Publications by authors named "Quirijn Jöbsis"

44 Publications

The risk of community-acquired pneumonia in children using gastric acid suppressants.

Eur Respir J 2021 Mar 18. Epub 2021 Mar 18.

Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical, Pharmacology, University of Utrecht, Utrecht, the Netherlands.

With the increased use of acid suppressants, significant potential complications, such as community-acquired pneumonia are becoming more apparent. Paradoxically, in spite of an increased focus on potential complications, there is an increased use of acid suppressants in children and a lack of data specifically targeting the association between acid suppressants and community-acquired pneumonia. Our main objective was to evaluate the risk of community-acquired pneumonia in children using acid suppressants (proton pump inhibitors and/or histamine-2-receptor antagonists).We performed a cohort study using data from the Clinical Practice Research Datalink. All patients aged 1 month to 18 years with a prescription of acid suppressants were included and matched to up to 4 unexposed children. Time-varying Cox proportional hazards models were used to estimate the risk of community-acquired pneumonia. The cohort consisted of 84 868 exposed and 325 329 unexposed children.Current use of proton pump inhibitors and histamine-2-receptor antagonists was associated with an increased risk of community acquired pneumonia, adjusted hazard ratio 2.05 (95% CI 1.90 to 2.22) and 1.80 (95% CI 1.67 to 1.94), respectively. The risk was even greater in patients with respiratory disease. Long term use >211 days of proton pump inhibitors and histamine-2-receptor antagonists led to a significantly greater risk of community-acquired pneumonia compared to short term use <31 days. After cessation of therapy, the risk remained increased for the following 7 months.The use of acid suppressants in children was associated with a doubled risk of community-acquired pneumonia. This risk increased with chronic use, respiratory disease and remained increased after discontinuation of therapy.
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http://dx.doi.org/10.1183/13993003.03229-2020DOI Listing
March 2021

Exhaled volatile organic compounds detect pulmonary exacerbations early in children with cystic fibrosis: results of a 1 year observational pilot study.

J Breath Res 2021 Feb 25;15(2):026012. Epub 2021 Feb 25.

Department of Paediatric Pulmonology, School for Public Health and Primary Health Care (CAPHRI), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.

In patients with cystic fibrosis (CF), pulmonary exacerbations (PEx) have an important influence on well-being, quality of life, and lung function decline. Early detection combined with early treatment may prevent severe PEx. To determine whether early detection of PEx is possible by non-invasive markers (volatile organic compounds) in exhaled breath. In a 1 year prospective observational pilot study, 49 children with CF were studied. At clinical visits with an interval of 2 months, lung function, volatile organic compounds (VOCs) in exhaled breath by means of gas chromatography-time-of-flight-mass spectrometry, and medication use were assessed. PEx were recorded. Random forest (RF) classification modelling was used to select discriminatory VOCs, followed by building of receiver operating characteristic curves. An inverse relation between the predictive power of a set of VOCs and time between exhaled breath sampling and the onset of PEx was found. When this time period was within 7 d, the RF model with the nine most discriminatory VOCs was able to correctly predict 79% of the children with an upcoming PEx or remaining stable (sensitivity 79% and specificity 78%). This result was validated by means of bootstrapping within the RF classification model. PEx in children with CF can be detected at an early stage by means of exhaled VOCs. The highest predictive value was reached if time between sampling and the onset of an exacerbation was no longer than 7 d.
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http://dx.doi.org/10.1088/1752-7163/abda55DOI Listing
February 2021

Exhaled volatile organic compounds detect pulmonary exacerbations early in children with Cystic Fibrosis: results of a one-year observational pilot study.

J Breath Res 2021 Jan 11. Epub 2021 Jan 11.

Department of Toxicology, Maastricht University, Maastricht, Limburg, NETHERLANDS.

Background: In patients with Cystic fibrosis (CF), pulmonary exacerbations (PEx) have an important influence on well-being, quality of life, and lung function decline. Early detection combined with early treatment may prevent severe PEx.

Aim: To determine whether early detection of PEx is possible by non-invasive markers (volatile organic compounds) in exhaled breath.

Methods: In a one-year prospective observational pilot study, 49 children with CF were studied. At clinical visits with an interval of 2 months, lung function, volatile organic compounds (VOCs) in exhaled breath by means of gas chromatography-time-of-flight-mass spectrometry, and medication use were assessed. PEx were recorded. Random Forest (RF) classification modelling was used to select discriminatory VOCs, followed by building of Receiver Operating Characteristic curves.

Results: An inverse relation between the predictive power of a set of VOCs and time between exhaled breath sampling and the onset of PEx was found. When this time period was within 7 days, the RF model with the 9 most discriminatory VOCs was able to correctly predict 79% of the children with an upcoming PEx or remaining stable (sensitivity 79% and specificity 78%). This result was validated by means of bootstrapping within the RF classification model.

Conclusion: PEx in children with CF can be detected at an early stage by means of exhaled VOCs. The highest predictive value was reached if time between sampling and the onset of an exacerbation was no longer than 7 days.
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http://dx.doi.org/10.1088/1752-7163/abda55DOI Listing
January 2021

Discrepancy between Lung Function Measurements at Home and in the Hospital in Children with Asthma and CF.

J Clin Med 2020 May 26;9(6). Epub 2020 May 26.

Department of Paediatric Pulmonology, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre (MUMC+), 6202 AZ Maastricht, The Netherlands.

