Airway tone dysfunction among pre-schoolers with positive asthma predictive index: A case–control study

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"apellidos" => "Castro-Rodriguez" "email" => array:1 [ 0 => "jacastro17@homail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Hospital Naval Almirante Nef, Viña del Mar, Chile" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Pediatrics, School of Medicine, Universidad de Valparaiso, Chile" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Division of Pediatrics, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1362 "Ancho" => 1452 "Tamanyo" => 80360 ] ] "descripcion" => array:1 [ "en" => "Comparison in basal central airway resistance (R20) by IOS, and post BD changes in FEV0.5 and FEF25–75 by spirometry, between positive API with and without ICS. Footnote: API, asthma predictive index; BD, bronchodilator; FEF, mid forced expiratory force; FEV0.5, forced expiratory volume in 0.5s; ICS, inhaled corticosteroids; IOS, impulse oscillometry." ] ] ] "textoCompleto" => "IntroductionWheezing is a common symptom in the first years of life, but a minority of children will continue to experience wheezing symptoms in school years and beyond.<a class="elsevierStyleCrossRef" href="#bib0165">1</a> Based on the epidemiological data on the natural history and temporal patterns of wheezing, several childhood wheezing phenotypes have been described. However, the use of these “epidemiological” phenotypes of wheezing is limited, since they can only be identified retrospectively; indeed, they were defined using statistical inference on longitudinally collected data, and not useful in the present as they are defined by events that will occur in the future.<a class="elsevierStyleCrossRef" href="#bib0170">2</a> Thus, it has been proposed that wheezing phenotypes be based on the trigger(s) and temporality of symptoms (such as episodic viral wheeze [EVW] and multiple-trigger wheeze [MTW]) which can be ascertained in a clinic and could be more practical for making treatment decisions.<a class="elsevierStyleCrossRef" href="#bib0175">3</a> However, it was reported that EVW and MTW had considerable overlap<a class="elsevierStyleCrossRef" href="#bib0180">4</a>; showing conflicting results as these differ in clinical features and have limited value in predicting asthma at school age.<a class="elsevierStyleCrossRef" href="#bib0185">5</a>In the past 15 years, the diagnosis of asthma has hinged on the ability to predict the persistence of asthma at six years.<a class="elsevierStyleCrossRef" href="#bib0190">6</a> Several asthma predictive rules have emerged. The Asthma Predictive Index (API)<a class="elsevierStyleCrossRef" href="#bib0195">7</a> used clinical parameters (paternal asthma, rhinitis, dermatitis, wheezing without cold and eosinophils in peripheral blood) and originally developed in the Tucson cohort study, is the most widely used. The API is simple and cheap, and its major strength is its good positive likelihood ratio ∼7.4 (the post-test probability of disease can improve from 2 to 7 times) and high specificity (∼97%).<a class="elsevierStyleCrossRef" href="#bib0200">8</a>Children with persistent wheeze, frequent asthma exacerbations, and multiple early atopy have diminished lung function (measured by specific airway resistance [sRaw]) throughout childhood, and are at risk of a progressive loss of lung function from age 3 to 11 years; these effects are more marked in boys.<a class="elsevierStyleCrossRef" href="#bib0205">9</a> One study from the Tucson cohort suggested that for persistent wheezers the deficit in lung function is not present soon after birth (lung function measure at age four weeks by chest compression technique [RCT]), but is acquired by age six years (measured by spirometry).<a class="elsevierStyleCrossRef" href="#bib0165">1</a>However, few studies on lung function and bronchodilator response were performed in children with API characteristics. A study on young Spanish children with a positive API had significant lower lung function (measured by RCT) than those with negative API.<a class="elsevierStyleCrossRef" href="#bib0210">10</a> A trial in recurrent wheeze pre-schoolers with positive API or a positive screening test for atopy treated with inhaled corticosteroids (ICS) for 24 weeks modestly reduces wheeze exacerbation rates and improves lung function (measured by spirometry).<a class="elsevierStyleCrossRef" href="#bib0215">11</a> A previous trial showed that ICS for 24 months improves lung function, but the effect disappears after the treatment is discontinued.<a class="elsevierStyleCrossRef" href="#bib0220">12</a> However, no group of pre-schoolers with negative API was involved in those trials.The objective of this case–control study is to compare the lung function (measured by impulse oscillometry [IOS] and spirometry) and post-bronchodilator (post-BD) response to salbutamol among pre-schoolers with positive and negative API.MethodsWe prospectively enrolled all the recurrent wheezing pre-schoolers attended at the paediatric pulmonology clinic at Hospital Almirante Nef, Viña del Mar, Chile, during a nine-month period (May 2012 to February 2013). In accordance with international guidelines, their paediatricians treated each child with ICS (fluticasone propionate 125mcg bid or budesonide 200mcg bid by metered dose inhaler and spacer with face mask) or montelukast (4mg/d).<a class="elsevierStyleCrossRef" href="#bib0225">13</a> The study was approved by the local ethics committee and parents gave written informed consent. Inclusion criteria: aged two to six years of age with recurrent wheezing, defined as having three or more wheezing episodes (confirmed by paediatrician) in the previous year; received ICS or montelukast for at least six months; and correctly performed IOS and spirometry according to ATS/ERS recommendation.<a class="elsevierStyleCrossRef" href="#bib0230">14</a> Exclusion criteria: cardiac or other chronic respiratory diseases (e.g. cystic fibrosis, bronchopulmonary dysplasia, post-infectious bronchiolitis obliterans, ciliary dyskinesia), airway malformations, endocrinological and neurological diseases, prematurity (<37 weeks), low weight for gestational age, undernourishment, parental or guardian failure to sign the informed consent form.A predefined questionnaire with demographic data and peripheral blood sample (during asymptomatic period) were performed on the children. According to the presence of stringent API<a class="elsevierStyleCrossRef" href="#bib0190">6</a> we divided the population into two groups: positive API if they had one major or two minor criteria, or negative API if they did not fulfil those criteria.Pulmonary lung function was performed only if the child was free of respiratory symptoms in the previous four weeks and following this protocol: first basal IOS, then basal spirometry, and finally post-BD measurements by IOS and spirometry after 15min of using two puffs (100mcg/puff) of salbutamol (Fesema®, GSK, Aranda de Duero, Spain) administered with three minutes of separation in between puffs and using a spacer with face mask (AeroChamber Plus® Flow-Vu®, Monaghan Medical Corp., USA). ICS treatment was not discontinued at the moment of lung function measurement. Weight and height were measured before lung function.The IOS was done by one paediatric lung function technician (SMO). For all subjects, three replicate measurements of impedance respiratory (Zrs) were obtained using the system software (MasterScreen-IOS, Jaeger® Co, Germany). Impedance measurements were retained for analysis if reproducible, that is, if the coefficient of variation between replicates measurements was <10%. Briefly, the sitting child was asked to breathe for 15–20s using a rigid oval mouthpiece with a tongue guard, with the head in a neutral position, nose clip in place, and while supporting both cheeks. For the respiratory system, resistance represents the effective resistance of lungs and chest wall, whereas reactance is the net effect of the two opposite (one compliant and one inertial) components. Each recording on the MasterScreen IOS assessment yielded both the expiratory resistance (R5 and R20) and reactance (X5) [kPa/l/s] at different oscillatory frequencies between 5Hz and 35Hz within the flow range of normal tidal breathing. R5 measure the total resistance (central and peripheral), R20 the central resistance and X5 the peripheral reactance. In addition, the resonant frequency (Fres) [i.e. the frequency at which the reactance was zero] was also computed.The spirometry (Jaeger Master-Screen®) was also performed by SMO. None of the participants had performed a spirometry before; each child did all possible expiratory force curves over a 15-minute period, with a nasal clip (unless it was not tolerated) and standing. Sometimes, according to operator criteria, animation programmes included in the software (e.g. candles, balloons) were used. We considered as acceptable spirometric curves those with evident peak expiratory forced (PEF), without abrupt end of flow >10% of PEF, with expiratory time >0.5s and without evidence of cough or glottis closure.