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Towards the elimination of chronic obstructive pulmonary disease: a Lancet Commission
... Hence, comprehensive investigation of the interactions between gene and environment over time is required to understand the pathogenesis of COPD. events (prematurity, childhood asthma), infection-related COPD (childhood infections, tuberculosis-associated COPD, AIDS-associated COPD), COPD related to smoking or vaping (fetal smoking exposure, secondhand smoke, e-cigarette, marijuana), and environmental exposure-related COPD (indoor air pollution, ambient air pollution, wild fire smoking, occupational exposure) 30 . The Lancet Commission report has provided new insights into the causes and potential future therapeutic approaches for COPD 30 unknown cause (COPD-U) ( Table 1) 4 . ...
... events (prematurity, childhood asthma), infection-related COPD (childhood infections, tuberculosis-associated COPD, AIDS-associated COPD), COPD related to smoking or vaping (fetal smoking exposure, secondhand smoke, e-cigarette, marijuana), and environmental exposure-related COPD (indoor air pollution, ambient air pollution, wild fire smoking, occupational exposure) 30 . The Lancet Commission report has provided new insights into the causes and potential future therapeutic approaches for COPD 30 unknown cause (COPD-U) ( Table 1) 4 . ...
... COPD etiotypes in GOLD document and Lancet Commission report4,30 . ...
COPD can be caused by various factors, including lung infections, asthma, air pollution, childhood growth disorders, and genetic factors, although smoking is a predominant risk factor. The main pathological mechanisms in COPD involve small airway disease, emphysema, mucus hypersecretion, and vascular disorders. COPD in non-smokers is characterized by normal FEV1 decline, equal distribution of sex, younger age of onset, fewer comorbidities, milder airflow obstruction, normal diffusing capacity of the lungs for carbon monoxide (DLCO) and radiological features such as more air-trapping and less severe emphysema, compared to COPD in smokers. COPD in non-smokers is still accompanied by a high prevalence of acute exacerbation almost equal to COPD in smokers. Moreover, COPD per se is an independent risk factor for the development of lung cancer, irrespective of smoking status. Considering that COPD coexists with numerous comorbidities, effective management of these comorbidities is essential, and multifaceted efforts are required for the comprehensive treatment of COPD.
... It is now believed that there are other risk factors for COPD in addition to smoking and alphaantitrypsin deficiency, and it is recognized that air pollution can exacerbate the disease and induce respiratory damage that predisposes to the development of the disease [8,9]. Increased air pollution has been documented to contribute to the incidence and prevalence of COPD [5,10], as exposure to air pollutants can lead to cellular damage mediated by oxidative processes and systemic inflammation [11]. ...
... Also, the adverse effects of air pollution affect older people more. Despite the WHO air quality guidelines for 2021 and national regulations [21], air pollution continues to contribute to the burden of disease due to this risk factor [9]. ...
... (www.preprints.org) | NOT PEER-REVIEWED | Posted: 1 October 2024 doi:10.20944/preprints202410.0075.v19 ...
(1)Background: Evidence on the association between air pollution and the risk of exacerbations of chronic obstructive pulmonary disease (COPD) is scarce and inconsistent. We aimed to analyze the association between long-term exposure to particulate matter with a diameter of less than 2.5 µm (PM2.5) and nitrogen dioxide (NO2) and exacerbation of COPD (COPD-E) in Bogotá, Colombia; (2) Methods: Retrospective cohort study of 722 COPD patients in the AIREPOC program of the Colombian Pneumological Foundation between 2018 and 2021. Exposure to PM2.5 and NO2 was estimated for residential locations using the inverse squared distance weighted regression (IDWR) method. Hazard Ratios (HR) were calculated for the first COPD-E during follow-up using Cox models, adjusted for meteorological, demographic, and clinical variables; (3) Results: COPD-E was associated with long-term exposure to PM2.5 (HR:1.03, 95%CI: 1.02-1.05) and NO2 (HR:1.05, 95%CI: 1.03-1.07) controlling for the effect of quality of life, history of COPD-E, Forced Expiratory Volume in One Second (FEV1) pre-bronchodilator and exposure to solar radiation. An association was found between COPD-E and concentrations ≥ 25µg/m3 of NO2 (HR:1.49, 95%CI: 1.12-1.98) but not with concentrations ≥15 µg/m3 of PM2.5; (4) Conclusions: This study suggests that people with COPD exposed to higher concentrations of PM2.5 and NO2 had an increased risk of COPD-E. Solar radiation was also associated with an increased risk of COPD-E. The results highlight the importance of continuing efforts to reduce air pollution.
... In 2022, the Lancet COPD commission report revealed that more than 70% of 22,000 participants surveyed via social media reported not having received any training on protecting lung health at work, and over 90% reported having to leave their previous job due to respiratory symptoms. 17 In a populationbased cross-sectional study, the likelihood of having COPD was found to be 5.8 and 6.9 times higher, respectively, in subjects exposed to tobacco and occupational smoke for more than 20 years compared to reference subjects exposed for less than 10 years. 18 As noted in the Lancet COPD commission report of 2022, occupational exposures have a significant relationship with the pathophysiological features of COPD, such as chronic cough, airway flat hypertrophy, persistent airflow limitation, and parenchymal destruction. ...
... 18 As noted in the Lancet COPD commission report of 2022, occupational exposures have a significant relationship with the pathophysiological features of COPD, such as chronic cough, airway flat hypertrophy, persistent airflow limitation, and parenchymal destruction. 17 Consistent with the industries represented in our cases, occupation-related causes of COPD have been identified in a wide range of industry-based studies. ...
... Although spirometry is considered the cornerstone for COPD diagnosis, it is not universally available at AF clinics, nor is the infrastructure for referral to a pulmonologist always present. A recent position paper from the Lancet Commission on COPD argued that chest computed tomography (CT) contains features diagnostic of COPD, including emphysema and bronchial wall thickening, and proposed that chest CT scans should be used to detect COPD in the absence of pulmonary function testing 9 . Cardiac computed tomographic angiography (CCTA) is routinely performed in AF patients as pre-procedural work up tool for AF ablation or to assess the coronary status if coronary disease is suspected. ...
... Thoracic imaging is increasingly advancing as a surrogate marker for COPD and is even proposed as a diagnostic tool in the absence of or in addition to pulmonary function testing. According to a position paper by the Lancet Commission on COPD, chest CT scans exhibit characteristics that can be used to diagnose COPD, and therefore, the paper suggests the use of chest CT imaging as a diagnostic tool for COPD in cases where pulmonary function testing is not available or is inconclusives 9 . The extent of emphysema has been shown to correlate with disease severity of COPD 18,19 , and is associated with future exacerbations in smokers 20 and increased mortality risk 15 . ...
Introduction Chronic obstructive pulmonary disease (COPD) commonly coexists in patients with atrial fibrillation (AF). Although diagnosis relies on spirometry, radiological features such as emphysema and airway abnormalities on chest computed tomography (CT) could be used for COPD screening. Methods This retrospective analysis included AF patients who had undergone both cardiac CT angiography (CCTA) and a conventional chest CT within a two-year timeframe. Both scans were visually evaluated for CT-features of COPD using the validated COPDgene screening tool. Based on these scores, the COPD phenotype was classified into four categories: normal, airway dominant, emphysema dominant, or mixed. Accuracy of CCTA to detect CT features of COPD was calculated using the full chest CT as the reference. Results In total, 63 patients (54% female, median age 69 [62-75] years, 79% paroxysmal and 21% persistent AF) were included in this study. CT features of COPD were detected in 35% of CCTA and 51% of conventional CTs. CCTA detected CT features of COPD with a sensitivity of 66%, specificity of 97%, positive predictive value of 95% and negative predictive value of 73%. Area under the receiver operator characteristic curve was 0.82 (95% confidence interval 0.70 – 0.92). The dominant feature among the false-negative tests results was mild emphysema located in the upper lung fields, which were out of the field-of-view of CCTA. Conclusions CCTA can identify AF patients with CT features indicating COPD, despite occasional misses due to out-of-view areas. When detected, they have a high positive predictive value, facilitating spirometry prioritization.
... In 2019, 212.3 million prevalent cases of COPD were reported globally, with COPD accounting for 3.3 million deaths (6), and with more than three-fourths of cases in LMICs. Research also shows that the morbidity and mortality due to chronic respiratory disease continue to increase, and the increase is driven primarily by the growth of COPD (7). Therefore, COPD is an increasingly important cause of morbidity, disability, and mortality worldwide; it remains a major public health problem, especially in LMICs (8). ...
... COPD is a global health emergency that affects people from all countries, socioeconomic classes, and age groups, although it disproportionately affects poor and disadvantaged people (7). In this ecological study, we used the COPD hospital admissions data from 25 hospitals and the air pollutants concentration monitoring data in Lanzhou City, and we used the DNLM method to analyze the impact of air pollutants on COPD. ...
Background
Lanzhou is the largest heavy industrial city in northwest China and it is a typical geographical valley-like city. However, there are few studies on the relationship between air pollutants and COPD, and their respective sample sizes are small, resulting in inconsistent results. The aim of this study is to analyze the effects of air pollutants on COPD hospitalizations in Lanzhou, China.
Methods
An ecological time series study with distributed lag non-linear model (DLNM) was used for analysis. Daily COPD hospitalization data in Lanzhou from 1 January 2015 to 31 December 2019 were collected from 25 hospitals, as well as air pollutant data and meteorological data.
Results
A total of 18,275 COPD hospitalizations were enrolled. For 10 μg/m³ increase in PM2.5, PM10, SO2, NO2, and 1 mg/m³ increase in CO at lag 07 day, the RR95%CI of COPD hospitalizations were 1.048 (1.030, 1.067), 1.008 (1.004, 1.013), 1.091 (1.048, 1.135), 1.043 (1.018, 1.068), and 1.160 (1.084, 1.242), respectively. The exposure–response curves between air pollutants (except O3-8h) and COPD hospitalizations were approximately linear with no thresholds. Female, and the harmful effect of PM on aged <65 years, the effect of gaseous pollutant on those aged ≥65 years, were stronger, particularly in the cold season. Exposure to air pollutants (except O3-8h) might increase the risk of COPD hospitalizations. O3-8h has a weak and unstable effect on COPD.
Conclusion
Exposure to air pollutants (except O3-8h) increases the risk of COPD hospitalizations. O3-8h has a weak and unstable effect on COPD hospital admissions. The harmful effect of gaseous pollutants (except O3-8h) on COPD-hospitalized patients was stronger than that of PM.
... Background Chronic obstructive pulmonary disease (COPD) is a growing global health problem [1][2][3][4], accounting for approximately 55% of all chronic respiratory diseases [5]. Between 1990 and 2017, COPD incidence showed a relative increase of 5.9% [6]. ...
... Between 1990 and 2017, COPD incidence showed a relative increase of 5.9% [6]. COPD affected over 300 million people and led to 3.3 million deaths [5,6]. COPD is characterised by progressive lung function decline [7], which is associated with exacerbations [8]. ...
Background
The effectiveness and safety of acupuncture therapy to delay lung function decline in chronic obstructive pulmonary disease (COPD) remain unclear. This study aimed to determine whether acupuncture, as an adjunctive therapy to COPD-guided medication, could prevent lung function decline.
Methods
This randomised, two-centre study was conducted between February 2022 and July 2023. Men and women aged 40–80 years with COPD were recruited. Participants received active or sham acupuncture three times a week (36 sessions total). The primary outcome was the change in the percentage of forced expiratory volume for 1 s to the predicted value (FEV1%) between the baseline and after the intervention.
Results
Overall, 238 participants were screened, and 74 (58 men [78.4%]; mean [standard deviation] age, 69.6 [7.2] years) were randomised into the acupuncture and sham acupuncture groups (37 per group). After the intervention, the change in FEV1% was 1.35 (95% confidence interval [CI]: -0.47 to 3.17) and -2.44 (95% CI: -4.56 to -0.33) in the acupuncture and sham acupuncture groups, respectively. The difference was -3.97 (95% CI: -6.2 to -1.74), and the adjusted difference was -3.46 (95% CI: -5.69 to -1.24, P = 0.003) between the groups. A significantly less decline was found in forced expiratory volume for 1 s in the acupuncture group. All treatment-related adverse events (acupuncture = 11, sham = 2) were mild.
Conclusions
Compared with sham acupuncture, acupuncture plus medication may delay lung function decline. However, further studies with a larger sample size and longer-term follow-up are needed to clarify the effects.
... It is now believed that there are other risk factors for COPD in addition to smoking and alpha-antitrypsin deficiency, and it is recognized that air pollution can exacerbate the disease and induce respiratory damage that predisposes people to the development of the disease [9,10]. Increased air pollution has been documented to contribute to the incidence and prevalence of COPD [11,12], as exposure to air pollutants can lead to cellular damage mediated by oxidative processes and systemic inflammation [13]. ...
