Increased sputum levels of thymus and activation-regulated chemokine in children with asthma not eosinophilic bronchitis

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Erdem, H.T. Nacaroglu, S. Karaman, C.B. Erdur, C.U. Karkıner, D. Can" "autores" => array:6 [ 0 => array:2 [ "nombre" => "S.B." "apellidos" => "Erdem" ] 1 => array:2 [ "nombre" => "H.T." "apellidos" => "Nacaroglu" ] 2 => array:2 [ "nombre" => "S." "apellidos" => "Karaman" ] 3 => array:2 [ "nombre" => "C.B." "apellidos" => "Erdur" ] 4 => array:2 [ "nombre" => "C.U." "apellidos" => "Karkıner" ] 5 => array:2 [ "nombre" => "D." "apellidos" => "Can" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054616301586?idApp=UINPBA00004N" "url" => "/03010546/0000004500000003/v1_201704140223/S0301054616301586/v1_201704140223/en/main.assets" ] "en" => array:21 [ "idiomaDefecto" => true "cabecera" => "Original Article" "titulo" => "Increased sputum levels of thymus and activation-regulated chemokine in children with asthma not eosinophilic bronchitis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "220" "paginaFinal" => "226" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "M.J. Kim, H.S. Lee, I.S. Sol, M.N. Kim, J.Y. Hong, K.E. Lee, Y.H. Kim, K.W. Kim, M.H. Sohn, K.-E. Kim" "autores" => array:10 [ 0 => array:3 [ "nombre" => "M.J." "apellidos" => "Kim" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "1" "identificador" => "fn1" ] ] ] 1 => array:3 [ "nombre" => "H.S." "apellidos" => "Lee" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "1" "identificador" => "fn1" ] ] ] 2 => array:2 [ "nombre" => "I.S." "apellidos" => "Sol" ] 3 => array:2 [ "nombre" => "M.N." "apellidos" => "Kim" ] 4 => array:2 [ "nombre" => "J.Y." "apellidos" => "Hong" ] 5 => array:2 [ "nombre" => "K.E." "apellidos" => "Lee" ] 6 => array:2 [ "nombre" => "Y.H." "apellidos" => "Kim" ] 7 => array:2 [ "nombre" => "K.W." "apellidos" => "Kim" ] 8 => array:4 [ "nombre" => "M.H." "apellidos" => "Sohn" "email" => array:1 [ 0 => "mhsohn@yuhs.ac" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 9 => array:2 [ "nombre" => "K.-E." "apellidos" => "Kim" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "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" => 1073 "Ancho" => 1506 "Tamanyo" => 52409 ] ] "descripcion" => array:1 [ "en" => "Sputum TARC levels versus sputum eosinophilia in asthma patients. Asthmatic children with sputum eosinophilia had significantly higher levels of sputum TARC than those without eosinophilia in sputum (p=0.035). Box-and whisker plots represent the 25th and 75th percentiles, with the median line and the error bars representing the 10th and 90th percentiles." ] ] ] "textoCompleto" => "IntroductionAsthma and eosinophilic bronchitis (EB) are considered the most common causes of chronic cough, accounting for ∼25% and 13% of cases, respectively.<a class="elsevierStyleCrossRefs" href="#bib0200">1,2</a> Asthma is a chronic inflammatory disorder of the airways characterised by recurrent episodes of airflow obstruction, airway hyper-responsiveness (AHR), and bronchodilator reversibility (BDR).<a class="elsevierStyleCrossRef" href="#bib0210">3</a> Structural alterations of the airway, namely remodelling, can be frequently observed in patients with asthma, even in children.<a class="elsevierStyleCrossRef" href="#bib0215">4</a> EB is defined as chronic cough in patients with no symptoms of objective airflow obstruction, sputum eosinophilia, and without AHR.<a class="elsevierStyleCrossRef" href="#bib0200">1</a> Sputum eosinophilia defined as greater than 3% of all non-squamous cells is always present in EB. Similar to asthma, EB shows eosinophilic infiltration of the epithelium and submucosa and remodelling features on an endobronchial biopsy.<a class="elsevierStyleCrossRef" href="#bib0220">5</a> Thymus and activation-regulated chemokine (TARC or CCL17) is a CC family chemokine that acts as a ligand of Th2-dominant CC chemokine receptor 4 (CCR4).<a class="elsevierStyleCrossRef" href="#bib0225">6</a> It has been proven that the CCR4-TARC interaction plays a role in allergic inflammation. CCR4/TARC expression can be increased by stimulation of Th2 cytokines, and TARC can induce selective migration of Th2 but not Th1 cells by triggering CCR4.<a class="elsevierStyleCrossRefs" href="#bib0230">7,8</a> Elevated serum TARC levels have been described in atopic dermatitis and are suggested as a useful clinical biomarker for assessing severity, disease activity, and response to treatment in patients with atopic dermatitis.<a class="elsevierStyleCrossRefs" href="#bib0240">9–11</a> TARC has also been studied in asthma, eosinophilic pneumonia, and allergic bronchopulmonary aspergillosis.<a class="elsevierStyleCrossRefs" href="#bib0255">12,13</a>In the present study, we hypothesised that TARC expression in induced (see Methods) sputum is elevated in patients with asthma or EB compared to control subjects. We also analysed the possible correlation of sputum TARC concentration with eosinophilic inflammation, pulmonary function, and AHR in children.Materials and methodsSubjectsA total of 173 children were enrolled in this study; 90 had a diagnosis of asthma in accordance with American Thoracic Society criteria.<a class="elsevierStyleCrossRef" href="#bib0265">14</a> Thirty-eight children had a diagnosis of EB based on the following criteria: chronic cough lasting more than four weeks without any clinical symptoms related to reversible airway obstruction, such as recurrent wheezing or dyspnoea; no reversible airway obstruction that could be demonstrated by a negative response to a short-acting bronchodilator (change in forced expiratory volume in 1s [FEV1]<12%); the absence of bronchial hyper-reactivity in a methacholine challenge test (PC20; the provocative concentration of methacholine causing a 20% decrease in the FEV1>16mg/mL); sputum eosinophilia>3%; and no lung parenchymal aberrations seen on a simple chest radiograph.<a class="elsevierStyleCrossRefs" href="#bib0270">15,16</a> Children treated with systemic corticosteroids due to asthma exacerbation in the preceding month were excluded from the study. The control group consisted of 45 children who had visited the hospital for a general health workup or vaccination and had no history of wheezing, recurrent or chronic diseases, or infection in the preceding two weeks, or hyper-responsiveness to methacholine. Total serum immunoglobulin E (IgE) levels and peripheral blood eosinophil counts were determined at the initiation of the analyses. A specific IgE test was performed with six allergens common in Korea: Dermatophagoides pteronyssinus, Dermatophagoides farina, egg white, cow milk, German cockroach, and Alternaria alternata. Atopy was defined as above 0.7 KUa/L specific IgE to more than one allergen, or 150IU/mL total IgE. Atopy was also defined as more than one positive skin test result among 12 common aeroallergens, including two types of house dust mites, cat and dog epithelium, and mould and pollen allergens.<a class="elsevierStyleCrossRefs" href="#bib0280">17,18</a> A saline solution was used as a negative control, and a 0.5% histamine HCl solution was used as a positive control. The wheal diameter was measured after 15min, and a positive reaction was defined as a wheal diameter >3mm.<a class="elsevierStyleCrossRef" href="#bib0290">19</a> This study was approved by the Institutional Review Board of Severance Hospital (Seoul, Korea; protocol No. 4-2004-0036). Informed written consent for participation was obtained from parents, with verbal assent from children.Sputum induction and processingThese procedures were performed as previously described by Yoshikawa et al.<a class="elsevierStyleCrossRef" href="#bib0295">20</a> All children were instructed to wash their mouths thoroughly with water. They then inhaled a 3% saline solution nebulised in an ultrasonic nebuliser (NE-U12; Omron Co., Tokyo, Japan) at maximum output at room temperature. The children were encouraged to cough deeply at 3-min intervals thereafter. After sputum induction, spirometry was repeated. If FEV1 fell, the child was required to wait until FEV1 returned to baseline values. Sputum samples were kept at 4°C for no longer than 2h before further processing. A portion of the samples was diluted with a phosphate-buffered saline solution containing 10mmol/L of dithiothreitol (WAKO Pure Chemical Industries, Ltd., Osaka, Japan) for cell counting and was gently vortexed at room temperature for 20min. After centrifugation at 400×g for 10min, the cell pellet was resuspended. We performed a sputum viability assay with the trypan blue exclusion method to ensure adequate viability. Total cell counts were obtained with a haemocytometer, and slides were prepared with cytospin (Cytospin3; Shandon, Tokyo, Japan) and stained with the May–Grunwald–Giemsa stain) for differential cell counts. The latter were performed by two observers who were blinded to the clinical details and who counted 400 non-squamous cells.Quantification of blood eosinophils, serum total IgE, and sputum TARCEosinophils were counted automatically (NE-8000 system; Sysmex; Kobe, Japan) in peripheral blood, and the serum total IgE levels were measured (CAP system; Pharmacia-Upjohn; Uppsala, Sweden). Concentration of TARC in induced sputum was individually detected with enzyme-linked immunosorbent assay kits (R&D Systems; Minneapolis, MN, USA). The lower detection limit of the assay was 7.81pg/mL.Spirometry and the methacholine challenge testSpirometry (VIASYS Healthcare, Inc., Conshohocken, PA, USA) was performed, and the flow-volume curves were constructed according to American Thoracic Society guidelines before and after bronchodilator (BD) inhalation.<a class="elsevierStyleCrossRef" href="#bib0300">21</a> A methacholine challenge test was performed according to standardised procedures.<a class="elsevierStyleCrossRef" href="#bib0305">22</a> Each child inhaled increasing concentrations of methacholine (0.075, 0.15, 0.31, 0.62, 1.25, 2.5, 5, 10, 25, and 50mg/mL) nebulised by a dosimeter (MB3; Mefar, Brescia, Italy) until the FEV1 decreased by 20% from a post-nebulised-saline solution value. The bronchial response was expressed as a provocative concentration of methacholine causing a 20% fall in the FEV1 (PC20; measured in milligrams per millilitre) and was calculated by linear interpolation of the log dose response curve.FeNO measurementFractional exhaled nitric oxide (FeNO) was measured as previously described<a class="elsevierStyleCrossRefs" href="#bib0285">18,23</a> using CLD 88 (Eco Medics, Duernten, Switzerland: measurement at a constant 50mL/s expiratory flow rate). Measurements were performed according to the ATS/ERS guidelines.<a class="elsevierStyleCrossRef" href="#bib0315">24</a> All children refrained from eating nitrate-rich foods for 24h before FeNO measurement because ingestion of nitrate-rich foods can affect the levels of FeNO.<a class="elsevierStyleCrossRef" href="#bib0320">25</a> The mean value for each of the three measurements was calculated.Statistical analysisNumerical variables were expressed as mean±SD. The normality of a distribution was determined by the Kolmogorov–Smirnov test. Numerical parameters with a non-normal distribution were presented as median and inter-quartile range (IQR). Comparisons among children with asthma and EB and control subjects were evaluated by the Kruskal–Wallis test. Statistical comparison of values between groups was done by the Mann–Whitney test. The correlation between sputum TARC concentrations and numerical parameters was determined using the Spearman rank correlation test. All comparisons were two-sided. Data with a p value <0.05 were considered statistically significant. Statistical software (SPSS, version 20.0; SPSS Inc.; Chicago, IL, USA) was used for all the analyses.ResultsSubjects’ characteristicsThe clinical characteristics of the study subjects are summarised in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. There were no significant differences in age and gender among the three groups. The percentage of children with atopy was significantly higher in the asthma group than in the control group (p<0.01). There were no differences in atopy between patients with asthma and EB, or between EB and the control group. Pulmonary function variables, including FEV1 (p<0.01), FEV1/FVC (the ratio of forced expiratory volume in 1 second and forced expiratory vital capacity) (p<0.01), forced expiratory flow between 25% and 75% (mid-expiratory phase, FEF25–75) (p<0.001), and PC20 (p<0.001) showed significantly lower values in children with asthma than in those with EB and in control subjects. The percentage change in FEV1 post-BD therapy was significantly higher in asthmatic children (p<0.001). Increased FeNO levels were observed in patients with asthma but there were no statistically significant differences among the groups.