Accurate diagnosis of latent tuberculosis in children, people who are immunocompromised or at risk from immunosuppression and recent arrivals from countries with a high incidence of tuberculosis: systematic review and economic evaluation

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 13/178/01. The contractual start date was in March 2014. The draft report began editorial review in March 2015 and was accepted for publication in September 2015. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Aileen Clarke is Professor of Public Health and Health Services Research, Warwick Medical School, University of Warwick, UK, and the Warwick Medical School receive payment for this work. Aileen Clarke is a member of the National Institute for Health Research (NIHR) Health Technology Assessment and Efficacy and Mechanism Evaluation editorial board. Ngianga-Bakwin Kandala and Aileen Clarke are also supported by the NIHR Collaboration for Leadership in Applied Health Research and Care West Midlands at University Hospitals Birmingham NHS Foundation Trust.

Copyright statement

© Queen’s Printer and Controller of HMSO 2016. This work was produced by Auguste et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

Overview

Tuberculosis (TB) is a major cause of morbidity and mortality globally. Nearly one-third of the world’s population is infected with Mycobacterium tuberculosis (MTB) [(Zopf 1883) Lehmann and Neumann 1896]; TB has an annual incidence of 9 million new cases and each year causes 2 million deaths annually worldwide. TB ranks as the second leading cause of death from an infectious disease. 1–3

In the UK, the prevalence of TB steadily decreased until the mid-1980s but has started to rise over the last 20 years, especially in ethnic minorities born in places with a high TB prevalence. 4,5 Between 1998 and 2009, annual TB notifications in the UK rose by 44%, from 6167 to 8900 cases. 4,6 Since 2005, this rate has remained high, leading to projections that in 2 years there will be more TB cases in the UK than in the USA,7 thereby posing a major public health challenge. The re-emergence has been largely driven by recently arriving immigrants in whom latent infection has been reactivated or who have acquired new infection as a result of their maintaining links with high-prevalence countries.

Aetiology and pathology of tuberculosis

Tuberculosis infection is transmitted to a healthy person through the air by inhaling respiratory fluids/sputum droplets containing MTB discharged by a person with active TB. The infected sputum droplets can dry and form into droplet nuclei, which can float in the air for a long period of time and penetrate the host. 8 TB can be transmitted through other routes including ingestion (e.g. from drinking unpasteurised cow’s milk)9 and inoculation (e.g. Prosector’s wart), although such cases are rare in the UK.

Once the bacteria are inhaled, the droplet nuclei travel through the mouth or nasal passages to the upper respiratory tract, bronchi and finally the alveoli of the lungs. The bacteria grow slowly and multiply in the alveoli over several weeks. Sometimes a small number of tubercle bacilli enter the bloodstream and spread throughout the body such as to the bones, lymph nodes or brain. 8 In > 80% of cases the immune system kills and removes the bacteria from the body. 10 If the immune system does not kill the bacteria, macrophages within the immune system ingest and surround the tubercle bacilli within 2–8 weeks. The cells form a barrier shell that keeps the bacteria suppressed and under control, resulting in latent tuberculosis infection (LTBI). Individuals with LTBI do not exhibit any clinical, radiological or bacteriological evidence of the pathogen. They are not infectious and may remain asymptomatic. 11 However, the latent infection may reactivate later in life, causing the individual to develop symptoms and become infectious. It has been estimated that people with LTBI are at 5–10% risk for developing active TB during their lifetime. 12,13 Therefore, this large pool of LTBI is an important reservoir of infection. 8,12

If the immune system cannot keep the bacteria suppressed or the barrier fails later, the bacilli begin to multiply and the individual develops active TB disease. Individuals who have active TB are infectious and each can spread MTB to up to 10–15 close contacts within a year. 14 The pathogen affects primarily the lungs (pulmonary TB) but can also involve other organs of the body (extrapulmonary TB). In the UK in 2012, pulmonary TB accounted for about 53% of all TB cases. 5

The period between infection and first signs of illness (incubation period) varies between 8 weeks and decades. The greatest chance of progressing to disease is within the first 2 years after infection, when approximately 50% of the 5–10% lifetime risk occurs. 15 The risk of infection and progression to active TB disease depends mostly on the host’s immune function as well as on the duration and proximity of exposure to a source afflicted with active MTB. 16 Therefore, certain population groups have a higher lifetime risk of developing TB. These vulnerable groups with low immunity and/or high exposure include long-term care facility workers, people born in or coming from countries with a high prevalence of TB, infants, children, those infected with human immunodeficiency virus (HIV), people with close contacts suspected of having active TB or those living in confined facilities (e.g. prison, homeless shelters). 5 These groups are particularly important as a reservoir of latent infection that could reactivate, and explain the trends observed for TB in the UK. 17

Active tuberculosis

When infection with MTB becomes active TB disease, the symptoms that occur are non-specific and depend on the site of TB infection. 18,19 Common signs and symptoms of active pulmonary TB may include a chronic cough for weeks or months accompanied by the coughing up of blood or blood-stricken mucus, pain in the chest, weight loss, intermittent fever and/or night sweats, poor appetite, chills, weakness or fatigue, and listlessness. 1,18,20 The clinical diagnosis of TB is based on TB-characteristic clinical signs and symptoms, chest radiography and microscopy of tissue biopsy or sputum samples. A definitive diagnosis of TB, however, is made through the identification of MTB in clinical samples (e.g. pus, tissue biopsy, sputum) using culture. 21,22 TB is difficult to culture and it takes several weeks to obtain a definitive result.

Tuberculosis is a curable disease; however, treatment is long and requires adherence, even through the side effects of treatment. 23 In the UK, most MTB infections are sensitive to the antibiotics used. 10 The routine management of active pulmonary TB includes a combination of antibiotics (e.g. isoniazid, rifampicin, pyrazinamide and ethambutol) given over 6 months. 18 Although patients start to feel better after 2 months of treatment and are not infectious any longer, it is vital that they complete their treatment. 24,25 This ensures that the TB bacteria are completely killed off, preventing the return of symptoms and the risk of bacteria becoming drug resistant. Treatment of drug-resistant forms of TB is less effective, requires longer than 6 months and causes greater side effects. 10,26

Measurement of latent tuberculosis infection

Unfortunately, there is no diagnostic gold standard for the identification of individuals with LTBI. Instead, the available screening tests for LTBI provide an indirect assessment of the presence of LTBI by relying on a host’s immunological response to TB antigens. 27 In addition, none of the available LTBI tests can accurately differentiate between people with LTBI and people with active TB. 11

There are two types of commercially available tests used to identify LTBI in the UK: (1) the tuberculin skin test (TST) and (2) the interferon gamma (IFN-γ) release assays (IGRAs). 5 Until recently, the TST (introduced by Mantoux in 1907) has been the only standard test used for the identification of LTBI. 13 The administration of the TST involves an intradermal injection of purified protein derivative (PPD) in the forearm. The immune response (i.e. delayed hypersensitivity caused by T cells) to the TST is determined 48–72 hours after the injection by measuring the transverse diameter (in mm) of skin induration. 13,16 There is no international agreement on cut-off values for the definition of a positive tuberculin reaction. 12 The choice among commonly used cut-off values (e.g. a diameter of induration of ≥ 5 mm, ≥ 10 mm or ≥ 15 mm) depends on an individual’s risk factor profile for TB. Usually, a lower cut-off value of ≥ 5 mm is used for individuals at higher risk of TB (e.g. patients with organ transplants, immunocompromised patients, patients with HIV infection and those who have had recent contacts with an active TB patient) and a higher cut-off value of ≥ 10 mm is applied for individuals at lower risk of TB (e.g. high-risk racial minorities, children, recently arrived immigrants from high-prevalence countries and patients with diabetes, malignancies or renal failure). 16 The administration of the TST is relatively cheap and does not require a laboratory, but it does require a skilled operator.

Interferon gamma release assays have been recently developed as alternative screening tests for LTBI. There are two types of IGRA: QuantiFERON^®-TB Gold-in-Tube (QFT-GIT) [old version: QuantiFERON^®-TB Gold (QFT-G)] (Cellestis/Qiagen, Carnegie, Australia) and T-SPOT. TB (Oxford Immunotec, Abingdon, UK). Both tests are commercially available in the UK. The QFT test is a whole-blood test based on an enzyme-linked immunosorbent assay whereas the T-SPOT. TB test uses peripheral blood mononuclear cells and is based on an enzyme-linked immunospot (ELISPOT) assay. 11 Both tests measure the cluster of differentiation 4 (CD4) cell-released IFN-γ response to MTB-specific antigens [early secretion antigen target 6 (ESAT-6), culture filtrate protein 10 (CFP-10) and tb7.7] in in vitro blood samples. 12,13,16

Incidence, prevalence and epidemiology

All forms of active TB are legally notifiable by the physician making or suspecting the diagnosis under the Public Health (Control of Disease) Act 198428 in England and Wales. It first became a statutory requirement to notify TB cases in 1913. Known as the Notifications of Infectious Diseases system, it continues to play a valuable role in the surveillance of TB; however, the information collected is limited and trends within subgroups of the population cannot be monitored. 29

In 1999, the Enhanced Tuberculosis Surveillance system was established to collect more detailed information on annual TB cases, including patient age, sex, ethnic group, country of birth, site of disease, NHS region and treatment outcomes. It has been reported that the Enhanced Tuberculosis Surveillance system reflects the true incidence of TB better than the Notifications of Infectious Diseases system as many measures are used to ensure that quality standards are met annually, thereby providing a corrected analysis of TB cases. 30 In 2012, completeness of data was 100% for mandatory fields and approximately 91% across other key fields for England and 89% for Wales. 5 This system provides the most comprehensive, timely and accurate information on active TB incidence in the UK29 and is therefore robust.

There is no national system that collects data for LTBI. For this reason there are no robust data for LTBI, although we can predict that for every person with active TB there are likely to be several with undiagnosed LTBI. Therefore, it seems reasonable to extrapolate from active TB and make the assumption that LTBI will follow a similar epidemiological pattern.

The rates of active TB peaked during the early 1900s with an annual incidence rate of approximately 320 per 100,000. The rate declined dramatically until at least 1987 to as low as 10.1 per 100,000 population per year. However, since the 1980s, the incidence rate began reversing and has reached highs of between 13.6 and 14.4 per 100,000 since 2005. 5 The most recent figures in 2012 report a total of 8751 active TB cases across the UK, giving an incidence rate of 13.9 per 100,000. 5 The burden of TB is highest in England, where in 2012 there were 8130 cases of active TB, a rate of 15.2 per 100,000; in Wales there were 136 active TB cases, a rate of 4.4 per 100,000. 5 Between 2010 and 2011, a total of 436 people died of TB in the UK. 5

Impact of the health problem

Current service provision

Management of latent tuberculosis infection

The goal of screening for LTBI is to identify individuals who are at high risk of developing active TB who would potentially benefit from prophylactic treatment. In the UK, LTBI screening is recommended for contacts of patients diagnosed with active TB and recently arrived migrants. Contacts include household contacts defined as those who share a bedroom, kitchen, bathroom or sitting room with the index active TB case, as well as boyfriends or girlfriends and frequent visitors to the home. Workplace associates in close proximity to a patient for extended periods may be judged to be household contacts; however, the majority of workplace contacts are not screened. Casual contacts should be assessed only if the index case is particularly infectious or the contact case is at increased risk from infection. Nevertheless, all contacts should be offered information and advice about TB. Similar risk assessments take place in schools, nurseries, institutions such as prisons and hospitals, and for aircraft passengers, leading to screening of those perceived to be at risk. 10,51

Active case finding is recommended for migrants who have recently arrived in the UK from countries with a TB incidence of ≥ 40 per 100,000. 10 Identification of new migrants is recommended from port of arrival reports, new registrations with primary care, entry to education and links with statutory or voluntary groups working with new migrants. Health-care professionals responsible for new migrant screening are advised to co-ordinate a programme to detect and treat active and latent TB, provide the bacillus Calmette–Guérin (BCG) vaccination when appropriate and provide relevant referrals and information. Commissioners, NHS employees and providers of TB services, and other statutory and voluntary organisations, are particularly advised to identify and manage TB in hard-to-reach groups such as the homeless, substance misusers, prisoners and vulnerable migrants. 52

A simplified care pathway for LTBI screening derived from the National Collaborating Centre for Chronic Conditions10,51 is presented in Figure 1 and further details about testing strategies for people being screened for LTBI are provided in Box 1.

FIGURE 1.

Care pathway of LTBI screening. 5,51

BOX 1 - Testing strategies for people being screened for LTBI

• Generally, individuals are tested for LTBI using TST (Mantoux), IGRA, both or a dual strategy of TST followed by IGRA. If the results are positive, individuals are assessed for active TB; if the results are positive they are treated for active TB and if they are negative they are then treated for LTBI. If the results for LTBI are negative the individual is offered a BCG vaccination if aged < 16 years or aged 16–35 years and from sub-Saharan Africa or from an area with an incidence of > 500 per 100,000. Individuals are given information and advice about TB. However, different testing and treatment pathways are recommended for different populations, including different age groups, new migrants and immunocompromised individuals. 10,51

• TST is recommended for contacts aged > 5 years for the diagnosis of LTBI. IGRA is recommended for individuals whose TST shows positive results (≥ 5 mm diameter for those who have not been vaccinated with BCG and ≥ 15 mm diameter for those who have been vaccinated) or in people for whom TST would be less reliable, such as BCG-vaccinated people. Individuals with a positive IGRA or inconclusive TST are referred to specialist TB care. For contacts who are aged 2–5 years, a TST should be offered as the initial diagnostic test and, if the result if positive, taking BCG history into account, they should be referred to a TB specialist to exclude the possibility of active disease and to determine treatment, depending on the result. If the result of the TST is negative but the child is a contact of a person with sputum smear-positive disease, then an IGRA should be offered after 6 weeks alongside a repeat TST to increase sensitivity. 10,51

• For child contacts of a person with sputum smear-positive disease aged 4 weeks to 2 years who have not been vaccinated, isoniazid should be started and a TST should be performed. If the TST is reported as positive, the child should be assessed for active TB and if active TB is excluded the child should then be offered full treatment for LTBI. If the TST is negative (< 5-mm induration), isoniazid should be continued for 6 weeks after which a repeat TST and IGRA should be performed. If repeat tests are negative, isoniazid should be stopped and BCG offered, whereas if either is positive active TB should be assessed and, if excluded, treatment for LTBI should be considered. For child contacts of a person with sputum smear-positive disease aged 4 weeks to 2 years who have been vaccinated, a TST should be performed and any positive results (≥ 15 mm) should be assessed for active TB. If active TB is excluded then a regimen of either 3 months of rifampicin and isoniazid or 6 months of isoniazid should be given. If the TST is negative (< 15 mm) it should be performed again with an IGRA after 6 weeks. If both tests are negative no further action is needed. If either is positive, active TB has to be excluded and treatment for LTBI followed. 10,51

• To diagnose LTBI in recently arriving migrants from high-incidence countries, for children aged 5–15 years a TST should be offered and if positive an IGRA should be performed. For individuals aged 16–35 years, either an IGRA alone or in a dual strategy with a TST should be offered. For those aged > 35 years, the individual risks and benefits of treatment should be considered before testing. For children aged < 5 years, a TST should be offered and if the initial test is positive taking BCG history into account then active TB disease should be excluded and LTBI treatment considered. 10,51

• Regarding those who are immunocompromised, children should be referred to a TB specialist. For people with HIV infection and a CD4 count of < 200 cells/mm³ or between 200 and 500 cells/mm³, an IGRA should be offered with a concurrent TST. If either is positive, active TB should be ruled out before LTBI treatment is given. For other people who are immunocompromised, an IGRA should be offered alone or with a TST. 10,51

• Once active TB has been excluded by chest radiography and examination, individuals should be offered treatment. Individuals aged ≥ 35 years without HIV infection should be assessed further and counselled about treatment because of the increasing risk of hepatotoxicity from medication. For those aged 16–35 years and not known to have HIV infection, treatment should include either 6 months of isoniazid or 3 months of rifampicin and isoniazid. 10,51

• Neonates who have been in close contact with people who have sputum smear-positive TB and who have not received at least 2 weeks of antiTB drug treatment should be started on isoniazid for 3 months and then a TST performed after 3 months of treatment. If the TST is positive, active TB should be assessed and, if found negative for active TB, isoniazid should be continued for a total of 6 months. If the TST is negative it should be repeated with an IGRA and if both are negative isoniazid should be stopped and BCG vaccination performed. In children aged > 2 years, 3 months of rifampicin and isoniazid or 6 months of isoniazid should be given.

Current service cost

Estimates for the costs of diagnosing and treating LTBI have been provided by the National Institute for Health and Care Excellence (NICE) (Table 1). These costs are based on NICE guidelines from 200651 and the partial update from 2011. 10 The costs shown include the unit costs of the disposables, the time to administer and read tests and the costs of collecting a blood sample per patient for the tests, calculated in 2011. The cost of chemoprophylaxis includes the cost of drugs, active TB tests, consultations and nurse visits, which were calculated in 2006. BCG costs are also from 2006. Compared with the cost of treating active TB (≥ £5000), diagnosing and treating LTBI per patient is less costly.

Variation in services and/or uncertainty about best practice

Relevant national guidelines including National Service Frameworks

The latest guidelines on the diagnosis, management and prevention of TB are available from NICE. There is a 2006 clinical guideline51 on the clinical diagnosis and management of TB and measures for its prevention and control, with a partial update in 2011,10 as well as 2012 public health guidance52 to identify and manage TB among hard-to-reach groups. The Department of Health has also published guidelines for the planning, commissioning and delivery of TB services,63 guidelines for testing health-care workers,64 a wider action plan for stopping TB in England65 and guidance for the prevention and control of HIV-related and drug-resistant TB. 66 Finally, the British Thoracic Society has published guidelines on the prevention, risk assessment and management of TB in adult patients with chronic kidney disease67 and in patients due to start antiTNF-α treatment,68 management of air travel passengers69 and management of opportunist mycobacterial infections. 70

Description of the technology under assessment

Current usage in the NHS

The UK National Screening Committee decided that TB screening should be organised locally rather than as a national programme. 79 Therefore, the implementation of NICE guidelines on LTBI testing using the TST and IGRAs has been very ad hoc across the NHS. In London, for example, it is reported that it has not been fully implemented and that current practice is not effective in detecting LTBI. 50

More recently, in March 2014, a tri-borough Joint Strategic Needs Assessment (JSNA) report80 stated that ‘However, GP screening has to date been inconsistent and no clear assessment and patient pathway exists for latent TB’. Leicester, Leicestershire and Rutland’s Tuberculosis Summary Needs Assessment from December 201381 mentions expanding numbers of cases of LTBI from IGRA testing but calls for a more systematic testing process for testing new entrants to make an impact on active TB cases. In addition, Kirklees’s JSNA82 mentions exploring funding to develop IGRA testing and Manchester City Council JSNA83 reports needing to improve LTBI screening.

Commissioners are currently looking at models for local service provision. This is in line with the suggested approach of TB control boards in the recent PHE consultation document Collaborative Tuberculosis Strategy for England 2014 to 2019. 7 There is not one agreed service model and PHE has recently sponsored several pilot projects, which are ongoing at present, looking at the feasibility of screening in different settings. These include the identification of eligible individuals from GP practice lists followed by an invitation for screening at the GP surgery by IGRA (Dr Huda Mohammed, PHE, West Midlands, 12 May 2014, personal communication) and a more innovative approach in which screening for LTBI was carried out using an IGRA at a college of further education among self-selected individuals taking part in English for Speakers of Other Languages classes following a campaign of education. 84 Neither of these studies has reported yet but they are expected to show positive result rates of between 17% and 20% (Dr Huda Mohammed, personal communication).

It is difficult to know how many GPs are identifying new entrants and organising testing for them or how many new entrants are contacting TB services directly for testing. The websites of several community TB85 teams list testing new entrants for LTBI as part of their remit and give a contact number or e-mail address. The Birmingham and Solihull Tuberculosis Service86 has a full page on its website with eligibility criteria for screening, whereas the Liverpool Community Health NHS Trust Tuberculosis Service87 excludes testing of new entrants who are students.

