Early Evidence of Chronic Obstructive Pulmonary Disease Obscured by Race-Specific Prediction Equations.

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White (n = 6,766) and AA (n = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Use of the Spirometric "Fixed-Ratio" Underdiagnoses COPD in African-Americans in a Longitudinal Cohort Study.

BACKGROUND: COPD diagnosis is tightly linked to the fixed-ratio spirometry criteria of FEV1/FVC < 0.7. African-Americans are less often diagnosed with COPD. OBJECTIVE: Compare COPD diagnosis by fixed-ratio with findings and outcomes by race. DESIGN: Genetic Epidemiology of COPD (COPDGene) (2007-present), cross-sectional comparing non-Hispanic white (NHW) and African-American (AA) participants for COPD diagnosis, manifestations, and outcomes. SETTING: Multicenter, longitudinal US cohort study. PARTICIPANTS: Current or former smokers with ≥ 10-pack-year smoking history enrolled at 21 clinical centers including over-sampling of participants with known COPD and AA. Exclusions were pre-existing non-COPD lung disease, except for a history of asthma. MEASUREMENTS: Subject diagnosis by conventional criteria. Mortality, imaging, respiratory symptoms, function, and socioeconomic characteristics, including area deprivation index (ADI). Matched analysis (age, sex, and smoking status) of AA vs. NHW within participants without diagnosed COPD (GOLD 0; FEV1 ≥ 80% predicted and FEV1/FVC ≥ 0.7). RESULTS: Using the fixed ratio, 70% of AA (n = 3366) were classified as non-COPD, versus 49% of NHW (n = 6766). AA smokers were younger (55 vs. 62 years), more often current smoking (80% vs. 39%), with fewer pack-years but similar 12-year mortality. Density distribution plots for FEV1 and FVC raw spirometry values showed disproportionate reductions in FVC relative to FEV1 in AA that systematically led to higher ratios. The matched analysis demonstrated GOLD 0 AA had greater symptoms, worse DLCO, spirometry, BODE scores (1.03 vs 0.54, p < 0.0001), and greater deprivation than NHW. LIMITATIONS: Lack of an alternative diagnostic metric for comparison. CONCLUSIONS: The fixed-ratio spirometric criteria for COPD underdiagnosed potential COPD in AA participants when compared to broader diagnostic criteria. Disproportionate reductions in FVC relative to FEV1 leading to higher FEV1/FVC were identified in these participants and associated with deprivation. Broader diagnostic criteria for COPD are needed to identify the disease across all populations.

Clinical Markers Associated With Risk of Suicide or Drug Overdose Among Individuals With Smoking Exposure: A Longitudinal Follow-up Study of the COPDGene Cohort.

BACKGROUND: Studies have shown that COPD and smoking are associated with increased suicide risk. To date, there are no prospective studies examining suicide risk among individuals with smoking exposure along a spectrum of pulmonary diseases ranging from normal spirometry to severe COPD. RESEARCH QUESTION: Which clinical variables predict death by suicide or overdose of indeterminate intent in a large cohort of individuals with smoking exposure within the Genetic Epidemiology of COPD (COPDGene) study? STUDY DESIGN AND METHODS: We studied data from 9,930 participants involved in COPDGene, a multisite, prospective cohort study of individuals with smoking exposure. Primary cause of adjudicated deaths was identified by using death certificates, family reports, and medical records. Time to death by suicide/overdose was examined as the primary outcome in Cox regression models including age, sex, race, BMI, pack-years, current smoking status, airflow limitation (FEV1 % predicted), dyspnea (modified Medical Research Council scale score ≥ 2), 6-min walk distance, supplemental oxygen use, and severe exacerbations in the prior year with time-varying covariates and other causes of death as a competing risk. RESULTS: The cohort was 47% female and 33% Black (67% White); they had a mean ± SD age of 59.6 ± 9.0 years and a mean FEV1 % predicted of 76.1 ± 25.5. Sixty-three individuals died by suicide/overdose. Factors associated with risk of suicide/overdose were current smoking (hazard ratio [HR], 6.44; 95% CI, 2.64-15.67), use of sedative/hypnotics (HR, 2.33; 95% CI, 1.24-4.38), and dyspnea (HR, 2.23; 95% CI, 1.34-3.70). Lower risk was associated with older age (per-decade HR, 0.45; 95% CI, 0.31-0.67), higher BMI (HR, 0.95; 95% CI, 0.91-0.99), and African-American race (HR, 0.41; 95% CI, 0.23-0.74). Severity of airflow limitation (FEV % predicted) was not associated with suicide risk. INTERPRETATION: In this well-characterized cohort of individuals with smoking exposure with and without COPD, risk factors for suicide/overdose were identified that emphasize the subjective experience of illness over objective assessments of lung function.

