Severity of Airflow Obstruction Based on FEV1/FVC vs FEV1% of Predicted in the General US Population.

RATIONALE: According to GOLD, the ratio of FEV1/FVC is used to confirm airflow obstruction in COPD diagnosis, whereas FEV1% of predicted (FEV1%pred) is used for severity grading. STaging of Airflow obstruction by the FEV1/FVC Ratio (STAR) and its prediction of adverse outcomes has not been evaluated in general populations. OBJECTIVE: To compare the STAR (FEV1/FVC) versus GOLD (FEV1%pred) classification for the severity of airflow limitation in terms of exertional breathlessness and mortality in the general US population. METHODS: Severity stages according to STAR and GOLD were applied to the multi-ethnic National Health and Nutrition Examination Survey (NHANES) 2007-2012 survey including ages 18-80 years, using post-bronchodilatory FEV1/FVC<0.70 to define airflow obstruction in both staging systems. Prevalence of severity stages STAR 1-4 and GOLD 1-4 was calculated and associations with breathlessness and mortality were analyzed by multinomial logistic regression and Cox regression, respectively. RESULTS: STAR versus GOLD severity staging of airflow obstruction showed similar associations with breathlessness and all-cause mortality, regardless of ethnicity/race. In those with airflow obstruction, the correlation between the two classification systems was 0.461 (p<0.001). STAR reclassified 59% of GOLD stage 2 as having mild airflow obstruction (STAR 1). STAR 1 was more clearly differentiated from the non-obstructive compared to GOLD stage 1 in terms of both breathlessness and mortality. CONCLUSIONS: FEV1/FVC and FEV1%pred as measures of severity of airflow limitation show similar prediction of breathlessness and mortality in the adult US population across ethnicity groups. However, stage 1 differed more clearly from non-obstructive based on FEV1/FVC than FEV1%pred. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Long-Term SGRQ Stability in a Cohort of Individuals with Alpha-1 Antitrypsin Deficiency-Associated Lung Disease.

Background: Health-related quality of life (HRQoL) assessments such as St. George's Respiratory Questionnaire (SGRQ) are often used as outcome measures to evaluate patient-perceived changes in health status among individuals with lung disease. Several factors have been linked to deterioration in SGRQ, including symptoms (dyspnea, wheezing) and exercise intolerance. Whether these findings apply to individuals with alpha-1 antitrypsin deficiency (AATD) remains incompletely studied. This longitudinal study examines the trajectory of SGRQ scores in a cohort of United States individuals with AATD-associated lung disease and defines factors associated with longitudinal change. Methods: Individuals with AATD-associated lung disease enrolled in AlphaNet, a disease management program, who had ≥3 SGRQ measurements collected between 2009 and 2019, and baseline data for clinically important variables were included in these analyses. Data collected after lung transplants were excluded. Mixed-effects model analyses were used to evaluate the changes in SGRQ total and subscale scores over time and by modified Medical Research Council (mMRC) Scale, use of oxygen, age, sex, productive cough, and exacerbation frequency at baseline. Sensitivity analyses were conducted to examine the potential effect of survivor bias. Results: Participants (n=2456, mean age 57.1±9.9 years, 47% female) had a mean SGRQ total score of 44.7±18.9 at baseline, 48% used oxygen regularly, and 55% had ≥2 exacerbations per year. The median length of follow-up was 6 (IQR 3-9) years. The SGRQ total score and subscales remained stable throughout the observation period. Age, mMRC categories, presence or absence of productive cough, frequency of exacerbations, and use of oxygen at baseline were significantly associated with the rate of change of SGRQ total (p<0.0001). Conclusion: We observed long-term stability in HRQoL and an association between the rate of change in SGRQ and baseline mMRC, exacerbation frequency, productive cough, and use of oxygen in this cohort of individuals with AATD-associated lung disease.

Characteristics associated with SF-36 in alpha-1 antitrypsin deficiency-associated COPD: a cross-sectional analysis.

