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Objective: To establish a high-performance liquid chromatography (HPLC)-based method for determining isoniazide concentration in pleural effusion and plasma of patients with tuberculous pleurisy, and evaluate the permeability of isoniazide from blood into pleural effusion., Methods: We collected pleural effusion from 15 patients with tuberculous pleurisy 2 h after administration 300 mg isoniazide in the morning of day 1. Pleural effusion and plasma were obtained 2 h after isoniazide administration on day 3. Isoniazide concentration was measured using HPLC, and the penetration rate of isoniazide in pleural effusion was calculated., Results: Isoniazide concentration in the pleural effusion averaged 1.156∓1.190 µg/ml in the 15 patients at 2 h after isoniazide administration on day 1. On day 3, isoniazide concentration was 1.920∓1.294 µg/ml in the pleural effusion and 2.445∓1.463 µg/ml in the plasma, and the mean penetration rate of isoniazide from blood into the pleural effusion was 86.0%., Conclusion: As isoniazide has a high penetration rate into the pleural effusion in most patients, continuous oral administration of isoniazid has been sufficient to achieve an effective treatment concentration, and intrapleural injection of isoniazide may seem unnecessary for non-drug-resistant tuberculosis pleurisy.

The aim of this study was to evaluate the diagnostic value of interleukin 21 (IL-21) and carcinoembryonic antigen (CEA) in tuberculous pleural effusions (TPEs) and malignant pleural effusions (MPEs). Pleural effusion samples from 103 patients were classified on the basis of diagnosis as TPE (n=51) and MPE (n=52). The concentration of IL-21 was determined by ELISA. Lactate dehydrogenase (LDH), adenosine dehydrogenase (ADA) and CEA levels were also determined in all patients. A significant difference was observed in the levels of ADA and CEA (P<0.01), but not in the levels of LDH (P>0.05) between TPE and MPE. The concentration of IL-21 in MPE was significantly higher compared to TPE (P<0.01). With a threshold value of 4.32 pg/ml, IL-21 had a sensitivity of 76.9% (40/52) and a specificity of 80.4% (41/51). Combined detection of IL-21 and CEA had a sensitivity of 69.2% (36/52) and a specificity of 92.2% (47/51). These two markers can contribute to the differential diagnosis of MPEs.

Background and Objective: The aim of this study was to determine whether high levels of pleural adenosine deaminase (pADA) are predictive for tuberculosis when pleural effusions do not satisfy the criteria for lymphocytic effusions or show neutrophil predominance., Methods: This was a retrospective observational study of 147 consecutive patients with exudative pleural effusions that were diagnosed by analysis of fluid samples during a 3-year period from 1 April 2007 to 31 March 2010. Multiple linear correlation tests were used to assess clinical variables as possible predictors of high pADA levels., Results: High pleural LDH (pLDH) and pleural potassium (pK) levels were associated with high pADA levels (P < 0.0001). Although there was a linear correlation between pLDH and pADA levels in patients with parapneumonic effusions (PPE) (n = 75), tubercular effusions (n = 21), malignant effusions (n = 41) and miscellaneous effusions (n = 10), a significant linear correlation between pK and pADA levels was observed only in patients with PPE (ρ = 0.525, P < 0.0001). When the cut-off value for pK was set at 5.0 mEq/L, pADA levels were >50 IU/L and pK levels were >5.0 mEq/L in only one patient (5%) in the tuberculosis group (n = 21) and 15 patients (12%, all with PPE) in the non-tuberculosis group (n = 126)., Conclusions: When pK levels exceed 5.0 mEq/L, high pADA levels do not necessarily indicate the presence of tuberculous pleuritis., (© 2011 The Authors. Respirology © 2011 Asian Pacific Society of Respirology.)

Objective: Current tools for the diagnosis of tuberculous pleural effusions are suboptimal. The study was undertaken to evaluate the accuracy of pleural fluid adenosine deaminase (ADA), interferon (IFN)-γ, interferon-γ-induced protein of 10 kDa (IP-10), and dipeptidyl peptidase (DPP) 4 levels in differentiating tuberculous pleural effusion (TPE) and non-TPE., Methods: A total of 122 samples of pleural effusion were studied. Pleural fluid ADA activity was measured with the colorimetric method, and IP-10, IFN-γ, and DPP4 levels were measured with enzyme-linked immunosorbent assay., Results: ADA activity and IP-10, IFN-γ, and DPP4 levels were significantly higher in TPE than in non-TPE (88.9 ± 62.7 U/L vs 18.1 ± 16.2 U/L, P < .05; 147.5 ± 117.3 ng/L vs 24.9 ± 19.7 ng/L, P < .05; 627.2 ± 345.3 ng/L vs 152.6 ± 71.4 ng/L, P < .05; and 560.6 ± 451.2 vs 56.8 ± 57.7, P < .05, respectively). The diagnostic sensitivity and specificity of ADA activity (cutoff value of 40 U/L) were 93.6% and 90.9%, respectively, and higher than those of IFN-γ (91.0% and 88.6% at the cutoff value of 225 ng/L, respectively), DPP4 (88.5% and 81.8% at the cutoff value of 75 ng/L, respectively), and IP-10 (83.3% and 86.4% at the cutoff value of 44 ng/L, respectively)., Conclusion: The roles of ADA and IFN-γ in the differential diagnosis of tuberculous pleurisy are pivotal. ADA or IFN-γ in combination with DPP4 or IP-10 can aid in differentiation between TPE and non-TPE with improved specificity and diagnostic efficiency., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In this study, copper, zinc, magnesium, manganese, selenium, and iron of urine and hair were measured in the patients with tuberculous (TB) pleurisy (n = 24) and in the control group (n = 20). Selenium, magnesium, and zinc of hair were found to be significantly lower in TB pleurisy cases than those in the control group (p < 0.05, p < 0.001, and p < 0.01, respectively). On the contrary, selenium and magnesium of urine were found to be significantly elevated in TB pleurisy cases than those in the control group (p < 0.05 and p < 0.001, respectively). There was no significant difference in the value of manganese and iron between TB pleurisy and the control group (p > 0.05). Copper level were significantly increased in hair and decreased in urine of the patients (p < 0.01). The occurrence of these abnormalities constitutes new information regarding trace elements in TB pleurisy patients. These results may provide an additional disease correlate for assessing TB pleurisy risk.

The diagnosis and treatment of TB infection is one of the public health priorities. Until recently, diagnosis of TB infection has been based on the tuberculin skin test (TST). However, this is neither 100% sensitive nor specific for the diagnosis of TB infection owing to its many drawbacks. More recently, T-cell-based IFN-γ release assays (IGRAs) have been developed. In this article, we review the clinical performance of one of the IGRAs, T-SPOT.TB assay, for the diagnosis of TB infection in adults and children. We discuss the principle of the assay, its utility in active TB diseases, latent TB infection and the performance of the test in specialized subgroups of patients, such as immunocompromised individuals. When compared with the TST, the T-SPOT.TB assay has better specificity in bacillus Calmette-Guérin-vaccinated individuals, and data suggest that T-SPOT.TB may be more sensitive than the TST. Data in groups at high risk of progression to disease support the idea that T-SPOT.TB performs better than the TST. In addition, application of T-SPOT.TB by using bodily fluids such as cerebrospinal fluid, bronchoalveolar lavage fluid and pleural fluid may offer new diagnostic approaches in extrapulmonary TB disease. Although IGRAs cannot distinguish active TB disease from latent TB infection, these assays perform better than the TST for the detection of TB infection.