The Coronavirus pandemic stresses the importance of eHealth techniques to monitor patients at home. Home monitoring of lung function in asthma and cystic fibrosis (CF) may help to detect deterioration of lung function at an early stage, but the reliability is unclear. We investigated whether lung function measurements at home were comparable to measurements during clinical visits. We analysed prospectively collected data of two one-year observational cohort studies in 117 children (36 with CF and 81 with asthma). All patients performed forced expiratory volume in one second (FEV) measurements with a monitor at home. Paired FEV measurements were included if the measurement on the home monitor was performed on the same day as the FEV measurement on the pneumotachometer during a two monthly clinical visit. Bland-Altman plots and linear mixed model analysis were used. The mean difference (home measurement was subtracted from clinical measurement) in FEV was 0.18 L in CF (95% confidence interval (CI) 0.08-0.27 L; < 0.001) and 0.12 L in asthma (95%CI 0.05-0.19 L; < 0.001). FEV measurements at home were significantly lower than clinically obtained FEV measurements, which has implications for the application of this technique in the daily clinical situation.
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http://dx.doi.org/10.3390/jcm9061617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355967PMC
May 2020

Longitudinal Relationships between Asthma-Specific Quality of Life and Asthma Control in Children; The Influence of Chronic Rhinitis.

J Clin Med 2020 Feb 18;9(2). Epub 2020 Feb 18.

Department of Paediatric Pulmonology, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre (MUMC+), 6202 AZ Maastricht, The Netherlands.

Managing pediatric asthma includes optimizing both asthma control and asthma-specific quality of life (QoL). However, it is unclear to what extent asthma-specific QoL is related to asthma control or other clinical characteristics over time. The aims of this study were to assess in children longitudinally: (1) the association between asthma control and asthma-specific QoL and (2) the relationship between clinical characteristics and asthma-specific QoL. In a 12-month prospective study, asthma-specific QoL, asthma control, dynamic lung function indices, fractional exhaled nitric oxide, the occurrence of exacerbations, and the use of rescue medication were assessed every 2 months. Associations between the clinical characteristics and asthma-specific QoL were analyzed using linear mixed models. At baseline, the QoL symptom score was worse in children with asthma and concomitant chronic rhinitis compared to asthmatic children without chronic rhinitis. An improvement of asthma control was longitudinally associated with an increase in asthma-specific QoL (-value < 0.01). An increased use of β-agonists, the occurrence of wheezing episodes in the year before the study, the occurrence of an asthma exacerbation in the 2 months prior to a clinical visit, and a deterioration of lung function correlated significantly with a decrease in the Pediatric Asthma Quality of Life Questionnaire (PAQLQ) total score (-values ≤ 0.01). Chronic rhinitis did not correlate with changes in the PAQLQ score over 1 year. The conclusion was that asthma control and asthma-specific QoL were longitudinally associated, but were not mutually interchangeable. The presence of chronic rhinitis at baseline did influence QoL symptom scores. β-agonist use and exacerbations before and during the study were inversely related to the asthma-specific QoL over time.
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http://dx.doi.org/10.3390/jcm9020555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074314PMC
February 2020

Gut microbiota in wheezing preschool children and the association with childhood asthma.

Allergy 2020 06 29;75(6):1473-1476. Epub 2020 Jan 29.

Department of Medical Microbiology, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Centre+, Maastricht, The Netherlands.

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http://dx.doi.org/10.1111/all.14156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317729PMC
June 2020

Exhaled Breath Condensate in Childhood Asthma: A Review and Current Perspective.

Front Pediatr 2019 25;7:150. Epub 2019 Apr 25.

Department of Pediatric Respiratory Medicine, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Center, Maastricht, Netherlands.

Exhaled breath condensate (EBC) was introduced more than two decades ago as a novel, non-invasive tool to assess airway inflammation. This review summarizes the latest literature on the various markers in EBC to predict asthma in children. Despite many recommendations and two comprehensive Task Force reports, there is still large heterogeneity in published data. The biggest issue remains a lack of standardization regarding EBC collection, preservation, processing, and analysis. As a result, published studies show mixed or conflicting results, questioning the reproducibility of findings. A joint, multicenter research study is urgently needed to address the necessary methodological standardization.
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http://dx.doi.org/10.3389/fped.2019.00150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494934PMC
April 2019

Publisher Correction: Early detection of pulmonary exacerbations in children with Cystic Fibrosis by electronic home monitoring of symptoms and lung function.

Sci Rep 2018 Dec 13;8(1):17946. Epub 2018 Dec 13.

Department of Paediatric Respiratory Medicine, School for Public Health and Primary Health Care (CAPHRI), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-36407-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292896PMC
December 2018

Feasibility and diagnostic accuracy of an electronic nose in children with asthma and cystic fibrosis.

J Breath Res 2019 05 8;13(3):036009. Epub 2019 May 8.

Department of Paediatric Respiratory Medicine, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre+, Maastricht, The Netherlands.

The measurement of volatile organic compounds (VOCs) in exhaled breath is a promising tool for diagnosing and monitoring various lung diseases in children. Gas chromatography mass spectrometry (GC-MS) analysis is a frequently used standard technique for VOCs analysis. However, as GC-MS is an expensive and time-consuming technique, hand-held devices or electronic noses have been developed. Recently, the Aeonose was introduced as an easy-to-use hand-held eNose capable of point-of-care testing. Although first results using this eNose in adults are promising, studies in children are lacking. We therefore performed a cross-sectional study in 55 children and adolescents ≥6 years of age (20 children with moderate to severe asthma, 13 children with CF, and 22 healthy controls). The feasibility of the Aeonose was high (>98% successful measurements). The diagnostic accuracy was high for discriminating asthma from CF (Area Under the Receiver Operating Characteristic Curve [AUC] 0.90 [95% Confidence Interval 0.78-1.00] sensitivity 89% [65%-98%], specificity 77% [46%-94%]), and for the distinction between CF and healthy controls (AUC 0.87 [0.74-1.00], sensitivity 85% [54%-97%], specificity 77% [54%-91%]). However, the diagnostic accuracy for the discrimination between asthma and healthy controls was modest (AUC 0.79 [0.63-0.94], sensitivity 74% [49%-90%], specificity 91% [69%-98%]). This is the first study to report test results of the Aeonose in children and adolescents ≥6 years. This eNose showed a high feasibility with modest to good diagnostic accuracies in asthma and CF. This study was registered at clinicaltrial.gov (NCT03377686).
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http://dx.doi.org/10.1088/1752-7163/aae158DOI Listing
May 2019

Risk factors for lung disease progression in children with cystic fibrosis.

