Original Article
Inflammatory Patterns in Asthmatic Children Based on Alveolar Nitric Oxide Determination
Patrones inflamatorios en niños asmáticos basados en la determinación de óxido nítrico alveolar
Paula Corcuera-Eloseguia, Olaia Sardón-Pradoa,b,
, Ane Aldasoro-Ruiza, Javier Korta-Muruaa,b, Javier Mintegui-Aramburua, José I. Emparanza-Knorrc, Eduardo G. Pérez-Yarzaa,b,d
Corresponding author
a Sección de Neumología Infantil, Hospital Universitario Donostia, San Sebastián, Guipúzcoa, Spain
b Departamento de Pediatría, Universidad del País Vasco (UPV/EHU), San Sebastián, Guipúzcoa, Spain
c Unidad de Epidemiología (CIBER-ESP), Hospital Universitario Donostia, San Sebastián, Guipúzcoa, Spain
d Centro de Investigación Biomédica en Red, Enfermedades Respiratorias (CIBERES), San Sebastián, Guipúzcoa, Spain
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PM-stimulated cells generate numerous inflammatory mediators, including IL-6, IL-8, TNF-α, MCP-1, MIP2α and GROα. These can generate a second wave of mediators that include enzymes, such as MMP-9 and MMP-12, involved in tissue remodeling typical of COPD. It has been suggested that TRP ion channels in various lung cells can be activated by PMs in biomass smoke. This would lead to increased cytoplasmic Ca<span class="elsevierStyleSup">2+</span> and an intracellular signaling cascade that would increase the production of these pro-inflammatory mediators. The biological material in biomass smoke PMs (e.g., endotoxin) may also activate pro-inflammatory transcription factors AP-1 y NF-κβ via signaling initiated in the TLR receptors. 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J′aw<span class="elsevierStyleInf">NO</span> vs CA<span class="elsevierStyleInf">NO</span> scatterplot. Normal J′aw<span class="elsevierStyleInf">NO</span><1470 (pl/s) and normal CA<span class="elsevierStyleInf">NO</span><4.5 (ppb) (in purple). Type I (circle): Normal J′aw<span class="elsevierStyleInf">NO</span> and CA<span class="elsevierStyleInf">NO</span>; Type II (<span class="elsevierStyleItalic">x</span>): elevated J′aw<span class="elsevierStyleInf">NO</span> and normal CA<span class="elsevierStyleInf">NO</span>; Type III (cross): elevated J′aw<span class="elsevierStyleInf">NO</span> and CA<span class="elsevierStyleInf">N</span>O; Type IV (triangle): normal J′aw<span class="elsevierStyleInf">NO</span> and elevated CA<span class="elsevierStyleInf">NO</span>.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Asthma is the most common chronic disease of the lower airways in childhood. It presents with bronchial hyperreactivity and variable airflow obstruction, and is characterized by episodes of wheezing, cough and difficulty in breathing.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">International guidelines for the management of asthma<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">1,2</span></a> classify the disease according to its severity or level of control, and do not consider the degree of airway inflammation. However they do suggest studies to evaluate whether monitoring inflammation could improve disease management in clinical practice.<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">3,4</span></a> In this regard, there is evidence indicating that asthma control is correlated with the degree of inflammation, and that symptoms are more severe when this reaches the most distal lung compartments.<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">5,6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">A number of studies have focused on differentiating between the proximal origin of the inflammation (measured indirectly via the fractional exhaled nitric oxide [NO] at a flow of 50<span class="elsevierStyleHsp" style=""></span>ml/s: FE<span class="elsevierStyleInf">NO,50</span>, and maximum airway NO flux: J′aw<span class="elsevierStyleInf">NO</span>) and/or distal inflammation (measured by the alveolar NO concentration: CA<span class="elsevierStyleInf">NO</span>) in children<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">7</span></a> and adults with asthma.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">8</span></a> Elevated CA<span class="elsevierStyleInf">NO</span> values have been related with poorly controlled asthma in children<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">7</span></a> and adults, persistent nocturnal symptoms,<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">9</span></a> poorly controlled severe asthma<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">10</span></a> and disease refractory to treatment,<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">11</span></a> as well as with the risk of exacerbation.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">12</span></a> However, few studies in adults have attempted to classify patients according to the location and/or spread of the inflammation,<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">13</span></a> and even fewer have done so by determining NO in children.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">14</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">One such study, conducted by Puckett et al.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">14</span></a> reported distinct clinical patterns of asthma when asthmatics were classified into 4 inflammatory types based on CA<span class="elsevierStyleInf">NO</span> and J′aw<span class="elsevierStyleInf">NO</span> measurements. Children with elevated CA<span class="elsevierStyleInf">NO</span> values had poorer asthma control and higher morbidity, regardless of atopy, inhaled glucocorticoid therapy, and lung function. Nevertheless, the utility of this compartmentalization in routine practice remains to be clarified, and the technique has not yet been standardized.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The primary objective of this study was to define four inflammatory phenotypes in asthmatic children by determining nitric oxide in the proximal (J′aw<span class="elsevierStyleInf">NO</span>) and distal or alveolar (CA<span class="elsevierStyleInf">NO</span>) airways, and to relate these with their clinical manifestations.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and Methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">This study was approved by the Ethics and Research Committee of the University Hospital where it was conducted. Informed consent was obtained in all cases, and permission to use the data was granted by the parents and/or guardians and the child when required under current legislation due to the child's age.</p><p id="par0035" class="elsevierStylePara elsevierViewall">This was a cross-sectional study with prospective data collection from a consecutive sample of children aged between 6 and 16 years old diagnosed with asthma according to GINA 2012.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">2</span></a> Patients were screened in Pediatric Respiratory Medicine outpatient clinics between January and August 2012. Asthmatic patients with no background treatment and those on inhaled glucocorticoids (IGC) were included. A sample of healthy children of the same age was also recruited during the same period using the same methodology.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Patients with asthma exacerbation or respiratory infection at the time of the visit were excluded. Also excluded were those who declined to participate, those who did not meet the inclusion criteria, those who did not cooperate in performing the required techniques, and those with associated diseases or morbidities.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Asthma severity and level of control were classified according to GINA 2012.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">2</span></a> Allergic rhinitis was defined as signs and symptoms consistent with this diagnosis, allergen-specific immunoglobulin E in blood (class III or higher) and/or skin prick test positive for 1 or more airborne allergens; food allergy as signs and symptoms consistent with this diagnosis and allergen-specific IgE in blood (class III or higher); and atopic dermatitis as signs and symptoms consistent with this diagnosis.