ERJ Open Research

IntroductionPatients with primary ciliary dyskinesia (PCD) present a variety of respiratory symptoms. Spirometry, particularly forced expiratory volume in 1 s (FEV1), is the most commonly used outcome measure in clinical follow-up, however, it is not known how well it captures the range of respiratory symptoms experienced by patients. MethodsWe sent the FOLLOW-PCD questionnaire to all patients [≥]14 years and parents of children, registered in the Swiss PCD Registry, asking about upper and lower respiratory symptoms. In patients who had a routine lung function done within a year of survey completion, we extracted data from clinical records and calculated spirometric indices z-scores based on the Global Lung Function Initiative references. We used linear regression to study associations between FEV1, forced vital capacity (FVC), FEV1/FVC and frequency of respiratory symptoms, adjusted for age, sex, and regular physiotherapy. Results64 out of 99 invited patients (67%) completed the survey; for 54 of them (median age 24 years, IQR 15-47; 50% females) we also had an FEV1 measurement (mean z-score - 2.29 [- 3.37 - -1.03]), with 2.2 months median time between survey and lung function test. Patients reporting wheeze (76%) had lower FEV1 and FEV1/FVC z-scores (FEV1 z-score for infrequent and frequent wheeze compared to no wheeze: -1.13 [95%CI -2.13 - -0.12] and -1.11 [-2.20 - - 0.20] respectively). Similarly patients reporting frequent shortness of breath (29.5%) had also lower FEV1 and FEV1/FVC z-scores (FEV1 z-score for frequent shortness of breath compared to no shortness of breath: -1.27 [-2.50 - -0.04]). We found no signs of association between reported nasal symptoms, snoring, cough, sputum production, and chest pain with FEV1, FVC or FEV1/FVC. ConclusionIn our study, self-reported wheeze and frequent shortness of breath were associated with lower FEV1 and FEV1/FVC, commonly used for patient follow-up. However, we need additional outcome measures e.g., lung clearance index, imaging outcomes, or upper airway assessments, together with regular and standardised assessment of patient-reported symptoms, to capture the range of respiratory morbidity patients with PCD experience in daily life and guide management successfully.

BackgroundPrimary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by deficient mucociliary clearance and development of chronic lung disease. Pulmonary exacerbations (PEx) in chronic lung diseases increase morbidity and lung function decline, but their frequency in PCD has been understudied. We aimed to prospectively determine the annual frequency of PEx in PCD and identify related risk factors. MethodsIn a multicentre, observational study conducted in 11 centres from seven countries, we prospectively collected data from a well-described patient cohort with genetically confirmed PCD over a year via monthly telephone questionnaires and clinical visits. We assessed the annual PEx frequency using three definitions: i) clinical definition 1 (Def-1) when three out of seven clinical items were positive; clinical definition 2 (Def-2) if the patient started or changed antibiotic treatment; self-reported PEx by the patient). For paired statistical comparisons we used the Friedman test and the Wilcoxon matched-pairs test and tested their agreement (Cohens kappa statistics). We also determined related risk factors using a mixed-effects model. ResultsWe recruited 271 individuals with PCD of all ages. Among patients with complete annual records (n=248), approximately 80% experienced at least one PEx per year, as assessed by the three definitions used. Self-reported PEx per year (median 2, interquartile range (IQR) 1-5) were higher (p<0.0001) than the PEx assessed by Def-1 (median 2, IQR 0-4) and Def-2 (median 1, IQR 0.25-3). Self-reported PEx had a substantial agreement with Def-1 [kappa (SE) =0.61 (0.05)] and a moderate agreement with Def-2 [kappa (SE) =0.51 (0.05)]. Female sex and autumn season were associated with significantly higher number of PEx, independent of the definition used. Increasing age was correlated with higher annual PEx frequency by Def-1. ConclusionIn this multicentre study, we prospectively assessed the annual PEx frequency in patients genetically diagnosed with PCD, demonstrating the importance of the definition used in capturing the exacerbation burden of PCD, as well as the influence of sex, age and season on exacerbation frequency.

