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To explore whether fractional exhaled nitric oxide (FeNO) non-suppression identifies corticosteroid resistance, we analysed inflammatory mediator changes during a FeNO suppression test with monitored high-intensity corticosteroid therapy. In linear mixed-effects models analysed over time, the 15 clinically distinct 'suppressors' (ie, ≥42% FeNO suppression) normalised Asthma Control Questionnaire scores (mean±SD, start to end of test: 2.8±1.4 to 1.4±0.9, p<0.0001) and sputum eosinophil counts (median (IQR), start to end of test: 29% (6%-41%) to 1% (1%-5%), p=0.0003) while significantly decreasing sputum prostaglandin D2 (254 (89-894) to 93 (49-209) pg/mL, p=0.004) and numerically decreasing other type-2 cytokine, chemokine and alarmin levels. In comparison, the 19 non-suppressors had persistent sputum eosinophilia (10% (1%-67%) despite high-intensity therapy) with raised end-test inflammatory mediator levels (1.9 (0.9-2.8)-fold greater than suppressors). FeNO non-suppression during monitored treatment implies biological corticosteroid resistance. [ABSTRACT FROM AUTHOR]

Introduction: COPD is a heterogeneous disorder with varied phenotypes. We aimed to determine the prevalence of asthma history, peripheral eosinophilia and elevated FeNO levels along with the diagnostic utility of peripheral eosinophilia in identifying airway eosinophilic inflammation.Methods: National Health and Nutrition Examination Survey data were analysed for the study period 2007-2010. Subjects aged ≥40 years with postbronchodilator FEV1/FVC ratio <0.70 were included. Receiver operator curve analysis was performed for sensitivity analysis. A p value of <0.001 is considered statistically significant.Results: A total of 3 110 617 weighted COPD cases were identified; predominantly male (64.4%) and non-Hispanic whites (86.1%). Among our COPD subjects, 14.6% had a history of doctor diagnosed asthma, highest among females and other race Americans. The overall prevalence of peripheral eosinophilia is 36%, 38.3% among COPD subjects with asthma history, and 35.6% among COPD without asthma history. The overall prevalence of elevated FeNO ≥25 ppb is 14.3%; 28.7% among COPD subjects with asthma history and 13.0% among COPD without asthma history.Discussion: The prevalence of FeNO levels ≥25 ppb and peripheral eosinophilia was significantly higher among COPD subjects with asthma compared with COPD without asthma history. Not all COPD subjects with peripheral eosinophilia and elevated FeNO levels have a reported history of asthma. Our study supports clinically phenotyping COPD subjects with eosinophilic inflammation be independent of their asthma history and peripheral eosinophilia can be used as a surrogate marker in resource-limited settings. [ABSTRACT FROM AUTHOR]

Reduction of the risk of asthma attacks is a major goal of current asthma management. We propose to derive a risk scale predicting asthma attacks based on the blood eosinophil count and exhaled nitric oxide (FeNO). Biomarker-stratified trial-level attack rates were extracted and pooled from the control arms of the Novel START, CAPTAIN, QUEST, Benralizumab Phase 2b, PATHWAY, STRATOS 1-2 and DREAM trials (n=3051). These were used to derive rate ratios and the predicted asthma attack rate for different patient groups. The resultant prototype risk scale shows potential to predict asthma attacks, which may be prevented by anti-inflammatory treatment. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the effect of short-term inhalational exposure to nanoparticles released during dental composite grinding on oxidative stress and antioxidant capacity markers., Materials and Methods: Twenty-four healthy volunteers were examined before and after exposure in dental workshop. They spent 76.8 ± 0.7 min in the testing room during grinding of dental nanocomposites. The individual exposure to aerosol particles in each participant´s breathing zones was monitored using a personal nanoparticle sampler (PENS). Exhaled breath condensate (EBC), blood, and urine samples were collected pre- and post-exposure to measure one oxidative stress marker, i.e., thiobarbituric acid reactive substances (TBARS), and two biomarkers of antioxidant capacity, i.e., ferric-reducing antioxidant power (FRAP) and reduced glutathione (GSH) by spectrophotometry. Spirometry and fractional exhaled nitric oxide (FeNO) were used to evaluate the effect of acute inhalational exposure., Results: Mean mass of dental nanocomposite ground away was 0.88 ± 0.32 g. Average individual doses of respirable particles and nanoparticles measured by PENS were 380 ± 150 and 3.3 ± 1.3 μg, respectively. No significant increase of the post-exposure oxidative stress marker TBARS in EBC and plasma was seen. No decrease in antioxidant capacity biomarkers FRAP and GSH in EBC post-exposure was seen, either. Post-exposure, conjunctival hyperemia was seen in 62.5% volunteers; however, no impairment in spirometry or FeNO results was observed. No correlation of any biomarker measured with individual exposure was found, however, several correlations with interfering factors (age, body mass index, hypertension, dyslipidemia, and environmental pollution parameters) were seen., Conclusions: This study, using oxidative stress biomarker and antioxidant capacity biomarkers in biological fluids of volunteers during the grinding of dental nanocomposites did not prove a negative effect of this intense short-term exposure. However, further studies are needed to evaluate oxidative stress in long-term exposure of both stomatologists and patients and diverse populations with varying health statuses., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Airspace dimension assessment with nanoparticles (AiDA) is a novel method to measure distal airspace radius non-invasively. In this study, AiDA radii were measured in 618 individuals from the population-based Swedish CArdiopulmonary BioImaging Study, SCAPIS. Subjects with emphysema detected by computed tomography were compared to non-emphysematous subjects. The 47 individuals with mainly mild-to-moderate visually detected emphysema had significantly larger AiDA radii, compared with non-emphysematous subjects (326±48 µm vs 291±36 µm); OR for emphysema per 10 µm: 1.22 (1.13-1.30, p<0.0001). Emphysema according to CT densitometry was similarly associated with larger radii compared with non-emphysematous CT examinations (316±41 µm vs 291 µm±26 µm); OR per 10 µm: 1.16 (1.08-1.24, p<0.0001). The results are in line with comparable studies. The results show that AiDA is a potential biomarker for emphysema in individuals in the general population. [ABSTRACT FROM AUTHOR]

