Immunodiagnosis of active tuberculosis

ABSTRACT

Introduction: There is an unmet clinical need for improved diagnostic tests for active tuberculosis (TB) to provide high sensitivity for all cases, accelerate time to diagnosis and ensure timely and appropriate treatment. Whilst the measurement of M.tb-specific immune responses is widely used for detecting infection in the absence of TB symptoms (i.e. latent TB infection), there is currently no role for immunodiagnostics in active TB disease. This is primarily due to insufficient sensitivity, and an inability to discriminate between active disease and controlled, latent TB infection.

Areas covered: In this review, we focus on recent developments in the use of immune-based tests to provide a point of care test for the rule-in or rule-out of active TB.

Expert opinion: Recent studies have demonstrated that second-generation IGRAs have the potential to rule-out active TB, particularly in low burden settings. Newer technological platforms, including systems serology and flow cytometry, offer the means to measure specific M.tb specific immune signatures which have been shown to have a high level of accuracy for active TB. However, it is now crucial that new and promising test undergo validation in clinically relevant cohorts which include the full spectrum of TB patients and differential diagnoses.

KEYWORDS:

• Active tuberculosis
• immunodiagnosis
• immune response
• diagnostic test
• latent tuberculosis

Article Highlights

• Current commercial IGRAs do not have high enough sensitivity to act as a rule-out test for active TB or even have high enough specificity to discriminate between the different states of infection and disease.

• Second-generation IGRAs, incorporating additional M.tb antigens, have the potential to be used as a triage rule-out test for active TB suspects.

• Though many new tests have shown improvement in sensitivity and specify in a case-control cohort setting, promising assays must be validated in a well-defined clinical cohort which includes all the hard to diagnose TB cases (i.e. EPTB and paucibacillary TB).

• The findings of studies evaluating diagnostic performance from a low endemic setting are unlikely to be generalizable to high endemic settings, given the varying rates of infection and the differing manifestations of TB disease.

• Furthermore, many of the immunodiagnostic test platforms are too costly and/or complex to be used in many rural or low-income country settings.

• Future research in the field of immunodiagnosis for active TB should focus towards a point-of-care test.

• Ultimately, we must ensure that promising new tests are appropriately validated in large prospective cohort studies where participants are enrolled during routine clinical practice.

Declaration of interest

The salaries of AH, TM, MTW, and AL were supported by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership during the time most of this work was prepared (Project: EME - 12/65/27). AL also acknowledges the support of the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Respiratory Infections at Imperial College London in partnership with Public Health England (PHE) and to the NIHR Imperial Biomedical Research Centre (BRC). VM’s contribution was mostly made during a placement visit to AL’s group in the summer of 2017, supported by Imperial College’s Undergraduate Research Opportunities Programme. AH reports a patent application pending relating to the use of T Cell Diagnosis in Tuberculosis infection. AL is a named inventor on patents (EP05729257.5, EP1735623[B1], US8,105,797[B2], EP2069792, P2069792[B1], EP2005182, EP2005182[B1], US8,765,336[B2], EP10716313.1, EP2417456[B1], US9,377,460[B2], US9360480[B2], EP0941478[B2], EP1152012[B1], P1735623[B1], US8105797[B2], EP1144447[B1], and US9005902[B2]) pertaining to T cell-based diagnosis, including current and second-generation IGRA technologies. AL acknowledges that some of these patents were assigned by the University of Oxford, Oxford, UK, to Oxford Immunotec plc, resulting in royalty entitlements for the University of Oxford and AL. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England. Health and Social Care, or PHE. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers Disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript was not funded.