(1) Background: Evidence on the association between air pollution and the risk of exacerbations of chronic obstructive pulmonary disease (COPD) is scarce and inconsistent. We aimed to analyze the association between long-term exposure to particulate matter with a diameter of less than 2.5 µm (PM2.5) and nitrogen dioxide (NO2) and exacerbation of COPD (COPD-E) in Bogotá, Colombia. (2) Methods: We conducted a retrospective cohort study of 722 COPD patients in the AIREPOC program of the Colombian Pneumological Foundation between 2018 and 2021. Exposure to PM2.5 and NO2 was estimated for residential locations using the inverse squared-distance weighted regression (IDWR) method. Hazard ratios (HRs) were calculated for the first COPD-E during follow-up using Cox models, adjusted for meteorological, demographic, and clinical variables. (3) Results: COPD-E was associated with long-term exposure to PM2.5 (HR: 1.03, 95%CI: 1.02–1.05) and NO2 (HR: 1.05, 95%CI: 1.03–1.07), controlling for the effect of quality of life, history of COPD-E, Forced Expiratory Volume in One Second (FEV1) pre-bronchodilator, and exposure to solar radiation. An association was found between COPD-E and concentrations ≥ 25 µg/m3 of NO2 (HR: 1.49, 95%CI: 1.12–1.98) but not with concentrations ≥ 15 µg/m3 of PM2.5. (4) Conclusions: This study suggests that people with COPD exposed to higher concentrations of PM2.5 and NO2 had an increased risk of COPD-E. Solar radiation was also associated with an increased risk of COPD-E. The results highlight the importance of continuing efforts to reduce air pollution. COPD patients should be aware of air quality indices and follow the recommendations, as well as participate in air governance spaces.
... The Lancet Commission paper suggested that even without spirometric obstruction, COPD can be diagnosed. 8 Choi and Rhee 9 also suggested that the 0.7 criterion should be discarded. COPD can be defined in patients with features of COPD (chronic bronchitis/small airway disease/emphysema) (Fig. 2). ...
... In conclusion, this study suggests that the use of GOLDdefined diagnostic thresholds in a clinical algorithm classified older smokers into more severe COPD risk phenotypes than the use of GLI-defined thresholds, supporting the idea that GOLD may misclassify subjects with a normal or less affected phenotype as having respiratory impairment [13][14][15][16]. This has clinical implications, as COPD is a heterogeneous disease and spirometry, along with other parameters, will remain essential for diagnosis [7][8][9]. Misclassification of elderly smokers into severe COPD phenotypes could lead to inappropriate and harmful treatment. While the economic cost of such misclassification is difficult to estimate, the psychological impact on misdiagnosed individuals could be significant. ...
Purpose
In aging populations, the Global Initiative for Obstructive Lung Disease (GOLD) spirometry threshold may misclassify normal spirometry as airflow limitation. The Global Lung Initiative (GLI) method provides age-adjusted criteria. We investigated how the use of GOLD or GLI thresholds in an algorithm affects the classification of elderly smokers into COPD risk phenotypes.
Methods
Using a modified COPDGene algorithm, including exposure, symptoms, and abnormal spirometry, 200 smokers aged 60 years and older were classified into 4 mutually exclusive phenotypes: Phenotype A (no symptoms, normal spirometry; reference), Phenotype B (symptoms, normal spirometry; possible COPD), Phenotype C (no symptoms, abnormal spirometry; possible COPD), and Phenotype D (symptoms, abnormal spirometry; probable COPD). Abnormal spirometry was defined according to the GOLD or GLI criteria. A comparison was made between the GOLD- and GLI-defined phenotypes.
Results
Using GLI criteria/cut-offs, 18.5% (n = 37) had phenotype A (no COPD), 42% (n = 84) had phenotype B (possible COPD), 7.5% (n = 15) had phenotype C (possible COPD), and 32% (n = 64) had phenotype D (probable COPD). Using GOLD criteria cut-offs, 14.5% (n-29) had phenotype A (no COPD); 31% (n = 62) had phenotype B, 11.5% (n = 23) had phenotype C (probable COPD), and 43% (n = 86) had phenotype D (probable COPD). Eight smokers with GOLD phenotype C were reclassified as GLI phenotype A, while 22 with GOLD phenotype D were reclassified as GLI phenotype B. Smokers identified as ‟probable COPD” by GOLD alone (potential false positives) had better spirometry results than those identified as ‟probable COPD” by both GOLD and GLI.
Conclusion
The use of the GOLD threshold in an algorithm resulted in older smokers being classified into more severe COPD risk phenotypes compared to the GLI threshold. This suggests that GOLD may misclassify smokers with less affected phenotypes as having respiratory impairment, potentially leading to unnecessary and harmful treatments.
... 2 Moreover, with the aging population worldwide, COPD is anticipated to pose an even greater social and economic burden in the coming years. 3 Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) denotes a sudden persist across different disease populations. 29 Enhancing the accuracy of these scoring systems and exploring their applicability in diverse disease contexts remain areas of ongoing investigation. ...
Purpose
Elevated red blood cell distribution width (RDW) and decreased hematocrit (HCT) levels are associated with poor prognosis in chronic obstructive pulmonary disease (COPD) patients, but their significance in intensive care unit (ICU) patients with acute exacerbation of COPD (AECOPD) remains uncertain. The RDW/HCT ratio may offer a more comprehensive assessment compared to individual markers, potentially enhancing prognostic accuracy. Furthermore, the utility of RDW/HCT in improving traditional ICU scoring systems remains unexplored.
Patients and Methods
The optimal RDW/HCT ratio cutoff was identified via ROC curve analysis, guiding classification into high and low ratio groups. Univariate and multivariate logistic regression analyses, Kaplan-Meier survival curves, and propensity score matching (PSM) were performed to evaluate the association between RDW/HCT ratio and 28-day all-cause mortality. The predictive value of RDW/HCT ratio compared to traditional ICU scoring systems was assessed using the area under the curve (AUC). Additionally, the eICU database was utilized to validate the robustness of the association between RDW/HCT and mortality in patients with AECOPD.
Results
624 patients were included, with 361 in the low RDW/HCT ratio group and 263 in the high ratio group. PSM yielded 145 matched pairs of patients with balanced baseline characteristics. Multivariate logistic regression analysis revealed that patients with RDW/HCT ratio ≥ 0.473 had significantly higher 28-day all-cause mortality compared to those with RDW/HCT ratio < 0.473 (p < 0.001). Combining RDW/HCT ratio with SOFA score improved the diagnostic accuracy significantly (p=0.029).
Conclusion
The RDW/HCT ratio is an independent predictor of 28-day all-cause mortality in AECOPD patients in the ICU. It can be used for a preliminary assessment before a systematic evaluation of the patient, indicating its potential value in early assessment of disease severity. In a comprehensive evaluation, combining the RDW/HCT ratio with the SOFA score can further enhance predictive accuracy.
... This also applies to future investigation methods that are yet to be developed. 10 All patients showing one or more of the symptoms mentioned above should be re-examined regularly (once a year or whenever they consult their doctor after a longer period) by a suitable health professional. In addition to the information available from guidelines, each practitioner managing patients labeled as Pre-COPD should receive brief training to clarify and detect the diagnostic criteria in a standardized way, which needs to be defined after further research. ...
... 18 Several etiotypes and phenotypes have been proposed, but GWAS of these traits have been limited. 19 Investigation of genetic predisposition could have an important role in the early recognition of COPD. Hence, it may be time to refocus on genetic research on COPD. ...
Background
A rapid decline in forced expiratory volume in 1 second (FEV1) is considered an important phenotype of the development of chronic obstructive pulmonary disease (COPD). However, the associations between specific genetic variants (single-nucleotide polymorphisms; SNPs) and this phenotype remain uncertain.
Methods
We enrolled 6,516 individuals from the Korean Genome and Epidemiology Study (KoGES). A rapid decline in FEV1 was defined as an annual decrease of FEV1 ≥ 60 mL/year. A multivariable logistic regression model was used to assess the associations between SNP variants and the rapid decline in FEV1. Considering the significant impact of smoking on lung function, a subgroup analysis based on smoking history was also conducted.
Results
A genome-wide association analysis of the rapid decline in FEV1 identified 15 association signals (P < 5.0 × 10⁻⁸). Among the 15 nucleotide variants, rs9833533 and rs1496255 have been previously reported to be associated with lung function development. In the subgroup analysis, rs16951883 (adjusted odds ratio [aOR], 3.24; P = 5.87 × 10⁻⁸) was the most significant SNP associated with rapid decline in FEV1 among never smokers, followed by rs41476549, rs16840064, and rs1350110. Conversely, among ever smokers, rs10959478 (aOR, 4.74; P = 8.27 × 10⁻⁷) showed the highest significance, followed by rs6805861, rs9833533, and rs16906215.
Conclusion
We identified 15 nucleotide variants linked to a rapid decline in FEV1, including two SNPs previously reported to be associated with lung function development. Additional SNPs, which were associated with COPD, may be found using novel phenotypes.
... Recent studies report a high frequency of the presence of MetS in young patients with COPD and less severe forms of the disease [31][32][33]. Considering this aspect, special attention is required in the evaluation of these patients. Moreover, good self-management of the disease can improve the prognosis and decrease the risk of cardiovascular morbimortality [34][35][36] (Figure 1). the disease can improve the prognosis and decrease the risk of cardiovascular morbi-mortality [34][35][36] (Figure 1). ...
Background/Objectives: The association between chronic obstructive pulmonary disease (COPD) and metabolic syndrome (MetS) is a common one, with long-term therapeutic and prognostic impact. In view of the high pulmonary and cardiovascular morbidity and mortality, self-management contributes to decreasing the risk of an acute cardiac event or pulmonary decompensation. Methods: We conducted a prospective cohort study on 100 patients admitted to Iasi Clinical Rehabilitation Hospital who were divided into two groups according to the presence (67 patients) or absence (33 patients) of MetS. All patients benefited from multidisciplinary counseling sessions on their active role in improving modifiable cardiovascular risk factors and thus increasing quality of life. The aim of this study was to examine the impact of metabolic syndrome on lung function and the role of self-management in a 6-month follow-up period. The demographic, anthropometric, cardiovascular risk factors, and respiratory function were analyzed at baseline and at 6 months. Results: The presence of MetS was associated with higher fasting blood glucose (p = 0.004) and triglycerides (p = 0.003) but not with higher levels of interleukins or TNF-alpha. At the 6-month follow-up, abdominal circumference, forced expiratory volume in one second (FEV1), dyspnea severity, and blood pressure values improved in male patients with COPD. Systolic and diastolic blood pressure decreased in the COPD group as a whole, but especially in male patients with and without associated MetS. BMI was positively correlated with FEV1 (r = 0.389, p = 0.001) and the FEV1/forced vital capacity (FVC) ratio (r = 0.508, p < 0.001) in all COPD patients and in the MetS subgroup. In the COPD group as a whole. the six-minute walk test (6MWT) results (m) were positively correlated with FEV1 and FVC. The correlation remained significant for FVC in COPD patients with and without MetS. An increase in BMI by one unit led to an increase in TG values by 3.358 mg/dL, and the presence of metabolic syndrome led to an increase in TG values by 17.433 mg/dL. Conclusions: In our study, MetS is a common comorbidity in patients with COPD and is associated with higher BMI, fasting glucose, and triglycerides but not with the inflammatory parameters. A mixed pulmonary–cardiovascular rehabilitation intervention leads to improvement in various parameters in both female and male COPD patients.
... 11 However, decline in FEV1 occurs late in COPD trajectory and the recent Lancet Commission paper on COPD has suggested other tests to capture airflow obstruction, and thus COPD earlier. 36 Such developing airflow obstruction promotes dynamic hyperinflation which is potentially an important stressor to the CV system. [37][38][39][40] Dynamic pulmonary hyperinflation is a transient and variable increase in end-expiratory lung volume observed during increased ventilation, particularly during exercise or an exacerbation, among flow-limited patients. ...
Introduction
Exacerbations of chronic obstructive pulmonary disease (COPD) are risk factors for severe cardiovascular (CV) events, with the risk remaining significantly elevated long after the symptomatic phase of the exacerbation. The pathophysiology underpinning the relationship between acute events of both COPD and CV diseases has been understudied. Our objectives were to review the mechanisms by which COPD exacerbations increase the risk of CV events and understand the temporality of this risk.
Methods
A pragmatic and targeted literature review was conducted with a focus on identifying recent, high-impact papers up to June 2023, guided by insights from subject matter experts including pulmonologists and cardiologists.
Results
A substantial number of inter-related mechanisms underpin the spiral of anatomical and functional deterioration of lung and heart affecting COPD patients during stable state. In turn, an exacerbation of COPD may trigger a CV event, during and beyond the symptomatic phase, due to ventilation/perfusion mismatch, oxygen supply-demand imbalance, oxidative stress, systemic inflammation, hypercoagulable state, dynamic hyperinflation, pulmonary hypertension, and sympathetic activation. However, no study was identified that explored the mechanisms by which an exacerbation confers a sustained risk of CV event.
