European Respiratory Society Statement on preschool wheezing disorders: updated definitions, knowledge gaps, and proposed future research directions.

Since the publication of the European Respiratory Society (ERS) Task Force reports on the management of preschool wheezing in 2008 and 2014, a large body of evidence has accumulated suggesting the clinical phenotypes that were proposed, episodic (viral) wheezing and multiple-trigger wheezing, do not relate to underlying airway pathology and may not help determine response to treatment. Specifically, using clinical phenotypes alone may no longer be appropriate, and new approaches that can be used to inform clinical care are needed for future research. This ERS Task Force reviewed the literature published after 2008 related to preschool wheezing and has suggested the criteria used to define wheezing disorders in preschool children should include age of diagnosis (0 to <6 years), confirmation of wheezing on at least one occasion, and more than one episode of wheezing ever.Furthermore, diagnosis and management may be improved by identifying treatable traits, including inflammatory biomarkers (blood eosinophils, aeroallergen sensitisation) associated with type-2 immunity and differential response to inhaled corticosteroids, lung function parameters, and airway infection. However, more comprehensive use of biomarkers/treatable traits in predicting the response to treatment requires prospective validation. There is evidence that specific genetic traits may help guide management, but these must be adequately tested. In addition, the Task Force identified an absence of caregiver-reported outcomes, caregiver/self-management options, and features that should prompt specialist referral for this age group. Priorities for future research include a focus on identifying i) mechanisms driving preschool wheezing, ii) biomarkers of treatable traits and efficacy of interventions in those without allergic sensitisation/eosinophilia, iii) the need to include both objective outcomes and caregiver-reported outcomes in clinical trials, iv) the need for a suitable action plan for children with preschool wheezing and v) a definition of severe/difficult-to-treat preschool wheezing.

Home monitoring in asthma: towards digital twins.

PURPOSE OF REVIEW: We highlight the recent advances in home monitoring of patients with asthma, and show that these advances converge towards the implementation of digital twin systems. RECENT FINDINGS: Connected devices for asthma are increasingly numerous, reliable and effective: new electronic monitoring devices extend to nebulizers and spacers, are able to assess the quality of the inhalation technique, and to identify asthma attack triggers when they include a geolocation function; environmental data can be acquired from databases and refined by wearable air quality sensors; smartwatches are better validated. Connected devices are increasingly integrated into global monitoring systems. At the same time, machine learning techniques open up the possibility of using the large amount of data collected to obtain a holistic assessment of asthma patients, and social robots and virtual assistants can help patients in the daily management of their asthma. SUMMARY: Advances in the internet of things, machine learning techniques and digital patient support tools for asthma are paving the way for a new era of research on digital twins in asthma.

Childhood asthma: pathogenesis and phenotypes.

In the pathogenesis of asthma in children there is a pivotal role for a type 2 inflammatory response to early life exposures or events. Interactions between infections, atopy, genetic susceptibility and environmental exposures (such as farmyard environment, air pollution and tobacco smoke exposure) influence the development of wheezing illness and the risk of progression to asthma. The immune system, lung function and the microbiome in gut and airways develop in parallel, and dysbiosis of the microbiome may be a critical factor in asthma development. Increased infant weight gain and preterm birth are other risk factors for development of asthma and reduced lung function. The complex interplay between these factors explains the heterogeneity of asthma in children. Subgroups of patients can be identified as phenotypes, based on clinical parameters, or endotypes, based on a specific pathophysiological mechanism. Paediatric asthma phenotypes and endotypes may ultimately help to improve diagnosis of asthma, prediction of asthma development and treatment of individual children, based on clinical, temporal, developmental or inflammatory characteristics. Unbiased, data-driven clustering, using a multidimensional or systems biology approach may be needed to better define phenotypes. The present knowledge on inflammatory phenotypes of childhood asthma has now been successfully applied in the treatment with biologicals of children with severe therapy-resistant asthma, and it is to be expected that more personalised treatment options may become available.

Persistence of parental-reported asthma at early ages: A longitudinal twin study.

