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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.

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 FEV 1  ≥ 13%). The severity of EIB, as measured by the maximum fall in FEV 1 , 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 FEV 1 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., (© 2017 Wiley Periodicals, Inc.)

Preschool rhinovirus-induced wheeze is associated with an increased risk of asthma. In adult asthma, exhaled volatile organic compounds (VOC) are associated with inflammatory activity. We therefore hypothesised that acute preschool wheeze is accompanied by a differential profile of exhaled VOC, which is maintained after resolution of symptoms in those children with rhinovirus-induced wheeze. We included 178 children (mean±sd age 22±9 months) from the EUROPA cohort comparing asymptomatic and wheezing children during respiratory symptoms and after recovery. Naso- and oropharyngeal swabs were tested for rhinovirus by quantitative PCR. Breath was collected via a spacer and analysed using an electronic nose. Between-group discrimination was assessed by constructing a 1000-fold cross-validated receiver operating characteristic curve. Analyses were stratified by rhinovirus presence/absence. Wheezing children demonstrated a different VOC profile when compared with asymptomatic children (p<0.001), regardless of the presence (area under the curve (AUC) 0.77, 95% CI 0.07) or absence (AUC 0.81, 95% CI 0.05) of rhinovirus. After symptomatic recovery, discriminative accuracy was maintained in children with rhinovirus-induced wheeze (AUC 0.84, 95% CI 0.06), whereas it dropped significantly in infants with non-rhinovirus-induced wheeze (AUC 0.67, 95% CI 0.06). Exhaled molecular profiles differ between preschool children with and without acute respiratory wheeze. This appears to be sustained in children with rhinovirus-induced wheeze after resolution of symptoms. Therefore, exhaled VOC may qualify as candidate biomarkers for early signs of asthma., (Copyright ©ERS 2015.)

Background: Multidisciplinary treatment at high altitude is a possible treatment option for problematic severe asthma (PSA) in children. This management can result in the tapering of inhaled corticosteroids., Aim: Our aim was to analyze the effect of multidisciplinary treatment at high altitude, notably the ability to taper corticosteroids. To get an insight into possible factors influencing tapering, we examined whether demographic variables, disease control and quality of life at treatment entrance could predict the tapering of corticosteroids., Methods: This prospective open-phase cohort study analyzed the data of 43 children aged 8-17 years referred to a specialized high altitude treatment centre. Lung function (FEV1, FEV1/VC), inflammation (FeNO), medication level, asthma control (ACT) and quality of life [PAQLQ(S)] were evaluated on admission and at discharge., Results: Thirty-two (74%) children fulfilled PSA criteria. Three (7%) children used daily oral steroids. After 72 ± 30 (mean ± SD) days of treatment, the mean dosage of inhaled corticosteroids (ICS) could be significantly reduced from 1315 μg ± 666 budesonide equivalent to 1132 μg ± 514. Oral steroid maintenance therapy could be stopped in all patients. FeNO, asthma control and quality of life improved (p < 0.001) from admission to discharge; FEV1 was in the normal range on both occasions. Apart from ICS levels at entrance, multiple regression analyses did not show any associated factor predicting the reduction of ICS dosage during treatment., Conclusion: The results indicate that high altitude treatment may be a treatment option for children with PSA, but it is not possible to predict ICS tapering off from health status variables at treatment entrance.

Background: A setting-specific asthma prediction score for preschool children with wheezing and/or dyspnoea presenting in primary healthcare is needed since existing indices are mainly based on general populations., Aims: To find an optimally informative yet practical set of predictors for the prediction of asthma in preschool children at high risk who present in primary healthcare., Methods: A total of 771 Dutch preschool children at high risk of asthma were followed prospectively until the age of six years. Data on asthma symptoms and environmental conditions were obtained using validated questionnaires and specific IgE was measured. At the age of six years the presence of asthma was assessed based on asthma symptoms, medication, and bronchial hyper-responsiveness. A clinical asthma prediction score (CAPS) was developed using bootstrapped multivariable regression methods., Results: In all, 438 children (56.8%) completed the study; the asthma prevalence at six years was 42.7%. Five parameters optimally predicted asthma: age, family history of asthma or allergy, wheezing-induced sleep disturbances, wheezing in the absence of common colds, and specific IgE. CAPS scores range from 0 to 11 points; scores <3 signified a negative predictive value of 78.4% while scores of >7 signified a positive predictive value of 74.3%., Conclusions: We have developed an easy-to-use CAPS for preschool children with symptoms suggesting asthma who present in primary healthcare. After suitable validation, the CAPS may assist in guiding shared decision-making to tailor the need for medical or non-medical interventions. External validation of the CAPS is needed.