BACKGROUND: Generic measures of health-related quality of life (HRQoL), such as the 36-Item Short Form Survey (SF-36), are widely used in assessing chronic conditions. These tools have an advantage over disease-specific instruments, as they allow comparisons across different health conditions and with the general population. In alpha-1 antitrypsin deficiency (AATD)-associated chronic obstructive pulmonary disease (COPD), HRQoL research remains scarce. This cross-sectional study evaluates the factors associated with HRQoL in a cohort of patients with AATD-associated COPD. METHODS: Our study included participants of AlphaNet (2008-2019), a health management organization for people with AATD in the US who are prescribed augmentation therapy. Norm-based SF-36 scores for the mental and physical component summary scores (MCS and PCS, mean of 50 ± 10 in the general US population) and 8 individual scales were evaluated. Individuals with lung disease and data available on ≥1 measurement on any SF-36 scale and clinically relevant characteristics such as modified Medical Research Council (mMRC) scale, exacerbation frequency, productive cough, and use of oxygen were included in these analyses. Generalized linear regression models were fit to examine the association of baseline characteristics with MCS and PCS scores. Age, sex, regular use of oxygen, exacerbation frequency, mMRC, and productive cough were included in these models. RESULTS: Participants (n=4398, mean age 57.6 [SD=10.6] years, 45.4% female) had a mean MCS score of 51.2 ± 10.8 and PCS of 36.3 ± 9.8. The average mMRC score was 2.4 ± 1.3, and 56.4% had 2 or more exacerbations per year. Overall, the physical component of SF-36 was more severely impacted compared to the mental component. In multivariable regression analyses, PCS scores were significantly associated with exacerbation frequency, mMRC, regular use of oxygen, and productive cough; MCS was associated with age, sex, exacerbation frequency, mMRC, and productive cough. CONCLUSIONS: These findings demonstrate that patient-perceived physical health is significantly impaired in this cohort of people with AATD-associated COPD compared to mental health. Longitudinal studies are needed to evaluate the change in physical and mental health status over time in this population.

Risk of Death and Cardiovascular Events Following an Exacerbation of COPD: The EXACOS-CV US Study.

Purpose: This study estimated the magnitude and duration of risk of cardiovascular events and mortality following acute exacerbations of chronic obstructive pulmonary disease (AECOPD), and whether risks varied by number and severity of exacerbation in a commercially insured population in the United States. Methods: This was a retrospective cohort study of newly diagnosed COPD patients ≥40 years old in the Healthcare Integrated Research Database from 2012 to 2019. Patients experiencing exacerbations comprised the "exacerbation cohort". Moderate exacerbations were outpatient visits with contemporaneous antibiotic or glucocorticoid administration; severe exacerbations were emergency department visits or hospitalizations for AECOPD. Follow-up started on the exacerbation date. Distribution of time between diagnosis and first exacerbation was used to assign index dates to the "unexposed" cohort. Cox proportional hazards models estimated risks of a cardiovascular event or death following an exacerbation adjusted for medical and prescription history and stratified by follow-up time, type of cardiovascular event, exacerbation severity, and rank of exacerbation (first, second, or third). Results: Among 435,925 patients, 170,236 experienced ≥1 exacerbation. Risk of death was increased for 2 years following an exacerbation and was highest during the first 30 days (any exacerbation hazard ratio (HR)=1.79, 95% CI=1.58-2.04; moderate HR=1.22, 95% CI=1.04-1.43; severe HR=5.09, 95% CI=4.30-6.03). Risks of cardiovascular events were increased for 1 year following an AECOPD and highest in the first 30-days (any exacerbation HR=1.34, 95% CI=1.23-1.46; moderate HR=1.23 (95% CI 1.12-1.35); severe HR=1.93 (95% CI=1.67-2.22)). Each subsequent AECOPD was associated with incrementally higher rates of both death and cardiovascular events. Conclusion: Risk of death and cardiovascular events was greatest in the first 30 days and rose with subsequent exacerbations. Risks were elevated for 1-2 years following moderate and severe exacerbations, highlighting a sustained increased cardiopulmonary risk associated with exacerbations.