Conclusion
While our review identified multiple dynamic and interacting pathophysiological mechanisms during and after an exacerbation of COPD that contribute to increasing the risk of a wide range of cardiac events, little is known regarding the precise long-term mechanisms after acute exacerbation to explain the persistent increased CV event risk beyond the symptomatic phase. The temporal changes in static and dynamic substrates need further characterization to better understand the different risk factors and risk periods for a CV event following the onset of an exacerbation. Moreover, guideline-directed cardiopulmonary therapies should be implemented at every opportunity; preventing exacerbations and intensively treating traditional CV risk factors should be a focus in COPD management.
... Despite the global burden of COPD and the repeated warnings to our healthcare systems of the imminent crisis that this disease will cause as our population ages and climate heats up, therapies for COPD remain inadequate, failing to meaningfully reverse outcomes [19]. In the face of slow drug development, our study presents evidence in support of a novel strategy towards COPD therapeutics by considering the pathogenic potential of the home environment. ...
Background
Sensitisation to Aspergillus fumigatus is linked to worse outcomes in patients with chronic obstructive pulmonary disease (COPD), however, its prevalence and clinical implications in domestic (residential) settings remains unknown.
Methods
Individuals with COPD (n=43) recruited in Singapore had their residences prospectively sampled and assessed by shotgun metagenomic sequencing including indoor air, outdoor air, and touch surfaces (total: 126 specimens). The abundance of environmental A. fumigatus and the occurrence of A. fumigatus (Asp f) allergens in the environment were determined and immunological responses to A. fumigatus allergens determined in association with clinical outcomes including exacerbation frequency. Findings were validated in 12 individuals (31 specimens) with COPD in Vancouver, Canada, a climatically different region.
Results
157 metagenomes from 43 homes were assessed. Eleven and nine separate Aspergillus spp. were identified in Singapore and Vancouver respectively. Despite climatic, temperature, and humidity variation, A. fumigatus was detectable in the environment from both locations. The relative abundance of environmental A. fumigatus was significantly associated with exacerbation frequency in both Singapore (r=0.27, p=0.003) and Vancouver (r=0.49, p=0.01) and individuals with higher Asp f 3 sensitisation responses lived in homes with a greater abundance of environmental Asp f 3 allergens (p=0.037). Patients exposed and sensitised to Asp f 3 allergens demonstrated a higher rate of COPD exacerbations at 1-year follow-up (p=0.021).
Conclusion
Environmental A. fumigatus exposure in the home environment including air and surfaces with resulting sensitisation carries pathogenic potential in individuals with COPD. Targeting domestic A. fumigatus abundance may reduce COPD exacerbations.
... Additionally, advancements in treatment protocols may have played a role in this decrease There has been a decrease in deaths due to circulatory system diseases and cancers worldwide, while deaths related to chronic respiratory tract diseases have continued to increase. It is plausible to attribute this increase primarily to the rise in chronic obstructive pulmonary disease (13). In our study, a moderate decrease in cancer-specific mortality rate was observed, while a mild decrease was observed in cardiovascular diseasesspecific mortality rate until the onset of the pandemic. ...
Background: Examining death statistics at regular intervals is highly useful for assessing public health. This study aimed to analyze cause-specific mortality statistics, to ascertain their distribution over the years, and to offer remedial solutions to enhance public health outcomes.
Methods: In this retrospective descriptive study, an analysis was conducted on data sourced from the "Death and Cause of Death Statistics" provided by the Turkish Statistical Institute between 2017 and 2022.
Results: While the crude mortality rate remained stable from 2017 to 2019, a discernible increase in mortality rates has been observed since 2020, attributed to the impact of the pandemic. The crude death rate was the highest in the <5 yr and ≥65 yr age groups. Approximately 70% of the total mortality cases in Turkey were attributed to cardiovascular diseases, cancers, respiratory diseases, and diabetes.
Conclusion: Given the world's rapidly aging population, an increase in deaths related to the four major noncommunicable diseases is foreseen. Therefore, there is an imperative need to enhance efforts aimed at preventing and controlling these diseases.
... COPD is a progressive respiratory ailment characterised by chronic bronchitis and emphysema, often leading to persistent airflow limitation and a diminished quality of life [1]. The significance of COPD cannot be overstated, as it ranks among the leading causes of morbidity and mortality worldwide, placing a substantial economic and healthcare burden on society [2]. ...
... In 2019, the World Health Organization reported it as the third leading cause of death worldwide (Collaborators, G. C. R. D, 2020). As the population ages (Mathers and Loncar, 2006), the prevalence of COPD will continue to grow, which not only reduces the quality of life, but also creates a huge health, social, and economic burden (Stolz et al., 2022). However, the effectiveness of relevant treatments is limited, in which drug side effects, especially inhaled glucocorticoids, may exacerbate the risk of pneumonia (Celli and Wedzicha, 2019). ...
Objective
In recent years, the lung-gut axis has received increasing attention. The oxidative stress and systemic hypoxia occurring in chronic obstructive pulmonary disease (COPD) are related to gut dysfunction. That suggests probiotics have a potential therapeutic role in COPD. In this study, we therefore evaluated the ameliorative effects of probiotics on COPD.
Methods
Searches were conducted in four electronic databases, including PubMed, Cochrane Library, the NIH clinical registry Clinical Trials. Gov and EMBASE. The data extracted was analyzed statistically in this study using StataMP17 software, with mean difference (MD) chosen as the effect size for continuous variables, and the results expressed as effect sizes and their 95% confidence intervals (CIs). Standardized Mean Difference (SMD) was used if the data units were different.
Results
We included three randomized, controlled, double-blind clinical trials and five randomized controlled animal studies. The results show that for lung function, probiotics improved %FEV1 in COPD patients (MD = 3.02, 95%CI: 1.10, 4.93). Additionally, in inflammation, probiotics increased IL-10 (SMD = 1.99, 95%CI: 1.02, 2.96) and decreased inflammatory markers such as TNF-α (SMD= -2.64, 95%Cl: -3.38, -1.90), IL-1β (SMD= -3.49, 95%Cl: -4.58, -2.40), and IL-6 (SMD= -6.54, 95%Cl: -8.36, -4.73) in COPD animals, while having no significant effect on C-reactive protein (MD = 0.30, 95%CI: -0.71, 1.32) in COPD patients. For lung structure, probiotics significantly reduced the degree of pulmonary collagen fibers deposition in COPD animals (SMD = -2.25, 95%CI: -3.08, -1.41).
Conclusion
Overall, probiotics may be an additional approach that can improve COPD. Further clinical trials are needed to evaluate the efficacy, safety, and impact factors of probiotics for COPD.
Systematic Review Registration
https://inplasy.com/inplasy-2023-4-0023/, identifier INPLASY202340023.
... Given that there are no curative therapies for COPD, the Lancet Commission introduced 1) genetics, 2) early-life events, 3) pulmonary infections, 4) tobacco smoke exposure, 5) pollution and pre-COPD for future research and a better understanding of COPD pathogenesis. [5,6]. ...
Rationale: COPD patients are largely asymptomatic until the late stages when prognosis is generally poor. In this study, we shifted the focus to pre-COPD and smoking stages, and found enrichment of hypoxia inducible factor (HIF)-3α is in pre-COPD samples. Smoking induced regional tissue hypoxia and emphysema have been found in COPD patients. However, the mechanisms underlying hypoxia especially HIF-3α and COPD have not been investigated. Methods: We performed bulk-RNA sequencing on 36 peripheral lung tissue specimens from non-smokers, smokers, pre-COPD and COPD patients, and using "Mfuzz" algorithm to analysis the dataset dynamically. GSE171541 and EpCAM co-localization analyses were used to explore HIF-3α localization. Further, SftpcCreert2/+R26LSL-Hif3a knock-in mice and small molecular inhibitors in vitro were used to explore the involvement of HIF-3α in the pathophysiology of COPD. Results: Reactive oxygen species (ROS) and hypoxia were enriched in pre-COPD samples, and HIF-3α was downregulated in alveolar epithelial cells in COPD. In vitro experiments using lentivirus transfection, bulk-RNA seq, and RSL3 showed that the activation of the HIF-3α-GPx4 axis inhibited alveolar epithelial cell ferroptosis when treated with cigarettes smoking extracts (CSE). Further results from SftpcCreert2/+R26LSL-Hif3a knock-in mice demonstrated overexpression of HIF-3α inhibited alveolar epithelial cells ferroptosis and prevented the decline of lung function. Conclusion: Hypoxia and oxidation-related damage begins years before the onset of COPD symptoms, suggesting the imbalance and impairment of intracellular homeostatic system. The activation of the HIF-3α-GPx4 axis is a promising treatment target. By leveraging this comprehensive analysis method, more potential targets could be found and enhancing our understanding of the pathogenesis.
... Therefore, lung capacity measurements cannot sensitively predict symptoms, exercise capacity, and overall quality of life, nor can they reflect disease heterogeneity. Only after irreversible pathological changes occur in the lungs, lung capacity crosses the threshold of disease (Agusti et al., 2010;Reyfman et al., 2018;Stolz et al., 2022). Interesting, we noted Bailing capsule was associated with high cough score in severity of AECB during treatment, which could explained by Bailing capsules show limited efficacy in reducing inflammation during acute phases. ...
Background: Cordyceps sinensis is a traditional Chinese medicine that has shown promise for the management of chronic bronchitis (CB). We aim to assess the efficacy and safety of a preparation of C sinensis named Bailing capsule (Hirsutella sinensis, Cs-C-Q80) compared with a placebo in patients with CB.
Methods: This randomized, double-blind, placebo-controlled, parallel-group clinical trial (Chinese Clinical Trial Registry; registration number: ChiCTR1900025707) recruited patients with CB from eight hospitals in China between May 2019 and December 2020. Patients were randomized 2:1 to receive Bailing capsule or a placebo orally for 48 weeks (2.0 g, three times a day).
Results: Among 240 patients who were randomized, 238 (Bailing capsule: 159, placebo: 79) were included in the primary analysis. Bailing capsule significantly reduced the frequency of acute exacerbation of CB (AECB) compared with the placebo during treatment (0.43 ± 0.82 vs. 1.56 ± 1.34; P < 0.001) and follow-up (0.21 ± 0.64 vs. 0.45 ± 0.93; P = 0.026). Bailing capsule improved the severity of expectoration (P = 0.046) and wheezing (P = 0.010) in AECB during follow-up. The severity of CB after treatment was significantly improved in the Bailing capsule group compared with the placebo group (P = 0.035), particularly in terms of expectoration (P = 0.012) and wheezing (P = 0.003). The risk of adverse events, mainly including infectious and invasive diseases and gastrointestinal symptoms, did not significantly differ between the two groups (29.6% vs. 30.4%).
Conclusion: In patients with CB, Bailing capsule significantly reduces the frequency of AECB and ameliorates the severity of AECB and CB symptoms.
Clinical Trail Registration: https://www.chictr.org.cn, identifer ChiCTR1900025707.
... As seen in the GOLD 2022 definition of COPD (Gold Science Committee 2022) there is a paradigm shift in the taxonomy of COPD, as it is now recognized that it may be caused by non-infectious risk factors, such as poor outdoor or indoor air quality (Roque et al. 2023;Stolz et al. 2022), that may play a clinically relevant role for the disease. Documentation and understanding of the relationship between COPD-E and pollutant levels is crucial because it may increase COPD patients' survival and quality of life and reduce healthcare costs and disease burden. ...
Introduction
Air pollution poses a risk for people with Chronic Obstructive Pulmonary Disease (COPD). This study estimated the short-term effect of variations in air pollutant concentrations on exacerbations of COPD (COPD-E) in Bogotá, Colombia.
Methods
We performed an ecological time series study from 2014 to 2021 to evaluate the short-term effect of fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) levels on COPD-E treated in the emergency and hospitalization services. Daily counts of patients with COPD-E discharge diagnoses were obtained from the National Health Information System, and daily measurements of PM2.5, NO2, and O3 concentrations and meteorological data were obtained from air monitoring stations. A Generalized Additive Model was used with Distributed Lag Non-Linear Models to control for confounders.
Results
An increase of 10 μg/m³ in PM2.5 and O3 was associated with increased COPD-E admissions (lagged 0-3 days) with Relative Risk (RR) of 1.04 (95%CI: 1.02 -1.07) and RR:1.03 (95%CI:1.01 – 1.04), respectively. During the rainy season and minimum temperature of the series, for every 10 μg/m³ increase in PM2.5 concentration, COPD-E admissions (lagged 0-3 days) increased with RR 1.03 (95%CI: 1.01-1.06). A higher magnitude of association was observed in men (PM2.5, 1.04 95%CI:1.01 – 1.06 and O3, 1.04 95%CI:1.02 – 1.05, lag 0-7 days) than in women.
Conclusions
A higher air pollution was associated with more COPD-E. These results highlight the importance of actions aimed at improving air quality.