Eur Respir J 2018 06 7;51(6). Epub 2018 Jun 7.

Dept of Paediatric Respiratory Medicine, Care and Public Health Research Institute (CAPHRI), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.

To identify potential risk factors for lung disease progression in children with cystic fibrosis (CF), we studied the longitudinal data of all children with CF (aged ≥5 years) registered in the Dutch CF Registry (2009-2014).Lung disease progression was expressed as a decline in lung function (forced expiratory volume in 1 s (FEV) % pred) and pulmonary exacerbation rate. Potential risk factors at baseline included sex, age, best FEV % pred, best forced vital capacity % pred, genotype, body mass index z-score, pancreatic insufficiency, medication use (proton pump inhibitors (PPIs), prophylactic antibiotics and inhaled corticosteroids), CF-related diabetes, allergic bronchopulmonary aspergillosis and colonisation with The data of 545 children were analysed. PPI use was associated with both annual decline of FEV % pred (p=0.017) and future pulmonary exacerbation rate (p=0.006). Moreover, lower FEV % pred at baseline (p=0.007), prophylactic inhaled antibiotic use (p=0.006) and pulmonary exacerbations in the baseline year (p=0.002) were related to pulmonary exacerbations in subsequent years.In a cohort of Dutch children with CF followed for 5 years, we were able to identify several risk factors for future exacerbations. In particular, the association between PPI use and lung disease progression definitely requires further investigation.
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http://dx.doi.org/10.1183/13993003.02509-2017DOI Listing
June 2018

Early detection of pulmonary exacerbations in children with Cystic Fibrosis by electronic home monitoring of symptoms and lung function.

Sci Rep 2017 09 27;7(1):12350. Epub 2017 Sep 27.

Department of Paediatric Respiratory Medicine, School for Public Health and Primary Health Care (CAPHRI), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.

Pulmonary exacerbations (PEx) in Cystic Fibrosis (CF) are associated with an increased morbidity and even mortality. We investigated whether early detection of PEx in children with CF is possible by electronic home monitoring of symptoms and lung function. During this one-year prospective multi-centre study, 49 children with CF were asked to use a home monitor three times a week. Measurements consisted of a respiratory symptom questionnaire and assessment of Forced Expiratory Volume in one second (FEV1). Linear mixed-effects and multiple logistic regression analyses were used. In the 2 weeks before a PEx, the Respiratory Symptom Score (RSS) of the home monitor increased (p = 0.051). The FEV1 as percentage of predicted (FEV1%pred) did not deteriorate in the 4 weeks before a PEx. Nevertheless, the FEV1%pred at the start of exacerbation was significantly lower than the FEV1%pred in the non-exacerbation group (mean difference 16.3%, p = 0.012). The combination of FEV1%pred and RSS had a sensitivity to predict an exacerbation of 92.9% (CI 75.0-98.8%) and a specificity of 88.9% (CI 50.7-99.4%). The combination of home monitor FEV1%pred and RSS can be helpful to predict a PEx in children with CF at an early stage.
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http://dx.doi.org/10.1038/s41598-017-10945-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617859PMC
September 2017

Factors associated with changes in health-related quality of life in children with cystic fibrosis during 1-year follow-up.

Eur J Pediatr 2017 Aug 9;176(8):1047-1054. Epub 2017 Jun 9.

Department of Paediatric Respiratory Medicine, School for Public Health and Primary Health Care (CAPHRI), Maastricht University Medical Centre + (MUMC+), Maastricht, The Netherlands.

There are limited data on health-related quality of life (HRQoL) changes over time in children with cystic fibrosis (CF). We investigated associations between clinical and treatment variables with changes in HRQoL during 1 year. Forty-nine children with CF aged 6-18 years were followed in this multicentre, observational cohort study during 1 year. HRQoL was measured by the validated disease specific cystic fibrosis questionnaire-revised (CFQ-R). The CFQ-R total score as well as most domain scores improved significantly (8.0 points and [3.3-31.7] points respectively) during the one-year follow-up. Age at baseline demonstrated a strong longitudinal association with the change of CFQ-R total score (2.853 points decrease of CFQ-R total score per year increase in age) and several domain scores. Below 12 years of age, CFQ-R total score improved in most children, whereas a deterioration was observed in most children above 12 years. The number of PEx was associated with an increase of treatment burden score (4.466 points decrease per extra PEx).

Conclusion: In the group as a whole, HRQoL improved significantly over time. However, changes over time were significantly influenced by age: below 12 years of age, HRQoL improved in most patients whereas a deterioration was observed in most children >12 years. Strategies how to preserve or ideally to improve HRQoL in adolescence should be developed. What is known: • Quality of life in patient with CF is diminished • Although CF is a chronic disease, longitudinal data on QoL in children with CF are scarce. What is new: • Below 12 years of age, quality of life improved in most children during the 1-year follow-up whereas a deterioration in quality of life was observed in most children above 12 years. • the treatment burden score of QoL correlated with the exacerbation rate.
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http://dx.doi.org/10.1007/s00431-017-2928-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511302PMC
August 2017

A European Respiratory Society technical standard: exhaled biomarkers in lung disease.

Eur Respir J 2017 04 26;49(4). Epub 2017 Apr 26.

Philips Research, High Tech Campus 11, Eindhoven, The Netherlands.

