Paschalis Steiropoulos

Global Impairment of CD4+CD25+FOXP3+ Regulatory T Cells in Idiopathic Pulmonary Fibrosis

RATIONALE The implication of T cells in the pathogenesis of idiopathic pulmonary fibrosis (IPF) is controversial. CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) are pivotal in maintaining immune homeostasis, but their role in IPF pathophysiology has not yet been studied. OBJECTIVES To explore Treg dynamics and function in IPF. METHODS Treg levels and dynamics were analyzed by flow cytometry in the peripheral blood (PB) and bronchoalveolar lavage (BAL) of 21 patients with IPF, 35 patients with lung diseases other than IPF (patients without IPF), 20 patients with collagen vascular diseases with pulmonary parenchymal involvement (CVD-IP), and 28 healthy volunteers. The suppression of autologous CD4(+)CD25(-) cell-proliferative responses and cytokine release by magnetic bead-isolated Tregs was evaluated by proliferation assays and cytometric bead array. Correlations of Treg function and levels with lung function parameters were also performed. MEASUREMENTS AND MAIN RESULTS In patients with IPF, both BAL and PB Tregs were reduced compared with those of healthy volunteers and patients without IPF, although not always significantly. Treg levels were not affected by the administration of low-dose prednisone in four nonresponding patients. The suppressor potential of BAL and PB Tregs was compromised in patients with IPF and patients with CVD-IP, compared with healthy volunteers and patients without IPF. Similarly, the Treg-induced suppression of helper T-cell type 1 and 2 cytokine secretion was impaired in the BAL of patients with IPF and patients with CVD-IP. Moreover, the defective function of BAL Tregs correlated highly with parameters of disease severity. CONCLUSIONS This study provides the first evidence of global Treg impairment in IPF that strongly correlates with disease severity, suggesting a role for Tregs in the fibrotic process.

Diabetes Mellitus Prevalence and Control in Sleep-Disordered Breathing: The European Sleep Apnea Cohort (ESADA) Study

BACKGROUND OSA is associated with an increased risk of cardiovascular morbidity. A driver of this is metabolic dysfunction and in particular type 2 diabetes mellitus (T2DM). Prior studies identifying a link between OSA and T2DM have excluded subjects with undiagnosed T2DM, and there is a lack of population-level data on the interaction between OSA and glycemic control among patients with diabetes. We assessed the relationship between OSA severity and T2DM prevalence and control in a large multinational population. METHODS We performed a cross-sectional analysis of 6,616 participants in the European Sleep Apnea Cohort (ESADA) study, using multivariate regression analysis to assess T2DM prevalence according to OSA severity, as measured by the oxyhemoglobin desaturation index. Patients with diabetes were identified by previous history and medication prescription, and by screening for undiagnosed diabetes with glycosylated hemoglobin (HbA1c) measurement. The relationship of OSA severity with glycemic control was assessed in diabetic subjects. RESULTS T2DM prevalence increased with OSA severity, from 6.6% in subjects without OSA to 28.9% in those with severe OSA. Despite adjustment for obesity and other confounding factors, in comparison with subjects free of OSA, patients with mild, moderate, or severe disease had an OR (95% CI) of 1.33 (1.04-1.72), 1.73 (1.33-2.25), and 1.87 (1.45-2.42) (P < .001), respectively, for prevalent T2DM. Diabetic subjects with more severe OSA had worse glycemic control, with adjusted mean HbA1c levels 0.72% higher in patients with severe OSA than in those without sleep-disordered breathing (analysis of covariance, P < .001). CONCLUSIONS Increasing OSA severity is associated with increased likelihood of concomitant T2DM and worse diabetic control in patients with T2DM.

Markers of glycemic control and insulin resistance in non-diabetic patients with Obstructive Sleep Apnea Hypopnea Syndrome: Does adherence to CPAP treatment improve glycemic control?

BACKGROUND AND AIM Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) is associated with glucose dysmetabolism and insulin resistance, therefore the amelioration of breathing disturbances during sleep can allegedly modify the levels of markers of glucose regulation and insulin resistance, such as glycated hemoglobin, fasting glucose, insulin and HOMA(IR). The aim of this study was to explore the association between these parameters and sleep characteristics in non-diabetic OSAHS patients, as well as the effect of 6 months CPAP therapy on these markers, according to adherence to CPAP treatment. METHODS Euglycemic patients (n=56; mean age+/-SD: 46.07+/-10.67 years) with newly diagnosed OSAHS were included. Glycated hemoglobin, fasting glucose, insulin levels and HOMA(IR) were estimated at baseline and 6 months after CPAP application. According to CPAP adherence, patients were classified as follows: group 1 (mean CPAP use 4 h/night), group 2 (mean CPAP use < 4 h/night) and group 3 (refused CPAP treatment), and comparisons of levels of the examined parameters were performed. RESULTS At baseline, average SpO(2) during sleep was negatively correlated with insulin levels and HOMA(IR) while minimum SpO(2) during sleep was also negatively correlated with insulin levels. After 6 months, only group 1 patients demonstrated a significant decrease in glycated hemoglobin (p=0.004) accompanied by a decrease in hs-CRP levels (p=0.002). No other statistically significant change was observed. CONCLUSIONS Nighttime hypoxia can affect fasting insulin levels in non-diabetic OSAHS patients. Good adherence to long-term CPAP treatment can significantly reduce HbA(1C) levels, but has no effect on markers of insulin resistance.