<a class="elsevierStyleCrossRef" href="#bib0230">14</a> For each test, we recorded time-volume and flow-volume curves and tabulated the real expiratory time of the curve with the best forced vital capacity (FVC). Moreover, to calculate the reproducibility, variation coefficient, and coefficient of repeatability, we registered the three best basal forced expiratory volume (FEV)0.5, FEV1, flow expiratory forced (FEF)25–75, FEF25, FEF50 and FEF75 values for each patient. Since no local spirometry reference values exist for pre-schoolers, we used values from the Spanish population.<a class="elsevierStyleCrossRef" href="#bib0235">15</a>Statistical analysisWe compared children in the positive and negative API groups. For categorical variables, contingency tables were used (chi2 with Fisher exact test). For continuous variables with normal distribution, an average comparison and analysis of variance (ANOVA) were used; and Wilcoxon test was used in other cases. For lung function variables between groups, a Mann–Whitney was performed; and Pearson correlation was used for comparing the post-BD response to salbutamol. Statistically significant differences were considered for a p value <0.05. All statistical analyses were done with STATA® software v.11.0. To ensure that the bronchodilator response was a clinically significant change and was not due to technique variability, we considered it above the coefficient of repeatability.<a class="elsevierStyleCrossRef" href="#bib0230">14</a>ResultsIn the nine-month period, we enrolled 109 pre-schoolers. One patient (belonging to the positive API) was excluded because of being unable to correctly perform lung function (post-BD IOS), therefore 108 pre-schoolers (56 males, age range from 24 to 72 months) completed the study; 50 belong to positive API and 58 to negative API group. There were no differences in demographic parameters (e.g. age, gender, nutritional status, weight and height) between groups (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). There was more prevalence of ICS used in the pre-schoolers with positive API than negative API (62% vs. 12%, respectively, p=0.001). No difference in ICS type and daily doses was found between groups (data not shown).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>In terms of lung function (% of predicted), no significant difference between positive and negative API pre-schoolers was found in the basal or post-BD response in all the parameters in neither the IOS nor the spirometry (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). In order to see if the effect of ICS therapy can modify the lung function, we did a comparison in pre-schoolers with positive API between those who used ICS (n=31) vs. did not use ICS (n=19). The only significant parameters between positive API with ICS vs. positive API without ICS were: basal resistance at 20Hz (median [interquartile range]) 89% [79–108] vs. 81% [67–99], respectively, p=0.047), post-BD change FEF25–75 (20.5% [2–48] vs. 6.5% [−2 to 23]), respectively, p=0.043), and post-BD change FEV0.5 (3.5% ([3–24] vs. 6.5% [−1 to 12], respectively, p=0.047), <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>. No significant differences were observed in IOS or spirometry parameters between pre-schoolers with negative API who used ICS (n=7) vs. did not use ICS (n=51) (data not shown).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia>DiscussionThis case–control study shows that recurrent wheeze pre-schoolers with positive API had similar lung function (measured by IOS and spirometry) to those with negative API. However, those positive API pre-schoolers with ICS had significantly higher basal central airway resistance at 20Hz, and higher post-BD response in flow (% change in FEF25–75 and in FEV0.5) than those positive API without ICS, suggesting that a kind of airway dysfunction occurred in the former.To our knowledge, only two other studies have measured lung function in pre-schoolers according to API condition. Borrego et al.<a class="elsevierStyleCrossRef" href="#bib0240">16</a> using tidal and raised volume RTC in 50 recurrent wheezer pre-schoolers (aged 8–20 months) prior to receiving ICS or montelukast found that compared with healthy controls, those pre-schoolers with positive API (n=17) or negative API (n=33) had significantly lower FEV0.5, FEF75 and FEF25–75. After controlling for confounders, FVC z-score was significantly reduced in the positive API vs. negative API by 45ml [−89 to −2ml]; whereas, despite a trend towards lower values among positive API, there were no significant differences in FEV0.5 or FEF25–75. Later, Keklikian et al.<a class="elsevierStyleCrossRef" href="#bib0210">10</a> measured lung function by using RCT in recurrent wheezer infants (11.9±4.9 months of age). Then, they adjusted by covarirantes and found that infants with positive API (n=51) had significant lower VmaxFRC z-score than those with negative API (n=41) (2.01±0.79 vs. 1.64±0.77, p=0.026, respectively).We can speculate that in the present study pre-schoolers positive API with ICS have higher central airway resistance (increased RA at 20Hz) and higher BD response (in FEV0.5 and FEF25–75) than positive API without ICS because the former have more severe disease that make their paediatricians more prone to prescribe ICSs. However, unfortunately we do not have information about severity of recurrent wheezing in our population. Nevertheless, in general those pre-schoolers with ICS had a higher proportion of peripheral eosinophils >4% than those without ICS (data not shown). It is well known that high peripheral eosinophils is a marker for asthma severity in children and adult population.<a class="elsevierStyleCrossRef" href="#bib0245">17</a>In a post hoc study on pre-schoolers aged four,<a class="elsevierStyleCrossRef" href="#bib0250">18</a> atopic pre-schoolers with asthma had significantly more BD response to albuterol in the IOS parameters (RA at 5Hz, RA at 10Hz, and reactance at 10Hz) than atopic children without asthma; but no difference was seen in the spirometry. Among non-atopic children, there were no significant differences between asthmatic and non-asthmatic children at baseline or post-BD response measured by IOS nor spirometry.<a class="elsevierStyleCrossRef" href="#bib0250">18</a> However, a study on 325 children (four years of age) showed that those children with persistent wheeze phenotype had significant larger baseline resistance at 4Hz (measured by force oscillation technique) than children with early transient wheeze, and the decrease in post-BD resistance at 4Hz was significantly larger than the children who never had wheeze and those with early transient wheeze.<a class="elsevierStyleCrossRef" href="#bib0255">19</a>Data from the Tucson birth cohort showed that children with transient early and persistent wheezers had significantly lower FEF25–75, FEV1 and FEV:FEV1 ratio through age 16 years compared with never wheezers. Levels of lung function are established by age six years and do not appear to change significantly by age 16 years.<a class="elsevierStyleCrossRefs" href="#bib0165">1,20</a> However, in the COPSAC birth cohort, children developing asthma by age seven had a lung function deficit (FEF50) and increased bronchial responsiveness to methacholine as neonates; regardless of their atopic condition.<a class="elsevierStyleCrossRef" href="#bib0265">21</a> Recently, the MAAS birth cohort<a class="elsevierStyleCrossRef" href="#bib0205">9</a> demonstrated that persistent wheezers (but not transient and late-onset phenotypes) and multiple early atopy (but not dust mite, non-dust mite, multiple late phenotypes) have established airway dysfunction as early as three years of age; possibly because it was at least partly present at birth.<a class="elsevierStyleCrossRefs" href="#bib0265">21,22</a> However, since measures of sRaw after BD are not reported in the MAAS birth cohort,<a class="elsevierStyleCrossRef" href="#bib0205">9</a> it is not known whether the observed increase in sRaw is due to increased airway tone or to an effect of remodelling on airway growth.Low lung function at birth could lead to increased risk for wheeze, as suggested by both the transient and persistent wheeze groups.<a class="elsevierStyleCrossRefs" href="#bib0165">1,21</a> In the absence of early environmental sensitisation, the wheezing stops during school age in the transient non-atopic wheeze group.<a class="elsevierStyleCrossRef" href="#bib0275">23</a> In contrast, early allergic airway inflammation exacerbation during viral infections may lead to remodelling, which then impairs airway growth with long-term increase in airway resistance and reduced FEF.<a class="elsevierStyleCrossRef" href="#bib0280">24</a> Recently, a study in severe recurrent wheezer pre-schoolers showed that markers of remodelling and inflammation are unrelated, but atopy is associated with airway smooth muscle.<a class="elsevierStyleCrossRef" href="#bib0285">25</a> In contrast, Saglani et al.