The role of CD16(-) and CD16(+) Mo subsets in human TB remains unknown. Our aim was to characterize Mo subsets from TB patients and to assess whether the inflammatory milieu from TB pleurisy modulate their phenotype and recruitment. We found an expansion of peripheral CD16(+) Mo that correlated with disease severity and with TNF-α plasma levels. Circulating Mo from TB patients are activated, showing a higher CD14, CD16, and CD11b expression and Mtb binding than HS. Both subsets coexpressed CCR2/CCR5, showing a potential ability to migrate to the inflammatory site. In tuberculous PF, the CD16(+) subset was the main Mo/MΦ population, accumulation that can be favored by the induction of CD16 expression in CD16(-) Mo triggered by soluble factors found in this inflammatory milieu. CD16(+) Mo in PF were characterized by a high density of receptors for Mtb recognition (DC-SIGN, MR, CD11b) and for lipid-antigens presentation (CD1b), allowing them to induce a successful, specific T cell proliferation response. Hence, in tuberculous PF, CD16(+) Mo constitute the main APC population; whereas in PB, their predominance is associated with the severity of pulmonary TB, suggesting a paradoxical role of the CD16(+) Mo subset that depends on the cellular localization.

Associations of interleukin-10 (IL-10) gene promoter polymorphisms and pleural tuberculosis risk remain unclear. The objective of this study was to determine IL-10 gene promoter polymorphisms at -1082, -819 and -592 sites and their protein production in pleural fluid (PF) in patients with and without pleural tuberculosis. IL-10 gene promoter polymorphisms at the -1082, -819 and -592 sites were genotyped using a SNaPshot assay. Protein levels of IL-10 in PF were measured using an enzyme-linked immunosorbent assay. There were no significant differences in the genotype and allele frequencies of IL-10 gene promoter polymorphisms at position -1082 between the pleural tuberculosis and the control groups. However, the frequency of -819 T or -592 A alleles was significantly more common in patients with pleural tuberculosis than controls. The protein levels of IL-10 in PF were statistically higher in the pleural tuberculosis group than in the control group. Moreover, the polymorphisms at the -1082, -819 and -592 sites were associated with protein levels of IL-10 in PF in the pleural tuberculosis group, while in the control group, only the polymorphism at position -1082 correlated with the protein levels. These findings support the association between IL-10 promoter polymorphisms at -819 and -592 sites and their protein production with pleural tuberculosis risk., (© 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

Th17 cells have emerged as an important mediator in inflammatory and autoimmune diseases. Recent studies suggest a potential impact of Th17 cells on tuberculosis (TB) infection. This study was designed to investigate the possible involvement of Th17 cells in tuberculous pleural effusion. Compared with healthy volunteers, patients with TB had a higher proportion of Th17 cells in peripheral blood mononuclear cells (PBMCs). Moreover, the percentage of Th17 cells in pleural effusions of TB patients was obviously higher than that in PBMC from TB patients or healthy controls. Furthermore, the mRNA and protein expression levels of IL-17 and IL-6 were significantly increased in the patients with tuberculous pleural effusion, while expression level of TGF-β was decreased in the pleural effusion. Correlation analysis showed a significant correlation between IFN-γ concentrations and the frequencies of Th17 cells in tuberculous pleural effusion. These results indicate that Th17 cells may contribute to the immunopathogenesis of tuberculous pleural effusion., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: Pleural tuberculosis (TB) is a diagnostic challenge because of its non-specific clinical presentation and paucibacillary nature. Conventional diagnosis methods have limitations. We evaluated the real-time polymerase chain reaction (PCR), interferon-gamma (IFN-γ), adenosine deaminase (ADA), and immunoglobulin A (IgA)., Methods: We assessed 204 cases: 50 were confirmed pleural TB, 104 were probable pleural TB, and 50 formed the non-TB group. IFN-γ and IgA were measured by enzyme-linked immunosorbent assay and ADA was measured by colorimetric assay. Real-time PCR was carried out using the 16S rRNA sequence, pleural biopsy specimens were submitted to histopathologic examination, pleural fluid culture was undertaken using Lowenstein-Jensen and MGIT-BACTEC, and pleural fluid smears were stained with auramine O., Results: For confirmed and probable pleural TB cases, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was highest for IFN-γ (0.994 and 0.963, respectively), followed by ADA (0.989 and 0.945, respectively), real-time PCR (0.898 and 0.784, respectively), and IgA (0.817 and 0.784, respectively). For confirmed and probable pleural TB cases, IFN-γ showed the highest sensitivity (98% and 76.9%, respectively), followed by ADA (92% and 73%, respectively), real-time PCR (80% and 57.7%, respectively), and IgA (70% and 57.7%, respectively). With regard to combined positivity, the combination of 'either real-time PCR or IFN-γ' showed the highest sensitivity: 100% in confirmed pleural TB and 96.2% in probable pleural TB., Conclusions: IFN-γ showed the highest sensitivity as an individual diagnostic test. When a combination of tests was used, positivity of 'either IFN-γ or real-time PCR' appeared valuable for the diagnosis of pleural TB., (Copyright © 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Accurately differentiating tuberculous pleurisy from lung cancer is important for disease management but difficult using conventional laboratory methods. This study assessed the value of adenosine deaminase (ADA) and interferon gamma (IFN-γ) for differentiating the two conditions in a region of Taiwan with a high prevalence of tuberculosis. The study population comprised patients with lymphocytic exudative pleural effusions: tuberculous (n=24) and malignant (n=42). Mean levels of ADA and IFN-γ in pleural fluid, measured with commercial standardized kits, were significantly higher for tuberculous than for malignant pleurisy (p<0.001 for both). For differentiating the two effusions, results for ADA versus IFN-γ were: sensitivity, 70.8% versus 91.7%; specificity, 95.2% versus 97.6%; positive predictive value, 89.5% versus 96.7%; and negative predictive value, 85.1% versus 95.3%. IFN-γ allows precise diagnosis of pleural tuberculosis, but ADA is easier to use, has a low cost, and results are quickly available. Our study confirms previous studies and extends the usefulness of these diagnostic methods to a wider group of clinical laboratories by showing the reliability of standardized relatively inexpensive commercial kits. We recommend that initial ADA screening be used in conjunction with IFN-γ measurements for differential diagnosis of tuberculous pleurisy., (Copyright © 2011. Published by Elsevier B.V.)

Th1 cell-mediated adaptive immune response is very important but may not be sufficient to control Mycobacterium tuberculosis (M. tuberculosis) infection. The roles of the various T cell subsets and cytokines in the inflammatory processes are not clearly elucidated. We investigated whether Th1, Th22 and Th17 cells mediated cellular immunity at the local site of M. tuberculosis infection in patients with tuberculous pleurisy (TBP). The results showed that the cytokines IFN-γ and IL-22 but not IL-17 were elevated in tubercular pleural fluid. Following stimulation with immune-dominant peptides of early secreted antigenic target-6 (ESAT-6), culture filtrate protein-10 (CFP-10) or Bacille Calmette-Guerin, pleural fluid mononuclear cells expressed high levels of cytokines IFN-γ, IL-22 and IL-17 as revealed by mRNA and protein measurements. In addition, we showed that cytokines IFN-γ, IL-22 and IL-17 were produced in M. tuberculosis-specific immune response by distinct subsets of CD4+ T cells with the phenotype of CD45RA-CD62L-CCR7+CD27+ . Our results demonstrated for the first time that ESAT-6- and CFP-10-specific Th1, Th22 and Th17 cells existed in the patients with TBP and might play an essential role against M. tuberculosis infection. The findings of this study raised the possibility of unravelling the critical targets for therapeutic intervention in chronic inflammatory diseases such as TBP., (© 2011 The Authors. Scandinavian Journal of Immunology © 2011 Blackwell Publishing Ltd.)

