Cluster randomised controlled trial of specialist-led integrated COPD care (INTEGR COPD).

OBJECTIVE: Studies in hospital settings demonstrate that there is greater guideline adherence when care is delivered by a respiratory specialist, however, this has not been explored in primary care. The aim of this study is to determine the impact integrating respiratory specialists into primary care has on the delivery of guideline adherent chronic obstructive pulmonary disease (COPD) care. METHODS: 18 general practitioner (GP) practices were randomised to provide either usual or specialist-led COPD care. Patients at participating practices were included if they had an existing diagnosis of COPD. Outcomes were measured at the individual patient level. The primary outcome was guideline adherence, assessed as achieving four or more items of the COPD care bundle. Secondary outcome measures included quality of life, number of exacerbations, number of COPD-related hospitalisations and respiratory outpatient attendances. RESULTS: 586 patients from 10 practices randomised to the intervention and 656 patients from 8 practices randomised to the control arm of the study were included. The integration of respiratory specialists into GP practices led to a statistically significant (p<0.001) improvement in the provision of guideline adherent care when compared with usual care in this cohort (92.7% vs 70.1%) (OR 4.14, 95% CI 2.14 to 8.03). CONCLUSION: This is the first study to demonstrate that guideline adherence is improved through the integration of respiratory specialists into GP practices to deliver annual COPD reviews. To facilitate changes in current healthcare practice and policy, the findings of this paper need to be viewed in combination with qualitative research exploring the acceptability of specialist integration. TRIAL REGISTRATION NUMBER: NCT03482700.

Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ).

BACKGROUND & AIMS: α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. METHODS: Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. RESULTS: Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. CONCLUSIONS: The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.

Risk of lung disease in the PI*SS genotype of alpha-1 antitrypsin: an EARCO research project.

BACKGROUND: The PI*S variant is one of the most prevalent mutations within alpha-1 antitrypsin deficiency (AATD). The risk of developing AATD-related lung disease in individuals with the PI*SS genotype is poorly defined despite its substantial prevalence. Our study aimed to characterize this genotype and its risk for lung disease and compare it with the PI*ZZ and PI*SZ genotypes using data from the European Alpha-1 antitrypsin Deficiency Research Collaboration international registry. METHOD: Demographic, clinical, functional, and quality of life (QoL) parameters were assessed to compare the PI*SS characteristics with the PI*SZ and PI*ZZ controls. A propensity score with 1:3 nearest-neighbour matching was performed for the most important confounding variables. RESULTS: The study included 1007 individuals, with PI*SS (n = 56; 5.6%), PI*ZZ (n = 578; 57.4%) and PI*SZ (n = 373; 37.0%). The PI*SS population consisted of 58.9% men, with a mean age of 59.2 years and a mean FEV1(% predicted) of 83.4%. Compared to PI*ZZ individuals they had less frequent lung disease (71.4% vs. 82.2%, p = 0.037), COPD (41.4% vs. 60%, p = 0.002), and emphysema (23.2% vs. 51.9%, p < 0.001) and better preserved lung function, fewer exacerbations, lower level of dyspnoea, and better QoL. In contrast, no significant differences were found in the prevalence of lung diseases between PI*SS and PI*SZ, or lung function parameters, exacerbations, dyspnoea, or QoL. CONCLUSIONS: We found that, as expected, the risk of lung disease associated with the PI*SS genotype is significantly lower compared with PI*ZZ, but does not differ from that observed in PI*SZ individuals, despite having higher serum AAT levels. TRIAL REGISTRATION: www. CLINICALTRIALS: gov (ID: NCT04180319).

Alcohol consumption and liver phenotype of individuals with alpha-1 antitrypsin deficiency.