Perspectives on Ensifentrine and Its Therapeutic Potential in the Treatment of COPD: Evidence to Date.

Ensifentrine is a novel inhalational phosphodiesterase (PDE)3 and PDE4 inhibitor which improves bronchodilation and decreases inflammatory markers by acting locally on the bronchial tissue, with minimal systemic effects. Both preclinical and clinical trials have demonstrated benefits of this therapy, including improvement in lung function and reduction in exacerbations. This therapy is currently under review by the US Food and Drug Administration with a decision expected in 2024.

National and Local Direct Medical Cost Burden of COPD in the United States From 2016 to 2019 and Projections Through 2029.

BACKGROUND: Despite the significant burden posed by COPD to health-care systems, there is a lack of up-to-date information quantifying the general COPD burden, costs, and long-term projections to various stakeholders in the United States. RESEARCH QUESTION: What are the updated state-specific and nationwide estimates of the COPD disease burden and direct costs in 2019, along with projections of COPD-attributable medical costs through 2029?. STUDY DESIGN AND METHODS: A cross-sectional, retrospective study design using the 2016 to 2019 Medical Expenditure Panel Survey, 2019 American Community Survey, and 2019 Behavioral Risk Factor Surveillance System data was applied to generate COPD-attributable expenditure estimates. Cost projections for the years 2020 to 2029 were based on 2017 National Population Projections reported by the Census Bureau, and all costs were adjusted to 2019 US dollars. RESULTS: In total, 4,135 people living with COPD were included; a higher proportion had other concurrent conditions such as cardiovascular-related conditions compared with people without COPD (n = 86,021). Overall, in 2019, COPD-attributable medical costs after adjusting for demographic characteristics and 19 concurrent conditions (including COPD-related and non-COPD-related conditions) were estimated at $31.3 billion, with state-specific cost estimates reporting wide variation, from $44.8 million in Alaska to $3.1 billion in Florida. Nationwide COPD-attributable medical costs borne by payer type were as follows: private insurance, $11.4 billion; Medicare, $10.8 billion; and Medicaid, $3.0 billion. Projections of national medical costs attributable to COPD are reported to increase to $60.5 billion in 2029. INTERPRETATION: Understanding the current disease and economic burden of COPD in the United States, along with the projected costs attributable to COPD in the next decade, will highlight unmet needs and gaps in care that help inform health-care decision-makers in planning future actions to alleviate this disease burden.

Guidance on Mitigating the Risk of Transmitting Respiratory Infections During Nebulization by the COPD Foundation Nebulizer Consortium.

BACKGROUND: Nebulizers are used commonly for inhaled drug delivery. Because they deliver medication through aerosol generation, clarification is needed on what constitutes safe aerosol delivery in infectious respiratory disease settings. The COVID-19 pandemic highlighted the importance of understanding the safety and potential risks of aerosol-generating procedures. However, evidence supporting the increased risk of disease transmission with nebulized treatments is inconclusive, and inconsistent guidelines and differing opinions have left uncertainty regarding their use. Many clinicians opt for alternative devices, but this practice could impact outcomes negatively, especially for patients who may not derive full treatment benefit from handheld inhalers. Therefore, it is prudent to develop strategies that can be used during nebulized treatment to minimize the emission of fugitive aerosols, these comprising bioaerosols exhaled by infected individuals and medical aerosols generated by the device that also may be contaminated. This is particularly relevant for patient care in the context of a highly transmissible virus. RESEARCH QUESTION: ▪▪▪ STUDY DESIGN AND METHODS: The COPD Foundation Nebulizer Consortium (CNC) was formed in 2020 to address uncertainties surrounding administration of nebulized medication. The CNC is an international, multidisciplinary collaboration of patient advocates, pulmonary physicians, critical care physicians, respiratory therapists, clinical scientists, and pharmacists from research centers, medical centers, professional societies, industry, and government agencies. The CNC developed this expert guidance to inform the safe use of nebulized therapies for patients and providers and to answer key questions surrounding medication delivery with nebulizers during pandemics or when exposure to common respiratory pathogens is anticipated. RESULTS: CNC members reviewed literature and guidelines regarding nebulization and developed two sets of guidance statements: one for the health care setting and one for the home environment. INTERPRETATION: Future studies need to explore the risk of disease transmission with fugitive aerosols associated with different nebulizer types in real patient care situations and to evaluate the effectiveness of mitigation strategies.

