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.

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.

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.

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.

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.

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.

BackgroundLong Covid remains a relatively new phenomenon with emerging understanding. Estimated UK prevalence of Long Covid with three or more symptoms lasting for 12 weeks or more was 2.2% at the end of 2021. The population-based French SAPRIS-SERO cohort has novel information about the pattern of symptoms of Long Covid that has been obscured by controversy around the original paper. MethodsSecondary analysis was used to describe and re-interpret the frequencies of persistent symptoms by IgG seropositivity and self-reported Long Covid in the published report of the SAPRIS-SERO survey. Participants in the cross-sectional analysis were 26 823 individuals from the French population-based CONSTANCES cohort, included between 2012 and 2019, who took part in the nested SAPRIS and SAPRIS-SERO surveys. Between May and November 2020, the Euroimmun enzyme-linked immunosorbent assay was used to detect anti-SARS-CoV-2 antibodies. Surveyed online between December 2020 and January 2021, participants self-reported previous COVID-19 infection and physical symptoms during the previous four weeks that were new since March 2020, and had persisted for at least eight weeks. ResultsThere was similarity of prevalence over the majority of symptoms in those self-reporting COVID-19 infection, regardless of blood test result. Persistent symptoms significantly associated with self-reported COVID-19 infection and common in both groups include respiratory tract symptoms and a group of symptoms that might be related to chronic fatigue, malaise or postural issues. Seropositivity for IgG antibodies did not predict symptoms independently of self-reported Long Covid, except for anosmia. ConclusionsThere may be three common sub-syndromes of Long Covid, one with persistent anosmia, another with other respiratory tract symptoms and a third, currently under researched, with symptoms relatable to chronic fatigue. Antibody tests are insufficient for case detection while Long Covid remains poorly understood. Key MessagesO_LIIgG seropositivity is insufficient to identify potential cases of Long Covid C_LIO_LIPersistent anosmia is very strongly associated with IgG seropositivity and may define a subsyndrome of Long Covid C_LIO_LIOther potential subsyndromes are those with persistent respiratory symptoms and those with persistent symptoms relatable to fatigue, malaise or postural issues C_LIO_LIThe Long Covid research effort should be rebalanced towards understanding the fatigue/tiredness subsyndrome. C_LI

BackgroundFatigue, breathlessness and cough are prevalent symptoms of Interstitial Lung Disease (ILD) adversely impacting quality-of-life and contributing to psychological distress. The Fatigue and Breathlessness (FAB) programme facilitates supported self-management for people living with life-limiting conditions such as cancer. We explore its utility when adapted for people living with ILD. MethodsThe 4-week ILD-FAB programme offers each group of up to 6 participants weekly two-hour sessions led by an ILD-specialist Physiotherapist and Clinical Nurse Specialist (CNS). Primary focus is on strategies to manage breathlessness, fatigue and wellbeing. Further, a 1:1 session with the ILD-CNS enables participants to set personalised goals and explore individual health beliefs/behaviours using a Cognitive Behavioural Therapy (CBT) assessment framework. The self-reporting Chronic Respiratory Questionnaire (CRQ-SR) evaluates breathlessness, fatigue, emotional function and mastery at baseline and after 4 weeks. We facilitated eleven groups between March 2023 and December 2024. ResultsForty-nine participants (26 male; median age 76 years [IQR=14]) were diagnosed with Idiopathic Pulmonary Fibrosis/IPF (n=21), Progressive Pulmonary Fibrosis/PPF (n=17) or non-progressive ILD (n=11) of various aetiologies. Lung function indicated a range of disease severity (FVC % predicted median: 70% [IQR=34]) Thirty-seven (76%) participants attended all four sessions, 6 (12%) attended three sessions, 2 (4%) attended two sessions and 4 (8%) attended one session. Thirty-seven patients, all who attended at least 3 sessions, completed the CRQ-SR at baseline and Week 4. Fifty-nine percent of respondents (n=22) demonstrated clinically significant improvements in dyspnoea scores, 51% (n=19) in emotional functioning scores and 49% (n=18) in fatigue and mastery scores. Thirty-five respondents (95%) demonstrated a clinically significant improvement in at least one domain. All participants (100%) would recommend this programme to others. ConclusionThese data demonstrate feasibility, acceptability and clinical effectiveness of an ILD-specific FAB programme. Further research will explore a range of outcome measures longitudinally in a larger cohort. Key MessagesO_LIWhat is already known on this topic -The FAB programme is delivered in hospices and NHS trusts UK-wide to improve confidence in fatigue and breathlessness management and reduce anxiety for people living with life-limiting illnesses such as cancer. Formal evaluations are positive but limited by small sample sizes and the use of non-validated outcome measures. C_LIO_LIWhat this study adds -Our FAB programme, adapted for people with ILD, is feasible, acceptable and clinically effective. C_LIO_LIHow this study might affect research, practice or policy - The FAB programme offers one multimodal approach to improving self-management in people with ILD. Further research in a larger, more heterogeneous patient population will optimise outcome measures, broaden acceptability and determine cost-effectiveness. C_LI