Abstract Background Blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO) concentration are established biomarkers in asthma, associated particularly with the risk of exacerbations. We evaluated the relationship of BEC and FeNO as complementary and independent biomarkers of severe asthma exacerbations. Methods This observational study included data from the Optimum Patient Care Research Database. Asthma patients (18–80 years) with valid continuous data for 1 year before FeNO reading, ≥ 1 inhaled corticosteroid prescription, and BEC recorded ≤ 5 years before FeNO reading were separated into cohorts. Categorisation 1 was based on the American Thoracic Society criteria for elevated FeNO concentration (high: ≥ 50 ppb; non-high:

Exhaled breath analysis has the potential to provide valuable insight on the status of various metabolic pathways taking place in the lungs locally and other vital organs, via systemic circulation. For years, volatile organic compounds (VOCs) have been proposed as feasible alternative diagnostic and prognostic biomarkers for different respiratory pathologies.We reviewed the currently published literature on the discovery of exhaled breath VOCs and their utilisation in various respiratory diseasesKey barriers in the development of clinical breath tests include the lack of unified consensus for breath collection and analysis and the complexity of understanding the relationship between the exhaled VOCs and the underlying metabolic pathways. We present a comprehensive overview, in light of published literature and our experience from coordinating a national breathomics centre, of the progress made to date and some of the key challenges in the field and ways to overcome them. We particularly focus on the relevance of breathomics to clinicians and the valuable insights it adds to diagnostics and disease monitoring.Breathomics holds great promise and our findings merit further large-scale multicentre diagnostic studies using standardised protocols to help position this novel technology at the centre of respiratory disease diagnostics. [ABSTRACT FROM AUTHOR]