BACKGROUND AND AIMS: Alpha-1 antitrypsin deficiency is an inherited disorder caused by alpha-1 antitrypsin (AAT) mutations. We analysed the association between alcohol intake and liver-related parameters in individuals with the heterozygous/homozygous Pi*Z AAT variant (Pi*MZ/Pi*ZZ genotype) found in the United Kingdom Biobank and the European Alpha1 liver consortium. METHODS: Reported alcohol consumption was evaluated in two cohorts: (i) the community-based United Kingdom Biobank (17 145 Pi*MZ, 141 Pi*ZZ subjects, and 425 002 non-carriers [Pi*MM]); and (ii) the European Alpha1 liver consortium (561 Pi*ZZ individuals). Cohort (ii) included measurements of carbohydrate-deficient transferrin (CDT). RESULTS: In both cohorts, no/low alcohol intake was reported by >80% of individuals, while harmful consumption was rare (~1%). Among Pi*MM and Pi*MZ individuals from cohort (i), moderate alcohol consumption resulted in a <30% increased rate of elevated transaminases and ~50% increase in elevated gamma-glutamyl transferase values, while harmful alcohol intake led to an at least twofold increase in the abnormal levels. In Pi*ZZ individuals from both cohorts, moderate alcohol consumption had no marked impact on serum transaminase levels. Among Pi*ZZ subjects from cohort (ii) who reported no/low alcohol consumption, those with increased CDT levels more often had signs of advanced liver disease. CONCLUSIONS: Pi*MZ/Pi*ZZ genotype does not seem to markedly aggravate the hepatic toxicity of moderate alcohol consumption. CDT values might be helpful to detect alcohol consumption in those with advanced fibrosis. More data are needed to evaluate the impact of harmful alcohol consumption.

Immersive virtual reality as a novel approach to investigate the association between adverse events and adolescent paranoid ideation.

PURPOSE: Paranoid ideation is common among adolescents, yet little is known about the precursors. Using a novel immersive virtual reality (VR) paradigm, we tested whether experiences of bullying, and other interpersonal/threatening events, are associated with paranoid ideation to a greater degree than other types of (i) non-interpersonal events or (ii) adverse childhood experiences. METHODS: Self-reported exposure to adverse life events and bullying was collected on 481 adolescents, aged 11-15. We used mixed effects (multilevel) linear regression to estimate the magnitude of associations between risk factors and paranoid ideation, assessed by means of adolescents' reactions to ambiguously behaving avatars in a VR school canteen, adjusting for putative confounders (gender, year group, ethnicity, free school meal status, place of birth, family mental health problems). RESULTS: Lifetime exposure to interpersonal/threatening events, but not non-interpersonal events or adverse circumstances, was associated with higher levels of state paranoid ideation, with further evidence that the effect was cumulative (1 type: ϐadj 0.07, 95% CI -0.01-0.14; 2 types: ϐadj 0.14, 95% CI 0.05-0.24; 3 + types: ϐadj 0.24, 95% CI 0.12-0.36). More tentatively, for girls, but not boys, recent bullying was associated with heightened paranoid ideation with effect estimates ranging from ϐadj 0.06 (95% CI -0.02-0.15) for physical bullying to ϐadj 0.21 (95% CI 0.10-0.32) for cyber bullying. CONCLUSIONS: Our data suggest a degree of specificity for adversities involving interpersonal threat or hostility, i.e. those that involve unwanted interference and/or attempted control of an individual's personal boundaries being associated with heightened levels of state paranoid ideation among adolescents.

Engaging stakeholders to level up COPD care in LMICs: lessons learned from the "Breathe Well" programme in Brazil, China, Georgia, and North Macedonia.

BACKGROUND: Effective stakeholder engagement in health research is increasingly being recognised and promoted as an important pathway to closing the gap between knowledge production and its use in health systems. However, little is known about its process and impacts, particularly in low-and middle-income countries. This opinion piece draws on the stakeholder engagement experiences from a global health research programme on Chronic Obstructive Pulmonary Disease (COPD) led by clinician researchers in Brazil, China, Georgia and North Macedonia, and presents the process, outcomes and lessons learned. MAIN BODY: Each country team was supported with an overarching engagement protocol and mentored to develop a tailored plan. Patient involvement in research was previously limited in all countries, requiring intensive efforts through personal communication, meetings, advisory groups and social media. Accredited training programmes were effective incentives for participation from healthcare providers; and aligning research findings with competing policy priorities enabled interest and dialogue with decision-makers. The COVID-19 pandemic severely limited possibilities for planned engagement, although remote methods were used where possible. Planned and persistent engagement contributed to shared knowledge and commitment to change, including raised patient and public awareness about COPD, improved skills and practice of healthcare providers, increased interest and support from clinical leaders, and dialogue for integrating COPD services into national policy and practice. CONCLUSION: Stakeholder engagement enabled relevant local actors to produce and utilise knowledge for small wins such as improving day-to-day practice and for long-term goals of equitable access to COPD care. For it to be successful and sustained, stakeholder engagement needs to be valued and integrated throughout the research and knowledge generation process, complete with dedicated resources, contextualised and flexible planning, and commitment.

