Foteini Malli

The role of leptin in the respiratory system: an overview

Since its cloning in 1994, leptin has emerged in the literature as a pleiotropic hormone whose actions extend from immune system homeostasis to reproduction and angiogenesis. Recent investigations have identified the lung as a leptin responsive and producing organ, while extensive research has been published concerning the role of leptin in the respiratory system. Animal studies have provided evidence indicating that leptin is a stimulant of ventilation, whereas researchers have proposed an important role for leptin in lung maturation and development. Studies further suggest a significant impact of leptin on specific respiratory diseases, including obstructive sleep apnoea-hypopnoea syndrome, asthma, COPD and lung cancer. However, as new investigations are under way, the picture is becoming more complex. The scope of this review is to decode the existing data concerning the actions of leptin in the lung and provide a detailed description of leptins involvement in the most common disorders of the respiratory system.

Leptin, adiponectin, and ghrelin levels in female patients with asthma during stable and exacerbation periods.

Objective. The mechanisms underlying the relationship between obesity and asthma have not been fully established. Data in the literature suggest that adipose tissue-derived hormones may be implicated. However, no definite conclusions regarding the role of leptin and adiponectin with asthma are available. No studies have examined the role of ghrelin in asthma. Methods. We assessed the circulating concentrations of leptin, adiponectin, and ghrelin in 32 postmenopausal stable asthma patients, 37 female asthmatics during exacerbations and 8 weeks later, and 22 controls. We examined the relationship between the three peptides and indexes of pulmonary function, airway inflammation, and atopy. Results. Stable asthma patients exhibited higher leptin and lower ghrelin concentrations compared with controls. Patients with severe asthma had higher leptin and lower adiponectin levels versus patients with mild to moderate asthma. Both leptin concentrations and leptin/adiponectin ratio served as markers for discriminating asthma patients from controls on the one hand, and severe from mild to moderate asthmatics on the other. Leptin levels were inversely correlated with both FEV1/FVC and FEF25–75 in patients with mild to moderate asthma. Atopic asthma patients had higher leptin concentrations than nonatopic asthma patients. There was a positive correlation between serum leptin and total IgE levels in atopic asthmatics. Finally, serum leptin levels and leptin/adiponectin ratio were significantly increased during asthma exacerbations, while adiponectin and ghrelin levels were significantly decreased. Conclusion. Our findings suggest that leptin, adiponectin, and ghrelin may play a significant role in the pathogenesis of asthma during both stable state and asthma exacerbation, independent of obesity.

Endothelial Progenitor Cells in the Pathogenesis of Idiopathic Pulmonary Fibrosis: An Evolving Concept

Background Idiopathic pulmonary fibrosis (IPF) has been associated with abnormal vascular remodeling. Bone marrow derived endothelial progenitor cells (EPCs) are considered to possess lung tissue repair and vascular remodeling properties. Objectives The study aimed to assess early EPCs levels and EPCs endogenous vascular endothelial growth factor (VEGF) expression in IPF. In order to examine alterations in the mobilization of EPCs from the bone marrow we measured plasma VEGF. Main Results Twenty-three patients with IPF and fifteen healthy subjects were included. The number of early EPCs colonies was markedly reduced in IPF patients vs controls (6.00±6.49 vs 49.68±16.73, respectively, p<0.001). EPCs were further decreased in patients presenting systolic pulmonary arterial pressure (sPAP)≥35 mmHg. The number of colonies per well correlated negatively with P(A-a)O2 (r =  −0.750, p<0.001). Additionally, VEGF mRNA levels were significantly increased in IPF patients. There were no differences observed in VEGF plasma levels in IPF patients when compared to controls. Conclusions The current data suggest that inadequate levels of early EPCs may potentially contribute to suppressed repair and recovery of the damaged pulmonary endothelium and thereby may drive the sequence of events in profibrogenic direction. Increased VEGFmRNA levels in the clinical context of IPF may represent a compensatory mechanism to overcome reduced EPCs levels.

