Medium-Term Disability and Long-Term Functional Impairment Persistence in Survivors of Severe COVID-19 ARDS: Clinical and Physiological Insights.

BACKGROUND: Although the medium- and long-term sequelae of survivor of acute respiratory distress syndrome (ARDS) of any cause have been documented, little is known about the way in which COVID-19-induced ARDS affects functional disability and exercise components. Our aims were to examine the medium-term disability in severe COVID-19-associated ARDS survivors, delineate pathophysiological changes contributing to their exercise intolerance, and explore its utility in predicting long-term functional impairment persistence. METHODS: We studied 108 consecutive subjects with severe COVID-19 ARDS who remained alive 6 months after intensive care unit (ICU) discharge. Lung morphology was assessed with chest non-contrast CT scans and CT angiography. Functional evaluation included spirometry, plethysmography, muscle strength, and diffusion capacity, with assessment of gas exchange components through diffusing capacity of nitric oxide. Disability was assessed through an incremental exercise test, and measurements were repeated 12 and 24 months later in patients with functional impairments. RESULTS: At 6 months after ICU discharge, a notable dissociation between morphological and clinical-functional sequelae was identified. Moderate-severe disability was present in 47% of patients and these subjects had greater limitation of ventilatory mechanics and gas exchange, as well as greater symptomatic perception during exercise and a probable associated cardiac limitation. Female sex, hypothyroidism, reduced membrane diffusion component, lower functional residual capacity, and high-attenuation lung volume were independently associated with the presence of moderate-severe functional disability, which in turn was related to higher frequency and greater intensity of dyspnea and worse quality of life. Out of the 71 patients with reduced lung volumes or diffusion capacity at 6 months post-ICU discharge, only 19 maintained a restrictive disorder associated with gas exchange impairment at 24 months post-discharge. In these patients, 6-month values for diffusion membrane component, maximal oxygen uptake, ventilatory equivalent for CO2, and dead space to tidal volume ratio were identified as independent risk factors for persistence of long-term functional sequelae. CONCLUSIONS: Less than half of survivors of COVID-19 ARDS have moderate-severe disability in the medium term, identifying several risk factors. In turn, diffusion membrane component and exercise tolerance at 6-month ICU discharge are independently associated with the persistence of long-term functional sequelae.

Characteristics of obstructive sleep apnea related to insulin resistance.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with multiple comorbidities, including diabetes. Its development is preceded by alterations in the initial phase of carbohydrate metabolism characterized by insulin resistance. This study aims to evaluate the role of intermittent hypoxia and sleep fragmentation characteristic of OSA on the risk of insulin resistance among apneic patients without diabetes. METHODOLOGY: 92 consecutive patients with OSA without evidence of diabetes were recruited. Overnight video polysomnography was performed and, the following morning, fasting blood glucose, insulin and glycosylated hemoglobin were determined. Insulin resistance was measured using the HOMA-IR index. RESULTS: Insulin resistance was present in 52.2% of OSA patients. In these subjects, insulin resistance was independently associated to the apnea index during REM sleep (adjusted odds ratio [aOR] 1.09; 95% CI, 1.03 to 1.16; p = 0.004), desaturation index (aOR 1.08; 95% CI: 1.04 to 1.13; p = 0.027), and sleep time with oxygen saturation below 90% (aOR 1.04; 95% CI 1.00 to 1.08; p = 0.049). Furthermore, the HOMA-IR level was also directly related to the desaturation index (standardized regression coefficient [B] = 0.514, p < 0.001) and to the apnea index during REM sleep (B = 0.344, p = 0.002). CONCLUSIONS: Intermittent hypoxia and disturbances in REM sleep emerge as main contributors to insulin resistance in OSA patients yet to experience diabetes onset.

Dynamic hyperinflation is a risk factor for mortality and severe exacerbations in COPD patients.