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>In serum, the levels of total IgE (p<0.01) and blood eosinophils (p<0.05) were increased in children with asthma compared to control subjects. The percentage of eosinophils in induced sputum was significantly higher in children with asthma or EB than in control subjects (p<0.001 and p<0.05, respectively).Measurement of TARC levels in sputumAs shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, sputum TARC concentrations were significantly greater in children with asthma (median 9.34pg/mL; IQR 3.81–24.81pg/mL) than in those with EB (median 4.03pg/mL; IQR 1.04–10.30pg/mL; p=0.004) or control subjects (median 4.37pg/mL; IQR 1.06–10.93pg/mL; p=0.014). No significant differences were found between children with EB and control subjects. Sputum TARC levels did not show any differences between children with atopy and without atopy among all groups (data not shown).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The relation between sputum TARC and eosinophilic airway inflammationIn subjects with asthma, sputum TARC concentrations were significantly higher in children with sputum eosinophilia (median 13.51pg/mL; IQR 5.59–30.40pg/mL) compared to those without sputum eosinophilia (median 7.21pg/mL; IQR 1.91–16.29pg/mL; p=0.035; <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Furthermore, sputum TARC concentrations positively correlated with sputum eosinophils (r=0.210, p=0.047), blood eosinophils (r=0.279, p=0.012), and serum total IgE (r=0.224, p=0.041). Another biomarker of eosinophilic inflammation, FeNO, also showed a positive correlation with sputum TARC levels (r=0.265, p=0.028; <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Significant positive correlations were also observed between sputum TARC levels and sputum eosinophils (r=0.414, p<0.001), blood eosinophils (r=0.205, p=0.009), serum total IgE (r=0.205, p=0.009), and FeNO (r=0.459, p<0.001) in all children under study (Supplement 1).Correlation of sputum TARC with pulmonary function and AHRRegarding the pulmonary function parameters, sputum TARC levels in children with asthma showed a significant inverse correlation with FEV1/FVC (r=−0.326, p=0.002; <a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>A) and FEF25–75 (r=−0.260, p=0.014; <a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>B). In addition, a positive correlation was detected between sputum TARC and the percentage change in FEV1 post-BD therapy (r=0.311, p=0.038; <a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>C). There was no relation between sputum TARC levels and FEV1 (data not shown). In the methacholine challenge test, another significant negative correlation was observed: between sputum TARC levels and PC20 (r=−0.454, p<0.001; <a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>D). These associations between sputum TARC concentrations and lung function measurements were also observed in all subjects (Supplement 2).<elsevierMultimedia ident="fig0020"></elsevierMultimedia>DiscussionSince the interaction of CCR4 with TARC was found to serve as a chemoattractant for Th2 cells, TARC has been studied as a clinical biomarker in allergic diseases.<a class="elsevierStyleCrossRefs" href="#bib0325">26,27</a> In addition to its well-known role in atopic dermatitis, the relation between TARC and asthma has also been studied. It was demonstrated that TARC is intimately involved in the development of AHR and eosinophilia through the recruitment of Th2 lymphocytes, and a specific antibody against TARC attenuates airway eosinophilia.<a class="elsevierStyleCrossRef" href="#bib0335">28</a> Increased levels of TARC in serum and sputum are observed in adult patients with asthma.<a class="elsevierStyleCrossRef" href="#bib0340">29</a> Plasma TARC concentration is also elevated in children with asthma<a class="elsevierStyleCrossRef" href="#bib0235">8</a> and with asthma exacerbation<a class="elsevierStyleCrossRef" href="#bib0345">30</a>; therefore, TARC was suggested as a useful marker of childhood asthma. Furthermore, it was reported that expression of CCR4+CD4+cells and levels of TARC in bronchoalveolar lavage (BAL) fluid are significantly increased in children with asthma.<a class="elsevierStyleCrossRef" href="#bib0350">31</a>Asthma and EB have shown similar immunopathological features such as submucosal eosinophilic inflammation, thickening of the basement membrane, and increased levels of exhaled nitric oxide. Nonetheless, EB differs from asthma in that there is no variable airflow obstruction or AHR<a class="elsevierStyleCrossRef" href="#bib0270">15</a> and mast cell infiltration in airway's smooth muscle is smaller than in asthma.<a class="elsevierStyleCrossRef" href="#bib0355">32</a> In the present study, we tested whether sputum TARC levels are elevated in children with asthma or EB. In comparison with the children with EB or control subjects, children with asthma showed significantly higher levels of TARC in induced sputum, but no significant differences were found between children with EB and control subjects. And TARC levels in sputum were found to be associated with sputum eosinophilia and positively correlated with FeNO, reflecting eosinophilic airway inflammation.<a class="elsevierStyleCrossRef" href="#bib0360">33</a>In addition, sputum TARC levels showed significant negative correlations with the FEV1/FVC ratio, FEF25–75, and PC20 and a positive correlation with BDR in the present study. Increased sputum TARC levels in children with asthma may indicate poor lung function, with decreased values of the FEV1/FVC ratio indicating an airflow limitation.<a class="elsevierStyleCrossRef" href="#bib0365">34</a> Increased concentration of TARC with decreased FEF25–75<a class="elsevierStyleCrossRefs" href="#bib0370">35,36</a> and persistent BDR<a class="elsevierStyleCrossRef" href="#bib0360">33</a> may also predict poor asthma control such as persistent asthma symptoms, emergency room visits, or a more frequent need for oral steroids. These findings indicate that sputum TARC may play a role in asthmatic airways including airflow limitation, airway reversibility, and hyperresponsiveness in children.According to other studies involving BAL, sputum induction is a relatively safer and more convenient procedure. Because BAL analysis is an invasive procedure, especially in children, we suggest sputum induction as an alternative method for quantification of TARC. In addition, asthmatic children treated with an inhaled corticosteroid show higher plasma TARC levels than those without treatment.<a class="elsevierStyleCrossRef" href="#bib0235">8</a> In our study, patients who were treated with an inhaled corticosteroid were excluded.The mechanism of different TARC levels between asthma and EB patients is not unclear. But Th2 cytokines (IL-4 and IL-13) expression were found to be co-localized to mast cells within the allergic airway smooth muscle<a class="elsevierStyleCrossRef" href="#bib0380">37</a> and to promote TARC release in airway smooth muscle cells.<a class="elsevierStyleCrossRef" href="#bib0385">38</a> In addition, increased CCR 4-expressing mast cells in allergic asthma were observed in bronchial biopsy.<a class="elsevierStyleCrossRef" href="#bib0390">39</a> Therefore, the differences in sputum TARC levels between asthma and EB patients might come from TARC expression on mast cells in the airway smooth muscle. An interaction between CCR4 on mast cells and TARC could contribute to allergic airway inflammation and remodelling.In summary, we showed that sputum TARC is increased in childhood asthma and associated with the functioning of asthmatic airways and eosinophilic inflammation in children. Our findings suggest that sputum TARC may be a supportive marker reflecting airway eosinophilic inflammation in childhood asthma. Furthermore, these findings also suggest that sputum TARC may differentiate asthma from EB in children.Ethical disclosuresConfidentiality of dataThe authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study.Right to privacy and informed consentThe authors have obtained the informed consent of the patients and/or subjects mentioned in the article. The author for correspondence is in possession of this document.Protection of human subjects and animals in researchThe authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration.Conflict of interestThere are no financial or other issues that might lead to a conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres827748" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec824062" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Subjects" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Sputum induction and processing" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Quantification of blood eosinophils, serum total IgE, and sputum TARC" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Spirometry and the methacholine challenge test" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "FeNO measurement" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Statistical analysis" ] ] ] 4 => array:3 [ "identificador" => "sec0045" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Subjects’ characteristics" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Measurement of TARC levels in sputum" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "The relation between sputum TARC and eosinophilic airway inflammation" ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "Correlation of sputum TARC with pulmonary function and AHR" ] ] ] 5 => array:2 [ "identificador" => "sec0070" "titulo" => "Discussion" ] 6 => array:3 [ "identificador" => "sec0075" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0080" "titulo" => "Confidentiality of data" ] 1 => array:2 [ "identificador" => "sec0085" "titulo" => "Right to privacy and informed consent" ] 2 => array:2 [ "identificador" => "sec0090" "titulo" => "Protection of human subjects and animals in research" ] ] ] 7 => array:2 [ "identificador" => "sec0095" "titulo" => "Conflict of interest" ] 8 => array:2 [ "identificador" => "xack277728" "titulo" => "Acknowledgements" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-06-16" "fechaAceptado" => "2016-12-03" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec824062" "palabras" => array:7 [ 0 => "Asthma" 1 => "Biomarkers" 2 => "Bronchitis" 3 => "Chemokine" 4 => "Child" 5 => "Sputum" 6 => "Thymus and activation-regulated chemokine" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundThymus and activation-regulated chemokine (TARC), a member of the CC chemokine family, plays a crucial role in Th2-specific inflammation. We aimed to determine the concentration of sputum TARC in children with asthma and eosinophilic bronchitis (EB) and its relation with eosinophilic inflammation, pulmonary function, and bronchial hyper-responsiveness. MethodsIn total, 90 children with asthma, 38 with EB, and 45 control subjects were enrolled. TARC levels were measured in sputum supernatants using an ELISA. We performed pulmonary function tests and measured exhaled fractional nitric oxide, eosinophil counts in blood, and sputum and serum levels of total IgE in all children. ResultsSputum TARC levels were significantly higher in children with asthma than in either children with EB (p=0.004) or the control subjects (p=0.014). Among patients with asthma, sputum TARC concentration was higher in children with sputum eosinophilia than in those without sputum eosinophilia (p=0.035). Sputum TARC levels positively correlated with eosinophil counts in sputum, serum total IgE levels, exhaled fractional nitric, and the bronchodilator response. Negative significant correlations were found between sputum TARC and FEV1/FVC (the ratio of forced expiratory volume in one second and forced expiratory vital capacity) or PC20 (the provocative concentration of methacholine causing a 20% decrease in the FEV1). ConclusionElevated TARC levels in sputum were detected in children with asthma but not in children with EB. Sputum TARC could be a supportive marker for discrimination of asthma from EB in children showing characteristics of eosinophilic airway inflammation." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "This study was approved by the Institutional Review Board of Severance Hospital (Seoul, Korea) (protocol No. 4-2004-0036)." ] 1 => array:3 [ "etiqueta" => "1" "nota" => "These authors contributed equally to this work." "identificador" => "fn1" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "The following are the supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0110" ] ] ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1044 "Ancho" => 1493 "Tamanyo" => 51063 ] ] "descripcion" => array:1 [ "en" => "Comparison of sputum TARC levels among the asthma, EB, and control groups. Sputum TARC levels were significantly higher in children with asthma than either children with EB (p=0.004) or control subjects (p=0.014). No significant differences were found between children with EB and control subjects. Box-and whisker plots represent the 25th and 75th percentiles, with the median line and the error bars representing the 10th and 90th percentiles." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1073 "Ancho" => 1506 "Tamanyo" => 52409 ] ] "descripcion" => array:1 [ "en" => "Sputum TARC levels versus sputum eosinophilia in asthma patients. Asthmatic children with sputum eosinophilia had significantly higher levels of sputum TARC than those without eosinophilia in sputum (p=0.035). Box-and whisker plots represent the 25th and 75th percentiles, with the median line and the error bars representing the 10th and 90th percentiles." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1118 "Ancho" => 1488 "Tamanyo" => 75664 ] ] "descripcion" => array:1 [ "en" => "Correlation of sputum TARC with FeNO in the asthma group. A positive correlation of FeNO with sputum TARC levels (r=0.265, p=0.028) was detected in asthma patients." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1795 "Ancho" => 2357 "Tamanyo" => 250355 ] ] "descripcion" => array:1 [ "en" => "Correlation of sputum TARC with airflow obstruction, bronchial hyperresponsiveness, and bronchodilator reversibility in asthma patients. Negative significant correlations were found between sputum TARC and (A) FEV1/FVC (r=−0.326, p=0.002), (B) FEF25–75 (r=−0.260, p=0.014), and (D) PC20 (r=−0.454, p<0.001). (C) Sputum TARC levels positively correlated with bronchodilator response (r=0.311, p=0.038)." ] ] 4 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "EB, eosinophilic bronchitis; FVC, forced expiratory vital capacity; FEV1, forced expiratory volume in 1 second; FEF25–75, forced expiratory flow between 25% and 75% of forced vital capacity; PC20; a provocative concentration of methacholine causing a 20% fall in the FEV1; FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E. Values are expressed as a number (percentage), mean±SD, or median (interquartile range)." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics \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">Asthma (n=90) \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">EB (n=38) \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">Control (n=45) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age, years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8.86±3.32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.21±2.02 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.78±2.70 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sex, M (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">64 (71.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26 (68.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28 (62.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Atopy (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">78 (86.7)<a class="elsevierStyleCrossRef" href="#tblfn0010">**</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 (78.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28 (62.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEV1, % predicted \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">96.0 (82.8–107.0)<a class="elsevierStyleCrossRef" href="#tblfn0020">†</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">106.0 (96.8–114.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">106.0(94.5–115.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEV1/FVC, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">86.8 (82.2–91.5)<a class="elsevierStyleCrossRef" href="#tblfn0020">†</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">91.2 (86.3–95.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">90.8 (87.4–95.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FEF25-75, % predicted \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">76.0 (58.3–95.8)<a class="elsevierStyleCrossRef" href="#tblfn0025">‡</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">98.0 (82.0–104.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">105.0 (86.5–118.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Change in FEV1, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.14±8.37<a class="elsevierStyleCrossRef" href="#tblfn0025">‡</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.31±4.69 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.20±3.61 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PC20, mg/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8.82±12.2<a class="elsevierStyleCrossRef" href="#tblfn0025">‡</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">49.8±1.10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48.7±4.30 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FeNO, ppb \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">42.2±26.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">29.8±20.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">32.1±23.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total IgE, log IU/mL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.51±0.48<a class="elsevierStyleCrossRef" href="#tblfn0010">**</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.33±0.41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.15±0.59 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Blood eosinophils, log/μL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.50±0.44<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.51±0.34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.30±0.40 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sputum eosinophils, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12.62±1.90<a class="elsevierStyleCrossRef" href="#tblfn0015">***</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.17±1.65<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.40±0.10 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1392722.png" ] ] ] "notaPie" => array:5 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "p<0.05." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "**" "nota" => "p<0.01." ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "***" "nota" => "p<0.001 compared to control subjects." ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "†" "nota" => "p<0.01." ] 4 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "‡" "nota" => "p<0.001 compared to children with EB and control subjects." ] ] ] "descripcion" => array:1 [ "en" => "Characteristics of the subjects." ] ] 5 => array:5 [ "identificador" => "upi0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "Ecomponente" => array:2 [ "fichero" => "mmc1.docx" "ficheroTamanyo" => 185501 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:39 [ 0 => array:3 [ "identificador" => "bib0200" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cough due to asthma and nonasthmatic eosinophilic bronchitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "C.E. Brightling" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00408-009-9163-5" "Revista" => array:7 [ "tituloSerie" => "Lung" "fecha" => "2010" "volumen" => "188" "numero" => "Suppl 1" "paginaInicial" => "S13" "paginaFinal" => "S17" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19669108" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0205" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Eosinophilic airway disorders" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K.A. Scott" 1 => "A.J. Wardlaw" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-2006-939515" "Revista" => array:6 [ "tituloSerie" => "Semin Respir Crit Care Med" "fecha" => "2006" "volumen" => "27" "paginaInicial" => "128" "paginaFinal" => "133" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16612763" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0210" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "F.D. Martinez" 1 => "D. Vercelli" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "The Lancet" "fecha" => "2013" "volumen" => "382" "paginaInicial" => "1360" "paginaFinal" => "1372" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0215" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Basement membrane thickening and clinical features of children with asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.S. Kim" 1 => "S.H. Kim" 2 => "K.W. Kim" 3 => "J.W. Park" 4 => "Y.S. Kim" 5 => "M.H. Sohn" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1398-9995.2007.01375.x" "Revista" => array:6 [ "tituloSerie" => "Allergy" "fecha" => "2007" "volumen" => "62" "paginaInicial" => "635" "paginaFinal" => "640" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17508967" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0220" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Eosinophilic airway disorders associated with chronic cough" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A. Niimi" 1 => "H. Matsumoto" 2 => "M. Mishima" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.pupt.2008.12.001" "Revista" => array:6 [ "tituloSerie" => "Pulm Pharmacol Ther" "fecha" => "2009" "volumen" => "22" "paginaInicial" => "114" "paginaFinal" => "120" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19121405" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0225" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Panina-Bordignon" 1 => "A. Papi" 2 => "M. Mariani" 3 => "P. Di Lucia" 4 => "G. Casoni" 5 => "C. Bellettato" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI12655" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest." "fecha" => "2001" "volumen" => "107" "paginaInicial" => "1357" "paginaFinal" => "1364" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11390417" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0230" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "F. Perros" 1 => "H.C. Hoogsteden" 2 => "A.J. Coyle" 3 => "B.N. Lambrecht" 4 => "H. Hammad" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1398-9995.2009.02095.x" "Revista" => array:6 [ "tituloSerie" => "Allergy" "fecha" => "2009" "volumen" => "64" "paginaInicial" => "995" "paginaFinal" => "1002" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19630858" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0235" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Plasma concentration of thymus and activation-regulated chemokine is elevated in childhood asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Leung T-f" 1 => "Wong C-k" 2 => "I.H.S. Chan" 3 => "Ip W-k" 4 => "C.W.K. Lam" 5 => "G.W.K. Wong" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2002" "volumen" => "110" "paginaInicial" => "404" "paginaFinal" => "409" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12209086" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0240" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thymus and activation-regulated chemokine as a clinical biomarker in atopic dermatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Y. Kataoka" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/1346-8138.12440" "Revista" => array:6 [ "tituloSerie" => "J Dermatol" "fecha" => "2014" "volumen" => "41" "paginaInicial" => "221" "paginaFinal" => "229" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24628072" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0245" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Utility of serum thymus and activation-regulated chemokine as a biomarker for monitoring of atopic dermatitis severity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J. Landheer" 1 => "M. de Bruin-Weller" 2 => "C. Boonacker" 3 => "D. Hijnen" 4 => "C. Bruijnzeel-Koomen" 5 => "H. Rockmann" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2014.07.031" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2014" "volumen" => "71" "paginaInicial" => "1160" "paginaFinal" => "1166" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25199679" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0250" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Increased