Raquel Casitas

Prognostic Value of the Objective Measurement of Daily Physical Activity in Patients With COPD

BACKGROUND Subjective measurement of physical activity using questionnaires has prognostic value in COPD. However, their lack of accuracy and large individual variability limit their use for evaluation on an individual basis. We evaluated the capacity of the objective measurement of daily physical activity in patients with COPD using accelerometers to estimate their prognostic value. METHODS In 173 consecutive subjects with moderate to very severe COPD, daily physical activity was measured using a triaxial accelerometer providing a mean of 1-min movement epochs as vector magnitude units (VMUs). Patients were evaluated by lung function testing and 6-min walk, incremental exercise, and constant work rate tests. Patients were followed for 5 to 8 years, and the end points were all-cause mortality, hospitalization for COPD exacerbation, and annual declining FEV(1). RESULTS After adjusting for relevant confounders, a high VMU decreased the mortality risk (adjusted hazard ratio [HR], 0.986; 95% CI, 0.981-0.992), and in a multivariate model, comorbidity, endurance time, and VMU were retained as independent predictors of mortality. The time until first admission due to COPD exacerbation was shorter for the patients with lower levels of VMU (adjusted HR, 0.989; 95% CI, 0.983-0.995). Moreover, patients with higher VMU had a lower hospitalization risk than those with a low VMU (adjusted incidence rate ratio, 0.099; 95% CI, 0.033-0.293). In contrast, VMU was not identified as an independent predictor of the annual FEV(1) decline. CONCLUSION The objective measurement of the daily physical activity in patients with COPD using an accelerometer constitutes an independent prognostic factor for mortality and hospitalization due to severe exacerbation.

Effect of Continuous Positive Airway Pressure on Glycemic Control in Patients with Obstructive Sleep Apnea and Type 2 Diabetes. A Randomized Clinical Trial

RATIONALE Obstructive sleep apnea (OSA) is a risk factor for type 2 diabetes that adversely impacts glycemic control. However, there is little evidence about the effect of continuous positive airway pressure (CPAP) on glycemic control in patients with diabetes. OBJECTIVES To assess the effect of CPAP on glycated hemoglobin (HbA1c) levels in patients with suboptimally controlled type 2 diabetes and OSA, and to identify its determinants. METHODS In a 6-month, open-label, parallel, and randomized clinical trial, 50 patients with OSA and type 2 diabetes and two HbA1c levels equal to or exceeding 6.5% were randomized to CPAP (n = 26) or no CPAP (control; n = 24), while their usual medication for diabetes remained unchanged. MEASUREMENTS AND MAIN RESULTS HbA1c levels, Homeostasis Model Assessment and Qualitative Insulin Sensitivity Check Index scores, systemic biomarkers, and health-related quality of life were measured at 3 and 6 months. After 6 months, the CPAP group achieved a greater decrease in HbA1c levels compared with the control group. Insulin resistance and sensitivity measurements (in noninsulin users) and serum levels of IL-1β, IL-6, and adiponectin also improved in the CPAP group compared with the control group after 6 months. In patients treated with CPAP, mean nocturnal oxygen saturation and baseline IL-1β were independently related to the 6-month change in HbA1c levels (r(2) = 0.510, P = 0.002). CONCLUSIONS Among patients with suboptimally controlled type 2 diabetes and OSA, CPAP treatment for 6 months resulted in improved glycemic control and insulin resistance compared with results for a control group. Clinical trial registered with www.clinicaltrials.gov (NCT01801150).

Dynamic Hyperinflation, Arterial Blood Oxygen, and Airway Oxidative Stress in Stable Patients With COPD

BACKGROUND There is considerable evidence that oxidative stress is increased in patients with COPD, although little information is available about its relationship with the structural and functional alterations produced by COPD. In this study, we evaluated the relationship between 8-isoprostane in exhaled breath condensate (EBC) of stable patients with COPD and the main parameters of the disease (such as dyspnea), stages of severity, lung parenchyma densities, lung function impairment, and exercise tolerance in order to identify the predictors of airway oxidative stress. METHODS In a cross-sectional study, we included 76 men with moderate to very severe COPD. 8-Isoprostane levels in EBC were measured by enzyme immunoassay. Regional lung densities were measured by lung densitometry with high-resolution CT scanning. Arterial blood gas levels, lung volumes, and diffusing capacity were determined. Patients performed a 6-min walk test and an incremental exercise test with measurement of breathing pattern and operating lung volumes. RESULTS Significant severity-related differences in 8-isoprostane were identified according to the BMI, obstruction, dyspnea, and exercise (BODE) index. 8-Isoprostane levels were related to smoking intensity, lung densities in expiration, static lung volumes, PaO(2), diffusion capacity, distance walked in 6 min, peak oxygen uptake, and anaerobic threshold. Concentration of 8-isoprostane was higher in the 60 patients (79%) who developed dynamic hyperinflation than in the remaining 16 (21%) who did not. In a multivariate linear regression analysis using 8-isoprostane as a dependent variable, end-expiratory lung volume change and PaO(2) were retained in the prediction model (r(2) = 0.734, P < .001). CONCLUSIONS In stable patients with COPD, oxygen level and dynamic hyperinflation are related to airway oxidative stress.