Graphical Abstract
Chronic obstructive pulmonary disease (COPD), commonly defined as irreversible airflow limitation, is associated with specific morphological changes involving all three parts of the lung, namely the bronchi, parenchyma and pulmonary vessels. In vivo imaging, with its ability to describe the different types of lung alterations and their regional distribution, helps to elucidate the relationship between lung structure and respiratory function. High-resolution computed tomography (CT) of the lung is the imaging modality best suited to assessing the pathological changes associated with airflow obstruction occurring in COPD. Over the last few decades, numerous studies have demonstrated the role of CT as a morphological and functional method conducive to the phenotyping of COPD patients. This review proposes to examine the data on CT imaging of COPD with a critical approach to recent data, and to determine the extent to which CT could be integrated into care or clinical research on patients with this/these disease(s).
Background
Evidence on how decisions regarding escalation to triple therapy and de- or re-escalation are taken and the rationale on which these decisions are based is currently limited in Germany.
Objectives
The TETRIS study aims to elucidate influences on treatment decisions surrounding triple therapy in a real-world practice setting in Germany.
Design
TETRIS is an ongoing, multicenter, prospective, observational cohort study recruiting patients with chronic obstructive pulmonary disease (COPD) with or without asthma who have already been treated with triple therapy for 2–48 weeks.
Methods
For better representation of the treatment reality in Germany, patients are recruited from general practitioners and pulmonologists. Data are collected in two parts. Part 1 involves cross-sectional phenotyping of patients at enrollment. Part 2 involves a 2-year longitudinal follow-up period to monitor/document all visits by the patients during the 24-month observation period per routine clinical practice. Here, we report the demographic and baseline characteristics of 1213 eligible patients recruited to part 1 of the study.
Results
The mean patient age was 66.4 years overall, and 29.3% (356/1213) of patients had no comorbidities. The mean CAT score was 19.4; the number of exacerbations and hospitalizations due to exacerbations in the past 3 years before starting triple therapy was 0.6 and 0.1, respectively. Dual bronchodilation with a long-acting muscarinic antagonist (LAMA) plus a long-acting β-2 agonist (LABA) was the most common therapy for COPD before initiation of triple therapy in 58.3% of patients.
Conclusion
In this real-world setting in Germany, patients with COPD have a relatively low reported exacerbation rate but high symptom burden, and over 70% are multimorbid. Triple therapy is initiated in patients who are primarily highly symptomatic despite being on LAMA + LABA. Future prospective studies in patients with multimorbidity are warranted to better understand the treatment landscape across the disease spectrum.
Trial registration
https://clinicaltrials.gov/study/NCT04657211
Background
Data regarding the effectiveness and safety of endoscopic lung volume reduction with valves (ELVR) in emphysema patients with very low 6-Minute Walk Test (6-MWT) is limited. Patients with severe emphysema and very low exercise capacity, as indicated by a 6-MWT ≤140 m, are often excluded from clinical studies on ELVR, assuming limited therapeutics benefits and increased complication risk.
Study Designs and Methods
This study utilized data from the Lungenemphysemregister e.V., a large German national multi-center prospective open label clinical trial, and aimed to assess the outcomes of ELVR in patients with a baseline 6-MWT ≤140 m and dyspnea primarily attributed to hyperinflation.
Results
Fifty-four patients with a baseline 6-MWT ≤140 m and 365 patients with a baseline 6-MWT between 140 m and 450 m were included in the study. Baseline characteristics were representative for patients with advanced lung emphysema. Patients with a 6-MWT ≤140 m at baseline had a lower FEV1, DLCO and higher symptom burden. In the 3-month-follow-up, patients of both groups showed statistically significant improvements in lung function parameters, exercise capacity and quality of life parameters compared to baseline. Patients with a 6-MWT ≤140 m at baseline showed significantly more 6-MWT improvement compared to patients with baseline 6-MWT between 140 m–450 m. Moreover, complication rates were similar in both groups.
Interpretation
In summary, the data indicates that ELVR may be an effective and safe treatment for emphysema patients with a very low 6-MWT ≤140 m, if very limited exercise capacity is predominately caused by lung emphysema. Therefore future studies should include emphysema patients with a very low 6-MWT.
Background
Clinical studies have shown that glucagon-like peptide-1 receptor agonists (GLP-1 RA) can have beneficial effects on cardiopulmonary function. We conducted this longitudinal cohort study to compare the risk of cardiopulmonary outcomes and mortality between GLP-1 RA use and no use in patients with type 2 diabetes (T2D) and chronic obstructive pulmonary disease (COPD).
Methods
The study identified 8060 matched GLP-1 RA users and non-users from Taiwan’s National Health Insurance Research Database from 1 January 2008 to 31 December 2019. Cox proportional hazards models were used to determine the risk of cardiopulmonary outcomes between GLP-1 RA users and non-users.
Results
The mean follow-up time was 2.51 and 2.46 years for GLP-1 RA users and non-users, respectively. In the matched cohorts, GLP-1 RA users had a significantly lower risk of mortality (adjusted HR (aHR) 0.46, 95% CI 0.38 to 0.56), cardiovascular events (aHR 0.73, 95% CI 0.65 to 0.82), non-invasive positive pressure ventilation (aHR 0.66, 95% CI 0.47 to 0.93), invasive mechanical ventilation (aHR 0.64, 95% CI 0.51 to 0.8) and bacterial pneumonia (aHR 0.76, 95% CI 0.65 to 0.88) than GLP-1 RA non-users. The subsequent analyses for various subgroup and medication duration also showed that GLP-1 RA was associated with a significantly lower risk of mortality, cardiovascular events, ventilation support and bacterial pneumonia than non-GLP-1 RA.
Conclusion
This nationwide cohort study showed that GLP-1 RA had a lower risk of cardiopulmonary outcomes and all-cause mortality than non-GLP-1 RA in patients with T2D and COPD. GLP-1 RA may help manage diabetes in people with COPD.
Chronic inflammatory airway diseases, such as chronic bronchitis, chronic obstructive pulmonary disease, emphysema, and bronchial asthma, pose significant healthcare challenges. Interventional treatments offer promise as valuable complements to the optimal medical therapy recommended by the Global Initiative for Chronic Obstructive Lung Disease guideline and the Global Initiative for Asthma guideline. By directly accessing the airways, these minimally invasive procedures enable precise interventions. They encompass a wide range of techniques including bronchial thermoplasty and targeted lung denervation for both chronic obstructive pulmonary disease and severe asthma, bronchoscopic lung volume reduction (including the use of endobronchial valves, coils, and bronchoscopic thermal vapor ablation), airway bypass and peripheral stent placement for emphysema, bronchial rheoplasty and spray cryotherapy for chronic bronchitis, and other emerging methods. These interventional treatments aim to improve patients’ symptoms by reducing lung volume, alleviating hyperinflation, eliminating vagal innervation, disrupting hyperplastic goblet cells and thus reducing excessive mucus secretion, and weakening submucosal smooth muscles. This review highlights the potential advantages of interventional treatments for chronic inflammatory airway diseases and discusses relevant techniques tailored to specific disease subtypes. The overall aim is to assist interventional pulmonologists in selecting the most appropriate techniques for individual patients.
Introduction:
Chronic obstructive pulmonary disease (COPD) has traditionally been diagnosed based on the criterion of an FEV1/FVC <0.70. However, this definition has limitations as it may only detect patients with later-stage disease, when pathologic changes have become irreversible. Consequently, it potentially omits individuals with early-stage disease, in whom the pathologic changes could be delayed or reversed.
Areas covered:
This narrative review summarizes recent evidence regarding early-stage COPD, which may not fulfill the spirometric criteria but nonetheless exhibits features of COPD or is at risk of future COPD progression.
Expert opinion:
A comprehensive approach, including symptoms assessment, various physiologic tests, and radiologic features, is required to diagnose COPD. This approach is necessary to identify currently underdiagnosed patients and to halt disease progression in at- risk patients.
Background
Pneumonias are events of great prognostic significance in COPD, so it is important to identify predictive factors.
Objective
To determine whether poor glycemic control is related to an increased risk of pneumonia in COPD.
Method
A historical cohort study conducted in a COPD clinic. The first severe exacerbation after the first visit was analyzed. Exacerbations that presented with pulmonary infiltrates were identified. A Cox proportional hazards analysis was performed including the values of glycosylated hemoglobin (Hb1Ac) in patients with diabetes mellitus (DM) and variables that could plausibly be related to the risk of pneumonia. The best Hb1Ac value to predict pneumonia was assessed using receiver-operating characteristics analysis.
Results
There were 1124 cases included in the study. A total of 411 patients were admitted to the hospital at least once and 87 were diagnosed with pneumonia. Variables associated with the risk of pneumonia were previous admissions due to COPD and Hb1Ac values (HR: 2.33, 95% CI: 1.06 – 5.08, p = 0.03). A higher body mass index (BMI) was associated with a lower risk of pneumonia. The optimal cutoff point for Hb1Ac to predict pneumonia risk was 7.8 %. The patients were classified into 3 groups: (1) no DM, (2) controlled DM (Hb1AC < 7.8 %), (3) uncontrolled DM (Hb1AC ≥ 7.8 %). The risk of pneumonia for group 2 was not different from group 1, while the risk for group 3 was significantly higher than for groups 1 and 2 (HR: 4.52, 95 % CI: 1.57 – 13.02).
Conclusions
Poor control of DM is a predictor of the risk of pneumonia in COPD. The cutoff point of 7.8 % for this variable seems to be the most useful to identify patients at risk.
Objective
A bibliometric analysis was conducted using VOSviewer and CiteSpace to examine studies published between 2009 and 2023 on the utilization of artificial intelligence (AI) in chronic obstructive pulmonary disease (COPD).
Methods
On March 24, 2024, a computer search was conducted on the Web of Science (WOS) core collection dataset published between January 1, 2009, and December 30, 2023, to identify literature related to the application of artificial intelligence in chronic obstructive pulmonary disease (COPD). VOSviewer was utilized for visual analysis of countries, institutions, authors, co-cited authors, and keywords. CiteSpace was employed to analyze the intermediary centrality of institutions, references, keyword outbreaks, and co-cited literature. Relevant descriptive analysis tables were created using Excel2021 software.
Results
This study included a total of 646 papers from WOS. The number of papers remained small and stable from 2009 to 2017 but started increasing significantly annually since 2018. The United States had the highest number of publications among countries/regions while Silverman Edwin K and Harvard Medical School were the most prolific authors and institutions respectively. Lynch DA, Kirby M. and Vestbo J. were among the top three most cited authors overall. Scientific Reports had the largest number of publications while Radiology ranked as one of the top ten influential journals. The Genetic Epidemiology of COPD (COPDGene) Study Design was frequently cited. Through keyword clustering analysis, all keywords were categorized into four groups: epidemiological study of COPD; AI-assisted imaging diagnosis; AI-assisted diagnosis; and AI-assisted treatment and prognosis prediction in the COPD research field. Currently, hot research topics include explainable artificial intelligence framework, chest CT imaging, and lung radiomics.
Conclusion
At present, AI is predominantly employed in genetic biology, early diagnosis, risk staging, efficacy evaluation, and prediction modeling of COPD. This study’s results offer novel insights and directions for future research endeavors related to COPD.
Rationale:
The slope of FEV1 decline is commonly used to reflect the rate of disease progression for descriptive studies and therapeutic trials in COPD. Frequency and duration of spirometric testing needed to report the true slope is unknown.
Objective:
To define the minimum frequency and follow-up duration needed to accurately describe the annualized rate of FEV1 change among patients with moderate-to-very severe COPD.
Methods:
We performed a post-hoc analysis of the annualized rate of FEV1 change among 4412 subjects previously enrolled in the four-year UPLIFT trial of tiotropium versus placebo. Slope estimates were modeled for different iterations of semiannual or annual testing over a variable duration up to four years. All models were compared to a reference of semiannual spirometry for four years.
Measurements and main results:
The overall rate of post-bronchodilator FEV1 decline measured semi-annually for four years (44.6 ml; 95% CI:42.5-46.6) did not differ significantly from annual spirometry over the same period (43.7 ml; 95% CI:41.3-46.1) or semiannual spirometry over the first two years (44.3 ml; 95% CI:41.1-47.5). Agreement was consistent for two follow-up values as far as 24 months apart (43.3ml; 95% CI:39.9-46.8). Models based on less than two follow-up values or duration less than 18 months were characterized by relative underestimation of the slope.
Conclusions:
In a large cohort of patients with moderate-to-very severe COPD, the annualized rate of change in FEV1 was accurately represented by a minimum of two follow-up measurements over 18 months compared to semiannual testing over four years.
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We comment on
"Free-breathing 3D phase-resolved functional lung MRI vs breath-hold hyperpolarized 129Xe ventilation MRI in patients with chronic obstructive pulmonary disease and healthy volunteers."
by
Klimeš F, Kern AL, Voskrebenzev A, Gutberlet M, Grimm R, Müller RA, Behrendt L, Kaireit TF, Glandorf J, Alsady TM, Wacker F, Hohlfeld JM, Vogel-Claussen J.
