RESUMEN
BACKGROUND: Indoor pollutants have been associated with worse clinical outcomes in chronic obstructive pulmonary disease (COPD). Elevated biomarkers are associated with ambient pollution exposure, however the association with indoor pollution remains unclear. METHODS: Former smokers with spirometry-confirmed COPD were randomized to portable air cleaner or placebo. Indoor particulate matter (PM2.5, PM10, and ultrafine particles [UFP; PM<0.1]) and biomarkers were measured longitudinally at pre-specified intervals and course PM fraction (PM10-2.5) was calculated. Biomarkers were categorized based on associations with biologic mechanisms: inflammation (white blood cell count, interleukin [IL]-6, IL-8, IL-1ß, tumor necrosis factor-α, interferon-γ, serum amyloid A), platelet activation (P-selectin, CD40 ligand [CD40L], 11-dehdydro-thromboxane-B2 [11dTxB2]), endothelial dysfunction (Vascular Cell Adhesion Molecule [VCAM]-1, Intercellular Adhesion Molecule [ICAM]-1), and oxidative stress (thiobarbituric acid reactive substances [TBARS], 8-hydroxydeoxyguanosine, 8-isoprostane). Associations between PM concentrations and each biomarker were analyzed using multivariable linear mixed models. An intention-to-treat analysis was performed to evaluate the air cleaner intervention on the biomarker levels longitudinally. RESULTS: Fifty-eight participants were randomized to each group. Finer PM was more strongly associated with higher IL-8 (mean difference per doubling: UFP 13.9% [p = 0.02], PM2.5 6.8% [p = 0.002], PM10-2.5 5.0% [p = 0.02]) while interferon-γ was associated with UFP and IL-1ß with PM10-2.5. UFP and PM2.5 were associated with elevated levels of the oxidative stress biomarkers TBARS and 8-isoprostane respectively. For platelet activation markers, UFP was associated with higher 11dTxB2 while PM2.5 was associated with higher P-selectin and CD40L. Pollutants were not associated with biomarkers of endothelial dysfunction. In intention-to-treat analysis there was no association of the air cleaner intervention with any of the biomarkers. DISCUSSION: Among former smokers with COPD, elevated levels of indoor air pollutants, particularly ultrafine particles (PM<0.1), were associated with elevated biomarkers of inflammation, platelet activation, and oxidative stress. However, an air cleaner intervention that reduced PM did not significantly reduce biomarker levels.
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Contaminantes Atmosféricos , Contaminación del Aire Interior , Contaminación del Aire , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Material Particulado/análisis , Selectina-P/análisis , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis , Ligando de CD40/análisis , Interferón gamma , Interleucina-8/análisis , Fumadores , Contaminantes Atmosféricos/análisis , Biomarcadores , Inflamación/metabolismo , Contaminación del Aire/análisis , Contaminación del Aire Interior/análisis , Exposición a Riesgos Ambientales/análisisRESUMEN
BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) affects â¼16 million U.S. adults. Phthalates, synthetic chemicals in consumer products, may adversely impact pulmonary function and airway inflammation; however, their role on COPD morbidity remains unknown. OBJECTIVE: We examined associations between phthalate exposures and respiratory morbidity among 40 COPD patients who were former smokers. METHODS: We quantified 11 phthalate biomarkers in urine samples collected at baseline in a 9-month prospective cohort study in Baltimore, Maryland. COPD baseline morbidity measures included: health status and quality of life measures (CAT: COPD Assessment Test, CCQ: Clinical COPD Questionnaire, SGRQ: St. George's Respiratory Questionnaire; mMRC: Modified Medical Research Council Dyspnea Scale), and lung function. Information on prospective exacerbation data was monitored monthly during the 9-month longitudinal follow-up period. To examine associations between morbidity measures and phthalate exposures, we used multivariable linear and Poisson regression models for continuous and count outcomes, respectively, adjusting for age, sex, race/ethnicity, education, and smoking pack-years. RESULTS: Higher mono-n-butyl phthalate (MBP) concentrations were associated with increased CAT(ß, 2.41; 95%CI, 0.31-4.51), mMRC (ß, 0.33; 95%CI 0.11-0.55), and SGRQ (ß, 7.43; 95%CI 2.70-12.2) scores at baseline. Monobenzyl phthalate (MBzP) was also positively associated with CCQ and SGRQ scores at baseline. Higher concentrations of the molar sum of Di (2-ethylhexyl) phthalate (DEHP) were associated with increased incidence of exacerbations during the follow-up period (incidence rate ratio, IRR = 1.73; 95%CI 1.11, 2.70 and IRR = 1.94; 95%CI 1.22, 3.07, for moderate and severe exacerbations, respectively). MEP concentrations were inversely associated with incidence of exacerbations during the follow-up period. CONCLUSIONS: We found that exposure to select phthalates was associated with respiratory morbidity among COPD patients. Findings warrant further examination in larger studies given widespread phthalate exposures and potential implications for COPD patients should relationships observed be causal.