Taking the Coventry and Warwickshire area as a case study, the Meridian Practice in Coventry, a specialist service that cares for refugees and asylum seekers, offers IGRA testing to all registered patients (Najeeb Wai, practice manager, Meridian Practice, 8 July 2014, personal communication). The Coventry and Warwickshire Tuberculosis Service reports that it ‘indirectly tr[ies] to identify high TB risk individuals other than identified contacts and offer screening’ (Debbie Crisp, lead TB nurse specialist and primary care services for the Arden Community TB Service, 9 July 2014, personal communication). Apart from supporting the work at the Meridian Practice, it also supports the Warwickshire programme for looked-after children, which has an established TB screening programme incorporated into its medical review, and has plans to discuss the programme with the Coventry team. In addition, the Coventry and Warwickshire Partnership Trust commenced a TB screening programme for HIV-infected individuals in July 2013 and supports the LTBI treatment programme.

In summary, it is difficult to know how much awareness there is for LTBI screening in the primary care setting in the NHS. Pathways are not widely available, if they exist at all. Secondary care specialist services are more aware, but do not employ standard criteria for testing. There is great variability within the system. There is a clear need for new evidence to provide information on the most appropriate strategies available for identifying LTBI in the three subgroups of interest: children, immunocompromised individuals and recently arrived immigrants from high-incidence countries. This evidence will aid in the decision-making process on whether IGRAs should be used as a replacement or as an adjunct to the TST for the diagnosis of LTBI in these populations.

The next chapter discusses the decision problem and outlines the key clinical questions and objectives of this work.

Identification and selection of studies

Study selection strategy

Two independent reviewers screened all identified bibliographic records on title/abstract (screening level I) using a prespecified and piloted questionnaire form. Full-text reports of all potentially relevant records passing screening level I were then retrieved and independently reviewed using the same study eligibility criteria (screening level II). Any disagreements over inclusion/exclusion were resolved by discussion between two reviewers or by recourse to a third-party reviewer.

Data extraction strategy

Two reviewers independently extracted relevant data using an a priori defined pre-piloted data extraction sheet (see Appendix 3). Data extracted were cross-checked and any disagreements were resolved by discussion or by recourse to a third-party reviewer. Data extracted included information on the study [e.g. author, country, publication year, design, setting, sample size, follow-up duration, risk of bias (ROB) items such as blinding or incomplete outcome data], participants (e.g. age, sex, study eligibility criteria, comorbidities, BCG vaccination status/time, immune status), intervention/comparator tests (type of test/assay used for identification of LTBI, definition of positivity/negativity thresholds/cut-off values for each test, methods of laboratory analysis used for the derivation of test results, repeat testing), construct validity (e.g. definition of exposure to MTB in terms of proximity, length of time and/or type of contact; incidence of progression to active TB; timing of exposure to MTB/incidence of active TB; definition of low-risk populations; type of summary effect measures).

For individual studies, 2 × 2 contingency tables were constructed by cross-tabulating test results (separately for IGRAs and TST) with construct validity responses in relation to exposure level or incidence of progression to active TB. The proportions of subjects with positive and negative test results were extracted. For each test, all summary parameters of interest (see the list of outcomes) with corresponding measures of variability (95% CIs, p-values) were ascertained or calculated, if reported data permitted. A value of 0.5 was imputed for incidence studies with zero events for one of the compared tests to allow the calculation of CIRs and their ratios (R-CIRs). The R-CIRs were rendered indeterminate in the case of zero events in the 2 × 2 tables of both tests compared (no imputation was carried out). All relevant summary parameters were entered into the data extraction sheets and evidence and summary tables. Calculated parameters were marked as ‘calculated’.

Study quality assessment

The methodological quality of the incidence and exposure studies included in the current review was assessed using the Quality in Prognosis Studies (QUIPS) tool90 and a modified tool reported by Dinnes et al. ,44 respectively (see Appendix 4).

The QUIPS tool90 (also referred to as the ‘Methodology checklist: prognostic studies’, developed by Hayden et al. ,90 in the NICE Guidelines Manual89) was used to assess studies reporting the diagnostic performance/validation of tests (e.g. sensitivity, specificity, incidence density rate/CIRs, PPVs/NPVs, DORs, regression-based ORs). The QUIPS tool assesses the ROB in the six domains of patient selection/participation, study sample attrition, index test measurement, outcome/construct validity measurement, confounding and statistical analysis/outcome reporting. According to responses to prompting items, each of the six domains is rated as high, moderate or low ROB. The overall summary ROB rating for each study is then derived based on the domain-specific ROB ratings.

We used a modified tool reported by Dinnes et al. 44 to assess the quality of retrospective/cross-sectional studies reporting associations between test results and exposures. The QUIPS tool is not directly applicable to assessing the quality of retrospective/cross-sectional studies of association between test results and exposure because of the non-prognostic nature of their design (exposure is ascertained retrospectively, which is then correlated with test results). Appendix 4 outlines the criteria used to appraise these exposure studies. Each study was assessed for blinding of test results from exposure, description of index test and threshold (TST and IGRA), definition/description of exposure, completeness of verification of exposure and sample attrition. Each study was then awarded an overall quality score defined as:

• low quality: studies with 0–2 satisfied (yes response) quality features

• moderate quality: studies with three satisfied (yes response) quality features

• high quality: studies with 4–5 satisfied (yes response) quality features.

Study quality was assessed independently by two reviewers (PS and KF). Any disagreements were resolved by discussion or by a third reviewer. The evidence across studies was summarised qualitatively using the overall ROB ratings (low, moderate, high).

Data synthesis and analysis

Given the absence of a gold standard for diagnosing LTBI, the performance of tests was compared using alternative methodologies that rely on validation of test results against predetermined validity constructs (i.e. proxies for a reference standard). Thus, our analyses focused on the following recommended approaches: (1) we evaluated and compared predictive values of IGRAs and the TST in relation to construct validity I (i.e. progression rate to active TB); (2) we evaluated and compared the degree of association/correlation of IGRA and TST results with construct validity II (i.e. exposure to MTB defined by proximity, duration or dose–response gradient); (3) we estimated and compared the specificity (or false positives) of IGRAs and the TST in relation to construct validity III (i.e. people at low risk of MTB or healthy populations); and (4) we measured the degree of concordance/discordance between IGRA and TST results. 44,91–94

For each index test (TST, IGRAs), if data permitted (either directly reported or, if not reported, calculated if possible), relevant statistical parameters of diagnostic test accuracy are presented per individual study. For statistics measuring agreement/disagreement between two tests, values for concordant (both tests positive or negative) and discordant (one test negative, the other test positive or vice versa) test results are presented or calculated if data permitted. Moreover, when possible, the likelihood of indeterminate test results was calculated.

The performance of the tests (in terms of diagnostic accuracy and concordance) was compared (e.g. IGRA vs. TST) using sensitivity, specificity, PPVs/NPVs, ratio of diagnostic odds ratios (R-DOR), ratio of incidence density rate ratios (R-IDRR) (or CIRs), regression-based ORs, kappa statistics, per cent discordance and likelihood of indeterminate test results. Note that, as there is no gold standard for the diagnosis of LTBI, specificity and sensitivity does not have the same meaning as in the conventional paradigm (i.e. against a gold standard) but reflects the performance of tests in relation to predetermined proxy constructs of validity (i.e. past exposure to TB or future progression to active TB).

The association between BCG vaccination and test performance in terms of specificity was explored by comparing false-positive rates (or odds of false positivity) of the TST and IGRAs in both BCG-vaccinated and unvaccinated individuals (i.e. dependence of false-positive rates on BCG vaccination status).

Summary measures of effectiveness (e.g. sensitivity, specificity, DOR, R-DOR, R-CIR) were pooled when deemed appropriate and feasible (based on the absence of clinical/methodological heterogeneity, the same cut-off values of a test or the absence of a test threshold effect on the DOR) using univariate95 and/or bivariate random-effects meta-analysis models. 19 The presence of heterogeneity across studies was determined using visual inspection of forest plots (of individual study ORs and R-DOR estimates and degree of overlap across 95% CIs) and chi-squared tests (two tailed, p ≤ 0.10). 96,97 A series of subgroup and sensitivity analyses (see below) was undertaken to explore potential reasons for statistical heterogeneity, if present. When pooling was not feasible, because of a lack of sufficient data or important clinical/statistical heterogeneity across studies (e.g. significant test threshold effect),98 the findings from individual studies were summarised qualitatively.

Data synthesis for the summary outcome measures is presented in evidence/summary tables and text overall and/or stratified by demographic characteristics (e.g. age), TST thresholds (≥ 5 mm, ≥ 10 mm, ≥ 15 mm), intervention (T-SPOT. TB vs. QFT) and prevalence/burden of TB in country of origin (high burden vs. low burden). 1 In addition, for people who were immunocompromised or at risk from immunosuppression (research question 2), when possible outcomes have been stratified by type of immunosuppression, use of immunosuppressive drugs (e.g. steroids, antiTNF-α treatment, antirheumatic drugs) and comorbidity condition (e.g. HIV infection, renal disease, diabetes, liver disease, haematological disease, cancer, autoimmune disease, transplant recipients).

It was planned to conduct subgroup analysis according to BCG vaccination status, TST threshold (≥ 5 mm, ≥ 10 mm, ≥ 15 mm) and prevalence of TB in country of origin, if data permitted.

Calculations were performed using Meta-DiSc version 1.4 (Unit of Clinical Biostatistics, Ramón y Cajal Hospital, Madrid, Spain)99 and Stata version 14 (StataCorp LP, College Station, TX, USA). 100

Overall quality of evidence

There is no formally accepted and validated approach for the assessment of the overall quality of evidence that would be appropriate to the type of evidence synthesised in this review. Work on the formulation of this approach is still ongoing [Grading of Recommendations Assessment, Development and Evaluation Working Group; see www.gradeworkinggroup.org (accessed 15 December 2015)]. 101

Derivation of summary measures of diagnostic accuracy

We used Bayesian meta-analysis to derive the sensitivity and specificity for various testing strategies for LTBI in the various population subcategories. The methods and results for this are reported in Chapter 6 [see Performance of screening texts (sensitivity and specificity)].

Number of studies identified

A total of 6687 bibliographic records were identified through electronic database searches. After removing duplicates, 3757 records were screened for inclusion. On the basis of title/abstract, 3279 records were excluded. The remaining 478 records were included for full-text screening. A further 424 records were excluded at the full-text stage. The remaining 54 records102–155 (53 unique studies) were considered relevant to the review since the previous NICE clinical guidance work in 2011 (CG117). 10 One study by Rutherford et al. 110,111 was presented in two publications. In addition, 37 studies156–192 from CG11710 were included in the current evidence synthesis (see Appendix 5). The study flow and the reasons for exclusion are shown in Figure 2 and Appendix 6. A search for ongoing trials was undertaken in different databases (Clinical Trials.gov, WHO ICTRP) up to August 2014. A total of 50 ongoing trials were identified, of which 30 were excluded; the reasons for exclusion are presented in Appendix 7. Twenty ongoing trials were therefore considered relevant for inclusion in our review (see Appendix 8).

FIGURE 2.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses study flow diagram of studies identified since 2011. a, An additional 37 studies were included from CG117. 10

Description of included studies and synthesis

In the following sections we describe the baseline characteristics and study quality for the incidence and exposure studies of the three populations of interest: (1) children, (2) immunocompromised individuals and (3) those recently arrived from countries with a high TB incidence. Full data-extraction sheets including baseline characteristics for all recently identified studies since CG11710 are provided in Appendix 9. For each of the three populations we present the synthesis of the evidence in terms of the comparative performance of tests (diagnostic accuracy indices for identifying LTBI) and between-test concordance, discordance and agreement. Appendix 10 provides the incidence rates of TB for each included study since CG117. 10

Children and adolescents

Comparative performance of tests (diagnostic accuracy indices for identifying latent tuberculosis infection): children

Incidence of active tuberculosis

Ratios of cumulative incidence ratios

This analysis included seven studies: two studies161,162 reviewed in CG11710 (see Appendix 5) and five more recent studies, three published in 2011102–104 and two published in 2014150,152 (see Appendix 9). For three150,161,162 of the studies, R-CIRs could not be calculated because none of the children developed active TB. The R-CIRs in the remaining four studies102–104,152 were pooled (Table 6), with one analysis comparing QFT-GIT with TST 5 mm and the other comparing QFT-GIT with TST 10 mm (they were pooled separately because TST performance differs according to its threshold). The pooled estimates indicated that there was no significant difference in performance between QFT-GIT and TST 5 mm (pooled R-CIR 1.12, 95% CI 0.72 to 1.75) (Figure 3),102,103 whereas QFT-GIT was better than TST 10 mm in identifying/predicting LTBI (pooled R-CIR 4.33, 95% CI 1.32 to 14.23) (Figure 4). 102,104,152

TABLE 6 - Comparison of test performance: diagnostic accuracy indices for identifying LTBI (incidence studies) – children and adolescents

CI (–), cumulative incidence in those who tested negative; CI (+), cumulative incidence in those who tested positive; ID, identification; IDR, incidence density rate; NA, not applicable; NR, not reported; R-OR, ratio of odds ratios; SN, sensitivity; SP, specificity.

Study ID, country (burden)	Test results	Test diagnostic accuracy (95% CI) (%)		Development of active TB
				Cumulative incidence (%), CIR, IDR, IDRR (95% CI)		R-CIR, R-IDRR (95% CI), IGRA vs. TST (by threshold)
		IGRA: QFT-GIT/G and/or T-SPOT.TB	TST (by threshold)	IGRA: QFT-GIT/G and/or T-SPOT.TB	TST (by threshold)
Diel 2011,102 Germany (low)	Number of test results: QFT-GIT 106; T-SPOT.TB NA; TST 106 Test (+/–): QFT-GIT 23/83; T-SPOT.TB NA; TST ≥ 5 mm 40/66; TST ≥ 10 mm 20/86 Number of indeterminate results: QFT-GIT NR; T-SPOT.TB NA; TST NR Number lost to follow-up: NR	QFT-GIT: SN 100 (60.97 to 100); SP 84.69 (76.27 to 90.5); PPV 28.57 (13.81 to 49.96); NPV 100 (95.58 to 100)	TST ≥ 5 mm: SN 100 (60.97 to 100); SP 65.31 (55.47 to 73.99); PPV 15.00 (7.06 to 29.07); NPV 100 (94.34 to 100) TST ≥ 10 mm: SN 66.67 (30.00 to 90.32); SP 63.27 (53.39 to 72.14); PPV 10.00 (3.96 to 23.05); NPV 96.88 (89.3 to 99.14)	QFT-GIT: CI (+) 28.57 (13.81 to 49.96); CI (–) 1.20 (0.03 to 6.53); CIR 23.7 (2.57 to 110.3)	TST ≥ 5 mm: CI (+) 15.00 (7.06 to 29.07); CI (–) 1.55 (0.04 to 8.4); CIR 9.6 (1.08 to 448.2) TST ≥ 10 mm: CI (+) 10.00 (3.95 to 23.05); CI (–): 3.12 (0.22 to 11.33); CIR 3.20 (0.61 to 16.67)	R-CIR (QFT-GIT vs. TST ≥ 5 mm): 2.47 (0.40 to 15.12) R-CIR (QFT-GIT vs. TST ≥ 10 mm): 7.41 (2.06 to 26.57)
Mahomed 2011,103 South Africa (high)	Number of test results: QFT-GIT 5244; T-SPOT.TB NA; TST 5244 Test (+/–): QFT-GIT 2669/2575; T-SPOT.TB NA; TST ≥ 5 mm 2894/2350 Number of indeterminate results: QFT-GIT NR; T-SPOT.TB NA; TST NR Number lost to follow-up: 18%	QFT-GIT: SN 75.00 (61.79 to 84.77); SP 49.35 (47.99 to 50.71); PPV 1.46 (1.07 to 1.99); NPV 99.50 (99.14 to 99.7)	TST ≥ 5 mm: SN 76.92 (63.87 to 86.28); SP 45.03 (43.68 to 46.39); PPV 1.38 (1.02 to 1.88); NPV 99.49 (99.11 to 99.71)	QFT-GIT: CI (+) 1.46 (1.07 to 1.99); CI (–) 0.50 (0.28 to 0.87); CIR 2.89 (1.55 to 5.40); IDR (+) 0.64 (0.45 to 0.87) per 100 person-years; IDR (–) 0.22 (0.12 to 0.38) per 100 person-years; IDRR 2.92 (1.58 to 5.67)	TST ≥ 5 mm: CI (+) 1.38 (1.02 to 1.87); CI (–) 0.51 (0.28 to 0.90); CIR 2.71 (1.42 to 5.14); IDR (+) 0.60 (0.43 to 0.82) per 100 person-years; IDR (–) 0.22 (0.11 to 0.39) per 100 person-years; IDRR 2.73 (1.45 to 5.42)	R-CIR (QFT-GIT vs. TST ≥ 5 mm): 1.07 (0.68 to 1.68); R-IDRR (QFT-GIT vs. TST ≥ 5 mm): 1.07 (0.67 to 1.71)
Metin Timur 2014,150 Turkey (intermediate)	Number of test results: QFT-GIT 81; T-SPOT.TB NA; TST 81 Test (+/–): QFT-GIT 12/69; T-SPOT.TB NA; TST ≥ 15 mm 81/0 Number of indeterminate results: QFT-GIT 0; T-SPOT.TB NA; TST 0 Number lost to follow-up: NR	QFT-GIT: SN NA; SP 100 (NR); PPV NA; NPV 100 (NR)	TST ≥ 15 mm: SN NA; SP 0.0 (NR); PPV 0.0 (NR); NPV NA	QFT-GIT: CI (+) NA; CI (–) 0.0 (NR); CIR NA	TST ≥ 15 mm: CI (+) 0.0 (NR); CI (–) NA; CIR: NA	R-CIR (QFT-GIT vs. TST ≥ 15 mm): NA
Noorbakhsh 2011,104 Iran (intermediate)	Number of test results: QFT-G 59; T-SPOT.TB NA; TST 58 Test (+/–): QFT-G 18/41; T-SPOT.TB NA; TST ≥ 10 mm 8/50 Number of indeterminate results: QFT-G NR; T-SPOT.TB NA; TST 1 Number lost to follow-up: NR	QFT-G: SN 100 (72.25 to 100); SP 83.67 (70.96 to 91.49); PPV 55.56 (33.72 to 75.44); NPV 100 (91.43 to 100)	TST ≥ 10 mm: SN 30.00 (10.78 to 60.32); SP 89.58 (77.83 to 95.47); PPV 37.50 (13.68 to 69.43); NPV 86.00 (73.81 to 93.05)	QFT-G: CI (+) 55.56 (33.72 to 75.44); CI (–) 2.41 (0.06 to 12.9); CIR 22.78 (2.75 to 101.1)	TST ≥ 10 mm: CI (+) 37.5 (13.49 to 69.62); CI (–) 14.00 (6.63 to 26.50); CIR 2.68 (0.86 to 8.27)	R-CIR (QFT-G vs. TST ≥ 10 mm): 8.50 (2.87 to 25.17)
Song 2014,152 South Korea (high)	Number of test results: QFT-GIT 2966; T-SPOT.TB NA; TST 2982 Test (+/–): QFT-GIT 317/2649; T-SPOT.TB NA; TST ≥ 10 mm 663/2319; TST ≥ 15 mm 231/2751 Number of indeterminate results: QFT-GIT 16; T-SPOT.TB NA; TST 0 Number lost to follow-up: NR	QFT-GIT: SN 47.83 (29.24 to 67.04); SP 89.6 (88.45 to 90.65); PPV 3.47 (1.94 to 6.10); NPV 99.55 (99.21 to 99.74)	TST ≥ 10 mm: SN 56.52 (36.81 to 74.37); SP 78.03 (76.51 to 79.49); PPV 1.96 (1.14 to 3.32); NPV 99.57 (99.21 to 99.77) TST ≥ 15 mm: SN 56.52 (36.81 to 74.37); SP 92.63 (91.64 to 93.52); PPV 5.62 (3.31 to 9.38); NPV 99.64 (99.33 to 99.80)	QFT-GIT: CI (+) 3.47 (1.87 to 6.17); CI (–) 0.45 (0.24 to 0.79); CIR 7.66 (3.41 to 17.21); OR 7.90 (3.46 to 18.06)	TST ≥ 10 mm: CI (+) 1.96 (1.11 to 3.36); CI (–) 0.43 (0.22 to 0.80); CIR 4.55 (2.00 to 10.32) ; OR 4.62 (2.02 to 10.58) TST ≥ 15 mm: CI (+) 5.62 (3.23 to 9.47); CI (–) 0.36 (0.18 to 0.67); CIR 15.48 (6.86 to 34.92); OR 16.35 (7.08 to 37.71)	R-CIR (QFT-GIT vs. TST ≥ 10 mm): 1.68 (0.94 to 3.03); R-OR (QFT-GIT vs. TST ≥ 10 mm): 1.71 (0.94 to 3.11) R-CIR (QFT-GIT vs. TST ≥ 15 mm): 0.49 (0.28 to 0.89); R-OR (QFT-GIT vs. TST ≥ 15 mm): 0.48 (0.27 to 0.88)

FIGURE 3.

