.F. Lin" 1 => "S.W. Wan" 2 => "H.J. Cheng" 3 => "H.Y. Lei" 4 => "Y.S. 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Singh" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1179/102453308X316095" "Revista" => array:6 [ "tituloSerie" => "Hematology" "fecha" => "2008" "volumen" => "13" "paginaInicial" => "286" "paginaFinal" => "288" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18854091" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A case of dengue fever with viral-associated hemophagocytic syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "I. Nakamura" 1 => "F. Nakamura-Uchiyama" 2 => "N. Komiya" 3 => "K. Ohnishi" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Kansenshogaku Zasshi" "fecha" => "2009" "volumen" => "83" "paginaInicial" => "60" "paginaFinal" => "63" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19227227" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hemophagocytic lymphohistiocytosis and related disorders" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A.H. Filipovich" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/01.all.0000246626.57118.d9" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Allergy Clin Immunol" "fecha" => "2006" "volumen" => "6" "paginaInicial" => "410" "paginaFinal" => "415" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17088644" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of Epstein–Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH); update 2010" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "S. Imashuku" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MPH.0b013e3181f84a52" "Revista" => array:6 [ "tituloSerie" => "J Pediatr Hematol Oncol" "fecha" => "2011" "volumen" => "33" "paginaInicial" => "35" "paginaFinal" => "39" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21088619" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rapidly fatal reactive hemophagocytosis syndrome associated with visceral leishmaniasis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "L.K. Tiwari" 1 => "R. Devidayal Das" 2 => "S. Grover" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Pediatr Infect Dis" "fecha" => "2011" "volumen" => "6" "paginaInicial" => "269" "paginaFinal" => "271" ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Macrophage activation syndrome in juvenile systemic lupus erythematosus. A multinational multicenter study of thirty-eight patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Parodi" 1 => "S. Davi" 2 => "A.B. Pringe" 3 => "A. Pistorio" 4 => "N. Ruperto" 5 => "S. Magni-Manzoni" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.24883" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2009" "volumen" => "60" "paginaInicial" => "3388" "paginaFinal" => "3399" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19877067" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recognition and management of macrophage activation syndrome in juvenile arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A. Kelly" 1 => "A.V. Ramanan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/BOR.0b013e32825a6a79" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Rheumatol" "fecha" => "2007" "volumen" => "19" "paginaInicial" => "477" "paginaFinal" => "481" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17762614" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Síndrome hemofagocítico: expresión de diversas entidades nosológicas" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.L. Dapena Díaz" 1 => "C. Díaz de Heredia Rubio" 2 => "P. BastidaVila" 3 => "A. Llort Sales" 4 => "I. Elorza Alvarez" 5 => "T. Olivé Oliveras" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "An Pediatr (Barc)" "fecha" => "2009" "volumen" => "71" "paginaInicial" => "110" "paginaFinal" => "116" ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/21735743/0000001000000004/v1_201406280041/S2173574314000586/v1_201406280041/en/main.assets" "Apartado" => array:4 [ "identificador" => "17376" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Case Report" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/21735743/0000001000000004/v1_201406280041/S2173574314000586/v1_201406280041/en/main.pdf?idApp=UINPBA00004M&text.app=https://reumatologiaclinica.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574314000586?idApp=UINPBA00004M" ]
| Year/Month | Html | Total | |
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| 2017 August | 87 | 10 | 97 |
| 2017 July | 96 | 17 | 113 |
| 2017 June | 148 | 21 | 169 |
| 2017 May | 79 | 9 | 88 |
| 2017 April | 71 | 20 | 91 |
| 2017 March | 89 | 18 | 107 |
| 2017 February | 56 | 14 | 70 |
| 2017 January | 42 | 9 | 51 |
| 2016 December | 95 | 18 | 113 |
| 2016 November | 59 | 12 | 71 |
| 2016 October | 103 | 20 | 123 |
| 2016 September | 132 | 15 | 147 |
| 2016 August | 82 | 18 | 100 |
| 2016 July | 42 | 20 | 62 |
| 2015 December | 2 | 0 | 2 |
| 2015 August | 2 | 0 | 2 |
| 2015 July | 31 | 7 | 38 |
| 2015 June | 35 | 11 | 46 |
| 2015 May | 95 | 13 | 108 |
| 2015 April | 44 | 14 | 58 |
| 2015 March | 57 | 11 | 68 |
| 2015 February | 43 | 10 | 53 |
| 2015 January | 74 | 18 | 92 |
| 2014 December | 84 | 12 | 96 |
| 2014 November | 102 | 19 | 121 |
| 2014 October | 84 | 16 | 100 |
| 2014 September | 41 | 23 | 64 |
| 2014 August | 57 | 24 | 81 |
| 2014 July | 56 | 23 | 79 |
Show all
