Biomarkers Can Identify Pulmonary Tuberculosis in HIV-infected Drug Users Months Prior to Clinical Diagnosis

Sloot, Rosa; Loeff, Maarten F. Schim van der; Zwet, Erik W. van; Haks, Mariëlle C.; Keizer, Sytze; Scholing, Maarten; Ottenhoff, Tom H. M.; Borgdorff, Martien W.; Joosten, Simone A.

doi:10.1016/j.ebiom.2014.12.001

Cited by 34 publications

(22 citation statements)

References 31 publications

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“…The dcRT-MLPA method has been applied in different studies assessing TB biomarkers for different purposes 15 16 21 22 23 24 25 , but few studies have been conducted in children 17 . A recent publication, which provides a proof-of-concept for the use of this assay in a large cohort of adults across four different African populations, identified increased FCGR1A expression as the single most consitent classifier of TB disease compared to latent TB infection (LTBI) irrespective of HIV-infection 22 .…”

Section: Discussionmentioning

confidence: 99%

Approaching a diagnostic point-of-care test for pediatric tuberculosis through evaluation of immune biomarkers across the clinical disease spectrum

Jenum

Dhanasekaran

Lodha

et al. 2016

Sci Rep

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The World Health Organization (WHO) calls for an accurate, rapid, and simple point-of-care (POC) test for the diagnosis of pediatric tuberculosis (TB) in order to make progress “Towards Zero Deaths”. Whereas the sensitivity of a POC test based on detection of Mycobacterium tuberculosis (MTB) is likely to have poor sensitivity (70–80% of children have culture-negative disease), host biomarkers reflecting the on-going pathological processes across the spectrum of MTB infection and disease may hold greater promise for this purpose. We analyzed transcriptional immune biomarkers direct ex-vivo and translational biomarkers in MTB-antigen stimulated whole blood in 88 Indian children with intra-thoracic TB aged 6 months to 15 years, and 39 asymptomatic siblings. We identified 12 biomarkers consistently associated with either clinical groups “upstream” towards culture-positive TB on the TB disease spectrum (CD14, FCGR1A, FPR1, MMP9, RAB24, SEC14L1, and TIMP2) or “downstream” towards a decreased likelihood of TB disease (BLR1, CD3E, CD8A, IL7R, and TGFBR2), suggesting a correlation with MTB-related pathology and high relevance to a future POC test for pediatric TB. A biomarker signature consisting of BPI, CD3E, CD14, FPR1, IL4, TGFBR2, TIMP2 and TNFRSF1B separated children with TB from asymptomatic siblings (AUC of 88%).

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Section: Discussionmentioning

confidence: 99%

Approaching a diagnostic point-of-care test for pediatric tuberculosis through evaluation of immune biomarkers across the clinical disease spectrum

Jenum

Dhanasekaran

Lodha

et al. 2016

Sci Rep

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“…The first study to report an association between gene expression in peripheral blood cells and risk of TB disease compared 15 HIV-infected drug users who ultimately progressed to active TB with 16 who remained disease free. Expression of two transcripts, IL-13 and AIRE, was found to correlate with risk of TB (207).…”

Section: Biomarkers In Human Tbmentioning

confidence: 96%

Human Immunology of Tuberculosis

2017

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Immunology is a central theme when it comes to tuberculosis (TB). The outcome of human infection with Mycobacterium tuberculosis is dependent on the ability of the immune response to clear or contain the infection.In cases where this fails, the bacterium replicates, disseminates within the host, and elicits a pathologic inflammatory response, and disease ensues. Clinical presentation of TB disease is remarkably heterogenous, and the disease phenotype is largely dependent on host immune status. Onward transmission of M. tuberculosis to new susceptible hosts is thought to depend on an excessive inflammatory response causing a breakdown of the lung matrix and formation of lung cavities, but this varies in cases of underlying immunological dysfunction: for example, HIV is associated with less cavitation, while diabetes mellitus is associated with increased cavitation and risk of transmission. In compliance with the central theme of immunology in tuberculosis, we rely on detection of an adaptive immune response, in the form of interferon-gamma release assays or tuberculin skin tests, to diagnose infection with M. tuberculosis. Here we review the immunology of tuberculosis in the human host, focusing on cellular and humoral adaptive immunity as well as key features of innate immune responses and the underlying immunological dysfunction which associates with human TB risk factors. Our review is restricted to human immunology, and we highlight distinctions from the immunological dogma originating from animal models of tuberculosis, which pervade the field.

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“…In a smaller study, we previously reported a simple CoR that predicted onset of TB disease months before clinical manifestation of disease in HIV-infected intravenous drug users from the longitudinal Amsterdam cohort study. Targeted host blood gene expression profiling by dual colour reverse transcriptase multiplex ligand probe amplification 90 found that elevated expression of IL-13 in the absence of AIRE discriminated those who would develop future TB from those who remained TB-free for at least 2 years. Interestingly, individuals carrying the IL-13/AIRE CoR had increased expression of type I IFN-related genes, agreeing with the African CoR signature discussed above.…”

Section: Predictive Correlates Of Tb Riskmentioning

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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Biomarkers Can Identify Pulmonary Tuberculosis in HIV-infected Drug Users Months Prior to Clinical Diagnosis

Cited by 34 publications

References 31 publications

Approaching a diagnostic point-of-care test for pediatric tuberculosis through evaluation of immune biomarkers across the clinical disease spectrum

Approaching a diagnostic point-of-care test for pediatric tuberculosis through evaluation of immune biomarkers across the clinical disease spectrum

Human Immunology of Tuberculosis

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

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