In recent years, better diagnostics for tuberculosis (TB) has received increasing attention, especially the diagnosis of tuberculous pleural effusion, which is difficult and at present the main tool in TPE diagnostic is pleural effusion smear and culture, but unfortunately, sensitivities are low, therefore better TPE diagnostic tools are needed. The aim of this study was to find a diagnostic algorithm to assess the progress in TPE diagnostic at the Hospital Vargas de Caracas, that permits identification of the majority of patients, at a satisfactory cost-benefit ratio, evaluating the levels of IFN-gamma and IL-12p40 in pleural effusion and serum, as well as the antibody reactivity in order to compare it with microbiological tests. A total of 60 individuals with pleural effusion were studied; 20 patients with tuberculous pleural effusion (TPE) formed the patient group and 40 patients with non-tuberculous pleural effusion (NTPE) formed the control group. The levels of IFN-gamma and IL-12p40 in effusion and serum and class and subclasses of IgG reactivity to Mycobacterium tuberculosis antigens were measured by ELISA. The utility of these methods for diagnosis of TPE was evaluated using receiver operating characteristic (ROC) curve analysis. The results of the 11 immunological methods evaluated showed that the anti-PPD IgG2 method was able to reach the highest specificity of 95% (CI: 88.3-101.8), positive predictive value (PPV) = 75 (at 30% sensitivity); while that the overall sensitivity of methods was between 95% and 30%, of these, two methods reached higher sensitivities; increased levels of pleural IFN-gamma, with a sensitivity of 95% (CI: 85.5-104.5) with the highest negative predictive value (NPV) = 97, (at 82.5% specificity), followed by decreased levels of serum IL-12p40 with a sensitivity of 95% (CI: 85.5-104.5), NPV = 95.2 (at 50% specificity). In contrast, microbiological methods showed that smear had a sensitivity of only 20%, while smear plus culture had, a sensitivity of 70%. Considering that TPE represents approximately 15 percent of all the TB clinically diagnosed at the Hospital Vargas de Caracas, in those patients with preliminary microbiology negativity in the effusion, the combined analysis of pleural IFN-gamma and anti-PPD IgG2 could represent a fast and effective diagnostic algorithm for improving the diagnosis previous to obtain culture results. In this way treatment against TB could be initiated or the need to cytological and pleural biopsy could be considered.

Pleural tuberculosis (TB) remains a common presentation of Mycobacterium tuberculosis (MTB) infection in HIV/TB dually infected subjects, and both cellular and acellular components of the pleural milieu promote HIV-1 replication; however, they remain uncharacterized. Using cytokine array of pleural fluid and real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunophenotype analysis, pleural fluid mononuclear cells (PFMC) were compared to systemic counterparts [i.e. plasma and peripheral blood mononuclear cells (PBMC)]. Significant increases in pleural fluid cytokines compared to plasma were limited to interleukin (IL)-6, IL-8, interferon (IFN)-γ and transforming growth factor (TGF)-β, and did not include other T helper type 1 (Th1) (IL-2, IL-15), Th2 or Th17 cytokines. Patterns and levels of cytokines were indistinguishable between pleural fluid from HIV/TB and TB patients. Forkhead box P3 (FoxP3) mRNA in PFMC was increased significantly and correlated highly with levels of IL-6 and IL-8, less with TGF-β, and not with IFN-γ. Among CD4 T cells, FoxP3-reactive CD25(hi) were increased in HIV/TB dually infected subjects compared to their PBMC, and up to 15% of FoxP3(+) CD25(hi) CD4 T cells were positive for IL-8 by intracellular staining. These data implicate a dominant effect of MTB infection (compared to HIV-1) at pleural sites of dual HIV/TB infection on the local infectious milieu, that include IL-6, IL-8, IFN-γ and TGF-β and regulatory T cells (T(reg) ). A correlation in expansion of T(reg) with proinflammatory cytokines (IL-6 and IL-8) in pleural fluid was shown. T(reg) themselves may promote the inflammatory cytokine milieu through IL-8., (© 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.)

The T lymphocyte-mediated immune response to Mycobacterium tuberculosis infection in the parietal pleura of patients with tuberculous pleurisy is unknown. The aim of this study was to investigate the immune response in the parietal pleura of tuberculous pleurisy compared with nonspecific pleuritis. We have measured the numbers of inflammatory cells particularly T-cell subsets (Th1/Th2/Th17/Treg cells) in biopsies of parietal pleura obtained from 14 subjects with proven tuberculous pleurisy compared with a control group of 12 subjects with nonspecific pleuritis. The number of CD3+, CD4+ and CCR4+ cells and the expression of RORC2 mRNA were significantly increased in the tuberculous pleurisy patients compared with the nonspecific pleuritis subjects. The number of toluidine blue+ cells, tryptase+ cells and GATA-3+ cells was significantly decreased in the parietal pleura of patients with tuberculous pleurisy compared with the control group of nonspecific pleuritis subjects. Logistic regression with receiver operator characteristic (ROC) analysis for the three single markers was performed and showed a better performance for GATA-3 with a sensitivity of 75%, a specificity of 100% and an AUC of 0.88. There was no significant difference between the two groups of subjects in the number of CD8, CD68, neutrophil elastase, interferon (IFN)-γ, STAT4, T-bet, CCR5, CXCR3, CRTH2, STAT6 and FOXP3 positive cells. Elevated CD3, CD4, CCR4 and Th17 cells and decreased mast cells and GATA-3+ cells in the parietal pleura distinguish patients with untreated tuberculous pleurisy from those with nonspecific pleuritis.

Aim: To evaluate cytokine production by CD4(+); T cells and frequency of multifunctional CD4(+); T cells after stimulation with ESAT-6 peptide pool. To understand the role of ESAT-6 specific CD4(+); T cells in the control of local TB infection., Methods: PFCs were isolated from patients with tuberculous pleurisy, and assessed by flow cytometry for cytokine production, subpopulation, frequency and function of multifunctional CD4(+);T cells after stimulation with ESAT-6 peptide pool., Results: Following stimulation with BCG, ESAT-6 peptide pool and recombinant ESAT-6 protein, CD4(+); but not CD8(+); T cells expressed IFN-γ, IL-2 and TNF-α. Distinct from BCG, ESAT-6 peptide pool and recombinant ESAT-6 protein induced similar frequencies of IFN-γ, IL-2 and TNF-α. High frequency of multifunctional CD4(+);T cells was observed. Analysis of mean fluorescence intensity (MFI) indicated that triple positive cells produced most amounts of cytokines on single cell level compared with double positive and single positive cells., Conclusion: ESAT-6 peptide pool predominantly induced Th1 cytokine production by CD4(+);T cells in PFCs. Multifunctional CD4(+); T cells were observed and secreted most amounts of cytokines on single cell level, suggesting that these cells probably played essential role in local TB infection.