Environmental exposures and pulmonary function among adult residents of rural Appalachian Kentucky.

BACKGROUND: Estimated residential exposures of adults to roadway density and several metrics of resource extraction, including coal mining and oil and gas drilling, were hypothesized to contribute to the prevalence of respiratory disease in rural Appalachia. OBJECTIVE: Determine how small-area geographic variation in residential environmental exposures impacts measures of pulmonary function among adults in a community-based study. METHODS: We examined associations between residential environmental respiratory exposures and pulmonary function among 827 adult participants of the "The Mountain Air Project", a community-based, cross-sectional study in Southeastern Kentucky during 2016-2018. Exposures characterized the density of roadways, oil/gas wells, or current/past surface and underground coal mining at the level of 14-digit hydrologic unit code (HUC), or valley "hollow" where participants resided. Each participant completed an in-person interview to obtain extensive background data on risk factors, health history, and occupational and environmental exposures, as well as a spirometry test administered by experienced study staff at their place of residence. Multivariable linear regression was used to model the adjusted association between each environmental exposure and percent predicted forced expiratory volume in one second (FEV1PP) and forced vital capacity (FVCPP). RESULTS: Adjusted regression models indicate persons living in HUCs with the highest level of roadway density experienced a reduction in both FEV1PP (-4.3: 95% CI: -7.44 -1.15;) and FVCPP (-3.8: 95% CI: -6.38, -1.21) versus persons in HUCs with the lowest roadway density. No associations were detected between the metrics associated with mining and oil and gas operations and individual pulmonary function. IMPACT STATEMENT: Our work demonstrates the potential adverse impact of roadway-related exposures on the respiratory health of rural Appalachia residents. We employed a novel method of small-area exposure classification based on the hydrologic unit code (HUC), representing potential exposure levels per hollow occurring  in proximity to the residence, and controlled for individual-level risk factors for reduced respiratory health. We highlight an overlooked yet ubiquitous source of residential exposure from motor vehicles that may contribute to the regionally high prevalence of respiratory disease in rural Appalachia.

Quality of Life and Mortality Outcomes for Augmentation Naïve and Augmented Patients with Severe Alpha-1 Antitrypsin Deficiency.

Background: Intravenous alpha-1 antitrypsin (AAT) augmentation therapy is the only specific treatment available for alpha-1 antitrypsin deficiency (AATD)-related lung disease. It is widely used worldwide but remains unavailable to patients with AATD in the United Kingdom. While randomized trials of augmentation therapy have demonstrated biochemical efficacy and lung tissue preservation using computed tomography (CT) densitometry, these studies were not adequately powered to demonstrate effectiveness in well-accepted clinical endpoints such as quality of life (QOL) or survival. We used large, prospectively followed AATD patient populations in the United States and United Kingdom to explore these important clinical endpoints. Methods: Our inclusion criterion was adults with severe AATD and associated lung disease. The treatment group was U.S. AATD patients receiving augmentation therapy for lung disease. The control group was augmentation therapy naïve AATD patients. Multivariable regression and survival analyses were used to assess QOL and mortality outcomes respectively. Results: Mean annual deterioration of the St George's Respiratory Questionnaire total score was 1.43 points greater/year in the control group compared to those receiving augmentation therapy (95% confidence interval [CI] 0.47 to 2.39, p=0.003). At 7 years, median survival was 82.7% (95% CI 75.3 to 90.7) for the control group versus 87.8% (95% CI 82.8 to 93.2) in the augmentation group, p=0.66. There was significant heterogeneity between cohorts. Conclusions: A comparison of 2 highly characterized AATD cohorts was not able to reliably determine if AAT augmentation therapy improves QOL or mortality in patients with severe AATD-related lung disease. Alternative surrogate biomarkers of disease progression, such as CT lung density, may be a more pragmatic option.

