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RATIONALE: Serum Immunoglobulin G (IgG) deficiency is associated with morbidity in chronic obstructive pulmonary disease (COPD) but it is unclear whether concentrations in the lower end of the normal range still confer risk. OBJECTIVES: To determine if levels above traditional cutoffs for serum IgG deficiency are associated with exacerbations among current and former smokers with or at risk for COPD. MEASUREMENTS AND MAIN RESULTS: Former and current smokers in SPIROMICS (n=1,497) were studied, n=1,026 with and n=471 at risk for COPD. In a subset (n=1,031), IgG subclasses were measured. Associations between total IgG or subclasses and prospective exacerbations were evaluated with multivariable models adjusting for demographics, current smoking, smoking history, FEV1% predicted, inhaled corticosteroids, and serum IgA. RESULTS: The 35th percentile (1225 mg/dL in this cohort) of IgG was the best cutoff by Akaike Information Criterion (AIC). Below this, there was increased exacerbation risk (IRR 1.28, 95% CI 1.08-1.51). Among subclasses, IgG1 and IgG2 below 35th percentile (354 and 105 mg/dL, respectively) were both associated with increased risk of severe exacerbation (IgG1: IRR 1.39, 95% CI 1.06-1.84; IgG2: IRR 1.50, 95% CI 1.14-1.1.97). These associations remained significant when additionally adjusting for history of exacerbations. CONCLUSIONS: Lower serum IgG is prospectively associated with exacerbations in individuals with or at risk for COPD. Among subclasses, lower IgG1 and IgG2 are prospectively associated with severe exacerbations. The optimal IgG cutoff was substantially higher than traditional cutoffs for deficiency, suggesting subtle impairment of humoral immunity may be associated with exacerbations.
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Background: The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition. Objectives: Accordingly, with National Heart, Lung and Blood Institute support, we initiated the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression. Methods/Discussion: SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global initiative for chronic Obstructive Lung Disease (GOLD) groups 0-2 or with preserved ratio-impaired spirometry; and an additional n=40 never-smoker controls. Participants undergo baseline and 3-year follow-up visits, each including high-resolution computed tomography, respiratory oscillometry and spirometry (pre- and postbronchodilator administration), exhaled breath condensate (baseline only), and extensive biospecimen collection, including sputum induction. Symptoms, interim health care utilization, and exacerbations are captured every 6 months via follow-up phone calls. An embedded bronchoscopy substudy involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture. Conclusion: SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis.
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Importance: Persistent symptoms and disability following SARS-CoV-2 infection, known as post-COVID-19 condition or "long COVID," are frequently reported and pose a substantial personal and societal burden. Objective: To determine time to recovery following SARS-CoV-2 infection and identify factors associated with recovery by 90 days. Design, Setting, and Participants: For this prospective cohort study, standardized ascertainment of SARS-CoV-2 infection was conducted starting in April 1, 2020, across 14 ongoing National Institutes of Health-funded cohorts that have enrolled and followed participants since 1971. This report includes data collected through February 28, 2023, on adults aged 18 years or older with self-reported SARS-CoV-2 infection. Exposure: Preinfection health conditions and lifestyle factors assessed before and during the pandemic via prepandemic examinations and pandemic-era questionnaires. Main Outcomes and Measures: Probability of nonrecovery by 90 days and restricted mean recovery times were estimated using Kaplan-Meier curves, and Cox proportional hazards regression was performed to assess multivariable-adjusted associations with recovery by 90 days. Results: Of 4708 participants with self-reported SARS-CoV-2 infection (mean [SD] age, 61.3 [13.8] years; 2952 women [62.7%]), an estimated 22.5% (95% CI, 21.2%-23.7%) did not recover by 90 days post infection. Median (IQR) time to recovery was 20 (8-75) days. By 90 days post infection, there were significant differences in restricted mean recovery time according to sociodemographic, clinical, and lifestyle characteristics, particularly by acute infection severity (outpatient vs critical hospitalization, 32.9 days [95% CI, 31.9-33.9 days] vs 57.6 days [95% CI, 51.9-63.3 days]; log-rank P < .001). Recovery by 90 days post infection was associated with vaccination prior to infection (hazard ratio [HR], 1.30; 95% CI, 1.11-1.51) and infection during the sixth (Omicron variant) vs first wave (HR, 1.25; 95% CI, 1.06-1.49). These associations were mediated by reduced severity of acute infection (33.4% and 17.6%, respectively). Recovery was unfavorably associated with female sex (HR, 0.85; 95% CI, 0.79-0.92) and prepandemic clinical cardiovascular disease (HR, 0.84; 95% CI, 0.71-0.99). No significant multivariable-adjusted associations were observed for age, educational attainment, smoking history, obesity, diabetes, chronic kidney disease, asthma, chronic obstructive pulmonary disease, or elevated depressive symptoms. Results were similar for reinfections. Conclusions and Relevance: In this cohort study, more than 1 in 5 adults did not recover within 3 months of SARS-CoV-2 infection. Recovery within 3 months was less likely in women and those with preexisting cardiovascular disease and more likely in those with COVID-19 vaccination or infection during the Omicron variant wave.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Idoso , Adulto , Síndrome de COVID-19 Pós-Aguda , Pandemias , Estados Unidos/epidemiologiaRESUMO
