Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma: Results from the SysPharmPediA Study.

RATIONALE: Early identification of children with poorly controlled asthma is imperative for optimizing treatment strategies. The analysis of exhaled volatile organic compounds (VOCs) is an emerging approach to identify prognostic and diagnostic biomarkers in pediatric asthma. OBJECTIVES: To assess the accuracy of gas chromatography-mass spectrometry based exhaled metabolite analysis to differentiate between controlled and uncontrolled pediatric asthma. METHODS: This study encompassed a discovery (SysPharmPediA) and validation phase (U-BIOPRED, PANDA). Firstly, exhaled VOCs that discriminated asthma control levels were identified. Subsequently, outcomes were validated in two independent cohorts. Patients were classified as controlled or uncontrolled, based on asthma control test scores and number of severe attacks in the past year. Additionally, potential of VOCs in predicting two or more future severe asthma attacks in SysPharmPediA was evaluated. MEASUREMENTS AND MAIN RESULTS: Complete data were available for 196 children (SysPharmPediA=100, U-BIOPRED=49, PANDA=47). In SysPharmPediA, after randomly splitting the population into training (n=51) and test sets (n=49), three compounds (acetophenone, ethylbenzene, and styrene) distinguished between uncontrolled and controlled asthmatics. The area under the receiver operating characteristic curve (AUROCC) for training and test sets were respectively: 0.83 (95% CI: 0.65-1.00) and 0.77 (95% CI: 0.58-0.96). Combinations of these VOCs resulted in AUROCCs of 0.74 ±0.06 (UBIOPRED) and 0.68 ±0.05 (PANDA). Attacks prediction tests, resulted in AUROCCs of 0.71 (95% CI 0.51-0.91) and 0.71 (95% CI 0.52-0.90) for training and test sets. CONCLUSIONS: Exhaled metabolites analysis might enable asthma control classification in children. This should stimulate further development of exhaled metabolites-based point-of-care tests in asthma.

Clinical efficacy and satisfaction of a digital wheeze detector in a multicentre randomised controlled trial: the WheezeScan study.

Introduction: Wheezing is common in preschool children and its clinical assessment often challenging for caretakers. This study aims to evaluate the impact of a novel digital wheeze detector (WheezeScan™) on disease control in a home care setting. Methods: A multicentre randomised open-label controlled trial was conducted in Berlin, Istanbul and London. Participants aged 4-84 months with a doctor's diagnosis of recurrent wheezing in the past 12 months were included. While the control group followed usual care, the intervention group received the WheezeScan™ for at-home use for 120 days. Parents completed questionnaires regarding their child's respiratory symptoms, disease-related and parental quality of life, and caretaker self-efficacy at baseline (T0), 90 days (T1) and 4 months (T2). Results: A total of 167 children, with a mean±sd age of 3.2±1.6 years, were enrolled in the study (intervention group n=87; control group n=80). There was no statistically significant difference in wheeze control assessed by TRACK (mean difference 3.8, 95% CI -2.3-9.9; p=0.2) at T1 between treatment groups (primary outcome). Children's and parental quality of life and parental self-efficacy were comparable between both groups at T1. The evaluation of device usability and perception showed that parents found it useful. Conclusion: In the current study population, the wheeze detector did not show significant impact on the home management of preschool wheezing. Hence, further research is needed to better understand how the perception and usage behaviour may influence the clinical impact of a digital support.

Oropharyngeal Microbiota Clusters in Children with Asthma or Wheeze Associate with Allergy, Blood Transcriptomic Immune Pathways, and Exacerbation Risk.

Rationale: Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. Objectives: To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. Methods: Oropharyngeal swabs from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) pediatric asthma or wheezing cohort were characterized using 16S ribosomal RNA gene sequencing, and unsupervised hierarchical clustering was performed on the Bray-Curtis ß-diversity. Enrichment scores of the Molecular Signatures Database hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessment of the frequency of exacerbations. Measurements and Main Results: Oropharyngeal samples from 241 children (age range, 1-17 years; 40% female) revealed four taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia, and Haemophilus. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1% predicted after salbutamol, and annual asthma exacerbation frequency during follow-up. The Veillonella cluster was the most allergic and included the highest percentage of children with two or more exacerbations per year during follow-up. The oropharyngeal clusters were different in the enrichment scores of TGF-ß (transforming growth factor-ß) (highest in the Veillonella cluster) and Wnt/ß-catenin signaling (highest in the Haemophilus cluster) transcriptomic pathways in blood (all q values <0.05). Conclusions: Analysis of the oropharyngeal microbiota of children with asthma or wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with risk for exacerbation and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiologic insights and potentially new treatment approaches.

