The Effect of Age on Whole Blood Interferon-Gamma Release Assay Response among Children Investigated for Latent Tuberculosis Infection

Critselis, Elena; Amanatidou, Virginia; Syridou, Garyfallia; Spyridis, Νikos; Mavrikou, M.; Papadopoulos, Nikolaos G.; Τσολιά, Μαρία

doi:10.1016/j.jpeds.2012.04.007

Cited by 59 publications

(29 citation statements)

References 22 publications

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“…Unlike previous studies (33,41,42), we detected no difference in IGRA performance or the frequency of indeterminate results in younger children, even in children 6 months of age. These contradictory findings likely result from differences in covariates considered and study populations (i.e., contacts vs. children with broadly defined presumed TB and administrative screening).…”

Section: Table 4 Association Between Tests Of Mycobacterium Tuberculcontrasting

confidence: 99%

Optimizing the Detection of Recent Tuberculosis Infection in Children in a High Tuberculosis–HIV Burden Setting

Mandalakas

Kirchner²,

Walzl

et al. 2015

Am J Respir Crit Care Med

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Rationale: 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.Objectives: Identify improved testing to detect pediatric TB infection.Methods: This was a prospective community-based study assessing use of the tuberculin skin test and IFN-g release assays among children (n = 1,343; 6 mo to ,15 yr) in TB-HIV high-burden settings; associations with child characteristics were measured.Measurements and Main Results: 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-g release assay positive and skin test negative discordance. In a model accounting for confounders, all tests correlate with TB contact, but IFN-g release assays correlate better than the tuberculin skin test (P = 0.0011). Indeterminate IFN-g 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.Conclusions: Where resources allow, use of IFN-g 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.Keywords: HIV; latent tuberculosis infection; pediatrics; IFN-g release tests; tuberculin test Following infection with Mycobacterium tuberculosis, the 5-year risk of tuberculosis (TB) is 33% in children younger than 5 years and 20% for 5-14 years of age (1).TB risk is greatest in the year following infection and highest among young, malnourished, and immune-compromised children; up to 50% of children infected during the first year of life develop disease in the absence of preventive therapy (PT) (2). PT decreases TB morbidity and mortality among adult contacts (3, 4) and Author Contributions: A.M.M., H.L.K., R.P.G., and A.C.H. designed the study. A.M.M. and A.C.H. alternately served as on-site project leaders during study implementation. A.M.M. and H.L.K. planned and executed the statistical analyses, which were reviewed by all authors. All authors contributed to the interpretation of the findings. A.M.M. wrote the first draft of the paper. All authors commented extensively, critically revised the report, and approved the final version.Correspondence and requests for reprints should be addressed to Anna M. Mandalakas, M.D., Sect...

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Section: Table 4 Association Between Tests Of Mycobacterium Tuberculcontrasting

confidence: 99%

Optimizing the Detection of Recent Tuberculosis Infection in Children in a High Tuberculosis–HIV Burden Setting

Mandalakas

Kirchner²,

Walzl

et al. 2015

Am J Respir Crit Care Med

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“…Results have been conflicting at times, with some studies showing comparable sensitivity and specificity to TST, whereas others found higher or lower sensitivity. 3,[26][27][28][29][30][31][32] Rates of indeterminate QFT tests have been higher in young children than in adults; 26,[33][34][35][36] although in this study, we noted a low rate of indeterminate tests (0·4% of all tests).…”

Section: Discussioncontrasting

confidence: 52%

Serial QuantiFERON testing and tuberculosis disease risk among young children: an observational cohort study

