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1.  Factors affecting pleural fluid adenosine deaminase level and the implication on the diagnosis of tuberculous pleural effusion: a retrospective cohort study 
BMC Infectious Diseases  2013;13:546.
Background
Adenosine deaminase (ADA) is useful in the diagnosis of tuberculous pleural effusion (TPE). This study aims to determine the factors affecting pleural fluid ADA levels and to establish the optimal ADA levels for diagnosis of TPE for different age groups.
Methods
This was a retrospective study from January 2007 to October 2011. One hundred and sixty patients who had pleural fluid ADA performed for investigation of pleural effusion were analyzed. Variables examined included demographics, pleural fluid characteristics and peripheral blood counts. The ADA cut-offs according to age were selected using the receiver operating characteristic (ROC) curve.
Results
The mean pleural fluid ADA was significantly higher in the TPE group (100 ± 35 IU/L) compared to non TPE patients (30 ± 37 IU/L). There was significant correlation between pleural fluid ADA and age, pleural fluid protein, LDH, and fluid absolute lymphocyte count. The strongest correlation was seen with age (r = −0.621). For patients ≤ 55 years old the ROC for ADA had area under curve (AUC) of 0.887. A pleural fluid ADA of 72 IU/L had sensitivity of 95.1%, specificity of 87.5%, positive predictive value (PPV) of 95.1% and negative predictive value (NPV) of 87.5% for the diagnosis of TPE. For patients > 55 years old the AUC is 0.959. ADA of 26 IU/L had a sensitivity of 94.7%, specificity of 80.4%, PPV of 62% and NPV of 97.8%.
Conclusions
There is a significant negative correlation between pleural fluid ADA and age. For older patients, a lower ADA cut-off should be used to exclude TPE.
doi:10.1186/1471-2334-13-546
PMCID: PMC3835552  PMID: 24238276
Adenosine deaminase; Tuberculosis; Pleural effusion; Biological markers
2.  Pleural tuberculosis: is radiological evidence of pulmonary-associated disease related to the exacerbation of the inflammatory response? 
Clinics  2012;67(11):1259-1263.
OBJECTIVE:
Pleural tuberculosis is the most frequently occurring form of extra pulmonary disease in adults. In up to 40% of cases, the lung parenchyma is concomitantly involved, which can have an epidemiological impact. This study aims to evaluate the pleural and systemic inflammatory response of patients with pleural or pleuropulmonary tuberculosis.
METHODS:
A prospective study of 39 patients with confirmed pleural tuberculosis. After thoracentesis, a high resolution chest tomography was performed to evaluate the pulmonary involvement. Of the 39 patients, 20 exhibited only pleural effusion, and high resolution chest tomography revealed active associated-pulmonary disease in 19 patients. The total protein, lactic dehydrogenase, adenosine deaminase, vascular endothelial growth factor, interleukin-8, tumor necrosis factor-α, and transforming growth factor-β1 levels were quantified in the patient serum and pleural fluid.
RESULTS:
All of the effusions were exudates with high levels of adenosine deaminase. The levels of vascular endothelial growth factor and transforming growth factor-β1 were increased in the blood and pleural fluid of all of the patients with pleural tuberculosis, with no differences between the two forms of tuberculosis. The tumor necrosis factor-α levels were significantly higher in the pleural fluid of the patients with the pleuropulmonary form of tuberculosis. The interleukin-8 levels were high in the pleural fluid of all of the patients, without any differences between the forms of tuberculosis.
CONCLUSION:
Tumor necrosis factor-α was the single cytokine that significantly increased in the pleural fluid of the patients with pulmonary involvement. However, an overlap in the results does not permit us to suggest that cytokine is a biological marker of concomitant parenchymal involvement. Although high resolution chest tomography can be useful in identifying these patients, the investigation of fast acid bacilli and cultures for M. tuberculosis in the sputum is recommended for all patients who are diagnosed with pleural tuberculosis.
doi:10.6061/clinics/2012(11)06
PMCID: PMC3488982  PMID: 23184200
Cytokines; Inflammation; Pleural Diseases; Tuberculosis
3.  Different Subsets of Macrophages in Patients with New Onset Tuberculous Pleural Effusion 
PLoS ONE  2014;9(2):e88343.
Objective
Macrophages are the infiltrate components of tuberculous pleural effusion (TPE). This study is aimed at examining the role of different subsets of macrophages in pleural fluid (PF) and peripheral blood (PB) from patients with new onset TPE.
Methods
The numbers of PB and PF CD163+, CD206+ and CD115+ macrophages in 25 patients with new onset TPE and 17 healthy controls (HC) were determined by flow cytometry. The concentrations of serum and PF cytokines were determined by cytometric bead array (CBA) and enzyme-linked immunosorbentassay (ELISA). The potential association between the numbers of different subsets of macrophages and the values of clinical measures in TPE patients were analyzed.
Results
The numbers of PB CD14+CD163− M1-like and CD14+CD163− interleukin (IL)-12+ M1 macrophages were significantly higher than that in the HC, but lower than PF, and the numbers of PF CD14+CD163+, CD14+CD163+CD206+, CD14+CD163+CDll5+ M2-like, and CD14+CD163+IL-10+ M2 macrophages were less than PB in the TPE patients. The levels of serum IL-1, IL-6, IL-8, IL-12, tumor growth factor (TGF)-β1, and tumor necrosis factor (TNF)-α in the TPE patients were significantly higher than that in the HC, but lower than that in the PF. The levels of PF IL-10 were significantly higher than that in the PB of patients and HC. In addition, the levels of serum IL-12 and TNF-α were correlated positively with the values of erythrocyte sedimentation rate (ESR) and the numbers of ESAT-6- and culture filtrate protein 10 (CFP-10)-specific IFN-γ-secreting T cells, and the levels of PF TNF-α were correlated positively with the levels of PF adenosine deaminase (ADA) and lactate dehydrogenase (LDH) in those patients.