Eur Radiol. 2024 Jul 26. doi: 10.1007/s00330-024-10893-3. Online ahead of print.
PMID: 39060494
The chronic respiratory non-communicable diseases, asthma and chronic obstructive pulmonary disease (COPD) are among the leading causes of global mortality and morbidity. Individuals suffering from these diseases are particularly susceptible to respiratory infections caused by bacterial and/or viral pathogens, which frequently result in exacerbation of symptoms, lung function decline, frequent hospital emergency visits and increased socioeconomic burden. Human rhinoviruses (HRV) remain the major viral pathogen group implicated in exacerbations of both asthma and COPD. The rhinoviral entry into the host lung epithelium is facilitated primarily by the adhesion site (“receptor”) intercellular adhesion molecule-1 (ICAM-1), coincidentally expressed on the respiratory epithelium in these conditions. Multiple observations of increased airway ICAM-1 protein in asthmatics, smokers and smoking-related COPD have been recorded in the literature. However, the lack of robust therapies for COPD in particular has triggered a renewed interest in assessing receptor antagonism-based anti-viral strategies for treatment of intercurrent viral infections in those with pre-existing chronic lung diseases. Given the crucial role ICAM-1 plays in facilitating HRV adhesion and, thus, transmissibility to the host respiratory system, as well as the up-regulation of ICAM-1 by smoking, we summarize the role of HRV in smoking-induced COPD and especially highlight the role of ICAM-1 in epithelial viral adhesion and chronic lung disease progression. Further, the review also sheds light specifically on evolving precision therapeutic strategies in blocking ICAM-1 for preventing viral adhesion and exacerbations of COPD.
Evidence of influenza vaccine effectiveness in preventing confirmed influenza among persons diagnosed with chronic obstructive pulmonary disease (COPD) is scarce. We assessed the average effect of influenza vaccination in the current and prior seasons in preventing laboratory-confirmed influenza in COPD patients. We carried out a pooled test-negative case–control design in COPD patients hospitalized or presented to primary healthcare centres with influenza-like illness who were tested for influenza in 2015/2016 to 2019/2020 seasons in Navarre, Spain. Influenza vaccination status in the current and 5 prior seasons was compared between confirmed-influenza cases and test-negative controls. Vaccination effect was compared between target patients for vaccination with and without COPD. Out of 1761 COPD patients tested, 542 (31%) were confirmed for influenza and 1219 were test-negative controls. Average effect for current-season vaccination in preventing influenza was 40% (95% CI 20–54%), and for vaccination in prior seasons only was 24% (95% CI –10 to 47%). Point estimates seemed higher in preventing outpatient cases (60% and 58%, respectively) than inpatient cases (37% and 19%, respectively), but differences were no statistically significant. Influenza vaccination effect was similar in target population with and without COPD (p = 0.339). Influenza vaccination coverage in control patients with COPD was 68.3%. A 13.7% of the influenza cases in patients with COPD could be prevented by extending the influenza vaccine coverage. Average effect of current-season influenza vaccination was moderate to prevent influenza in COPD persons. The increase of influenza vaccination coverage can still prevent COPD exacerbations.
Background:
Heated tobacco products (HTPs) are designed to heat tobacco to a high enough temperature to release aerosol, without burning it or producing smoke. They differ from e-cigarettes because they heat tobacco leaf/sheet rather than a liquid. Companies who make HTPs claim they produce fewer harmful chemicals than conventional cigarettes. Some people report stopping smoking cigarettes entirely by switching to using HTPs, so clinicians need to know whether they are effective for this purpose and relatively safe. Also, to regulate HTPs appropriately, policymakers should understand their impact on health and on cigarette smoking prevalence.
Objectives:
To evaluate the effectiveness and safety of HTPs for smoking cessation and the impact of HTPs on smoking prevalence. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's Specialised Register, CENTRAL, MEDLINE, and six other databases for relevant records to January 2021, together with reference-checking and contact with study authors and relevant groups.
Selection criteria:
We included randomised controlled trials (RCTs) in which people who smoked cigarettes were randomised to switch to exclusive HTP use or a control condition. Eligible outcomes were smoking cessation, adverse events, and selected biomarkers. RCTs conducted in clinic or in an ambulatory setting were deemed eligible when assessing safety, including those randomising participants to exclusively use HTPs, smoke cigarettes, or attempt abstinence from all tobacco. Time-series studies were also eligible for inclusion if they examined the population-level impact of heated tobacco on smoking prevalence or cigarette sales as an indirect measure.
Data collection and analysis:
We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking at the longest follow-up point available, adverse events, serious adverse events, and changes in smoking prevalence or cigarette sales. Other outcomes included biomarkers of harm and exposure to toxicants/carcinogens (e.g. NNAL and carboxyhaemoglobin (COHb)). We used a random-effects Mantel-Haenszel model to calculate risk ratios (RR) with 95% confidence intervals (CIs) for dichotomous outcomes. For continuous outcomes, we calculated mean differences on the log-transformed scale (LMD) with 95% CIs. We pooled data across studies using meta-analysis where possible.
Main results:
We included 13 completed studies, of which 11 were RCTs assessing safety (2666 participants) and two were time-series studies. We judged eight RCTs to be at unclear risk of bias and three at high risk. All RCTs were funded by tobacco companies. Median length of follow-up was 13 weeks. No studies reported smoking cessation outcomes. There was insufficient evidence for a difference in risk of adverse events between smokers randomised to switch to heated tobacco or continue smoking cigarettes, limited by imprecision and risk of bias (RR 1.03, 95% CI 0.92 to 1.15; I2 = 0%; 6 studies, 1713 participants). There was insufficient evidence to determine whether risk of serious adverse events differed between groups due to very serious imprecision and risk of bias (RR 0.79, 95% CI 0.33 to 1.94; I2 = 0%; 4 studies, 1472 participants). There was moderate-certainty evidence for lower NNAL and COHb at follow-up in heated tobacco than cigarette smoking groups, limited by risk of bias (NNAL: LMD -0.81, 95% CI -1.07 to -0.55; I2 = 92%; 10 studies, 1959 participants; COHb: LMD -0.74, 95% CI -0.92 to -0.52; I2 = 96%; 9 studies, 1807 participants). Evidence for additional biomarkers of exposure are reported in the main body of the review. There was insufficient evidence for a difference in risk of adverse events in smokers randomised to switch to heated tobacco or attempt abstinence from all tobacco, limited by risk of bias and imprecision (RR 1.12, 95% CI 0.86 to 1.46; I2 = 0%; 2 studies, 237 participants). Five studies reported that no serious adverse events occurred in either group (533 participants). There was moderate-certainty evidence, limited by risk of bias, that urine concentrations of NNAL at follow-up were higher in the heated tobacco use compared with abstinence group (LMD 0.50, 95% CI 0.34 to 0.66; I2 = 0%; 5 studies, 382 participants). In addition, there was very low-certainty evidence, limited by risk of bias, inconsistency, and imprecision, for higher COHb in the heated tobacco use compared with abstinence group for intention-to-treat analyses (LMD 0.69, 95% CI 0.07 to 1.31; 3 studies, 212 participants), but lower COHb in per-protocol analyses (LMD -0.32, 95% CI -1.04 to 0.39; 2 studies, 170 participants). Evidence concerning additional biomarkers is reported in the main body of the review. Data from two time-series studies showed that the rate of decline in cigarette sales accelerated following the introduction of heated tobacco to market in Japan. This evidence was of very low-certainty as there was risk of bias, including possible confounding, and cigarette sales are an indirect measure of smoking prevalence.
Authors' conclusions:
No studies reported on cigarette smoking cessation, so the effectiveness of heated tobacco for this purpose remains uncertain. There was insufficient evidence for differences in risk of adverse or serious adverse events between people randomised to switch to heated tobacco, smoke cigarettes, or attempt tobacco abstinence in the short-term. There was moderate-certainty evidence that heated tobacco users have lower exposure to toxicants/carcinogens than cigarette smokers and very low- to moderate-certainty evidence of higher exposure than those attempting abstinence from all tobacco. Independently funded research on the effectiveness and safety of HTPs is needed. The rate of decline in cigarette sales accelerated after the introduction of heated tobacco to market in Japan but, as data were observational, it is possible other factors caused these changes. Moreover, falls in cigarette sales may not translate to declining smoking prevalence, and changes in Japan may not generalise elsewhere. To clarify the impact of rising heated tobacco use on smoking prevalence, there is a need for time-series studies that examine this association.
Chronic obstructive pulmonary disease (COPD) manifests with a variety of clinical presentations, reflecting its complex pathology. Currently, care focuses on symptom amelioration and prevention of complications, thus is generally tailored to disease severity rather than targeting specific pathophysiologic mechanisms. Chronic inflammation and mucus hypersecretion are key features of COPD. Epithelial ion channel dysfunction may be important as it results in airway dehydration and defective host defense, contributing to chronic airway inflammation. Recent evidence suggests considerable similarities between COPD and cystic fibrosis (CF), a disease in which chloride ion channel dysfunction has been extensively studied (in particular, CF transmembrane conductance regulator [CFTR]). Understanding commonalities between CF and COPD, and the role of CFTR in CF, may help in designing strategies targeting ion channel dysfunction, and lead to new treatments with potential to alter the natural history of disease progression. Here, we review the roles of airway mucus and CFTR in normal lung function, the previously underestimated contribution of mucus stasis to the development of COPD, and the evidence for targeting CFTR to counteract mucus accumulation.
Background and Objectives
Chronic obstructive pulmonary disease (COPD) is characterized by the destruction of alveolar walls, chronic inflammation and persistent respiratory symptoms. There is no curative clinical treatment for COPD. In this context, cell-based therapy is a promising therapeutic alternative for COPD. Thus, in this open, controlled and randomized Phase I Clinical Trial, we aimed to assess the safety of the infusion of autologous bone marrow mononuclear cells (BMMC), adipose-derived mesenchymal stromal cells (ADSC) and, especially, the safety of concomitant infusion (co-infusion) of BMMC and ADSC as a new therapeutic alternative for COPD. The rationale for co-infusion of BMMC and ADSC is based on the hypothesis of an additive or synergistic therapeutic effect resulting from this association.
Methods
To achieve the proposed objectives, twenty patients with moderate-to-severe COPD were randomly divided into four groups: control group – patients receiving conventional treatment; BMMC group – patients receiving only BMMC; ADSC group – patients receiving only ADSC, and co-infusion group – patients receiving the concomitant infusion of BMMC and ADSC. Patients were assessed for pulmonary function, biochemical profile, and quality of life over a 12 months follow-up.
Results
No adverse events were detected immediately after the infusion of BMMC, ADSC or co-infusion. In the 12-month follow-up, no causal relationship was established between adverse events and cell therapy procedures. Regarding the efficacy, the BMMC group showed an increase in forced expiratory volume (FEV1) and diffusing capacity for carbon monoxide (DLCO). Co-infusion group showed a DLCO, and gas exchange improvement and a better quality of life.
Conclusion
The results obtained allow us to conclude that cell-based therapy with co-infusion of BMMC and ADSC is a safe procedure and a promising therapeutic for COPD. However, additional studies with a greater number of patients are needed before randomized and controlled Phase III clinical trials can be implemented.
Background
To document a generalizable process for developing a patient-prioritized chronic obstructive pulmonary disease (COPD) research agenda and to provide an overview of domains that were developed in response to people living with COPD and caregivers’ suggestions for research.
Methods
Adults with COPD and caregivers who are members of the COPD Patient-Powered Research Network (PPRN) provided suggestions for COPD-related research through a self-administered, online survey. These responses were analyzed with a content analysis approach: domains for categorizing all survey responses were created, then all responses were categorized independently by a group of researchers, then these categorizations were adjudicated, and finally a density map was created that represented the number of responses in each of the domains.
Results
At the time of analysis, 6157 adults had fully completed the baseline survey. Survey responses were categorized across seven domains as follows: 22.5% of all responses fell into the domain family/social/community research, 20.8% of all responses fell into the domain well-being, 15% of all responses fell into the domain curative research, 14.6% of all responses fell into the domain biomedical therapies, 10.5% of all responses fell into the domain policy concerns, 6% of all responses fell into the domain holistic therapies and 10.7% of all responses fell into the domain ambiguous comments that could not be translated into concrete research topics.
Conclusion
Using qualitative open-ended survey responses from the COPD PPRN registrants, we were able to identify six key domains of research about COPD that are considered most important by patients. These domains differ in content from prior scientist-led efforts to develop priorities for COPD research, demonstrating the ongoing importance of involving patients and their caregivers in determining research priorities. The results suggest the field can more closely align research efforts to patient priorities by considering the identified domains.