Background: Asthma is the most common chronic disease in childhood and prevalence is also high in adulthood, thereby placing a considerable burden on healthcare resources. Therefore, effective asthma management is important to reduce morbidity and to optimise utilisation of healthcare facilities., Objectives: To review the effectiveness of nurse-led asthma care provided by a specialised asthma nurse, a nurse practitioner, a physician assistant or an otherwise specifically trained nursing professional, working relatively independently from a physician, compared to traditional care provided by a physician. Our scope included all outpatient care for asthma, both in primary care and in hospital settings., Search Methods: We carried out a comprehensive search of databases including The Cochrane Library, MEDLINE and EMBASE to identify trials up to August 2012. Bibliographies of relevant papers were searched, and handsearching of relevant publications was undertaken to identify additional trials., Selection Criteria: Randomised controlled trials comparing nurse-led care versus physician-led care in asthma for the same aspect of asthma care., Data Collection and Analysis: We used standard methodological procedures expected by The Cochrane Collaboration., Main Results: Five studies on 588 adults and children were included concerning nurse-led care versus physician-led care. One study included 154 patients with uncontrolled asthma, while the other four studies including 434 patients with controlled or partly controlled asthma. The studies were of good methodological quality (although it is not possible to blind people giving or receiving the intervention to which group they are in). There was no statistically significant difference in the number of asthma exacerbations and asthma severity after treatment (duration of follow-up from six months to two years). Only one study had healthcare costs as an outcome parameter, no statistical differences were found. Although not a primary outcome, quality of life is a patient-important outcome and in the three trials on 380 subjects that reported on this outcome, there was no statistically significant difference (standardised mean difference (SMD) -0.03; 95% confidence interval (CI) -0.23 to 0.17)., Authors' Conclusions: We found no significant difference between nurse-led care for patients with asthma compared to physician-led care for the outcomes assessed. Based on the relatively small number of studies in this review, nurse-led care may be appropriate in patients with well-controlled asthma. More studies in varied settings and among people with varying levels of asthma control are needed with data on adverse events and health-care costs.

Background: The recommendations for the treatment of moderate persistent asthma in the Global Initiative for Asthma (GINA) guidelines for paediatric asthma are mainly based on scientific evidence extrapolated from studies in adults or on consensus. Furthermore, clinical decision-making would benefit from formal ranking of treatments in terms of effectiveness.Our objective is to assess all randomized trial-based evidence specifically pertaining to 5-18 year olds with moderate persistent asthma. Rank the different drug treatments of GINA guideline steps 3&4 in terms of effectiveness., Methods: Systematic review with network meta-analysis. After a comprehensive search in Central, Medline, Embase, CINAHL and the WHO search portal two reviewers selected RCTs performed in 4,129 children from 5-18 year old, with moderate persistent asthma comparing any GINA step 3&4 medication options. Further quality was assessed according the Cochrane Collaboration's tool and data-extracted included papers and built a network of the trials. Attempt at ranking treatments with formal statistical methods employing direct and indirect (e.g. through placebo) connections between all treatments., Results: 8,175 references were screened; 23 randomized trials (RCT), comparing head-to-head (n=17) or against placebo (n=10), met the inclusion criteria. Except for theophylline as add-on therapy in step 4, a closed network allowed all comparisons to be made, either directly or indirectly. Huge variation in, and incomplete reporting of, outcome measurements across RCTs precluded assessment of relative efficacies., Conclusion: Evidence-based ranking of effectiveness of drug treatments in GINA steps 3&4 is not possible yet. Existing initiatives for harmonization of outcome measurements in asthma trials need urgent implementation.