Conclusion
Our data indicate that Mycobacterium tuberculosis (M. tb) infection induces M1 predominant pro-inflammatory responses, contributing to the development of TPE in humans.
doi:10.1371/journal.pone.0088343
PMCID: PMC3919770  PMID: 24520370
4.  Association between Elevated Pleural Interleukin-33 Levels and Tuberculous Pleurisy 
Annals of Laboratory Medicine  2012;33(1):45-51.
Background
Interferon-γ (IFN-γ) plays a crucial role in Mycobacterium tuberculosis induced pleural responses. Interleukin (IL)-33 up-regulates the production of IFN-γ. We aimed to identify whether an association between pleural IL-33 levels and tuberculous pleurisy exists and determine its diagnostic value.
Methods
Pleural IL-33, ST2 (a receptor of IL-33), adenosine deaminase (ADA), and IFN-γ, as well as serum IL-33 and ST2 were measured in 220 patients with pleural effusions (PEs). Patients with malignant (MPEs), parapneumonic (PPEs), tuberculous (TPEs), and cardiogenic (CPEs) pleural effusions were included.
Results
Pleural and serum IL-33 levels were highest or tended to be higher in patients with TPEs than in those with other types of PEs. The median pleural fluid-to-serum IL-33 ratio was higher in TPE cases (≥ 0.91) than in other PE cases (≤ 0.56). Pleural IL-33 levels correlated with those of pleural ADA and IFN-γ. However, the diagnostic accuracies of pleural IL-33 (0.74) and pleural fluid-to-serum IL-33 ratio (0.75) were lower than that of ADA (0.95) or IFN-γ (0.97). Pleural ST2 levels in patients with MPEs were higher than in patients with TPEs. Serum ST2 levels did not differ among the groups.
Conclusions
We identified an association between elevated pleural IL-33 levels and tuberculous pleurisy. However, we recommend conventional pleural markers (ADA or IFN-γ) as diagnostic markers of TPE.
doi:10.3343/alm.2013.33.1.45
PMCID: PMC3535196  PMID: 23301222
Interleukin-33; ST2; Tuberculosis; Pleural effusion
5.  Diagnostic value of interleukin 22 and carcinoembryonic antigen in tuberculous and malignant pleural effusions 
The aim of this study was to investigate the diagnostic value of interleukin 22 (IL-22) and carcinoembryonic antigen (CEA) in tuberculous pleural effusions (TPEs) and malignant pleural effusions (MPEs). Pleural effusion samples from 56 patients were classified on the basis of diagnosis as TPE (n=28) and MPE (n=28). The concentration of IL-22 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-22 in TPE was significantly higher compared to MPE (P<0.01). With a threshold value of 49 pg/ml, IL-22 had a sensitivity of 82.14% (23/28) and a specificity of 96.43% (27/28) for differential diagnosis. The combined detection of IL-22 and CEA had a sensitivity of 100% (28/28) and a specificity of 96.43% (27/28) to distinguish TPE from MPE. TPEs showed significantly higher levels of IL-22 compared to MPEs. The combined detection of IL-22 and CEA may be more valuable in the differential diagnosis between TPE and MPE.
doi:10.3892/etm.2011.344
PMCID: PMC3440797  PMID: 22977645
interleukin 22; carcinoembryonic antigen; pleural effusion; differential diagnosis
6.  Localized Eosinophil Degranulation Mediates Disease in Tropical Pulmonary Eosinophilia  
Infection and Immunity  2003;71(3):1337-1342.
To explore the mechanisms underlying the eosinophil-mediated inflammation of tropical pulmonary eosinophilia (TPE), bronchoalveolar lavage (BAL) fluid, serum, and supernatants from pulmonary and blood leukocytes (WBC) from patients with acute TPE (n = 6) were compared with those obtained from healthy uninfected individuals (n = 4) and from patients with asthma (n = 4) or elephantiasis (n = 5). Although there were no significant differences in the levels of interleukin-4 (IL-4), IL-5, IL-13, eotaxin, granulocyte-macrophage colony-stimulating factor, RANTES, or eosinophil cationic protein, there was a marked increase in eosinophil-derived neurotoxin (EDN) both systemically and in the lungs of individuals with TPE compared to each of the control groups (P < 0.02). Moreover, there was a compartmentalization of this response, with EDN levels being higher in the BAL fluid than in the serum (P < 0.02). Supernatants from WBC from either whole blood or BAL cells were examined for chemokines, cytokines, eosinophil degranulation products, and arachidonic acid metabolites. Of the many mediators examined—particularly those associated with eosinophil trafficking—only EDN (in BAL fluid and WBC) and MIP-1α (in WBC) levels were higher for TPE patients than for the non-TPE control groups (P < 0.02). These data suggest it is the eosinophilic granular protein EDN, an RNase capable of damaging the lung epithelium, that plays the most important role in the pathogenesis of TPE.
doi:10.1128/IAI.71.3.1337-1342.2003
PMCID: PMC148813  PMID: 12595450
7.  Factors Influencing Residual Pleural Opacity in Tuberculous Pleural Effusion 
Journal of Korean Medical Science  2008;23(4):616-620.