BACKGROUND: Currently, we cannot predict whether a pre-school child with asthma-like symptoms will have asthma at school age. Whether genetic information can help in this prediction depends on the role of genetic factors in persistence of pre-school to school-age asthma. We examined to what extent genetic and environmental factors contribute to persistence of asthma-like symptoms at ages 3 to asthma at age 7 using a bivariate genetic model for longitudinal twin data. METHODS: We performed a cohort study in monozygotic and dizygotic twins from the Netherlands Twin Register (NTR, n = 21,541 twin pairs). Bivariate genetic models were fitted to longitudinal data on asthma-like symptoms reported by parents at age 3 and 7 years to estimate the contribution of genetic and environmental factors. RESULTS: Bivariate genetic modeling showed a correlation on the liability scale between asthma-like symptoms at age 3 and asthma at age 7 of 0.746 and the contribution of genetics was estimated to be 0.917. The genetic analyses indicated a substantial influence of genetic factors on asthma-like symptoms at ages 3 and 7 (heritability 80% and 90%, respectively); hence, contribution of environmental factors was low. Persistence was explained by a high (rg = 0.807) genetic correlation. CONCLUSION: Parental-reported asthma-like symptoms at age 3 and asthma at age 7 are highly heritably. The phenotype of asthma-like symptoms at age 3 and 7 was highly correlated and mainly due to heritable factors, indicating high persistence of asthma development over ages 3 and 7.

Small airways targeted treatment with smart nebulizer technology could improve severe asthma in children: a retrospective analysis.

OBJECTIVE: Conventional inhaler devices have a low efficacy in targeting small airways. Smart nebulizers can be used to increase deposition to small airways by adjusting the flow and depth of each inhalation based on patients 'individual inspiratory capacity. We investigated whether targeting of high dose inhaled corticosteroids (ICS) to small airways with a smart nebulizer could reduce exacerbation rate in children with severe asthma (SA). METHODS: We conducted a retrospective study in children with SA using a smart nebulizer (Akita® Jet nebulizer) for the administration of high dose ICS in our outpatient clinic at the Erasmus MC - Sophia Children's Hospital. Clinical data before and after start of treatment were collected. The primary outcome was exacerbation rate, defined as: number of asthma exacerbations for which oral corticosteroid courses (OCS) were prescribed. The exacerbation rate 1 year before treatment was compared with the exacerbation rate 1 year after start of treatment. Secondary outcomes were changes in spirometry parameters, hospital admissions and medication use. RESULTS: Data on OCS use was available for 28/31 patients. Median number of asthma exacerbations requiring OCS courses 1 year before decreased from 2 (interquartile range(IQR) 2) to 0.5 (IQR 3) 1 year after treatment (p = 0.021). Hospital admission decreased from 1 (IQR 3) to 0 (IQR 1)(p = 0.028). FEV1, FEF25-75 and FEF75 were not significantly improved after one year of treatment with the smart nebulizer (p = 0.191; p = 0.248; p = 0.572). CONCLUSION: Targeting small airways with high dose ICS using a smart nebulizer resulted in a significant reduction in exacerbations requiring OCS after one year of treatment.

Does lung function change in the months after an asthma exacerbation in children?

BACKGROUND: There are limited data describing lung function changes in children after an asthma exacerbation. Our hypothesis was that lung function does not fully recover in children in the months following an asthma exacerbation. METHODS: We used a data set of children with asthma where lung function (including FEV1 , FEV1 /FVC ratio and FEF25-75 ) was measured at 3-month intervals over a year. Mixed-level models compared spirometry measured on two occasions 3 months apart before a single exacerbation (assessments 1 and 2) with measurements made on two occasions after the exacerbation (assessments 3 and 4), with adjustment for covariates. Changes in spirometry over a year were also analysed across those with exacerbations in no, one or more than one 3-month periods. RESULTS: For the 113 children who had a single exacerbation, spirometry measured at assessments 1 or 2 did not differ from measurements at assessments 3 or 4 when the whole population was considered. When stratified into tertiles by change in %FEV1 between assessments 2 and 3, those with the greater reduction were more likely to be treated with long-acting beta-agonist, but in this category, %FEV1 at assessment 4 had returned to the value at assessment 1. %FEV1 did not change over a 12-month period within and between the three exacerbation categories (n = 809). CONCLUSION: One or more asthma exacerbation was not associated with a fall in lung function for the whole population. In a subset of individuals, lung function does fall after an exacerbation but returns to pre-exacerbation values after a period of months.

Genome-wide association studies of exacerbations in children using long-acting beta2-agonists.

BACKGROUND: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium. METHODS: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma. RESULTS: Genome-wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (P-value threshold ≤5 × 10-6 ) associated with exacerbations despite LABA use. CONCLUSION: No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7) that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use.

