Background Asthma is misdiagnosed in one-third of patients. Due to its variable nature, international guidelines recommend performing key diagnostic tests during symptomatic periods or in the morning to improve accuracy. Limited access to timely clinic appointments and community-based diagnostics makes this difficult. Handheld spirometry and fractional exhaled nitric oxide (FeNO) are feasible for home use, enabling timely and flexible testing.Objective To explore patients’ views on performing spirometry and FeNO at home during the asthma diagnostic process.Design A qualitative study using semistructured interviews. Data were analysed using the framework approach.Setting This prospective observational study was conducted at a National Institute for Health and Care Research Clinical Research Facility, based within a large National Health Service Trust, as part of the Rapid-Access Diagnostics for Asthma (RADicA) study (ISRCTN11676160).Participants A purposive sample of 15 symptomatic adult patients with general practitioner-suspected asthma who were referred for diagnostic evaluation of the condition; all patients were given home spirometry and FeNO devices during their diagnostic processes.Results Three themes emerged from the analysis: ‘Perceived value of, and burdens of home testing’, ‘Views on device usability and acceptability’ and ‘Information and support needs’. Home testing was generally welcomed by patients as a way of improving their understanding of their condition and enabling an accurate diagnosis of their symptoms. Key barriers (eg, testing frequency, lack of privacy) and enablers to improve feasibility (eg, training and support) were also identified.Conclusion This study provides valuable insights into the barriers and enablers of home-based diagnostic strategies for asthma. Findings can inform service design and implementation approaches to enhance the feasibility and effectiveness of home testing.Trial registration number ISRCTN11676160.

Approximately 30% of people with a clinical diagnosis of asthma do not have the condition. Exhaled volatile organic compounds (VOCs) hold promise for non-invasive asthma testing; however, discovery of breath biomarkers is confounded by high biological and technical variability. We collected repeated breath samples from symptomatic patients being tested for asthma before starting treatment. Background samples were collected immediately before patient sampling to characterize VOCs present in the preconditioned inspired airstream. VOCs were measured by thermal desorption-gas chromatography-mass spectrometry. Data from two cohorts (n = 62, 53) were processed independently and used as training and validation datasets. VOCs were classified as breath-enriched or ambiguous based on comparison between breath and background abundance using Wilcoxon test and log fold change. Associations between breath VOCs and diagnosis were tested with univariate mixed-effect models and multivariate classification models. Here we show that background has significant effect on breath VOC abundance in 60% of identified compounds. Breath VOCs show high inter-session and inter-patient variability, reflected by increase in multivariate model classification error in cross-validation (37%) and validation (52%) cohorts. Among VOCs positively associated with asthma, 30% are breath-enriched. Ethyl butanoate, 2-methylfuran and 3-methylpentane show consistent discrimination performance across the cohorts. When used in conjunction with clinical tests, these breath VOCs have comparable contribution to asthma prediction accuracy to established clinical diagnostics such as fractional exhaled nitric oxide. Measuring exhaled VOCs could add value to diagnosis of asthma based on routine clinical tests. However, developing measures to limit technical variation in breath analysis is needed to support discovery and clinical translation of such biomarkers.

BACKGROUND:The association between allergic sensitization and asthma is well-documented, but its precise role in asthma remains uncertain. Component-resolved diagnostics allows detailed assessment of IgE-sensitization to multiple allergenic molecules (c-sIgE). We applied advanced network embedding techniques to investigate the dynamics of temporal development of multiple c-sIgE and identify networks associated with asthma. METHODS:In a population-based birth cohort, we measured c-sIgE to 112 proteins using multiplex array at 6 time points from infancy to adolescence. We built weighted co-occurrence networks between c-sIgEs to investigate connectivity structures at different ages. To identify critical periods where networks are similar/divergent, we applied graph embedding and dimensionality reduction techniques. We then compared network development structure between subjects with and without asthma at different ages and analyzed topological features to compare network structures. RESULTS:c-sIgE sensitization networks across ages revealed significant changes and a continuous evolution rather than abrupt shifts, with networks at ages 5 and 8 being very similar. Individuals with asthma consistently exhibited more complex and interconnected networks of c-sIgEs, which became more pronounced with age. Graph embedding showed that profiles of those with and without asthma were distinct and the separation persisted across ages. A specific set of c-sIgEs and their interactions were responsible for this distinction. Topological features of networks that distinguished between sensitized individuals with and without asthma were age-dependent. CONCLUSIONS:The differences in c-sIgE networks between subjects with and without asthma are consistently observed throughout childhood. Age needs to be considered when developing interpretation algorithms for asthma diagnosis/prediction.