Background: Methods used to assess ventilation heterogeneity through inert gas washout have been standardised and showed high sensitivity in diagnosing many respiratory diseases. We hypothesised that nitrogen single or multiple breath washout tests, respectively nitrogen single breath washout (N 2 SBW) and nitrogen multiple breath washout (N 2 MBW), may be pathological in patients with clinical suspicion of asthma but normal spirometry. Our aim was to assess whether N 2 SBW and N 2 MBW are associated with methacholine challenge test (MCT) results in this population. We also postulated that an alteration in S III at N 2 SBW could be detected before the 20% fall of forced expiratory volume in the first second (FEV 1 ) in MCT., Study Design and Methods: This prospective, observational, single-centre study included patients with suspicion of asthma with normal spirometry. Patients completed questionnaires on symptoms and health-related quality-of-life and underwent the following lung function tests: N 2 SBW (S III ), N 2 MBW (Lung clearance index (LCI), S cond , S acin ), MCT (FEV 1 and sGeff) as well as N 2 SBW between each methacholine dose., Results: 182 patients were screened and 106 were included in the study, with mean age of 41.8±14 years. The majority were never-smokers (58%) and women (61%). MCT was abnormal in 48% of participants, N 2 SBW was pathological in 10.6% at baseline and N 2 MBW abnormality ranged widely (LCI 81%, S cond 18%, S acin 43%). The dose response rate of the MCT showed weak to moderate correlation with the subsequent N 2 SBW measurements during the provocation phases (ρ 0.34-0.50) but no correlation with N 2 MBW., Conclusions: Both MCT and N 2 washout tests are frequently pathological in patients with suspicion of asthma with normal spirometry. The weak association and lack of concordance across the tests highlight that they reflect different but not interchangeable pathological pathways of the disease., Competing Interests: Competing interests: DS (second author) is currently employed at Tillotts Pharma AG, however, during the period of the study was an employee of the University Hospital of Basel. AMD has received a grant from University Hospital Basel, PL has a grant/contract to Vertex and OM Pharma. DS (last author) reports grants from Astra-Zeneca AG, Curetis AG, BostonScientific, Novartis AG, GSK AG, Roche AG, Zambon, Pfizer, Schwabe Pharma AG, Vifor AG. Other authors have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: No studies have investigated whether high-sensitivity C reactive protein (hsCRP) can be used to predict the forced expiratory volume in 1 s (FEV1)/estimated value of FEV1 (FEV1%pred). This study aimed to assess the association between hsCRP and FEV1%pred in middle-aged and elderly individuals without underlying lung disease., Methods: The data for this study were obtained from a prospective cohort study that included 1047 middle-aged and elderly citizens from Beijing aged 40-75 years without any evidence of underlying lung diseases with FEV1 >70% after receiving inhalational bronchodilators. The baseline analysis of the participants was performed from 30 May 2018 to 31 October 2018. Restricted cubic spline regression and multivariate linear regression models were used to assess the non-linear association and linear association between hsCRP and FEV1/FEV in 6 s (FEV6) and FEV1%pred, respectively., Results: The hsCRP values of 851 participants were recorded; the values were normal in 713 (83.8%) participants. The remaining 196 participants (18.7%) had missing data. A non-linear association was observed between normal hsCRP values and FEV1/FEV6. hsCRP was linearly and negatively correlated with FEV1%pred, and each 1 SD increase in hsCRP was significantly associated with a 2.4% lower in FEV1%pred. Significantly higher FEV1/FEV6 differences were observed in the female subgroup than those in the male subgroup (p=0.011 for interaction)., Conclusions: hsCRP had a non-linear association with FEV1/FEV6 and a linear negative association with FEV1%pred in individuals with normal hsCRP values. hsCRP can be used to predict FEV1%pred, which can be used to predict the development of chronic obstructive pulmonary disease. hsCRP has a stronger association with lung function in women than that in men., Trial Registration Number: NCT03532893., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The genetic determinants of fractional exhalation of nitric oxide (FeNO), a marker of lung inflammation, are understudied in Black individuals. Alpha globin ( HBA ) restricts nitric oxide signalling in arterial endothelial cells via interactions with nitric oxide synthase; however, its role in regulating the release of NO from respiratory epithelium is less well understood. We hypothesised that an HBA gene deletion, common among Black individuals, would be associated with higher FeNO., Methods: Healthy Black adults were enrolled at four study sites in North Carolina from 2005 to 2008. FeNO was measured in triplicate using a nitric oxide analyzer. The -3.7 kb HBA gene deletion was genotyped using droplet digital PCR on genomic DNA. The association of FeNO with HBA copy number was evaluated using multivariable linear regression employing a linear effect of HBA copy number and adjusting for age, sex and serum immunoglobulin-E levels. Post-hoc analysis employing a recessive mode of inheritance was performed., Results: 895 individuals were in enrolled in the study and 720 consented for future genetic research; 643 had complete data and were included in this analysis. Median (25th, 75th) FeNO was 20 (13, 31) ppb. HBA genotypes were: 30 (4.7%) -a/-a, 197 (30.6%) -a/aa, 405 (63%) aa/aa and 8 (1.2%) aa/aaa. Subjects were 35% male with median age 20 (19, 22) years. Multivariable linear regression analysis revealed no association between FeNO and HBA copy number (β=-0.005 (95% CI -0.042 to 0.033), p=0.81). In the post-hoc sensitivity analysis, homozygosity for the HBA gene deletion was associated with higher FeNO (β=0.107 (95% CI 0.003 to 0.212); p=0.045)., Conclusion: We found no association between HBA copy number and FeNO using a prespecified additive genetic model. However, a post hoc recessive genetic model found FeNO to be higher among subjects homozygous for the HBA deletion., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO) concentration are established biomarkers in asthma, associated particularly with the risk of exacerbations. We evaluated the relationship of BEC and FeNO as complementary and independent biomarkers of severe asthma exacerbations. Methods: This observational study included data from the Optimum Patient Care Research Database. Asthma patients (18–80 years) with valid continuous data for 1 year before FeNO reading, ≥ 1 inhaled corticosteroid prescription, and BEC recorded ≤ 5 years before FeNO reading were separated into cohorts. Categorisation 1 was based on the American Thoracic Society criteria for elevated FeNO concentration (high: ≥ 50 ppb; non‐high: < 25 ppb) and BEC (high: ≥ 0.300 × 109 cells/L; non‐high: < 0.300 × 109 cells/L). Categorisation 2 (FeNO concentration, high: ≥ 35 ppb; non‐high: < 35 ppb) was based on prior research. Reference groups included patients with neither biomarker raised. Results: In categorisation 1, patients with either high FeNO or high BEC (n = 200) had a numerically greater exacerbation rate (unadjusted rate ratio, 1.31 [95% confidence interval: 0.97, 1.76]) compared with patients in the reference group. Combination of high FeNO and high BEC (n = 27) resulted in a significantly greater exacerbation rate (3.67 [1.49, 9.04]). Similarly, for categorisation 2, when both biomarkers were raised (n = 53), a significantly greater exacerbation rate was observed (1.72 [1.00, 2.93]). Conclusion: The combination of high FeNO and high BEC was associated with significantly increased severe exacerbation rates in the year preceding FeNO reading, suggesting that combining FeNO and BEC measurements in primary care may identify asthma patients at risk of exacerbations. [ABSTRACT FROM AUTHOR]

False negatives from nasopharyngeal swabs (NPS) using reverse transcriptase PCR (RT-PCR) in SARS-CoV-2 are high. Exhaled breath condensate (EBC) contains lower respiratory droplets that may improve detection. We performed EBC RT-PCR for SARS-CoV-2 genes (E, S, N, ORF1ab) on NPS-positive (n=16) and NPS-negative/clinically positive COVID-19 patients (n=15) using two commercial assays. EBC detected SARS-CoV-2 in 93.5% (29/31) using the four genes. Pre-SARS-CoV-2 era controls (n=14) were negative. EBC was positive in NPS negative/clinically positive patients in 66.6% (10/15) using the identical E and S (E/S) gene assay used for NPS, 73.3% (11/15) using the N/ORF1ab assay and 14/15 (93.3%) combined. [ABSTRACT FROM AUTHOR]

