Sensitivity, Specificity, and Safety of a Novel ESAT6-CFP10 Skin Test for Tuberculosis Infection in China: 2 Randomized, Self-Controlled, Parallel-Group Phase 2b Trials

Miao Xu, Wei Lu, Tao Li, Jingxin Li, Weixin Du, Qi Wu, Qiao Liu, Baodong Yuan, Jinbiao Lu, Xiaoyan Ding, Feng Li, Min Liu, Baowen Chen, Jiang Pu, Rongping Zhang, Xiuhong Xi, Rongguang Zhou, Zaoxian Mei, Ronghui Du, Lifeng Tao, Leonardo Martinez, Shuihua Lu, Guozhi Wang, Fengcai Zhu, Miao Xu, Wei Lu, Tao Li, Jingxin Li, Weixin Du, Qi Wu, Qiao Liu, Baodong Yuan, Jinbiao Lu, Xiaoyan Ding, Feng Li, Min Liu, Baowen Chen, Jiang Pu, Rongping Zhang, Xiuhong Xi, Rongguang Zhou, Zaoxian Mei, Ronghui Du, Lifeng Tao, Leonardo Martinez, Shuihua Lu, Guozhi Wang, Fengcai Zhu

Abstract

Background: Diagnostics to identify tuberculosis infection are limited. We aimed to assess the diagnostic accuracy and safety of ESAT6-CFP10 (EC) skin test for tuberculosis infection in Chinese adults.

Methods: We conducted 2 randomized, parallel-group clinical trials in healthy participants and tuberculosis patients. All participants were tested with the T-SPOT.TB test, then received an EC skin test and tuberculin skin test (TST). The diameter of skin indurations and/or redness at injection sites were measured at different time periods. A bacillus Calmette Guerin (BCG) model was established to assess the diagnosis of tuberculosis infection using an EC skin test.

Results: In total, 777 healthy participants and 96 tuberculosis patients were allocated to receive EC skin test at 1.0 μg/0.1 mL or 0.5 μg/0.1 mL. The area under the curve was 0.95 (95% confidence interval [CI], .91-.97) for the EC skin test at 1.0 μg/0.1 mL at 24-72 hours. Compared with the T-SPOT.TB test, the EC skin test demonstrated similar sensitivity (87.5, 95% CI, 77.8-97.2 vs 86.5, 95% CI, 79.5-93.4) and specificity (98.9, 95% CI, 96.0-99.9 vs 96.1, 95% CI, 93.5-97.8). Among BCG vaccinated participants, the EC skin test had high consistency with the T-SPOT.TB test (96.3, 95% CI, 92.0-100.0). No serious adverse events related to the EC skin test were observed.

Conclusions: The EC skin test demonstrated both high specificity and sensitivity at a dose of 1.0 μg/0.1 mL, comparable to the T-SPOT.TB test. The diagnostic accuracy of the EC skin test was not impacted by BCG vaccination.

Clinical trials registration: NCT02389322 and NCT02336542.

Keywords: ESAT6-CFP10; diagnostics; tuberculosis; tuberculosis infection.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Study profile of the pooled participants from healthy participants (A) and patients participants (B). Abbreviations: BCG, bacillus Calmette-Guerin; DBP, diastolic blood pressure; EC, ESAT6-CFP10; SBP, systolic blood pressure; TB, tuberculosis; TST, tuberculin skin test.
Figure 2.
Figure 2.
Estimated AUC for diagnosis with the ESAT6-CFP10 skin test with different indicators at different doses and time points. Abbreviations: AUC, area under the curve; EC, ESAT6-CFP10.
Figure 3.
Figure 3.
Incidence of adverse reactions at injection sites after receiving the ESAT6-CFP10 skin test and TST. Courbature means muscle aches. Abbreviations: EC, ESAT6-CFP10; TST, tuberculin skin test.

