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X-linked agammaglobulinemia: Experience in a Portuguese hospital
Agammaglobulinemia ligada al cromosoma X: experiencia en un hospital portugués
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Madrid Rodríguez, P.L. Martínez Martínez, J.M. Ramos Fernández, A. Urda Cardona, J. Martínez Antón" "autores" => array:5 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Madrid Rodríguez" ] 1 => array:2 [ "nombre" => "P.L." "apellidos" => "Martínez Martínez" ] 2 => array:2 [ "nombre" => "J.M." "apellidos" => "Ramos Fernández" ] 3 => array:2 [ "nombre" => "A." "apellidos" => "Urda Cardona" ] 4 => array:2 [ "nombre" => "J." 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"apellidos" => "Fernandes" "email" => array:1 [ 0 => "xanofernandes@gmail.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" => "M." "apellidos" => "Guedes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "J." "apellidos" => "Vasconcelos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "E." "apellidos" => "Neves" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "S." "apellidos" => "Fernandes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 5 => array:3 [ "nombre" => "L." "apellidos" => "Marques" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidade de Infecciologia Pediátrica e Imunodeficiências, Serviço de Pediatria, Centro Hospitalar Porto, Oporto, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Genética, Faculdade de Medicina da Universidade do Porto, Oporto, Portugal" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Agammaglobulinemia ligada al cromosoma X: experiencia en un hospital portugués" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 467 "Ancho" => 991 "Tamanyo" => 93114 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">IgG levels during followup. Each line represents one patient. The values above the black horizontal line were considered normal. The bold Xs represent the moment at which IVIg was switched to SCIg.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">X-linked agammaglobulinaemia (XLA [MIM 300755]) is a primary immunodeficiency characterised by the arrest of B cell differentiation,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> leading to a considerably reduced B lymphocyte count and low serum immunoglobulin (Ig) levels that make patients more susceptible to recurrent and severe infections.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> The infections usually start appearing between 3 and 6 months of age, when maternal IgG levels start to decline. If there is a family history of the disease, XLA may be suspected and diagnosed prenatally.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a> Respiratory tract infections by encapsulated bacteria, especially otitis, sinusitis, and pneumonia, are characteristic of XLA.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">2,4,5</span></a> Most of these infections are caused by encapsulated pyogenic bacteria (<span class="elsevierStyleItalic">Streptococcus pneumoniae, Haemophilus influenzae</span> and <span class="elsevierStyleItalic">Staphylococcus aureus</span>).<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> The literature shows that the pathogens isolated most frequently from patients with septicaemia correspond to various <span class="elsevierStyleItalic">Pseudomonas</span> species.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">2,6</span></a> Digestive tract infections by <span class="elsevierStyleItalic">Giardia lamblia</span> are also frequent.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> Patients with XLA are particularly vulnerable to enteroviruses, especially polioviruses and coxsackieviruses. There have been reports of poliomyelitis caused by administration of the live attenuated vaccine, associated with high mortality rates.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The estimated incidence of XLA ranges from 1:100,000 to 1:200,000 cases per live births.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> The disease is caused by mutations in the <span class="elsevierStyleItalic">BTK</span> gene that encodes Bruton tyrosine kinase, located in the X chromosome (Xq21.3–Xq22).<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">7</span></a> The BTK protein is involved in every stage of the development of the B cell lineage and in the myeloid and erythroid precursors, and does not affect T lymphocytes or NK cells. Mutations in this protein cause defects in the early stages of B cell development, leading to a considerable reduction in B cell blood levels.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> Over 800 different mutations have been described to date.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">8</span></a> The detection of mutations in the <span class="elsevierStyleItalic">BTK</span> gene is a necessary criterion for the definitive diagnosis of XLA and for genetic counselling.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">9</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Lifelong immunoglobulin replacement therapy (IRT) is indicated for patients with XLA. If the disease is diagnosed early, patients can have a good quality of life. Early treatment with IRT is essential to reduce the recurrence and severity of infections, the number of hospital admissions, and morbidity due to chronic complications of the disease.