RATIONAL: Ground glass opacities (GGO) in the absence of interstitial lung disease are understudied. OBJECTIVE: To assess the association of GGO with white blood cells (WBCs) and progression of quantified chest CT emphysema. METHODS: We analyzed data of participants in the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). Chest radiologists and pulmonologists labeled regions of the lung as GGO and adaptive multiple feature method (AMFM) trained the computer to assign those labels to image voxels and quantify the volume of the lung with GGO (%GGOAMFM). We used multivariable linear regression, zero-inflated negative binomial, and proportional hazards regression models to assess the association of %GGOAMFM with WBC, changes in %emphysema, and clinical outcomes. MEASUREMENTS AND MAIN RESULTS: Among 2,714 participants, 1,680 had COPD and 1,034 had normal spirometry. Among COPD participants, based on the multivariable analysis, current smoking and chronic productive cough was associated with higher %GGOAMFM. Higher %GGOAMFM was cross-sectionally associated with higher WBCs and neutrophils levels. Higher %GGOAMFM per interquartile range at visit 1 (baseline) was associated with an increase in emphysema at one-year follow visit by 11.7% (Relative increase; 95%CI 7.5-16.1%;P<0.001). We found no association between %GGOAMFM and one-year FEV1 decline but %GGOAMFM was associated with exacerbations and all-cause mortality during a median follow-up time of 1,544 days (Interquartile Interval=1,118-2,059). Among normal spirometry participants, we found similar results except that %GGOAMFM was associated with progression to COPD at one-year follow-up. CONCLUSIONS: Our findings suggest that GGOAMFM is associated with increased systemic inflammation and emphysema progression.
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Mucus plugs occlude airways to obstruct airflow in asthma. Studies in patients and in mouse models show that mucus plugs occur in the context of type 2 inflammation, and studies in human airway epithelial cells (HAECs) show that IL-13-activated cells generate pathologic mucus independently of immune cells. To determine how HAECs autonomously generate pathologic mucus, we used a magnetic microwire rheometer to characterize the viscoelastic properties of mucus secreted under varying conditions. We found that normal HAEC mucus exhibited viscoelastic liquid behavior and that mucus secreted by IL-13-activated HAECs exhibited solid-like behavior caused by mucin cross-linking. In addition, IL-13-activated HAECs shows increased peroxidase activity in apical secretions, and an overlaid thiolated polymer (thiomer) solution shows an increase in solid behavior that was prevented by peroxidase inhibition. Furthermore, gene expression for thyroid peroxidase (TPO), but not lactoperoxidase (LPO), was increased in IL-13-activated HAECs and both TPO and LPO catalyze the formation of oxidant acids that cross-link thiomer solutions. Finally, gene expression for TPO in airway epithelial brushings was increased in patients with asthma with high airway mucus plug scores. Together, our results show that IL-13-activated HAECs autonomously generated pathologic mucus via peroxidase-mediated cross-linking of mucin polymers.
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Células Epiteliais , Interleucina-13 , Muco , Humanos , Interleucina-13/metabolismo , Interleucina-13/farmacologia , Células Epiteliais/metabolismo , Muco/metabolismo , Mucinas/metabolismo , Asma/metabolismo , Asma/patologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Lactoperoxidase/metabolismo , GéisRESUMO
Rationale: It is unknown whether air pollution is associated with radiographic features of interstitial lung disease in individuals with chronic obstructive pulmonary disease (COPD). Objectives: To determine whether air pollution increases the prevalence of interstitial lung abnormalities (ILA) or percent high-attenuation areas (HAA) on computed tomography (CT) in individuals with a heavy smoking history and COPD. Methods: We performed a cross-sectional study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), focused on current or former smokers with COPD. Ten-year exposure to particulate matter ⩽2.5 µm in aerodynamic diameter (PM2.5), nitrogen oxides (NOx), nitrogen dioxide (NO2), and ozone before enrollment CT (completed between 2010 and 2015) were estimated with validated spatiotemporal models at residential addresses. We applied adjusted multivariable modified Poisson regression and linear regression to investigate associations between pollution exposure and relative risk (RR) of ILA or increased percent HAA (between -600 and -250 Hounsfield units), respectively. We assessed for effect modification by MUC5B-promoter polymorphism (variant allele carriers GT or TT vs. GG at rs3705950), smoking status, sex, and percent emphysema. Results: Among 1,272 participants with COPD assessed for HAA, 424 were current smokers, and 249 were carriers of the variant MUC5B allele. A total of 519 participants were assessed for ILA. We found no association between pollution exposure and ILA or HAA. Associations between pollutant exposures and risk of ILA were modified by the presence of MUC5B polymorphism (P value interaction term for NOx = 0.04 and PM2.5 = 0.05) and smoking status (P value interaction term for NOx = 0.05; NO2 = 0.01; and ozone = 0.05). With higher exposure to NOx and PM2.5, MUC5B variant carriers had an increased risk of ILA (RR per 26 ppb NOx, 2.41; 95% confidence interval [CI], 0.97-6.0; and RR per 4 µg â m-3 PM2.5, 1.43; 95% CI, 0.93-2.2, respectively). With higher exposure to NO2, former smokers had an increased risk of ILA (RR per 10 ppb, 1.64; 95% CI, 1.0-2.7). Conclusions: Exposure to ambient air pollution was not associated with interstitial features on CT in this population of heavy smokers with COPD. MUC5B modified the association between pollution and ILA, suggesting that gene-environment interactions may influence prevalence of interstitial lung features in COPD.
