Executive summary

Tuberculosis (TB) infection is a state that is characterized by persistent immune response to stimulation by Mycobacterium tuberculosis (Mtb) antigens with no evidence of clinically manifest TB disease.¹ It is estimated that about a quarter of the world’s population is infected with Mtb. Testing for TB infection increases the probability that individuals who are the target for TB preventive treatment (TPT) will benefit from such treatment. However, there is no gold-standard test to diagnose TB infection. The two currently available classes of tests – interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST) – are indirect and require a competent immune response to identify people infected with TB. A positive test result by either method is not, by itself, a reliable indicator of the risk of progression to active disease.

In 2011, WHO issued recommendations on the use of IGRAs for the diagnosis of TB infection. The following technologies were included in the evaluation:

  • TST;
  • QIAGEN QuantiFERON®-TB Gold (QFT-G); 
  • QIAGEN QuantiFERON-TB Gold In-Tube (QFT-GIT); and 
  • Oxford Immunotec T-SPOT®.TB (T-Spot) assays.

In 2018, WHO updated the recommendations stipulating that the TST or IGRAs (or both) can be used for TB infection. This recommendation was included in the WHO consolidated guidelines on tuberculosis Module 1: Prevention – tuberculosis preventive treatment.¹

In 2021, the WHO recommendations were extended for the following technologies ²:

  • Beijing Wantai’s TB-IGRA;
  • QIAGEN QuantiFERON-TB Gold Plus

Newer Mtb antigen-based skin tests (TBSTs) based on specific Mtb antigens have been developed, using the early secretory antigenic target 6 kDa protein (ESAT-6) and culture filtrate protein 10 (CFP-10) antigens; these tests combine the simpler skin-test platform with the specificity of IGRAs. Emerging evidence suggests that, compared with IGRAs, TBSTs may have similar specificity and provide more reliable results in children, adolescents and in people living with HIV (People with HIV). However, the evidence has not been systematically reviewed.

In 2022, WHO issued recommendations on the use of TBSTs for the diagnosis of TB infection. The following technologies were included in the evaluation:

  • Cy-Tb (Serum Institute of India, India); 
  • Diaskintest® (Generium, Russian Federation); and
  • C-TST (formerly known as ESAT6-CFP10 test, Anhui Zhifei Longcom, China)
Objectives of the current guidelines

The objectives of the current guidelines are to:

  • assess the available data on the diagnostic accuracy (sensitivity and specificity) of the TST, IGRAs and TBSTs for the diagnosis of TB infection; 
  • assess the available data on the concordance of the TST, IGRAs and TBSTs;
  • assess the available data related to the impact of the TST, IGRAs and TBSTs on patientimportant outcomes: efficacy of TPT based on diagnostic test results, predictive value for progression to TB disease, correlation with exposure gradient and proportion started on TPT (if available); 
  • present a review of the published qualitative data on feasibility, accessibility, equity and enduser values related to TST, IGRAs and TBST implementation;
  • review the published economic data on affordability, cost and cost–effectiveness of TST, IGRAs and TBST implementation; and 
  • determine questions for future research and issues to be addressed by WHO in subsequent policy recommendations.
Target audience

The target audience for these guidelines are policy-makers, clinicians and other health care staff, laboratory specialists, managers of TB and HIV programmes, technical agencies, donors and implementing partners supporting the use of TB diagnostics in resource-limited settings.

Methods

A systematic, structured, evidence-based process for TB diagnostic policy generation was followed. The first step constituted systematic reviews and meta-analysis of available data on respective tests for TB infection (published and unpublished), using standard methods appropriate for diagnostic accuracy studies. The second step involved the convening of a GDG to evaluate the strength of the evidence base, evaluate the risks and benefits of using IGRAs and identify gaps to be addressed in future research. The third and final step involved development of a WHO policy guidance, with eventual dissemination to WHO Member States for implementation.

The GRADE system, adopted by WHO for all policy and guideline development, was used by the GDG. Given the absence of studies evaluating patient-important outcomes among people with presumed TB randomized to treatment based on TB infection results, reviews were focused on the diagnostic accuracy of respective TB infection tests (TBSTs, IGRAs and TST) in detecting TB infection or TB disease. Recognizing that test results may be surrogates for patient-important outcomes, the GDGs evaluated the accuracy of TB infection tests while also drawing inferences on the likely impact of these tests on patient outcomes, as reflected by false negatives (i.e. cases of TB infection missed) or false positives.