Prediction Equations for Single-Breath Diffusing Capacity in Subjects Aged 65 to 85 Years

BACKGROUND In senior subjects, diffusing capacity of the lung for carbon monoxide (Dlco) is interpreted using prediction equations derived from primarily younger adult populations. Our objectives were to provide reference equations for single-breath Dlco for a cohort of healthy, never-smoking, white, European adults between 65 and 85 years of age and to compare the predicted values of this sample with those from other studies involving middle-aged adults. METHODS Reference equations were derived from a randomly selected sample from the general population of 431 healthy never smoker subjects aged 65 to 85 years (262 women and 169 men). Spirometry, lung volume determinations by plethysmography, and single-breath Dlco (corrected for hemoglobin) were performed following the American Thoracic Society/European Respiratory Society guidelines. Reference values and lower and upper limits of normal were derived using a piecewise polynomial model. RESULTS In addition to age, our reference equations confirmed the height and body size dependence of Dlco and diffusing capacity for alveolar volume (Dlco/Va) in older subjects. Practically all of the reference values obtained by extrapolating reference equations of middle-aged adults underestimated the true diffusing capacity of the healthy elderly volunteers. Middle-aged reference equations underestimated Dlco by 2.1% to 22.3% in women and 2.8% to 37.8% in men. In addition, Dlco/Va was overestimated up to 18% and 39.8% in women and men, respectively, whereas other equations underestimated Dlco/Va up to 22.2% and 11.9% in women and men, respectively. CONCLUSIONS These results underscore the importance of using prediction equations appropriate to the origin and age characteristics of the subjects being studied.

Classification of Airflow Limitation Based on z-Score Underestimates Mortality in Patients with Chronic Obstructive Pulmonary Disease

&NA; Rationale: Global Lung Function Initiative recommends reporting lung function measures as z‐score, and a classification of airflow limitation (AL) based on this parameter has recently been proposed. Objectives: To evaluate the prognostic capacity of the AL classifications based on z‐score or percentage predicted of FEV1 in patients with chronic obstructive pulmonary disease (COPD). Methods: A cohort of 2,614 patients with COPD recruited outside the hospital setting was examined after a mean (± SD) of 57 ± 13 months of follow‐up, totaling 10,322 person‐years. All‐cause mortality was analyzed, evaluating the predictive capacity of several AL staging systems. Measurements and Main Results: Based on Global Initiative for Chronic Obstructive Lung Disease guidelines, 461 patients (17.6%) had mild, 1,452 (55.5%) moderate, 590 (22.6%) severe, and 111 (4.2%) very severe AL. According to z‐score classification, 66.3% of patients remained with the same severity, whereas 23.7% worsened and 10.0% improved. Unlike other staging systems, patients with severe AL according to z‐score had higher mortality than those with very severe AL (increase of risk by 5.2 and 3.9 times compared with mild AL, respectively). The predictive capacity for 5‐year survival was slightly higher for FEV1 expressed as percentage of predicted than as z‐score (area under the curve: 0.714‐0.760 vs. 0.649‐0.708, respectively). A severity‐dependent relationship between AL grades by z‐score and mortality was only detected in patients younger than age 60 years. Conclusions: In patients with COPD, the AL classification based on z‐score predicts worse mortality than those based on percentage of predicted. It is possible that the z‐score underestimates AL severity in patients older than 60 years of age with severe functional impairment.

Utility of Two-Compartment Models of Exhaled Nitric Oxide in Patients with Asthma

Two-compartment models provide more precise information about the contribution of the different portions of the airways to exhaled nitric oxide (NO). Airway wall concentration of NO (Caw,NO) and maximum flux of NO in the airways (J′aw,NO) reflect the tissue production rate of NO and they can be modified by corticosteroids. The airway wall diffusing capacity of NO (Daw,NO) depends on diverse physical and anatomical determinants of the airways, such as gas exchange surface area. Daw,NO can be modified by structural and physiological changes that are characteristic of airway remodeling, which take place over the long term. The alveolar concentration of NO (Calv,NO) represents the degree of small airway inflammation. The persistence of high Calv,NO in patients treated with inhaled corticosteroids could reflect the incapacity of these drugs to reach distal locations due to the heterogeneity of the acinar ventilation. In this review, we evaluate the parameters provided by the compartmentalized analysis of exhaled NO that could be useful in characterizing asthma patients.