Background Lung function during childhood is an important predictor of subsequent health and disease. Understanding patterns of lung function and development of airflow limitation through childhood is necessary to inform lung function trajectories in relation to health and chronic airway disease. We aimed to derive trajectories of airflow limitation from childhood (age 5-8 years) into early adulthood (age 20-26 years) using repeated spirometry data from birth cohorts. Methods In this study, we drew forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) data from six population-based birth cohorts: the UK-based Avon Longitudinal Study of Parents and Children (ALSPAC), Isle of Wight cohort (IOW), Manchester Asthma and Allergy Study (MAAS), and Aberdeen Study of Eczema and Asthma (SEATON) as well as the Swedish Child (Barn), Allergy, Milieu, Stockholm, Epidemiological survey (BAMSE) and the Dutch Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort. For the discovery analysis, we pooled data from ALSPAC, IOW, MAAS, and BAMSE with spirometry data recorded at middle childhood (age 8-10 years), adolescence (age 15-18 years), and early adulthood (age 20-26 years). For the replication analysis, we pooled middle childhood and adolescence spirometry data from PIAMA and SEATON. We used latent class trajectory modelling to derive trajectory classes based on joint modelling of FEV1 and FEV1/FVC ratio regression residuals ascertained from all age groups. The final model was selected using the lowest Bayesian information criterion. Participants were assigned to the trajectory with the highest posterior probability. Weighted random-effect multinomial logistic regression models were used to investigate factors associated with joining each trajectory, the results of which are reported as relative risk ratios (RRRs) with 95% CIs. Findings The discovery population included 8114 participants: 4710 from ALSPAC, 808 from IOW, 586 from MAAS, and 2010 from BAMSE and was modelled into one of four lung function trajectories that showed normal airflow (6555 [808%] of 8114 people), persistent airflow obstruction (1280 [158%]), worsening airflow obstruction (161 [20%]), and improved airflow obstruction (118 [15%]). Both improvement in and worsening airflow obstruction by early adulthood were seen from all initial severity levels. Whereas improvement in airflow obstruction was more prominent between middle childhood and adolescence (578%) than between adolescence and early adulthood (134%), worsening airflow obstruction was more prominent between adolescence and early adulthood (615%) than between middle childhood and adolescence (326%). Among current wheezers, higher BMI was associated with a lower relative risk of joining the trajectory with improvement in airflow obstruction (RRR 069 [95% CI 049-095]), whereas among non- wheezers, higher BMI increased the relative risk of being in the improved airflow obstruction trajectory (138 [104-185]). A higher BMI at first lung function assessment was associated with a higher relative risk of joining the trajectory for improvement in airflow obstruction trajectory in participants with low birthweight and no current asthma diagnosis (RRR 244 [117-512]); by contrast, higher BMI is associated with a lower relative risk of joining the trajectory with improvement in airflow obstruction among those with low birthweight and current asthma diagnosis (037 [018-076]). Results in replication cohorts (n=1337) were consistent with those in the discovery cohort. Interpretation Worsening and improvement in airflow limitation from school age to adulthood might occur at all ages and all airflow obstruction severity levels. Interventions to optimise healthy weight, including tackling overweight and obesity (particularly among children with wheezing) as well as treating underweight among non-wheezers, could help to improve lung health across the lifespan.