ObjectivesLong COVID, defined as diverse symptoms persisting >3 months post-infection, remains a major post-pandemic healthcare burden. Here we investigate risk factor posed by pre-existing respiratory symptoms and illnesses for development of long COVID, with focus on individuals with mild-to-moderate COVID-19 at the primary infection, that did not require hospitalization during the primary SARS-CoV-2 infection. MethodsThis case-control study was designed to investigate the prevalence of respiratory system-related diagnoses in adult, non-hospitalized long COVID patients (cases) compared to matched controls without a history of long COVID. Data was extracted from the Stockholm Regions database (VAL) and included diagnoses 12 months pre- and 6 months post-long COVID diagnosis as well as pre-pandemic diagnoses (year 2019). Adjusted logistic regression models were applied. ResultsPatients with Long COVID displayed higher frequencies of pre-pandemic respiratory conditions (year 2019) as well as 12 months before long COVID diagnosis compared to controls, including acute upper respiratory tract infections (men: Odds ratio (OR) 2.47, women: OR 2.22), asthma (men: OR 1.76, women: OR 1.95), and bronchitis (men: OR 2.15, women: OR 2.71). ORs for asthma were the highest 12 months before long COVID diagnosis (men: OR 4.18, women: OR 3.76). ConclusionPatients with Long COVID with a mild-to-moderate primary SARS-CoV-2 infection had higher prevalence of pre-existing respiratory conditions than controls, suggesting that respiratory diseases including asthma were a significant risk factor for long COVID also in the non-hospitalized population. Understanding the link between chronic respiratory illnesses and long COVID is vital for refining clinical strategies and improving outcomes in post-viral conditions. Key take-home messagePre-pandemic respiratory diagnoses, including asthma, as well as female sex represent significant risk factors for developing long COVID in individuals with a mild-to-moderate primary SARS-CoV-2 infection not requiring hositalization.

Mucociliary clearance is a key component of the pathophysiology of bronchiectasis but cilia function is poorly defined. This study aims to characterize nasal ciliary function in bronchiectasis and examine associations with disease severity, infection, inflammation and outcome. Adults with bronchiectasis and healthy volunteers were recruited to the international observational study EMBARC-BRIDGE. Individuals with a known diagnosis of Primary Ciliary Dyskinesia (PCD) were excluded. Nasal respiratory epithelium was sampled by brush biopsy. Ciliary function was assessed by high-speed video microscopy in primary samples and following re-differentiation in air-liquid interface (ALI) culture. Ciliary parameters (cilia length, angle, amplitude, clearance, frequency and ciliation) were quantified and compared with disease severity, microbiology, inflammation and future risk of exacerbations. 171 participants with bronchiectasis were recruited (54% female, age 68years (59-74)). Bronchiectasis nasal brushings showed greater epithelial disruption compared to healthy volunteers (p=0.0006). Six individuals with previously undiagnosed PCD were identified and excluded. In the remaining bronchiectasis cohort, ciliary beat frequency and length were similar to healthy controls. In contrast ciliary beat amplitude, angle, amplitude per second and clearance capacity, were significantly reduced (all p<0.001). These parameters were restored following ALI culture. Regenerated epithelia from bronchiectasis donors exhibited reduced ciliated area. Ciliary dysfunction was strongly associated with future risk of severe exacerbations. The upper airway epithelium is disrupted in bronchiectasis; ciliary movement is impaired and is associated with future risk of exacerbation. Ciliary dysmotility is reversible following ALI culture. This indicates that impaired ciliary function is secondary to the airway environment and therapeutically targetable.

