Spirometric Transition of at Risk Individuals and Risks for Progression to Chronic Obstructive Pulmonary Disease in General Population.

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 (FEV1)/forced vital capacity ratio≥70% and FEV1<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.

Treatable traits in pre-COPD: Time to extend the treatable traits paradigm beyond established disease.

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.

Heterogeneities and impact profiles of early chronic obstructive pulmonary disease status: findings from the China Pulmonary Health Study.

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).

Effect of twice daily inhaled albuterol on cardiopulmonary exercise outcomes, dynamic hyperinflation, and symptoms in secondhand tobacco-exposed persons with preserved spirometry and air trapping: a randomized controlled trial.

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 < 0.05), but no change in symptoms or physical activity. CONCLUSIONS: Albuterol may improve exercise capacity in the subgroup of SHS tobacco-exposed persons with preserved spirometry and substantial air trapping. These findings suggest that air trapping in pre-COPD may be related to small airway disease that is not considered significant by spirometric indices of airflow obstruction.

Potential pre-COPD indicators in association with COPD development and COPD prediction models in Chinese: a prospective cohort study.

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.

Can We Use Lung Function Thresholds and Respiratory Symptoms to Identify Pre-Chronic Obstructive Pulmonary Disease? A Prospective, Population-based Cohort Study.

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.

Breathlessness and "exacerbation" questions predictive for incident COPD (MARKO study): data after two years of follow-up.

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.

Understanding Early COPD.

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.

Treatment Trials in Young Patients with Chronic Obstructive Pulmonary Disease and Pre-Chronic Obstructive Pulmonary Disease Patients: Time to Move Forward.

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.

Actigraphy informs distinct patient-centered outcomes in Pre-COPD.

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/m2; FEV1/FVC = 0.75 ± 0.05; FEV1 = 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 (VO2AT), 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 VO2AT. 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.