BACKGROUND:Many studies used information on wheeze presence/absence to determine asthma-related phenotypes. We investigated whether clinically intuitive asthma subtypes can be identified by applying data-driven semi-supervised techniques to information on frequency and triggers of different respiratory symptoms. METHODS:Partitioning Around Medoids clustering was applied to data on multiple symptoms and their triggers in school-age children from three birth cohorts: MAAS (n = 947, age 8 years), SEATON (n = 763, age 10) and ASHFORD (n = 584, age 8). 'Guided' clustering, incorporating asthma diagnosis, was used to select the optimal number of clusters. RESULTS:Five-cluster solution was optimal. Based on their clinical characteristics, including frequency of asthma diagnosis, we interpreted one cluster as 'Healthy'. Two clusters were characterised by high asthma prevalence (95.89% and 78.13%). We assigned children with asthma in these two clusters as 'persistent, multiple-trigger, more severe' (PMTS) and 'persistent, triggered by infection, milder' (PIM). Children with asthma in the remaining two clusters were assigned as 'mild-remitting wheeze' (MRW) and 'post-bronchiolitis resolving asthma' (PBRA). PBRA was associated with RSV bronchiolitis in infancy. In most children with asthma in this cluster wheezing resolved by age 5-6, and predominant symptoms were shortness of breath and chest tightness. Children in PBRA had the highest hospitalisation rates and wheeze exacerbations in infancy. From age 8 years (cluster derivation) to early adulthood (18-20 years), lung function was significantly lower, and FeNO and airway hyperreactivity significantly higher in PMTS compared to all other clusters. CONCLUSIONS:Patterns of coexisting symptoms identified by semi-supervised data-driven methods may reflect pathophysiological mechanisms of distinct subtypes of childhood wheezing disorders.

Introduction: Mepolizumab has proved efficacious in severe asthma in adult clinical trials, but data are limited in children. Less than 5% of patients recruited into the mepolizumab Phase III clinical trials were adolescents, and data on the efficacy and safety of mepolizumab in children 6-11 years with severe asthma are currently limited to two clinical trials. Real-world clinical practice data in children and young people (CYP) with severe asthma is lacking. We assessed the effectiveness and safety of mepolizumab prescribed for CYP with severe eosinophilic asthma over 12 months Methods: CASAM is a multinational, multicentre, observational cohort study. Data from routine healthcare visits was collected. CYP prescribed mepolizumab for severe eosinophilic asthma, in line with national guidelines, were enrolled with 12 months of pertinent medical history pre-Mepolizumab, which was gathered retrospectively and prospectively. An initial analysis of data from early starters who completed twelve months of follow-up was conducted. The primary objective was to compare the rate of clinically significant exacerbations (exacerbation requiring systemic corticosteroids and/or ED visit and/or hospital admission) and change in asthma control before and after one year of mepolizumab treatment. Treatment-related adverse events were reported. Results: Overall, 84 CYP were included with a mean age of 11.17(SD ± 2.86) years at mepolizumab initiation. The proportion of CYP experiencing clinically significant exacerbations reduced at the 12-month follow-up from 77 (93%) to 45 (55%) (P<0.0001). Rates of CSE reduced from 3.7 exacerbations per person per year pre-treatment to 2.03 exacerbations per person per year at six months and to 1.6 per person per year at 12 months, a reduction of 45% and 57% from baseline respectively. A significant reduction was observed in healthcare utilisation for asthma exacerbations in terms of emergency visits (P<0.001) and hospital admissions (P=0.01). Severe exacerbations requiring hospital admission were reduced by 39%. After 12 months, significant improvement in asthma control was observed, with c-ACT scores increasing from 13.02 to 18.95 (P<0.0001) and ACT scores from 15.09 to 20.68 (P<0.0029). Sixteen patients were switched from Omalizumab to Mepolizumab. At the end of 12 months the proportion of patients on maintenance oral corticosteroids (OCS) was reduced from 25 to 15 (P=0.0075) No new safety signals were reported. Conclusion: This 12-month analysis demonstrates that mepolizumab is effective in CYP with severe asthma in real-world settings, significantly reducing exacerbations and improving asthma control. In selected patients, Mepolizumab also demonstrated steroid-sparing effects in terms of reducing maintenance OCS.

