Chronic Obstructive Pulmonary Disease Trials Research Articles

Quality of aerobic training description and its relation to intervention efficacy in chronic obstructive pulmonary disease trials: study protocol for a systematic review, meta-analysis and meta-regression

IntroductionChronic obstructive pulmonary disease (COPD) is a major global health concern, characterised by ventilatory constraints, decreased cardiovascular fitness and reduced limb muscle function, profoundly affecting patients’ quality of life. Aerobic...

Real-World Effectiveness of Single-Inhaler Triple Therapy for COPD: Impact of Diabetes Comorbidity

Background Type 2 diabetes is a frequent comorbidity in chronic obstructive pulmonary disease (COPD) patients, with the GOLD treatment recommendations asserting that the presence of diabetes be disregarded in the choice of treatment. Methods In a cohort of COPD patients with frequent exacerbations, initiators of single-inhaler triple therapy or dual bronchodilators were compared on the incidence of COPD exacerbation and pneumonia over one year, adjusted by propensity score weighting and stratified by type 2 diabetes. Results The COPD cohort included 1,114 initiators of triple inhalers and 4,233 of dual bronchodilators (28% with type 2 diabetes). The adjusted hazard ratio (HR) of exacerbation with triple therapy was 1.04 (95% CI: 0.86–1.25) among COPD patients with type 2 diabetes and 0.74 (0.65–0.85) in those without. The incidence of severe pneumonia was elevated with triple therapy among patients with type 2 diabetes (HR 1.77; 1.14–2.75). Conclusion Triple therapy in COPD is effective among those without, but not those with, type 2 diabetes. Future therapeutic trials in COPD should consider diabetes comorbidity.

Estimating individual treatment effects on COPD exacerbations by causal machine learning on randomised controlled trials

RationaleEstimating the causal effect of an intervention at individual level, also called individual treatment effect (ITE), may help in identifying response prior to the intervention.ObjectivesWe aimed to develop machine learning...

Joint longitudinal model-based meta-analysis of FEV1 and exacerbation rate in randomized COPD trials.

Model-based meta-analysis (MBMA) is an approach that integrates relevant summary level data from heterogeneously designed randomized controlled trials (RCTs). This study not only evaluated the predictability of a published MBMA for forced expiratory volume in one second (FEV1) and its link to annual exacerbation rate in patients with chronic obstructive pulmonary disease (COPD) but also included data from new RCTs. A comparative effectiveness analysis across all drugs was also performed. Aggregated level data were collected from RCTs published between July 2013 and November 2020 (n = 132 references comprising 156 studies) and combined with data used in the legacy MBMA (published RCTs up to July 2013 - n = 142). The augmented data (n = 298) were used to evaluate the predictive performance of the published MBMA using goodness-of-fit plots for assessment. Furthermore, the model was extended including drugs that were not available before July 2013, estimating a new set of parameters. The legacy MBMA model predicted the post-2013 FEV1 data well, and new estimated parameters were similar to those of drugs in the same class. However, the exacerbation model overpredicted the post-2013 mean annual exacerbation rate data. Inclusion of year when the study started on the pre-treatment placebo rate improved the model predictive performance perhaps explaining potential improvements in the disease management over time. The addition of new data to the legacy COPD MBMA enabled a more robust model with increased predictability performance for both endpoints FEV1 and mean annual exacerbation rate.

The Current Landscape of COPD-Related Clinical Trials Registered on the World Health Organization's International Clinical Trials Registry Platform: A Comprehensive Analysis of Study Characteristics and Publication Status.

Despite studies investigating the publication rates and factors influencing publication outcomes of clinical trials in some disease fields, there is a notable lack of research focusing on chronic obstructive pulmonary disease (COPD) clinical trials. This study aims to explore the characteristics of COPD-related clinical trials and identify factors associated with publication status and publication time. A systematic search was conducted on the World Health Organization International Clinical Trials Registry Platform on April 28, 2022, to identify completed interventional clinical trials related to COPD. Various trial features were analyzed, and factors influencing publication status and time were examined. A total of 2577 completed interventional clinical trials focusing on COPD were identified. A total of 42.76% of trials enrolled ≤50 participants. The majority of trials were randomized (81.72%), blind (57.39%), parallel-assignment (59.14%), single-center (51.30%), multi-arm (83.86%), nonindustry funded (52.00%), and conducted for therapeutic purposes (73.11%). The 2-year cumulative publication rate was found to be 27.9%. The median time of study duration, dissemination lag, and publication lag were 17.27, 21.07, and 24.70 months, respectively. Multivariate analysis revealed that sample size, blind design, and study phase significantly influenced the likelihood of publication, while intervention model, primary purpose, study phase, funder, and study duration were significant factors affecting publication time. The findings highlight the inadequacy of large multi-center interventional clinical trials for COPD and indicate a low 2-year cumulative publication rate. Strengthening collaboration among investigators and adopting scientifically robust designs for larger phase 3 clinical trials are crucial to advancing COPD research and enhancing publication outcomes.