Fractional Dynamics Foster Deep Learning of COPD Stage Prediction.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. Current COPD diagnosis (i.e., spirometry) could be unreliable because the test depends on an adequate effort from the tester and testee. Moreover, the early diagnosis of COPD is challenging. The authors address COPD detection by constructing two novel physiological signals datasets (4432 records from 54 patients in the WestRo COPD dataset and 13824 medical records from 534 patients in the WestRo Porti COPD dataset). The authors demonstrate their complex coupled fractal dynamical characteristics and perform a fractional-order dynamics deep learning analysis to diagnose COPD. The authors found that the fractional-order dynamical modeling can extract distinguishing signatures from the physiological signals across patients with all COPD stages-from stage 0 (healthy) to stage 4 (very severe). They use the fractional signatures to develop and train a deep neural network that predicts COPD stages based on the input features (such as thorax breathing effort, respiratory rate, or oxygen saturation). The authors show that the fractional dynamic deep learning model (FDDLM) achieves a COPD prediction accuracy of 98.66% and can serve as a robust alternative to spirometry. The FDDLM also has high accuracy when validated on a dataset with different physiological signals.

Patient-Reported Pulmonary Symptoms, Exacerbations, and Management in a Cohort of Patients With Alpha-1 Antitrypsin Deficiency.

Rationale: Identifying pulmonary exacerbations in patients with alpha-1 antitrypsin deficiency (AATD) is critical as they are associated with disease progression and poor health-related quality of life. Not all changes in usual respiratory symptoms will be identified as exacerbations by patients with AATD. Methods: Data collected via regular monthly telephone calls during the first year of the AlphaNet Step Forward Study were analyzed. AlphaNet subscribers were asked about changes in their usual respiratory symptoms, whether they considered changes in symptoms to be pulmonary exacerbations, and their management. Participants who reported changes in their usual respiratory symptoms throughout the year were included in the study. Per-patient and per-event analyses were performed. Results: Participants (n=316, age 58±10 years, 53% female) reported 797 events of changes in their usual respiratory symptoms in 1 year. Almost half (48%) of these symptom events were identified as pulmonary exacerbations by the study participants. The average number of symptoms was higher in events recognized by participants as exacerbations than those not identified as exacerbations (3.3±1.5 versus 1.8±1.1, respectively). A greater proportion of the exacerbation events were managed by taking antibiotics or corticosteroids or both (81%, 53%, and 41% of the events, respectively). With exacerbations, participants mainly spoke to the pulmonary specialist (39%) or went to the doctor's office (37%). Symptom events not recognized as exacerbations were mostly self-treated (56%). Conclusions: Changes in usual pulmonary symptoms are not universally recognized as exacerbations. Patients' perspectives in recognizing changes in pulmonary symptoms as exacerbation events are critical.

Tobacco industry ownership of pharmaceutical companies: an international survey of people with respiratory disease.

The 2021 purchase of the respiratory pharmaceutical company Vectura by Phillip Morris International has been criticised by the public health and medical community, as a conflict of interest, with little input to date, from the patient community or the public. To address this gap, the COPD Foundation, along with global partners, surveyed 1196 people with chronic respiratory disease. 70% were bothered by a tobacco company making an inhaler to treat lung conditions and 48% reported that they would want to switch inhalers if they knew that a tobacco company made or sold their inhaler devices. Patients care about who makes the therapies used to treat their diseases.

