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Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. Lastly, TLR7 mRNA is increased in pre-existing datasets from patients with COPD, while TLR7 + mast cells are increased in COPD lungs and associated with severity of COPD. Our results thus support roles for TLR7 in mediating emphysema and COPD through mast cell activity, and may implicate TLR7 as a potential therapeutic target. Toll-like receptor 7 (TLR7) normally recognizes exogenous single-stranded RNA for the activation of innate immunity. Here the authors show that TLR7 may also contribute, via the modulation of mast cell functions, to experimental, cigarette smoke-induced mouse models of emphysema, thereby hinting TLR7 as a potential therapeutic target for human lung inflammation.

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.

Ayedh D Alahmari,1 Hams M Shrourou2 1Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia; 2Department of Respiratory Therapy, Batterjee Medical College, Jeddah, 21442, Saudi ArabiaCorrespondence: Ayedh D Alahmari, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia, Email aalahmari9@ksu.edu.saIntroduction: Chronic obstructive pulmonary disease (COPD) is a common disease and the third leading cause of death, although it remains misdiagnosed and untreated. Individuals at risk of developing COPD, when detected early, have a significant chance to alter the progression of the disease by prompt medical and non-medical care.Objective: To evaluate the risk level of COPD in Saudi Arabia regions by using an Arabic-translated COPD Population Screener (COPD-PS) questionnaire.Methods: This is a cross-sectional study conducted from October 12, 2023, to October 29, 2024. A convenience sampling method was used to recruit participants. This study utilized a self-administered Arabic-translated version of the COPD-PS, which evaluates various subjects related to COPD.Results: In this study of 2002 participants, a majority of them 74.39% (n = 1494) were from the Western region of Saudi Arabia. Most participants 76.72% (n = 1536) were below 35 years of age, and over half 57.39% (n = 1149) were non-smokers. The result of the COPD-PS scoring indicated 88.76% (n = 1777) of participants at low risk of COPD, while 11.24% (n = 225) participants were at high risk of COPD. Also, this study showed a statistically significant difference regarding the risk level of COPD among regions (p < 0.0001). In addition, the risk level of COPD and smoking status revealed a statistically significant difference (p ≤ 0.0001). Further analysis demonstrated that the risk level of COPD has an association with the existence of Diabetes/Hypertension (p = 0.0013).Conclusion: The Arabic-translated version of COPD-PS is an effective tool for screening the risk level of COPD among the Arabic responders in Saudi Arabia. There are various factors, including smoking status, the existence of Diabetes/ Hypertension, and regions associated with higher COPD-PS risk.Keywords: COPD, COPD-PS, screening

The heterogeneity of chronic obstructive pulmonary disease (COPD) creates many diagnostic, prognostic, treatment and management challenges, as the pathogenesis of COPD is highly complex and the underlying cellular and molecular mechanisms remain poorly understood. A reliable, easy-to-measure, clinically relevant biomarker would be invaluable for improving outcomes for patients. International and national guidance for COPD suggests using blood eosinophil counts as a biomarker to help estimate likely responsiveness to inhaled corticosteroids (ICS) and, potentially, to aid effective management strategies. However, with the mechanism underlying the association between higher eosinophil levels and ICS effect unknown, use of the blood eosinophil count in COPD continues to be widely debated by the respiratory community.Two international meetings involving respiratory medicine specialists, immunologists and primary and secondary care clinicians were held in November 2018 and March 2019, facilitated and funded by GlaxoSmithKline plc. The aims of these meetings were to explore the role of eosinophils in the disease processes of COPD and as prognostic and diagnostic markers, and to identify areas of deficient knowledge that warrant further research. The consensus views of the attendees on key topics, contextualised with current literature, are summarised in this review article, with the aim of aiding ongoing research into the disease processes of COPD and the development of biomarkers to aid clinical management.Under certain conditions, eosinophils can be recruited to the lung, and increasing evidence supports a role for eosinophilic inflammation in some patients with COPD. Infiltration of eosinophils across the bronchial vascular epithelium into the airways is promoted by the actions of immunoregulatory cells, cytokines and chemokines, where eosinophil-mediated inflammation is driven by the release of proinflammatory mediators.Multiple studies and two meta-analyses suggest peripheral blood eosinophils may correlate positively with an increased likelihood of exacerbation reduction benefits of ICS in COPD. The studies, however, vary in design and duration and by which eosinophil levels are viewed as predictive of an ICS response. Generally, the response was seen when eosinophil levels were 100–300 cells/µL (or higher), levels which are traditionally viewed within the normal range. Some success with interleukin-5-targeted therapy suggests that the eosinophilic phenotype may be a treatable trait.The use of biomarkers could help to stratify treatment for COPD—the goal of which is to improve patient outcomes. Some evidence supports eosinophils as a potential biomarker of a treatable trait in COPD, though it is still lacking and research is ongoing. A unified consensus and a practical, accessible and affordable method of utilising any biomarker for COPD was thought to be of most importance. Challenges around its utilisation may include presenting a clear and pragmatic rationale for biomarker-driven therapy, guidance on ICS withdrawal between primary and secondary care and a lack of financial incentives supporting broad application in clinical practice. Future treatments should, perhaps, be more targeted rather than assuming the primary disease label (COPD or asthma) will define treatment response.