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Enfermedad Pulmonar Obstructiva Crónica , Calidad de Vida , Humanos , Estudios Prospectivos , Proyectos Piloto , Estudios Transversales , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Progresión de la EnfermedadRESUMEN
Rationale: Black adults have worse health outcomes compared with white adults in certain chronic diseases, including chronic obstructive pulmonary disease (COPD).Objectives: To determine to what degree disadvantage by individual and neighborhood socioeconomic status (SES) may contribute to racial disparities in COPD outcomes.Methods: Individual and neighborhood-scale sociodemographic characteristics were determined in 2,649 current or former adult smokers with and without COPD at recruitment into SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). We assessed whether racial differences in symptom, functional, and imaging outcomes (St. George's Respiratory Questionnaire, COPD Assessment Test score, modified Medical Research Council dyspnea scale, 6-minute-walk test distance, and computed tomography [CT] scan metrics) and severe exacerbation risk were explained by individual or neighborhood SES. Using generalized linear mixed model regression, we compared respiratory outcomes by race, adjusting for confounders and individual-level and neighborhood-level descriptors of SES both separately and sequentially.Measurements and Main Results: After adjusting for COPD risk factors, Black participants had significantly worse respiratory symptoms and quality of life (modified Medical Research Council scale, COPD Assessment Test, and St. George's Respiratory Questionnaire), higher risk of severe exacerbations and higher percentage of emphysema, thicker airways (internal perimeter of 10 mm), and more air trapping on CT metrics compared with white participants. In addition, the association between Black race and respiratory outcomes was attenuated but remained statistically significant after adjusting for individual-level SES, which explained up to 12-35% of racial disparities. Further adjustment showed that neighborhood-level SES explained another 26-54% of the racial disparities in respiratory outcomes. Even after accounting for both individual and neighborhood SES factors, Black individuals continued to have increased severe exacerbation risk and persistently worse CT outcomes (emphysema, air trapping, and airway wall thickness).Conclusions: Disadvantages by individual- and neighborhood-level SES each partly explain disparities in respiratory outcomes between Black individuals and white individuals. Strategies to narrow the gap in SES disadvantages may help to reduce race-related health disparities in COPD; however, further work is needed to identify additional risk factors contributing to persistent disparities.
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Disparidades en el Estado de Salud , Disparidades en Atención de Salud/estadística & datos numéricos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/terapia , Factores Raciales/estadística & datos numéricos , Fumar/efectos adversos , Adulto , Negro o Afroamericano/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Clase Social , Factores Socioeconómicos , Encuestas y Cuestionarios , Población Blanca/estadística & datos numéricosRESUMEN
Treatment outcomes for Mycobacteroides abscessus (Mab, also known as Mycobacterium abscessus) disease are still unsatisfactory, mainly due to issues with drug toxicity, tolerability, and efficacy. Treating Mab disease is challenging due to its high baseline antibiotic resistance, initial requirement for intravenous therapy, and poor medication tolerance. Omadacycline, a new tetracycline, is active against Mab. Since any new antibiotic effective against Mab is expected to be used in combination with other antibiotics, we evaluated the efficacy of two triple-drug combinations comprising omadacycline, omadacycline + amikacin + imipenem, and omadacycline + clofazimine + linezolid against two contemporary Mab clinical isolates in a mouse model of Mab lung disease. Antibiotic administration was initiated 1-week post-infection and was given daily, with Mab burden in the lungs at treatment completion serving as the endpoint. Omadacycline alone moderately reduced Mab levels and maintained better health in mice compared to untreated ones, which typically suffered from the infection. The omadacycline + clofazimine + linezolid combination showed immediate bactericidal activity and enhanced efficacy over 6 weeks, particularly against the more resistant strain (M9507). However, the clofazimine + linezolid combination lacked early bactericidal activity. When combined with amikacin and imipenem, omadacycline did not improve the regimen's effectiveness over 4 weeks of treatment. Our study showed that omadacycline + clofazimine + linezolid exhibited significant bactericidal activity over an extended treatment duration. However, adding omadacycline to amikacin and imipenem did not improve regimen effectiveness against the evaluated clinical isolates within 4 weeks. Further research in Mab disease patients is needed to determine the most effective omadacycline-containing regimen.IMPORTANCEMycobacteroides abscessus is a common environmental bacterium that causes infections in people with compromised lung function, including those with bronchiectasis, cystic fibrosis, chronic obstructive pulmonary disease, and weakened immune systems, especially among older individuals. Treating M. abscessus disease is challenging due to the limited effectiveness and toxicity of current antibiotics, which often require prolonged use. Omadacycline, a new antibiotic, shows promise against M. abscessus. Using a mouse model that mimics M. abscessus disease in humans, we studied the effectiveness of including omadacycline with recommended antibiotics. Adding omadacycline to clofazimine and linezolid significantly improved treatment outcomes, rapidly clearing the bacteria from the lungs and maintaining effectiveness throughout. This oral combination is convenient for patients. However, adding omadacycline to amikacin and imipenem did not improve treatment effectiveness within 4 weeks. Further study with M. abscessus patients is necessary to optimize omadacycline-based treatment strategies for this disease.