OBJECTIVE: To assess if dynamic hyperinflation is an independent risk factor for mortality and severe exacerbations in COPD patients. METHODS: A cohort of 141 patients with stable COPD and moderate to very severe airflow limitation, treated according to conventional guidelines, was followed for a median of 9 years. Clinical characteristics were recorded and arterial blood gases, pulmonary function tests, 6-min walk and incremental exercise test with measurement of respiratory pattern and operative lung volumes were performed. Endpoints were all-cause mortality and hospitalization for COPD exacerbation. RESULTS: 58 patients died during the follow-up period (1228 patients x year). The mortality rate was higher in patients with dynamic hyperinflation (n = 106) than in those without it (n = 35) (14.6; 95% CI, 14.5-14.8 vs. 7.2; 95% CI, 7.1-7.4 per 1000 patients-year). After adjusting for sex, age, body mass index, pack-years and treatment with inhaled corticosteroids, dynamic hyperinflation was associated with a higher mortality risk (adjusted hazard ratio [aHR], 2.725; 95% CI, 1.010-8.161), and in a multivariate model, comorbidity, peak oxygen uptake and dynamic hyperinflation were retained as independent predictors of mortality. The time until first severe exacerbation was shorter for patients with dynamic hyperinflation (aHR, 3.961; 95% CI, 1.385-11.328), and dynamic hyperinflation, FEV1 and diffusing capacity were retained as independent risk factors for severe exacerbation. Moreover, patients with dynamic hyperinflation had a higher hospitalization risk than those without it (adjusted incidence rate ratio, 1.574; 95% CI, 1.087-2.581). CONCLUSION: In stable COPD patients, dynamic hyperinflation is an independent prognostic factor for mortality and severe exacerbations.

Continuous Positive Airway Pressure Effect on Progression of Retinal Disease in Patients with Sleep Apnea and Nonproliferative Diabetic Retinopathy: A Randomized Clinical Trial.

Rationale: Obstructive sleep apnea (OSA) is associated with impaired glycemic control and a higher risk of vascular complications, such as diabetic retinopathy. However, the effect of apnea-hypopnea suppression on retinal disease progression is unclear. Objectives: To evaluate the efficacy and safety of continuous positive airway pressure (CPAP) for the reduction of retinal lesions in patients with non-proliferative diabetic retinopathy (NPDR) and OSA. Methods: This open-label, parallel-group, randomized controlled trial was conducted between October 2016 and February 2020 at a university hospital in Spain. The date of final follow-up was March 2, 2021. Eighty-three patients with OSA and mild to moderate NPDR receiving stable treatment were randomized to receive CPAP and usual care (43 patients with 79 available eyes) or usual care alone (40 patients with 67 available eyes) for 52 weeks. The primary outcomes were the change in the percentage of eyes with retinal exudates and the number of retinal microhemorrhages from baseline to week 52. We also assessed the effects of both interventions on retinal thickness by means of optical coherence tomography, serum concentrations of glycated hemoglobin, blood pressure, lipid concentrations, sleepiness, and quality of life. Results: Fifty-two weeks of CPAP treatment was associated with reductions from baseline in the percentage of eyes with hard exudates (overall difference, -21.7%; P = 0.035) and in optical coherence tomography indices of retinal edema, including central subfield thickness and cube volume. However, in patients who met prespecified criteria for CPAP adherence, treatment was also associated with a higher number of retinal microhemorrhages at 52 weeks (intergroup adjusted difference, 6.0 [95% confidence interval, 0.6-11.5]; P = 0.029), which was directly related to prescribed pressure levels. CPAP treatment also improved glycemic control, sleepiness, and general health-related quality of life. Conclusions: In patients with OSA and NPDR, long-term CPAP treatment in addition to usual care may result in slower progression of retinal disease, although it could also induce an increase in retinal microhemorrhages. Clinical trial registered with www.clinicaltrials.gov (NCT02874313).

Continuous Positive Airway Pressure Effect on Albuminuria Progression in Patients with Obstructive Sleep Apnea and Diabetic Kidney Disease: A Randomized Clinical Trial.

Rationale: Obstructive sleep apnea (OSA) is associated with impaired glycemic control and a higher risk of vascular complications, such as diabetic kidney disease (DKD). However, the effect of apnea-hypopnea suppression on DKD progression is unclear. Objectives: To assess the effect of continuous positive airway pressure (CPAP) on the urinary albumin-to-creatinine ratio (UACR) in patients with DKD and OSA. Methods: In a 52-week, multicentric, open-label, parallel, and randomized clinical trial, 185 patients with OSA and DKD were randomized to CPAP and usual care (n = 93) or usual care alone (n = 92). Measurements and Main Results: UACR, estimated glomerular filtration rate, serum concentrations of creatinine and glycated hemoglobin, insulin resistance, lipid concentrations, sleepiness, and quality of life. A 52-week change in UACR from baseline did not differ significantly between the CPAP group and the usual-care group. However, in per-protocol analyses that included 125 participants who met prespecified criteria for adherence, CPAP treatment was associated with a great reduction in UACR (mean difference, -10.56% [95% confidence interval, -19.06 to -2.06]; P = 0.015). CPAP effect on UACR was higher in nonsleepy patients with more severe OSA, worse renal function, and a more recent diagnosis of DKD. CPAP treatment also improved glycemic control and insulin resistance, as well as sleepiness and health-related quality of life. Conclusions: In patients with OSA and DKD, the prescription of CPAP did not result in a statistically significant reduction in albuminuria. However, good adherence to CPAP treatment in addition to usual care may result in long-term albuminuria reduction compared with usual care alone. Clinical trial registered with www.clinicaltrials.gov (NCT02816762).