References

    1. World Health Organization. Global tuberculosis report 2019. Geneva, Switzerland: WHO, 2019.
    1. Houben RM, Dodd PJ. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med 2016; 13:e1002152.
    1. Gao L, Li X, Liu J, et al. ; LATENTTB-NSTM Study Team . Incidence of active tuberculosis in individuals with latent tuberculosis infection in rural China: follow-up results of a population-based, multicentre, prospective cohort study. Lancet Infect Dis 2017; 17:1053-61.
    1. Pai M, Denkinger CM, Kik SV, et al. . Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev 2014; 27:3-20.
    1. Yang H, Kruh-Garcia NA, Dobos KM. Purified protein derivatives of tuberculin—past, present, and future. FEMS Immunol Med Microbiol 2012; 66:273-80.
    1. Lu P, Liu Q, Zhou Y, et al. . Predictors of discordant tuberculin skin test and quantiFERON-TB gold in-tube results in Eastern China: a population-based, cohort study. Clin Infect Dis 2021; 72:2006-15.
    1. Trajman A, Steffen R, Menzies D. Interferon-gamma release assays versus tuberculin skin testing for the diagnosis of latent tuberculosis infection: an overview of the evidence. Pulm Med 2013; 2013: 601737.
    1. Pai M, Riley LW, Colford JM Jr. Interferon-γ assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004; 4:761-76.
    1. Jung Y, Lyu J, Yoo B, et al. . Combined use of a TST and the T-SPOT®. TB assay for latent tuberculosis infection diagnosis before anti-TNF-α treatment. Int J Tuberculosis Lung Dis 2012; 16:1300-6.
    1. Metcalfe JZ, Everett CK, Steingart KR, et al. . Interferon-γ release assays for active pulmonary tuberculosis diagnosis in adults in low- and middle-income countries: systematic review and meta-analysis. J Infect Dis 2011; 204:S1120-9.
    1. King TC, Upfal M, Gottlieb A, et al. . T-SPOT.TB interferon-γ release assay performance in healthcare worker screening at nineteen U.S. hospitals. Am J Respir Crit Care Med 2015; 192:367-73.
    1. Li F, Xu M, Qin C, et al. . Recombinant fusion ESAT6-CFP10 immunogen as a skin test reagent for tuberculosis diagnosis: an open-label, randomized, two-centre phase 2a clinical trial. Clin Microbiol Infect 2016; 22:889.e9-16.
    1. Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect Dis 1993; 17:968-75.
    1. Losi M, Bossink A, Codecasa L, et al. . Use of a T-cell interferon-γ release assay for the diagnosis of tuberculous pleurisy. Eur Resp J 2007; 30:1173-9.
    1. Akobeng AK. Understanding diagnostic tests 1: sensitivity, specificity and predictive values. Acta Paediatr 2007; 96:338-41.
    1. Brock I, Weldingh K, Lillebaek T, Follmann F, Andersen P. Comparison of tuberculin skin test and new specific blood test in tuberculosis contacts. Am J Resp Critical Care Med 2004; 170:65-9.
    1. Fietta A, Meloni F, Cascina A, et al. . Comparison of a whole-blood interferon-gamma assay and tuberculin skin testing in patients with active tuberculosis and individuals at high or low risk of Mycobacterium tuberculosis infection. Am J Infect Control 2003; 31:347-53.
    1. Vanhoof J, Landewe S, Van Wijngaerden E, Geusens P. High incidence of hepatotoxicity of isoniazid treatment for tuberculosis chemoprophylaxis in patients with rheumatoid arthritis treated with methotrexate or sulfasalazine and anti-tumour necrosis factor inhibitors. Ann Rheum Dis 2003; 62:1241-2.
    1. Liu Q, Lu P, Leonardo M, et al. . Undiagnosed diabetes mellitus and tuberculosis infection: a population‐based, observational study from eastern China. Diabetes/Metab Res and Rev 2020; 36:e3227.
    1. Rodger M, Ramsay T, Fergusson D. Diagnostic randomized controlled trials: the final frontier. Trials 2012; 13:1-7.
    1. Moon HW, Hur M. Interferon-gamma release assays for the diagnosis of latent tuberculosis infection: an updated review. Ann Clin Lab Sci 2013; 43:221-9.
    1. World Health Organization. Use of tuberculosis interferon-gamma release assays (IGRAs) in low-and middle-income countries: policy statement. 2011.
    1. Health Commission of China. Diagnostic criteria for pulmonary tuberculosis (WS 288-2017). 2017.
    1. Li F, Xu M, Zhou L, et al. . Safety of recombinant fusion protein ESAT6-CFP10 as a skin test reagent for tuberculosis diagnosis: an open-label, randomized, single-center phase I clinical trial. Clin Vaccine Immunol 2016; 23:767-73.
    1. Herrera V, Perry S, Parsonnet J, Banaei N. Clinical application and limitations of interferon-γ release assays for the diagnosis of latent tuberculosis infection. Clin Infect Dis 2011; 52:1031-7.
    1. Kleinert S, Tony HP, Krueger K, et al. . Screening for latent tuberculosis infection: performance of tuberculin skin test and interferon-γ release assays under real-life conditions. Ann Rheum Dis 2012; 71:1791-5.
    1. Menzies R, Vissandjee B, Rocher I, St Germain Y. The booster effect in two-step tuberculin testing among young adults in Montreal. Ann Intern Med 1994; 120:190-8.
    1. Hizel K, Maral I, Karakus R, Aktas F. The influence of BCG immunisation on tuberculin reactivity and booster effect in adults in a country with a high prevalence of tuberculosis. Clin Microbiol Infect 2004; 10:981-4.
    1. Menzies D. Interpretation of repeated tuberculin tests. Boosting, conversion, and reversion. Am J Resp Critical Care Med 1998; 159:15-21.
    1. Menzies R, Vissandjee B. Effect of bacille Calmette-Guérin vaccination on tuberculin reactivity. Am Rev Respir Dis 1992; 145:621-5.
    1. Soborg B, Andersen AB, Larsen HK, et al. . Detecting a low prevalence of latent tuberculosis among health care workers in Denmark detected by M. tuberculosis specific IFN-gamma whole-blood test. Scand J Infect Dis 2007; 39:554-9.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere