Increased airway iron parameters and risk for exacerbation in COPD: an analysis from SPIROMICS.
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ABSTRACT:
SUBMITTER: Zhang WZ
PROVIDER: S-EPMC7324559 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
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Increased airway iron parameters and risk for exacerbation in COPD: an analysis from SPIROMICS.
Zhang William Z WZ Oromendia Clara C Kikkers Sarah Ann SA Butler James J JJ O'Beirne Sarah S Kim Kihwan K O'Neal Wanda K WK Freeman Christine M CM Christenson Stephanie A SA Peters Stephen P SP Wells J Michael JM Doerschuk Claire C Putcha Nirupama N Barjaktarevic Igor I Woodruff Prescott G PG Cooper Christopher B CB Bowler Russell P RP Comellas Alejandro P AP Criner Gerard J GJ Paine Robert R Hansel Nadia N NN Han Meilan K MK Crystal Ronald G RG Kaner Robert J RJ Ballman Karla V KV Curtis Jeffrey L JL Martinez Fernando J FJ Cloonan Suzanne M SM
Scientific reports 20200629 1
Levels of iron and iron-related proteins including ferritin are higher in the lung tissue and lavage fluid of individuals with chronic obstructive pulmonary disease (COPD), when compared to healthy controls. Whether more iron in the extracellular milieu of the lung associates with distinct clinical phenotypes of COPD, including increased exacerbation susceptibility, is unknown. We measured iron and ferritin levels in the bronchoalveolar lavage fluid (BALF) of participants enrolled in the SubPopu ...[more]
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Project description:BACKGROUND:Matrix metalloprotease 9 (MMP-9) is associated with inflammation and lung remodeling in chronic obstructive pulmonary disease (COPD). We hypothesized that elevated circulating MMP-9 represents a potentially novel biomarker that identifies a subset of individuals with COPD with an inflammatory phenotype who are at increased risk for acute exacerbation (AECOPD). METHODS:We analyzed Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene) cohorts for which baseline and prospective data were available. Elevated MMP-9 was defined based on >95th percentile plasma values from control (non-COPD) sample in SPIROMICS. COPD subjects were classified as having elevated or nonelevated MMP-9. Logistic, Poisson, and Kaplan-Meier analyses were used to identify associations with prospective AECOPD in both cohorts. RESULTS:Elevated MMP-9 was present in 95/1,053 (9%) of SPIROMICS and 41/140 (29%) of COPDGene participants with COPD. COPD subjects with elevated MMP-9 had a 13%-16% increased absolute risk for AECOPD and a higher median (interquartile range; IQR) annual AECOPD rate (0.33 [0-0.74] versus 0 [0-0.80] events/year and 0.9 [0.5-2] versus 0.5 [0-1.4] events/year for SPIROMICS and COPDGene, respectively). In adjusted models within each cohort, elevated MMP-9 was associated with increased odds (odds ratio [OR], 1.71; 95%CI, 1.00-2.90; and OR, 3.03; 95%CI, 1.02-9.01), frequency (incidence rate ratio [IRR], 1.45; 95%CI, 1.23-1.7; and IRR, 1.24; 95%CI, 1.03-1.49), and shorter time-to-first AECOPD (21.7 versus 31.7 months and 14 versus 21 months) in SPIROMICS and COPDGene, respectively. CONCLUSIONS:Elevated MMP-9 was independently associated with AECOPD risk in 2 well-characterized COPD cohorts. These findings provide evidence for MMP-9 as a prognostic biomarker and potential therapeutic target in COPD. TRIAL REGISTRATION:ClinicalTrials.gov: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene). FUNDING:This work was funded by K08 HL123940 to JMW; R01HL124233 to PJC; Merit Review I01 CX000911 to JLC; R01 (R01HL102371, R01HL126596) and VA Merit (I01BX001756) to AG. SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study) is funded by contracts from the NHLBI (HHSN268200900013C, HHSN268200900014C,HHSN268200900015C HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HHSN268200900020C) and a grant from the NIH/NHLBI (U01 HL137880), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals Inc.; Chiesi Farmaceutici; Forest Research Institute Inc.; GlaxoSmithKline; Grifols Therapeutics Inc.; Ikaria Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan. COPDGene is funded by the NHLBI (R01 HL089897 and R01 HL089856) and by the COPD Foundation through contributions made to an Industry Advisory Board composed of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.