serum thymus and activation-regulated chemokine and cutaneous T cell-attracting chemokine levels in children with atopic dermatitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "T.W. Song" 1 => "M.H. Sohn" 2 => "E.S. Kim" 3 => "K.W. Kim" 4 => "K.E. Kim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2222.2006.02430.x" "Revista" => array:6 [ "tituloSerie" => "Clin Exp Allergy" "fecha" => "2006" "volumen" => "36" "paginaInicial" => "346" "paginaFinal" => "351" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16499646" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0255" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Novel biomarkers in asthma: chemokines and chitinase-like proteins" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "D. Hartl" 1 => "C.G. Lee" 2 => "C.A. Da Silva" 3 => "G.L. Chupp" 4 => "J.A. Elias" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/ACI.0b013e32831f8ee0" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Allergy Clin Immunol" "fecha" => "2009" "volumen" => "9" "paginaInicial" => "60" "paginaFinal" => "66" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19532094" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0260" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CCR4 and its ligands: from bench to bedside" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "O. Yoshie" 1 => "K. Matsushima" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/intimm/dxu079" "Revista" => array:6 [ "tituloSerie" => "Int Immunol" "fecha" => "2015" "volumen" => "27" "paginaInicial" => "11" "paginaFinal" => "20" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25087232" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0265" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma–Summary Report 2007" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P. NAEaP" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaci.2007.09.043" "Revista" => array:6 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2007" "volumen" => "120" "paginaInicial" => "S94" "paginaFinal" => "S138" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17983880" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0270" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Eosinophilic bronchitis without asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "U. Gonlugur" 1 => "T.E. Gonlugur" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000128580" "Revista" => array:6 [ "tituloSerie" => "Int Arch Allergy Immunol" "fecha" => "2008" "volumen" => "147" "paginaInicial" => "1" "paginaFinal" => "5" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18446047" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0275" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Differences in radiological/HRCT findings in eosinophilic bronchitis and asthma: implication for bronchial responsiveness" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.W. Park" 1 => "J.S. Park" 2 => "Y.M. Lee" 3 => "J.H. Lee" 4 => "A.S. Jang" 5 => "D.J. Kim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/thx.2005.044420" "Revista" => array:6 [ "tituloSerie" => "Thorax" "fecha" => "2006" "volumen" => "61" "paginaInicial" => "41" "paginaFinal" => "47" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16244090" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0280" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Relationship between amphiregulin and airway inflammation in children with asthma and eosinophilic bronchitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "K.W. Kim" 1 => "H.M. Jee" 2 => "Y.H. Park" 3 => "B.S. Choi" 4 => "M.H. Sohn" 5 => "K.E. Kim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1378/chest.08-2972" "Revista" => array:6 [ "tituloSerie" => "Chest" "fecha" => "2009" "volumen" => "136" "paginaInicial" => "805" "paginaFinal" => "810" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19447920" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0285" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Usefulness of impulse oscillometry and fractional exhaled nitric oxide in children with Eosinophilic bronchitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y.H. Kim" 1 => "K.W. Kim" 2 => "J. Baek" 3 => "H.B. Park" 4 => "H. Kim" 5 => "K.J. Song" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ppul.22631" "Revista" => array:6 [ "tituloSerie" => "Pediatr Pulmonol" "fecha" => "2013" "volumen" => "48" "paginaInicial" => "221" "paginaFinal" => "228" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22825832" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0290" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The relationship of respiratory allergy, skin test reactivity, and serum IgE in a community population sample" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "W.G. Brown" 1 => "M.J. Halonen" 2 => "W.T. Kaltenborn" 3 => "R.A. Barbee" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "1979" "volumen" => "63" "paginaInicial" => "328" "paginaFinal" => "335" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/429712" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0295" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severity of exercise-induced bronchoconstriction is related to airway eosinophilic inflammation in patients with asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. Yoshikawa" 1 => "S. Shoji" 2 => "T. Fujii" 3 => "H. Kanazawa" 4 => "S. Kudoh" 5 => "K. Hirata" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Eur Respir J" "fecha" => "1998" "volumen" => "12" "paginaInicial" => "879" "paginaFinal" => "884" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9817162" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0300" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Standardisation of spirometry" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.R. Miller" 1 => "J. Hankinson" 2 => "V. Brusasco" 3 => "F. Burgos" 4 => "R. Casaburi" 5 => "A. Coates" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/09031936.05.00034805" "Revista" => array:6 [ "tituloSerie" => "Eur Respir J" "fecha" => "2005" "volumen" => "26" "paginaInicial" => "319" "paginaFinal" => "338" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16055882" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0305" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Guidelines for Methacholine and Exercise Challenge Testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Crapo" 1 => "R. Casaburi" 2 => "A. Coates" 3 => "P. Enright" 4 => "J. Hankinson" 5 => "C. Irvin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/ajrccm.161.1.ats11-99" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med" "fecha" => "2000" "volumen" => "161" "paginaInicial" => "309" "paginaFinal" => "329" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10619836" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0310" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fractional exhaled nitric oxide and impulse oscillometry in children with allergic rhinitis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y.H. Kim" 1 => "H.B. Park" 2 => "M.J. Kim" 3 => "H.S. Kim" 4 => "H.S. Lee" 5 => "Y.K. Han" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.4168/aair.2014.6.1.27" "Revista" => array:6 [ "tituloSerie" => "Allergy Asthma Immunol Res" "fecha" => "2014" "volumen" => "6" "paginaInicial" => "27" "paginaFinal" => "32" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24404390" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0315" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "American Thoracic Society" 1 => "European Respiratory Society" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/rccm.200406-710ST" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med" "fecha" => "2005" "volumen" => "171" "paginaInicial" => "912" "paginaFinal" => "930" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15817806" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0320" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Time-dependent effect of nitrate-rich meals on exhaled nitric oxide in healthy subjects" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A.M. Vints" 1 => "E. Oostveen" 2 => "G. Eeckhaut" 3 => "M. Smolders" 4 => "W.A. De Backer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1378/chest.128.4.2465" "Revista" => array:6 [ "tituloSerie" => "Chest" "fecha" => "2005" "volumen" => "128" "paginaInicial" => "2465" "paginaFinal" => "2470" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16236910" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0325" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "TARC in allergic disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "N.YT Sugawara" 1 => "Y. Ote" 2 => "M. Miura" 3 => "N. Terada" 4 => "M. Kurosawa" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Allergy" "fecha" => "2002" "volumen" => "57" "paginaInicial" => "180" "paginaFinal" => "181" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11929428" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0330" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "TARC: novel mediator of allergic inflammation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "G.T.L. Sandoval-López" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Exp Allergy" "fecha" => "2001" "volumen" => "31" "paginaInicial" => "1809" "paginaFinal" => "1812" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11737030" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0335" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Intervention of thymus and activation-regulated chemokine attenuates the development of allergic airway inflammation and hyperresponsiveness in mice" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Kawasaki" 1 => "H. Takizawa" 2 => "H. Yoneyama" 3 => "T. Nakayama" 4 => "R. Fujisawa" 5 => "M. Izumizaki" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Immunol" "fecha" => "2001" "volumen" => "166" "paginaInicial" => "2055" "paginaFinal" => "2062" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11160256" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0340" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Increased levels of a TH2-type CC chemokine thymus and activation-regulated chemokine (TARC) in serum and induced sputum of asthmatics" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. Sekiya" 1 => "H. Yamada" 2 => "M. Yamaguchi" 3 => "K. Yamamoto" 4 => "A. Ishii" 5 => "O. Yoshie" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Allergy" "fecha" => "2002" "volumen" => "57" "paginaInicial" => "173" "paginaFinal" => "177" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11929424" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0345" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Plasma TARC concentration may be a useful marker for asthmatic exacerbation in children" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.F. Leung" 1 => "C.K. Wong" 2 => "C.W.K. Lam" 3 => "A.M. Li" 4 => "W.K. Ip" 5 => "G.W.K. 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Gormand" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaci.2015.10.029" "Revista" => array:3 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2015" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24139497" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0380" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interleukin-4 and -13 expression is co-localized to mast cells within the airway smooth muscle in asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "C.E. Brightling" 1 => "F.A. Symon" 2 => "S.T. Holgate" 3 => "A.J. Wardlaw" 4 => "I.D. Pavord" 5 => "P. Bradding" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Exp Allergy" "fecha" => "2003" "volumen" => "33" "paginaInicial" => "1711" "paginaFinal" => "1716" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14656359" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0385" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "IL-13 and IL-4 promote TARC release in human airway smooth muscle cells: role of IL-4 receptor genotype" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.S. Faffe" 1 => "T. Whitehead" 2 => "P.E. Moore" 3 => "S. Baraldo" 4 => "L. Flynt" 5 => "K. 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Original Article

M.J. Kim1, H.S. Lee1, I.S. Sol, M.N. Kim, J.Y. Hong, K.E. Lee, Y.H. Kim, K.W. Kim, M.H. Sohn

Corresponding author

mhsohn@yuhs.ac

Corresponding author.