The P2X3 receptor antagonist filapixant in patients with refractory chronic cough: a randomized controlled trial.

BACKGROUND: P2X3 receptor antagonists seem to have a promising potential for treating patients with refractory chronic cough. In this double-blind, randomized, placebo-controlled study, we investigated the efficacy, safety, and tolerability of the novel selective P2X3 receptor antagonist filapixant (BAY1902607) in patients with refractory chronic cough. METHODS: Following a crossover design, 23 patients with refractory chronic cough (age: 60.4 ± 9.1 years) received ascending doses of filapixant in one period (20, 80, 150, and 250 mg, twice daily, 4-days-on/3-days-off) and placebo in the other. The primary efficacy endpoint was the 24-h cough frequency on Day 4 of each dosing step. Further, subjective cough severity and health-related quality of life were assessed. RESULTS: Filapixant at doses ≥ 80 mg significantly reduced cough frequency and severity and improved cough health-related quality of life. Reductions in 24-h cough frequency over placebo ranged from 17% (80 mg dose) to 37% (250 mg dose), reductions over baseline from 23% (80 mg) to 41% (250 mg) (placebo: 6%). Reductions in cough severity ratings on a 100-mm visual analog scale ranged from 8 mm (80 mg) to 21 mm (250 mg). No serious or severe adverse events or adverse events leading to discontinuation of treatment were reported. Taste-related adverse events occurred in 4%, 13%, 43%, and 57% of patients treated with filapixant 20, 80, 150, and 250 mg, respectively, and in 12% treated with placebo. CONCLUSIONS: Filapixant proved to be efficacious, safe, and-apart from the occurrence of taste disturbances, especially at higher dosages-well tolerated during the short therapeutic intervention. Clinical trial registration EudraCT, eudract.ema.europa.eu, 2018-000129-29; ClinicalTrials.gov, NCT03535168.

Baseline characteristics from a 3-year longitudinal study to phenotype subjects with COPD: the FOOTPRINTS study.

BACKGROUND: FOOTPRINTS® is a prospective, longitudinal, 3-year study assessing the association between biomarkers of inflammation/lung tissue destruction and chronic obstructive pulmonary disease (COPD) severity and progression in ex-smokers with mild-to-severe COPD. Here, we present baseline characteristics and select biomarkers of study subjects. METHODS: The methodology of FOOTPRINTS® has been published previously. The study population included ex-smokers with a range of COPD severities (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 1-3), ex-smokers with COPD and alpha-1-antitrypsin deficiency (A1ATD) and a control group of ex-smokers without airflow limitation (EwAL). At study entry, data were collected for: demographics, disease characteristics, history of comorbidities and COPD exacerbations, symptoms, lung function and volume, exercise capacity, soluble biomarkers, and quantitative and qualitative computed tomography. Baseline data are presented with descriptive statistical comparisons for soluble biomarkers in the individual GOLD and A1ATD groups versus EwAL. RESULTS: In total, 463 subjects were enrolled. The per-protocol set comprised 456 subjects, mostly male (64.5%). The mean (standard deviation) age was 60.7 (6.9) years. At baseline, increasing pulmonary symptoms, worse lung function, increased residual volume, reduced diffusing capacity of the lung for carbon monoxide (DLco) and greater prevalence of centrilobular emphysema were observed with increasing disease severity amongst GOLD 1-3 subjects. Subjects with A1ATD (n = 19) had similar lung function parameters to GOLD 2-3 subjects, a high residual volume comparable to GOLD 3 subjects, and similar air trapping to GOLD 2 subjects. Compared with EwAL (n = 61), subjects with A1ATD had worse lung function, increased residual volume, reduced DLco, and a greater prevalence of confluent or advanced destructive emphysema. The soluble inflammatory biomarkers white blood cell count, fibrinogen, high-sensitivity C-reactive protein and plasma surfactant protein were higher in GOLD 1-3 groups than in the EwAL group. Interleukin-6 was expressed less often in EwAL subjects compared with subjects in the GOLD and A1ATD groups. Soluble receptor for advanced glycation end product was lowest in GOLD 3 subjects, indicative of more severe emphysema. CONCLUSIONS: These findings provide context for upcoming results from FOOTPRINTS®, which aims to establish correlations between biomarkers and disease progression in a representative COPD population. TRIAL REGISTRATION NUMBER: NCT02719184, study start date 13/04/2016.

