Previous meta-analysis regarding the performance of QuantiFERON Gold-In-Tube in children have yielded contrasting results. Emerging data in children younger than 5 years of age necessitates a new analysis.

Systematic searches were conducted of MedLINE, EMBASE and Cochrane databases between 1998-2023. Pooled estimates of sensitivities and specificities of QFT-GIT compared to tuberculin skin test (TST) were calculated. The Kappa (k) coefficient was calculated for each study to determine the degree of congruence between TST and QFT-GIT results. Studies including patients co-infected with HIV or other immune compromising conditions or those treated with anti-tubercular treatment were excluded.

Seventeen studies (4335 patients) were included in quantitative analysis. All studies were conducted in middle to high income countries. They were conducted across 14 countries and 4 studies in countries with high TB incidence. The pooled sensitivity, specificity and DOR were 0.45 (0.42-0.48), 0.96 (0.96-0.97) and 18.84 (7.33-48.41) respectively. The ability of QFT-GIT to discriminate with disease and no disease was "good" as demonstrated by a summary receiver operating characteristic curve with area under curve of 0.7812. The average Kappa (k) co-efficient was 0.501 with a wide variety of values between studies (0.167 to 0.800).

The findings of this meta-analysis support the judicious use of QFT-GIT in children 5 years and under, with caution as a sole test to exclude Tuberculosis in this age group. The heterogeneity and methodological quality of diagnostic studies limits the generalisability of results.

Limited data exist on assessing the risk of active tuberculosis (TB) in immunocompromised individuals during screening for latent tuberculosis infection (LTBI).

To assess the risk of progression to active TB for indeterminate interferon-γ release assays (IGRA) results in immunocompromised individuals during screening for LTBI.

PubMed, Embase, Web of Science, and the Cochrane Library were searched without start date or language restrictions on 18 April 2023.

Cohort study or randomized controlled trials that investigated the risk of progression to active TB for indeterminate IGRA during LTBI screening.

Immunocompromised individuals. TEST: IGRA (T-SPOT.TB and QuantiFERON).

None.

A modified version of the Newcastle-Ottawa Scale.

Fixed effects meta-analysis was used to obtain two pooled risk ratios (RRs). RR-ip represented disease progression rate in untreated individuals with indeterminate IGRA versus positive IGRA. RR-in represented disease progression rate in untreated individuals with indeterminate IGRA versus negative IGRA.

Among the 5102 identified studies, 28 (14 792 immunocompromised individuals) were included. The pooled RR-ip and RR-in for cumulative incidence were 0.51 (95% CI, 0.32-0.82; I2 = 0%) and 2.94 (95% CI, 1.78-4.85; I2 = 0%), respectively. In addition, 11 studies reporting person-year data were included to verify the reliability of cumulative incidence results. The pooled RR-ip and RR-in for person-year incidence were 0.40 (95% CI, 0.19-0.82; I2 = 13%) and 2.67 (95% CI, 1.24-5.79; I2 = 23%), respectively.

Indeterminate IGRA results in immunocompromised individuals may represent an intermediate risk of progression to active TB, with half the risk for positive results and three times for negative results. Proper follow-up and management of patients with indeterminate results are crucial for mitigating progression risk and improving patient outcomes.

We aimed to evaluate the indeterminate rate of interferon gamma release assays (IGRAs) in the detection of latent tuberculosis infection (LTBI).

On 15 November 2022, we searched the PubMed® (National Library of Medicine, Bethesda, MD, USA), Embase® (Elsevier, Amsterdam, the Netherlands), and Cochrane Library databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two investigators independently extracted the study data and assessed their quality using a modified quality assessment of diagnostic accuracy studies (i.e., QUADAS-2) tool. A random-effects model was used to calculate pooled results.

We included 403 studies involving 486,886 individuals and found that the pooled indeterminate rate was 3.9% (95% CI 3.5%-4.2%). The pooled indeterminate rate for QuantiFERON®-TB (QFT) was similar to that for T-SPOT®.TB (T-SPOT) [odds ratio (OR) = 0.88, 95% CI 0.59-1.32]; however, the indeterminate rate for a new generation of QFT (QFT-plus) was lower than that of T-SPOT (OR = 0.24, 95% CI 0.16-0.35). The indeterminate rate in the immunocompromised population was significantly higher than that in healthy controls (OR = 3.51, 95% CI 2.11-5.82), and it increased with the reduction of CD4+ cell count in HIV-positive patients. Children's pooled indeterminate rates (OR = 2.56, 95% CI 1.79-3.57) were significantly higher than those of adults, and the rates increased as the children's age decreased.