Effect of Dynamic Hyperinflation on Cardiac Response to Exercise of Patients With Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Although the major limitation to exercise performance in patients with COPD is dynamic hyperinflation (DH), little is known about its relation with cardiac response to exercise. Our objectives were to compare the exercise response of stroke volume (SV) and cardiac output (CO) between COPD patients with or without DH and control subjects, and to assess the main determinants. METHODS: Fifty-seven stable COPD patients without cardiac comorbidity and 25 healthy subjects were recruited. Clinical evaluation, baseline function tests, computed tomography and echocardiography were conducted in all subjects. Patients performed consecutive incremental exercise tests with measurement of operating lung volumes and non-invasive measurement of SV, CO and oxygen uptake (VO2) by an inert gas rebreathing method. Biomarkers of systemic inflammation and oxidative stress, tissue damage/repair, cardiac involvement and airway inflammation were measured. RESULTS: COPD patients showed a lower SV/VO2 slope than control subjects, while CO response was compensated by a higher heart rate increase. COPD patients with DH experienced a reduction of SV/VO2 and CO/VO2 compared to those without DH. In COPD patients, the end-expiratory lung volume (EELV) increase was related to SV/VO2 and CO/VO2 slopes, and it was the only independent predictor of cardiac response to exercise. However, in the regression models without EELV, plasma IL-1ß and high-sensitivity cardiac troponin T were also retained as independent predictors of SV/VO2 slope. CONCLUSION: Dynamic hyperinflation decreases the cardiac response to exercise of COPD patients. This effect is related to systemic inflammation and myocardial stress but not with left ventricle diastolic dysfunction.

Contribution of sleep characteristics to the association between obstructive sleep apnea and dyslipidemia.

OBJECTIVES/BACKGROUND: Little information is available about the association of obstructive sleep apnea (OSA) with atherogenic dyslipidemia and the contribution of sleep characteristics to lipid alterations. We compare dyslipidemia prevalence among non-apneic subjects and mild-severe OSA patients to identify the sleep characteristics that are independently associated with dyslipidemia and serum lipid levels in OSA patients. PATIENTS/METHODS: We recruited 809 consecutive patients who had been referred for polysomnography study by OSA suspicion. Anthropometric characteristics, body composition and comorbidities were recorded. Spirometry and 24-h ambulatory blood pressure monitoring were performed the same day of the sleep study. The day after attended polysomnography, fasting blood samples were drawn to measure the lipid profile. RESULTS: Dyslipidemia prevalence increased with the presence of OSA, from non-OSA subjects to mild, moderate and severe OSA patients (31%, 33%, 42% and 51%, respectively; p < 0.001). After adjusting for sex, age, body mass index and smoking habit, only severe OSA had an independent association with dyslipidemia when compared to non-OSA subjects (adjusted odds ratio 1.71, 95%CI 1.09 to 2.69, p = 0.019). In OSA patients, multivariate logistic regression identified active smoking, apnea-hypopnea index (AHI) and mean nocturnal saturation as variables independently associated with dyslipidemia. However, in these patients, arousal index, slow wave sleep duration and REM latency were also independently associated with cholesterol and low-density lipoprotein levels. CONCLUSIONS: The association between dyslipidemia and OSA is limited to severe patients, with high AHI and nocturnal hypoxemia. However, sleep fragmentation and increased sympathetic activity could also contribute to OSA-related lipid dysregulation.

