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      Influence of age on the diagnostic accuracy of soluble biomarkers for tuberculous pleural effusion: a post hoc analysis

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          Abstract

          Background

          Accurately diagnosing pleural effusion is a frequent and significant problem in clinical practice. Combining pleural biomarkers with patients’ age may be a valuable method for diagnosing TPE. We sought to evaluate the influence of age on diagnostic values of pleural adenosine deaminase (ADA), interferon-gamma (IFN-γ), and interleukin 27 (IL-27) for tuberculous pleural effusion (TPE).

          Methods

          Two hundred seventy-four consecutive adult patients with pleural effusion were selected from Beijing and Wuhan between January 1, 2014 and June 30, 2015, and their pleural fluid concentrations of ADA, IFN-γ, and IL-27 were tested. Biomarker performance was analyzed by standard receiver operating characteristic (ROC) curves according to different ages.

          Results

          Data from the Beijing cohort showed that ADA, IFN-γ, and IL-27 could all accurately diagnose TPE in young patients (≤ 40 years of age). With a cutoff of 21.4 U/L, the area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ADA for diagnosing TPE were 1.000 (95% confidence interval: 0.884–1.000), 100.0, 100.0%, 100.0, and 100.0, respectively. In older patients (> 40 years of age), IL-27 and IFN-γ were excellent biomarkers for discriminating TPE versus non-TPE cases. With a cutoff of 591.4 ng/L, the AUC, sensitivity, specificity, PPV, and NPV of IL-27 for diagnosing TPE were 0.976 (95% confidence interval: 0.932–0.995), 96.3, 99.0%, 96.3, and 99.0, respectively. Similar diagnostic accuracy among the three pleural biomarkers was validated in the Wuhan cohort.

          Conclusions

          Among young patients, ADA is reliable for diagnosing TPE. Conversely, in older patients, IL-27 and IFN-γ are excellent biomarkers to differentiate TPE versus non-TPE cases.

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          Most cited references24

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          The meaning and use of the area under a receiver operating characteristic (ROC) curve.

          A representation and interpretation of the area under a receiver operating characteristic (ROC) curve obtained by the "rating" method, or by mathematical predictions based on patient characteristics, is presented. It is shown that in such a setting the area represents the probability that a randomly chosen diseased subject is (correctly) rated or ranked with greater suspicion than a randomly chosen non-diseased subject. Moreover, this probability of a correct ranking is the same quantity that is estimated by the already well-studied nonparametric Wilcoxon statistic. These two relationships are exploited to (a) provide rapid closed-form expressions for the approximate magnitude of the sampling variability, i.e., standard error that one uses to accompany the area under a smoothed ROC curve, (b) guide in determining the size of the sample required to provide a sufficiently reliable estimate of this area, and (c) determine how large sample sizes should be to ensure that one can statistically detect differences in the accuracy of diagnostic techniques.
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            Update on tuberculous pleural effusion.

            The possibility of tuberculous pleuritis should be considered in every patient with an undiagnosed pleural effusion, for if this diagnosis is not made the patient will recover only to have a high likelihood of subsequently developing pulmonary or extrapulmonary tuberculosis Between 3% and 25% of patients with tuberculosis will have tuberculous pleuritis. The incidence of pleural tuberculosis is higher in patients who are HIV positive. Tuberculous pleuritis usually presents as an acute illness with fever, cough and pleuritic chest pain. The pleural fluid is an exudate that usually has predominantly lymphocytes. Pleural fluid cultures are positive for Mycobacterium tuberculosis in less than 40% and smears are virtually always negative. The easiest way to establish the diagnosis of tuberculous pleuritis in a patient with a lymphocytic pleural effusion is to generally demonstrate a pleural fluid adenosine deaminase level above 40 U/L. Lymphocytic exudates not due to tuberculosis almost always have adenosine deaminase levels below 40 U/L. Elevated pleural fluid levels of gamma-interferon also are virtually diagnostic of tuberculous pleuritis in patients with lymphocytic exudates. In questionable cases the diagnosis can be established by demonstrating granulomas or organisms on tissue specimens obtained via needle biopsy of the pleura or thoracoscopy. The chemotherapy for tuberculous pleuritis is the same as that for pulmonary tuberculosis.
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              Diagnostic accuracy of adenosine deaminase in tuberculous pleurisy: a meta-analysis.

              Conventional tests are not always helpful in making a diagnosis of tuberculous pleurisy. Many studies have investigated the usefulness of adenosine deaminase (ADA) in pleural fluid for the early diagnosis of tuberculous pleurisy. We conducted a meta-analysis to determine the accuracy of ADA measurements in the diagnosis of tuberculous pleurisy. After a systematic review of English language studies, sensitivity, specificity, and other measures of accuracy of ADA concentration in the diagnosis of pleural effusion were pooled using random effects models. Summary receiver operating characteristic curves were used to summarize overall test performance. Sixty-three studies met our inclusion criteria. The summary estimates for ADA in the diagnosis of tuberculous pleurisy in the studies included were sensitivity 0.92 (95% confidence interval 0.90-0.93), specificity 0.90 (95% confidence interval 0.89-0.91), positive likelihood ratio 9.03 (95% confidence interval 7.19-11.35), negative likelihood ratio 0.10 (95% confidence interval 0.07-0.14), and diagnostic odds ratio 110.08 (95% confidence interval 69.96-173.20). ADA determination is a relative sensitive and specific test for the diagnosis of tuberculous pleurisy. Measurement of ADA in pleural effusion is thus likely to be a useful diagnostic tool for tuberculous pleurisy. The results of ADA assays should be interpreted in parallel with clinical findings and the results of conventional tests.
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                Author and article information

                Contributors
                shihuanzhong@sina.com
                Journal
                BMC Pulm Med
                BMC Pulm Med
                BMC Pulmonary Medicine
                BioMed Central (London )
                1471-2466
                22 June 2020
                22 June 2020
                2020
                : 20
                : 178
                Affiliations
                [1 ]GRID grid.24696.3f, ISNI 0000 0004 0369 153X, Department of Respiratory and Critical Care Medicine, , Beijing Chaoyang Hospital, Capital Medical University, ; 8 Gongti Nanlu, Chaoyang District, Beijing, 100020 China
                [2 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Respiratory and Critical Care Medicine, , Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, ; Wuhan, China
                Article
                1219
                10.1186/s12890-020-01219-2
                7310016
                32571326
                94b53327-8e02-4671-be37-6b46e3ea3de4
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 14 February 2020
                : 16 June 2020
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81970088
                Award ID: 81900093
                Award ID: 81900094
                Award ID: 81400044
                Award Recipient :
                Funded by: Beijing Municipal Administration of Hospitals’ Mission Plan
                Award ID: SML20150301
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2020

                Respiratory medicine
                adenosine deaminase,interferon-gamma,interleukin 27,tuberculous pleural effusion

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