On average, 1 in 26 tests yields indeterminate IGRA results in LTBI screening. The use of advanced versions of the QuantiFERON-TB assay (QFT-plus), may potentially reduce the occurrence of an indeterminate result. Our study emphasizes the high risk of immunosuppression and young age in relation to indeterminate IGRA, which should receive more attention in the management of LTBI.

PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020211363, CRD42020211363.

Tuberculosis (TB) remains an important problem among children in the United States and throughout the world. There is no diagnostic reference standard for latent tuberculosis infection (also referred to as tuberculosis infection [TBI]). The tuberculin skin test (TST) has many limitations, including difficulty in administration and interpretation, the need for a return visit by the patient, and false-positive results caused by cross-reaction with Mycobacterium bovis-bacille Calmette-Guerin vaccines and many nontuberculous mycobacteria. Interferon-gamma release assays (IGRAs) are blood tests that use antigens specific for M tuberculosis; as a result, IGRAs yield fewer false-positive results than the TST. Both IGRAs and the TST have reduced sensitivity in immunocompromised children, including children with severe TB disease. Both methods have high positive predictive value when applied to children with risk factors for TBI, especially recent contact with a person who has TB disease. The advantages of using IGRAs and diminished experience with the placement and interpretation of the TST favor expanded use of IGRAs in children in the United States. There are now several effective and safe regimens for the treatment of TBI in children. For improved adherence to therapy, the 3 rifamycin-based regimens are preferred because of their short duration. Daily isoniazid can be used if there is intolerance or drug interactions with rifamycins. A TB specialist should be involved when there are questions regarding testing interpretation, selection of an appropriate treatment regimen, or management of adverse effects.

Accurate diagnosis of TB in children is hampered by poor specificity of symptoms in endemic countries and the paucibacillary nature of childhood TB. This study was done to compare the accuracy and agreement of the tuberculin skin test (TST) and the QuantiFERON-TB Gold In-tube test (QFT) in diagnosing tuberculosis (TB) in a predominantly BCG-vaccinated population of children.

This retrospective cohort study enrolled all children aged 1-15 years who underwent TST and QFT testing as part of screening for TB. Children were classified according to the 2014 WHO case definition of TB, and statistical analysis was done to generate data on concordance between the TST and the QFT as well as sensitivity and specificity within WHO-defined groups.

TST and QFT concordance was 83.9% overall (kappa 0.51), 79% in those with WHO-defined TB and 89% in those without TB. TST+/QFT-discordance was commoner than QFT+/TST- discordance across groups. The sensitivity of the TST vs. the QFT was 70.8% vs. 50% for WHO-defined TB, with comparable specificity at 89% vs. 90% respectively.

The higher sensitivity of the cheaper and simpler TST supports its use for TB diagnosis in a normally nourished population of BCG-vaccinated children.

New guidelines support using interferon-γ release assays (IGRAs) in children ≥2 years for diagnosis of latent tuberculosis infection (LTBI). However, lack of experience in young children and concern that IGRAs are less sensitive than tuberculin skin tests (TSTs) limit their use. Our aim was to identify active tuberculosis (TB) cases among high risk children <5 years and tested for LTBI with an IGRA.

. Retrospective review of domestic TB screening data from California's Refugee Health Electronic Information System for children <5 years old who resettled in California between October, 2013 and December, 2016. Children were crossmatched with the California TB registry to identify cases of TB disease between October 2013 and December 2018.

A total of 3371 children <5 years were identified; the majority were born in countries with high TB incidence (>150 cases per 100 000). Half received IGRAs (n = 1878; 56%), a quarter received TSTs (n = 811; 24%); 1.4% of children were IGRA-positive (n = 26) and 13% were TST-positive (n = 106). Twenty-two IGRA results were indeterminate (1.2%). Sixteen children had both tests; 9 were discrepant (positive TST with negative IGRA). No cases of TB disease were identified during 10 797 person-years of follow-up.

IGRA positivity was less than TST positivity in high risk children <5 years old. Despite fewer LTBI diagnoses in the IGRA-tested population, no cases of TB disease among children who tested negative were identified, suggesting IGRA is valuable tool for identifying LTBI in this population.

