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Lancet Systematic Review: Disease risk & preventive therapy for TB-exposed infants & young children

TB-CRE investigators provide recent data of the risk of tuberculosis and benefits of preventive therapy in children following close exposure in a systematic review and meta-analysis published in the Lancet.

Tuberculosis (TB) is a global pandemic causing 10 million new cases of disease that killed 1.5 million people in 2018. With extremely high global infection rates, children across the world and particularly in TB endemic regions such as the Asia Pacific are regularly exposed to the disease and run the risk of developing TB. In 2018, an estimated 1.1 million new TB cases and 205,000 deaths were in children but it is still not widely recognised that TB is a major global cause of child morbidity and mortality.

Consistent published evidence from the first half of the 20th century (reviewed and summarised by Prof Ben Marais as part of his PhD studies) documented that infants and young children (<5 years) were at high risk of developing TB disease following infection. It has also been known for more than a century that young children with TB are at very high risk of severe disease and mortality, compared to older age groups, if not detected early and treated. This is the rationale for BCG vaccination of newborns and for universal recommendations to screen contacts following close exposure to infectious TB cases to: detect and treat those contacts with TB disease; and to provide preventive therapy for eligible, high-risk contacts such as young children without evidence of disease.

This week in a seminal Lancet publication, TB-CRE investigators and affiliates Prof Steve Graham, A/Prof Greg Fox, A/Prof Justin Denholm, Dr Claudia Dobler, Prof Philip Hill, and Dr Rina Triasih, in collaboration with other global TB experts led by Dr Leo Martinez from Stanford, provide a timely update from the meta-analysis of over 130,000 TB-exposed children followed for 430,000 child years of observation in 46 cohort studies from 34 countries. The findings emphasise that the abovementioned age-related risk of disease still holds true, as well as provide important additional data for implementation of preventive therapy.

The risk of disease in infants and young children with evidence of infection was around 20% if they did not receive preventive therapy. An important finding of this study was that most child contacts, and especially young children, who developed TB disease, did so soon after exposure often before or within weeks of the diagnosis of the index case. This study also provides recent evidence of benefit of preventive therapy in young child contacts, which reduced disease risk by 91% in those with a positive test for infection. Though less effective, preventive therapy reduced TB risk in all exposed children by 63%, a finding that is very relevant for programmatic implementation as a test for infection is rarely available or readily accessible in most TB endemic settings.

Therefore, while findings highlight the strong rationale for and efficacy of current preventive therapy strategies, the study also shows that effectiveness can be greatly reduced by delayed diagnosis of infectious cases and by delayed or no implementation of contact screening and management, including initiation of preventive therapy. The study concludes that for TB control strategies to optimally protect this vulnerable age group, earlier initiation of preventive therapy is needed through rapid diagnosis of index* cases or community-wide screening approaches.

The study, entitled "The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis" is free-to-access on the Lancet website, and was undertaken with funding from the National Institutes of Health.

*Note here and above, same applies if index case is adolescent or older child with bacteriologically positive PTB

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