BackgroundThe value of quantitative CT (QCT) to identify chronic obstructive pulmonary disease (COPD) phenotypes is increasingly appreciated. The authors hypothesised that QCT-defined emphysema and airway abnormalities relate to St George's Respiratory Questionnaire (SGRQ) and Body-Mass Index, Airflow Obstruction, Dyspnea and Exercise Capacity Index (BODE).Methods1200 COPDGene subjects meeting Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD with QCT analysis were included. Total lung emphysema was measured using the density mask technique with a −950 Hounsfield unit threshold. An automated programme measured mean wall thickness (WT), wall area percentage (WA%) and 10 mm lumenal perimeter (pi10) in six segmental bronchi. Separate multivariate analyses examined the relative influence of airway measures and emphysema on SGRQ and BODE.ResultsIn separate models predicting SGRQ score, a 1 unit SD increase in each airway measure predicted higher SGRQ scores (for WT, 1.90 points higher, p=0.002; for WA%, 1.52 points higher, p=0.02; for pi10, 2.83 points higher p<0.001). The comparable increase in SGRQ for a 1 unit SD increase in emphysema percentage in these models was relatively weaker, significant only in the pi10 model (for emphysema percentage, 1.45 points higher, p=0.01). In separate models predicting BODE, a 1 unit SD increase in each airway measure predicted higher BODE scores (for WT, 1.07-fold increase, p<0.001; for WA%, 1.20-fold increase, p<0.001; for pi10, 1.16-fold increase, p<0.001). In these models, emphysema more strongly influenced BODE (range 1.24–1.26-fold increase, p<0.001).ConclusionEmphysema and airway disease both relate to clinically important parameters. The relative influence of airway disease is greater for SGRQ; the relative influence of emphysema is greater for BODE.

IntroductionAutomatic titration modes of non-invasive ventilation, including average volume assured pressure support (AVAPS), are hybrid technologies that target a set volume by automated adjustment of pressure support (PS). These automated modes could offer potential advantages over fixed level PS, in particular, in patients who are super obese.MethodsConsecutive patients with obesity hypoventilation syndrome were enrolled in a two-centre prospective single-blind randomised controlled trial of AVAPS versus fixed-level PS using a strict protocolised setup.MeasurementsThe primary outcome was change in daytime arterial PCO2 (PaCO2) at 3 months. Body composition, physical activity (7-day actigraphy) and health-related quality of life (severe respiratory insufficiency questionnaire, SRI) were secondary outcome measures.Results50 patients (body mass index 50±7 kg/m2; 55±11 years; 53% men) were enrolled with a mean PaCO2 of 6.9±0.8 kPa and SRI of 53±17. 46 patients (23 AVAPS and 23 PS) completed the trial. At 3 months, improvements in PaCO2 were observed in both groups (AVAPS ∆0.6 kPa, 95% CI 0.2 to 1.1, p<0.01 vs PS ∆0.6 kPa, 95% CI 0.1 to 1.1, p=0.02) but no between-group difference (∆−0.1 kPa, 95% CI −0.7 to 0.6, p=0.87). SRI also improved in both groups (AVAPS ∆11, 95% CI 6 to 17, p<0.001 vs PS ∆7, 95% CI 1 to 12, p=0.02; between groups ∆5, 95% CI −3 to 12, p=0.21). Secondary analysis of both groups combined showed improvements in daytime physical activity that correlated with reduction in fat mass (r=0.48; p=0.01).ConclusionThe study demonstrated no differences between automated AVAPS mode and fixed-level PS mode using a strict protocolised setup in patients who were super obese. The data suggest that the management of sleep-disordered breathing may enhance daytime activity and promote weight loss in super-obese patients. Trial registration details available at http://www.controlled-trials.com/ISRCTN63940700

BackgroundThe genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear.ObjectiveTo identify common genetic variants affecting susceptibility to severe asthma.MethodsA genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies.ResultsAn association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance.ConclusionsThe largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