During 2000 to 2018, 1831 children were screened as part of tuberculosis contact investigation at the Stockholm Northern Clinic. The risk of a child having a positive tuberculin skin test was 33% and positive interferon-gamma release assay 12%. The risk of tuberculosis disease was 6.1% (tuberculin skin test) and 13% (interferon-gamma release assay) in positive-testing children.

The T-SPOT.TB, an interferon-gamma release assay, is an indirect test of Mycobacterium tuberculosis infection. Due to sparse and conflicting evidence, the use of interferon-gamma release assay is limited in young and HIV-infected children. We determined the prevalence of invalid, borderline, positive and negative results and associations with key demographic variables during routine pediatric use in a low tuberculosis burden setting.

For pediatric samples received at Oxford Diagnostic Laboratories between 2010 and 2015, the associations between initial test outcome and demographics were estimated by bivariate analysis and logistic regression.

A total of 44,289 samples (median age 12.5 years; interquartile range 7.7-15.5), including 5057 samples (11.6%) from children under 5 years old, were received from 46 U.S. states, Washington, DC and Puerto Rico. A total of 592 samples (1.3%) could not be tested. T-SPOT.TB positivity was strongly correlated (r = 0.60; P < 0.0001) with state TB incidence. Compared with negative results, positive results were more likely in samples from older children (P < 0.0001), public health clinics (P < 0.0001) and rural locations (P = 0.005). Although infrequent (0.6%), invalid results were more common in samples collected at HIV clinics (odds ratio = 2.5, 95% confidence interval: 1.3-4.9) and from younger children (P = 0.03). These invalid results were more likely due to a robust nil (negative) control response rather than a weak mitogen (positive) control response.

The T-SPOT.TB test correlated strongly with well-recognized risk factors for tuberculosis infection and provided evaluable results in 98% of children. To optimize the impact of testing on clinical decision making and patient outcomes, local epidemiology and individual patient risk should be considered when incorporating IGRAs into pediatric guidelines.

The rate of low-mitogen indeterminate interferon-gamma release assay results at a hospital with expert pediatric phlebotomy and rapid incubation of specimens was 0.96%. All low-mitogen indeterminate results were found to be associated with an immunocompromised or anergic state. We describe a child where an unexpected indeterminate interferon-gamma release assay test pointed to an underlying anergic condition and was of diagnostic significance.

Accurate diagnosis and subsequent treatment of latent tuberculosis infection (LTBI) is essential for TB elimination. However, the absence of a gold standard test for diagnosing LTBI makes assessment of the true prevalence of LTBI and the accuracy of diagnostic tests challenging. Bayesian latent class models can be used to make inferences about disease prevalence and the sensitivity and specificity of diagnostic tests using data on the concordance between tests. We performed the largest meta-analysis to date aiming to evaluate the performance of tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) for LTBI diagnosis in various patient populations using Bayesian latent class modelling.

Systematic search of PubMeb, Embase and African Index Medicus was conducted without date and language restrictions on September 11, 2017 to identify studies that compared the performance of TST and IGRAs for LTBI diagnosis. Two IGRA methods were considered: QuantiFERON-TB Gold In Tube (QFT-GIT) and T-SPOT.TB. Studies were included if they reported 2x2 agreement data between TST and QFT-GIT or T-SPOT.TB. A Bayesian latent class model was developed to estimate the sensitivity and specificity of TST and IGRAs in various populations, including immune-competent adults, immune-compromised adults and children. A TST cut-off value of 10 mm was used for immune-competent subjects and 5 mm for immune-compromised individuals.

A total of 157 studies were included in the analysis. In immune-competent adults, the sensitivity of TST and QFT-GIT were estimated to be 84% (95% credible interval [CrI] 82-85%) and 52% (50-53%), respectively. The specificity of QFT-GIT was 97% (96-97%) in non-BCG-vaccinated and 93% (92-94%) in BCG-vaccinated immune-competent adults. The estimated figures for TST were 100% (99-100%) and 79% (76-82%), respectively. T-SPOT.TB has comparable specificity (97% for both tests) and better sensitivity (68% versus 52%) than QFT-GIT in immune-competent adults. In immune-compromised adults, both TST and QFT-GIT display low sensitivity but high specificity. QFT-GIT and TST are equally specific (98% for both tests) in non-BCG-vaccinated children; however, QFT-GIT is more specific than TST (98% versus 82%) in BCG-vaccinated group. TST is more sensitive than QFT-GIT (82% versus 73%) in children.

