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Pulmonary surfactant is a highly surface-active mixture of proteins and lipids that is synthesized and secreted in the alveoli by type II epithelial cells and is found in the fluid lining the alveolar surface. The protein part of surfactant constitutes two hydrophilic proteins (SP-A and SP-D) that regulate surfactant metabolism and have immunologic functions, and two hydrophobic proteins (SP-B and SP-C), which play a direct role in the organization of the surfactant structure in the interphase and in the stabilization of the lipid layers during the respiratory cycle. Several studies have shown that cigarette smoke seems to affect, in several ways, both surfactant homeostasis and function. The alterations in surfactants' biophysical properties caused by cigarette smoking, contribute to the development of several smoking related lung diseases. In this review we provide information on biochemical and physiological aspects of the pulmonary surfactant and on its possible association with the development of two major chronic diseases of the lung known to be related to smoking, i.e. chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Additional information on the possible role of surfactant protein alterations and/or dysfunction in the combination of these two conditions, recently described as combined pulmonary fibrosis and emphysema (CPFE) are also provided.

Unilateral hypertransparent hemithorax requires a particular diagnostic approach as it can be the result of diverse pulmonary diseases, including pneumothorax, large pulmonary embolus, unilateral large bullae, mucous plag, airway obstruction and contralateral pleural effusion. Congenital syndromes with chest wall abnormalities, are rare, but often underdiagnosed causes. Poland Syndrome consists of such a rare, congenital anomaly and is characterized by the absence of the pectoralis major muscle and upper limb ipsilateral abnormalities. We present a case of a patient with acute exacerbation of chronic obstructive pulmonary disease (COPD) and a unilateral hypertransparency on chest radiology, attributed to the underlying Poland Syndrome.

Background: Idiopathic pulmonary fibrosis acute exacerbation (IPF-AE) constitutes IPF's most devastating event, representing the unexpected superimposition of diffuse alveolar damage of unknown etiology. Guidelines recommend high-dose steroids treatment despite unproven benefit. We hypothesized that previous immunosuppression and the administration of high-dose steroids adversely affect IPF-AE outcome., Methods: We studied all consecutive patients hospitalized in our department for IPF deterioration from 2007 to June 2013. Our protocol consisted of immediate cessation of immunosuppression (if any), best supportive care, broad-spectrum antimicrobials and thorough evaluation to detect reversible causes of deterioration. Patients were followed-up for survival; post-discharge none received immunosuppression., Results: Twenty-four out of 85 admissions (28%) fulfilled IPF-AE criteria. IPF-AE were analyzed both as unique events and as unique patients. As unique events 50% survived; 3 out of 12 (25%) in the group previously treated with immunosuppression whereas nine out of 12 (75%) in the group not receiving immunosuppression (p = 0.041). As unique patients 35.3% survived; 3 out of 6 (50%) in the never treated group whereas three out of 11 (27.3%) in the group receiving immunosuppression (p = 0.685). The history of immunosuppression significantly and adversely influenced survival (p = 0.035). Survival was greater in the never treated group compared to the immunosuppressed patients (p = 0.022). Post-discharge, our IPF-AE survivors had an 83% 1-year survival., Conclusions: By applying the above mentioned protocol half of our patients survived. The history of immunosuppression before IPF-AE adversely influences survival. Avoiding steroids in IPF patients may favor the natural history of the disease even at the moment of its most devastating event.

Background: Some patients with asthma present persistent airflow limitation but their clinical and inflammatory characteristics have not been extensively described. In this study we aimed to identify differences in the clinical, functional and inflammatory characteristics between patients with asthma with and without persistent airflow obstruction., Methods: Patients (n = 170) were consecutively recruited from two tertiary Asthma Clinics. Patients' demographics, pulmonary function tests, inflammatory cells in induced sputum, bronchial hyperresponsiveness (BHR, PD15 to methacholine) and treatment regimens were recorded., Results: Sixty patients (35.3%) presented persistent airflow obstruction. Besides differences in lung function, patients with persistent obstruction presented, lower methacholine PD20, higher exhaled NO, and higher eosinophil and neutrophil counts in induced sputum. The majority (71.7%) of the patients with persistent obstruction fulfilled the ATS criteria for severe refractory asthma (SRA), in contrast to 4.5% in the group without persistent obstruction. A cluster analysis identified three clinically relevant clusters: Cluster 1 (n = 56, not related to persistent airflow obstruction) included non-atopic patients, who did not receive high-dose ICS without SRA; Cluster 2 (n = 53, related to persistent airflow obstruction) included atopic patients, receiving high-dose ICS and/or oral CS, fulfilling SRA criteria; Cluster 3 (n = 61, not related to persistent airflow obstruction) included atopic patients not receiving high-dose ICS, without SRA., Conclusions: Asthma patients with persistent airflow obstruction present a distinct asthma phenotype, with significant differences in clinical, functional and inflammatory characteristics compared to patients without fixed airway obstruction. These patients present more often severe refractory asthma and require more intense treatment., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Pulmonary alveolar proteinosis (PAP) is categorized into hereditary, secondary and autoimmune PAP (aPAP) types. The common pathogenesis is the ability of the alveolar macrophages to catabolize phagocytized surfactant is affected. Hereditary PAP is caused by mutations involving the GM-CSF signaling, particularly in genes for the GM-CSF receptor and sometimes by GATA2 mutations. Secondary PAP occurs in hematologic malignancies, other hematologic disorders, miscellaneous malignancies, fume and dust inhalation, drugs, autoimmune disorders and immunodeficiencies. aPAP is related to the production of GM-CSF autoantibodies. PAP is characterized morphologically by the inappropriate and progressive 'occupation' of the alveolar spaces by an excessive amount of unprocessed surfactant, limiting gas exchange and gradually exhausting the respiratory reserve. Myeloid cells' immunity deteriorates, increasing the risk of infections. Treatment of PAP is based on its etiology. In aPAP, recent therapeutic advances might shift the treatment option from the whole lung lavage procedure under general anesthesia to the inhalation of GM-CSF 'as needed'.

