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Aminofenoles , Benzodioxoles , Fibrosis Quística , Combinación de Medicamentos , Indoles , Pirazoles , Quinolonas , Humanos , Benzodioxoles/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/fisiopatología , Aminofenoles/uso terapéutico , Indoles/uso terapéutico , Quinolonas/uso terapéutico , Pirazoles/uso terapéutico , Masculino , Niño , Adolescente , Femenino , Piridinas/uso terapéutico , Pirroles/uso terapéutico , Quinolinas/uso terapéutico , Agonistas de los Canales de Cloruro/uso terapéutico , Clorobencenos/uso terapéutico , Pruebas de Función Respiratoria , PirrolidinasRESUMEN
Rescue of N1303K CFTR by highly effective modulator therapy (HEMT) is enabled by CF airway inflammation. These findings suggest that evaluation of HEMT for rare CFTR mutations must be performed under inflammatory conditions relevant to CF airways. https://bit.ly/3tTcoJE.
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Nine people with cystic fibrosis (pwCF) were found to have isolated elevations in serum total bilirubin after starting elexacaftor/tezacaftor/ivacaftor (ETI) that were associated with Gilbert's Syndrome. In longitudinal examination, total bilirubin levels increased substantially after initiation of ETI without elevations in liver transaminases in those with this syndrome. Because elevated bilirubin levels in Gilbert's Syndrome are benign, ETI was able to be continued in these individuals. Genetic testing for this relatively common syndrome should be strongly considered for pwCF experiencing isolated hyperbilirubinemia after starting ETI, since appropriate diagnosis may help pwCF avoid unnecessary interruption in this therapy with significant health benefits in CF.
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Fibrosis Quística , Enfermedad de Gilbert , Indoles , Pirazoles , Piridinas , Pirrolidinas , Quinolonas , Humanos , Fibrosis Quística/complicaciones , Fibrosis Quística/tratamiento farmacológico , Síndrome , Bilirrubina , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Mutación , Benzodioxoles/uso terapéutico , Aminofenoles/uso terapéuticoRESUMEN
BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) is highly effective clinically for those with at least one F508del-CFTR allele. The effects of E/T/I on mucociliary clearance (MCC) and sputum properties are unknown. We, therefore, sought to characterize the effects of E/T/I on in vivo MCC and sputum characteristics hypothesized to impact mucus transport. METHODS: Forty-four participants ≥12 years of age were enrolled into this prospective, observational trial prior to initiation of E/T/I and had baseline measurement of MCC and characterization of induced sputum and exhaled breath condensate (EBC) samples. Study procedures were repeated after 1 month of E/T/I treatment. RESULTS: Average age was 27.7 years with baseline forced expiratory volume in 1 second (FEV1) of 78.2 % predicted. 52 % of subjects had previously been treated with a 2-drug CFTR modulator combination. The average whole lung MCC rate measured over 60 min (WLAveClr60) significantly improved from baseline to post-E/T/I (14.8 vs. 22.8 %; p = 0.0002), as did other MCC indices. Sputum% solids also improved (modeled mean 3.4 vs. 2.2 %; p<0.0001), whereas non-significant reductions in sputum macrorheology (G', G") were observed. No meaningful changes in exhaled breath condensate endpoints (sialic acid:urea ratio, pH) were observed. CONCLUSIONS: E/T/I improved the hydration of respiratory secretions (% solids) and markedly accelerated MCC. These data confirm the link between CFTR function, mucus solid content, and MCC and help to define the utility of MCC and mucus-related bioassays in future efforts to restore CFTR function in all people with CF.