<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">2,15</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Prior to the forced spirometry, all study patients underwent determination of single-breath and multiple flow (50, 100 and 200<span class="elsevierStyleHsp" style=""></span>ml/s) exhaled NO using an online system and stationary chemiluminescent analyzer (Eco Medics AG-CLD 88 sp- Switzerland) with DENOX 88 flow adaptors, following <span class="elsevierStyleItalic">European Respiratory Society</span> (ERS) and <span class="elsevierStyleItalic">American Thoracic Society</span> (ATS) recommendations published in 2005.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">16</span></a> The tests were performed in triplicate, and the mean value of the three measurements was calculated for each corresponding flow rate with less than 10% variability.</p><p id="par0055" class="elsevierStylePara elsevierViewall">The Tsoukias and George two-compartment model and equation<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">17</span></a> was applied to calculate the CA<span class="elsevierStyleInf">NO</span> and J′aw<span class="elsevierStyleInf">NO</span>. Although other more complex models have since been developed, we did not use them for this study.<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">18–20</span></a> The flow rate and volume were calibrated daily, and the NO was calibrated monthly.</p><p id="par0060" class="elsevierStylePara elsevierViewall">All study asthmatics underwent forced spirometry (MasterLab. Version 5.3. Viasis<span class="elsevierStyleSup">®</span>, Wuerzburg, Germany) as per ATS/ERS recommendations.<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">21</span></a> Zapletal equations<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">22,23</span></a> were used to calculate the percentage of normal.</p><p id="par0065" class="elsevierStylePara elsevierViewall">The patient's medical history was taken and physical examination carried out; parents (of children aged under 9 years) or the patients themselves (children aged over 9 years) were also asked to complete the asthma control questionnaire (CAN).<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">24</span></a> The CAN questionnaire consists of nine questions related to symptoms presented in the past 4 weeks, with four possible answers (0–4) each and a final score ranging between 0 (best control) and 36 points (worst control).</p><p id="par0070" class="elsevierStylePara elsevierViewall">The following are considered the cut-off points for normal values according to the literature: ≤25<span class="elsevierStyleHsp" style=""></span>ppb for FE<span class="elsevierStyleInf">NO,50</span><a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">25,26</span></a>; ≥80% for the relative value of FEV<span class="elsevierStyleInf">1</span> (% predicted),<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">1,2</span></a> and a score of less than 8 points on the CAN questionnaire.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">24</span></a> In the case of CA<span class="elsevierStyleInf">NO</span> and J′aw<span class="elsevierStyleInf">NO</span>, the cut-off point for normal values was considered to be the upper limit calculated for the group of healthy children included in this study.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Four inflammatory types were established in the asthmatic group based on CA<span class="elsevierStyleInf">NO</span> and J′aw<span class="elsevierStyleInf">NO</span>: type I (normal J¿aw<span class="elsevierStyleInf">NO</span> and CA<span class="elsevierStyleInf">NO</span>), type II (elevated J¿aw<span class="elsevierStyleInf">NO</span> and normal CA<span class="elsevierStyleInf">NO</span>), type III (elevated J¿aw<span class="elsevierStyleInf">NO</span> and CA<span class="elsevierStyleInf">NO</span>) and type IV (normal J¿aw<span class="elsevierStyleInf">NO</span> and elevated CA<span class="elsevierStyleInf">NO</span>).</p><p id="par0080" class="elsevierStylePara elsevierViewall">The quantitative variables analyzed were age (years), weight (kg), height (cm), determination of NO (ppb) at three expiratory flows (FE<span class="elsevierStyleInf">NO,50</span>, FE<span class="elsevierStyleInf">NO,100</span>, FE<span class="elsevierStyleInf">NO,200</span>), CA<span class="elsevierStyleInf">NO</span> (ppb) and J′aw<span class="elsevierStyleInf">NO</span> (pl/s). The following were also analyzed in the asthmatic group: score obtained in the CAN questionnaire (points), forced expiratory volume in the first second (FEV<span class="elsevierStyleInf">1</span> as a percentage of predicted), forced vital capacity (FVC as a percentage of predicted), FEV<span class="elsevierStyleInf">1</span>/FVC ratio (as a percentage of predicted) and forced expiratory flow between 25% and 75% of FVC (FEF<span class="elsevierStyleInf">25–75</span> as a percentage of predicted).</p><p id="par0085" class="elsevierStylePara elsevierViewall">The following qualitative variables were analyzed: sex, allergic rhinitis, sensitization to respiratory allergens, atopic dermatitis, food allergies, severity and level of asthma control, treatment received and morbidity presented in the past month defined as the occurrence of at least one exacerbation, including those that required oral glucocorticoids, visits to the emergency department and/or hospital admission in the previous 4 weeks.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Correlation between FE<span class="elsevierStyleInf">NO,50</span>, J′aw<span class="elsevierStyleInf">NO</span> and C<span class="elsevierStyleInf">ANO</span> was analyzed using Spearman's R Correlation Test. Since usual treatment with IGC can act as a confounding factor in FE<span class="elsevierStyleInf">NO,50</span>, J¿aw<span class="elsevierStyleInf">NO</span> and CA<span class="elsevierStyleInf">NO</span> values, statistical analysis was adjusted for the IGC variable by multiple regression analysis.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Descriptive analysis of the variables was carried out for each inflammatory type, and clinical characteristics were compared using the <span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span> test for qualitative variables: sex, personal atopy, treatment, level of control, FEV<span class="elsevierStyleInf">1</span><span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>80%, CAN<span class="elsevierStyleHsp" style=""></span><8, and morbidity. The Kruskal–Wallis test was used for the remaining variables. Analysis of variance and paired comparisons between the inflammatory types were performed using the Bonferroni post hoc correction.</p><p id="par0100" class="elsevierStylePara elsevierViewall">The sample size was estimated based on predicted correlation coefficients according to data published in the literature.<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">7,9,14</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">An alpha level of 5% was established in all cases. Statistical analysis was performed using statistical package SYSTAT 9.0™.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0110" class="elsevierStylePara elsevierViewall">A cohort made up of 162 children was studied. All measurements were correctly performed in 158 (97.5%) patients: 49 (32.2%) healthy controls, 23 (15.1%) untreated asthmatics and 80 (52.5%) asthmatics on IGC. Four children (2.4%) in whom the NO determinations were not correctly performed were excluded. Of those included, the NO measurements did not follow the linear model (negative CA<span class="elsevierStyleInf">NO</span> values) in six cases (all asthmatics), so they were also excluded. There were no significant differences in age, weight, FE<span class="elsevierStyleInf">NO,50</span> or forced spirometry with respect to the study groups.</p><p id="par0115" class="elsevierStylePara elsevierViewall">There were no significant differences in age, weight, height or sex between the healthy control group and the asthmatic group (<span class="elsevierStyleItalic">P</span>>.05) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">In the healthy control group, FE<span class="elsevierStyleInf">NO,50</span> (ppb) (median and range) was 11.5 (1.6–27.3), J¿aw<span class="elsevierStyleInf">NO</span> (pl/s) 516 (98.3–1470) and CA<span class="elsevierStyleInf">NO</span> (ppb) 2.2 (0.1–4.5) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><p id="par0125" class="elsevierStylePara elsevierViewall">In the case of CA<span class="elsevierStyleInf">NO</span> and J′aw<span class="elsevierStyleInf">NO</span>, the normal cut-off point was considered to be the upper limit calculated for the group of healthy children (<4.5<span class="elsevierStyleHsp" style=""></span>ppb for CA<span class="elsevierStyleInf">NO</span> and <1470<span class="elsevierStyleHsp" style=""></span>pl/s for J′aw<span class="elsevierStyleInf">NO</span>).