Sex discrepancies in COPD patients and burden of the disease in females: a nationwide study in Greece (Greek Obstructive Lung Disease Epidemiology and health ecoNomics: GOLDEN study)

Background The prevalence of chronic obstructive pulmonary disease (COPD) in females appears to be increasing. Recent studies have revealed that the percentage of women with COPD in Greece is approximately 12.5%. Aims To evaluate the burden of COPD among males and females in Greece through a nationwide cross-sectional survey and to explore sex differences regarding functional characteristics and exacerbation frequency. Methods Data collection was completed in a 6-month period. The present study followed a nationwide sampling approach of respiratory medicine physicians. The sampling approach included three steps: 1) estimation of expected incidence and prevalence of COPD cases in each prefecture of Greece and in total; 2) estimation of expected incidence of COPD cases per physician in each prefecture; and 3) creation of a frame of three different sampling zones. Following this sampling, data were provided by 199 respiratory physicians. Results The participating physicians provided data from 6,125 COPD patients. Female patients represented 28.7% of the study participants. Female COPD patients were, on average, 5 years younger than male COPD patients. Never smokers accounted for 9.4% within female patients, compared to 2.7% of males (P<0.001). Female patients were characterized by milder forms of the disease. Comorbidities were more prevalent in men, with the exception of gastroesophageal reflux (14.6% versus 17.1% for men and women, respectively, P=0.013). Female COPD patients had a higher expected number of outpatient visits per year (by 8.9%) than males (P<0.001), although hospital admissions did not differ significantly between sexes (P=0.116). Females had fewer absences from work due to COPD per year, by 19.0% (P<0.001), compared to males. Conclusion The differences observed between male and female COPD patients provide valuable information which could aid the prevention and management of COPD in Greece.

Systemic oxidative stress in patients with pulmonary sarcoidosis.

BACKGROUND A local redox imbalance has been reported in pulmonary sarcoidosis. However, so far no study has described a systemic redox imbalance in this context. The aim of the present study was to evaluate the systemic oxidative stress in patients with sarcoidosis and determine its relationship to treatment and indices of disease severity. METHODS 35 patients with histologically proven pulmonary sarcoidosis and 13 healthy volunteers were included in the study. All patients were studied during a stable phase of their disease. Systemic oxidative stress was quantified in serum with the use of a commercially available spectrophotometric method (D-ROM test) which determines overall oxidative stress, by measuring total hydroperoxides. Oxidative stress was expressed in conventional units, i.e. Carratelli Units (UCarr), where 1 UCarr corresponds to 0.8 mg/L H(2)O(2). RESULTS Serum oxidative stress levels were significantly higher in patients with sarcoidosis compared to those of normal subjects (390+/-25 vs 300+/-18 UCarr respectively, p=0.04). Patients not receiving systemic corticosteroids had higher levels of oxidative stress compared to steroid-treated patients (461.5+/-38 vs 315+/-20, p<0.01) and compared to controls (461.5+/-38 vs 300+/-18 UCarr, p<0.01). Oxidative stress did not correlate with diffusion lung capacity (DLCO), partial arterial oxygen tension (PaO(2)), MRC dyspnoea scale or chest X-ray stage. CONCLUSIONS Systemic oxidative stress is increased in patients with stable pulmonary sarcoidosis who do not receive systemic corticosteroids. This finding suggests a sustained oxidative burden even when clinical, functional and radiological criteria indicate disease stability.

Frequency and risk factors of COPD exacerbations and hospitalizations: a nationwide study in Greece (Greek Obstructive Lung Disease Epidemiology and health ecoNomics: GOLDEN study).