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Poluição do Ar , Material Particulado , Doença Pulmonar Obstrutiva Crônica , Tomografia Computadorizada por Raios X , Humanos , Masculino , Feminino , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Idoso , Pessoa de Meia-Idade , Estudos Transversais , Material Particulado/efeitos adversos , Poluição do Ar/efeitos adversos , Mucina-5B/genética , Doenças Pulmonares Intersticiais/epidemiologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Exposição Ambiental/efeitos adversos , Estados Unidos/epidemiologia , Dióxido de Nitrogênio/efeitos adversos , Dióxido de Nitrogênio/análise , Óxidos de Nitrogênio/efeitos adversos , Óxidos de Nitrogênio/análise , Modelos Lineares , Fumar/efeitos adversos , Fumar/epidemiologia , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Ozônio/efeitos adversos , PrevalênciaRESUMO
This study investigates correlates of anti-S1 antibody response following COVID-19 vaccination in a U.S. population-based meta-cohort of adults participating in longstanding NIH-funded cohort studies. Anti-S1 antibodies were measured from dried blood spots collected between February 2021-August 2022 using Luminex-based microsphere immunoassays. Of 6245 participants, mean age was 73 years (range, 21-100), 58% were female, and 76% were non-Hispanic White. Nearly 52% of participants received the BNT162b2 vaccine and 48% received the mRNA-1273 vaccine. Lower anti-S1 antibody levels are associated with age of 65 years or older, male sex, higher body mass index, smoking, diabetes, COPD and receipt of BNT16b2 vaccine (vs mRNA-1273). Participants with a prior infection, particularly those with a history of hospitalized illness, have higher anti-S1 antibody levels. These results suggest that adults with certain socio-demographic and clinical characteristics may have less robust antibody responses to COVID-19 vaccination and could be prioritized for more frequent re-vaccination.
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Vacina de mRNA-1273 contra 2019-nCoV , COVID-19 , Adulto , Humanos , Feminino , Masculino , Idoso , Formação de Anticorpos , Vacina BNT162 , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , Demografia , VacinaçãoRESUMO
BACKGROUNDInformation about the size, airway location, and longitudinal behavior of mucus plugs in asthma is needed to understand their role in mechanisms of airflow obstruction and to rationally design muco-active treatments.METHODSCT lung scans from 57 patients with asthma were analyzed to quantify mucus plug size and airway location, and paired CT scans obtained 3 years apart were analyzed to determine plug behavior over time. Radiologist annotations of mucus plugs were incorporated in an image-processing pipeline to generate size and location information that was related to measures of airflow.RESULTSThe length distribution of 778 annotated mucus plugs was multimodal, and a 12 mm length defined short ("stubby", ≤12 mm) and long ("stringy", >12 mm) plug phenotypes. High mucus plug burden was disproportionately attributable to stringy mucus plugs. Mucus plugs localized predominantly to airway generations 6-9, and 47% of plugs in baseline scans persisted in the same airway for 3 years and fluctuated in length and volume. Mucus plugs in larger proximal generations had greater effects on spirometry measures than plugs in smaller distal generations, and a model of airflow that estimates the increased airway resistance attributable to plugs predicted a greater effect for proximal generations and more numerous mucus plugs.CONCLUSIONPersistent mucus plugs in proximal airway generations occur in asthma and demonstrate a stochastic process of formation and resolution over time. Proximal airway mucus plugs are consequential for airflow and are in locations amenable to treatment by inhaled muco-active drugs or bronchoscopy.TRIAL REGISTRATIONClinicaltrials.gov; NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01716494, and NCT01760915.FUNDINGAstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi-Genzyme-Regeneron, and TEVA provided financial support for study activities at the Coordinating and Clinical Centers beyond the third year of patient follow-up. These companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative.