Airborne occupational exposures associated with pulmonary sarcoidosis: a systematic review and meta-analysis.

The aetiology and pathophysiology of sarcoidosis is ill defined-current hypotheses centre on complex genetic-immune-environmental interactions in an individual, triggering a granulomatous process. The aim of this systematic review is to define and describe which airborne occupational exposures (aOE) are associated with and precede a diagnosis of pulmonary sarcoidosis. The methodology adopted for the purpose was systematic review and meta-analyses of ORs for specified aOE associated with pulmonary sarcoidosis (DerSimonian Laird random effects model (pooled log estimate of OR)). Standard search terms and dual review at each stage occurred. A compendium of aOE associated with pulmonary sarcoidosis was assembled, including mineralogical studies of sarcoidosis granulomas. N=81 aOE were associated with pulmonary sarcoidosis across all study designs. Occupational silica, pesticide and mould or mildew exposures were associated with increased odds of pulmonary sarcoidosis. Occupational nickel and aluminium exposure were associated with a non-statistically significant increase in the odds of pulmonary sarcoidosis. Silica exposure associated with pulmonary sarcoidosis was reported most frequently in the compendium (n=33 studies) and was the most common mineral identified in granulomas. It was concluded that aOE to silica, pesticides and mould or mildew are associated with increased odds of pulmonary sarcoidosis. Equipoise remains concerning the association and relationship of metal dusts with pulmonary sarcoidosis.

Randomised controlled trial testing effectiveness of feedback about lung age or exhaled CO combined with very brief advice for smoking cessation compared to very brief advice alone in North Macedonia: findings from the Breathe Well group.

INTRODUCTION: In 2019, smoking prevalence in North Macedonia was one of the world's highest at around 46% in adults. However, access to smoking cessation treatment is limited and no co-ordinated smoking cessation programmes are provided in primary care. METHODS: We conducted a three parallel-armed randomised controlled trial (n = 1368) to investigate effectiveness and cost-effectiveness of lung age (LA) or exhaled carbon monoxide (CO) feedback combined with very brief advice (VBA) to prompt smoking cessation compared with VBA alone, delivered by GPs in primary care in North Macedonia. All participants who decided to attempt to quit smoking were advised about accessing smoking cessation medications and were also offered behavioural support as part of the "ACT" component of VBA. Participants were aged ≥ 35 years, smoked ≥ 10 cigarettes per day, were recruited from 31 GP practices regardless of motivation to quit and were randomised (1:1:1) using a sequence generated before the start of recruitment. The primary outcome was biochemically validated 7-day point prevalence abstinence at 4 weeks (wks). Participants and GPs were not blinded to allocation after randomisation, however outcome assessors were blind to treatment allocation. RESULTS: There was no evidence of a difference in biochemically confirmed quitting between intervention and control at 4wks (VBA + LA RR 0.90 (97.5%CI: 0.35, 2.27); VBA + CO RR 1.04 (97.5%CI: 0.44, 2.44)), however the absolute number of quitters was small (VBA + LA 1.6%, VBA + CO 1.8%, VBA 1.8%). A similar lack of effect was observed at 12 and 26wks, apart from in the VBA + LA arm where the point estimate was significant but the confidence intervals were very wide. In both treatment arms, a larger proportion reported a reduction in cigarettes smoked per day at 4wks (VBA + LA 1.30 (1.10, 1.54); VBA + CO 1.23 (1.03, 1.49)) compared with VBA. The point estimates indicated a similar direction of effect at 12wks and 26wks, but differences were not statistically significant. Quantitative process measures indicated high fidelity to the intervention delivery protocols, but low uptake of behavioural and pharmacological support. VBA was the dominant intervention in the health economic analyses. CONCLUSION: Overall, there was no evidence that adding LA or CO to VBA increased quit rates. However, a small effect cannot be ruled out as the proportion quitting was low and therefore estimates were imprecise. There was some evidence that participants in the intervention arms were more likely to reduce the amount smoked, at least in the short term. More research is needed to find effective ways to support quitting in settings like North Macedonia where a strong smoking culture persists. TRIAL REGISTRATION: The trial was registered at http://www.isrctn.com (ISRCTN54228638) on the 07/09/2018.