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Fibrosis Quística , Indoles , Pirazoles , Piridinas , Pirrolidinas , Quinolonas , Humanos , Adulto , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Depuración Mucociliar , Estudios Prospectivos , Aminofenoles/uso terapéutico , Benzodioxoles/uso terapéutico , Moco , Mutación , Agonistas de los Canales de Cloruro/uso terapéuticoRESUMEN
Background: Concerns about the pediatric pulmonology workforce suggest a need to improve fellowship recruitment. Program size is related to the financial health and recruitment success of pediatric subspecialty education programs, but there are few data on how program size impacts recruitment and workforce in pediatric pulmonology. Objective: Assess the impact of program size in pediatric pulmonology through examination of the distribution of applicants matching into pediatric pulmonology training programs over time and relationships to workforce distribution. Methods: Data from the National Residency Match Program from 2010 to 2022 were extracted from published documents. Positions offered, positioned filled, and match rates were calculated for each appointment year. Statewide statistics for the number of fellows matched were analyzed relative to the number of pediatric pulmonologists per capita using data from the American Board of Pediatrics. Results: From 2010 to 2018, the size and distribution of programs in pediatric pulmonology were stable, with most fellows (82.4%) matching into programs with one or two positions per cycle. Starting in 2019, programs offering three or more positions steadily increased in number and aggregate positions offered. This change was associated with an increase in total filled positions (38.9 ± 7.3 in 2010-2018 vs. 50.5 ± 8.7 in 2019-2022; P < 0.03) and an increased fraction who matched into larger programs (17.6% in 2010-2018 vs. 36.9% in 2019-2022; P < 0.001). Among states with fellowship programs, the number of fellows matched over the past 5 years correlated with the number of practicing pediatric pulmonologists per capita (r = 0.78; P < 0.001). Conclusion: The period 2019-2022 saw a marked shift of pediatric pulmonary trainees matching into a relatively small number of larger programs. This shift was associated with overall growth in the number of trainees but may have implications on geographical distribution of practicing pediatric pulmonologists.
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BACKGROUND: Improvement in exocrine pancreatic function in persons with CF (pwCF) on cystic fibrosis transmembrane conductance regulator (CFTR) modulators has been documented in clinical trials using fecal pancreatic elastase-1 (FE-1). Our group endeavored to evaluate real-world data on FE-1 in children on CFTR modulator therapy at three pediatric cystic fibrosis (CF) centers. METHODS: Pediatric pwCF were offered FE-1 testing if they were on pancreatic enzyme replacement therapy (PERT) and on CFTR modulator therapy according to their center's guideline. FE-1 data were collected retrospectively. The primary outcome was absolute change in FE-1. RESULTS: 70 pwCF were included for analysis. 53 had baseline and post-modulator FE-1 values. There was a significant increase in FE-1 from median 25 mcg/g (IQR 25-60) at baseline to 57 mcg/g (IQR 20-228) post-modulator (p<0.001 by Wilcoxon matched pairs), with an absolute change in FE-1 of median 28 mcg/g (IQR -5-161) and mean 93.5 ± 146.8 mcg/g. Age was negatively correlated with change in FE-1 (Spearman r=-0.48, p<0.001). 15 pwCF (21%) had post-modulator FE-1 values ≥200 mcg/g, consistent with pancreatic sufficiency (PS). The PS group was significant for younger age at initiation of first CFTR modulator and a higher baseline FE-1. CONCLUSIONS: Most pwCF experienced an increase in FE-1 while receiving CFTR modulator treatment and a small percentage demonstrated values reflective of PS. These data suggest that PS may be attained in those that initiated modulator therapy at a younger age or had a higher baseline FE-1. FE-1 testing is suggested for children on any CFTR modulator therapy.
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Fibrosis Quística , Niño , Humanos , Fibrosis Quística/tratamiento farmacológico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Mutación , Páncreas , Elastasa Pancreática/metabolismo , Estudios RetrospectivosRESUMEN
The use of Electronic Nicotine Delivery Systems (ENDS) is increasing in prevalence and popularity. ENDS are a rapidly evolving technology as devices and e-liquid formulations adapt to policy restrictions and market demand To identify the impacts of nicotine formulation and concentration, we exposed female and male C57BL/6J mice to passive electronic vaporization of different nicotine formulations (freebase or salt) and concentrations (1% or 3%) and measured serum nicotine metabolite levels, brain activity by cFos expression, and anxiety-like and motivated behavior using the novelty suppressed feeding test. We found that the 3% freebase nicotine vapor group displayed significantly higher serum nicotine levels than either 1% or 3% nicotine salt formulations, and female mice displayed higher serum nicotine and cotinine levels compared to males. Central amygdala (CeA) activity was significantly elevated in male mice following nicotine vapor exposure, but the increase was not significantly different between nicotine vapor groups. CeA activity in female mice was unaffected. In contrast increased activity in the ventral tegmental area (VTA) was only observed in female mice exposed to 3% nicotine freebase and specifically in the dopaminergic population. Anxiety-like behavior in female mice was relatively unaffected by nicotine vapor exposure, however male mice displayed increased anxiety-like behavior and reduced motivation to feed after vapor exposure, specifically in the 3% freebase group. These results identify important sex differences in the impact of nicotine formulation and concentration on nicotine metabolism, brain region-specific activity and anxiety-like behavior, which may have significant relevance for different consequences of vaping in men and women.