BackgroundBronchodilator responsiveness is a potential phenotypic characteristic of chronic obstructive pulmonary disease (COPD). We studied whether change in lung function after a bronchodilator is abnormal in COPD, whether stable responder subgroups can be identified, and whether these subgroups experience different clinical outcomes.Methods1831 patients with COPD, 285 smoking (SC) and 228 non-smoking (NSC) controls from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort. Spirometric reversibility to 400 μg inhaled salbutamol was assessed on four occasions over 1 year.ResultsForced expiratory volume in 1 s (FEV1) increase after salbutamol was similar in SC (mean 0.14 litres (SD 0.15)) and COPD (0.12 litres (0.15)) and was significantly greater than NSC (0.08 litres (0.14)). Reversibility status varied with repeated testing in parallel with the day-to-day variation in pre-bronchodilator FEV1, which was similar in control subjects and patients with COPD. Absolute FEV1 change decreased by Global initiative for chronic Obstructive Lung Disease (GOLD) stage in patients with COPD (GOLD II, mean 0.16 litres (SD 0.17); III, 0.10 litres (0.13); IV, 0.05 litres (0.08) as did chances of being classified as reversible. CT-defined emphysema was weakly related to the absolute change in FEV1 post salbutamol. Consistently reversible patients (n=227) did not differ in mortality, hospitalisation or exacerbation experience from irreversible patients when allowing for differences in baseline FEV1.LimitationsReversibility only assessed with salbutamol and defined by FEV1 criteria. The COPD population was older than the control populations.ConclusionsPost-salbutamol FEV1 change is similar in patients with COPD and smoking controls but is influenced by baseline lung function and the presence of emphysema. Bronchodilator reversibility status varies temporally and does not distinguish clinically relevant outcomes, making it an unreliable phenotype.Clinical trial registration numberNCT00292552 (http://ClinicalTrials.gov).

BackgroundThere is emerging evidence suggesting a link between ambient heat exposure and chronic obstructive pulmonary disease (COPD) hospitalisations. Individual and contextual characteristics can affect population vulnerabilities to COPD hospitalisation due to heat exposure. This study quantifies the effect of ambient heat on COPD hospitalisations and examines population vulnerabilities by age, sex and contextual characteristics.MethodsIndividual data on COPD hospitalisation at high geographical resolution (postcodes) during 2007–2018 in England was retrieved from the small area health statistics unit. Maximum temperature at 1 km ×1 km resolution was available from the UK Met Office. We employed a case-crossover study design and fitted Bayesian conditional Poisson regression models. We adjusted for relative humidity and national holidays, and examined effect modification by age, sex, green space, average temperature, deprivation and urbanicity.ResultsAfter accounting for confounding, we found 1.47% (95% Credible Interval (CrI) 1.19% to 1.73%) increase in the hospitalisation risk for every 1°C increase in temperatures above 23.2°C (lags 0–2 days). We reported weak evidence of an effect modification by sex and age. We found a strong spatial determinant of the COPD hospitalisation risk due to heat exposure, which was alleviated when we accounted for contextual characteristics. 1851 (95% CrI 1 576 to 2 079) COPD hospitalisations were associated with temperatures above 23.2°C annually.ConclusionOur study suggests that resources should be allocated to support the public health systems, for instance, through developing or expanding heat-health alerts, to challenge the increasing future heat-related COPD hospitalisation burden.

BackgroundThe natural history and time course of the onset of exacerbation events of chronic obstructive pulmonary disease (COPD) is incompletely understood.MethodsA prospective cohort of 212 patients with COPD was monitored using daily symptom diaries for a median of 2.8 years to characterise the time course of COPD exacerbation onset. Decision rules based on weighted self-reported symptoms were used to define opening and closing of exacerbation events. Event time intervals were analysed and logistic regression was used to determine the effects of patient covariates on exacerbation events.ResultsPatients recorded 4439 episodes of worsening respiratory symptoms from baseline; 2444 (55%) events resolved spontaneously and 1995 (45%) resulted in a COPD exacerbation. In 1115 of the 1995 COPD exacerbations (56%) the onset was sudden and the exacerbation threshold was crossed on the same day symptoms began. In contrast, 44% of exacerbations were characterised by gradual onset of symptoms (median duration from symptom onset to exacerbation 4 days). Patients who experienced sudden onset exacerbations had greater mean daily symptom scores (7.86 vs 6.55 points, p<0.001), greater peak symptom scores (10.7 vs 10.2 points, p=0.003), earlier peak symptoms (4.5 vs 8.0 days, p<0.001) and shorter median recovery times back to baseline health status (11 vs 13 days, p<0.001). Multivariable analysis showed that gradual onset exacerbations were statistically associated with a longer duration of exacerbation recovery (OR 1.28, 95% CI 1.06 to 1.54, p=0.010).ConclusionsCOPD exacerbations exhibit two distinct patterns—sudden and gradual onset. Sudden onset exacerbations are associated with increased respiratory symptoms but shorter exacerbation recovery times.