Tuberculous pleural effusion (TPE) leads to residual pleural opacity (RPO) in a significant proportion of cases. The aim of this study was to investigate which TPE patients would have RPO following the treatment. This study was performed prospectively for a total of 60 TPE patients, who underwent pleural fluid analysis on the initial visit and chest radiographs and computed tomography (CT) scans before and after the administration of antituberculous medication. At the end of antituberculous medication, the incidence of RPO was 68.3% (41/60) on CT with a range of 2-50 mm. Compared with the non-RPO group, the RPO group had a longer symptom duration and lower pleural fluid glucose level. On initial CT, loculation, extrapleural fat proliferation, increased attenuation of extrapleural fat, and pleura-adjacent atelectasis were more frequent, and parietal pleura was thicker in the RPO group compared with the non-RPO group. By multivariate analysis, extrapleural fat proliferation, loculated effusion, and symptom duration were found to be predictors of RPO in TPE. In conclusion, RPO in TPE may be predicted by the clinico-radiologic parameters related to the chronicity of the effusion, such as symptom duration and extrapleural fat proliferation and loculated effusion on CT.
doi:10.3346/jkms.2008.23.4.616
PMCID: PMC2526418  PMID: 18756047
Computed Tomography; Pleural Effusion; Residual Thickening; Tuberculosis
8.  Evaluation of polymerase chain reaction for rapid diagnosis of clinically suspected tuberculous pleurisy 
Pleural effusion is one of the commonest presentations of tuberculosis, the clinical manifestations being typically abrupt resembling bacterial pneumonia. Since delayed hypersensitivity is the underlying immune response, bacterial load is very low. Owing to these facts, tuberculous pleurisy as an extra-pulmonary disease poses a diagnostic dilemma. The conventional bacteriological methods rarely detect Mycobacterium tuberculosis in pleural fluid and are of limited use in diagnosis of tuberculous pleurisy. We evaluated the efficacy of polymerase chain reaction (PCR) in the diagnosis of tuberculous pleurisy by targeting the gene segment coding for MPB64 protein specific forMycobacterium tuberculosis. Based on the clinical criteria, 82 patients with lymphocytic exudative pleural effusion were included in the study. Patients were analyzed in two groups; one group consisting of 48 patients of tubercular pleural effusion confimed by various diagnostic procedures and another group of 34 patients comprising of non-tubercular pleural effusion. There were no false positive results by PCR and the specificity worked out to be 100%. Twenty two patients tested positive for Mantoux with a sensitivity of 45%. ZN-staining for AFB was found in samples from 15 patients (20% sensitivity). ADA was positive for 28 patients with a sensitivity of 53%. PCR was positive for 32/48 patients (67% sensitivity). Thus, PCR was found to be more sensitive than any other conventional method in diagnosis of clinically suspected tubercular pleurisy.
doi:10.1007/BF02912917
PMCID: PMC3454004  PMID: 23105619
Polymerase chain reaction; Mycobacterium tuberculosis; MPB64; tubercular pleurisy
9.  Acute tropical pulmonary eosinophilia. Characterization of the lower respiratory tract inflammation and its response to therapy. 
Journal of Clinical Investigation  1987;80(1):216-225.
Although acute tropical pulmonary eosinophilia (TPE) is well recognized as a manifestation of filarial infection, the processes that mediate the abnormalities of the lung in TPE are unknown. To evaluate the hypothesis that the derangements of the lower respiratory tract in this disorder are mediated by inflammatory cells in the local milieu, we utilized bronchoalveolar lavage to evaluate affected individuals before and after therapy. Inflammatory cells recovered from the lower respiratory tract of individuals with acute, untreated TPE (n = 8) revealed a striking eosinophilic alveolitis, with marked elevations in both the proportion of eosinophils (TPE 54 +/- 5%; normal 2 +/- 5%; P less than 0.001) and the concentration of eosinophils in the recovered epithelial lining fluid (ELF) (TPE 63 +/- 20 X 10(3)/microliter; normal 0.3 +/- 0.1 X 10(3)/microliter; P less than 0.01). Importantly, when individuals (n = 5) with acute TPE were treated with diethylcarbamazine (DEC), there was a marked decrease of the lung eosinophils and concomitant increase in lung function. These observations are consistent with the concept that at least some of the abnormalities found in the lung in acute TPE are mediated by an eosinophil-dominated inflammatory process in the lower respiratory tract.
Images
PMCID: PMC442221  PMID: 3298321
10.  Lymphocyte and lymphocyte subset numbers in blood and in bronchoalveolar lavage and pleural fluid in various forms of human pulmonary tuberculosis at presentation and during recovery. 
Thorax  1992;47(7):513-518.
