Clinical Importance of Angiogenic Cytokines, Fibrinolytic Activity and Effusion Size in Parapneumonic Effusions

Fibrinolytic Activity and Effusion Size in Parapneumonic Effusions. PLoS ONE 8(1): e53169. doi:10.1371/journal.pone.0053169 Clinical Importance of Angiogenic Cytokines, Fibrinolytic Activity and Effusion Size in Parapneumonic Effusions Chi-Li Chung 0 Shih-Hsin Hsiao 0 George Hsiao 0 Joen-Rong Sheu 0 Wei-Lin Chen 0 Shi-Chuan Chang 0 T. Mark Doherty, Statens Serum Institute, Denmark 0 1 Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital , Taipei, Taiwan , 2 School of Respiratory Therapy, College of Medicine, Taipei Medical University , Taipei, Taiwan , 3 Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University , Taipei, Taiwan , 4 Department of Chest Medicine, Taipei Veterans General Hospital , Taipei, Taiwan , 5 Institute of Emergency and Critical Care Medicine, National Yang-Ming University , Taipei , Taiwan Objective: To investigate the relationship among angiogenic cytokines, fibrinolytic activity and effusion size in parapneumonic effusion (PPE) and their clinical importance. Methods: From January 2008 through December 2010, 26 uncomplicated (UPPE) and 38 complicated (CPPE) PPE were studied. Based on chest ultrasonography, there were non-loculated in 30, uni-loculated in 12, and multi-loculated effusions in 22 patients. The effusion size radiological scores, and effusion vascular endothelial growth factor (VEGF), interleukin (IL)-8, plasminogen activator inhibitor type-1 (PAI-1) and tissue type plasminogen activator (tPA) were measured on admission. Treatment outcome and pleural fibrosis, defined as radiological residual pleural thickening (RPT), were assessed at 6-month follow-up. Results: The effusion size and effusion VEGF, IL-8 and PAI-1/tPA ratio were significantly higher in CPPE than in UPPE, and significantly higher in multi-loculated PPE than in non-locualted and uni-loculated PPE, respectively. VEGF (cutoff value 1975 pg/ml) and IL-8 (cutoff value 1937 pg/ml) seemed best to discriminate between UPPE and CPPE. VEGF, IL-8 and effusion size correlated positively with PAI-1/tPA ratio in both UPPE and CPPE. Moreover, the level of VEGF, but not IL-8, correlated positively with effusion size in all patients (r = 0.79, p,0.001) and in UPPE (r = 0.64, p,0.001) and CPPE (r = 0.71, p,0.001) groups. The patients with higher VEGF or greater effusion were prone to have medical treatment failure (n = 10; VEGF, odds ratio 1.01, p = 0.02; effusion size, odds ratio 1.26, p = 0.01). Additionally, ten patients with RPT had larger effusion size and higher levels of VEGF and PAI-1/tPA ratio than did those without. Conclusions: In PPE, VEGF and IL-8 levels are valuable to identify CPPE, and higher VEGF level or larger effusion is associated with decreased fibrinolytic activity, development of pleural loculation and fibrosis, and higher risk of medical treatment failure. - Funding: This study was supported by a grant from the National Science Council of Taiwan (NSC98-2314-B-038-022-MY2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Formation of parapneumonic effusion (PPE) involves increased vascular permeability of the pleura induced by the contiguous pneumonia. Exposure of pleural mesothelial cells to bacteria or lipopolysaccharide may increase release of angiogenic factors, including vascular endothelial growth factor (VEGF) and interleukin (IL)-8, induce vascular hyperpermeability and pleural fluid production, activate coagulation cascade, and repress fibrinolytic activity within the pleural cavity [1,2], leading to the development of a fibrinopurulent or complicated PPE (CPPE) [3]. Fluid loculation with fibrin septation is commonly found to be the initial presentation of CPPE and associated with poor outcome [4,5]. Fibrin turnover in the pleural cavity is affected by fibrinolytic activity mediated by plasmin, which is regulated by the equilibrium between plasminogen activators (PAs) and plasminogen activator inhibitors (PAIs) [6]. An imbalance between PAI-1 and tissue type plasminogen activator (tPA) may elicit fibrin formation and subsequent pleural fluid loculation and fibrosis [5,7]. VEGF may facilitate the genesis of fibrin gel in PPE [8]. Previous studies reported that VEGF might play a role in the modulation of tPA and PAI-1 [9], and that anti-VEGF antibody could attenuate pleurodesis and reduced fluid volume of inflammatory pleural effusion in experimental models [1012]. These findings suggest that VEGF may be involved in the regulation of fibrin turnover and fluid loculation in the pleural cavity and subsequent residual pleural thickening (RPT) or fibrosis [8]. However, the clinical relevance of angiogenic cytokines, fibrinolytic activity and effusion volume in PPE remains unclear. The aim of the present study was to evaluate the relationship among angiogenic cytokines (VEGF, IL-8), fibrinolytic parameters (tPA and PAI-1) and effusion size in PPE, and their clinical importance. Study Design This single-center, prospective study intended to assess the clinical importance of angiogenic cytokines, fibrinolytic activity and effusion size in PPE. Ethics approval (CRC-05-11-01) was obtained from the Institutional Review Board of Taipei Medical University (Taipei, Taiwan), and all patients gave written informed consent before entering the study. Patient Selection Consecutive patients with pleural effusions (PE) of unknown causes admitted to Taipei Medical University Hospital were eligible for this study, and were included when a diagnosis of PPE was established. Exclusion criteria were as follows: history of invasive procedures directed into the pleural cavity; recent severe trauma, hemorrhage, or stroke; bleeding disorder or anticoagulant therapy; use of streptokinase in the previous 2 years. Imagings of PE PE were evaluated and divided into loculated or non-loculated effusions by chest radiography (CXR), chest ultrasonography (US), or thoracic computed tomography (CT) scans as previously described [5]. Patients with loculated effusions were subdivided into uni-loculated and multi-loculated effusion groups by chest US. The patients with multiple loculi of effusions divided by fibrin septa were classified into multi-loculated effusion group, and those who had a single loculated effusion without fibrin septation were classified into uni-loculated effusion group (see Protocol S1) [13]. CXR Scoring The posteroanterior CXR films were read and scored by two radiologists who were blind to any clinical information to determine (a) the largest linear width of pleural opacity and (b) effusion size CXR score: the estimated overall percentage of pleural shadowing in the hemithorax (see Protocol S2) [14]. Thoracentesis and Pleural Fluid Analysis With the guidance of chest US, 50 ml of pleural flui (...truncated)