Assessing the feasibility and acceptability of online measurements of exhaled volatile organic compounds (VOCs) in children with preschool wheeze: A pilot study

Background Investigating airway inflammation and pathology in wheezy preschool children is both technically and ethically challenging. Identifying and validating non-invasive tests would be a huge clinical advance. Real-time analysis of exhaled volatile organic compounds (VOCs) in adults is established, however, the feasibility of this non-invasive method in young children remains undetermined.Aim To determine the feasibility and acceptability of obtaining breath samples from preschool children by means of real-time mass spectrometry analysis of exhaled VOCs.Methods Breath samples from preschool children were collected and analysed in real time by proton transfer reaction–time of flight–mass spectrometry (PTR–TOF–MS) capturing unique breath profiles. Acetone (mass channel m/z 59) was used as a reference profile to investigate the breath cycle in more detail. Dynamic time warping (DTW) was used to compare VOC profiles from adult breath to those we obtained in preschool children.Results 16 children were recruited in the study, of which eight had acute doctor-diagnosed wheeze (mean (range) age 3.2 (1.9–4.5) years) and eight had no history of wheezing (age 3.3 (2.2–4.1) years). Fully analysable samples were obtained in 11 (68%). DTW was used to ascertain the distance between the time series of mass channel m/z 59 (acetone) and the other 193 channels. Commonality of 12 channels (15, 31, 33, 41, 43, 51, 53, 55, 57, 60, 63 and 77) was established between adult and preschool child samples despite differences in the breathing patterns.Conclusion Real-time measurement of exhaled VOCs by means of PTR–MS is feasible and acceptable in preschool children. Commonality in VOC profiles was found between adult and preschool children.</div

Differences in hospital admissions for acute exacerbations of COPD during the COVID-19 pandemic stratified by stable-state blood eosinophil count

Hospital admission for exacerbations of COPD fell only in non-T2-high patients during the COVID-19 pandemic and only in non-eosinophilic admissions. Phenotyping of AECOPD, including at time of exacerbation, is needed for personalised management. </p

Longitudinal changes to quadriceps thickness demonstrate acute sarcopenia following admission to hospital for an exacerbation of chronic respiratory disease

Acute admission to hospital for an exacerbation of chronic respiratory disease (CRD) may impair skeletal muscle mass and function. We measured quadriceps thickness (Qthick), as a surrogate marker of muscle mass, at hospital admission, discharge, 6 weeks and 3 months in 55 patients with CRD. Qthick fell by 8.3% during the period of hospitalisation, which was sustained at 6 weeks, and only partially recovered at 3 months. Sustained loss was most marked in patients readmitted during the follow-up period. Acute reduction in quadriceps muscle mass occurs during hospitalisation, with prolonged and variable recovery, which is prevented with subsequent hospital readmission

Particles in exhaled air (PExA): non-invasive phenotyping of small airways disease in adult asthma.

RATIONALE: Asthma is often characterised by inflammation, damage and dysfunction of the small airways, but no standardised biomarkers are available. OBJECTIVES: Using a novel approach-particles in exhaled air (PExA)-we sought to (a) sample and analyse abundant protein biomarkers: surfactant protein A (SPA) and albumin in adult asthmatic and healthy patients and (b) relate protein concentrations with physiological markers using phenotyping. METHODS: 83 adult asthmatics and 21 healthy volunteers were recruited from a discovery cohort in Leicester, UK, and 32 adult asthmatics as replication cohort from Sweden. Markers of airways closure/small airways dysfunction were evaluated using forced vital capacity, impulse oscillometry and multiple breath washout. SPA/albumin from PEx (PExA sample) were analysed using ELISA and corrected for acquired particle mass. Topological data analysis (TDA) was applied to small airway physiology and PExA protein data to identify phenotypes. RESULTS: PExA manoeuvres were feasible, including severe asthmatic subjects. TDA identified a clinically important phenotype of asthmatic patients with multiple physiological markers of peripheral airway dysfunction, and significantly lower levels of both SPA and albumin. CONCLUSION: We report that the PExA method is feasible across the spectrum of asthma severity and could be used to identify small airway disease phenotypes

Risk factors for asthma attacks and poor control in children: a prospective observational study in UK primary care