Effect of Dynamic Hyperinflation on Cardiac Response to Exercise of Patients With Chronic Obstructive Pulmonary Disease / Efecto de la hiperinsuflación dinámica en la respuesta cardíaca al ejercicio de pacientes con enfermedad pulmonar obstructiva crónica

Introduction: Although the major limitation to exercise performance in patients with COPD is dynamic hyperinflation (DH), little is known about its relation with cardiac response to exercise. Our objectives were to compare the exercise response of stroke volume (SV) and cardiac output (CO) between COPD patients with or without DH and control subjects, and to assess the main determinants.Methods: Fifty-seven stable COPD patients without cardiac comorbidity and 25 healthy subjects were recruited. Clinical evaluation, baseline function tests, computed tomography and echocardiography were conducted in all subjects. Patients performed consecutive incremental exercise tests with measurement of operating lung volumes and non-invasive measurement of SV, CO and oxygen uptake (VO2) by an inert gas rebreathing method. Biomarkers of systemic inflammation and oxidative stress, tissue damage/repair, cardiac involvement and airway inflammation were measured.Results: COPD patients showed a lower SV/VO2 slope than control subjects, while CO response was compensated by a higher heart rate increase. COPD patients with DH experienced a reduction of SV/VO2 and CO/VO2 compared to those without DH. In COPD patients, the end-expiratory lung volume (EELV) increase was related to SV/VO2 and CO/VO2 slopes, and it was the only independent predictor of cardiac response to exercise. However, in the regression models without EELV, plasma IL-1β and high-sensitivity cardiac troponin T were also retained as independent predictors of SV/VO2 slope.(AU)

Introducción: Aunque la principal limitación para el rendimiento durante el ejercicio en pacientes con EPOC es la hiperinsuflación dinámica (HD), se sabe poco sobre su relación con la respuesta cardíaca al ejercicio. Nuestros objetivos fueron comparar la respuesta al ejercicio del volumen sistólico (VS) y el gasto cardíaco (GC) entre los pacientes con EPOC con o sin HD y sujetos control, y evaluar los principales determinantes.Métodos: Se reclutaron 57 pacientes con EPOC estable sin comorbilidad cardíaca y 25 sujetos sanos. En todos los sujetos se realizó una evaluación clínica, pruebas de función basal, una tomografía computarizada y una ecocardiografía. Los pacientes realizaron pruebas de esfuerzo incrementales consecutivas con medición de los volúmenes pulmonares operativos y medición no invasiva del VS, el GC y el consumo de oxígeno (VO2) mediante un método de reinhalación de gas inerte. Se midieron los biomarcadores de inflamación sistémica y estrés oxidativo, daño/reparación tisular, afectación cardíaca e inflamación de las vías respiratorias.Resultados:Los pacientes con EPOC presentaron una curva más baja de VS/VO2 que los controles, mientras que la respuesta del GC se compensó con un mayor aumento del ritmo cardíaco. Los pacientes con EPOC e HD experimentaron una reducción de VS/VO2 y de GC/VO2 en comparación con aquellos sin HD. En los pacientes con EPOC, el aumento del volumen pulmonar teleespiratorio (EELV, por sus siglas en inglés) se relacionó con las curvas de VS/VO2 y GC/VO2, y fue el único factor predictivo independiente de la respuesta cardíaca al ejercicio. Sin embargo, en los modelos de regresión sin EELV, la IL-1β plasmática y la troponina T cardíaca ultrasensible también se mantuvieron como factores predictivos independientes de la curva de VS/VO2. (AU)

[Palliative Sedation at the End of Life: A Comparative Study of Chronic Obstructive Pulmonary Disease and Lung Cancer Patients].

BACKGROUND: Although patients with chronic obstructive pulmonary disease (COPD) receive poor-quality palliative care, information about the use of palliative sedation (PS) in the last days of life is very scarce. OBJECTIVES: To compare the use of PS in hospitalized patients who died from COPD or lung cancer and identify factors correlating with PS application. METHODS: In a retrospective observational cohort study, from 1,675 patients died at a teaching hospital between 2013 and 2015, 109 patients who died from COPD and 85 from lung cancer were compared. Sociodemographic data, clinical characteristics, health care resource utilization, application of PS and prescribed drugs were recorded. RESULTS: In the last 6 months of life, patients who died from COPD had more hospital admissions due to respiratory causes and less frequent support by a palliative home care team (PHCT). Meanwhile, during their last hospitalization, patients who died from COPD had fewer do-not-resuscitate orders and were subjected to more intensive care unit admissions and cardiopulmonary resuscitation maneuvers. PS was applied less frequently in patients who died from COPD than in those who died from lung cancer (31 vs. 53%, p = 0.002). Overall, previous use of opioid drugs, support by a PHCT, and a diagnosis of COPD (adjusted odds ratio 0.48, 95% CI: 0.26-0.89, p = 0.020) were retained as factors independently related to PS. In COPD patients, only previous use of opioid drugs was identified as a PS-related factor. CONCLUSION: During their last days of life, hospitalized COPD patients receive PS less frequently than patients with lung cancer.

