Kan Zhai

Diagnostic values of soluble mesothelin-related peptides for malignant pleural mesothelioma: updated meta-analysis

Objective Although the values of soluble mesothelin-related peptides (SMRPs), including mesothelin and megakaryocyte potentiating factor, in serum and/or pleural fluid for diagnosing malignant pleural mesothelioma (MPM) have been extensively studied, the exact diagnostic accuracy of these SMRPs remains controversial. The purpose of the present meta-analysis is to update the overall diagnostic accuracy of SMRPs in serum and, furthermore, to establish diagnostic accuracy of SMRPs in pleural fluid for MPM. Design Systematic review and meta-analysis. Methods A total of 30 articles of diagnostic studies were included in the current meta-analysis. Sensitivity, specificity and other measures of accuracy of SMRPs in serum and pleural fluid for the diagnosis of MPM were pooled using random effects models. Summary receiver operating characteristic curves were used to summarise overall test performance. Results The summary estimates of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic OR were 0.61, 0.87, 5.71, 0.43 and 14.43, respectively, for serum and 0.79, 0.85, 4.78, 0.30 and 19.50, respectively, for pleural fluid. It was also found that megakaryocyte potentiating factor in serum had a superior diagnostic accuracy compared with mesothelin for MPM. Conclusions SMRPs in both serum and pleural fluid are helpful markers for diagnosing MPM with similar diagnostic accuracy. The negative results of SMRP determinations are not sufficient to exclude non-MPM, and the positive test results indicate that further invasive diagnostic steps might be necessary for the diagnosis of MPM.

Tuberculous pleural effusion

Although it is curable, tuberculosis remains one of the most frequent causes of pleural effusions on a global scale, especially in developing countries. Tuberculous pleural effusion (TPE) is one of the most common forms of extrapulmonary tuberculosis. TPE usually presents as an acute illness with fever, cough and pleuritic chest pain. The pleural fluid is an exudate that usually has predominantly lymphocytes. The gold standard for the diagnosis of TPE remains the detection of Mycobacterium tuberculosis in pleural fluid, or pleural biopsy specimens, either by microscopy and/or culture, or the histological demonstration of caseating granulomas in the pleura along with acid fast bacilli, Although adenosine deaminase and interferon-γ in pleural fluid have been documented to be useful tests for the diagnosis of TPE. It can be accepted that in areas with high tuberculosis prevalence, the easiest way to establish the diagnosis of TPE in a patient with a lymphocytic pleural effusion is to generally demonstrate a adenosine deaminase level above 40 U/L. The recommended treatment for TPE is a regimen with isoniazid, rifampin, and pyrazinamide for two months followed by four months of two drugs, isoniazid and rifampin.

Recruitment of IL-27-Producing CD4+ T Cells and Effect of IL-27 on Pleural Mesothelial Cells in Tuberculous Pleurisy

BackgroundThe numbers of IL-27-producing CD4+ T cells and the concentration of soluble IL-27 have been found to be increased in tuberculous pleural effusion (TPE). The objective of the present study was to explore the mechanism by which IL-27+CD4+ T cells are recruited into the pleural space, and to explore the impact of IL-27 on pleural mesothelial cells (PMCs).MethodsThe expression profiles of chemokine receptor (CCR) were determined by flow cytometry. The chemoattractant activity of chemokines CCL20 and CCL22 for IL–27+CD4+ T cells in vitro was observed. Effects of IL-27 on wound healing, proliferation and apoptosis of PMCs were also investigated.ResultsIL-27+CD4+ T cells in TPE expressed high level of CCR6, medium level of CCR4, and low levels of CCR2, CCR3, CCR5, CCR7, CCR10, and CXCR3. Recruitment of IL-27+CD4+ T cells into TPE could be induced by pleural CCL20 and CCL22. By activating STAT3 signaling, IL-27 significantly improved wound healing and promoted proliferation of PMCs, and completely prevented apoptosis of PMCs induced by IFN-γ.ConclusionsAfter being recruited into pleural space by CCL20 or/and CCL22, these pleural IL-27-producing CD4+ T cells may play important roles in tuberculosis immunity by affecting PMC functions.

Body Fluid Interferon-γ Release Assay for Diagnosis of Extrapulmonary Tuberculosis in Adults: A Systematic Review and Meta-Analysis