<a class="elsevierStyleCrossRef" href="#bib0290">26</a> reported reticular basement membrane (RBM) thickness in children with confirmed wheezers (median age 29 months) and controls, without difference in atopy characteristic. However, Berankova et al.,<a class="elsevierStyleCrossRef" href="#bib0295">27</a> reported a significant difference in the thickness of the RBM between pre-schoolers (median age 13.5 months) with major criteria of the API (parental asthma or atopic eczema) before any wheezing episode occurred vs. controls.A non-invasive common way to determine eosinophil airway inflammation is by exhaled nitric oxide (FeNO). Cross-sectional worldwide studies demonstrate that recurrent wheezer infant<a class="elsevierStyleCrossRef" href="#bib0300">28</a> or pre-schoolers<a class="elsevierStyleCrossRefs" href="#bib0305">29,30</a> with positive API have significant higher FeNO than those with negative API or healthy controls. A recent report from the ALSPAC birth cohort<a class="elsevierStyleCrossRef" href="#bib0315">31</a> showed that compared to never/infrequent wheeze during the first seven years of life, FeNO (assessed at 14–15 years) was significantly higher in intermediate-onset, late-onset and persistent wheezer phenotypes, and lower FEV1:FVC ratio and FEF25–75 (measured by spirometry at 14–15 years) were seen in those with intermediate-onset and persistent wheezing. Recently, the CAPS birth cohort<a class="elsevierStyleCrossRef" href="#bib0320">32</a> using a latent transition model that can allow to see changes or transition of wheezing phenotype over time (from 1.5 years to 11.5 years) found that transition between phenotypes was common in early childhood, but less common in later childhood. The atopic asthma phenotype was much more stable over time (over 80%) and non-atopic asthma phenotype was less stable.This study has limitations. First, no lung function before recurrent wheezing episodes or controller therapy was done. Second, no information about other factors that could influence lung function (e.g. secondhand-tobacco exposure or hospitalisation due to wheezing episodes) was available. Third, no exact data on duration of controller therapy was recorded; yet all of the patients were treated with ICS for at least six months. However, all except one of the enrolment pre-schoolers finished the study and correctly performed the spirometry/IOS tests according to international guidelines.In conclusion, recurrent wheezers pre-schoolers positive API with ICS had significantly higher basal central airway resistance (at 20Hz), and higher response post-BD (% change in FEF25–75 and in FEV0.5) than positive API without ICS, suggesting a kind of airway dysfunction. More studies are needed to confirm these findings.Conflicts of interestThe authors declare that there are no conflicts of interest.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." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres802991" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 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" => "xpalclavsec801323" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Statistical analysis" ] ] ] 4 => array:2 [ "identificador" => "sec0020" "titulo" => "Results" ] 5 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflicts of interest" ] 7 => array:3 [ "identificador" => "sec0035" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Confidentiality of data" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Right to privacy and informed consent" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Protection of human subjects and animals in research" ] ] ] 8 => array:2 [ "identificador" => "xack269021" "titulo" => "Acknowledgments" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-04-18" "fechaAceptado" => "2016-05-27" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec801323" "palabras" => array:7 [ 0 => "Asthma" 1 => "Wheezing" 2 => "Preschool" 3 => "Asthma predictive index" 4 => "Lung function" 5 => "IOS" 6 => "Spirometry" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectiveTo measure lung function by impulse oscillometry (IOS) and spirometry in recurrent wheezer pre-schoolers according to their asthma predictive index (API) condition. MethodsWe performed a case–control study enrolling all pre-schoolers with recurrent wheezing episodes (>3 episodes confirmed by physician) who presented at a paediatric pulmonology clinic. The population was divided according to stringent API criteria into positive or negative. ResultsIn the nine-month period, 109 pre-schoolers were enrolled. After excluding one patient (due to lung function technique problems) 108 pre-schoolers (56 males, age range from 24 to 72 months) completed the study; 50 belong to positive API and 58 to negative API group. There were no differences in demographics between groups. More use of ICS was found in those with positive API than with negative API (62% vs. 12%, respectively, p=0.001). No differences in basal lung function and post-bronchodilator response to salbutamol (by IOS or spirometry) were found between positive and negative API pre-schoolers. However, those positive API pre-schoolers with ICS had significantly higher central basal airway resistance (RA at 20Hz) and higher post-BD response (% change in FEF25–75 and in FEV0.5) than those positive API without ICS. ConclusionRecurrent wheezer pre-schoolers with positive API and ICS used may have airway dysfunction. More studies are needed to confirm this finding." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1362 "Ancho" => 1452 "Tamanyo" => 80360 ] ] "descripcion" => array:1 [ "en" => "Comparison in basal central airway resistance (R20) by IOS, and post BD changes in FEV0.5 and FEF25–75 by spirometry, between positive API with and without ICS. Footnote: API, asthma predictive index; BD, bronchodilator; FEF, mid forced expiratory force; FEV0.5, forced expiratory volume in 0.5s; ICS, inhaled corticosteroids; IOS, impulse oscillometry." ] ] 1 => 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:2 [ "leyenda" => "Numbers are expressed in % or median±SD.API, asthma predictive index; ICS, inhaled corticosteroids; LTRA, leukotriene antagonist." "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="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Positive API n=50 \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">Negative API n=58 \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">p Value \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">Gender (% male) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.721 \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">Age (months) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53.8±13.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">54.6±10.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.733 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nutritional status \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.88 \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">Eutrophic (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Overweight (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Obese (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Risk of malnourishment (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weight (kg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19.9±3.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20.2±3.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.676 \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">Height (cm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">103±8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">108.9±8.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.42 \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">Use of ICS (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">62 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.001 \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">Use of LTRA (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1347760.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Demographic characteristics between pre-schoolers with positive and negative API." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Numbers are expressed in median [interquartile range].BD, bronchodilator; FEF, mid forced expiratory force; FEV, forced expiratory volume in 0.5s or 1s; FVC, forced vital capacity; R 5Hz, resistance at 5Hz; R 20Hz, resistance at 20Hz; X 5Hz, reactance at 5Hz." "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="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Positive API n=50 \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">Negative API n=58 \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">p Value \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top">IOS pre-BD:</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">X 5Hz, % of predicted \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">75.0 [99.5–37.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">63.0 [114.0–18.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.886 \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">R 5Hz, % of predicted \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">121.5 [147.5–99.5] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">114.0 [134.0–93.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.444 \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">R 20Hz, % of predicted \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">84.0 [103.0–75.5] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">81.5 [103.0–69.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.381 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top">IOS post-BD (% of change):</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">R 5Hz \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−21.0 [−7.0 to −30.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−18.0 [1.0 to −32.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.390 \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">R 20Hz \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−17.0 [2.0 to −28.