Hypermethylation of Anti-oncogenic MicroRNA 7 is Increased in Emphysema Patients / La hipermetilación del microrna antioncogénico 7 se encuentra aumentada en pacientes con enfisema

INTRODUCTION: MicroRNA-7 (miR-7) has a suppressive role in lung cancer and alterations in its DNA methylation may contribute to tumorigenesis. As COPD patients with emphysema have a higher risk of lung cancer than other COPD phenotypes, we compared the miR-7 methylation status among smoker subjects and patients with various COPD phenotypes to identify its main determinants. METHODS: 30 smoker subjects without airflow limitation and 136 COPD patients without evidence of cancer were recruited in a prospective study. Clinical and functional characteristics were assessed and patients were classified into: frequent exacerbator, emphysema, chronic bronchitis and asthma COPD overlap (ACO). DNA collected from buccal epithelial samples was isolated and bisulfite modified. miR-7 methylation status was evaluated by quantitative methylation-specific polymerase chain reaction (qMSP). RESULTS: miR-7 Methylated levels were higher in COPD patients than in smokers without airflow limitation (23.7 ± 12.4 vs. 18.5 ± 8.8 %, p = 0.018). Among COPD patients, those with emphysema had higher values of methylated miR-7 (27.1 ± 10.2 %) than those with exacerbator (19.4 ± 9.9 %, p = 0.004), chronic bronchitis (17.3 ± 9.0 %, p = 0.002) or ACO phenotypes (16.0 ± 7.2 %, p = 0.010). After adjusting for clinical parameters, differences between emphysematous patients and those with other phenotypes were retained. In COPD patients, advanced age, mild-moderate airflow limitation, reduced diffusing capacity and increased functional residual capacity were identified as independent predictors of methylated miR-7 levels. CONCLUSION: The increase of miR-7 methylation levels experienced by COPD patients occurs mainly at the expense of the emphysema phenotype, which might contribute to explain the higher incidence of lung cancer in these patients

INTRODUCCIÓN: El microRNA-7 (miR-7) tiene un papel supresor en el cáncer de pulmón, y las alteraciones en la metilación de su DNA podrían contribuir a la tumorogénesis. Como los pacientes con EPOC y enfisema presentan un mayor riesgo de sufrir cáncer de pulmón frente a otros fenotipos de EPOC, comparamos la metilación de miR-7 entre los pacientes fumadores y los pacientes con varios fenotipos de EPOC para identificar sus factores determinantes principales. MÉTODOS: Se reclutaron para un estudio prospectivo 30 sujetos fumadores sin restricciones en el flujo aéreo y 136 pacientes con EPOC sin evidencia de cáncer. Se valoraron las características clínicas y funcionales y se clasificaron a los pacientes en: exacerbaciones frecuentes, enfisema, bronquitis crónica y solapamiento de asma y EPOC (ACO, por sus siglas en inglés). Se recogió ADN a partir de muestras de epitelio bucal, se aisló y se modificó con bisulfito. El estado de metilación del miR-7 se evaluó mediante la reacción cuantitativa en cadena de la polimerasa específica de la metilación (qMPS por sus siglas en inglés). RESULTADOS: Los niveles de metilación del miR-7 fueron más altos en los pacientes con EPOC que en los fumadores sin restricciones en el flujo aéreo (23,7 ± 12,4 frente a 18,5 ± 8,8%, p = 0,018). Entre los pacientes con EPOC, aquellos con enfisema presentaban valores más altos de miR-7 metilado (27,1 ± 10,2%) que aquellos con exacerbaciones (19,4 ± 9,9%, p = 0,004), bronquitis crónica (17,3 ± 9,0%, p = 0,002) o los fenotipos ACO (16,0 ± 7,2%, p = 0,010). Tras ajustar los resultados a los parámetros clínicos, las diferencias entre los pacientes enfisematosos y aquellos con otros fenotipos permanecieron. En los pacientes con EPOC, se identificaron como predictores independientes de los niveles de metilación del miR-7 a: la edad avanzada, limitación al flujo aéreo leve-moderada, capacidad de difusión reducida y capacidad residual funcional aumentada. CONCLUSIÓN: El aumento de los niveles de metilación del miR-7 que experimentan los pacientes con EPOC ocurre principalmente a expensas del fenotipo con enfisema, lo que podría contribuir a explicar la mayor incidencia de cáncer de pulmón en estos pacientes