Asthma and Wheeze Severity and the Oropharyngeal Microbiota in Children and Adolescents.

Rationale: There is a major unmet need for improving the care of children and adolescents with severe asthma and wheeze. Identifying factors contributing to disease severity may lead to improved diagnostics, biomarkers, or therapies. The airway microbiota may be such a key factor. Objectives: To compare the oropharyngeal airway microbiota of children and adolescents with severe and mild/moderate asthma/wheeze. Methods: Oropharyngeal swab samples from school-age and preschool children in the European U-BIOPRED (Unbiased BIOmarkers in the PREDiction of respiratory disease outcomes) multicenter study of severe asthma, all receiving severity-appropriate treatment, were examined using 16S ribosomal RNA gene sequencing. Bacterial taxa were defined as amplicon sequence variants. Results: We analyzed 241 samples from four cohorts: A) 86 school-age children with severe asthma; B) 39 school-age children with mild/moderate asthma; C) 65 preschool children with severe wheeze; and D) 51 preschool children with mild/moderate wheeze. The most common bacteria were Streptococcus (mean relative abundance, 33.5%), Veillonella (10.3%), Haemophilus (7.0%), Prevotella (5.9%), and Rothia (5.5%). Age group (school-age vs. preschool) was associated with the microbiota in ß-diversity analysis (F = 3.32, P = 0.011) and in a differential abundance analysis (28 significant amplicon sequence variants). Among all children, we found no significant difference in the microbiota between children with severe and mild/moderate asthma/wheeze in univariable ß-diversity analysis (F = 1.99, P = 0.08, N = 241), but a significant difference in a multivariable model (F = 2.66, P = 0.035), including the number of exacerbations in the previous year. Age was also significant when expressed as a microbial maturity score (Spearman Rho, 0.39; P = 4.6 × 10-10); however, this score was not associated with asthma/wheeze severity. Conclusions: There was a modest difference in the oropharyngeal airway microbiota between children with severe and mild/moderate asthma/wheeze across all children but not in individual age groups, and a strong association between the microbiota and age. This suggests the oropharyngeal airway microbiota as an interesting entity in studying asthma severity, but probably without the strength to serve as a biomarker for targeted intervention.

The impact of a digital wheeze detector on parental disease management of pre-school children suffering from wheezing-a pilot study.

BACKGROUND: Viral airway infections are a major reason for doctor's visits at pre-school age, especially when associated with wheezing. While proper treatment requires adequate recognition of airway obstruction, caretakers are often struggling with this judgment, consequently leading to insufficient or late treatment and an unnecessary discomfort of the patient. Digital technologies may serve to support parental decision taking. The aim of the present pilot study is to acquire data on the feasibility of recruitment and observation procedures for a randomized controlled trial on the impact of a digital wheeze detector in a home management setting of pre-school wheezing. METHODS: This single-armed pilot study enrolled patients with a doctor's diagnosis of wheezing aged 9 to 72 months. Participants were asked to use a digital wheeze detector (WheezeScan, Omron Healthcare, Japan) 2×/day for 30 days and record the child's respiratory symptoms, detection of wheezing, and medication intake via an electronic diary (eDiary) app. Demographic and clinical data were collected at the recruitment visit. The asthma control test and the Parent Asthma Management Self-Efficacy Scale (PAMSES) were assessed both, at recruitment and follow-up. RESULTS: Twenty families were recruited and completed the monitoring. All but one completed the follow-up after 30 days. The recruitment procedures were feasible, and adherence to daily monitoring reached an average of 81%. The use of the wheeze detector was rated as uncomplicated. Parents detected wheezing without digital support in only 22/708 (3.1%) of the recorded events. By contrast, the wheeze detector indicated an airway obstruction in 140/708 (19.8%) of the recordings. CONCLUSION: In parallel to feasible recruitment procedures, we observed good usability of the wheeze detection device and high adherence to eDiary recording. The positive outcomes show that the WheezeScan may empower parents by increasing their capacity for wheeze detection. This deserves to be investigated in a larger randomized controlled trial.