Despite the widespread use of vaping, a very limited number of clinical studies have investigated the effects of this habit on the lungs of healthy individuals. Our group recently initiated the Vaping Adverse Lung and Heart Events Cohort (VapALERT), a prospective study aiming to identify the impacts of vaping on respiratory and cardiovascular health. We elected to report early findings from the pulmonary function tests performed at the initial visit of the first 83 participants recruited so far. Almost 80% of volunteers with no diagnosis of lung disease and who vape daily have an abnormal airway reactivity to metacholine and/or lung clearance index and/or diffusion capacity. We can conclude from this study that adult individuals who vape daily are very likely to present asymptomatic functional respiratory abnormalities, especially airway hyperresponsiveness, ventilation heterogeneity and reduced gas diffusion regardless of past or current tobacco and/or cannabis smoking. Longitudinal studies are crucial to determine how respiratory abnormalities observed in individuals who vape will progress over time.

IntroductionPulmonary exacerbations contribute to disease progression in chronic lung diseases. In a large prospective cohort study, we studied the incidence and predictors of pulmonary exacerbations among persons with primary ciliary dyskinesia (PCD), which can inform follow-up care. We also assessed healthcare use, changes in management, and pathogens during exacerbations. MethodsParticipants in the Living with PCD study reported increased respiratory symptoms in the past seven days, indicating a pulmonary exacerbation, from June 2020 through May 2022 via online questionnaires. We derived incidence rates and studied predictors of pulmonary exacerbation incidence by fitting multivariable negative binomial regression models. ResultsWe obtained data from 660 persons (408 adults, 57 adolescents, 195 children) who completed 17,853 follow-up questionnaires (median 17, range 1-84). The 1026 reported exacerbations indicate an incidence rate of 3.1 pulmonary exacerbations per person per year, with minor variation across age groups, but changes over time. Incidence was higher among adult females [incidence rate ratio (IRR) 2.0, 95% confidence interval (CI) 1.4-2.7] and those in whom Pseudomonas aeruginosa was isolated (children IRR 1.9, 95% CI 1.1-3.6; adults IRR 1.4, 95% CI 1.0-1.9). Participants saw a health professional during only 185 of 1404 exacerbation weeks (13%). Pseudomonas aeruginosa was the pathogen most frequently observed during exacerbations in children (18 of 118 samples, 15%) and adults (132 of 303 samples, 44%). ConclusionPulmonary exacerbations are frequent in PCD and heighten the disease burden. Patients for whom targeted management is particularly important include adult females and those who carry Pseudomonas aeruginosa.

BackgroundSex is an important part of life for many adults, yet sexual function may be impacted by chronic respiratory diseases such as pulmonary fibrosis (PF). This multinational study sought to characterize the impact of PF on sex and sexual function, using mixed quantitative and qualitative methodology. MethodsPatients were retrospectively included from a prospective registry and prospective clinical cohort if they had completed UCSD-SOBQ or SPARC questionnaire, respectively. An online multi-lingual survey used the Changes in Sexual Function Questionnaire (CSFQ) to assess sexual dysfunction, and qualitative evaluation of individual patient interviews was conducted using thematic analysis. ResultsDyspnea with sexual activity affected 2,054/2,759 (74%) of registry patients, associated with male sex, lower FVC%, lower DLCO%, and worse cough. Distress due to the effect of PF on their sex life was reported in 52/225 (23%) of the clinical cohort, associated with younger age, male sex, lower DLCO%, and worse cough. Sexual dysfunction was common, affecting 56/67 (83%) of female and 63/73 (86%) male survey respondents. Qualitative analysis of patient interviews identified several themes including sex life limitations, changes in inter-personal relationships, quality of life, and emotions. All patients wanted to discuss sex with trusted healthcare providers. ConclusionIn this multinational study, patients with PF reported engaging in sex and sexual activities but were adversely impacted by the effect of PF on sex life, with both physical and psychological limitations. Sexual dysfunction was common, driven by multiple disease domains. Sexual health appears to be an important component of comprehensive patient care. FundingThe Canadian Registry for Pulmonary Fibrosis is sponsored by Boehringer Ingelheim, but had no input on any aspect of this study.

