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In study after study, marijuana use has been found to be associated with increased forced vital capacity (FVC). This is puzzling, because marijuana is commonly consumed by inhalation of its smoke, and smoke exposure of any kind is not generally considered a cause of increased FVC. Although this observation was first made decades ago, a satisfactory explanation remains elusive. In this review we survey the evidence supporting the relationship between marijuana use and increased FVC, discuss potential threats to validity when inferring causation, and, presupposing a possible causal relationship, pose two key questions. First, what are possible physiologic or pathophysiologic mechanisms by which marijuana use might increase FVC? Second, why might this effect be consistently observed with marijuana use but not with tobacco use? Explanations for the first question include lung and chest growth and remodeling from strenuous marijuana smoke inhalation and reductions in lung elastic recoil from marijuana smoke exposure. Explanations for the second include differences between marijuana and tobacco in smoke composition and patterns of consumption, such as smoking topography. Finally, the possibility that smoke, whether from marijuana or tobacco, might have nonmonotonic effects on FVC depending on the degree of exposure is explored. In synthesizing a curated breadth of epidemiologic and physiologic science, we leverage a perplexing observation to generate potential insights and avenues for further research into the biological effects of smoke, from marijuana or otherwise, on the respiratory system.
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Uso de la Marihuana , Humanos , Capacidad Vital , Uso de la Marihuana/efectos adversos , Pulmón/fisiopatología , Fumar Marihuana/efectos adversos , Cannabis/efectos adversosAsunto(s)
Pulmón , Humanos , Espirometría , Valores de Referencia , Capacidad Vital , Volumen Espiratorio ForzadoRESUMEN
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 , Broncoscopía , Pulmón/diagnóstico por imagen , Moco , Tomografía Computarizada por Rayos XRESUMEN
This document updates the 2005 European Respiratory Society (ERS) and American Thoracic Society (ATS) technical standard for the measurement of lung volumes. The 2005 document integrated the recommendations of an ATS/ERS task force with those from an earlier National Heart, Lung, and Blood Institute workshop that led to the publication of background papers between 1995 and 1999 and a consensus workshop report with more in-depth descriptions and discussion. Advancements in hardware and software, new research and emerging approaches have necessitated an update to the 2005 technical standard to guide laboratory directors, physiologists, operators, pulmonologists and manufacturers. Key updates include standardisation of linked spirometry, new equipment quality control and validation recommendations, generalisation of the multiple breath washout concept beyond nitrogen, a new acceptability and grading system with addition of example tracings, and a brief review of imaging and other new techniques to measure lung volumes. Future directions and key research questions are also noted.
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Pulmón , Sociedades Médicas , Humanos , Estados Unidos , Pulmón/diagnóstico por imagen , Pruebas de Función Respiratoria/métodos , Espirometría , Mediciones del Volumen PulmonarRESUMEN
BACKGROUND: Calls have been made to discontinue the routine use of race and ethnicity in medicine. Specific to respiratory medicine, the use of race- and ethnicity-specific reference equations for the interpretation of pulmonary function test (PFT) results has been questioned. RESEARCH QUESTIONS: Three key questions were addressed: (1) What is the current evidence supporting the use of race- and ethnicity-specific reference equations for the interpretation of PFTs? (2) What are the potential clinical implications of the use or nonuse of race and ethnicity in interpreting PFT results? and (3) What research gaps and questions must be addressed and answered to understand better the effect of race and ethnicity on PFT results interpretation and potential clinical and occupational health implications? STUDY DESIGN AND METHODS: A joint multisociety (American College of Chest Physicians, American Association for Respiratory Care, American Thoracic Society, and Canadian Thoracic Society) expert panel was formed to undertake a comprehensive evidence review and to develop a statement with recommendations to address the research questions. RESULTS: Several assumptions and gaps, both in the published literature and in our evolving understanding of lung health, were identified. It seems that many past perceptions and practices regarding the effect of race and ethnicity on PFT results interpretation are based on limited scientific evidence and measures that lack reliability. INTERPRETATION: A need exists for more and better research that will inform our field about these many uncertainties and will serve as a foundation for future recommendations in this area. The identified shortcomings should not be discounted or dismissed because they may enable flawed conclusions, unintended consequences, or both. Addressing the identified research gaps and needs would allow a better-a more informed-understanding of the effects of race and ethnicity on PFT results interpretation.
