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BACKGROUND: In tobacco-exposed persons with preserved spirometry (active smoking or secondhand smoke [SHS] exposure), air trapping can identify a subset with worse symptoms and exercise capacity. The physiologic nature of air trapping in the absence of spirometric airflow obstruction remains unclear. The aim of this study was to examine the underlying pathophysiology of air trapping in the context of preserved spirometry and to determine the utility of bronchodilators in SHS tobacco-exposed persons with preserved spirometry and air trapping. METHODS: We performed a double-blinded placebo-controlled crossover randomized clinical trial in nonsmoking individuals at risk for COPD due to exposure to occupational SHS who had preserved spirometry and air trapping defined as either a residual volume-to-total lung capacity ratio (RV/TLC) > 0.35 or presence of expiratory flow limitation (EFL, overlap of tidal breathing on maximum expiratory flow-volume loop) on spirometry at rest or during cardiopulmonary exercise testing (CPET). Those with asthma or obesity were excluded. Participants underwent CPET at baseline and after 4-week trials of twice daily inhalation of 180 mcg of albuterol or placebo separated by a 2-week washout period. The primary outcome was peak oxygen consumption (VO2) on CPET. Data was analyzed by both intention-to-treat and per-protocol based on adherence to treatment prescribed. RESULTS: Overall, 42 participants completed the entire study (66 ± 8 years old, 91% female; forced expiratory volume in 1 s [FEV1] = 103 ± 16% predicted; FEV1 to forced vital capacity [FVC] ratio = 0.75 ± 0.05; RV/TLC = 0.39 ± 0.07; 85.7% with EFL). Adherence was high with 87% and 93% of prescribed doses taken in the treatment and placebo arms of the study, respectively (P = 0.349 for comparison between the two arms). There was no significant improvement in the primary or secondary outcomes by intention-to-treat or per-protocol analysis. In per-protocol subgroup analysis of those with RV/TLC > 0.35 and ≥ 90% adherence (n = 27), albuterol caused an improvement in peak VO2 (parameter estimate [95% confidence interval] = 0.108 [0.014, 0.202]; P = 0.037), tidal volume, minute ventilation, dynamic hyperinflation, and oxygen-pulse (all P

BackgroundPreserved Ratio Impaired Spirometry (PRISm) is increasingly recognized as a precursor to Chronic Obstructive Pulmonary Disease (COPD). The impact of Ultra-Processed Foods (UPFs) intake on PRISm and lung function remains underexplored, and we aimed to explore their associations.MethodsThis study included 8,336 U.S. adults. Weighted logistic and linear regression models were employed for main analysis. Dose–response relationship was examined through restricted cubic spline (RCS) analysis, and subgroup analyses explored interactions with selected covariates.ResultsParticipants in the PRISm group were older and exhibited various adverse health characteristics. The percentage of total daily energy intake from UPFs (%Kcal) intake was associated with a non-significant increase in PRISm risk (OR 1.67, 95% CI: 0.96–2.92, p = 0.07). However, the highest quartile of UPFs (%Kcal) intake was significantly linked to increased PRISm risk (OR 1.36, 95% CI: 0.99–1.86, P for trend = 0.043). Furthermore, higher UPFs (%Kcal) intake negatively affected lung function, with participants in the highest quartile showing a significant reduction in forced expiratory volume in 1 s (FEV1) of −45.5 mL (95% CI: −87.6 to −3.4, P for trend = 0.045) and a decrease in forced vital capacity (FVC) of −139.4 mL (95% CI: −223.5 to −55.4, p