Functional capacity, muscle strength, and patient-reported outcome measures are important indicators of health. In chronic obstructive pulmonary disease (COPD), these traits are often impaired beyond normal age-related decline. Substantial variability exists in both COPD and healthy populations, the biological basis of which remains poorly understood. Given the known contribution of genetics to complex traits, genetic factors may partly explain this variability. This study aimed to identify genetic variants associated with measures used to characterise extrapulmonary traits in COPD. Genome-wide association studies were conducted on the Lab3R-ESSUA cohort for the 6-minute walk test (6MWT), the 1-minute sit-to-stand test (1-min STS), the quadriceps maximal voluntary contraction (QMVC), the handgrip muscle strength, and the chronic airways assessment test (CAAT), adjusting for age, sex, body mass index, pack-years and ancestry. Variants with P<1E-05 were selected for replication in the EARLYCOPD cohort, and effects compared between COPD and healthy populations (two-way ANOVA). A total of 639 participants (364 people with COPD, 275 healthy; 75% male, median age 67 years; BMI of 27 Kg/m2; 10 pack-years) were included. Significant variants were identified for the 6MWT (rs1108983:G, {beta}=-186.5m, P=4.8E-08), the 1-min STS (rs5889103:GTT, {beta}=4.2reps, P=4.8E-08), the Handgrip (rs67352743:A, {beta}=-4.4Kg, P=2.8E-08), and for the CAAT (rs11747040:C, {beta}=4.4points, P=4.0E-09; rs11041680:A, {beta}=-2.6points, P=2.5E-08). Effects were independent of COPD diagnosis. Replication in EARLYCOPD (n=282) confirmed one SNP for 6MWT and three for CAAT. These findings highlight genetic contributions to functional capacity, muscle strength, and disease burden. COPD-related impairments appear to build on pre-existing genetic predisposition, contributing to disease heterogeneity.

BackgroundPulmonary Radioaerosol Mucociliary Clearance (PRMC) is an in vivo whole lung ciliary function test reliable for assessing mucociliary clearance for diagnostic purposes in individuals suspected of primary ciliary dyskinesia (PCD). We aimed to evaluate expanded use of PRMC by providing advantages and limitations for its potential use in providing outcome parameters in future trials aiming to restore ciliary activity. Material and MethodsIn this retrospective study, PRMC tests performed over a period of 24 years (1999-2022) were meticulously re-analyzed. Patients with genetically verified PCD and non-PCD controls were included. Originally, nebulized 99mTc-albumin colloid was inhaled, and static and dynamic imaging acquired for 60 and 120 minutes, and 24 hours. For the purpose of the present study 3 PRMC parameters were defined: 1 hour lung retention (LR1), tracheobronchial velocity (TBV), and cough clearance. ResultsSixty-nine patients were included from the Danish PCD cohort. PRMC was overall completely absent regardless of PCD genotypes. In one patient with CCDC103 mutation, residual ciliary function and normal nasal NO, we found normal PRMC LR1 and measurable, however low, TBV. Voluntary cough significantly increased clearance with a median (IQR) of 11 (4;24) %. ConclusionAbsolute absence of PRMC would be the expected baseline result in by far the majority of patients with PCD regardless of genotype before introducing ciliary protein correctors in a clinical trial. Measurable PRMC TBV and normal LR1 in one patient with residual ciliary function, indicated that PRMC parameters could potentially improve if ciliary function was to be restored during a clinical trial. Involuntary cough and peripheral radioaerosol deposition were the main challenges of the PRMC method.

