Forskolin-induced organoid swelling is associated with long-term cystic fibrosis disease progression.

RATIONALE: Cystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC). METHODS: We retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed-effect models and multivariable logistic regression to estimate the association of FIS with long-term forced expiratory volume in 1 s % predicted (FEV1pp) decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC. RESULTS: FIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV1pp decline of 0.32% (95% CI 0.11-0.54%; p=0.004) per 1000-point change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR 0.18, 95% CI 0.07-0.46; p<0.001), CF-related liver disease (adjusted OR 0.18, 95% CI 0.06-0.54; p=0.002) and diabetes (adjusted OR 0.34, 95% CI 0.12-0.97; p=0.044). These associations were absent for SCC. CONCLUSION: This study exemplifies the prognostic value of a patient-derived organoid-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences.

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

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.

Feasibility study on exhaled-breath analysis by untargeted Selected-Ion Flow-Tube Mass Spectrometry in children with cystic fibrosis, asthma, and healthy controls: Comparison of data pretreatment and classification techniques.

Selected-Ion Flow-Tube Mass Spectrometry (SIFT-MS) has been applied in a clinical context as diagnostic tool for breath samples using target biomarkers. Exhaled breath sampling is non-invasive and therefore much more patient friendly compared to bronchoscopy, which is the golden standard for evaluating airway inflammation. In the actual pilot study, 55 exhaled breath samples of children with asthma, cystic-fibrosis and healthy individuals were included. Rather than focusing on the analysis of target biomarkers or on the identification of biomarkers, different data analysis strategies, including a variety of pretreatment, classification and discrimination techniques, are evaluated regarding their capacity to distinguish the three classes based on subtle differences in their full scan SIFT-MS spectra. Proper data-analysis strategies are required because these full scan spectra contain much external, i.e. unwanted, variation. Each SIFT-MS analysis generates three spectra resulting from ion-molecule reactions of analyte molecules with H3O+, NO+ and O2+. Models were built with Linear Discriminant Analysis, Quadratic Discriminant Analysis, Soft Independent Modelling by Class Analogy, Partial Least Squares - Discriminant Analysis, K-Nearest Neighbours, and Classification and Regression Trees. Perfect models, concerning overall sensitivity and specificity (100% for both) were found using Direct Orthogonal Signal Correction (DOSC) pretreatment. Given the uncertainty related to the classification models associated with DOSC pretreatments (i.e. good classification found also for random classes), other models are built applying other preprocessing approaches. A Partial Least Squares - Discriminant Analysis model with a combined pre-processing method considering single value imputation results in 100% sensitivity and specificity for calibration, but was less good predictive. Pareto scaling prior to Quadratic Discriminant Analysis resulted in 41/55 correctly classified samples for calibration and 34/55 for cross-validation. In future, the uncertainty with DOSC and the applicability of the promising preprocessing methods and models must be further studied applying a larger representative data set with a more extensive number of samples for each class. Nevertheless, this pilot study showed already some potential for the untargeted SIFT-MS application as a rapid pattern-recognition technique, useful in the diagnosis of clinical breath samples.

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

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 (FEV1) measurements with a monitor at home. Paired FEV1 measurements were included if the measurement on the home monitor was performed on the same day as the FEV1 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 FEV1 was 0.18 L in CF (95% confidence interval (CI) 0.08-0.27 L; p < 0.001) and 0.12 L in asthma (95%CI 0.05-0.19 L; p < 0.001). FEV1 measurements at home were significantly lower than clinically obtained FEV1 measurements, which has implications for the application of this technique in the daily clinical situation.

Towards Prepared mums (TOP-mums) for a healthy start, a lifestyle intervention for women with overweight and a child wish: study protocol for a randomised controlled trial in the Netherlands.