Atopic Eczema-Associated Fracture Risk and Oral Corticosteroids: A Population-Based Cohort Study.

BACKGROUND: Evidence suggests adults with atopic eczema have increased fracture risk. However, it is unclear whether oral corticosteroids explain the association. OBJECTIVE: To assess to what extent oral corticosteroids mediate the relationship between atopic eczema and fractures. METHODS: We conducted a cohort study using English primary care (Clinical Practice Research Datalink) and hospital admissions (Hospital Episode Statistics) records (1998-2016) including adults (18 years old and older) with atopic eczema matched (age, sex, and general practice) with up to 5 adults without atopic eczema. We used Cox regression to estimate hazard ratios (HRs) for specific major osteoporotic fractures (hip, spine, pelvis, or wrist) and for any-site fracture comparing individuals with atopic eczema with those without, adjusting for 6 different definitions of time-updated oral corticosteroid use (ever any prescription, ever high-dose, and recent, cumulative, current, or peak dose). RESULTS: We identified 526,808 individuals with atopic eczema and 2,569,030 without. We saw evidence of an association between atopic eczema and major osteoporotic fractures (eg, spine HR 1.15, 99% CI 1.08-1.22; hip HR 1.11, 99% CI 1.08-1.15) that remained after additionally adjusting for oral corticosteroids (eg, cumulative corticosteroid dose: spine HR 1.09, 99% CI 1.03-1.16; hip HR 1.09, 99% CI 1.06-1.12). Fracture rates were higher in people with severe atopic eczema than in people without even after adjusting for oral corticosteroids (eg, spine HR [99% CI]: confounder-adjusted 2.31 [1.91-2.81]; additionally adjusted for cumulative dose 1.71 [1.40-2.09]). CONCLUSIONS: Our findings suggest that little of the association between atopic eczema and major osteoporotic fractures is explained by oral corticosteroid use.

Climate Change and Medical Education: An Integrative Model.

Medical schools face a challenge when trying to include new topics, such as climate change and health (CCH), in their curricula because of competing demands from more traditional biomedical content. At the same time, an understanding of CCH topics is crucial for physicians as they have clear implications for clinical practice and health care delivery. Although some medical schools have begun to incorporate CCH into curricula, the inclusion usually lacks a comprehensive framework for content and implementation. The authors propose a model for integrating CCH into medical school curricula using a practical, multistakeholder approach designed to mitigate competition for time with existing content by weaving meaningful CCH examples into current curricular activities. After the authors identified stakeholders to include in their curricular development working group, this working group determined the goals and desired outcomes of the curriculum; aligned those outcomes with the school's framework of educational objectives, competencies, and milestones; and strove to integrate CCH goals into as many existing curricular settings as possible. This article includes an illustration of the proposed model for one of the curricular goals (understanding the impacts of climate change on communities), with examples from the CCH curriculum integration that began in the fall of 2020 at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. The authors have found that this approach does minimize competition for time with existing content and allows mapping of content to existing curricular competencies and milestones, while encouraging a broad understanding of CCH in the context of individual patients, populations, and communities. This model for curricular integration can be applied to other topics such as social determinants of health, health equity, disability studies, and structural racism.

Diffuse Idiopathic Skeletal Hyperostosis in Smokers and Restrictive Spirometry Pattern: An Analysis of the COPDGene Cohort.