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Etnicidad , Médicos , Humanos , Estados Unidos , Reproducibilidad de los Resultados , Canadá , Pruebas de Función RespiratoriaRESUMEN
Current American Thoracic Society (ATS) standards promote the use of race and ethnicity-specific reference equations for pulmonary function test (PFT) interpretation. There is rising concern that the use of race and ethnicity in PFT interpretation contributes to a false view of fixed differences between races and may mask the effects of differential exposures. This use of race and ethnicity may contribute to health disparities by norming differences in pulmonary function. In the United States and globally, race serves as a social construct that is based on appearance and reflects social values, structures, and practices. Classification of people into racial and ethnic groups differs geographically and temporally. These considerations challenge the notion that racial and ethnic categories have biological meaning and question the use of race in PFT interpretation. The ATS convened a diverse group of clinicians and investigators for a workshop in 2021 to evaluate the use of race and ethnicity in PFT interpretation. Review of evidence published since then that challenges current practice and continued discussion concluded with a recommendation to replace race and ethnicity-specific equations with race-neutral average reference equations, which must be accompanied with a broader re-evaluation of how PFTs are used to make clinical, employment, and insurance decisions. There was also a call to engage key stakeholders not represented in this workshop and a statement of caution regarding the uncertain effects and potential harms of this change. Other recommendations include continued research and education to understand the impact of the change, to improve the evidence for the use of PFTs in general, and to identify modifiable risk factors for reduced pulmonary function.
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Etnicidad , Sociedades , Humanos , Estados Unidos , Pruebas de Función RespiratoriaRESUMEN
Rationale: Currently used spirometry measures of airflow obstruction are influenced by demographics, predominantly by age, complicating selection of diagnostic thresholds for the presence of airflow obstruction. Objectives: To develop diagnostic thresholds for Parameter D, a new metric for detection of airflow obstruction, which quantifies the rate of rise of expiratory volume over time. Methods: We analyzed spirometry data of normal subjects enrolled in the 2007-2008, 2009-2010, and 2011-2012 NHANES (National Health and Nutrition Examination Survey) cohorts and calculated Parameter D using the expiratory volume-time curve. Relationships between demographics and lung function (forced expiratory volume in 1 second [FEV1], FEV1/forced vital capacity [FVC], and Parameter D) were tested using generalized linear models in NHANES and UK Biobank. The variation in lung function explained by demographics was estimated using R2. A diagnostic threshold was developed for Parameter D using population-based percentiles. Based on concordance between the lower limit of normal (LLN) for FEV1/FVC and the Parameter D threshold, four groups were identified: normal (no airflow obstruction by either criterion), D+chronic obstructive pulmonary disease (D+COPD; positive by Parameter D only), D-COPD (positive by LLN only), and COPD (positive by both criteria), and associations with structural lung disease, exacerbations, and mortality were tested using multivariable analyses. Results: In contrast to FEV1 and FEV1/FVC, demographics cumulatively explained only 9% of the variance in Parameter D in NHANES (n = 4,945) and 3% in UK BioBank (n = 109,623). In COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) (n = 9,542), a diagnostic threshold of -3.15 resulted in the identification of an additional 10.8% of participants with airflow obstruction. A total of 3.7% had FEV1/FVC < LLN but were missed by the Parameter D threshold. Compared with subjects in the normal group, after adjustment for age, sex, race, body mass index, pack-years of smoking, and current smoking status, D+COPD was associated with worse structural lung disease (odds ratio [OR] for ⩾5% emphysema, 1.71; 95% confidence interval [CI], 1.37-2.12; OR for functional small airway disease ⩾ 15%, 2.1; 95% CI, 1.79-2.67) and significant symptoms (OR for modified Medical Research Council dyspnea score ⩾ 2, 1.25; 95% CI, 1.07-1.47; OR for St. George's respiratory questionnaire ⩾ 25, 1.31; 95% CI, 1.13-1.53), a greater frequency of exacerbations (incidence rate ratio, 1.26; 95% CI, 1.10-1.46), and higher mortality (hazard ratio, 1.32; 95% CI, 1.10-1.57). Over 5 years, 28% of the D+COPD group versus 8% of normal group progressed to COPD by traditional criteria. Conclusions: Parameter D is not affected by age, and a normal population-based diagnostic threshold results in the early identification of additional individuals with airflow obstruction with a substantial amount of structural lung disease and respiratory symptoms.