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Amicacina , Antibacterianos , Clofazimina , Modelos Animales de Enfermedad , Quimioterapia Combinada , Imipenem , Linezolid , Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Tetraciclinas , Animales , Clofazimina/administración & dosificación , Clofazimina/uso terapéutico , Linezolid/administración & dosificación , Linezolid/uso terapéutico , Ratones , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Amicacina/administración & dosificación , Amicacina/uso terapéutico , Tetraciclinas/administración & dosificación , Tetraciclinas/uso terapéutico , Tetraciclinas/farmacología , Mycobacterium abscessus/efectos de los fármacos , Imipenem/administración & dosificación , Imipenem/uso terapéutico , Imipenem/farmacología , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Femenino , Resultado del Tratamiento , Pruebas de Sensibilidad Microbiana , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/microbiología , Administración Oral , Pulmón/microbiologíaRESUMEN
Mycobacteroides abscessus (Mab, also known as Mycobacterium abscessus) causes opportunistic pulmonary and soft tissue infections that are difficult to cure with existing treatments. Omadacycline, a new tetracycline antibiotic, exhibits potent in vitro and in vivo activity against Mab. As regimens containing multiple antibiotics are required to produce a durable cure for Mab disease, we assessed efficacies of three three-drug combinations in a pre-clinical mouse model of pulmonary Mab disease to identify companion drugs with which omadacycline exhibits the highest efficacy. Additionally, we assessed the susceptibility of Mab recovered from mouse lungs after four weeks of exposure to the three triple-drug regimens. Among the three-drug regimens, omadacycline + imipenem + amikacin produced the largest reduction in Mab burden, whereas omadacycline + imipenem + linezolid exhibited the most effective early bactericidal activity. Omadacycline + linezolid + clofazimine, a regimen that can be administered orally, lacked early bactericidal activity but produced a gradual reduction in the lung Mab burden over time. The robust efficacy exhibited by these three regimens in the mouse model supports their further evaluation in patients with Mab lung disease. As we were unable to isolate drug-resistant Mab mutants at the completion of four weeks of treatment, these triple-drug combinations show promise of producing durable cure and minimizing selection of resistant mutants.
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Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Mycobacterium tuberculosis , Humanos , Animales , Ratones , Linezolid/farmacología , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Tetraciclinas/farmacología , Tetraciclinas/uso terapéutico , Imipenem/farmacología , Combinación de Medicamentos , Pruebas de Sensibilidad MicrobianaRESUMEN
Background: Low socioeconomic status (SES) has been associated with worse clinical outcomes in chronic obstructive pulmonary disease (COPD). Food insecurity is more common among individuals with low SES and has been associated with poor outcomes in other chronic illnesses, but its impact on COPD has not been studied. Methods: Former smokers with spirometry-confirmed COPD were recruited from low-income areas of Baltimore, Maryland, and followed for 9 months as part of a cohort study of diet and indoor air pollution. Food insecurity and respiratory outcomes, including COPD exacerbations and patient-reported outcomes, were assessed at regular intervals. The association between food insecurity and COPD outcomes was analyzed using generalized linear mixed models. Additional analyses examined the association of COPD morbidity with subdomains of food insecurity and the association of food insecurity with psychological well-being measures. Results: Ninety-nine participants had available data on food insecurity and COPD outcomes. A total of 26.3% of participants were food insecure at 1 or more times during the study. After adjusting for individual SES, neighborhood poverty, and low healthy food access, food insecurity was associated with a higher incidence rate of moderate and severe exacerbations and worse dyspnea, COPD health status, and respiratory-specific quality of life. Subdomains of food insecurity were independently associated with worse patient-reported outcomes. Food insecurity was additionally associated with higher perceived stress. Discussion: Among former smokers with COPD, food insecurity was associated with a higher incidence of exacerbations, worse patient-reported outcomes, and higher perceived stress. Subdomains of food insecurity were independently associated with worse patient-reported outcomes.