Breath tests cover the fraction of nitric oxide in expired gas (), volatile organic compounds (VOCs), variables in exhaled breath condensate (EBC) and other measurements. For EBC and for , official recommendations for standardised procedures are more than 10 years old and there is none for exhaled VOCs and particles. The aim of this document is to provide technical standards and recommendations for sample collection and analytic approaches and to highlight future research priorities in the field. For EBC and , new developments and advances in technology have been evaluated in the current document. This report is not intended to provide clinical guidance on disease diagnosis and management.Clinicians and researchers with expertise in exhaled biomarkers were invited to participate. Published studies regarding methodology of breath tests were selected, discussed and evaluated in a consensus-based manner by the Task Force members.Recommendations for standardisation of sampling, analysing and reporting of data and suggestions for research to cover gaps in the evidence have been created and summarised.Application of breath biomarker measurement in a standardised manner will provide comparable results, thereby facilitating the potential use of these biomarkers in clinical practice.
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http://dx.doi.org/10.1183/13993003.00965-2016DOI Listing
April 2017

Can exhaled volatile organic compounds predict asthma exacerbations in children?

J Breath Res 2017 03 1;11(1):016016. Epub 2017 Mar 1.

Department of Pediatric Pulmonology, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.

Background: Asthma control does not yet meet the goals of asthma management guidelines. Non-invasive monitoring of airway inflammation may help to improve the level of asthma control in children.

Objectives: (1) To identify a set of exhaled volatile organic compounds (VOCs) that is most predictive for an asthma exacerbation in children. (2) To elucidate the chemical identity of predictive biomarkers.

Methods: In a one-year prospective observational study, 96 asthmatic children participated . During clinical visits at 2 month intervals, asthma control, fractional exhaled nitric oxide, lung function (FEV, FEV/VC) and VOCs in exhaled breath were determined by means of gas chromatography time-of-flight mass spectrometry. Random Forrest classification modeling was used to select predictive VOCs, followed by plotting of receiver operating characteristic-curves (ROC-curves).

Results: An inverse relationship was found between the predictive power of a set of VOCs and the time between sampling of exhaled breath and the onset of exacerbation. The sensitivity and specificity of the model predicting exacerbations 14 days after sampling were 88% and 75%, respectively. The area under the ROC-curve was 90%. The sensitivity for prediction of asthma exacerbations within 21 days after sampling was 63%. In total, 7 VOCs were selected for the classification model: 3 aldehydes, 1 hydrocarbon, 1 ketone, 1 aromatic compound, and 1 unidentified VOC.

Conclusion: VOCs in exhaled breath showed potential for predicting asthma exacerbations in children within 14 days after sampling. Before using this in clinical practice, the validity of predicting asthma exacerbations should be studied in a larger cohort.
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http://dx.doi.org/10.1088/1752-7163/aa5a8bDOI Listing
March 2017

Biomarkers in Exhaled Breath Condensate Are Not Predictive for Pulmonary Exacerbations in Children with Cystic Fibrosis: Results of a One-Year Observational Study.

PLoS One 2016 6;11(4):e0152156. Epub 2016 Apr 6.

Department of Pediatric Pulmonology, School for Public Health and Primary Health Care (CAPHRI), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.

Background: Cystic Fibrosis (CF) is characterized by chronically inflamed airways, and inflammation even increases during pulmonary exacerbations. These adverse events have an important influence on the well-being, quality of life, and lung function of patients with CF. Prediction of exacerbations by inflammatory markers in exhaled breath condensate (EBC) combined with early treatment may prevent these pulmonary exacerbations and may improve the prognosis.

Aim: To investigate the diagnostic accuracy of a set of inflammatory markers in EBC to predict pulmonary exacerbations in children with CF.

Methods: In this one-year prospective observational study, 49 children with CF were included. During study visits with an interval of 2 months, a symptom questionnaire was completed, EBC was collected, and lung function measurements were performed. The acidity of EBC was measured directly after collection. Inflammatory markers interleukin (IL)-6, IL-8, tumor necrosis factor α (TNF-α), and macrophage migration inhibitory factor (MIF) were measured using high sensitivity bead based flow immunoassays. Pulmonary exacerbations were recorded during the study and were defined in two ways. The predictive power of inflammatory markers and the other covariates was assessed using conditionally specified models and a receiver operating characteristic curve (SAS version 9.2). In addition, k-nearest neighbors (KNN) algorithm was applied (SAS version 9.2).

Results: Sixty-five percent of the children had one or more exacerbations during the study. The conditionally specified models showed an overall correct prediction rate of 55%. The area under the curve (AUC) was equal to 0.62. The results obtained with the KNN algorithm were very similar.

Conclusion: Although there is some evidence indicating that the predictors outperform random guessing, the general diagnostic accuracy of EBC acidity and the EBC inflammatory markers IL-6, IL-8, TNF-α and MIF is low. At present it is not possible to predict pulmonary exacerbations in children with CF with the chosen biomarkers and the method of EBC analysis. The biochemical measurements of EBC markers should be improved and other techniques should be considered.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152156PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822839PMC
August 2016

Prediction of asthma exacerbations in children by innovative exhaled inflammatory markers: results of a longitudinal study.

PLoS One 2015 23;10(3):e0119434. Epub 2015 Mar 23.

Department of Pediatric Pulmonology, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre (MUMC+),Maastricht, The Netherlands.

Background: In asthma management guidelines the primary goal of treatment is asthma control. To date, asthma control, guided by symptoms and lung function, is not optimal in many children and adults. Direct monitoring of airway inflammation in exhaled breath may improve asthma control and reduce the number of exacerbations.

Aim: 1) To study the use of fractional exhaled nitric oxide (FeNO) and inflammatory markers in exhaled breath condensate (EBC), in the prediction of asthma exacerbations in a pediatric population. 2) To study the predictive power of these exhaled inflammatory markers combined with clinical parameters.