Performance of the Cough and Sputum Assessment Questionnaire (CASA-Q) in COPD: Evidence from Clinical and Online Patient Interaction Studies.

Patient perception of the burden of chronic bronchitis symptoms in chronic obstructive pulmonary disease (COPD) can be assessed using patient-reported outcome measures (PROMs). The Cough and Sputum Assessment Questionnaire (CASA-Q) was developed and tested for this purpose. This study reviewed the performance of the CASA-Q in published online studies and tested a novel approach to complement traditional methods of qualitative content validation. A targeted literature search was performed to identify published clinical studies of COPD using the CASA-Q as an endpoint. The performance of the questionnaire was examined in relation to other study endpoints, including clinical and functional measurements and other PROMs. Assessment of the content validity of the CASA-Q was carried out by comparing the content and structure of the questionnaire with published qualitative patient data from previously conducted online social media listening (SML) and online bulletin board (OBB) studies. In the interventional clinical trials, CASA-Q change scores were consistent with study objectives and other endpoints, including FEV1 and other PROMs. Two observational studies showed cross-sectional correlations with other PROMs like the St.-George's Respiratory Questionnaire (SGRQ) and COPD assessment test (CAT) scores. Qualitative data from the SML and OBB patient studies were consistent with the content and structure of the CASA-Q, supporting the content validity of the measure. Results suggest that the CASA-Q is appropriately responsive to changes in cough and sputum symptoms and clinical impact in trials of COPD. The mapping of qualitative findings from online SML and OBB studies to CASA-Q domains and items confirm the content validity of the instrument. These results suggest the CASA-Q can be a valuable tool for evaluating treatment effect in COPD trials.

Using a Taxonomy to Systematically Identify and Describe Self-Management Interventions Components in Randomized Trials for COPD.

Self-management interventions (SMIs) may improve outcomes in Chronic Obstructive Pulmonary Disease (COPD). However, accurate comparisons of their relative effectiveness are challenging, partly due to a lack of clarity and detail regarding the intervention content being evaluated. This study systematically describes intervention components and characteristics in randomized controlled trials (RCTs) related to COPD self-management using the COMPAR-EU taxonomy as a framework, identifying components that are insufficiently incorporated into the design of the intervention or insufficiently reported. Overall, 235 RCTs published between 2010 and 2018, from a systematic review were coded using the taxonomy, which includes 132 components across four domains: intervention characteristics, expected patient (or caregiver) self-management behaviours, patient relevant outcomes, and target population characteristics. Risk of bias was also assessed. Interventions mainly focused on physical activity (67.4%), and condition-specific behaviours like breathing exercise (63.5%), self-monitoring (50.8%), and medication use (33.9%). Support techniques like education and skills-training, self-monitoring, and goal setting (over 35% of the RCTs) were mostly used for this. Emotional-based techniques, problem-solving, and shared decision-making were less frequently reported (less than 15% of the studies). Numerous SMIs components were insufficiently incorporated into the design of COPD SMIs or insufficiently reported. Characteristics like mode of delivery, intensity, location, and providers involved were often not described. Only 8% of the interventions were tailored to the target population’s characteristics. Outcomes that are considered important by patients were hardly taken into account. There is still a lot to improve in both the design and description of SMIs for COPD. Using a framework such as the COMPAR-EU SMI taxonomy may contribute to better reporting and to better informing of replication efforts. In addition, prospective use of the taxonomy for developing and reporting intervention content would further aid in building a cumulative science of effective SMIs in COPD.