Connectivity patterns between multiple allergen specific IgE antibodies and their association with severe asthma.

BACKGROUND: Allergic sensitization is associated with severe asthma, but assessment of sensitization is not recommended by most guidelines. OBJECTIVE: We hypothesized that patterns of IgE responses to multiple allergenic proteins differ between sensitized participants with mild/moderate and severe asthma. METHODS: IgE to 112 allergenic molecules (components, c-sIgE) was measured using multiplex array among 509 adults and 140 school-age and 131 preschool children with asthma/wheeze from the Unbiased BIOmarkers for the PREDiction of respiratory diseases outcomes cohort, of whom 595 had severe disease. We applied clustering methods to identify co-occurrence patterns of components (component clusters) and patterns of sensitization among participants (sensitization clusters). Network analysis techniques explored the connectivity structure of c-sIgE, and differential network analysis looked for differences in c-sIgE interactions between severe and mild/moderate asthma. RESULTS: Four sensitization clusters were identified, but with no difference between disease severity groups. Similarly, component clusters were not associated with asthma severity. None of the c-sIgE were identified as associates of severe asthma. The key difference between school children and adults with mild/moderate compared with those with severe asthma was in the network of connections between c-sIgE. Participants with severe asthma had higher connectivity among components, but these connections were weaker. The mild/moderate network had fewer connections, but the connections were stronger. Connectivity between components with no structural homology tended to co-occur among participants with severe asthma. Results were independent from the different sample sizes of mild/moderate and severe groups. CONCLUSIONS: The patterns of interactions between IgE to multiple allergenic proteins are predictors of asthma severity among school children and adults with allergic asthma.

Young children experience little emotional burden during invasive procedures in asthma research.

Research in children should strike the right balance between protecting underage study subjects and advancing the medical field. This study gives insight into the emotional burden that common invasive research procedures in asthma research have on young children, both from the child and parent perspective. Puppetry was used to stimulate children (age 5-6 years) to explain their emotional burden prior to and after the research procedures. We operationalised emotional burden as willingness to participate in future research and reluctance towards participation. Parents filled out a questionnaire on this topic. Symptomatic patients as well as healthy controls were analysed. Forty-one children were included. Children's anticipatory fear for future research showed a clear decrease of 0.7 ± 1.6 on a 5-point Likert scale as a consequence of participation (p = 0.02). Sixty percent of all participating children explicitly indicated willingness to undergo identical research procedures again. Children uninformed by their parents about the venipuncture were significantly more reluctant to the venipuncture after the procedure (p < 0.01), compared to children who had been informed (4.0 ± 0.9 resp. 2.8 ± 1.2).Conclusion: This study suggests that the emotional burden of participation in asthma research for underage children can be prevented when they are properly informed and decreases as a consequence of participations. We believe increased emphasis should be placed on informing children and evaluating the emotional impact of research to help caretakers and research ethics committees make informed decisions about participation of children in medical research. What is Known: • Medical professionals and parents are likely to overestimate children's discomfort undergoing (invasive) research procedures. • Two thirds of children (age 6-18 years) participating in medical research indicated that they would participate in the same research study again. What is New: • Pre-school children experience little emotional burden during invasive procedures in asthma research. • Proper communication about (invasive) research procedures in pre-school children helps to reduce the anticipatory fear of these procedures in the future.

Exploring Immune Development in Infants With Moderate to Severe Atopic Dermatitis.

