Blood-based Host Biomarker Diagnostics in Active Case Finding for Pulmonary Tuberculosis: A Diagnostic Case-control Study

Overview

Journal EClinicalMedicine

Specialty General Medicine

Date 2021 Apr 12

PMID 33842866

Citations 18

Authors

Flora Martinez Figueira Moreira

Renu Verma

Paulo Cesar Pereira Dos Santos

Alessandra Leite

Andrea da Silva Santos

Rafaele Carla Pivetta de Araujo

Bruna Oliveira da Silva

Julio Henrique Ferreira de Sa Queiroz

David H Persing

Erik Sodersten

Devasena Gnanashanmugam

Purvesh Khatri

Julio Croda

Jason R Andrews

Affiliations

Soon will be listed here.

Abstract

Background: There is a need to identify scalable tuberculosis screening strategies among high burden populations. The WHO has identified a non-sputum-based triage test as a development priority.

Methods: We performed a diagnostic case-control study of point-of-care C-reactive protein (CRP) and Prototype-Xpert-MTB-Host-Response (Xpert-MTB-HR) assays in the context of a mass screening program for tuberculosis in two prisons in Brazil. All incarcerated individuals irrespective of symptoms were screened by sputum Xpert MTB/RIF and sputum culture. Among consecutive, Xpert MTB/RIF or culture-confirmed cases and Xpert MTB/RIF and culture-negative controls, CRP was quantified in serum by a point-of-care assay (iChroma-II) and a 3-gene expression score was quantified from whole blood using the Xpert-MTB-HR cartridge. We evaluated receiver operating characteristic area under the curve (AUC) and assessed specificity at 90% sensitivity and sensitivity at 70% specificity, consistent with WHO target product profile (TPP) benchmarks.

Findings: Two hundred controls (no TB) and 100 culture- or Xpert MTB/RIF-positive tuberculosis cases were included. Half of tuberculosis cases and 11% of controls reported any tuberculosis symptoms. AUC for CRP was 0·79 (95% CI: 0·73-0·84) and for Xpert-MTB-HR was 0·84 (95% CI: 0·79-0·89). At 90% sensitivity, Xpert-MTB-HR had significantly higher specificity (53·0%, 95% CI: 45·0-69·0%) than CRP (28·1%, 95% CI: 20·2-41·8%) ( = 0·003), both well below the TPP benchmark of 70%. Among individuals with medium or high sputum Xpert MTB/RIF semi-quantitative load, sensitivity (at 70% specificity) of CRP (90·3%, 95% CI: 74·2-98·0) and Xpert-MTB-HR (96·8%, 95% CI: 83·3-99·9%) was higher.

Interpretation: For active case finding in this high tuberculosis-burden setting, CRP and Xpert-MTB-HR did not meet TPP benchmarks for a triage test. However, Xpert-MTB-HR was highly sensitive in detecting individuals with medium or high sputum bacillary burden.

Funding: National Institutes of Health (R01 AI130058 and R01 AI149620) and Brazilian National Council for Scientific and Technological Development (CNPq-404182/2019-4).

Citing Articles

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Single molecule measurements of microRNAs in the serum of patients with pulmonary tuberculosis.

Wu Z, Tan Q, Jia X, Wu H, Liang J, Wen W Front Immunol. 2024; 15:1418085.

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Accuracy of C-Reactive Protein for Tuberculosis Detection in General-Population Screening and Ambulatory-Care Triage in Uganda.

Cox S, Erisa K, Kitonsa P, Nalutaaya A, Nantale M, Kayondo F Ann Am Thorac Soc. 2024; 21(6):875-883.

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Public health implications of the evolving understanding of tuberculosis natural history.

Herrera M, Taguiam E, Laupland K, Rueda Z, Keynan Y J Assoc Med Microbiol Infect Dis Can. 2024; 8(4):241-244.

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Evaluation of the Xpert MTB Host Response assay for the triage of patients with presumed pulmonary tuberculosis: a prospective diagnostic accuracy study in Viet Nam, India, the Philippines, Uganda, and South Africa.

Gupta-Wright A, Ha H, Abdulgadar S, Crowder R, Emmanuel J, Mukwatamundu J Lancet Glob Health. 2024; 12(2):e226-e234.

PMID: 38245113 PMC: 11046618. DOI: 10.1016/S2214-109X(23)00541-7.

References

Meyer A, Ochom E, Turimumahoro P, Byanyima P, Sanyu I, Lalitha R . C-Reactive Protein Testing for Active Tuberculosis among Inpatients without HIV in Uganda: a Diagnostic Accuracy Study. J Clin Microbiol. 2020; 59(1). PMC: 7771459. DOI: 10.1128/JCM.02162-20. View

Yoon C, Davis J, Huang L, Muzoora C, Byakwaga H, Scibetta C . Point-of-care C-reactive protein testing to facilitate implementation of isoniazid preventive therapy for people living with HIV. J Acquir Immune Defic Syndr. 2013; 65(5):551-6. PMC: 3999220. DOI: 10.1097/QAI.0000000000000085. View

Warsinske H, Rao A, Moreira F, Santos P, Liu A, Scott M . Assessment of Validity of a Blood-Based 3-Gene Signature Score for Progression and Diagnosis of Tuberculosis, Disease Severity, and Treatment Response. JAMA Netw Open. 2019; 1(6):e183779. PMC: 6324428. DOI: 10.1001/jamanetworkopen.2018.3779. View