Methods: 96 asthmatic children were included in this one-year prospective observational study, with clinical visits every 2 months. Between visits, daily symptom scores and lung function were recorded using a home monitor. During clinical visits, asthma control and FeNO were assessed. Furthermore, lung function measurements were performed and EBC was collected. Statistical analysis was performed using a test dataset and validation dataset for 1) conditionally specified models, receiver operating characteristic-curves (ROC-curves); 2) k-nearest neighbors algorithm.

Results: Three conditionally specified predictive models were constructed. Model 1 included inflammatory markers in EBC alone, model 2 included FeNO plus clinical characteristics and the ACQ score, and model 3 included all the predictors used in model 1 and 2. The area under the ROC-curves was estimated as 47%, 54% and 59% for models 1, 2 and 3 respectively. The k-nearest neighbors predictive algorithm, using the information of all the variables in model 3, produced correct predictions for 52% of the exacerbations in the validation dataset.

Conclusion: The predictive power of FeNO and inflammatory markers in EBC for prediction of an asthma exacerbation was low, even when combined with clinical characteristics and symptoms. Qualitative improvement of the chemical analysis of EBC may lead to a better non-invasive prediction of asthma exacerbations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119434PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370663PMC
March 2016

An ADAM33 polymorphism associates with progression of preschool wheeze into childhood asthma: a prospective case-control study with replication in a birth cohort study.

PLoS One 2015 13;10(3):e0119349. Epub 2015 Mar 13.

Department of Paediatric Respiratory Medicine, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre (MUMC+), Maastricht, the Netherlands.

Background: The influence of asthma candidate genes on the development from wheeze to asthma in young children still needs to be defined.

Objective: To link genetic variants in asthma candidate genes to progression of wheeze to persistent wheeze into childhood asthma.

Materials And Methods: In a prospective study, children with recurrent wheeze from the ADEM (Asthma DEtection and Monitoring) study were followed until the age of six. At that age a classification (transient wheeze or asthma) was based on symptoms, lung function and medication use. In 198 children the relationship between this classification and 30 polymorphisms in 16 asthma candidate genes was assessed by logistic regression. In case of an association based on a p<0.10, replication analysis was performed in an independent birth cohort study (KOALA study, n = 248 included for the present analysis).

Results: In the ADEM study, the minor alleles of ADAM33 rs511898 and rs528557 and the ORMDL3/GSDMB rs7216389 polymorphisms were negatively associated, whereas the minor alleles of IL4 rs2243250 and rs2070874 polymorphisms were positively associated with childhood asthma. When replicated in the KOALA study, ADAM33 rs528557 showed a negative association of the CG/GG-genotype with progression of recurrent wheeze into childhood asthma (0.50 (0.26-0.97) p = 0.04) and no association with preschool wheeze.

Conclusion: Polymorphisms in ADAM33, ORMDL3/GSDMB and IL4 were associated with childhood asthma in a group of children with recurrent wheeze. The replication of the negative association of the CG/GG-genotype of rs528557 ADAM33 with childhood asthma in an independent birth cohort study confirms that a compromised ADAM33 gene may be implicated in the progression of wheeze into childhood asthma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119349PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358930PMC
February 2016

Exhaled biomarkers and gene expression at preschool age improve asthma prediction at 6 years of age.

Am J Respir Crit Care Med 2015 Jan;191(2):201-7

1 Department of Pediatric Pulmonology and.

Rationale: A reliable asthma diagnosis is difficult in wheezing preschool children.

Objectives: To assess whether exhaled biomarkers, expression of inflammation genes, and early lung function measurements can improve a reliable asthma prediction in preschool wheezing children.

Methods: Two hundred two preschool recurrent wheezers (aged 2-4 yr) were prospectively followed up until 6 years of age. At 6 years of age, a diagnosis (asthma or transient wheeze) was based on symptoms, lung function, and asthma medication use. The added predictive value (area under the receiver operating characteristic curve [AUC]) of biomarkers to clinical information (assessed with the Asthma Predictive Index [API]) assessed at preschool age in diagnosing asthma at 6 years of age was determined with a validation set. Biomarkers in exhaled breath condensate, exhaled volatile organic compounds (VOCs), gene expression, and airway resistance were measured.

Measurements And Main Results: At 6 years of age, 198 children were diagnosed (76 with asthma, 122 with transient wheeze). Information on exhaled VOCs significantly improved asthma prediction (AUC, 89% [increase of 28%]; positive predictive value [PPV]/negative predictive value [NPV], 82/83%), which persisted in the validation set. Information on gene expression of toll-like receptor 4, catalase, and tumor necrosis factor-α significantly improved asthma prediction (AUC, 75% [increase of 17%]; PPV/NPV, 76/73%). This could not be confirmed after validation. Biomarkers in exhaled breath condensate and airway resistance (pre- and post- bronchodilator) did not improve an asthma prediction. The combined model with VOCs, gene expression, and API had an AUC of 95% (PPV/NPV, 90/89%).

Conclusions: Adding information on exhaled VOCs and possibly expression of inflammation genes to the API significantly improves an accurate asthma diagnosis in preschool children. Clinical trial registered with www.clinicaltrial.gov (NCT 00422747).
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http://dx.doi.org/10.1164/rccm.201408-1537OCDOI Listing
January 2015

CD14/Toll-like receptors interact with bacteria and regulatory T-cells in the development of childhood asthma.

Eur Respir J 2014 Sep 17;44(3):799-802. Epub 2014 Jul 17.

Dept of Paediatric Respiratory Medicine, School for Public Health and Primary Care, Maastricht University Medical Centre, Maastricht, The Netherlands.

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http://dx.doi.org/10.1183/09031936.00020314DOI Listing
September 2014

Electronic monitoring of symptoms and lung function to assess asthma control in children.