BACKGROUND: Lymphocytes have a central role in human defences against mycobacteria. A study was designed to assess the relation between lymphocyte responses and clinical pattern of disease, nutrition and recovery during treatment in patients with tuberculosis. METHODS: Lymphocyte numbers and subsets (on the basis of CD3, CD4, and CD8 monoclonal antibodies) were measured in peripheral blood and, where appropriate, bronchoalveolar lavage or pleural fluid of patients with different forms of pulmonary tuberculosis. Eleven had localised pulmonary tuberculosis, 18 miliary tuberculosis and seven a tuberculous pleural effusion. RESULTS: CD4 lymphocytes were found in greatly increased numbers in pleural fluid and were relatively depleted in the blood. Lymphocyte numbers in bronchoalveolar lavage fluid varied widely in localised pulmonary and miliary tuberculosis but were highest in lavage fluid from patients with miliary tuberculosis. This was due to an increase in CD8 lymphocytes, which were also increased in the blood. Lymphocyte numbers bore no relation to nutrition, symptom duration, or radiographic profusion scores. In miliary tuberculosis the time taken for the chest radiograph to clear (mean (SD) 17.6 (7.8) weeks) correlated with lymphocyte numbers in lavage fluid, especially CD8 cells (r = 0.74), but not with the patients' age or nutrition. After 8 weeks' treatment, total and CD4 lymphocyte numbers in lavage fluid showed a substantial increase. CONCLUSION: The association of CD8 cells with delayed recovery is compatible with suppression of the antimycobacterial action of macrophages. The switch to predominance of CD4 cells in lavage fluid during successful treatment supports the view that they may have a role in eliminating mycobacteria.
Images
PMCID: PMC463860  PMID: 1412093
11.  Higher Frequency of T-Cell Response to M. tuberculosis Latency Antigen Rv2628 at the Site of Active Tuberculosis Disease than in Peripheral Blood 
PLoS ONE  2011;6(11):e27539.
Rationale
Due to the invasive nature of the procedures involved, most studies of Mycobacterium tuberculosis (Mtb)-specific immunity in humans have focused on the periphery rather than the site of active infection, the lung. Recently, antigens associated with Mtb-latency and -dormancy have been described using peripheral blood (PB) cells; however their response in the lung is unknown. The objective of this report was to evaluate, in patients prospectively enrolled with suspected active tuberculosis (TB), whether the latency antigen Rv2628 induces local-specific immune response in bronchoalveolar lavage (BAL) cells compared to PB cells.
Material/Methods
Among the 41 subjects enrolled, 20 resulted with active TB. Among the 21 without active disease, 9 were defined as subjects with latent TB-infection (LTBI) [Quantiferon TB Gold In-tube positive]. Cytokine responses to Rv2628 were evaluated by enzyme linked immunospot (ELISPOT) assay and flow cytometric (FACS) analysis. RD1-secreted antigen stimulation was used as control.
Results
There was a significantly higher frequency of Rv2628- and RD1-specific CD4+ T-cells in the BAL of active TB patients than in PB. However the trend of the response to Rv2628 in subjects with LTBI was higher than in active TB in both PB and BAL, although this difference was not significant. In active TB, Rv2628 and RD1 induced a cytokine-response profile mainly consisting of interferon (IFN)-γ-single-positive over double-IFN-γ/interleukin (IL)-2 T-cells in both PB and BAL. Finally, BAL-specific CD4+ T-cells were mostly effector memory (EM), while peripheral T-cell phenotypes were distributed among naïve, central memory and terminally differentiated effector memory T-cells.
Conclusions
In this observational study, we show that there is a high frequency of specific T-cells for Mtb-latency and RD1-secreted antigens (mostly IFN-γ-single-positive specific T-cells with an EM phenotype) in the BAL of active TB patients. These data may be important for better understanding the pathogenesis of TB in the lung.
doi:10.1371/journal.pone.0027539
PMCID: PMC3213161  PMID: 22102905
12.  Regulation of CD4+ T Cells by Pleural Mesothelial Cells via Adhesion Molecule-Dependent Mechanisms in Tuberculous Pleurisy 
PLoS ONE  2013;8(9):e74624.
Background
Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been demonstrated to be expressed on pleural mesothelial cells (PMCs), and to mediate leukocyte adhesion and migration; however, little is known about whether adhesion molecule-dependent mechanisms are involved in the regulation of CD4+ T cells by PMCs in tuberculous pleural effusion (TPE).
Methods
Expressions of ICAM-1 and VCAM-1 on PMCs, as well as expressions of CD11a and CD29, the counter-receptors for ICAM-1 and VCAM-1, respectively, expressed on CD4+ T cells in TPE were determined using flow cytometry. The immune regulations on adhesion, proliferation, activation, selective expansion of CD4+ helper T cell subgroups exerted by PMCs via adhesion molecule-dependent mechanisms were explored.
Results
Percentages of ICAM-1-positive and VCAM-1‒positive PMCs in TPE were increased compared with PMC line. Interferon-γ enhanced fluorescence intensity of ICAM-1, while IL-4 promoted VCAM-1 expression on PMCs. Percentages of CD11ahighCD4+ and CD29highCD4+ T cells in TPE significantly increased as compared with peripheral blood. Prestimulation of PMCs with anti‒ICAM-1 or ‒VCAM-1 mAb significantly inhibited adhesion, activation, as well as effector regulatory T cell expansion induced by PMCs.
Conclusions
Our current data showed that adhesion molecule pathways on PMCs regulated adhesion and activation of CD4+ T cells, and selectively promoted the expansion of effector regulatory T cells.
doi:10.1371/journal.pone.0074624
PMCID: PMC3777994  PMID: 24069325
13.  Imbalance of Th17 Cells and Regulatory T Cells in Tuberculous Pleural Effusion ▿ 
Clinical and Vaccine Immunology : CVI  2011;18(10):1608-1615.