To date, the treatable traits (TTs) approach has been applied in the context of managing diagnosed diseases. TTs are clinical characteristics and risk factors that can be identified clinically and/or biologically, and that merit treatment if present. There has been an exponential increase in the uptake of this approach by both researchers and clinicians. Realizing the potential of the TTs approach to pre‐clinical disease, this expert review proposes that it is timely to consider acting on TTs present before a clinical diagnosis is made, which might help to prevent development of the full disease. Such an approach is ideal for diseases where there is a long pre‐clinical phase, such as in chronic obstructive pulmonary disease (COPD). The term 'pre‐COPD' has been recently proposed to identify patients with respiratory symptoms and/or structural or functional abnormalities without airflow limitation. They may eventually develop airflow limitation with time but patients with pre‐COPD are likely to have traits that are already treatable. This review first outlines the contribution of recently generated knowledge into lifetime lung function trajectories and the conceptual framework of 'GETomics' to the field of pre‐COPD. GETomics is a dynamic and cumulative model of interactions between genes and the environment throughout the lifetime that integrates information from multi‐omics to understand aetiology and mechanisms of diseases. This review then discusses the current evidence on potential TTs in pre‐COPD patients and makes recommendations for practice and future research. At a broader level, this review proposes that introducing the TTs in pre‐COPD may help reenergize the preventive approaches to health and diseases. [ABSTRACT FROM AUTHOR]

Rationale: The term "pre–chronic obstructive pulmonary disease" ("pre-COPD") refers to individuals at high risk of developing COPD who do not meet conventional spirometric criteria for airflow obstruction. New approaches to identifying these individuals are needed, particularly in younger populations. Objectives: To determine whether lung function thresholds and respiratory symptoms can be used to identify individuals at risk of developing COPD. Methods: The Tasmanian Longitudinal Health Study comprises a population-based cohort first studied in 1968 (at age 7 yr). Respiratory symptoms, pre- and post-bronchodilator (BD) spirometry, diffusing capacity, and static lung volumes were measured in a subgroup at age 45, and the incidence of COPD was assessed at age 53. For each lung function measure, z-scores were calculated using Global Lung Function Initiative references. The optimal threshold for best discrimination of COPD incidence was determined by the unweighted Youden index. Measurements and Main Results: Among 801 participants who did not have COPD at age 45, the optimal threshold for COPD incidence by age 53 was pre-BD FEV1/FVC z-score less than −1.264, corresponding to the lowest 10th percentile. Those below this threshold had a 36-fold increased risk of developing COPD over an 8-year follow-up period (risk ratio, 35.8; 95% confidence interval, 8.88 to 144), corresponding to a risk difference of 16.4% (95% confidence interval, 3.7 to 67.4). The sensitivity was 88%, and the specificity was 87%. Positive and negative likelihood ratios were 6.79 and 0.14, respectively. Respiratory symptoms, post-BD spirometry, diffusing capacity, and static lung volumes did not improve on the classification achieved by pre-BD FEV1/FVC alone. Conclusions: This is the first study, to our knowledge, to evaluate the discriminatory accuracy of spirometry, diffusing capacity, and static lung volume thresholds for COPD incidence in middle-aged adults. Our findings support the inclusion of pre-BD spirometry in the physiological definition of pre-COPD and indicate that pre-BD FEV1/FVC at the 10th percentile accurately identifies individuals at high risk of developing COPD in community-based settings. [ABSTRACT FROM AUTHOR]