RESUMEN
Mycobacteroides abscessus is an opportunistic pathogen in people with structural lung conditions such as bronchiectasis, chronic obstructive pulmonary disease, and cystic fibrosis. Pulmonary M. abscessus infection causes progressive symptomatic and functional decline as well as diminished lung function and is often incurable with existing antibiotics. We investigated the efficacy of a new tetracycline, omadacycline, in combination with existing antibiotics recommended to treat this indication, in a mouse model of M. abscessus lung disease. Amikacin, azithromycin, bedaquiline, biapenem, cefoxitin, clofazimine, imipenem, linezolid, and rifabutin were selected as companions to omadacycline. M. abscessus burden in the lungs of mice over a 4-week treatment duration was considered the endpoint. Omadacycline in combination with linezolid, imipenem, cefoxitin, biapenem, or rifabutin exhibited early bactericidal activity compared to any single drug. Using three M. abscessus isolates, we also determined the in vitro frequency of spontaneous resistance against omadacycline to be between 1.9 × 10-10 and 6.2 × 10-10 and the frequency of persistence against omadacycline to be between 5.3 × 10-6 and 1.3 × 10-5. Based on these findings, the combination of omadacycline and select drugs that are included in the recent treatment guidelines may exhibit improved potency to treat M. abscessus lung disease. IMPORTANCE M. abscessus disease incidence is increasing in the United States. This disease is difficult to cure with existing antibiotics. In this study, we describe the efficacy of a new tetracycline antibiotic, omadacycline, in combination with an existing antibiotic to treat this disease. A mouse model of M. abscessus lung disease was used to assess the efficacies of these experimental treatment regimens. Omadacycline in combination with select existing antibiotics exhibited bactericidal activity during the early phase of treatment.
Asunto(s)
Fibrosis Quística , Mycobacterium abscessus , Animales , Ratones , Linezolid , Cefoxitina , Pruebas de Sensibilidad Microbiana , Antibacterianos/uso terapéutico , Tetraciclinas/uso terapéutico , Imipenem , RifabutinaRESUMEN
BACKGROUND: Neighborhood poverty has been associated with poor health outcomes. Previous studies have also identified adverse respiratory effects of long-term ambient ozone. Factors associated with neighborhood poverty may accentuate the adverse impact of ozone on respiratory health. OBJECTIVES: To evaluate whether neighborhood poverty modifies the association between ambient ozone exposure and respiratory morbidity including symptoms, exacerbation risk, and radiologic parameters, among participants of the SPIROMICS AIR cohort study. METHODS: Spatiotemporal models incorporating cohort-specific monitoring estimated 10-year average outdoor ozone concentrations at participants' homes. Adjusted regression models were used to determine the association of ozone exposure with respiratory outcomes, accounting for demographic factors, education, individual income, body mass index (BMI), and study site. Neighborhood poverty rate was defined by percentage of families living below federal poverty level per census tract. Interaction terms for neighborhood poverty rate with ozone were included in covariate-adjusted models to evaluate for effect modification. RESULTS: 1874 participants were included in the analysis, with mean (± SD) age 64 (± 8.8) years and FEV1 (forced expiratory volume in one second) 74.7% (±25.8) predicted. Participants resided in neighborhoods with mean poverty rate of 9.9% (±10.3) of families below the federal poverty level and mean 10-year ambient ozone concentration of 24.7 (±5.2) ppb. There was an interaction between neighborhood poverty rate and ozone concentration for numerous respiratory outcomes, including COPD Assessment Test score, modified Medical Research Council Dyspnea Scale, six-minute walk test, and odds of COPD exacerbation in the year prior to enrollment, such that adverse effects of ozone were greater among participants in higher poverty neighborhoods. CONCLUSION: Individuals with COPD in high poverty neighborhoods have higher susceptibility to adverse respiratory effects of ambient ozone exposure, after adjusting for individual factors. These findings highlight the interaction between exposures associated with poverty and their effect on respiratory health.