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

Abstract

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...

BUTIMBA: Intensifying the Hunt for Child TB in Swaziland through Household Contact Tracing

“…Although previous studies have shown that TB diseased individuals with advanced HIV disease may be less infectious [25, 26], we demonstrated a 1.43 fold increased chance of detecting an additional TB case in households known to be HIV-affected. Consistent with findings of smaller household contact tracing studies conducted within a research platform [19], we demonstrate that in our large interventional program contacts continued to be more likely to have TB disease if they were younger than 5 years of age (OR = 2.01), reported HIV-infection (OR = 4.9), reported one or more TB symptoms (OR = 7.70), or shared a bed with the index case (OR = 1.65). In contrast, contacts with unknown HIV status were less likely to have TB disease (OR = 0.63).…”

“…This was similar to yield reported from other contact tracing programs conducted in TB high-burden settings that included adult and child index cases with all forms of TB; three studies from the Democratic Republic of Congo (2.2%, 2.8%, and 1.3% yield) and one from Pakistan (0.6% yield) [9]. In comparison, research studies have identified TB in 8 to 10% of child contacts in TB high-burden settings, highlighting the potential yield of child TB contact tracing given robust resources[19, 20]. The NNS to find an additional bacteriologically confirmed TB case consistently decreased as the age of the index case and the age of the contacts increased.…”

What steps do we need to take to improve diagnosis of tuberculosis in children?

“…Otherwise, evidence from the available studies are contrasting and some reports suggest that IGRAs are not more sensitive than TST in identifying M. tuberculosis infection in children, particularly <5 years of age and in high TB burden settings (TABLE 1) [9][10][11][12][13][14][15]. However, a recent study in TB-HIV high-burden settings on 1343 children between 6 months and 15 years of age showed that IGRA correlated better than the TST (p = 0.0011) and indeterminate IGRA results were not associated with age [16]. Combining IGRA with TST may improve the sensitivity and the use of both tests can increase the rate of positive results in high-risk settings [3,6,14,[17][18][19].…”

Update in Tuberculosis/Pulmonary Infections 2015

“…A study done in South African children by Mandalakas and colleagues also suggests that the T-SPOT.TB may offer advantages over the QGIT in the pediatric population, where diagnosis of latent and active TB is notoriously difficult (9). This prospective, observational cohort study assessed the likelihood of the tuberculin skin test (TST), the QGIT, and the T-SPOT.TB to predict latent disease in more than 1,300 children aged 6 months to 15 years.…”