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−11.5 [6.0 to −20.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.290 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top">Spirometry pre-BD:</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FVC, % of predicted \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">113.0 [130.0–100.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">111.0 [127.0–98.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.414 \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">FEV0.5, % of predicted \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">101.0 [117.0–86.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">96.0 [108.0–81.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.235 \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, % of predicted \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">105.0 [120.0–89.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">100.0 [111.0–89.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.353 \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, % of predicted \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">96.0 [114.0–73.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">90.0 [111.5–69.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.365 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top">Spirometry post-BD (%change)</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FVC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.0 [12.0–1.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.0 [0.3–9] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.489 \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">FEV0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.5 [20.5–2.5] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14.5 [24.0–1.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.387 \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.0 [12.0–1.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.0 [18.0–0.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.859 \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13.0 [35.0–1.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26.0 [60.0–7.0] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.067 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1347759.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Lung function (by IOS and spirometry) between pre-schoolers with positive and negative API." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:32 [ 0 => array:3 [ "identificador" => "bib0165" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Asthma and wheezing in the first six years of life. 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V. Lezanaa,b, A. Gajardob, L. Bofillb, M. Gutierreza, S. Moraa, J.A. Castro-Rodriguezc,

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jacastro17@homail.com

Corresponding author.

a Hospital Naval Almirante Nef, Viña del Mar, Chile

b Department of Pediatrics, School of Medicine, Universidad de Valparaiso, Chile

c Division of Pediatrics, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile

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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Comparison in basal central airway resistance &#40;R20&#41; by IOS&#44; and post BD changes in FEV<span class="elsevierStyleInf">0&#46;5</span> and FEF<span class="elsevierStyleInf">25&#8211;75</span> by spirometry&#44; between positive API with and without ICS&#46; <span class="elsevierStyleItalic">Footnote</span>&#58; API&#44; asthma predictive index&#59; BD&#44; bronchodilator&#59; FEF&#44; mid forced expiratory force&#59; FEV0&#46;5&#44; forced expiratory volume in 0&#46;5<span class="elsevierStyleHsp" style=""></span>s&#59; ICS&#44; inhaled corticosteroids&#59; IOS&#44; impulse oscillometry&#46;</p>"
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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">Wheezing is a common symptom in the first years of life&#44; but a minority of children will continue to experience wheezing symptoms in school years and beyond&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">1</span></a> Based on the epidemiological data on the natural history and temporal patterns of wheezing&#44; several childhood wheezing phenotypes have been described&#46; However&#44; the use of these &#8220;epidemiological&#8221; phenotypes of wheezing is limited&#44; since they can only be identified retrospectively&#59; indeed&#44; they were defined using statistical inference on longitudinally collected data&#44; and not useful in the present as they are defined by events that will occur in the future&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">2</span></a> Thus&#44; it has been proposed that wheezing phenotypes be based on the trigger&#40;s&#41; and temporality of symptoms &#40;such as episodic viral wheeze &#91;EVW&#93; and multiple-trigger wheeze &#91;MTW&#93;&#41; which can be ascertained in a clinic and could be more practical for making treatment decisions&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">3</span></a> However&#44; it was reported that EVW and MTW had considerable overlap<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">4</span></a>&#59; showing conflicting results as these differ in clinical features and have limited value in predicting asthma at school age&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In the past 15 years&#44; the diagnosis of asthma has hinged on the ability to predict the persistence of asthma at six years&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">6</span></a> Several asthma predictive rules have emerged&#46; The Asthma Predictive Index &#40;API&#41;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">7</span></a> used clinical parameters &#40;paternal asthma&#44; rhinitis&#44; dermatitis&#44; wheezing without cold and eosinophils in peripheral blood&#41; and originally developed in the Tucson cohort study&#44; is the most widely used&#46; The API is simple and cheap&#44; and its major strength is its good positive likelihood ratio &#8764;7&#46;4 &#40;the post-test probability of disease can improve from 2 to 7 times&#41; and high specificity &#40;&#8764;97&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Children with persistent wheeze&#44; frequent asthma exacerbations&#44; and multiple early atopy have diminished lung function &#40;measured by specific airway resistance &#91;sRaw&#93;&#41; throughout childhood&#44; and are at risk of a progressive loss of lung function from age 3 to 11 years&#59; these effects are more marked in boys&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">9</span></a> One study from the Tucson cohort suggested that for persistent wheezers the deficit in lung function is not present soon after birth &#40;lung function measure at age four weeks by chest compression technique &#91;RCT&#93;&#41;&#44; but is acquired by age six years &#40;measured by spirometry&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">However&#44; few studies on lung function and bronchodilator response were performed in children with API characteristics&#46; A study on young Spanish children with a positive API had significant lower lung function &#40;measured by RCT&#41; than those with negative API&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">10</span></a> A trial in recurrent wheeze pre-schoolers with positive API or a positive screening test for atopy treated with inhaled corticosteroids &#40;ICS&#41; for 24 weeks modestly reduces wheeze exacerbation rates and improves lung function &#40;measured by spirometry&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">11</span></a> A previous trial showed that ICS for 24 months improves lung function&#44; but the effect disappears after the treatment is discontinued&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">12</span></a> However&#44; no group of pre-schoolers with negative API was involved in those trials&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The objective of this case&#8211;control study is to compare the lung function &#40;measured by impulse oscillometry &#91;IOS&#93; and spirometry&#41; and post-bronchodilator &#40;post-BD&#41; response to salbutamol among pre-schoolers with positive and negative API&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">We prospectively enrolled all the recurrent wheezing pre-schoolers attended at the paediatric pulmonology clinic at Hospital Almirante Nef&#44; Vi&#241;a del Mar&#44; Chile&#44; during a nine-month period &#40;May 2012 to February 2013&#41;&#46; In accordance with international guidelines&#44; their paediatricians treated each child with ICS &#40;fluticasone propionate 125<span class="elsevierStyleHsp" style=""></span>mcg bid or budesonide 200<span class="elsevierStyleHsp" style=""></span>mcg bid by metered dose inhaler and spacer with face mask&#41; or montelukast &#40;4<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">13</span></a> The study was approved by the local ethics committee and parents gave written informed consent&#46; Inclusion criteria&#58; aged two to six years of age with recurrent wheezing&#44; defined as having three or more wheezing episodes &#40;confirmed by paediatrician&#41; in the previous year&#59; received ICS or montelukast for at least six months&#59; and correctly performed IOS