Georgios Kyriazis

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.

Levels of inflammatory mediators in chronic obstructive pulmonary disease patients with anemia of chronic disease: a case–control study

BACKGROUND Although a subset of patients with chronic obstructive pulmonary disease (COPD) display anemia, the role of elevated pro-inflammatory cytokines in COPD-related anemia of chronic disease (ACD) has not been fully investigated. AIM To examine the levels of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor-alpha (TNFα), interferon-gamma (IFNγ), C-reactive protein (CRP) and erythropoietin in stable COPD outpatients with and without ACD. DESIGN A case-control design was followed. METHODS Fifty-four patients with stable COPD were studied. Among them, 27 had ACD according to strict clinical and laboratory criteria (group of cases), while another 27 nonanemic COPD patients, carefully matched to cases for age, gender, height, lung function and smoking status represented the controls. Serum levels of IL-1β, IL-6, IL-10, TNFα, IFNγ, CRP and erythropoietin were measured in both groups. RESULTS Patients with ACD had significantly higher levels of IL-10 [25.6 (1.9-95.2) vs. 4.1 (1.9-31.9) pg/ml, P = 0.049] and IFNγ [15.2 (2.2-106.9) vs. 2 (1.2-18.3) pg/ml, P = 0.026] and had more frequently elevated CRP than controls. Levels of IL-1β [26.2 (9.8-96.4) vs. 7.9 (2.1-28.4) pg/ml, P = 0.073], IL-6 [20.3 (2.1-125.4) vs. 6.2 (1.2-33.8) pg/ml, P = 0.688] and TNFα [30.1 (3.2-107.5) vs. 10.1 (3.2-50.4) pg/ml, P = 0.131] were also higher in cases, but the differences did not reach statistical significance. Patients with ACD also displayed significantly higher erythropoietin levels than controls [(21.9 (8.4-101.7) vs. 9.7 (6.3-21.7) mIU/ml, P = 0.010], indicating erythropoietin resistance. CONCLUSION This study shows that in stable COPD outpatients with strictly defined ACD, levels of inflammatory mediators and erythropoietin are elevated compared to nonanemic controls.

Immunomodifiers in combination with conventional chemotherapy in small cell lung cancer: a Phase II, randomized study

Purpose To evaluate the effect of immunotherapy on response, survival, and certain immune markers in patients with small cell lung cancer (SCLC) who are receiving chemotherapy. Patients and methods Patients with SCLC (n = 164) were assigned to receive either chemotherapy alone (group A) or a combination of chemotherapy and immunotherapy as follows: interferon α (IFN-α; 3 million IU) 3 times per week (group B); IFN-γ (3 million IU) 3 times per week (group C); and IFN-α and IFN-γ (1.5 million IU of each) 3 times per week (group D). Chemotherapy was the same for all groups and consisted of eight cycles with carboplatin 5.5 mg/m2 intravenously on day 1, ifosfamide 3.5 mg/m2 intravenously on day 1, and etoposide 200 mg/m2 total dose taken orally on days 1 through 3, every 28 days. Patients completing chemotherapy were restaged, and those who were found to have limited disease received primary site and prophylactic cranial irradiation. Immunotherapy was continued throughout these treatments and during the follow-up period. Blood was taken before each course of chemotherapy and during follow-up to measure CD3+ lymphocytes, CD3+CD4+ lymphocytes, CD3+CD8+ lymphocytes, natural killer cells, and natural killer T cells. Results Differences in response and survival were not significantly different when all patients were considered. However, among patients with limited disease, Kaplan–Meier analysis disclosed a survival benefit for group B (P , 0.05). The analysis of immunologic measurements revealed that the improvement of immune markers was always accompanied by clinical improvement, whereas deterioration of all markers was accompanied by disease progression (result not statistically significant except for group C; P , 0.05). Conclusion Among cytokines used in the study, only IFN-α seems to confer a survival benefit to patients with SCLC with limited disease. However, immunotherapy remains a challenge in the treatment of lung neoplasms and should be further explored.

Reduction of serum retinol-binding protein-4 levels in nondiabetic obstructive sleep apnea patients under continuous positive airway pressure treatment.

Background: Obstructive sleep apnea syndrome (OSAS) is associated with impaired glucose metabolism and insulin resistance. Retinol-binding protein-4 (RBP-4) is an adipokine, hypothesized to induce insulin resistance. Objectives: The aim of the study was to explore the association between serum RBP-4 levels and OSAS severity in nondiabetic, adherent to therapy OSAS patients and to investigate the role of continuous positive airway pressure (CPAP) in the alteration of RBP-4 levels. Methods: OSAS patients (n = 62) without comorbidities or medication use were included. Fasting RBP-4, glucose and insulin levels, HbA1c, homeostatic model assessment of insulin resistance index and lipid profile were measured at baseline and after 6 months of CPAP use. Patients were divided into group A (with fasting glucose levels <110 mg/dl, n = 47), and group B (with impaired fasting glucose (IFG), i.e. fasting glucose levels ≧110 mg/dl, n = 15). Results: RBP-4 levels were not associated with apnea-related indices, anthropometric characteristics or markers of glycemic control, insulin resistance or lipid profile. In group A (but not in group B), a significant reduction was observed in RBP-4 (p = 0.046), HbA1c (p = 0.005), LDL cholesterol (p = 0.034), and high-sensitivity C-reactive protein (hs-CRP, p = 0.033) levels after 6 months of CPAP use. Conclusions: RBP-4 levels were not correlated with sleep, anthropometric characteristics, markers of glycemic control and insulin sensitivity. OSAS patients without IFG respond well to CPAP use as evidenced by the significant reduction in RBP-4, HbA1c and, additionally, hs-CRP and LDL- cholesterol levels. This treatment effect is not observed in patients with IFG.