Both T helper interleukin 17 (IL-17)-producing cells (Th17 cells) and regulatory T cells (Tregs) have been found to be increased in human tuberculous pleural effusion (TPE); however, the possible interaction between Th17 cells and Tregs in TPE remains to be elucidated. The objective of the present study was to investigate the distribution of Th17 cells in relation to Tregs, as well as the mechanism of Tregs in regulating generation and differentiation of Th17 cells in TPE. In the present study, the numbers of Th17 cells and Tregs in TPE and blood were determined by flow cytometry. The regulation and mechanism of CD39+ Tregs on generation and differentiation of Th17 cells were explored. Our data demonstrated that the numbers of Th17 cells and CD39+ Tregs were both increased in TPE compared with blood. Th17 cell numbers were correlated negatively with Tregs in TPE but not in blood. When naïve CD4+ T cells were cultured with CD39+ Tregs, Th17 cell numbers decreased as CD39+ Treg numbers increased, and the addition of the anti-latency-associated peptide monoclonal antibody to the coculture reversed the inhibitory effect exerted by CD39+ Tregs. This study shows that Th17/Treg imbalance exists in TPE and that pleural CD39+ Tregs inhibit generation and differentiation of Th17 cells via a latency-associated peptide-dependent mechanism.
doi:10.1128/CVI.05214-11
PMCID: PMC3187020  PMID: 21813663
14.  Clonal Immune Responses of Mycobacterium-Specific γδ T Cells in Tuberculous and Non-Tuberculous Tissues during M. tuberculosis Infection 
PLoS ONE  2012;7(2):e30631.
Background
We previously demonstrated that unvaccinated macaques infected with large-dose M.tuberculosis(Mtb) exhibited delays for pulmonary trafficking of Ag-specific αβ and γδ T effector cells, and developed severe lung tuberculosis(TB) and “secondary” Mtb infection in remote organs such as liver and kidney. Despite delays in lungs, local immunity in remote organs may accumulate since progressive immune activation after pulmonary Mtb infection may allow IFNγ-producing γδ T cells to adequately develop and traffic to lately-infected remote organs. As initial efforts to test this hypothesis, we comparatively examined TCR repertoire/clonality, tissue trafficking and effector function of Vγ2Vδ2 T cells in lung with severe TB and in liver/kidney without apparent TB.
Methodology/Principal Findings
We utilized conventional infection-immunity approaches in macaque TB model, and employed our decades-long expertise for TCR repertoire analyses. TCR repertoires in Vγ2Vδ2 T-cell subpopulation were broad during primary Mtb infection as most TCR clones found in lymphoid system, lung, kidney and liver were distinct. Polyclonally-expanded Vγ2Vδ2 T-cell clones from lymphoid tissues appeared to distribute and localize in lung TB granuloms at the endpoint after Mtb infection by aerosol. Interestingly, some TCR clones appeared to be more predominant than others in lymphocytes from liver or kidney without apparent TB lesions. TCR CDR3 spetratyping revealed such clonal dominance, and the clonal dominance of expanded Vγ2Vδ2 T cells in kidney/liver tissues was associated with undetectable or low-level TB burdens. Furthermore, Vγ2Vδ2 T cells from tissue compartments could mount effector function for producing anti-mycobacterium cytokine.
Conclusion
We were the first to demonstrate clonal immune responses of mycobacterium-specific Vγ2Vδ2 T cells in the lymphoid system, heavily-infected lungs and lately subtly-infected kidneys or livers during primary Mtb infection. While clonally-expanded Vγ2Vδ2 T cells accumulated in lately-infected kidneys/livers without apparent TB lesions, TB burdens or lesions appeared to impact TCR repertoires and tissue trafficking patterns of activated Vγ2Vδ2 T cells.
doi:10.1371/journal.pone.0030631
PMCID: PMC3271047  PMID: 22319574
15.  Identification of M.tuberculosis-Specific Th1 Cells Expressing CD69 Generated in vivo in Pleural Fluid Cells from Patients with Tuberculous Pleurisy 
PLoS ONE  2011;6(8):e23700.
Th1 cell-mediated immune responses at the site of active infection are important to restrict the growth of M.tuberculosis (MTB) and for the spontaneous resolution of patients with tuberculous pleurisy (TBP). In the present study, we found that without any stimulation, CD4+ T cells in pleural fluid cells (PFCs) from patients with TBP expressed significantly higher levels of CD69 than PBMCs from patients with tuberculosis (TB) or healthy donors. CD4+CD69+ T cells expressed T-bet and IL-12Rβ2. After stimulation with MTB-specific antigens, CD4+CD69+ T cells expressed significantly higher levels of IFN-γ, IL-2 and TNF-α than CD4+CD69− T cells, demonstrating that CD4+CD69+ T cells were MTB-specific Th1 cells. In addition, CD4+CD69+ T cells were mostly polyfunctional Th1 cells that simultaneously produced IFN-γ, IL-2, TNF-α and displayed an effector or effector memory phenotype (CD45RA−CCR7−CD62L−CD27−). Moreover, the percentages of CD4+CD69+ T cells were significantly and positively correlated with polyfunctional T cells. Interestingly, sorted CD4+CD69+ but not CD4+CD69− fractions by flow cytometry produced IFN-γ, IL-2 and TNF-α that were significantly regulated by CD4+CD25+ Treg cells. Taken together, based on the expression of CD69, we found a direct quantitative and qualitative method to detect and evaluate the in vivo generated MTB-specific polyfunctional CD4+ T cells in PFCs from patients with TBP. This method can be used for the potential diagnosis and enrichment or isolation of MTB-specific Th1 cells in the investigations.
doi:10.1371/journal.pone.0023700
PMCID: PMC3161751  PMID: 21887301
16.  Amplified Mycobacterium Tuberculosis Direct Test for Diagnosing Tuberculous Pleurisy—A Diagnostic Accuracy Study 
PLoS ONE  2012;7(9):e44842.