Soluble Fas ligand (sFasL) is abundant in effusions of tuberculous (TB) pleurisy; however, its diagnostic value has not been scrutinized. We collected pleural effusions from 79 patients, including 23 with TB pleurisy and 56 without TB, and measured sFasL, adenosine deaminase (ADA), and interferon-γ (IFN-γ) concentrations of each specimen. The median of the sFasL concentration of the TB group was 57.3 pg/mL, which was significantly higher than that of the non-TB group (27.4 pg/mL) (P < 0.001). When cutoff value was 39.85 pg/mL, the sensitivity and specificity of sFasL were 95.7% and 80.4%, respectively. The area under the receiver operating characteristic curve for sFasL was not significantly different from those of ADA and IFN-γ. Soluble FasL concentrations of TB patients were significantly higher than those of parapneumonic effusion subgroup (P = 0.039). In conclusion, pleural effusion sFasL is another good diagnostic marker for TB pleurisy., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: To determine the diagnostic utility of adenosine deaminase (ADA) in a large series of pleural effusions of different etiologies., Methods: A retrospective study of 2104 consecutive patients presenting with pleural effusion was carried out at a Spanish university hospital. ADA levels in pleural fluid were determined using a non-Giusti automatic kinetic assay, and a receiver operating characteristics curve analysis was applied to estimate their discriminative properties., Results: Pleural tuberculosis (TB) accounted for 221 (10.5%) effusions. Pleural fluid ADA >35U/L yielded 93% sensitivity, 90% specificity, a positive likelihood ratio (LR) of 10.05 and a negative LR of 0.07 for the diagnosis of TB among lymphocytic exudates. The ADA activity was significantly higher in neutrophil- (111.6U/L) than in lymphocyte-rich (62.4U/L; p=0.002) TB effusions. Overall, more than 40% of parapneumonics and half of lymphomatous effusions exceeded the cutoff set for TB. These were the only causes of ADA activity above 250U/L. When the prevalence of TB as a cause of exudative effusions is low (e.g., 1%), the estimated positive predictive value of the ADA test may be as low as 7%, although the negative predictive value remains high (99.9%)., Conclusion: Where available, pleural ADA should be routinely used to rule TB in or out in areas with moderate to high or low TB prevalence, respectively. A high ADA level is a characteristic not only of lymphocytic, but also of neutrophilic TB effusions. An extremely high ADA activity should raise suspicion of empyema or lymphoma., (Copyright (c) 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Tuberculous pleural effusions (TPE) are common. The diagnosis is often problematic. As the determination of ADA is often unavailable in some countries, the aim of this study was to evaluate the diagnostic usefulness of other data from pleural fluid analysis, in young patients from populations with high prevalence of tuberculosis (TB)., Methods: We analysed 218 patients with pleural effusion (165 tuberculous, 21 infectious, 11 neoplastic, 16 miscellaneous, 3 idiopathic). We performed two regression models; one included pleural fluid ADA values (model 1), and the other without ADA (model 2)., Results: Model 1 selected two variables (ADA >35U/L) and lymphocytes (>31.5%) and correctly classified 216/218 effusions (1 false negative, 1 false positive). Model 2 (without ADA) selected three variables: lymphocytes (>31.5%), fever and cough, and correctly classified 207/218 effusions (8 false negatives, 3 false positives). The sensitivity of models 1 and 2 was 99.4% and 95.2%, specificity 98.1% and 94.3% and accuracy 99% and 95%., Conclusions: In geographic areas with high prevalence of TB and a low prevalence of HIV, in young patients (

Purpose: To investigate diagnostic values of pleural fluid matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitors of metalloproteinase-1 (TIMP-1) and TIMP-2 measurements in tuberculous pleurisy(TP) and malignat pleurisy (MP)., Methods: The study included 24 patients with TP, 22 patients with MP and 15 patients with pleural effusion of non-tuberculous and non-malignant origin as controls. MMP-2,-9 and TIMP-1,-2 levels in pleural fluid were measured by ELISA method., Results: Pleural fluid MMP-2 and MMP-9 levels were higher (P < 0.001, P < 0.001, respectively) in TP than in MP and controls. MP patients have higher pleural fluid MMP-2 and MMP-9 levels (P < 0.01, P < 0.05, respectively) than controls. Pleural fluid TIMP-2 levels were higher (P < 0.01 and P < 0.001, respectively) in MP than in TP and controls. Pleural fluid MMP-9 levels were negatively correlated with pleural fluid TIMP-2 levels (r: 0.464, P=0.029) in patients with MP., Conclusions: Determination of TIMP-2 in pleural fluid may contribute to differentiate TP from MP. These results suggest that overproduction of MMP-9 and TIMP-2 is associated with accumulation of the pleural effusion in malignancy. Further studies with a greater number of patients are needed to confirm this hypothesis.

Several biological markers have been proposed to improve the efficacy of diagnosing tuberculous pleurisy. The study was undertaken to evaluate the accuracy of pleural fluid adenosine deaminase (ADA) activity and interferon-gamma (IFN-gamma) concentration in differentiating tuberculous pleural effusion (TPE) and nontuberculous pleural effusion (non-TPE). Ninety four patients (50 M and 44 F, mean age 60+/-18, range 18-95 years) with pleural effusion (PE) were studied. TPE was diagnosed in patients with: (i) positive pleural fluid or pleural biopsy culture or (ii) granulomas in the pleural biopsy specimen, after exclusion of other granulomatous diseases. Pleural fluid ADA activity was measured with the colorimetric method of Giusti, while IFN-gamma level was measured with ELISA. TPE was diagnosed in 28 patients. The non-TPE group consisted of 35 patients with malignant PE, 20 patients with parapneumonic effusion/pleural empyema, 5 with pleural transudate, and 6 with miscellaneous PE. The ADA activity and IFN-gamma concentration were significantly higher in TPE than in non-TPE (614.1+/-324.5 vs. 15.1+/-36.0 pg/ml, P<0.0001 and 75.1+/-39.1 vs. 11.0+/-16.6 U/l respectively, P<0.0001). The diagnostic sensitivity and specificity of IFN-gamma measurement (cut-off value of 75.0 pg/ml) were 100% and 98.5% respectively and were similar to those of ADA (100% and 93.9% at the cut-off value of 40.3 U/L). We conclude that pleural fluid ADA activity and IFN-gamma concentration are highly sensitive and specific markers of tuberculous pleurisy.

Leukocyte-derived matrix metalloproteinases (MMP) are implicated in the tissue destruction characteristic of tuberculosis (TB). The contribution of lung stromal cells to MMP activity in TB is unknown. Oncostatin M (OSM) is an important stimulus to extrapulmonary stromal MMP induction, but its role in regulation of pulmonary MMP secretion or pathophysiology of TB is unknown. We investigated OSM secretion from Mycobacterium tuberculosis (Mtb)-infected human monocytes/macrophages and the networking effects of such OSM on lung fibroblast MMP secretion. Mtb increased monocyte OSM secretion dose dependently in vitro. In vivo tuberculous granulomas immunostained positively for OSM. Further, conditioned media from Mtb-infected monocytes (CoMTb) induced monocyte OSM secretion (670 +/- 55 versus 166 +/- 14 pg/mL in controls), implicating an autocrine loop. Mtb-induced OSM secretion was prostaglandin (PG) sensitive, and required activation of surface G-protein coupled receptors. OSM induction was ERK MAP kinase dependent, p38-requiring but JNK-independent. OSM synergized with TNF-alpha, a key cytokine in TB granuloma formation, to stimulate pulmonary fibroblast MMP-1/-3 secretion, while suppressing secretion of tissue inhibitors of metalloproteinases-1/-2. In summary, Mtb infection of monocytes results in PG-dependent OSM secretion, which synergizes with TNF-alpha to drive functionally unopposed fibroblast MMP-1/-3 secretion, demonstrating a previously unrecognized role for OSM in TB.

Background: The aim of our study was to identify predictive factors for the development of residual pleural thickening (RPT) in patients with tuberculous pleurisy (TP)., Methods: A retrospective study of patients with pleural tuberculosis. The clinical and radiological characteristics, and measurements of microbiological and biochemical parameters or markers such as adenosine deaminase (ADA), interferon-gamma (IFN-gamma) and vascular endothelial growth factor (VEGF) in pleural fluid were studied., Results: Thirty one patients (24 male and 7 female) with a mean age of 55.9 years were studied. There were 25 (80.6%) patients with RPT > 2 mm and 6 (19.4%) patients without RPT. Ten patients (32.2%) had RPT > or = 10 mm. The rate of pleural thickening was less in small effusions (p<0.05). IFN-gamma was higher in patients with RPT > or = 10 mm (p < 0.05) in comparison with those with RPT < 10 mm., Conclusions: Pleural fluid IFN-gamma may deserve further investigation in order to build up preventive and therapeutic strategies against RPT and its clinical complications.

The pleural fluid concentration of gamma-interferon (gamma-IFN) was studied in 44 patients with exudative pleurisy. The tuberculous nature of exudative pleurisy was established in 25 patients on the basis of X-ray study, a follow-up, microbiological study of pleural exudate specimens, and morphological studies of biopsy specimens obtained at video-assisted thoracoscopy or surgery. The the pleural exudate concentrations of gamma-IFN were over 300 pg/ml (mean 1019 +/- 161 pg/ml) in 19 out of 21 patients with exudative pleuritis in a phase of active inflammation. The patients with the fibrous outcome of pleurisy of tuberculous etiology and those with exudative pleurisy of non-tuberculous etiology, including that in malignancies and papapneumonic pleurisy, were observed to have lower concentrations of gamma-IFN (mean 118 +/- 16 pg/ml). With the discriminating level of above 300 pg/ml, the sensitivity and specificity of the test were 90.5 and 100%, respectively.