The diagnosis of extrapulmonary tuberculosis (EPTB) is difficult. In recent years, T-cell interferon-γ release assays (IGRAs) are widely used in diagnosing tuberculosis. The aim of this meta-analysis is to evaluate the diagnostic accuracy of body fluid IGRAs in diagnosing EPTB. The PubMed, EMBASE, Web of Science, and Cochrane bibliographies were searched for English language articles. 22 studies met the inclusion criteria. The pooled sensitivity and specificity of body fluid IGRAs for diagnosing EPTB were 0.87 [95% confidence interval (CI): 0.83–0.92] and 0.85 (95% CI: 0.79–0.90), respectively. For the fluid T-SPOT.TB, the pooled sensitivity and specificity were 0.92 (95% CI: 0.88–0.95) and 0.85 (95% CI: 0.78–0.91), respectively. The diagnostic odds ratio (DOR) of the fluid T-SPOT.TB was 46.99 (95% CI: 13.69–161.28) for tuberculosis pleurisy, 26.46 (95% CI: 11.38–61.56) for tuberculosis peritonitis, and 97.86 (95% CI: 25.31–378.45) for tuberculosis meningitis. The application of T-SPOT. TB in the diagnosis of EPTB performed better in the body fluid than in the blood. The diagnostic values of the fluid T-SPOT.TB varied for different fluid categories. However, the utility of T-SPOT.TB was limited due to its suboptimal accuracy and higher cost compared with conventional tests.

Diagnostic accuracy of interleukin 27 for tuberculous pleural effusion: two prospective studies and one meta-analysis

Background Accurate differentiating diagnosis is essential for choosing treatment for exudative pleural effusions. Objective To establish the diagnostic accuracy of interleukin 27 for tuberculous pleural effusion (TPE). Methods First, the concentrations of pleural interleukin 27, interferon-gamma and adenosine deaminase were compared between 51 patients with TPE and 103 with non-TPEs (Beijing cohort), and their diagnostic values were evaluated. These were further verified in another independent population (Wuhan cohort, n=120). In the second part of the study, we performed a meta-analysis. Results With a cut-off value of 591.4 ng/L in the Beijing cohort, the area under the curve, sensitivity, specificity, positive predictive value and negative predictive value of interleukin 27 to diagnose TPE were 0.983 (95% CI 0.947 to 0.997), 96.1% (86.5% to 99.5%), 99.0% (94.7% to 100%), 98.0 (89.4 to 99.9) and 98.1 (93.3 to 99.8), respectively. Excellent diagnostic accuracy of interleukin 27 was also found in the Wuhan cohort and was further confirmed in the meta-analysis. The diagnostic performance of interleukin 27 was comparable to that of interferon-gamma and was more accurate than that of adenosine deaminase. Since the post-test probability of a negative result was always <0.1%, a negative test was considered to exclude TPE in all tuberculosis prevalence settings. Conclusions Interleukin 27 can be used to diagnose TPE in a high prevalence setting, and a negative result can also be reliably used to rule out TPE in all prevalence settings.

Toll-like receptor 4 signaling inhibits malignant pleural effusion by altering Th1/Th17 responses.

Toll‐like receptor 4 (TLR4) is involved in multiple malignancies; however, the role of TLR4 in the pathogenesis of malignant pleural effusion (MPE) remains unknown. The objectives of this study were to explore the impact of TLR4 signaling on the development of MPE in a murine model and to define the underline mechanisms by which TLR works. Development of MPE as well as proliferation and angiogenesis of pleural tumor were determined in TLR4–/– and wild type mice. Differentiation of Th1 and Th17 cells as well as their signal transductions was explored. The effects of TLR4 signaling on survival of mice bearing MPE were also investigated. Compared with wild type mice, Th1 cells were augmented, and Th17 cells were suppressed in MPE from TLR4–/– mice. The in vitro experiments showed that TLR4 deficiency promoted Th1 cell differentiation via enhancing STAT1 pathway and inhibited Th17 cell differentiation via suppressing STAT3 pathway. TLR4 deficiency promoted MPE formation and, thus, accelerated the death of mice bearing MPE, whereas intraperitoneal injection of anti‐IFN‐γ mAb or recombinant mouse IL‐17 protein into TLR4–/– mice was associated with improved survival. Our data provides the first definitive evidence of a role for TLR4 signaling in protective immunity in the development of MPE. Our findings also demonstrate that TLR4 deficiency promotes MPE formation and accelerates mouse death by enhancing Th1 and suppressing Th17 response.

Immune Regulation of TLR2 Engagement on CD4(+) T Cells in Murine Models of Malignant Pleural Effusion.

&NA; Toll‐like receptor (TLR) 2 has a well‐known role in sensing multiple ligands that include microbial products, endotoxin, and some extracellular matrix molecules; however, its role in the development of malignant pleural effusion (MPE) remains unknown. We performed the present study to explore the impact of TLR2 signaling on the development of MPE and to define the underlying mechanisms by which TLR2 works. Development of MPE was compared between TLR2‐/‐ and wild‐type (WT) mice. The effect of TLR2 on differentiation of T helper type 17 (Th17), Th9, and Th2 cells in MPE was explored. The mechanisms of TLR2 on survival of mice bearing MPE were also investigated. MPE volume in TLR2‐/‐ mice was lower than that in WT mice, and the survival of TLR2‐/‐ mice bearing MPE was longer than that of WT mice. TLR2 deficiency increased, and TLR2 activation decreased, Th17 cells in MPE, whereas TLR2 signaling showed the contrary effects on Th2 cells. Th9 cells were increased in MPE of TLR2‐/‐ mice but were not influenced by TLR2 signaling. Intraperitoneal injection of anti‐IL‐17 monoclonal antibody (mAb), anti‐IL‐9 mAb, or recombinant mouse IL‐4 accelerated the death of TLR2‐/‐ mice bearing MPE, and intraperitoneal injection anti‐IL‐17 mAb in TLR2‐/‐ mice was associated with a significantly shorter survival time than in WT mice. We have demonstrated, for the first time, that TLR2 signaling promotes the development of MPE and accelerates the death of mice bearing MPE by directly suppressing Th17 cell differentiation and directly promoting Th2 cell differentiation, and also by indirectly suppressing Th9 cell differentiation via an IL‐17‐dependent mechanism.