RationaleCombining traditional therapies such as pulmonary rehabilitation with brain- targeted drugs may offer new therapeutic opportunities for the treatment of chronic breathlessness. Recent work has shown that D-cycloserine, a partial NMDA-receptor agonist which has been shown to enhance cognitive behavioural therapies, modifies the relationship between breathlessness related brain activity and breathlessness anxiety over pulmonary rehabilitation. However, whether these changes are supported by alterations to underlying brain structure remains unknown. Here we examine the effect of D-cycloserine over a course of pulmonary rehabilitation on regional brain volume and connectivity. Methods72 participants with mild-to-moderate COPD took part in a longitudinal study in parallel to their pulmonary rehabilitation course. Diffusion tensor brain imaging, self-report questionnaires and clinical measures of respiratory function were collected at three time points (before, during and after pulmonary rehabilitation). Participants were assigned to 250mg of D-cycloserine or placebo, which they were administered with on four occasions in a randomised, double-blind procedure. ResultsFollowing four sessions of pulmonary rehabilitation, improvements in breathlessness anxiety were linked with increased insula-hippocampal structural connectivity in the D-cycloserine group. No group differences were found following the completion of pulmonary rehabilitation, or in the integrity of structural connectivity. ConclusionsThe action of D-cycloserine on brain connectivity appears to be restricted to within a short time-window of its administration. This temporary boost of the brain connectivity of two key regions associated with the evaluation of unpleasantness may support the re-evaluation of breathlessness cues, illustrated improvements in breathlessness anxiety. This work highlights the relevance of targeting breathlessness expectation in pulmonary rehabilitation.

BackgroundCOVID-19-related Acute Respiratory Distress Syndrome (CARDS) is the severe evolution of the Sars-Cov-2 infection leading to an intensive care unit (ICU) stay. Its onset is associated with "long-covid" including persisting respiratory disorders up to one year. Rehabilitation is suggested by most guidelines in the treatment of "long-covid". As no randomised controlled trial did support its use in "long-covid" we aimed to evaluate the effects of endurance training rehabilitation (ETR) on dyspnoea in "long-covid" following CARDS. MethodsIn this multicentre, two-arm, parallel, open, assessor-blinded, randomised, controlled trial performed in three French ICU, we enrolled adults previously admitted for CARDS, discharged for at least three months and presenting an mMRC dyspnea scale score > 1. Eligible patients were randomly allocated (1:1) to receive either ETR or standard physiotherapy (SP), both for three months. Outcomes assessors were masked to treatment assignment. Primary outcome was dyspnoeas evolution, measured by Multidimensional Dyspnea Profile (MDP) at inclusion and after 90 days. ResultsBetween August 7, 2020 and January 26, 2022, 871 COVID-19 patients were screened, of whom 60 were randomly assigned to ETR (n=27) or SP (n=33). Mean MDP score after treatment was significantly lower in the ETR group than in the SP group (26.15 [SD 15.48] vs. 44.76 [SD 19.25]; mean difference -18.61 [95% CI -27.78 to -9.44]; p<0.0001). ConclusionCARDS patients suffering from breathlessness three months after discharge improved their dyspnoea significantly more when treated with ETR for three months rather than with SP.

The authors have withdrawn this manuscript version because the FEV1 percent predicted variable (UK biobank data field 20154) that was used was to determine spirometric pattern was constructed in only "healthy never smokers" or heavy smokers. This means the paper is affected by selection bias and is not generalizable. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