La disfunción de las pequeñas vías aéreas deteriora la calidad de vida de fumadores sin limitación al flujo aéreo / Small Airway Dysfunction Impairs Quality of Life Among Smokers With No Airflow Limitation

Introducción: La disfunción de las pequeñas vías aéreas (DPV) inducida por el tabaco contribuye precozmente a la patogenia de la limitación al flujo aéreo (LFA), aunque resulta poco conocida su repercusión en la percepción de salud. Se pretende evaluar la frecuencia de DPV en fumadores activos sin LFA y comparar la calidad de vida relacionada con la salud (CVRS) de no fumadores, fumadores sin DPV, fumadores con DPV y fumadores con LFA. Métodos: En 53 fumadores activos sin LFA, 20 fumadores con LFA y 20 no fumadores, se utilizaron los cuestionarios SF-36 y EuroQoL y se realizó oscilometría de impulsos, espirometría y determinación de las densidades de atenuación del parénquima pulmonar en inspiración y espiración máximas. Se consideró que existía DPV cuando la resistencia a 5 Hz (R5), la diferencia R5-R20 y el área de reactancia (AX) excedían su límite superior de la normalidad. Resultados: El 35,8% de los fumadores sin LFA tenía DPV. No se detectaron diferencias en los parámetros espirométricos ni la atenuación pulmonar entre los fumadores con o sin DPV y los no fumadores. Sin embargo, los fumadores con DPV presentaban una peor puntuación en los cuestionarios de CVRS que los fumadores sin DPV o los no fumadores, e intermedia a los fumadores con LFA. R5 y X5 fueron identificados como determinantes independientes de la CVRS en los fumadores sin LFA. Conclusiones: La DPV es frecuente en fumadores sin LFA, afectando a un tercio de los mismos, y condicionando de forma independiente su percepción de salud

Introduction: Small airway dysfunction (SAD) caused by smoking contributes to the early onset of airflow limitation (AFL), although its impact on patients’ perception of health is largely unknown. We aimed to evaluate the frequency of SAD in active smokers without AFL, and to compare health-related quality of life (HRQoL) of non-smokers, smokers without SAD, smokers with SAD, and smokers with AFL. Methods: A total of 53 active smokers without AFL, 20 smokers with AFL, and 20 non-smokers completed the SF-36 and EuroQoL questionnaires and performed impulse oscillometry and spirometry. Pulmonary parenchymal attenuation was determined in inspiration and expiration. SAD was determined to exist when resistance at 5Hz (R5), the difference between R5 and R20, and reactance area (AX) exceeded the upper limit of normal. Results: In total, 35.8% of smokers without AFL had SAD. No differences were detected in spirometric parameters or pulmonary attenuation between smokers with or without AFL and non-smokers. However, smokers with SAD had worse scores on HRQoL questionnaires than smokers without SAD or non-smokers, and scores compared to smokers with AFL were intermediate. R5 and X5 were identified as independent determinants of HRQoL in smokers without AFL. Conclusions: SAD is common in smokers without AFL, affecting one third of this population, and independently affecting their perception of health

Small Airway Dysfunction Impairs Quality of Life Among Smokers With No Airflow Limitation. / La disfunción de las pequeñas vías aéreas deteriora la calidad de vida de fumadores sin limitación al flujo aéreo.