Background COPD exacerbations and hospitalizations have been associated with poor prognosis for the COPD patient. Objective To evaluate the frequency and risk factors of COPD exacerbations, hospitalizations, and admissions to intensive care units (ICUs) in Greece by a nationwide cross-sectional study. Materials and methods A nationwide observational, multicenter, cross-sectional study was conducted in the clinical practice setting of respiratory medicine physicians over a 6 month-period (October 2010 to March 2011). A total of 6,125 COPD patients were recruited by 199 respiratory physicians. Results Participants had a median age of 68.0 years, 71.3% were males, and 71.8% suffered from comorbidities. The median disease duration was 10.0 years. Of the patients, 45.3% were classified as having GOLD (Global initiative for chronic Obstructive Lung Disease) stage III or IV COPD. Patients with four or more comorbidities had 78.5% and threefold-higher than expected number of exacerbations and hospitalizations, respectively, as well as fivefold-higher risk of admission to the ICU compared to those with no comorbidities. Obese patients had 6.2% fewer expected exacerbations compared to those with a normal body mass index. Patients with GOLD stage IV had 74.5% and fivefold-higher expected number of exacerbations and hospitalizations, respectively, and nearly threefold-higher risk of admission to the ICU compared to stage I patients. An additional risk factor for exacerbations and hospitalizations was low compliance with treatment: 45% of patients reported forgetting to take their medication, and 81% reported a preference for a treatment with a lower dosing frequency. Conclusion Comorbidities, disease severity, and compliance with treatment were identified as the most notable risk factors for exacerbations, hospitalizations, and ICU admissions. The results point to the need for a multifactorial approach for the COPD patient and for the development of strategies that can increase patient compliance with treatment.

8-Isoprostane levels in serum and bronchoalveolar lavage in idiopathic pulmonary fibrosis and sarcoidosis

OBJECTIVE AND DESIGN Sarcoidosis and idiopathic pulmonary fibrosis (IPF) are both associated with deregulated inflammatory mechanisms partially triggered by aggravated oxidative stress. 8-Isoprostane has been proposed as a reliable marker of oxidative stress, linked to several pulmonary diseases. We aimed to explore differences in 8-isoprostane levels in IPF and sarcoidosis patients, and controls. METHODS We included 16 IPF and 55 sarcoidosis patients, as well as 17 controls in the study. 8-Isoprostane levels were measured in serum and in bronchoalveolar lavage (BAL). RESULTS Serum 8-isoprostane levels were increased in all patient groups vs controls (p<0.001). The systemic 8-isoprostane concentrations were higher in sarcoidosis patients as compared to IPF subjects and controls (p=0.017 and p<0.001, respectively). IPF patients exhibited increased serum 8-isoprostane levels when compared to controls (p<0.001). Sarcoidosis patients presented significantly increased 8-isoprostane BAL levels when compared to IPF patients (p=0.002). CONCLUSION Our data indicate that the level of oxidative stress, as reflected by 8-isoprostane concentrations, is enhanced in patients with sarcoidosis, and to a lesser extent, in IPF patients when compared to controls, suggesting a potential implication of redox imbalance in both diseases.

Increased primary autoimmune thyroid diseases and thyroid antibodies in sarcoidosis: evidence for an under-recognised extrathoracic involvement in sarcoidosis?

OBJECTIVE AND DESIGNSarcoidosis has been associated with thyroid diseases. However, until today no definite conclusions have been drawn. We aimed to assess the frequency of thyroid disorders and the levels of thyroid hormones and thyroid antibodies in 68 sarcoidosis patients and 75 controls. Additionally, we performed ultrasonography and fine-needle aspiration.RESULTSIn this prospective case control study conducted in the University Hospital of Larissa, Greece, overt thyroid disease was present in 29.4% of patients and 16.1% of patients presented clinical autoimmune thyroid disease. sarcoidosis patients had a significantly higher frequency of serological autoimmunity. Female patients had significantly increased frequency of positive TSH receptor antibodies (TRAbs) and antithyroid peroxidase antibodies (TPOAbs) when compared to gender-matched controls (40% vs 0%, p<0.001, and 28.8% vs 11.86%, p = 0.029, respectively). The hypoechoic pattern of the thyroid was more frequent in female patients vs controls (p<0.001). Male patients had a higher frequency of TRAbs and hypoechoic pattern of the thyroid gland (43.4% vs 0%, p = 0.002, and 39.1% vs 6.25%, p = 0.021, respectively). Indices of thyroid autoimmune disease were significantly more frequent in sarcoidosis patients vs gender-matched controls. Increased TPOAbs were significantly associated with clinical autoimmune disease in sarcoidosis.CONCLUSIONSOverall, the findings derived from this study suggest that thyroid disorders are frequent in sarcoidosis. This association may potentially be the result of increased thyroid antibodies.