Background: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in infancy with a complex pathology. In adults, the clinical severity of AD has been associated with increases in T helper cell type (Th) 2, Th22, and Th17 serum markers, including high levels of CC chemokine ligand (CCL) 17 and CCL22 chemokines. Objective: To explore the possible association between serum chemokine levels and AD severity in infants with moderate-to-severe AD and elevated immunoglobulin E (IgE). Subjects and methods: Serum samples (n = 41) obtained from a randomized, double-blind, and clinical dietary intervention study were used to study biomarkers in infants with AD. Baseline- and post-intervention samples (4 months) were used, six chemokines and nine ratios thereof were analyzed using Luminex and correlated to AD severity. In the initial study, the infants were randomized to receive extensively hydrolyzed whey-based formula without (control) or with short-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides (9:1) and Bifidobacterium breve M-16V (active). Results: 31 Infants up to 11 months of age, with an objective-SCORAD score (oSCORAD) ≥ 20 and elevated total-IgE and/or specific-IgE levels were included. In time, the median oSCORAD decreased in both groups by -8 (control, p < 0.05; active, p < 0.01). Irrespective of dietary intervention, several changes in Th2 chemokines (CCL17 and CCL22), inflammatory chemokine (CCL20), and the Th1 chemokine, CXC chemokine ligand (CXCL) 9, were detected over time. Overall CCL17 correlated to oSCORAD (r = 0.446, p < 0.01). After 4 months of dietary intervention, CXCL9 was higher (p < 0.01) in the active group compared with control [active, 2.33 (1.99-2.89); controls, 1.95 (1.77-2.43) log 10 median (range)]. In addition, a reduction in Th2/Th1 chemokine ratios for CCL17/CXCL9, CCL22/CXCL9, CCL20/CXCL10, and CCL20/CXCL11 was detected associated with the active intervention. Conclusion: While this study is small and exploratory in nature, these data contribute to immune biomarker profiling and understanding of AD in infants.

Severe Paediatric Asthma Collaborative in Europe (SPACE): protocol for a European registry.

The development of new asthma biologics and receptor blockers for the treatment of paediatric severe asthma raises challenges. It is unclear whether there are sufficient children in Europe to recruit into randomised placebo-controlled trials to establish efficacy and safety in this age group. In February 2016, the European Respiratory Society funded a clinical research collaboration entitled "Severe Paediatric Asthma Collaborative in Europe" (SPACE). We now report the SPACE protocol for a prospective pan-European observational study of paediatric severe asthma. Inclusion criteria are: 1) age 6-17 years, 2) severe asthma managed at a specialised centre for ≥6 months, 3)clinical and spirometry evidence of asthma, and 4) reaching a pre-defined treatment threshold. The exclusion criterion is the presence of conditions which mimic asthma symptoms. Eligible children will be prospectively recruited into a registry, recording demographics, comorbidities, quality of life, family history, neonatal history, smoking history, asthma background, investigations, and treatment. Follow-up will provide longitudinal data on asthma control and treatment changes. The SPACE registry, by identifying well-phenotyped children eligible for clinical trials, and the amount of overlap in eligibility criteria, will inform the design of European trials in paediatric severe asthma, and facilitate observational research where data from single centres are limited.

Exposure to Environmental Contaminants and Lung Function in Adolescents-Is There a Link?

Dioxins (polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDF)), polychlorinated biphenyls (PCBs), and brominated flame retardants (BDEs) are well known toxic environmental contaminants. Their possible role in the incidence of respiratory disease is not yet well understood. Previous studies showed a negative effect on lung function in relation to prenatal and lactational dioxin exposure in pre-pubertal children. Effects of BDE exposure on the lung function have not previously been evaluated. As part of a longitudinal cohort study, the effects of perinatal dioxin (PCDD/F) exposure and serum PCDD/F, dl-PCB, and BDE levels on lung function in adolescents were assessed using spirometry, a body box, and diffusion measurements. Thirty-three children (born between 1986 and 1991) consented to the current follow-up study. Prenatal, lactational, and current dioxin, PCB, and BDE concentrations were determined using GC-MS. No relationship was seen between prenatal and lactational dioxin exposure, nor with current PCB body burden, and lung function. Indications of increasing airway obstruction were seen in relation to increasing current BDE exposure. This is a novel finding and certainly warrants further research.

The Trigger Tool as a Method to Measure Harmful Medication Errors in Children.