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Asma , Enfermedades Pulmonares , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Encuestas Nutricionales , Pulmón , Volumen Espiratorio Forzado , Capacidad Vital , Espirometría/métodosRESUMEN
Rationale: The use of self-reported race and ethnicity to interpret lung function measurements has historically assumed that the observed differences in lung function between racial and ethnic groups were because of thoracic cavity size differences relative to standing height. Very few studies have considered the influence of environmental and social determinants on pulmonary function. Consequently, the use of race and ethnicity-specific reference equations may further marginalize disadvantaged populations. Objectives: To develop a race-neutral reference equation for spirometry interpretation. Methods: National Health and Nutrition Examination Survey (NHANES) III data (n = 6,984) were reanalyzed with sitting height and the Cormic index to investigate whether body proportions were better predictors of lung function than race and ethnicity. Furthermore, the original GLI (Global Lung Function Initiative) data (n = 74,185) were reanalyzed with inverse-probability weights to create race-neutral GLI global (2022) equations. Measurements and Main Results: The inclusion of sitting height slightly improved the statistical precision of reference equations compared with using standing height alone but did not explain observed differences in spirometry between the NHANES III race and ethnic groups. GLI global (2022) equations, which do not require the selection of race and ethnicity, had a similar fit to the GLI 2012 "other" equations and wider limits of normal. Conclusions: The use of a single global spirometry equation reflects the wide range of lung function observed within and between populations. Given the inherent limitations of any reference equation, the use of GLI global equations to interpret spirometry requires careful consideration of an individual's symptoms and medical history when used to make clinical, employment, and insurance decisions.
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Etnicidad , Pulmón , Humanos , Encuestas Nutricionales , Volumen Espiratorio Forzado , Valores de Referencia , Capacidad Vital , EspirometríaRESUMEN
The practice of using race or ethnicity in medicine to explain differences between individuals is being called into question because it may contribute to biased medical care and research that perpetuates health disparities and structural racism. A commonly cited example is the use of race or ethnicity in the interpretation of pulmonary function test (PFT) results, yet the perspectives of practicing pulmonologists and physiologists are missing from this discussion. This discussion has global relevance for increasingly multicultural communities in which the range of values that represent normal lung function is uncertain. We review the underlying sources of differences in lung function, including those that may be captured by race or ethnicity, and demonstrate how the current practice of PFT measurement and interpretation is imperfect in its ability to describe accurately the relationship between function and health outcomes. We summarize the arguments against using race-specific equations as well as address concerns about removing race from the interpretation of PFT results. Further, we outline knowledge gaps and critical questions that need to be answered to change the current approach of including race or ethnicity in PFT results interpretation thoughtfully. Finally, we propose changes in interpretation strategies and future research to reduce health disparities.
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Etnicidad , Disparidades en el Estado de Salud , Enfermedades Pulmonares/fisiopatología , Pulmón , Grupos Raciales , Pruebas de Función Respiratoria , Pueblo Asiatico , Población Negra , Humanos , Enfermedades Pulmonares/etnología , Valores de Referencia , Espirometría , Población BlancaAsunto(s)
Asma , Tos , Asma/complicaciones , Asma/diagnóstico , Tos/diagnóstico , Tos/etiología , Femenino , HumanosRESUMEN
IL-13-induced goblet cell metaplasia contributes to airway remodeling and pathological mucus hypersecretion in asthma. miRNAs are potent modulators of cellular responses, but their role in mucus regulation is largely unexplored. We hypothesized that airway epithelial miRNAs play roles in IL-13-induced mucus regulation. miR-141 is highly expressed in human and mouse airway epithelium, is altered in bronchial brushings from asthmatic subjects at baseline, and is induced shortly after airway allergen exposure. We established a CRISPR/Cas9-based protocol to target miR-141 in primary human bronchial epithelial cells that were differentiated at air-liquid-interface, and goblet cell hyperplasia was induced by IL-13 stimulation. miR-141 disruption resulted in decreased goblet cell frequency, intracellular MUC5AC, and total secreted mucus. These effects correlated with a reduction in a goblet cell gene expression signature and enrichment of a basal cell gene expression signature defined by single cell RNA sequencing. Furthermore, intranasal administration of a sequence-specific mmu-miR-141-3p inhibitor in mice decreased Aspergillus-induced secreted mucus and mucus-producing cells in the lung and reduced airway hyperresponsiveness without affecting cellular inflammation. In conclusion, we have identified a miRNA that regulates pathological airway mucus production and is amenable to therapeutic manipulation through an inhaled route.
