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Background: The heterogeneous nature of chronic obstructive pulmonary disease (COPD) complicates the identification of the predictors of disease progression. We aimed to improve the prediction of disease progression in COPD by using machine learning and incorporating a rich dataset of phenotypic features. Methods: We included 4496 smokers with available data from their enrollment and 5-year follow-up visits in the COPD Genetic Epidemiology (COPDGene(®)) study. We constructed linear regression (LR) and supervised random forest models to predict 5-year progression in forced expiratory in 1 second (FEV(1)) from 46 baseline features. Using cross-validation, we randomly partitioned participants into training and testing samples. We also validated the results in the COPDGene 10-year follow-up visit. Results: Predicting the change in FEV(1) over time is more challenging than simply predicting the future absolute FEV(1) level. For random forest, R-squared was 0.15 and the area under the receiver operator characteristic (ROC) curves for the prediction of participants in the top quartile of observed progression was 0.71 (testing) and respectively, 0.10 and 0.70 (validation). Random forest provided slightly better performance than LR. The accuracy was best for Global initiative for chronic Obstructive Lung Disease (GOLD) grades 1–2 participants, and it was harder to achieve accurate prediction in advanced stages of the disease. Predictive variables differed in their relative importance as well as for the predictions by GOLD. Conclusion: Random forest, along with deep phenotyping, predicts FEV(1) progression with reasonable accuracy. There is significant room for improvement in future models. This prediction model facilitates the identification of smokers at increased risk for rapid disease progression. Such findings may be useful in the selection of patient populations for targeted clinical trials.

Background: Apparent increased female susceptibility to chronic obstructive pulmonary disease (COPD) suggests sex hormones modulate disease pathogenesis. Little is known about associations between multiparity and lung function in smokers. Research Question: We hypothesized that multiparity is associated with lung function and measures of emphysema and airway disease. Study Design and Methods: Utilizing female participants from the 5-year follow up of the COPD Genetic Epidemiology (COPDGene(®)) study we performed multivariable linear regressions to assess the effect of multiparity and number of pregnancies on forced expiratory volume in 1 second (FEV(1)) percentage of predicted (% predicted), FEV(1)/forced vital capacity (FVC), percent emphysema on computed tomography (CT) scans, and Pi10, a measure of airway thickening. We sampled never smokers and those with lower smoking exposure from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 dataset. Results: We included 1820 participants from COPDGene(®) and 418 participants from NHANES (321 never smokers, 97 ever smokers). In COPDGene(®), multiparity (beta coefficient [β] = -3.8, 95% confidence interval [CI]: [-6.5, -1.1], p = 0.005) and higher number of pregnancies were associated with lower FEV(1) % predicted. Multiparity was not associated with percent emphysema or Pi10. In individuals with no or mild obstruction, multiparity was associated with lower FEV(1) % predicted. There was an interaction with multiparity and age on FEV(1) % predicted (p = 0.025). In NHANES, there was no association between multiparity and FEV(1) % predicted in never smokers or the lower smoking exposure group. Interpretation: Multiparity was associated with lower FEV(1) % predicted in current and former smokers in COPDGene(®) study participants. These preliminary results emphasize the importance of smoking abstinence in women of child-bearing age.