OBJECTIVES: The aim of this study was to improve medication safety for children; it is important to quantify the occurrence of preventable medication errors (MEs). A trigger tool may be an effective and time-saving strategy, but its measurement performance is unclear. Therefore, we aimed to estimate the performance of a pediatric medication-focused trigger tool in detecting harmful MEs. METHODS: First, we established a multifaceted method as a reference comparison. Second, we compared the pediatric medication-focused trigger tool with the multifaceted method in a new cohort of patients. All patients admitted in February and March 2013 were screened using the trigger tool and the multifaceted method to obtain full verification. Data collection was performed in separate teams to guarantee blinding of the test results. RESULTS: Review of the clinical records and the voluntary incident reports was most effective in detecting harmful MEs, so this approach was chosen as a reference comparison. In the second part of the study, 369 patients were included. The multifaceted method identified 33 harmful MEs. In contrast, the trigger tool did not identify any harm. When the 2 symptoms pain and nausea/vomiting were added to the trigger tool, 19 harmful MEs were identified. This extended trigger tool resulted in a sensitivity of 21.2 and a positive predictive value of 36.8. CONCLUSIONS: The original pediatric medication-focused trigger tool yielded only false-positive scores and left unsafe situations undiscovered. We conclude that a multifaceted method remains the preferred method to detect harmful MEs. The additional value of the trigger tool stays unclear.

Alterations in the programming of energy metabolism in adolescents with background exposure to dioxins, dl-PCBs and PBDEs.

OBJECTIVES: Dioxins and PCBs are highly toxic and persistent environmental pollutants that are measurable in humans worldwide. These persistent organic pollutants are associated with a higher incidence of diabetes mellitus. We hypothesise that perinatal (background) exposure to industrial pollutants like dioxins also influences body mass development and energy metabolism in later life. STUDY DESIGN: In The Netherlands, the perinatal exposure (prenatal exposure and postnatal lactational intake) to dioxins has been studied prospectively since 1987. Fasting glucose, insulin, HbA1c and leptin were analysed in 33 children of the original cohort of 60. BMI, glucose:insulin and BMI:leptin ratios were calculated. Prenatal exposure, lactational intake and current serum levels of dioxins (PCDD/F), dl-PCBs and PBDE concentrations were determined using (HR)GC-MS. RESULTS: Prenatal dioxin (PCDD/F) exposure was positively correlated to the glucose:insulin ratio (p = 0.024) and negatively correlated to the fasting insulin concentration (p = 0.017) in adolescence. Postnatal lactational PCDD/F intake was also negatively correlated to fasting insulin concentration (p = 0.028). Current serum levels of PCDD/Fs and total TEQ (dl-PCBs+PCDD/Fs) were positively correlated to the fasting serum glucose concentration (p = 0.015 and p = 0.037, respectively).No metabolic effects were seen in association with current serum levels of PBDEs. A positive correlation between the insulin and leptin concentrations (p = 0.034) was observed. No effects were found on leptin levels, BMI:leptin ratio, HbA1c levels or BMI. DISCUSSION/CONCLUSION: This study indicates that prenatal and lactational exposure influences glucose metabolism in adolescents, presumably through a negative effect on insulin secretion by pancreatic beta cells. Additionally, the very low recent background exposure to dioxins in puberty possibly has an effect on the glucose level.

BMI predicts exercise induced bronchoconstriction in asthmatic boys.

BACKGROUND: Exercise induced bronchoconstriction (EIB) is a frustrating morbidity of asthma in children. Obesity has been associated with asthma and with more severe EIB in asthmatic children. OBJECTIVES: To quantify the effect of BMI on the risk of the occurrence of EIB in children with asthma. METHODS: Data were collected from six studies in which exercise challenge tests were performed according to international guidelines. We included 212 Children aged 7-18 years, with a pediatrician-diagnosed mild-to-moderate asthma. RESULTS: A total of 103 of 212 children (49%) had a positive exercise challenge (fall of FEV1 ≥ 13%). The severity of EIB, as measured by the maximum fall in FEV1 , was significantly greater in overweight and obese children compared to normal weight children (respectively 23.9% vs 17.9%; P = 0.045). Asthmatic children with a BMI z-score around +1 had a 2.9-fold higher risk of the prevalence of EIB compared to children with a BMI z-score around the mean (OR 2.9; 95%CI: 1.3-6.1; P < 0.01). An increase in BMI z-score of 0.1 in boys led to a 1.4-fold increased risk of EIB (OR 1.4; 95%CI: 1.0-1.9; P = 0.03). A reduction in pre-exercise FEV1 was associated with a higher risk of EIB (last quartile six times higher risk compared to highest quartile (OR 6.1 [95%CI 2.5-14.5]). CONCLUSIONS: The severity of EIB is significantly greater in children with overweight and obesity compared to non-overweight asthmatic children. Furthermore, this study shows that the BMI-z-score, even with a normal weight, is strongly associated with the incidence of EIB in asthmatic boys.