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Remodelación de las Vías Aéreas (Respiratorias) , Asma , Células Caliciformes , Interleucina-13/metabolismo , Pulmón , MicroARNs/metabolismo , Moco/metabolismo , Animales , Aspergillus , Asma/metabolismo , Asma/patología , Proteína 9 Asociada a CRISPR , Diferenciación Celular , Células Cultivadas , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Células Caliciformes/metabolismo , Células Caliciformes/patología , Humanos , Pulmón/citología , Pulmón/metabolismo , Pulmón/patología , Masculino , Metaplasia , Ratones Endogámicos C57BL , Mucina 5AC/metabolismoRESUMEN
BACKGROUND: Mild expiratory flow limitation may not be recognized using traditional spirometric criteria based on the ratio of FEV1/FVC. RESEARCH QUESTION: Does slow vital capacity (SVC) instead of FVC increase the sensitivity of spirometry to identify patients with early or mild obstructive lung disease? STUDY DESIGN AND METHODS: We included 854 current and former smokers from the Subpopulations and Intermediate Outcome Measures in COPD Study cohort with a postbronchodilator FEV1/FVC ≥ 0.7 and FEV1 % predicted of ≥ 80% at enrollment. We compared baseline characteristics, chest CT scan features, exacerbations, and progression to COPD (postbronchodilator FEV1/FVC, < 0.7) during the follow-up period between 734 participants with postbronchodilator FEV1/SVC of ≥ 0.7 and 120 with postbronchodilator FEV1/SVC < 0.7 at the enrollment. We performed multivariate linear and logistic regression models and negative binomial and interval-censored proportion hazards regression models adjusted for demographics and smoking exposure to examine the association of FEV1/SVC < 0.7 with those characteristics and outcomes. RESULTS: Participants with FEV1/SVC < 0.7 were older and had lower FEV1 and more emphysema than those with FEV1/SVC ≥ 0.7. In adjusted analysis, individuals with postbronchodilator FEV1/SVC < 0.7 showed a greater percentage of emphysema by 0.45% (95% CI, 0.09%-0.82%), percentage of gas trapping by 2.52% (95% CI, 0.59%-4.44%), and percentage of functional small airways disease based on parametric response mapping by 2.78% (95% CI, 0.72%-4.83%) at baseline than those with FEV1/SVC ≥ 0.7. During a median follow-up time of 1,500 days, an FEV1/SVC < 0.7 was not associated with total exacerbations (incident rate ratio [IRR], 1.61; 95% CI, 0.97-2.64), but was associated with severe exacerbations (IRR, 2.60; 95% CI, 1.04-4.89). An FEV1/SVC < 0.7 was associated with progression to COPD during a 3-year follow-up even after adjustment for demographics and smoking exposure (hazard ratio, 3.93; 95% CI, 2.71-5.72). We found similar results when we examined the association of prebronchodilator FEV1/SVC < 0.7 or FEV1/SVC less than the lower limit of normal with chest CT scan features and progression to COPD. INTERPRETATION: Low FEV1 to SVC in current and former smokers with normal spirometry results can identify individuals with CT scan features of COPD who are at risk for severe exacerbations and is associated with progression to COPD in the future. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344T4; URL: www.clinicaltrials.gov.