Summary: Background: The prevalence, epidemiological and clinical heterogeneities, and impact profiles of individuals with preserved ratio impaired spirometry (PRISm), pre-COPD, young COPD, and mild COPD in general Chinese population were not known yet. Methods: Data were obtained from the China Pulmonary Health study (2012–2015), a nationally representative cross-sectional survey that recruited 50,991 adults aged 20 years or older. Definitions of the four early disease status were consistent with the latest publications and the Global Initiative for Chronic Obstructive Lung Disease criteria. Findings: The age-standardised prevalences of PRISm, pre-COPD, young COPD, and mild COPD were 5.5% (95% confidence interval, 4.3–6.9), 7.2% (5.9–8.8), 1.1% (0.7–1.8), and 3.1% (2.5–3.8), respectively. In summary, mild COPD was under more direct or established impact factor exposures, such as older age, male gender, lower education level, lower family income, biomass use, air pollution, and more accumulative cigarette exposures; young COPD and pre-COPD experienced more personal and parents’ events in earlier lives, such as history of bronchitis or pneumonia in childhood, frequent chronic cough in childhood, parental history of respiratory diseases, passive smoke exposure in childhood, and mother exposed to passive smoke while pregnant; pre-COPD coexisted with heavier symptoms and comorbidities burdens; young COPD exhibited worse airway obstruction; and most of the four early disease status harbored small airway dysfunction. Overall, older age, male gender, lower education level, living in the urban area, occupational exposure, frequent chronic cough in childhood, more accumulated cigarette exposure, comorbid with cardiovascular disease and gastroesophageal reflux disease were all associated with increased presence of the four early COPD status; different impact profiles were additionally observed with distinct entities. Over the four categories, less than 10% had ever taken pulmonary function test; less than 1% reported a previously diagnosed COPD; and no more than 13% had received pharmaceutical treatment. Interpretation: Significant heterogeneities in prevalence, epidemiological and clinical features, and impact profiles were noted under varied defining criteria of early COPD; a unified and validated definition for an early disease stage is warranted. Closer attention, better management, and further research need to be administrated to these population. Funding: Chinese Academy of Medical Sciences Institute of Respiratory Medicine Grant for Young Scholars (No. 2023-ZF-9); China International Medical Foundation (No. Z-2017-24-2301); Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2021-I2M-1-049); National High Level Hospital Clinical Research Funding (No. 2022-NHLHCRF-LX-01); Major Program of National Natural Science Foundation of China (No. 82090011).

Summary: Background: Lung injury might take place before chronic obstructive pulmonary disease (COPD) occurs. A clearer definition of “pre-COPD” based on the effects of potential indicators on increasing risk of COPD development and a prediction model involving them are lacking. Methods: A total of 3526 Chinese residents without COPD aged 40 years or older derived from the national cross-sectional survey of COPD surveillance in 2014–2015 were followed up for a mean of 3.59 years. We examined the associations of chronic bronchitis, preserved ratio impaired spirometry (PRISm), low peak expiratory flow (PEF), spirometric small airway dysfunction (sSAD), low maximal mid-expiratory flow (MMEF), low forced expiratory flow 50% of pulmonary volume (FEF50), and low FEF75 with subsequent COPD and constructed a prediction model with LASSO-Cox regression. Findings: 235 subjects in the cohort developed COPD during the follow-up. Subjects with PRISm, low PEF, sSAD, low MMEF, low FEF50, and low FEF75 had an increased risk of developing COPD (adjusted hazard ratio [HR] ranging from 1.57 to 3.01). Only chronic bronchitis (HR 2.84 [95% CI 1.38–5.84] and 2.94 [1.43–6.04]) and sSAD/low MMEF (HR 2.74 [2.07–3.61] and 2.38 [1.65–3.43]) showed effects independent of the other indicators and their concurrence had the strongest effect (HR 5.89 and 4.80). The prediction model including age, sex, low MMEF, low FEF50, and indoor exposure to biomass had good performance both internally and temporally. The corrected C-index was 0.77 (0.72–0.81) for discrimination in internal validation. For temporal validation, the area under the receiver operating characteristic curve was 0.73 (0.63–0.83). Good calibration was indicated in plot for internal validation and by Hosmer–Lemeshow test for temporal validation. Interpretation: Individuals with concurrent chronic bronchitis and sSAD/low MMEF indicating pre-COPD optimally require more high attention from physicians. Our prediction model could serve as a multi-dimension tool to predict COPD comprehensively. Funding: The Ministry of Finance and the Ministry of Science and Technology of the People's Republic of China and the National Natural Science Foundation of China. 摘要: 背景: 在慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)出现前, 肺损伤可能已经发生。目前尚缺乏依据潜在指标对升高COPD发生风险的影响而产生的更明确的''慢阻肺前期''的定义, 以及包含这些潜在指标的慢阻肺发病预测模型。 方法: 本研究基于2014–2015年中国居民慢阻肺监测横断面调查, 对3526名40岁及以上的非慢阻肺居民进行了平均3.59年的随访；旨在分析慢性支气管炎、保留比值的肺功能损伤 (preserved ratio impaired spirometry, PRISm)、低呼气峰流速 (peak expiratory flow, PEF)、小气道功能障碍 (spirometric small airway dysfunction, sSAD)、低最大呼气中期流速 (maximal mid-expiratory flow, MMEF)、低呼出50%用力肺活量时的最大呼气流速 (forced expiratory flow 50% of pulmonary volume, FEF50)、低FEF75与COPD发生的关系, 并采用LASSO-Cox回归构建预测模型。 结果: 本前瞻性队列中共有235名研究对象在随访期间发展为COPD患者。PRISm、低PEF、sSAD、低MMEF、低FEF50和低FEF75者发生COPD的风险增加(调整后的风险比 [hazard ratio, HR] 在1.57至3.01之间)。只有慢性支气管炎 (HR 2.84 [95% CI 1.38–5.84] 和2.94 [1.43–6.04]) 和sSAD/低MMEF (HR 2.74 [2.07–3.61] 和2.38 [1.65–3.43]) 的效应独立于其他指标, 且慢性支气管炎和sSAD共存或慢性支气管炎和低MMEF共存的效应最强 (HR 5.89和4.80)。本研究构建的预测模型因子包括年龄、性别、低MMEF、低FEF50和室内生物燃料暴露。该模型在内部验证和外部验证中均表现出良好的预测性能。内部验证中该模型的区分度即校正后C-index为0.77 (0.72–0.81)。外部验证中受试者工作特征曲线下面积为0.73 (0.63–0.83)。该模型在内部验证的校准图和外部验证的Hosmer-Lemeshow检验中均显示出良好的校准度。 解读: 慢性支气管炎和sSAD/低MMEF是提示COPD前期的最佳指标, 同时存在这两种表现的个体需引起临床医生的高度重视。本研究构建的预测模型可以作为一个多维度的综合预测COPD的工具。 资助: 中华人民共和国财政部、科学技术部和国家自然科学基金。