Unlabelled: The purpose of the study was to evaluate predictive value of vascular endothelial growth factor (VEGF) in the differential diagnosis of pleural effusion., Material and Methods: By Light's criteria in 29 cases exudates and 10 transudates was recognized. We investigated 39 patients with pleural effusion (congestive heart failure--10, parapneumonic--11, tuberculous--6, malignant--12, transudate--10)., Results: The mean VEGF value were significantly higher (p = 0.002) in the effusion of lung cancer patient (3958.33 pg/ml) than in the serum (1030.33 pg/ml). The mean VEGF levels were significantly higher (p = 0.004) in patient with exudates (2711.10 pg/ml) than in transudates (683 pg/ml). Based on the receiver operating characteristic (ROC) curve analysis, cut off value in differentiation of exudates and transudates was accepted at the level of 560 pg/ml (sensitivity 80% and specificity 70%). The mean VEGF levels were significantly higher (p = 0.008) in the malignant effusion (3958.33 pg/ml) than in the tuberculous effusion (1308.90 pg/ml). Based on the ROC curve analysis, cut off value in differentiation of malignant and tuberculous effusion was accepted at the level of 2000 pg/ml (sensitivity 92% and specificity 83%). The positive correlation between pleural VEGF concentrations and pleural lactate dehydrogenase (LDH) level were observed (r = 0.67, p < 0.05)., Conclusion: We conclude that pleural effusion VEGF level could be useful in the differentiation between exudates and transudate and also between malignant and tuberculous exudates.

Introduction: Pleural effusion secondary to various diseases is associated with the presence of different inflammatory cells. The C-C chemokines (MCP-1 and MIP-1alpha), produced by pleural mesothelial cells, plays an important role in the recruitment of inflammatory cells to the pleural space. The purpose of the study was to evaluate predictive value of MCP-1 and MIP-1alpha in the differential diagnosis of pleural effusion., Material and Methods: Based on Light's criteria in 29 cases exudates and in 10 transudates were recognized. We investigated 39 patients with pleural effusion (congestive heart failure - 10, parapneumonic - 11, tuberculous - 6, malignant - 12). The C-C chemokines MCP-1 and MIP-1alpha levels in pleural effusion and serum were measured by ELISA., Results: The MCP-1 was significantly higher (p = 0.009) in the patient with exudates than in patients with transudates (2436 pg/ml and 794 pg/ml respectively). ROC curve analysis revealed however that this parameter has limited value in the differentiation of exudates an transudates (MCP-1 cut off value 1060 pg/ml, sensitivity 48%, specificity 90%, PPV 93%, NPV 37%). The chemokine MIP-1alpha were significantly higher (p = 0.001) in tuberculous than in the malignant effusion (405 pg/ml and 30 pg/ml respectively). Based on the ROC curve analysis, as a cut off value in the differentiation of tuberculous and malignant pleural effusion a value 120 pg/ml was accepted. The sensitivity of this test was 66% and specificity 99%, PPV 80%, NPV 84%., Conclusions: The chemokine MCP-1 has a limited value in the differentiation between transudate and exudates; MIP-1alpha could be helpful in the differentiation between tuberculous and malignant pleural effusion.

Background: Pleural tuberculosis (TB) remains difficult to diagnose despite numerous diagnostic tools. Recently, in vitro interferon (IFN)-gamma-based assays have been introduced in the diagnosis of latent TB, but these techniques have not been established in the diagnosis of active TB disease, including pleural TB., Objectives: It was the aim of this study to assess the accuracy of the commercially available QuantiFERON TB Gold assay and adapted variants of the assay, using pleural fluid or isolated pleural fluid cells for the diagnosis of pleural TB., Methods: We recruited 66 consecutive patients with a pleural effusion of unknown cause presenting at a tertiary academic health care centre in Cape Town, South Africa, a high prevalence area of TB. Blood and pleural fluid were collected at presentation for IFN-gamma assays and the results evaluated for diagnostic accuracy., Results: The clinical diagnosis was TB in 30 (46%), malignancy in 20 (30%), parapneumonic effusion/empyema in 8 (12%) and effusion due to other causes in 8 patients (12%). Ex vivo pleural fluid IFN-gamma levels accurately identified TB in all patients and were superior to the QuantiFERON In Tube assay using blood and pleural fluid (73 and 57% sensitivity, with 71 and 87% specificity, respectively) and the QuantiFERON Gold assay applied to isolated pleural fluid cells (100% sensitivity and 67% specificity)., Conclusion: The ex vivo pleural fluid interferon-gamma level is an accurate marker for the diagnosis of pleural TB, and the QuantiFERON TB Gold assay performed with peripheral blood or adapted for pleural fluid cells does not add diagnostic value., (Copyright 2008 S. Karger AG, Basel.)

Background: Pleural effusion is not a pathognomonic sign and distinguishing between transudates and exudates often presents a diagnostic dilemma., Objective: To examine whether the NT pro-brain natriuretic peptide (NT-proBNP) in pleural fluid is a diagnostic tool for determining the cardiac etiology of pleural effusions., Methods: We measured pleural fluid and serum NT-proBNP levels in a consecutive series of 98 patients with heart failure and in 142 patients with other causes., Results: The median pleural fluid NT-proBNP levels among the heart failure patients were significantly higher (3,310 pg/mL) than hepatic hydrothorax (16 patients, 531 pg/mL), malignant pleural effusion (38 patients, 733 pg/mL), parapneumonic pleural effusion (40 patients, 294 pg/mL), and tuberculous pleural effusion (64 patients, 214 pg/mL) (p<0.001). At a cut-off point of > or = 1,714 pg/mL, the test had a sensitivity of 99%, a specificity of 99 % for the diagnosis of heart failure. There were 28 patients with pleural effusion due to heart failure misclassified as exudates by Light's criteria. Ten cases of misclassified heart failure (36% of 28 patients) showed serum-effusion protein gradient less than 3.1 g/dL; 26 of them exhibited pleural fluid NT-proBNP levels of > or = 1,714 pg/mL. The 26 patients of misclassified heart failure received diuretics before thoracentesis. Pleural fluid NT-proBNP levels were correlated with serum NT-proBNP levels (R(2)=0.928, p<0.001)., Conclusion: Pleural fluid NT-proBNP may be useful in the diagnosis of pleural effusion resulting from heart failure. The test may be especially useful in heart failure patients with exudates who have been treated with diuretics.

Objective: The purpose of this study was to investigate whether the expression of AQP-1 on the pleura is altered in a rat model with a tuberculous pleural effusion (TPE) and to study its function., Methods: A TPE model was established by intrapleural inoculation with 0.03 mg (2 ml) standard tuberculosis bacillus (H(37)Rv). The rats with TPE were sacrificed at different time points (day 1, 3, or 5) after inoculation. The control group received a 2-ml intrapleural injection of saline. The visceral and parietal pleural tissues were harvested and processed for real-time RT-PCR, Western blot, immunohistochemistry, and determination of tissue AQP-1 levels. Recombinant adenovirus Ad-rAQP-1 containing full-length cDNA of AQP-1 was constructed. Six groups of seven Wistar rats were assigned to receive the following treatments: group 1: intrapleural administration of normal saline; group 2: intrapleural administration of tuberculosis bacilli (TB); group 3: intrapleural inoculation with TB at day 7 following intrapleural administration of Ad-rAQP-1 vector; group 4: intrapleural inoculation with 0.03 mg TB at day 7 following intrapleural administration of control Ad-GFP vector; group 5: intrapleural administration of Ad-rAQP-1; group 6: intrapleural administration of control Ad-GFP vector. The expression of AQP-l on the pleural tissue was detected by immunohistochemistry and Western blot analysis. Histopathologic changes of the pleura and the volume of pleural fluid were examined on day 7 following gene intervention or on day 3 following TB inoculation., Results: Bilateral pleural effusions appeared within 5 days in all rats who received an intrapleural inoculation with TB. The peak amount of pleural fluid occurred on day 3. The AQP-1 expression at protein and mRNA was increased in the early phase of TPE. The expression of AQP-1 was increased in the Ad-rAQP-1 gene transfer group, indicating successful adenovirus gene transfer. The volume of pleural fluid in group 3 (6.1 +/- 0.7 ml) was significantly increased compared with that in group 2 (3.8 +/- 1.0 ml) and group 4 (4.0 +/- 1.1 ml)., Conclusion: These findings suggested that AQP-1 was increased in TPE and it may be involved in the formation of TPE.