, K.-E. Kim

Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Asthma and eosinophilic bronchitis &#40;EB&#41; are considered the most common causes of chronic cough&#44; accounting for &#8764;25&#37; and 13&#37; of cases&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">1&#44;2</span></a> Asthma is a chronic inflammatory disorder of the airways characterised by recurrent episodes of airflow obstruction&#44; airway hyper-responsiveness &#40;AHR&#41;&#44; and bronchodilator reversibility &#40;BDR&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">3</span></a> Structural alterations of the airway&#44; namely remodelling&#44; can be frequently observed in patients with asthma&#44; even in children&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">4</span></a> EB is defined as chronic cough in patients with no symptoms of objective airflow obstruction&#44; sputum eosinophilia&#44; and without AHR&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">1</span></a> Sputum eosinophilia defined as greater than 3&#37; of all non-squamous cells is always present in EB&#46; Similar to asthma&#44; EB shows eosinophilic infiltration of the epithelium and submucosa and remodelling features on an endobronchial biopsy&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">5</span></a> Thymus and activation-regulated chemokine &#40;TARC or CCL17&#41; is a CC family chemokine that acts as a ligand of Th2-dominant CC chemokine receptor 4 &#40;CCR4&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">6</span></a> It has been proven that the CCR4-TARC interaction plays a role in allergic inflammation&#46; CCR4&#47;TARC expression can be increased by stimulation of Th2 cytokines&#44; and TARC can induce selective migration of Th2 but not Th1 cells by triggering CCR4&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">7&#44;8</span></a> Elevated serum TARC levels have been described in atopic dermatitis and are suggested as a useful clinical biomarker for assessing severity&#44; disease activity&#44; and response to treatment in patients with atopic dermatitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">9&#8211;11</span></a> TARC has also been studied in asthma&#44; eosinophilic pneumonia&#44; and allergic bronchopulmonary aspergillosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">12&#44;13</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In the present study&#44; we hypothesised that TARC expression in induced &#40;see Methods&#41; sputum is elevated in patients with asthma or EB compared to control subjects&#46; We also analysed the possible correlation of sputum TARC concentration with eosinophilic inflammation&#44; pulmonary function&#44; and AHR in children&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Subjects</span><p id="par0015" class="elsevierStylePara elsevierViewall">A total of 173 children were enrolled in this study&#59; 90 had a diagnosis of asthma in accordance with American Thoracic Society criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">14</span></a> Thirty-eight children had a diagnosis of EB based on the following criteria&#58; chronic cough lasting more than four weeks without any clinical symptoms related to reversible airway obstruction&#44; such as recurrent wheezing or dyspnoea&#59; no reversible airway obstruction that could be demonstrated by a negative response to a short-acting bronchodilator &#40;change in forced expiratory volume in 1<span class="elsevierStyleHsp" style=""></span>s &#91;FEV<span class="elsevierStyleInf">1</span>&#93;<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>12&#37;&#41;&#59; the absence of bronchial hyper-reactivity in a methacholine challenge test &#40;PC<span class="elsevierStyleInf">20</span>&#59; the provocative concentration of methacholine causing a 20&#37; decrease in the FEV<span class="elsevierStyleInf">1</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#41;&#59; sputum eosinophilia<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>3&#37;&#59; and no lung parenchymal aberrations seen on a simple chest radiograph&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">15&#44;16</span></a> Children treated with systemic corticosteroids due to asthma exacerbation in the preceding month were excluded from the study&#46; The control group consisted of 45 children who had visited the hospital for a general health workup or vaccination and had no history of wheezing&#44; recurrent or chronic diseases&#44; or infection in the preceding two weeks&#44; or hyper-responsiveness to methacholine&#46; Total serum immunoglobulin E &#40;IgE&#41; levels and peripheral blood eosinophil counts were determined at the initiation of the analyses&#46; A specific IgE test was performed with six allergens common in Korea&#58; <span class="elsevierStyleItalic">Dermatophagoides pteronyssinus</span>&#44; <span class="elsevierStyleItalic">Dermatophagoides farina</span>&#44; egg white&#44; cow milk&#44; German cockroach&#44; and <span class="elsevierStyleItalic">Alternaria alternata</span>&#46; Atopy was defined as above 0&#46;7 KUa&#47;L specific IgE to more than one allergen&#44; or 150<span class="elsevierStyleHsp" style=""></span>IU&#47;mL total IgE&#46; Atopy was also defined as more than one positive skin test result among 12 common aeroallergens&#44; including two types of house dust mites&#44; cat and dog epithelium&#44; and mould and pollen allergens&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">17&#44;18</span></a> A saline solution was used as a negative control&#44; and a 0&#46;5&#37; histamine HCl solution was used as a positive control&#46; The wheal diameter was measured after 15<span class="elsevierStyleHsp" style=""></span>min&#44; and a positive reaction was defined as a wheal diameter &#62;3<span class="elsevierStyleHsp" style=""></span>mm&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">19</span></a> This study was approved by the Institutional Review Board of Severance Hospital &#40;Seoul&#44; Korea&#59; protocol No&#46; 4-2004-0036&#41;&#46; Informed written consent for participation was obtained from parents&#44; with verbal assent from children&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Sputum induction and processing</span><p id="par0020" class="elsevierStylePara elsevierViewall">These procedures were performed as previously described by Yoshikawa et al&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">20</span></a> All children were instructed to wash their mouths thoroughly with water&#46; They then inhaled a 3&#37; saline solution nebulised in an ultrasonic nebuliser &#40;NE-U12&#59; Omron Co&#46;&#44; Tokyo&#44; Japan&#41; at maximum output at room temperature&#46; The children were encouraged to cough deeply at 3-min intervals thereafter&#46; After sputum induction&#44; spirometry was repeated&#46; If FEV<span class="elsevierStyleInf">1</span> fell&#44; the child was required to wait until FEV<span class="elsevierStyleInf">1</span> returned to baseline values&#46; Sputum samples were kept at 4<span class="elsevierStyleHsp" style=""></span>&#176;C for no longer than 2<span class="elsevierStyleHsp" style=""></span>h before further processing&#46; A portion of the samples was diluted with a phosphate-buffered saline solution containing 10<span class="elsevierStyleHsp" style=""></span>mmol&#47;L of dithiothreitol &#40;WAKO Pure Chemical Industries&#44; Ltd&#46;&#44; Osaka&#44; Japan&#41; for cell counting and was gently vortexed at room temperature for 20<span class="elsevierStyleHsp" style=""></span>min&#46; After centrifugation at 400<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">g</span> for 10<span class="elsevierStyleHsp" style=""></span>min&#44; the cell pellet was resuspended&#46; We performed a sputum viability assay with the trypan blue exclusion method to ensure adequate viability&#46; Total cell counts were obtained with a haemocytometer&#44; and slides were prepared with cytospin &#40;Cytospin3&#59; Shandon&#44; Tokyo&#44; Japan&#41; and stained with the May&#8211;Grunwald&#8211;Giemsa stain&#41; for differential cell counts&#46; The latter were performed by two observers who were blinded to the clinical details and who counted 400 non-squamous cells&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Quantification of blood eosinophils&#44; serum total IgE&#44; and sputum TARC</span><p id="par0025" class="elsevierStylePara elsevierViewall">Eosinophils were counted automatically &#40;NE-8000 system&#59; Sysmex&#59; Kobe&#44; Japan&#41; in peripheral blood&#44; and the serum total IgE levels were measured &#40;CAP system&#59; Pharmacia-Upjohn&#59; Uppsala&#44; Sweden&#41;&#46; Concentration of TARC in induced sputum was individually detected with enzyme-linked immunosorbent assay kits &#40;R&#38;D Systems&#59; Minneapolis&#44; MN&#44; USA&#41;&#46; The lower detection limit of the assay was 7&#46;81<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Spirometry and the methacholine challenge test</span><p id="par0030" class="elsevierStylePara elsevierViewall">Spirometry &#40;VIASYS Healthcare&#44; Inc&#46;&#44; Conshohocken&#44; PA&#44; USA&#41; was performed&#44; and the flow-volume curves were constructed according to American Thoracic Society guidelines before and after bronchodilator &#40;BD&#41; inhalation&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">21</span></a> A methacholine challenge test was performed according to standardised procedures&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">22</span></a> Each child inhaled increasing concentrations of methacholine &#40;0&#46;075&#44; 0&#46;15&#44; 0&#46;31&#44; 0&#46;62&#44; 1&#46;25&#44; 2&#46;5&#44; 5&#44; 10&#44; 25&#44; and 50<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#41; nebulised by a dosimeter &#40;MB3&#59; Mefar&#44; Brescia&#44; Italy&#41; until the FEV<span class="elsevierStyleInf">1</span> decreased by 20&#37; from a post-nebulised-saline solution value&#46; The bronchial response was expressed as a provocative concentration of methacholine causing a 20&#37; fall in the FEV<span class="elsevierStyleInf">1</span> &#40;PC<span class="elsevierStyleInf">20</span>&#59; measured in milligrams per millilitre&#41; and was calculated by linear interpolation of the log dose response curve&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">FeNO measurement</span><p id="par0035" class="elsevierStylePara elsevierViewall">Fractional exhaled nitric oxide &#40;FeNO&#41; was measured as previously described<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">18&#44;23</span></a> using CLD 88 &#40;Eco Medics&#44; Duernten&#44; Switzerland&#58; measurement at a constant 50<span class="elsevierStyleHsp" style=""></span>mL&#47;s expiratory flow rate&#41;&#46; Measurements were performed according to the ATS&#47;ERS guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">24</span></a> All children refrained from eating nitrate-rich foods for 24<span class="elsevierStyleHsp" style=""></span>h before FeNO measurement because ingestion of nitrate-rich foods can affect the levels of FeNO&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">25</span></a> The mean value for each of the three measurements was calculated&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Statistical analysis</span><p id="par0040" class="elsevierStylePara elsevierViewall">Numerical variables were expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#46; The normality of a distribution was determined by the Kolmogorov&#8211;Smirnov test&#46; Numerical parameters with a non-normal distribution were presented as median and inter-quartile range &#40;IQR&#41;&#46; Comparisons among children with asthma and EB and control subjects were evaluated by the Kruskal&#8211;Wallis test&#46; Statistical comparison of values between groups was done by the Mann&#8211;Whitney test&#46; The correlation between sputum TARC concentrations and numerical parameters was determined using the Spearman rank correlation test&#46; All comparisons were two-sided&#46; Data with a <span class="elsevierStyleItalic">p</span> value &#60;0&#46;05 were considered statistically significant&#46; Statistical software &#40;SPSS&#44; version 20&#46;0&#59; SPSS Inc&#46;&#59; Chicago&#44; IL&#44; USA&#41; was used for all the analyses&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Subjects&#8217; characteristics</span><p id="par0045" class="elsevierStylePara elsevierViewall">The clinical characteristics of the study subjects are summarised in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; There were no significant differences in age and gender among the three groups&#46; The percentage of children with atopy was significantly higher in the asthma group than in the control group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; There were no differences in atopy between patients with asthma and EB&#44; or between EB and the control group&#46; Pulmonary function variables&#44; including FEV<span class="elsevierStyleInf">1</span> &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#44; FEV<span class="elsevierStyleInf">1</span>&#47;FVC &#40;the ratio of forced expiratory volume in 1 second and forced expiratory vital capacity&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#44; forced expiratory flow between 25&#37; and 75&#37; &#40;mid-expiratory phase&#44; FEF<span class="elsevierStyleInf">25&#8211;75</span>&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; and PC<span class="elsevierStyleInf">20</span> &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; showed significantly lower values in children with asthma than in those with EB and in control subjects&#46; The percentage change in FEV<span class="elsevierStyleInf">1</span> post-BD therapy was significantly higher in asthmatic children &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Increased FeNO levels were observed in patients with asthma but there were no statistically significant differences among the groups&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">In serum&#44; the levels of total IgE &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41; and blood eosinophils &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; were increased in children with asthma compared to control subjects&#46; The percentage of eosinophils in induced sputum was significantly higher in children with asthma or EB than in control subjects &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; respectively&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Measurement of TARC levels in sputum</span><p id="par0055" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; sputum TARC concentrations were significantly greater in children with asthma &#40;median 9&#46;34<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#59; IQR 3&#46;81&#8211;24&#46;81<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#41; than in those with EB &#40;median 4&#46;03<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#59; IQR 1&#46;04&#8211;10&#46;30<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#41; or control subjects &#40;median 4&#46;37<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#59; IQR 1&#46;06&#8211;10&#46;93<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;014&#41;&#46; No significant differences were found between children with EB and control subjects&#46; Sputum TARC levels did not show any differences between children with atopy and without atopy among all groups &#40;data not shown&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">The relation between sputum TARC and eosinophilic airway inflammation</span><p id="par0060" class="elsevierStylePara elsevierViewall">In subjects with asthma&#44; sputum TARC concentrations were significantly higher in children with sputum eosinophilia &#40;median 