Asthma is a heterogeneous condition often studied through wheeze alone, yet the interplay between lung function and reported symptoms remains underexplored. To capture this heterogeneity, we applied Bayesian Profile Regression to data from school-age children in two prospective birth cohorts, integrating airway hyperresponsiveness, lung function, bronchodilator reversibility, allergic sensitisation, reported symptoms, and physician diagnosis. In the Manchester Allergy and Asthma Study (discovery cohort), five reproducible clusters were identified: HA-LLF (high asthma-low lung function), HA-NLF (high asthma normal lung function), LA-RLF (low asthma-reduced lung function), LA-NLF (low asthma normal lung function), and MA-NLF (moderate asthma normal lung function). The HA-LLF and HA-NLF clusters had very high asthma prevalence (80–100

BACKGROUND:Sufficient levels of club cell secretory protein (CC16) are essential to protect against lung function impairments. Experimental studies have demonstrated that CC16 modulates inflammatory responses and protects against airway hyperresponsiveness following Mycoplasma pneumoniae (Mp) infection. Individuals with asthma have low CC16 levels and increased susceptibility to Mp infection. Here we determine whether low CC16 and Mp seropositivity have combined effects on lung function deficits predisposing to airflow limitation, particularly in asthma. METHODS:Serum levels of CC16 and IgG antibodies against Mp (MpIgG) were measured in adult participants from cohorts BAMSE, MAAS, LSC, and TESAOD. Participants were then stratified into four groups: normal CC16/MpIgG-, normal CC16/MpIgG+, low CC16/MpIgG-, low CC16/MpIgG+. Associations between these groups and lung function (FEV1 and FEV1/FVC) were assessed by linear regression, adjusting for covariates. Meta-analyzed estimates were calculated. RESULTS:Low CC16 was associated with decreased lung function in the total population, but no combined effects of CC16 and MpIgG were observed. Among asthmatic participants, the low CC16/MpIgG + group had remarkably lower FEV1/FVC z-scores (-0.84, CI: 1.29, -0.38) compared to the reference group, and Mp seropositivity was associated with significant deficits in FEV1/FVC z-scores among those with low CC16 (-0.60, CI: 1.08, -0.12), but not among those with normal CC16 (-0.10, CI: 0.56, 0.36). CONCLUSION:This suggests that individuals with asthma with low levels of CC16 combined with a history of Mp infection may be more susceptible to deficits in FEV1/FVC, the hallmark of airflow limitation, emphasizing the need for prospective studies designed to test this hypothesis.

BACKGROUND:Preschool wheeze is a heterogenous and poorly understood clinical syndrome. As a result, current treatments are insufficient, and prevention is not possible. OBJECTIVE:We sought to increase understanding of the genetic susceptibility and underlying disease mechanisms of wheeze phenotypes in early childhood through large-scale genome-wide association study analyses. METHODS:We performed meta-analyses of genome-wide association study on early-onset wheeze, defined as recurrent wheeze or asthma in the first 3 years of life, and its subtypes, including early transient and persistent wheeze, defined by asthma/wheeze at age 3 and subsequent remission or persistence at age 6, respectively. The discovery analyses included data on more than 13,000 children from 15 cohorts; replication was sought through meta-analyses of data from 7 additional cohorts including up to 5000 children. Genetic variants associated with asthma-related traits in adulthood (adult asthma, atopy, eosinophils, and lung function) were used to quantify the degree to which genetic risk influencing asthma-related adult traits also influences genetic risk of preschool wheeze. RESULTS:Variants near the GSDMB gene in the 17q region showed genome-wide significant association with early-onset wheeze (rs2305480; odds ratio [95% confidence interval] = 1.26 [1.17-1.33], P = 2.30E-16) and persistent wheeze (rs11078926; 1.43 [1.30-1.578], P = 2.14E-11), but not with early transient wheeze (rs1054609; 1.08 [0.98-1.18], P = .094). Other known asthma loci were associated with early-onset wheeze, particularly CDHR3. Additionally, increased genetic risk to early-onset wheeze was associated with genetic risk for asthma at older ages, atopy, eosinophil count, and lower adult lung function. This was driven by persistent wheeze, whereas transient early wheeze was only associated with low lung function. CONCLUSIONS:Preschool wheeze phenotypes displayed distinct patterns of single nucleotide polymorphism associations and genetic enrichment with asthma-related traits. These results indicate distinct etiologies of wheeze phenotypes, which could inform studies in optimization of prevention and treatment strategies.