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Volumen Espiratorio Forzado/fisiología , Pulmón/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Fumadores , Tomografía Computarizada por Rayos X/métodos , Capacidad Vital/fisiología , Progresión de la Enfermedad , Estudios de Seguimiento , Humanos , Pulmón/diagnóstico por imagen , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Espirometría/métodosRESUMEN
Whereas the human fetal immune system is poised to generate immune tolerance and suppress inflammation in utero, an adult-like immune system emerges to orchestrate anti-pathogen immune responses in post-natal life. It has been posited that cells of the adult immune system arise as a discrete ontological "layer" of hematopoietic stem-progenitor cells (HSPCs) and their progeny; evidence supporting this model in humans has, however, been inconclusive. Here, we combine bulk and single-cell transcriptional profiling of lymphoid cells, myeloid cells, and HSPCs from fetal, perinatal, and adult developmental stages to demonstrate that the fetal-to-adult transition occurs progressively along a continuum of maturity-with a substantial degree of inter-individual variation at the time of birth-rather than via a transition between discrete waves. These findings have important implications for the design of strategies for prophylaxis against infection in the newborn and for the use of umbilical cord blood (UCB) in the setting of transplantation.
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Feto/metabolismo , Células Madre Hematopoyéticas/metabolismo , Linfocitos/metabolismo , Células Mieloides/metabolismo , Análisis de la Célula Individual , Linfocitos T/metabolismo , Transcriptoma , Médula Ósea/metabolismo , Técnicas de Cultivo de Célula , Femenino , Sangre Fetal , Humanos , Inmunidad , Embarazo , Análisis de Secuencia de ARNRESUMEN
Background: In March 2020, many elective medical services were canceled in response to the coronavirus disease 2019 (COVID-19) pandemic. The daily case rate is now declining in many states and there is a need for guidance about the resumption of elective clinical services for patients with lung disease or sleep conditions.Methods: Volunteers were solicited from the Association of Pulmonary, Critical Care, and Sleep Division Directors and American Thoracic Society. Working groups developed plans by discussion and consensus for resuming elective services in pulmonary and sleep-medicine clinics, pulmonary function testing laboratories, bronchoscopy and procedure suites, polysomnography laboratories, and pulmonary rehabilitation facilities.Results: The community new case rate should be consistently low or have a downward trajectory for at least 14 days before resuming elective clinical services. In addition, institutions should have an operational strategy that consists of patient prioritization, screening, diagnostic testing, physical distancing, infection control, and follow-up surveillance. The goals are to protect patients and staff from exposure to the virus, account for limitations in staff, equipment, and space that are essential for the care of patients with COVID-19, and provide access to care for patients with acute and chronic conditions.Conclusions: Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a dynamic process and, therefore, it is likely that the prevalence of COVID-19 in the community will wax and wane. This will impact an institution's mitigation needs. Operating procedures should be frequently reassessed and modified as needed. The suggestions provided are those of the authors and do not represent official positions of the Association of Pulmonary, Critical Care, and Sleep Division Directors or the American Thoracic Society.