Does treatment guided by exhaled nitric oxide fraction improve outcomes in subgroups of children with asthma?

INTRODUCTION: Exhaled nitric oxide fraction (F ENO), a biomarker of eosinophilic airway inflammation, may be useful to guide asthma treatment. F ENO-guided treatment may be more effective in certain subgroups for improving asthma outcomes compared to standard treatment. METHODS: An individual patient data analysis was performed using data from seven randomised clinical trials (RCTs) which used F ENO to guide asthma treatment. The incidence of an asthma exacerbation and loss of control, and the time to first exacerbation and loss of control were described between five subgroups of RCT participants. RESULTS: Data were available in 1112 RCT participants. Among those not treated with leukotriene receptor antagonists (LTRA), but not among those who were treated with LTRA, F ENO-guided treatment was associated with reduced exacerbation risk (OR 0.68, 95% CI 0.49-0.94), longer time to first exacerbation (hazard ratio (HR) 0.76, 95% CI 0.57-0.99) and borderline reduced risk for loss of control (OR 0.70, 95% CI 0.49-1.00). Nonobese children, compared to obese children, were less likely to lose asthma control when treatment was guided by F ENO (OR 0.69, 95% CI 0.48-0.99) and time to loss of control was longer (HR 0.77, 95% CI 0.61-0.99). CONCLUSIONS: Asthma treatment guided by F ENO may be more effective in achieving better asthma outcomes for patients who are not treated with LTRA and who are not obese, compared to standard practice.

Early-life antibiotic use and risk of asthma and eczema: results of a discordant twin study.

RATIONALE: Early-life antibiotic use has been associated with the development of atopic diseases, but the aetiology remains unclear. To elucidate the aetiology, we used a discordant twin design to control for genetic and environmental confounding. METHODS: We conducted a retrospective cohort study in twins aged 3-10 years from the Netherlands Twin Register (NTR, n=35 365) and a replication study in twins aged 9 years from the Childhood and Adolescent Twin Study in Sweden (CATSS, n=7916). Antibiotic use was recorded at age 0-2 years. Doctor-diagnosed asthma and eczema were reported by parents when children were aged 3-12 years in both cohorts. Individuals were included in unmatched analyses and in co-twin control analyses with disease discordant twin pairs. RESULTS: Early-life antibiotic use was associated with increased risk of asthma (NTR OR 1.34, 95% CI 1.28-1.41; CATSS OR 1.45, 95% CI 1.34-1.56) and eczema (NTR OR 1.08, 95% CI 1.03-1.13; CATSS OR 1.07, 95% CI 1.01-1.14) in unmatched analyses. Co-twin analyses in monozygotic and dizygotic twin pairs showed similar results for asthma (NTR OR 1.54, 95% CI 1.20-1.98; CATSS OR 2.00, 95% CI 1.28-3.13), but opposing results for eczema in the NTR (OR 0.99, 95% CI 0.80-1.25) and the CATSS (OR 1.67, 95% CI 1.12-2.49). The risk of asthma increased for antibiotics prescribed for respiratory infections (CATSS OR 1.45, 95% CI 1.34-1.56), but not for antibiotics commonly used for urinary tract/skin infections (CATSS OR 1.02, 95% CI 0.88-1.17). CONCLUSION: Children exposed to early-life antibiotic use, particularly prescribed for respiratory infections, may be at higher risk of asthma. This risk can still be observed when correcting for genetic and environmental factors. Our results could not elucidate whether the relationship between early-life antibiotic use and eczema is confounded by familial and genetic factors.

European Respiratory Society guideline on long-term management of children with bronchopulmonary dysplasia.

This document provides recommendations for monitoring and treatment of children in whom bronchopulmonary dysplasia (BPD) has been established and who have been discharged from the hospital, or who were >36 weeks of postmenstrual age. The guideline was based on predefined Population, Intervention, Comparison and Outcomes (PICO) questions relevant for clinical care, a systematic review of the literature and assessment of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. After considering the balance of desirable (benefits) and undesirable (burden, adverse effects) consequences of the intervention, the certainty of the evidence, and values, the task force made conditional recommendations for monitoring and treatment of BPD based on very low to low quality of evidence. We suggest monitoring with lung imaging using ionising radiation in a subgroup only, for example severe BPD or recurrent hospitalisations, and monitoring with lung function in all children. We suggest to give individual advice to parents regarding daycare attendance. With regards to treatment, we suggest the use of bronchodilators in a subgroup only, for example asthma-like symptoms, or reversibility in lung function; no treatment with inhaled or systemic corticosteroids; natural weaning of diuretics by the relative decrease in dose with increasing weight gain if diuretics are started in the neonatal period; and treatment with supplemental oxygen with a saturation target range of 90-95%. A multidisciplinary approach for children with established severe BPD after the neonatal period into adulthood is preferable. These recommendations should be considered until new and urgently needed evidence becomes available.