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">2,10</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The purpose of this study was to learn the characteristics of patients with XLA followed up at the paediatric infectious diseases and immunodeficiencies unit of the department of paediatrics of a tertiary hospital in northern Portugal, analysing their clinical presentations and outcomes.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Study design and protocol</span>: we performed a descriptive retrospective study of the patients diagnosed with XLA and followed up at the paediatric infectious diseases and immunodeficiencies unit of the department of paediatrics of a tertiary hospital in northern Portugal between January 1991 and December 2013. We collected the data from the patients’ medical records.</p><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Data:</span> we collected data on the factors that led to the diagnosis (positive family history or presence of infections); age at clinical onset (based on the date of the first infection); age at diagnosis; type of infections developed prior to diagnosis and hospitalisations; IgG levels; CD19<span class="elsevierStyleSup">+</span> B cell number at diagnosis; identified <span class="elsevierStyleItalic">BTK</span> mutation; duration of IRT administration; and infections and non-infectious complications during followup.</p><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Definitions used by the authors</span>: the diagnosis of XLA was based on established criteria: male patient with fewer than 2% CD19<span class="elsevierStyleSup">+</span> B cells and mutation in the <span class="elsevierStyleItalic">BTK</span> gene, in accordance to the definition of the European Society for Immunodeficiencies.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">11</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">We considered that there was a family history of XLA if any family members had been diagnosed with it.</p><p id="par0045" class="elsevierStylePara elsevierViewall">We defined delay in diagnosis as the time difference between the age at the onset of symptoms (first infection) and the age at diagnosis.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Recurrent otitis media was defined as the occurrence of 3 or more episodes of acute otitis media, and recurrent pneumonia as the occurrence of more than one episode of pneumonia.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Intravenous replacement therapy involved the intravenous administration of IgG every 3 or 4 weeks in the dosage needed to maintain minimum serum IgG levels above 800<span class="elsevierStyleHsp" style=""></span>mg/dL, or the subcutaneous administration of IgG once or twice a week. The subcutaneous preparation has been available in Portugal since 2007.</p><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Descriptive analysis</span>: the results of the quantitative variables are expressed as mean, median, and range, and the results of categorical variables as percentages.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0065" class="elsevierStylePara elsevierViewall">Of the 247 patients with antibody deficiencies followed up in our paediatric infectious diseases and immunodeficiencies unit, 9 (3.6%) were diagnosed with XLA (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> presents their clinical and laboratory data).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">In most cases, the diagnosis stemmed from severe or recurrent infections (8–89%), with a mean age at diagnosis of 3.4 years (range, 1–6 years) and of 13 months at clinical onset (median, 7.5 months; range, 2–35 months). Most patients (63%) had clinical manifestations in the first year of life. Five cases (63%) were diagnosed before 3 years of age. The mean time elapsed from the onset of symptoms to diagnosis was 2.5 years. All of these patients had been hospitalised due to infections.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Respiratory infections were the most common type of infection before diagnosis, with otitis media, complicated by mastoiditis in one case, being the most frequent (88%). Pneumonias also occurred frequently (56%), and they were recurrent in 4 of the patients. Two patients had septic arthritis, and one was admitted to the hospital with ecthyma gangrenosum associated with a <span class="elsevierStyleItalic">Pseudomonas</span> infection. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the infections that occurred before diagnosis.</p><p id="par0080" class="elsevierStylePara elsevierViewall">A patient with a family history of XLA was diagnosed prenatally and treated during the neonatal period before acquiring any infections.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Most patients had very low serum IgG levels at diagnosis, with a mean of 114<span class="elsevierStyleHsp" style=""></span>mg/dL, with 7 patients (78%) having levels below 200<span class="elsevierStyleHsp" style=""></span>mg/dL. The B cell counts ranged from 0% to 1.4%.