Abstract:Background Tens of millions of children are exposed to Mycobacterium tuberculosis globally every year; however, there are no contemporary estimates of the risk of developing tuberculosis in exposed children. The effectiveness of contact investigations and preventive therapy remains poorly understood.Methods In this systematic review and meta-analysis, we investigated the development of tuberculosis in children closely exposed to a tuberculosis case and followed for incident disease. We restricted our search to… Show more
“…1 ), but overall impact on TB incidence and mortality was reduced (Appendix Table S4). If reactivation rates were considered to be age-specific (20% two-year cumulative incidence for children 0–4 years and 10% for children 5–14%) [6] , corresponding ICERs were $154 per DALY averted among children 0–4 years old and $412 per DALY averted among children 5–14 years old. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Household contact investigation of individuals diagnosed with active TB can ensure that pediatric household contacts receive prompt treatment (if diagnosed with active TB) or preventive therapy, which can reduce their subsequent risk of morbidity and mortality [ 1 , 5 , 6 ]. The World Health Organization (WHO) recommends contact investigation and symptom-based screening for identifying active TB, plus provision of a short-course regimen for preventive therapy for children in high burden settings [2] .…”
Background
While household contact investigation is widely recommended as a means to reduce the burden of tuberculosis (TB) among children, only 27% of eligible pediatric household contacts globally received preventive treatment in 2018. We assessed the cost-effectiveness of household contact investigation for TB treatment and short-course preventive therapy provision for children under 15 years old across 12 high TB burden countries.
Methods
We used decision analysis to compare the costs and estimated effectiveness of three intervention scenarios: (a) status quo (existing levels of coverage with isoniazid preventive therapy), (b) contact investigation with treatment of active TB but no additional preventive therapy, and (c) contact investigation with TB treatment and provision of short-course preventive therapy. Using country-specific demographic, epidemiological and cost data from the literature, we estimated annual costs (in 2018 USD) and the number of TB cases and deaths averted across 12 countries. Incremental cost effectiveness ratios were assessed as cost per death and per disability-adjusted life year [DALY] averted.
Findings
Our model estimates that contact investigation with treatment of active TB and provision of preventive therapy could be highly cost-effective compared to the status quo (ranging from $100 per DALY averted in Malawi to $1,600 in Brazil; weighted average $383 per DALY averted [uncertainty range: $248 – $1,130]) and preferred to contact investigation without preventive therapy (weighted average $751 per DALY averted [uncertainty range: $250 – $1,306]). Key drivers of cost-effectiveness were TB prevalence, sensitivity of TB diagnosis, case fatality for untreated TB, and cost of household screening.
Interpretation
Based on this modeling analysis of available published data, household contact investigation with provision of short-course preventive therapy for TB has a value-for-money profile that compares favorably with other interventions.
Funding
Unitaid (2017–20-IMPAACT4TB).
“…1 ), but overall impact on TB incidence and mortality was reduced (Appendix Table S4). If reactivation rates were considered to be age-specific (20% two-year cumulative incidence for children 0–4 years and 10% for children 5–14%) [6] , corresponding ICERs were $154 per DALY averted among children 0–4 years old and $412 per DALY averted among children 5–14 years old. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Household contact investigation of individuals diagnosed with active TB can ensure that pediatric household contacts receive prompt treatment (if diagnosed with active TB) or preventive therapy, which can reduce their subsequent risk of morbidity and mortality [ 1 , 5 , 6 ]. The World Health Organization (WHO) recommends contact investigation and symptom-based screening for identifying active TB, plus provision of a short-course regimen for preventive therapy for children in high burden settings [2] .…”
Background
While household contact investigation is widely recommended as a means to reduce the burden of tuberculosis (TB) among children, only 27% of eligible pediatric household contacts globally received preventive treatment in 2018. We assessed the cost-effectiveness of household contact investigation for TB treatment and short-course preventive therapy provision for children under 15 years old across 12 high TB burden countries.
Methods
We used decision analysis to compare the costs and estimated effectiveness of three intervention scenarios: (a) status quo (existing levels of coverage with isoniazid preventive therapy), (b) contact investigation with treatment of active TB but no additional preventive therapy, and (c) contact investigation with TB treatment and provision of short-course preventive therapy. Using country-specific demographic, epidemiological and cost data from the literature, we estimated annual costs (in 2018 USD) and the number of TB cases and deaths averted across 12 countries. Incremental cost effectiveness ratios were assessed as cost per death and per disability-adjusted life year [DALY] averted.
Findings
Our model estimates that contact investigation with treatment of active TB and provision of preventive therapy could be highly cost-effective compared to the status quo (ranging from $100 per DALY averted in Malawi to $1,600 in Brazil; weighted average $383 per DALY averted [uncertainty range: $248 – $1,130]) and preferred to contact investigation without preventive therapy (weighted average $751 per DALY averted [uncertainty range: $250 – $1,306]). Key drivers of cost-effectiveness were TB prevalence, sensitivity of TB diagnosis, case fatality for untreated TB, and cost of household screening.