This study is the first to assess the utility of TST and IGRAs for LTBI diagnosis in different population groups using all available data with Bayesian latent class modelling. Our results challenge the current beliefs about the performance of LTBI screening tests, and have important implications for LTBI screening policy and practice. We estimated that the performance of IGRAs is not as reliable as previously measured in the general population. However, IGRAs are not or minimally affected by BCG and should be the preferred tests in this setting. Adoption of IGRAs in settings where BCG is widely administered will allow for a more accurate identification and treatment of LTBI.

Infectious diseases are common in internationally adopted children (IAC).With the objective to evaluate infectious diseases prevalence in a large cohort of IAC and to explore possible risk factors for tuberculosis (TB) and parasitic infections, clinical and laboratory data at first screening visit of all IAC (<18 years) consecutively referred to our Center in 2009 to 2015 were collected and analyzed.In total, 1612 children (median age: 5.40 years; interquartile range: 3.00-7.90) were enrolled, 123/1612 (7.60%) having medical conditions included in the special needs definition. The most frequent cutaneous infections were Molluscum contagiosum (42/1612; 2.60%) and Tinea capitis (37/1612; 2.30%). Viral hepatitis prevalence was <1% (hepatitis B virus [HBV]: 13 children, 0.80%; hepatitis C virus: 1 child, 0.10%; hepatitis A virus: 6 children, 0.40%). A parasitic infection was diagnosed in 372/1612 (23.10%) children. No risk factors for parasitosis were evidenced. Active TB was diagnosed in 4/1355 (0.3%) children, latent TB in 222/1355 (16.40%). Only 3.7% (51/1355) children had concordant positive tuberculin skin test (TST) and QuantiFERON-TB-Gold In-Tube (QFT-G-IT) results. Risk factors for TST+/QFT-G-IT- results were previous Bacille de Calmette-Guérin vaccination (adjusted odds ratio [aOR]: 2.18; 96% confidence interval [CI]: 1.26-3.79; P = 0.006), and age ≥5 years (aOR: 1.49; 95% CI: 1.06-2.11; P = 0.02). The proportion of children with nonprotective titers for vaccine-preventable diseases (VPD) ranged from 15.70% (208/1323) for tetanus to 35.10% (469/1337) for HBV.Infectious diseases were commonly observed in our cohort. The high rate of discordant TST/QFT-G results brings up questions regarding the optimal management of these children, and suggests that, at least in children older than 5 years, only QFT-G-IT results may be reliable. The low proportion of children protected for VPD, confirms importance of a timely screening.

Children who are young, malnourished, and infected with HIV have significant risk of tuberculosis (TB) morbidity and mortality following TB infection. Treatment of TB infection is hindered by poor detection and limited pediatric data.

Identify improved testing to detect pediatric TB infection.

This was a prospective community-based study assessing use of the tuberculin skin test and IFN-γ release assays among children (n = 1,343; 6 mo to <15 yr) in TB-HIV high-burden settings; associations with child characteristics were measured.

Contact tracing detects TB in 8% of child contacts within 3 months of exposure. Among children with no documented contact, tuberculin skin test and QuantiFERON-TB Gold In-Tube positivity was greater than T-SPOT.TB. Nearly 8% of children had IFN-γ release assay positive and skin test negative discordance. In a model accounting for confounders, all tests correlate with TB contact, but IFN-γ release assays correlate better than the tuberculin skin test (P = 0.0011). Indeterminate IFN-γ release assay results were not associated with age. Indeterminate QuantiFERON-TB Gold In-Tube results were more frequent in children infected with HIV (4.7%) than uninfected with HIV (1.9%), whereas T-SPOT.TB indeterminates were rare (0.2%) and not affected by HIV status. Conversion and reversion were not associated with HIV status. Among children infected with HIV, tests correlated less with contact as malnutrition worsened.

Where resources allow, use of IFN-γ release assays should be considered in children who are young, recently exposed, and infected with HIV because they may offer advantages compared with the tuberculin skin test for identifying TB infection, and improve targeted, cost-effective delivery of preventive therapy. Affordable tests of infection could dramatically impact global TB control.

Although often regarded as a foreign disease, latent tuberculosis or tuberculosis disease will be encountered in many clinical situations by the Canadian child health practitioner. There are key differences between tuberculosis in children and adults. In the present article, the changing epidemiology of tuberculosis in children in Canada and around the world, the pathogenesis of infection, diagnostic tests, and clinical management of childhood latent tuberculosis and tuberculosis disease are reviewed.