Andriana I. Papaioannou

Clinical implications for Vascular Endothelial Growth Factor in the lung: friend or foe?

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.

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.

Discrimination of exudative pleural effusions based on multiple biological parameters

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-γ, C-reactive protein (CRP), carcinoembryonic antigen, interleukin-6, tumour necrosis factor-α 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.

Systemic and airway inflammation and the presence of emphysema in patients with COPD

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.

The impact of depressive symptoms on recovery and outcome of hospitalised COPD exacerbations.

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 Becks 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.

COPD prevalence and the differences between newly and previously diagnosed COPD patients in a spirometry program.

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.

Serum VEGF levels are related to the presence of pulmonary arterial hypertension in systemic sclerosis

BackgroundThe 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.MethodsSerum VEGF levels were measured in 40 patients with systemic sclerosis and 13 control subjects. All patients underwent clinical examination, pulmonary function tests and echocardiography.ResultsSerum VEGF levels were higher in systemic sclerosis patients with sPAP ≥ 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 DLCO were independent predictors of systolic pulmonary artery pressure.ConclusionSerum VEGF levels are increased in systemic sclerosis patients with sPAP ≥ 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.

Exhaled NO and exhaled breath condensate pH in the evaluation of asthma control

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.

The role of macrophages in obstructive airways disease: Chronic obstructive pulmonary disease and asthma

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.

Serum uric acid as a predictor of mortality and future exacerbations of COPD

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. Serum uric acid was linked with airflow limitation in COPD and predicted mortality and future exacerbations http://ow.ly/qflaZ