Background
The study was designed to investigate the clinical usefulness of Amplified Mycobacterium Tuberculosis Direct (AMTD) tests for diagnosing TB pleurisy.
Methods
One hundred and fifty-two patients for whom the exclusion of tuberculous pleural effusion was necessary were retrospectively analyzed.
Results
The sensitivity of AMTD in diagnosing pleural TB was 36.4% (20 of 55). Combining sputum and pleural effusion AFB smear, pleural biopsy, and AMTD test of pleural effusion increased sensitivity to 82.5% (33/40). There were significantly higher percentages of neutrophils in the pleural effusion in the positive than in the negative AMTD group (38.0±6.7% vs. 11.1±3.7%, p<0.001). Patients with symptom duration <18 days prior to pleural effusion studies had more positive AMTD tests than those with symptom >18 days (70% vs. 31.4%; OR 5.09; 95% CI 1.54–16.79; p = 0.011).
Conclusions
Combining AMTD tests with conventional diagnostic methods offer good sensitivity for pleural TB diagnosis. Patients in the early course of the disease are better candidates for AMTD tests.
doi:10.1371/journal.pone.0044842
PMCID: PMC3438172  PMID: 22970318
17.  Predominance of interleukin-22 over interleukin-17 at the site of disease in human tuberculosis 
Tuberculosis (Edinburgh, Scotland)  2011;91(6-3):587-593.
Summary
The inflammatory response to Mycobacterium tuberculosis (M.tb) at the site of disease is Th1 driven. Whether the Th17 cytokines, IL-17 and IL-22, contribute to this response in humans is unknown. We hypothesized that IL-17 and IL-22 contribute to the inflammatory response in pleural and pericardial disease sites of human tuberculosis (TB).
We studied pleural and pericardial effusions, established TB disease sites, from HIV-uninfected TB patients. Levels of soluble cytokines were measured by ELISA and MMP-9 by luminex. Bronchoalveolar lavage or pericardial mycobacteria-specific T cell cytokine expression was analyzed by intracellular cytokine staining.
IL-17 was not abundant in pleural or pericardial fluid. IL-17 expression by mycobacteria-specific disease site T cells was not detected in healthy, M.tb-infected persons, or patients with TB pericarditis. These data do not support a major role for IL-17 at established TB disease sites in humans.
IL-22 was readily detected in fluid from both disease sites. These IL-22 levels exceeded matching peripheral blood levels. Further, IL-22 levels in pericardial fluid correlated positively with MMP-9, an enzyme known to degrade the pulmonary extracellular matrix. We propose that our findings support a role for IL-22 in TB-induced pathology or the resulting repair process.
doi:10.1016/j.tube.2011.06.009
PMCID: PMC3220762  PMID: 21767990
Pleural tuberculosis; Pericardial tuberculosis; IL-17; IL-22; Inflammation
18.  Pleural Fluid Pentraxin-3 for the Differential Diagnosis of Pleural Effusions 
Background
Conventional biomarkers cannot always establish the cause of pleural effusions; thus, alternative tests permitting rapid and accurate diagnosis are required. The primary aim of this study is to assess the ability of pentraxin-3 (PTX3) in order to diagnose the cause of pleural effusion and compare its efficacy to that of other previously identified biomarkers.
Methods
We studied 118 patients with pleural effusion, classified as transudates and exudates including malignant, tuberculous, and parapneumonic effusions (MPE, TPE, and PPE). The levels of PTX3, C-reactive protein (CRP), procalcitonin (PCT) and lactate in the pleural fluid were assessed.
Results
The levels of pleural fluid PTX3 were significantly higher in patients with PPE than in those with MPE or TPE. PTX3 yielded the most favorable discriminating ability to predict PPE from MPE or TPE by providing the following: area under the curve, 0.74 (95% confidence interval, 0.63-0.84), sensitivity, 62.07%; and specificity, 81.08% with a cut-off point of 25.00 ng/mL.
Conclusion
Our data suggests that PTX3 may allow improved differentiation of PPE from MPE or TPE compared to the previously identified biomarkers CRP and PCT.
doi:10.4046/trd.2013.75.6.244
PMCID: PMC3884112  PMID: 24416055
PTX3 Protein; Pleural Effusion
19.  Anergic Pulmonary Tuberculosis Is Associated with Contraction of the Vd2+T Cell Population, Apoptosis and Enhanced Inhibitory Cytokine Production 
PLoS ONE  2013;8(8):e71245.
Objective
To study the association of anergic pulmonary tuberculosis with Vδ2+ T cells and related cytokine levels.
Methods
82 pulmonary tuberculosis patients were divided into two groups according to their purified protein derivative tuberculin skin test (TST) results: 39 with TST-negative anergic pulmonary tuberculosis and 43 with TST-positive pulmonary tuberculosis, while 40 healthy volunteers were used as control. Based on chest X-ray results, the tuberculosis lesions were scored according to their severity, with a score of ≤ 2.5 ranking as mild, 2.5-6 as moderate and ≥ 6 as severe. The Vδ2+ T cell percentage and their expression levels of the apoptosis-related membrane surface molecule FasL in peripheral blood and bronchoalveolar lavage fluids (BALF) were analyzed by flow cytometry, while IL-2, IL-4, IL-6 and IL-10 cytokine and γ-interferon (γ-IFN) concentrations in peripheral blood were determined by ELISA.