Although studies show that control of asthma can be achieved in the majority of patients, surveys repeatedly show that this is not the case in real life. Important measures to implement in order to achieve asthma control are trained healthcare professionals, a good patient-doctor relationship, patient education, avoidance of exposure to triggers, personalised management and adherence to treatment. These measures help the majority of asthma patients but have not yet been widely implemented and there should be a concerted action for their implementation. Moreover, further and focused research is needed in severe/refractory asthma., (Copyright ©ERS 2015.)

Background: Hospital admissions for COPD exacerbations account for 70% of total costs of COPD treatment, and the duration of hospital stay is directly related to this cost. The aim of this study was to investigate possible associations of demographic, clinical, laboratory, and functional parameters with stay of subjects admitted for COPD exacerbations and to provide a score for the prediction of the need for prolonged hospitalization., Methods: We included 164 consecutive subjects admitted to 2 respiratory medicine departments of 2 tertiary hospitals for a COPD exacerbation, and we evaluated laboratory, clinical, and functional parameters possibly related to the duration of hospital stay., Results: Seven parameters evaluated on subject admission (Antonisen type of exacerbation, number of Exacerbations in the previous year, Charlson index of comorbidities, Oxygenation, Partial pressure of P(aCO2) in arterial blood gases, Dyspnea according to the Borg dyspnea scale, and history of chronic respiratory Failure) were able to predict stay and were included in a simple score named AECOPD-F. The area under the curve of the score for the prediction of prolonged hospital stay is 0.960, and a cutoff point ≥ 3 predicts prolonged stay with a sensitivity of 84.5% and a specificity of 92.5% (95% CI 0.917-0.984). The AECOPD-F score was validated in a second group of 88 subjects admitted to the hospital for a COPD exacerbation. In the validation group, subjects with a score ≥ 3 required prolonged stay compared with those with a score < 3 (8.0 [6.0-10.0] vs 6.5 [4.0-9.0] d, respectively, P = .007)., Conclusion: The AECOPD-F score could accurately predict stay in hospitalized COPD subjects. The implementation of this score in clinical practice could be useful in the discharge planning of such subjects., (Copyright © 2014 by Daedalus Enterprises.)

Background and Objectives: Granulocyte macrophage-colony-stimulating factor (GM-CSF) causes variable improvement in autoimmune pulmonary alveolar proteinosis (aPAP). Upon response to short-term treatment, patients are divided into responders and non-responders. The aim of this study was to test the hypothesis that long-term inhaled GM-CSF (iGM-CSF) is effective in all patients and that attainment of remission permits gradual de-escalation of the dose to the lowest effective safe dose., Methods: Patients were treated with iGM-CSF 250 μg once a day given 4 days on and 4 days off for as long as necessary (the "as far as it takes" protocol). Upon remission, defined as absence of symptoms, oxygen desaturation <4 % at the walking test, and significant radiographic reduction of the infiltrates, or at least two of the above, the iGM-CSF dose was de-escalated. In the case of relapse, the patient was repositioned at the previous effective dose. Patients were investigated at 6-month intervals. To detect hematopoietic effects, blood cell counts, CD34+ cells, granulocyte macrophage progenitor colony-forming-units, and burst-forming-unit erythroid were measured., Results: Six (five female) patients 43.8 ± 15.7 years of age were treated for 14-65 months and all responded to treatment. Remission was achieved after 25.6 ± 10 months. Three patients maintained remission at their lowest effective dose. Two patients relapsed at de-escalating doses. One patient remains on full-dose treatment. iGM-CSF had no impact on any of the hematological parameters tested., Conclusions: In aPAP, long-term adherence to the dose schedule permitted remission in all patients. Long-term treatment with iGM-CSF also permitted the definition of lower effective doses, minimizing disease burden and treatment costs safely, since no stimulating activity on hematopoiesis was observed, a fact that is of paramount importance for those aPAP patients needing lifelong treatment.

Background: Depression is a frequent comorbidity in COPD patients and is associated with greater physical impairment, increased health-care utilization, and worse outcomes. The presence of depressive symptoms in the partners of COPD patients has not been evaluated., Methods: We evaluated the partners of 230 consecutive COPD patients included in a prospective study. Depressive symptoms were evaluated using Beck's Depression Inventory (BDI) on the first day of admission for COPD exacerbation. Patients were followed-up for 1 year., Results: Significant depressive symptoms were present in 39.6 % of the COPD patients and in 40.9 % of their partners. Beck scores were higher in the partners of patients with severe airflow obstruction and in those with ≥2 exacerbations and ≥1 hospitalizations for COPD exacerbation during the 1-year follow-up. The BDI score of the patients' partners was significantly correlated with the BDI score of the COPD patients (r s = 0.422). In multivariate analysis, depressive symptoms in the COPD patients were an independent predictor of depressive symptoms in their partners (OR 4.136, 95 % CI 1.991-8.594; p < 0.001)., Conclusions: A large proportion of the partners of COPD patients present significant depressive symptoms. The identification of those patients and their partners represents a possible target for intervention.

Serum uric acid is increased in respiratory disease, especially in the presence of hypoxia and systemic inflammation. We evaluated serum uric acid as a biomarker for prediction of mortality and future acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Serum uric acid was measured in 314 eligible consecutive patients on admission for AECOPD. Patients were evaluated monthly for 1 year. Uric acid levels were higher in patients with more severe airflow limitation and in those experiencing frequent exacerbations. High uric acid levels (≥6.9 mg·dL(-1)) were an independent predictor of 30-day mortality in multivariate Cox regression analysis (HR 1.317, 95% CI 1.011-1.736; p=0.044), but not of 1-year mortality. Patients with high serum uric acid required more prolonged hospitalisation, and more often needed noninvasive ventilation and admission to the intensive care unit within 30 days. In addition, high uric acid levels were associated with increased risk and hospitalisation for AECOPD in 1 year in multivariate Poisson regression analysis (incidence rate ratio 1.184 (95% CI 1.125-1.246) and 1.190 (95% CI 1.105-1.282), respectively; both p<0.001). Serum uric acid is associated with increased 30-day mortality and risk for AECOPD and hospitalisations in 1-year follow-up. This low-cost biomarker may be useful in the identification of high-risk chronic obstructive pulmonary disease patients that could benefit from intensive management.