Aims: To determine the predictability of the MARKO questionnaire and/or its domains, individually or in combination with other markers and characteristics (age, gender, smoking history, lung function, 6-min walk test (6 MWT), exhaled breath temperature (EBT), and hsCRP for the incident chronic obstructive pulmonary disease (COPD) in subjects at risk over 2 years follow-up period). Participants and Methods: Patients, smokers/ex-smokers with >20 pack-years, aged 40-65 years of both sexes were recruited and followed for 2 years. After recruitment and signing the informed consent at the GP, a detailed diagnostic workout was done by the pulmonologist; they completed three self-assessment questionnaires--MARKO, SGRQ and CAT, detailed history and physical, laboratory (CBC, hsCRP), lung function tests with bronchodilator and EBT. At the 2 year follow-up visit they performed: the same three self-assessment questionnaires, history and physical, lung function tests and EBT. Results: A sample of 320 subjects (41.9% male), mean (SD) age 51.9 (7.4) years with 36.4 (17.4) pack-years of smoking was reassessed after 2.1 years. Exploratory factor analysis of MARKO questionnaire isolated three distinct domains (breathlessness and fatigue, "exacerbations", cough and expectorations). We have determined a rate for incident COPD that was 4.911/100 person-years (95% CI [3.436-6.816]). We found out that questions about breathlessness and "exacerbations", and male sex were predictive of incident COPD after two years follow-up (AUC 0.79, 95% CI [0.74-0.84], p < 0.001). When only active smokers were analyzed a change in EBT after a cigarette (ΔEBT) was added to a previous model (AUC 0.83, 95% CI [0.78-0.88], p < 0.001). Conclusion: Our preliminary data shows that the MARKO questionnaire combined with EBT (change after a cigarette smoke) could potentially serve as early markers of future COPD in smokers. [ABSTRACT FROM AUTHOR]

