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Adenosine deaminases ADA1 and ADA2 reduce adenosine concentrations, which regulate cellular immune responses to activation signals. It has been shown that ADA2 activity increases in the pleural fluid of patients with tuberculosis (TB). We engineered recombinant scFv-AP antibodies using phage display technology to select high-affinity binders against ADA2. These were incorporated into a sandwich ELISA, allowing for the precise measurement of ADA2 levels in pleural fluid. The assay was tested on pleural samples from 41 patients with TB and 47 with non-TB effusions, including those with malignancies and parapneumonic effusions. Results showed that ADA2 concentrations were significantly higher in patients with TB than in other groups, and the ADA2-based assay exhibited improved diagnostic specificity (91%) compared with total ADA testing (76%). A cutoff of 300 ng/mL for ADA2 yielded a sensitivity of 98% and a negative likelihood ratio of 0.03, effectively ruling out TB when the result was negative. The new ADA2 assay offers a simple, reliable, and more specific alternative for diagnosing pleural TB, with potential applications in other ADA2-related disorders.

Pleural tuberculosis (pTB) is a grave form of extrapulmonary tuberculosis. Microbiological tests are usually found to be inadequate for pTB diagnosis. The absence of a uniform 'composite reference standard' is challenging; therefore, diagnosis is usually performed using a combination of diversified criteria. Nucleic acid tests vary in diagnostic accuracy and have not yet been integrated into clinical decision making. This review assesses the varied criteria used for pTB classification and the challenges afflicting pleural fluid-based DNA diagnostic tests, namely, PCR and Xpert MTB/RIF. In the 58 studies (PCR: n = 33; Xpert: n = 25) analyzed, reference standards were heterogeneous and PCR/Xpert pooled sensitivity values (range: 0-100%) were inadequate. However, the consistent high specificity of Xpert (range: 90-100%) indicated its utility as a 'rule-in' test. There is an urgent need to evaluate existing and new molecular tests in well-designed studies to accurately assess their utility for pTB diagnosis. To conclude, rapid and accurate tests are warranted for pTB diagnosis.

The use of biomarkers on pleural fluid (PF) specimens may assist the decision-making process and enhance clinical diagnostic pathways. Three paradigmatic examples are heart failure, tuberculosis and, particularly, malignancy. An elevated PF concentration of the amino-terminal fragment of probrain natriuretic peptide (>1500 pg/ml) is a hallmark of acute decompensated heart failure. Adenosine deaminase, interferon-γ and interleukin-27 are three valuable biomarkers for diagnosing tuberculous pleurisy, yet only the first has been firmly established in clinical practice. Diagnostic PF biomarkers for malignancy can be classified as soluble-protein based, immunocytochemical and nucleic-acid based. Soluble markers (e.g. carcinoembryonic antigen (CEA), carbohydrate antigen 15–3, mesothelin) are only indicative of cancer, but not confirmatory. Immunocytochemical studies on PF cell blocks allow: (a) to distinguish mesothelioma from reactive mesothelial proliferations (e.g. loss of BAP1 nuclear expression, complemented by the demonstration of p16 deletion using fluorescence in situ hybridization, indicate mesothelioma); (b) to separate mesothelioma from adenocarcinoma (e.g. calretinin, CK 5/6, WT-1 and D2-40 are markers of mesothelioma, whereas CEA, EPCAM, TTF-1, napsin A, and claudin 4 are markers of carcinoma); and (c) to reveal tumor origin in pleural metastases of an unknown primary site (e.g. TTF-1 and napsin A for lung adenocarcinoma, p40 for squamous lung cancer, GATA3 and mammaglobin for breast cancer, or synaptophysin and chromogranin A for neuroendocrine tumors). Finally, PF may provide an adequate sample for analysis of molecular markers to guide patients with non-small cell lung cancer to appropriate targeted therapies. Molecular testing must include, at least, mutations of epidermal growth-factor receptor and BRAF V600E, translocations of rat osteosarcoma and anaplastic lymphoma kinase, and expression of programmed death ligand 1.