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Fibrosis Quística , Humanos , Fibrosis Quística/complicaciones , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Piridinas , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Aminofenoles/uso terapéutico , Benzodioxoles/uso terapéutico , Mutación , Agonistas de los Canales de Cloruro/uso terapéutico , Combinación de MedicamentosAsunto(s)
Neumología , Niño , Humanos , Estados Unidos , Recursos Humanos , Encuestas y CuestionariosRESUMEN
Nicotine from cigarette smoke is a biologically active molecule that has pleiotropic effects in the airway, which could play a role in smoking-induced lung disease. However, whether nicotine and its metabolites reach sustained, physiologically relevant concentrations on airway surfaces of smokers is not well defined. To address these issues, concentrations of nicotine, cotinine, and hydroxycotinine were measured by mass spectrometry (MS) in supernatants of induced sputum obtained from participants in the subpopulations and intermediate outcome measures in COPD study (SPIROMICS), an ongoing observational study that included never smokers, former smokers, and current smokers with and without chronic obstructive pulmonary disease (COPD). A total of 980 sputum supernatants were analyzed from 77 healthy never smokers, 494 former smokers (233 with COPD), and 396 active smokers (151 with COPD). Sputum nicotine, cotinine, and hydroxycotinine concentrations corresponded to self-reported smoking status and were strongly correlated to urine measures. A cutoff of â¼8-10 ng/mL of sputum cotinine distinguished never smokers from active smokers. Accounting for sample dilution during processing, active smokers had airway nicotine concentrations in the 70-850 ng/mL (â¼0.5-5 µM) range, and concentrations remained elevated even in current smokers who had not smoked within 24 h. This study demonstrates that airway nicotine and its metabolites are readily measured in sputum supernatants and can serve as biological markers of smoke exposure. In current smokers, nicotine is present at physiologically relevant concentrations for prolonged periods, supporting a contribution to cigarette-induced airway disease.
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Nicotina , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Nicotina/metabolismo , Cotinina/análisis , Cotinina/metabolismo , Fumadores , Sistema Respiratorio/metabolismo , Biomarcadores/análisisAsunto(s)
Becas , Neumología , Niño , Humanos , Estados Unidos , Recursos Humanos , Educación de Postgrado en MedicinaRESUMEN
Elexacaftor-tezacaftor-ivacaftor (ETI) is known to pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding. Toxicity studies of ivacaftor in rats demonstrated infant cataracts, but cataracts were not reported in human infants exposed to ivacaftor. We describe 3 cases of infants exposed to elexacaftor-tezacaftor-ivacaftor (ETI) in utero and while breast feeding who were found to have bilateral congenital cataracts within six months of birth. None of the infants had significant visual impairment from the cataracts nor any report of elevated liver function testing. These data highlight the need to counsel females who continue ETI throughout pregnancy and while breast feeding to consider cataract screen for their infants.