</p><p id="par0130" class="elsevierStylePara elsevierViewall">A close association was observed between J′aw<span class="elsevierStyleInf">NO</span> and FE<span class="elsevierStyleInf">NO,50</span> (<span class="elsevierStyleItalic">r</span>=0.97; <span class="elsevierStyleItalic">P</span><.05) and also (although to a lesser extent) between J′aw<span class="elsevierStyleInf">NO</span> and FE<span class="elsevierStyleInf">NO,100</span> (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.62) and J′aw<span class="elsevierStyleInf">NO</span> and FE<span class="elsevierStyleInf">NO,200</span> (<span class="elsevierStyleItalic">r</span>=0.4). However, no significant association was found between CA<span class="elsevierStyleInf">NO</span> and J′aw<span class="elsevierStyleInf">NO</span> (<span class="elsevierStyleItalic">r</span>=<span class="elsevierStyleHsp" style=""></span>−0.001) or between CA<span class="elsevierStyleInf">NO</span> and FE<span class="elsevierStyleInf">NO,50</span> (<span class="elsevierStyleItalic">r</span>=<span class="elsevierStyleHsp" style=""></span>−0.002). Statistical analysis was adjusted for usual treatment with IGC by multiple linear regression; no differences were found in the results obtained. Starting from this point, and based on the upper limits for J′aw<span class="elsevierStyleInf">NO</span> and CA<span class="elsevierStyleInf">NO</span> in the group of healthy subjects, asthmatic children (n=103) were classified into the four abovementioned inflammatory types (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>). In the asthmatic group, the most common type was type I (n=44; 42.7%), followed by type II (n=41; 39.8%), while type III and IV inflammatory patterns were much less frequent (n=14; 13.5% and n=4; 3.8%, respectively).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">There were no gender or age differences in the four inflammatory types (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">With respect to atopy, significantly lower sensitization (positive skin prick test) to the respiratory allergens studied was found (<span class="elsevierStyleItalic">P</span>=.01) in the group of asthmatics included in phenotype I (70.4%) compared to the rest (95.1%, 92.8% and 100% for phenotypes II, III and IV, respectively).</p><p id="par0145" class="elsevierStylePara elsevierViewall">There were no differences in terms of background treatment with IGC in the four groups (86.3%, 70.7%, 71% and 75% for types I, II, III and IV, respectively).</p><p id="par0150" class="elsevierStylePara elsevierViewall">The differences amongst the 4 inflammatory phenotypes with respect to J′aw<span class="elsevierStyleInf">NO</span>, CA<span class="elsevierStyleInf">NO</span> and FE<span class="elsevierStyleInf">NO,50</span> are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.</p><p id="par0155" class="elsevierStylePara elsevierViewall">The asthmatic group was, overall, a group of children with mild, well-controlled asthma (median CAN score<span class="elsevierStyleHsp" style=""></span>=5; range 0–29) and normal baseline spirometry (mean FEV<span class="elsevierStyleInf">1</span>=99.7%; mean FEV<span class="elsevierStyleInf">1</span>/FVC=85%). With respect to lung function (baseline forced spirometry), the FEV<span class="elsevierStyleInf">1</span>/FVC ratio was significantly lower in phenotype III (mean 79.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.5) compared to type I (mean 85.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.3). No significant differences in FEV<span class="elsevierStyleInf">1</span>/FVC ratio were found in the rest of the phenotypes. Other spirometric variables studied did not differ in the 4 groups (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Taking into account the number of participants included in type IV (only 4), a new analysis was carried out, combining groups III and IV as a group with high CA<span class="elsevierStyleInf">NO</span>; no differences were found in the results obtained.</p><p id="par0160" class="elsevierStylePara elsevierViewall">The percentage of patients with FEV<span class="elsevierStyleInf">1</span><80% (indicative of poor control)<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">2</span></a> was 4.5%, 7.3%, 7.1% and 25% for types I, II, III and IV respectively. Although fewer patients in the low CA<span class="elsevierStyleInf">NO</span> group (phenotypes I and II) had an FEV<span class="elsevierStyleInf">1</span><80 compared to those in the elevated CA<span class="elsevierStyleInf">NO</span> group (phenotypes III and IV) (6.2% vs 11.1%), the differences were not significant (<span class="elsevierStyleItalic">P</span>=.42).</p><p id="par0165" class="elsevierStylePara elsevierViewall">Similarly, no differences were found (<span class="elsevierStyleItalic">P</span>=.5) in the CAN questionnaire score in the 4 categories studied (4, 6, 6 and 7.5 for phenotypes I, II, III, and IV, respectively). No significant differences were found on combining the low CA<span class="elsevierStyleInf">NO</span> (phenotypes I and II) and high CA<span class="elsevierStyleInf">NO</span> (phenotypes III and IV) groups. The percentage of patients with CAN<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>8, indicative of poor control,<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">21</span></a> was 27.2%, 39.2%, 42.8% and 50% for types I, II, III and IV, respectively. There were no differences (<span class="elsevierStyleItalic">P</span>=.35) between patients included in the low CA<span class="elsevierStyleInf">NO</span> (phenotypes I and II) and elevated CA<span class="elsevierStyleInf">NO</span> (phenotypes III and IV) groups (33% vs 44.4%).</p><p id="par0170" class="elsevierStylePara elsevierViewall">The percentage of patients with partially or poorly controlled asthma<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">2</span></a> was 15.9%, 29.2%, 42.8% and 25% for phenotypes I, II, III and IV, respectively. The differences were not significant (<span class="elsevierStyleItalic">P</span>=.15). There were no differences either (<span class="elsevierStyleItalic">P</span>=.35) in the degree of control when low CA<span class="elsevierStyleInf">NO</span> groups (phenotypes I and II) were compared to elevated CA<span class="elsevierStyleInf">NO</span> groups (phenotypes III and IV) (22.3% vs 38.8%).</p><p id="par0175" class="elsevierStylePara elsevierViewall">Significant differences (<span class="elsevierStyleItalic">P</span>=.001) were found in morbidity in the past month amongst the inflammatory phenotypes. The percentage of patients with at least 1 exacerbation, including having to visit the emergency department and/or admission for asthma in the past month, was 4.5%, 7%, 50% and 25% for phenotypes I, II, III and iv respectively. This difference was significant between phenotype III and phenotypes I (<span class="elsevierStyleItalic">P</span><.001) and II (<span class="elsevierStyleItalic">P</span>=.017) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). As previously shown, combining the elevated CA<span class="elsevierStyleInf">NO</span> (phenotypes III and IV) and low CA<span class="elsevierStyleInf">NO</span> (phenotypes I and II) groups, the morbidity recorded was significantly higher in patients with elevated CA<span class="elsevierStyleInf">NO</span> values.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0180" class="elsevierStylePara elsevierViewall">In line with the findings of other authors,<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">7,14,27</span></a> our cohort showed no association between proximal (J′aw<span class="elsevierStyleInf">NO</span>) and distal (CA<span class="elsevierStyleInf">NO</span>) NO; however, J′aw<span class="elsevierStyleInf">NO</span> and FE<span class="elsevierStyleInf">NO,50</span> were strongly associated. With respect to lung function, the FEV<span class="elsevierStyleInf">1</span>/FVC ratio was significantly lower in phenotype III (mean 79.