In order to investigate the clinical value of vascular endothelial growth factor (VEGF) combined with interferon-gamma (IFN-gamma) in diagnosing malignant pleural effusion and tuberculous pleural effusion, 42 cases of malignant pleural effusion and 45 cases of tuberculous pleural effusion in Tongji Hospital, from March 2004 to May 2005, were included. The carcinoembryonic antigen (CEA), VEGF and IFN-gamma levels of pleural effusion were detected by using ELISA, and adenosine deaminase (ADA) activity was determined by using enzyme kinetic analytical method. The sensitivity, specificity, accuracy and area under the curve (AUC(ROC)) of CEA and VEGF, VEGF/IFN-gamma ratio, ADA and IFN-gamma were measured by receiver operating characteristic curve (ROC). The results showed that CEA, VEGF levels and VEGF/IFN-gamma ratio were significantly higher and the ADA and IFN-gamma levels were significantly lower in malignant group than those in tuberculous group (P<0.01). The sensitivity, specificity, accuracy and AUC(ROC) of VEGF/IFN-gamma ratio (88.7%, 99.8%, 94.4%, 0.96 respectively) were higher than those of CEA (67.8%, 96.1%, 82.4%, 0.78 respectively) and VEGF (81.5%, 84.3%, 82.9%, 0.79 respectively). The sensitivity, specificity, accuracy and AUC(ROC) of IFN-gamma (85.7%, 96.4%, 90.9%, 0.94 respectively) were higher than those of ADA (80.2%, 87.6%, 83.8%, 0.81 respectively). It was concluded that VEGF/IFN-gamma ratio and IFN-gamma could be used as valuable parameters for the differential diagnosis of malignant pleural effusion and tuberculous pleural effusion.

Objectives: Neopterin is produced by stimulated macrophages under the influence of gamma interferon of lymphocyte origin. It is regarded as a biochemical marker of cell-mediated immune response. This study was designed to assess the diagnostic value of pleural fluid neopterin levels in tuberculous pleurisy in comparison with adenosine deaminase activity., Design and Methods: Pleural fluid adenosine deaminase (ADA) activity and neopterin levels were measured in 16 patients with tuberculous pleurisy (TP) and 19 patients with malignant pleurisy (MP). ADA activity was determined by a colorimetric method, whereas neopterin levels were determined by a reversed-phase liquid chromatography technique. All values were given as median (min-max)., Results: The mean age was 45.43+/-20.39 years in the TP group and 60.42+/-11.02 years in the MP group (p=0.026). The median pleural fluid ADA activity was 51.75 U/L (3.50-62.40 U/L) in the TP group and was 2.30 U/L (1-8.20 U/L) in the MP group. The difference was statistically significant (p<0.001). The median pleural fluid neopterin levels were 13.15 nmol/L (1.86-59.50 nmol/L) and 2.44 nmol/L (0.92-27.60 nmol/L) in the TP group and the MP group, respectively (p=0.021). In order to evaluate the diagnostic value of pleural fluid neopterin concentrations, receiver-operating-characteristic curve analysis was performed., Conclusion: Pleural fluid neopterin concentration is significantly higher in TP when compared to MP, however when compared, its clinical use as a diagnostic marker is not valuable as ADA.

Background and Objectives: Macrophage-derived chemokine (MDC/CCL22) is recognized as a T-helper (Th) 2-type chemokine. Both malignant and tuberculous pleural effusions are typically lymphocytic pleural effusions. Tuberculous pleural effusions have a more polarized Th1 reaction than malignant effusions, which are predominantly Th2 in nature. The aim of this study was to compare the levels of MDC in malignant pleural effusions with those in tuberculous pleural effusions to help delineate the role of MDC in Th2 versus Th1 effusions., Methods: Forty-three patients with pleural effusions (32 malignant, 11 tuberculous) were studied. The concentration of MDC in the pleural effusion was measured by ELISA., Results: The median concentration of MDC was lower in malignant pleural effusions than in tuberculous pleural effusions (P < 0.005)., Conclusions: MDC has been reported to both promote and suppress antitumour immunity. The low concentration of MDC in malignant effusions is likely to minimise its antitumour activity but the precise role of MDC in malignant and tuberculous effusions needs to be investigated further.

Background: Conventional tests are not always helpful in making a diagnosis of tuberculous pleurisy. Many studies have investigated the usefulness of interferon (IFN)-gamma measurements in pleural fluid for the early diagnosis of tuberculous pleurisy. We conducted a metaanalysis to determine the accuracy of IFN-gamma measurements in the diagnosis of tuberculous pleurisy., Methods: After a systematic review of English-language studies, sensitivity, specificity, and other measures of accuracy of IFN-gamma concentrations in the diagnosis of pleural effusion were pooled using random-effects models. Summary receiver operating characteristic curves were used to summarize overall test performance., Results: Twenty-two studies met our inclusion criteria. The summary estimates for IFN-gamma in the diagnosis of tuberculous pleurisy in the studies included were as follows: sensitivity, 0.89 (95% confidence interval [CI], 0.87 to 0.91); specificity, 0.97 (95% CI, 0.96 to 0.98); positive likelihood ratio, 23.45 (95% CI, 17.31 to 31.78); negative likelihood ratio, 0.11 (95% CI, 0.07 to 0.16); and diagnostic odds ratio, 272.7 (95% CI, 147.5 to 504.2)., Conclusions: IFN-gamma determination is a sensitive and specific test for the diagnosis of tuberculous pleurisy. The measurement of IFN-gamma levels in pleural effusions is thus likely to be a useful tool for diagnosing tuberculous pleurisy. The results of IFN-gamma assays should be interpreted in parallel with clinical findings and the results of conventional tests.

Objective: To explore the level of mononuclear cell oxidative DNA damage and the total antioxidative capacity (TAC) in patients with tuberculous pleurisy. To evaluate the in vitro repair effects of melatonin on mononuclear cell DNA damage in pleural effusion of the patients., Methods: The mononuclear cell DNA damages in pleural effusion and peripheral blood of 28 patients with tuberculous pleurisy and in peripheral blood of 25 healthy persons were detected by single cell gel electrophoresis (comet%). The levels of TAC in supernatant of pleural effusion and blood plasma of 28 patients and in blood plasma of 25 healthy persons were measured by o-phenanthroline colorimetric analysis. The mononuclear cells from pleural effusions of 20 patients were treated by melatonin in vitro., Results: The comet percentage of mononuclear cells in pleural effusion from patients with tuberculous pleurisy was (41.3 +/- 14.5)%, which was higher than in peripheral blood (21.2 +/- 4.2)%, P < 0.01. The level of TAC in supernatant of pleural effusion was (5.17 +/- 1.19) U/ml, which was lower than in blood plasma (8.66 +/- 1.59) U/ml, P < 0.01. There was a negative correlation between the comet percentage of mononuclear cells and the level of TAC (r = -0.425, P < 0.05) in pleural effusion. The comet percentage of mononuclear cells in peripheral blood from patients was (21.2 +/- 4.2)%, which was higher than from controls (8.9 +/- 3.7)%, P < 0.01. The level of TAC in blood plasma was (8.66 +/- 1.59) U/ml, which was lower than from the controls (10.61 +/- 1.39) U/ml, P < 0.01. After treatment with melatonin, the comet percentage of mononuclear cells in pleural effusion decreased from (40.8 +/- 9.3)% to (11.0 +/- 3.7)%, P < 0.01., Conclusion: There are oxidative DNA damage and oxidation/antioxidation imbalance in patients with tuberculous pleurisy, particularly in the diseased pleural cavity. Melatonin can facilitate, probably by its antioxidative effects, the in vitro repair of the damaged DNA of mononuclear cells from pleural effusion of patients with tuberculous pleurisy.