| S-EPMC6302944 | biostudies-literature
Project description:BACKGROUND:High N-terminal pro-brain natriuretic peptide (NT-proBNP) during COPD exacerbations is associated with worse clinical outcomes. The prognostic value of NT-proBNP measured during clinical stability has not been well characterized. METHODS:We studied SPIROMICS participants 40-80 years of age with COPD GOLD spirometric stages 1-4. The association between baseline NT-proBNP and incident COPD exacerbations within one year of follow-up was tested using zero-inflated Poisson regression models adjusted for age, gender, race, body mass index, current smoking status, smoking history, FEV1 percent predicted, COPD Assessment Test score, exacerbation history, total lung capacity on chest CT and cardiovascular disease (any of coronary artery disease, myocardial infarction or congestive heart failure). RESULTS:Among 1051 participants (mean age 66.1 years, 41.4% women), mean NT-proBNP was 608.9?pg/ml. Subjects in GOLD stage D had the highest mean NT-proBNP. After one year of follow-up, 268 participants experienced one or more COPD exacerbations. One standard deviation increase in baseline NT-proBNP was associated with a 13% increase in the risk of incident exacerbations (incident risk ratio 1.13; 95% CI 1.06-1.19; p?<?0.0001). This association was maintained in participants with and without cardiovascular disease. CONCLUSION:Baseline NT-proBNP in COPD is an independent predictor of respiratory exacerbations, even in individuals without overt cardiac disease. The impact of detection and treatment of early cardiovascular dysfunction on COPD exacerbation frequency warrants further investigation.
| S-EPMC6084793 | biostudies-literature
Project description:Background: Decreased but measurable serum IgA levels (?70 mg/dL) have been associated with risk for infections in some populations, but are unstudied in COPD. This study tested the hypothesis that subnormal serum IgA levels would be associated with exacerbation risk in COPD.Methods: Data were analyzed from 1,049 COPD participants from the observational cohort study SPIROMICS (535 (51%) women; mean age 66.1 (SD 7.8), 338 (32%) current smokers) who had baseline serum IgA measured using the Myriad RBM biomarker discovery platform. Exacerbation data was collected prospectively (mean 944.3 (SD 281.3) days), and adjusted linear, logistic and zero-inflated negative binomial regressions were performed.Results: Mean IgA was 269.1 mg/dL (SD 150.9). One individual had deficient levels of serum IgA (<7 mg/dL) and 25 (2.4%) had IgA level ?70 mg/dL. Participants with IgA ?70 mg/dL were younger (62 vs. 66 years, p = 0.01) but otherwise similar to those with higher IgA. In adjusted models, IgA ?70 mg/dL was associated with higher exacerbation incidence rates (IRR 1.71, 95% CI 1.01-2.87, p = 0.044) and greater risk for any severe exacerbation (OR 2.99, 95% CI 1.30-6.94, p = 0.010). In adjusted models among those in the lowest decile (<120 mg/dL), each 10 mg/dL decrement in IgA (analyzed continuously) was associated with more exacerbations during follow-up (? 0.24, 95% CI 0.017-0.46, p = 0.035).Conclusions: Subnormal serum IgA levels were associated with increased risk for acute exacerbations, supporting mildly impaired IgA levels as a contributing factor in COPD morbidity. Additionally, a dose-response relationship between lower serum IgA and number of exacerbations was found among individuals with serum IgA in the lowest decile, further supporting the link between serum IgA and exacerbation risk. Future COPD studies should more comprehensively characterize immune status to define the clinical relevance of these findings and their potential for therapeutic correction.