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.5) than in phenotype I (mean 85.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.3), which is consistent with published studies.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">14</span></a> The morbidity presented in the past month was higher in phenotype III compared to phenotypes I (<span class="elsevierStyleItalic">P</span><.001) and II (<span class="elsevierStyleItalic">P</span>=.017). Finally, the normal values found for J′aw<span class="elsevierStyleInf">NO</span> and CA<span class="elsevierStyleInf">NO</span> were similar to those published in the literature.</p><p id="par0185" class="elsevierStylePara elsevierViewall">Our failure to find an association between J′aw<span class="elsevierStyleInf">NO</span> and CA<span class="elsevierStyleInf">NO</span> indicates that these two measurements provide independent information. Moreover, the strong association found between J′aw<span class="elsevierStyleInf">NO</span> and FE<span class="elsevierStyleInf">NO,50</span> indicates that a flow rate of 50<span class="elsevierStyleHsp" style=""></span>ml/s is adequate for determining the proximal NO. J′aw<span class="elsevierStyleInf">NO</span> did not appear to provide any additional information, so the determination of FE<span class="elsevierStyleInf">NO,50</span> could be sufficient to characterize proximal inflammation. Proximal inflammation was not consistently associated with the level of control or with the risk of exacerbation in children.<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">28,29</span></a> One possible explanation for these findings is the confounding influence of factors such as IGC treatment or atopy, which affect proximal NO. In our sample, asthmatic patients were included consecutively regardless of the treatment they received. Statistical analysis was therefore adjusted for IGC treatment by multiple regression analysis; no differences were found in the results. Most asthmatics (80/103) received daily treatment with low or medium doses of IGC (fluticasone 100 or 200<span class="elsevierStyleHsp" style=""></span>μg/day); there were no differences in the use of IGC in the 4 inflammatory types.</p><p id="par0190" class="elsevierStylePara elsevierViewall">On the basis of these findings, 4 inflammatory types were established: type I (normal NO), type II (predominantly proximal NO), type III (proximal and distal NO) and type IV (predominantly distal NO) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). In our study, as in other published series,<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">14</span></a> the phenotypes without distal inflammation (phenotypes I and II) were the most common (82.5%).</p><p id="par0195" class="elsevierStylePara elsevierViewall">In forced spirometry, the FEV<span class="elsevierStyleInf">1</span>/FVC ratio was significantly lower in phenotype III compared to phenotype I. Although the percentage of patients with FEV<span class="elsevierStyleInf">1</span><80% (indicative of poor control)<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">2</span></a> in the low CA<span class="elsevierStyleInf">NO</span> group (phenotypes I and II) was lower than those in the elevated CA<span class="elsevierStyleInf">NO</span> group (phenotypes III and IV) (6.2% vs 11.1%), no differences were found. There were no differences amongst the 4 groups for the other spirometric variables studied (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><p id="par0200" class="elsevierStylePara elsevierViewall">The percentage of patients with at least 1 exacerbation, including the need for oral glucocorticoids, visits to the emergency department and/or admission in the last month, was significantly higher in phenotype III compared with phenotypes I (<span class="elsevierStyleItalic">P</span><.001) and II (<span class="elsevierStyleItalic">P</span>=.017) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). As mentioned above, the recorded morbidity was higher in patients with elevated CA<span class="elsevierStyleInf">NO</span> when groups III and IV (elevated CA<span class="elsevierStyleInf">NO</span>) and groups I and II (low CA<span class="elsevierStyleInf">NO</span>) were combined. These findings, which are consistent with the literature,<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">6,14</span></a> support the appearance of distinct inflammatory types based on the location and spread of NO, and suggest that measuring distal inflammation could be complementary to spirometry and/or the determination of proximal NO for assessing disease control. This association between elevated CA<span class="elsevierStyleInf">NO</span> and higher morbidity in the past month could be due to inflammation in the more distal territory, which could contribute to airflow limitation.<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">30</span></a> However, some authors<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">31,32</span></a> did not find any association between CA<span class="elsevierStyleInf">NO</span>, level of control and disease severity in children and adults with stable asthma, although other studies have found abnormal FE<span class="elsevierStyleInf">NO,50</span> and normal CA<span class="elsevierStyleInf">NO</span> during exacerbations. In this respect, Mahut et al.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">33</span></a> have stated that the usefulness of alveolar NO in asthma has yet to be determined.</p><p id="par0205" class="elsevierStylePara elsevierViewall">No differences were found between patients in the low CA<span class="elsevierStyleInf">NO</span> and elevated CA<span class="elsevierStyleInf">NO</span> phenotypes as regards CAN questionnaire score<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>8 (indicative of poor control),<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">24</span></a> in contrast to the findings of other authors<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">14</span></a> and the <span class="elsevierStyleItalic">Asthma control test.</span><a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">34</span></a> We chose the CAN questionnaire for our study, as it is currently the only questionnaire validated in the Spanish pediatric population.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">24</span></a> Likewise, although the proportion of well-controlled asthmatics was higher in phenotypes I and II, and the proportion of poorly or partially controlled asthmatics was higher in phenotypes III and IV, no differences were found in the level of control when low CA<span class="elsevierStyleInf">NO</span> types were compared with elevated CA<span class="elsevierStyleInf">NO</span> types. The fact that differences were found on analyzing the qualitative variable “morbidity” and not on analyzing the CAN could be due to the absence of an item regarding use of oral glucocorticoids during exacerbations in the questionnaire. Moreover, completing the questionnaire could have underestimated the symptomatology presented in the last month if we compare it with the objective measure of the number of admissions, number of visits to the emergency department (collected from medical reports) or use of oral glucocorticoids (data collected through prescription use).</p><p id="par0210" class="elsevierStylePara elsevierViewall">We should point out, however, that our study cohort of asthmatics was generally a group with mild, well-controlled asthma and normal baseline spirometry. The inclusion of more severe asthmatics could perhaps have modified our results.</p><p id="par0215" class="elsevierStylePara elsevierViewall">Like other authors,<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">14</span></a> we found differences in atopy amongst phenotypes. The group of asthmatics included in phenotype I (70.4%) were found to have lower sensitization (positive skin prick test) to the respiratory allergens studied, compared with the others (types II, III and IV) (<span class="elsevierStyleItalic">P</span>=.01).