Risk of pneumonia in obstructive lung disease: A real-life study comparing extra-fine and fine-particle inhaled corticosteroids.

BACKGROUND: Regular use of inhaled corticosteroids (ICS) in patients with obstructive lung diseases has been associated with a higher risk of pneumonia, particularly in COPD. The risk of pneumonia has not been previously evaluated in relation to ICS particle size and dose used. METHODS: Historical cohort, UK database study of 23,013 patients with obstructive lung disease aged 12-80 years prescribed extra-fine or fine-particle ICS. The endpoints assessed during the outcome year were diagnosis of pneumonia, acute exacerbations and acute respiratory events in relation to ICS dose. To determine the association between ICS particle size, dose and risk of pneumonia in unmatched and matched treatment groups, logistic and conditional logistic regression models were used. RESULTS: 14788 patients were stepped-up to fine-particle ICS and 8225 to extra-fine ICS. On unmatched analysis, patients stepping-up to extra-fine ICS were significantly less likely to be coded for pneumonia (adjusted odds ratio [aOR] 0.60; 95% CI 0.37, 0.97]); experience acute exacerbations (adjusted risk ratio [aRR] 0.91; 95%CI 0.85, 0.97); and acute respiratory events (aRR 0.90; 95%CI 0.86, 0.94) compared with patients stepping-up to fine-particle ICS. Patients prescribed daily ICS doses in excess of 700 mcg (fluticasone propionate equivalent) had a significantly higher risk of pneumonia (OR [95%CI] 2.38 [1.17, 4.83]) compared with patients prescribed lower doses, irrespective of particle size. CONCLUSIONS: These findings suggest that patients with obstructive lung disease on extra-fine particle ICS have a lower risk of pneumonia than those on fine-particle ICS, with those receiving higher ICS doses being at a greater risk.

Real-Life Outcomes for Patients with Asthma Prescribed Spacers for Use with Either Extrafine- or Fine-Particle Inhaled Corticosteroids.

BACKGROUND: Spacers are often used with pressurized metered-dose inhalers (pMDIs) to eliminate the need for coordinating inhalation with actuation. OBJECTIVE: To investigate the real-life effectiveness of spacers prescribed for use with either extrafine- or fine-particle inhaled corticosteroids (ICSs). METHODS: This historical matched cohort study examined anonymous medical record data over 2 years (1-year baseline, 1-year outcome) for patients with asthma aged 12 to 80 years initiating ICSs by pMDI with or without prescribed spacer. We compared outcomes for spacer versus no-spacer arms, matched for key baseline and asthma-related characteristics, within 2 ICS cohorts: (1) extrafine-particle ICS (beclomethasone) and (2) fine-particle ICS (fluticasone). Effectiveness end points were compared using conditional regression methods. RESULTS: Matched spacer and no-spacer arms of the extrafine-particle ICS cohort each included 2090 patients (69% females; median age, 46-47 years) and the 2 arms of the fine-particle ICS cohort each included 444 patients (67% females; median age, 45 years). With extrafine-particle ICS, we observed no significant difference between spacer and no-spacer arms in severe exacerbation rate (primary end point): adjusted rate ratio, 1.01 (95% CI, 0.83-1.23). With fine-particle ICS, the severe exacerbation rate ratio with spacers was 0.77 (0.47-1.25). Oropharyngeal candidiasis incidence was low and similar in spacer and no-spacer arms for both ICS cohorts. CONCLUSIONS: We found no evidence that prescribed spacer devices are associated with improved asthma outcomes for extrafine- or fine-particle ICS administered by pMDI. These findings challenge long-standing assumptions that spacers should improve pMDI effectiveness and indicate the need for pragmatic trials of spacers in clinical practice.

Asthma-Related Outcomes in Patients Initiating Extrafine Ciclesonide or Fine-Particle Inhaled Corticosteroids.