Pooled R-CIR (QFT-GIT vs. TST 5 mm) in children and adolescents. df, degrees of freedom; IV, inverse variance; SE, standard error.

FIGURE 4.

Pooled R-CIR (QFT-GIT vs. TST 10 mm) in children and adolescents. df, degrees of freedom; IV, inverse variance; SE, standard error.

Sensitivity and specificity

There was wide variability in the sensitivity and specificity of IGRAs (QFT-GIT/G) and the TST (5 mm or 10 mm) across newly identified studies. 102–104,150,152 TST sensitivity was higher at 5 mm than at 10 mm/15 mm and, vice versa, specificity was better at 10 mm/15 mm than at 5 mm. IGRAs (QFT-GIT/G) demonstrated a similar sensitivity (range 48–100%) to that of TST 5 mm (sensitivity range 57–100%) and slightly better specificity (range 49–90%) than that of TST 5 mm (range 45–65%). Although the sensitivities of the IGRAs and TST 5 mm were higher than those for TST 10 mm/15 mm (range 30–56%), the corresponding specificities of these tests were lower than those for TST 10 mm/15 mm (range 63–93%). Forest plots of sensitivities and specificities were generated and because of high unexplained heterogeneity (not explained by IGRA type and TST threshold, different methods for diagnosing active TB), no meta-analysis could be performed (Figures 5–8).

FIGURE 5.

Forest plot of sensitivity based on incidence of active TB (QFT-GIT/G) in children and adolescents. df, degrees of freedom.

FIGURE 6.

Forest plot of sensitivity based on incidence of active TB (TST) in children and adolescents. df, degrees of freedom.

FIGURE 7.

Forest plot of specificity based on incidence of active TB (QFT-GIT/G) in children and adolescents. df, degrees of freedom.

FIGURE 8.

Forest plot of specificity based on incidence of active TB (TST) in children and adolescents. df, degrees of freedom.

Exposure levels

Ratios of diagnostic odds ratios

This analysis included 17 studies: six studies156,157,160,162–164 from CG11710 (see Appendix 5) and 11 studies105–113,148,151,154 from the updated review (see Appendix 9). The association between the screening test results and the risk of LTBI/exposure level measured using the R-DORs (IGRA vs. TST) in individual studies ranged from 0.27105 to 11.01113 (Table 7).

TABLE 7 - Comparison of test performance: diagnostic accuracy indices for identifying LTBI (exposure studies) – children and adolescents

DORa, adjusted diagnostic odds ratio; ID, identification; MTC, M. tuberculosis contact; NR, not reported; R-DORa, adjusted ratio of diagnostic odds ratios; SN, sensitivity; SP, specificity.

Study ID, country (burden)	Test results	Test diagnostic accuracy (95% CI) (%)		Construct validity (i.e. LTBI exposure-based proxy)
				DOR (95% CI) (vs. non-exposed; reference group)		R-DOR (95% CI), IGRA vs. TST (by threshold)
		IGRA: QFT-GIT/G and/or T-SPOT.TB	TST (by threshold)	IGRA: QFT-GIT/G and/or T-SPOT.TB	TST (by threshold)
Adetifa 2010,105 Gambia (high)	Number of test results: QFT-GIT 215; T-SPOT.TB 215; TST 215 Test (+/–): QFT-GIT 72/143; T-SPOT.TB 71/144; TST ≥ 10 mm 57/158 Number of indeterminate results: QFT-GIT/G 2; T-SPOT.TB 0; TST 0	QFT-GIT: Same house/different room vs. different house: SN NR; SP NR; PPV NR; NPV NR Same house/same room vs. different house: SN NR; SP NR; PPV NR; NPV NR T-SPOT.TB: Same house/different room vs. different house: SN NR; SP NR; PPV NR; NPV NR Same house/same room vs. different house: SN NR; SP NR; PPV NR; NPV NR	TST ≥ 10 mm: Same house/different room vs. different house: SN NR; SP NR; PPV NR; NPV NR Same house/same room vs. different house: SN NR; SP NR; PPV NR; NPV NR	QFT-GIT: Same house/different room vs. different house: DOR 1.20 (0.60 to 2.60); DORa 1.50 (0.70 to 3.10) Same house/same room vs. different house: DOR 3.20 (1.20 to 9.10); DORa 4.00 (1.40 to 11.40) T-SPOT.TB: Same house/different room vs. different house: DOR 2.00 (0.80 to 5.10); DORa 2.60 (0.90 to 7.10) Same house/same room vs. different house: DOR 5.30 (1.50 to 18.50); DORa 6.60 (1.70 to 25.20)	TST ≥ 10 mm: Same house/different room vs. different house: DOR 2.40 (1.00 to 5.80) DORa: 2.90 (1.30 to 6.70) Same house/same room vs. different house: DOR 10.10 (3.20 to 32.10); DORa 15.00 (4.70 to 47.20) T-SPOT.TB: Same house/different room vs. different house: DOR 2.40 (1.00 to 5.80); DORa 2.90 (1.30 to 6.70) Same house/same room vs. different house: DOR 10.10 (3.20 to 32.10); DORa 15.00 (4.70 to 42.20)	QFT-GIT vs. TST ≥ 10 mm: Same house/different room: R-DOR 0.58 (0.28 to 0.90); R-DORa 0.52 (0.29 to 0.91) Same house/same room: R-DOR 0.32 (0.14 to 0.69); R-DORa 0.27 (0.12 to 0.59) T-SPOT vs. TST ≥ 10 mm: Same house/different room: R-DOR 0.83 (0.43 to 1.60); R-DORa 0.90 (0.46 to 1.76) Same house/same room: R-DOR 0.52 (0.22 to 1.25); R-DORa 0.44 (0.18 to 1.09)
Cruz 2011,106 USA (low)	Number of test results: T-SPOT.TB 163; TST 163 Test (+/–): T-SPOT.TB 94/69; TST ≥ 15 mm 94/69 Number of indeterminate results: T-SPOT.TB 22; TST 22	T-SPOT.TB: Contact with an identifiable source case vs. no such contact: SN NR; SP NR; PPV NR; NPV NR	TST ≥ 15 mm: Contact with an identifiable source case vs. no such contact: SN NR; SP NR; PPV NR; NPV NR	T-SPOT.TB: Contact with an identifiable source case vs. no such contact: DOR NR; DORa 4.41 (1.78 to 10.94)	TST ≥ 15 mm Contact with an identifiable source case vs. no such contact: DOR NR; DORa 0.48 (0.26 to 0.91)	T-SPOT vs. TST ≥ 15 mm Contact with an identifiable source case: R-DOR NR; R-DORa 9.19 (5.23 to 16.3)
Kasambira 2011,107 South Africa (high)	Number of test results: QFT-GIT 251; TST 254 Test (+/–): QFT-GIT 79/172; TST ≥ 5 mm 71/183 Number of indeterminate results: QFT-GIT 19; TST 16	QFT-GIT: Exposure to index case during the majority of the day (> 7 hours) vs. minority of the day (< 6 hours): SN 29.87 (23.2 to 37.52); SP 71.68 (62.77 to 79.17); PPV 58.97 (47.89 to 69.22); NPV 42.86 (36.01 to 49.99)	TST ≥ 5 mm: Exposure to index case during the majority of the day (> 7 hours) vs. minority of the day (< 6 hours): SN 29.79 (22.86 to 37.79); SP 73.64 (64.71 to 80.97); PPV 59.15 (47.54 to 69.83); NPV 45.00 (37.91 to 52.30)	QFT-GIT: Exposure to index case during the majority of the day (> 7 hours) vs. minority of the day (< 6 hours): DOR 1.10 (0.63 to 1.80); DORa 1.30 (0.69 to 2.30) Adult index case smear grade (vs. negative): scanty: DOR 0.30 (0.05 to 1.60), DORa NR; 1+: DOR 1.50 (0.70 to 3.60), DORa 5.50 (0.89 to 34.70); 2+: DOR 1.50 (0.50 to 4.90), DORa 8.70 (1.20 to 62.00); 3+: DOR 3.20 (1.40 to 7.40), DORa 11.40 (1.80 to 72.00)	TST ≥ 5 mm: Exposure to index case during the majority of the day (> 7 hours) vs. minority of the day (< 6 hours): DOR 1.20 (0.67 to 2.10); DORa 1.10 (0.58 to 2.10) Adult index case smear grade (vs. negative): scanty: DOR NR, DORa NR; 1+: DOR 2.81 (1.20 to 6.70), DORa 7.90 (1.50 to 41.00); 2+: DOR 2.90 (0.80 to 10.60), DORa 15.70 (2.60 to 92.0); 3+: DOR 4.10 (1.50 to 11.10), DORa 11.70 (2.20 to 62.00)	QFT-GIT vs. TST ≥ 5 mm: Exposure to index case during the majority of the day (> 7 hours): R-DOR 0.92 (0.62 to 1.36); R-DORa 1.18 (0.75 to 1.85) Adult index case smear grade (3+): R-DOR 0.78 (0.40 to 1.52); R-DORa 0.97 (0.27 to 3.47)
Laniado-Laborin 2014,148 Mexico (intermediate)	Number of test results: QFT-GIT 172; TST 172 Test (+/–): QFT-GIT 71/101; TST ≥ 5 mm 136/36 Number of indeterminate results: QFT-GIT 1; TST 1	QFT-GIT: Exposure to source, hours per day exposure, number of cohabitants, number of rooms: SN NR; SP NR; PPV NR; NPV NR	TST ≥ 5 mm: Exposure to source, hours per day exposure, number of cohabitants, number of rooms: SN NR; SP NR; PPV NR; NPV NR	QFT-GIT : Exposure to source: DORa 0.91 (0.57 to 1.45) Hours per day exposure: DORa 1.03 (0.96 to 1.10) Number of cohabitants: DORa 0.91 (0.79 to 1.05) Number of rooms: DORa 1.12 (0.77 to 1.61)	TST ≥ 5 mm: Exposure to source: NR (p = NR) Hours per day exposure: NR (p = NR) Number of cohabitants: NR (p = NR) Number of rooms: NR (p = NR)	QFT-GIT vs. TST ≥ 5 mm: R-DORa NR
Mahomed 2011,108 South Africa (high)	Number of test results: QFT-GIT 5244; TST 5244 Test (+/–): QFT-GIT 2669/2562; TST ≥ 5 mm 2894/2350 Number of indeterminate results: QFT-GIT 13; TST 0	QFT-GIT: Current or previous TB household contact vs. no such contact: SN 66.67 (64.09 to 69.15); SP 54.32 (52.75 to 55.88); PPV 33.27 (31.51 to 35.08); NPV 82.67 (81.16 to 84.09)	TST ≥ 5 mm: Current or previous TB household contact vs. no such contact: SN 71.32 (68.83 to 73.69); SP 50.31 (48.74 to 51.87); PPV 32.83 (31.14 to 34.56); NPV 83.74 (82.2 to 85.18)	QFT-GIT: Current or previous TB household contact vs. no such contact: DOR 2.40 (2.11 to 2.74); DORa 1.90 (1.70 to 2.20)	TST ≥ 5 mm: Current or previous TB household contact vs. no such contact: DOR 2.52 (2.20 to 2.88); DORa 2.00 (1.70 to 2.30)	QFT-GIT vs. TST ≥ 5 mm: Current or previous TB household contact: R-DOR 0.94 (0.86 to 1.04); R-DORa 0.95 (0.86 to 1.05)
Pavic 2011,109 Croatia (low)	Number of test results: QFT-GIT 141; TST 142 Test (+/–): QFT-GIT 18/123; TST ≥ 10 mm 24/118 Number of indeterminate results: QFT-GIT 1; TST 0	QFT-GIT: Close contact (household contact with aggregate exposure to a patient with active TB of ≥ 40 hours in closed rooms) vs. distant contact (occasional or unclear exposure time or < 40 hours of exposure during the presumed period of infectiousness): SN 19.54 (12.57 to 29.08); SP 98.15 (90.23 to 99.67); PPV 94.44 (74.24 to 99.01); NPV 43.09 (34.68 to 51.92)	TST ≥ 10 mm: Close contact (household contact with aggregate exposure to a patient with active TB of ≥ 40 hours in closed rooms) vs. distant contact (occasional or unclear exposure time or < 40 hours of exposure during the presumed period of infectiousness): SN 26.44 (18.31 to 36.56); SP 98.18 (90.39 to 99.68); PPV 95.83 (79.76 to 99.26); NPV 45.76 (37.05 to 54.74)	QFT-GIT: Close contact (household contact with aggregate exposure to a patient with active TB of ≥ 40 hours in closed rooms) vs. distant contact (occasional or unclear exposure time or < 40 hours of exposure during the presumed period of infectiousness): DOR 12.87 (1.66 to 99.80); DORa NR	TST ≥ 10 mm: Close contact (household contact with aggregate exposure to a patient with active TB of ≥ 40 hours in closed rooms) vs. distant contact (occasional or unclear exposure time or < 40 hours of exposure during the presumed period of infectiousness): DOR 19.41 (2.53 to 148.40); DORa NR	QFT-GIT vs. TST ≥ 10 mm: Close contact (household contact with aggregate exposure to a patient with active TB of ≥ 40 hours in closed rooms): R-DOR 0.66 (0.15 to 2.89); R-DORa NR
Perez-Porcuna 2014,151 Brazil (intermediate)	Number of test results: QFT-GIT 116; TST 135 Test (+/–): QFT-GIT 36/80; TST ≥ 10 mm 47/88 Number of indeterminate results: QFT-GIT 19; TST 0	QFT-GIT: Time of exposure to the index case (number of months): SN NR; SP NR; PPV NR; NPV NR MTC score 0–15: SN NR; SP NR; PPV NR; NPV NR	TST ≥ 10 mm: Time of exposure to the index case (number of months): SN NR; SP NR; PPV NR; NPV NR MTC score 0–15: SN NR; SP NR; PPV NR; NPV NR	QFT-GIT: Time of exposure to the index case (number of months): DOR NR (p = 0.024); DORa NR (p = 0.537) MTC score 0–15: DOR NR (p = 0.021); DORa 1.16 (1.01 to 1.33; p = 0.035)	TST ≥ 10 mm: Time of exposure to the index case (number of months): DOR NR (p < 0.001); DORa 1.15 (1.04 to 1.27; p = 0.009) MTC score 0–15: DOR NR (p < 0.001); DORa 1.29 (1.08 to 1.54; p = 0.005)	QFT-GIT vs. TST ≥ 10 mm: Time of exposure to the index case (number of months): R-DOR NR; R-DORa NR MTC score 0–15: R-DOR NR; R-DORa 0.90 (0.80 to 1.01)
Rutherford 2012,110,111 Indonesia (high)	Number of test results: QFT-GIT 290; TST 302 Test (+/–): QFT-GIT 152/138; TST ≥ 10 mm 145/157 Number of indeterminate results: QFT-GIT 14; TST 2	QFT-GIT: Characteristics of TB case smear positivity (3+ vs. scanty/1+): SN 62.5 (53.58 to 70.65); SP 59.6 (49.75 to 68.73); PPV 65.22 (56.15 to 73.3); NPV 56.73 (47.14 to 65.85) Relationship to child (parent vs. other): SN 61.19 (54.59 to 67.4); SP 77.27 (63.01 to 87.16); PPV 93.06 (87.69 to 96.18); NPV 28.57 (21.22 to 37.26) Sleeping proximity to child (same bed vs. different room): SN 59.24 (51.42 to 66.61); SP 59.05 (49.48 to 67.97); PPV 68.38 (60.15 to 75.6); NPV 49.21 (40.63 to 57.83) Time spent with child (number of hours per day: > 8 vs. < 2): SN 52.00 (44.06 to 59.85); SP 42.55 (29.51 to 56.72); PPV 74.29 (65.17 to 81.68); NPV 21.74 (14.54 to 31.21)	TST ≥ 10 mm: Characteristics of TB case smear positivity (3+ vs. scanty/1+): SN 61.9 (53.19 to 69.91); SP 68.27 (58.81 to 76.43); PPV 70.27 (61.21 to 77.98); NPV 59.66 (50.68 to 68.04) Relationship to child (parent vs. other): SN 55.9 (49.42 to 62.18); SP 90.71); PPV 94.12 (88.82 to 96.99); NPV 26.81 (20.12 to 34.76) Sleeping proximity to child (same bed vs. different room): SN 51.52 (43.94 to 59.02); SP 56.88 (47.51 to 65.79); PPV 64.39 (55.92 to 72.05); NPV 43.66 (35.78 to 51.88) Time spent with child (number of hours per day: > 8 vs. < 2): SN 47.47 (39.83 to 55.22); SP 41.67 (28.85 to 55.72); PPV 72.82 (63.52 to 80.47); NPV 19.42 (12.94 to 28.1)	QFT-GIT: Characteristics of TB case smear positivity (2+ vs. scanty/1+): DOR 1.56 (0.78 to 3.11); DORa NR Characteristics of TB case smear positivity (3+ vs. scanty/1+): DOR 2.43 (1.21 to 4.86); DORa 2.28 (1.06 to 4.90) Relationship to child (aunt/uncle vs. other): R-DOR 1.51 (0.44 to 5.17); R-DORa NR Relationship to child (parent vs. other): R-DOR 5.61 (2.40 to 13.12); R-DORa 4.30 (1.48 to 12.45) Sleeping proximity to child (same room vs. different room): R-DOR 1.87 (0.70 to 5.02); R-DORa NR Sleeping proximity to child (same bed vs. different room): R-DOR 2.01 (1.12 to 3.61); R-DORa 1.45 (0.70 to 2.99) Time spent with child (number of hours per day: 2–8 vs. < 2): R-DOR 0.78 (0.33 to 1.80); R-DORa NR Time spent with child (number of hours per day: > 8 vs. < 2): R-DOR 0.83 (0.38 to 1.79); R-DORa NR	TST ≥ 10 mm: Characteristics of TB case smear positivity (2+ vs. scanty/1+): DOR 1.80 (0.89 to 3.63); DORa NR Characteristics of TB case smear positivity (3+ vs. scanty/1+): DOR 3.35 (1.81 to 6.21); DORa 2.93 (1.59 to 5.39) Relationship to child (aunt/uncle vs. other): R-DOR 2.31 (0.77 to 6.79); R-DORa NR Relationship to child (parent vs. other): R-DOR 5.85 (2.56 to 13.38); R-DORa 7.04 (2.23 to 22.28) Sleeping proximity to child (same room vs. different room): R-DOR 1.21 (0.41 to 3.53); R-DORa NR Sleeping proximity to child (same bed vs. different room): R-DOR 1.35 (0.79 to 2.32); R-DORa NR Time spent with child (number of hours per day: 2–8 vs. < 2): R-DOR 0.55 (0.24 to 1.24); R-DORa NR Time spent with child (number of hours per day: > 8 vs. < 2): R-DOR 0.64 (0.31 to 1.36); R-DORa NR	QFT-GIT vs. TST ≥ 10 mm: Characteristics of TB case smear positivity (3+): R-DOR 0.73 (0.45 to 1.17); R-DORa 0.78 (0.47 to 1.28) Relationship to child (parent vs. other): R-DOR 0.96 (0.52 to 1.61); R-DORa 0.78 (0.47 to 1.28) Sleeping proximity to child (same bed): R-DOR 1.47 (1.05 to 2.16); R-DORa NR Time spent with child (> 8 hours per day): R-DOR 1.30 (0.75 to 2.24); R-DORa NR
Talbot 2012,112 USA (low)	Number of test results: T-SPOT.TB 143; TST 143 Test (+/–): T-SPOT.TB 5/138; TST ≥ 15 mm 6/137 Number of indeterminate results: T-SPOT.TB 15; TST 22	T-SPOT.TB: Non-low TB exposure risk group vs. low TB exposure risk group: SN NR; SP 100 (97.00 to 100); PPV NR; NPV NR	TST ≥ 15 mm: Non-low TB exposure risk group vs. low TB exposure risk group: SN NR; SP 98.39 (94.31 to 99.56); PPV NR; NPV NR	T-SPOT.TB: Non-low TB exposure risk group vs. low TB exposure risk group: DOR NR; DORa NR	TST ≥ 15 mm: Non-low TB exposure risk group vs. low TB exposure risk group: DOR NR; DORa NR	T-SPOT.TB vs. TST ≥ 15 mm: Non-low TB exposure risk group vs. low TB exposure risk group: R-DOR NR; R-DORa NR
Tieu 2014,154 Thailand (high)	Number of test results: QFT-GIT 136; T-SPOT.TB 136; TST 136 Test (+/–): QFT-GIT 40/96; T-SPOT.TB 36/100; TST ≥ 10 mm 88/48; TST ≥ 15 mm 48/88 Number of indeterminate results: QFT-GIT 0; T-SPOT.TB 0; TST 0	QFT-GIT, T-SPOT.TB: TB contact score: SN NR; SP NR; PPV NR; NPV NR	TST ≥ 10 mm, TST ≥ 15 mm: TB contact score: SN NR; SP NR; PPV NR; NPV NR	QFT-GIT: TB contact score (≥ 13 vs. 8–12): DOR 4.04 (1.81 to 8.99); DORa 1.98 (0.64 to 6.11) T-SPOT.TB: TB contact score (≥ 13 vs. 8–12): DOR 3.50 (1.57 to 7.81); DORa 3.15 (1.35 to 7.34)	TST ≥ 10 mm : TB contact score (≥ 13 vs. 8–12): DOR 2.59 (1.28 to 5.23); DORa 2.21 (0.99 to 4.98) TST ≥ 15 mm: TB contact score (≥ 13 vs. 8–12): DOR 2.19 (1.09 to 4.43); DORa 0.83 (0.35 to 1.99)	QFT-GIT vs. TST ≥ 10 mm: TB contact score (≥ 13 vs. 8–12): R-DOR 1.56 (0.91 to 2.69); R-DORa 0.90 (0.44 to 1.82) QFT-GIT vs. TST ≥ 15 mm: TB contact score (≥ 13 vs. 8–12): R-DOR 1.84 (1.07 to 3.18); R-DORa 2.39 (1.15 to 4.93) T-SPOT.TB vs. TST ≥ 10 mm: TB contact score (≥ 13 vs. 8–12): R-DOR 1.35 (0.78 to 2.33); R-DORa 1.43 (0.78 to 2.59) T-SPOT.TB vs. TST ≥ 15 mm: TB contact score (≥ 13 vs. 8–12): R-DOR 1.60 (0.93 to 2.75); R-DORa 3.80 (2.04 to 7.05)
Tsolia 2010,113 Greece (low)	Number of test results: QFT-GIT 95; TST 99 Test (+/–): QFT-GIT 32/63; TST ≥ 5 mm 55/44 Number of indeterminate results: QFT-GIT 4; TST 0	QFT-GIT: Contact with an adult TB case (non-household regular vs. non-household occasional): SN 33.33 (18.64 to 52.18); SP 90.91 (62.26 to 98.38); PPV 90.00 (59.58 to 98.21); NPV 35.71 (20.71 to 54.17) Contact with an adult TB case (household vs. non-household occasional): SN 38.6 (27.06 to 51.57); SP 90.91 (62.26 to 98.38); PPV 95.65 (79.01 to 99.23); NPV 22.22 (12.54 to 36.27)	TST ≥ 5 mm: Contact with an adult TB case (non-household regular vs. non-household occasional): SN 64.29 (45.83 to 79.29); SP 36.36 (15.17 to 64.62); PPV 72.00 (52.42 to 85.72); NPV 28.57 (11.72 to 54.65) Contact with an adult TB case (household vs. non-household occasional): SN 50.00 (37.73 to 62.27); SP 36.36 (15.17 to 64.62); PPV 81.08 (65.79 to 90.52); NPV 11.76 (4.67 to 26.62)	QFT-GIT: Contact with an adult TB case (non-household regular vs. non-household occasional): DOR 5.00 (0.55 to 45.39); DORa NR Contact with an adult TB case (household vs. non-household occasional): DOR 6.28 (0.75 to 52.56); DORa NR	TST ≥ 5 mm: Contact with an adult TB case (non-household regular vs. non-household occasional): DOR 1.03 (0.24 to 4.39); DORa NR Contact with an adult TB case (household vs. non-household occasional): DOR 0.57 (0.15 to 2.15); DORa NR	QFT-GIT vs. TST ≥ 5 mm: Contact with an adult TB case (non-household regular): R-DOR 4.85 (1.26 to 18.69); R-DORa NR Contact with an adult TB (household regular): R-DOR 11.02 (3.07 to 39.60); R-DORa NR