INTRODUCTION: Periconception obesity is associated with a higher risk for adverse perinatal outcomes such as gestational diabetes mellitus, preeclampsia, large for gestational age, operative delivery and preterm birth. Lifestyle interventions during pregnancy have resulted in insufficient effects on reducing these perinatal complications. A few reasons for this disappointing effect can be suggested: (1) the time period during pregnancy for improvement of developmental circumstances is too short; (2) the periconception period in which complications originate is not included; and (3) lifestyle interventions may not have been sufficiently multidisciplinary and customised. A preconception lifestyle intervention might be more effective to reduce perinatal complications. Therefore, the aim of the Towards Prepared mums study is to evaluate the effect of a lifestyle intervention starting prior to conception on lifestyle behaviour change. METHODS AND ANALYSIS: This protocol outlines a non-blinded, randomised controlled trial. One hundred and twelve women (18-40 years of age) with overweight or obesity (body mass index≥25.0 kg/m2) who plan to conceive within 1 year will be randomised to either the intervention or care as usual group. The intervention group will receive a multidisciplinary, customised lifestyle intervention stimulating physical activity, a healthy diet and smoking cessation, if applicable. The lifestyle intervention and monitoring will take place until 12 months postpartum. The primary outcome is difference in weight in kg from baseline to 6 weeks postpartum. Secondary outcomes are gestational weight gain, postpartum weight retention, smoking cessation, dietary and physical activity habits. Furthermore, exploratory outcomes include body composition, cardiometabolic alterations, time to pregnancy, need for assisted reproductive technologies, perinatal complications of mother and child, and lung function of the child. Vaginal and oral swabs, samples of faeces, breast milk, placenta and cord blood will be stored for evaluation of microbial flora, epigenetic markers and breast milk composition. Furthermore, a cost-effectiveness analysis will take place. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Medical Ethical Committee of Maastricht University Medical Centre+ (NL52452.068.15/METC152026). Knowledge derived from this study will be made available by publications in international peer-reviewed scientific journals and will be presented at (inter)national scientific conferences. A dissemination plan for regional and national implementation of the intervention is developed. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02703753.

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

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).

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

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.

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

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 (FEV1) % pred) and pulmonary exacerbation rate. Potential risk factors at baseline included sex, age, best FEV1 % 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 Pseudomonas aeruginosaThe data of 545 children were analysed. PPI use was associated with both annual decline of FEV1 % pred (p=0.017) and future pulmonary exacerbation rate (p=0.006). Moreover, lower FEV1 % 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.

Recruiting families for an intervention study to prevent second-hand smoke exposure in children.

BACKGROUND: We evaluated the effectiveness of different recruitment strategies used in a study aimed at eliminating/reducing second-hand smoke (SHS) exposure in Dutch children 0-13 years of age with a high risk of asthma. METHODS: The different strategies include: 1) questionnaires distributed via home addresses, physicians or schools of the children; 2) cohorts from other paediatric studies; 3) physicians working in the paediatric field (family physicians, paediatricians and Youth Health Care (YHC) physicians); and 4) advertisements in a local newsletter, at child-care facilities, and day-care centres. RESULTS: More than 42,782 families were approached to take part in the screening of which 3663 could be assessed for eligibility. Of these responders, 196 families met the inclusion criteria for the study. However, only 58 (one third) could be randomised in the trial, mainly because of no interest or time of the parents. The results showed that recruiting families who expose their children to SHS exposure is very challenging, which may be explained by lack of 'recognition' or awareness that SHS occurs in homes. The presence of asthma in the family, respiratory symptoms in the children, and even incentives did not increase parental motivation for participation in the study. CONCLUSIONS: The recruitment process for an intervention program addressing SHS exposure in children was considerably more challenging and time consuming than anticipated. Barriers at both a parents level and a doctor's level can be discriminated.

Motivational interviewing and urine cotinine feedback to stop passive smoke exposure in children predisposed to asthma: a randomised controlled trial.

We tested the effectiveness of a program consisting of motivational interviewing (MI) and feedback of urine cotinine to stop passive smoking (PS) in children at risk for asthma. Fifty-eight families with children 0-13 years with a high risk of asthma and PS exposure were randomised in a one-year follow-up study. The intervention group received the intervention program during 6 sessions (1/month) and the control group received measurements (questionnaires, urine cotinine, and lung function) only. The primary outcome measure was the percentage of families stopping PS (parental report verified and unverified with the child's urine cotinine concentration <10 µg/l) in children during the intervention program. The analyses were performed with Mixed Logistic Regression. After 6 months, a significant group difference was observed for the unverified parental report of stopping PS in children: 27% of parents in the intervention group versus 7% in the control group. For the verified parental report, the difference was similar (23% versus 7%) but was not statistically significant. Despite a limited sample size, the results suggest that the intervention program is probably an effective strategy to stop PS in children. A program longer than 6 months might be necessary for a longer lasting intervention effect.