In 2018, a systematic review has informed the comparison of the predictive performance of IGRAs and the TST for identifying incident active TB in countries with a TB incidence of more than 100 per 100 000 population. Only studies in which the TST was compared with IGRAs in the same population (i.e. “head-to-head” studies) were included. Relative risk ratios for TB for people who tested positive and those who tested negative with the TST and IGRAs were estimated. The data on cost and cost-effectiveness as well as qualitative evidence were assessed where possible.

Systematic reviews were undertaken following detailed protocols with predefined questions relevant to the individual topics. Summaries of methodologies followed for each topic are given in the relevant sections below.

Recommendations

Recommendations

Justification

Based on available evidence, in 2022 the WHO GDG panel concluded that the diagnostic accuracy of TBSTs is similar to that of IGRAs and greater than that of the TST. The GDG panel expressed concerns about the certainty (quality) of evidence in many areas and the lack of longitudinal studies that include impact on people affected by important outcomes of TB. The risk of bias was primarily from non-blinded studies, and the quantity and quality of evidence varied among the different tests. For two of the three tests (Diaskintest and C-TST) evaluated during the GDG meeting, evidence on specificity was generated in high TB burden settings; therefore, additional analysis considered the concordance in specificity with existing WHOrecommended IGRAs. All three evaluated TBSTs have the potential to be used for the detection of TB infection and are recommended.

In 2018 the GDG concluded that the comparison of the TST and IGRAs in the same population does not provide strong evidence that one test should be preferred over the other for predicting progression to active TB disease. The TST may require significantly fewer resources than IGRAs and may be more familiar to practitioners in resource-limited settings. The GDG also noted that equity and access could affect the choice and type of test used. The preferences of people to be tested and programmes depend on several factors, such as the requirement for an adequately equipped laboratory (e.g. for IGRAs) and possible additional costs for people being tested (e.g. for travel) and programmes (e.g. for infrastructure and testing). The GDG strongly recommended the two tests as equivalent options, with relatively similar advantages and disadvantages.

In 2011, the GDG concluded that both the sensitivity and specificity of IGRAs in detecting active TB among individuals presumed of having TB were suboptimal and the quality of evidence was low. They also recommended that these tests not be used as a replacement for conventional microbiological diagnosis of pulmonary and extrapulmonary TB. Furthermore, the GDG noted that current evidence did not support the use of IGRAs or the TST as part of the diagnostic work-up of adults presumed of active TB, irrespective of HIV status. This recommendation placed a high value on avoiding the consequences of unnecessary treatment (owing to a high number of false positive results), given the low specificity of IGRAs and the TST in these settings.

The current recommendations are based on evaluation of data for all classes of TB infection diagnostic tests that were included in the respective evaluations. The findings cannot be extrapolated to other brand-specific tests. Also, any new in-class technologies will need to be specifically evaluated by WHO, in line with updated WHO procedures, to determine procurement eligibility for in vitro diagnostics for TB. ³

Dissemination and evaluation

Guidelines are disseminated through the WHO Global TB Programme (WHO/GTB) listservs to WHO regional offices, Member States, the Stop TB Partnership and other stakeholders (e.g. the Global Laboratory Initiative and the TB Supranational Reference Laboratory Network); they are also published on the websites of the WHO/GTB and Global Laboratory Initiative. The updated policy is incorporated into the WHO TB Knowledge Sharing Platform – an online reference resource for global TB policies and derivative products. Global TB report is collecting and reporting data on TB infection tests for all country-members used in respective year, which include information on all WHO recommended TB infection tests use, being direct indicators of current guidelines uptake. In addition, data on TB patient contacts investigation and TB preventive treatment, included in the same report, are indirect indicators of the current guidelines uptake.

¹ WHO consolidated guidelines on tuberculosis Module 1: Prevention – tuberculosis preventive treatment. Geneva: World Health Organization; 2020 (https://www.who.int/publications/i/item/9789240001503).

² Use of alternative interferon-gamma release assays for the diagnosis of TB infection: WHO policy statement. Geneva: World Health Organization; 2022 (https://www.who.int/publications/i/item/9789240042346).

³ Public announcement to TB in vitro diagnostics manufacturers, procurement agencies and national TB programmes on inclusion of WHO prequalification for TB in vitro diagnostics. Geneva: World Health Organization; 2021 (https://extranet.who.int/pqweb/ sites/default/files/documents/210211_PublicAnnouncement_TB_%20in-vitro-diagnostics.pdf).

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