Ann Allergy Asthma Immunol 2014 Sep 18;113(3):257-262.e1. Epub 2014 Jun 18.

Department of Pediatric Pulmonology, School for Public Health and Primary Care, Maastricht University Medical Center, Maastricht, the Netherlands.

Background: Asthma remains poorly controlled in children. Home monitoring of asthma control may help to improve the level of asthma control.

Objectives: To compare 2 methods to assess asthma control: (1) prospective home monitoring, based on daily assessment of forced expiratory volume in 1 second (FEV1) and electronic symptom score, and (2) Asthma Control Questionnaire (ACQ) with retrospective assessment of symptoms and FEV1.

Methods: Ninety-six children with asthma were prospectively followed up during 1 year. Asthma control was assessed by home monitoring, including an electronic symptom score based on Global Initiative for Asthma (GINA) criteria and FEV1 measurements. In the hospital, the ACQ was completed and FEV₁ was measured. Kappa analysis was performed to assess levels of agreement between the 2 methods.

Results: Agreement between the 2 methods was low (κ coefficient of 0.393). In 29 children (37%), prospective home monitoring was less optimistic than the retrospective assessment of asthma control by the ACQ.

Conclusion: This study found low agreement between asthma control based on GINA criteria by means of prospective home monitoring and the hospital ACQ. The prospective home monitor detected more cases of less well-controlled asthma than the ACQ. However, optimization of adherence to home monitor use is necessary.

Trial Registration: clinicaltrials.gov Identifier: NCT01239238.
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http://dx.doi.org/10.1016/j.anai.2014.05.015DOI Listing
September 2014

Profiling of volatile organic compounds in exhaled breath as a strategy to find early predictive signatures of asthma in children.

PLoS One 2014 21;9(4):e95668. Epub 2014 Apr 21.

Department of Toxicology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands.

Wheezing is one of the most common respiratory symptoms in preschool children under six years old. Currently, no tests are available that predict at early stage who will develop asthma and who will be a transient wheezer. Diagnostic tests of asthma are reliable in adults but the same tests are difficult to use in children, because they are invasive and require active cooperation of the patient. A non-invasive alternative is needed for children. Volatile Organic Compounds (VOCs) excreted in breath could yield such non-invasive and patient-friendly diagnostic. The aim of this study was to identify VOCs in the breath of preschool children (inclusion at age 2-4 years) that indicate preclinical asthma. For that purpose we analyzed the total array of exhaled VOCs with Gas Chromatography time of flight Mass Spectrometry of 252 children between 2 and 6 years of age. Breath samples were collected at multiple time points of each child. Each breath-o-gram contained between 300 and 500 VOCs; in total 3256 different compounds were identified across all samples. Using two multivariate methods, Random Forests and dissimilarity Partial Least Squares Discriminant Analysis, we were able to select a set of 17 VOCs which discriminated preschool asthmatic children from transient wheezing children. The correct prediction rate was equal to 80% in an independent test set. These VOCs are related to oxidative stress caused by inflammation in the lungs and consequently lipid peroxidation. In conclusion, we showed that VOCs in the exhaled breath predict the subsequent development of asthma which might guide early treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095668PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994075PMC
January 2015

Integrative genomic analysis identifies a role for intercellular adhesion molecule 1 in childhood asthma.

Pediatr Allergy Immunol 2014 Mar 6;25(2):166-72. Epub 2014 Jan 6.

Department of Pediatric Pulmonology, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre (MUMC+), Maastricht, the Netherlands.

Background: Childhood asthma is characterized by chronic airway inflammation. Integrative genomic analysis of airway inflammation on genetic and protein level may help to unravel mechanisms of childhood asthma. We aimed to employ an integrative genomic approach investigating inflammation markers on DNA, mRNA, and protein level at preschool age in relationship to asthma development.

Methods: In a prospective study, 252 preschool children (202 recurrent wheezers, 50 controls) from the Asthma DEtection and Monitoring (ADEM) study were followed until the age of six. Genetic variants, mRNA expression in peripheral blood mononuclear cells, and protein levels in exhaled breath condensate for intercellular adhesion molecule 1 (ICAM1), interleukin (IL)4, IL8, IL10, IL13, and tumor necrosis factor α were analyzed at preschool age. At six years of age, a classification (healthy, transient wheeze, or asthma) was based on symptoms, lung function, and medication use.

Results: The ICAM1 rs5498 A allele was positively associated with asthma development (p = 0.02) and ICAM1 gene expression (p = 0.01). ICAM1 gene expression was positively associated with exhaled levels of soluble ICAM1 (p = 0.04) which in turn was positively associated with asthma development (p = 0.01). Furthermore, rs1800872 and rs1800896 in IL10 were associated with altered IL10 mRNA expression (p < 0.01). Exhaled levels of IL4, IL10, and IL13 were positively associated with asthma development (p < 0.01).

Conclusions: In this unique prospective study, we demonstrated that ICAM1 is associated with asthma development on DNA, mRNA, and protein level. Thus, ICAM1 is likely to be involved in the development of childhood asthma.
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http://dx.doi.org/10.1111/pai.12187DOI Listing
March 2014

Exhaled volatile organic compounds predict exacerbations of childhood asthma in a 1-year prospective study.

Eur Respir J 2013 Jul 3;42(1):98-106. Epub 2013 May 3.

Dept of Paediatric Pulmonology, Maastricht University Medical Centre, Research Institute CAPHRI, The Netherlands.