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

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.

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

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.

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

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.

Evidence for a Cystic Fibrosis Enteropathy.

BACKGROUND: Previous studies have suggested the existence of enteropathy in cystic fibrosis (CF), which may contribute to intestinal function impairment, a poor nutritional status and decline in lung function. This study evaluated enterocyte damage and intestinal inflammation in CF and studied its associations with nutritional status, CF-related morbidities such as impaired lung function and diabetes, and medication use. METHODS: Sixty-eight CF patients and 107 controls were studied. Levels of serum intestinal-fatty acid binding protein (I-FABP), a specific marker for enterocyte damage, were retrospectively determined. The faecal intestinal inflammation marker calprotectin was prospectively studied. Nutritional status, lung function (FEV1), exocrine pancreatic insufficiency (EPI), CF-related diabetes (CFRD) and use of proton pump inhibitors (PPI) were obtained from the medical charts. RESULTS: Serum I-FABP levels were elevated in CF patients as compared with controls (p<0.001), and correlated negatively with FEV1 predicted value in children (r-.734, p<0.05). Faecal calprotectin level was elevated in 93% of CF patients, and correlated negatively with FEV1 predicted value in adults (r-.484, p<0.05). No correlation was found between calprotectin levels in faeces and sputum. Faecal calprotectin level was significantly associated with the presence of CFRD, EPI, and PPI use. CONCLUSION: This study demonstrated enterocyte damage and intestinal inflammation in CF patients, and provides evidence for an inverse correlation between enteropathy and lung function. The presented associations of enteropathy with important CF-related morbidities further emphasize the clinical relevance.

Clinical evaluation of the Nanoduct sweat test system in the diagnosis of cystic fibrosis after newborn screening.

UNLABELLED: After a positive newborn screening test for cystic fibrosis (CF), a sweat test is performed to confirm the diagnosis. The success rate of the generally acknowledged methods (Macroduct/Gibson and Cooke) in newborns varies between 73 and 99%. The Nanoduct sweat test system is easier to perform and less sweat is needed. The main aim of this study was to measure the success rate of the Nanoduct compared to current approved sweat test methods in a newborn population. After informed consent of the parents, newborns with a positive screening test for CF were included. The Macroduct or Gibson and Cooke and Nanoduct were performed in all infants, during the same appointment. The chloride concentration was determined by standard coulorimetry; conductivity was measured directly and converted to a NaCl molarity. One hundred eight newborns were included: 17 with CF, 7 with cystic fibrosis transmembrane regulator (CFTR)-related metabolic syndrome (CRMS), and 84 healthy children. The success rate of the Nanoduct was 93% and for the Macroduct/Gibson and Cooke 79% (McNemar, p = 0.002). The Nanoduct detected the same CF patients as the Macroduct/Gibson and Cooke; one CF patient had an equivocal result for both tests, and no patients were missed. The area under the receiver operating characteristic curve for detection of CF with the Nanoduct was 0.999, with ideal cutoff levels of 91 and 66 mmol/l, comparable to former studies. CONCLUSION: The success rate of the Nanoduct to collect sufficient sweat in infants was higher compared to the Macroduct and Gibson and Cooke.

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

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).

Addressing passive smoking in children.