BackgroundA significant proportion of patients experience prolonged pulmonary, cardiocirculatory or neuropsychiatric symptoms after Coronavirus disease 2019 (COVID-19), termed post-acute sequelae of COVID (PASC). Lung manifestations of PASC include cough, dyspnea on exertion and persistent radiologic abnormalities and have been linked to viral persistence, ongoing inflammation and immune dysregulation. So far, there is limited data on lung histopathology and tissue-based immune cell subtyping in PASC. Methods51 unvaccinated patients (median age, 40 years; 43% female) with a median of 17 weeks (range, 2-55 weeks) after mild SARS-CoV-2 infection (without hospitalization) underwent full clinical evaluation including high-resolution computed tomography (HR-CT) and transbronchial biopsy. We used RT-PCR/FISH and immunohistochemistry (nucleocapsid/spike/CD3/CD4/CD8) for residual SARS-CoV-2 detection and T lymphocyte subtyping, respectively. We assessed interstitial fibrosis and macrophage profiles by transmission electron microscopy (TEM) and immunofluorescence multiplex staining, while cytokine profiling in bronchoalveolar lavage (BAL) fluid was performed by legendplex immunoassay. ResultsDyspnea on exertion was the leading symptom of pulmonary PASC in our cohort. In 16% and 42.9% of patients, FEV1 and MEF50 were [&le;] 80% and 35.3% showed low attenuation volume (LAV) in >5% of lung area, in line with airflow obstruction. There was a significant correlation between oxygen pulse and time since COVID (p=0.009). Histopathologically, PASC manifested as organizing pneumonia (OP), fibrinous alveolitis and increased CD4+ T cell infiltrate predominantly around airways (bronchiolitis), while the residual virus components were detectable in only a single PASC patient (2%). T cell infiltrates around small airways were inversely correlated with time since COVID, however, this trend failed to reach statistical significance. We identified discrete interstitial fibrosis and a pro-fibrotic macrophage subtype (CD68/CD163/S100A9) as well as significantly elevated interleukin 1{beta} in BAL fluid from PASC patients (p=0.01), but H-scores for fibrotic macrophage population did not correlate with severity of clinical symptoms or T cell infiltration. InterpretationWe show decreased FEV1/MEF50 and increased LAV in line with obstructive lung disease due to CD4+ T cell-predominant bronchiolitis as well as evidence of pro-fibrotic signaling in a subset of unvaccinated PASC patients. Since our results point towards self-limiting inflammation of small airways without detectable viral reservoirs, it remains unclear whether pulmonary symptoms in PASC are SARS-CoV-2-specific or represent a general response to viral infection. Still, evidence of pro-fibrotic signaling should warrant clincal follow-up and further research into possible long-time fibrotic remodeling in PASC patients. Key pointsO_LIDyspnea on exertion is the leading clinical manifestation of PASC in the lung C_LIO_LIa minority of pts have significantly impaired lung function (FVC/TLC[&le;]80% or DLCO[&le;]70%) in spiroergometry and/or radiologic abnormalities, oxygen pulse seems to normalize over time O_LI16% and 42.9% of pts have FEV1 and MEF50[&le;]80% and 35.3% have LAV>5% of lung area, in line with airflow obstruction due to bronchiolitis C_LI C_LIO_LIResidual virus was not detectable in the lung tissue of all but one PASC patient (2%) C_LIO_LIHistologically, PASC may manifest as T cell-mediated bronchiolitis, OP and fibrinous alveolitis C_LIO_LIThere is evidence of fibrotic remodeling (ultrastructural interstitial fibrosis, pro-fibrotic macrophage subpopulation, pro-fibrotic cytokine IL-1{beta} in BAL) but this did not correlate with the degree of T cell infiltrate/bronchiolitis C_LI