The hypothesis was that prediction of asthma exacerbations in children is possible by profiles of exhaled volatile organic compounds (VOCs), a noninvasive measure of airway inflammation. The aims of the present study were to determine: 1) whether VOCs in exhaled breath are able to predict asthma exacerbations; and 2) the time course and chemical background of the most predictive VOCs. A prospective study was performed in 40 children with asthma over 1 year. At standard 2-month intervals, exhaled nitric oxide fraction (FeNO), VOC profiles in exhaled breath samples, lung function and symptoms were determined in a standardised way. VOC profiles were analysed by gas chromatography-time-of-flight mass spectrometry. 16 out of 40 children experienced an exacerbation. With support vector machine analysis, the most optimal model of baseline measurements versus exacerbation within patients was based on six VOCs (correct classification 96%, sensitivity 100% and specificity 93%). The model of baseline values of patients with compared to those without an exacerbation consisted of seven VOCs (correct classification 91%, sensitivity 79% and specificity 100%). FeNO and lung function were not predictive for exacerbations. This study indicates that a combination of different exhaled VOCs is able to predict exacerbations of childhood asthma.
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http://dx.doi.org/10.1183/09031936.00010712DOI Listing
July 2013

A systematic review of CD14 and toll-like receptors in relation to asthma in Caucasian children.

Allergy Asthma Clin Immunol 2013 Mar 15;9(1):10. Epub 2013 Mar 15.

Department of Paediatric Pulmonology, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre (MUMC), P,O, Box 5800, Maastricht, 6202 AZ, the Netherlands.

The aetiology of childhood asthma is complex. An early dysfunction in the immunological development of the innate immune system in combination with environmental factors possibly triggers asthma. CD14 and toll-like receptors are important components of the innate immune system. The aim of this systematic review was to obtain a better insight into the relation between CD14 and toll-like receptors and childhood asthma in Caucasians. We searched PubMed and EMBASE for relevant articles. In total, 44 articles were included. The quality of the selected studies was independently assessed by the first two authors using the Newcastle-Ottawa quality assessment scale. Toll-like receptor 2, toll-like receptor 6, toll-like receptor 9, and toll-like receptor 10 appear to have some association with childhood asthma in Caucasians. The evidence for a relation of CD14 with childhood asthma is limited. In conclusion, there is no convincing evidence yet for a role of CD14 and toll-like receptors in relation to childhood asthma. Future studies should include haplotype analysis and take environmental factors into account to further clarify the role of CD14 and toll-like receptors on childhood asthma.
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http://dx.doi.org/10.1186/1710-1492-9-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602113PMC
March 2013

Exhaled breath profiling in diagnosing wheezy preschool children.

Eur Respir J 2013 Jan;41(1):183-8

Dept of Paediatric Pulmonology, School for Public Health and Primary Care, CAPHRI, Maastricht University Medical Centre, Maastricht, The Netherlands

Although wheeze is common in preschool children, the underlying pathophysiology has not yet been disentangled. Volatile organic compounds (VOCs) in exhaled breath may serve as noninvasive markers of early wheeze. We aimed to assess the feasibility of VOC collection in preschool children, and to study whether a VOC profile can differentiate between children with and without recurrent wheeze. We included children (mean (range) age 3.3 (1.9-4.5) yrs) with (n=202) and without (n=50) recurrent wheeze. Exhaled VOCs were analysed by gas chromatography-time-of-flight mass spectrometry. VOC profiles were generated by ANOVA simultaneous component analysis (ASCA) and sparse logistic regression (SLR). Exhaled breath collection was possible in 98% of the children. In total, 913 different VOCs were detected. The signal-to-noise ratio improved after correction for age, sex and season using ASCA pre-processing. An SLR model with 28 VOCs correctly classified 83% of the children (84% sensitivity, 80% specificity). After six-fold cross-validation, 73% were correctly classified (79% sensitivity, 50% specificity). Assessment of VOCs in exhaled breath is feasible in young children. VOC profiles are able to distinguish children with and without recurrent wheeze with a reasonable accuracy. This proof of principle paves the way for additional research on VOCs in preschool wheezing.
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http://dx.doi.org/10.1183/09031936.00122411DOI Listing
January 2013

Clinical use of exhaled volatile organic compounds in pulmonary diseases: a systematic review.

Respir Res 2012 Dec 21;13:117. Epub 2012 Dec 21.

Department of Pediatric Pulmonology, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Center (MUMC), P,O, Box 5800, 6202, AZ, Maastricht, the Netherlands.

There is an increasing interest in the potential of exhaled biomarkers, such as volatile organic compounds (VOCs), to improve accurate diagnoses and management decisions in pulmonary diseases. The objective of this manuscript is to systematically review the current knowledge on exhaled VOCs with respect to their potential clinical use in asthma, lung cancer, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and respiratory tract infections. A systematic literature search was performed in PubMed, EMBASE, Cochrane database, and reference lists of retrieved studies. Controlled, clinical, English-language studies exploring the diagnostic and monitoring value of VOCs in asthma, COPD, CF, lung cancer and respiratory tract infections were included. Data on study design, setting, participant characteristics, VOCs techniques, and outcome measures were extracted. Seventy-three studies were included, counting in total 3,952 patients and 2,973 healthy controls. The collection and analysis of exhaled VOCs is non-invasive and could be easily applied in the broad range of patients, including subjects with severe disease and children. Various research groups demonstrated that VOCs profiles could accurately distinguish patients with a pulmonary disease from healthy controls. Pulmonary diseases seem to be characterized by a disease specific breath-print, as distinct profiles were found in patients with dissimilar diseases. The heterogeneity of studies challenged the inter-laboratory comparability. In conclusion, profiles of VOCs are potentially able to accurately diagnose various pulmonary diseases. Despite these promising findings, multiple challenges such as further standardization and validation of the diverse techniques need to be mastered before VOCs can be applied into clinical practice.
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http://dx.doi.org/10.1186/1465-9921-13-117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549749PMC
December 2012

Impact of bacterial colonization on exhaled inflammatory markers in wheezing preschool children.

J Breath Res 2012 Dec 18;6(4):046001. Epub 2012 Sep 18.