The updated meta-analysis included 14 studies: six studies156,157,160,162–164 from CG11710 (see Appendix 5) and eight more recent studies105–111,113,154 published from 2009 onwards (see Appendix 9). One study112 did not provide sufficient information to calculate the R-DOR and therefore this study could not be included in the meta-analysis. In a random-effects meta-analysis of the 14 studies,105–111,113,154,156,157,160,162–164 of which two studies106,160 used T-SPOT. TB and the remaining 12 studies used QFT-GIT [or QuantiFERON-Gold (QFT-G)], the pooled R-DOR showed a significantly stronger association for the IGRAs than for the TST in relation to a risk of LTBI/exposure level (pooled R-DOR 1.98, 95% CI 1.19 to 3.28; I² = 89%) (Figure 9).

FIGURE 9.

Pooled R-DOR of IGRA vs. TST based on high- and low-risk exposure in children and adolescents. df, degrees of freedom; IV, inverse variance; SE, standard error.

Heterogeneity was high (I² = 89%) and the sources of heterogeneity were explored through subgroup analyses with regard to burden of TB incidence, IGRA type, TST threshold and study setting. The simultaneous meta-analytical stratification by IGRA type (QFT-GIT/G and T-SPOT. TB) and TST threshold (5 mm, 10–15 mm) (Figures 10–12) as well as study setting (community-based contact and hospital-based studies) (Figures 13 and 14) did not help to explain the presence of heterogeneity (i.e. heterogeneity persisted in these analyses). The study by Adetifa et al. 105 displayed a very aberrant result (see Figure 9; R-DOR 0.27, 95% CI 0.12 to 0.59) indicating a significant superiority of TST (10 mm) over IGRA (QFT-GIT), which could not be readily explained. The report did not provide the raw data needed for the calculation and verification of the correctness of the reported DORs for the IGRA and TST. The authors explained this finding by the delayed presentation of TB cases (mean time 9 weeks) with early reversion of the IGRA and about 30% of TB cases in the Gambia being infected with Mycobacterium africanum (Castets et al. 1969), which has a reduced response to ESAT-6.

FIGURE 10.

Pooled R-DOR of QFT vs. TST 5 mm based on high- and low-risk exposure in children and adolescents. df, degrees of freedom; IV, inverse variance; SE, standard error.

FIGURE 11.

Pooled R-DOR of QFT vs. TST 10–15 mm based on high- and low-risk exposure in children and adolescents. df, degrees of freedom; IV, inverse variance; SE, standard error.

FIGURE 12.

Pooled R-DOR of T-SPOT. TB vs. TST 10–15 mm based on high- and low-risk exposure in children and adolescents. df, degrees of freedom; IV, inverse variance; SE, standard error.

FIGURE 13.

Pooled R-DOR of IGRA vs. TST based on high- and low-risk exposure in children and adolescents: community-based contact studies only. df, degrees of freedom; IV, inverse variance; SE, standard error.

FIGURE 14.

Pooled R-DOR of IGRA vs. TST based on high- and low-risk exposure in children and adolescents: hospital-based studies only. df, degrees of freedom; IV, inverse variance; SE, standard error.

However, the subgroup analysis by country of burden explained some (but not all) of the observed heterogeneity and revealed an interesting trend, showing no difference between IGRAs and the TST in identifying LTBI across studies conducted in countries of high TB burden (pooled R-DOR 1.13, 95% CI 0.78 to 1.65; I² = 71%) (Figure 15).

FIGURE 15.

Pooled R-DOR of IGRA vs. TST based on high- and low-risk exposure in children and adolescents: studies conducted in high-burden countries. df, degrees of freedom; IV, inverse variance; SE, standard error.

In contrast, IGRAs were significantly superior to the TST in identifying LTBI in the settings of low TB burden (pooled R-DOR 4.74, 95% CI 2.15 to 10.44; I² = 67%) (Figure 16).

FIGURE 16.

Pooled R-DOR of IGRA vs. TST based on high- and low-risk exposure in children and adolescents: studies conducted in low-burden countries. df, degrees of freedom; IV, inverse variance; SE, standard error.

In five studies, trends for exposure gradient (across more than two ordinal exposure groups) for IGRAs and the TST were explored with respect to sleeping proximity (same house/same room, same house/different room, different house),105,110,111 adult index case type of TB diagnosis,107 adult index case smear grade (negative, scanty, 1+, 2+, 3+),107,110,111 duration of exposure to index case (time spent with child),107,110,111,154 relationship to index case (parent, aunt/uncle, other),110,111,154 TB contact score (score-based categories)154 and type of contact (household, non-household regular, occasional). 113 In general, for both IGRAs and the TST there was an increasing trend in DOR across the exposure groups. In two studies this trend was absent for both tests in relation to duration of exposure to the index case110,111 and for the TST in relation to type of contact. 113 See Appendix 9 for full extraction sheets.

Sensitivity and specificity

In this analysis, six105,106,112,148,151,154 of the included 11 recent studies105–113,148,151,154 failed to provide sufficient information for calculating both sensitivity and specificity. There was wide variability in the sensitivity and specificity of the IGRAs (QFT-GIT/G) and TST (5 mm or 10 mm), with overlapping values across the five remaining studies107–111,113 (Figures 17–24).

FIGURE 17.

Forest plot of sensitivity based on exposure groups (QFT-GIT) in children and adolescents. df, degrees of freedom.

FIGURE 18.

Forest plot of sensitivity based on exposure groups (TST) in children and adolescents. df, degrees of freedom.

FIGURE 19.

Forest plot of sensitivity based on exposure groups (TST 5 mm) in children and adolescents. df, degrees of freedom.

FIGURE 20.

Forest plot of sensitivity based on exposure groups (TST 10 mm) in children and adolescents. df, degrees of freedom.

FIGURE 21.

Forest plot of specificity based on exposure groups (QFT-GIT) in children and adolescents. df, degrees of freedom.

FIGURE 22.

Forest plot of specificity based on exposure groups (TST) in children and adolescents. df, degrees of freedom.

FIGURE 23.

Forest plot of specificity based on exposure groups (TST 5 mm) in children and adolescents. df, degrees of freedom.

FIGURE 24.

Forest plot of specificity based on exposure groups (TST 10 mm) in children and adolescents. df, degrees of freedom.

Both the QFT-GIT/G and TST (5 mm or 10 mm) demonstrated better specificity (range 36–98%) than sensitivity (range 20–71%). There was no clear numerical pattern indicating the superiority of the IGRA over the TST (or vice versa) with respect to sensitivity and specificity. Forest plots of sensitivities and specificities showed a great extent of heterogeneity that was not explained by IGRA type and/or TST threshold and therefore a meta-analysis was not performed.

Influence of bacillus Calmette–Guérin vaccination status on test positivity

In this analysis, four109,112,148,154 of the included 11 recent studies105–113,148,151,154 did not report any information needed to determine whether or not BCG vaccination status influenced the odds of test positivity differentially for the IGRAs and TST. Of the seven remaining studies reporting this evidence, only three106,108,113 demonstrated significantly increased ORs for TST positivity in relation to BCG vaccination status (range of ORs 1.16–20.34). The odds of test positivity for IGRAs across the seven studies were not significantly different between the BCG-vaccinated group and the non-vaccinated group (Table 8). One study with a relatively large sample size and narrow CIs demonstrated more conclusively that BCG vaccination status was associated with an increased odds of test positivity for TST (OR 1.16, 95% CI 1.0 to 1.33) but not for IGRA (OR 0.99, 95% CI 0.86 to 1.12). 108

TABLE 8 - Association between test positivity and BCG vaccination status in children and adolescents: exposure studies

ID, identification; NR, not reported.

Study ID, country (burden)	Sample size, n	Type of IGRA/TST induration threshold	Association between test positivity and BCG vaccination status: OR (95% CI)
			Crude/unadjusted	Adjusted
Adetifa 2010,105 Gambia (low)	199	QFT-GIT	1.10 (0.60 to 2.00)	NR
	199	T-SPOT.TB	1.10 (0.61 to 2.09)	NR
	199	TST 10 mm	0.89 (0.50 to 1.70)	NR
Cruz 2011,106 USA (low)	NR	T-SPOT.TB	0.69 (0.37 to 1.31)	NR
	NR	TST 15 mm	4.32 (1.02 to 18.35)	NR
Kasambira 2011,107 South Africa (high)	262	QFT-GIT	0.62 (0.08 to 4.76)	0.83 (0.08 to 8.33)
	247	TST 5 mm	0.38 (0.05 to 2.85)	0.52 (0.06 to 4.00)
Laniado-Laborın 2014,148 Mexico (intermediate)	172	QFT-GIT	NR	NR
	172	TST 5 mm	NR	NR
Mahomed 2011,108 South Africa (high)	3554	QFT-GIT	0.99 (0.86 to 1.12)	NR
	3554	TST 5 mm	1.16 (1.00 to 1.33)	NR
Pavic 2011,109 Croatia (low)	NR	QFT-GIT	NR	NR
	NR	TST 10 mm	NR	NR
Perez-Porcuna 2014,151 Brazil (intermediate)	116	QFT-GIT	3.89 (0.46 to 32.33)	NR
	135	TST 10 mm	1.85 (0.36 to 9.36)	NR
Rutherford 2012,110,111 Indonesia (high)	260	QFT-GIT	0.51 (0.26 to 1.00)	0.60 (0.26 to 1.38)
	272	TST 10 mm	0.68 (0.35 to 1.35)	NR
Talbot 2012,112 USA (low)	NR	T-SPOT.TB	NR	NR
	NR	TST 15 mm	NR	NR
Tieu 2014,154 Thailand (high)	136	QFT-GIT	NR	NR
	136	TST 10 mm	NR	NR
	136	T-SPOT.TB	NR	NR
	136	TST 15 mm	NR	NR
Tsolia 2010,113 Greece (low)	NR	QFT-GIT	0.19 (0.06 to 0.60)	NR
	NR	TST 5 mm	20.34 (5.60 to 73.89)	NR

Between-test concordance, discordance and agreement

This section included five studies156–159,164 reviewed in CG11710 (see Appendix 5) and 16 more recent studies102–113,148,150–152,154 (see Appendix 9). The agreement kappa statistic was not available for four studies. 102,104,106,150 There was a wide variation in the kappa statistic across the remaining studies, ranging from 0.13113 to 0.91113 (Table 9). In the post-2009 studies,103,105,107–113,148,151,152,154 the ranges of the kappa statistic according to specific TST threshold and IGRA type were as follows: QFT-GIT compared with TST 5 mm – range 0.27–0.91; QFT-GIT compared with TST 10 mm – range 0.13–0.64; and T-SPOT. TB compared with TST 10 mm – range 0.53–0.71. According to one study, both between-test per cent concordance and the kappa statistic were lower among participants with a BCG vaccination history (concordance 46.5%, kappa 0.16) than among those without such history (concordance 96.20%, kappa 0.91). 113

TABLE 9 - Between-test concordance and discordance in children and adolescents: exposure and incidence studies

ID, identification; NR, not reported.

For four people BCG status was unknown.

Study ID, country (burden)	Sample size, total or by subgroup, n	Type of IGRA vs. TST induration threshold	Concordance (95% CI) (%)	Discordance (95% CI) (%)	Agreement kappa (95% CI)
Adetifa 2010,105 Gambia (low)	217	QFT-GIT vs. TST 10 mm	80.00 (74.15 to 84.80)	20.00 (15.2 to 25.85)	0.52 (0.39 to 0.65)
	215	T-SPOT.TB vs. TST 10 mm	80.47 (74.65 to 85.21)	19.53 (14.79 to 25.35)	0.53 (0.40 to 0.66)
Cruz 2011,106 USA (low)	NR	T-SPOT.TB vs. TST 15 mm	NR	NR	NR
Diel 2011,102 Germany (low)	NR	QFT-GIT vs. TST 5/10 mm	NR	NR	NR
Kasambira 2011,107 South Africa (high)	254	QFT-GIT vs. TST 5 mm	86.86 (81.96 to 90.59)	13.14 (9.41 to 18.04)	0.68 (0.56 to 0.81)
	254	QFT-GIT vs. TST 10 mm	85.59 (80.54 to 89.5)	14.41 (10.5 to 19.46)	0.64 (0.51 to 0.76)
Laniado-Laborın 2014,148 Mexico (intermediate)	172	QFT-GIT vs. TST 5 mm	59.88 (52.42 to 66.92)	40.12 (33.08 to 47.58)	0.27 (0.17 to 0.38)
Mahomed 2011,108 South Africa (high)	NR	QFT-GIT vs. TST 5 mm	84.8 (NR)	NR	0.70 (0.68 to 0.71)
	NR	QFT-GIT vs. TST 10 mm	81.4 (NR)	NR	0.63 (0.61 to 0.65)
	NR	QFT-GIT vs. TST 15 mm	64.3 (NR)	NR	0.30 (0.27 to 0.32)
Mahomed 2011,103 South Africa (high)	5244	QFT-GIT vs. TST 5 mm	84.80 (83.80 to 85.75)	15.20 (14.25 to 16.20)	0.69 (0.66 to 0.72)
Metin Timur 2014,150 Turkey (intermediate)	81	QFT-GIT vs. TST 15 mm	NR	NR	NR
Noorbakhsh 2011,104 Iran (intermediate)	NR	QFT-GIT vs. TST 10 mm	NR	NR	NR
Pavic 2011,109 Croatia (low)	141	QFT-GIT vs. TST 10 mm	89.36 (83.19 to 93.45)	10.64 (6.554 to 16.81)	0.59 (0.42 to 0.75)
Perez-Porcuna 2014,151 Brazil (intermediate)	116	QFT-GIT vs. TST 10 mm	71.55 (62.75 to 78.97)	28.44 (21.03 to 37.25)	0.35 (0.16 to 0.53)
Rutherford 2012,110,111 Indonesia (high)	292	QFT-GIT vs. TST 10 mm	80.48 (75.55 to 84.62)	19.52 (15.38 to 24.45)	0.61 (0.49 to 0.72)
Song 2014,152 South Korea (high)	2982	QFT-GIT vs. TST 10 mm	82.6 (81.2 to 83.92)	17.4 (16.08 to 18.80)	0.38 (0.34 to 0.42)
	2982	QFT-GIT vs. TST 15 mm	92.52 (91.51 to 93.41)	7.48 (6.59 to 8.48)	0.55 (0.50 to 0.61)
Talbot 2012,112 USA (low)	143	T-SPOT.TB vs. TST 15 mm	97.9 (94.01 to 99.28)	2.01 (0.72 to 5.99)	0.71 (0.55 to 0.88)
Tieu 2014,154 Thailand (high)	131	QFT-GIT vs. TST 10 mm	59.54 (50.98 to 67.56)	40.46 (32.44 to 49.02)	0.29 (0.18 to 0.40)
	131	QFT-GIT vs. TST 15 mm	79.39 (71.67 to 85.43)	20.61 (14.57 to 28.33)	0.53 (0.38 to 0.69)
	131	T-SPOT.TB vs. TST 10 mm	55.73 (47.18 to 63.95)	44.27 (36.05 to 52.82)	0.23 (0.12 to 0.34)
	131	T-SPOT.TB vs. TST 15 mm	78.63 (70.84 to 84.78)	21.37 (15.22 to 29.16)	0.51 (0.35 to 0.66)
Tsolia 2010,113 Greece (low)	99	QFT-GIT vs. TST NR	71.58 (61.81 to 79.67)	28.42 (20.33 to 38.19)	0.45 (0.27 to 0.63)
	43 with BCG historya	QFT-GIT vs. TST 10 mm	46.50 (NR)	NR	0.13 (p = 0.06)
	52 no BCG historya	QFT-GIT vs. TST 5 mm	96.20 (NR)	NR	0.91 (p = 0.06)

Immunocompromised people

Comparative performance of tests (diagnostic accuracy indices for identifying latent tuberculosis infection)

Incidence of active tuberculosis

Ratios of cumulative incidence ratios

This section included eight newly identified studies (Table 14). 114–119,149,155 Of these, R-CIRs were not available for four studies114,116,117,119 because of missing incidence data for one or both compared tests. Of the remaining four studies, R-CIRs in three studies comparing IGRAs (QFT-G/GIT or T-SPOT. TB) with the TST in haematopoietic stem cell transplant candidates115 and haemodialysis ESRD patients118,155 were not statistically significant, rendering these results inconclusive (wide 95% CIs). Only one study,149 which was conducted in haematopoietic stem cell transplant recipients, showed that QFT-GIT performed significantly better than the TST (at ≥ 5 mm or ≥ 10 mm) in identifying people with LTBI (TST at ≥ 5 mm: R-CIR 9.71, 95% CI 1.71 to 55.15; TST at ≥ 10 mm: R-CIR 5.85, 95% CI 1.05 to 32.70). A meta-analysis of R-CIRs could not be performed because of differences in the study populations and tests used.