RationaleEmphysema is defined by progressive alveolar destruction and impaired tissue repair, with diminished Wnt/{beta}-catenin signaling implicated in its pathogenesis. Preclinical studies suggest that lithium, a pharmacologic activator of Wnt/{beta}-catenin signaling, may attenuate emphysema. However, its effects in humans remain unknown. ObjectivesTo investigate whether individuals using lithium for neuropsychiatric conditions have reduced susceptibility to emphysema compared to users of other neuropsychiatric medications. MethodsWe analyzed cross-sectional data from two large cohorts - the UK Biobank and COPDGene - comprising over 800 individuals using oral lithium. Lithium users were compared to individuals using other neuropsychiatric medications. In the UK Biobank, outcomes included spirometry and self-reported physician-diagnosed emphysema. In COPDGene, outcomes included spirometry and quantitative CT measures of emphysema. Multivariable regression and propensity score matching accounted for demographics, smoking history, and psychiatric diagnoses. Measurements and Main ResultsIn the UK Biobank, lithium use was associated with higher FEV and FVC (% predicted) and [~]50% lower adjusted odds of emphysema diagnosis. In COPDGene, lithium users exhibited significantly higher FEV, FVC, and FEV/FVC ratios, lower CT-measured emphysema (%LAA-950), and higher lung density. These associations persisted after multivariable adjustment and across sensitivity analyses. ConclusionsLithium use is associated with less emphysema in two independent cohorts. These findings align with preclinical evidence supporting Wnt/{beta}-catenin activation as a protective mechanism and warrant further investigation of lithium and related agents as potential therapies for emphysema.

BackgroundClinical practice guidelines for asthma diagnosis are rarely evaluated in real-life practice. Within the Swiss Paediatric Airway Cohort (SPAC), we initiated the SPAC-asthma project to develop a standardised diagnostic approach for school-aged asthma, based on the algorithm recommended by the European Respiratory Society (ERS) guideline. Here, we report the development and feasibility of this approach after implementation across multiple paediatric pulmonology clinics. MethodWe used a modified Delphi process with paediatric pulmonologists from participating clinics to tailor the ERS algorithm for feasible implementation in children aged 5-17 years with suspected asthma. Key adaptations included selection of initial tests, criteria for further testing, test cutoffs, the role of medication trial and follow-up procedures. One year after implementation, we evaluated adherence to the adapted approach at four clinics and explored the reasons for any deviations. ResultsThe final SPAC-asthma approach included spirometry, fractional exhaled nitric oxide and allergy testing as initial tests, followed by either bronchodilator reversibility testing, bronchial challenge test or medication trial. Overall adherence after one year was 77% (182/236 patients). Deviations were due to practice-related (e.g., different criteria for bronchial obstruction), patient-related (e.g., inability to perform spirometry), and logistical reasons (e.g., scheduling difficulties). ConclusionThe diagnostic approach was well implemented, but the observed deviations highlighted the need for flexibility when applying guidelines in real-world settings. As a next step, we will assess whether implementing the ERS asthma guidelines in school-aged children improves diagnostic accuracy. Take home messageWe tested a standardised ERS guideline-based approach to diagnose school-age asthma across Swiss paediatric pulmonology clinics. After expert adaptation and a year, adherence was good and we identified areas to improve guideline implementation.