</p><p id="par0090" class="elsevierStylePara elsevierViewall">One third of the children had neutropaenia associated with infection. The minimum concentrations ranged from 0 to 510<span class="elsevierStyleHsp" style=""></span>cells/mm<span class="elsevierStyleSup">3</span>, and 2 children had neutrophil counts below 500<span class="elsevierStyleHsp" style=""></span>cells/mm<span class="elsevierStyleSup">3</span>. The values normalised in all three during the first week of treatment with antibiotics and IRT. Neutropaenia did not recur in any of them.</p><p id="par0095" class="elsevierStylePara elsevierViewall">A different mutation of the <span class="elsevierStyleItalic">BTK</span> gene was identified in each case except in patients 3 and 4, who were siblings (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><p id="par0100" class="elsevierStylePara elsevierViewall">All patients started IRT through the intravenous route (IVIg) to quickly reach adequate levels of IgG. Once this happened, all patients chose to switch to subcutaneous IgG (SCIg) to self-administer at home.</p><p id="par0105" class="elsevierStylePara elsevierViewall">The mean duration of IRT was 10.7 years, with a cumulative total of 97 years. Eight patients reached adequate minimum levels of IgG; minimum concentrations above 800<span class="elsevierStyleHsp" style=""></span>mg/dL could not be achieved despite high doses of replacement IgG in only one case (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). This last patient developed a nephrotic syndrome at 10 years of age, with severe protein loss through urine.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">We observed mild infectious complications—acute otitis media and conjunctivitis—in most patients after initiating IRT. None of them required admission to the hospital. Two patients developed bronchiectasis (patients 4 and 8).</p><p id="par0115" class="elsevierStylePara elsevierViewall">There were no deaths. All patients have grown normally, and to date none of them have developed autoimmune diseases or cancer.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">The current literature shows that about 50% of patients with XLA have clinical manifestations before one year of age, and that approximately 50% of cases are diagnosed before 2 years of age.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a> The results of our study were similar on both aspects. Consistent with previous studies, the most common clinical presentation was infection (89%). Recurrent bacterial infections and lack of response to oral antibiotics were the main clues that led to the diagnosis of immunodeficiency. Recurrent otitis media was the most frequent infection among our patients before diagnosis, followed by pneumonia, which is consistent with the literature.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">12–14</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Patient 1 had the classical presentation of XLA (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), with recurrent episodes of acute otitis media starting at 2 months of age, 3 episodes of mastoiditis, and one bacterial pneumonia with pleural effusion at 3 years of age, which is when XLA was diagnosed. Patient 2 had an atypical presentation of XLA (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>): he was admitted to the hospital with septicaemia associated with <span class="elsevierStyleItalic">Pseudomonas</span> and ecthyma gangrenosum at 16 months of age. This presentation has been described previously in the literature, and may occur in 10% of cases.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">In our study, the mean age at diagnosis was 3.4 years, with a diagnostic delay of 2.5 years. Since a higher degree of suspicion may shorten the diagnostic delay, we should increase paediatricians’ awareness of this rare condition. Analysing serum Ig levels is cheap and easy. If the diagnosis is made earlier, treatment can be initiated earlier, leading to better outcomes.</p><p id="par0135" class="elsevierStylePara elsevierViewall">One of the children benefited from a prenatal diagnosis that allowed the initiation of IRT before acquiring any infections, illustrating the importance of genetic tests to detect mutations in the <span class="elsevierStyleItalic">BTK</span> gene both for confirming the diagnosis and for detecting carriers and offering prenatal counselling to families.</p><p id="par0140" class="elsevierStylePara elsevierViewall">The published data show that neutropaenia is found in patients with XLA in variable percentages that range between 10% and 25%.<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">15,16</span></a> Neutropaenia was part of the clinical presentation of 11% of the cases in a United States registry before initiation of IRT,<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">3</span></a> and was described in 18% of the cases in a nationwide study in Japan.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">17</span></a> While the role of the <span class="elsevierStyleItalic">BTK</span> gene in neutrophil development has yet to be determined, this gene is associated with high bacterial loads characteristic of active infections that usually respond to treatment with antibiotics and Ig.