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Asma , Humanos , Broncoscopia , Pulmão/diagnóstico por imagem , Muco , Tomografia Computadorizada por Raios XRESUMO
Importance: People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies. Objective: To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS). Design, Setting, and Participants: SPIROMICS II was an extension of SPIROMICS I, a multicenter study of persons aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without COPD and controls without tobacco exposure or airflow obstruction. Participants were enrolled in SPIROMICS I and II from November 10, 2010, through July 31, 2015, and followed up through July 31, 2021. Exposures: Participants in SPIROMICS I underwent spirometry, 6-minute walk distance testing, assessment of respiratory symptoms, and computed tomography of the chest at yearly visits for 3 to 4 years. Participants in SPIROMICS II had 1 additional in-person visit 5 to 7 years after enrollment in SPIROMICS I. Respiratory symptoms were assessed with the COPD Assessment Test (range, 0 to 40; higher scores indicate more severe symptoms). Participants with symptomatic TEPS had normal spirometry (postbronchodilator ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity >0.70) and COPD Assessment Test scores of 10 or greater. Participants with asymptomatic TEPS had normal spirometry and COPD Assessment Test scores of less than 10. Patient-reported respiratory symptoms and exacerbations were assessed every 4 months via phone calls. Main Outcomes and Measures: The primary outcome was assessment for accelerated decline in lung function (FEV1) in participants with symptomatic TEPS vs asymptomatic TEPS. Secondary outcomes included development of COPD defined by spirometry, respiratory symptoms, rates of respiratory exacerbations, and progression of computed tomographic-defined airway wall thickening or emphysema. Results: Of 1397 study participants, 226 had symptomatic TEPS (mean age, 60.1 [SD, 9.8] years; 134 were women [59%]) and 269 had asymptomatic TEPS (mean age, 63.1 [SD, 9.1] years; 134 were women [50%]). At a median follow-up of 5.76 years, the decline in FEV1 was -31.3 mL/y for participants with symptomatic TEPS vs -38.8 mL/y for those with asymptomatic TEPS (between-group difference, -7.5 mL/y [95% CI, -16.6 to 1.6 mL/y]). The cumulative incidence of COPD was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio, 1.05 [95% CI, 0.76 to 1.46]). Participants with symptomatic TEPS had significantly more respiratory exacerbations than those with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; rate ratio, 2.38 [95% CI, 1.71 to 3.31], P < .001). Conclusions and Relevance: Participants with symptomatic TEPS did not have accelerated rates of decline in FEV1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.
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Fumar Cigarros , Pneumopatias , Espirometria , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Progressão da Doença , Seguimentos , Volume Expiratório Forçado , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Capacidade Vital , Estudos Longitudinais , Fumar Cigarros/efeitos adversos , Fumar Cigarros/fisiopatologia , Pneumopatias/diagnóstico por imagem , Pneumopatias/etiologia , Pneumopatias/fisiopatologia , Testes de Função RespiratóriaRESUMO
Rationale: Indoor pollutants have been associated with chronic obstructive pulmonary disease morbidity, but it is unclear whether they contribute to disease progression. Objectives: We aimed to determine whether indoor particulate matter (PM) and nitrogen dioxide (NO2) are associated with lung function decline among current and former smokers. Methods: Of the 2,382 subjects with a history of smoking in SPIROMICS AIR, 1,208 participants had complete information to estimate indoor PM and NO2, using individual-based prediction models, in relation to measured spirometry at two or more clinic visits. We used a three-way interaction model between time, pollutant, and smoking status and assessed the indoor pollutant-associated difference in FEV1 decline separately using a generalized linear mixed model. Measurements and Main Results: Participants had an average rate of FEV1 decline of 60.3 ml/yr for those currently smoking compared with 35.2 ml/yr for those who quit. The association of indoor PM with FEV1 decline differed by smoking status. Among former smokers, every 10 µg/m3 increase in estimated indoor PM was associated with an additional 10 ml/yr decline in FEV1 (P = 0.044). Among current smokers, FEV1 decline did not differ by indoor PM. The results of indoor NO2 suggest trends similar to those for PM ⩽2.5 µm in aerodynamic diameter. Conclusions: Former smokers with chronic obstructive pulmonary disease who live in homes with high estimated PM have accelerated lung function loss, and those in homes with low PM have lung function loss similar to normal aging. In-home PM exposure may contribute to variability in lung function decline in people who quit smoking and may be a modifiable exposure.