Pragmatic randomised controlled trials in COPD and asthma: how to guide clinical practice

The use of real-world evidence (RWE) studies, including pragmatic randomised controlled trials (RCTs; randomised RWE studies), to aid the development of treatment guidelines, is gradually becoming a mainstay within clinical...

Lung Function and the Risk of Exacerbation in the β-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease Trial.

Rationale: The BLOCK COPD (β-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease) study found that metoprolol was associated with a higher risk of severe exacerbation. Objectives: To determine the mechanism underlying these results, we compared changes in lung function over the course of the study between treatment groups and evaluated whether baseline bronchodilator response or early reduction in forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) was associated with exacerbation risk. Methods: We compared changes in lung function (FEV1 and FVC) over the treatment period between treatment groups using linear mixed-effect models. Cox proportional hazards models were used to evaluate the association between baseline bronchodilator responsiveness (FEV1, FVC, and combined FEV1 and FVC), early post-randomization (14 d) change in lung function, and the interaction between treatment assignment and these measures with risk of any or severe or very severe exacerbations. Negative binomial models were used to evaluate the relationship between bronchodilator responsiveness, the interaction between bronchodilator responsiveness and treatment assignment, and exacerbation rate. Results: Over the 336-day treatment period, individuals in the metoprolol group had a significantly greater decrease in logarithmic FEV1 from baseline to visit on Day 28 than individuals in the placebo group. Individuals in the metoprolol group had a significantly greater decrease in FVC from baseline to visits on Days 14 and 28, and also a significantly greater decrease in logarithmic FVC from baseline to visits on Days 42 and 112 than individuals in the placebo group. There were no associations between early lung function reduction or interactions between lung function reduction and treatment assignment and time to any or severe or very severe exacerbations. There were no interactions between treatment arm and baseline bronchodilator responsiveness measures on risk or rate of exacerbations. However, those with baseline FVC bronchodilator responsiveness had a higher rate of severe or very severe exacerbations (adjusted rate ratio, 1.62; 95% confidence interval, 1.04-2.48). Conclusions: Metoprolol was associated with reduced lung function during the early part of the treatment period, but these effects were modest and did not persist. Early lung function reduction and baseline bronchodilator responsiveness did not interact with the treatment arm to predict exacerbations; however, baseline FVC bronchodilator responsiveness was associated with a 60% higher rate of severe or very severe exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT02587351).

International Differences in the Frequency of Chronic Obstructive Pulmonary Disease Exacerbations Reported in Three Clinical Trials.

Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) are an important endpoint in multinational clinical treatment trials, but the observed event rate is often lower than anticipated and appears to vary between countries. Objectives: We investigated whether systematic differences in national exacerbation rates might explain this observed variation. Methods: We reviewed data from three large multicenter international randomized trials conducted over an 18-year period with different designs and clinical severities of COPD, comparing bronchodilator and/or inhaled corticosteroids with bronchodilators alone and/or placebo. Exacerbations were defined by antibiotic and/or oral corticosteroid use (moderate) or need for hospitalization (severe). We calculated crude exacerbation rates in the 30 countries contributing 30 or more patients to at least two trials. We grouped data by exacerbation rate based on their first study contribution. Measurements and Main Results: For the 29,756 patients in 41 countries analyzed, the mean exacerbation rate was two- to threefold different between the highest and lowest tertiles of the recruiting nations. These differences were not explained by demographic features, study protocol, or reported exacerbation history at enrollment. Of the 18 countries contributing to all trials, half of those in the highest and half in the lowest tertiles of exacerbation history remained in these groups across trials. Severe exacerbations showed a different rank order internationally. Conclusions: Countries contributing to COPD trials differ consistently in their reporting of healthcare-defined exacerbations. These differences help explain why large studies have been needed to show differences between treatments that decrease exacerbation risk.

Heart Rate Variability on 10-Second Electrocardiogram and Risk of Acute Exacerbation of COPD: A Secondary Analysis of the BLOCK COPD Trial.