Severe asthma often remains uncontrolled despite effective treatments and evidence-based guidelines. A group of global experts in asthma and biologic medications from nine countries considered the most relevant clinical variables to manage severe asthma in adult patients and guide treatment choice. The resulting recommendations address the investigation of biomarker levels (blood eosinophil count along with fractional concentration of exhaled nitric oxide [FeNO]), clinical features (oral corticosteroid [OCS] dependency, specific comorbid disease entities associated with severe type 2 asthma), and safety considerations. Current evidence suggests that biomarkers, including both blood or sputum eosinophil counts as well as FeNO, add prognostic and predictive value and should be measured in all patients with severe asthma. OCS use is an important factor in biologic selection, especially given the documented ability of some biologics to reduce OCS dependency. Comorbid diseases and relevant safety considerations to each biologic should also be considered. More data are needed to determine whether biomarker profiles identify patients suited to one biologic versus another as limited data support differential predictors of response. Further prospective head-to-head trials and post hoc analyses of clinical trial data are warranted. The authors believe these recommendations have value as they offer expert opinion to assist health care providers in making difficult decisions regarding the quality of care in severe, type 2 asthma with biologic medications. They remain conditional and are based on limited data owing to a lack of head-to-head comparisons.
Early identification of subjects running an increased risk of contracting COPD enables focus on individual preventive measures. The slope of the alveolar plateau of the single-breath nitrogen washout test (N 2 -slope) is a sensitive measure of small-airway dysfunction. However, its role remains unexplored in predicting hospital admission or death related to COPD, i.e. incident COPD events, in relation to the presence of various respiratory symptoms.
A random population sample of 625 men, aged 50 (n=218) or 60 years (n=407), was followed for 38 years for incident COPD events. At baseline, a questionnaire on respiratory symptoms and smoking habits was collected, spirometry and the single-breath nitrogen test were performed, and the N 2 -slope was determined. Proportional hazard regression (Cox regression) analysis was used for the prediction model.
The N 2 -slope improved the prediction of COPD events significantly beyond that of respiratory symptoms weighted all together and other covariates (hazard ratio 1.63, 95% CI 1.20–2.22; p<0.005), a prediction applicable to subjects without (p=0.001) and with (p<0.05) airway obstruction. Dyspnoea and wheezing were the most predictive symptoms. The combination of the N 2 -slope and number of respiratory symptoms notably resulted in an effective prediction of incident COPD events even in nonobstructive subjects, as evidenced by a predicted incidence of ∼70% and ∼90% for a very steep N 2 -slope combined with many respiratory symptoms in subject without and with airway obstruction, respectively.
The alveolar N 2 -slope should be considered in the critical need for further research on early diagnosis of COPD.
Neutrophil elastase (NE) is a major inflammatory protease released by neutrophils and is present in the airways of patients with cystic fibrosis (CF), chronic obstructive pulmonary disease, non-CF bronchiectasis, and bronchopulmonary dysplasia. Although NE facilitates leukocyte transmigration to the site of infection and is required for clearance of Gram-negative bacteria, it also activates inflammation when released into the airway milieu in chronic inflammatory airway diseases. NE exposure induces airway remodeling with increased mucin expression and secretion and impaired ciliary motility. NE interrupts epithelial repair by promoting cellular apoptosis and senescence and it activates inflammation directly by increasing cytokine expression and release, and indirectly by triggering extracellular trap release and exosome release, which magnify protease activity and inflammation in the airway. NE inhibits innate immune function by digesting opsonins and opsonin receptors, degrading innate immune proteins such as lactoferrin, and inhibiting macrophage phagocytosis. Importantly, NE-directed therapies have not yet been effective in preventing the pathologic sequelae of NE exposure, but new therapies are being developed that offer both direct antiprotease activity and multifunctional anti-inflammatory properties.
Background
Correct inhaler use can be challenging in real life, with incorrect use resulting in poor symptom control. The aim of this study was to examine factors associated with poor inhaler technique and poor therapy adherence among patients with obstructive lung disease in community pharmacies.
Methods
A cross-sectional study was conducted in patients with obstructive lung diseases in nine Belgian community pharmacies. Logistic regression analyses identified factors associated with poor inhaler technique and poor therapy adherence (assessed by the Test of Adherence to Inhalers and the modified Medication Possession Ratio).
Results
Seventy obstructively impaired community patients (median age 64 y, 56% females) were included and the technique of 122 inhalers was assessed. Inhaler technique scored generally poor, with half of patients making critical errors in using at least one of their inhalers. In multivariable analysis, the use of multiple devices (adjusted OR, aOR 11.68; 95% CI 3.29 to 41.51) and a diagnosis of asthma-Chronic Obstructive Pulmonary Disease overlap (ACO; aOR 7.06; 95% CI 1.15 to 43.35), were associated with making critical errors in inhaler technique independent of quality of life. Non-adherence occurred in more than one-third of patients, and occurred in up to one half of the patients when also taking overuse into account. In multivariable analysis for therapy adherence, current smoking was associated with poor therapy adherence (aOR 0.15; 95% CI 0.02 to 0.96) independently of age and poor treatment knowledge. Therapy adherence was poor in patients with asthma compared with those with ACO. Current smokers and highly educated patients seemed to be at increased risk for inhaler overuse.
Conclusions
Given the important role of a correct inhaler technique and therapy adherence in disease control, these findings emphasise the need for patient education and aiming uniformity in the inhaler device.
Trial registration number
B670201835229.
Hypertension remains the leading cause of cardiovascular disease worldwide and disproportionately impacts patients living in low- and middle-income countries (LMICs). Telemedicine offers a potential solution for improving access to health care for vulnerable patients in LMICs.
Objectives
The purpose of this scoping review was to summarize the evidence for telemedicine interventions for blood pressure management in LMICs and assess the relationships between the telemedicine intervention characteristics and clinical outcomes.
Design
Published studies were identified from the following databases (from their inception to May 2020): PubMed, Scopus, and Embase. Search terms related to “Low and Middle Income Countries,” “Telemedicine,” and “Hypertension” were used, and clinical outcomes were extracted from the screened articles.
Results
Our search resulted in 530 unique articles, and 14 studies were included in this review. Five studies assessed telemedicine interventions for patient-provider behavioral counseling, four assessed patient-provider medical management, and five assessed provider-provider consultation technologies. Out of fourteen individual studies, eleven demonstrated a significant improvement in systolic or diastolic blood pressure in the intervention group. Of the eight studies that reported difference-in-differences changes in systolic blood pressure, between-arm differences ranged from 13.2 mmHg to 0.4 mmHg.
Conclusions
The majority of the studies in this review demonstrated a significant reduction in blood pressure with use of the telemedicine intervention, though the magnitude of benefit was not consistently large. Limitations of the studies included small sample sizes, short duration, and intervention heterogeneity. Current evidence suggests that telemedicine may provide a promising approach to increase access to care and improve outcomes for hypertension in LMICs, especially during events that limit access to in-person care, such as the COVID-19 pandemic. However, high-quality clinical trials of sufficient size and duration are needed to establish the impact and role of telemedicine in hypertension care. The protocol for this review was not registered.
Introduction
The current framework for investigating respiratory diseases is based on defining lung health as the absence of lung disease. In order to develop a comprehensive approach to prevent the development of lung disease, there is a need to evaluate the full spectrum of lung health spanning from ideal to impaired lung health. The American Lung Association (ALA) Lung Health Cohort is a new, population-based, cohort study focused primarily on characterising lung health in members of the millennial generation without diagnosed severe respiratory disease. Participants will be enrolled for the baseline study visit starting in 2021, and funding will be sought to support future study exams as part of a longitudinal cohort study. This study will be crucial for developing a novel paradigm of lung health throughout the adult life course.
Methods and analysis
This study will leverage the existing infrastructure of the ALA Airways Clinical Research Centers network to enrol 4000 participants between ages 25 and 35 years old at 39 sites across the USA between April 2021 and December 2024. Study procedures will include physical assessment, spirometry, chest CT scan, accelerometry and collection of nasal epithelial lining fluid, nasal epithelial cells, blood and urine. Participants will complete questionnaires about their sociodemographic characteristics, home address histories and exposures, work history and exposure, medical histories, lung health and health behaviours and activity.
Ethics and dissemination
The study was approved by the Johns Hopkins Medicine Institutional Review Board. Findings will be disseminated to the scientific community through peer-reviewed journals and at professional conferences. The lay public will receive scientific findings directly through the ALA infrastructure including the official public website. Deidentified datasets will be deposited to BioLINCC, and deidentified biospecimens may be made available to qualified investigators along with a limited-use datasets.
Background
Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation and bacterial dysbiosis. The relationship between the airway microbiome and bronchial gene expression in COPD is poorly understood. We aimed to identify differences in the airway microbiome from bronchial brushings in patients with COPD and healthy individuals and to investigate whether any distinguishing bacteria are related to bronchial gene expression.
Methods
For this 16S rRNA gene sequencing and host transcriptomic analysis, individuals aged 45–75 years with mild-to-moderate COPD either receiving or not receiving inhaled corticosteroids and healthy individuals in the same age group were recruited as part of the Emphysema versus Airways Disease (EvA) consortium from nine centres in the UK, Germany, Italy, Poland, and Hungary. Individuals underwent clinical characterisation, spirometry, CT scans, and bronchoscopy. From bronchoscopic bronchial brush samples, we obtained the microbial profiles using 16S rRNA gene sequencing and gene expression using the RNA-Seq technique. We analysed bacterial genera relative abundance and the associations between genus abundance and clinical characteristics or between genus abundance and host lung transcriptional signals in patients with COPD versus healthy individuals, and in patients with COPD with versus without inhaled corticosteroids treatment.
Findings
Between February, 2009, and March, 2012, we obtained brush samples from 574 individuals. We used 546 of 574 samples for analysis, including 207 from healthy individuals and 339 from patients with COPD (192 with inhaled corticosteroids and 147 without). The bacterial genera that most strongly distinguished patients with COPD from healthy individuals were Prevotella (median relative abundance 33·5%, IQR 14·5–49·4, in patients with COPD vs 47·7%, 31·1–60·7, in healthy individuals; p<0·0001), Streptococcus (8·6%, 3·8–15·8, vs 5·3%, 3·0–10·1; p<0·0001), and Moraxella (0·05%, 0·02–0·14, vs 0·02%, 0–0·07; p<0·0001). Prevotella abundance was inversely related to COPD severity in terms of symptoms and positively related to lung function and exercise capacity. 446 samples had assessable RNA-seq data, 257 from patients with COPD (136 with inhaled corticosteroids and 121 without) and 189 from healthy individuals. No significant associations were observed between lung transcriptional signals from bronchial brushings and abundance of bacterial genera in patients with COPD without inhaled corticosteroids treatment and in healthy individuals. In patients with COPD treated with inhaled corticosteroids, Prevotella abundance was positively associated with expression of epithelial genes involved in tight junction promotion and Moraxella abundance was associated with expression of the IL-17 and TNF inflammatory pathways.
Interpretation
With increasing severity of COPD, the airway microbiome is associated with decreased abundance of Prevotella and increased abundance of Moraxella in concert with downregulation of genes promoting epithelial defence and upregulation of pro-inflammatory genes associated with inhaled corticosteroids use. Our work provides further insight in understanding the relationship between microbiome alteration and host inflammatory response, which might lead to novel therapeutic strategies for COPD.
Funding
EU Seventh Framework Programme, National Institute for Health Research.
Background: Ending the global tobacco epidemic is a defining challenge in global health. Timely and comprehensive estimates of the prevalence of smoking tobacco use and attributable disease burden are needed to guide tobacco control efforts nationally and globally. Methods: We estimated the prevalence of smoking tobacco use and attributable disease burden for 204 countries and territories, by age and sex, from 1990 to 2019 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study. We modelled multiple smoking-related indicators from 3625 nationally representative surveys. We completed systematic reviews and did Bayesian meta-regressions for 36 causally linked health outcomes to estimate non-linear dose-response risk curves for current and former smokers. We used a direct estimation approach to estimate attributable burden, providing more comprehensive estimates of the health effects of smoking than previously available. Findings: Globally in 2019, 1·14 billion (95% uncertainty interval 1·13–1·16) individuals were current smokers, who consumed 7·41 trillion (7·11–7·74) cigarette-equivalents of tobacco in 2019. Although prevalence of smoking had decreased significantly since 1990 among both males (27·5% [26·5–28·5] reduction) and females (37·7% [35·4–39·9] reduction) aged 15 years and older, population growth has led to a significant increase in the total number of smokers from 0·99 billion (0·98–1·00) in 1990. Globally in 2019, smoking tobacco use accounted for 7·69 million (7·16–8·20) deaths and 200 million (185–214) disability-adjusted life-years, and was the leading risk factor for death among males (20·2% [19·3–21·1] of male deaths). 6·68 million [86·9%] of 7·69 million deaths attributable to smoking tobacco use were among current smokers. Interpretation: In the absence of intervention, the annual toll of 7·69 million deaths and 200 million disability-adjusted life-years attributable to smoking will increase over the coming decades. Substantial progress in reducing the prevalence of smoking tobacco use has been observed in countries from all regions and at all stages of development, but a large implementation gap remains for tobacco control. Countries have a clear and urgent opportunity to pass strong, evidence-based policies to accelerate reductions in the prevalence of smoking and reap massive health benefits for their citizens.