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Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados , Poluição do Ar , Poluentes Ambientais , Doença Pulmonar Obstrutiva Crônica , Humanos , Fumantes , Poluição do Ar em Ambientes Fechados/efeitos adversos , Poluição do Ar em Ambientes Fechados/análise , Dióxido de Nitrogênio/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Material Particulado/efeitos adversos , Pulmão , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversosRESUMO
Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete. Objectives: To determine what proteins and pathways are associated with impaired pulmonary function in a diverse population. Methods: We studied 6,722 participants across six cohort studies with both aptamer-based proteomic and spirometry data (4,566 predominantly White participants in a discovery analysis and 2,156 African American cohort participants in a validation). In linear regression models, we examined protein associations with baseline forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC). In linear mixed effects models, we investigated the associations of baseline protein levels with rate of FEV1 decline (ml/yr) in 2,777 participants with up to 7 years of follow-up spirometry. Results: We identified 254 proteins associated with FEV1 in our discovery analyses, with 80 proteins validated in the Jackson Heart Study. Novel validated protein associations include kallistatin serine protease inhibitor, growth differentiation factor 2, and tumor necrosis factor-like weak inducer of apoptosis (discovery ß = 0.0561, Q = 4.05 × 10-10; ß = 0.0421, Q = 1.12 × 10-3; and ß = 0.0358, Q = 1.67 × 10-3, respectively). In longitudinal analyses within cohorts with follow-up spirometry, we identified 15 proteins associated with FEV1 decline (Q < 0.05), including elafin leukocyte elastase inhibitor and mucin-associated TFF2 (trefoil factor 2; ß = -4.3 ml/yr, Q = 0.049; ß = -6.1 ml/yr, Q = 0.032, respectively). Pathways and processes highlighted by our study include aberrant extracellular matrix remodeling, enhanced innate immune response, dysregulation of angiogenesis, and coagulation. Conclusions: In this study, we identify and validate novel biomarkers and pathways associated with lung function traits in a racially diverse population. In addition, we identify novel protein markers associated with FEV1 decline. Several protein findings are supported by previously reported genetic signals, highlighting the plausibility of certain biologic pathways. These novel proteins might represent markers for risk stratification, as well as novel molecular targets for treatment of COPD.
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Pulmão , Doença Pulmonar Obstrutiva Crônica , Humanos , Volume Expiratório Forçado/fisiologia , Proteômica , Capacidade Vital/fisiologia , Espirometria , BiomarcadoresRESUMO
STUDY OBJECTIVES: To examine the association of self-identified race with sleep quality in heavy smokers. METHODS: We studied baseline data from 1965 non-Hispanic White and 462 African American participants from SPIROMICS with ≥ 20 pack-years smoking history. We first examined the Pittsburgh Sleep Quality Index's (PSQI) internal consistency and item-total correlation in a population with chronic obstructive pulmonary disease. We then used staged multivariable regression to investigate the association of race and sleep quality as measured by the PSQI) The first model included demographics, the second added measures of health status, and the third, indicators of socioeconomic status. We next explored the correlation between sleep quality with 6-minute walk distance and St. George's Respiratory Questionnaire score as chronic obstructive pulmonary disease-relevant outcomes. We tested for interactions between self-identified race and the most important determinants of sleep quality in our conceptual model. RESULTS: We found that the PSQI had good internal consistency and item-total correlation in our study population of heavy smokers with and without chronic obstructive pulmonary disease. African American race was associated with increased PSQI in univariable analysis and after adjustment for demographics, health status, and socioenvironmental exposures (P = .02; 0.44 95%CI: .06 to .83). Increased PSQI was associated with higher postbronchodilator forced expiratory volume in 1 second and lower household income, higher depressive symptoms, and female sex. We identified an interaction wherein depressive symptoms had a greater impact on PSQI score for non-Hispanic White than African American participants (P for interaction = .01). CONCLUSIONS: In heavy smokers, self-reported African American race is independently associated with worse sleep quality. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Study of COPD Subgroups and Biomarkers (SPIROMICS); URL: https://clinicaltrials.gov/ct2/show/NCT01969344; Identifier: NCT01969344. CITATION: Baugh AD, Acho M, Arhin A, et al. African American race is associated with worse sleep quality in heavy smokers. J Clin Sleep Med. 2023;19(8):1523-1532.
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Doença Pulmonar Obstrutiva Crônica , Fumantes , Humanos , Feminino , Negro ou Afro-Americano , Qualidade do Sono , Qualidade de VidaRESUMO
Accelerated progression of chronic obstructive pulmonary disease (COPD) is associated with increased risks of hospitalization and death. Prognostic insights into mechanisms and markers of progression could facilitate development of disease-modifying therapies. Although individual biomarkers exhibit some predictive value, performance is modest and their univariate nature limits network-level insights. To overcome these limitations and gain insights into early pathways associated with rapid progression, we measured 1305 peripheral blood and 48 bronchoalveolar lavage proteins in individuals with COPD [n = 45, mean initial forced expiratory volume in one second (FEV1) 75.6 ± 17.4% predicted]. We applied a data-driven analysis pipeline, which enabled identification of protein signatures that predicted individuals at-risk for accelerated lung function decline (FEV1 decline ≥ 70 mL/year) ~ 6 years later, with high accuracy. Progression signatures suggested that early dysregulation in elements of the complement cascade is associated with accelerated decline. Our results propose potential biomarkers and early aberrant signaling mechanisms driving rapid progression in COPD.