Can guidelines rein in oxygen use? A retrospective cross-sectional study using routinely collected data.

Oxygen is one of the most commonly used emergency therapies. Like other therapies, oxygen can cause harm if used inappropriately. During the COVID-19 pandemic, guidelines were released to optimize oxygen and medication use. In the current study, we examine whether oxygen and medication use during the first wave of the COVID-19 pandemic was in concordance with new guidelines. A retrospective cross-sectional study was conducted using routinely collected data from University of Birmingham NHS Foundation Trust in England. Patients were admitted between April 2020 and September 2020, were over the age of 18 years, and had a confirmed diagnosis of COVID-19. To assess adherence to the oxygen guidelines (i.e. SpO2 adherence), the percentage of times oxygen therapy was administered within, over, and under guideline specifications were calculated for patients overall, and then for patients with and without chronic obstructive pulmonary disease (COPD)/pulmonary disease separately. Next, two multinomial regression analyses were conducted to assess whether clinical processes, pre-admission diagnoses, and other demographic factors were related to oxygen use. Analysis 1 included patients not diagnosed with COPD/pulmonary disease. Analysis 2 included patients diagnosed with COPD/pulmonary disease. Results are reported as tallies, percentages, and odds ratios with 95% confidence intervals. To assess adherence to a new medication guideline, the percentage of patients administered oxygen and dexamethasone was calculated for those admitted after 25 June 2020. The overall number of patients included in our SpO2 adherence analyses was 8751 (female = 4168). Oxygen was used within guideline specifications less than half the time, i.e. 41.6% (n = 3638/8751); non-adherence involving under-administering (3.5%, n = 304/8751) was markedly lower than over-administering (55.0%, n = 4809/8751). Adherence was higher for patients without COPD (43.7%, n = 3383/7741) than with COPD (25.2%, n = 255/1010). Under-administering was low across groups (non-COPD 3.5%, n = 274/7741 and COPD 2.9%, n = 30/1010). Over-administering was markedly lower for non-COPD (52.3%, n = 4084/7741) than COPD (71.8%, n = 725/1010) patients. Diagnoses associated with over-administering varied across the groups. Regarding the dexamethasone guidelines, of the 6397 patients admitted after the 24th of June, only 12.6% (n = 805) received dexamethasone. Suboptimal use of oxygen and medication were common during the first wave of the COVID-19 pandemic. As found in previous studies, over-administering was more common than under-administering. The new guidelines issued during the COVID-19 pandemic were not by themselves sufficient to optimize oxygen use. Behavioural strategies are explored which may help policymakers optimize oxygen use.

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. DESIGN: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. RESULTS: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. CONCLUSION: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

Cardiovascular disease in chronic obstructive pulmonary disease: a narrative review.

Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular disease (CVD) and concomitant disease leads to reduced quality of life, increased hospitalisations and worse survival. Acute pulmonary exacerbations are an important contributor to COPD burden and are associated with increased cardiovascular (CV) events. Both COPD and CVD represent a significant global disease impact and understanding the relationship between the two could potentially reduce this burden. The association between CVD and COPD could be a consequence of (1) shared risk factors (environmental and/or genetic) (2) shared pathophysiological pathways (3) coassociation from a high prevalence of both diseases (4) adverse effects (including pulmonary exacerbations) of COPD contributing to CVD and (5) CVD medications potentially worsening COPD and vice versa. CV risk in COPD has traditionally been associated with increasing disease severity, but there are other relevant COPD subtype associations including radiological subtypes, those with frequent pulmonary exacerbations and novel disease clusters. While the prevalence of CVD is high in COPD populations, it may be underdiagnosed, and improved risk prediction, diagnosis and treatment optimisation could lead to improved outcomes. This state-of-the-art review will explore the incidence/prevalence, COPD subtype associations, shared pathophysiology and genetics, risk prediction, and treatment of CVD in COPD.

Cost-effectiveness of domiciliary non-invasive ventilation in patients with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic disease associated with recurring exacerbations, which influence morbidity and mortality for the patient, while placing significant resource burdens on healthcare systems. Non-invasive ventilation (NIV) in a domiciliary setting can help prevent admissions, but the economic evidence to support NIV use is limited. METHODS: A Markov model-based cost-utility analysis from the UK National Health Service perspective compared the cost-effectiveness of domiciliary NIV with usual care for two end-stage COPD populations; a stable COPD population commencing treatment with no recent hospital admission; and a posthospital population starting treatment following admission to hospital for an exacerbation. Hospitalisation rates in patients receiving domiciliary NIV compared with usual care were derived from randomised controlled studies in a recent systematic review. Other model parameters were updated with recent evidence. RESULTS: At the threshold of £20 000 per quality-adjusted life-year (QALY) domiciliary NIV is 99.9% likely cost-effective in a posthospital population, but unlikely (4%) to be cost-effective in stable populations. The incremental cost-effective ratio (ICER) was £11 318/QALY gained in the posthospital population and £27 380/QALY gained in the stable population. Cost-effectiveness estimates were sensitive to longer-term readmission and mortality risks, and duration of benefit from NIV. Indeed, for stable Global Initiative for Chronic Obstructive Lung Disease (GOLD) for stage 4 patients, or with higher mortality and exacerbation risks, ICERs were close to the £20 000/QALY threshold. CONCLUSION: Domiciliary NIV is likely cost-effective for posthospitalised patients, with uncertainty around the cost-effectiveness of domiciliary NIV in stable patients with COPD on which further research should focus.

Impact of PD1 and PDL1 immunotherapy on non-small cell lung cancer outcomes: a systematic review.

INTRODUCTION: Despite comprising many cancer diagnoses, few treatments are suitable for patients with advanced non-small cell lung cancer (aNSCLC). Trials suggest blockade of programmed death 1 (PD1) or its ligand (PDL1) may be effective for these patients. However, this therapy's impact on outcomes other than survival, and outcomes of patients not in trials, remains largely unknown. Therefore, we compared the effectiveness of PD1 and PDL1 immunotherapy to chemotherapy and placebo across multiple clinical outcomes. METHODS: Six databases were searched on 12-13 October 2019 for randomised controlled trials (RCTs) and observational studies investigating nivolumab, pembrolizumab, atezolizumab or durvalumab. Study selection was performed independently by two reviewers. Data for overall survival, progression-free survival, adverse effects (AEs) and quality of life (QoL) were descriptively and meta-analysed. Factors impacting treatment outcomes, including PDL1 expression, were explored. The similarity between RCT and observational data was assessed. RESULTS: From 5423 search results, 139 full texts and abstracts were included. Immunotherapy was associated with a lower risk of death than both comparators. In RCTs, the incidence of treatment-related AEs was approximately 20% lower among patients using immunotherapy compared with chemotherapy. However, no other consistent benefits were observed. Progression-free survival results were inconsistent. Improvements to QoL varied according to the instrument used; however, QoL was not recorded widely. Survival results were similar between study designs; however, AEs incidence was lower in observational studies. DISCUSSION: Among patients with aNSCLC, immunotherapy improved overall survival and incidence of treatment-related AEs compared with chemotherapy. Benefits to progression-free survival and QoL were less consistent. PROSPERO REGISTRATION NUMBER: CRD42019153345.