INTRODUCTION: Small airway dysfunction (SAD) caused by smoking contributes to the early onset of airflow limitation (AFL), although its impact on patients' perception of health is largely unknown. We aimed to evaluate the frequency of SAD in active smokers without AFL, and to compare health-related quality of life (HRQoL) of non-smokers, smokers without SAD, smokers with SAD, and smokers with AFL. METHODS: A total of 53 active smokers without AFL, 20 smokers with AFL, and 20 non-smokers completed the SF-36 and EuroQoL questionnaires and performed impulse oscillometry and spirometry. Pulmonary parenchymal attenuation was determined in inspiration and expiration. SAD was determined to exist when resistance at 5Hz (R5), the difference between R5 and R20, and reactance area (AX) exceeded the upper limit of normal. RESULTS: In total, 35.8% of smokers without AFL had SAD. No differences were detected in spirometric parameters or pulmonary attenuation between smokers with or without AFL and non-smokers. However, smokers with SAD had worse scores on HRQoL questionnaires than smokers without SAD or non-smokers, and scores compared to smokers with AFL were intermediate. R5 and X5 were identified as independent determinants of HRQoL in smokers without AFL. CONCLUSIONS: SAD is common in smokers without AFL, affecting one third of this population, and independently affecting their perception of health.

Hypermethylation of Anti-oncogenic MicroRNA 7 is Increased in Emphysema Patients.

INTRODUCTION: MicroRNA-7 (miR-7) has a suppressive role in lung cancer and alterations in its DNA methylation may contribute to tumorigenesis. As COPD patients with emphysema have a higher risk of lung cancer than other COPD phenotypes, we compared the miR-7 methylation status among smoker subjects and patients with various COPD phenotypes to identify its main determinants. METHODS: 30 smoker subjects without airflow limitation and 136 COPD patients without evidence of cancer were recruited in a prospective study. Clinical and functional characteristics were assessed and patients were classified into: frequent exacerbator, emphysema, chronic bronchitis and asthma COPD overlap (ACO). DNA collected from buccal epithelial samples was isolated and bisulfite modified. miR-7 methylation status was evaluated by quantitative methylation-specific polymerase chain reaction (qMSP). RESULTS: miR-7 Methylated levels were higher in COPD patients than in smokers without airflow limitation (23.7±12.4 vs. 18.5±8.8%, p=0.018). Among COPD patients, those with emphysema had higher values of methylated miR-7 (27.1±10.2%) than those with exacerbator (19.4±9.9%, p=0.004), chronic bronchitis (17.3±9.0%, p=0.002) or ACO phenotypes (16.0±7.2%, p=0.010). After adjusting for clinical parameters, differences between emphysematous patients and those with other phenotypes were retained. In COPD patients, advanced age, mild-moderate airflow limitation, reduced diffusing capacity and increased functional residual capacity were identified as independent predictors of methylated miR-7 levels. CONCLUSION: The increase of miR-7 methylation levels experienced by COPD patients occurs mainly at the expense of the emphysema phenotype, which might contribute to explain the higher incidence of lung cancer in these patients.

Static lung hyperinflation is an independent risk factor for lung cancer in patients with chronic obstructive pulmonary disease.

INTRODUCTION: Static hyperinflation, a hallmark characteristic of some patients with chronic obstructive pulmonary disease, is related to higher mortality and cardiovascular morbidity. However, information about its association with lung cancer is scarce. Our aim was to evaluate whether static hyperinflation is associated with future risk of lung cancer in COPD patients. METHODS: A cohort of 848 COPD patients recruited outside the hospital setting was monitored for an average period of 4.3 years, totaling 2858 person-years, regarding diagnosis of cancer of any origin or lung cancer. Static hyperinflation was defined by functional residual capacity measured by plethysmography greater than 120% of the predicted value. RESULTS: The incidence rates for cancer of any origin and lung cancer were 16.0 (95%CI, 15.1-17.8) and 8.7 (95%CI, 7.7-9.8) per 1000 patient-years, respectively. Among the patients with lung cancer, non-small cell lung cancer predominated (88%). In a stepwise multivariate Cox regression model, body mass index (BMI), pack-years, Charlson index, and postbronchodilator FEV1/FVC ratio were retained as independent predictors of cancer of any origin. In contrast, features associated with a future risk of lung cancer included older age, low BMI, increased pack-years and presence of static hyperinflation (adjusted hazard ratio: 4.617, 95%CI: 1.007-21.172, p = 0.049). CONCLUSION: In a general COPD outpatient population, static hyperinflation is an independent risk factor for the development of lung cancer, which might contribute towards justifying the excess mortality identified in COPD patients with hyperinflation.

Prediction of postoperative lung function after major lung resection for lung cancer using volumetric computed tomography.