Background: Chronic obstructive pulmonary disease (COPD), which is a disease characterized by dyspnea, cough, and respiratory symptoms, leading to impaired health-related quality of life (HRQL) and exercise capacity, is highly prevalent worldwide. Some studies demonstrated that acupuncture point stimulation treatments (APSTs) are effective and safe in treating patients with COPD. The aim of this systematic review and network meta-analysis is to analyze the effects on HRQL and FEV1% predicted of diverse APSTs in treating patients with COPD.
Materials and Methods: We searched seven electronic databases. Randomized controlled trials (RCTs) with stable COPD patients comparing APSTs and conventional treatment (Tx) were included. The primary outcome was HRQL measured by COPD Assessment Test or St. George's Respiratory Questionnaire. The secondary outcome was FEV1% predicted. We performed random effect network meta-analysis using a consistency model.
Results: This network meta-analysis analyzed 21 RCTs with 1,577 stable COPD participants. In comparison with Tx, acupressure massage (AM) + Tx [−5.11; 95% confidence interval (CI), −6.65 to −3.57] was the most effective intervention in improving HRQL, followed by moxibustion (Mx) + Tx (−2.86; 95% CI, −3.86 to −1.86). Moreover, in comparison with Tx, Mx + Tx (7.79; 95% CI, 2.16 to 13.42) was the most effective intervention in improving FEV1% predicted, followed by acupuncture (A) + Tx (5.79; 95% CI, 2.90 to 8.68).
Conclusions: Combined interventions (APSTs + Tx) are more effective than single intervention in improving both HRQL and FEV1% predicted. AM, Mx, and A can be considered effective non-pharmacological complementary interventions in treating patients with COPD under Tx.
Background
Ending the global tobacco epidemic is a defining challenge in global health. Timely and comprehensive estimates of the prevalence of smoking tobacco use and attributable disease burden are needed to guide tobacco control efforts nationally and globally.
Methods
We estimated the prevalence of smoking tobacco use and attributable disease burden for 204 countries and territories, by age and sex, from 1990 to 2019 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study. We modelled multiple smoking-related indicators from 3625 nationally representative surveys. We completed systematic reviews and did Bayesian meta-regressions for 36 causally linked health outcomes to estimate non-linear dose-response risk curves for current and former smokers. We used a direct estimation approach to estimate attributable burden, providing more comprehensive estimates of the health effects of smoking than previously available.
Findings
Globally in 2019, 1·14 billion (95% uncertainty interval 1·13–1·16) individuals were current smokers, who consumed 7·41 trillion (7·11–7·74) cigarette-equivalents of tobacco in 2019. Although prevalence of smoking had decreased significantly since 1990 among both males (27·5% [26·5–28·5] reduction) and females (37·7% [35·4–39·9] reduction) aged 15 years and older, population growth has led to a significant increase in the total number of smokers from 0·99 billion (0·98–1·00) in 1990. Globally in 2019, smoking tobacco use accounted for 7·69 million (7·16–8·20) deaths and 200 million (185–214) disability-adjusted life-years, and was the leading risk factor for death among males (20·2% [19·3–21·1] of male deaths). 6·68 million [86·9%] of 7·69 million deaths attributable to smoking tobacco use were among current smokers.
Interpretation
In the absence of intervention, the annual toll of 7·69 million deaths and 200 million disability-adjusted life-years attributable to smoking will increase over the coming decades. Substantial progress in reducing the prevalence of smoking tobacco use has been observed in countries from all regions and at all stages of development, but a large implementation gap remains for tobacco control. Countries have a clear and urgent opportunity to pass strong, evidence-based policies to accelerate reductions in the prevalence of smoking and reap massive health benefits for their citizens.
Funding
Bloomberg Philanthropies and the Bill & Melinda Gates Foundation.
During the COVID-19 pandemic, a countrywide lockdown of nearly twelve weeks in India reduced access to regular healthcare services. As a policy response, the Ministry of Health & Family Welfare which exercises jurisdiction over telemedicine in India, rapidly issued India’s first guidelines for use of telemedicine. The authors argue that: guidelines must be expanded to address ethical concerns about the use of privacy, patient data and its storage; limited access to the internet and weaknesses in the telecom infrastructure challenge widespread adoption of telemedicine; only by simultaneously improving both will use of telemedicine become equitable; Indian medical education curricula should include telemedicine and India should rapidly extend training to practitioner. They determine that for low- and middle-income countries (LMIC), including India, positive externalities of investing in telemedicine are ample, thus use of this option can render healthcare more accessible and equitable in future.
Pulmonary rehabilitation is a highly effective treatment for people with chronic lung disease but remains underused across the world. Recent years have seen the emergence of new program models that aim to improve access and uptake, including telerehabilitation and low-cost, home-based models. This workshop was convened to achieve consensus on the essential components of pulmonary rehabilitation and to identify requirements for successful implementation of emerging program models. A Delphi process involving experts from across the world identified 13 essential components of pulmonary rehabilitation that must be delivered in any program model, encompassing patient assessment, program content, method of delivery, and quality assurance, as well as 27 desirable components. Only those models of pulmonary rehabilitation that have been tested in clinical trials are currently considered as ready for implementation. The characteristics of patients most likely to succeed in each program model are not yet known, and research is needed in this area. Health professionals should use clinical judgment to determine those patients who are best served by a center-based, multidisciplinary rehabilitation program. A comprehensive patient assessment is critical for personalization of pulmonary rehabilitation and for effectively addressing individual patient goals. Robust quality-assurance processes are important to ensure that any pulmonary rehabilitation service delivers optimal outcomes for patients and health services. Workforce capacity-building and training should consider the skills necessary for emerging models, many of which are delivered remotely. The success of all pulmonary rehabilitation models will be judged on whether the essential components are delivered and on whether the expected patient outcomes, including improved exercise capacity, reduced dyspnea, enhanced health-related quality of life, and reduced hospital admissions, are achieved.
It is known that the cell environment such as biomechanical properties and extracellular matrix (ECM) composition dictate cell behaviour including migration, proliferation, and differentiation. Important constituents of the microenvironment, including ECM molecules such as proteoglycans and glycosaminoglycans (GAGs), determine events in both embryogenesis and repair of the adult lung. Mesenchymal stromal/stem cells (MSC) have been shown to have immunomodulatory properties and may be potent actors regulating tissue remodelling and regenerative cell responses upon lung injury. Using MSC in cell-based therapy holds promise for treatment of chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). However, so far clinical trials with MSCs in COPD have not had a significant impact on disease amelioration nor on IPF, where low cell survival rate and pulmonary retention time are major hurdles to overcome. Research shows that the microenvironment has a profound impact on transplanted MSCs. In our studies on acellular lung tissue slices (lung scaffolds) from IPF patients versus healthy individuals, we see a profound effect on cellular activity, where healthy cells cultured in diseased lung scaffolds adapt and produce proteins further promoting a diseased environment, whereas cells on healthy scaffolds sustain a healthy proteomic profile. Therefore, modulating the environmental context for cell-based therapy may be a potent way to improve treatment using MSCs. In this review, we will describe the importance of the microenvironment for cell-based therapy in chronic lung diseases, how MSC-ECM interactions can affect therapeutic output and describe current progress in the field of cell-based therapy.
Mechanistic research suggests that lifestyle and environmental factors impact respiratory health across generations by epigenetic changes transmitted through male germ cells. Evidence from studies on humans is very limited.
We investigated multi-generation causal associations to estimate the causal effects of tobacco smoking on lung function within the paternal line. We analysed data from 383 adult offspring (age: 18–47; female: 52.0%) and their 274 fathers, who had participated in the ECRHS/RHINESSA generation study and had provided valid measures of pre-bronchodilator lung function. Two counterfactual-based, multi-level mediation models were developed with: paternal grandmothers’ smoking in pregnancy and fathers’ smoking initiation in prepuberty as exposures; fathers’ FEV 1 and FVC, or FEV 1 /FVC z-scores as potential mediators (proxies of unobserved biological mechanisms that are true mediators); offspring's FEV 1 and FVC, or FEV 1 /FVC z-scores as outcomes. All effects were summarised as differences in expected z-scores related to fathers’ and grandmothers’ smoking history.
Fathers’ smoking initiation in prepuberty had a negative direct effect on both offspring's FEV 1 (−0.36; 95% confidence interval: −0.63, −0.10) and FVC (−0.50; −0.80, −0.20) compared to fathers’ never smoking. Paternal grandmothers’ smoking in pregnancy had a negative direct effect on fathers’ FEV 1 /FVC (−0.57; −1.09, −0.05) and a negative indirect effect on offspring's FEV 1 /FVC (−0.12; −0.21, −0.03) compared to grandmothers’ not smoking before fathers’ birth nor during fathers’ childhood.
Fathers’ smoking in prepuberty and paternal grandmothers’ smoking in pregnancy may cause lower lung function in offspring. Our results support the concept that lifestyle-related exposures during these susceptibility periods influence the health of future generations.
Objective:
To determine the effectiveness of telemedicine in the delivery of diabetes care in low- and middle-income countries.
Methods:
We searched seven databases up to July 2020 for randomized controlled trials investigating the effectiveness of telemedicine in the delivery of diabetes care in low- and middle-income countries. We extracted data on the study characteristics, primary end-points and effect sizes of outcomes. Using random effects analyses, we ran a series of meta-analyses for both biochemical outcomes and related patient properties.
Findings:
We included 31 interventions in our meta-analysis. We observed significant standardized mean differences of -0.38 for glycated haemoglobin (95% confidence interval, CI: -0.52 to -0.23; I2 = 86.70%), -0.20 for fasting blood sugar (95% CI: -0.32 to -0.08; I2 = 64.28%), 0.81 for adherence to treatment (95% CI: 0.19 to 1.42; I2 = 93.75%), 0.55 for diabetes knowledge (95% CI: -0.10 to 1.20; I2 = 92.65%) and 1.68 for self-efficacy (95% CI: 1.06 to 2.30; I2 = 97.15%). We observed no significant treatment effects for other outcomes, with standardized mean differences of -0.04 for body mass index (95% CI: -0.13 to 0.05; I2 = 35.94%), -0.06 for total cholesterol (95% CI: -0.16 to 0.04; I2 = 59.93%) and -0.02 for triglycerides (95% CI: -0.12 to 0.09; I2 = 0%). Interventions via telephone and short message service yielded the highest treatment effects compared with services based on telemetry and smartphone applications.
Conclusion:
Although we determined that telemedicine is effective in improving several diabetes-related outcomes, the certainty of evidence was very low due to substantial heterogeneity and risk of bias.
This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2‐fold to 3‐fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2‐fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
Background
Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) carry significant morbidity and mortality. AECOPD treatment remains limited. High molecular weight hyaluronan (HMW-HA) is a glycosaminoglycan sugar, which is a physiological constituent of the lung extracellular matrix and has notable anti-inflammatory and hydrating properties.
Research question
We hypothesized that inhaled HMW-HA will improve outcomes in AECOPD.
Methods
We conducted a single center, randomized, placebo-controlled, double-blind study to investigate the effect of inhaled HMW-HA in patients with severe AECOPD necessitating non-invasive positive-pressure ventilation (NIPPV). Primary endpoint was time until liberation from NIPPV.
Results
Out of 44 screened patients, 41 were included in the study (21 for placebo and 20 for HMW-HA). Patients treated with HMW-HA had significantly shorter duration of NIPPV. HMW-HA treated patients also had lower measured peak airway pressures on the ventilator and lower systemic inflammation markers after liberation from NIPPV. In vitro testing showed that HMW-HA significantly improved mucociliary transport in air–liquid interface cultures of primary bronchial cells from COPD patients and healthy primary cells exposed to cigarette smoke extract.
Interpretation
Inhaled HMW-HA shortens the duration of respiratory failure and need for non-invasive ventilation in patients with AECOPD. Beneficial effects of HMW-HA on mucociliary clearance and inflammation may account for some of the effects (NCT02674880, www.clinicaltrials.gov).
Chronic obstructive pulmonary disease (COPD) and lung cancer (LC) are common global causes of morbidity and mortality. Because both diseases share several predisposing risks, the two diseases may occur concurrently in susceptible individuals. The diagnosis of COPD has important implications for the diagnostic approach and treatment options if lesions concerning for LC are identified during screening. Importantly, the presence of COPD has significant implications on prognosis and management of patients with LC. In this monograph, we review the mechanistic linkage between LC and COPD, the impact of LC screening in patients at risk, and the implications of the presence of COPD on the approach to the diagnosis and treatment of LC. This manuscript succinctly reviews the epidemiology and common pathogenetic factors for the concurrence of COPD and LC. Importantly for the clinician, it summarizes the indications, benefits, and complications of LC screening in patients with COPD, and the assessment of risk factors for patients with COPD undergoing consideration of various treatment options for LC.