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">16</span></a> Our data showed neutropaenia in one third of the cases (patients 2, 10 and 12), which was severe in 2. Neutrophil levels normalised after infection resolved and with IRT, and we did not observe any recurrences.</p><p id="par0145" class="elsevierStylePara elsevierViewall">The distinctive feature of patients with XLA is a marked reduction in all classes of Ig and B cell types. In our study, all patients had B cell counts below 2%, and most had extremely low levels (<1%). We also observed low levels of all classes of Igs, with 78% of the patients having IgG levels below 200<span class="elsevierStyleHsp" style=""></span>mg/dL. We would like to highlight the difficulty of diagnosing patient 4 due to his atypical presentation of XLA, with recurrent otitis media and pneumonia but with serum IgG levels at around 720<span class="elsevierStyleHsp" style=""></span>mg/dL. Further investigation revealed the absence of isohaemagglutinins, a poor response to vaccination, and very low B cell counts (0.6%), leading to the diagnosis of XLA, which was later confirmed by the identification of a <span class="elsevierStyleItalic">BTK</span> mutation.</p><p id="par0150" class="elsevierStylePara elsevierViewall">Our data showed that a <span class="elsevierStyleItalic">BTK</span> mutation was found in all of our patients. According to various published studies, a positive family history is only found in 30–50% of XLA patients.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">1</span></a> In our series, 2 patients had a family history of XLA, but all the mothers were carriers. We found the same mutation in 2 cases, patients 3 and 4, who were siblings.</p><p id="par0155" class="elsevierStylePara elsevierViewall">IRT is the cornerstone of treatment of XLA. There are 2 IRT preparations, IVIg and SCIg, both of which are available in Portugal. Data from observational studies show that IRT reduces the rates of infection and hospitalisation in patients with XLA.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">1,18</span></a> In our study, every patient had a favourable outcome with IRT: a low number of infections and no severe infections. All patients switched to SCIg for self-administration at the home to reduce the number of visits to the hospital. Another key feature in the ongoing management of these patients is the intensive antibiotic treatment of any suspected or confirmed infections.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">2</span></a> Patients also benefit from advice on how to prevent exposure to pathogens.</p><p id="par0160" class="elsevierStylePara elsevierViewall">It has been observed that respiratory infections are a considerable clinical problem even when IRT is underway.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">1,4</span></a> Some studies have shown that pneumonia and chronic or acute sinusitis are the most common respiratory tract infections after initiation of IRT,<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">2,3</span></a> infections that were also found in our patients: most of them had mild infectious complications, which were most frequently otitis medias (67%). Our data did not show any severe infections during IRT.</p><p id="par0165" class="elsevierStylePara elsevierViewall">There are known limitations to IRT. Treatment with high-dose IRT cannot be expected to contribute significantly to the prevention of infectious sinusitis, not only because of the scarce availability of IgG at mucosal surfaces, but also because mucosal protection is mostly provided by secretory IgA and IgM antibodies, which are also lacking in XLA.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">13</span></a> The finding of a significantly reduced incidence of severe bacterial infections with residual concentrations of serum IgG above 800<span class="elsevierStyleHsp" style=""></span>mg/dL compared to 500<span class="elsevierStyleHsp" style=""></span>mg/dL suggests that the 500<span class="elsevierStyleHsp" style=""></span>mg/dL threshold is too low.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">10</span></a> Our patients received replacement doses aimed at reaching a threshold of 800<span class="elsevierStyleHsp" style=""></span>mg/dL, and all but one achieved stable high concentrations (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>); one boy that had severe proteinuria (patient 5) was not able to maintain high levels in spite of receiving high-dose IRT.</p><p id="par0170" class="elsevierStylePara elsevierViewall">Several studies show that even if patients with XLA are treated correctly, they may end up developing a chronic respiratory disease,<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a> underscoring the importance of monitoring patients in order to detect any subclinical but progressive lung damage.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">3,4</span></a> This followup is performed by means of pulmonary function tests and chest radiology.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">4</span></a> An Italian study of 73 patients found no association between the development of chronic lung damage and the age at diagnosis or the serum Ig levels.