Baussano I, Williams B, Nunn P, Beggiato M, Fedeli U, Scano F . Tuberculosis incidence in prisons: a systematic review. PLoS Med. 2011; 7(12):e1000381. PMC: 3006353. DOI: 10.1371/journal.pmed.1000381. View

Maclean E, Broger T, Yerlikaya S, Fernandez-Carballo B, Pai M, Denkinger C . A systematic review of biomarkers to detect active tuberculosis. Nat Microbiol. 2019; 4(5):748-758. DOI: 10.1038/s41564-019-0380-2. View

Suliman S, Thompson E, Sutherland J, Weiner 3rd J, Ota M, Shankar S . Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis. Am J Respir Crit Care Med. 2018; 197(9):1198-1208. PMC: 6019933. DOI: 10.1164/rccm.201711-2340OC. View

Mihret A, Abebe M, Bekele Y, Aseffa A, Walzl G, Howe R . Impact of HIV co-infection on plasma level of cytokines and chemokines of pulmonary tuberculosis patients. BMC Infect Dis. 2014; 14:125. PMC: 3974017. DOI: 10.1186/1471-2334-14-125. View

Francisco N, Fang Y, Ding L, Feng S, Yang Y, Wu M . Diagnostic accuracy of a selected signature gene set that discriminates active pulmonary tuberculosis and other pulmonary diseases. J Infect. 2017; 75(6):499-510. DOI: 10.1016/j.jinf.2017.09.012. View

Yoon C, Semitala F, Atuhumuza E, Katende J, Mwebe S, Asege L . Point-of-care C-reactive protein-based tuberculosis screening for people living with HIV: a diagnostic accuracy study. Lancet Infect Dis. 2017; 17(12):1285-1292. PMC: 5705273. DOI: 10.1016/S1473-3099(17)30488-7. View

10.

Sweeney T, Braviak L, Tato C, Khatri P . Genome-wide expression for diagnosis of pulmonary tuberculosis: a multicohort analysis. Lancet Respir Med. 2016; 4(3):213-24. PMC: 4838193. DOI: 10.1016/S2213-2600(16)00048-5. View

11.

Carbone A, Paiao D, Viebrantz Enne Sgarbi R, Ferreira Lemos E, Cazanti R, Ota M . Active and latent tuberculosis in Brazilian correctional facilities: a cross-sectional study. BMC Infect Dis. 2015; 15:24. PMC: 4307675. DOI: 10.1186/s12879-015-0764-8. View

12.

Warsinske H, Vashisht R, Khatri P . Host-response-based gene signatures for tuberculosis diagnosis: A systematic comparison of 16 signatures. PLoS Med. 2019; 16(4):e1002786. PMC: 6478271. DOI: 10.1371/journal.pmed.1002786. View

13.

Gupta R, Turner C, Venturini C, Esmail H, Rangaka M, Copas A . Concise whole blood transcriptional signatures for incipient tuberculosis: a systematic review and patient-level pooled meta-analysis. Lancet Respir Med. 2020; 8(4):395-406. PMC: 7113839. DOI: 10.1016/S2213-2600(19)30282-6. View

14.

Sodersten E, Ongarello S, Mantsoki A, Wyss R, Persing D, Banderby S . Diagnostic Accuracy Study of a Novel Blood-Based Assay for Identification of Tuberculosis in People Living with HIV. J Clin Microbiol. 2020; 59(3). PMC: 8106701. DOI: 10.1128/JCM.01643-20. View

15.

Walter K, Martinez L, Arakaki-Sanchez D, Sequera V, Estigarribia Sanabria G, Cohen T . The escalating tuberculosis crisis in central and South American prisons. Lancet. 2021; 397(10284):1591-1596. PMC: 9393884. DOI: 10.1016/S0140-6736(20)32578-2. View

16.

Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez J . pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics. 2011; 12:77. PMC: 3068975. DOI: 10.1186/1471-2105-12-77. View

17.

Beynon F, Theron G, Respeito D, Mambuque E, Saavedra B, Bulo H . Correlation of Xpert MTB/RIF with measures to assess Mycobacterium tuberculosis bacillary burden in high HIV burden areas of Southern Africa. Sci Rep. 2018; 8(1):5201. PMC: 5980110. DOI: 10.1038/s41598-018-23066-2. View

18.

Hernandez-Garduno E, Cook V, Kunimoto D, Elwood R, Black W, Fitzgerald J . Transmission of tuberculosis from smear negative patients: a molecular epidemiology study. Thorax. 2004; 59(4):286-90. PMC: 1763818. DOI: 10.1136/thx.2003.011759. View

19.

Yoon C, Semitala F, Asege L, Katende J, Mwebe S, Andama A . Yield and Efficiency of Novel Intensified Tuberculosis Case-Finding Algorithms for People Living with HIV. Am J Respir Crit Care Med. 2018; 199(5):643-650. PMC: 6396864. DOI: 10.1164/rccm.201803-0490OC. View

20.

Zak D, Penn-Nicholson A, Scriba T, Thompson E, Suliman S, Amon L . A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet. 2016; 387(10035):2312-2322. PMC: 5392204. DOI: 10.1016/S0140-6736(15)01316-1. View