PURPOSE: Extrafine-particle inhaled corticosteroids (ICS) have greater small airway deposition than standard fine-particle ICS. We sought to compare asthma-related outcomes after patients initiated extrafine-particle ciclesonide or fine-particle ICS (fluticasone propionate or non-extrafine beclomethasone). METHODS: This historical, matched cohort study included patients aged 12-60 years prescribed their first ICS as ciclesonide or fine-particle ICS. The 2 cohorts were matched 1:1 for key demographic and clinical characteristics over the baseline year. Co-primary endpoints were 1-year severe exacerbation rates, risk-domain asthma control, and overall asthma control; secondary endpoints included therapy change. RESULTS: Each cohort included 1,244 patients (median age 45 years; 65% women). Patients in the ciclesonide cohort were comparable to those in the fine-particle ICS cohort apart from higher baseline prevalence of hospitalization, gastroesophageal reflux disease, and rhinitis. Median (interquartile range) prescribed doses of ciclesonide and fine-particle ICS were 160 (160-160) µg/day and 500 (250-500) µg/day, respectively (P<0.001). During the outcome year, patients prescribed ciclesonide experienced lower severe exacerbation rates (adjusted rate ratio [95% CI], 0.69 [0.53-0.89]), and higher odds of risk-domain asthma control (adjusted odds ratio [95% CI], 1.62 [1.27-2.06]) and of overall asthma control (2.08 [1.68-2.57]) than those prescribed fine-particle ICS. The odds of therapy change were 0.70 (0.59-0.83) with ciclesonide. CONCLUSIONS: In this matched cohort analysis, we observed that initiation of ICS with ciclesonide was associated with better 1-year asthma outcomes and fewer changes to therapy, despite data suggesting more difficult-to-control asthma. The median prescribed dose of ciclesonide was one-third that of fine-particle ICS.

Effectiveness of initiating extrafine-particle versus fine-particle inhaled corticosteroids as asthma therapy in the Netherlands.

BACKGROUND: Most randomised clinical trials typically exclude a significant proportion of asthma patients, including those at higher risk of adverse events, with comorbidities, obesity, poor inhaler technique and adherence, or smokers. However, these patients might differentially benefit from extrafine-particle inhaled corticosteroids (ICS). This matched cohort, database study, compared the effectiveness of extrafine-particle with fine-particle ICS in a real-life population initiating ICS therapy in the Netherlands. METHODS: Data were from the Pharmo Database Network, comprising pharmacy and hospital discharge records, representative of 20 % of the Dutch population. The study population included patients aged 12 - 60, with a General Practice-recorded diagnosis for asthma (International Classification of Primary Care code R96), when available, ≥2 prescriptions for asthma therapy at any time in their recorded history, and receiving first prescription of ICS therapy as either extrafine-particle (ciclesonide or hydrofluoroalkane beclomethasone dipropionate [BDP]) or fine-particle ICS (fluticasone propionate or non-extrafine-particle-BDP). Patients were matched (1:1) on relevant demographic and clinical characteristics over 1-year baseline. Primary outcomes were severe exacerbation rates, risk domain asthma control and overall asthma control during the year following first ICS prescription. Secondary outcomes, treatment stability and being prescribed higher versus lower category of short-acting ß2 agonists (SABA) dose, were compared over a 1-year outcome period using conditional logistic regression models. RESULTS: Following matching, 1399 patients were selected in each treatment cohort (median age: 43 years; males: 34 %). Median (interquartile range) initial ICS doses (fluticasone-equivalents in µg) were 160 (160 - 320) for extrafine-particle versus 500 (250 - 500) for fine-particle ICS (p < 0.001). Following adjustment for residual confounders, matched patients prescribed extrafine-particle ICS had significantly lower rates of exacerbations (adjusted rate ratio [95 % CI], 0.59 [0.47-0.73]), and significantly higher odds of achieving asthma control and treatment stability in the year following initiation than those prescribed fine-particle ICS, and this occurred at lower prescribed doses. Patients prescribed extrafine-particle ICS had lower odds of being prescribed higher doses of SABA (0.50 [0.44-0.57]). CONCLUSION: In this historical, matched study, extrafine-particle ICS was associated with better odds of asthma control than fine-particle ICS in patients prescribed their first ICS therapy in the Netherlands. Of importance, this was reached at significantly lower prescribed dose.

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.