Extrapulmonary tuberculosis (EPTB) accounts for a significant proportion of tuberculosis cases worldwide. Nevertheless, the diagnosis is often delayed or even missed due to insidious clinical presentation and poor performance of diagnostic tests. Culture, the classical gold standard for tuberculosis, suffers from increased technical and logistical constraints in EPTB cases. In this review the authors outline current diagnostic options for the main forms of EPTB. The authors also discuss the opportunities and challenges linked in particular to microbiological diagnostics and to the attempts to find a new gold standard test for EPTB. Finally, new biomarkers and tests currently under evaluation are hopefully on the way to introduce significant improvements in EPTB diagnosis, for which clinical suspicion will nevertheless be essential.

To clarify the predominance of Th1 or Th2 immune responses in malignant and tuberculous pleural effusion (MPE and TPE, respectively), we performed a meta-analysis of previously published results of the levels of Th1/Th2 cytokines associated with these two types of pleural effusion to evaluate the use of Th1/Th2 cytokine profiles in distinguishing TPE from MPE. We searched the PubMed and EMBASE databases for studies indexed from 2000 to March 2021. We included studies that (a) diagnosed TPE and MPE based on culture or pleural tissue biopsy and that (b) compared levels of Th1/Th2 cytokines between TPE and MPE. Pooled data based on a random-effects model or fixed-effects model and standardized mean differences (SMDs) across studies were used to compare TPE and MPE. We also performed Egger’s test to assess publication bias. Of 917 identified studies, a total of 42 studies were selected for the meta-analysis. Compared with MPE subjects, TPE subjects had a significantly higher level of TNF-α [2.22, (1.60–2.84)], an elevated level of IFN-γ [3.30, (2.57–4.40)] in pleural effusion, a situation where the Th1 immune response dominated. Conversely, the levels of interleukin-4 (IL-4) and IL-10 (Th2 cytokines) were higher in the MPE subjects than in the TPE subjects, showing statistically nonsignificant tiny effects [−0.15, (−0.94 to 0.63) and −0.04, (−0.21 to 0.12), respectively]. We confirmed that TPE, a situation in which the Th1 cytokines are predominant. The slight preponderance of Th2 cytokines in MPE, which is not convincing enough to prove.

In the 1980s, after a steady decline during preceding decades, there was a resurgence in the rate of tuberculosis in the United States that coincided with the acquired immunodeficiency syndrome epidemic. Disease patterns since have changed, with a higher incidence of disseminated and extrapulmonary disease now found. Extrapulmonary sites of infection commonly include lymph nodes, pleura, and osteoarticular areas, although any organ can be involved. The diagnosis of extrapulmonary tuberculosis can be elusive, necessitating a high index of suspicion. Physicians should obtain a thorough history focusing on risk behaviors for human immunodeficiency virus (HIV) infection and tuberculosis. Antituberculous therapy can minimize morbidity and mortality but may need to be initiated empirically. A negative smear for acid-fast bacillus, a lack of granulomas on histopathology, and failure to culture Mycobacterium tuberculosis do not exclude the diagnosis. Novel diagnostic modalities such as adenosine deaminase levels and polymerase chain reaction can be useful in certain forms of extrapulmonary tuberculosis. In general, the same regimens are used to treat pulmonary and extrapulmonary tuberculosis, and responses to antituberculous therapy are similar in patients with HIV infection and in those without. Treatment duration may need to be extended for central nervous system and skeletal tuberculosis, depending on drug resistance, and in patients who have a delayed or incomplete response. Adjunctive corticosteroids may be beneficial in patients with tuberculous meningitis, tuberculous pericarditis, or miliary tuberculosis with refractory hypoxemia.