Results
Most of the patients with chest X-ray lesion scores higher than 6 belonged to the anergic tuberculosis group (P<0.05). Anergic pulmonary tuberculosis patients displayed reduced peripheral blood Vδ2+ T cell counts (P<0.05) and higher FasL expression in peripheral blood Vδ2 + T cells (P <0.05). The Vδ2+ T cell percentages in the BALF of all tuberculosis patients were lower than in their peripheral blood (P <0.05), and IL-4 and IL-10 concentrations in peripheral blood of anergic tuberculosis patients were higher than in TST-positive tuberculosis patients and healthy controls (P <0.05).
Conclusion
Anergic pulmonary tuberculosis is accompanied by reduced Vδ2+ T cell percentage, and elevated Vδ2+ T cell FasL expression as well as enhanced IL-4 and IL-10 levels in peripheral blood.
doi:10.1371/journal.pone.0071245
PMCID: PMC3732239  PMID: 23936496
20.  Hypercalcemia in patients with newly diagnosed tuberculosis in Abuja, Nigeria 
BACKGROUND
The prevalence of hypercalcemia has not previously been determined in newly diagnosed tuberculosis (TB) patients in Nigeria.
OBJECTIVE
To determine the incidence of hypercalcemia in Nigerian patients with newly diagnosed TB before the commencement of anti-TB treatment.
METHODS
The present study is a prospective examination of consecutive patients with newly diagnosed TB confirmed by bacteriological and/or histological methods at the National Hospital (Abuja, Nigeria) from January 2004 to December 2004.
RESULTS
Of 120 patients (70 males and 50 females), 70 had pulmonary TB, 10 had pulmonary and pleural TB, 20 had pleural TB without radiographic evidence of lung involvement, 18 had various other forms of extrapulmonary TB and two had disseminated TB. The mean age of the patients was 38.3±12.0 years. The mean albumin-adjusted serum calcium concentration was 2.53±0.22 mmol/L. Hypercalcemia was present in 27.5% of the patients, but only 12% of these patients showed symptoms of hypercalcemia. The type of TB and, in the case of pulmonary TB, the extent of lung involvement, had no effect on the serum calcium concentration.
CONCLUSION
Hypercalcemia is not uncommon among Nigerian patients with newly diagnosed TB, but it is rarely symptomatic.
PMCID: PMC2539012  PMID: 16550265
Albumin-adjusted serum calcium; Newly diagnosed; Tuberculosis
21.  Value of adenosine deaminase in the diagnosis of tuberculous pleural effusions in young patients in a region of high prevalence of tuberculosis. 
Thorax  1995;50(6):600-603.
BACKGROUND--Pleural biopsy is usually considered important for the diagnosis of pleural effusions, especially for distinguishing between tuberculosis and neoplasia, even though tuberculous pleural fluid contains sensitive biochemical markers. In regions with a high prevalence of tuberculosis, and in patient groups with a low risk of other causes of pleurisy, the positive predictive value of these markers is increased. The criteria for performing a pleural biopsy under these circumstances have been investigated, using adenosine deaminase (ADA) as a pleural fluid marker for tuberculosis. METHODS--One hundred and twenty nine patients with a pleural effusion aged < or = 35 years (mean (SD) 25.2 (4.9) years) were studied. Seventy three were men. Eighty one effusions (62.8%) were tuberculous, 12 (9.3%) parapneumonic, and 10 (7.7%) neoplastic, five were caused by pulmonary thromboembolism, four by systemic lupus erythematosus, seven by empyema, three following surgery, one was the result of asbestosis, and one of nephrotic syndrome. In five cases no definitive diagnosis was reached. ADA levels were determined by the method of Galanti and Giusti. RESULTS--The diagnostic yield of procedures not involving biopsy was 94.5% (122/129). Pleural biopsy provided a diagnosis in a further two cases, but not in the remaining five. All tuberculous cases had pleural fluid levels of ADA of > 47 U/l (mean (SD) 111.1 (36.6) U/l). The only other cases in which ADA exceeded this level were six of the seven patients with empyema. Cytological examination of the pleural fluid diagnosed eight of the 10 neoplastic cases, compared with six diagnosed by pleural biopsy. CONCLUSIONS--In a region with a high prevalence of tuberculosis procedures not involving pleural biopsy have a very high diagnostic yield in patients with a pleural effusion aged < or = 35 years, making biopsy necessary only in cases in which pleural levels of ADA are below 47 U/l, pleural fluid cytology is negative and, in the absence of a positive basis for some other diagnosis, neoplasia is suspected.
PMCID: PMC1021255  PMID: 7638798
22.  Asymptomatic primary tuberculous pleurisy with intense 18-fluorodeoxyglucose uptake mimicking malignant mesothelioma 
Background
The pathogenesis of primary tuberculous pleurisy is a delayed-type hypersensitivity immunogenic reaction to a few mycobacterial antigens entering the pleural space rather than direct tissue destruction by mycobacterial proliferation. Although it has been shown that pulmonary tuberculosis induces 18-fluorodeoxyglucose (FDG) uptake in active lesions, little is known about the application of FDG positron emission/computed tomography (FDG PET/CT) to the management of primary tuberculous pleurisy.