TABLE 14 - Comparison of test performance in immunocompromised patients: diagnostic accuracy indices for identifying LTBI – incidence studies

CI (–), cumulative incidence in those who tested negative; CI (+), cumulative incidence in those who tested positive; ID, identification; IDR, incidence density rate; NR, not reported; SN, sensitivity; SP, specificity.

Study ID, country (burden)	Test results	Test diagnostic accuracy (95% CI) (%)		Development of active TB
				Cumulative incidence (%), CIR, IDR, IDRR (95% CI)		R-CIR, R-IDRR (95% CI), IGRA vs. TST (by threshold)
		IGRA: QFT-GIT/G and/or T-SPOT.TB	TST (by threshold)	IGRA: QFT-GIT/G and/or T-SPOT.TB	TST (by threshold)
Anibarro 2012,117 Spain (low)	Number of test results: QFT-GIT 52; TST 52 Test (+/–): QFT-GIT 18/34; TST ≥ 5 mm 11/41 Number of indeterminate results: QFT-GIT 0; TST 0 Number lost to follow-up: 4	QFT-GIT: SN NR; SP NR; PPV NR; NPV 100 (89.28 to 100)	TST ≥ 5 mm: SN NR; SP NR; PPV NR; NPV 100 (89.28 to 100)	QFT-GIT: CI (+) NR; CI (–) 0/32 (0.00); CIR NR; IDR (+) NR; IDR (–) NR; IDRR NR	TST ≥ 5 mm: CI (+) NR; CI (–) 0/32 (0.00); CIR NR; IDR (+) NR; IDR (–) NR; IDRR NR	R-CIR (QFT-GIT vs. TST ≥ 5 mm) NR; R-IDRR (QFT-GIT vs. TST ≥ 5 mm) NR
Chang 2011,119 South Korea (high)	Number of test results: QFT-GIT 100; TST 107 Test (+/–): QFT-GIT 36/64; TST ≥ 10 mm 36/71 Number of indeterminate results: QFT-GIT 7; TST 0 Number lost to follow-up: 0	QFT-GIT: SN NR; SP 100 (94.8 to 100); PPV NR; NPV 100 (94.8 to 100)	TST ≥ 10 mm: SN NR; SP 77.14 (66.05 to 85.41); PPV 0/16 (CI 0.0); NPV 100 (93.4 to 100)	QFT-GIT: CI (+) NR; CI (–) 0/64 (0.00); CIR NR; IDR (+) NR; IDR (–) NR; IDRR NR	TST ≥ 10 mm: CI (+) 0/16 (0.00); CI (–) 0/54 (0.00); CIR NR; IDR (+) NR; IDR (–) NR; IDRR NR	R-CIR (QFT-GIT vs. TST ≥ 10 mm) NR; R-IDRR (QFT-GIT vs. TST ≥ 10 mm) NR
Elzi 2011,114 Switzerland (low)	Number of test results: T-SPOT.TB 43; TST 44 Test (+/–): T-SPOT.TB 25/18; TST ≥ 5 mm 22/22 Number of indeterminate results: T-SPOT.TB 21; TST 0 Number lost to follow-up: NR	T-SPOT.TB: SN 58.14 (43.33 to 71.62); SP NR; PPV NR; NPV NR T-SPOT.TB and TST ≥ 5 mm: SN 65.91 (51.14 to 78.12); SP NR; PPV NR; NPV NR	TST ≥ 5 mm: SN 50.00 (35.83 to 64.17); SP NR; PPV NR; NPV NR	T-SPOT.TB: CI (+) NR; CI (–) NR; CIR NR; IDR (+) NR; IDR (–) NR; IDRR NR T-SPOT.TB and TST ≥ 5 mm: CI (+) NR; CI (–) NR; CIR NR; IDR (+) NR; IDR (–) NR; IDRR NR	TST ≥ 5 mm: CI (+) NR; CI (–) NR; CIR NR; IDR (+) NR; IDR (–) NR; IDRR NR	R-CIR (T-SPOT.TB vs. TST ≥ 5 mm) NR; R-IDRR (T-SPOT.TB vs. TST ≥ 5 mm) NR; R-CIR (T-SPOT.TB and TST ≥ 5 mm vs. TST ≥ 5 mm) NR; R-IDRR (T-SPOT.TB and TST ≥ 5 mm vs. TST ≥ 5 mm) NR
Kim 2011,116 South Korea (high)	Number of test results: T-SPOT.TB 242; TST 272 Test (+/–): T-SPOT.TB 71/171; TST ≥ 10 mm 0/272 Number of indeterminate results: T-SPOT.TB 30; TST 0 Number lost to follow-up: 2	T-SPOT.TB: SN 100 (51.01 to 100.00); SP 71.84 (65.82 to 77.18); PPV 5.63 (2.21 to 13.61); NPV 100 (97.80 to 100)	TST ≥ 10 mm: SN NR; SP NR; PPV NR; NPV 98.53 (96.28 to 99.43)	T-SPOT.TB: CI (+) 5.63 (2.21 to 13.61); CI (–) 0/171 (0.0); CIR NR; IDR (+) 3.28 per 100 person-years (0.89 to 8.39 per 100 person-years); IDR (–) 0.00 per 100 person-years (NR); IDR difference: 3.3 per 100 person-years (1.3 to 5.3 per 100 person-years)	TST ≥ 10 mm: CI (+) NR; CI (–) 1.47 (0.43 to 3.85); CIR NR; IDR (+) NR; IDR (–) 0.83 per 100 person-years (0.23 to 2.12 per 100 person-years); IDRR NR	R-CIR (T-SPOT.TB vs. TST ≥ 10 mm) NR; R-IDRR (T-SPOT.TB vs. TST ≥ 10 mm) NR
Lee 2009,118 Taiwan (high)	Number of test results: QFT-G 30; T-SPOT.TB 32; TST 32 Test (+/–): QFT-G 12/18; T-SPOT.TB 15/17; TST ≥ 10 mm 20/12 Number of indeterminate results: QFT-G 2; T-SPOT.TB 0; TST 0 Number lost to follow-up: 0	QFT-G: SN 100 (20.65 to 100); SP 60.00 (44.00 to 77.31); PPV 8.33 (1.49 to 35.39); NPV 100 (82.41 to 100) T-SPOT.TB: SN 0.00 (0.00 to 65.76); SP 50.00 (33.15 to 66.85); PPV 0.00 (0.00 to 20.39); NPV 88.24 (65.66 to 96.71)	TST ≥ 10 mm (two step): SN 50.00 (9.45 to 90.55); SP 36.67 (21.87 to 54.49); PPV 5.00 (0.89 to 23.61); NPV 100 (74.12 to 100)	QFT-G: CI (+) 8.33 (1.49 to 35.39); CI (–) 5.56 (5.40 to 27.29); CIR 1.55 (0.02 to 124.2); IDR (+) 3.40 per 100 person-years (NR); IDR (–) NR; IDRR NR T-SPOT.TB: CI (+) 6.67 (0.17 to 31.9); CI (–) 11.76 (2.03 to 35.59); CIR 0.57 (0.01 to 12.1); IDR (+) NR; IDR (–) NR; IDRR NR	TST ≥ 10 mm (two step): CI (+) 5.00 (0.89 to 23.61); CI (–) 9.09 (0.23 to 41.3); CIR 0.55 (0.01 to 47.06); IDR (+) NR; IDR (–) NR; IDRR NR	R-CIR [QFT-G vs. TST ≥ 10 mm (two step)] 2.82 (0.13 to 62.64); R-IDRR [QFT-G vs. TST ≥ 10 mm (two step)] NR; R-CIR [T-SPOT.TB vs. TST ≥ 10 mm (two step)] 1.04 (0.06 to 17.34); R-IDRR [T-SPOT.TB vs. TST ≥ 10 mm (two step)] NR
Lee 2014,149 South Korea (high)	Number of test results: QFT-GIT 159; TST 169 Test (+/–): QFT-GIT 26/133; TST ≥ 5 mm 19/150 TST ≥ 10 mm (12/157) Number of indeterminate results: QFT-GIT 10; TST 0 Number lost to follow-up: 0	QFT-GIT: SN 60.00 (23.07 to 88.24); SP 85.06 (78.59 to 89.84); PPV 11.54 (4.00 to 28.98); NPV 98.5 (94.68 to 99.59)	TST ≥ 5 mm: SN 0.0 (0.0 to 43.45); SP 88.41 (82.61 to 92.46); PPV 0.0 (0.0 to 16.82); NPV 96.67 (92.43 to 98.57) TST ≥ 10 mm: SN 0.0 (0.0 to 43.45); SP 92.68 (87.65 to 95.77); PPV 0.0 (0.0 to 24.25); NPV 96.82 (92.76 to 98.63)	QFT-GIT: CI (+) 11.54 (3.17 to 29.80); CI (–) 1.50 (0.07 to 5.66); CIR 7.67 (1.34 to 43.67); IDR (+) 5.43 per 100 person-years (1.12 to 15.88 per 100 person-years); IDR (–) 0.80 per 100 person-years (0.10 to 2.88 per 100 person-years); IDRR 6.78 per 100 person-years (NR)	TST ≥ 5 mm: CI (+) 2.63 (0.0 to 23.22); CI (–) 3.33 (1.22 to 7.77); CIR 0.79 (0.04 to 13.89); IDR (+) 0 per 100 person-years (0.00 to 8.41 per 100 person-years); IDR (–) 1.79 per 100 person-years (0.58 to 4.18 per 100 person-years); IDRR 0 per 100 person-years (NR) TST ≥ 10 mm: CI (+) 4.16 (0.0 to 33.00); CI (–) 3.18 (1.16 to 7.43); CIR 1.31 (0.07 to 22.55); IDR (+) 0.0 per 100 person-years (0.0 to 14.93 per 100 person-years); IDR (–) NR; IDRR NR	R-CIR (QFT-GIT vs. TST ≥ 5 mm) 9.71 (1.71 to 55.15); R-IDRR (QFT-GIT vs. TST ≥ 5 mm) NR; R-CIR (QFT-GIT vs. TST ≥ 10 mm) 5.85 (1.05 to 32.70); R-IDRR (QFT-GIT vs. TST ≥ 10 mm) NR
Moon 2013,115 South Korea (high)	Number of test results: QFT-GIT 210; TST 244 Test (+/–): QFT-GIT 40/170; TST ≥ 5 mm 39/205 Number of indeterminate results: QFT-GIT 34; TST 0 Number lost to follow-up: 2	QFT-GIT: SN 50.00 (9.45 to 90.55); SP 81.25 (75.4 to 85.97); PPV 2.50 (0.44 to 12.88); NPV 99.41 (96.74 to 99.9)	TST ≥ 5 mm: SN 0.00 (0.00 to 65.76); SP 83.88 (78.73 to 87.98); PPV 0.00 (0.00 to 8.96); NPV 99.02 (96.51 to 99.73)	QFT-GIT: CI (+) 2.50 (0.44 to 12.88); CI (–) 0.58 (0.00 to 3.59); CIR 4.25 (0.27 to 66.49); IDR (+) 2.80 per 100 person-years (0.07 to 15.81 per 100 person-years); IDR (–) NR; IDRR NR	TST ≥ 5 mm: CI (+) 2.56 (0.06 to 13.5); CI (–) 0.97 (0.03 to 3.71); CIR 2.63 (0.04 to 51.4); IDR (+) 0 per 100 person-years (0.00 to 8.00 per 100 person-years); IDR (–) NR; IDRR NR	R-CIR (QFT-GIT vs. TST ≥ 5 mm) 1.62 (0.16 to 16.18); R-IDRR (QFT-GIT vs. TST ≥ 5 mm) 1.62 (0.16 to 16.18)
Sherkat 2014,155 Iran (intermediate)	Number of test results: T-SPOT.TB 44; TST 44 Test (+/–): T-SPOT.TB 6/38; TST ≥ 10 mm 8/36 Number of indeterminate results: T-SPOT.TB NR; TST NR Number lost to follow-up: 1	T-SPOT.TB: SN 100 (20.65 to 100); SP 88.37 (75.52 to 94.93); PPV 16.67 (3.00 to 56.35); NPV 100 (90.82 to 100)	TST ≥ 10 mm: SN 100 (20.65 to 100); SP 83.72 (70.03 to 91.88); PPV 12.5 (2.24 to 47.09); NPV 100 (90.36 to 100)	T-SPOT.TB: CI (+) 16.67 (3.00 to 56.35); CI (–) 1.31 (0.00 to 12.86); CIR 12.67 (0.47 to 337.8)	TST ≥ 10 mm: CI (+) 12.5 (0.11 to 47.09); CI (–) 1.39 (0.00 to 13.49); CIR 9.00 (0.33 to 245.7)	R-CIR (T-SPOT.TB vs. TST ≥ 10 mm) 1.41 (0.13 to 15.20)

Sensitivity and specificity

This section included eight newly identified studies. 114–119,149,155 The study by Anibarro et al. 117 did not report test performance parameters of sensitivity and specificity. Across the remaining seven studies there was wide variability and the absence of a clear pattern in the estimates of sensitivity (IGRA/TST range 0–100%) (Figures 25 and 26) and specificity (IGRAs range 50–88%; TST range 37–93%) (Figures 27 and 28). Some or all of this variation was the result of zero count events (unstable estimates) and underlying differences in study populations/conditions and TST thresholds. No meta-analysis was performed given the observed heterogeneity.

FIGURE 25.

Forest plot of sensitivity based on incidence of active TB (IGRA) in immunocompromised patients. df, degrees of freedom; KT, kidney transplant.

FIGURE 26.

Forest plot of sensitivity based on incidence of active TB (TST) in immunocompromised patients. df, degrees of freedom; KT, kidney transplant.

FIGURE 27.

Forest plot of specificity based on incidence of active TB (IGRA) in immunocompromised patients. df, degrees of freedom; KT, kidney transplant.

FIGURE 28.

Forest plot of specificity based on incidence of active TB (TST) in immunocompromised patients. AS, ankylosing spondylitis; df, degrees of freedom; KT, kidney transplant; RA, rheumatoid arthritis.

Exposure levels

Ratios of diagnostic odds ratios

This section included 26 studies: two studies174,180 from CG11710 and 24 more recent studies120–142,153 (Table 15). The association between the screening test results and the risk of LTBI/exposure measured using the R-DOR (IGRA vs. TST) in individual studies ranged from 0.07131 to 8.45. 140 R-DORs for three studies120,132,135 could not be estimated because of missing data.

TABLE 15 - Comparison of test performance in immunocompromised patients: diagnostic accuracy indices for identifying LTBI – exposure studies

–ve, negative; +ve, positive; CRF, compound risk factor; DORa, adjusted diagnostic odds ratio; ID, identification; NR, not reported; R-DORa, adjusted ratio of diagnostic odds ratios; SN, sensitivity; SP, specificity.