BackgroundChronic breathlessness profoundly affects quality of life for its sufferers. Often, reported breathlessness is inconsistent with airway pathophysiology and objective disease markers. While a mechanistic understanding of this discordance has thus far remained elusive, factors such as mood, attention and expectation have all been implicated as important perceptual modulators. Therefore, here we have developed a model capable of exploring these relationships aiding patient stratification and revealing clinically-relevant neuro-biomarkers. MethodsA cohort of 100 participants with mild-to-moderate chronic obstructive pulmonary disease (COPD) underwent a comprehensive assessment that included functional brain imaging while viewing and rating breathlessness-related word cues, self-report questionnaires and clinical measures. ResultsUsing an exploratory factor analysis across psychological and physiological measures, we identified two distinctive neuropsychological behavioural profiles that differed across four key factors corresponding to mood, symptom burden, and two capability measures. These profiles stratified participants into high and low symptom groups, which did not differ in spirometry values. The low symptom load group demonstrated greater FMRI activity to breathlessness-related word cues in the anterior insula. ConclusionsOur findings reveal two clear groups of individuals within our COPD cohort, divided by behavioural rather than clinical factors. Furthermore, indices of depression, anxiety, vigilance and perceived capability were linked to differences in brain activity within key regions thought to be involved in monitoring bodily sensations (interoception). These findings demonstrate the complex relationship between affect and interoceptive processing, providing the foundations for the development of targeted treatment programmes that harness clinical and symptom-relevant biomarkers.

Rationale: Air trapping in functional areas of the lung is common in chronic obstructive pulmonary disease (COPD). We developed a novel music-based intervention, Engagement of Music for Pulmonary Obstruction With Expiratory Restoration (EMPOWER) aimed at reducing air trapping and functional small airways disease (fSAD) in patients with COPD. Objectives: We conducted a pilot study to assess if air trapping and fSAD in COPD patients are reduced by our targeted EMPOWER music-based singing intervention. Methods: Participants completed four weeks of singing and vocalizing with a board-certified music therapist. Pre- and post-intervention assessments of standard pulmonary function tests (PFTs), and quantitative computed tomography (qCT) lung imaging documented changes in air trapping. Pre- and post-intervention change in psychological and patient-reported outcomes of hope, emotional wellbeing, agency and COPD symptom burden were also obtained. Main Results: All five adult participants with COPD who enrolled completed the study and reported strong interest in continuing with a similar program. Additionally, we observed trends toward improvement in qCT-measured fSAD, six-minute walk distance, and patient-reported symptoms on the COPD Assessment Test. Conclusion: Results of this preliminary study showed improvements in both patient-reported and imaging-indicated respiratory outcomes, suggesting that targeted singing components in music-based interventions such as the EMPOWER intervention may support physiological lung function changes in COPD patients.

BackgroundChildhood cancer survivors (CCS) are at risk of pulmonary late effects, but post-treatment lung function remains understudied. Current guidelines recommend screening only for symptomatic survivors treated with lung-damaging treatments. We evaluated pulmonary function, risk factors, and respiratory symptoms in a broad paediatric CCS cohort, including those with standard treatments. MethodsIn this prospective multicenter study, we included CCS aged 6-21 years, stratified as high-risk (thoracic radiotherapy/surgery, busulfan/bleomycin/nitrosourea chemotherapy, haematopoietic stem cell transplantation [HSCT]) or standard-risk (other systemic treatment). Pulmonary function was assessed via spirometry (forced expiratory volume in 1 second [FEV], forced vital capacity [FVC]), body plethysmography (total lung capacity [TLC]), and diffusing capacity for carbon monoxide (DLCO), expressed as z-scores using Global Lung Initiative references. We assessed respiratory symptoms via questionnaires and analysed treatment associations with pulmonary function using multivariable linear regression. ResultsWith a response rate of 90%, 251 CCS participated (median 7 years post-diagnosis). Mean z-scores for FEV1, FVC, TLC, and DLCO were lower in high-risk (-0.70, -0.91, -0.54, -0.17, respectively) than standard-risk survivors (-0.10, -0.22, -0.17, 0.32). Thoracic surgery and nitrosoureas were associated with lower TLC (-0.53, -1.37), HSCT with reduced FEV1 and FVC (-0.80, -0.84), and thoracic radiotherapy with lower DLCO (-0.63). Respiratory symptoms were reported by 32%, but 64% of those with impaired lung function were asymptomatic. ConclusionPulmonary function was mostly normal in standard-risk CCS, but impaired in high-risk, although often asymptomatic. These findings support targeted surveillance based on treatment exposure rather than symptoms to guide long-term care.