Clinical and functional characteristics of individuals with alpha-1 antitrypsin deficiency: EARCO international registry.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a rare disease that is associated with an increased risk of pulmonary emphysema. The European AATD Research Collaboration (EARCO) international registry was founded with the objective of characterising the individuals with AATD and investigating their natural history. METHODS: The EARCO registry is an international, observational and prospective study of individuals with AATD, defined as AAT serum levels < 11 µM and/or proteinase inhibitor genotypes PI*ZZ, PI*SZ and compound heterozygotes or homozygotes of other rare deficient variants. We describe the characteristics of the individuals included from February 2020 to May 2022. RESULTS: A total of 1044 individuals from 15 countries were analysed. The most frequent genotype was PI*ZZ (60.2%), followed by PI*SZ (29.2%). Among PI*ZZ patients, emphysema was the most frequent lung disease (57.2%) followed by COPD (57.2%) and bronchiectasis (22%). Up to 76.4% had concordant values of FEV1(%) and KCO(%). Those with impairment in FEV1(%) alone had more frequently bronchiectasis and asthma and those with impairment in KCO(%) alone had more frequent emphysema and liver disease. Multivariate analysis showed that advanced age, male sex, exacerbations, increased blood platelets and neutrophils, augmentation and lower AAT serum levels were associated with worse FEV1(%). CONCLUSIONS: EARCO has recruited > 1000 individuals with AATD from 15 countries in its first 2 years. Baseline cross sectional data provide relevant information about the clinical phenotypes of the disease, the patterns of functional impairment and factors associated with poor lung function. Trial registration www. CLINICALTRIALS: gov (ID: NCT04180319).

Covid-19, social restrictions, and mental distress among young people: a UK longitudinal, population-based study.

BACKGROUND: Adolescence is a critical period for social and emotional development. We sought to examine the impacts of Covid-19 and related social restrictions and school closures on adolescent mental health, particularly among disadvantaged, marginalised, and vulnerable groups. METHODS: We analysed four waves of data - 3 pre-Covid-19 (2016-2019) and 1 mid-Covid-19 (May-Aug 2020; n, 1074; 12-18 years old, >80% minority ethnic groups, 25% free school meals) from REACH (Resilience, Ethnicity, and AdolesCent Mental Health), an adolescent cohort based in inner-London, United Kingdom. Mental health was assessed using validated measures at each time point. We estimated temporal trends in mental distress and examined variations in changes in distress, pre- to mid-Covid-19, by social group, and by pre- and mid-pandemic risks. RESULTS: We found no evidence of an overall increase in mental distress midpandemic (15.9%, 95% CI: 13.0, 19.4) compared with prepandemic (around 18%). However, there were variations in changes in mental distress by subgroups. There were modest variations by social group and by pre-Covid risks (e.g., a small increase in distress among girls (b [unstandardised beta coefficient] 0.42 [-0.19, 1.03]); a small decrease among boys (b - 0.59 [-1.37, 0.19]); p for interaction .007). The most notable variations were by midpandemic risks: that is, broadly, increases in distress among those reporting negative circumstances and impacts (e.g., in finances, housing, social support and relationships, and daily routines) and decreases in distress among those reporting positive impacts. CONCLUSIONS: We found strong evidence that mental distress increased among young people who were most negatively impacted by Covid-19 and by related social restrictions during the first lockdown in the United Kingdom.

Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study.