13&#46;51<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#59; IQR 5&#46;59&#8211;30&#46;40<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#41; compared to those without sputum eosinophilia &#40;median 7&#46;21<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#59; IQR 1&#46;91&#8211;16&#46;29<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#59; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Furthermore&#44; sputum TARC concentrations positively correlated with sputum eosinophils &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;210&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;047&#41;&#44; blood eosinophils &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;279&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;012&#41;&#44; and serum total IgE &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;224&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;041&#41;&#46; Another biomarker of eosinophilic inflammation&#44; FeNO&#44; also showed a positive correlation with sputum TARC levels &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;265&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;028&#59; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Significant positive correlations were also observed between sputum TARC levels and sputum eosinophils &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;414&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; blood eosinophils &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;205&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;009&#41;&#44; serum total IgE &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;205&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;009&#41;&#44; and FeNO &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;459&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; in all children under study &#40;Supplement 1&#41;&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Correlation of sputum TARC with pulmonary function and AHR</span><p id="par0070" class="elsevierStylePara elsevierViewall">Regarding the pulmonary function parameters&#44; sputum TARC levels in children with asthma showed a significant inverse correlation with FEV<span class="elsevierStyleInf">1</span>&#47;FVC &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;326&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#59; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>A&#41; and FEF<span class="elsevierStyleInf">25&#8211;75</span> &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;260&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;014&#59; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>B&#41;&#46; In addition&#44; a positive correlation was detected between sputum TARC and the percentage change in FEV<span class="elsevierStyleInf">1</span> post-BD therapy &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;311&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;038&#59; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>C&#41;&#46; There was no relation between sputum TARC levels and FEV<span class="elsevierStyleInf">1</span> &#40;data not shown&#41;&#46; In the methacholine challenge test&#44; another significant negative correlation was observed&#58; between sputum TARC levels and PC<span class="elsevierStyleInf">20</span> &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;454&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#59; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>D&#41;&#46; These associations between sputum TARC concentrations and lung function measurements were also observed in all subjects &#40;Supplement 2&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">Since the interaction of CCR4 with TARC was found to serve as a chemoattractant for Th2 cells&#44; TARC has been studied as a clinical biomarker in allergic diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">26&#44;27</span></a> In addition to its well-known role in atopic dermatitis&#44; the relation between TARC and asthma has also been studied&#46; It was demonstrated that TARC is intimately involved in the development of AHR and eosinophilia through the recruitment of Th2 lymphocytes&#44; and a specific antibody against TARC attenuates airway eosinophilia&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">28</span></a> Increased levels of TARC in serum and sputum are observed in adult patients with asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">29</span></a> Plasma TARC concentration is also elevated in children with asthma<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a> and with asthma exacerbation<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">30</span></a>&#59; therefore&#44; TARC was suggested as a useful marker of childhood asthma&#46; Furthermore&#44; it was reported that expression of CCR4<span class="elsevierStyleSup">&#43;</span>CD4<span class="elsevierStyleSup">&#43;</span>cells and levels of TARC in bronchoalveolar lavage &#40;BAL&#41; fluid are significantly increased in children with asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">31</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Asthma and EB have shown similar immunopathological features such as submucosal eosinophilic inflammation&#44; thickening of the basement membrane&#44; and increased levels of exhaled nitric oxide&#46; Nonetheless&#44; EB differs from asthma in that there is no variable airflow obstruction or AHR<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">15</span></a> and mast cell infiltration in airway&#39;s smooth muscle is smaller than in asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">32</span></a> In the present study&#44; we tested whether sputum TARC levels are elevated in children with asthma or EB&#46; In comparison with the children with EB or control subjects&#44; children with asthma showed significantly higher levels of TARC in induced sputum&#44; but no significant differences were found between children with EB and control subjects&#46; And TARC levels in sputum were found to be associated with sputum eosinophilia and positively correlated with FeNO&#44; reflecting eosinophilic airway inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">33</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In addition&#44; sputum TARC levels showed significant negative correlations with the FEV<span class="elsevierStyleInf">1</span>&#47;FVC ratio&#44; FEF<span class="elsevierStyleInf">25&#8211;75</span>&#44; and PC<span class="elsevierStyleInf">20</span> and a positive correlation with BDR in the present study&#46; Increased sputum TARC levels in children with asthma may indicate poor lung function&#44; with decreased values of the FEV<span class="elsevierStyleInf">1</span>&#47;FVC ratio indicating an airflow limitation&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">34</span></a> Increased concentration of TARC with decreased FEF<span class="elsevierStyleInf">25&#8211;75</span><a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">35&#44;36</span></a> and persistent BDR<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">33</span></a> may also predict poor asthma control such as persistent asthma symptoms&#44; emergency room visits&#44; or a more frequent need for oral steroids&#46; These findings indicate that sputum TARC may play a role in asthmatic airways including airflow limitation&#44; airway reversibility&#44; and hyperresponsiveness in children&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">According to other studies involving BAL&#44; sputum induction is a relatively safer and more convenient procedure&#46; Because BAL analysis is an invasive procedure&#44; especially in children&#44; we suggest sputum induction as an alternative method for quantification of TARC&#46; In addition&#44; asthmatic children treated with an inhaled corticosteroid show higher plasma TARC levels than those without treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a> In our study&#44; patients who were treated with an inhaled corticosteroid were excluded&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The mechanism of different TARC levels between asthma and EB patients is not unclear&#46; But Th2 cytokines &#40;IL-4 and IL-13&#41; expression were found to be co-localized to mast cells within the allergic airway smooth muscle<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">37</span></a> and to promote TARC release in airway smooth muscle cells&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">38</span></a> In addition&#44; increased CCR 4-expressing mast cells in allergic asthma were observed in bronchial biopsy&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">39</span></a> Therefore&#44; the differences in sputum TARC levels between asthma and EB patients might come from TARC expression on mast cells in the airway smooth muscle&#46; An interaction between CCR4 on mast cells and TARC could contribute to allergic airway inflammation and remodelling&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In summary&#44; we showed that sputum TARC is increased in childhood asthma and associated with the functioning of asthmatic airways and eosinophilic inflammation in children&#46; Our findings suggest that sputum TARC may be a supportive marker reflecting airway eosinophilic inflammation in childhood asthma&#46; Furthermore&#44; these findings also suggest that sputum TARC may differentiate asthma from EB in children&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Ethical disclosures</span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Confidentiality of data</span><p id="par0105" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Right to privacy and informed consent</span><p id="par0110" class="elsevierStylePara elsevierViewall">The authors have obtained the informed consent of the patients and&#47;or subjects mentioned in the article&#46; The author for correspondence is in possession of this document&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Protection of human subjects and animals in research</span><p id="par0115" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration&#46;</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">There are no financial or other issues that might lead to a conflict of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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        0 => array:3 [
          "identificador" => "xres827748"
          "titulo" => "Abstract"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "abst0005"
              "titulo" => "Background"
            ]
            1 => array:2 [
              "identificador" => "abst0010"
              "titulo" => "Methods"
            ]
            2 => array:2 [
              "identificador" => "abst0015"
              "titulo" => "Results"
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            3 => array:2 [
              "identificador" => "abst0020"
              "titulo" => "Conclusion"
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        1 => array:2 [
          "identificador" => "xpalclavsec824062"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        3 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Materials and methods"
          "secciones" => array:6 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Subjects"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Sputum induction and processing"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Quantification of blood eosinophils&#44; serum total IgE&#44; and sputum TARC"
            ]
            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Spirometry and the methacholine challenge test"
            ]
            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "FeNO measurement"
            ]
            5 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Statistical analysis"
            ]
          ]
        ]
        4 => array:3 [
          "identificador" => "sec0045"
          "titulo" => "Results"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Subjects&#8217; characteristics"
            ]
            1 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Measurement of TARC levels in sputum"
            ]
            2 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "The relation between sputum TARC and eosinophilic airway inflammation"
            ]
            3 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Correlation of sputum TARC with pulmonary function and AHR"
            ]
          ]
        ]
        5 => array:2 [
          "identificador" => "sec0070"
          "titulo" => "Discussion"
        ]
        6 => array:3 [
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          "titulo" => "Ethical disclosures"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Confidentiality of data"
            ]
            1 => array:2 [
              "identificador" => "sec0085"
              "titulo" => "Right to privacy and informed consent"
            ]
            2 => array:2 [
              "identificador" => "sec0090"
              "titulo" => "Protection of human subjects and animals in research"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0095"
          "titulo" => "Conflict of interest"
        ]
        8 => array:2 [
          "identificador" => "xack277728"
          "titulo" => "Acknowledgements"
        ]
        9 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2016-06-16"
    "fechaAceptado" => "2016-12-03"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec824062"
          "palabras" => array:7 [
            0 => "Asthma"
            1 => "Biomarkers"
            2 => "Bronchitis"
            3 => "Chemokine"
            4 => "Child"
            5 => "Sputum"
            6 => "Thymus and activation-regulated chemokine"
          ]
        ]
      ]
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    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Thymus and activation-regulated chemokine &#40;TARC&#41;&#44; a member of the CC chemokine family&#44; plays a crucial role in Th2-specific inflammation&#46; We aimed to determine the concentration of sputum TARC in children with asthma and eosinophilic bronchitis &#40;EB&#41; and its relation with eosinophilic inflammation&#44; pulmonary function&#44; and bronchial hyper-responsiveness&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">In total&#44; 90 children with asthma&#44; 38 with EB&#44; and 45 control subjects were enrolled&#46; TARC levels were measured in sputum supernatants using an ELISA&#46; We performed pulmonary function tests and measured exhaled fractional nitric oxide&#44; eosinophil counts in blood&#44; and sputum and serum levels of total IgE in all children&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Sputum TARC levels were significantly higher in children with asthma than in either children with EB &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#41; or the control subjects &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;014&#41;&#46; Among patients with asthma&#44; sputum TARC concentration was higher in children with sputum eosinophilia than in those without sputum eosinophilia &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41;&#46; Sputum TARC levels positively correlated with eosinophil counts in sputum&#44; serum total IgE levels&#44; exhaled fractional nitric&#44; and the bronchodilator response&#46; Negative significant correlations were found between sputum TARC and FEV1&#47;FVC &#40;the ratio of forced expiratory volume in one second and forced expiratory vital capacity&#41; or PC<span class="elsevierStyleInf">20</span> &#40;the provocative concentration of methacholine causing a 20&#37; decrease in the FEV<span class="elsevierStyleInf">1</span>&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Elevated TARC levels in sputum were detected in children with asthma but not in children with EB&#46; Sputum TARC could be a supportive marker for discrimination of asthma from EB in children showing characteristics of eosinophilic airway inflammation&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0030">This study was approved by the Institutional Review Board of Severance Hospital &#40;Seoul&#44; Korea&#41; &#40;protocol No&#46; 4-2004-0036&#41;&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0035">These authors contributed equally to this work&#46;</p>"