OBJECTIVES: The study objectives were to assess the accuracy of volumetric computed tomography to predict postoperative lung function in patients with lung cancer in relation to anatomic segments counting and perfusion scintigraphy, to generate specific predictive equations for each functional parameter, and to evaluate accuracy and precision of these in a validation cohort. METHODS: We assessed pulmonary functions preoperatively and 3 to 4 months postoperatively after lung resection for lung cancer (n = 114). Absolute and relative lung volumes (total and upper/middle/lower) were determined using volumetric software analysis for staging thoracic computed tomography scans. Predicted postoperative function was calculated by segments counting, scintigraphy, and volumetric computed tomography. RESULTS: Volumetric computed tomography achieves a higher correlation and precision with measured postoperative lung function than segments counting or scintigraphy (correlation and intraclass correlation coefficients, 0.779-0.969 and 0.776-0.969; 0.573-0.887 and 0.552-0.882; and 0.578-0.834 and 0.532-0.815, respectively), as well as greater accuracy, determined by narrower agreement coefficients for forced vital capacity, forced expiratory volume in 1 second, lung diffusing capacity, and peak oxygen uptake. After validation in an independent cohort (n = 43), adjusted linear regression including volumetric estimation of decreased postoperative ventilation for postoperative lung function parameters explains 98% to 99% of variance. CONCLUSIONS: Volumetric computed tomography is a reliable and accurate method to predict postoperative lung function in patients undergoing lung resection that provides better accuracy than conventional procedures. Because lung computed tomography is systematically performed in the staging of patients with suspected lung cancer, this volumetric analysis might simultaneously provide the information necessary to evaluate operability.

The effect of treatment for sleep apnoea on determinants of blood pressure control.

Our aim was to assess the effect of continuous positive airway pressure (CPAP) on the nocturnal evolution of peripheral chemosensitivity, renin-angiotensin-aldosterone system activity, sympathetic tone and endothelial biomarkers in obstructive sleep apnoea (OSA) patients with isolated nocturnal hypertension (INH) or day-night sustained hypertension (D-NSH).In a crossover randomised trial, 32 OSA patients newly diagnosed with hypertension and without antihypertensive treatment were randomly assigned to 12 weeks of CPAP or sham CPAP. Peripheral chemosensitivity was evaluated before and after sleep using the hypoxic withdrawal test (%ΔVI).At baseline, D-NSH patients showed higher %ΔVI before sleep and higher levels of aldosterone and diurnal catecholamines. CPAP only reduced the nocturnal increase of %ΔVI in INH patients (6.9%, 95% CI 1.0-12.8%; p=0.026). CPAP-induced change from baseline in %ΔVI after sleep was 7.5% (95% CI 2.6-12.2%, p=0.005) in the INH group and 5.7% (95% CI 2.2-9.3%, p=0.004) in the D-NSH group. In contrast, %ΔVI before sleep only decreased with CPAP in the D-NSH patients (3.0%, 95% CI 0.5-5.6%; p=0.023).In conclusion, CPAP reduces the nocturnal increase of peripheral chemosensitivity experienced by INH patients and corrects the high daytime sensitivity of patients with D-NSH. Differences in response to CPAP between these patients can help better understand the mechanisms of perpetuation of hypertension in sleep apnoea.

Small airway dysfunction in smokers with stable ischemic heart disease.

BACKGROUND: A higher prevalence of airflow limitation (AL) has been described in patients with ischemic heart disease (IHD). Although small airway dysfunction (SAD) is an early feature of AL, there is little information about its occurrence in IHD patients. Our objective was to describe the prevalence of SAD in IHD patients, while comparing patient-related outcomes and future health risk among IHD patients with AL, SAD and normal lung function. METHODS: In 118 consecutive smoking patients with stable IHD, comorbidities, utilization of healthcare resources, current treatment, blood biochemistry and health status were recorded. SAD was evaluated by impulse oscillometry, and pre- and post-bronchodilator spirometry was performed. RESULTS: The prevalence of AL and SAD were 20.3 (95% CI, 13.1-27.6%) and 26.3% (95% CI, 18.3-34.2%), respectively. Compared to the normal lung function group, patients with SAD and without AL had lower spirometric values, poorer quality of life and higher levels of C-reactive protein (CRP), as well as increased cardiovascular risk and more vascular age. In patients with normal spirometry, the presence of SAD was independently associated with pack-years, HDL-cholesterol and CRP levels. CONCLUSION: In patients with IHD, the presence of SAD is common and that it is associated with reduced health status and increased future cardiac risk.