Respiratory Symptoms among US Adults: a Cross-Sectional Health Survey Study.

INTRODUCTION: Data collected through ongoing, state-based, cross-sectional health surveys could be used to better understand the contribution of respiratory symptoms to impaired health among the US adult population. METHODS: We used the 2015 Behavioral Risk Factor Surveillance System telephone health survey in four states (Kentucky, Florida, South Carolina, Texas) to describe the relationship between symptoms, associated factors such as tobacco smoking, and health impairments. Self-reported productive cough, shortness of breath (SOB), and dyspnea on exertion (DOE) were categorized as minimal, moderate, or severe. Data were analyzed using multiple logistic regression models with age as a covariate to assess relationships of symptoms with other factors. RESULTS: Among adults ≥ 18 years, respiratory impairment [current asthma, chronic obstructive pulmonary disease (COPD), or a current moderate or severe symptom] occurred in 39.1% of the population. More than half of adults reporting moderate or severe symptoms had not been diagnosed with asthma or COPD, particularly with DOE and productive cough. Subjects were at greater risk of moderate and severe SOB or productive cough with increasing age, prolonged smoking duration (≥ 20 years), being an ever-smoker, or if reporting COPD, current asthma, or any other comorbidity except cancer. Morbid obesity [body mass index (BMI) > 35 kg/m2] was associated with severe DOE at a rate similar to current asthma or COPD (25.6%, 95% CI 20.9-30.3%; 20.8%, 95% CI 16.4-25.1%; 21.3%, 95% CI 17.5-25.1%, respectively); it was the most common cause of DOE. SOB was associated with worse general health impairment and limited ambulation compared with other symptoms. Tobacco smoking prevalence and race varied among states, affecting symptom prevalence. CONCLUSION: In the largest US survey in decades, we provide a current perspective of respiratory symptoms among adults of all ages. While known risk factors were apparent, low-risk persons also frequently reported symptoms and impairments.

Race and Sex Differences in Mortality in Individuals with Chronic Obstructive Pulmonary Disease.

Rationale: Despite differences in chronic obstructive pulmonary disease (COPD) comorbidities, race- and sex-based differences in all-cause mortality and cause-specific mortality are not well described. Objectives: To examine mortality differences in COPD by race-sex and underlying mechanisms. Methods: Medicare claims were used to identify COPD among REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort participants. Mortality rates were calculated using adjudicated causes of death. Hazard ratios (HRs) for mortality comparing race-sex groups were modeled with Cox proportional hazards regression. Results: In the 2,148-member COPD subcohort, 49% were women, and 34% were Black individuals; 1,326 deaths occurred over a median 7.5 years (interquartile range, 3.9-10.5 yr) follow-up. All-cause mortality per 1,000 person-years comparing Black versus White men was 101.1 (95% confidence interval [CI], 88.3-115.8) versus 93.9 (95% CI, 86.3-102.3; P = 0.99); comparing Black versus White women, all-cause mortality per 1,000 person-years was 74.2 (95% CI, 65.0-84.8) versus 70.6 (95% CI, 63.5-78.5; P = 0.99). Cardiovascular disease (CVD) was the leading cause-specific mortality among all race-sex groups. HR for CVD and chronic lung disease mortality were nonsignificant comparing Black versus White men. HR for CVD death was higher in Black compared with White women (HR, 1.44; 95% CI, 1.06-1.95), whereas chronic lung disease death was lower (HR, 0.44; 95% CI, 0.25-0.77). These differences were attributable to higher CVD risk factor burden among Black women. Conclusions: In the REGARDS COPD cohort, there were no race-sex differences in all-cause mortality. CVD was the most common cause of death for all race-sex groups with COPD. Black women with COPD had a higher risk of CVD-related mortality than White women. CVD comorbidity management, especially among Black individuals, may improve mortality outcomes.