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            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Comparison of sputum TARC levels among the asthma&#44; EB&#44; and control groups&#46; Sputum TARC levels were significantly higher in children with asthma than either children with EB &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#41; or control subjects &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;014&#41;&#46; No significant differences were found between children with EB and control subjects&#46; Box-and whisker plots represent the 25th and 75th percentiles&#44; with the median line and the error bars representing the 10th and 90th percentiles&#46;</p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Sputum TARC levels versus sputum eosinophilia in asthma patients&#46; Asthmatic children with sputum eosinophilia had significantly higher levels of sputum TARC than those without eosinophilia in sputum &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41;&#46; Box-and whisker plots represent the 25th and 75th percentiles&#44; with the median line and the error bars representing the 10th and 90th percentiles&#46;</p>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Correlation of sputum TARC with FeNO in the asthma group&#46; A positive correlation of FeNO with sputum TARC levels &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;265&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;028&#41; was detected in asthma patients&#46;</p>"
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Correlation of sputum TARC with airflow obstruction&#44; bronchial hyperresponsiveness&#44; and bronchodilator reversibility in asthma patients&#46; Negative significant correlations were found between sputum TARC and &#40;A&#41; FEV<span class="elsevierStyleInf">1</span>&#47;FVC &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;326&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41;&#44; &#40;B&#41; FEF<span class="elsevierStyleInf">25&#8211;75</span> &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;260&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;014&#41;&#44; and &#40;D&#41; PC<span class="elsevierStyleInf">20</span> &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;454&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; &#40;C&#41; Sputum TARC levels positively correlated with bronchodilator response &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;311&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;038&#41;&#46;</p>"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">EB&#44; eosinophilic bronchitis&#59; FVC&#44; forced expiratory vital capacity&#59; FEV1&#44; forced expiratory volume in 1 second&#59; FEF<span class="elsevierStyleInf">25&#8211;75</span>&#44; forced expiratory flow between 25&#37; and 75&#37; of forced vital capacity&#59; PC<span class="elsevierStyleInf">20</span>&#59; a provocative concentration of methacholine causing a 20&#37; fall in the FEV<span class="elsevierStyleInf">1</span>&#59; FeNO&#44; fractional exhaled nitric oxide&#59; IgE&#44; immunoglobulin E&#46; Values are expressed as a number &#40;percentage&#41;&#44; mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#44; or median &#40;interquartile range&#41;&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\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">Asthma &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>90&#41;&nbsp;\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">EB &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>38&#41;&nbsp;\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">Control &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>45&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age&#44; years&nbsp;\t\t\t\t\t\t\n
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                      "Revista" => array:6 [
                        "tituloSerie" => "Allergy"
                        "fecha" => "2009"
                        "volumen" => "64"
                        "paginaInicial" => "995"
                        "paginaFinal" => "1002"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19630858"
                            "web" => "Medline"
                          ]
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                      ]
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                ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Plasma concentration of thymus and activation-regulated chemokine is elevated in childhood asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Leung T-f"
                            1 => "Wong C-k"
                            2 => "I&#46;H&#46;S&#46; Chan"
                            3 => "Ip W-k"
                            4 => "C&#46;W&#46;K&#46; Lam"
                            5 => "G&#46;W&#46;K&#46; Wong"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "2002"
                        "volumen" => "110"
                        "paginaInicial" => "404"
                        "paginaFinal" => "409"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12209086"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0240"
              "etiqueta" => "9"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thymus and activation-regulated chemokine as a clinical biomarker in atopic dermatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Y&#46; Kataoka"
                          ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/1346-8138.12440"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Dermatol"
                        "fecha" => "2014"
                        "volumen" => "41"
                        "paginaInicial" => "221"
                        "paginaFinal" => "229"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24628072"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Utility of serum thymus and activation-regulated chemokine as a biomarker for monitoring of atopic dermatitis severity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "J&#46; Landheer"
                            1 => "M&#46; de Bruin-Weller"
                            2 => "C&#46; Boonacker"
                            3 => "D&#46; Hijnen"
                            4 => "C&#46; Bruijnzeel-Koomen"
                            5 => "H&#46; Rockmann"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2014.07.031"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2014"
                        "volumen" => "71"
                        "paginaInicial" => "1160"
                        "paginaFinal" => "1166"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25199679"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            10 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Increased serum thymus and activation-regulated chemokine and cutaneous T cell-attracting chemokine levels in children with atopic dermatitis"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "T&#46;W&#46; Song"
                            1 => "M&#46;H&#46; Sohn"
                            2 => "E&#46;S&#46; Kim"
                            3 => "K&#46;W&#46; Kim"
                            4 => "K&#46;E&#46; Kim"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2222.2006.02430.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Allergy"
                        "fecha" => "2006"
                        "volumen" => "36"
                        "paginaInicial" => "346"
                        "paginaFinal" => "351"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16499646"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0255"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Novel biomarkers in asthma&#58; chemokines and chitinase-like proteins"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "D&#46; Hartl"
                            1 => "C&#46;G&#46; Lee"
                            2 => "C&#46;A&#46; Da Silva"
                            3 => "G&#46;L&#46; Chupp"
                            4 => "J&#46;A&#46; Elias"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/ACI.0b013e32831f8ee0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Allergy Clin Immunol"
                        "fecha" => "2009"
                        "volumen" => "9"
                        "paginaInicial" => "60"
                        "paginaFinal" => "66"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19532094"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0260"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CCR4 and its ligands&#58; from bench to bedside"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "O&#46; Yoshie"
                            1 => "K&#46; Matsushima"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/intimm/dxu079"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int Immunol"
                        "fecha" => "2015"
                        "volumen" => "27"
                        "paginaInicial" => "11"
                        "paginaFinal" => "20"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25087232"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Expert Panel Report 3 &#40;EPR-3&#41;&#58; Guidelines for the Diagnosis and Management of Asthma&#8211;Summary Report 2007"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "P&#46; NAEaP"
                          ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaci.2007.09.043"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "2007"
                        "volumen" => "120"
                        "paginaInicial" => "S94"
                        "paginaFinal" => "S138"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17983880"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Eosinophilic bronchitis without asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "U&#46; Gonlugur"
                            1 => "T&#46;E&#46; Gonlugur"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000128580"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int Arch Allergy Immunol"
                        "fecha" => "2008"
                        "volumen" => "147"
                        "paginaInicial" => "1"
                        "paginaFinal" => "5"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18446047"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Differences in radiological&#47;HRCT findings in eosinophilic bronchitis and asthma&#58; implication for bronchial responsiveness"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;W&#46; Park"
                            1 => "J&#46;S&#46; Park"
                            2 => "Y&#46;M&#46; Lee"
                            3 => "J&#46;H&#46; Lee"
                            4 => "A&#46;S&#46; Jang"
                            5 => "D&#46;J&#46; Kim"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/thx.2005.044420"
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                        "tituloSerie" => "Thorax"
                        "fecha" => "2006"
                        "volumen" => "61"
                        "paginaInicial" => "41"
                        "paginaFinal" => "47"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16244090"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Relationship between amphiregulin and airway inflammation in children with asthma and eosinophilic bronchitis"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "K&#46;W&#46; Kim"
                            1 => "H&#46;M&#46; Jee"
                            2 => "Y&#46;H&#46; Park"
                            3 => "B&#46;S&#46; Choi"
                            4 => "M&#46;H&#46; Sohn"
                            5 => "K&#46;E&#46; Kim"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1378/chest.08-2972"
                      "Revista" => array:6 [
                        "tituloSerie" => "Chest"
                        "fecha" => "2009"
                        "volumen" => "136"
                        "paginaInicial" => "805"
                        "paginaFinal" => "810"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19447920"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Usefulness of impulse oscillometry and fractional exhaled nitric oxide in children with Eosinophilic bronchitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46;H&#46; Kim"
                            1 => "K&#46;W&#46; Kim"
                            2 => "J&#46; Baek"
                            3 => "H&#46;B&#46; Park"
                            4 => "H&#46; Kim"
                            5 => "K&#46;J&#46; Song"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/ppul.22631"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Pulmonol"
                        "fecha" => "2013"
                        "volumen" => "48"
                        "paginaInicial" => "221"
                        "paginaFinal" => "228"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22825832"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The relationship of respiratory allergy&#44; skin test reactivity&#44; and serum IgE in a community population sample"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "W&#46;G&#46; Brown"
                            1 => "M&#46;J&#46; Halonen"
                            2 => "W&#46;T&#46; Kaltenborn"
                            3 => "R&#46;A&#46; Barbee"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "1979"
                        "volumen" => "63"
                        "paginaInicial" => "328"
                        "paginaFinal" => "335"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/429712"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Severity of exercise-induced bronchoconstriction is related to airway eosinophilic inflammation in patients with asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Yoshikawa"
                            1 => "S&#46; Shoji"
                            2 => "T&#46; Fujii"
                            3 => "H&#46; Kanazawa"
                            4 => "S&#46; Kudoh"
                            5 => "K&#46; Hirata"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "1998"
                        "volumen" => "12"
                        "paginaInicial" => "879"
                        "paginaFinal" => "884"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9817162"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Standardisation of spirometry"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;R&#46; Miller"
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                            3 => "F&#46; Burgos"
                            4 => "R&#46; Casaburi"
                            5 => "A&#46; Coates"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/09031936.05.00034805"
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                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2005"
                        "volumen" => "26"
                        "paginaInicial" => "319"
                        "paginaFinal" => "338"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16055882"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Guidelines for Methacholine and Exercise Challenge Testing-1999&#46; This official statement of the American Thoracic Society was adopted by the ATS Board of Directors&#44; July 1999"