Background and objectiveHighly effective CFTR modulators, particularly elexacaftor/tezacaftor/ivacaftor (ETI), produce rapid clinical improvements in people with cystic fibrosis. Yet early treatment effects may be difficult to capture with spirometry or a sweat test in patients with a mild disease or atypical mutations. Exhaled breath is rich in volatile organic compounds (VOCs) reflecting metabolic and inflammatory processes. We aimed to determine whether ETI induces early, measurable changes in breath composition and whether these changes relate to clinical outcomes. MethodsTen adults initiating ETI were enrolled in a prospective, open-label study with breath sampling at baseline, week one and month one. VOCs were measured using real-time proton-transfer-reaction - mass spectrometry (PTR-MS). Longitudinal changes were assessed using multilevel statistics, including univariate linear mixed-effects models and multivariate RM-ASCA+; repeated-measures correlations examined associations with lung function and sweat chloride concentration. Results were compared with a healthy cohort. ResultsAmongst the eight responders, 11 VOC features changed significantly after ETI initiation. Eight differed from healthy controls at baseline and shifted towards healthy levels over one month. RM-ASCA+ identified linear and non-linear temporal patterns capturing acute and progressive metabolic responses. A 14-feature PLS-DA model classified visits with high accuracy (AUC=0.96-1.00). Ten VOCs correlated with clinical readouts. Features of interest were tentatively identified and pointed towards a shift in the microbiome and/or energy metabolism. ConclusionETI induces rapid alterations in exhaled VOCs, many trending towards healthy values and correlating with clinical improvement. Real-time breath analysis offers a promising non-invasive surrogate for early monitoring of therapeutic response. SUMMARYReal-time PTR-MS breath analysis revealed rapid metabolic changes in adults with cystic fibrosis starting ETI therapy. Several VOCs shifted towards healthy levels within one month and correlated with lung function and sweat chloride. These findings support breathomics as a non-invasive surrogate for early monitoring of CFTR modulator response.

BackgroundPrevious studies indicate a protective role for SARS-CoV-2 vaccination against development of pulmonary post-acute sequelae of COVID (PASC). We compared clinical, imaging, histopathology and ultrastructural features of pulmonary PASC with and without prior vaccination in a consecutive cohort of 54 unvaccinated, 17 partially vaccinated and 28 fully vaccinated patients who presented with dyspnea on exertion after mild COVID-19 (without hospitalization). MethodsPatients underwent full clinical evaluation including autoantibody (ANA/ENA) serology, high-resolution computed tomography (HRCT), bronchioloalveolar lavage fluid (BAL) analysis and transbronchial biopsy followed by histopathological and ultrastructural analysis and SARS-CoV-2 immunohistochemistry. ResultsWhile vaccinated patients were younger (p=0.0056), included more active smokers (p=0.0135) and a longer interval since infection (35 vs. 17 weeks, p=0.0002), dyspnea on exertion and impaired lung function were not different between vaccinated and unvaccinated patients. Ground glass opacities in HRCT and centrilobular fibrosis were more frequent in unvaccinated patients (p=0.0154 and p=0.0353), but presence of autoantibodies, BAL lymphocytosis and bronchiolitis were common findings in all groups. While vaccination against SARS-CoV-2 is associated with a longer time span between infection and consultation along with a reduced frequency of ground glass opacities and centrilobular fibrosis, impaired lung function, bronchiolitis and presence of autoantibodies are comparable between vaccinated and unvaccinated patients. Residual virus was not detected in lung tissue in all but 1 patient. ConclusionWhile differences between the investigated groups with regard to age, smoking status and SARS-CoV-2 variants have to be taken into account, a proposed protective role of SARS-CoV-2 vaccination against pulmonary PASC is so far not fully explained by clinical and histopathology findings. KEY MESSAGESThe role of SARS-CoV-2 vaccination in the protection against pulmonary post-acute sequelae of COVID-19 (PASC) is unclear. Using a multidimensional approach integrating clinical, serological, imaging and histopathology data as well as ultrastructural analyses, we show here that previous vaccination has no impact on lung function, bronchiolitis or the detection of autoantibodies or residual virus in a previously healthy cohort of 99 PASC patients after mild COVID-19. While a higher frequency of ground glass opacities in unvaccinated patients might be due to the longer interval between infection and consultation, the observed fibrotic remodeling should prompt further investigation of a possible pro-fibrotic role of SARS-CoV-2 infection in the lung.