and spirometry according to ATS&#47;ERS recommendation&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">14</span></a> Exclusion criteria&#58; cardiac or other chronic respiratory diseases &#40;e&#46;g&#46; cystic fibrosis&#44; bronchopulmonary dysplasia&#44; post-infectious bronchiolitis obliterans&#44; ciliary dyskinesia&#41;&#44; airway malformations&#44; endocrinological and neurological diseases&#44; prematurity &#40;&#60;37 weeks&#41;&#44; low weight for gestational age&#44; undernourishment&#44; parental or guardian failure to sign the informed consent form&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">A predefined questionnaire with demographic data and peripheral blood sample &#40;during asymptomatic period&#41; were performed on the children&#46; According to the presence of stringent API<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">6</span></a> we divided the population into two groups&#58; positive API if they had one major or two minor criteria&#44; or negative API if they did not fulfil those criteria&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Pulmonary lung function was performed only if the child was free of respiratory symptoms in the previous four weeks and following this protocol&#58; first basal IOS&#44; then basal spirometry&#44; and finally post-BD measurements by IOS and spirometry after 15<span class="elsevierStyleHsp" style=""></span>min of using two puffs &#40;100<span class="elsevierStyleHsp" style=""></span>mcg&#47;puff&#41; of salbutamol &#40;Fesema<span class="elsevierStyleSup">&#174;</span>&#44; GSK&#44; Aranda de Duero&#44; Spain&#41; administered with three minutes of separation in between puffs and using a spacer with face mask &#40;AeroChamber Plus&#174; Flow-Vu&#174;&#44; Monaghan Medical Corp&#46;&#44; USA&#41;&#46; ICS treatment was not discontinued at the moment of lung function measurement&#46; Weight and height were measured before lung function&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The IOS was done by one paediatric lung function technician &#40;SMO&#41;&#46; For all subjects&#44; three replicate measurements of impedance respiratory &#40;Zrs&#41; were obtained using the system software &#40;MasterScreen-IOS&#44; Jaeger&#174; Co&#44; Germany&#41;&#46; Impedance measurements were retained for analysis if reproducible&#44; that is&#44; if the coefficient of variation between replicates measurements was &#60;10&#37;&#46; Briefly&#44; the sitting child was asked to breathe for 15&#8211;20<span class="elsevierStyleHsp" style=""></span>s using a rigid oval mouthpiece with a tongue guard&#44; with the head in a neutral position&#44; nose clip in place&#44; and while supporting both cheeks&#46; For the respiratory system&#44; resistance represents the effective resistance of lungs and chest wall&#44; whereas reactance is the net effect of the two opposite &#40;one compliant and one inertial&#41; components&#46; Each recording on the MasterScreen IOS assessment yielded both the expiratory resistance &#40;R5 and R20&#41; and reactance &#40;X5&#41; &#91;kPa&#47;l&#47;s&#93; at different oscillatory frequencies between 5<span class="elsevierStyleHsp" style=""></span>Hz and 35<span class="elsevierStyleHsp" style=""></span>Hz within the flow range of normal tidal breathing&#46; R5 measure the total resistance &#40;central and peripheral&#41;&#44; R20 the central resistance and X5 the peripheral reactance&#46; In addition&#44; the resonant frequency &#40;Fres&#41; &#91;i&#46;e&#46; the frequency at which the reactance was zero&#93; was also computed&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The spirometry &#40;Jaeger Master-Screen&#174;&#41; was also performed by SMO&#46; None of the participants had performed a spirometry before&#59; each child did all possible expiratory force curves over a 15-minute period&#44; with a nasal clip &#40;unless it was not tolerated&#41; and standing&#46; Sometimes&#44; according to operator criteria&#44; animation programmes included in the software &#40;e&#46;g&#46; candles&#44; balloons&#41; were used&#46; We considered as acceptable spirometric curves those with evident peak expiratory forced &#40;PEF&#41;&#44; without abrupt end of flow &#62;10&#37; of PEF&#44; with expiratory time &#62;0&#46;5<span class="elsevierStyleHsp" style=""></span>s and without evidence of cough or glottis closure&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">14</span></a> For each test&#44; we recorded time-volume and flow-volume curves and tabulated the real expiratory time of the curve with the best forced vital capacity &#40;FVC&#41;&#46; Moreover&#44; to calculate the reproducibility&#44; variation coefficient&#44; and coefficient of repeatability&#44; we registered the three best basal forced expiratory volume &#40;FEV&#41;<span class="elsevierStyleInf">0&#46;5</span>&#44; FEV<span class="elsevierStyleInf">1</span>&#44; flow expiratory forced &#40;FEF&#41;<span class="elsevierStyleInf">25&#8211;75</span>&#44; FEF<span class="elsevierStyleInf">25</span>&#44; FEF<span class="elsevierStyleInf">50</span> and FEF<span class="elsevierStyleInf">75</span> values for each patient&#46; Since no local spirometry reference values exist for pre-schoolers&#44; we used values from the Spanish population&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">15</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Statistical analysis</span><p id="par0055" class="elsevierStylePara elsevierViewall">We compared children in the positive and negative API groups&#46; For categorical variables&#44; contingency tables were used &#40;chi2 with Fisher exact test&#41;&#46; For continuous variables with normal distribution&#44; an average comparison and analysis of variance &#40;ANOVA&#41; were used&#59; and Wilcoxon test was used in other cases&#46; For lung function variables between groups&#44; a Mann&#8211;Whitney was performed&#59; and Pearson correlation was used for comparing the post-BD response to salbutamol&#46; Statistically significant differences were considered for a <span class="elsevierStyleItalic">p</span> value &#60;0&#46;05&#46; All statistical analyses were done with STATA<span class="elsevierStyleSup">&#174;</span> software v&#46;11&#46;0&#46; To ensure that the bronchodilator response was a clinically significant change and was not due to technique variability&#44; we considered it above the coefficient of repeatability&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">14</span></a></p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Results</span><p id="par0060" class="elsevierStylePara elsevierViewall">In the nine-month period&#44; we enrolled 109 pre-schoolers&#46; One patient &#40;belonging to the positive API&#41; was excluded because of being unable to correctly perform lung function &#40;post-BD IOS&#41;&#44; therefore 108 pre-schoolers &#40;56 males&#44; age range from 24 to 72 months&#41; completed the study&#59; 50 belong to positive API and 58 to negative API group&#46; There were no differences in demographic parameters &#40;e&#46;g&#46; age&#44; gender&#44; nutritional status&#44; weight and height&#41; between groups &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; There was more prevalence of ICS used in the pre-schoolers with positive API than negative API &#40;62&#37; vs&#46; 12&#37;&#44; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; No difference in ICS type and daily doses was found between groups &#40;data not shown&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">In terms of lung function &#40;&#37; of predicted&#41;&#44; no significant difference between positive and negative API pre-schoolers was found in the basal or post-BD response in all the parameters in neither the IOS nor the spirometry &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; In order to see if the effect of ICS therapy can modify the lung function&#44; we did a comparison in pre-schoolers with positive API between those who used ICS &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>31&#41; vs&#46; did not use ICS &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>19&#41;&#46; The only significant parameters between positive API with ICS vs&#46; positive API without ICS were&#58; basal resistance at 20<span class="elsevierStyleHsp" style=""></span>Hz &#40;median &#91;interquartile range&#93;&#41; 89&#37; &#91;79&#8211;108&#93; vs&#46; 81&#37; &#91;67&#8211;99&#93;&#44; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;047&#41;&#44; post-BD change FEF<span class="elsevierStyleInf">25&#8211;75</span> &#40;20&#46;5&#37; &#91;2&#8211;48&#93; vs&#46; 6&#46;5&#37; &#91;&#8722;2 to 23&#93;&#41;&#44; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;043&#41;&#44; and post-BD change FEV<span class="elsevierStyleInf">0&#46;5</span> &#40;3&#46;5&#37; &#40;&#91;3&#8211;24&#93; vs&#46; 6&#46;5&#37; &#91;&#8722;1 to 12&#93;&#44; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;047&#41;&#44; <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#46; No significant differences were observed in IOS or spirometry parameters between pre-schoolers with negative API who used ICS &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41; vs&#46; did not use ICS &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>51&#41; &#40;data not shown&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Discussion</span><p id="par0070" class="elsevierStylePara