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">13</span></a> Two patients (22%) developed bronchiectases during the follow-up period, 3 and 11 years after initiation of IRT. They had pneumonia at the time of diagnosis, after which computer tomography of the lungs was normal, and received adequate IgG replacement therapy. This poses the problem that adequate serum IgG levels were not enough to prevent this complication, and that there must be other factors at play in the development of bronchiectases, such as low mucosal levels of IgA and IgG.</p><p id="par0175" class="elsevierStylePara elsevierViewall">Recurrent conjunctivitis was an important and hard to manage problem in our patients (44%). Some experts recommend the topical administration of IgG, but its use is not based on evidence and there are no ocular preparations.</p><p id="par0180" class="elsevierStylePara elsevierViewall">The data on the risk of cancer in patients with XLA is contradictory, especially as it pertains to lymphoid malignancies.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">19</span></a> The relationship between XLA and cancer has yet to be determined.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">19</span></a> The data in our study did not include any cancer cases.</p><p id="par0185" class="elsevierStylePara elsevierViewall">The prognosis of XLA has improved considerably in the past 25 years thanks to earlier diagnoses, the use of IRT to raise levels above established thresholds, and early treatment of infections. Good outcomes can be achieved with an early diagnosis and immediate initiation of IRT, as observed in our series. The number of patients included in the study was small, so we could not reach any other conclusions. Gaining a better understanding of the pathophysiology of mucosal damage (ocular, respiratory and gastrointestinal) would be helpful in order to develop better therapeutic strategies and prevent complications.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflicts of interest</span><p id="par0190" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres476152" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec498185" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres476153" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec498184" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Materials and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-07-06" "fechaAceptado" => "2014-08-25" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec498185" "palabras" => array:4 [ 0 => "Agammaglobulinemia" 1 => "Immunoglobulins" 2 => "Infection" 3 => "X linked agammaglobulinemia" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec498184" "palabras" => array:4 [ 0 => "Agammaglobulinemia" 1 => "Inmunoglobulinas" 2 => "Infección" 3 => "Agammaglobulinemia ligada al cromosoma X" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">X-linked agammaglobulinemia (XLA) is characterised by an arrest of B cell differentiation, leading to recurrent bacterial infections. Lifelong immunoglobulin replacement therapy (IRT) is indicated to prevent infections and their complications.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A retrospective study of patients with XLA followed in a level three hospital was performed; data was collected retrospectively by review of clinical files.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">XLA was diagnosed in 9 children. One (11%) had a positive family history with a prenatal diagnosis. Infection was the clinical presentation in all the others (89%), at an average age of 13 months; diagnosis was established at a mean age of 3.4 years. Acute otitis media (7/9) and pneumonia (5/9) were the most frequently observed. Seven (78%) presented serum immunoglobulin G (IgG) levels below 200<span class="elsevierStyleHsp" style=""></span>mg/dL and all of them had CD19<span class="elsevierStyleSup">+</span> B cells below 2%. Neutropenia was present at diagnosis in three patients (33%). Bruton tyrosine kinase (<span class="elsevierStyleItalic">BTK</span>) mutations were identified in all cases. Intravenous IRT was initiated, switched later to subcutaneous administration, in all. The mean time of follow-up was 10.7 years with cumulative time of 97 years. Eight children (89%) achieved IgG serum levels above 800<span class="elsevierStyleHsp" style=""></span>mg/dL. One presented lower values due to renal loss. No deaths occurred. After diagnosis the most frequent infections were acute otitis media (6/9). In spite of stable adequate IgG levels on IRT, two patients developed bronchiectasis.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">XLA overall prognosis is good, as long as patients have an early and adequate treatment. However, bronchiectasis can occur even on adequate immunoglobulin replacement therapy.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La agammaglobulinemia ligada al cromosoma X (ALX) se caracteriza por la detención de la diferenciación celular de los linfocitos B, que da lugar a infecciones bacterianas recurrentes. La terapia de por vida de reemplazo de inmunoglobulina (TRI) está indicada para prevenir infecciones y sus complicaciones.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se hizo un estudio retrospectivo de pacientes con ALX en un hospital terciario. Los datos se revisaron retrospectivamente revisando historias clínicas.