Introduction: Asthma and its associated exacerbation are heterogeneous. Although severe asthma attacks are systematically prescribed corticosteroids and often antibiotics, little is known about the variability of response to these therapies. Blood eosinophils and fractional exhaled nitric oxide (FeNO) are type 2 inflammation biomarkers that have established mechanistic, prognostic and theragnostic values in chronic asthma, but their utility in acute asthma is unclear. We speculate that the clinical and biological response to those treatments varies according to inflammometry and microbiological test results., Methods and Analysis: An observational longitudinal pilot study with multimodal clinical and translational assessments will be performed on 50 physician-diagnosed ≥12-year-old asthmatics presenting with an asthma attack and 12 healthy controls, including blood eosinophil count (venous and point-of-care (POC) capillary blood), FeNO and testing for airway infection (sputum cultures and POC nasopharyngeal swabs). People with asthma will be assessed on day 0 and after a 7-day corticosteroid course, with home monitoring performed in between. The primary analysis will be the change in the forced expiratory volume in 1 s according to type 2 inflammatory status (blood eosinophils ≥0.15×10 9 /L and/or FeNO ≥25 ppb) after treatment. Key secondary analyses will compare changes in symptom scores and the proportion of patients achieving a minimal clinically important difference. Exploratory analyses will assess the relationship between clinical, lung function, inflammatory and microbiome parameters; satisfaction plus reliability indices of POC tests; and sex-gender variability in treatment response. Ultimately, this pilot study will serve to plan a larger trial comparing the clinical and biological response to systemic corticosteroids according to inflammatory biomarkers, offering valuable guidance for more personalised therapeutic strategies in asthma attacks., Ethics and Dissemination: The protocol has been approved by the Research Ethics Committee of the CIUSSS de l'Estrie-CHUS, Sherbrooke, Quebec, Canada (#2023-4687). Results will be communicated in an international meeting and submitted to a peer-reviewed journal., Trial Registration Number: ClinicalTrials.gov Registry (NCT05870215)., Competing Interests: Competing interests: CAC-P reports he has received speaker honoraria from AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron; and received consultancy fees from AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron. PL reports speaker honoraria from AstraZeneca, Sanofi-Regeneron, GlaxoSmithKline, Boehringer Ingelheim and Novartis outside of the submitted work; and received consultancy fees from AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron. AC reports she has received non-restricted research grants from the Quebec Respiratory Health Research Network, the Fondation Québécoise en Santé Respiratoire and GlaxoSmithKline; received speaker honoraria from AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron and Valeo Pharma; and received consultancy fees for AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron and Valeo Pharma. She advised the Institut national d’excellence en santé et services sociaux (INESSS) for an update of the asthma general practice information booklet for general practitioners. SC reports the following interests: he has received non-restricted research grants from the NIHR Oxford BRC, the Quebec Respiratory Health Research Network, the Fondation Québécoise en Santé Respiratoire, AstraZeneca, bioMérieux and Sanofi-Genyme-Regeneron; he is the holder of the Association Pulmonaire du Québec’s Research Chair in Respiratory Medicine and is a clinical research scholar of the Fonds de recherche du Québec; he received speaker honoraria from AstraZeneca, GlaxoSmithKline, Sanofi-Regeneron and Valeo Pharma; he received consultancy fees for FirstThought, AstraZeneca, GlaxoSmithKline and Sanofi-Regeneron; he has received sponsorship to attend/speak at international scientific meetings by/for AstraZeneca and Sanofi-Regeneron. He is an advisory board member and will have stock options for Biometry—a company developing a FeNO device (myBiometry). He advised the INESSS for an update of the asthma general practice information booklet for general practitioners., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Assessment of lung function is essential for the early screening chronic airway diseases (CADs). Nevertheless, it is still not widely used for early diagnosing CADs in epidemiological or primary care settings. Thus, we used data from the US National Health and Nutrition Examination Survey (NHANES) to discuss the relationship between the serum uric acid/serum creatinine (SUA/SCr) ratio and lung function in general adults to gain the role of SUA/SCr in early assessment of lung function abnormalities., Methods: From 2007 to 2012 NHANES, a total of 9569 people were included in our study. Using the regression model, XGBoost algorithm model, generalised linear model and two-piecewise linear regression model, the link between the SUA/SCr ratio and lung function was investigated., Results: After correcting for confounding variables, the data revealed that forced vital capacity (FVC) declined by 47.630 and forced expiratory volume in one second (FEV1) decreased by 36.956 for each additional unit of SUA/SCr ratio. However, there was no association between SUA/SCr and FEV1/FVC. In the XGBoost model of FVC, the top five most important were glycohaemoglobin, total bilirubin, SUA/SCr, total cholesterol and aspartate aminotransferase, whereas in FEV1, were glycohaemoglobin, total bilirubin, total cholesterol, SUA/SCr and serum calcium. In addition, we determined the linear and inverse association between SUA/SCr ratio and FVC or FEV1 by constructing a smooth curve., Conclusions: In the general American population, the SUA/SCr ratio is inversely linked with FVC and FEV1, but not with FEV1/FVC, according to our research. Future studies should investigate the impact of SUA/SCr on lung function and identify possible mechanisms of action., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Few studies have investigated the short-term respiratory effects of ambient air pollution in chronic obstructive pulmonary disease (COPD) patients in the context of high pollution levels in Asian cities. Methods A panel of 23 stable COPD patients was repeatedly measured for biomarkers of airway inflammation including exhaled nitric oxide (FeNO) and exhaled hydrogen sulfide (FeH 2 S) (215 measurements) and recorded for daily respiratory symptoms (794 person-days) in two study periods in Beijing, China in January–September 2014. Daily ambient air pollution data were obtained from nearby central air-monitoring stations. Mixed-effects models were used to estimate the associations between exposures and health measurements with adjustment for potential confounders including temperature and relative humidity. Results Increasing levels of air pollutants were associated with significant increases in both FeNO and FeH 2 S. Interquartile range (IQR) increases in PM 2.5 (76.5 μg/m 3 , 5-day), PM 10 (75.0 μg/m 3 , 5-day) and SO 2 (45.7 μg/m 3 , 6-day) were associated with maximum increases in FeNO of 13.6% (95% CI: 4.8%, 23.2%), 9.2% (95% CI: 2.1%, 16.8%) and 34.2% (95% CI: 17.3%, 53.4%), respectively; and the same IQR increases in PM 2.5 (6-day), PM 10 (6-day) and SO 2 (7-day) were associated with maximum increases in FeH 2 S of 11.4% (95% CI: 4.6%, 18.6%), 7.8% (95% CI: 2.3%, 13.7%) and 18.1% (95% CI: 5.5%, 32.2%), respectively. Increasing levels of air pollutants were also associated with increased odds ratios of sore throat, cough, sputum, wheeze and dyspnea. Conclusions FeH 2 S may serve as a novel biomarker to detect adverse respiratory effects of air pollution. Our results provide potential important public health implications that ambient air pollution may pose risk to respiratory health in the context of high pollution levels in densely-populated cities in the developing world. [ABSTRACT FROM AUTHOR]

Background: Nitric oxide in exhaled air (eNO) is used as a marker of type 2 immune response-induced airway inflammation. We aimed to investigate the association between eNO and bronchiolitis incidence and respiratory symptoms in infancy, and its correlation with eosinophil protein X (EPX)., Methods: We followed up infants at 6 weeks of age born to mothers with asthma in pregnancy and measured eNO during natural sleep using a rapid response chemiluminescense analyser (CLD88; EcoMedics), collecting at least 100 breaths, interpolated for an expiratory flow of 50 mL/s. EPX normalised to creatinine was measured in urine samples (uEPX/c). A standardised questionnaire was used to measure symptoms in first year of life. Associations were investigated using multiple linear regression and robust Poisson regression models., Results: eNO levels were obtained in 184 infants, of whom 125/184 (68%) had 12 months questionnaire data available and 51/184 (28%) had uEPX/c measured. Higher eNO was associated with less respiratory symptoms during the first 6 weeks of life (n=184, ß-coefficient: -0.49, 95% CI -0.95 to -0.04, p=0.035). eNO was negatively associated with uEPX/c (ß-coefficient: -0.004, 95% CI -0.008 to -0.001, p=0.021). Risk incidence of bronchiolitis, wheeze, cold or influenza illness and short-acting beta-agonist use significantly decreased by 18%-24% for every unit increase in eNO ppb., Conclusion: Higher eNO levels at 6 weeks of age may be a surrogate for an altered immune response that is associated with less respiratory symptoms in the first year of life., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Metabolomic profiling of exhaled breath condensate offers opportunities for the development of noninvasive diagnostics in asthma. We aimed to determine and validate discriminatory metabolomic profiles in adult asthma and to explore profiles in clinically relevant disease phenotypes. Methods Nuclear magnetic resonance spectroscopy was used to analyse breath condensate samples from 82 subjects with asthma and 35 healthy volunteers. Multivariate modelling was performed on a 'training set' (70% of the total sample) in order to produce a discriminatory model classifying asthmatics from healthy controls, and the model tested in the remaining subjects. Secondary analyses were performed to determine the models for the identification of asthmatic subgroups based on sputum eosinophilia, neutrophilia, asthma control and inhaled corticosteroid use. Results A classification model consisting of five discriminating spectral regions was derived using data from the training set with an area under the receiver operating curve ( AUROC) of 0.84. In the test set (the remaining 30% of subjects), the AUROC was 0.91, thus providing external validation for the model. The success of the technique for classifying asthma phenotypes was variable, with AUROC for: sputum eosinophilia (3% cut-off) 0.69; neutrophilia (65% cut-off) 0.88; asthma control (cut-off Asthma Control Questionnaire score of 1) 0.63; and inhaled corticosteroid use 0.89. Conclusion Nuclear magnetic resonance spectroscopy of breath condensate successfully differentiates asthmatics from healthy subjects. With identification of the discriminatory compounds, this technique has the potential to provide novel diagnostics and identify novel pathophysiological mechanisms, biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

Introduction Inhaled corticosteroid therapy ( ICS) for asthma is currently modified according to symptoms and lung function. Fractional exhaled nitric oxide ( FENO) has been demonstrated to be a non-invasive marker of eosinophilic inflammation. Studies of FENO-driven asthma management show variable success. Objectives This study aimed to evaluate whether monitoring FENO can improve outpatient management of children with moderate to severe asthma using a pragmatic design. Methods Children aged 6-17 years with moderate to severe asthma were recruited. Their asthma was stabilised before randomisation to FENO-driven therapy or to a standard management group where therapy was driven by conventional markers of asthma control. ICS or long-acting bronchodilator therapies were altered according to FENO levels in combination with reported symptoms in the FENO group. Participants were assessed 2 monthly for 12 months. ICS dose and exacerbation frequency change were compared between groups in an intention to treat analysis. Results Ninety children were randomised. No difference was found between the two groups in either change in corticosteroid dose or exacerbation frequency. Results were similar in a planned secondary analysis of atopic asthmatics. Conclusion FENO-guided ICS titration does not appear to reduce corticosteroid usage or exacerbation frequency in paediatric outpatients with moderate to severe asthma. This may reflect limitations in FENO-driven management algorithms, as there are now concerns that FENO levels relate to atopy as much as they relate to asthma control. [ABSTRACT FROM AUTHOR]