elsevierViewall">This case&#8211;control study shows that recurrent wheeze pre-schoolers with positive API had similar lung function &#40;measured by IOS and spirometry&#41; to those with negative API&#46; However&#44; those positive API pre-schoolers with ICS had significantly higher basal central airway resistance at 20<span class="elsevierStyleHsp" style=""></span>Hz&#44; and higher post-BD response in flow &#40;&#37; change in FEF<span class="elsevierStyleInf">25&#8211;75</span> and in FEV<span class="elsevierStyleInf">0&#46;5</span>&#41; than those positive API without ICS&#44; suggesting that a kind of airway dysfunction occurred in the former&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">To our knowledge&#44; only two other studies have measured lung function in pre-schoolers according to API condition&#46; Borrego et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">16</span></a> using tidal and raised volume RTC in 50 recurrent wheezer pre-schoolers &#40;aged 8&#8211;20 months&#41; prior to receiving ICS or montelukast found that compared with healthy controls&#44; those pre-schoolers with positive API &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>17&#41; or negative API &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>33&#41; had significantly lower FEV<span class="elsevierStyleInf">0&#46;5</span>&#44; FEF<span class="elsevierStyleInf">75</span> and FEF<span class="elsevierStyleInf">25&#8211;75</span>&#46; After controlling for confounders&#44; FVC <span class="elsevierStyleItalic">z</span>-score was significantly reduced in the positive API vs&#46; negative API by 45<span class="elsevierStyleHsp" style=""></span>ml &#91;&#8722;89 to &#8722;2<span class="elsevierStyleHsp" style=""></span>ml&#93;&#59; whereas&#44; despite a trend towards lower values among positive API&#44; there were no significant differences in FEV<span class="elsevierStyleInf">0&#46;5</span> or FEF<span class="elsevierStyleInf">25&#8211;75</span>&#46; Later&#44; Keklikian et al&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">10</span></a> measured lung function by using RCT in recurrent wheezer infants &#40;11&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;9 months of age&#41;&#46; Then&#44; they adjusted by covarirantes and found that infants with positive API &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>51&#41; had significant lower <span class="elsevierStyleItalic">V</span><span class="elsevierStyleInf">max</span>FRC <span class="elsevierStyleItalic">z</span>-score than those with negative API &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41; &#40;2&#46;01<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;79 vs&#46; 1&#46;64<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;77&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;026&#44; respectively&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">We can speculate that in the present study pre-schoolers positive API with ICS have higher central airway resistance &#40;increased RA at 20<span class="elsevierStyleHsp" style=""></span>Hz&#41; and higher BD response &#40;in FEV<span class="elsevierStyleInf">0&#46;5</span> and FEF<span class="elsevierStyleInf">25&#8211;75</span>&#41; than positive API without ICS because the former have more severe disease that make their paediatricians more prone to prescribe ICSs&#46; However&#44; unfortunately we do not have information about severity of recurrent wheezing in our population&#46; Nevertheless&#44; in general those pre-schoolers with ICS had a higher proportion of peripheral eosinophils &#62;4&#37; than those without ICS &#40;data not shown&#41;&#46; It is well known that high peripheral eosinophils is a marker for asthma severity in children and adult population&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">17</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In a post hoc study on pre-schoolers aged four&#44;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">18</span></a> atopic pre-schoolers with asthma had significantly more BD response to albuterol in the IOS parameters &#40;RA at 5<span class="elsevierStyleHsp" style=""></span>Hz&#44; RA at 10<span class="elsevierStyleHsp" style=""></span>Hz&#44; and reactance at 10<span class="elsevierStyleHsp" style=""></span>Hz&#41; than atopic children without asthma&#59; but no difference was seen in the spirometry&#46; Among non-atopic children&#44; there were no significant differences between asthmatic and non-asthmatic children at baseline or post-BD response measured by IOS nor spirometry&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">18</span></a> However&#44; a study on 325 children &#40;four years of age&#41; showed that those children with persistent wheeze phenotype had significant larger baseline resistance at 4<span class="elsevierStyleHsp" style=""></span>Hz &#40;measured by force oscillation technique&#41; than children with early transient wheeze&#44; and the decrease in post-BD resistance at 4<span class="elsevierStyleHsp" style=""></span>Hz was significantly larger than the children who never had wheeze and those with early transient wheeze&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">19</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Data from the Tucson birth cohort showed that children with transient early and persistent wheezers had significantly lower FEF<span class="elsevierStyleInf">25&#8211;75</span>&#44; FEV<span class="elsevierStyleInf">1</span> and FEV&#58;FEV<span class="elsevierStyleInf">1</span> ratio through age 16 years compared with never wheezers&#46; Levels of lung function are established by age six years and do not appear to change significantly by age 16 years&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">1&#44;20</span></a> However&#44; in the COPSAC birth cohort&#44; children developing asthma by age seven had a lung function deficit &#40;FEF<span class="elsevierStyleInf">50</span>&#41; and increased bronchial responsiveness to methacholine as neonates&#59; regardless of their atopic condition&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">21</span></a> Recently&#44; the MAAS birth cohort<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">9</span></a> demonstrated that persistent wheezers &#40;but not transient and late-onset phenotypes&#41; and multiple early atopy &#40;but not dust mite&#44; non-dust mite&#44; multiple late phenotypes&#41; have established airway dysfunction as early as three years of age&#59; possibly because it was at least partly present at birth&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">21&#44;22</span></a> However&#44; since measures of sRaw after BD are not reported in the MAAS birth cohort&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">9</span></a> it is not known whether the observed increase in sRaw is due to increased airway tone or to an effect of remodelling on airway growth&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Low lung function at birth could lead to increased risk for wheeze&#44; as suggested by both the transient and persistent wheeze groups&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">1&#44;21</span></a> In the absence of early environmental sensitisation&#44; the wheezing stops during school age in the transient non-atopic wheeze group&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">23</span></a> In contrast&#44; early allergic airway inflammation exacerbation during viral infections may lead to remodelling&#44; which then impairs airway growth with long-term increase in airway resistance and reduced FEF&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">24</span></a> Recently&#44; a study in severe recurrent wheezer pre-schoolers showed that markers of remodelling and inflammation are unrelated&#44; but atopy is associated with airway smooth muscle&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">25</span></a> In contrast&#44; Saglani et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">26</span></a> reported reticular basement membrane &#40;RBM&#41; thickness in children with confirmed wheezers &#40;median age 29 months&#41; and controls&#44; without difference in atopy characteristic&#46; However&#44; Berankova et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">27</span></a> reported a significant difference in the thickness of the RBM between pre-schoolers &#40;median age 13&#46;5 months&#41; with major criteria of the API &#40;parental asthma or atopic eczema&#41; before any wheezing episode occurred vs&#46; controls&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">A non-invasive common way to determine eosinophil airway inflammation is by exhaled nitric oxide &#40;FeNO&#41;&#46; Cross-sectional worldwide studies demonstrate that recurrent wheezer infant<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">28</span></a> or pre-schoolers<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">29&#44;30</span></a> with positive API have significant higher FeNO than those with negative API or healthy controls&#46; A recent report from the ALSPAC birth cohort<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">31</span></a> showed that compared to never&#47;infrequent wheeze during the first seven years of life&#44; FeNO &#40;assessed at 14&#8211;15 years&#41; was significantly higher in intermediate-onset&#44; late-onset and persistent wheezer phenotypes&#44; and lower FEV<span