BACKGROUND: ATP acting via P2X3 receptors is an important mediator of refractory chronic cough (RCC). This phase 2a double-blinded crossover study assessed the safety, tolerability and efficacy of eliapixant (BAY 1817080), a selective P2X3 receptor antagonist, in adults with RCC attending specialist centres. METHODS: In period A, patients received placebo for 2 weeks then eliapixant 10 mg for 1 week. In period B, patients received eliapixant 50, 200 and 750 mg twice daily for 1 week per dose level. Patients were randomised 1:1 to period A-B (n=20) or B-A (n=20). The primary efficacy end-point was change in cough frequency assessed over 24 h. The primary safety end-point was frequency and severity of adverse events (AEs). RESULTS: 37 patients completed randomised therapy. Mean cough frequency fell by 17.4% versus baseline with placebo. Eliapixant reduced cough frequency at doses ≥50 mg (reduction versus placebo at 750 mg: 25% (90% CI 11.5-36.5%); p=0.002). Doses ≥50 mg also significantly reduced cough severity. AEs, mostly mild or moderate, were reported in 65% of patients with placebo and 41-49% receiving eliapixant. Cumulative rates of taste-related AEs were 3% with placebo and 5-21% with eliapixant; all were mild. CONCLUSIONS: Selective P2X3 antagonism with eliapixant significantly reduced cough frequency and severity, confirming this as a viable therapeutic pathway for RCC. Taste-related side-effects were lower at therapeutic doses than with the less selective P2X3 antagonist gefapixant. Selective P2X3 antagonism appears to be a novel therapeutic approach for RCC.

Prevalence, Pattern, Risks Factors and Consequences of Antibiotic Resistance in COPD: A Systematic Review.

A concern of antibiotic use in chronic obstructive pulmonary disease (COPD) is the emergence and propagation of antimicrobial resistance (AMR). A systematic review was conducted to determine prevalence, pattern, risk factors and consequences of AMR in COPD. Bibliographic databases were searched from inception to November 2020, with no language restrictions, including studies of any design that included patients with COPD and reported prevalence and pattern of AMR. 2748 unique titles and abstracts were identified, of which 63 articles, comprising 26,387 patients, met inclusion criteria. Forty-four (69.8%) studies were performed during acute exacerbation. The median prevalence of AMR ranged from 0-100% for Pseudomonas aeruginosa, Moraxella catarrhalis, Klebsiella pneumoniae and Acinetobacter baumannii. Median resistance rates of H influenzae and S pneumoniae were lower by comparison, with maximum rates ≤40% and ≤46%, respectively, and higher for Staphylococcus aureus. There was a trend towards higher rates of AMR in patients with poorer lung function and greater incidence of previous antibiotic exposure and hospitalisation. The impact of AMR on mortality was unclear. Data regarding antimicrobial susceptibility testing techniques and the impact of other risk factors or consequences of AMR were variable or not reported. This is the first review to systematically unify data regarding AMR in COPD. AMR is relatively common and strategies to optimise antibiotic use could be valuable to prevent the currently under-investigated potential adverse consequences of AMR.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.2000957 .

Relationship between Depression and Anxiety, Health Status and Lung Function in Patients with Alpha-1 Antitrypsin Deficiency.

Alpha-1 Antitrypsin deficiency (AATD) is a genetic condition that can lead to Chronic Obstructive Pulmonary Disease. The burden of psychological disease, its impact and contributing factors in patients with AATD are largely unknown. This study determined the prevalence of depression and anxiety in AATD and its clinical impact. All subjects with PiZZ/PiZnull (n = 635) and PiSZ (n = 111) genotypes within the AATD registry who had sufficient data to calculate pulmonary physiological and health status (HS) decline were grouped as those with or without a diagnosis of depression and/or anxiety. Univariate and multivariate analyses were performed on physiological, demographic and HS parameters. Depression and/or anxiety was present in 16.4% overall in both PiSZ and PiZZ/PiZnull cohorts and was associated with lower baseline pulmonary function and worse HS. In the multivariable analysis of the PiZZ/PiZnull cohort, a greater average decline in FEV1% predicted was observed in those with depression and/or anxiety than those without (-1.53 SD ± 2.26 per year, -0.99 ± 1.79, respectively; p = 0.03) but there was no difference in HS decline (p = 0.33). No differences were seen in the PiSZ cohort. Dyspnoea (mMRC score) was generally worse in those with depression and/or anxiety than those without. Comorbidity burden did not differ between those with or without depression and/or anxiety. Disease severity and progression may be contributing to the prevalence of psychological factors in PiZZ/PiZnull patients. Patients who are declining rapidly should be actively monitored for psychological co-morbidity and treated by cognitive or pharmacological means.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1991904 .