Autonomic dysfunction is common in chronic obstructive pulmonary disease (COPD), and worse autonomic function may be a marker of risk for acute exacerbations of COPD (AECOPD). Heart rate variability (HRV) is a measure of autonomic function. Our objective was to test whether lower (worse) HRV is a risk factor for AECOPD. We measured standard deviation of normal RR intervals (SDNN) and root mean square of successive RR interval differences (RMSSD) on 10-second electrocardiograms (ECGs) performed at screening and day 42 in participants in the Beta Blockers for the Prevention of Acute Exacerbations of COPD trial ( BLOCK-COPD), a placebo-controlled trial of metoprolol for prevention of AECOPD. We used Cox-proportional hazards models to test if these HRV measures were associated with risk of any AECOPD, and separately, hospitalized AECOPD. We tested associations using baseline HRV measures and incorporating HRV measures from day 42 as a time-varying covariate. We also tested for interactions with metoprolol assignment. Of 532 trial participants, 529 (forced expiratory volume in 1 second [FEV1 ]41 ± 16.3 % predicted) were included in this analysis. We did not find a significant association between HRV measures and risk of AECOPD when all participants were analyzed together. There was a significant interaction between RMSSD and assignment to metoprolol on time to first hospitalized AECOPD; in the placebo group greater RMSSD was associated with a lower risk of hospitalized AECOPD (adjusted hazard ratio0.71, 95% confidence interval: 0.52 to 0.96, per 10 ms increase) but there was no association in the metoprolol group. Autonomic dysfunction as measured by HRV may be a risk factor for AECOPD. Future studies should analyze longer HRV recordings and their performance in broader samples of people with COPD, including those on beta-blockers.

Short-Term Impact of the Frequency of COPD Exacerbations on Quality of Life.

Chronic obstructive pulmonary disease (COPD) patients in the Simvastatin for the Prevention of Exacerbations in Moderate-to-Severe COPD (STATCOPE) and Azithromycin for Prevention of Exacerbations of COPD (MACRO) trials provide an opportunity to prospectively study the short-term effect of acute exacerbations of COPD (AECOPDs). We hypothesized that those patients with frequent exacerbations (≥2 AECOPDs per patient year) would experience greater short-term decline in quality of life as measured by the St George's Respiratory Questionnaire (SGRQ). A total of 1934 COPD patients were randomized in STATCOPE or MACRO. Patients who were randomized to azithromycin in MACRO or were followed less than 180 days were excluded. A total of 1219 patients were included. Patients were divided into 2 groups: infrequent exacerbators (< 2 exacerbations per patient year), and frequent exacerbators (≥2 exacerbations per year.) Data were collected at baseline, measured over time, and compared between groups. Of the patients studied, 871 were in the infrequent exacerbators group. A total of 348 were in the frequent exacerbators group. Frequent exacerbators used more respiratory medications, were more likely to have used oxygen, steroids, or antibiotics in the 12 months preceding study entry, had more obstruction on spirometry, and had more severe symptoms as measured by SGRQ at baseline. Over at least 180 days, symptom scores worsened in frequent exacerbators and improved in infrequent exacerbators. Patients with frequent exacerbations of COPD experienced a short-term slight worsening of severely impaired SGRQ symptoms scores, while patients with infrequent exacerbations experienced improvement while on COPD therapies.

Designing Clinical Trials in "Regular" COPD Versus Alpha-1 Antitrypsin Deficiency-Associated COPD: "More Alike Than Unalike?"

Alpha-1 antitrypsin deficiency (AATD) predisposes to emphysema, liver disease, and panniculitis. This emphysema risk naturally invites a comparison between "regular" chronic obstructive pulmonary disease (COPD) (i.e., unrelated to AATD) and AATD-associated emphysema. Several features characterize both conditions. Both can be life-limiting and highly debilitating. Both are highly under-recognized. An important corollary of this comparison between "regular" COPD and AATD-associated COPD is whether both should be treated similarly and whether clinical trials to assess new therapies can be conducted similarly in both. Here, the distinctions between "regular" COPD and AATD-associated COPD are quite pronounced. Therapeutically, sparse available data suggest that lung volume reduction surgery confers less improvement in forced expiratory volume in 1 second (FEV1) in AATD and that such benefits are shorter-lived. Perhaps the most striking contrast between the 2 conditions is that clinical trial designs and conduct are necessarily very different. The relative scarcity of diagnosed individuals with AATD hampers recruitment to trials. Furthermore, primary outcome measures in trials of "regular" COPD must differ markedly from those of AATD-associated emphysema. Specifically, power calculations show that FEV1 and exacerbation frequency, which are amply represented as endpoints in large COPD trials, are infeasible in studies of AATD-associated emphysema. Rather, in the 3 available randomized controlled trials of intravenous augmentation therapy, the rate of emphysema progression based on serial computed tomography densitometry measurements has been the only feasible primary outcome measure. These considerations underscore the distinctive challenges and needs of conducting treatment trials in AATD-associated emphysema and emphasize that, with regard to clinical study design, the 2 conditions are "more unalike than alike."