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Pulmão , Doença Pulmonar Obstrutiva Crônica , Humanos , Progressão da Doença , Fumar/efeitos adversos , Volume Expiratório Forçado , Lavagem Broncoalveolar , BiomarcadoresRESUMO
Rationale: Bronchiectasis is common among those with heavy smoking histories, but risk factors for bronchiectasis, including alpha-1 antitrypsin deficiency, and its implications for COPD severity are uncharacterized in such individuals. Objectives: To characterize the impact of bronchiectasis on COPD and explore alpha-1antitrypsin as a risk factor for bronchiectasis. Methods: SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) participants (N=914; ages 40-80 years; ≥20-pack-year smoking) had high-resolution computed tomography (CT) scans interpreted visually for bronchiectasis, based on airway dilation without fibrosis or cicatrization. We performed regression-based models of bronchiectasis with clinical outcomes and quantitative CT measures. We deeply sequenced the gene encoding -alpha-1 antitrypsin, SERPINA1, in 835 participants to test for rare variants, focusing on the PiZ genotype (Glu366Lys, rs28929474). Measurements and Main Results: We identified bronchiectasis in 365 (40%) participants, more frequently in women (45% versus 36%, p=0.0045), older participants (mean age=66[standard deviation (SD)=8.3] versus 64[SD=9.1] years, p=0.0083), and those with lower lung function (forced expiratory volume in 1 second [FEV1 ] percentage predicted=66%[SD=27] versus 77%[SD=25], p<0.0001; FEV1 to forced vital capacity [FVC] ratio=0.54[0.17] versus 0.63[SD=0.16], p<0.0001). Participants with bronchiectasis had greater emphysema (%voxels ≤-950 Hounsfield units, 11%[SD=12] versus 6.3%[SD=9], p<0.0001) and parametric response mapping functional small airways disease (26[SD=15] versus 19[SD=15], p<0.0001). Bronchiectasis was more frequent in the combined PiZZ and PiMZ genotype groups compared to those without PiZ, PiS, or other rare pathogenic variants (N=21 of 40 [52%] versus N=283 of 707[40%], odds ratio [OR]=1.97; 95% confidence interval [CI]=1.002, 3.90, p=0.049), an association attributed to White individuals (OR=1.98; 95%CI = 0.9956, 3.9; p=0.051). Conclusions: Bronchiectasis was common in those with heavy smoking histories and was associated with detrimental clinical and radiographic outcomes. Our findings support alpha-1antitrypsin guideline recommendations to screen for alpha-1 antitrypsin deficiency in an appropriate bronchiectasis subgroup with a significant smoking history.
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Background: Limited data are available regarding marijuana smoking's impact on the development or progression of chronic obstructive pulmonary disease (COPD) in middle-aged or older adults with a variable history of tobacco cigarette smoking. Methods: We divided ever-tobacco smoking participants in the SubPopulations and InteRmediate Outcomes In COPD Study (SPIROMICS) into 3 groups based on self-reported marijuana use: current, former, or never marijuana smokers (CMSs, FMSs or NMSs, respectively). Longitudinal data were analyzed in participants with ≥2 visits over a period of ≥52 weeks. Measurements: We compared CMSs, FMSs, and NMSs, and those with varying amounts of lifetime marijuana use. Mixed effects linear regression models were used to analyze changes in spirometry, symptoms, health status, and radiographic metrics; zero-inflated negative binomial models were used for exacerbation rates. All models were adjusted for age, sex, race, baseline tobacco smoking amount, and forced expiratory volume in 1 second (FEV1) %predicted. Results: Most participants were followed for ≥4 years. Annual rates of change in FEV1, incident COPD, respiratory symptoms, health status, radiographic extent of emphysema or air trapping, and total or severe exacerbations were not different between CMSs or FMSs versus NMSs or between those with any lifetime amount of marijuana use versus NMSs. Conclusions: Among SPIROMICS participants with or without COPD, neither former nor current marijuana smoking of any lifetime amount was associated with evidence of COPD progression or its development. Because of our study's limitations, these findings underscore the need for further studies to better understand longer-term effects of marijuana smoking in COPD.