Background: The epidemiology of pulmonary nontuberculous mycobacteria (NTM) in Greece is largely unknown., Objectives: To determine the incidence and the demographic, microbiological, and clinical characteristics of patients with pulmonary NTM infection and pulmonary NTM disease., Methods: A retrospective review of the demographic, microbiological, and clinical characteristics of patients with NTM culture-positive respiratory specimens from January 2007 to May 2013., Results: A total of 120 patients were identified with at least one respiratory NTM isolate and 56 patients (46%) fulfilled the microbiological ATS/IDSA criteria for NTM disease. Of patients with adequate data, 16% fulfilled the complete ATS/IDSA criteria for NTM disease. The incidence of pulmonary NTM infection and disease was 18.9 and 8.8 per 100.000 inpatients and outpatients, respectively. The spectrum of NTM species was high (13 species) and predominated by M. avium-intracellulare complex (M. avium (13%), M. intracellulare (10%)), M. gordonae (14%), and M. fortuitum (12%). The ratio of isolation of NTM to M. tuberculosis in all hospitalized patients was 0.59., Conclusions: The first data on the epidemiology of pulmonary NTM in Athens, Greece, are presented. NTM infection is common in patients with chronic respiratory disease. However, only a significantly smaller proportion of patients fulfill the criteria for NTM disease.

Macrophages are a major cellular component of the innate immune system, and play an important role in the recognition of microbes, particulates, and immunogens and to the regulation of inflammatory responses. In the lung, macrophages react with soluble proteins that bind microbial products in order to remove pathogens and particles and to maintain the sterility of the airway tract. Chronic obstructive pulmonary disease and asthma are both obstructive airway diseases that involve chronic inflammation of the respiratory tract which contributes to disease progression. In the case of COPD, there is increasing evidence that lung macrophages orchestrate inflammation through the release of chemokines that attract neutrophils, monocytes and T cells and the release of several proteases. On the other hand, in asthma, it seems that alveolar macrophages are inappropriately activated and are implicated in the development and progression of the disease. In this review we summarize the current basic and clinical research studies which highlight the role of macrophages in asthma and COPD., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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.

Former studies of our group have shown that the innate and adaptive immune status may differ in relation with the causative infection. To this same end, it was investigated if kinetics of circulating lipopolysaccharide (LPS) leading to inflammatory response may differ. Blood was sampled from 189 patients with sepsis and 206 with severe sepsis/shock starting 24h from advent of sepsis and repeating on day 3. Serum LPS was measured by Limulus Amebocyte Lysate (LAL) assay. From 59 patients, circulating monocytes were isolated and incubated in the absence/presence of LPS. Concentrations of tumor necrosis factor-alpha (TNFα) were measured in supernatants by an enzyme immunoassay. In either category of severity, circulating LPS was greater among sufferers from primary Gram-negative bacteremia (BSI) and from community-acquired pneumonia (CAP) than sufferers from other underlying infections. LPS were greater among patients with BSI compared to patients with secondary Gram-negative bacteremia and patients without bacteremia. Greater decrease of circulating LPS over 48h was recorded for survivors compared to non-survivors only within sufferers from BSI and CAP. Significant endotoxemia was considered for patients with serum LPS within the upper quartile of distribution; their monocytes were less potent for release of TNFα. It is concluded that endotoxemia in sepsis varies greatly with the underlying infection; this is related with immunoparalysis of monocytes with implications on final outcome., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The impact of depressive symptoms on outcomes of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) has not been thoroughly evaluated in prospective studies. We prospectively enrolled 230 consecutive patients hospitalised for AECOPD, without previous diagnosis of depression. Depressive symptoms were evaluated with Beck's depression inventory. Pulmonary function tests, arterial blood gases, COPD assessment test (CAT) and Borg dyspnoea scale were recorded on admission and on days 3, 10 and 40. Patients were evaluated monthly for 1 year. Patients with depressive symptoms required longer hospitalisation (mean ± sd 11.6 ± 3.7 versus 5.6 ± 4.1 days, p<0.001). Clinical variables improved during the course of AECOPD, but depressive symptoms on admission had a significant impact on dyspnoea (p<0.001) and CAT score (p = 0.012) improvement. Patients with depressive symptoms presented more AECOPD (p<0.001) and more hospitalisations for AECOPD (p<0.001) in 1 year. In multivariate analysis, depressive symptoms were an independent predictor of mortality (hazard ratio 3.568, 95% CI 1.302-9.780) and risk for AECOPD (incidence rate ratio (IRR) 2.221, 95% CI 1.573-3.135) and AECOPD hospitalisations (IRR 3.589, 95% CI 2.319-5.556) in 1 year. The presence of depressive symptoms in patients admitted for AECOPD has a significant impact on recovery and is related to worse survival and increased risk for subsequent COPD exacerbations and hospitalisations in 1 year.