BackgroundFractional exhaled nitric oxide (FeNO) is used to differentiate asthma inflammatory phenotypes and guide its management. However, data on FeNO reference values in a representative adult population is limited. ObjectiveTo derive reference values and determinants of FeNO in a representative adult population. MethodsThe West Sweden Asthma Study is a clinical-epidemiological population- representative study of randomly selected adults in Western Sweden. From this cohort, 943 subjects participated in comprehensive clinical investigations, including skin prick testing (SPT), specific immunoglobulin E (sIgE) analysis, and FeNO measurement. Clinical allergy was defined as co-occurrence of atopy (positivity to SPT or sIgE) and self-reported allergic symptoms to the same allergen family. FeNO levels were analysed in relation to the presence or absence of clinical allergy, asthma, and other factors. ResultsThe 95th percentile of FeNO ranged from 34 to 52 parts per billion (ppb) in the entire sample (N=943), and from 26 to 37 ppb among individuals without clinical allergy, asthma, or chronic obstructive pulmonary disease (COPD) (n=587), depending on age. Sex, smoking, clinical allergy, atopy, asthma, and hypertension influenced FeNO levels, meanwhile, age, asthma, clinical allergy, and reversibility- related variables were significant determinants of FeNO levels. ConclusionThe 95th percentile (upper normal limit) for FeNO ranges from 34 to 52 ppb overall, and from 26 to 37 ppb in those without clinical allergy, asthma, or COPD, depending on age. These findings provide a guide for interpreting FeNO in the general population and in asthma and COPD clinics.

RationaleAsthma and Chronic Obstructive Pulmonary Disease (COPD) are the two main chronic airway inflammatory diseases related to aging. Cellular aging is prevented by telomeres and their shortening induces cellular senescence. Human Telomerase Reverse Transcriptase Enzyme (hTERT) can act directly on DNA and prevent telomere shortening. The goal of this study was to assess hTERT expression in the bronchial mucosa of patients suffering from chronic airway obstructive diseases and to relate the hTERT expression to demographics and lung function characteristics. MethodsWe collected bronchial biopsies from 38 patients suffering from chronic airway diseases including 21 severe asthmatics and 17 COPD who underwent bronchoscopy in routine practice. hTERT expression was assessed by immunochemistry and co-immunostaining was performed to identify hTERT positive cells within the different immune cell populations. ResultshTERT expression in airway mucosa was essentially found in structural cells. Among leukocytes, lymphocytes were the principal cells expressing hTERT. On the whole cohort, hTERT expression score was not different between men and women and not influenced by the age nor by the smoking history as reflected by the pack years. Total airway hTERT positive staining score positively correlated with post-bronchodilation (post-BD) FEV1 % predicted and FEV1/FVC. (r=0.38, p<0.05 for both). hTERT+ lymphocytes were also positively correlated to post-BD FEV1/FVC (r=0.37, p<0.05). Consequently, hTERT expression was lower in those patients with fixed airway obstruction (post-BD FEV1/FVC < 70%). There was no difference between asthmatics and COPD. ConclusionsIn patients with chronic airway diseases, total and lymphocyte hTERT expressions inversely correlate with the degree of airway obstruction and are reduced in patients with fixed airway obstruction, which supports a role of hTERT in airway remodeling.