Predicting Short-term Mortality in Patients With Pulmonary Embolism: A Simple Model

Background:The aim of the present study was to develop a simple prognostic rule that could classify patients with pulmonary embolism (PE) into categories of increased risk of 30-day mortality. Methods:One hundred patients with PE were enrolled. Clinical and laboratory findings were recorded on admission for each patient. Differences between groups’ survival and death were tested, and the association with the 30-day mortality was determined. Results:Three variables had a significant effect on survival: age, Charlson index and the alveolar to arterial (A-a) gradient. A receiver operating characteristic analysis was performed, and the cut-off points used for the comparison of survival were 67 years of age, A-a gradient over 52.8 mm Hg and Charlson index over 2. By combining these variables, a score was established for distinguishing patients with PE who are at high risk. This score was also validated in a group of 30 consecutive patients admitted to the hospital for PE Additionally, a tree method was applied and showed that for patients with a history of diabetes and Charlson index >3, the expected outcome is death. Conclusions:The results of this study suggest that patients with PE could be stratified into categories of increasing risk of 30-day mortality using a simple score based only on routinely available variables. Future studies are needed to validate our prognostic model in a large cohort of patients with PE.

Subdiagnóstico de doenças respiratórias durante uma desaceleração econômica e necessidade do uso da espirometria como teste de triagem

In a very interesting paper published recently in the Brazilian Journal of Pulmonology, Queiroz et al. (1) reported a COPD underdiagnosis rate of 71.4% in a primary health care setting. In addition, the authors observed that only 5.6% of the subjects previously diagnosed with COPD had undergone pulmonary function tests (PFTs). We would like to recount our experience concerning the underutilization of diagnostic tools, such as spirometry, and the consequent underestimation of respiratory diseases. The underdiagnosis of major health problems, such as asthma and COPD, has to be noted, especially in a period during which access to health care is no longer a universal, inalienable right, because of the recent economic downturn. Greece is currently dealing with a major financial crisis, which has had disheartening effects on every aspect of life, including not only access to health care but also the quality of the health care services available. In particular, the reduction in family income and the inability of individuals to afford health insurance coverage, has limited the use of high-quality health care services. The total government expenditure on (budget for) health care has been also affected by the economic crisis. The World Health Organization reported that, due to the economic downturn, patients in Greece are either seeking medical assistance at public health care facilities or deferring health care completely. As a result, an increasing number of patients remain undiagnosed even if they are symptomatic or have specific risk factors for a particular disease, such as COPD. Our group, in cooperation with the Hellenic Thoracic Society, evaluated 267 individuals (183 males; mean age: 53.5 ± 14.3 years). All of the participants completed a questionnaire that included demographic and clinical data, as well as information about any previous PFTs. The participants then underwent spirometry in accordance with international recommendations. Of the 267 individuals studied, 167 (62.5%) had never undergone PFTs. Therefore, for the majority of the participants, this project constituted the first evaluation of their pulmonary function. Of the 167 participants who had never undergone PFTs, 84 were current smokers and 48 were former smokers. More importantly, 55.1% presented with at least one respiratory symptom (such as dyspnea, expectoration, and wheezing). Despite presenting with these risk factors for a major respiratory disease, those participants had never sought medical attention. In addition, of the 167 participants who had never undergone PFTs, 32 (19.2%) showed abnormal spirometric results and 110 (65.6%) presented with …