As the burden of tuberculosis (TB) in South Korea decreases while that of malignancy increases with an aging society, the composition of etiology for pleural effusion is changing. The aim of this study was to investigate the diagnostic value of adenosine deaminase (ADA) for diagnosis of tuberculous pleural effusion (TPE) in this circumstance. Medical records of patients who underwent medical thoracoscopy from May 2015 to September 2020 in Incheon St. Mary Hospital, Korea were retrospectively reviewed. TPE was diagnosed if one of the following criteria was met: (1) granuloma in pleura, (2) positive TB polymerase chain reaction or culture in pleural fluid or tissue with non-specific pathologic findings in pleura, or (3) bacteriologically confirmed pulmonary TB with non-specific pathologic findings in pleura. A total of 292 patients, including 156 with malignant pleural effusion (MPE), 52 with TPE, and 84 with other benign effusion, were analyzed. Among 206 patients with lymphocyte dominant pleural effusion, the area under receiver characteristic curve of ADA for diagnosis of TPE was 0.971. The sensitivity and specificity of a current cutoff value of 40 IU/L were 1.00 and 0.61, respectively, whereas those of a raised cutoff value of 70 IU/L were 0.93 and 0.93, respectively. Among 54 patients with ADA levels of 40–70 IU/L, 30 (55.6%) patients were diagnosed as MPE, 21 (38.9%) as other benign effusion, and only 3 (5.6%) as TPE. Caution is needed in clinical diagnosis of TPE with current ADA cutoff value in countries with decreasing TB incidence, due to many false positive cases.

To perform an external validation of a previously reported machine learning (ML) approach for predicting the diagnosis of pleural tuberculosis. We defined two cohorts: a Training group, comprising 273 out of 1,220 effusions from our prospective study (2013-2022); and a Testing group, from a retrospective analysis of 360 effusions from 832 consecutive patients in Bajo Deba health district (1996-2012). All the effusions included were exudative and lymphocytic. In Training and Testing groups respectively, 49 and 104 cases were tuberculous, 143 and 92 were malignant, and 81 and 164 were diagnosed with \"other diseases\"; pre-test probabilities of pleural tuberculosis were 4% and 12.7%. Variables included were: age, pH, adenosine deaminase, glucose, protein, and lactate dehydrogenase levels, and white cell counts (total and differential) in pleural fluid. We used two ML classifiers: binary (tuberculous and non-tuberculous), and three-class (tuberculous, malignant, and others); and compared them with Bayesian analysis. The best binary classifier yielded a sensitivity of 88%, specificity of 98%, and accuracy of 95%. The best three-class classifier achieved the same accuracy and correctly classified 83% (77/92) of malignant cases. The ML models yielded higher positive predictive values than Bayesian analysis based on ADA > 40 U/l and lymphocyte percentage ≥ 50% (92%). This external validation confirms the good performance of the previously reported ML approach for predicting the diagnosis of pleural tuberculosis based on exudative and lymphocytic pleural effusions, and for discriminating the cases most likely to be malignant. Additionally, ML was more accurate than the Bayesian approach in our study.

To analyze the performance of adenosine deaminase in pleural fluid combined with other parameters routinely measured in clinical practice and assisted by machine learning algorithms for the diagnosis of pleural tuberculosis in a low prevalence setting, and secondly, to identify effusions that are non-tuberculous and most likely malignant. We prospectively analyzed 230 consecutive patients diagnosed with lymphocytic exudative pleural effusion from March 2013 to June 2020. Diagnosis according to the composite reference standard was achieved in all cases. Pre-test probability of pleural tuberculosis was 3.8% throughout the study period. Parameters included were: levels of adenosine deaminase, pH, glucose, proteins, and lactate dehydrogenase, red and white cell counts and lymphocyte percentage in pleural fluid, as well as age. We tested six different machine learning-based classifiers to categorize the patients. Two different classifications were performed: a) tuberculous/non-tuberculous and b) tuberculous/malignant/other. Out of a total of 230 patients with pleural effusion included in the study, 124 were diagnosed with malignant effusion and 44 with pleural tuberculosis, while 62 were given other diagnoses. In the tuberculous/non-tuberculous classification, and taking into account the validation predictions, the support vector machine yielded the best result: an AUC of 0.98, accuracy of 97%, sensitivity of 91%, and specificity of 98%, whilst in the tuberculous/malignant/other classification, this type of classifier yielded an overall accuracy of 80%. With this three-class classifier, the same sensitivity and specificity was achieved in the tuberculous/other classification, but it also allowed the correct classification of 90% of malignant cases. The level of adenosine deaminase in pleural fluid together with cell count, other routine biochemical parameters and age, combined with a machine-learning approach, is suitable for the diagnosis of pleural tuberculosis in a low prevalence scenario. Secondly, non-tuberculous effusions that are suspected to be malignant may also be identified with adequate accuracy.