Abstract
BackgroundSensitive point-of-care screening tests are urgently needed to identify individuals at highest risk of tuberculosis. We prospectively tested performance of host-blood transcriptomic tuberculosis signatures.MethodsAdults without suspicion of tuberculosis were recruited from five endemic South African communities. Eight parsimonious host-blood transcriptomic tuberculosis signatures were measured by microfluidic RT-qPCR at enrolment. Upper respiratory swab specimens were tested with a multiplex bacterial-viral RT-qPCR panel in a subset of participants. Diagnostic and prognostic performance for microbiologically confirmed prevalent and incident pulmonary tuberculosis was tested in all participants at baseline and during active surveillance through 15 months follow-up, respectively.ResultsAmong 20,207 HIV-uninfected and 963 HIV-infected adults screened; 2923 and 861 were enroled. There were 61 HIV-uninfected (weighted prevalence 1.1%) and 10 HIV-infected (prevalence 1.2%) tuberculosis cases at baseline. Parsimonious signature diagnostic performance was superior among symptomatic (AUCs 0.85–0.98) as compared to asymptomatic (AUCs 0.61–0.78) HIV-uninfected participants. Thereafter, 24 HIV-uninfected and 9 HIV-infected participants progressed to incident tuberculosis (1.1 and 1.0 per 100 person-years, respectively). Among HIV-uninfected individuals, prognostic performance for incident tuberculosis occurring within 6–12 months was higher relative to 15 months. 1000 HIV-uninfected participants were tested for respiratory microorganisms and 413 HIV-infected for HIV plasma viral load; 7/8 signature scores were higher (p < 0.05) in participants with viral respiratory infections or detectable HIV viraemia than those without.ConclusionsSeveral parsimonious tuberculosis transcriptomic signatures met triage test targets among symptomatic participants, and incipient test targets within 6 months. However, the signatures were upregulated with viral infection and offered poor specificity for diagnosing sub-clinical tuberculosis.
Highlights
3, Kogieleum Naidoo[4,5], Gavin Churchyard[6,7,8], Abstract Background Sensitive point-of-care screening tests are urgently needed to identify individuals at highest risk of tuberculosis
In this paper we report the results of a multicentre observational study, which prospectively tested the performance of eight parsimonious host-blood TB interferon-stimulated gene (ISG) signatures measured by microfluidic real-time quantitative PCR (RTqPCR), for diagnosing prevalent pulmonary TB and predicting progression to incident TB disease, in a predominantly asymptomatic community cohort of HIV-uninfected and HIV-infected South African adults
We found that diagnostic performance of the parsimonious signatures was superior among symptomatic as compared to asymptomatic participants; While none of the signatures met World Health Organization (WHO) triage test Target Product Profile (TPP) criteria to diagnose subclinical TB, several signatures met or approached the criteria for diagnosing clinical TB
Summary
Adults without suspicion of tuberculosis were recruited from five endemic South African communities. Eight parsimonious host-blood transcriptomic tuberculosis signatures were measured by microfluidic RT-qPCR at enrolment. Diagnostic and prognostic performance for microbiologically confirmed prevalent and incident pulmonary tuberculosis was tested in all participants at baseline and during active surveillance through 15 months follow-up, respectively. In this diagnostic and prognostic accuracy study, we evaluated parsimonious blood-based host transcriptomic signature performance in four South African cohorts (Supplementary Fig. S1). We first translated the signatures to a RT-qPCR platform and validated performance in a case-control study of HIV-uninfected and HIV-infected individuals with and without pulmonary TB, the Cross-sectional TB Cohort (CTBC) study (Supplementary Fig. S1a). We evaluated the effects of upper respiratory microorganisms on transcriptomic signatures in a subset of HIV-uninfected participants screened for the CORTIS-01 trial (Supplementary Fig. S1c). This study is reported in accordance with the Standards for Reporting Diagnostic Accuracy Studies initiative guidelines[22]
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