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Infecciones por Coronavirus/prevención & control , Cuidados Críticos , Pandemias/prevención & control , Neumonía Viral/prevención & control , Neumología , Sueño , Comités Consultivos , Betacoronavirus , COVID-19 , Consenso , Infecciones por Coronavirus/diagnóstico , Humanos , Neumonía Viral/diagnóstico , SARS-CoV-2 , Sociedades Médicas , Estados UnidosRESUMEN
BACKGROUNDCurrently recommended traditional spirometry outputs do not reflect the relative contributions of emphysema and airway disease to airflow obstruction. We hypothesized that machine-learning algorithms can be trained on spirometry data to identify these structural phenotypes.METHODSParticipants enrolled in a large multicenter study (COPDGene) were included. The data points from expiratory flow-volume curves were trained using a deep-learning model to predict structural phenotypes of chronic obstructive pulmonary disease (COPD) on CT, and results were compared with traditional spirometry metrics and an optimized random forest classifier. Area under the receiver operating characteristic curve (AUC) and weighted F-score were used to measure the discriminative accuracy of a fully convolutional neural network, random forest, and traditional spirometry metrics to phenotype CT as normal, emphysema-predominant (>5% emphysema), airway-predominant (Pi10 > median), and mixed phenotypes. Similar comparisons were made for the detection of functional small airway disease phenotype (>20% on parametric response mapping).RESULTSAmong 8980 individuals, the neural network was more accurate in discriminating predominant emphysema/airway phenotypes (AUC 0.80, 95%CI 0.79-0.81) compared with traditional measures of spirometry, FEV1/FVC (AUC 0.71, 95%CI 0.69-0.71), FEV1% predicted (AUC 0.70, 95%CI 0.68-0.71), and random forest classifier (AUC 0.78, 95%CI 0.77-0.79). The neural network was also more accurate in discriminating predominant emphysema/small airway phenotypes (AUC 0.91, 95%CI 0.90-0.92) compared with FEV1/FVC (AUC 0.80, 95%CI 0.78-0.82), FEV1% predicted (AUC 0.83, 95%CI 0.80-0.84), and with comparable accuracy with random forest classifier (AUC 0.90, 95%CI 0.88-0.91).CONCLUSIONSStructural phenotypes of COPD can be identified from spirometry using deep-learning and machine-learning approaches, demonstrating their potential to identify individuals for targeted therapies.TRIAL REGISTRATIONClinicalTrials.gov NCT00608764.FUNDINGThis study was supported by NIH grants K23 HL133438 and R21EB027891 and an American Thoracic Foundation 2018 Unrestricted Research Grant. The COPDGene study is supported by NIH grants NHLBI U01 HL089897 and U01 HL089856. The COPDGene study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprising AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, and Sunovion.
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Redes Neurales de la Computación , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfisema Pulmonar/fisiopatología , Espirometría , Adulto , Anciano , Femenino , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Fumar/efectos adversosRESUMEN
BACKGROUND: Whether microbiome characteristics of induced sputum or oral samples demonstrate unique relationships to features of atopy or mild asthma in adults is unknown. OBJECTIVE: We sought to determine sputum and oral microbiota relationships to clinical or immunologic features in mild atopic asthma and the impact on the microbiota of inhaled corticosteroid (ICS) treatment administered to ICS-naive subjects with asthma. METHODS: Bacterial microbiota profiles were analyzed in induced sputum and oral wash samples from 32 subjects with mild atopic asthma before and after inhaled fluticasone treatment, 18 atopic subjects without asthma, and 16 nonatopic healthy subjects in a multicenter study (NCT01537133). Associations with clinical and immunologic features were examined, including markers of atopy, type 2 inflammation, immune cell populations, and cytokines. RESULTS: Sputum bacterial burden inversely associated with bronchial expression of type 2 (T2)-related genes. Differences in specific sputum microbiota also associated with T2-low asthma phenotype, a subgroup of whom displayed elevations in lung inflammatory mediators and reduced sputum bacterial diversity. Differences in specific oral microbiota were more reflective of atopic status. After ICS treatment of patients with asthma, the compositional structure of sputum microbiota showed greater deviation from baseline in ICS nonresponders than in ICS responders. CONCLUSIONS: Novel associations of sputum and oral microbiota to immunologic features were observed in this cohort of subjects with or without ICS-naive mild asthma. These findings confirm and extend our previous report of reduced bronchial bacterial burden and compositional complexity in subjects with T2-high asthma, with additional identification of a T2-low subgroup with a distinct microbiota-immunologic relationship.