</p><p id="par0220" class="elsevierStylePara elsevierViewall">Unlike other published series,<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">14</span></a> no differences were found as regards IGC treatment. According to some studies,<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">11,35</span></a> IGC therapy does not appear to affect CA<span class="elsevierStyleInf">NO</span> or improve control in asthmatics with elevated CA<span class="elsevierStyleInf">NO</span> values. CA<span class="elsevierStyleInf">NO</span> and asthma control did, however, respond to systemic corticosteroids and to leukotriene antagonists. Although well-designed longitudinal studies are needed to determine the best therapy for asthmatics with elevated CA<span class="elsevierStyleInf">NO</span>, these findings suggest that confirming the presence of distal inflammation could help in choosing treatment in these patients.</p><p id="par0225" class="elsevierStylePara elsevierViewall">Since significant differences have been described in CA<span class="elsevierStyleInf">NO</span> measurements according to the methodology used,<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">36</span></a> CA<span class="elsevierStyleInf">NO</span> and J′aw<span class="elsevierStyleInf">NO</span> were determined in healthy controls using the methodology described above.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">17</span></a> The results obtained for CA<span class="elsevierStyleInf">NO</span> (median 2.2<span class="elsevierStyleHsp" style=""></span>ppb; range 0.1–4.5) and J′aw<span class="elsevierStyleInf">NO</span> (median 516<span class="elsevierStyleHsp" style=""></span>pl/s; range 98.33–1470<span class="elsevierStyleHsp" style=""></span>pl/s) were similar to those described by other authors.<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">7,14,27,37</span></a> In contrast, Mahut et al.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">6</span></a> found more elevated CA<span class="elsevierStyleInf">NO</span> levels (mean 4.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>ppb) and lower J′aw<span class="elsevierStyleInf">NO</span> levels (mean 320<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>130<span class="elsevierStyleHsp" style=""></span>pl/s). These differences could be explained by the different populations and/or methodology used.<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">36</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">One of the major limitations of this study was the lack of a standardized technique for determination of CA<span class="elsevierStyleInf">NO</span> and J′aw<span class="elsevierStyleInf">NO</span>. The two-compartment model<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">17</span></a> has some limitations: the compartments proposed may not be completely airtight, and the measurements obtained may vary according to the flow rate selected. The selection of flows used depends on the patients’ lung capacity and extent of cooperation.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclusions</span><p id="par0235" class="elsevierStylePara elsevierViewall">The main outcome of this study was that inflammatory types with elevated alveolar NO values (types III and IV) have greater morbidity. These findings support the appearance of distinct inflammatory types based on the location and/or spread of NO, and suggest that measuring distal inflammation by CA<span class="elsevierStyleInf">NO</span> could complement spirometry and/or determination of proximal NO by J′aw<span class="elsevierStyleInf">NO</span> or FE<span class="elsevierStyleInf">NO,50</span> in the assessment of disease control.</p><p id="par0240" class="elsevierStylePara elsevierViewall">Finally, the normal values found for both J′aw<span class="elsevierStyleInf">NO</span> and CA<span class="elsevierStyleInf">NO</span> were similar to those published previously in the literature.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflict of Interests</span><p id="par0245" class="elsevierStylePara elsevierViewall">The authors declare that there are no conflicts of interest in drafting this manuscript.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres516630" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec537549" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres516631" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec537548" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Materials and Methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflict of Interests" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-05-11" "fechaAceptado" => "2014-07-01" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec537549" "palabras" => array:4 [ 0 => "Asthma" 1 => "Children" 2 => "Alveolar nitric oxide" 3 => "Inflammatory categories" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec537548" "palabras" => array:4 [ 0 => "Asma" 1 => "Niños" 2 => "Óxido nítrico alveolar" 3 => "Categorías inflamatorias" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Nitric oxide (NO) levels can be measured at proximal (maximum airway NO flux [J′aw<span class="elsevierStyleInf">NO</span>]) and distal (alveolar NO concentration [C<span class="elsevierStyleInf">ANO</span>]) levels. Four inflammatory patterns have been described in asthmatic individuals, although their relevance has not been well established. The objective was to determine J′aw<span class="elsevierStyleInf">NO</span> and C<span class="elsevierStyleInf">ANO</span> in order to establish four inflammatory categories in asthmatics.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Cross-sectional study of a sample consisting of healthy and asthmatic children. Exhaled NO was determined at multiple flows. J′aw<span class="elsevierStyleInf">NO</span> and C<span class="elsevierStyleInf">ANO</span> were obtained according to the two-compartment model. The asthma control questionnaire (ACQ) and spirometry were administered to asthmatic children. Patients were categorized as type I (normal J′aw<span class="elsevierStyleInf">NO</span> and C<span class="elsevierStyleInf">ANO</span>), type II (elevated J′aw<span class="elsevierStyleInf">NO</span> and normal C<span class="elsevierStyleInf">ANO</span>), type III (elevated J′aw<span class="elsevierStyleInf">NO</span> and C<span class="elsevierStyleInf">ANO</span>) and type IV (normal J′aw<span class="elsevierStyleInf">NO</span> and elevated C<span class="elsevierStyleInf">ANO</span>). Correlation between FE<span class="elsevierStyleInf">NO,50</span>, J′aw<span class="elsevierStyleInf">NO</span> and C<span class="elsevierStyleInf">ANO</span> was analyzed using Spearman's R Correlation Test. Analysis of variance and paired comparisons were performed using the Bonferroni correction.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">One hundred sixty-two children were studied, of whom 49 (32.23%) were healthy controls and 103 (67.76%) asthmatics. In the control subjects, FE<span class="elsevierStyleInf">NO,50</span> (ppb) (median and range) was 11.5 (1.6–27.3), J′aw<span class="elsevierStyleInf">NO</span> (pl/s) was 516 (98.3–1470) and C<span class="elsevierStyleInf">ANO</span> (ppb) was 2.2 (0.1–4.5). Forty-four (42.7%) of the asthmatic participants were categorized as type I, 41 (39.8%) as type II, 14 (13.5%) as type III and 4 (3.88%) as type IV. Good correlation was observed between J′aw<span class="elsevierStyleInf">NO</span> and FE<span class="elsevierStyleInf">NO,50</span> (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.97). There was no association between J′aw<span class="elsevierStyleInf">NO</span> and C<span class="elsevierStyleInf">ANO</span>. FEV<span class="elsevierStyleInf">1</span>/FVC decreased significantly in type III (mean 79.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.5). Morbidity was significantly higher in types III and IV.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Normal values obtained are similar to those previously reported. Asthmatics with high C<span class="elsevierStyleInf">ANO</span> showed higher morbidity. No correlation was found between proximal and distal inflammation.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El óxido nítrico (NO) puede medirse a nivel proximal (flujo máximo NO en vía aérea [J¿aw<span class="elsevierStyleInf">NO</span>]) y distal (concentración alveolar de NO [CA<span class="elsevierStyleInf">NO</span>]). Se han descrito 4 patrones inflamatorios en asmáticos, aunque su relevancia no ha sido bien establecida. El objetivo ha sido determinar el J¿aw<span class="elsevierStyleInf">NO</span> y la CA<span class="elsevierStyleInf">NO</span> para establecer 4 categorías inflamatorias en asmáticos.