Whether smoking exacerbates Coronavirus disease 2019 is still debated. Ex-vivo Infection of reconstituted epithelial tissues from smoker versus non-smoker donors suggested comparable susceptibility to SARS-CoV-2 in epithelia from both groups.

Therapeutic bacteriophages are promising alternatives to antibiotics for treating antimicrobial-resistant bacterial infections. For pulmonary infections, direct respiratory delivery offers therapeutic advantages; however, preclinical evaluation of respiratory safety remains underdeveloped. Bacteriophages exhibit genomic and biological diversity, and safety cannot be assumed for individual candidates. Here, we evaluated the respiratory safety of lytic Staphylococcus aureus bacteriophages, Koomba kaat 1 and Biyabeda mokiny 1, using human and murine preclinical models. Differentiated primary airway epithelial cells derived from six healthy paediatric donors were exposed apically to purified phage (1 x 109 PFU/mL) for 24 hours. Barrier integrity, epithelial morphology, mucus production, cytotoxicity, and interleukin-8 release were assessed. Safety was further investigated in adult C57BL/6J mice receiving intranasal phage administration (1 x 109 PFU) twice daily (14 days). Clinical observations, body weight, organ pathology, blood biochemistry, bronchoalveolar lavage cellularity, protein concentration, and inflammatory mediators were evaluated. Neither phage altered epithelial morphology, barrier integrity, mucus production, cytotoxicity, nor inflammatory responses in differentiated cultures. Repeated intranasal administration was well tolerated in vivo, with no adverse clinical signs, weight loss, macroscopic pathology, or treatment-associated changes in pulmonary cellularity or tissue histopathology. Differences in blood biochemistry and inflammatory mediators were small and not accompanied by epithelial injury or pulmonary inflammation. Collectively, these findings demonstrate that Koomba kaat 1 and Biyabeda mokiny 1 exhibit favourable safety profiles following repeated airway administration. This study establishes a comprehensive framework for the preclinical respiratory safety assessment of bacteriophages and provides support for the clinical development of inhaled phage for S. aureus respiratory infections.

In a normal year, the fatal lung disease Idiopathic Pulmonary Fibrosis (IPF) accounts for [~]1% of UK deaths. Smoking is a recognised risk factor for IPF but the question of causality remains unanswered. Here, we used data from the UK Biobank (UKBB) and the well-established genetic technique of Mendelian randomisation (MR) methods to investigate whether smoking is causal for IPF compared with COPD, where causality is established. We looked at observational associations in unrelated Europeans, with 871 IPF cases, 11,413 COPD cases and 366,942 controls. We performed analyses using one-sample MR to test for inferred smoking causality in ever smokers using genetic variants that have a previously demonstrated association with smoking heaviness. Strong associations between disease status and ever having smoked were found in both IPF (OR = 1.52; 95%CI:1.32-1.74; P=2.4x10-8) and COPD (OR= 5.77; 95%CI:5.48-6.07; P<1x10-15). Using MR, a one allele increase in smoking volume genetic risk score was associated with higher odds of COPD in ever smokers, (OR = 4.32; 95%CI:3.37-5.54; P<1x10-15), but no association was seen in IPF (OR=0.55; 95%CI: 0.17-1.81; P=0.33). No association was found between the genetic risk score and disease prevalence in never smokers with IPF (OR = 1.00; 95%CI:0.98-1.02; P=1.00) or COPD (OR = 1.00; 95%CI:0.99-1.01; P=0.53). Although both IPF and COPD are observationally associated with smoking, our analysis provides evidence inferring that the association is causal in COPD but there is no such evidence in IPF. This suggests that other environmental exposures also need consideration in IPF.