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.
Chronic obstructive pulmonary disease (COPD) is a deadly and highly morbid disease. Susceptibility to and heterogeneity of COPD are incompletely explained by environmental factors such as cigarette smoking. Family-based and population-based studies have shown that a substantial proportion of COPD risk is related to genetic variation. Genetic association studies have identified hundreds of genetic variants that affect risk for COPD, decreased lung function, and other COPD-related traits. These genetic variants are associated with other pulmonary and non-pulmonary traits, demonstrate a genetic basis for at least part of COPD heterogeneity, have a substantial effect on COPD risk in aggregate, implicate early-life events in COPD pathogenesis, and often involve genes not previously suspected to have a role in COPD. Additional progress will require larger genetic studies with more ancestral diversity, improved profiling of rare variants, and better statistical methods. Through integration of genetic data with other omics data and comprehensive COPD phenotypes, as well as functional description of causal mechanisms for genetic risk variants, COPD genetics will continue to inform novel approaches to understanding the pathobiology of COPD and developing new strategies for management and treatment.
Chronic obstructive pulmonary disease (COPD) was traditionally thought to be caused by tobacco smoking. However, recognition of the importance of non-smoking-related risk factors for COPD has increased over the past decade, with evidence on the burden, risk factors, and clinical presentations of COPD in never-smokers. About half of all COPD cases worldwide are due to non-tobacco-related risk factors, which vary by geographical region. These factors include air pollution, occupational exposures, poorly controlled asthma, environmental tobacco smoke, infectious diseases, and low socioeconomic status. Impaired lung growth during childhood, caused by a range of early-life exposures, is associated with an increased risk of COPD. Potential mechanisms for the pathogenesis of COPD in never-smokers include inflammation, oxidative stress, airway remodelling, and accelerated lung ageing. Compared with smokers who develop COPD, never-smokers with COPD have relatively mild chronic respiratory symptoms, little or no emphysema, milder airflow limitation, and fewer comorbidities; however, exacerbations can still be frequent. Further research—including epidemiological, translational, clinical, and implementation studies—is needed to address gaps in understanding and to advance potential solutions to reduce the burden of COPD in never-smokers.
The traditional view of chronic obstructive pulmonary disease (COPD) as a self-inflicted disease caused by tobacco smoking in genetically susceptible individuals has been challenged by recent research findings. COPD can instead be understood as the potential end result of the accumulation of gene–environment interactions encountered by an individual over the life course. Integration of a time axis in pathogenic models of COPD is necessary because the biological responses to and clinical consequences of different exposures might vary according to both the age of an individual at which a given gene–environment interaction occurs and the cumulative history of previous gene–environment interactions. Future research should aim to understand the effects of dynamic interactions between genes (G) and the environment (E) by integrating information from basic omics (eg, genomics, epigenomics, proteomics) and clinical omics (eg, phenomics, physiomics, radiomics) with exposures (the exposome) over time (T)—an approach that we refer to as GETomics. In the context of this approach, we argue that COPD should be viewed not as a single disease, but as a clinical syndrome characterised by a recognisable pattern of chronic symptoms and structural or functional impairments due to gene–environment interactions across the lifespan that influence normal lung development and ageing.
Background
Chronic obstructive pulmonary disease (COPD) is an increasingly important cause of morbidity, disability, and mortality worldwide. We aimed to estimate global, regional, and national COPD prevalence and risk factors to guide policy and population interventions.
Methods
For this systematic review and modelling study, we searched MEDLINE, Embase, Global Health, and CINAHL, for population-based studies on COPD prevalence published between Jan 1, 1990, and Dec 31, 2019. We included data reported using the two main case definitions: the Global Initiative for Chronic Obstructive Lung Disease fixed ratio (GOLD; FEV1/FVC<0·7) and the lower limit of normal (LLN; FEV1/FVC<LLN). We employed a multilevel multivariable mixed-effects meta-regression approach to generate the age-specific and sex-specific prevalence of COPD in 2019 for high-income countries (HICs) and low-income and middle-income countries (LMICs) according to the World Bank definition. Common risk factors for GOLD-COPD were evaluated using a random-effects meta-analysis.
Findings
We identified 162 articles reporting population-based studies conducted across 260 sites in 65 countries. In 2019, the global prevalence of COPD among people aged 30–79 years was 10·3% (95% CI 8·2–12·8) using the GOLD case definition, which translates to 391·9 million people (95% CI 312·6–487·9), and 7·6% (5·8–10·1) using the LLN definition, which translates to 292·0 million people (219·8–385·6). Using the GOLD definition, we estimated that 391·9 million (95% CI 312·6–487·9) people aged 30–79 years had COPD worldwide in 2019, with most (315·5 million [246·7–399·6]; 80·5%) living in LMICs. The overall prevalence of GOLD-COPD among people aged 30–79 years was the highest in the Western Pacific region (11·7% [95% CI 9·3–14·6]) and lowest in the region of the Americas (6·8% [95% CI 5·6–8·2]). Globally, male sex (OR 2·1 [95% CI 1·8–2·3]), smoking (current smoker 3·2 [2·5–4·0]; ever smoker 2·3 [2·0–2·5]), body-mass index of less than 18·5 kg/m² (2·2 [1·7–2·7]), biomass exposure (1·4 [1·2–1·7]), and occupational exposure to dust or smoke (1·4 [1·3–1·6]) were all substantial risk factors for COPD.
Interpretation
With more than three-quarters of global COPD cases in LMICs, tackling this chronic condition is a major and increasing challenge for health systems in these settings. In the absence of targeted population-wide efforts and health system reforms in these settings, many of which are under-resourced, achieving a substantial reduction in the burden of COPD globally might remain a difficult task.
Funding
National Institute for Health Research and Health Data Research UK.
Background
Prematurity has been linked to reduced lung function up to age 33 years, but its long-term effects on lung function and chronic obstructive pulmonary disease (COPD) are unknown. To address this question, we investigated associations between prematurity, lung function, and COPD in the sixth decade of life using data from the Tasmanian Longitudinal Health Study (TAHS).
Methods
Data were analysed from 1445 participants in the TAHS. Lung function was measured at 53 years of age. Gestational ages were very preterm (28 weeks to <32 weeks), moderate preterm (32 weeks to <34 weeks), late preterm (34 weeks to <37 weeks) and term (≥37 weeks). Linear and logistic regression models were fitted to investigate associations of prematurity with lung function measures (FEV1, forced vital capacity [FVC], FEV1/FVC ratio, forced expiratory flow at 25–75% of FVC [FEF25–75%], diffusing capacity for carbon monoxide [DLCO]) and COPD (post-bronchodilator FEV1/FVC less than the lower limit of normal), adjusting for sex, age, height, parental smoking during pregnancy, number of older siblings, maternal age at birth, and childhood socioeconomic status. Interactions with smoking and asthma were also investigated.
Results
Of 3565 individuals with available data on gestational age from the TAHS cohort, 1445 (41%) participants were included in this study, 740 (51%) of whom were female. Compared with term birth, very to moderate preterm birth was significantly associated with an increased risk of COPD at age 53 years (odds ratio 2·9 [95% CI 1·1–7·7]). Very-to-moderate preterm birth was also associated with lower post-bronchodilator FEV1/FVC ratio (beta-coefficient –2·9% [95% CI –4·9 to –0·81]), FEV1 (−190 mL [–339 to –40]), DLCO (−0·55 mmol/min/kPa [–0·97 to –0·13]), and FEF25–75% (−339 mL/s [–664 to –14]). The association between very-to-moderate preterm birth and FEV1/FVC ratio was only significant among smokers (pinteraction=0·0082). Similar findings were observed for moderate preterm birth when analysed as a separate group. Compared with term birth, late preterm birth was not associated with lower FEV1/FVC ratio or COPD.
Interpretation
This is the first study to investigate the effect of prematurity on lung function into middle-age. Data show that very-to-moderate prematurity is associated with obstructive lung function deficits including COPD well into the sixth decade of life and that this effect is compounded by personal smoking.
Funding
National Health and Medical Research Council (NHMRC) of Australia, European Union's Horizon 2020, The University of Melbourne, Clifford Craig Medical Research Trust of Tasmania, The Victorian, Queensland & Tasmanian Asthma Foundations, The Royal Hobart Hospital, Helen MacPherson Smith Trust, and GlaxoSmithKline.
Pulmonary hypertension is a syndrome characterized by marked remodeling of the pulmonary vasculature and a progressive rise in the pulmonary vascular load, leading to hypertrophy and remodeling of the right ventricle. Death results from right ventricular failure if pulmonary hypertension is left untreated. Pulmonary hypertension is currently defined hemodynamically by a mean pulmonary arterial pressure of higher than 20 mm Hg at rest, as measured by right heart catheterization.1 Precapillary pulmonary hypertension due to pulmonary vascular disease is further defined by an elevation in pulmonary vascular resistance of at least 3 Wood units (WU), in contrast to isolated postcapillary pulmonary hypertension, in which the pulmonary vascular resistance is less than 3 WU and the elevation in the mean pulmonary arterial pressure is due to elevated filling pressures on the left side of the heart.
Background
Genetic data implicate IL-33 in asthma susceptibility. Itepekimab, a monoclonal antibody targeting IL-33, demonstrated clinical activity in asthma, with potential in chronic obstructive pulmonary disease (COPD). In this study we first aimed to test the hypothesis that genetic variants in the IL-33 pathway were also associated with COPD. On the basis of the strong association of IL-33 pathway genes with pulmonary diseases like asthma and COPD, we conducted this phase 2a trial to assess the safety and efficacy of itepekimab in patients with moderate-to-severe COPD on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy.
Methods
In this two-part study, genetic analyses of loss-of-function and gain-of-function variants in the IL-33 pathway, previously associated with asthma risk, were initially characterised for COPD. We then did a double-blind, phase 2a trial comparing itepekimab with placebo in patients with moderate-to-severe COPD despite standard therapy, at 83 study sites in ten countries. Patients aged 40–75 years who were current or former smokers, had been diagnosed with COPD for at least 1 year, and were on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy, were randomly assigned (1:1) to receive itepekimab 300 mg or placebo, administered as two subcutaneous injections every 2 weeks for 24–52 weeks. The primary endpoint of the phase 2a trial was annualised rate of moderate-to-severe acute exacerbations of COPD during the treatment period. The key secondary outcome was change in prebronchodilator FEV1 from baseline to weeks 16–24. Prespecified subgroup analyses were done for each of the endpoints, including by smoking status. Efficacy and safety analyses were done in all participants who received at least one dose of assigned treatment (modified intention-to-treat population). This trial is registered at ClinicalTrials.gov (NCT03546907).
Findings
Genetic analyses demonstrated association of loss of function in IL33 with reduced COPD risk, and gain of function in IL33 and IL1RL1 variants with increased risk. Subsequent to this, in the phase 2 trial, 343 patients were randomly assigned to placebo (n=171) or itepekimab (n=172) from July 16, 2018, to Feb 19, 2020. Annualised rates of acute exacerbations of COPD were 1·61 (95% CI 1·32–1·97) in the placebo group and 1·30 (1·05–1·61) in the itepekimab group (relative risk [RR] 0·81 [95% CI 0·61–1·07], p=0·13), and least squares mean prebronchodilator FEV1 change from baseline to weeks 16–24 was 0·0 L (SD 0·02) and 0·06 L (0·02; difference 0·06 L [95% CI 0·01–0·10], p=0·024). When analysis was restricted to former smokers, treatment with itepekimab was associated with nominally significant reductions in acute exacerbations of COPD (RR 0·58 [95% CI 0·39–0·85], p=0·0061) and FEV1 improvement (least squares mean difference 0·09 L [0·02–0·15], p=0·0076) compared with placebo. Current smokers treated with itepekimab showed no treatment benefit versus placebo for exacerbations (RR 1·09 [0·74–1·61], p=0·65) or FEV1 (least squares mean difference 0·02 [−0·05 to 0·09], p=0·54). Treatment-emergent adverse events (TEAEs) occurred in 135 (78%) patients in the itepekimab group and 136 (80%) in the placebo group. The most common TEAEs were nasopharyngitis (28 [16%] in the itepekimab group vs 29 [17%] in the placebo group), bronchitis (18 [10%] vs 14 [8%]), headache (14 [8%] vs 23 [13%]), and upper respiratory tract infection (13 [8%] vs 15 [9%]).
Interpretation
The primary endpoint in the overall population was not met, subgroup analysis showed that itepekimab reduced exacerbation rate and improved lung function in former smokers with COPD. Two phase 3 clinical studies are ongoing to confirm the efficacy and safety profile of itepekimab in former smokers with COPD.
Funding
Sanofi and Regeneron Pharmaceuticals.