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Catarata , Fibrosis Quística , Recién Nacido , Femenino , Humanos , Ratas , Animales , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Lactancia Materna , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Mutación , Aminofenoles/efectos adversos , Benzodioxoles/efectos adversos , Combinación de Medicamentos , Catarata/inducido químicamente , Catarata/diagnóstico , Agonistas de los Canales de Cloruro/efectos adversosRESUMEN
INTRODUCTION: Therapeutic advances have markedly increased life expectancy for those with cystic fibrosis (CF), resulting in a median predicted survival over 50 years. Consequently, people with CF (pwCF) are living through their reproductive years and the rate of pregnancy is rapidly rising. Despite the increased relevance of this topic, multicentre studies investigating the association between maternal health and choices made during pregnancy on maternal and fetal outcomes do not exist. Furthermore, there are very limited data on the outcomes following CF transmembrane conductance regulator (CFTR) modulator use during pregnancy and lactation. METHODS AND ANALYSIS: Maternal and Fetal Outcomes in the Era of Modulators (MAYFLOWERS) is a prospective, multicentre observational clinical trial which will enrol approximately 285 pregnant pwCF including those who are modulator ineligible and those who choose to continue or discontinue CFTR modulator therapy during pregnancy and lactation. The primary aim of this 35-month study is to assess whether lung function changes during pregnancy differ based on the continued use of modulators or other factors such as pre-existing comorbid conditions. Secondary objectives include evaluation of pregnancy related and obstetrical complications and changes in mental health. ETHICS AND DISSEMINATION: The design of this study required special consideration of study burden on pregnant and lactating people with chronic illness in the setting of a substantial number of unanswered questions under these conditions. MAYFLOWERS is the first prospective clinical trial examining pregnancy in CF; the outcomes will guide providers on pregnancy management in pwCF and others with chronic respiratory disease.
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Fibrosis Quística , Quinolonas , Aminofenoles/uso terapéutico , Ensayos Clínicos como Asunto , Fibrosis Quística/complicaciones , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Femenino , Humanos , Lactancia , Estudios Multicéntricos como Asunto , Estudios Observacionales como Asunto , Embarazo , Estudios Prospectivos , Quinolonas/uso terapéuticoRESUMEN
While discovery metabolomic studies have identified many potential biomarkers of cystic fibrosis (CF) airways disease, relatively few have been validated. We review the recent literature to identify the most promising metabolomic findings as those repeatedly observed over multiple studies. Reproducible metabolomic findings include increased airway amino acids and small peptides in CF airways, as well as changes in phospholipids and sphingolipids. Other commonly altered pathways include adenosine metabolism, polyamine synthesis, and oxidative stress. These pathways represent potential biomarkers and therapeutic targets, though findings require reevaluation in the era of highly effective modulator therapies. Analysis of airway biomarkers in exhaled breath holds promise for non-invasive detection, though technical challenges will need to be overcome.
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Fibrosis Quística , Biomarcadores/metabolismo , Fibrosis Quística/metabolismo , Humanos , Metabolómica , Estrés OxidativoRESUMEN
Rationale: Chronic obstructive pulmonary disease (COPD) is variable in its development. Lung microbiota and metabolites collectively may impact COPD pathophysiology, but relationships to clinical outcomes in milder disease are unclear. Objectives: Identify components of the lung microbiome and metabolome collectively associated with clinical markers in milder stage COPD. Methods: We analyzed paired microbiome and metabolomic data previously characterized from bronchoalveolar lavage fluid in 137 participants in the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), or (GOLD [Global Initiative for Chronic Obstructive Lung Disease Stage 0-2). Datasets used included 1) bacterial 16S rRNA gene sequencing; 2) untargeted metabolomics of the hydrophobic fraction, largely comprising lipids; and 3) targeted metabolomics for a panel of hydrophilic compounds previously implicated in mucoinflammation. We applied an integrative approach to select features and model 14 individual clinical variables representative of known associations with COPD trajectory (lung function, symptoms, and exacerbations). Measurements and Main Results: The majority of clinical measures associated with the lung microbiome and metabolome collectively in overall models (classification accuracies, >50%, P < 0.05 vs. chance). Lower lung function, COPD diagnosis, and greater symptoms associated positively with Streptococcus, Neisseria, and Veillonella, together with compounds from several classes (glycosphingolipids, glycerophospholipids, polyamines and xanthine, an adenosine metabolite). In contrast, several Prevotella members, together with adenosine, 5'-methylthioadenosine, sialic acid, tyrosine, and glutathione, associated with better lung function, absence of COPD, or less symptoms. Significant correlations were observed between specific metabolites and bacteria (Padj < 0.05). Conclusions: Components of the lung microbiome and metabolome in combination relate to outcome measures in milder COPD, highlighting their potential collaborative roles in disease pathogenesis.