Inhaled corticosteroids (ICS) are the most effective anti-inflammatory drugs for the treatment of persistent asthma in children. Treatment with ICS decreases asthma mortality and morbidity, reduces symptoms, improves lung function, reduces bronchial hyperresponsiveness and reduces the number of exacerbations. The efficacy of ICS in preschool wheezing is controversial. A recent task force from the European Respiratory Society on preschool wheeze defined two different phenotypes: episodic viral wheeze, wheeze that occurs only during respiratory viral infections, and multiple-trigger wheeze, where wheeze also occurs in between viral episodes. Treatment with ICS appears to be more efficacious in the latter phenotype. Small particle ICS may offer a potential benefit in preschool children because of the favourable spray characteristics. However, the efficacy of small particle ICS in preschool children has not yet been evaluated in prospective clinical trials. The use of ICS in school children with asthma is safe with regard to systemic side effects on the hypothalamic-pituitary-adrenal axis, growth and bone metabolism, when used in low to medium doses. Although safety data in wheezing preschoolers is limited, the data are reassuring. Also for this age group, adverse events tend to be minimal when the ICS is used in appropriate doses.

Background: Asthma is a difficult diagnosis to establish in preschool children. A few years ago, our group presented a prediction rule for young children at risk for asthma in general practice. Before this prediction rule can safely be used in practice, cross-validation is required. In addition, general practitioners face many therapeutic management decisions in children at risk for asthma. The objectives of the study are: (1) identification of predictors for asthma in preschool children at risk for asthma with the aim of cross-validating an earlier derived prediction rule; (2) compare the effects of different treatment strategies in preschool children., Design: In this prospective cohort study one to five year old children at risk of developing asthma were selected from general practices. At risk was defined as 'visited the general practitioner with recurrent coughing (>or= 2 visits), wheezing (>or=1) or shortness of breath (>or=1) in the previous 12 months'. All children in this prospective cohort study will be followed until the age of six. For our prediction rule, demographic data, data with respect to clinical history and additional tests (specific immunoglobulin E (IgE), fractional exhaled nitric oxide (FENO), peak expiratory flow (PEF)) are collected. History of airway specific medication use, symptom severity and health-related quality of life (QoL) are collected to estimate the effect of different treatment intensities (as expressed in GINA levels) using recently developed statistical techniques. In total, 1,938 children at risk of asthma were selected from general practice and 771 children (40%) were enrolled. At the time of writing, follow-up for all 5-year olds and the majority of the 4-year olds is complete. The total and specific IgE measurements at baseline were carried out by 87% of the children. Response rates to the repeated questionnaires varied from 93% at baseline to 73% after 18 months follow-up; 89% and 87% performed PEF and FENO measurements, respectively., Discussion: In this study a prediction rule for asthma in young children, to be used in (general) practice, will be cross-validated. Our study will also provide more insight in the effect of treatment of asthma in preschool children.

Background: The monitoring of children with asthma in primary care is based on the occurrence and frequency of asthma symptoms. We questioned whether the current approach is adequate to identify all children in whom a sufficient level of asthma control is not achieved., Aim: The aim of this study is to illustrate that in some children asthma was incorrectly considered controlled, because the children failed to report current symptoms of asthma., Patients and Methods: One hundred and nineteen children were identified with recent wheezing plus moderate or severe airway hyperresponsiveness. We analyzed whether these children reported current symptoms of asthma (as normally questioned during a routine visit)., Results: In 20 children (18%) current asthma symptoms were absent despite moderately or severe airway hyperresponsiveness and wheezing in the last year. In addition, the usage of controller medication was very poor., Conclusion: We conclude that the general practitioner has insufficient tools to adequately assess asthma control in all children. The assessment of airway hyperresponsiveness as an additional guide to manage asthma in children in general practice is recommended. In this way, better asthma control can be achieved.

Aim: The aim of the study was to assess, in a randomised, controlled design, the efficacy of different strategies to improve childhood asthma management., Method: Three interventions directed to three groups of general practitioners were compared: Group A - dissemination of a guideline; Group B - guideline dissemination plus an educational session; Group C - guideline dissemination, educational session, plus individualised treatment advice based on airway hyperresponsiveness (AHR) and symptoms. Efficacy of the three strategies was assessed by evaluating change in AHR in 362 children after one year., Results: The overall between-group effect of the severity of AHR was not significantly different (P=0.09). In Groups A and C an improvement was seen in nocturnal symptoms (P=0.02) and in Group C an improvement was seen in the prescription of inhaled corticosteroids (P=0.03)., Conclusion: In this study, the combined implementation strategy did not show a clear improvement in the management of children with asthma in general practice.