Case presentation
We report a case of asymptomatic primary tuberculous pleurisy presenting with diffuse nodular pleural thickening without distinct pleural effusion and parenchymal lung lesions mimicking malignant mesothelioma. An initial FDG PET/CT scan demonstrated multiple lesions of intense FDG uptake in the right pleura and thoracoscopic biopsy of pleural tissue revealed caseous granulomatous inflammation. The patient received antituberculous therapy for 6 months, with clearly decreased positive signals on a repeated FDG PET/CT scan.
Conclusion
FDG PET/CT imaging may be useful for evaluating disease activity in tuberculous pleurisy patients with an unknown time of onset.
doi:10.1186/1471-2334-13-12
PMCID: PMC3568019  PMID: 23317113
Primary tuberculous pleurisy; Fluorodeoxyglucose; Positron emission tomography
23.  Vascular endothelial growth factor in malignant and tuberculous pleural effusions. 
Journal of Korean Medical Science  2000;15(3):279-283.
The purpose of this study is to assess the usefulness of soluble vascular endothelial growth factor (VEGF) in the effusions of patients with malignant and tuberculous diseases. Using a sandwich enzyme-linked immunoadsorbent assay, VEGF concentration was measured in malignant (n=17) and tuberculous (n=11) pleural effusions. Pleural biopsy, cytology or microbiological methods were used to make final diagnoses. Adenosine deaminase (ADA) levels in tuberculous pleural effusions were significantly higher than those in malignant pleural effusions. The median level of VEGF in patients with malignant effusions (median, 2418 pg/mL; range, 97-62103 pg/mL) was significantly higher than tuberculous effusions (median, 994 pg/mL; range, 44-3552 pg/mL). There were no significant differences in pleural VEGF levels in patients with different histological types of lung cancer. The VEGF level was not correlated with ADA, lactate dehydrogenase and total protein levels of pleural fluid. In conclusion, pleural VEGF levels in patients with malignant effusions were significantly higher than tuberculous effusions, and the measurement of pleural VEGF is helpful in discriminating between malignant and tuberculous effusions. Further studies are needed to determine the clinical value of VEGF as a tumor marker and a prognostic factor.
PMCID: PMC3054640  PMID: 10895968
24.  In vitro tuberculin reactivity of lymphocytes from patients with tuberculous pleurisy. 
Infection and Immunity  1982;35(2):402-409.
Mononuclear cells in pleural fluid from patients with tuberculous pleurisy were predominantly T cells. Responsiveness of pleural fluid T cells to purified protein derivative of tuberculin were studied by the assay of cell proliferation and production of lymphocyte mitogenic factor by the stimulation with purified protein derivative. Peripheral blood lymphocytes were also studied from patients and tuberculin-positive healthy controls. The order of responsiveness was as follows: pleural fluid lymphocytes greater than peripheral blood lymphocytes of patients without effusion = peripheral blood lymphocytes of healthy controls greater than peripheral blood lymphocytes of patients with effusion. The poor response of peripheral blood lymphocytes from pleurisy patients were recovered by the elimination of adherent cells in peripheral blood lymphocytes to the level of the response of peripheral blood lymphocytes from healthy controls. T cells purified from pleural fluid mononuclear cells responded more than those from peripheral blood. These results suggested that in the pleurisy patients purified protein derivative-reactive T cells in peripheral blood did not decrease in activity, but were depressed by suppressor cells, and further suggested that highly purified protein derivative-reactive T cells were accumulated in the pleural fluid.
PMCID: PMC351053  PMID: 6976936
25.  Diagnostic Accuracy of Adenosine Deaminase and Lymphocyte Proportion in Pleural Fluid for Tuberculous Pleurisy in Different Prevalence Scenarios 
PLoS ONE  2012;7(6):e38729.
Background
Tuberculous pleural effusion (TPE) is a paucibacillary manifestation of tuberculosis, so isolation of Mycobacterium tuberculosis is difficult, biomarkers being an alternative for diagnosis. Adenosine deaminase (ADA) is the most cost-effective pleural fluid marker and is routinely used in high prevalence settings, whereas its value is questioned in areas with low prevalence. The lymphocyte proportion (LP) is known to increase the specificity of ADA for this diagnosis. We analyse the diagnostic usefulness of ADA alone and the combination of ADA ≥40 U/l (ADA40) and LP≥50% (LP50) in three different prevalence scenarios over 11 years in our area.
Materials and Methods
Biochemistry, cytology and microbiology studies from 472 consecutive pleural fluid samples were retrospectively analyzed. ADA and differential cell count were determined in all samples. We established three different prevalence periods, based on percentage of pleural effusion cases diagnosed as tuberculosis: 1998–2000 (31.3%), 2001–2004 (11.8%), and 2005–2008 (7.4%). ROC curves, dispersion diagrams and pre/post-test probability graphs were produced. TPE accounted for 73 episodes (mean prevalence: 15.5%). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for ADA40 were 89%, 92.7%, 69.2% and 97.9%, respectively. For ADA40+LP50 the specificity and PPV increased (98.3% and 90%) with hardly any decrease in the sensitivity or NPV (86.3% and 97.5%). No relevant differences were observed between the three study periods.
Conclusions/Significance
ADA remains useful for the diagnosis of TPE even in low-to-intermediate prevalence scenarios when combined with the lymphocyte proportion.
doi:10.1371/journal.pone.0038729
PMCID: PMC3377686  PMID: 22723878

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