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Microbiota , Enfermedad Pulmonar Obstructiva Crónica , Adenosina , Humanos , Pulmón/patología , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , ARN Ribosómico 16S/genéticaRESUMEN
BACKGROUND: Mucus hyperconcentration in cystic fibrosis (CF) lung disease is marked by increases in both mucin and DNA concentration. Additionally, it has been shown that half of the mucins present in bronchial alveolar lavage fluid (BALF) from preschool-aged CF patients are present in as non-swellable mucus flakes. This motivates us to examine the utility of mucus flakes, as well as mucin and DNA concentrations in BALF as markers of infection and inflammation in CF airway disease. METHODS: In this study, we examined the mucin and DNA concentration, as well as mucus flake abundance, composition, and biophysical properties in BALF from three groups; healthy adult controls, and two CF cohorts, one preschool aged and the other school aged. BALFs were characterized via refractometry, PicoGreen, immunofluorescence microscopy, particle tracking microrheology, and fluorescence image tiling. RESULTS: Mucin and DNA BALF concentrations increased progressively from healthy young adult controls to preschool-aged people and school-aged people with CF. Notably, mucin concentrations were increased in bronchoalveolar lavage fluid (BALF) from preschool-aged patients with CF prior to decreased pulmonary function. Infrequent small mucus flakes were identified in normal subjects. A progressive increase in the abundance of mucus flakes in preschool and school-aged CF patients was observed. Compositionally, MUC5B dominated flakes from normal subjects, whereas an increase in MUC5AC was observed in people with CF, reflected in a reduced flaked MUC5B/MUC5AC mucin ratio. CONCLUSION: These findings suggest mucus composition and flake properties are useful markers of inflammatory and infection-based changes in CF airways.
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Fibrosis Quística , Adulto Joven , Humanos , Preescolar , Niño , Moco , Mucina 5AC , Sistema Respiratorio , Biomarcadores , ADNRESUMEN
As the nasal cavity is the portal of entry for inspired air in mammals, this region is exposed to the highest concentration of inhaled particulate matter and pathogens, which must be removed to keep the lower airways sterile. Thus, one might expect vigorous removal of these substances via mucociliary clearance (MCC) in this region. We have investigated the rate of MCC in the murine nasal cavity compared to the more distal airways (trachea). The rate of MCC in the nasal cavity (posterior nasopharynx, PNP) was â¼3-4× greater than on the tracheal wall. This appeared to be due to a more abundant population of ciliated cells in the nasal cavity (â¼80%) compared to the more sparsely ciliated trachea (â¼40%). Interestingly, the tracheal ventral wall exhibited a significantly lower rate of MCC than the tracheal posterior membrane. The trachealis muscle underlying the ciliated epithelium on the posterior membrane appeared to control the surface architecture and likely in part the rate of MCC in this tracheal region. In one of our mouse models (Bpifb1 KO) exhibiting a 3-fold increase in MUC5B protein in lavage fluid, MCC particle transport on the tracheal walls was severely compromised, yet normal MCC occurred on the tracheal posterior membrane. While a blanket of mucus covered the surface of both the PNP and trachea, this mucus appeared to be transported as a blanket by MCC only in the PNP. In contrast, particles appeared to be transported as discrete patches or streams of mucus in the trachea. In addition, particle transport in the PNP was fairly linear, in contrast transport of particles in the trachea often followed a more non-linear route. The thick, viscoelastic mucus blanket that covered the PNP, which exhibited â¼10-fold greater mass of mucus than did the blanket covering the surface of the trachea, could be transported over large areas completely devoid of cells (made by a breach in the epithelial layer). In contrast, particles could not be transported over even a small epithelial breach in the trachea. The thick mucus blanket in the PNP likely aids in particle transport over the non-ciliated olfactory cells in the nasal cavity and likely contributes to humidification and more efficient particle trapping in this upper airway region.