HbA1c is associated with severity of obstructive sleep apnea hypopnea syndrome in nondiabetic men

The aim of this study was to examine the potential correlation of sleep characteristics with glucose metabolism in nondiabetic men with obstructive sleep apnea syndrome (OSAS). Included were 31 male patients (mean age 46.7 ±11 years), recently diagnosed with OSAS by full polysomnography. There was a significant correlation of fasting glucose and glycosylated hemoglobin (HbA1c) levels with arousal index (P = 0.047 and P =0.014, respectively). Moreover, HbA1c levels were correlated with apnea hypopnea index (P =0.009), a widely accepted marker of the severity of OSAS, and with percentage of sleep time with saturation of hemoglobin with oxygen as measured by pulse oximetry (SpO2) < 90% (t < 90%) ( P =0.010). Finally, glucose and HbA1c levels showed a significant negative correlation with average SpO2 (P =0.013 and P = 0.012, respectively) and, additionally, glucose levels with minimum SpO 2 (P =0.027) during sleep. In conclusion, severity of OSAS among nondiabetic men is associated with increased HbA1c levels and increased fasting glucose. Thus, severity of OSAS may be an additional marker of cardiovascular risk, as well as of future diabetes, in these subjects. However, further work is needed to confirm the clinical significance of these observations.

Management of obstructive sleep apnea in Europe

OBJECTIVES In Europe, the services provided for the investigation and management of obstructive sleep apnoea (OSA) varies from country to country. The aim of this questionnaire-based study was to investigate the current status of diagnostic pathways and therapeutic approaches applied in the treatment of OSA in Europe, qualification requirements of physicians involved in diagnosis and treatment of OSA, and reimbursement of these services. METHODS Two questionnaires were sent to 39 physicians in 22 countries in Europe. In order to standardize the responses, the questionnaire was accompanied by an example. RESULTS Sleep centers from 21 countries (38 physicians) participated. A broad consistency among countries with respect to the following was found: pathways included referral to sleep physicians/sleep laboratories, necessity for objective diagnosis (primarily by polysomnography), use of polygraphic methods, analysis of polysomnography (PSG), indications for positive airway pressure (PAP) therapy, application of standard continuous PAP (CPAP) therapy (100% with an CPAP/APAP ratio of 2.24:1), and the need (90.5%) and management of follow-up. Differences were apparent in reimbursement of the diagnostic procedures and follow-up, in the procedures for PAP titration from home APAP titration with portable sleep apnea monitoring (38.1%) up to hospital monitoring with PSG and APAP (85.7%), and in the qualification requirements of sleep physicians. CONCLUSIONS Management of OSA in different European countries is similar except for reimbursement rules, qualification of sleep specialists and procedures for titration of the CPAP treatment. A European network (such as the one accomplished by the European Cooperation in Science and Technology [COST] B26 Action) could be helpful for implementing these findings into health-service research in order to standardize management in a cost effective perspective.

Lung Cancer and Interstitial Lung Diseases: A Systematic Review

Interstitial lung diseases (ILDs) represent a heterogeneous group of more than two hundred diseases of either known or unknown etiology with different pathogenesis and prognosis. Lung cancer, which is the major cause of cancer death in the developed countries, is mainly attributed to cigarette smoking and exposure to inhaled carcinogens. Different studies suggest a link between ILDs and lung cancer, through different pathogenetic mechanisms, such as inflammation, coagulation, dysregulated apoptosis, focal hypoxia, activation, and accumulation of myofibroblasts as well as extracellular matrix accumulation. This paper reviews current evidence on the association between lung cancer and interstitial lung diseases such as idiopathic pulmonary fibrosis, sarcoidosis, systemic sclerosis, dermatomyositis/polymyositis, rheumatoid arthritis, systemic lupus erythematosus, and pneumoconiosis.

Inflammatory Markers in Middle-Aged Obese Subjects: Does Obstructive Sleep Apnea Syndrome Play a Role?

