» Articles » PMID: 32178775

Blood Transcriptional Biomarkers for Active Pulmonary Tuberculosis in a High-burden Setting: a Prospective, Observational, Diagnostic Accuracy Study

Overview
Publisher Elsevier
Specialty Pulmonary Medicine
Date 2020 Mar 18
PMID 32178775
Citations 62
Authors
Affiliations
Soon will be listed here.
Abstract

Background: Blood transcriptional signatures are candidates for non-sputum triage or confirmatory tests of tuberculosis. Prospective head-to-head comparisons of their diagnostic accuracy in real-world settings are necessary to assess their clinical use. We aimed to compare the diagnostic accuracy of candidate transcriptional signatures identified by systematic review, in a setting with a high burden of tuberculosis and HIV.

Methods: We did a prospective observational study nested within a diagnostic accuracy study of sputum Xpert MTB/RIF (Xpert) and Xpert MTB/RIF Ultra (Ultra) tests for pulmonary tuberculosis. We recruited consecutive symptomatic adults aged 18 years or older self-presenting to a tuberculosis clinic in Cape Town, South Africa. Participants provided blood for RNA sequencing, and sputum samples for liquid culture and molecular testing using Xpert and Ultra. We assessed the diagnostic accuracy of candidate blood transcriptional signatures for active tuberculosis (including those intended to distinguish active tuberculosis from other diseases) identified by systematic review, compared with culture or Xpert MTB/RIF positivity as the standard reference. In our primary analysis, patients with tuberculosis were defined as those with either a positive liquid culture or Xpert result. Patients with missing blood RNA or sputum results were excluded. Our primary objective was to benchmark the diagnostic accuracy of candidate transcriptional signatures against the WHO target product profile (TPP) for a tuberculosis triage test.

Findings: Between Feb 12, 2016, and July 18, 2017, we obtained paired sputum and RNA sequencing data from 181 participants, 54 (30%) of whom had confirmed pulmonary tuberculosis. Of 27 eligible signatures identified by systematic review, four achieved the highest diagnostic accuracy with similar area under the receiver operating characteristic curves (Sweeney3: 90·6% [95% CI 85·6-95·6]; Kaforou25: 86·9% [80·9-92·9]; Roe3: 86·9% [80·3-93·5]; and BATF2: 86·8% [80·6-93·1]), independent of age, sex, HIV status, previous tuberculosis, or sputum smear result. At test thresholds that gave 70% specificity (the minimum WHO TPP specificity for a triage test), these four signatures achieved sensitivities between 83·3% (95% CI 71·3-91·0) and 90·7% (80·1-96·0). No signature met the optimum criteria, of 95% sensitivity and 80% specificity proposed by WHO for a triage test, or the minimum criteria (of 65% sensitivity and 98% specificity) for a confirmatory test, but all four correctly identified Ultra-positive, culture-negative patients.

Interpretation: Selected blood transcriptional signatures met the minimum WHO benchmarks for a tuberculosis triage test but not for a confirmatory test. Further development of the signatures is warranted to investigate their possible effects on clinical and health economic outcomes as part of a triage strategy, or when used as add-on confirmatory test in conjunction with the highly sensitive Ultra test for Mycobacterium tuberculosis DNA.

Funding: Royal Society Newton Advanced Fellowship, Wellcome Trust, National Institute of Health Research, and UK Medical Research Council.

Citing Articles

A new rapid lipoarabinomannan urine assay for tuberculosis: a two-centre diagnostic accuracy evaluation in outpatients with and without HIV.

Hamasur B, Okunola A, Sserubiri J, Nwamba W, Dube-Nwamba W, Abdulgader S Res Sq. 2025; .

PMID: 40034451 PMC: 11875286. DOI: 10.21203/rs.3.rs-5386988/v2.


An ultra-early, transient interferon-associated innate immune response associates with protection from SARS-CoV-2 infection despite exposure.

Fenn J, Madon K, Conibear E, Derelle R, Nevin S, Kundu R EBioMedicine. 2024; 111():105475.

PMID: 39667271 PMC: 11697275. DOI: 10.1016/j.ebiom.2024.105475.


Development of a Nomogram Based on Transcriptional Signatures, IFN-γ Response and Neutrophils for Diagnosis of Tuberculosis.

Liu Y, Su J, Jiang J, Yang B, Cao Z, Zhai F J Inflamm Res. 2024; 17:8799-8811.

PMID: 39559398 PMC: 11570532. DOI: 10.2147/JIR.S480173.


Specific human gene expression in response to infection is an effective marker for diagnosis of latent and active tuberculosis.

Nakiboneka R, Walbaum N, Musisi E, Nevels M, Nyirenda T, Nliwasa M Sci Rep. 2024; 14(1):26884.

PMID: 39505948 PMC: 11541504. DOI: 10.1038/s41598-024-77164-5.


Integration and validation of host transcript signatures, including a novel 3-transcript tuberculosis signature, to enable one-step multiclass diagnosis of childhood febrile disease.

Channon-Wells S, Habgood-Coote D, Vito O, Galassini R, Wright V, Brent A J Transl Med. 2024; 22(1):802.

PMID: 39210372 PMC: 11360490. DOI: 10.1186/s12967-024-05241-4.


References
1.
de Araujo L, Vaas L, Ribeiro-Alves M, Geffers R, Mello F, de Almeida A . Transcriptomic Biomarkers for Tuberculosis: Evaluation of , and mRNA Expression in Peripheral Blood. Front Microbiol. 2016; 7:1586. PMC: 5078140. DOI: 10.3389/fmicb.2016.01586. View

2.
Newcombe R . Interval estimation for the difference between independent proportions: comparison of eleven methods. Stat Med. 1998; 17(8):873-90. DOI: 10.1002/(sici)1097-0258(19980430)17:8<873::aid-sim779>3.0.co;2-i. View

3.
Gliddon H, Kaforou M, Alikian M, Habgood-Coote D, Zhou C, Oni T . Identification of Reduced Host Transcriptomic Signatures for Tuberculosis Disease and Digital PCR-Based Validation and Quantification. Front Immunol. 2021; 12:637164. PMC: 7982854. DOI: 10.3389/fimmu.2021.637164. View

4.
Anderson S, Kaforou M, Brent A, Wright V, Banwell C, Chagaluka G . Diagnosis of childhood tuberculosis and host RNA expression in Africa. N Engl J Med. 2014; 370(18):1712-1723. PMC: 4069985. DOI: 10.1056/NEJMoa1303657. View

5.
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