The proportion of indeterminate results as well as the influence of HIV-status and young age on IGRA performance were rated as important outcomes (4-6 points) for patients with suspected LTBI. However, due to the small number of studies no subgroup analysis for these outcomes was performed.

Active TB was used as a surrogate measure for LTBI. Tables 10 and 11 describe the evidence profile and summary of findings for studies assessing IGRAs in active TB suspects.

Footnotes

The quality of evidence was rated as high (no points subtracted), moderate (1 point subtracted), low (2 points subtracted), or very low (>2 points subtracted) based on five criteria: study limitations, indirectness of evidence, inconsistency in results across studies, imprecision in summary estimates, and likelihood of publication bias. For each outcome, the quality of evidence started at high, when there were randomized controlled trials or high quality observational studies (cross-sectional or cohort studies enrolling patients with diagnostic uncertainty) and at moderate, when these types of studies were absent. One point was then subtracted when there was a serious issue identified or two points, when there was a very serious issue identified in any of the criteria used to judge the quality of evidence.

Data included did not allow for formal assessment of publication bias using methods such as funnel plots or regression tests. Therefore, publication bias cannot be ruled out. Although no points were deducted, a degree of publication bias is likely because: 1) literature on IGRAs is rapidly exploding and currently unpublished studies may come out in future; 2) there are anecdotal examples of unpublished negative studies on IGRAs; and 3) because a sizeable proportion of IGRA studies have some level of industry involvement or support, the risk of unpublished negative studies (or delayed publication of negative studies) is not trivial.

Four studies identified: One evaluated T-SPOT, two evaluated T-SPOT and QFT-G, one evaluated T-SPOT and QFT-GIT. In total, QFT-G or QFT-GIT was evaluated in 59 children, T-SPOT in 170 children.

Study limitations were assessed using the QUADAS tool. Tw (50%) studies did not clearly enroll a representative spectrum (patient selection - random, consecutive or convenient - was not reported). Blinding of laboratory personnel was reported in 3/4 studies. Differential verification and execution of the reference standard were not considered important issues for exposure studies since all children were assessed for exposure.

1. All four studies were performed in upper middle-income countries; the data are not necessarily representative for low-income countries.
2. TB exposure is a surrogate measure for patient important outcomes and does not necessarily classify the target condition (LTBI) correctly. Exposure increases the risk of infection and correctly identified children with infection will highly benefit from preventive chemotherapy. (No points subtracted)

Heterogeneity was assessed by looking at the variation between odds ratios for the different studies. For QFT-G/QFT-GIT the ORs varied between 0.43 and 5, for T-SPOT between 1.5 and 24. Differences in the definition of exposure groups between the studies may be responsible for the heterogeneity of the results. Two studies were performed in immune-compromised children, one in 100% HIV-infected children, the other in oncology patients. (1 point subtracted)

The 95% CIs for the odds of detecting exposed versus unexposed children were very wide for both QFT-G/QFT-GIT (1.30, 95%-CI 0.2-8.3) and T-SPOT (2.24, 95%-CI 0.88-5.64). The data available from LMIC was very limited and the sample size for exposure groups 3/4 studies was <50, some subgroups analyzed had a sample size of n=2, which highly increases the risk of imprecision. (2 points subtracted)

Five studies identified: two evaluated QFT-GIT (one without using a mitogen control), one evaluated QFT-G and one evaluated T-SPOT and QFT-GIT. In total, QFT-G or QFT-GIT was evaluated in 773 and T-SPOT in 225 children.

Study limitations were assessed using the QUADAS tool. One study assessed a representative spectrum of children and recruitment was performed in a consecutive manner. Blinding of laboratory technicians was reported in one study. Like for dichotomous exposure studies, differential verification and execution of the reference standard were not considered important issues for exposure studies since all children were assessed for exposure.

1. Three studies were performed in low-income countries, one in a lower-middle, one in an upper middle income country.
2. TB exposure is a surrogate measure and does not necessarily classify the target condition (LTBI) correctly. Exposure increases the risk of infection and correctly identified children with infection will highly benefit from preventive chemotherapy. (No points subtracted)

Heterogeneity for T-SPOT could not be assessed since there was only one study. Heterogeneity for QFT was assessed using I-squared statistics and considered to be high (90%). Four studies used microbiological indicators (smear status), one used proximity to the index case as measure of exposure. (1 point subtracted)

The 95% CIs for the pooled random correlation between QFT-studies assessing exposure gradients were wide (QFT-G/QFT-GIT 0.28, 95%CI 0.06-0.86) For T-SPOT, the fixed correlation was 0.15, 95%CI 0.02-0.37. Similar, when calculating regression slopes for exposure gradients, confidence intervals were wide and overlapping for all tests assessed. The data available from LMIC was limited, and the sample sizes assessed small (2 points subtracted)