Aims To determine the predictability of the MARKO questionnaire and/or its domains, individually or in combination with other markers and characteristics (age, gender, smoking history, lung function, 6-min walk test (6 MWT), exhaled breath temperature (EBT), and hsCRP for the incident chronic obstructive pulmonary disease (COPD) in subjects at risk over 2 years follow-up period). Participants and Methods Patients, smokers/ex-smokers with >20 pack-years, aged 40–65 years of both sexes were recruited and followed for 2 years. After recruitment and signing the informed consent at the GP, a detailed diagnostic workout was done by the pulmonologist; they completed three self-assessment questionnaires—MARKO, SGRQ and CAT, detailed history and physical, laboratory (CBC, hsCRP), lung function tests with bronchodilator and EBT. At the 2 year follow-up visit they performed: the same three self-assessment questionnaires, history and physical, lung function tests and EBT. Results A sample of 320 subjects (41.9% male), mean (SD) age 51.9 (7.4) years with 36.4 (17.4) pack-years of smoking was reassessed after 2.1 years. Exploratory factor analysis of MARKO questionnaire isolated three distinct domains (breathlessness and fatigue, “exacerbations”, cough and expectorations). We have determined a rate for incident COPD that was 4.911/100 person-years (95% CI [3.436–6.816]). We found out that questions about breathlessness and “exacerbations”, and male sex were predictive of incident COPD after two years follow-up (AUC 0.79, 95% CI [0.74–0.84], p < 0.001). When only active smokers were analyzed a change in EBT after a cigarette (ΔEBT) was added to a previous model (AUC 0.83, 95% CI [0.78–0.88], p < 0.001). Conclusion Our preliminary data shows that the MARKO questionnaire combined with EBT (change after a cigarette smoke) could potentially serve as early markers of future COPD in smokers.

Chronic obstructive pulmonary disease (COPD) is a common chronic disease of the respiratory system that has high morbidity and mortality across the world. Like other chronic diseases, the development of COPD is a long process, and its prognosis could be improved significantly by early prevention and intervention. As the understanding of COPD in the international academic community gradually deepens, the 2022 Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) report first proposed the concept of pre-COPD. We reviewed the development of pre-COPD, analyzed its definition and diagnostic criteria, and summarized the significance of early identification of pre-COPD patients. Pre-COPD results from the widening and deepening of the existing concept of COPD prevention and treatment. A full understanding of pre-COPD will contribute to guiding the direction of COPD pathogenesis research and basic COPD research, and to improving the awareness of primary prevention of COPD in clinical practice, thereby reducing the prevalence and mortality of COPD and the burden of COPD on families and society.

Whereas COPD is currently defined as the presence of spirometric obstruction, the pathologic changes in individuals at risk including chronic mucus hypersecretion and emphysema have been recognized for centuries. At the same time, we have struggled to define criteria that would help us identify patients at an early stage, prior to the development of pulmonary function abnormality. The concept of GOLD 0 was introduced in the hopes that symptoms would help to identify those at greatest risk for progression. While symptoms are a risk factor, in particular chronic bronchitis, the term was abandoned as the majority of individuals at risk who progress to COPD do not have symptoms. Since then, the related terms pre-COPD and early COPD have been introduced. They are similar in that the term pre-COPD identifies individuals based on symptoms, physiologic, or radiographic abnormality that do not meet criteria for COPD but are clearly at risk. The term early COPD extends that concept further, focusing on individuals who have early physiologic or radiographic abnormality but at the same time are young, thereby excluding those with late mild disease who may be less likely to progress. Whereas individuals with early COPD are now being recruited for observational studies, we are still challenged with determining the best way to identify patients at risk who should undergo additional testing as well as developing specific therapies for patients with early-stage disease. [ABSTRACT FROM AUTHOR]