Interleukin-17 inhibits development of malignant pleural effusion via interleukin-9-dependent mechanism

Th17 and Th9 cells have been demonstrated to possess immune regulatory functions in malignant pleural effusion (MPE). However, whether IL-17 can affect differentiation and function of Th9 cells in MPE remains unknown. The objective of the present study was to explore the impact of IL-17 on the in vivo differentiation of Th9 cells in relation to Th2 cells in a murine model of MPE, and to explore whether IL-17 inhibits MPE formation via IL-9‒dependent mechanism. It was found that Th9 and Th2 cells were decreased in MPE from IL-17–/– mice as compared with wild type mice. IL-17 deficiency inhibited Th9 and Th2 cell differentiation via suppressing transcription factors IRF4 and GATA-3, respectively. IL-17 deficiency enhanced MPE formation by promoting angiogenesis and proliferation of pleural tumors, and thus accelerated the death of mice bearing MPE. The in vivo administration of anti-IL-9 neutralizing mAb accelerated the death of WT mice; whereas administration of exogenous IL-9 improved the survival of IL-17–/– mice. Our data provide the first definitive evidence that IL-17 promotes the differentiation of Th9 and Th2 cells in MPE. Our findings also demonstrate that IL-17 inhibits the formation of MPE and improves the survival of mice bearing MPE via an IL-9–dependent mechanism.

Determination of Interleukin 27-Producing CD4+ and CD8+ T Cells for The Differentiation Between Tuberculous and Malignant Pleural Effusions

The numbers of IL-27+ CD4+ and IL-27+ CD8+ T cells have been found to be increased in tuberculous pleural effusion (TPE) as compared with malignant pleural effusion (MPE). The objective of the present study was to investigate whether pleural IL-27+ CD4+ and IL-27+ CD8+ T cells can distinguish patients with TPE from those with MPE. Paired specimen of pleural fluid and peripheral blood were collected from 35 patients with TPE and 46 MPE. The numbers of IL-27+ CD4+ and IL-27+ CD8+ T cells were simultaneously determined by flow cytometry. Receiver operating characteristic curve analysis was used to evaluate the capacity of IL-27+ CD4+ and IL-27+ CD8+ T cells to differentiate TPE from MPE. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), positive predictive value (PPV), and negative predictive value (NPV) of IL-27+ CD4+ T cells were 94.3%, 93.5%, 14.46, 0.06, 91.7%, and 95.6%, respectively. The sensitivity, specificity, PLR, NLR, PPV and NPV of IL-27+ CD8+ T cells were 80.0%, 93.5%, 12.27, 0.21, 90.3% and 86.0%, respectively. The number of IL-27+ CD4+ in pleural fluid is a helpful diagnostic biomarker for the diagnosis of TPE, which performs better than that of IL-27+ CD8+ T cells.

IL-10 Producing B Cells Regulate Th1/Th17 Cell Immune Responses in Pneumocystis Pneumonia

Pneumocystis pneumonia (PCP) is a common opportunistic infectious disease that is prevalent in immunosuppressed hosts. Accumulating evidence shows that B cells play an important role in infectious diseases. In the present study, the immune regulatory role of mature B cells in host defense to Pneumocystis was evaluated. Pneumocystis infection resulted in a decrease in B cells in patients and mice, and the Pneumocystis burden in B cell-deficient mice also progressively increased from weeks 1 to 7 after infection. The clearance of Pneumocystis was delayed in B cell-activating factor receptor (BAFF-R)-deficient mice (BAFF-R-/- mice), which had few B cells and Pneumocystis-specific IgG and IgM antibodies, compared with clearance in wild-type (WT) mice. There were fewer effector CD4+ T cells and higher percentages of T helper (Th)1/Th17 cells in BAFF-R-/- mice than in WT mice. Adoptive transfer of naive B cells, mRNA sequencing, and IL-1β neutralization experiments indicated that IL-1β is a likely determinant of the IL-10-producing B cell-mediated suppression of Th1/Th17-cell immune responses in BAFF-R-/- PCP mice. Our data indicated that B cells play a vital role in the regulation of Th cells in response to Pneumocystis infection.