OBJECTIVE: Diffuse idiopathic skeletal hyperostosis (DISH) is a condition characterized by bony proliferation at sites of tendinous and ligamentous insertions in the spine. Spinal mobility is reduced in DISH and may affect movement in the thorax, potentially leading to restrictive pulmonary function. This study investigated whether DISH is associated with restrictive spirometric pattern (RSP) in former and current smokers. METHODS: Participants (n = 1784) with complete postbronchodilator spirometry who did not meet spirometric criteria for chronic obstructive pulmonary disease (COPD) at time of enrollment in the COPDGene study were included in this study. Subjects were classified as RSP if they had forced expiratory volume in 1 s(FEV1) to forced vital capacity (FVC) ratio > 0.7 with an FVC < 80%. Computed tomography (CT) scans were scored for the presence of DISH in accordance with the Resnick criteria. Chest CT measures of interstitial and alveolar lung disease, clinical symptoms, health surveys, and 6-min walking distance were recorded. Uni- and multivariable analyses were performed to test the association of DISH with RSP. RESULTS: DISH was present in 236 subjects (13.2%). RSP was twice as common in participants with DISH (n = 90/236, 38.1%) compared to those without DISH (n = 301/1548, 19.4%; p < 0.001). In multivariable analysis, DISH was significantly associated with RSP (OR 1.78; 95% CI 1.22-2.60; p = 0.003) after adjusting for potential confounders. The RSP group with and without DISH had significantly worse spirometry, dyspnea, St. George's Respiratory Questionnaire score, BODE index (Body mass index, airflow Obstruction, Dyspnea and Exercise capacity), and Medical Outcomes Study Short Form-36 questionnaire score. CONCLUSION: In heavy smokers with an FEV1/FVC ratio > 0.70, DISH is associated with RSP after adjustment for intrinsic and extrinsic causes of restrictive lung function. (Clinical trial registration number: NCT00608764.).

Atopic eczema and fracture risk in adults: A population-based cohort study.

BACKGROUND: Limited evidence suggests increased fracture risk in people with atopic eczema. Any link could have substantial effect; atopic eczema is common, and fractures have associated morbidity and mortality. OBJECTIVE: We sought to examine whether atopic eczema is associated with fracture and whether fracture risk varies with eczema severity. METHODS: We performed a matched cohort study set in primary care (Clinical Practice Research Datalink GOLD 1998-2016) and linked hospital admissions data (Hospital Episode Statistics), including adults (≥18 years old) with atopic eczema matched (by age, sex, general practice, and cohort entry date) with up to 5 individuals without eczema. We estimated hazard ratios (HRs) from stratified Cox regression comparing risk of major osteoporotic (hip, pelvis, spine, wrist, and proximal humerus) fractures individually and any fracture in those with and without atopic eczema. RESULTS: We identified 526,808 people with atopic eczema and 2,569,030 people without atopic eczema. Those with eczema had increased risk of hip (HR, 1.10; 99% CI, 1.06-1.14), pelvic (HR, 1.10; 99% CI, 1.02-1.19), spinal (HR, 1.18; 99% CI, 1.10-1.27), and wrist (HR, 1.07; 99% CI, 1.03,-1.11) fractures. We found no evidence of increased proximal humeral (HR, 1.06; 99% CI, 0.97-1.15) fracture risk. Fracture risk increased with increasing eczema severity, with the strongest associations in people with severe eczema (compared with those without) for spinal (HR, 2.09; 99% CI, 1.66-2.65), pelvic (HR, 1.66; 99% CI, 1.26-2.20), and hip (HR, 1.50; 99% CI, 1.30-1.74) fractures. Associations persisted after oral glucocorticoid adjustment. CONCLUSIONS: People with atopic eczema have increased fracture risk, particularly major osteoporotic fractures.

Pulmonary Subtypes Exhibit Differential Global Initiative for Chronic Obstructive Lung Disease Spirometry Stage Progression: The COPDGene® Study.