BackgroundThe imposition of restrictions on social mixing early in the COVID-19 pandemic was followed by a reduction in asthma exacerbations in multiple settings internationally. Temporal trends in social mixing, incident acute respiratory infections (ARI) and asthma exacerbations following relaxation of COVID-19 restrictions have not yet been described. MethodsWe conducted a population-based longitudinal study in 2,312 UK adults with asthma between November 2020 and April 2022. Details of face covering use, social mixing, incident ARI and moderate/severe asthma exacerbations were collected via monthly on-line questionnaires. Temporal changes in these parameters were visualised using Poisson generalised additive models. Multilevel logistic regression was used to test for associations between incident ARI and risk of asthma exacerbations, adjusting for potential confounders. ResultsRelaxation of COVID-19 restrictions from April 2021 coincided with reduced face covering use (p<0.001), increased frequency of indoor visits to public places and other households (p<0.001) and rising incidence of COVID-19 (p<0.001), non-COVID-19 ARI (p<0.001) and moderate/severe asthma exacerbations (p=0.007). Incident non-COVID-19 ARI associated independently with increased risk of asthma exacerbation (adjusted odds ratio 5.75, 95% CI 4.75 to 6.97) as did incident COVID-19, both prior to emergence of the omicron variant of SARS-CoV-2 (5.89, 3.45 to 10.04) and subsequently (5.69, 3.89 to 8.31). ConclusionsRelaxation of COVID-19 restrictions coincided with decreased face covering use, increased social mixing and a rebound in ARI and asthma exacerbations. Associations between incident ARI and risk of moderate/severe asthma exacerbation were similar for non-COVID-19 ARI and COVID-19, both before and after emergence of the SARS-CoV-2 omicron variant. FundingBarts Charity, UKRI

Background Scalable, non invasive tools are critically needed to improve early lung cancer detection and optimize primary care referral pathways. We evaluated Inflammacheck, a point-of-care device utilizing exhaled breath condensate (EBC) H2O2 and physiological parameters with machine learning, for non-invasive lung cancer detection in a real-world screening population. Methods ExPeL study participants, from the UK Targeted Lung Health Check (TLHC) programme, included individuals with suspected lung cancer and low-risk ever-smoker controls. EBC was collected via Inflammacheck, measuring H2O2;, end-tidal CO2;, humidity, temperature, and exhalation flow rate. Multivariate analyses (PCA, LDA, Mahalanobis distance) assessed intrinsic group separation. SMOTE-balanced data trained supervised machine learning models (stacked and voting ensembles), which were then evaluated on held-out test sets. In parallel, untargeted LCMS metabolomics was performed to identify discriminatory molecular features. Results Analysing 34 participants with valid EBC data, 83% of cancer cases were early-stage (I or II), reflecting a screening population. Multivariate analysis clearly separated lung cancer and controls across PCA, LDA, and Mahalanobis mapping. The voting ensemble model achieved: Accuracy 85.7%, Sensitivity 80%, Specificity 100%, Precision (PPV) 100%, ROC AUC 0.90, MCC 0.73. Crucially, no false positives were identified. EBC variables revealed greater dispersion in cancer patients, reflecting physiological heterogeneity missed by univariate analysis. Untargeted metabolomics identified 2,132 features, with four key metabolites yielding an AUC of 0.969 for cancer discrimination. Discussion Inflammacheck effectively distinguishes early-stage lung cancer via a rapid, non-invasive breath test, findings which are highly relevant for primary care and screening triage, where non-specific symptoms and low prevalence pose challenges.