BRONCHOALVEOLAR LAVAGE FLUID EOSINOPHILS ARE CORRELATED TO NATURAL KILLER CELLS IN EOSINOPHILIC PNEUMONIAS

Background: Eosinophilic lung diseases comprise a group of heterogeneous pulmonary disorders linked by increased eosinophils in bronchoalveolar lavage fluid (BALF). There is supporting evidence that natural killer (NK) cells participate in the regulation of eosinophilic inflammation. Objective: Our aim was to investigate the relationship between eosinophils and NK cells in BALF in patients with different interstitial lung diseases (ILDs) focusing on eosinophilic pneumonias. Methods: Of 114 patients who presented with increased BALF eosinophils (>5%), 74 patients were classified into the following groups: 27 had eosinophilic pneumonia (EP), 17 had idiopathic pulmonary fibrosis (IPF), 16 had hypersensitivity pneumonitis (HSP) and 14 had cryptogenic organizing pneumonia (COP/BOOP). Total BALF cells, cell density and cell differential counts were assessed and lymphocyte subsets CD3+, CD4+, CD8+, CD19+, CD3–CD16/56+ (NK) and CD3+CD16/56+ (NKT) were determined by flow cytometry. Results: Significant differences were observed in the percentages of lymphocytes (p < 0.001) and CD3+CD16/56+ cells (p = 0.023) among patient groups. In patients with EP, the percentage of eosinophils correlated positively with the number of CD3–CD16/56+ cells (r = 0.522, p = 0.005), the percentage of CD3–CD16/56+ cells (r = 0.690, p < 0.001), and the absolute count of CD3+CD16/56+ absolute cells (r = 0.609, p = 0.001). However, in patients with IPF, HSP or COP/BOOP, no correlation between the percentage of eosinophils and CD3–CD16/56+ or CD3+CD16/56+ cells was observed. Conclusions: Eosinophil inflammation seems to develop through a different pathway in EP compared to other ILDs.

Serum Levels of Vascular Endothelial Growth Factor and Insulin-likeGrowth Factor Binding Protein-3 in Obstructive Sleep Apnea Patients:Effect of Continuous Positive Airway Pressure Treatment

Background and Aim: Hypoxia, a major feature of obstructive sleep apnea (OSA), modifies Vascular Endothelial Growth Factor (VEGF) and Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) levels, which contribute to atherogenesis and occurrence of cardiovascular (CV) events. We assessed and compared serum levels of VEGF and IGFBP-3 in newly diagnosed OSA patients and controls, to explore associations with anthropometric and sleep parameters and to study the effect of continuous positive airway pressure (CPAP) treatment on these levels. Materials and Methods: Serum levels of VEGF and IGFBP-3 were measured in 65 OSA patients and 31 age- and body mass index- matched controls. In OSA patients, measurements were repeated after 6 months of CPAP therapy. All participants were non-smokers, without any comorbidities or systemic medication use. Results: At baseline, serum VEGF levels in OSA patients were higher compared with controls (p<0.001), while IGFBP-3 levels were lower (1.41±0.56 vs. 1.61±0.38 μg/ml, p=0.039). VEGF levels correlated with apnea-hypopnea index (r=0.336, p=0.001) and oxygen desaturation index (r=0.282, p=0.007). After 6 months on CPAP treatment, VEGF levels decreased in OSA patients (p<0.001), while IGFBP-3 levels increased (p<0.001). Conclusion: In newly diagnosed OSA patients, serum levels of VEGF are elevated, while IGFBP-3 levels are low. After 6 months of CPAP treatment these levels change. These results may reflect an increased CV risk in untreated OSA patients, which is ameliorated after CPAP therapy.

Potential Prognostic Value of Intracellular Cytokine Detection by Flow Cytometry in Pulmonary Sarcoidosis

In pulmonary sarcoidosis, differential cytokine production in the lungs could be related to variable prognosis of patients at different stages of disease. Twenty patients with pulmonary sarcoidosis (10 at radiographic stage I and 10 at stages II-IV), as well as 10 age-matched healthy volunteers participated in the study. A 4-colour flow cytometric technique was used to measure interferon-γ (IFN-γ), interleukin (IL)-2, tumour necrosis factor-α (TNF-α), IL-4, and IL-13 production in phorbol myristate acetate (PMA)/ionomycin-stimulated CD4+ and CD8+ T cells from bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) of patients, and PB of control subjects. CD4+ T cells from patients showed higher expression of IFN-γ in BALF than in PB. Significant correlations were observed between the percentages of BALF CD4+ and CD8+ T cells expressing intracellular IFN-γ, IL-2, and TNF-α. Stage I patients had lower percentages of IFN-γ-producing CD4+ and CD8+ T cells, as well as TNF-α-producing CD8+ T cells, in BALF (but not in PB) than stage II-IV patients. A decreased TH1 and TC1 response was demonstrated in BALF of patients at stage I of disease, which could explain their anticipated better prognosis.