Pharmacogenetics of inhaled long-acting beta2-agonists in asthma: A systematic review.

BACKGROUND: Long-acting beta2-agonists (LABA) are recommended in asthma therapy; however, not all asthma patients respond well to LABA. We performed a systematic review on genetic variants associated with LABA response in patients with asthma. METHODS: Articles published until April 2017 were searched by two authors using PubMed and EMBASE. Pharmacogenetic studies in patients with asthma and LABA response as an outcome were included. RESULTS: In total, 33 studies were included in this systematic review; eight focused on children (n = 6051). Nineteen studies were clinical trials, while 14 were observational studies. Studies used different outcomes to define LABA response, for example, lung function measurements (FEV1 , PEF, MMEF, FVC), exacerbations, quality of life, and asthma symptoms. Most studies (n = 30) focused on the ADRB2 gene, encoding the beta2-adrenergic receptor. Thirty studies (n = 14 874) addressed ADRB2 rs1042713, 7 ADRB2 rs1042714 (n = 1629), and 3 ADRB2 rs1800888 (n = 1892). The association of ADRB2 rs1042713 and rs1800888 with LABA response heterogeneity was successfully replicated. Other variants were only studied in three studies but not replicated. One study focused on the ADCY9 gene. Five studies and a meta-analysis found an increased risk of exacerbations in pediatrics using LABA carrying one or two A alleles (OR 1.52 [1.17; 1.99]). These results were not confirmed in adults. CONCLUSIONS: ADRB2 rs1042713 variant is most consistently associated with response to LABA in children but not adults. To assess the clinical value of ADRB2 rs1042713 in children with asthma using LABA, a randomized clinical trial with well-defined outcomes is needed.

A virtual asthma clinic for children: fewer routine outpatient visits, same asthma control.

eHealth is an appealing medium to improve healthcare and its value (in addition to standard care) has been assessed in previous studies. We aimed to assess whether an eHealth intervention could improve asthma control while reducing 50% of routine outpatient visits.In a multicentre, randomised controlled trial with a 16-month follow-up, asthmatic children (6-16 years) treated in eight Dutch hospitals were randomised to usual care (4-monthly outpatient visits) and online care using a virtual asthma clinic (VAC) (8-monthly outpatient visits with monthly web-based monitoring). Outcome measures were the number of symptom-free days in the last 4 weeks of the study, asthma control, forced expiratory volume in 1 s, exhaled nitric oxide fraction, asthma exacerbations, unscheduled outpatient visits, hospital admissions, daily dose of inhaled corticosteroids and courses of systemic corticosteroids.We included 210 children. After follow-up, symptom-free days differed statistically between the usual care and VAC groups (difference of 1.23 days, 95% CI 0.42-2.04; p=0.003) in favour of the VAC. In terms of asthma control, the Childhood Asthma Control Test improved more in the VAC group (difference of 1.17 points, 95% CI 0.09-2.25; p=0.03). No differences were found for other outcome measures.Routine outpatient visits can partly be replaced by monitoring asthmatic children via eHealth.

Cost-effectiveness of FENO-based and web-based monitoring in paediatric asthma management: a randomised controlled trial.