IntroductionWork-related asthma (WRA) is prevalent yet under-recognized in UK primary care. The aim of this systematic review was to identify behaviour change interventions (BCI) intended for use in a primary care setting to identify any chronic disease, that may be used in the context of WRA. The study was registered on the PROPSPERO database (19/04/2023; CRD42023418316) and received no funding. MethodsWe searched CCRCT, Embase, PsychINFO and Ovid MEDLINE databases (1st January 1946 - 6th March 2023) for any observational or experimental study which described the development or evaluation (or both) of a BCI for case finding any chronic disease in a primary care setting, aimed at either healthcare professionals or patients or both. We included case reports, series and conference abstracts, and excluded existing reviews and protocols, and abstracts not in English. Abstracts and subsequent full text articles were assessed by two blinded, independent reviewers, and disagreement resolved by consensus. The primary author undertook quality assessments for a variety of methodologies, with quality control by a second reviewer. We undertook narrative synthesis for a variety of outcomes of usability and effectiveness, and for BCI development. Results18 studies (14 papers and 4 conference abstracts) were included following full-text review, from an initial literature search yielding n=768 citations for screening, of which there were 3 randomised control trials, 1 uncontrolled experimental study, 4 primarily qualitative studies and 10 studies employing recognized multi-step BC methodologies. Quality varied depending upon the methodology used. None of the studies were concerned with identification of asthma. BCIs had been developed for facilitating screening programmes (5), implementing guidelines (5) and individual case finding (8). Six studies measured effectiveness, in terms of screening adherence rates, pre- and post-intervention competency, satisfaction and usability, for clinicians, though none measured diagnostic rates. DiscussionSingle and multi-component BCIs have been developed to aid identification of chronic diseases, though not asthma or work-related asthma specifically. Development for the majority has used BC methodologies that involve gathering data from a range of sources, and develop content specific to defined at-risk populations. Nevertheless, such methodologies could be used similarly to develop a BCI for WRA in primary care settings.

BackgroundTracheostomies in children are associated with significant morbidity, poor quality of life, excess healthcare costs, and excess mortality. The underlying mechanisms facilitating adverse outcomes in tracheostomised children are poorly understood. We aimed to characterise airway host defence in tracheostomised children using serial molecular analyses. MethodsTracheal aspirates, tracheal cytology brushings, nasal swabs and stool samples were prospectively collected from children with a tracheostomy and controls. Transcriptomic, proteomic, and metabolomic methods were applied to characterise the impact of tracheostomy on host immune response and the airway microbiome. ResultsChildren followed up serially from the time of tracheostomy up to three months post-procedure (n=9) were studied. A validation cohort of children with a long-term tracheostomy was also enrolled (n=24). Controls (n=13) comprised children without a tracheostomy undergoing bronchoscopy. Tracheostomy was associated with new, rapidly emergent and sustained airway neutrophilic inflammation, superoxide production and evidence of proteolysis when compared with controls. In contrast, reduced airway microbial diversity was established pre-tracheostomy and sustained thereafter. ConclusionsChildhood tracheostomy is associated with rapidly emergent and persistent airway neutrophil recruitment and activation, with sustained proteolysis and superoxide generation. These findings suggest neutrophil recruitment and activation as potential exploratory targets in seeking to prevent recurrent airway complications in this vulnerable group of patients. Key messageThe effect tracheostomy has on children is not described. Tracheostomy in children results in persistent local airway neutrophilic inflammation, proteolysis, superoxide production and dysbiosis.

BackgroundAcute COVID-19 clinical symptoms have been clearly documented, but long-term functional and symptomatic recovery from COVID -19 is less well described. MethodsA systematic review and meta-analysis were conducted to describe patient-reported outcome measures (PROMs) in adults at least 8 weeks post hospital discharge for COVID-19. Comprehensive database searches in accordance with the PRISMA statement were carried out up till 31/05/2021. Data were narratively synthesized, and a series of meta-analyses were performed using the random-effects inverse variance method. ResultsFrom 49 studies, across 14 countries with between 2-12 months follow up, the most common persisting symptom reported was fatigue with meta-analysis finding 36.6% (95 % CI 27.6 to 46.6, n=14) reporting it at 2-4 months, decreasing slightly to 32.5% still reporting it at >4 months (95% CI 22.6 to 44.2, n=15). This was followed by dyspnoea. Modified MRC score (mMRC) [&ge;]1 was reported in 48% (95% CI 30 to 37, n=5) at 2-4months reducing to 32% (95% CI 22 to 43, n=7) at 4 months. Quality of life (QOL) as assessed by the EQ-5D-5L VAS remained reduced at >4 months (73.6 95% CI 68.1 to 79.1, n=6). Hospitalisation with COVID-19 also resulted in persisting sick leave, change in scope of work, and continued use of primary and secondary healthcare. ConclusionThe symptomatic and functional impact of COVID-19 continues to be felt by patients months after discharge from hospital. This widespread morbidity points towards a multi-disciplinary approach to aid functional recovery.