Andrews

Nemes

Tameris

et al. 2017

The Lancet Respiratory Medicine

123

113

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Background: The value of quantitative interferon-γ release assay results for predicting progression from Mycobacterium tuberculosis infection to active disease is unknown. Methods: We analysed data from a reported vaccine efficacy trial of MVA85A in South Africa. QuantiFERON-TB Gold In-Tube (QFT) negative, HIV uninfected infants aged 18–24 weeks were enrolled. We stratified participants by quantitative QFT result (IFN-γ <0.35, 0·35–4·00, >4·00 IU/ml) at the intermediate study visit (Day 336) and determined risk of progression to active tuberculosis disease over the subsequent 6–24 months. No QFT differences were observed between placebo and MVA85A groups; therefore, both groups were included in analyses. Study clinicians were not blinded to QFT values, but strict case definitions were used and excluded QFT results. Findings: Among 2,512 infants with QFT tests performed at Day 336, 172 (6·8%) were positive. Compared with QFT non-converters (disease incidence 0·7 per 100 person-years; 95% CI: 0·4–1·1), children with QFT conversion at IFN-γ values between 0·35–4·00 IU/ml did not have significantly increased risk of disease (2·5 per 100 person-years; 95% CI: 0·4–9·4; IRR 3·7; p=0·23). However, QFT conversion at IFN-γ values >4·00 IU/ml was associated with markedly increased disease incidence (28·0 per 100 person-years; 95% CI: 14·9–45·7) compared to nonconverters (IRR 42·5; p<0·0001); and compared to children with IFN-γ values between 0·35–4·00 IU/ml (IRR: 11·4; p=0·00047). Among 91 QFT converters with a repeat test, 53 (58·2%) reverted from positive to negative. QFT reversion risk was inversely associated with IFN-γ value at QFT conversion and was highest (47/61; 77·0%) with IFN-γ values <4·00 IU/ml. Interpretation: In young children, tuberculosis disease risk was not significantly elevated, and QFT reversion was common, following QFT conversion at IFN-γ values up to 10 times the recommended test threshold. By contrast, QFT conversion at very high IFN-γ values (>4·00 IU/ml) warrants intensified diagnostic and preventive intervention for extremely high risk of tuberculosis disease.

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“…Studies from both high-and low-TB prevalence areas have shown that young children aged <5 years can mount robust IFN-γ responses to M. tuberculosis antigens, comparable to those of older children [27,28]. In this study, we found that a positive IGRA result is not a predictor of active TB disease, in keeping with earlier reports, which is attributable to the inability of IGRAs to distinguish between active TB disease and M. tuberculosis sensitisation [9,29].…”

Section: Discussionsupporting

confidence: 90%

No added value of interferon-γ release to a prediction model for childhood tuberculosis

et al. 2015

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The predictive value of a combination of clinical and radiological features with interferon-γ release assay (IGRA) for diagnosis of active tuberculosis (TB) disease among TB-exposed children is unknown.150 symptomatic HIV-negative children (aged 3 months to 14 years), prospectively recruited through active contact tracing, were included. Backward stepwise logistic regression and bootstrapping techniques were used for the development and internal validation of a clinical prediction model for active TB disease. Model discrimination and incremental value of a positive IGRA test were assessed by area under the receiver operating characteristic curve (AUC).35 (23%) children were diagnosed with active TB disease and started on treatment and 115 (77%) had other respiratory tract infections. A final parsimonious clinical model, comprising age <5 years (adjusted (a)OR 4.8, 95% CI 2.0-11.5) and lymphadenopathy on clinical examination (aOR 4.9, 95% CI 1.8-13.0) discriminated active TB disease from other disease with an AUC of 0.70 (95% CI 0.61-0.80). A positive IGRA result did not improve the discriminatory ability of the clinical model (c-statistic 0.72 versus 0.70; p=0.644).A clinical algorithm, including age <5 years and lymphadenopathy classified 70% of active TB disease among symptomatic TB-exposed children. IGRA does not add any discriminatory value to this prediction model. @ERSpublicationsNo added value of interferon-γ release to a prediction model for childhood TB in TB-exposed children

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The Effect of Age on Whole Blood Interferon-Gamma Release Assay Response among Children Investigated for Latent Tuberculosis Infection

Cited by 59 publications

References 22 publications

Optimizing the Detection of Recent Tuberculosis Infection in Children in a High Tuberculosis–HIV Burden Setting

Optimizing the Detection of Recent Tuberculosis Infection in Children in a High Tuberculosis–HIV Burden Setting

Serial QuantiFERON testing and tuberculosis disease risk among young children: an observational cohort study

No added value of interferon-γ release to a prediction model for childhood tuberculosis

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