Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response

Adékambi, Toïdi; Ibegbu, Chris; Cagle, Stephanie; Kalokhe, Ameeta S.; Wang, Yun F.; Hu, Yi‐Juan; Day, Cheryl L.; Ray, Susan M.; Rengarajan, Jyothi

doi:10.1172/jci77990

Cited by 140 publications

(217 citation statements)

References 51 publications

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“…A study evaluating serial sputum samples from patients with smear-positive TB found that assay positivity and grade decreased linearly starting at ∼2 wk (smear), 4 wk (culture), or 6 wk (Xpert) posttreatment (37). CD4 + T-cell responses also have been reported to differentiate LTBI and active TB cases and to monitor treatment responses, although only HIV-negative and culture-and/or smear-positive PTB patients were analyzed using this labor-intensive method, so that its clinical utility remains unclear (38). Circulating miRNA levels also may serve as TB biomarkers, but this idea has not yet been tested in longitudinal clinical studies (39).…”

Section: Discussionmentioning

confidence: 99%

Quantification of circulating Mycobacterium tuberculosis antigen peptides allows rapid diagnosis of active disease and treatment monitoring

Liu

Zhao

Fan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Tuberculosis (TB) is a major global health threat, resulting in an urgent unmet need for a rapid, non-sputum-based quantitative test to detect active Mycobacterium tuberculosis (Mtb) infections in clinically diverse populations and quickly assess Mtb treatment responses for emerging drug-resistant strains. We have identified Mtb-specific peptide fragments and developed a method to rapidly quantify their serum concentrations, using antibody-labeled and energy-focusing porous discoidal silicon nanoparticles (nanodisks) and high-throughput mass spectrometry (MS) to enhance sensitivity and specificity. NanoDisk-MS diagnosed active Mtb cases with high sensitivity and specificity in a case-control study with cohorts reflecting the complexity of clinical practice. Similar robust sensitivities were obtained for cases of culture-positive pulmonary TB (PTB; 91.3%) and extrapulmonary TB (EPTB; 92.3%), and the sensitivities obtained for culture-negative PTB (82.4%) and EPTB (75.0%) in HIV-positive patients significantly outperformed those reported for other available assays. NanoDisk-MS also exhibited high specificity (87.1-100%) in both healthy and high-risk groups. Absolute quantification of serum Mtb antigen concentration was informative in assessing responses to antimycobacterial treatment. Thus, a NanoDisk-MS assay approach could significantly improve the diagnosis and management of active TB cases, and perhaps other infectious diseases as well.D espite international efforts and initiatives, tuberculosis (TB) remains a major public health concern worldwide, associated with high morbidity and mortality (1, 2). Detecting active TB cases and monitoring their responses to therapy are fraught with challenges, relying predominantly on microbiologic techniques that use sputum samples, including acid-fast Bacillus (AFB) smear microscopy-widely used as an initial test for TB diagnosis (3, 4)-and Mycobacterium tuberculosis (Mtb) culture, both of which have only moderate sensitivity and specificity and a long turnaround time (5, 6). Moreover, sputum samples are difficult to obtain after symptom improvement, and often are not diagnostically useful for extrapulmonary TB (EPTB) cases. The PCR-based Xpert MTB/RIF sputum assay was introduced to improve the speed and specificity of TB diagnosis, but this assay has poor sensitivity under low bacterial loads and cannot distinguish live and nonviable Mtb contributions (7,8). A recent World Health Organization (WHO) policy update acknowledged the low quality of evidence supporting the use of Xpert MTB/RIF to diagnose EPTB (9). Diagnostic challenges can be further magnified in patients coinfected with HIV and TB (10). In addition, none of these techniques provides quantitative results that can be used to monitor treatment effects (11,12).Consequently, there is an urgent need, highlighted as a high priority in a recent WHO consensus report (13), for the development of rapid, quantitative, non-sputum-based biomarker tests that do not require bacterial isolation to detect active TB (13). Non-s...