Background. Obstructive Sleep Apnea Syndrome (OSAS) is associated with inflammation, but obesity may be a confounding factor. Thus, the aim of this study was to explore differences in serum levels of inflammation markers between obese individuals with or without OSAS. Methods. Healthy individuals (n = 61) from an outpatient obesity clinic were examined by polysomnography and blood analysis, for measurement of TNF-α, IL-6, CRP, and fibrinogen levels. According to Apnea-Hypopnea Index (AHI), participants were divided into two BMI-matched groups: controls (AHI < 15/h, n = 23) and OSAS patients (AHI ≥ 15/h, n = 38). Results. OSAS patients had significantly higher TNF-α levels (P < .001) while no other difference in the examined inflammation markers was recorded between groups. Overall, TNF-α levels were correlated with neck circumference (P < .001), AHI (P = .002), and Oxygen Desaturation Index (P = .002). Conclusions. Obese OSAS patients have elevated TNF-α levels compared to BMI-matched controls, suggesting a role of OSAS in promoting inflammation, possibly mediated by TNF-a.

Mean platelet volume and platelet distribution width in patients with chronic obstructive pulmonary disease: the role of comorbidities.

We evaluated mean platelet volume (MPV; an indicator of vascular risk) and platelet distribution width in patients with stable chronic obstructive pulmonary disease (COPD; n = 85). We also included a control group of 34 smokers without airflow limitation. Mean platelet volume was significantly higher in patients with COPD (10.69 ± 1.0 vs 9.96 ± 1.10 fL, P < .001) than in the smoker controls. White blood cell (WBC) count was also significantly higher in patients with COPD than in the smoker controls (10 642 ± 1247 vs 7136 ± 1887/μL, P < .001). There was a correlation between MPV and WBC in patients with COPD, especially in those at stage III (r = .530, P = .004) and IV (r = .389, P = .023). Mean platelet volume did not correlate with any indices of COPD severity. In patients with COPD, MPV and WBC levels are higher than those of smokers with normal pulmonary function and are significantly correlated. Whether these effects relate to vascular risk in patients with COPD remain to be established.

Sleepiness as a marker of glucose deregulation in obstructive sleep apnea

BackgroundExcessive daytime sleepiness (EDS) is a major but not universally present feature of obstructive sleep apnea syndrome (OSAS). The latter has been associated with glucose dysmetabolism and insulin resistance. The aim of this study was to examine the role of EDS by investigating potential differences between somnolent and non-somnolent OSAS patients in glucose metabolism, insulin resistance, and levels of cardiovascular risk factors.MethodsIncluded were 25 newly diagnosed otherwise healthy OSAS patients, reporting EDS (ESS ≥ 11) and 25 age- and BMI-matched, non-somnolent (ESS ≤ 10) OSAS patients, who served as controls. Fasting glucose and insulin levels, as well as homeostatic model assessment of insulin resistance (HOMAIR) index, levels of hs-CRP, and lipidemic profile were measured.ResultsThe two groups did not differ in anthropometric or sleep characteristics. A significant correlation of ESS with glucose (p = 0.004), insulin (p = 0.011), and HOMAIR (p = 0.031) was observed. Somnolent patients had higher levels of glucose (p = 0.045), insulin (p = 0.012), and HOMAIR (p = 0.027). No difference was detected in other markers between the two groups.ConclusionsDaytime sleepiness in OSAS patients is associated with hyperglycemia and hyperinsulinemia. These results suggest its potential use as a surrogate marker of insulin resistance in such patients.

Formoterol in the management of chronic obstructive pulmonary disease

Bronchodilators represent the hallmark of symptomatic treatment of Chronic Obstructive Pulmonary Disease (COPD). There are four categories of bronchodilators: anticholinergics, methylxanthines, short-acting β2-agonists, and long-acting β2-agonists such as formoterol. Significant research has been performed to investigate the efficacy, safety and tolerability of formoterol in the therapeutic field of COPD. Formoterol exhibits a rapid onset of bronchodilation similar to that observed with salbutamol, yet its long bronchodilatory duration is comparable to salmeterol. In addition, formoterol presents with a clear superiority in lung function improvement compared with either ipratropium bromide or oral theophylline, while its efficacy improves when administered in combination with ipratropium. Formoterol has been shown to better reduce dynamic hyperinflation, which is responsible for exercise intolerance and dyspnea in COPD patients, compared with other bronchodilators, whereas it exerts synergistic effect with tiotropium. Moreover, formoterol reduces exacerbations, increases days free of use of rescue medication and improves patients’ quality of life and disease symptoms. Formoterol has a favorable safety profile and is better tolerated than theophylline. Collectively, data extracted from multicenter clinical trials support formoterol as a valid therapeutic option in the treatment of COPD.