Previous studies have shown that secondhand smoke induces lung function impairment and increases proinflammatory cytokines. The aim of the present study was to evaluate the acute effects of secondhand smoke on airway acidification and airway oxidative stress in never-smokers. In a randomized controlled cross-over trial, 18 young healthy never-smokers were assessed at baseline and 0, 30, 60, 120, 180 and 240 min after one-hour secondhand smoke exposure at bar/restaurant levels. Exhaled NO and CO measurements, exhaled breath condensate collection (for pH, H(2)O(2) and NO(2)(-)/NO(3)(-) measurements) and spirometry were performed at all time-points. Secondhand smoke exposure induced increases in serum cotinine and exhaled CO that persisted until 240 min. Exhaled breath condensate pH decreased immediately after exposure (p < 0.001) and returned to baseline by 180 min, whereas H(2)O(2) increased at 120 min and remained increased at 240 min (p = 0.001). No changes in exhaled NO and NO(2)/NO(3) were observed, while decreases in FEV(1) (p < 0.001) and FEV(1)/FVC (p < 0.001) were observed after exposure and returned to baseline by 180 min. A 1-h exposure to secondhand smoke induced airway acidification and increased airway oxidative stress, accompanied by significant impairment of lung function. Despite the reversal in EBC pH and lung function, airway oxidative stress remained increased 4 h after the exposure. Clinical trial registration number (EudraCT): 2009-013545-28., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) has been recently characterized as a disease of accelerated lung aging. The prevalence of COPD is age-dependent suggesting an intimate relationship between the pathogenesis of COPD and aging. Lung function decline, the hallmark feature of COPD evolution, is more prominent with increasing age and this decline is greater in smoking individuals. One of the major goals of COPD pharmacotherapy is the development of drugs that would be able to result in a decrease of the decline in lung function over years. However, till nowadays smoking cessation is the only known intervention which is able to decelerate lung function decline. Several mechanisms of aging, including oxidative stress, inflammation and telomere shortening have been shown to be implicated in COPD. Furthermore, numerous anti-aging molecules, including sirtuins and Nrf-2 are reduced, and pathways such as mTOR and genes such as Klotho have also been shown to be abnormal in the lungs of COPD patients. The above mechanisms have been associated with the accelerated lung aging in COPD patients. Numerous therapeutic interventions have been studied in an attempt to reverse accelerated lung aging, and some of them have already been tested in clinical trials. The aim of the present review is to summarize the mechanisms associated with the accelerated lung aging in COPD and to provide information about the possible therapeutic implications targeting those mechanisms.

Chronic obstructive pulmonary disease (COPD) and metabolic syndrome represent common causes of morbidity and mortality in ageing populations. The effect of the co-existence of COPD and metabolic syndrome on adipose tissue hormones and insulin resistance as well as the differences between COPD patients with and without metabolic syndrome have not been adequately studied. The prevalence of metabolic syndrome, based on Adult Treatment Panel III (ATP III) criteria, was evaluated in 114 male patients with COPD without significant co-morbidities. Pulmonary functions tests (PFTs), arterial blood gases, quality of life and BODE index were assessed. Blood samples were obtained for the assessment of adipose tissue hormones and insulin resistance. The overall prevalence of metabolic syndrome was 21%, being more prevalent in earlier stages of COPD. Patients with COPD and metabolic syndrome were younger with higher body-mass index (BMI), had better pulmonary function, less static hyperinflation and air-trapping, better diffusing capacity for carbon monoxide and BODE index. These patients had higher levels of leptin, lower levels of adiponectin and increased insulin resistance, as expressed by HOMA index, compared with patients without metabolic syndrome. Metabolic syndrome was more prevalent in younger patients with less severe COPD. These patients may constitute a specific COPD phenotype with greater leptin to adiponectin imbalance and insulin resistance, despite smaller impairment in PFTs. The prognosis and differences of these patients compared with other COPD phenotypes needs to be determined in prospective studies.

Background: COPD is a multicomponent disease and systemic inflammation represents one of the possible mechanisms responsible for its systemic manifestations, including skeletal muscle weakness and cachexia. Fat-free mass index (FFMI) that reflects the skeletal muscle mass, has been shown to be associated with both dyspnoea and exercise capacity. We hypothesized that the multidimensional BODE index, that reflects the multicomponent nature of COPD, might be related to biomarkers of systemic inflammation. We further evaluated associations between FFMI and systemic inflammation., Methods: BODE index and FFMI were calculated in 222 stable COPD patients and 132 smokers or ex-smokers with normal lung function. Systemic inflammation was evaluated with the measurement of leptin, adiponectin, CRP, IL-6, and TNF-α in serum samples of COPD patients., Results: In patients with COPD, both BODE index and FFMI presented significant positive and negative associations respectively with leptin levels (R(2) 0.61 and 0.65, respectively), whereas FFMI presented an additional negative association with the levels of TNF-α (R(2) 0.38). No significant associations were observed in smokers or ex-smokers with normal lung function., Conclusions: Both BODE index and FFMI, are related to the circulating levels of leptin in patients with COPD, suggesting a possible role for leptin in the systemic component of COPD. The additional association of FFMI with TNF-α may further support a role of systemic inflammation in muscle wasting in COPD.

Background: Retrospective studies have shown that the use of statins is associated with reduced mortality and decreased hospitalizations from COPD, but data from prospective studies are lacking., Methods: We followed-up prospectively 245 patients admitted to hospital for exacerbations of COPD (ECOPD) with monthly evaluations for one year. The role of statins on outcomes was evaluated by Cox regression analysis after proper adjustments for age, gender, BMI, current smoking status, Charlson comorbidity index and COPD stage. Health-related quality of life (HRQoL) was evaluated by Saint George's Respiratory Questionnaire., Results: There was no effect of statins on either 30-day or 1-year mortality. Patients receiving statins presented a lower total number of ECOPD during the 1-year follow up (2.1 ± 2.7 vs. 2.8 ± 3.2 ECOPD/patient respectively, p = 0.037). After proper adjustments, the use of statins was associated with a lower risk for ECOPD [HR: 0.656 (95% CI: 0.454-0.946)] and severe ECOPD [HR: 0.608 (95%CI: 0.381-0.972)]. The group of statins presented better improvement in HRQoL at 2, 6 and 12 months (p < 0.001)., Conclusions: The use of statins in patients hospitalized for ECOPD was associated with a lower risk for subsequent ECOPD and severe ECOPD and improved HRQoL. These data support a possible beneficial role for these agents in COPD., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Endogenous airway acidification, as assessed by exhaled breath condensate (EBC) pH, is present in patients with stable COPD. The aim of this study was to measure EBC pH levels in a large cohort of COPD patients and to evaluate associations with functional parameters according to their smoking status.EBC was collected from 161 patients with stable COPD and 112 controls (current and ex-smokers). EBC pH was measured after Argon deaeration and all subjects underwent pulmonary function testing.EBC pH was lower in COPD patients compared to controls [7.21 (7.02, 7.44) vs. 7.50 (7.40, 7.66); p < 0.001] and ex-smokers with COPD had lower EBC pH compared to current smokers [7.16 (6.89, 7.36) vs 7.24 (7.09, 7.54), p = 0.03]. In ex-smokers with COPD, EBC pH was lower in patients with GOLD stage III and IV compared to patients with stage I disease (p = 0.026 and 0.004 respectively). No differences were observed among current smokers with different disease severity. EBC pH levels in ex-smokers were associated with static hyperinflation (as expressed by IC/TLC ratio), air trapping (as expressed by RV/TLC ratio) and diffusing capacity for carbon monoxide, whereas no associations were observed in current smokers.Endogenous airway acidification is related to disease severity and to parameters expressing hyperinflation and air trapping in ex-smokers with COPD. The possible role of EBC pH in COPD needs to be further evaluated in longitudinal studies.