Purpose: Alveolar nitric oxide (CA) has been suggested as a surrogate marker of distal airway inflammation in COPD. Coarse particle-inhaled corticosteroids (ICS) have been shown not to suppress CA. We evaluated whether extra-fine particle size ICS (HFA-BDP) or systemic oral corticosteroids could suppress CA in COPD. Methods: Chronic obstructive pulmonary disease (COPD) patients with a FEV1/FVC ratio <0.7, FEV1 <80% predicted with CA > 2 ppb underwent a double-blind randomized, controlled, crossover trial with an open-label systemic steroid comparator. After a 2 week steroid washout period, participants were randomized to 3 weeks of 100 mcg of HFA-BDP twice daily and then 3 weeks of 400 mcg of HFA-BDP twice daily, or matched placebos with subsequent crossover. All patients then received 1 week open-label, 25 mg/day of prednisolone. Exhaled nitric oxide, plasma cortisol, and lung function were recorded. CA was corrected for axial diffusion. Results: In 16 participants, there were no significant differences seen with either dose of HFA-BDP compared with placebo. Oral prednisolone significantly reduced FE and J'aw but not CA. Plasma cortisol was significantly suppressed by oral prednisolone only. Conclusions: Whilst CA remains a biomarker of interest in COPD, it is not suppressed by systemic or extra-fine particle ICS. CA is not a useful marker for monitoring response of small airway disease to therapies in COPD. The study was approved by the local Committee on Medical Research Ethics and registered on ClinicalTrials.Gov (NCT 00921921). [ABSTRACT FROM AUTHOR]

Background: Asthma is a chronic inflammatory disease of the airways but recent studies have shown that alveoli are also subject to pathophysiological changes. This study was undertaken to compare hydrogen peroxide (H2O2) concentrations in different parts of the lung using a new technique of fractioned breath condensate sampling. Methods: In 52 children (9-17 years, 32 asthmatic patients, 20 controls) measurements of exhaled nitric oxide (FENO), lung function, H2O2 in exhaled breath condensate (EBC) and the asthma control test (ACT) were performed. Exhaled breath condensate was collected in two different fractions, representing mainly either the airways or the alveoli. H2O2 was analysed in the airway and alveolar fractions and compared to clinical parameters. Results: The exhaled H2O2 concentration was significantly higher in the airway fraction than in the alveolar fraction comparing each single pair (p = 0.003, 0.032 and 0.040 for the whole study group, the asthmatic group and the control group, respectively). Asthma control, measured by the asthma control test (ACT), correlated significantly with the H2O2 concentrations in the alveolar fraction (r = 0.606, p = 0.004) but not with those in the airway fraction in the group of children above 12 years. FENO values and lung function parameters did not correlate to the H2O2 concentrations of each fraction. Conclusion: The new technique of fractionated H2O2 measurement may differentiate H2O2 concentrations in different parts of the lung in asthmatic and control children. H2O2 concentrations of the alveolar fraction may be related to the asthma control test in children. [ABSTRACT FROM AUTHOR]

Summary: Introduction: Current asthma guidelines recommend step-down of inhaled corticosteroids (ICS) to the minimum dose required for control of symptoms. Aim: To determine if supervised step-down of (ICS) in the community has any effect on asthmatic inflammation. Methods: 119 Community based asthmatics underwent progressive step-down of therapy until they became unstable or reached an (ICS) dose of ≤200 μg beclomethasone dipropionate (BDP) or equivalent. Once unstable, participants stepped back up to the last stable dose of ICS. Exhaled nitric oxide (NO) and mannitol challenge were performed at the start and end of step-down. Asthma Quality of Life Questionnaire (AQLQ) and spirometry were recorded at each step-down visit. Results: The median (interquartile range) BDP equivalent dose was significantly higher pre vs. post step-down: 400 μg (400–800) and 250 μg (200–400) per day respectively (P < 0.05). Examination of change in PD10 in individual patients revealed that 34% had an improvement (>+1 dd), 47% had no change (±−1 dd), and 19% had a worsening (<−1 dd). The geometric mean fold ratio in NO for pre vs. post was 0.96 (95% CI 0.87 to 1.06, P = 0.43). Mean (SEM) values for FEV1 were 86.2% (1.51) vs. 84.5% (1.46) (P = 0.04). There was a significant improvement in AQLQ. Conclusions: We have demonstrated that a significant reduction in ICS dose may be achieved in a community setting without any worsening of airways inflammation or lung function, and with an associated improvement quality of life in the majority of patients. This apparent disconnect may reflect enhanced adherence due to supervision of step-down. [ABSTRACT FROM AUTHOR]