class="elsevierStyleInf">1</span>&#58;FVC ratio and FEF<span class="elsevierStyleInf">25&#8211;75</span> &#40;measured by spirometry at 14&#8211;15 years&#41; were seen in those with intermediate-onset and persistent wheezing&#46; Recently&#44; the CAPS birth cohort<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">32</span></a> using a latent transition model that can allow to see changes or transition of wheezing phenotype over time &#40;from 1&#46;5 years to 11&#46;5 years&#41; found that transition between phenotypes was common in early childhood&#44; but less common in later childhood&#46; The atopic asthma phenotype was much more stable over time &#40;over 80&#37;&#41; and non-atopic asthma phenotype was less stable&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">This study has limitations&#46; First&#44; no lung function before recurrent wheezing episodes or controller therapy was done&#46; Second&#44; no information about other factors that could influence lung function &#40;e&#46;g&#46; secondhand-tobacco exposure or hospitalisation due to wheezing episodes&#41; was available&#46; Third&#44; no exact data on duration of controller therapy was recorded&#59; yet all of the patients were treated with ICS for at least six months&#46; However&#44; all except one of the enrolment pre-schoolers finished the study and correctly performed the spirometry&#47;IOS tests according to international guidelines&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In conclusion&#44; recurrent wheezers pre-schoolers positive API with ICS had significantly higher basal central airway resistance &#40;at 20<span class="elsevierStyleHsp" style=""></span>Hz&#41;&#44; and higher response post-BD &#40;&#37; change in FEF<span class="elsevierStyleInf">25&#8211;75</span> and in FEV<span class="elsevierStyleInf">0&#46;5</span>&#41; than positive API without ICS&#44; suggesting a kind of airway dysfunction&#46; More studies are needed to confirm these findings&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflicts of interest</span><p id="par0115" class="elsevierStylePara elsevierViewall">The authors declare that there are no conflicts of interest&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Ethical disclosures</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Confidentiality of data</span><p id="par0120" 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="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Right to privacy and informed consent</span><p id="par0125" 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="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Protection of human subjects and animals in research</span><p id="par0130" 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>"
    "textoCompletoSecciones" => array:1 [
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          "identificador" => "xres802991"
          "titulo" => "Abstract"
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          "identificador" => "xpalclavsec801323"
          "titulo" => "Keywords"
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          "titulo" => "Introduction"
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          "titulo" => "Methods"
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        5 => array:2 [
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        6 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Conflicts of interest"
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        7 => array:3 [
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          "titulo" => "Ethical disclosures"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Confidentiality of data"
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            1 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Right to privacy and informed consent"
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            2 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Protection of human subjects and animals in research"
            ]
          ]
        ]
        8 => array:2 [
          "identificador" => "xack269021"
          "titulo" => "Acknowledgments"
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        9 => array:1 [
          "titulo" => "References"
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    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2016-04-18"
    "fechaAceptado" => "2016-05-27"
    "PalabrasClave" => array:1 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec801323"
          "palabras" => array:7 [
            0 => "Asthma"
            1 => "Wheezing"
            2 => "Preschool"
            3 => "Asthma predictive index"
            4 => "Lung function"
            5 => "IOS"
            6 => "Spirometry"
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    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To measure lung function by impulse oscillometry &#40;IOS&#41; and spirometry in recurrent wheezer pre-schoolers according to their asthma predictive index &#40;API&#41; condition&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We performed a case&#8211;control study enrolling all pre-schoolers with recurrent wheezing episodes &#40;&#62;3 episodes confirmed by physician&#41; who presented at a paediatric pulmonology clinic&#46; The population was divided according to stringent API criteria into positive or negative&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">In the nine-month period&#44; 109 pre-schoolers were enrolled&#46; After excluding one patient &#40;due to lung function technique problems&#41; 108 pre-schoolers &#40;56 males&#44; age range from 24 to 72 months&#41; completed the study&#59; 50 belong to positive API and 58 to negative API group&#46; There were no differences in demographics between groups&#46; More use of ICS was found in those with positive API than with negative API &#40;62&#37; vs&#46; 12&#37;&#44; respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; No differences in basal lung function and post-bronchodilator response to salbutamol &#40;by IOS or spirometry&#41; were found between positive and negative API pre-schoolers&#46; However&#44; those positive API pre-schoolers with ICS had significantly higher central basal airway resistance &#40;RA at 20<span class="elsevierStyleHsp" style=""></span>Hz&#41; and higher post-BD response &#40;&#37; change in FEF<span class="elsevierStyleInf">25&#8211;75</span> and in FEV<span class="elsevierStyleInf">0&#46;5</span>&#41; than those positive API without ICS&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Recurrent wheezer pre-schoolers with positive API and ICS used may have airway dysfunction&#46; More studies are needed to confirm this finding&#46;</p></span>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Comparison in basal central airway resistance &#40;R20&#41; by IOS&#44; and post BD changes in FEV<span class="elsevierStyleInf">0&#46;5</span> and FEF<span class="elsevierStyleInf">25&#8211;75</span> by spirometry&#44; between positive API with and without ICS&#46; <span class="elsevierStyleItalic">Footnote</span>&#58; API&#44; asthma predictive index&#59; BD&#44; bronchodilator&#59; FEF&#44; mid forced expiratory force&#59; FEV0&#46;5&#44; forced expiratory volume in 0&#46;5<span class="elsevierStyleHsp" style=""></span>s&#59; ICS&#44; inhaled corticosteroids&#59; IOS&#44; impulse oscillometry&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Numbers are expressed in &#37; or median<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">API&#44; asthma predictive index&#59; ICS&#44; inhaled corticosteroids&#59; LTRA&#44; leukotriene antagonist&#46;</p>"
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                  \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="" valign="top" scope="col" style="border-bottom: 2px solid black">&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">Positive API<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>50&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">Negative API<br><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>58&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"><span class="elsevierStyleItalic">p</span> Value&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"><span class="elsevierStyleItalic">Gender &#40;&#37; male&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;721&nbsp;\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"><span class="elsevierStyleItalic">Age &#40;months&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">54&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;733&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Nutritional status</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;88&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Eutrophic &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Overweight &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Obese &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>Risk of malnourishment &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Weight &#40;kg&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">20&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;676&nbsp;\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"><span class="elsevierStyleItalic">Height &#40;cm&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">103<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">108&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;42&nbsp;\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"><span class="elsevierStyleItalic">Use of ICS &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">62&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">&#60;0&#46;001</span>&nbsp;\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"><span class="elsevierStyleItalic">Use of LTRA &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Numbers are expressed in median &#91;interquartile range&#93;&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">BD&#44; bronchodilator&#59; FEF&#44; mid forced expiratory force&#59; FEV&#44; forced expiratory volume in 0&#46;5<span class="elsevierStyleHsp" style=""></span>s or 1<span class="elsevierStyleHsp" style=""></span>s&#59; FVC&#44; forced vital capacity&#59; R 5<span class="elsevierStyleHsp" style=""></span>Hz&#44; resistance at 5<span class="elsevierStyleHsp" style=""></span>Hz&#59; R 20<span class="elsevierStyleHsp" style=""></span>Hz&#44; resistance at 20<span class="elsevierStyleHsp" style=""></span>Hz&#59; X 5<span class="elsevierStyleHsp" style=""></span>Hz&#44; reactance at 5<span class="elsevierStyleHsp" style=""></span>Hz&#46;</p>"
