Backgrounds Pulmonary tuberculosis (PTB) is a major health and economic burden. Accurate PTB detection is an important step to eliminating TB globally. Interferon gamma-induced protein 10 (IP-10) has been reported as a potential diagnostic marker for PTB since 2007. In this study, a meta-analysis approach was used to assess diagnostic value of IP-10 for PTB. Methods Web of Science, PubMed, the Cochrane Library, and Embase databases were searched for studies published in English up to February

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... 19. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and hierarchical summary receiver operating characteristic (HSROC) curve were estimated by a HSROC model. Results Eighteen studies including 2836 total participants met our inclusion criteria. The pooled sensitivity, specificity, PLR, and NLR of IP-10 for PTB detection were 86%, 88%, 7.00, and 0.16, respectively. The pooled DOR was 43.01, indicating a very powerful discriminatory ability of IP-10. Meta-regression showed that there was no heterogeneity with respect to TB burden, study design type, age, IP-10 assay method, IP-10 condition and HIV-infection status. Conclusions Our results showed that IP-10 is a promising marker for differentiating PTB from non-TB. Background Tuberculosis (TB), a highly contagious disease, is still a major health and economic burden [1]. Globally, approximately 10 million individuals developed TB and more than 1.3 million died of the disease in 2017, according to a WHO report [2]. Pulmonary tuberculosis (PTB), accounting for 75% of all TB cases, contributes substantially to TB mortality, especially with HIV co-infection [3, 4]. Correctly discriminating PTB is an important step to eliminate TB by 2030, a goal established by the WHO [2]. In clinical practice, sputum smear microscopy is ineffective for detecting PTB [5]. Specimen culture for Mtb provides the most accurate diagnosis [6]. However, this method is time-consuming and depends on specimen quality. Immunological tests, such as the tuberculin skin test (TST) and interferon-gamma release assay (IGRA), are auxiliary diagnostic tools for PTB [7]. TST has a low specificity in Bacilli Calmette Guerin (BCG)-vaccinated individuals [7]. In children, IGRAs can yield 4 many indeterminate results [8, 9]. Considering these limitations, additional valid tools are required to improve the diagnosis of PTB. Interferon gamma-induced protein 10 (IP-10), an IFN-gamma-inducible chemokine, could be expressed at 100-fold higher levels than those of IFN-gamma after TB infection [10, 11]. Age and gender do not affect the level of 12]. Since 2007, IP-10 has been reported as a potential parameter for PTB detection [7] [13] [14] [15] [16] [17] [18] [19] [20][21][22][23][24][25][26][27][28][29]. Many studies have evaluated the diagnostic potential of IP-10 for PTB, but the results are variable. Therefore, the aim of this study was to synthesize and analyze the diagnostic value of IP-10 for PTB. Methods Literature search This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Diagnostic Test Accuracy criteria 2018 (PRISMA-DTA 2018) [30]. The Web of Science, PubMed, the Cochrane Library and Embase databases were used to search for relevant English language citations published up to February 2019. Our search terms were "tuberculosis," "pulmonary tuberculosis," "Chemokine CXCL10," and "interferon gamma-induced protein 10." A comprehensive literature search strategy was used based on the following combination of MeSH terms and title/abstracts for the PubMed database (Supplementary Materials). Additionally, the reference lists of the applicable studies, relevant research letters, and reviews were manually searched to find other potentially relevant studies. Literature selection Two investigators independently determined literature eligibility. Studies reporting IP-10 levels for the detection of PTB were included according to the following criteria: (1) reporting on individuals with PTB and non-TB (population); (2) provision of IP-10 in whole blood and plasma as index test; (4) Mtb culture as a gold standard, and other reference standard including pathological examination, microscopy and genexpert MTB/RIF test (WHO recommended) [2]; (5) the primary outcomes including diagnostic performance of IP-10 (sensitivity and specificity); (5) randomized controlled trails, prospective and retrospective studies included (study design); (6) more than 10 individuals reported meeting the inclusion criteria. Studies not published in English, other letters (except research letters), conference abstracts, veterinary experiments, reviews and case reports were excluded. Data extraction The following data were extracted: the first author, year of publication, country, TB high-burden, study design, age, number of participants (patients with PTB and non-TB subjects), TB site, non-TB status, cut-off for index test (IP-10), diagnostic reference standard, method and condition for the IP-10 5 assay, HIV-infection status, sensitivity, specificity, true positive (TP), false positive (FP), false negative (FN), and true negative (TN) for IP-10. Two investigators independently extracted data from eligible articles, and disagreements were resolved by discussing and reaching a consensus. Quality assessment According to the Cochrane Collaboration, two investigators independently reviewed the methodological quality of eligible articles by Quality Assessment of Diagnostic Accuracy Studies tool-2 (QUADAS-2) [31, 32]. Disagreements were resolved by consensus. Revman (version 5.3) was used to perform the quality assessment. Data analysis Excel was used to construct a two-by-two table, including TP, FP, FN, and TN for patients with PTB. Stata (version 14.0) was used to perform the data analysis. The index