Background: Asthma is a chronic inflammatory airways disorder. However, no biomarker of airways inflammation has been included in the assessment of asthma control., Objective: To evaluate exhaled NO (FeNO) and exhaled breath condensate (EBC) pH in patients with asthma according to the level of control, and their performance in the identification of not well-controlled patients., Methods: FeNO and EBC pH after Argon deaeration were measured in 274 consecutive patients. Asthma control was evaluated by two asthma specialists blinded to FeNO and pH measurements according to GINA guidelines, as well as by asthma control test (ACT) and asthma control questionnaire (ACQ)., Results: FeNO was higher and EBC pH was lower in patients with not well-controlled compared to controlled asthma. In ROC analysis, FeNO presented an AUC of 0.790 for the identification of not well-controlled asthma performing better in non-smokers; EBC pH presented an AUC of 0.791 for the identification of not well-controlled asthma, performing better in smokers. The performance of both biomarkers was inferior to that of ACT and ACQ. FeNO values >30 ppb presented positive predictive values (PPV) > 0.85 with the exception of smokers treated with inhaled corticosteroids. EBC pH values ≤7.20 presented PPV >0.80 in all groups. The presence of FeNO >30 ppb and/or EBC pH ≤7.20 was indicative of not well-uncontrolled asthma in 88.3% of the patients., Conclusion: FeNO and EBC pH levels may identify patients with not well-controlled asthma. However, their performance was inferior to clinical judgment and may be limited to selected subgroups of asthmatic patients., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Approximately 20 years after the initial report of the measurement of exhaled nitric oxide (NO) in the exhaled air of humans, numerous publications have evaluated the possible applications of the fraction of exhaled NO (FeNO) in patients with asthma. The aim of the present review is to evaluate the technical issues and confounding factors related to FeNO measurements, as well as the role of FeNO in the diagnosis of asthma, the evaluation of asthmatic patients and the guidance of treatment. Several other issues, including the pursuit for "normal" and best personal values, the prediction of clinically relevant asthma outcomes and the identification of asthma phenotypes and future directions are discussed. FeNO represents the only exhaled biomarker that has reached clinical practice even in primary care settings and this review provides a critical view of the possible applications of this biomarker, both for the basic researcher and the clinician.

Aims: To evaluate the prevalence and severity of COPD in a primary care population participating in a spirometry program. Differences between newly and previously diagnosed COPD patients were identified., Methods: A spirometry program was conducted in 15 primary care centres. Visitors aged over 30 years who were willing to perform spirometry were included in this program., Results: A total of 1,526 subjects provided acceptable spirometries. COPD prevalence in our population was 18.4%, of whom 69.0% were newly diagnosed. Most patients were classified as GOLD stages I and II (26.0% and 54.0%, respectively). COPD diagnosis was related to gender (men), age (older subjects), history of repeated respiratory infection in childhood, smoking (>10 pack-years) and presence of symptoms (cough, dyspnoea, wheezing). Variables related to newly diagnosed COPD were younger age and absence of chronic cough., Conclusions: A primary care spirometry program may identify a large proportion of undiagnosed COPD patients especially in the early stages of the disease. Newly diagnosed COPD patients were of younger age and presented with less symptoms. These results support the need for spirometry programs in primary care for early COPD detection.

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 leptin's involvement in the most common disorders of the respiratory system.

Background: Body composition is an important parameter for patients with chronic obstructive pulmonary disease (COPD) whereas the association between asthma and obesity is not fully understood. The impact of severe refractory asthma (SRA) on fat free mass (FFM) has not been investigated., Methodology and Principal Findings: 213 subjects (70 healthy smokers, 71 COPD patients and 72 asthma patients) without significant comorbidities were included in the study. In all patients, body composition assessment (using bioelectrical impendance analysis, skinfold and anthropometric measurements) and spirometry were performed. Differences in fat free mass index (FFMI) between groups were assessed and determinants of FFMI in asthma were evaluated. Patients with SRA had lower values of FFMI compared to patients with mild-to-moderate asthma [18.0(17.3-18.3)-19.5(18.4-21.5), p<0.001], despite the fact that they were more obese. The levels of FFMI in SRA were lower than those of GOLD stage I-III COPD and comparable to those of stage IV COPD patients [18.0(17.3-18.3)-18.8(17.8-20.1), p = ns]. These differences were present even after proper adjustments for sex, age, smoking status, daily dose of inhaled corticosteroids (ICS) and daily use of oral corticosteroids (OCS). In multivariate analysis, independent predictors of FFMI in asthmatic patients were age, use of OCS and the presence of SRA, but not smoking, sex or cumulative dose of ICS used., Conclusions and Significance: SRA is related to the presence of low FFMI that is comparable to that of GOLD stage IV COPD. The impact of this observation on asthma mechanisms and outcomes should be further investigated in large prospective studies.