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                        0 => array:2 [
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                            2 => "A&#46; Coates"
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                            4 => "J&#46; Hankinson"
                            5 => "C&#46; Irvin"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.161.1.ats11-99"
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                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2000"
                        "volumen" => "161"
                        "paginaInicial" => "309"
                        "paginaFinal" => "329"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10619836"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0310"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fractional exhaled nitric oxide and impulse oscillometry in children with allergic rhinitis"
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                          "etal" => true
                          "autores" => array:6 [
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                            2 => "M&#46;J&#46; Kim"
                            3 => "H&#46;S&#46; Kim"
                            4 => "H&#46;S&#46; Lee"
                            5 => "Y&#46;K&#46; Han"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Allergy Asthma Immunol Res"
                        "fecha" => "2014"
                        "volumen" => "6"
                        "paginaInicial" => "27"
                        "paginaFinal" => "32"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24404390"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0315"
              "etiqueta" => "24"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "ATS&#47;ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide&#44; 2005"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1164/rccm.200406-710ST"
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                        "tituloSerie" => "Am J Respir Crit Care Med"
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                        "paginaInicial" => "912"
                        "paginaFinal" => "930"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15817806"
                            "web" => "Medline"
                          ]
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                ]
              ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Time-dependent effect of nitrate-rich meals on exhaled nitric oxide in healthy subjects"
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                            3 => "M&#46; Smolders"
                            4 => "W&#46;A&#46; De Backer"
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                            0 => "N&#46;YT Sugawara"
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                            2 => "M&#46; Miura"
                            3 => "N&#46; Terada"
                            4 => "M&#46; Kurosawa"
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                        "paginaFinal" => "181"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11929428"
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                      "titulo" => "TARC&#58; novel mediator of allergic inflammation"
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                          "autores" => array:1 [
                            0 => "G&#46;T&#46;L&#46; Sandoval-L&#243;pez"
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                        "paginaInicial" => "1809"
                        "paginaFinal" => "1812"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11737030"
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                    0 => array:2 [
                      "titulo" => "Intervention of thymus and activation-regulated chemokine attenuates the development of allergic airway inflammation and hyperresponsiveness in mice"
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                          "etal" => true
                          "autores" => array:6 [
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                            2 => "H&#46; Yoneyama"
                            3 => "T&#46; Nakayama"
                            4 => "R&#46; Fujisawa"
                            5 => "M&#46; Izumizaki"
                          ]
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                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Immunol"
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                        "volumen" => "166"
                        "paginaInicial" => "2055"
                        "paginaFinal" => "2062"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11160256"
                            "web" => "Medline"
                          ]
                        ]
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                    ]
                  ]
                ]
              ]
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              "etiqueta" => "29"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Increased levels of a TH2-type CC chemokine thymus and activation-regulated chemokine &#40;TARC&#41; in serum and induced sputum of asthmatics"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Sekiya"
                            1 => "H&#46; Yamada"
                            2 => "M&#46; Yamaguchi"
                            3 => "K&#46; Yamamoto"
                            4 => "A&#46; Ishii"
                            5 => "O&#46; Yoshie"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Allergy"
                        "fecha" => "2002"
                        "volumen" => "57"
                        "paginaInicial" => "173"
                        "paginaFinal" => "177"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11929424"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0345"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Plasma TARC concentration may be a useful marker for asthmatic exacerbation in children"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46;F&#46; Leung"
                            1 => "C&#46;K&#46; Wong"
                            2 => "C&#46;W&#46;K&#46; Lam"
                            3 => "A&#46;M&#46; Li"
                            4 => "W&#46;K&#46; Ip"
                            5 => "G&#46;W&#46;K&#46; Wong"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2003"
                        "volumen" => "21"
                        "paginaInicial" => "616"
                        "paginaFinal" => "620"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12762345"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0350"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pulmonary chemokines and their receptors differentiate children with asthma and chronic cough"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46; Hartl"
                            1 => "M&#46; Griese"
                            2 => "T&#46; Nicolai"
                            3 => "G&#46; Zissel"
                            4 => "C&#46; Prell"
                            5 => "N&#46; Konstantopoulos"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaci.2004.11.049"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "2005"
                        "volumen" => "115"
                        "paginaInicial" => "728"
                        "paginaFinal" => "736"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15805991"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0355"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mast-cell infiltration of airway smooth muscle in asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "C&#46;E&#46; Brightling"
                            1 => "P&#46; Bradding"
                            2 => "F&#46;A&#46; Symon"
                            3 => "S&#46;T&#46; Holgate"
                            4 => "A&#46;J&#46; Wardlaw"
                            5 => "I&#46;D&#46; Pavord"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "N Engl Med"
                        "fecha" => "2002"
                        "volumen" => "346"
                        "paginaInicial" => "1699"
                        "paginaFinal" => "1705"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0360"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Monitoring asthma in childhood&#58; lung function&#44; bronchial responsiveness and inflammation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Moeller"
                            1 => "K&#46;H&#46; Carlsen"
                            2 => "P&#46;D&#46; Sly"
                            3 => "E&#46; Baraldi"
                            4 => "G&#46; Piacentini"
                            5 => "I&#46; Pavord"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/16000617.00003914"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir Rev"
                        "fecha" => "2015"
                        "volumen" => "24"
                        "paginaInicial" => "204"
                        "paginaFinal" => "215"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26028633"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Lung function measurement in the assessment of childhood asthma&#58; recent important developments"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46;P&#46; Galant"
                            1 => "B&#46; Nickerson"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Curr Opin Allergy Clin Immunol"
                        "fecha" => "2010"
                        "volumen" => "10"
                        "paginaInicial" => "149"
                        "paginaFinal" => "154"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20035221"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "35"
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                    0 => array:2 [
                      "titulo" => "Clinical implications of having reduced mid forced expiratory flow rates &#40;FEF25-75&#41;&#44; independently of FEV1&#44; in adult patients with asthma"
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                        0 => array:2 [
                          "etal" => true
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                            1 => "S&#46;E&#46; Wenzel"
                            2 => "M&#46; Castro"
                            3 => "S&#46;C&#46; Erzurum"
                            4 => "K&#46;F&#46; Chung"
                            5 => "A&#46;M&#46; Fitzpatrick"
                          ]
                        ]
                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.1371/journal.pone.0145476"
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                        "tituloSerie" => "PLoS One"
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                        "volumen" => "10"
                        "paginaInicial" => "e0145476"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26717486"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "36"
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                    0 => array:2 [
                      "titulo" => "Forced midexpiratory flow between 25&#37; and 75&#37; of forced vital capacity is associated with long-term persistence of asthma and poor asthma outcomes"
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                        0 => array:2 [
                          "etal" => true
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                            2 => "M&#46; Dolgopoloff"
                            3 => "S&#46; Chanoine"
                            4 => "J&#46; Bousquet"
                            5 => "F&#46; Gormand"
                          ]
                        ]
                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.jaci.2015.10.029"
                      "Revista" => array:3 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "2015"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24139497"
                            "web" => "Medline"
                          ]
                        ]
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                    ]
                  ]
                ]
              ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Interleukin-4 and -13 expression is co-localized to mast cells within the airway smooth muscle in asthma"
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                    ]
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                    0 => array:1 [
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                        "paginaInicial" => "1711"
                        "paginaFinal" => "1716"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14656359"
                            "web" => "Medline"
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                      ]
                    ]
                  ]
                ]
              ]
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                    0 => array:2 [
                      "titulo" => "IL-13 and IL-4 promote TARC release in human airway smooth muscle cells&#58; role of IL-4 receptor genotype"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            3 => "S&#46; Baraldo"
                            4 => "L&#46; Flynt"
                            5 => "K&#46; Bourgeois"
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                        "tituloSerie" => "Am J Physiol Lung cell Mol Physiol"
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                        "paginaInicial" => "L907"
                        "paginaFinal" => "L914"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12871855"
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                      "titulo" => "CC chemokine receptors CCR1 and CCR4 are expressed on airway mast cells in allergic asthma"
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                        "link" => array:1 [
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Article information

ISSN: 03010546
Original language: English

DOI:10.1016/j.aller.2016.12.004

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	2	0	2
2024 October	14	5	19
2024 September	19	10	29
2024 August	22	8	30
2024 July	27	12	39
2024 June	9	4	13
2024 May	13	4	17
2024 April	16	11	27
2024 March	19	3	22
2024 February	26	10	36
2024 January	21	7	28
2023 December	15	6	21
2023 November	14	13	27
2023 October	23	12	35
2023 September	14	4	18
2023 August	17	6	23
2023 July	19	11	30
2023 June	43	6	49
2023 May	53	6	59
2023 April	46	3	49
2023 March	52	4	56
2023 February	25	8	33
2023 January	26	4	30
2022 December	38	8	46
2022 November	30	10	40
2022 October	24	11	35
2022 September	23	12	35
2022 August	36	16	52
2022 July	25	11	36
2022 June	36	11	47
2022 May	52	7	59
2022 April	78	14	92
2022 March	134	14	148
2022 February	134	14	148
2022 January	104	10	114
2021 December	67	14	81
2021 November	93	19	112
2021 October	37	16	53
2021 September	42	11	53
2021 August	29	7	36
2021 July	28	11	39
2021 June	21	22	43
2021 May	19	12	31
2021 April	42	28	70
2021 March	19	7	26
2021 February	34	10	44
2021 January	35	13	48
2020 December	5	3	8
2020 October	1	0	1
2020 July	0	1	1
2018 February	0	3	3
2017 November	1	0	1
2017 May	4	1	5
2017 April	3	0	3
2017 March	0	1	1

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Allergologia et Immunopathologia is no longer published on Elsevier since the 2021 year.Transferred to Codon Publications

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Allergologia et Immunopathologia is no longer published on Elsevier since the 2021 year.Transferred to Codon Publications

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