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                  \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="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">IOS pre-BD&#58;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>X 5<span class="elsevierStyleHsp" style=""></span>Hz&#44; &#37; of predicted&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;886&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>R 5<span class="elsevierStyleHsp" style=""></span>Hz&#44; &#37; of predicted&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;444&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>R 20<span class="elsevierStyleHsp" style=""></span>Hz&#44; &#37; of predicted&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">84&#46;0 &#91;103&#46;0&#8211;75&#46;5&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">81&#46;5 &#91;103&#46;0&#8211;69&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;381&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">IOS post-BD &#40;&#37; of change&#41;&#58;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>R 5<span class="elsevierStyleHsp" style=""></span>Hz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;21&#46;0 &#91;&#8722;7&#46;0 to &#8722;30&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;390&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>R 20<span class="elsevierStyleHsp" style=""></span>Hz&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#8722;17&#46;0 &#91;2&#46;0 to &#8722;28&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;290&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Spirometry pre-BD&#58;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FVC&#44; &#37; of predicted&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">113&#46;0 &#91;130&#46;0&#8211;100&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;414&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>FEV<span class="elsevierStyleInf">0&#46;5</span>&#44; &#37; of predicted&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">101&#46;0 &#91;117&#46;0&#8211;86&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">100&#46;0 &#91;111&#46;0&#8211;89&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;365&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Spirometry post-BD &#40;&#37;change&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>FVC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;0 &#91;12&#46;0&#8211;1&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;0 &#91;0&#46;3&#8211;9&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;489&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>FEV<span class="elsevierStyleInf">0&#46;5</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&#46;5 &#91;20&#46;5&#8211;2&#46;5&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#46;5 &#91;24&#46;0&#8211;1&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;387&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>FEV<span class="elsevierStyleInf">1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;0 &#91;12&#46;0&#8211;1&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;859&nbsp;\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"><span class="elsevierStyleHsp" style=""></span>FEF<span class="elsevierStyleInf">25&#8722;75</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&#46;0 &#91;35&#46;0&#8211;1&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">26&#46;0 &#91;60&#46;0&#8211;7&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;067&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Lung function &#40;by IOS and spirometry&#41; between pre-schoolers with positive and negative API&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:32 [
            0 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
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                      "autores" => array:1 [
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                            0 => "F&#46;D&#46; Martinez"
                            1 => "A&#46;L&#46; Wright"
                            2 => "L&#46;M&#46; Taussig"
                            3 => "C&#46;J&#46; Holberg"
                            4 => "M&#46; Halonen"
                            5 => "W&#46;J&#46; Morgan"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM199501193320301"
                      "Revista" => array:6 [
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                            "web" => "Medline"
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                    ]
                  ]
                ]
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            1 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                      "autores" => array:1 [
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                          "etal" => false
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                            1 => "D&#46;T&#46; Mauger"
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                  "host" => array:1 [
                    0 => array:2 [
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            2 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "3"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Definition&#44; assessment and treatment of wheezing disorders in preschool children&#58; an evidence-based approach"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46;L&#46; Brand"
                            1 => "E&#46; Baraldi"
                            2 => "H&#46; Bisgaard"
                            3 => "A&#46;L&#46; Boner"
                            4 => "J&#46;A&#46; Castro-Rodriguez"
                            5 => "A&#46; Custovic"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                      "Revista" => array:6 [
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                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
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            3 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The transient value of classifying preschool wheeze into episodic viral wheeze and multiple trigger wheeze"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46; Schultz"
                            1 => "S&#46;G&#46; Devadason"
                            2 => "O&#46;E&#46; Savenije"
                            3 => "P&#46;D&#46; Sly"
                            4 => "P&#46;N&#46; Le Souef"
                            5 => "P&#46;L&#46; Brand"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
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Article information

ISSN: 03010546
Original language: English

DOI:10.1016/j.aller.2016.05.006

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	4	0	4
2024 October	19	7	26
2024 September	32	8	40
2024 August	30	8	38
2024 July	20	6	26
2024 June	18	1	19
2024 May	21	3	24
2024 April	17	9	26
2024 March	17	6	23
2024 February	16	14	30
2024 January	411	11	422
2023 December	25	12	37
2023 November	19	4	23
2023 October	38	17	55
2023 September	23	7	30
2023 August	20	12	32
2023 July	28	30	58
2023 June	20	9	29
2023 May	41	6	47
2023 April	39	1	40
2023 March	31	9	40
2023 February	32	5	37
2023 January	24	10	34
2022 December	48	11	59
2022 November	42	10	52
2022 October	26	16	42
2022 September	23	8	31
2022 August	24	10	34
2022 July	26	15	41
2022 June	35	9	44
2022 May	50	13	63
2022 April	70	8	78
2022 March	119	9	128
2022 February	123	9	132
2022 January	104	4	108
2021 December	76	14	90
2021 November	69	16	85
2021 October	36	18	54
2021 September	23	13	36
2021 August	34	13	47
2021 July	24	13	37
2021 June	29	12	41
2021 May	26	8	34
2021 April	52	33	85
2021 March	31	17	48
2021 February	21	19	40
2021 January	16	12	28
2020 December	3	1	4
2020 October	1	1	2
2020 September	0	1	1
2020 August	0	3	3
2020 July	0	2	2
2020 June	0	1	1
2020 May	0	3	3
2020 April	0	1	1
2020 March	0	2	2
2020 January	0	9	9
2019 December	0	1	1
2019 November	0	7	7
2019 October	0	4	4
2019 August	0	9	9
2019 July	0	2	2
2019 May	0	16	16
2018 February	8	2	10
2018 January	14	3	17
2017 March	1	0	1
2017 February	3	0	3
2016 December	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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