The value of FENO measurements in patients with symptoms suggestive of asthma is unclear. We performed an observational study to assess the ability of FENO to diagnose asthma and to predict response to inhaled corticosteroids (ICS). Our findings suggest FENO is not useful for asthma diagnosis but is accurate at predicting ICS response. [ABSTRACT FROM AUTHOR]

Abstract Background Asthma is a chronic inflammatory disease of the airways but recent studies have shown that alveoli are also subject to pathophysiological changes. This study was undertaken to compare hydrogen peroxide (H2O2) concentrations in different parts of the lung using a new technique of fractioned breath condensate sampling. Methods In 52 children (9-17 years, 32 asthmatic patients, 20 controls) measurements of exhaled nitric oxide (FENO), lung function, H2O2 in exhaled breath condensate (EBC) and the asthma control test (ACT) were performed. Exhaled breath condensate was collected in two different fractions, representing mainly either the airways or the alveoli. H2O2 was analysed in the airway and alveolar fractions and compared to clinical parameters. Results The exhaled H2O2 concentration was significantly higher in the airway fraction than in the alveolar fraction comparing each single pair (p = 0.003, 0.032 and 0.040 for the whole study group, the asthmatic group and the control group, respectively). Asthma control, measured by the asthma control test (ACT), correlated significantly with the H2O2 concentrations in the alveolar fraction (r = 0.606, p = 0.004) but not with those in the airway fraction in the group of children above 12 years. FENO values and lung function parameters did not correlate to the H2O2 concentrations of each fraction. Conclusion The new technique of fractionated H2O2 measurement may differentiate H2O2 concentrations in different parts of the lung in asthmatic and control children. H2O2 concentrations of the alveolar fraction may be related to the asthma control test in children.