| S-EPMC5896903 | biostudies-literature
Project description:BackgroundAirway macrophages (AM), crucial for the immune response in chronic obstructive pulmonary disease (COPD), are exposed to environmental particulate matter (PM), which they retain in their cytoplasm as black carbon (BC). However, whether AM BC accurately reflects environmental PM2.5 exposure, and can serve as a biomarker of COPD outcomes, is unknown.MethodsWe analyzed induced sputum from participants at 7 of 12 sites SPIROMICS sites for AM BC content, which we related to exposures and to lung function and respiratory outcomes. Models were adjusted for batch (first vs. second), age, race (white vs. non-white), income (<$35,000, $35,000~$74,999, ≥$75,000, decline to answer), BMI, and use of long-acting beta-agonist/long-acting muscarinic antagonists, with sensitivity analysis performed with inclusion of urinary cotinine and lung function as covariates.ResultsOf 324 participants, 143 were current smokers and 201 had spirometric-confirmed COPD. Modeled indoor fine (< 2.5 μm in aerodynamic diameter) particulate matter (PM2.5) and urinary cotinine were associated with higher AM BC. Other assessed indoor and ambient pollutant exposures were not associated with higher AM BC. Higher AM BC was associated with worse lung function and odds of severe exacerbation, as well as worse functional status, respiratory symptoms and quality of life.ConclusionIndoor PM2.5 and cigarette smoke exposure may lead to increased AM BC deposition. Black carbon content in AMs is associated with worse COPD morbidity in current and former smokers, which remained after sensitivity analysis adjusting for cigarette smoke burden. Airway macrophage BC, which may alter macrophage function, could serve as a predictor of experiencing worse respiratory symptoms and impaired lung function.
| S-EPMC9664618 | biostudies-literature
Project description:BACKGROUND:Poorly controlled HIV infection is associated with increased risk for chronic obstructive pulmonary disease (COPD). Acute exacerbations of COPD (AECOPD) are major contributors to morbidity and mortality. Little is known about the association between HIV infection and AECOPD. METHODS:We identified 167 individuals with spirometry-confirmed COPD from a longitudinal study of current or former injection drug users at risk or with HIV infection. AECOPD, defined as self-report of worsening breathing requiring treatment with antibiotics or steroids, was assessed at 6-month study visits. Multivariable logistic regression identified factors associated with AECOPD. RESULTS:Of 167 participants, the mean age was 52 years; 89% were black, 30% female, and 32% HIV infected (median CD4 count: 312 cells per milliliter, 46% with detectable HIV RNA). After adjusting for age, gender, smoking history, comorbidity treatment, and airflow obstruction severity, HIV was independently associated with a 2.47 increased odds of AECOPD [95% confidence interval (CI): 1.22 to 5.00]. Compared with HIV-uninfected persons, HIV-infected persons with undetectable (<50 copies/mL) HIV RNA levels and those with a CD4 count ?350 cells per cubic millimeter demonstrated increased AECOPD (odds ratio, 2.91; 95% CI: 1.26 to 6.71; odds ratio, 4.16; 95% CI: 1.87 to 9.27, respectively). Higher AECOPD risk was observed with higher CD4 counts irrespective of treatment for comorbid diseases. CONCLUSIONS:HIV infection is independently associated with increased odds of AECOPD, potentially due to differences in treatment access and to variable disease manifestation by immune status. Providers should be aware that HIV infection may increase risk for AECOPD and that symptom may be more discernible with intact immune function.