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The miR-15/16 family is a highly expressed group of tumor suppressor miRNAs that target a large network of genes in T cells to restrict their cell cycle, memory formation and survival. Upon T cell activation, miR-15/16 are downregulated, allowing rapid expansion of differentiated effector T cells to mediate a sustained immune response. Here, using conditional deletion of miR-15/16 in immunosuppressive regulatory T cells (Tregs) that express FOXP3, we identify new functions of the miR-15/16 family in T cell immunity. miR-15/16 are indispensable to maintain peripheral tolerance by securing efficient suppression by a limited number of Tregs. miR-15/16-deficiency alters Treg expression of critical functional proteins including FOXP3, IL2Rα/CD25, CTLA4, PD-1 and IL7Rα/CD127, and results in accumulation of functionally impaired FOXP3loCD25loCD127hi Tregs. Excessive proliferation in the absence of miR-15/16 inhibition of cell cycle programs shifts Treg diversity and produces an effector Treg phenotype characterized by low expression of TCF1, CD25 and CD62L, and high expression of CD44. These Tregs fail to control immune activation of CD4+ effector T cells, leading to spontaneous multi-organ inflammation and increased allergic airway inflammation in a mouse model of asthma. Together, our results demonstrate that miR-15/16 expression in Tregs is essential to maintain immune tolerance.
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BACKGROUND: Inhaled corticosteroids (CSs) are the backbone of asthma treatment, improving quality of life, exacerbation rates, and mortality. Although effective for most, a subset of patients with asthma experience CS-resistant disease despite receiving high-dose medication. OBJECTIVE: We sought to investigate the transcriptomic response of bronchial epithelial cells (BECs) to inhaled CSs. METHODS: Independent component analysis was performed on datasets, detailing the transcriptional response of BECs to CS treatment. The expression of these CS-response components was examined in 2 patient cohorts and investigated in relation to clinical parameters. Supervised learning was used to predict BEC CS responses using peripheral blood gene expression. RESULTS: We identified a signature of CS response that was closely correlated with CS use in patients with asthma. Participants could be separated on the basis of CS-response genes into groups with high and low signature expression. Patients with low expression of CS-response genes, particularly those with a severe asthma diagnosis, showed worse lung function and quality of life. These individuals demonstrated enrichment for T-lymphocyte infiltration in endobronchial brushings. Supervised machine learning identified a 7-gene signature from peripheral blood that reliably identified patients with poor CS-response expression in BECs. CONCLUSIONS: Loss of CS transcriptional responses within bronchial epithelium was related to impaired lung function and poor quality of life, particularly in patients with severe asthma. These individuals were identified using minimally invasive blood sampling, suggesting these findings may enable earlier triage to alternative treatments.
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Asma , Qualidade de Vida , Humanos , Asma/tratamento farmacológico , Asma/genética , Asma/diagnóstico , Células Epiteliais/metabolismo , Corticosteroides/uso terapêuticoRESUMO
BACKGROUND: Quantitative CT is becoming increasingly common for the characterisation of lung disease; however, its added potential as a clinical tool for predicting severe exacerbations remains understudied. We aimed to develop and validate quantitative CT-based models for predicting severe chronic obstructive pulmonary disease (COPD) exacerbations. METHODS: We analysed the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS) cohort, a multicentre study done at 12 clinical sites across the USA, of individuals aged 40-80 years from four strata: individuals who never smoked, individuals who smoked but had normal spirometry, individuals who smoked and had mild to moderate COPD, and individuals who smoked and had severe COPD. We used 3-year follow-up data to develop logistic regression classifiers for predicting severe exacerbations. Predictors included age, sex, race, BMI, pulmonary function, exacerbation history, smoking status, respiratory quality of life, and CT-based measures of density gradient texture and airway structure. We externally validated our models in a subset from the Genetic Epidemiology of COPD (COPDGene) cohort. Discriminative model performance was assessed using the area under the receiver operating characteristic curve (AUC), which was also compared with other predictors, including exacerbation history and the BMI, airflow obstruction, dyspnoea, and exercise capacity (BODE) index. We evaluated model calibration using calibration plots and Brier scores. FINDINGS: Participants in SPIROMICS were enrolled between Nov 12, 2010, and July 31, 2015. Participants in COPDGene were enrolled between Jan 10, 2008, and April 15, 2011. We included 1956 participants from the SPIROMICS cohort who had complete 3-year follow-up data: the mean age of the cohort was 63·1 years (SD 9·2) and 1017 (52%) were men and 939 (48%) were women. Among the 1956 participants, 434 (22%) had a history of at least one severe exacerbation. For the CT-based models, the AUC was 0·854 (95% CI 0·852-0·855) for at least one severe exacerbation within 3 years and 0·931 (0·930-0·933) for consistent exacerbations (defined as ≥1 acute episode in each of the 3 years). Models were well calibrated with low Brier scores (0·121 for at least one severe exacerbation; 0·039 for consistent exacerbations). For the prediction of at least one severe event during 3-year follow-up, AUCs were significantly higher with CT biomarkers (0·854 [0·852-0·855]) than exacerbation history (0·823 [0·822-0·825]) and BODE index 0·812 [0·811-0·814]). 6965 participants were included in the external validation cohort, with a mean age of 60·5 years (SD 8·9). In this cohort, AUC for at least one severe exacerbation was 0·768 (0·767-0·769; Brier score 0·088). INTERPRETATION: CT-based prediction models can be used for identification of patients with COPD who are at high risk of severe exacerbations. The newly identified CT biomarkers could potentially enable investigation into underlying disease mechanisms responsible for exacerbations. FUNDING: National Institutes of Health and the National Heart, Lung, and Blood Institute.