Background: Some individuals never achieve normal peak FEV 1 in early adulthood. It is unknown if this is due to airflow limitation and/or lung restriction., Methods: To investigate this, we: (1) looked forward in 19,791 participants in the Dutch Lifelines general population cohort aged 25-35 years with 5-year follow-up; and (2) looked backwards in 2032 participants in the Swedish BAMSE birth cohort with spirometry at 24 years of age but also at 16 and/or 8 years., Results: (1) In Lifelines 8.5% of participants had reduced FEV 1 at 25-35 years, 68% due to Preserved Ratio Impaired Spirometry ('PRISm') and 32% to airflow limitation ('low-limited'); besides, 3.8% participants with normal FEV 1 showed airflow-limitation ('normal-limited'). Low-limited and normal-limited, but not PRISm, reported higher smoking exposures and asthma diagnosis than normal (p < 0.05). At 5-year follow-up, 91.2% of participants remained in the same group, and FEV 1 decline was similar in normal and normal-limited participants, but statistically smaller (p < 0.05) in PRISm and low-limited; (2) these observations were largely reproduced in BAMSE at 24 years of age; and, (3) in BAMSE, low-limited or PRISm individuals were already identifiable at 8-16 years of age., Conclusion: Low peak FEV 1 in early adulthood is most often due to PRISm and results in a significant burden of respiratory symptoms. Only low-limited and normal-limited, but not PRISm, associate with a doctor diagnosis of asthma, and FEV 1 decline was statistically different in PRISm indicating a need for differentiated clinical approaches. These spirometric abnormalities can be already identified in childhood and adolescence., (© 2025 The Author(s). Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Introduction: Chronic obstructive pulmonary disease (COPD) is a dynamic disease with a high socioeconomic burden. Using data collected prospectively from the general population, we examined factors related to the transition of at-risk individuals to COPD., Methods: We used the Korean Genome Epidemiology Study (KoGES) database, defining pre-COPD based on respiratory symptoms and radiological abnormalities suggestive of COPD; the preserved ratio impaired spirometry (PRISm) was defined as a forced expiratory volume in 1s (FEV 1 )/forced vital capacity ratio≥70% and FEV 1 <80%, as predicted by spirometry. We determined group differences in the rate of lung function decline, risk of future airflow obstruction (AFO)., Results: The study included 4762 individuals, and longitudinal analysis revealed distinct trends in pulmonary function indicators. Compared to the normal group, the pre-COPD group showed a more rapid decline in lung function, while the PRISm group showed a slower decline. In the pre-COPD and PRISm groups, 4.4% and 3.5%, and 13.6% and 10.8%, respectively, of patients had progressed to COPD at the first and second visits. Pre-COPD and PRISm contributed to an earlier time to first AFO, but consideration of comorbid cardiovascular disease weakened this relationship in the PRISm group. Multivariate logistic regression showed that pre-COPD and PRISm are significant risk factors for future development of COPD (OR 1.80, p<0.001; OR 4.26, p<0.001, respectively)., Conclusion: Pre-COPD and PRISm patients showed different trends in lung function changes over time and both were significant risk factors for future development of COPD., (Copyright © 2024 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: Chronic obstructive pulmonary disease (COPD) has traditionally been diagnosed based on the criterion of an FEV 1 /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.

Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene-environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: "young" individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider "young" patients with COPD those patients in the age range of 20-50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized controlled trials (RCTs). We highlight the need of RCTs focused on COPD in young patients or pre-COPD to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCT design, including potential outcomes such as lung function, patient-reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure, including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in 1) young adults with COPD and 2) those with pre-COPD at any age. [ABSTRACT FROM AUTHOR]

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, Sftpc Creert2/+ R26 LSL-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 Sftpc Creert2/+ R26 LSL-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., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Identifying patients with chronic obstructive pulmonary disease (COPD) at the earliest possible stage can achieve the best symptom control, disease progression and outcomes in COPD. However, in clinical practice, the ability to identify individuals at risk of progressing from early disease to clinically severe disease remains limited. Early COPD does not necessarily predict the progression to pre-COPD, mild COPD, preserved ratio with impaired spirometry or even Global Initiative for Chronic Obstructive Lung Disease (GOLD) 0 COPD. Early COPD should be recognized in adults younger than 50 years with a smoking history of more than 10 pack-years and who met one or more of the following criteria: (1) a forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio below the lower limit of normal after the use of bronchodilators, (2) compatible computed tomography abnormalities (visual emphysema, air trapping or bronchial thickening of a moderate or worse grade) and/or (3) evidence of a rapid decline in FEV1 of more than 60 mL/year. However, there are critical issues that contradict these criteria. As a result, other features have been proposed as indicators of early COPD. Although primary care clinicians play a key role in the early identification of asymptomatic people at risk, some experts oppose the detection of COPD in its early stages as it is not a disease and does not need to be identified or treated. Nevertheless, health authorities in several countries believe that COPD should be detected as early as possible and therefore fully support the intervention of trained general practitioners in the early detection of COPD. [ABSTRACT FROM AUTHOR]