Nearly 16 million Americans, and more than 250 million people around the world, live with chronic obstructive pulmonary disease (COPD) and millions more remain undiagnosed. The COPD Foundation has been monitoring the global pandemic of a disease caused by the recently identified coronavirus family member SARS-CoV-2 named coronavirus disease 2019 (COVID-19). On April 17th, 2020 the World Health Organization (WHO) reported 2,078,605 confirmed cases and 139,515 deaths globally.1 The COVID-19 pandemic has put patients with COPD and other comorbidities at a high risk for poor outcomes as noted by the U.S. Centers for Disease Control and Prevention (CDC).2 Although there is limited published data on COVID-19 in COPD individuals (only 15 out of > 4815 PubMed references on April 17th), a recent article in the European Respiratory Journal evaluated 1590 laboratory-confirmed hospitalized cases in China and highlighted a low incidence in COPD individuals (24 cases) and in overall comorbidities (25.1%).3 However, COPD had a significant impact on risk for poor outcome (composite endpoint of admission to an intensive care unit, invasive ventilation, or death) reflected by a hazard ratio (HR) of 2.681 [95% confidence interval (CI) 1.424–5.0480] after adjusting for age and smoking status. COPD comorbidity as a risk factor was second only to malignancy (HR 3.50, 95% CI 1.60–7.64). Although an initial publication from China suggested a statistically significant risk of poor outcome in active smokers,4 a recent meta-analysis of several studies indicated5 it was only a strong trend. However, another systematic review published on April 15th, confirmed the association of smoking with a risk for poor outcome in COVID-19.6 Therefore, more epidemiological data on COPD, smoking and vaping is needed to fully understand the impact of nicotine exposure and development of COPD on COVID-19 outcomes. As nicotine has previously been associated with upregulation of ACE2,7 the receptor for SARS-CoV-2,8 research suggests the importance of emphasizing smoking and vaping cessation. Inhaled corticosteroids (ICSs) are often prescribed to COPD patients at risk for exacerbations and a short course (5-10 days) of systemic steroids is commonly prescribed as standard of care for selected COPD exacerbations (notably, there is no evidence suggesting a role for chronic systemic steroid use in COPD). Current guidelines from the WHO1 and the CDC2 do not cover COPD specifically. On March 10th a working group of the Chinese Thoracic Society issued guidance on the treatment of COPD patients.9 On March 23rd, the Global initiative for chronic Obstructive Lung Disease (GOLD) issued guidance on keeping patients on their regular maintenance therapy10 and this was supported by the American Thoracic Society (ATS) guidance on COVID-19 which was issued on March 30th.11 However, the debate on treating COVID-19 with systemic steroids (regardless of underlying disease) continues. A small study in China demonstrated no benefit but also no harm12 in contrast to guidance by the CDC13 to avoid the use of systemic steroids when treating COVID-19 which is based on previous experience with SARS-CoV and Middle East respiratory syndrome.14 Another post-hoc study suggested a survival benefit in treating patients with COVID-19 and advanced respiratory distress syndrome.15 This adds to the confusion among physicians treating individuals with COVID-19, especially in the background of a respiratory comorbidity. Although 177 ongoing and planned global clinical trials are listed in ClinicalTrials.gov, none is specific for COPD. Based on a recent report (in press) from the COPD Group of the Chinese Thoracic Society and the COPD Working Committee of the Chinese Association of Chest Physicians,9 differential diagnosis of COVID-19 is challenging, due to the ongoing symptomatology of COPD, and often leads to delayed diagnosis as patients present with fever, fatigue and other systemic symptoms, and respiratory symptoms are relatively light. After 6 to 7 days, rapid deterioration of lung function may occur. Once infected with SARS-CoV-2 pneumonia, lung function in COPD patients can deteriorate rapidly leading to respiratory failure. In a small number of patients with COVID-19 pneumonitis (especially in the elderly) COVID-19 may initially present with delirium. The finding of delayed diagnosis of COPD patients infected with COVID-19 due to misdiagnosis as a COPD exacerbation was confirmed in a recent podcast from a physician on the frontlines interviewed by Steven Q. Simpson, MD, FCCP, American College of Chest Physicians President-Elect.16 Moreover, in an recently completed COPD Foundation patient and caregiver survey, we observed that out of 177 COPD individuals who reported exacerbations in 2020, 16 were suspected for COVID-19 but only 5 were tested (unpublished data, March/April 2020). Considering the high incidence of COVID-19, it seems imperative to test COPD patients presenting with symptoms of an exacerbation to prevent further dissemination. The COPD Foundation focuses on empowering and engaging the community to show that there is hope and that individuals with COPD and their families can take positive steps to lead meaningful and productive lives with COPD during this challenging global crisis. As the COVID-19 pandemic has put patients with COPD and other comorbidities at a high risk for poor outcomes, the COPD Foundation is keeping our community informed on emerging developments through a dedicated website which is updated regularly.17 Members of our Medical and Scientific Advisory Committee and other expert partners help ensure that accurate information is shared with our COPD community through blogs, webinars and Q&A posted on our website and on social media. Access to pulmonary rehabilitation (PR) is a key issue for patients with COPD. On March 26th the COPD Foundation, in collaboration with the ATS and the American Lung Association,18 published a guidance on what to do when PR is unavailable. In addition, we provided links to our exercise website19 and the free COPD Pocket Consultant Guide App which helps patients exercise at home.20 However, this crisis highlights a need for improved, remotely supervised physical therapy programs that utilize telehealth technology to advise patients on appropriate at home exercise that is tailored to their specific needs. Our global online community, COPD360social includes over 47,000 members from 151 countries and is currently serving a critically important role in communicating with the COPD community about COVID-19 by addressing the specific needs and risks that the individual with COPD may face.21 On March 29th we launched the first of a series of global surveys22 on COVID-19 which includes analysis of free text responses (funded by our industry partners) to ensure that the COPD Foundation programs will address all of the specific needs of the community. Combined with surveys to clinicians addressing questions on the use of ICSs, nebulizers and airway clearance devices for patients with COPD and experiencing COVID-19 infection, we aim to continue to support our community through this global crisis.