BACKGROUND: A significant number of parents are unaware or unconvinced of the health consequences of passive smoking (PS) in children. Physicians could increase parental awareness by giving personal advice. AIM: To evaluate the current practices of three Dutch health professions (paediatricians, youth health care physicians, and family physicians) regarding parental counselling for passive smoking (PS) in children. METHODS: All physicians (n = 720) representing the three health professions in Limburg, The Netherlands, received an invitation to complete a self-administered electronic questionnaire including questions on their: sex, work experience, personal smoking habits, counselling practices and education regarding PS in children. RESULTS: The response rate was 34%. One tenth (11%) of the responding physicians always addressed PS in children, 32% often, 54% occasionally and 4% reported to never attend to it. The three health professions appeared comparable regarding their frequency of parental counselling for PS in children. Addressing PS was more likely when children had respiratory problems. Lack of time was the most frequently mentioned barrier, being very and somewhat applicable for respectively 14% and 43% of the physicians. One fourth of the responders had received postgraduate education about PS. Additionally, 49% of the responders who did not have any education about PS were interested in receiving it. CONCLUSIONS: Physicians working in the paediatric field in Limburg, The Netherlands, could more frequently address PS in children with parents. Lack of time appeared to be the most mentioned barrier and physicians were more likely to counsel parents for PS in children with respiratory complaints/diseases. Finally, a need for more education on parental counselling for PS was expressed.

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

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.

Intact IFN-γR1 expression and function distinguishes Langerhans cell histiocytosis from mendelian susceptibility to mycobacterial disease.

PURPOSE: Poly-ostotic Langerhans Cell Histiocytosis (LCH) can be difficult to distinguish clinically and histologically from disseminated infection in manifesting specific subtypes of Mendelian Susceptibility to Mycobacterial Disease (MSMD). In MSMD-patients, dominant negative germline mutations in the IFN-γR1 gene, in particular in exon 6, lead to autosomal dominant IFN-γ receptor 1 deficiency (ADIFNGR1) and can mimic LCH. We hypothesized that similar defects might underlie the pathogenesis of LCH. METHODS: IFN-γR1 expression was immunohistochemically determined at disease onset in biopsies from 11 LCH-patients and four ADIFNGR1-patients. IFN-γR1 function was analyzed in 18 LCH-patients and 13 healthy controls by assessing the IFN-γ-induced upregulation of Fc-gamma-receptor I (FcγRI) expression on monocytes. Pro-inflammatory cytokine production was measured after stimulation of whole blood with LPS and IFN-γ. Exon 6 of the IFN-γR1 gene was sequenced in 67 LCH-patients to determine whether mutations were present. RESULTS: IFN-γR1 expression was high in three LCH-affected biopsies, similar to ADIFNGR1-affected biopsies, but varied from negative to moderate in eight other LCH-affected biopsies. No functional differences in IFN-γ signaling were detected between LCH-patients with active or non-active disease and healthy controls. No germline mutations in exon 6 of the IFN-γR1 gene were detected in any of the 67 LCH-patients. CONCLUSIONS: In contrast to ADIFNGR1-patients, IFN-γ signaling is fully functional in LCH-patients. Either performed before, during or after treatment, these non-invasive functional assays can distinguish LCH-patients from ADIFNGR1-patients and thereby facilitate correct therapy regimens for patients with recurrent osteolytic lesions.

Cost-effectiveness of primary prevention of paediatric asthma: a decision-analytic model.

BACKGROUND: Many children stand to benefit from being asthma-free for life with primary (i.e., prenatally started) prevention addressing one environmental exposure in a unifaceted (UF) approach or at least two in a multifaceted (MF) approach. We assessed the cost-effectiveness of primary prevention programmes for Dutch children in a decision-analytic framework. METHODS: A decision-analytic tree model analysing healthcare costs and asthma cases prevented was developed to compare usual care (UC) with two UF and three MF programmes on the primary prevention of asthma amongst children. Programmes were evaluated through incremental cost-effectiveness ratios and net monetary benefits. Decision and parameter uncertainty were subjected to value-of-information analyses. RESULTS: The current UC and one of three MF programmes dominated the other alternatives. The MF programme was more costly but also more effective than UC at an incremental cost-effectiveness ratio of 8,209.20/additional asthma case prevented. The value of perfect information to reduce uncertainty was 291.6M at its lowest. Most of the uncertainty in the cost-effectiveness threshold was attributable to the probability and cost estimates for low-risk children. CONCLUSION: This study supports the feasibility of a structured programme that simultaneously addresses exposure to house dust mites, pet dander, environmental tobacco, and breast-feeding as a cost-effective alternative to UC in the primary prevention of asthma amongst children.