Study ID, country (burden)	Test results	Test diagnostic accuracy (95% CI) (%)		Construct validity (i.e. LTBI exposure-based proxy)
				DOR (95% CI) (vs. non-exposed; reference group)		R-DOR (95% CI), IGRA vs. TST (by threshold)
		IGRA: QFT-GIT/G and/or T-SPOT.TB	TST (by threshold)	IGRA: QFT-GIT/G and/or T-SPOT.TB	TST (by threshold)
Ahmadinejad 2013,120 Iran (intermediate)	Number of test results: QFT-GIT 159; TST 164 Test (+/–): QFT-GIT 33/126; TST ≥ 10 mm 26/138 Number of indeterminate results: QFT-GIT 5; TST 0	QFT-GIT: Exposure history to active TB vs. no such history: SN 0.00; SP 78.57 (71.44 to 84.32); PPV 0.00; NPV 96.03 (91.05 to 98.29)	TST ≥ 10 mm: Exposure history to active TB vs. no such history: SN 0.00; SP: 83.65 (77.12 to 88.59); PPV 0.00; NPV 96.38 (91.8 to 98.44)	QFT-GIT: Exposure history to active TB vs. no such history: DOR 0.00; DORa NR	TST ≥ 10 mm: Exposure history to active TB vs. no such history: DOR 0.00; DORa NR	QFT-GIT vs. TST ≥ 10 mm: Exposure history to active TB vs. no such history: R-DOR NR; R-DORa NR
Al Jahdali 2013,121 Saudi Arabia (low)	Number of test results: QFT-GIT 200; TST 200 Test (+/–): QFT-GIT 65/135; TST ≥ 10 mm 26/174 Number of indeterminate results: QFT-GIT NR; TST NR	QFT-GIT: High likelihood of LTBI vs. no high likelihood of LTBI: SN 33.12 (26.00 to 41.00); SP 69.57 (55.19 to 80.92); PPV 78.46 (67.03 to 86.71); NPV 23.70 (17.32 to 31.54)	TST ≥ 10 mm (two step): High likelihood of LTBI vs. no high likelihood of LTBI: SN 12.34 (8.04 to 18.47); SP 84.78 (71.78 to 92.43); PPV 73.08 (53.92 to 86.3); NPV 22.41 (16.85 to 29.17)	QFT-GIT: High likelihood of LTBI vs. no high likelihood of LTBI: DOR 1.13 (0.55 to 2.31); DORa NR	TST ≥ 10 mm (two step): High likelihood of LTBI vs. no high likelihood of LTBI: DOR 0.78 (0.31 to 2.00); DORa NR	QFT-GIT vs. TST ≥ 10 mm (two step): High likelihood of LTBI vs. no high likelihood of LTBI: R-DOR 1.45 (0.79 to 2.64); R-DORa NR
Ates 2009,122 Turkey (intermediate)	Number of test results: QFT-GIT 246; TST 259 Test (+/–): QFT-GIT 115/131; TST ≥ 10 mm 92/167 Number of indeterminate results: QFT-GIT 29; TST 16	QFT-GIT: TB exposure vs. no TB exposure: SN 58.82 (36.01 to 78.39); SP 54.15 (47.68 to 60.48); PPV 8.69 (4.79 to 15.27); NPV 94.66 (89.38 to 97.39)	TST ≥ 10 mm: TB exposure vs. no TB exposure: SN 29.41 (13.28 to 53.13); SP 64.05 (57.83 to 69.83); PPV 5.43 (2.34 to 12.10); NPV 92.81 (87.86 to 95.84)	QFT-GIT: TB exposure vs. no TB exposure: DOR 1.68 (0.62 to 4.58); DORa 1.30 (0.43 to 3.91)	TST ≥ 10 mm: TB exposure vs. no TB exposure: DOR 0.74 (0.25 to 2.17); DORa 0.49 (0.17 to 1.45)	QFT-GIT vs. TST ≥ 10 mm: TB exposure vs. no TB exposure: R-DOR 2.27 (1.07 to 4.81); R-DORa 2.65 (1.21 to 5.82)
Casas 2011,123 Spain (low)	Number of test results: QFT-GIT 214; TST 214 Test (+/–): QFT-GIT 45/157; TST ≥ 5 mm 52/162 Number of indeterminate results: QFT-GIT 12; TST 0	QFT-GIT: Risk factors for TB infection vs. no risk factors for TB infection: SN NR; SP NR; PPV NR; NPV NR	TST ≥ 5 mm: Risk factors for TB infection vs. no risk factors for TB infection: SN: NR; SP NR; PPV NR; NPV NR	QFT-GIT: Risk factors for TB infection vs. no risk factors for TB infection: DOR 2.50 (1.20 to 5.10); DORa 2.90 (1.30 to 6.30)	TST ≥ 5 mm: Risk factors for TB infection vs. no risk factors for TB infection: DOR 2.80 (1.40 to 5.50); DORa 2.90 (1.40 to 6.00)	QFT-GIT vs. TST ≥ 5 mm: Risk factors for TB infection vs. no risk factors for TB infection: R-OR 0.89 (0.54 to 1.48); R-ORa 1.00 (0.58 to 1.73)
Casas 2011,124 Spain (low)	Number of test results: QFT-GIT 95; TST 95 Test (+/–): QFT-GIT 42/51; TST ≥ 5 mm 44/51 Number of indeterminate results: QFT-GIT 2; TST 0	QFT-GIT: Risk factors for TB infection vs. no risk factors for TB infection: SN 45.00 (33.09 to 57.51); SP 57.14 (40.86 to 72.02); PPV 64.29 (49.17 to 77.01); NPV 37.74 (25.94 to 51.19)	TST ≥ 5 mm (two step): Risk factors for TB infection vs. no risk factors for TB infection: SN 50.00 (37.73 to 62.27); SP 60.00 (43.57 to 74.45); PPV 68.18 (53.44 to 80.00); NPV 41.18 (28.75 to 54.83)	QFT-GIT: Risk factors for TB infection vs. no risk factors for TB infection: DOR 1.66 (0.66 to 3.33); DORa 1.50 (0.50 to 4.10)	TST ≥ 5 mm (two step): Risk factors for TB infection vs. no risk factors for TB infection: DOR 1.25 (0.50 to 2.50); DORa 1.80 (0.60 to 5.10)	QFT-GIT vs. TST ≥ 5 mm (two step): Risk factors for TB infection vs. no risk factors for TB infection: R-DOR 1.33 (0.74 to 2.38); R-DORa 0.83 (0.39 to 1.79)
Chkhartishvili 2013,125 Georgia (high)	Number of test results: QFT-GIT 237; T-SPOT.TB 218; TST 236 Test (+/–): QFT-GIT 70/167; T-SPOT.TB 56/162; TST ≥ 5 mm 41/195 Number of indeterminate results: QFT-GIT 3; T-SPOT.TB 22; TST 4	QFT-GIT: Household member treated for TB vs. no household member treated for TB: SN NR; SP NR; PPV NR; NPV NR T-SPOT.TB: Household member treated for TB vs. no household member treated for TB: SN NR; SP NR; PPV NR; NPV NR	TST ≥ 5 mm: Household member treated for TB vs. no household member treated for TB: SN NR; SP NR; PPV NR; NPV NR	QFT-GIT: Household member treated for TB vs. no household member treated for TB DOR 0.43 (0.09 to 1.97); DORa NR T-SPOT.TB: Household member treated for TB vs. no household member treated for TB: DOR 1.48 (0.44 to 5.00); DORa NR	TST ≥ 5 mm: Household member treated for TB vs. no household member treated for TB: DOR 1.48 (0.39 to 5.62); DORa NR	QFT-GIT vs. TST ≥ 5 mm: Household member treated for TB vs. no household member treated for TB: R-DOR 0.29 (0.10 to 0.82); R-DORa NR T-SPOT.TB vs. TST ≥ 5 mm Household member treated for TB vs. no household member treated for TB: R-DOR 1.00 (0.40 to 2.51); R-DORa NR
Chung 2010,126 South Korea (high)	Number of test results: QFT-G 146; T-SPOT.TB 146; TST 146 Test (+/–): QFT-G 56/90; T-SPOT.TB 83/63; TST ≥ 10 mm 32/114 Number of indeterminate results: QFT-G NR; T-SPOT.TB NR; TST NR	QFT-GIT: High risk for LTBI vs. low risk for LTBI: SN 52.94 (30.96 to 73.84); SP 63.57 (54.98 to 71.37); PPV 16.07 (8.69 to 27.81); NPV 91.11 (83.43 to 95.43) T-SPOT.TB: High risk for LTBI vs. low risk for LTBI: SN 47.06 (26.16 to 69.04); SP 41.86 (33.70 to 50.49); PPV 9.64 (4.96 to 17.88); NPV 85.71 (75.03 to 92.30)	TST ≥ 10 mm: High risk for LTBI vs. low risk for LTBI: SN 11.76 (3.28 to 34.34); SP 76.74 (68.75 to 83.20); PPV 6.25 (1.73 to 20.15); NPV 86.84 (79.42 to 91.86)	QFT-GIT: High risk for LTBI vs. low risk for LTBI: DOR 1.96 (0.71 to 5.43); DORa NR T-SPOT.TB: High risk for LTBI vs. low risk for LTBI: DOR 0.64 (0.23 to 1.76); DORa NR	TST ≥ 10 mm: High risk for LTBI vs. low risk for LTBI: DOR 0.44 (0.09 to 2.03); DORa NR	QFT-G vs. TST ≥ 10 mm: High risk for LTBI vs. low risk for LTBI: R-DOR 4.45 (1.72 to 11.51); R-DORa NR T-SPOT.TB vs. TST ≥ 10 mm High risk for LTBI vs. low risk for LTBI: R-DOR 1.45 (0.56 to 3.76); R-DORa NR
Costantino 2013,127 France (low)	Number of test results: T-SPOT.TB 475; TST 514 Test (+/–): T-SPOT.TB 122/353; TST ≥ 5 mm 196/318 Number of indeterminate results: T-SPOT.TB 88; TST 49	T-SPOT.TB: Conventional risk factors for LTBI vs. no risk factors for LTBI: SN 47.92 (34.47 to 61.67); SP 76.81 (72.58 to 80.57); PPV 18.85 (12.9 to 26.70); NPV 92.92 (89.75 to 95.16)	TST ≥ 5 mm: Conventional risk factors for LTBI vs. no risk factors for LTBI: SN 63.27 (49.27 to 75.34); SP 64.52 (60.06 to 68.73); PPV 15.82 (11.37 to 21.58); NPV 94.34 (91.23 to 96.39)	T-SPOT.TB: Conventional risk factors for LTBI vs. no risk factors for LTBI: DOR 3.05 (1.65 to 5.60); DORa 2.70 (1.49 to 4.89)	TST ≥ 5 mm: Conventional risk factors for LTBI vs. no risk factors for LTBI: DOR 3.13 (1.70 to 5.77); DORa 1.95 (1.13 to 3.36)	T-SPOT.TB vs. TST ≥ 5 mm: Conventional risk factors for LTBI vs. no risk factors for LTBI: R-DOR 0.97 (0.63 to 1.51); R-DORa 1.38 (0.92 to 2.09)
Hadaya 2013,128 Switzerland (low)	Number of test results: QFT-GIT 202; T-SPOT.TB 203; TST 200 Test (+/–): QFT-GIT 47/155; T-SPOT.TB 41/162; TST ≥ 5 mm 9/191 Number of indeterminate results: QFT-GIT 3; T-SPOT.TB 2; TST 0	QFT-GIT: Risk for LTBI vs. no risk for LTBI: SN 33.30 (19.60 to 49.50); SP 80.10 (72.90 to 86.20); PPV NR; NPV 81.10 (73.80 to 87.00) T-SPOT.TB: Risk for LTBI vs. no risk for LTBI: SN 33.30 (19.60 to 49.50); SP 85.50 (78.90 to 90.70); PPV NR; NPV 81.90 (75.00 to 87.60)	TST ≥ 5 mm: Risk for LTBI vs. no risk for LTBI: SN 7.10 (1.50 to 19.50); SP 95.50 (90.80 to 98.20); PPV NR; NPV 78.40 (71.70 to 84.20)	QFT-GIT: Risk for LTBI vs. no risk for LTBI: DOR 2.01 (1.25 to 2.76); DORa NR T-SPOT.TB: Risk for LTBI vs. no risk for LTBI: DOR 3.02 (1.36 to 6.71); DORa NR	TST ≥ 5 mm: Risk for LTBI vs. no risk for LTBI: DOR 1.73 (0.41 to 7.24); DORa NR	QFT-GIT vs. TST ≥ 5 mm: Risk for LTBI vs. no risk for LTBI: R-DOR 1.16 (0.51 to 2.66); R-DORa NR T-SPOT.TB vs. TST ≥ 5 mm: Risk for LTBI vs. no risk for LTBI: R-DOR 1.75 (0.76 to 4.04); R-DORa NR
Hsia 2012,129 USA (low)	Number of test results: QFT-GIT 2241; TST 2282 Test (+/–): QFT-GIT 160/2081; TST ≥ 5 mm 215/2067 Number of indeterminate results: QFT-GIT 41; TST 0	QFT-GIT: Geographical study location: SN NR; SP NR; PPV NR; NPV NR	TST ≥ 5 mm: Geographical study location: SN NR; SP NR; PPV NR; NPV NR	QFT-GIT: Western Europe vs. North America: DOR NR; DORa 3.41 (1.99 to 5.83) Latin America vs. North America: DOR NR; DORa 3.43 (1.64 to 7.19) Eastern Europe vs. North America: DOR NR; DORa 3.58 (1.93 to 6.63) Asia vs. North America: DOR NR; DORa 8.48 (4.78 to 15.03)	TST ≥ 5 mm: Western Europe vs. North America: DOR NR; DORa 2.10 (1.30 to 3.38) Latin America vs. North America: DOR NR; DORa 1.56 (0.80 to 3.05) Eastern Europe vs. North America: DOR NR; DORa 0.95 (0.53 to 1.70) Asia vs. North America: DOR NR; DORa 7.47 (4.61 to 12.08)	QFT-GIT vs. TST ≥ 5 mm: Western Europe vs. North America: R-DOR NR; R-DORa 1.62 (1.13 to 2.34) Latin America vs. North America: R-DOR NR; R-DORa 2.20 (1.32 to 3.66) Eastern Europe vs. North America: R-DOR NR; R-DORa 3.77 (2.44 to 5.81) Asia vs. North America: R-DOR NR; R-DORa 1.14 (0.77 to 1.66)
Kim 2010,130 South Korea (low)	Number of test results: T-SPOT.TB 184; TST ≥ 5 mm 209; TST ≥ 10 mm 209 Test (+/–): T-SPOT.TB 65/119; TST ≥ 5 mm 47/162; TST ≥ 10 mm 21/188 Number of indeterminate results: T-SPOT.TB 25; TST ≥ 5 mm 0; TST ≥ 10 mm 0	T-SPOT.TB: Risk group for LTBI vs. no risk group for LTBI: SN 52.63 (31.71 to 72.67); SP 66.67 (59.17 to 73.41); PPV 15.38 (8.57 to 26.06); NPV 92.44 (86.25 to 95.97)	TST ≥ 5 mm: Risk group for LTBI vs. no risk group for LTBI: SN 36.36 (19.73 to 57.05); SP 79.14 (72.76 to 84.35); PPV 17.02 (8.88 to 30.14); NPV 91.36 (86.02 to 94.78) TST ≥ 10 mm: Risk group for LTBI vs. no risk group for LTBI: SN 18.18 (7.31 to 38.52); SP 90.91 (85.92 to 94.25); PPV 19.05 (7.66 to 40.00); NPV 90.43 (85.37 to 93.86)	T-SPOT.TB: Risk group for LTBI vs. no risk group for LTBI: DOR 2.35 (0.90 to 6.12); DORa 2.38 (0.87 to 6.52)	TST ≥ 5 mm: Risk group for LTBI vs. no risk group for LTBI: DOR 2.17 (0.85 to 5.54); DORa 2.11 (0.82 to 5.46) TST ≥ 10 mm: Risk group for LTBI vs. no risk group for LTBI: DOR 2.22 (0.67 to 7.32); DORa 2.12 (0.60 to 7.49)	T-SPOT.TB vs. TST ≥ 5 mm: Risk group for LTBI vs. no risk group for LTBI: R-DOR 1.02 (0.52 to 2.03); R-DORa 1.08 (0.55 to 2.15) T-SPOT.TB vs. TST ≥ 10 mm: Risk group for LTBI vs. no risk group for LTBI: R-DOR 1.00 (0.46 to 2.19); R-DORa 1.06 (0.48 to 2.31)
Kim 2013,131 South Korea (high)	Number of test results: QFT-GIT 120; TST 119 Test (+/–): QFT-GIT 53/67; TST ≥ 10 mm 35/91 Number of indeterminate results: QFT-GIT 6; TST 7	QFT-GIT: Risk group for LTBI vs. no risk group for LTBI: SN 73.33 (48.05 to 89.1); SP 60.00 (50.44 to 68.86); PPV 20.75 (12.00 to 33.46); NPV 94.03 (85.63 to 97.65)	TST ≥ 10 mm: Risk group for LTBI vs. no risk group for LTBI: SN 86.67 (62.12 to 96.26); SP 90.38 (83.2 to 94.69); PPV 56.52 (36.81 to 74.37); NPV 97.92 (92.72 to 99.43)	QFT-GIT: Risk group for LTBI vs. no risk group for LTBI: DOR 4.13 (1.23 to 13.82); DORa 4.62 (1.15 to 18.64)	TST ≥ 10 mm: Risk group for LTBI vs. no risk group for LTBI: DOR 61.1 (12.03 to 310.4); DORa NR	QFT-GIT vs. TST ≥ 10 mm: Risk group for LTBI vs. no risk group for LTBI: R-DOR 0.07 (0.02 to 0.19); R-DORa NR
Kim 2013,132 South Korea (high)	Number of test results: QFT-GIT 102; TST 93 Test (+/–): QFT-GIT 21/81; TST ≥ 10 mm 12/81 Number of indeterminate results: QFT-GIT 4; TST 0	QFT-GIT: History of treated TB vs. no such history: SN 100 (34.24 to 100); SP 81.32 (72.10 to 88.00); PPV 10.53 (2.93 to 31.39); NPV 100 (95.06 to 100) Abnormal chest radiograph vs. no abnormal chest radiograph: SN 75.00 (30.06 to 95.44); SP 82.02 (72.77 to 88.62); PPV 15.79 (5.52 to 37.57); NPV 98.65 (92.73 to 99.76)	TST ≥ 10 mm: History of treated TB vs. no such history: SN NR; SP NR; PPV NR; NPV NR Abnormal chest radiograph vs. no abnormal chest radiograph: SN NR; SP NR; PPV NR; NPV NR	QFT-GIT: History of treated TB vs. no such history: DOR NR; DORa 9.21 (NR) Abnormal chest radiograph vs. no abnormal chest radiograph: DOR 13.69 (1.33 to 140.30); DORa 27.95 (1.22 to 636.62)	TST ≥ 10 mm: History of treated TB vs. no such history: DOR NR; DORa NR (NS) Abnormal chest radiograph vs. no abnormal chest radiograph: DOR NR; DORa NR (NS)	QFT-GIT vs. TST ≥ 10 mm: History of treated TB vs. no such history: R-DOR NR; R-DORa NR Abnormal chest radiograph vs. no abnormal chest radiograph: R-DOR NR; R-DORa NR
Kleinert 2012,133 Germany (low)	Number of test results: QFT-G 685; T-SPOT.TB 844; TST 1529 Test (+/–): QFT-G 50/635; T-SPOT.TB 70/774; TST ≥ 5 mm 173/1356 Number of indeterminate results: QFT-G + T-SPOT.TB 80; TST NR	QFT-G: Presence of CRF vs. absence of CRF: SN 16.67 (9.02 to 28.74); SP 93.5 (91.3 to 95.17); PPV 18.00 (9.77 to 30.8); NPV 92.91 (90.65 to 94.66) T-SPOT.TB: Presence of CRF vs. absence of CRF: SN 35.29 (25.00 to 47.16); SP 94.07 (92.18 to 95.53); PPV 34.29 (24.25 to 45.96); NPV 94.32 (92.45 to 95.74)	TST ≥ 5 mm: Presence of CRF vs. absence of CRF: SN 39.34 (31.13 to 48.21); SP 91.12 (89.52 to 92.49); PPV 27.75 (21.61 to 34.85); NPV 94.54 (93.2 to 95.63)	QFT-G: Presence of CRF vs. absence of CRF: DOR 2.88 (1.31 to 6.29); DORa 2.63 (1.15 to 5.98) T-SPOT.TB: Presence of CRF vs. absence of CRF: DOR 8.65 (4.84 to 15.46); DORa 8.74 (4.83 to 15.82)	TST ≥ 5 mm: Presence of CRF vs. absence of CRF: DOR 6.65 (4.42 to 9.99); DORa 6.20 (4.08 to 9.44)	QFT-G vs. TST ≥ 10 mm: Presence of CRF vs. absence of CRF: R-DOR 0.43 (0.28 to 0.68); R-DORa 0.42 (0.26 to 0.68) T-SPOT.TB vs. TST ≥ 10 mm: Presence of CRF vs. absence of CRF: R-DOR 1.30 (0.91 to 1.87); R-DORa 1.41 (0.97 to 2.04)
Laffitte 2009,134 Switzerland (low)	Number of test results: T-SPOT.TB 50; TST ≥ 5 mm 50; TST ≥ 10 mm 50 Test (+/–): T-SPOT.TB 10/40; TST ≥ 5 mm 20/30; TST ≥ 10 mm 18/32 Number of indeterminate results: T-SPOT.TB NR; TST ≥ 5 mm NR; TST ≥ 10 mm NR	T-SPOT.TB: Probable LTBI vs. no probable LTBI: SN 36.36 (19.73 to 57.05); SP 92.86 (77.35 to 98.02); PPV 80.00 (49.02 to 94.33); NPV 65.00 (49.51 to 77.87)	TST ≥ 5 mm: Probable LTBI vs. no probable LTBI: SN 50.00 (30.72 to 69.28); SP 67.86 (49.34 to 82.07); PPV 55.00 (34.21 to 74.18); NPV 63.33 (45.51 to 78.13) TST ≥ 10 mm: Probable LTBI vs. no probable LTBI: SN 54.55 (34.66 to 73.08); SP 78.57 (60.46 to 89.79); PPV 66.67 (43.75 to 83.72); NPV 68.75 (51.43 to 82.05)	T-SPOT.TB: Probable LTBI vs. no probable LTBI: DOR 7.43 (1.38 to 39.90); DORa NR	TST ≥ 5 mm: Probable LTBI vs. no probable LTBI: DOR 3.00 (0.93 to 9.70); DORa NR TST ≥ 10 mm: Probable LTBI vs. no probable LTBI: DOR 2.08 (0.64 to 6.73); DORa NR	T-SPOT.TB vs. TST ≥ 5 mm: Probable LTBI vs. no probable LTBI: R-DOR 3.52 (1.25 to 9.96); R-DORa NR T-SPOT.TB vs. TST ≥ 10 mm: Probable LTBI vs. no probable LTBI: R-DOR 1.69 (0.58 to 4.89); R-DORa NR
Maritsi 2011,135 UK (low)	Number of test results: QFT-GIT 23; TST 14 Test (+/–): QFT-GIT 1/20; TST ≥ NR mm 0/14 Number of indeterminate results: QFT-GIT 2; TST 0	QFT-GIT: High-risk group vs. low-risk group: SN 33.33 (6.15 to 79.23); SP 100 (82.41 to 100); PPV 100 (20.65 to 100); NPV 90.00 (69.9 to 97.21)	TST ≥ NR mm: High-risk group vs. low-risk group: SN 0.00 (0.00 to 56.15); SP 100 (74.12 to 100); PPV NR; NPV 78.57 (52.41 to 92.43)	QFT-GIT: High-risk group vs. low-risk group: DOR NR; DORa NR	TST ≥ NR mm: High-risk group vs. low-risk group: DOR NR; DORa NR	QFT-GIT vs. TST ≥ NR mm: High-risk group vs. low-risk group: R-DOR NR; R-DORa NR
Mutsvangwa 2010,136 Zimbabwe (high)	Number of test results: T-SPOT.TB 73; TST 73 Test (+/–): T-SPOT.TB 22/51; TST ≥ 10 mm 33/40 Number of indeterminate results: T-SPOT.TB NR; TST NR	T-SPOT.TB: Contact of index TB case vs. contact of index control: SN 34.55 (23.36 to 47.75); SP 83.33 (60.78 to 94.16); PPV 86.36 (66.66 to 95.25); NPV 29.41 (18.71 to 43.0) Smear status of index case (smear –ve, culture +ve vs. smear –ve, culture –ve): SN NR; SP NR; PPV NR; NPV NR Smear status of index case (smear +ve, culture +ve vs. smear –ve, culture –ve): SN NR; SP NR; PPV NR; NPV NR	TST ≥ 10 mm (two step): Contact of index TB case vs. contact of index control: SN 49.09 (36.38 to 61.92); SP 66.67 (43.75 to 83.72); PPV 81.82 (65.61 to 91.39); NPV 30.00 (18.07 to 45.43) Smear status of index case (smear –ve, culture +ve vs. smear –ve, culture –ve): SN NR; SP NR; PPV NR; NPV NR Smear status of index case (smear +ve, culture +ve vs. smear –ve, culture –ve): SN NR; SP NR; PPV NR; NPV NR	T-SPOT.TB: Contact of index TB case vs. contact of index control: DOR 2.64 (0.67 to 10.27); DORa NR Smear status of index case (smear –ve, culture +ve vs. smear –ve, culture –ve): DOR 1.60 (0.20 to 12.69); DORa 1.87 (0.22 to 16.16) Smear status of index case (smear +ve, culture +ve vs. smear –ve, culture –ve): DOR 4.80 (1.05 to 21.91); DORa 5.36 (1.11 to 25.93)	TST ≥ 10 mm (two step): Contact of index TB case vs. contact of index control: DOR 1.93 (0.63 to 5.87); DORa NR Smear status of index case (smear –ve, culture +ve vs. smear –ve, culture –ve): DOR 1.50 (0.24 to 9.46); DORa 1.09 (0.13 to 9.42) Smear status of index case (smear +ve, culture +ve vs. smear –ve, culture –ve): DOR 3.50 (0.88 to 13.93); DORa 3.43 (0.76 to 15.52)	T-SPOT.TB vs. TST ≥ 10 mm (two step): Contact of index TB case vs. contact of index: R-DOR 1.37 (0.56 to 3.36); R-DORa NR Smear status of index case (smear –ve, culture +ve vs. smear –ve, culture –ve): R-DOR 1.07 (0.26 to 4.39); R-DORa 1.72 (0.36 to 8.06) Smear status of index case (smear +ve, culture +ve vs. smear –ve, culture –ve): R-DOR 1.37 (0.48 to 3.91); R-DORa 1.56 (0.51 to 4.76)
Papay 2011,137 Austria (low)	Number of test results: QFT-GIT 192; TST 192 Test (+/–): QFT-GIT 15/177; TST ≥ 5 mm 26/166 Number of indeterminate results: QFT-GIT 0; TST 0	QFT-GIT: Presence of risk factors vs. absence of risk factors: SN 13.85 (7.45 to 24.27); SP 95.28 (90.08 to 97.82); PPV 60.00 (35.75 to 80.18); NPV 68.36 (61.18 to 74.76) Origin from a high-incidence country vs. origin from a low-incidence country: SN 14.29 (5.69 to 31.49); SP 93.29 (88.39 to 96.21); PPV 26.67 (10.9 to 51.95); NPV 86.44 (80.62 to 90.72) History of contact with index case vs. no history of contact: SN 20.00 (5.668 to 50.98); SP 92.86 (88.16 to 95.78); PPV 13.33 (3.736 to 37.88); NPV 95.48 (91.34 to 97.69)	TST ≥ 5 mm: Presence of risk factors vs. absence of risk factors: SN 21.74 (13.64 to 32.82); SP 92.09 (86.38 to 95.52); PPV 57.69 (38.95 to 74.46); NPV 70.33 (63.33 to 76.49) Origin from a high-incidence country vs. origin from a low-incidence country: SN 37.93 (22.69 to 56); SP 91.62 (86.64 to 94.86); PPV 42.31 (25.54 to 61.05); NPV 90.11 (84.91 to 93.65) History of contact with index case vs. no history of contact: SN 36.36 (15.17 to 64.62); SP 88.83 (83.67 to 92.51); PPV: 15.38 (6.15 to 33.53); NPV: 96.15 (92.27 to 98.12)	QFT-GIT: Presence of risk factors vs. absence of risk factors: DOR 3.24 (1.10 to 9.54); DORa NR Origin from a high-incidence country vs. origin from a low-incidence country: DOR 2.32 (0.68 to 7.87); DORa NR History of contact with index case vs. no history of contact: DOR 3.25 (0.62 to 16.91); DORa NR	TST ≥ 5 mm: Presence of risk factors vs. absence of risk factors: DOR 3.23 (1.39 to 7.49); DORa NR Origin from a high-incidence country vs. origin from a low-incidence country: DOR 6.68 (2.67 to 16.73); DORa NR History of contact with index case vs. no history of contact: DOR 4.54 (1.23 to 16.78); DORa NR	QFT-GIT vs. TST ≥ 5 mm: Presence of risk factors vs. absence of risk factors: R-DOR 1.00 (0.50 to 2.02); R-DORa NR Origin from a high-incidence country vs. origin from a low-incidence country: R-DOR 0.35 (0.16 to 0.76); R-DORa NR History of contact with index case vs. no history of contact: R-DOR 0.72 (0.24 to 2.10); R-DORa NR
Ramos 2013,138 Spain (low)	Number of test results: QFT-GIT 153; TST 153 Test (+/–): QFT-GIT 15/137; TST ≥ 5 mm 43/110 Number of indeterminate results: QFT-GIT 1; T-SPOT.TB 0; TST 0	QFT-GIT: Contact of index TB case vs. contact of index control: SN 42.86 (15.82 to 74.95); SP 91.72 (86.09 to 95.20); PPV 20.00 (7.04 to 45.19); NPV 97.08 (92.73 to 98.86) Born in an endemic country vs. not born in an endemic country: SN 50.00 (21.52 to 78.48); SP 92.36 (86.84 to 95.68); PPV 26.67 (10.90 to 51.95); NPV 97.08 (92.73 to 98.86)	TST ≥ 5 mm: Contact of index TB case vs. contact of index control: SN 57.14 (25.05 to 84.18); SP 73.29 (65.58 to 79.8); PPV 9.30 (3.67 to 21.6); NPV 97.27 (92.29 to 99.07) Born in an endemic country vs. not born in an endemic country: SN 50.00 (21.52 to 78.48); SP 73.1 (65.36 to 79.66); PPV 9.30 (3.67 to 21.60); NPV 96.36 (91.02 to 98.58)	QFT-GIT: Contact of index TB case vs. contact of index control: DOR 8.31 (1.66 to 41.56); DORa NR Born in an endemic country vs. not born in an endemic country: DOR 12.09 (2.65 to 55.07); DORa NR	TST ≥ 5 mm: Contact of index TB case vs. contact of index control: DOR 3.66 (0.78 to 17.08); DORa NR Born in an endemic country vs. not born in an endemic country: DOR 2.72 (0.65 to 11.40); DORa NR	QFT-GIT vs. TST ≥ 5 mm: Contact of index TB case vs. contact of index control: R-DOR 2.27 (0.73 to 7.08); R-DORa NR Born in an endemic country vs. not born in an endemic country: R-DOR 4.44 (1.53 to 12.89); R-DORa NR
Seyhan 2010,139 Turkey (intermediate)	Number of test results: QFT-GIT 100; TST 100 Test (+/–): QFT-GIT 43/57; TST ≥ 10 mm 34/66 Number of indeterminate results: QFT-GIT NR; TST 0	QFT-GIT: Previous contact with an index case vs. no contact: SN 76.92 (49.74 to 91.82); SP 62.07 (51.57 to 71.55); PPV 23.26 (13.15 to 37.74); NPV 94.74 CI (85.63 to 98.19) Previous TB disease vs. no previous disease: SN 75.0 (40.93 to 92.85); SP 59.78 (49.57 to 69.22); PPV 13.95 (6.556 to 27.26); NPV 96.49 (88.08 to 99.03)	TST ≥ 10 mm: Previous contact with an index case vs. no contact: SN 46.15 (23.21 to 70.86); SP 67.82 (57.43 to 76.7); PPV 17.65 (8.349 to 33.51); NPV 89.39 (79.69 to 94.77) Previous TB disease vs. no previous disease: SN 37.5 (13.68 to 69.43); SP 66.3 (56.17 to 75.14); PPV 8.824 (3.047 to 22.96); NPV 92.42 (83.46 to 96.72)	QFT-GIT: Previous contact with an index case vs. no contact: DOR 5.45 (1.40 to 21.27); DORa NR Previous TB disease vs. no previous disease: DOR 4.46 (0.85 to 23.31); DORa NR	TST ≥ 10 mm: Previous contact with an index case vs. no contact: DOR 1.81 (0.55 to 5.87); DORa NR Previous TB disease vs. no previous disease: DOR 1.18 (0.26 to 5.26); DORa NR	QFT-GIT vs. TST ≥ 10 mm: Previous contact with an index case vs. no contact: R-DOR 3.01 (1.20 to 7.56); R-DORa NR Previous TB disease vs. no previous disease: R-DOR 3.78 (1.21 to 11.83); R-DORa NR
Shen 2012,140 China (high)	Number of test results: T-SPOT.TB 70; TST 70 Test (+/–): T-SPOT.TB 26/44; TST ≥ 5 mm 34/36 Number of indeterminate results: T-SPOT.TB 0; TST 0	T-SPOT.TB: Suspected TB disease vs. no suspected TB: SN 70.97 (53.41 to 83.90); SP 89.74 (76.42 to 95.94); PPV 84.62 (66.47 to 93.85); NPV 79.55 (65.5 to 88.85)	TST ≥ 5 mm: Suspected TB disease vs. no suspected TB: SN 61.29 (43.82 to 76.27); SP 61.54 (45.9 to 75.11); PPV 55.88 (39.45 to 71.12); NPV 66.67 (50.33 to 79.79)	T-SPOT.TB: Suspected TB disease vs. no suspected TB: DOR 21.39 (5.87 to 77.93); DORa NR	TST ≥ 5 mm: Suspected TB disease vs. no suspected TB: DOR 2.53 (0.96 to 6.67); DORa NR	T-SPOT.TB vs. TST ≥ 5 mm: Suspected TB disease vs. no suspected TB: R-DOR 8.45 (3.71 to 19.28); R-DORa NR
Souza 2014,153 Brazil (intermediate)	Number of test results: QFT-GIT 299; TST 300 Test (+/–): QFT-GIT 14/285; TST ≥ 5 mm 10/290 Number of indeterminate results: QFT-GIT 1; TST 0	QFT-GIT: History of contact with index case vs. no history of contact with index case: SN 0.0 (0.00 to 9.89); SP 94.96 (91.57 to 97.03); PPV 0.0 (0.00 to 22.81); NPV 87.5 (83.11 to 90.87)	TST ≥ 5 mm: History of contact with index case vs. no history of contact with index case: SN 2.86 (0.50 to 14.53); SP 96.91 (94.02 to 98.43); PPV 11.11 (1.99 to 43.5); NPV 88.07 (83.79 to 91.34)	QFT-GIT: History of contact with index case vs. no history of contact with index case: DOR 0.50 (0.06 to 4.24); DORa NR	TST ≥ 5 mm: History of contact with index case vs. no history of contact with index case: DOR 0.93 (0.11 to 7.61); DORa 1.21 (0.13 to 11.16)	QFT-GIT vs. TST ≥ 5 mm: History of contact with index case vs. no history of contact with index case: R-DOR 0.54 (0.12 to 2.49); R-DORa NR
Takeda 2011,141 Japan (low)	Number of test results: QFT-GIT 71; TST 43 Test (+/–): QFT-GIT 2/46; TST ≥ 10 mm 3/40 Number of indeterminate results: QFT-GIT 23; T-SPOT.TB NR; TST 0	QFT-GIT: Risk of LTBI vs. no risk of LTBI: SN 11.11 (10 to 32.80); SP 100.00 (88.65 to 100.00); PPV 100.00 (34.24 to 100.00); NPV 65.22 (53.45 to 75.38)	TST ≥ 10 mm: Risk of LTBI vs. no risk of LTBI: SN 7.14 (1.27 to 31.47); SP 93.10 (78.04 to 98.09); PPV 33.33(6.15 to 79.23); NPV 67.50; (52.02 to 79.92)	QFT-GIT: Risk of LTBI vs. no risk of LTBI: DOR 3.75 (0.31 to 44.6); DORa NR	TST ≥ 10 mm: Risk of LTBI vs. no risk of LTBI: DOR 1.04 (0.08 to 12.53); DORa NR	QFT-GIT vs. TST ≥ 10 mm: Risk of LTBI vs. no risk of LTBI: R-DOR 3.61 (0.59 to 21.99); R-DORa NR
Vassilopoulos 2011,142 Greece (low)	Number of test results: QFT-GIT 157; T-SPOT.TB 157; TST 157 Test (+/–): QFT-GIT 32/123; T-SPOT.TB 39/116; TST ≥ 5 mm 58/97 Number of indeterminate results: QFT-GIT 2; T-SPOT.TB 2; TST 2	T-SPOT.TB: TB exposure vs. no exposure: SN 25.00 (11.19 to 46.87); SP 74.81 (66.88 to 81.38); PPV 12.82 (5.60 to 26.71); NPV 87.07 (79.76 to 92.00) QFT-GIT: TB exposure vs. no exposure: SN 15.00 (5.23 to 36.04); SP 78.52 (70.85 to 84.61); PPV 9.37 (3.24 to 24.22); NPV 86.18 (78.98 to 91.19)	TST ≥ 5 mm: TB exposure vs. no exposure: SN 50.00 (29.93 to 70.07); SP 64.44, (56.07 to 72.02); PPV 17.24 (9.64 to 28.91); NPV 89.69 (82.05 to 94.3)	T-SPOT.TB: TB exposure vs. no exposure: DOR 0.99 (0.33 to 2.92); DORa NR QFT-GIT: TB exposure vs. no exposure: DOR 0.64 (0.17 to 2.35); DORa NR	TST ≥ 5 mm: TB exposure vs. no exposure: DOR 1.81 (0.70 to 4.66); DORa NR	T-SPOT.TB vs. TST ≥ 5 mm: TB exposure vs. no exposure: R-DOR 0.55 (0.26 to 1.14); R-DORa NR QFT-GIT vs. TST ≥ 5 mm: TB exposure vs. no exposure: R-DOR 0.35 (0.15 to 0.81); R-DORa NR