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Section: Discussionmentioning

confidence: 99%

Quantification of circulating Mycobacterium tuberculosis antigen peptides allows rapid diagnosis of active disease and treatment monitoring

Liu

Zhao

Fan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Another interesting blood‐based study showed that the expression of immune activation markers CD38 and HLA‐DR and proliferation marker Ki‐67 on Mtb‐specific CD4 + T‐cells was associated with Mtb load. The modulation of these markers accurately distinguished active from LTBI with 100% specificity and over 96% sensitivity …”

Section: Bm For Diagnosing Active Tbmentioning

confidence: 99%

Update on tuberculosis biomarkers: From correlates of risk, to correlates of active disease and of cure from disease

et al. 2018

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Tuberculosis (TB) remains a devastating disease, yet despite its enormous toll on global health, tools to control TB are insufficient and often outdated. TB Biomarkers (TB-BM) would constitute extremely useful tools to measure infection status and predict outcome of infection, vaccination or therapy. There are several types of TB-BM: Correlate of Infection; Correlate of TB Disease; Correlate of Increased Risk of Developing Active TB Disease; Correlate of the Curative Response to Therapy; and Correlate of Protection (CoP). Most TB-BM currently studied are host-derived BM, and consist of transcriptomic, proteomic, metabolomic, cellular markers or marker combinations ('signatures'). In particular, vaccine-inducible CoP are expected to be transformative in developing new TB vaccines as they will de-risk vaccine research and development (R&D) as well as human testing at an early stage. In addition, CoP could also help minimizing the need for preclinical studies in experimental animals. Of key importance is that TB-BM are tested and validated in different well-characterized human TB cohorts, preferably with complementary profiles and geographically diverse populations: genetic and environmental factors such as (viral) coinfections, exposure to non-tuberculous mycobacteria, nutritional status, metabolic status, age (infants vs children vs adolescents vs adults) and other factors impact host immune set points and host responses across different populations. In this study, we review the most recent advances in research into TB-BM for the diagnosis of active TB, risk of TB development and treatment-induced TB cure.

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“…Differential human leukocyte antigen (HLA) expression in different populations may explain this variation [75]. A recent study also showed that MTB-specific T cell expression of activation status as measured by HLA-DR and CD38, along with the intracellular proliferation marker Ki-67 correlates with both bacillary burden and subsequent sputum conversion [76], but these findings need to be validated in larger prospective studies.…”

Section: Host Based Biomarkersmentioning

confidence: 99%

Assessment of treatment response in tuberculosis

Rockwood

Bruyn

Morris

et al. 2016

Expert Review of Respiratory Medicine

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Antibiotic treatment of tuberculosis has a duration of several months. There is significant variability of the host immune response and the pharmacokineticpharmacodynamic properties of Mycobacterium tuberculosis sub-populations at the site of disease. A limitation of sputum-based measures of treatment response may be sub-optimal detection and monitoring of Mycobacterium tuberculosis sub-populations. Potential biomarkers and surrogate endpoints should be benchmarked against hard clinical outcomes (failure/relapse/death) and may need tailoring to specific patient populations. Here, we assess the evidence supporting currently utilized and future potential host and pathogen-based models and biomarkers for monitoring treatment response in active and latent tuberculosis. Biomarkers for monitoring treatment response in extrapulmonary, pediatric and drug resistant tuberculosis are research priorities.

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Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response

Cited by 140 publications

References 51 publications

Quantification of circulating Mycobacterium tuberculosis antigen peptides allows rapid diagnosis of active disease and treatment monitoring

Quantification of circulating Mycobacterium tuberculosis antigen peptides allows rapid diagnosis of active disease and treatment monitoring

Update on tuberculosis biomarkers: From correlates of risk, to correlates of active disease and of cure from disease

Assessment of treatment response in tuberculosis

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