Telehealth in chronic obstructive pulmonary disease: before, during, and after the coronavirus disease 2019 pandemic.

Purpose of reviewMany healthcare systems rapidly implemented telehealth as a substitute for in-person care during the coronavirus disease 2019 (COVID-19) pandemic. The purpose of this review is to describe the evidence base supporting the use of telehealth for chronic obstructive pulmonary disease (COPD) prior to the COVID-19 pandemic, discuss the barriers to implementing telehealth during the pandemic, and share our opinion about the future of telehealth in COPD.Recent findingsThe evidence from randomized clinical trials in COPD completed prior to the COVID-19 pandemic indicate that the effectiveness of telehealth interventions compared to in-person usual care on clinical outcomes is inconclusive. Recent experience during the COVID-19 pandemic indicates that telehealth may increase access to healthcare and satisfaction with care when delivered in addition to usual in-person care. While some reimbursement-related barriers to telehealth have been alleviated during the COVID-19 pandemic, several patient, provider, and health-system barriers to implementation remain.SummaryThere is a need to further evaluate the delivery of telehealth services as an adjunct to traditional in-person models of COPD care. Standardization and reporting of core clinical, satisfaction, accessibility, and quality of care outcomes are needed to promote cross-study learning and more rapid translation of research evidence into practice.

The Long-term Efficacy of Domiciliary Noninvasive Positive-Pressure Ventilation in Chronic Obstructive Pulmonary Disease: A Meta-Analysis of Randomized Controlled Trials.

BackgroundWe evaluated the long-term effects of domiciliary noninvasive positive-pressure ventilation (NIPPV) used to treat patients with chronic obstructive pulmonary disease (COPD).MethodsDatabases were searched to identify randomized controlled trials of COPD with NIPPV for longer than 1 year. Mortality rates were the primary outcome in this meta-analysis. The eight trials included in this study comprised data from 913 patients.ResultsThe mortality rates for the NIPPV and control groups were 29% (118/414) and 36% (151/419), suggesting a statistically significant difference (risk ratio [RR], 0.79; 95% confidence interval [CI], 0.65–0.95). Mortality rates were reduced with NIPPV in four trials that included stable COPD patients. There was no difference in admission, acute exacerbation and quality of life between the NIPPV and control groups. There was no significant difference in withdrawal rates between the two groups (RR, 0.99; 95% CI, 0.72–1.36; p=0.94).ConclusionMaintaining long-term nocturnal NIPPV for more than 1 year, especially in patients with stable COPD, decreased the mortality rate, without increasing the withdrawal rate compared with long-term oxygen treatment.

Chronotropic Index and Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Secondary Analysis of BLOCK COPD.

Rationale: The chronotropic index quantifies the proportion of the expected heart rate increase that is attained during exercise. The relationship between the chronotropic index and acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) has not been evaluated. Objectives: To determine whether a higher chronotropic index during a 6-minute walk (CI-6MW) is associated with lower risk of AECOPD and whether the CI-6MW is a marker of susceptibility to adverse effects of metoprolol in chronic obstructive pulmonary disease (COPD). Methods: We analyzed data from the BLOCK COPD (Beta-Blockers for the Prevention of AECOPDs) trial. We used Cox proportional hazards models to investigate the relationship between the CI-6MW and the time to AECOPDs. We also tested for interactions between study group assignment (metoprolol vs. placebo) and the CI-6MW on the time to AECOPDs. Results: Four hundred seventy-seven participants with exacerbation-prone COPD (mean forced expiratory volume in 1 second, 41% of predicted) were included in this analysis. A higher CI-6MW was independently associated with a decreased risk of AECOPDs of any severity (adjusted hazard ratio per 0.1 increase in CI-6MW of 0.88; 95% confidence interval, 0.80-0.96) but was not independently associated with AECOPDs requiring hospitalization (adjusted hazard ratio, 0.94; 95% confidence interval, 0.81-1.05). There was a significant interaction by treatment assignment, and in a stratified analysis, the protective effects of a higher CI-6MW on AECOPDs were negated by metoprolol use. Conclusions: A higher CI-6MW is associated with a decreased risk of AECOPDs and may be an indicator of susceptibility to the adverse effects of metoprolol.