Department of Paediatric Pulmonology, School for Public Health and Primary Care (CAPHRI), Maastricht University Medical Centre (MUMC), PO Box 5800, 6202 AZ, Maastricht, The Netherlands.

Wheeze is a common symptom in preschool children. The role of bacteria, regulatory T (T(reg)) cells and their association with airway inflammation in preschool wheeze is largely unknown. We evaluated inflammatory markers in exhaled breath condensate (EBC), bacterial colonization and circulating T(reg) cells in preschool children with and without recurrent wheeze. We recruited 252 children (aged two to four years) with (N = 202) and without (N = 50) recurrent wheeze. EBC was collected using an efficient closed glass condenser. Inflammatory markers in EBC (Interleukin(IL)-2, IL-4, IL-8, IL-10, IL-13) were assessed using multiplex immunoassay. Nasal and throat swabs were analysed for presence of Streptococcus pneumoniae, Haemophilus (para)influenzae and Staphylococcus aureus. Proportions of T(reg) cells (CD4(+)CD25(high)CD127(-)) were quantified by flow cytometry. Recurrent wheezing children had elevated EBC levels of IL-2, IL-4, IL-10 and IL-13 compared to non-wheezers (odds ratio (95% confidence interval): 1.67 (1.23-2.27): 1.58 (1.15-2.18): 1.47 (1.14-1.90): 1.55 (1.16-2.06), p <0.05, respectively). Bacteria were frequently present in children with and without wheeze, with no difference in prevalence (16-52% versus 16-50%, respectively). Moreover, the proportion of T(reg) cells did not differ between both groups. Wheezing children with bacterial colonization did not significantly differ in exhaled levels of inflammatory markers or proportion of T(reg) cells compared to wheezing children without colonization. The analysis of EBC might serve as a helpful non-invasive tool to early assess airway inflammation in wheezing children. The various elevated exhaled inflammatory markers indicate increased airway inflammation in wheezing preschool children. In the presence of wheeze, we found no evidence for bacterial induced airway inflammation.
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http://dx.doi.org/10.1088/1752-7155/6/4/046001DOI Listing
December 2012

Elevated inflammatory markers at preschool age precede persistent wheezing at school age.

Pediatr Allergy Immunol 2012 May 23;23(3):259-64. Epub 2011 Dec 23.

Department of Paediatric Pulmonology, School for Public Health and Primary Care, Maastricht University Medical Centre, Maastricht, the Netherlands.

Background:   Wheeze is a heterogeneous symptom in preschool children. At preschool age it is hard to predict whether symptoms will pass or persist and develop into asthma. Our objective is to prospectively study whether inflammatory markers in exhaled breath condensate (EBC) and pre- and post-bronchodilator interrupter resistance (Rint) assessed at preschool age, are associated with wheezing phenotypes at school age.

Methods:   Children (N = 230) were recruited from the Asthma DEtection and Monitoring (ADEM) study. At preschool age [mean (SE): 3.3 (0.1) yr], pre- and post-bronchodilator Rint was assessed. EBC was collected using a closed glass condenser. Inflammatory markers (IL-2, IL-4, IL-8, IL-10, sICAM) were measured using multiplex immunoassay. Wheezing phenotypes at 5 yr of age were determined based on longitudinal assessment. Children were classified as: never (N = 47), early-transient (N = 89) or persistent wheezers (N = 94).

Results:   Persistent wheezers had elevated levels of all interleukins at preschool age compared to children who never wheezed (p < 0.05). EBC markers did not differ between the persistent and transient wheezers. There was no marked difference in Rint between wheezing phenotypes.

Conclusions:   We demonstrated that 5 yr old children with persistent wheeze already had elevated exhaled inflammatory markers at preschool age compared to never wheezers, indicating augmented airway inflammation in these children.
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http://dx.doi.org/10.1111/j.1399-3038.2011.01244.xDOI Listing
May 2012

Feasibility of exhaled nitric oxide measurements at various flow rates in children with asthma.

Pediatr Allergy Immunol 2010 Feb;21(1 Pt 2):e222-8

University Hospital Maastricht, Department of Paediatric Pulmonology, Maastricht, The Netherlands.

Measurement of bronchial and alveolar exhaled nitric oxide (NO) levels could be of clinical importance for the treatment of asthma. To discriminate between alveolar and bronchial NO, measurements need to be assessed at various flow rates. To study the feasibility, linearity, and long-term repeatability of NO measurements at four different exhalation flow rates in children with asthma. Twenty-one children with moderate persistent asthma, aged 6-12 yrs, were included in the study. NO was measured according to the ATS/ERS guidelines, using the NIOX analyzer with flow restrictors of 30, 50, 100, and 200 ml/s. Duration of the measurements ranged from 6-10 s, depending on the flow rate. The tests were repeated 3 and 6 months after the first NO measurement. Feasibility of NO measurements at these four flow rates increased from 67% to 91% and 95% at the first, second and third visit, respectively. A significant learning effect was present. Age and lung function indices did not influence success or failure of the tests. At the first measurements occasions, no problems occurred during the NO analysis at a 100 ml/s flow rate. There was a 75-90% success rate when performing the test using flow rates of 30, 50, and 200 ml/s. However, repeating the tests resulted in a 100% success rate. Measurements were not successful if: (i) children ran out of air; (ii) NO concentration exceeded 200 ppb; (iii) the measured NO flow was unstable; and (iv) the NO plateau was not formed. This study showed good feasibility and linearity of NO measurements in asthmatic children of 6 yrs and over at flow rates between 50-200 ml/s. A significant learning effect was present. The long-term reproducibility of alveolar and bronchial NO values during 6 months was moderate.
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http://dx.doi.org/10.1111/j.1399-3038.2009.00874.xDOI Listing
February 2010