The forest plot analysis of R-DORs from the remaining 21 studies is stratified according to specific conditions/procedures (HIV infection, solid organ transplantation candidates, post-kidney transplantation, haemodialysis – ESRD, immune-mediated inflammatory diseases before antiTNF-α therapy, hepatitis C and lupus erythematosus) (Figure 29). There was a significant amount of heterogeneity across all subgroups of participants except for those with haemodialysis in whom IGRA (QFT-GIT) was more strongly associated with exposure groups than TST 10 mm (pooled R-DOR 2.53, 95% CI 1.48 to 4.34; I² = 40%). Similarly, in participants with hepatitis C, IGRA (T-SPOT. TB) outperformed TST 5 mm in detecting LTBI (R-DOR 8.45, 95% CI 3.71 to 19.24).

FIGURE 29.

Pooled R-DOR of IGRAs vs. TST in all studies based on high- and low-risk exposure in immunocompromised patients. df, degrees of freedom; IMID, immune-mediated inflammatory disease; IV, inverse variance; SE, standard error.

Within-subgroup heterogeneity by IGRA type (QFT-GIT, T-SPOT. TB) and TST threshold (5 mm, 10 mm, 15 mm) could not be examined for most subgroups because of sparse data. The underlying differences in the definition/measurement of exposure and differential performance of tests across the disease spectrum may have additionally contributed to the non-uniformity observed in the R-DOR estimates (Figures 30–33). For example, for participants with immune-mediated inflammatory diseases before antiTNF-α therapy, the non-uniformity persisted even after accounting for the type of IGRA (QFT-GIT) and TST threshold (5 mm) (pooled R-DOR 0.90, 95% CI 0.52 to 1.54; I² = 80%; see Figure 30). However, the stratification by IGRA type and TST threshold revealed that the TST 5 mm was better than the IGRA (QFT-GIT) at detecting LTBI in participants with HIV infection (pooled R-DOR 0.35, 95% CI 0.15 to 0.83; I² = 0%; see Figure 30). Based on the results from two studies of solid organ transplantation candidates, there was no significant difference between the performance of IGRAs (T-SPOT. TB130 and QFT-GIT124) and the TST 5 mm in relation to the identification of LTBI (see Figures 30, 32 and 33). In contrast, in another study of solid organ transplantation candidates,131 the TST 10 mm outperformed QFT-GIT (R-DOR 0.07, 95% CI 0.02 to 0.19; see Figure 31). In two studies, the performance of QFT-GIT did not significantly differ from that of the TST among participants with lupus erythematosus (QFT-GIT vs. TST 10 mm: R-DOR 3.60, 95% CI 0.59 to 21.96; see Figure 31)141 and kidney transplant recipients (QFT-GIT vs. TST 5 mm: R-DOR 1.16, 95% CI 0.51 to 2.66; see Figure 30). 128

FIGURE 30.

Pooled R-DOR of QFT-GIT/G vs. TST 5 mm based on high- and low-risk exposure in immunocompromised patients. df, degrees of freedom; IMID, immune-mediated inflammatory disease; IV, inverse variance; SE, standard error.

FIGURE 31.

Pooled R-DOR of QFT-GIT/G vs. TST 10 mm based on high- and low-risk exposure in immunocompromised patients. df, degrees of freedom; IV, inverse variance; SE, standard error.

FIGURE 32.

Pooled R-DOR of T-SPOT. TB vs. TST 5 mm based on high- and low-risk exposure in immunocompromised patients. df, degrees of freedom; IMID, immune-mediated inflammatory disease; IV, inverse variance; SE, standard error.

FIGURE 33.

Pooled R-DOR of T-SPOT. TB vs. TST 10 mm based on high- and low-risk exposure in immunocompromised patients. df, degrees of freedom; IMID, immune-mediated inflammatory disease; IV, inverse variance; SE, standard error.

Sensitivity and specificity

This section incorporates 24 newly identified studies120–142,153 (see Table 15). Three studies123,125,129 did not report sensitivity and specificity parameters for both IGRA and TST and one study132 reported them only for TST. The forest plots for the remaining 21 studies displayed a wide variability in sensitivity (IGRA range 0–75%; TST 5 mm range 0–61%; TST 10 mm range 0–87%) and specificity (IGRA range 57–100%; TST 5 mm range 62–96%; TST 10 mm range 64–93%). The heterogeneity persisted even after stratifying the estimates by type of IGRA (QFT-GIT, T-SPOT. TB) and TST threshold (5 mm, 10 mm). Of the two IGRAs, QFT-GIT/G demonstrated markedly wider variation in the estimates of specificity and sensitivity than T-SPOT. TB. In general, for both the IGRAs and the TST, specificity tended to be greater than sensitivity (Figures 34–41). The absence of any clear pattern in the distribution of sensitivity and specificity values reflects the underlying between-study differences in study populations/conditions and settings and variation in exposure definitions and measurement. In light of the observed heterogeneity, no meta-analysis was undertaken.

FIGURE 34.

Forest plot of sensitivity based on exposure groups (QFT-GIT/G) in immunocompromised patients. df, degrees of freedom; HC, hepatitis C; IMID, immune-mediated inflammatory disease; LE, lupus erythematosus; PKT, post-kidney transplantation; SOTC, solid organ transplantation candidate.

FIGURE 35.

Forest plot of sensitivity based on exposure groups (T-SPOT. TB) in immunocompromised patients. df, degrees of freedom; HC, hepatitis C; IMID, immune-mediated inflammatory disease; PKT, post-kidney transplantation; SOTC, solid organ transplantation candidate.

FIGURE 36.