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Doença Pulmonar Obstrutiva Crônica , Qualidade de Vida , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Volume Expiratório Forçado , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Biomarcadores , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features. RESEARCH QUESTION: Is consistent BDR over time (always present) differentially associated with obstructive lung disease features relative to inconsistent (sometimes present) or never (never present) BDR in tobacco-exposed people with or without COPD? STUDY DESIGN AND METHODS: We retrospectively analyzed data from 2,269 tobacco-exposed participants in the Subpopulations and Intermediate Outcome Measures in COPD Study with or without COPD. We used various BDR definitions: change of ≥ 200 mL and ≥ 12% in FEV1 (FEV1-BDR), change in FVC (FVC-BDR), and change in in FEV1, FVC or both (ATS-BDR). Using generalized linear models adjusted for demographics, smoking history, FEV1 % predicted after bronchodilator administration, and number of visits that the participant completed, we assessed the association of BDR group: (1) consistent BDR, (2) inconsistent BDR, and (3) never BDR with asthma, CT scan features, blood eosinophil levels, and FEV1 decline in participants without COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 0) and the entire cohort (participants with or without COPD). RESULTS: Both consistent and inconsistent ATS-BDR were associated with asthma history and greater small airways disease (%parametric response mapping functional small airways disease) relative to never ATS-BDR in participants with GOLD stage 0 disease and the entire cohort. We observed similar findings using FEV1-BDR and FVC-BDR definitions. Eosinophils did not vary consistently among BDR groups. Consistent BDR was associated with FEV1 decline over time relative to never BDR in the entire cohort. In participants with GOLD stage 0 disease, both the inconsistent ATS-BDR group (OR, 3.20; 95% CI, 2.21-4.66; P < .001) and consistent ATS-BDR group (OR, 9.48; 95% CI, 3.77-29.12; P < .001) were associated with progression to COPD relative to the never ATS-BDR group. INTERPRETATION: Demonstration of BDR, even once, describes an obstructive lung disease phenotype with a history of asthma and greater small airways disease. Consistent demonstration of BDR indicated a high risk of lung function decline over time in the entire cohort and was associated with higher risk of progression to COPD in patients with GOLD stage 0 disease.
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Asma , Doença Pulmonar Obstrutiva Crônica , Humanos , Broncodilatadores/uso terapêutico , Nicotiana , Estudos Retrospectivos , Volume Expiratório Forçado/fisiologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Asma/tratamento farmacológico , Capacidade Vital/fisiologiaRESUMO
Rationale: CC16 is a protein mainly produced by nonciliated bronchial epithelial cells (BECs) that participates in host defense. Reduced CC16 protein concentrations in BAL and serum are associated with asthma susceptibility. Objectives: Few studies have investigated the relationship between CC16 and asthma progression, and none has focused on BECs. In this study, we sought to determine if CC16 mRNA expression levels in BECs are associated with asthma severity. Methods: Association analyses between CC16 mRNA expression levels in BECs (242 asthmatics and 69 control subjects) and asthma-related phenotypes in Severe Asthma Research Program were performed using a generalized linear model. Measurements and Main Results: Low CC16 mRNA expression levels in BECs were significantly associated with asthma susceptibility and asthma severity, high systemic corticosteroids use, high retrospective and prospective asthma exacerbations, and low pulmonary function. Low CC16 mRNA expression levels were significantly associated with high T2 inflammation biomarkers (fractional exhaled nitric oxide and sputum eosinophils). CC16 mRNA expression levels were negatively correlated with expression levels of Th2 genes (IL1RL1, POSTN, SERPINB2, CLCA1, NOS2, and MUC5AC) and positively correlated with expression levels of Th1 and inflammation genes (IL12A and MUC5B). A combination of two nontraditional T2 biomarkers (CC16 and IL-6) revealed four asthma endotypes with different characteristics of T2 inflammation, obesity, and asthma severity. Conclusions: Our findings indicate that low CC16 mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations, partially through immunomodulation of T2 inflammation. CC16 is a potential nontraditional T2 biomarker for asthma development and progression.