test had different optimal cutoffs. According to the recommendation of Cochrane Collaboration, the hierarchical summary receiver operating characteristic (HSROC) model by Rutter et al. was utilized when the index test was assessed by applying various thresholds [32, 33]. The HSROC curve was computed with the "metandi" command [34]. The main outcomes were the diagnostic performance of IP-10 for detecting PTB, as evaluated by the summary estimates of sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). DOR, a measure for overall accuracy of index test, could be calculated by the formula "DOR=(TP/FN)/(FP/TN)". The I 2 value was not suitable for the quantification of heterogeneity in accuracy studies [35]. Thus, to explore potential sources of heterogeneity, we used a meta-regression analysis with the "midas" command. Seven subgroups were created: TB high-burden country (yes or no), study design type (cohort or not), age (adults or not), IP-10 method (multiplex cytokines assay or ELISA), IP-10 condition (unstimulated or stimulated), and HIV-infection status (yes/some or no). The Deeks test was used to assess publication bias using the "midas" command [36]. Results Search results In total, 1349 records were identified from our literature searches (Figure 1 ). After removing 623 duplicates, we read titles and abstracts and excluded 682 records. An additional 447 records were non-eligible for various reasons (e.g., studies involving leprosy, Crohn's disease, pneumonia, monocyte chemotactic protein-1, interleukin-12, and interleukin-18), 73 records were animal experiments (mouse, calves, warthogs, etc.), 69 records were reviews, abstracts, and letters, 58 records focused on extra-PTB (pleural TB, TB meningitis, osteoarticular TB, etc.), and 5 records were non-English (Chinese, Russian, Polish, etc.). Then, we reviewed the full texts of 44 articles. Ultimately, PTB is still a major cause of death worldwide, especially in immunocompromised individuals and children younger than 5 years [37, 38]. The accurate detection and timely treatment of PTB are important components of the "End TB Strategy" globally [39]. Currently, methods for detecting PTB depend on the region, BCG-vaccinated status, HIV status, etc. The search for new markers for the auxiliary diagnosis of PTB is ongoing. Several studies have shown that IP-10 is a promising marker for PTB detection [7] [13] [14] [15] [16] [17] [18] [19] [20][21][22][23][24][25][26][27][28][29]. In 2014, Guo et al. published a meta-analysis of studies of IP-10 for diagnosing TB [40]. The diagnostic performance of IP-10 was moderate. In this study, both PTB and extra-PTB individuals were included, and plasma and pleural effusion samples were included. However, the diagnostic standards for PTB and extra-PTB were different. Pleural effusion detection is more traumatic than the use of peripheral venous blood. Considering these limitations, we performed a meta-analysis to evaluate the overall diagnostic performance of blood IP-10 as a potential biomarker for detecting PTB. We found that IP-10 could be a valuable detection tool (sensitivity: 86%, specificity: 88%). The PLR (7.001.00) suggested that IP-10 had good detection potential for PTB. The NLR (0.161.00) indicated that IP-10 distinguished non-TB individuals well. The DOR (43.01) indicated a good overall performance of IP-10 in discriminating between PTB and non-TB. The TST and IGRA, as immunodiagnostic tests, are recommended for the auxiliary diagnosis of PTB by the WHO [2]. The TST could show cross-reactivity in BCG-vaccinated individuals. However, IP-10 is less influenced by BCG vaccination [7]. Ruhwald et al. reported that IP-10 has a much higher sensitivity (92.5%) when compared to the TST (73.9%), and suggested that IP-10 is an alternative biomarker of TST [41]. The recently developed IGRA can overcome some limitations of TST. However, it lacks power when applied to children and individuals coinfected with HIV [9, 14]. IP-10 could be produced at a high level in these populations [42, 43]. Vanini et al. showed that the sensitivity is 66.7% for IP-10-based test and 52.4% for the IGRA in HIV-infected individuals [44]. In bivariate analyses, TB-burden country, study design, age, IP-10 detection method, assay conditions, and HIV infection status were not significant sources of heterogeneity. We also found that the diagnostic performance of IP-10 was similar in multiplex cytokine assays and ELISA (sensitivity: 84% vs. 87%, specificity: 89% vs. 87%). These two methods were comparable with respect to reliability and reproducibility [20]. Considering the cost, ELISA is preferred over multiplex cytokine assays. Stimulated and unstimulated IP-10 had similar diagnostic accuracies for PTB, suggesting that IP-10 could be detected in both conditions. IP-10 had a higher diagnostic potential in HIV-infected individuals, consistent with previous findings [45]. 2. The World Health Organizations. Global tuberculosis report 2018. Available at: www.aidsdatahub.org/global-tuberculosis-report-2018-who-2018. 3. Denkinger CM, Schumacher SG, Boehme CC, Dendukuri N, Pai M, Steingart KR. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. Eur Respir J. 2014; 44(2):435-46. 4. Ford N, Matteelli A, Shubber Z, Hermans S, Meintjes G, Grinsztejn B, et al. TB as a cause of hospitalization and in-hospital mortality among people living with HIV worldwide: a systematic review and meta-analysis. J Int AIDS Soc. 2016;19(1):20714. 5. O'Garra A, Redford PS, McNab FW, Bloom CI, Wilkinson RJ, Berry MP. The immune response in tuberculosis. Annu Rev Immunol. 2013;31:475-527. 10 6. Wallis RS, Pai M, Menzies D, Doherty TM, Walzl G, Perkins MD, et al. Biomarkers and diagnostics for tuberculosis: progress, needs, and translation into practice. Lancet. 2010;375(9729):1920-37. 7.