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BACKGROUND: The nose is the portal for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, suggesting the nose as a target for topical antiviral therapies. The purpose of this study was to assess both the in vivo and in vitro efficacy of a detergent-based virucidal agent, Johnson and Johnson's Baby Shampoo (J&J), in SARS-CoV-2-infected subjects. METHODS: Subjects were randomized into three treatment groups: (1) twice daily nasal irrigation with J&J in hypertonic saline, (2) hypertonic saline alone, and (3) no intervention. Complementary in vitro experiments were performed in cultured human nasal epithelia. The primary outcome measure in the clinical trial was change in SARS-CoV-2 viral load over 21 days. Secondary outcomes included symptom scores and change in daily temperature. Outcome measures for in vitro studies included change in viral titers. RESULTS: Seventy-two subjects completed the clinical study (n = 24 per group). Despite demonstrated safety and robust efficacy in in vitro virucidal assays, J&J irrigations had no impact on viral titers or symptom scores in treated subjects relative to controls. Similar findings were observed administering J&J to infected cultured human airway epithelia using protocols mimicking the clinical trial regimen. Additional studies of cultured human nasal epithelia demonstrated that lack of efficacy reflected pharmacokinetic failure, with the most virucidal J&J detergent components rapidly absorbed from nasal surfaces. CONCLUSION: In this randomized clinical trial of subjects with SARS-CoV-2 infection, a topical detergent-based virucidal agent had no effect on viral load or symptom scores. Complementary in vitro studies confirmed a lack of efficacy, reflective of pharmacokinetic failure and rapid absorption from nasal surfaces.
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COVID-19 , Resfriado Común , Antivirales , Detergentes , Humanos , SARS-CoV-2 , Carga ViralRESUMEN
Elexacaftor, tezacaftor, ivacaftor (ETI) have been associated with marked clinical improvements in adults with CF, which appears to be associated with increased fertility. However, maternal and fetal effects of therapy continued during pregnancy are not well understood. We collected maternal blood, infant blood, cord blood, and breast milk from 3 mother-infant pairs from women who elected to remain on ETI therapy while pregnant. Our results demonstrated relatively high levels of ETI in cord blood, suggesting placental transfer of these compounds, as well as low levels of ETI in breast milk and infant blood, suggesting further transfer of these compounds to breast-fed infants in the postnatal period. These data underscore the need for larger studies on the effects of modulator surrounding reproduction.
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Agonistas de los Canales de Cloruro , Fibrosis Quística , Exposición Materna , Madres , Adulto , Aminofenoles , Benzodioxoles , Agonistas de los Canales de Cloruro/administración & dosificación , Fibrosis Quística/tratamiento farmacológico , Combinación de Medicamentos , Femenino , Humanos , Indoles , Lactante , Placenta , Embarazo , Pirazoles , Piridinas , Pirrolidinas , QuinolonasRESUMEN
BACKGROUND: Improved understanding of the pathways associated with airway pathophysiologic features in COPD will identify new predictive biomarkers and novel therapeutic targets. RESEARCH QUESTION: Which physiologic pathways are altered in the airways of patients with COPD and will predict exacerbations? STUDY DESIGN AND METHODS: We applied a mass spectrometric panel of metabolomic biomarkers related to mucus hydration and inflammation to sputa from the multicenter Subpopulations and Intermediate Outcome Measures in COPD Study. Biomarkers elevated in sputa from patients with COPD were evaluated for relationships to measures of COPD disease severity and their ability to predict future exacerbations. RESULTS: Sputum supernatants from 980 patients were analyzed: 77 healthy nonsmokers, 341 smokers with preserved spirometry, and 562 patients with COPD (178 with Global Initiative on Chronic Obstructive Lung Disease [GOLD] stage 1 disease, 303 with GOLD stage 2 disease, and 81 with GOLD stage 3 disease) were analyzed. Biomarkers from multiple pathways were elevated in COPD and correlated with sputum neutrophil counts. Among the most significant analytes (false discovery rate, 0.1) were sialic acid, hypoxanthine, xanthine, methylthioadenosine, adenine, and glutathione. Sialic acid and hypoxanthine were associated strongly with measures of disease severity, and elevation of these biomarkers was associated with shorter time to exacerbation and improved prediction models of future exacerbations. INTERPRETATION: Biomarker evaluation implicated pathways involved in mucus hydration, adenosine metabolism, methionine salvage, and oxidative stress in COPD airway pathophysiologic characteristics. Therapies that target these pathways may be of benefit in COPD, and a simple model adding sputum-soluble phase biomarkers improves prediction of pulmonary exacerbations. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344; URL: www. CLINICALTRIALS: gov.