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio transversal de una muestra de niños sanos y asmáticos. Determinación de NO exhalado a flujos múltiples. De acuerdo con el modelo bicompartimental se obtuvieron la CA<span class="elsevierStyleInf">NO</span> y el J¿aw<span class="elsevierStyleInf">NO</span>. En asmáticos se realizó cuestionario de control de asma (CAN) y espirometría forzada. Categorización de pacientes en tipo <span class="elsevierStyleSmallCaps">i</span> (J¿aw<span class="elsevierStyleInf">NO</span> y CA<span class="elsevierStyleInf">NO</span> normal), tipo <span class="elsevierStyleSmallCaps">ii</span> (J¿aw<span class="elsevierStyleInf">NO</span> elevado y CA<span class="elsevierStyleInf">NO</span> normal), tipo <span class="elsevierStyleSmallCaps">iii</span> (J¿aw<span class="elsevierStyleInf">NO</span> y CA<span class="elsevierStyleInf">NO</span> elevados) y tipo <span class="elsevierStyleSmallCaps">iv</span> (J¿aw<span class="elsevierStyleInf">NO</span> normal y CA<span class="elsevierStyleInf">NO</span> elevado). Estudio de correlación entre FE<span class="elsevierStyleInf">NO,50</span>, J¿aw<span class="elsevierStyleInf">NO</span> y CA<span class="elsevierStyleInf">NO</span> mediante R de Spearman. Análisis de la varianza y comparaciones pareadas, mediante corrección post hoc de Bonferroni.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se estudiaron 162 niños: 49 (32,23%) controles sanos y 103 (67,76%) asmáticos. Se excluyeron 10 niños, 4 (2.4%) porque las determinaciones fueron incorrectas y 6 (3,7%) porque las determinaciones no siguieron el modelo lineal (valores de CA<span class="elsevierStyleInf">NO</span> negativos). En controles la FE<span class="elsevierStyleInf">NO,50</span> (ppb) (mediana y rango) fue 11,5 (1,6–27,3), J¿aw<span class="elsevierStyleInf">NO</span> (pl/s) 516 (98,3–1.470) y CA<span class="elsevierStyleInf">NO</span> (ppb) 2,2 (0,1–4,5). De los asmáticos, 44 (42,7%) se categorizaron en tipo <span class="elsevierStyleSmallCaps">i</span>, 41 (39,8%) en tipo <span class="elsevierStyleSmallCaps">ii</span>, 14 (13,5%%) en tipo <span class="elsevierStyleSmallCaps">iii</span> y 4 (3,88%) en tipo <span class="elsevierStyleSmallCaps">iv</span>. Buena correlación entre J¿aw<span class="elsevierStyleInf">NO</span> y FE<span class="elsevierStyleInf">NO,50</span> (r<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,97). No hubo asociación entre J¿aw<span class="elsevierStyleInf">NO</span> y CA<span class="elsevierStyleInf">NO</span>. Disminución significativa de FEV<span class="elsevierStyleInf">1</span>/FVC en tipo <span class="elsevierStyleSmallCaps">iii</span> (media 79,8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7,5). La morbilidad fue significativamente superior en tipos <span class="elsevierStyleSmallCaps">iii</span> y <span class="elsevierStyleSmallCaps">iv</span>.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los valores de normalidad obtenidos son similares a los previamente publicados. Los asmáticos con CA<span class="elsevierStyleInf">NO</span> elevado presentaron mayor morbilidad. No hay correlación entre inflamación proximal y distal.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Corcuera-Elosegui P, Sardón-Prado O, Aldasoro-Ruiz A, Korta-Murua J, Mintegui-Aramburu J, Emparanza-Knorr JI, et al. Patrones inflamatorios en niños asmáticos basados en la determinación de óxido nítrico alveolar. Arch Bronconeumol. 2015;51:279-284.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1294 "Ancho" => 1597 "Tamanyo" => 84287 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Exhaled nitric oxide categories based on the upper threshold for J′aw<span class="elsevierStyleInf">NO</span> and CA<span class="elsevierStyleInf">NO</span> obtained in the group of healthy children. J′aw<span class="elsevierStyleInf">NO</span> vs CA<span class="elsevierStyleInf">NO</span> scatterplot. Normal J′aw<span class="elsevierStyleInf">NO</span><1470 (pl/s) and normal CA<span class="elsevierStyleInf">NO</span><4.5 (ppb) (in purple). Type I (circle): Normal J′aw<span class="elsevierStyleInf">NO</span> and CA<span class="elsevierStyleInf">NO</span>; Type II (<span class="elsevierStyleItalic">x</span>): elevated J′aw<span class="elsevierStyleInf">NO</span> and normal CA<span class="elsevierStyleInf">NO</span>; Type III (cross): elevated J′aw<span class="elsevierStyleInf">NO</span> and CA<span class="elsevierStyleInf">N</span>O; Type IV (triangle): normal J′aw<span class="elsevierStyleInf">NO</span> and elevated CA<span class="elsevierStyleInf">NO</span>.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">CAN: asthma control questionnaire; CA<span class="elsevierStyleInf">NO</span>: alveolar nitric acid concentration; FEF<span class="elsevierStyleInf">25–75</span>: forced expiratory flow between 25% and 75% of the FVC; FE<span class="elsevierStyleInf">NO,100:</span> fractional exhaled nitric oxide at a flow rate of 100<span class="elsevierStyleHsp" style=""></span>ml/s; FE<span class="elsevierStyleInf">NO,200</span>: fractional exhaled nitric oxide at a flow rate of 200<span class="elsevierStyleHsp" style=""></span>ml/s; FE<span class="elsevierStyleInf">NO,50</span>: fractional exhaled nitric oxide at a flow rate of 50<span class="elsevierStyleHsp" style=""></span>ml/s; FEV<span class="elsevierStyleInf">1</span>: forced expiratory volume in the first second; FVC: forced vital capacity; J¿aw<span class="elsevierStyleInf">NO</span>: maximum airway nitric oxygen flux; NO: nitric oxide; pl/s: picoliters/second; ppb: parts per billion; SD: standard deviation.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" 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">Healthy (n=49) \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">Asthmatic (n=103) \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> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Age (years), mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.1<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Weight (kg), mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">38<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>13.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">41.6<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>13.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.17 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Height (cm), mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">139.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>13.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">144.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>15.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">FE<span class="elsevierStyleInf">NO,50</span> (ppb), median (range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11.5 (1.6–27.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">35.4 (3.5–234) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">FE<span class="elsevierStyleInf">NO,100</span> (ppb), median (range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.6 (1–18.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 (3–200) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">FE<span class="elsevierStyleInf">NO,200</span> (ppb), median (range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.7 (0.96–10.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12.3 (2.7–187) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CA<span class="elsevierStyleInf">NO</span> (ppb), median (range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.2 (0.1–4.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.7 (0.1–24) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.022 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">J′aw<span class="elsevierStyleInf">NO</span> (pl/s), median (range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">516 (98.3–1.470) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.703 (120–11.805) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">FEV<span class="elsevierStyleInf">1</span> (% predicted), mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">x</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">99.