Objective To identify risk factors for asthma attacks and poor asthma control in children aged 5–16 years. Methods Prospective observational cohort study of 460 children with asthma or suspected asthma from 10 UK general practices. Gender, age, ethnicity, body mass index, practice deprivation decile, spirometry and fraction of exhaled nitric oxide (FeNO) were recorded at baseline. Asthma control scores, asthma medication ratio (AMR) and the number of asthma attacks were recorded at baseline and at 6 months. The above independent variables were included in binary multiple logistic regression analyses for the dependent variables of: (1) poor symptom control and (2) asthma attacks during follow-up. Results Poor symptom control at baseline predicted poor symptom control at 6 months (OR 4.4, p=0.001), while an increase in deprivation decile (less deprived) was negatively associated with poor symptom control at 6 months (OR 0.79, p=0.003). Higher FeNO levels (OR 1.02, p A decrease in AMR was also associated with an increased OR for future asthma attacks (OR 2.99, p=0.003) when included as an independent variable. Conclusions We identified risk factors for poor symptom control and asthma attacks in children. Routine assessment of these factors should form part of the asthma review to identify children at an increased risk of adverse asthma-related events.</p

Lung function and asthma control in school-age children managed in UK primary care: A cohort study

Background: Spirometry and fraction of exhaled nitric oxide (FeNO) are commonly used in specialist centres to monitor children with asthma. The National Institute for Health and Care Excellence recommends spirometry for asthma monitoring from 5 years in all healthcare settings. There is little spirometry and FeNO data in children managed for asthma in UK primary care to support their use. Objectives: To study the prevalence of abnormal spirometry and FeNO in children with asthma managed in primary care and to explore their relationship with asthma control and unplanned healthcare attendances (UHA). Methods: Prospective observational cohort study in children aged 5-16 years with suspected or doctor-diagnosed asthma attending an asthma review in UK general practice. Spirometry, FeNO, asthma control test (ACT) scores and number of UHAs were studied. Results: Of 612 children from 10 general practices, 23.5% had abnormal spirometry, 36.0% had raised FeNO ≥35 parts per billion and 41.8% reported poor control. Fifty-four per cent of children reporting good asthma control had abnormal spirometry and/or raised FeNO. At follow-up, the mean number of UHAs fell from 0.31/child in the 6 months preceding review to 0.20/child over the 6 months following review (p=0.0004). Median ACT scores improved from 20 to 22 (p=0.032), and children's ACT from 21 to 23 (p<0.0001). Conclusions: Abnormal lung function and FeNO are common in children attending for asthma review in primary care and relate poorly to symptom scores. A symptoms-based approach to asthma monitoring without objective testing is likely to miss children at high risk of future severe asthma attacks

Parametric response map registered CT feature and small airway physiology analysis in asthma

Asthma is a disease characterized by spatiotemporal ventilation heterogeneity (VH). We hypothesized that imaging biomarkers of VH, extracted from parametric response map (PRM) registered inspiratory and expiratory CT scans in asthma, would be associated with asthma severity and small airway physiology. We aimed to evaluate PRM based CT features including a novel spatially regionalized approach, stratified axial analysis (SAA), in a cohort of asthma patients and healthy volunteers. We hypothesized that SAA biomarkers would associate with VH small airway biomarkers Sacin and R5-R20. 41 patients with asthma and 11 healthy age-matched volunteers underwent inspiratory (expiratory) volumetric CT scanning at TLC (FRC). CT biomarkers, notably SAA based inferior-superior ventilation slope (SAAz), were calculated. Linear discriminant analysis (LDA) was utilized to understand how spirometry, clinical and CT feature sets could discriminate Sacin and R5-R20. SAAz was found to provide the best single feature discriminator for both Sacin and R5-R20. LDA demonstrated that CT based feature sets can contribute significantly to VH discrimination. Polar analysis of SAAz revealed statistically significant (p < 0.05) ventilation gradient reversal [Figure 1]. We developed a novel stratified axial based CT imaging biomarker of inferior-superior ventilation gradient in asthma, which associates with small airway biomarkers of VH

Functional Ct Imaging For Identification Of The Spatial Determinants Of Small Airways Disease In Adult Asthma.