| S-EPMC4422097 | biostudies-literature
Project description:BackgroundThe relationship between 25-hydroxyvitamin D (25-OH-vitamin D) and COPD outcomes remains unclear. Using the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), we determined associations among baseline 25-OH-vitamin D and cross-sectional and longitudinal lung function and COPD exacerbations.MethodsSerum 25-OH-vitamin D level was measured in stored samples from 1,609 SPIROMICS participants with COPD. 25-OH-vitamin D levels were modeled continuously and dichotomized as deficient (< 20 ng/mL) vs not deficient (≥ 20 ng/mL). Outcomes of interest included % predicted FEV1 (current and 1-year longitudinal decline) and COPD exacerbations (separately any and severe, occurring in prior year and first year of follow-up).ResultsVitamin D deficiency was present in 21% of the cohort and was more prevalent in the younger, active smokers, and blacks. Vitamin D deficiency was independently associated with lower % predicted FEV1 (by 4.11%) at enrollment (95% CI, -6.90% to -1.34% predicted FEV1; P = .004), 1.27% predicted greater rate of FEV1 decline after 1 year (95% CI, -2.32% to -0.22% predicted/y; P = .02), and higher odds of any COPD exacerbation in the prior year (OR, 1.32; 95% CI, 1.00-1.74; P = .049). Each 10-ng/mL decrease in 25-OH-vitamin D was associated with lower baseline lung function (-1.04% predicted; 95% CI, -1.96% to -0.12% predicted; P = .03) and increased odds of any exacerbation in the year before enrollment (OR, 1.11; 95% CI, 1.01-1.22; P = .04).ConclusionsVitamin D deficiency is associated with worse cross-sectional and longitudinal lung function and increased odds of prior COPD exacerbations. These findings identify 25-OH-vitamin D levels as a potentially useful marker of adverse COPD-related outcomes.
| S-EPMC7118244 | biostudies-literature
Project description:RATIONALE:Rural residence is associated with poor outcomes in several chronic diseases. The association between rural residence and chronic obstructive pulmonary disease (COPD) exacerbations remains unclear. OBJECTIVE:To determine the independent association between rural residence and COPD-related outcomes including COPD exacerbations, airflow obstruction and symptom burden. METHODS:A total of 1684 Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) participants with FEV1/FVC<0.70 had geocoding-defined rural-urban residence status determined (N=204 rural and N=1480 urban). Univariate and multivariate logistic and negative binomial regressions were performed to assess the independent association between rurality and COPD outcomes including exacerbations, lung function, and symptom burden. The primary exposure of interest was rural residence, determined by geocoding of home address to the block level at time of study enrollment. Additional covariates of interest included demographic and clinical characteristics, occupation, and occupational exposures.The primary outcome measures were exacerbations determined over the one-year course after enrollment by quarterly telephone calls and at an annual research clinic visit. Odds ratio and incidence rate of exacerbations that required treatment with medications including steroids or antibiotics (total exacerbations), and exacerbations leading to hospitalization (severe exacerbations) were determined after adjusting for relevant covariates. RESULTS:Rural residence was independently associated with 70% increase in odds of total exacerbations [OR 1.70 (95% CI 1.13-2.56); p=0.012] and 46% higher incidence rate of total exacerbations [IRR 1.46 (95% CI 1.02-2.10); p=0.039]. There was no association between rural residence and severe exacerbations. Agricultural occupation was independently associated with increased odds and incidence of total and severe exacerbations. Inclusion of agricultural occupation to analysis attenuated the association between rural residence and odds and incidence rate of total exacerbations [OR 1.52 (95% CI 1.00-2.32; p=0.05) and IRR 1.39 (95% CI 0.97 - 1.99); p=0.07]. There was no difference in symptoms or airflow obstruction between rural and urban participants. CONCLUSIONS:Rural residence is independently associated with increased odds and incidence of total, but not severe COPD exacerbations. These associations are not fully explained by agriculture-related exposures, highlighting the need for future research into potential mechanisms of increased risk of COPD exacerbations in the rural population.