BACKGROUND: In children with asthma, web-based monitoring and inflammation-driven therapy may lead to improved asthma control and reduction in medications. However, the cost-effectiveness of these monitoring strategies is yet unknown. OBJECTIVE: We assessed the cost-effectiveness of web-based monthly monitoring and of 4-monthly monitoring of FENO as compared with standard care. METHODS: An economic evaluation was performed alongside a randomised controlled multicentre trial with a 1-year follow-up. Two hundred and seventy-two children with asthma, aged 4-18 years, were randomised to one of three strategies. In standard care, treatment was adapted according to Asthma Control Test (ACT) at 4-monthly visits, in the web-based strategy also according to web-ACT at 1 month intervals, and in the FENO-based strategy according to ACT and FENO at 4-monthly visits. Outcome measures were patient utilities, healthcare costs, societal costs and incremental cost per quality-adjusted life year (QALY) gained. RESULTS: No statistically significant differences were found in QALYs and costs between the three strategies. The web-based strategy had 77% chance of being most cost-effective from a healthcare perspective at a willingness to pay a generally accepted €40 000/QALY. The FENO-based strategy had 83% chance of being most cost-effective at €40 000/QALY from a societal perspective. CONCLUSIONS: Economically, web-based monitoring was preferred from a healthcare perspective, while the FENO-based strategy was preferred from a societal perspective, although in QALYs and costs no statistically significant changes were found as compared with standard care. As clinical outcomes also favoured the web-based and FENO-based strategies, these strategies may be useful additions to standard care. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR1995).

Monitoring strategies in children with asthma: a randomised controlled trial.

BACKGROUND: Asthma guidelines recommend monitoring of asthma control. However, in a substantial proportion of children, asthma is poorly controlled and the best monitoring strategy is not known. OBJECTIVES: We studied two monitoring strategies for their ability to improve asthma outcomes in comparison with standard care (SC): web-based monthly monitoring with the (Childhood) Asthma Control Test (ACT or C-ACT) and 4-monthly monitoring of FENO. METHODS: In this randomised controlled, partly blinded, parallel group multicentre trial with a 1-year follow-up, children aged 4-18 with a doctor's diagnosis of asthma treated in seven hospitals were randomised to one of the three groups. In the web group, treatment was adapted according to ACT obtained via a website at 1-month intervals; in the FENO group according to ACT and FENO, and in the SC group according to the ACT at 4-monthly visits. The primary endpoint was the change from baseline in the proportion of symptom-free days (SFD). RESULTS: Two-hundred and eighty children (mean age 10.4 years, 66% boys) were included; 268 completed the study. Mean changes from baseline in SFD were similar between the groups: -2.1% (web group, n=90), +8.9% (FENO group, n=91) versus 0.15% (SC, n=87), p=0.15 and p=0.78. Daily dose of inhaled corticosteroids (ICS) decreased more in the web-based group compared with both other groups (-200 µg/day, p<0.01), while ACT and SFD remained similar. CONCLUSIONS: The change from baseline in SFD did not differ between monitoring strategies. With web-based ACT monitoring, ICS could be reduced substantially while control was maintained. TRIAL REGISTRATION NUMBER: NTR 1995.

Monitoring asthma in children.

The goal of asthma treatment is to obtain clinical control and reduce future risks to the patient. To reach this goal in children with asthma, ongoing monitoring is essential. While all components of asthma, such as symptoms, lung function, bronchial hyperresponsiveness and inflammation, may exist in various combinations in different individuals, to date there is limited evidence on how to integrate these for optimal monitoring of children with asthma. The aims of this ERS Task Force were to describe the current practise and give an overview of the best available evidence on how to monitor children with asthma. 22 clinical and research experts reviewed the literature. A modified Delphi method and four Task Force meetings were used to reach a consensus. This statement summarises the literature on monitoring children with asthma. Available tools for monitoring children with asthma, such as clinical tools, lung function, bronchial responsiveness and inflammatory markers, are described as are the ways in which they may be used in children with asthma. Management-related issues, comorbidities and environmental factors are summarised. Despite considerable interest in monitoring asthma in children, for many aspects of monitoring asthma in children there is a substantial lack of evidence.

Personalized medicine in children with asthma.

Personalized medicine for children with asthma aims to provide a tailored management of asthma, which leads to faster and better asthma control, has less adverse events and may be cost saving. Several patient characteristics, lung function parameters and biomarkers have been shown useful in predicting treatment response or predicting successful reduction of asthma medication. As treatment response to the main asthma therapies is partly genetically determined, pharmacogenetics may open the way for personalized medicine in children with asthma. However, the number of genes identified for the various asthma drug response phenotypes remains small and randomized controlled trials are lacking. Biomarkers in exhaled breath or breath condensate remain promising but did not find their way from bench to bedside yet, except for the fraction of exhaled nitric oxide. E-health will most likely find its way to clinical practice and most interventions are at least non-inferior to usual care. More studies are needed on which interventions will benefit most individual children.