The aim of this study was to determine the impact of HRCT-confirmed emphysema on biomarkers evaluating airway and systemic inflammation in COPD patients. Forty-nine consecutive male COPD outpatients with stable COPD were divided in two groups according to the presence or absence of emphysema on HRCT. Patients underwent pulmonary function tests, plus assessment of exercise capacity, body composition and quality of life. Biomarkers were measured in serum (CRP, interleukin-6, TNF-alpha, leptin, adiponectin, osteocalcin, insulin growth factor-1, and systemic oxidative stress), in plasma (fibrinogen and VEGF) and in whole blood (B-type natriuretic peptide). TNF-alpha, 8-isoprostane and pH were additionally measured in exhaled breath condensate. Patients with emphysema had more severe lung function impairment, lower body-mass index and fat-free mass index, and poorer quality of life. Additionally, they presented increased systemic oxidative stress and plasma fibrinogen and lower BNP compared to patients without emphysema. After proper adjustment for disease severity, all differences remained with the exceptions of body-mass index, fat-free mass index and BNP. COPD patients with HRCT-confirmed emphysema present increased systemic oxidative stress and fibrinogen, suggesting that they may be more prone to the systemic consequences of COPD compared to patients without emphysema.

Background: Acute exposure to cigarette smoke is related to airway and systemic inflammation and oxidative stress. Little is known about the acute effect of cigarette smoking in smoking asthmatics. The aim of this study was to evaluate the acute effect of smoking in airway and systemic inflammation and oxidative stress in normal smokers and patients with properly treated well-controlled persistent asthma., Materials and Methods: Ten normal smokers and 10 smokers with moderate persistent asthma controlled with LABA and ICS were recruited. Subjects refrained from smoking for at least 12 h prior to their inclusion. We compared the effects of smoking of two cigarettes on airway obstruction, airway inflammation and oxidative stress [by measuring fraction of exhaled nitric oxide (FeNO), plus pH and 8-isoprostane in exhaled breath condensate (EBC)] before and 30, 90 and 180 min after smoking. Furthermore, we evaluated systemic oxidative stress, C-reactive protein (CRP) and serum amyloid A (SAA) and urine leukotriene E(4) (LTE(4)) before and 180 min after smoking., Results: No differences were observed in EBC pH and 8-isoprostane, FeNO and systemic oxidative stress between the groups at baseline. In asthmatics, EBC pH decreased 30 min and EBC 8-isoprostane increased 90 min after smoking (P = 0.039 and P = 0.029 respectively), which was not evident in smoking controls. Serum oxidative stress increased only in asthmatic smokers at 180 min (P = 0.001). No differences were observed in SAA, CRP and urine LTE(4) levels before and after smoking., Conclusion: Acute smoking has more deleterious effects in well-controlled properly treated asthmatic smokers compared with matched normal smokers.

Background: Many patients with pneumonia develop pleural effusions. Pleural fluid vascular endothelial growth factor (VEGF) levels are known to be elevated in complicated parapneumonic effusion and seem to play a major role in the fibrotic process in the pleura., Objectives: To test whether VEGF levels in pleural effusions of infectious origin correlate with the residual pleural thickening., Methods: VEGF levels were measured in the pleural fluid of 45 patients with pleural effusion of infectious origin. Patients were reassessed 3 months after hospital discharge and residual pleural thickening (RPT) was recorded using a simple chest radiograph., Results: Pleural fluid VEGF was higher in empyemas compared to simple parapneumonic and complicated parapneumonic effusions. RPT was higher in patients with empyemas compared to simple parapneumonic effusions. Patients with RPT >2 mm had higher pleural fluid LDH and pleural fluid to serum LDH ratio, lower glucose and pH and higher VEGF levels. However, patients with RPT ≥10 mm differed only in pleural fluid VEGF levels. Pleural fluid VEGF levels correlated to RPT and to pleural fluid pH. VEGF presented moderate performance for the prediction of RPT 3 months after hospital discharge. Its performance was comparable to that of pleural fluid glucose and pH for the development of a radiologically significant RPT >2 mm, whereas it was the only statistically significant predictor of a clinically significant RPT ≥10 mm., Conclusion: VEGF levels are elevated in complicated parapneumonic effusions and empyemas compared to simple parapneumonic effusions and are a significant predictor for the development of clinically significant RPT., (Copyright © 2009 S. Karger AG, Basel.)

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.

The pathways underlying chronic obstructive pulmonary disease exacerbations (ECOPD) remain unclear. This study describes the clinical, functional and biochemical changes during recovery from ECOPD. Thirty hospitalized patients with Anthonisen's type-I ECOPD were evaluated on days 0 (admission), 3, 10 and 40. A five-symptom score (TSS), performance status and quality of life were evaluated. Post-bronchodilator spirometry, blood gases, oxidative stress, C-reactive protein (CRP), serum amyloid-A (SAA), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and fibrinogen were also measured. Patients were classified as early- or late-recoverers, based on whether dyspnea had returned to pre-exacerbation level by day 10. Most clinical, functional and biochemical parameters improved during follow-up. CRP and IL-6 levels reduced on Day 3 (p<0.05), whereas SAA on Day 10 (p<0.01). TNF-alpha was reduced on Days 3 and 10, but on Day 40 its levels returned to baseline. Fibrinogen and WBC reduced only by day 40. TSS and dyspnea were correlated inversely with FEV(1) on days 3, 10 and 40. Although late-recoverers had lower FEV(1) on admission, none of the reported measurements on admission and day 3 predicted early recovery. During recovery from ECOPD, symptomatic improvement correlates only with post-bronchodilator FEV(1) whereas systemic inflammatory burden subsidence does not correlate with clinical and functional changes. Although late-recoverers have lower FEV(1) on admission, none of the measured parameters is able to predict early symptomatic recovery.