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Corticoesteroides/uso terapéutico , Asma/microbiología , Hipersensibilidad Inmediata/microbiología , Microbiota/genética , Boca/microbiología , Esputo/microbiología , Células Th2/inmunología , Administración por Inhalación , Adulto , Asma/tratamiento farmacológico , Biomarcadores , Citocinas/metabolismo , Femenino , Humanos , Hipersensibilidad Inmediata/tratamiento farmacológico , Masculino , Resultado del TratamientoRESUMEN
Conjugated bile acids (CBAs), such as tauroursodeoxycholic acid (TUDCA), are known to resolve the inflammatory and unfolded protein response (UPR) in inflammatory diseases, such as asthma. Whether CBAs exert their beneficial effects on allergic airway responses via 1 arm or several arms of the UPR, or alternatively through the signaling pathways for conserved bile acid receptor, remains largely unknown. We used a house dust mite-induced (HDM-induced) murine model of asthma to evaluate and compare the effects of 5 CBAs and 1 unconjugated bile acid in attenuating allergen-induced UPR and airway responses. Expression of UPR-associated transcripts was assessed in airway brushings from human patients with asthma and healthy subjects. Here we show that CBAs, such as alanyl ß-muricholic acid (AßM) and TUDCA, significantly decreased inflammatory, immune, and cytokine responses; mucus metaplasia; and airway hyperresponsiveness, as compared with other CBAs in a model of allergic airway disease. CBAs predominantly bind to activating transcription factor 6α (ATF6α) compared with the other canonical transducers of the UPR, subsequently decreasing allergen-induced UPR activation and resolving allergic airway disease, without significant activation of the bile acid receptors. TUDCA and AßM also attenuated other HDM-induced ER stress markers in the lungs of allergic mice. Quantitative mRNA analysis of airway epithelial brushings from human subjects demonstrated that several ATF6α-related transcripts were significantly upregulated in patients with asthma compared with healthy subjects. Collectively, these results demonstrate that CBA-based therapy potently inhibits the allergen-induced UPR and allergic airway disease in mice via preferential binding of the canonical transducer of the UPR, ATF6α. These results potentially suggest a novel avenue to treat allergic asthma using select CBAs.
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Alérgenos/inmunología , Asma/inmunología , Inflamación/inmunología , Hipersensibilidad Respiratoria/inmunología , Respuesta de Proteína Desplegada/inmunología , Animales , Ácidos y Sales Biliares/efectos adversos , Quimiocinas , Citocinas/metabolismo , Femenino , Humanos , Hipersensibilidad , Pulmón/inmunología , Pulmón/metabolismo , Metaplasia/inmunología , Metaplasia/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Deficiencias en la Proteostasis , Pyroglyphidae/inmunología , Receptores Acoplados a Proteínas G/metabolismo , Hipersensibilidad Respiratoria/tratamiento farmacológico , Ácido Tauroquenodesoxicólico/farmacología , Respuesta de Proteína Desplegada/efectos de los fármacosRESUMEN
Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation. Spirometry loops are not smooth curves and have undulations and peaks that likely reflect heterogeneity of airflow.Objectives: To assess whether the Peak Index, the number of peaks adjusted for lung size, is associated with clinical outcomes.Methods: We analyzed spirometry data of 9,584 participants enrolled in the COPDGene study and counted the number of peaks in the descending part of the expiratory flow-volume curve from the peak expiratory flow to end-expiration. We adjusted the peaks count for the volume of the lungs from peak expiratory flow to end-expiration to derive the Peak Index. Multivariable regression analyses were performed to test associations between the Peak Index and lung function, respiratory morbidity, structural lung disease on computed tomography (CT), forced expiratory volume in 1 second (FEV1) decline, and mortality.Results: The Peak Index progressively increased from Global Initiative for Chronic Obstructive Lung Disease stage 0 through 4 (P < 0.001). On multivariable analysis, the Peak Index was significantly associated with CT emphysema (adjusted ß = 0.906; 95% confidence interval [CI], 0.789 to 1.023; P < 0.001) and small airways disease (adjusted ß = 1.367; 95% CI, 1.188 to 1.545; P < 0.001), St. George's Respiratory Questionnaire score (adjusted ß = 1.075; 95% CI, 0.807 to 1.342; P < 0.001), 6-minute-walk distance (adjusted ß = -1.993; 95% CI, -3.481 to -0.506; P < 0.001), and FEV1 change over time (adjusted ß = -1.604; 95% CI, -2.691 to -0.516; P = 0.004), after adjustment for age, sex, race, body mass index, current smoking status, pack-years of smoking, and FEV1. The Peak Index was also associated with the BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index and mortality (P < 0.001).Conclusions: The Peak Index is a spirometry metric that is associated with CT measures of lung disease, respiratory morbidity, lung function decline, and mortality.Clinical trial registered with www.clinicaltrials.gov (NCT00608764).