In a general practice based population 76% of 530 children inhaling asthma medication inhaled correctly. However, important differences among inhalers were found. Children with a pressurized metered-dose inhaler without a spacer device performed worst, with only 22% inhaling without essential errors. At a second evaluation of the inhaler technique, one year after the first assessment, performances with a new device were more often incorrect versus the unchanged devices (21.1% and 10.8%, respectively; p = 0.01). Providing children with a new device should be carefully controlled over time especially because these children are error prone.

The Asthma Insight and Reality in Europe (AIRE) study showed that the current management and treatment of asthma in Europe falls short of the goals set in the GINA guidelines. Patient care may be negatively influenced by the physicians' underestimation of their patients' disease state, and overestimation of their patients' knowledge of asthma management. We interviewed 118 paediatricians and 152 general practitioners (response rate 70 and 86%, respectively) in order to get an insight into the physicians view on his patients' asthma management. A questionnaire containing similar items to those used in the AIRE study was used. Dutch physicians believe that the asthma of the majority of their patients is well controlled and underestimate the prevalence of daytime symptoms. They believe that their patients are aware of the differences between reliever medication and maintenance medication and overestimate the number of patients in possession of a written action plan. Dutch paediatricians and general practitioners underestimate the severity of their patients' disease state and overestimate their patients' knowledge of disease management.

Nocturnal airway obstruction occurs frequently in childhood asthma and results from increased airway inflammation. Lymphocytes are believed to be key effector cells of airway wall inflammation, releasing pro-inflammatory mediators and cytokines. A previous study showed that hydrocortisone infusion, an effective anti-inflammatory treatment, improves nocturnal and daytime FEV(1) values. This study in 16 children with moderate asthma was designed to assess whether there exists day and night differences in IL-4, IL-5, IL-8, and IFN-gamma production of concanavaline A stimulated peripheral blood mononuclear cells. Furthermore, we investigated whether substitution of low serum cortisol levels with intravenous hydrocortisone would affect those parameters. Saline (as a placebo) or hydrocortisone (30 microg/m(2) body surface area/24 h) was intravenously administered in a randomized, double blind, cross-over design. Measurements under saline or hydrocortisone infusions were separated by 1 wk. At 04:00 and 16:00 hours 10 ml blood was taken for determination of peripheral blood mononuclear cell isolation and stimulation, and an eosinophil count. Hydrocortisone infusion significantly reduced the nocturnal fall in FEV(1). Median values of IFNgamma, IL-4, IL-5, and IL-8 produced by peripheral blood mononuclear cells did not significantly differ at 04:00 and 16:00 hours, both with saline and hydrocortisone infusion. Our results suggest that FEV(1) improvement is not due to suppression of circulating peripheral blood mononuclear cell activation. We hypothesize that it is rather due to its effect on local lung tissue epithelial and/or fibroblasts thereby reducing airway inflammation and vascular leakage.

Background: For the diagnosis of asthma in young children, GPs have to rely on history taking and physical examination, as spirometry is not possible. The additional diagnostic value of specific immunoglobulin E (IgE) to inhalent allergens remains unclear., Aim: To assess the predictive accuracy of specific IgE to cat, dog, and/or house dust mites in young children for the subsequent development of asthma at the age of 6 years., Design of Study: Prospective follow-up study., Setting: Seventy-two general practices., Method: A total of 654 children, aged 1-4 years, visiting their GPs for persistent coughing (>/= 5 days), were tested for IgE antibodies by radio allergosorbent testing (RAST). Parents completed a questionnaire on potential risk indicators. Those children who showed an IgE-positive status (12.7%) and a random sample of those with an IgE-negative status (<0.5 U/ml) were followed up to the age of 6 years when the asthma status was established. The main outcome measure was asthma at the age of 6 years (combination of both symptoms and/or use of asthma medication, and impaired lung function)., Results: Addition of RAST results to a prediction model based on age, wheeze, and family history of pollen allergy increased the area under the receiver operating characteristic (ROC) curve from 0.76 to 0.87. Furthermore, RAST improved patient differentiation as indicated by a change in the range of asthma probabilities from 6-75% before the IgE test, to 1-95% after the IgE-test., Conclusion: Sensitisation to inhalant allergens in 1-4-year-olds, as shown by RAST, is a useful diagnostic indicator for the presence of asthma at the age of 6 years, even after a clinical history has been obtained. This model should preferably be validated in a new population before it can be applied in practice.