RATIONALE: We classified individuals into pulmonary disease subtypes based on 2 underlying pathophysiologic disease axes (airway-predominant and emphysema-predominant) and their increased mortality risk. Our next objective was to determine whether some subcomponents of these subtypes are additionally associated with unique patterns of Global initiative for chronic Obstructive Lung Disease (GOLD) spirometry stage progression. METHODS: After accounting for intra-individual measurement variability in spirometry measures between baseline (Phase 1) and the 5-year follow up (Phase 2) of the COPD Genetic Epidemiology (COPDGene®) study, 4615 individuals had complete data that would characterize patterns of disease progression over 5 years (2033 non-Hispanic whites; 827 African Americans; 48% female). Individuals could express increased risk for mortality on one or both of the primary subtype axes (airway-predominant or emphysema-predominant) and thus they were further classified into 6 groups: high-risk airway-predominant disease only (APD-only), moderate-risk airway-predominant disease only (MR-APD-only), high-risk emphysema-predominant disease only (EPD-only), combined high-risk airway- and emphysema-predominant disease (combined APD-EPD), combined moderate-risk airway- and emphysema-predominant disease (combined MR-APD-EPD), and no high-risk pulmonary subtype. Outcomes were dichotomized for GOLD spirometry stage progression from Phase 1 to Phase 2. Logistic regression of the progression outcomes on the pulmonary subtypes were adjusted for age, sex, race, and change in smoking status. RESULTS: The MR-APD-only group was associated with conversion from GOLD 0 to preserved ratio-impaired spirometry (PRISm) status (odds ratio [OR] 11.3, 95% confidence interval [CI] 5.7-22.1) and GOLD 0 to GOLD 2-4 (OR 6.0, 95% CI 2.0-18.0). The EPD-only group was associated with conversion from GOLD 0 to GOLD 1 (OR 2.4, 95% CI 1.2-4.6), and GOLD 1 to GOLD 2-4 (OR 2.6, 95% CI 1.0-6.9). Conversion between PRISm and GOLD 2-4 (31%-38%) occurred in both the APD-only and the MR-APD-only groups. CONCLUSION: Differential conversion occurs from GOLD 0 to PRISm and GOLD 0 to GOLD 1 based on groups expressing airway-predominant disease or emphysema-predominant disease independently or in combination. Airway-predominant and emphysema-predominant subtypes are highly important in determining patterns of early disease progression.

COPDGene® 2019: Redefining the Diagnosis of Chronic Obstructive Pulmonary Disease.

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 (FEV1 > 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.

Identifying Smoking-Related Disease on Lung Cancer Screening CT Scans: Increasing the Value.

BACKGROUND: Lung cancer screening (LCS) via chest computed tomography (CT) scans can save lives by identifying early-stage tumors. However, most smokers die of comorbid smoking-related diseases. LCS scans contain information about smoking-related conditions that is not currently systematically assessed. Identifying these common comorbid diseases on CT could increase the value of screening with minimal impact on LCS programs. We determined the prevalence of 3 comorbid diseases from LCS eligible scans and quantified related adverse outcomes. METHODS: We studied COPD Genetic Epidemiology study (COPDGene®) participants (n=4078) who met criteria for LCS screening at enrollment (age > 55 years, and < 80 years, > 30 pack years smoking, current smoker or former smoker within 15 years of smoking cessation). CT scans were assessed for coronary artery calcification (CAC), emphysema, and vertebral bone density. We tracked the following clinically significant events: myocardial infarctions (MIs), strokes, pneumonia, respiratory exacerbations, and hip and vertebral fractures. RESULTS: Overall, 77% of eligible CT scans had one or more of these diagnoses identified. CAC (> 100 mg) was identified in 51% of scans, emphysema in 44%, and osteoporosis in 54%. Adverse events related to the underlying smoking-related diseases were common, with 50% of participants reporting at least one. New diagnoses of cardiovascular disease, emphysema and osteoporosis were made in 25%, 7% and 46%, of participants respectively. New diagnosis of disease was associated with significantly more adverse events than in participants who did not have CT diagnoses for both osteoporosis and cardiovascular risk. CONCLUSIONS: Expanded analysis of LCS CT scans identified individuals with evidence of previously undiagnosed cardiovascular disease, emphysema or osteoporosis that corresponded with adverse events. LCS CT scans can potentially facilitate diagnoses of these smoking-related diseases and provide an opportunity for treatment or prevention.

Primary adrenal insufficiency in the United States: diagnostic error and patient satisfaction with treatment.