Forest plot of sensitivity based on exposure groups (TST 5 mm) in immunocompromised patients. df, degrees of freedom; IMID, immune-mediated inflammatory disease; LE, lupus erythematosus; PKT, post-kidney transplantation; SOTC, solid organ transplantation candidate.

FIGURE 37.

Forest plot of sensitivity based on exposure groups (TST 10 mm) in immunocompromised patients. df, degrees of freedom; IMID, immune-mediated inflammatory disease; LE, lupus erythematosus; SOTC, solid organ transplantation candidate.

FIGURE 38.

Forest plot of specificity based on exposure groups (QFT-GIT/G) in immunocompromised patients. df, degrees of freedom; HC, hepatitis C; IMID, immune-mediated inflammatory disease; LE, lupus erythematosus; PKT, post-kidney transplantation; SOTC, solid organ transplantation candidate.

FIGURE 39.

Forest plot of specificity based on exposure groups (T-SPOT. TB) in immunocompromised patients. df, degrees of freedom; HC, hepatitis C; IMID, immune-mediated inflammatory disease; PKT, post-kidney transplantation; SOTC, solid organ transplantation candidate.

FIGURE 40.

Forest plot of specificity based on exposure groups (TST 5 mm) in immunocompromised patients. df, degrees of freedom; HC, hepatitis C; IMID, immune-mediated inflammatory disease; PKT, post-kidney transplantation; SOTC, solid organ transplantation candidate.

FIGURE 41.

Forest plot of specificity based on exposure groups (TST 10 mm) in immunocompromised patients. df, degrees of freedom; IMID, immune-mediated inflammatory disease; LE, lupus erythematosus; SOTC, solid organ transplantation candidate.

Influence of bacillus Calmette–Guérin vaccination status on test positivity

Of the 24 newly identified studies included in this section,120–142,153 only 14120,122–125,127,129–131,133,134,138,139,142 reported on the association between test positivity and BCG vaccination status. Overall, there was no evidence indicating a differential effect of BCG vaccination status on IGRA and TST positivity. 120,122–125,130,131,133,134,137–142 In other words, the odds of test positivity for the IGRA and TST were not significantly different between the BCG vaccinated and the non-vaccinated groups (Table 16). Only one study139 demonstrated a significantly increased OR for TST 10 mm positivity (OR 4.28, 95% CI 1.35 to 13.64) as opposed to a non-significant OR for the IGRA (OR 1.89, 95% CI 0.75 to 4.73) in relation to BCG vaccination status.

TABLE 16 - Association between test positivity and BCG vaccination status in immunocompromised patients: exposure studies

ID, identification; NA, not applicable; NR, not reported; NS, not significant.

Study ID, country (burden)	Sample size, n	Type of IGRA/TST induration threshold	Association between test positivity and BCG vaccination status: OR (95% CI)
			Crude/unadjusted	Adjusted
Ahmadinejad 2013,120 Iran (intermediate)	159	QFT-GIT	0.38 (0.11 to 1.24)	NR
	164	TST 10 mm	0.60 (0.15 to 2.34)	NR
Al Jahdali 2013,121 Saudi Arabia (low)	NA	QFT-GIT	NR	NR
	NA	TST 10 mm (two step)	NR	NR
Ates 2009,122 Turkey (intermediate)	246	QFT-GIT	1.13 (0.68 to 1.86)	1.14 (0.68 to 1.92)
	259	TST 10 mm	0.85 (0.51 to 1.43)	0.87 (0.50 to 1.51)
Casas 2011,123 Spain (low)	214	QFT-GIT	1.20 (0.50 to 3.20)	NR
	214	TST 5 mm	1.70 (0.90 to 3.40)	1.50 (0.70 to 3.40)
Casas 2011,124 Spain (low)	95	QFT-GIT	0.62 (0.26 to 1.42)	NR
	95	TST 5 mm (two step)	0.83 (0.35 to 2.00)	NR
Chkhartishvili 2013,125 Georgia (high)	240	QFT-GIT	1.41 (0.38 to 5.29)	NR
	240	T-SPOT.TB	1.78 (0.38 to 8.28)	NR
	240	TST 5 mm	2.55 (0.32 to 20.18)	NR
Chung 2010,126 South Korea (high)	146	QFT-GIT	NR	NR
	146	T-SPOT.TB	NR	NR
	146	TST 10 mm	NR	NR
Costantino 2013,127 France (low)	563	T-SPOT.TB	NR	0.39 (0.24 to 0.62)
	563	TST 5 mm	NR	NR (p = 0.11, NS)
Hadaya 2013,128 Switzerland (low)	183	QFT-GIT	NR	NR
	183	T-SPOT.TB	NR	NR
	183	TST 5 mm	NR	NR
Hsia 2012,129 USA (low)	2029	QFT-GIT	NR	1.00 (0.66 to 1.51)
	2029	TST 5 mm	NR	2.47 (1.71 to 3.55)
Kim 2010,130 South Korea (high)	184	T-SPOT.TB	0.69 (0.36 to 1.34)	NR
	209	TST 5 mm	1.25 (0.55 to 2.82)	NR
	209	TST 10 mm	0.89 (0.31 to 2.58)	NR
Kim 2013,131 South Korea (high)	120	QFT-GIT	1.94 (0.48 to 7.91)	2.32 (0.50 to 10.66)
	119	TST 10 mm	2.56 (0.31 to 21.06)	3.32 (0.38 to 28.97)
Kim 2013,132 South Korea (high)	93	QFT-GIT	NR	NR
	93	TST 10 mm	NR	NR
Kleinert 2012,133 Germany (low)	685	QFT-G	NR	0.43 (0.17 to 1.10)
	844	T-SPOT.TB	NR	1.07 (0.47 to 2.43)
	1529	TST 5 mm	3.17 (2.19 to 4.58)	2.95 (2.00 to 4.35)
Laffitte 2009,134 Switzerland (low)	50	T-SPOT.TB	1.00 (0.01 to 10.07)	NR
	50	TST 5 mm	2.92 (0.30 to 28.29)	NR
	50	TST 10 mm	2.43 (0.25 to 23.57)	NR
Maritsi 2011135 UK (low)	NR	QFT-GIT	NR	NR
	NR	TST NR mm	NR	NR
Mutsvangwa 2010,136 Zimbabwe (high)	NR	T-SPOT.TB	NR	NR
	NR	TST 10 mm (two step)	NR	NR
Papay 2011,137 Austria (low)	192	QFT-GIT	NR	NR
	192	TST 5 mm	NR	NR
Ramos 2013,138 Spain (low)	153	QFT-GIT	NR	5.10 (1.50 to 17.50)
	153	TST 5 mm	NR	2.40 (1.01 to 5.80)
Seyhan 2010,139 Turkey (intermediate)	100	QFT-G	NR	NR
	100	TST 10 mm	NR	4.10 (1.30 to 13.90)
Shen 2012,140 China (high)	70	T-SPOT.TB	NR	NR
	70	TST 5 mm	NR	NR
Souza 2014,153 Brazil (intermediate)	299	QFT-GIT	NR	NR
	300	TST 5 mm	NR	NR
Takeda 2011,141 Japan (low)	71	QFT-2G (QFT-G)	NR	NR
	43	TST 10 mm	NR	NR
Vassilopoulos 2011,142 Greece (low)	157	T-SPOT.TB	0.75 (NR; p = 0.45)	0.51 (NR; p = 0.17)
	157	TST	1.36 (NR; p = 0.39)	1.43 (NR; p = 0.34)
	157	QFT-GIT	1.14 (NR; p = 0.76)	1.05 (NR; p = 0.90)

Between-test concordance, discordance and agreement

This section included 16 studies167–182 reviewed in CG11710 (see Appendix 5) and 32 more recent studies114–142,149,153,155 reviewed in this update (see Appendix 9). Overall, nine studies114,125,136,153,167,170–172,181 were conducted in people with HIV infection, three studies115,149,175 in people with haematological disorders, four studies120,124,130,131 in solid organ transplantation candidates, three studies116,128,132 in people who had undergone kidney transplantation, seven studies117,118,121,122,126,139,155 in people with ESRD/haemodialysis, one study140 in those with hepatitis C, one study141 in those with lupus erythematosus and 18 studies119,123,127,129,133–135,137,138,142,168,169,174,176,178–180,182 in patients with immune-mediated inflammatory diseases before antiTNF-α therapy (rheumatoid arthritis, rheumatic or inflammatory diseases). The remaining two studies looked at patients with chronic liver173 and mixed (HIV infection with liver transplantation)177 conditions.

The data on between-test concordance, discordance and agreement from the 32 more recent studies are presented in Table 17. Six116,126,133,135,140,141 of the 32 studies did not report these data (see Table 17). Overall, the per cent concordance and kappa ranges between QFT-GIT and TST according to each condition were as follows: HIV infection – concordance 75–96%, kappa 0.29–0.48; haematological disorders – concordance 70.6–80%, kappa 0.09–0.16; solid organ transplantation candidates – concordance 65–80%, kappa 0.19–0.57; post-kidney transplantation – concordance 80%, kappa 0.09–0.27; ESRD/haemodialysis – concordance 60–86.4%, kappa 0.21–0.49; and immune-mediated inflammatory diseases before antiTNF-α therapy – concordance 60–93%, kappa 0.08–0.56 (see Table 17).

TABLE 17 - Between-test concordance and discordance in immunocompromised patients: exposure and incidence studies

AS, ankylosing spondylitis; ID, identification; NR, not reported; RA, rheumatoid arthritis.

Study ID, country (burden)	Sample size, total or by subgroup, n	Type of IGRA vs. TST induration threshold	Concordance (95% CI) (%)	Discordance (95% CI) (%)	Agreement kappa (95% CI)
HIV infection
Chkhartishvili 2013,125 Georgia (high)	233	QFT-GIT vs. TST 5 mm	74.25 (68.27 to 79.44)	25.75 (20.56 to 31.73)	0.29 (0.16 to 0.42)
	217	T-SPOT.TB vs. TST 5 mm	75.12 (68.96 to 80.4)	24.88 (19.6 to 31.04)	0.22 (0.07 to 0.29)
Elzi 2011,114 Switzerland (low)	32	T-SPOT.TB vs. TST 5 mm	56.25 (39.33 to 71.83)	43.75 (28.17 to 60.67)	0.12 (–0.22 to 0.46)
Mutsvangwa 2010,136 Zimbabwe (high)	Total	T-SPOT.TB vs. TST 10 mm (two step)	NR	NR	NR
	55 TB index case contacts	T-SPOT.TB vs. TST 10 mm (two step)	70.91 (57.86 to 81.23)	29.09 (18.77 to 42.14)	0.41 (0.16 to 0.66)
	18 control index contacts	T-SPOT.TB vs. TST 10 mm (two step)	72.22 (49.13 to 87.5)	27.78 (12.5 to 50.87)	0.28 (–0.13 to 0.70)
Souza 2014,153 Brazil (intermediate)	299	QFT-GIT vs. TST 5 mm	96.00 (93.12 to 97.69)	4.01 (2.31 to 6.88)	0.48 (0.37 to 0.59)
Haematopoietic stem cell transplantation candidates
Lee 2014,149 South Korea (high)	159	QFT-GIT vs. TST 5 mm	79.87 (72.97 to 85.37)	20.13 (14.63 to 27.03)	0.16 (0.01 to 0.31)
	159	QFT-GIT vs. TST 10 mm	NR	NR	NR
Moon 2013,115 South Korea (high)	210	QFT-GIT vs. TST 5 mm	73.81 (67.47 to 79.29)	26.19 (20.71 to 32.53)	0.09 (–0.04 to 0.22)
	210	QFT-GIT vs. TST 10 mm	78.57 (72.53 to 83.58)	21.43 (16.42 to 27.47)	0.15 (0.02 to 0.27)
	176 with BCG history	QFT-GIT vs. TST 5 mm	74.43 (67.51 to 80.31)	25.57 (19.69 to 32.49)	0.13 (–0.02 to 0.27)
	34 with no BCG history	QFT-GIT vs. TST 5 mm	70.59 (53.83 to 83.17)	29.41 (16.83 to 46.17)	–0.10 (–0.35 to 0.14)
Solid organ transplantation candidates
Ahmadinejad 2013,120 Iran (intermediate)	159	QFT-GIT vs. TST 10 mm	79.87 (72.97 to 85.37)	20.13 (14.63 to 27.03)	0.32 (0.17 to 0.47)
Casas 2011,124 Spain (low)	95	QFT-GIT vs. TST 5 mm (two step)	78.95 (69.71 to 85.94)	36.36 (24.93 to 49.58)	0.57 (0.37 to 0.77)
Kim 2010,130 South Korea (high)	184 total	T-SPOT.TB vs. TST 10 mm	71.2 (64.27 to 77.25)	28.8 (22.75 to 35.73)	0.23 (0.12 to 0.34)
	145 BCG vaccinated	T-SPOT.TB vs. TST 10 mm	70.34 (62.46 to 77.18)	29.66 (22.82 to 37.54)	0.19 (0.06 to 0.31)
Kim 2013,131 South Korea (high)	119	QFT-G vs. TST 10 mm	65.49 (56.34 to 73.61)	34.51 (26.39 to 43.66)	0.26 (0.10 to 0.41)
Post-kidney transplantation
Hadaya 2013,128 Switzerland (low)	200	QFT-GIT vs. TST 5 mm	NR	NR	0.11 (p = 0.010)
	200	T-SPOT.TB vs. TST 5 mm	NR	NR	0.09 (p = 0.034)
Kim 2011,116 South Korea (high)	NR	NR	NR	NR	NR
Kim 2013,132 South Korea (high)	93	QFT-G vs. TST 10 mm	79.57 (70.28 to 86.51)	20.43 (13.49 to 29.72)	0.27 (0.07 to 0.46)
Haemodialysis – ESRD
Al Jahdali 2013,121 Saudi Arabia (low)	200	QFT-GIT vs. TST 10 mm (two step)	75.50 (69.10 to 80.94)	24.50 (19.06 to 30.90)	0.34 (0.22 to 0.45)
Anibarro 2012,117 Spain (low)	52	QFT-GIT vs. TST 5 mm	71.15 (57.73 to 81.67)	28.85 (18.33 to 42.27)	0.21 (0.04 to 0.37)
	52	QFT-GIT vs. TST 5 mm (two step)	78.85 (65.97 to 87.76)	21.15 (12.24 to 34.03)	0.49 (0.22 to 0.74)
Ates 2009,122 Turkey (intermediate)	230	QFT-GIT vs. TST 10 mm	67.83 (61.54 to 73.53)	32.17 (26.47 to 38.46)	0.34 (0.21 to 0.47)
Chung 2010,126 South Korea (high)	146	QFT-G vs. TST 10 mm	NR	NR	NR
	146	T-SPOT.TB vs. TST 10 mm	NR	NR	NR
Lee 2009,118 Taiwan (high)	32	QFT-G vs. TST 10 mm (two step)	60.00 (NR)	40.00 (NR)	0.25 (–0.06 to 0.56)
	32	T-SPOT.TB vs. TST 10 mm (two step)	65.60 (NR)	34.40 (NR)	0.32 (–0.01 to 0.65)
Seyhan 2010,139 Turkey (intermediate)	100	QFT-GIT vs.TST 10 mm	65.00 (55.25 to 73.64)	35.00 (26.36 to 44.75)	0.27 (0.07 to 0.46)
Sherkat 2014,155 Iran (intermediate)	44	T-SPOT.TB vs. TST 10 mm	86.36 (73.29 to 93.6)	13.64 (6.40 to 26.71)	0.49 (0.20 to 0.78)
Immune-mediated inflammatory diseases before antiTNF-α therapy
Casas 2011,123 Spain (low)	202	QFT-GIT vs.TST 5 mm	84.16 (78.49 to 88.55)	15.84 (11.45 to 21.51)	0.56 (0.42 to 0.70)
Chang 2011,119 South Korea (high)	100	QFT-GIT vs. TST 10 mm	67.0 (57.31 to 75.44)	33.0 (24.56 to 42.69)	0.26 (0.07 to 0.45)
	42 RA sample	QFT-GIT vs. TST 10 mm	76.20 (61.47 to 86.52)	23.80 (13.48 to 38.53)	0.46 (0.21 to 0.72)
	58 AS sample	QFT-GIT vs. TST 10 mm	60.34 (47.49 to 71.91)	39.66 (28.09 to 52.51)	0.14 (–0.10 to 0.39)
Costantino 2013,127 France (low)	444 total	T-SPOT.TB vs. TST 5 mm	62.84 (58.25 to 67.2)	37.16 (32.8 to 41.75)	0.16 (0.07 to 0.25)
	NR BCG vaccinated	T-SPOT.TB vs. TST 5 mm	NR	NR	0.15 (NR)
	NR BCG non-vaccinated	T-SPOT.TB vs. TST 5 mm	NR	NR	0.22 (NR)
Hsia 2012,129 USA (low)	2282 total	QFT-GIT vs. TST 5 mm	NR	NR	0.22 (0.15 to 0.27)
	781 BCG vaccinated	QFT-GIT vs. TST 5 mm	82.84 (80.04 to 85.32)	17.16 (14.68 to 19.96)	0.20 (0.13 to 0.27)
	1248 BCG non-vaccinated	QFT-GIT vs. TST 5 mm	93.11 (91.57 to 94.39)	6.89 (5.61 to 8.43)	0.32 (0.26 to 0.37)
Kleinert 2012,133 Germany (low)	685	QFT-G vs. TST 5 mm	NR	NR	NR
	844	T-SPOT.TB vs. TST 5 mm	NR	NR	NR
Laffitte 2009,134 Switzerland (low)	50	T-SPOT.TB vs. TST 5 mm	72.00 (58.33 to 82.53)	28.00 (17.47 to 41.67)	0.36 (0.12 to 0.61)
Maritsi 2011,135 South Africa (high)	NR	QFT-G vs. TST NR mm	NR	NR	NR
Papay 2011,137 Austria (low)	192	QFT-GIT vs. TST 5 mm	84.90 (79.15 to 89.27)	15.10 (10.73 to 20.85)	0.21 (0.07 to 0.34)
Ramos 2013,138 Spain (low)	90	QFT-GIT vs. TST 5 mm	75.56 (65.75 to 83.27)	24.44 (16.73 to 34.25)	0.08 (–0.05 to 0.22)
Vassilopolous 2011,142 Greece (low)	155	QFT-GIT vs. TST 5 mm	63.87 (56.06 to 71.01)	36.13 (28.99 to 43.94)	0.15 (0.01 to 0.29)
	155	T-SPOT.TB vs. TST 5 mm	71.0 (63.38 to 77.54)	29.03 (22.46 to 36.62)	0.34 (0.17 to 0.50)
Hepatitis C
Shen 2012,140 China (high)	70	T-SPOT.TB vs. TST 5 mm	NR	NR	NR
Lupus erythematosus
Takeda 2011,141 Japan (low)	NR	QFT-GIT vs. TST 10 mm	NR	NR	NR

Four studies115,127,129,130 reported between-test agreement parameters by BCG vaccination status, three127,129,130 of which showed a lower per cent concordance and kappa values for BCG-vaccinated participants than for non-vaccinated participants (see Table 17).

Indeterminate test results

This section included three studies170,171,181 reviewed in CG11710 (see Appendix 5) and 32 more recent studies (see previous section) (see Appendix 9). Of the recent studies, six121,126,133,134,136,155 did not report this outcome.

The proportions of indeterminate results according to each condition and type of IGRA test were follows: HIV infection – QFT-GIT 0.30–17.87%, T-SPOT. TB 32.80%;114,125,153,170,171,181 haematological disorders – QFT-GIT 6.00–13.93%;115,149 solid organ transplantation candidates – QFT-GIT 2.11–4.76%, T-SPOT. TB 11.96%;120,124,130,131 post-kidney transplantation – QFT-GIT 1.64–4.30%, T-SPOT. TB 11%;116,128,132 ESRD/haemodialysis – QFT-GIT 0–10.55%, T-SPOT. TB 0%;117,118,122,139 immune-mediated inflammatory diseases before antiTNF-α therapy – QFT-GIT 0–7.69%, T-SPOT. TB 0–15.63%;119,123,127,129,137,138,142 hepatitis C – T-SPOT. TB 0%;140 and lupus erythematosus – QFT-GIT 32.39%. 141