An acute and persistent eosinophil infiltration is observed during Mycobacterium bovis BCG pleural infection in mice. Eosinophil accumulation, lipid body formation, and eotaxin production were significantly reduced in BCG-infected Toll-like receptor-2 (TLR2)-deficient mice compared to wild-type mice. Neutralization of eotaxin or CCR3 drastically inhibited BCG-induced eosinophil accumulation and lipid body formation, indicating that BCG-induced eosinophil recruitment and activation is largely dependent of TLR2-mediated eotaxin generation.

Objective: To determine if telomerase activity can differentiate malignant from tuberculous pleural effusions., Design: Telomerase activity in malignant and tuberculous pleural effusions was measured in a blinded manner using a PCR-based telomeric repeat amplification protocol (TRAP) assay., Material and Method: Fifty-two patients with lymphocytic exudative pleural effusions were identified on thoracocentasis over a period of 18 months., Results: Telomerase activity was detected in 34% of malignant pleural fluid samples and 50% of tuberculous pleural effusions. The positive rate of telomerase activity was 30.7% for primary lung cancer and 37.5% for metastatic pleural effusion. The sensitivity and specificity of telomerase activity assay were extremely low (35.7% and 52.9%, respectively), compared with that of cytological examination (52.6% and 65.4%, respectively). Moreover the diagnostic accuracy of telomerase activity in combination with cytology was even lower than cytological examination alone (46.7% vs. 60%, respectively). This finding was in contrast to previous reports and demonstrated that the detection rate of telomerase activity in tuberculous pleural effusions was greater than that observed in malignant pleural exudates., Conclusion: Telomerase activity does not appear to be a useful marker for differentiating malignant from tuberculous effusions.

Objective: Interleukin-16 (IL-16) is a chemoattractant of CD4+ lymphocytes, and it has been implicated in the pathogenesis of various inflammatory diseases. The aim of the present study was to measure IL-16 in pleural effusions caused by tuberculosis and malignancy and its relationship with cell and differential counts as well as lymphocyte subsets., Methods: Pleural effusion and venous blood samples were collected from 32 patients with tuberculous pleuritis and 30 lung cancer patients with malignant effusion. Analysis of pleural effusion for total leukocytes and cell differentials of leukocytes was performed. Three-color flow cytometry was performed to determine T lymphocyte subsets in cell pellets of pleural effusion. The concentration of IL-16 in cell-free supernatants of pleural effusion and sera was measured by a sandwich enzyme-linked immunosorbent assay., Results: In all the studied patients, the level of IL-16 was significantly higher in pleural effusion than in serum. The levels of IL-16 were significantly higher in tuberculous than in malignant effusions. In pleural effusion, positive correlations were found between the IL-16 levels and total cell counts, lymphocytes, CD3+ T cells, as well as CD4+ T cells., Conclusions: Compared to malignant pleural effusion, IL-16 appeared to be increased in tuberculous pleural effusion. The pleural effusion IL-16 levels were positively related to the numbers of CD4+ T cells, suggesting that IL-16 might be capable of inducing CD4+ T cell infiltration into pleural space.

In order to identify mediators involved in immune-mediated disease regression, the pleural cytokine and histopathological profile was evaluated in tuberculous pleurisy patients with varied disease duration and clinical presentation, previous to chemotherapy. Interleukin (IL)-10, interferon (IFN)-gamma and tumor necrosis factor (TNF) levels in pleural fluids were shown to decrease with disease time. IL-10 was positively correlated with IFN-gamma, TNF and necrosis area in pleural sections. To parallel these findings with disease regression, individuals showing fever, anorexia, and progressive exudate in the pleural cavity (active disease) were compared with patients without symptoms and with a decrease in exudate volume (regressive disease). IFN-gamma and TNF levels were lower in regressive disease, as well as reduced necrosis area in pleural sections. Our results indicate that tissue destruction and a prominent Th1 response mark the early phase of tuberculous pleurisy and suggest that down-modulation of this response, with the possible participation of IL-10, is associated with disease resolution.

Differentiation of macrophages into foamy (lipid-laden) macrophages is a common pathological observation in tuberculous granulomas both in experimental settings as well as in clinical conditions; however, the mechanisms that regulate intracellular lipid accumulation in the course of mycobacterial infection and their significance to pathophysiology of tuberculosis are not well understood. In this study, we investigated the mechanisms of formation and function of lipid-laden macrophages in a murine model of tuberculosis. Mycobacterium bovis bacillus Calmette-Guérin (BCG), but not Mycobacterium smegmatis, induced a dose- and time-dependent increase in lipid body-inducible nonmembrane-bound cytoplasmic lipid domain size and numbers. Lipid body formation was drastically inhibited in TLR2-, but not in TLR4-deficient mice, indicating a role for TLR2 in BCG recognition and signaling to form lipid bodies. Increase in lipid bodies during infection correlated with increased generation of PGE2 and localization of cyclooxygenase-2 within lipid bodies. Moreover, we demonstrated by intracellular immunofluorescent localization of newly formed eicosanoid that lipid bodies were the predominant sites of PGE2 synthesis in activated macrophages. Our findings demonstrated that BCG-induced lipid body formation is TLR2 mediated and these structures function as signaling platforms in inflammatory mediator production, because compartmentalization of substrate and key enzymes within lipid bodies has impact on the capacity of activated leukocytes to generate increased amounts of eicosanoids during experimental infection by BCG.

Interleukins IL-1beta, IL-6 and TNF are increased in plasma of patients with severe infections and septic shock. Our objective was the evaluation of IL-1beta, IL-6 and TNF in plasma and exudates of pleural fluid and their contribution to the diagnosis. We studied 44 patients, 27 men and 17 women with mean age 66.81 +/- 11.75 years; 16 with pneumonia and parapneumonic effusion, 14 with primary lung cancer and pleural effusion and 14 with tuberculous pleuritis. We measured IL-1beta, IL-6 and TNF in serum and pleural fluid with ELISA. In patients with pneumonia and parapneumonic effusion the mean value of IL-1beta IL-6 and TNF in plasma was 9.05, 19.24 and 21.34 pg/ml and in pleural fluid 10.34, 32.19 and 25.30 pg/ml. In patients with lung cancer the mean values of IL-1beta, IL-6 and TNF were 5.33, 11.74 and 11.51 pg/ml and 6.70, 13.13, 20.89 pg/ml, respectively. In those with tuberculous pleuritis the respective mean values were 10.33, 49.94, 21.27 pg/ml and 14, 56.59, 23.58 pg/ml. In conclusion, IL-1beta and IL-6 were found increased in plasma and tuberculous pleural fluid, indicating an inflammatory status.