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">FVC (%predicted), mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">x</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>9.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">FEV<span class="elsevierStyleInf">1</span>/FVC (%predicted), mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">x</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">83.9<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">FEF<span class="elsevierStyleInf">25–75</span> (%predicted), mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">x</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">82.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CAN (score), mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">x</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab833839.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Descriptive Characteristics of Healthy and Asthmatic Study Patients.</p>" ] ] 2 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">A. dermatitis: atopic dermatitis; A. rhinitis: allergic rhinitis; CAN: asthma control questionnaire; CA<span class="elsevierStyleInf">NO</span>: alveolar nitric acid concentration; FEF<span class="elsevierStyleInf">25–75</span>: forced expiratory flow between 25% and 75% of vital capacity; FE<span class="elsevierStyleInf">NO,50</span>: fractional exhaled nitric oxide at a flow rate of 50<span class="elsevierStyleHsp" style=""></span>ml/s; FEV<span class="elsevierStyleInf">1</span>: forced expiratory volume in the first second; FVC: forced vital capacity; IGC: inhaled glucocorticoids; J¿aw<span class="elsevierStyleInf">NO</span>: maximum airway nitric oxygen flux; M/F: male/female; Morbidity: presence of at least one exacerbation including those requiring oral corticosteroids, visits to the Emergency Department or admission, in the past 4 weeks; NO: nitric oxide; pl/s: picoliters/second; ppb: parts per billion;. SD: standard deviation.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Type I \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Type II \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Type III \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Type IV \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Overall <span class="elsevierStyleItalic">P</span> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Paired comparison \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Normal NO \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Predominantly proximal NO \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Proximal and distal NO \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Predominantly distal NO \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Asthmatics (103)</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">n (%)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">44 (42.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">41 (39.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 (13.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 (3.8) \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></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Age (years), mean</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">±</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.9<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.7<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11.9<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Sex (M/F)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">27/17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24/17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10/4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3/1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Atopy, n (%)</span></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>A. rhinitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">33 (75) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">36 (87.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 (85.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>A. dermatitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 (31.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 (48.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 (21.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (25) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Food allergy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 (20.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (2.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Respiratory allergen sensitization \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">31 (70.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">39 (95.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 (92.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.009 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">I<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>II, III, IV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">FE</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">NO,50</span></span><span class="elsevierStyleItalic">(ppb)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15.4 (3.5–54.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">53 (19–109.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">95.7 (28.6–234) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">36.5 (14.5–44.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">II, III<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>I/III >II/III<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>IV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">CA</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">NO</span></span><span class="elsevierStyleItalic">(ppb)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.8 (0.1–4.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.45 (0.2–4.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.9 (4.7–24) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.6 (4.7–12.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">I<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>III, IV/II<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>III, IV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">J′aw</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">NO</span></span><span class="elsevierStyleItalic">(pl/s) (median and range)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">684 (120–2.348) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.651 (1.515–6.475) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.894 (1.770–11.805) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.003 (466–1.445) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">II, III<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>I/III<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>II/II, III<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>IV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">FEV</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">1</span></span><span class="elsevierStyleItalic">(%)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">102<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>13.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">96.1<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>12.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">96.7<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">98.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>14.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">FVC (%)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>9.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">98.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>10.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">101.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>10.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">97.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">FEV</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">1</span></span><span class="elsevierStyleItalic">/FVC (%)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">85.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">82.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">79.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">85.