Introduction: Tobacco smoking is a significant source of cadmium exposure among smokers. Most of inhaled heavy metals, including cadmium, are attached to ultrafine particles (UFPs) surface. A low inhaled UFP content in exhaled breath condensate reflects a high inflammatory status of airways. Increased respiratory epithelial permeability and translocation to the circulation is the proposed mechanism. UFP recovered from smokers' airways have high levels of cadmium compared with the airways of non-smokers., Methods: Urine was collected from 22 smokers subjects and 43 non-smokers. Samples were analysed for UFP and cadmium content. UFP were measured in urine samples by means of the NanoSight LM20 system (NanoSight, UK). A Niton XL3 X-ray fluorescence spectrometer analyzer (Thermo Fischer Scientific, Germany) quantified heavy metal contents in the urine samples., Results: Smokers had elevated UFP and cadmium content in urine compared with non-smokers (4.6 E8/mL and 20.6 ppm vs 3.4 E8/mL and 18.5 ppm, p=0.05 and p=0.05, respectively). Smokers had elevated levels of lead and rubidium compared with non-smokers (8.9 ppm and 27 ppm vs 7.8 ppm and 2 ppm, p=0.05 and p=0.04, respectively) DISCUSSION: We suggest that the trajectory of cadmium-related UFP in smokers begins by its inhalation into the airways. The UFPs induce inflammation and oxidative stress in the small airways, are subsequently translocated from the interstitium to the circulation and are finally detected and secreted in urine., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Respiratory tract lining fluid of small airways mainly consists of surfactant that can be investigated by collection of the particles of exhaled aerosol (PExA) method. This offers an exciting prospect to monitor small airway pathology, including subjects with asthma and smokers., Aim: To explore the influence of anthropometric factors and gender on phospholipids, surfactant protein A (SP-A) and albumin of the lining fluid of small airwaysand to examine the association with asthma and smoking. Furthermore, to examine if the surfactant components can predict lung function in terms of spirometry variables., Method: This study employs the population-based cohort of the European Community Respiratory Health Survey III, including participants from Gothenburg city, Sweden (n=200). The PExA method enabled quantitative description and analytical analysis of phospholipids, SP-A and albumin of the lining fluid of small airways., Results: Age was a significant predictor of the phospholipids. The components PC14:0/16:0, PC16:0/18:2 (PC, phosphatidylcholine) and SP-A were higher among subjects with asthma, whereas albumin was lower. Among smokers, there were higher levels particularly of di-palmitoyl-di-phosphatidyl-choline compared with non-smokers. Most phospholipids significantly predicted the spirometry variables., Conclusion: This non-invasive PExA method appears to have great potential to explore the role of lipids and proteins of surfactant in respiratory disease., Competing Interests: Competing interests: Anna-Carin Olin was one of the inventors of the PExA method and is a board member and shareholder in PExA AB., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Air pollution is a risk factor for chronic obstructive pulmonary disease (COPD). Fraction of exhaled nitric oxide (FeNO) could be a useful biomarker for health effects of air pollutants. However, there were limited data from older populations with higher prevalence of COPD and other inflammatory conditions., Methods: We obtained data from the German Study on the influence of Air pollution on Lung function, Inflammation and Ageing. Spirometry and FeNO were measured by standard techniques. Air pollutant exposures were estimated following the European Study of Cohorts for Air Pollution Effects protocols, and ozone (O 3 ) measured at the closest ground level monitoring station. Multiple linear regression models were fitted to FeNO with each pollutant separately and adjusted for potential confounders., Results: In 236 women (mean age 74.6 years), geometric mean FeNO was 15.2ppb. Almost a third (n=71, 30.1%) of the women had some chronic inflammatory respiratory condition. A higher FeNO concentration was associated with exposures to fine particles (PM 2.5 ), PM 2.5absorbance and respirable particles (PM 10 ). There were no significant associations with PM coarse , NO 2 , NO x , O 3 or length of major roads within a 1 km buffer. Restricting the analysis to participants with a chronic inflammatory respiratory condition, with or without impaired lung function produced similar findings. Adjusting for diabetes did not materially alter the findings. There were no significant interactions between individual pollutants and asthma or current smoking., Conclusions: This study adds to the evidence to reduce ambient PM 2.5 concentrations as low as possible to protect the health of the general population., Competing Interests: Competing interests: Michael Abramson holds investigator initiated grants for unrelated research from Pfizer and Boehringer-Ingelheim. He has undertaken an unrelated consultancy for Sanofi and received a speaker’s fee from GSK. The other authors have no competing interests to declare., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Asthma guidelines guide health practitioners to adjust treatments to the minimum level required for asthma control. As many people with asthma have an eosinophilic endotype, tailoring asthma medications based on airway eosinophilic levels (sputum eosinophils or exhaled nitric oxide, FeNO) may improve asthma outcomes., Objective: To synthesise the evidence from our updated Cochrane systematic reviews, for tailoring asthma medication based on eosinophilic inflammatory markers (sputum analysis and FeNO) for improving asthma-related outcomes in children and adults., Data Sources: Cochrane reviews with standardised searches up to February 2017., Study Selection: The Cochrane reviews included randomised controlled comparisons of tailoring asthma medications based on sputum analysis or FeNO compared with controls (primarily clinical symptoms and/or spirometry/peak flow)., Results: The 16 included studies of FeNO-based management (seven in adults) and 6 of sputum-based management (five in adults) were clinically heterogeneous. On follow-up, participants randomised to the sputum eosinophils strategy (compared with controls) were significantly less likely to have exacerbations (62 vs 82/100 participants with ≥1 exacerbation; OR 0.36, 95% CI 0.21 to 0.62). For the FeNO strategy, the respective numbers were adults OR 0.60 (95% CI 0.43 to 0.84) and children 0.58 (95% CI 0.45 to 0.75). However, there were no significant group differences for either strategy on daily inhaled corticosteroids dose (at end of study), asthma control or lung function., Conclusion: Adjusting treatment based on airway eosinophilic markers reduced the likelihood of asthma exacerbations but had no significant impact on asthma control or lung function., Competing Interests: Competing interests: HLP, and ABC have conducted a randomised controlled trial in children on this subject. Other authors have no competing interests to declare., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Measurement of FE NO might substitute bronchial provocation for diagnosing asthma. We aimed to investigate the diagnostic accuracy of FE NO measurement compared with established reference standard., Methods: Systematic review and diagnostic meta-analysis. Data sources were Medline, Embase and Scopus up to 29 November 2015. Sensitivity and specificity were estimated using a bivariate model. Additionally, summary receiver-operating characteristic curves were estimated., Results: 26 studies with 4518 participants (median 113) were included. Risk of bias was considered low for six of seven items in five studies and for five items in seven studies. The overall sensitivity in the meta-analysis was 0.65 (95% CI 0.58 to 0.72), the overall specificity 0.82 (0.76 to 0.86), the diagnostic OR 9.23 (6.55 to 13.01) and the area under the curve 0.80 (0.77 to 0.85). In meta-regression analyses, higher cut-off values were associated with increasing specificity (OR 1.46 per 10 ppb increase in cut-off) while there was no association with sensitivity. Sensitivities varied significantly within the different FE NO devices, but not specificities. Neither prevalence, age, use of bronchoprovocation in >90% of participants or as exclusive reference standard test, nor risk of bias were significantly associated with diagnostic accuracy., Conclusions: There appears to be a fair accuracy of FE NO for making the diagnosis of asthma. The overall specificity was higher than sensitivity, which indicates a higher diagnostic potential for ruling in than for ruling out the diagnosis of asthma., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Obstructive sleep apnoea (OSA) is highly prevalent and associated with cardiovascular and metabolic changes. OSA is usually diagnosed by polysomnography which is time-consuming and provides little information on the patient's phenotype thus limiting a personalised treatment approach. Exhaled breath contains information on metabolism which can be analysed by mass spectrometry within minutes. The objective of this study was to identify a breath profile in OSA recurrence by use of secondary-electrospray-ionization-mass spectrometry (SESI-MS)., Methods: Patients with OSA effectively treated with CPAP were randomised to either withdraw treatment (subtherapeutic CPAP) or continue therapeutic CPAP for 2 weeks. Exhaled breath analysis by untargeted SESI-MS was performed at baseline and 2 weeks after randomisation. The primary outcome was the change in exhaled molecular breath pattern., Results: 30 patients with OSA were randomised and 26 completed the trial according to the protocol. CPAP withdrawal led to a recurrence of OSA (mean difference in change of oxygen desaturation index between groups +30.3/h; 95% CI 19.8/h,40.7/h, p<0.001) which was accompanied by a significant change in 62 exhaled features (16 metabolites identified). The panel of discriminating mass-spectral features allowed differentiation between treated and untreated OSA with a sensitivity of 92.9% and a specificity of 84.6%., Conclusion: Exhaled breath analysis by SESI-MS allows rapid and accurate detection of OSA recurrence. The technique has the potential to characterise an individual's metabolic response to OSA and thus makes a comprehensible phenotyping of OSA possible., Trial Registration Number: NCT02050425 (registered at ClinicalTrials.gov)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)