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se diagnosticó ALX en 9 niños. Uno de ellos (11%) tenía antecedentes familiares y había sido diagnosticado prenatalmente. El resto presentaron signos de infección (89%) a una edad media de 13 meses, siendo su edad media al diagnóstico de 3,4 años de edad. Las infecciones más frecuentes fueron otitis media aguda (7/9) y neumonía (5/9). Siete niños (78%) presentaron niveles séricos de inmunoglobulina G (IgG) inferiores a 200<span class="elsevierStyleHsp" style=""></span>mg/dL, y todos tenían niveles de células B CD19<span class="elsevierStyleSup">+</span> B por debajo del 2%. Tres pacientes tuvieron neutropenia al diagnóstico (33%). En todos los casos se detectaron mutaciones en la tirosina cinasa de Bruton (<span class="elsevierStyleItalic">BTK</span>). También en todos se inició la TRI por la vía intravenosa, que luego continuó por la vía subcutánea. La duración media del seguimiento fue de 10,7 años, con un número total acumulado de 97 años. Ocho niños (89%) alcanzaron niveles séricos de IgG superiores a los 800<span class="elsevierStyleHsp" style=""></span>mg/dL. En un caso se observaron niveles más bajos por pérdida renal. No hubo ninguna defunción. El tipo de infección más frecuente tras el diagnóstico fue la otitis media aguda (6/9). A pesar de haberse conseguido niveles estables adecuados de IgG mediante la TRI, 2 pacientes desarrollaron bronquiectasias.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">En general, el pronóstico de la ALX es bueno siempre y cuando los pacientes reciban el tratamiento adecuado de manera precoz. Aún así, es posible que a pesar de ser tratados correctamente con TRI desarrollen bronquiectasias.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as: Fernandes A, Guedes M, Vasconcelos J, Neves E, Fernandes S, Marques L. Agammaglobulinemia ligada al cromosoma X: experiencia en un hospital portugués. An Pediatr (Barc). 2015;82:166–171.</p>" ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Previous presentation: This study was presented as an oral communication at the XXXVIII Reunião Anual da Sociedade Portuguesa de Imunologia—Dos distúrbios imunológicos às imunoterapias, November 25–27, 2012, Porto, Portugal.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 467 "Ancho" => 991 "Tamanyo" => 93114 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">IgG levels during followup. Each line represents one patient. The values above the black horizontal line were considered normal. The bold Xs represent the moment at which IVIg was switched to SCIg.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">OM, otitis media.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col">Patient \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Age at onset of symptoms (months) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Age at diagnosis (months) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Infections before diagnosis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Neutropaenia at diagnosis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Serum IgG (mg/dL) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">CD19<span class="elsevierStyleSup">+</span> (% of total lymphocyte count) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col"><span class="elsevierStyleItalic">BTK</span> mutation \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Complications during followup</th><th class="td" title="table-head " align="left" valign="top" scope="col">Duration of IRT (years) \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Infectious \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Non-infectious \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recurrent OM; otitis with mastoiditis; pneumonia with pleural effusion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">p.Arg641His \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acute OM; conjunctivitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recurrent OM; ecthyma gangrenosum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">p.Tyr361X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acute OM; conjunctivitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recurrent OM; septic arthritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">214 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">c.1178-1G>A (intron 13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acute OM; giardiasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recurrent pneumonia; recurrent OM; acute gastroenteritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">720 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">c.1178-1G>A (intron 13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acute OM; giardiasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bronchiectasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Neonatal period<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">p.Arg288Gln \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pneumonia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Membranoproliferative glomerulonephritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recurrent