Background: The association between systemic sclerosis and pulmonary arterial hypertension (PAH) is well recognized. Vascular endothelial growth factor (VEGF) has been reported to play an important role in pulmonary hypertension. The aim of the present study was to examine the relationship between systolic pulmonary artery pressure, clinical and functional manifestations of the disease and serum VEGF levels in systemic sclerosis., Methods: Serum VEGF levels were measured in 40 patients with systemic sclerosis and 13 control subjects. All patients underwent clinical examination, pulmonary function tests and echocardiography., Results: Serum VEGF levels were higher in systemic sclerosis patients with sPAP >or= 35 mmHg than in those with sPAP < 35 mmHg (352 (266, 462 pg/ml)) vs (240 (201, 275 pg/ml)) (p < 0.01), while they did not differ between systemic sclerosis patients with sPAP < 35 mmHg and controls. Serum VEGF levels correlated to systolic pulmonary artery pressure, to diffusing capacity for carbon monoxide and to MRC dyspnea score. In multiple linear regression analysis, serum VEGF levels, MRC dyspnea score, and D(LCO) were independent predictors of systolic pulmonary artery pressure., Conclusion: Serum VEGF levels are increased in systemic sclerosis patients with sPAP >or= 35 mmHg. The correlation between VEGF levels and systolic pulmonary artery pressure may suggest a possible role of VEGF in the pathogenesis of PAH in systemic sclerosis.

COPD is a diverse disease entity with multiple dimensions that uniquely define the patient's performance, morbidity and mortality. FEV(1) is both the traditional metric used to define the progression of COPD as well as the strongest spirometric predictor of mortality in COPD patients. However, besides pulmonary functional abnormalities, COPD is also associated with significant systemic effects. Therefore, the global assessment of an affected patient should include different aspects of the consequences of this disorder, beyond the "gold-standard" assessment of airflow limitation. Quantification of the patient's dyspnea, body composition as expressed by BMI, simple measures of exercise capacity such as the 6MWD, assessment of comorbidities and identification of characteristics related to different phenotypes are features that may lead to more optimal management of such patients.

Background: Accumulating evidence confirms the presence of pan-airway inflammation in allergic rhinitis patients. Smoking is known to affect the asthmatic airway inflammation. However, no study has evaluated the impact of smoking on airway inflammation of allergic rhinitis patients., Objective: The aim of the present study was to evaluate the impact of smoking on inflammatory and oxidative stress biomarkers in patients with seasonal allergic rhinitis, using non-invasive methods for sample collection., Methods: Forty patients with seasonal allergic rhinitis (20 smokers and 20 non-smokers) and 30 healthy subjects (15 smokers and 15 non-smokers) were recruited for the study during pollen season. All subjects were submitted to measurement of the fraction of exhaled NO (FeNO), exhaled breath condensate (EBC) collection, nasal lavage collection, pre- and post- bronchodilation spirometry and metacholine bronchial challenge testing. pH, leukotriene B(4) (LTB(4)) and 8-isoprostane were determined in EBC and nasal lavage samples., Results: Patients with allergic rhinitis presented higher LTB(4) and 8-isoprostane levels in nasal lavage (P<0.0001 for both comparisons), with no significant differences between smokers and non-smokers. Patients with allergic rhinitis also presented higher LTB(4) levels and lower pH in EBC (P<0.001 and P=0.004, respectively), with prominent differences between smokers and non-smokers (P<0.0001 and P=0.003, for LTB(4) and pH, respectively). A significant correlation between nasal lavage and EBC LTB(4) values was observed (r(s)=0.313, P=0.048)., Conclusions: Patients with allergic rhinitis present increased LTB(4) and 8-isoprostane in their nasal cavity, however, with no significant differences between smokers and non-smokers. In contrast, smokers with allergic rhinitis present higher LTB(4) levels and lower pH in EBC, suggesting that these patients may be more susceptible to the deleterious effects of smoking, compared with non-smokers.

Values of spirometry indices vary among subjects of similar age, gender and somatometrics but of different ethnic origins. Low socioeconomic status in childhood is inversely related to lung growth. The aim of this investigation was to assess spirometry values in Gypsy children and compare them to reported values for Caucasians. Gypsy students attending primary schools in Central Greece were recruited. Spirometry indices were measured using a portable spirometer. Regression analysis was applied to construct prediction equations for forced vital capacity (FVC) and other spirometric indices (FEV(1), FEF(50), FEF(25), FEF(25-75)) based on standing height. Predicted spirometric values were compared to values for Caucasians from published studies. In 152 children (ages 5-14 years; 57 girls) lung function increased linearly with height: spirometry index=intercept+[slopexheight], (r(2)=0.68 for FVC and FEV(1) in girls; r(2)=0.78 for FVC and r(2)=0.74 for FEV(1) in boys). Excluding boys-but not girls-in puberty increased fit for FVC (r(2)=0.83) and FEV(1) (r(2)=0.79). Mean predicted values were 5-10% lower than values for Caucasians. In Gypsy children, FVC and expiratory flow function increase linearly with standing height and predicted values are lower than those for Caucasians of similar height.

Vascular endothelial growth factor (VEGF) is known to play crucial role in tumour angiogenesis. It is demonstrated that VEGF can be up-regulated by oxidative stress. The aim of this study was to determine the serum VEGF levels and oxidative stress in patients with primary lung cancer and to investigate their association with clinicopathologic factors. We measured serum VEGF levels and oxidative stress in 63 patients (age 63.02+/-1.12 S.E.M.) with primary lung cancer before any treatment (39 NSCLC and 24 SCLC; 6 patients stage I, 3 stage II, 25 stage III and 29 stage IV) and 25 normal subjects. The serum VEGF levels were measured with enzyme linked immunosorbent assay. Serum oxidative stress levels were detected by a commercially available assay (D-ROMs test, Diacron, Grossetto, Italy). The levels of oxidative stress in patients were higher than those in normal subjects (555.3+/-30.35 UCarr vs. 360.1+/-17.46 UCarr). Additionally, a significant difference was found in serum VEGF levels between lung cancer patients and healthy control subjects (428.1+/-38.42pg/ml vs. 298.8+/-19.89pg/ml, respectively, p=0.040). Interestingly, serum oxidative stress presented a significant correlation with serum VEGF levels in patients with lung cancer (r=0.542, p=0.002). Serum VEGF levels were significantly associated with the clinical staging (N-stage) of the patients (p=0.023), performance status (p=0.004) and age (p=0.004). In conclusion, oxidative stress and VEGF are significantly increased in patients with primary lung cancer. The correlation between them might implicate new aspects of the mechanisms controlling tumour angiogenesis and may present clinical interest in the future. Further studies are warranted to evaluate the role of oxidative stress and VEGF as possible biomarkers for the diagnosis and follow-up of patients with lung cancer.