Background: C-reactive protein (CRP) pleural fluid levels have been found to be higher in tuberculosis and parapneumonic effusions than in other causes of pleural effusion., Objective: The aim of this study was to analyze whether CRP (a simple and inexpensive test) may be a diagnostic aid for tuberculosis in lymphocytic pleural effusions., Methods: One hundred and forty-four patients with a lymphocytic pleural effusion (more than 50% lymphocytes in the differential white blood cell count) were included. The patients were 93 men (65%) and 51 women (35%), aged 64 +/- 18 years (mean +/- SD). The diagnoses were as follows: tuberculosis, 20; pleural effusion associated with malignancy, 69; transudates, 38; other benign exudates, 17., Results: The CRP pleural fluid level was higher in tuberculous pleuritis (54 +/- 24 mg/l) than in lymphocytic effusions of other origin (21 +/- 16 mg/l; p < 0.001). High CRP levels (>or=50 mg/l) have a high specificity for tuberculosis (95%), and low levels (<30 mg/l) have a high sensitivity (95%) for excluding disease., Conclusions: CRP pleural fluid level determination is useful in the diagnostic workup of lymphocytic pleural effusions. High CRP levels are very suggestive of tuberculous pleuritis, and low CRP levels make this diagnosis unlikely., (Copyright (c) 2005 S. Karger AG, Basel.)

Tuberculous (TB) pleurisy and parapneumonic effusion (PPE) are common causes of pleural fibrosis. The mechanisms underlying fibrin deposition may be different since involved inflammatory cells are distinct. In this study, we measured various cytokines and fibrinolytic enzymes and compared the differences between the two effusions. PPE was further divided into noncomplicated PPE and complicated PPE/empyema subgroups. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8, macrophage inflammatory protein (MIP)-1beta, monocyte chemoattractant protein (MCP)-1, plasminogen activator inhibitor type 1 (PAI-1) and tissue type plasminogen activator (tPA) were measured using enzyme-linked immunosorbent assays. Significantly higher values of PAI-1, PAI-1/tPA ratio, IL-1beta, IL-8 and MIP-1beta and significantly lower values of TNF-alpha, IL-6 and MCP-1 were observed in PPE/empyema than in TB effusions. Compared to noncomplicated PPE, complicated PPE/empyema had significantly higher levels of TNF-alpha, IL-1beta, IL-8 and MIP-1beta. TB pleurisy patients who had higher effusion levels of TNF-alpha, IL-1beta and IL-8 were predisposing to residual pleural thickening. The underlying mechanisms of fibrin formation and deposition between the two effusions studied (PPE/empyema and TB pleurisy) could not be fully explained by the results of the present study. More studies are needed to explore this further.

Background: Diagnosis of tuberculous pleuritis is difficult because of its nonspecific clinical presentation and decreased efficiency of traditional diagnostic methods. We investigated the use of procalcitonin (PCT) concentration in tuberculous pleuritis diagnosis., Methods: A prospective clinical study was performed with two different patient groups. A total of 28 patients were included: 18 with tuberculosis and 10 with nontuberculous pleurisy. Serum and pleural fluid PCT concentrations were evaluated before treatment., Results: Serum and pleural fluid PCT concentrations were statistically different between tuberculous and nontuberculous pleurisy groups (P = 0.012 and P = 0.004, respectively), even though they were not elevated in relation to the cut-off level of 0.5 ng/mL. A positive and significant correlation was detected between serum and pleural fluid PCT levels (r = 0.49, P = 0.008). Diagnostic specificity and sensitivity values for serum and pleural fluid PCT in discriminating tuberculous from nontuberculous pleurisy were 80% and 72.2%, and 90% and 66.7% at the 0.081 and 0.113 ng/mL cut-off values, respectively., Conclusion: Relative to the current cut-off level of 0.5 ng/mL, PCT concentration is not a useful parameter for the diagnosis of tuberculous pleurisy. Because there were PCT levels in patients with tuberculous pleurisy that were below the current cut-off level but were significantly different from those of the nontuberculous group, the use of PCT should be further investigated.

The aim is to examine whether the changes in pleural fluid interleukin (IL)-1beta, IL-2, IL-6, and IL-8 levels were significant in differential diagnosis of childhood pleural effusions. IL-1beta, IL-2, IL-6, and IL-8 levels in pleural fluids of all 36 patients were measured. The levels of IL-1beta, IL-2, IL-6, and IL-8 in pleural fluids were statistically significantly higher in the transudate group compared with those of the exudate group. The levels of IL-1 beta, IL-6, and IL-8 were also found to be statistically significantly higher in the empyema group compared with both the parapneumonic and the tuberculous pleural effusion groups. The levels of IL-2 and IL-6 were detected to be statistically significantly higher in the tuberculous pleural effusion group in comparison with those of the parapneumonic effusion group. The results showed that pleural fluids IL-1beta, IL-2, IL-6, and IL-8 could be used in pleural fluids exudate and transudate distinction.

Objective: To develop a rat model of tuberculous pleurisy and to explore the mechanism of intrapleural inflammatory and immunological responses., Methods: Fifty Wistar rats were injected intrapleurally with 0.03 mg of standard human mycobacterium tuberculous bacilli H37Rv each. The rats were killed in group on days 1, 2, 3, 5, 7, 10, 15, 20, 30 and 60 after the day of intrapleural injection. The thorax was opened and the amount of pleural effusion was recorded, and histopathology of pleural tissues and lung tissues were observed. The white blood cell (WBC) count and differentials, levels of total protein (TP), glucose (GLU) and lactic dehydrogenase (LDH) of pleural effusions were determined. Pleural fluid was analyzed for the levels of soluble intercellular adhesion molecule-1 (sICAM-1), transforming growth factor beta1 (TGF-beta1) and interferon gamma (IFN-gamma) by using appropriate bioassays. Ten rats were intrapleurally received 2 ml of normal saline and another 10 rats received 2 ml of undiluted PPD solution each as control., Results: Bilateral pleural effusions appeared within 15 days in all rats intrapleurally received tuberculous bacilli. The peak amount of pleural fluid was on day 5 (6.7 +/- 0.5 ml). The neutrophils were the predominant cells for the first 24 hours, and then were followed by lymphocytes. In the pleural fluid, total protein concentration was between 51-55 g/L. The levels of glucose and LDH were 5.2 mmol/L and 18.1 micromol.s(-1).L(-1) on day 1 and changed to 2.8 mmol/L and 28.9 micromol.s(-1).L(-1) on day 15 respectively. The biochemistry parameters were in accordance with characteristics of tuberculous pleurisy. The sICAM-1 level increased early (21.9 ng/ml on day 1) and peaked on day 3 (38.0 ng/ml), then decreased over time (4.4 ng/ml on day 15). The level of IFN-gamma was 41.2 pg/ml on day 1 and increased and maintained at high levels over time. TGF-beta1 levels increased and peaked on day 7 (47.2 ng/ml), and then on day 15 decreased to a level lower than that of day 1. The ratio of IFN-gamma/TGF-beta1 increased from 1.32 on day 1 to 5.69 on day 15. Correlation analysis showed that sICAM-1 and IFN-gamma were closely related with WBC count and its differentials, as well as with LDH levels. Histopathological study revealed early pleural inflammation and late caseation., Conclusions: Wistar rats can be used as an experimental model for tuberculous pleurisy. Tuberculous inflammatory and immunological responses in acute tuberculous pleurisy is enhanced rather than suppressed.

The assessment of the adenosine deaminase activity (ADA) in the pleural effusion is used for the diagnosis of tuberculous pleural effusion (TPE). To examine whether the procedure can be applied to immunocompromised patients, we analyzed the ADA activity in the pleural fluid of renal transplant recipients. We studied 23 renal transplant patients with TPE (21 men and 2 women; the mean age, 33 years). They were treated at the Yonsei University Hospital between January 1985 and December 2001. Patients with granuloma in the pleural biopsy specimen or positive for Mycobacterium tuberculosis in the pleural fluid culture were recruited. The ADA activity in the pleural effusion of 23 renal transplant patients with TPE was compared with 23 immunocompetent patients with TPE. The mean ADA activity was 69.5 +/- 4.6 in renal transplant patients and 65.0 +/- 4.9 U/L in immunocompetent patients. Applying the 40 U/L cut-off point, the positivity of ADA was 91.3% in renal transplant patients, and 86.9% in immunocompetent patients. We thus concluded that the measurement of ADA in the pleural fluid is a useful means in the diagnosis of TPE in renal transplant patients.