Whereas COPD is currently defined as the presence of spirometric obstruction, the pathologic changes in individuals at risk including chronic mucus hypersecretion and emphysema have been recognized for centuries. At the same time, we have struggled to define criteria that would help us identify patients at an early stage, prior to the development of pulmonary function abnormality. The concept of GOLD 0 was introduced in the hopes that symptoms would help to identify those at greatest risk for progression. While symptoms are a risk factor, in particular chronic bronchitis, the term was abandoned as the majority of individuals at risk who progress to COPD do not have symptoms. Since then, the related terms pre-COPD and early COPD have been introduced. They are similar in that the term pre-COPD identifies individuals based on symptoms, physiologic, or radiographic abnormality that do not meet criteria for COPD but are clearly at risk. The term early COPD extends that concept further, focusing on individuals who have early physiologic or radiographic abnormality but at the same time are young, thereby excluding those with late mild disease who may be less likely to progress. Whereas individuals with early COPD are now being recruited for observational studies, we are still challenged with determining the best way to identify patients at risk who should undergo additional testing as well as developing specific therapies for patients with early-stage disease., Competing Interests: Dr Han discloses relationships with GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Cipla, Chiesi, Novartis, Pulmonx, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, Regeneron, UpToDate, Altesa Biopharma, Medscape, NACE, MDBriefCase, Integrity, the National Institutes of Health, Sunovion, Nuvaira, Gala Therapeutics, Biodesix, Medtronic, Meissa Vaccines, the COPD Foundation, and the American Lung Association. Dr Lee has disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

Background: Actigraphy can provide useful patient-centered outcomes for quantification of physical activity in the "real-world" setting., Methods: To characterize the relationship of actigraphy outputs with "in-laboratory" measures of cardiopulmonary function and respiratory symptoms in pre-COPD, we obtained actigraphy data for 8 h/day for 5 consecutive days a week before in-laboratory administration of respiratory questionnaires, PFT, and CPET to a subgroup of subjects participating in the larger study of the health effects of exposure to secondhand tobacco smoke who had air trapping but no spirometric obstruction (pre-COPD). Using machine learning approaches, we identified the most relevant actigraphy predictors and examined their associations with symptoms, lung function, and exercise outcomes., Results: Sixty-one subjects (age = 66±7 years; BMI = 24±3 kg/m 2 ; FEV 1 /FVC = 0.75 ± 0.05; FEV 1  = 103 ± 17 %predicted) completed the nested study. In the hierarchical cluster analysis, the activity, distance, and energy domains of actigraphy, including moderate to vigorous physical activity, were closely correlated with each other, but were only loosely associated with spirometric and peak exercise measures of oxygen consumption, ventilation, oxygen-pulse, and anaerobic threshold (VO 2AT ), and were divergent from symptom measures. Conversely, the sedentary domain clustered with respiratory symptoms, air trapping, airflow indices, and ventilatory efficiency. In Regression modeling, sedentary domain was inversely associated with baseline lung volumes and tidal breathing at peak exercise, while the activity domains were associated with VO 2AT . Respiratory symptoms and PFT data were not associated with actigraphy outcomes., Discussion: Outpatient actigraphy can provide information for "real-world" patient-centered outcomes that are not captured by standardized respiratory questionnaires, lung function, or exercise testing. Actigraphy activity and sedentary domains inform of distinct outcomes., (Published by Elsevier Ltd.)