BACKGROUND: Asthma is a disease characterised by ventilation heterogeneity (VH). A number of studies have demonstrated that VH markers derived using impulse oscillometry (IOS) or multiple breath washout (MBW) are associated with key asthma patient related outcome measures and airways hyper responsiveness. However the topographical mechanisms of VH in the lung remain poorly understood. OBJECTIVES: We hypothesised that specific regionalisation of topographical small airway disease would best account for IOS and MBW measured indices in patients. METHODS: We evaluated paired expiratory/inspiratory computed tomography in a cohort of asthmatic (n=41) and healthy volunteers (n=11) to understand the determinants of clinical VH indices commonly reported using IOS and MBW. Parametric response mapping (PRM) was utilised to calculate functional small airways disease marker PRMfSAD and Hounsfield unit (HU) based density change from total lung capacity to functional residual capacity (ΔHU); gradients of ΔHU, in gravitationally perpendicular (parallel), inferior-superior (anterior-posterior) axes, were quantified. RESULTS: ΔHU gradient in the inferior-superior axis provided the highest level of discrimination of both Sacin and R5-20. Patients with a high inferior-superior ΔHU gradient demonstrated evidence of reduced specific ventilation in the lower lobes of the lungs and high levels of PRMfSAD. A computational small airway tree model confirmed that constriction of gravitationally dependant lower zone small airway branches would promote the largest increases in R5-R20. Ventilation gradients correlated with asthma control and quality of life but not with exacerbation frequency. CONCLUSIONS: Lower lobe predominant small airways disease is a major driver of clinically measured VH in adult asthma

The utility of a standardised breath sampler in school age children within a real-world prospective study

Clinical assessment of children with asthma is problematic, and non-invasive biomarkers are needed urgently. Monitoring exhaled volatile organic compounds (VOCs) is an attractive alternative to invasive tests (blood and sputum) and may be used as frequently as required. Standardised reproducible breath-sampling is essential for exhaled-VOC analysis, and although the ReCIVA (Owlstone Medical Limited) breath-sampler was designed to satisfy this requirement, paediatric use was not in the original design brief. The efficacy of the ReCIVA at sampling breath from children has been studied, and 90 breath-samples from 64 children (5-15 years) with, and without asthma (controls), were collected with two different ReCIVA units. Seventy samples (77.8%) contained the specified 1 l of sampled-breath. Median sampling times were longer in children with acute asthma (770.2 s, range: 532.2-900.1 s) compared to stable asthma (690.6 s, range: 477.5-900.1 s;p= 0.01). The ReCIVA successfully detected operational faults, in 21 samples. A leak, caused by a poor fit of the face mask seal was the most common (15); the others were USB communication-faults (5); and, a single instance of a file-creation error. Paediatric breath-profiles were reliably monitored, however synchronisation of sampling to breathing-phases was sometimes lost, causing some breaths not to be sampled, and some to be sampled continuously. This occurred in 60 (66.7%) of the samples and was a source of variability. Importantly, multi-variate modelling of untargeted VOC analysis indicated the absence of significant batch effects for eight operational variables. The ReCIVA appears suitable for paediatric breath-sampling. Post-processing of breath-sample meta-data is recommended to assess the quality of sample-acquisition. Further, future studies should explore the effect of pump-synchronisation faults on recovered VOC profiles, and mask sizes to fit all ages will reduce the potential for leaks and importantly, provide higher levels of comfort to children with asthma

Sputum Streptococcus pneumoniae is reduced in COPD following treatment with benralizumab.

We hypothesized whether the reduction in eosinophilic airway inflammation in patients with chronic obstructive pulmonary disease (COPD) following treatment with benralizumab, a humanized, afucosylated, monoclonal antibody that binds to interleukin-5 receptor α, increases the airway bacterial load. Analysis of sputum samples of COPD patients participating in a Phase II trial of benralizumab indicated that sputum 16S rDNA load and Streptococcus pneumoniae were reduced following treatment with benralizumab. However, in vitro, eosinophils did not affect the killing of the common airway pathogens S. pneumoniae or Haemophilus influenzae. Thus, benralizumab may have an indirect effect upon airway bacterial load