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">I<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>III \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">FEF</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">25–75</span></span><span class="elsevierStyleItalic">(%), mean</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">±</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">88.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>22.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">76.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>21.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">73.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">82.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">CAN (points), median and range</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 (0–29) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 (0–26) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 (0–27) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7.5 (3–17) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">CAN</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">≥</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">8, n (%)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 (27.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16 (39.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 (42.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \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 " align="left" valign="top"><span class="elsevierStyleItalic">Poor or partial control, n (%)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 (15.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 (29.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 (42.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (25) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Treatment, n (%) – IGC</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">38 (86.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">29 (70.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 (71.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 (75) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Morbidity, n (%)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (4.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 (17) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (25) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">.001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>I, II \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab833840.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Characteristics of the Four Inflammatory Categories Defined According to the J′aw<span class="elsevierStyleInf">NO</span> and CA<span class="elsevierStyleInf">NO</span> Values Obtained in Healthy Children.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:37 [ 0 => array:3 [ "identificador" => 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Chapman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.rmed.2008.08.007" "Revista" => array:7 [ "tituloSerie" => "Respir Med" "fecha" => "2009" "volumen" => "103" "paginaInicial" => "296" "paginaFinal" => "300" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18805684" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0022347607011389" "estado" => "S300" "issn" => "00223476" ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0365" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impact of analysis interval on the multiple exhalation flow technique to partition exhaled nitric oxide" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "J.L. Puckett" 1 => "R.W. Taylor" 2 => "S.P. Galant" 3 => "S.C. George" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ppul.21182" "Revista" => array:6 [ "tituloSerie" => "Pediatr Pulmonol" "fecha" => "2010" "volumen" => "45" "paginaInicial" => "182" "paginaFinal" => "191" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20082344" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0370" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Alveolar and bronchial nitric oxide output in healthy children" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A. Sepponen" 1 => "L. Lehtimäki" 2 => "H. Huhtala" 3 => "M. Kaila" 4 => "H. Kankaanranta" 5 => "E. Moilanen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ppul.20953" "Revista" => array:6 [ "tituloSerie" => "Pediatr Pulmonol" "fecha" => "2008" "volumen" => "43" "paginaInicial" => "1242" "paginaFinal" => "1248" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19009623" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:3 [ "titulo" => "Acknowledgements" "texto" => "<p id="par0250" class="elsevierStylePara elsevierViewall">We thank all the patients who participated and their families, as well as all the staff of the Pediatric Respiratory Medicine Section for their cooperation and dedication in conducting this study.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/15792129/0000005100000006/v1_201505280222/S1579212915000658/v1_201505280222/en/main.assets" "Apartado" => array:4 [ "identificador" => "9374" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original Articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/15792129/0000005100000006/v1_201505280222/S1579212915000658/v1_201505280222/en/main.pdf?idApp=UINPBA00003Z&text.app=https://archbronconeumol.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212915000658?idApp=UINPBA00003Z" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 2 | 6 |
| 2024 October | 44 | 22 | 66 |
| 2024 September | 47 | 18 | 65 |
| 2024 August | 80 | 36 | 116 |
| 2024 July | 43 | 25 | 68 |
| 2024 June | 56 | 28 | 84 |
| 2024 May | 121 | 26 | 147 |
| 2024 April | 40 | 25 | 65 |
| 2024 March | 40 | 24 | 64 |
| 2024 February | 42 | 21 | 63 |
| 2023 March | 9 | 7 | 16 |
| 2023 February | 37 | 19 | 56 |
| 2023 January | 44 | 33 | 77 |
| 2022 December | 54 | 41 | 95 |
| 2022 November | 71 | 42 | 113 |
| 2022 October | 50 | 32 | 82 |
| 2022 September | 33 | 28 | 61 |
| 2022 August | 30 | 55 | 85 |
| 2022 July | 27 | 40 | 67 |
| 2022 June | 33 | 39 | 72 |
| 2022 May | 48 | 46 | 94 |
| 2022 April | 41 | 29 | 70 |
| 2022 March | 40 | 50 | 90 |
| 2022 February | 36 | 38 | 74 |
| 2022 January | 52 | 43 | 95 |
| 2021 December | 43 | 41 | 84 |
| 2021 November | 37 | 47 | 84 |
| 2021 October | 56 | 54 | 110 |
| 2021 September | 41 | 55 | 96 |
| 2021 August | 42 | 34 | 76 |
| 2021 July | 29 | 39 | 68 |
| 2021 June | 50 | 32 | 82 |
| 2021 May | 48 | 33 | 81 |
| 2021 April | 104 | 82 | 186 |
| 2021 March | 51 | 23 | 74 |
| 2021 February | 31 | 19 | 50 |
| 2021 January | 35 | 29 | 64 |
| 2020 December | 27 | 20 | 47 |
| 2020 November | 24 | 16 | 40 |
| 2020 October | 31 | 15 | 46 |
| 2020 September | 26 | 12 | 38 |
| 2020 August | 27 | 18 | 45 |
| 2020 July | 44 | 22 | 66 |
| 2020 June | 27 | 8 | 35 |
| 2020 May | 29 | 22 | 51 |
| 2020 April | 47 | 26 | 73 |
| 2020 March | 47 | 13 | 60 |
| 2020 February | 36 | 17 | 53 |
| 2020 January | 34 | 19 | 53 |
| 2019 December | 43 | 32 | 75 |
| 2019 November | 28 | 23 | 51 |
| 2019 October | 26 | 20 | 46 |
| 2019 September | 32 | 25 | 57 |
| 2019 August | 27 | 16 | 43 |
| 2019 July | 30 | 33 | 63 |
| 2019 June | 33 | 21 | 54 |
| 2019 May | 46 | 18 | 64 |
| 2019 April | 47 | 14 | 61 |
| 2019 March | 42 | 27 | 69 |
| 2019 February | 31 | 16 | 47 |
| 2019 January | 31 | 20 | 51 |
| 2018 December | 36 | 18 | 54 |
| 2018 November | 82 | 20 | 102 |
| 2018 October | 146 | 36 | 182 |
| 2018 September | 128 | 8 | 136 |
| 2018 May | 10 | 1 | 11 |
| 2018 April | 30 | 5 | 35 |
| 2018 March | 17 | 5 | 22 |
| 2018 February | 22 | 6 | 28 |
| 2018 January | 22 | 5 | 27 |
| 2017 December | 21 | 9 | 30 |
| 2017 November | 24 | 6 | 30 |
| 2017 October | 30 | 12 | 42 |
| 2017 September | 17 | 5 | 22 |
| 2017 August | 21 | 17 | 38 |
| 2017 July | 21 | 7 | 28 |
| 2017 June | 27 | 14 | 41 |
| 2017 May | 19 | 7 | 26 |
| 2017 April | 22 | 13 | 35 |
| 2017 March | 14 | 3 | 17 |
| 2017 February | 7 | 3 | 10 |
| 2017 January | 9 | 3 | 12 |
| 2016 December | 14 | 7 | 21 |
| 2016 November | 28 | 16 | 44 |
| 2016 October | 30 | 12 | 42 |
| 2016 September | 19 | 18 | 37 |
| 2016 August | 33 | 9 | 42 |
| 2016 July | 16 | 11 | 27 |
| 2016 March | 3 | 0 | 3 |
| 2015 December | 3 | 0 | 3 |
| 2015 October | 21 | 1 | 22 |
| 2015 September | 14 | 11 | 25 |
| 2015 July | 0 | 1 | 1 |
| 2015 June | 0 | 1 | 1 |
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