Background: The fraction of exhaled NO (FeNO) is valuable for the follow-up of asthmatic patients. However, its usefulness as a screening tool for asthma is not established., Methods: We screened a population of 961 university students with a modified European Community Respiratory Health Survey questionnaire that has been previously used for the screening of respiratory symptoms related to asthma. All subjects with a positive answer to at least one question (n = 149) were submitted to FeNO measurement with a portable nitric oxide analyzer. Subsequently, they were submitted to spirometry and evaluated by a physician blinded to FeNO measurements. Seventy students with no respiratory symptoms served as control subjects., Results: Asthma was diagnosed in 63 subjects, and allergic rhinitis was diagnosed in 57 subjects. Asthmatics presented higher FeNO values than control subjects (median, 20 parts per billion [ppb]; interquartile range, 14 to 31 ppb; vs median, 11 ppb; interquartile range, 7 to 13 ppb, respectively; p < 0.0001), whereas they did not differ from patients with allergic rhinitis (median, 17 ppb; interquartile range, 12 to 23 ppb; p = 0.28). FeNO values > 19 ppb presented 85.2% specificity and 52.4% sensitivity for the diagnosis of asthma (area under the curve [AUC], 0.723). The diagnostic performance of FeNO was better in nonsmokers (AUC, 0.805), yet FeNO values > 25 ppb were characterized by specificity > 90% for the diagnosis of asthma both in smokers and in nonsmokers. However, FeNO was not a good marker for the differentiation between asthma and allergic rhinitis., Conclusions: FeNO measurement with a portable analyzer is useful for the screening for asthma in young adults. Significant confounding factors are allergic rhinitis and current smoking.

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal illness characterized by progressive fibrosis resulting in severe dyspnea and impairment of lung function. Although the mechanisms by which lung fibrosis develops are not fully ascertained, recent findings suggest that oxidative stress may play an important role in the pathogenesis of tissue fibrosis., Aim: To evaluate the oxidative stress in the serum of patients with IPF and to explore the relationship between oxidative stress levels, dyspnea and impairment of lung function., Material and Methods: Blood samples from 21 untreated patients with IPF, sequentially recruited over a period of 2 years, and 12 controls were analyzed. The level of oxidative stress in the blood was determined through a spectrophotometric procedure (D-ROMs test). FVC and DLCO were measured in all patients. The level of dyspnea was assessed by the Medical Research Council (MRC) chronic dyspnea scale., Results: Serum levels of oxidative stress were significantly increased in patients with IPF compared to controls (mean+/-SEM: 356.8+/-14 and 201+/-10 Carratelli units respectively, p<0.001). Oxidative stress was negatively associated with FVC (p<0.01, r=-0.79) and with DLCO (p<0.01, r=-0.75). Furthermore, oxidative stress was significantly correlated with MRC dyspnea score (p<0.01, r=0.87). Oxidative stress measurements were highly reproducible on two consecutive measurements in the same patients., Conclusion: The levels of systemic oxidative stress are enhanced in patients with IPF and could provide useful information about the classification of IPF severity. Strategies to reduce the oxidant burden in IPF may be beneficial in reducing the progressive deterioration of these patients.

Pleural effusion is a common complication of various diseases. Conventional methods are not always capable of establishing the cause of pleural effusion, so alternative tests are needed. The aim of this study was to explore means of discriminating between different pleural effusion groups, malignant, parapneumonic and tuberculous, based on the combined function of seven biological markers. Adenosine deaminase (ADA), interferon-gamma, C-reactive protein (CRP), carcinoembryonic antigen, interleukin-6, tumour necrosis factor-alpha and vascular endothelial growth factor concentration levels were measured in pleural fluid from 45 patients with malignant, 15 with parapneumonic and 12 with tuberculous pleural effusion. Receiver operating characteristic curve analysis, multinomial logit modelling and canonical variate analysis were applied to discriminate the pleural effusion groups. The three groups could be discriminated successfully using the measured markers. The most important parameters for discrimination were ADA and CRP concentration levels. An individual with an ADA concentration level of >45 U.L(-1) and a CRP concentration of <4 mg.dL(-1) was more likely to belong to the tuberculous pleural effusion group, whereas one with an ADA concentration level of <40 U.L(-1) and a CRP concentration of >6 mg.dL(-1) was more likely to belong to the parapneumonic pleural effusion group, and one with a CRP concentration of <4 mg.dL(-1) to the malignant pleural effusion group. The combination of adenosine deaminase and C-reactive protein levels might be sufficient for discriminating between the three different groups of exudative pleural effusion: malignant, tuberculous and parapneumonic.

Vascular endothelial growth factor (VEGF) is a potent mediator of angiogenesis which has multiple effects in lung development and physiology. VEGF is expressed in several parts of the lung and the pleura while it has been shown that changes in its expression play a significant role in the pathophysiology of some of the most common respiratory disorders, such as acute lung injury, asthma, chronic obstructive pulmonary disease, obstructive sleep apnea, idiopathic pulmonary fibrosis, pulmonary hypertension, pleural disease, and lung cancer. However, the exact role of VEGF in the lung is not clear yet, as there is contradictory evidence that suggests either a protective or a harmful role. VEGF seems to interfere in a different manner, depending on its amount, the location, and the underlying pathologic process in lung tissue. The lack of VEGF in some disease entities may provide implications for its substitution, whereas its overexpression in other lung disorders has led to interventions for the attenuation of its action. Many efforts have been made in order to regulate the expression of VEGF and anti-VEGF antibodies are already in use for the management of lung cancer. Further research is still needed for the complete understanding of the exact role of VEGF in health and disease, in order to take advantage of its benefits and avoid its adverse effects. The scope of the present review is to summarize from a clinical point of view the changes in VEGF expression in several disorders of the respiratory system and focus on its diagnostic and therapeutic implications.