The aim of the study was to investigate the association between electromyography (EMG) of the diaphragm and intercostal muscles and the forced expiratory volume in 1 s (FEV(1)) at different levels of histamine-induced airflow limitation, and the response to salbutamol. Moreover, we assessed the reproducibility of the EMG measurements on 2 different occasions during different levels of airflow limitation in asthmatic school children. Fourteen children with asthma performed 2 histamine challenges with a 24-h time interval and 1 child performed 1 histamine challenge. The EMG signals were derived from surface electrodes. The logarithm of the EMG-activity-ratio (log EMGAR; mean peak-bottom ratio of respiratory muscle activity) was used as EMG parameter. The log EMGAR of the diaphragm (di) and the log EMGAR of the intercostal muscles (int) associated well with the histamine-induced fall in FEV(1) at 5% steps from the baseline value. After administration of salbutamol log EMGARdi and log EMGARint returned to baseline mean peak-bottom values (for all leads P<0.001). The EMGARdi and EMGARint values were reproducible at different levels of airflow limitation. This study showed that EMGARdi and EMGARint as a parameter for a change in electrical activity of the diaphragm and intercostal muscles associated well with FEV(1), was reversible after salbutamol and was reproducible at different levels of histamine-induced airflow limitation in asthmatic school children.

Decreased serum cortisol levels have been proposed to contribute to nocturnal airway obstruction. We investigated whether endogenous cortisol levels are lower, and also whether the 24-h cortisol variation is greater, in children with asthma than in control subjects and assessed the relationship between serum cortisol and nocturnal airflow limitation in children with asthma. Cortisol and FEV(1) were measured every 4 h over 24 h; blood eosinophils, airway responsiveness to methacholine and adenosine 5'-monophosphate (AMP) were measured at 0400 and 1600. Children with asthma had lower cortisol levels than did control subjects; at midnight the difference was significant. Subjects with nocturnal asthma (24-h FEV(1) variation > or =15%) had significantly lower cortisol levels than did control subjects at 0000, 0800, and 1200. A higher mean 24-h cortisol level in subjects with asthma was associated with a significantly higher FEV(1) as a percentage of the predicted value (FEV(1) %pred) at 0400, 0800, and 2000, yet not in control subjects. Higher 24-h cortisol variation was associated with lower FEV(1) %pred at all time points in both control subjects and subjects with nonnocturnal asthma. There was no significant association between the level or variation of cortisol and PD(20) methacholine (provocative dose of methacholine causing a 20% fall in FEV(1)), PD(20) AMP, or eosinophils. Our data suggest that lower cortisol levels contribute to both overall lower levels of FEV(1) especially at night. This may be due to a lack of suppression of airway inflammation.

Aim: The aim of the study was to assess, in a randomised, controlled design, the efficacy of different strategies to improve childhood asthma management. Method: Three interventions directed to three groups of general practitioners were compared: Group A - dissemination of a guideline; Group B - guideline dissemination plus an educational session; Group C - guideline dissemination, educational session, plus individualised treatment advice based on airway hyperresponsiveness (AHR) and symptoms. Efficacy of the three strategies was assessed by evaluating change in AHR in 362 children after one year. Results: The overall between-group effect of the severity of AHR was not significantly different (P=0.09). In Groups A and C an improvement was seen in nocturnal symptoms (P=0.02) and in Group C an improvement was seen in the prescription of inhaled corticosteroids (P=0.03). Conclusion: In this study, the combined implementation strategy did not show a clear improvement in the management of children with asthma in general practice. [ABSTRACT FROM AUTHOR]

In a general practice based population 76% of 530 children inhaling asthma medication inhaled correctly. However, important differences among inhalers were found. Children with a pressurized metered-dose inhaler without a spacer device performed worst, with only 22% inhaling without essential errors. At a second evaluation of the inhaler technique, one year after the first assessment, performances with a new device were more often incorrect versus the unchanged devices (21.1% and 10.8%, respectively; p = 0.01). Providing children with a new device should be carefully controlled over time especially because these children are error prone. [ABSTRACT FROM AUTHOR]