Background The objective of the study was to assess the diagnostic process, access to care and treatment adequacy for primary adrenal insufficiency (PAI) patients from a US-based online registry. Methods The National Adrenal Diseases Foundation (NADF) patient registry from 2015 to 2016 was used for a cross-sectional assessment of PAI patients. Five hundred and forty-one adults met the study inclusion criteria (US residents, age >20, self-reported physician diagnosis of PAI and replacement dosing for cortisol). Issues in diagnosis, comorbid conditions, symptoms, with demographic and socioeconomic characteristics were determined. Disease management assessment included medication dose, patient satisfaction with function, and education. Factors associated with adrenal crisis were noted. Results The cohort was predominantly female (83%), non-Hispanic White (97%), and well-educated (94% > high school education). A majority (57%) of patients reported difficulty with initial diagnosis, while 27% felt that their current steroid replacement was not adequate. Comorbid thyroid disease and other autoimmune conditions were common among PAI patients in the registry. More than three-quarters (78%) of patients used hydrocortisone for glucocorticoid replacement with a mean dose of 24.4 (standard deviation [SD]: 8.7) mg. Mean dose of hydrocortisone has declined over time following current treatment recommendations. Conclusions Timely, accurate diagnosis remains a problem for patients with primary adrenal insufficiency in an affluent, well-educated US cohort. Episodes of adrenal crisis are common and replacement steroid treatment is not always effective for patient function. Comprehensive information about outcomes of care for PAI in the US remains limited and the establishment of a research-specific registry to foster future research may be desirable. Patient registry data is a valuable source of information on diagnostic error and outcomes of care in rare diseases.

Symptoms of anxiety and depression and use of anxiolytic-hypnotics and antidepressants in current and former smokers with and without COPD - A cross sectional analysis of the COPDGene cohort.

OBJECTIVES: To compare the frequency of anxiety/depressive symptoms and use of anxiolytic-hypnotics/antidepressants in smokers with and without COPD and to identify characteristics associated with having unmedicated symptoms. METHODS: Cross-sectional analysis of ambulatory, current/former smokers ≥10 pack years enrolled in the COPDGene study. We measured anxiety/depressive symptoms using the Hospital Anxiety and Depression Scale (subscales ≥8), recorded anxiolytic-hypnotic/antidepressant use, and defined unmedicated symptoms as elevated anxiety/depressive symptoms and not on medications. Regression analysis identified characteristics associated with having unmedicated symptoms. KEY RESULTS: Of 5331 current/former smokers (45% with and 55% without COPD), 1332 (25.0%) had anxiety/depressive symptoms. Anxiety symptoms were similar in frequency in smokers with and without COPD (19.7% overall), while depressive symptoms were most frequent in severe-very severe COPD at 20.7% (13.1% overall). In the entire cohort, 1135 (21.2%) were on medications. Anxiolytic-hypnotic use was highest in severe-very severe COPD (range 7.6%-12.0%), while antidepressant use showed no significant variation in smokers with and without COPD (range 14.7%-17.1%). Overall, 881 (66% of those with symptoms) had unmedicated symptoms, which was associated with African American race (adjusted OR 2.95, 95% CI 2.25-3.87), male gender (adjusted OR 1.93, 95% CI 1.57-2.36), no health insurance (adjusted OR 2.38, 95% CI 1.30-4.35), severe-very severe COPD (adjusted OR 1.48, 95% CI 1.04-2.11), and higher respiratory symptoms/exacerbation history (adjusted OR 2.21, 95% CI 1.62-3.02). CONCLUSIONS: Significant unmet mental health care needs exist in current and former smokers with and without COPD. One in five have unmedicated symptoms, identified by key demographic and clinical characteristics. PRIMARY FUNDING SOURCE: National Institutes of Health and The COPD Foundation.

Association of low income with pulmonary disease progression in smokers with and without chronic obstructive pulmonary disease.

Low socioeconomic status has been associated with chronic obstructive pulmonary disease (COPD) but little is known about its impact on disease progression. We assessed the association of income to symptoms, pulmonary disease severity and progression in smokers with and without COPD. The COPDGene cohort of 4826 smokers who reported annual income in phase 2 was analysed. Those who reported annual income