| S-EPMC6207115 | biostudies-other
Project description:Study objectivesSleep is an important dimension in the care of chronic obstructive pulmonary disease (COPD), but its relevance to exacerbations is unclear. We wanted to assess whether sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI) is associated with an increased risk of COPD exacerbations and does this differ by socio-environmental exposures.MethodsWe included 1647 current and former smokers with spirometrically confirmed COPD from the SPIROMICS cohort. We assessed incidence rate ratios for exacerbation using zero-inflated negative binomial regression adjusting for demographics, medical comorbidities, and multiple metrics of disease severity, including respiratory medications, airflow obstruction, and symptom burden. Our final model adjusted for socio-environmental exposures using the Area Deprivation Index, a composite measure of contemporary neighborhood quality, and Adversity-Opportunity Index, a composite measure of individual-level historic and current socioeconomic indicators. We used a pre-determined threshold of 20% missingness to undertake multiple imputation by chained equations. As sensitivity analyses, we repeated models in those with complete data and after controlling for prior exacerbations. As an exploratory analysis, we considered an interaction between socio-environmental condition and sleep quality.ResultsAfter adjustment for all co-variates, increasing PSQI scores (range 0-21) were associated with a 5% increased risk for exacerbation per point (p = .001) in the imputed dataset. Sensitivity analyses using complete cases and after controlling for prior exacerbation history were similar. Exploratory analysis suggested less effect among those who lived in poor-quality neighborhoods (p-for-interaction = .035).ConclusionsPoor sleep quality may contribute to future exacerbations among patients with COPD. This represents one target for improving disease control.Clinical trial registrationSubpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). ClinicalTrials.gov Identifier# NCT01969344. Registry URL: https://clinicaltrials.gov/ct2/show/.
| S-EPMC9366643 | biostudies-literature
Project description:BackgroundLow handgrip strength (HGS) is independently associated with a higher exacerbation risk in stable chronic obstructive pulmonary disease (COPD); however, the relationship between HGS while being admitted for COPD exacerbation and further exacerbation risk after discharge remains unclear.MethodsWe enrolled patients admitted for COPD exacerbation between January 2018 and June 2019. HGS tests were done within 3 days after admission. The primary endpoint was exacerbations within 12 months after the index admission, which needed emergency room visits or hospital admission. We analyzed the relationships among demographics, HGS, pulmonary function parameters, and acute exacerbation events.ResultsAmong 43 enrolled patients, 31 (72.1%) participants (HGSw) had HGS weakness (22.1 ± 4.1 kg). The other 12 (27.9%) participants (non-HGSw) had the strength of handgrips 33.7 ± 3.1 kg. HGSw group showed a significantly higher rate of emergency room visits within 6, 9, and 12 months after the index admission than non-HGSw group (0.81 ± 1.30 vs. 0.08 ± 0.29, p = 0.045; 1.26 ± 1.59 vs. 0.17 ± 0.38, P = 0.019; 1.48 ± 1.86 vs. 0.25 ± 0.62, P = 0.027, respectively). There was a trend to have higher admission rate within 9 and 12 months in HGSw group, which did not achieve statistical significance (0.77 ± 1.38 vs. 0.08 ± 0.29, P = 0.064; 0.94 ± 1.56 vs. 0.08 ± 0.29, P = 0.062, respectively).ConclusionsHGS weakness measured upon admission for COPD exacerbation was associated with a higher risk of exacerbation in the next year. Trial registration ClinicalTrials.gov Identifier: NCT04885933.
| S-EPMC8296662 | biostudies-literature
Project description:BackgroundThe mechanism by which various classes of medication reduce COPD exacerbation risk remains unknown. We hypothesized a correlation between reduced exacerbation risk and improvement in airway patency as measured according to FEV1.MethodsBy systematic review, COPD trials were identified that reported therapeutic changes in predose FEV1 (dFEV1) and occurrence of moderate to severe exacerbations. Using meta-regression analysis, a model was generated with dFEV1 as the moderator variable and the absolute difference in exacerbation rate (RD), ratio of exacerbation rates (RRs), or hazard ratio (HR) as dependent variables.ResultsThe analysis of RD and RR included 119,227 patients, and the HR analysis included 73,475 patients. For every 100-mL change in predose FEV1, the HR decreased by 21% (95% CI, 17-26; P < .001; R2 = 0.85) and the absolute exacerbation rate decreased by 0.06 per patient per year (95% CI, 0.02-0.11; P = .009; R2 = 0.05), which corresponded to an RR of 0.86 (95% CI, 0.81-0.91; P < .001; R2 = 0.20). The relationship with exacerbation risk remained statistically significant across multiple subgroup analyses.ConclusionsA significant correlation between increased FEV1 and lower COPD exacerbation risk suggests that airway patency is an important mechanism responsible for this effect.
| S-EPMC6026240 | biostudies-literature