Interpretation
Based on this modeling analysis of available published data, household contact investigation with provision of short-course preventive therapy for TB has a value-for-money profile that compares favorably with other interventions.
Funding
Unitaid (2017–20-IMPAACT4TB).
“…Research has consistently shown that TB disease in young children usually occurs soon after exposure and infection, that the risk of disease if infected is high, and that TB preventive therapy (TPT) can significantly reduce the risk of disease following exposure and infection [ 4 ]. A meta-analysis reported that 10% of young child contacts had TB disease at the time of screening, and 35% had evidence of infection [ 5 ].…”
Background
There are major gaps in the management of pediatric tuberculosis (TB) contact investigation for rapid identification of active tuberculosis and initiation of preventive therapy. This study aims to evaluate the impact of a community-based intervention as compared to facility-based model for the management of children in contact with bacteriologically confirmed pulmonary TB adults in low-resource high-burden settings.
Methods/design
This multicenter parallel open-label cluster randomized controlled trial is composed of three phases: I, baseline phase in which retrospective data are collected, quality of data recording in facility registers is checked, and expected acceptability and feasibility of the intervention is assessed; II, intervention phase with enrolment of index cases and contact cases in either facility- or community-based models; and III, explanatory phase including endpoint data analysis, cost-effectiveness analysis, and post-intervention acceptability assessment by healthcare providers and beneficiaries. The study uses both quantitative and qualitative analysis methods. The community-based intervention includes identification and screening of all household contacts, referral of contacts with TB-suggestive symptoms to the facility for investigation, and household initiation of preventive therapy with follow-up of eligible child contacts by community healthcare workers, i.e., all young (< 5 years) child contacts or older (5–14 years) child contacts living with HIV, and with no evidence of TB disease. Twenty clusters representing TB diagnostic and treatment facilities with their catchment areas are randomized in a 1:1 ratio to either the community-based intervention arm or the facility-based standard of care arm in Cameroon and Uganda. Randomization was stratified by country and constrained on the number of index cases per cluster. The primary endpoint is the proportion of eligible child contacts who initiate and complete the preventive therapy. The sample size is of 1500 child contacts to identify a 10% difference between the arms with the assumption that 60% of children will complete the preventive therapy in the standard of care arm.
Discussion
This study will provide evidence of the impact of a community-based intervention on household child contact screening and management of TB preventive therapy in order to improve care and prevention of childhood TB in low-resource high-burden settings.
Trial registration
ClinicalTrials.gov NCT03832023. Registered on 6 February 2019
“…Children represent a particularly important and interesting population, as although young children are susceptible to disease progression and have high morbidity and mortality, early school-age children appear to be relatively protected against development of tuberculosis, and some children show no signs of disease or asymptomatic infection despite defined exposure to infectious cases of pulmonary tuberculosis [ 5 , 6 ]. Latent tuberculosis infection (LTBI) is a clinically relevant phenotype because the risk of incident tuberculosis is significantly higher in children of all ages with a positive baseline tuberculin skin test (TST) or Interferon Gamma Release Assay (IGRA) compared to those with negative baseline tests [ 7 , 8 ]. Building on paediatric observational data, there is now clinical trial evidence that Bacillus Calmette–Guérin (BCG) vaccine protects against TB infection [9] , [10] , [11] .…”
Background
Children are particularly susceptible to tuberculosis. However, most children exposed to
Mycobacterium tuberculosis
are able to control the pathogen without evidence of infection. Correlates of human protective immunity against tuberculosis infection are lacking, and their identification would aid vaccine design.
Methods
We recruited pairs of asymptomatic children with discordant tuberculin skin test status but the same sleeping proximity to the same adult with sputum smear-positive tuberculosis in a matched case-control study in The Gambia. Participants were classified as either Highly TB-Exposed Uninfected or Highly TB-Exposed Infected children. Serial luminescence measurements using an
in vitro
functional auto-luminescent Bacillus Calmette–Guérin (BCG) whole blood assay quantified the dynamics of host control of mycobacterial growth. Assay supernatants were analysed with a multiplex cytokine assay to measure associated inflammatory responses.
Findings
29 pairs of matched Highly TB-Exposed Uninfected and Highly TB-Exposed Infected children aged 5 to 15 years old were enroled. Samples from Highly TB-Exposed Uninfected children had higher levels of mycobacterial luminescence at 96 hours than Highly TB-Exposed Infected children. Highly TB-Exposed Uninfected children also produced less BCG-specific interferon-γ than Highly TB-Exposed Infected children at 24 hours and at 96 hours.
Interpretation
Highly TB-Exposed Uninfected children showed less control of mycobacterial growth compared to Highly TB-Exposed Infected children in a functional assay, whilst cytokine responses mirrored infection status.
Funding
Clinical Research Training Fellowship funded under UK Medical Research Council/Department for International Development Concordat agreement and part of EDCTP2 programme supported by European Union (MR/K023446/1). Also MRC Program Grants (MR/K007602/1, MR/K011944/1, MC_UP_A900/1122).
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