Background: The efficacy of dupilumab in children in the age group 6–11 years with type 2 asthma was reported in VOYAGE (NCT02948959) and the EXCURSION (NCT03560466) extension study. The aim of the study was to evaluate the efficacy of dupilumab in children with and without an early increase in eosinophils (<500 cells/µL at baseline and ≥500 cells/µL at VOYAGE Week 12). Methods: In VOYAGE, patients received add-on dupilumab 100/200 mg (based on body weight) or matched placebo every 2 weeks for 52 weeks; patients who completed the VOYAGE study were enrolled in the EXCURSION study and received dupilumab for 52 weeks (all patients). The endpoints estimated were severe exacerbation rates and change in total IgE. Results: There was a significant reduction in the severe exacerbation rates in the patients on dupilumab vs placebo. These reductions were maintained in EXCURSION, regardless of changes in eosinophils from baseline to Week 12 of VOYAGE (Figure). At Week 52 of VOYAGE, dupilumab reduced total IgE levels vs placebo in all patients (median [Q1−Q3]: children with eosinophil changes, 30 [−9 to 143 IU/mL] for placebo and −518 [−1097 to −162 IU/mL] for dupilumab; children without eosinophil changes, 3 [−64 to 110 IU/mL] for placebo and −369 [−870 to −136 IU/mL] for dupilumab). These findings were maintained through EXCURSION. The study findings were similar when eosinophils were stratified by <2- or ≥2-fold change from baseline to Week 12. Conclusions: Dupilumab reduced exacerbation rates and total IgE levels for up to 2 years in children with type 2 asthma vs placebo, irrespective of increased eosinophil count from baseline to VOYAGE Week 12.

Background:Environmental factors play a role in the pathogenesis of complex traits including atopic eczema (AE) and a greater understanding of gene-environment interactions (G*E) is needed to define pathomechanisms for disease prevention. We analysed data from 16 European studies to test for interaction between the 24 most significant AE-associated loci identified from genome-wide association studies and 18 early-life environmental factors. We tested for replication using a further 10 studies and in vitro modelling to independently assess findings. Results:The discovery analysis showed suggestive evidence for interaction (p<0.05) between 7 environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking and washing practices) and at least one established variant for AE, 14 interactions in total (maxN=25,339). In replication analysis (maxN=252,040) dog exposure*rs10214237 (on chromosome 5p13.2 near IL7R) was nominally significant (ORinteraction=0.91 [0.83-0.99] P=0.025), with a risk effect of the T allele observed only in those not exposed to dogs. A similar interaction with rs10214237 was observed for siblings in the discovery analysis (ORinteraction=0.84[0.75-0.94] P=0.003), but replication analysis was under-powered ORinteraction=1.09[0.82-1.46]). Rs10214237 homozygous risk genotype is associated with lower IL-7R expression in human keratinocytes, and dog exposure modelled in vitro showed a differential response according to rs10214237 genotype. Conclusions:Interaction analysis and functional assessment provide evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE via IL7R, supporting observational epidemiology showing a protective effect for dog ownership. The lack of evidence for other G*E studied here implies that only weak effects are likely to occur.