Background: Previous attempts to explore the heterogeneity of chronic obstructive pulmonary disease (COPD) clustered individual patients using clinical, demographic, and disease features. We developed continuous multidimensional disease axes based on radiographic and spirometric variables that split into an airway-predominant axis and an emphysema-predominant axis. Methods: The COPD Genetic Epidemiology study (COPDGene(®)) is a cohort of current and former smokers, > 45 years, with at least 10 pack years of smoking history. Spirometry measures, blood pressure and body mass were directly measured. Mortality was assessed through continuing longitudinal follow-up and cause of death was adjudicated. Among 8157 COPDGene(®) participants with complete spirometry and computed tomography (CT) measures, the top 2 deciles of the airway-predominant and emphysema-predominant axes previously identified were used to categorize individuals into 3 groups having the highest risk for mortality using Cox proportional hazard ratios. These groups were also assessed for causal mortality. Biomarkers of COPD (fibrinogen, soluble receptor for advanced glycation end products [sRAGE], C-reactive protein [CRP], clara cell secretory protein [CC16], surfactant-D [SP-D]) were compared by group. Findings: High-risk subtype classification was defined for 2638 COPDGene(®) participants who were in the highest 2 deciles of either the airway-predominant and/or emphysema-predominant axis (32% of the cohort). These high-risk participants fell into 3 groups: airway-predominant disease only (APD-only), emphysema-predominant disease only (EPD-only) and combined APD-EPD. There was 26% mortality for the APD-only group, 21% mortality for the EPD-only group, and 54% mortality for the combined APD-EPD group. The APD-only group (n=1007) was younger, had a lower forced expiratory volume in 1 second (FEV(1)) percent (%) predicted and a strong association with the preserved ratio-impaired spirometry (PRISm) quadrant. The EPD-only group (n=1006) showed a relatively higher FEV(1) % predicted and included largely GOLD stage 0, 1 and 2 partipants. Individuals in each of the 3 high-risk groups were at greater risk for respiratory mortality, while those in the APD-only group were additionally at greater risk for cardiovascular mortality. Biomarker analysis demonstrated a significant association of the APD-only group with CRP, and sRAGE demonstrated greatest significance with both the EPD-only and the combined APD-EPD groups. Interpretation: Among current and former smokers, individuals in the highest 2 deciles for mortality risk on the airway-predominant axis and the emphysema-predominant axis have unique associations to spirometric patterns, different imaging characteristics, biomarkers and causal mortality.

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene(®)), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality. Methods: Four key disease characteristics – environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry – were evaluated in a group of 8784 current and former smokers who were participants in COPDGene(®) Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV(1) > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined. Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene(®) 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15–6.48) in those with all 4 disease characteristics. Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.

Background: The Global initiative for chronic Obstructive Lung Disease (GOLD) ABCD groupings were recently modified. The GOLD 2011 guidelines defined increased risk as forced expiratory volume in 1 second (FEV1) < 50% predicted or ≥ 2 outpatient or ≥ 1 hospitalized exacerbation in the prior year, whereas the GOLD 2017 guidelines use only exacerbation history. We compared mortality and exacerbation rates in the Genetic Epidemiology of COPD Study cohort (COPDGene®) by 2011 (exacerbation history/FEV1 and dyspnea) versus 2017 (exacerbations and dyspnea) classifications. Methods: Using data from COPDGene®, we tested associations of ABCD groups with all-cause mortality (Cox models, adjusted for age, sex, race and comorbidities) and longitudinal exacerbations (zero-inflated Poisson models). Results: In 4469 individuals (mean age 63.1 years, 44% female), individual distributions in 2011 versus 2017 systems were: A, 32.0% versus 37.0%; B, 17.6% versus 36.3%; C, 9.4% versus 4.4%; D, 41.0% versus 22.3%; (observed agreement 76% [expected 27.8%], Kappa 0.67, p

The COPD Foundation Pocket Consultant Guide (PCG) was first released in 2007 as a practice tool for use at point of service for clinicians, especially primary care clinicians diagnosing and treating patients with chronic obstructive pulmonary disease (COPD). Over the years, the PCG has been supplemented with a mobile app that presents the tool in an online smart phone accessible version that also allows the clinician to enter patient specific data for guidance to next steps of diagnosis or management. In November 2016, a new update of the PCG was released that incorporates a flow diagram for stepped care that includes the newest recommendation for diagnosis, assessment and treatment; including the broad use of dual bronchodilator therapy and consideration of asthma COPD overlap syndrome (ACOS). The current controversy regarding when to add inhaled corticosteroids (ICSs) is addressed to support clinical decision making. The PCG comes in 2 versions, one with generic names for COPD drugs available in the United States and one with trade names for those drugs. The update continues to recommend spirometry for those at highest risk, also emphasizing the need to assess symptoms, exacerbation risks and comorbidity before selecting appropriate non-pharmacological as well as pharmacological therapy. The tool is designed to facilitate COPD management in daily practice.