Does airway hyperresponsiveness monitoring lead to improved asthma control

The current guidelines recommend an approach to asthma management based on asthma control, rather than asthma severity. Although several specific questionnaires have been developed and control criteria have been established based on clinical guidelines, the evaluation of asthma control is still not optimal. In general, these indicators provide adequate assessment of current control, but they are more limited when estimating future risk. There is much evidence demonstrating the persistence of airway inflammation and airway hyperresponsiveness (AHR) in patients with total control. Therefore, the objective of this review was to analyse the possible role of AHR monitoring as an instrument for assessing asthma control. We will evaluate its capacity as an indicator for future risk, both for estimating the possibility of clinical deterioration and loss of lung function or exacerbations. Furthermore, its relationship with inhaled corticosteroid treatment will be analysed, while emphasizing its capacity for predicting response and adjusting dosage, as well as information about the capability of AHR for monitoring treatment. Last of all, we will discuss the main limitations and emerging opportunities of AHR as an assessment instrument for asthma control.

Identification of non-coding genetic variants in samples from hypoxemic respiratory disease patients that affect the transcriptional response to hypoxia

A wide range of diseases course with an unbalance between the consumption of oxygen by tissues and its supply. This situation triggers a transcriptional response, mediated by the hypoxia inducible factors (HIFs), that aims to restore oxygen homeostasis. Little is known about the inter-individual variation in this response and its role in the progression of disease. Herein, we sought to identify common genetic variants mapping to hypoxia response elements (HREs) and characterize their effect on transcription. To this end, we constructed a list of genome-wide HIF-binding regions from publicly available experimental datasets and studied the genetic variability in these regions by targeted re-sequencing of genomic samples from 96 chronic obstructive pulmonary disease and 144 obstructive sleep apnea patients. This study identified 14 frequent variants disrupting potential HREs. The analysis of the genomic regions containing these variants by means of reporter assays revealed that variants rs1009329, rs6593210 and rs150921338 impaired the transcriptional response to hypoxia. Finally, using genome editing we confirmed the functional role of rs6593210 in the transcriptional regulation of EGFR. In summary, we found that inter-individual variability in non-coding regions affect the response to hypoxia and could potentially impact on the progression of pulmonary diseases.

Clinical, operational and economic outcomes of point-of-care blood gas analysis in COPD patients.

INTRODUCTION Arterial blood gas analysis is relevant in chronic obstructive pulmonary disease (COPD) management. The aim of this study was to evaluate whether the use of a blood gas analyzer in pulmonology departments improves the clinical, operational and economic outcomes when compared with clinical laboratory measurements. PATIENTS AND METHODS It is an observational prospective study. 112 patients were selected. After specimen collection, the measurement was performed both in pulmonology office as point-of-care and in laboratory. We evaluated clinical outcomes (modification of the indication of long-term oxygen therapy (LTOT) according to results, changes in blood gas analysis results, relationship of the partial pressure of oxygen (PaO2) obtained in the medical visit and velocity of change of the PaO2, influence of total haemoglobin concentration and the change in PaO2), operational outcomes (turnaround time (TAT) from specimen collection to receiving the blood gas analysis report) and economic outcomes (overall cost per process of patient care). RESULTS There were discrepancies in the indication of LTOT in 13.4% of patients. All parameters showed changes. PaO2 levels showed changes in 2 ways, though they frequently increase over time. The correlation was not good in the other two clinical outcomes. The median TATs in pulmonology office were 1 min versus 79 in laboratory, with 52 min for specimen preparation and transport and 17 min for TAT intralaboratory. The overall cost for the 112 patients in pulmonology office and laboratory was 16,769.89€ and 22,260.97€ respectively. CONCLUSIONS The use of a blood gas analyzer in a pulmonology office improves clinical, operational and economic outcomes when compared with clinical laboratory.

Hypoxia-induced PD-L1/PD-1 crosstalk impairs T-cell function in sleep apnoea.

Obstructive sleep apnoea (OSA) is associated with higher cancer incidence, tumour aggressiveness and cancer mortality, as well as greater severity of infections, which have been attributed to an immune deregulation. We studied the expression of programmed cell death (PD)-1 receptor and its ligand (PD-L1) on immune cells from patients with OSA, and its consequences on immune-suppressing activity. We report that PD-L1 was overexpressed on monocytes and PD-1 was overexpressed on CD8+ T-cells in a severity-dependent manner. PD-L1 and PD-1 overexpression were induced in both the human in vitro and murine models of intermittent hypoxia, as well as by hypoxia-inducible factor-1α transfection. PD-L1/PD-1 crosstalk suppressed T-cell proliferation and activation of autologous T-lymphocytes and impaired the cytotoxic activity of CD8+ T-cells. In addition, monocytes from patients with OSA exhibited high levels of retinoic acid related orphan receptor, which might explain the differentiation of myeloid-derived suppressor cells. Intermittent hypoxia upregulated the PD-L1/PD-1 crosstalk in patients with OSA, resulting in a reduction in CD8+ T-cell activation and cytotoxicity, providing biological plausibility to the increased incidence and aggressiveness of cancer and the higher risk of infections described in these patients. PD-L1/PD-1 crosstalk is upregulated in obstructive sleep apnoea patients and immunomodulates T-cell response http://ow.ly/gBEx30dZ7dd