Is bilevel PAP more effective than CPAP in treating hypercapnic obese patients with COPD and severe OSA?

Commentary on Zheng Y, Yee BJ, Wong K, Grunstein R, Piper A. A pilot randomized trial comparing CPAP versus bilevel PAP spontaneous mode in the treatment of hypoventilation disorder in patients with obesity and obstructive airway disease. J Clin Sleep Med. 20XX;XX(XX):XXX-XXX. doi:10.5664/jcsm.9506.

Impact of COPD exacerbations leading to hospitalization on general and disease-specific quality of life

RationaleAcute exacerbations negatively impact quality of life in patients with chronic obstructive pulmonary disease (COPD), but the impact of hospitalized exacerbations on quality of life is not clear. We hypothesized that patients with hospitalized exacerbations would benefit from hospitalization and experience improvement in general and disease-specific quality of life (as measured by the St. George's respiratory questionnaire (SGRQ) and the medical outcomes study 36-item short form health survey (SF-36)) compared to those without exacerbations, or with non-hospitalized acute exacerbations. Methods1219 COPD patients enrolled in either the simvastatin for the prevention of exacerbations in moderate-to severe COPD Trial (STATCOPE) or azithromycin for prevention of exacerbations of COPD trial (MACRO) were analyzed. Demographic information, spirometry, and symptom scores were noted at baseline. Exacerbation events and changes in quality of life scores were assessed over a mean of 538 days of follow-up. ResultsOf patients studied, 25.6% were hospitalized, 44.0% had at least one outpatient exacerbation, and 30.4% had no exacerbation. Baseline SGRQ and SF-36 scores were severely impaired in all groups studied. Over time, SF-36 scores did not change significantly between groups. SGRQ symptom domain scores improved in other groups but did not improve in those hospitalized for a COPD exacerbation. ConclusionsAt baseline, patients hospitalized for acute exacerbations of COPD had more impaired quality of life scores. Over time, SGRQ symptom domain scores improved in other groups but did not in those who were hospitalized. Other measurements of quality of life were not improved by hospitalization for COPD.

Perplexing mortality data from triple therapy trials in COPD

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, which has resulted in several large trials studying the impact of COPD-associated treatments on mortality. 1 Rabe KF Hurd S Anzueto A et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007; 176: 532-555 Crossref PubMed Scopus (4256) Google Scholar The Global Initiative for Chronic Obstructive Lung Disease group recognises the inconsistent results of the data on mortality and the need for evidence on the escalation from dual bronchodilator therapy to triple therapy. 2 Vogelmeier CF Criner GJ Martinez FJ et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Eur Respir J. 2017; 491700214 Crossref PubMed Scopus (411) Google Scholar , 3 Rodriguez-Roisin R Rabe KF Vestbo J Vogelmeier C Agustí A Global Initiative for Chronic Obstructive Lung Disease (GOLD) 20th Anniversary: a brief history of time. Eur Respir J. 2017; 501700671 Crossref PubMed Scopus (29) Google Scholar

PI3K signalling in chronic obstructive pulmonary disease and opportunities for therapy.

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterised by airway inflammation and progressive obstruction of the lung airflow. Current pharmacological treatments include bronchodilators, alone or in combination with steroids, or other anti-inflammatory agents, which have only partially contributed to the inhibition of disease progression and mortality. Therefore, further research unravelling the underlying mechanisms is necessary to develop new anti-COPD drugs with both lower toxicity and higher efficacy. Extrinsic signalling pathways play crucial roles in COPD development and exacerbations. In particular, phosphoinositide 3-kinase (PI3K) signalling has recently been shown to be a major driver of the COPD phenotype. Therefore, several small-molecule inhibitors have been identified to block the hyperactivation of this signalling pathway in COPD patients, many of them showing promising outcomes in both preclinical animal models of COPD and human clinical trials. In this review, we discuss the critically important roles played by hyperactivated PI3K signalling in the pathogenesis of COPD. We also critically review current therapeutics based on PI3K inhibition, and provide suggestions focusing on PI3K signalling for the further improvement of the COPD phenotype. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.