OM; pneumonia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">p.Glu7X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acute OM; conjunctivitis; giardiasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recurrent pneumonia; septic arthritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Exon 6 deletion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Conjunctivitis; sinusitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recurrent OM; pneumonia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Exon 16 deletion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acute OM; conjunctivitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bronchiectasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recurrent OM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">p.Arg255X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab752225.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Had positive family history of XLA; the values of serum IgG and CD19<span class="elsevierStyleSup">+</span> cells are the values at diagnosis.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Clinical presentation and laboratory data.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:19 [ 0 => array:3 [ "identificador" => "bib0100" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Analysis of clinical presentations of Bruton disease: a review of 20 years of accumulated data from pediatric patients at severance hospital" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "J.K. Chun" 1 => "T.J. Lee" 2 => "J.W. Song" 3 => "J.A. Linton" 4 => "D.S. Kim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3349/ymj.2008.49.1.28" "Revista" => array:6 [ "tituloSerie" => "Yonsei Med J" "fecha" => "2008" "volumen" => "49" "paginaInicial" => "28" "paginaFinal" => "36" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18306466" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0105" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Predominantly antibody deficiencies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A. Aghamohammadi" 1 => "V. Lougaris" 2 => "A. Plebani" 3 => "T. Miyawaki" 4 => "A. Durandy" 5 => "L. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 10 | 17 |
| 2024 October | 47 | 33 | 80 |
| 2024 September | 62 | 44 | 106 |
| 2024 August | 59 | 71 | 130 |
| 2024 July | 35 | 37 | 72 |
| 2024 June | 69 | 44 | 113 |
| 2024 May | 58 | 38 | 96 |
| 2024 April | 52 | 43 | 95 |
| 2024 March | 46 | 36 | 82 |
| 2024 February | 34 | 32 | 66 |
| 2024 January | 40 | 20 | 60 |
| 2023 December | 33 | 14 | 47 |
| 2023 November | 32 | 22 | 54 |
| 2023 October | 33 | 20 | 53 |
| 2023 September | 21 | 21 | 42 |
| 2023 August | 27 | 15 | 42 |
| 2023 July | 27 | 31 | 58 |
| 2023 June | 26 | 25 | 51 |
| 2023 May | 60 | 19 | 79 |
| 2023 April | 41 | 14 | 55 |
| 2023 March | 61 | 20 | 81 |
| 2023 February | 50 | 15 | 65 |
| 2023 January | 35 | 28 | 63 |
| 2022 December | 59 | 26 | 85 |
| 2022 November | 68 | 39 | 107 |
| 2022 October | 45 | 34 | 79 |
| 2022 September | 79 | 35 | 114 |
| 2022 August | 74 | 47 | 121 |
| 2022 July | 60 | 66 | 126 |
| 2022 June | 42 | 34 | 76 |
| 2022 May | 48 | 50 | 98 |
| 2022 April | 43 | 38 | 81 |
| 2022 March | 59 | 46 | 105 |
| 2022 February | 70 | 34 | 104 |
| 2022 January | 53 | 37 | 90 |
| 2021 December | 50 | 42 | 92 |
| 2021 November | 63 | 46 | 109 |
| 2021 October | 69 | 61 | 130 |
| 2021 September | 47 | 57 | 104 |
| 2021 August | 70 | 40 | 110 |
| 2021 July | 46 | 33 | 79 |
| 2021 June | 34 | 30 | 64 |
| 2021 May | 42 | 21 | 63 |
| 2021 April | 126 | 63 | 189 |
| 2021 March | 58 | 19 | 77 |
| 2021 February | 59 | 17 | 76 |
| 2021 January | 59 | 18 | 77 |
| 2020 December | 51 | 20 | 71 |
| 2020 November | 67 | 14 | 81 |
| 2020 October | 103 | 36 | 139 |
| 2020 September | 59 | 21 | 80 |
| 2020 August | 86 | 18 | 104 |
| 2020 July | 78 | 20 | 98 |
| 2020 June | 70 | 11 | 81 |
| 2020 May | 73 | 20 | 93 |
| 2020 April | 36 | 9 | 45 |
| 2020 March | 45 | 32 | 77 |
| 2020 February | 34 | 15 | 49 |
| 2020 January | 30 | 10 | 40 |
| 2019 December | 44 | 17 | 61 |
| 2019 November | 29 | 9 | 38 |
| 2019 October | 27 | 12 | 39 |
| 2019 September | 33 | 11 | 44 |
| 2019 August | 27 | 25 | 52 |
| 2019 July | 33 | 29 | 62 |
| 2019 June | 31 | 41 | 72 |
| 2019 May | 55 | 20 | 75 |
| 2019 April | 73 | 36 | 109 |
| 2019 March | 38 | 24 | 62 |
| 2019 February | 40 | 27 | 67 |
| 2019 January | 33 | 21 | 54 |
| 2018 December | 37 | 16 | 53 |
| 2018 November | 56 | 37 | 93 |
| 2018 October | 111 | 18 | 129 |
| 2018 September | 56 | 24 | 80 |
| 2018 June | 4 | 0 | 4 |
| 2018 May | 7 | 0 | 7 |
| 2018 April | 23 | 0 | 23 |
| 2018 March | 24 | 0 | 24 |
| 2018 February | 10 | 0 | 10 |
| 2018 January | 12 | 0 | 12 |
| 2017 December | 25 | 0 | 25 |
| 2017 November | 10 | 0 | 10 |
| 2017 October | 14 | 0 | 14 |
| 2017 September | 10 | 0 | 10 |
| 2017 August | 8 | 0 | 8 |
| 2017 July | 21 | 2 | 23 |
| 2017 June | 26 | 9 | 35 |
| 2017 May | 22 | 11 | 33 |
| 2017 April | 21 | 7 | 28 |
| 2017 March | 15 | 2 | 17 |
| 2017 February | 7 | 5 | 12 |
| 2017 January | 7 | 4 | 11 |
| 2016 December | 42 | 3 | 45 |
| 2016 November | 56 | 8 | 64 |
| 2016 October | 60 | 6 | 66 |
| 2016 September | 47 | 5 | 52 |
| 2016 August | 29 | 2 | 31 |
| 2016 July | 12 | 5 | 17 |
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