Prevalence and Predictors of Tuberculosis Infection in Children and Adolescents in Rural Uganda: A Cross-sectional Study.

BACKGROUND: Much of the latent tuberculosis (TB) reservoir is established in childhood and adolescence. Yet, age-specific data on prevalence and predictors of infection in this population are sparse and needed to guide prevention and case finding. METHODS: From December 2021 to June 2023, we measured TB infection in children 1-17 years in 25 villages in rural Southwestern Uganda. We defined TB infection as a positive QuantiFERON Gold Plus Test (QFT). We estimated overall and age-stratified population-level prevalence and adjusted risk ratios (aRR) of TB infection for individual, household, and community-based predictors, accounting for age, TB contact, and clustering by household. RESULTS: Estimated TB infection prevalence was 9.6% [95% confidence interval (CI): 8.7-10.5%] among the 5789 participants, and prevalence varied slightly with age. Household-level risk factors included crowding (aRR: 1.25, 95% CI: 1.03-1.53), indoor cooking (aRR: 1.62, 95% CI: 1.14-2.30), living with ≥2 persons who drink alcohol (aRR: 1.47, 95% CI: 1.04-2.07). The predominant community-based risk factor was child mobility (aRR: 1.67, 95% CI: 1.24-2.26). In age-stratified analyses, household predictors were important in early childhood but not adolescence, where mobility was predominant (aRR: 1.66, 95% CI: 1.13-2.44). CONCLUSION: We detected a high prevalence of TB infection in children and adolescents in rural Uganda. On a population level, TB risk factors change throughout the early life course, with child mobility a key risk factor in adolescence. Age-specific TB case finding and prevention strategies that address both household and extra-household risk factors are needed to address TB transmission.

Integration of HIV Testing in a Community Intervention for Tuberculosis Screening Among Household Contacts of Patients with Tuberculosis in Cameroon and Uganda.

INTRODUCTION: People living with HIV are considered at higher risk of developing severe forms of tuberculosis (TB) disease. Providing HIV testing to TB-exposed people is therefore critical. We present the results of integrating HIV testing into a community-based intervention for household TB contact management in Cameroon and Uganda. METHODS: Trained community health workers visited the households of index patients with TB identified in 3 urban/semiurban and 6 rural districts or subdistricts as part of a cluster-randomized trial and provided TB screening to all household contacts. Voluntary HIV counseling and testing were offered to contacts aged 5 years or older with unknown HIV status. We describe the cascade of care for HIV testing and the factors associated with the acceptance of HIV testing. RESULTS: Overall, 1983 household contacts aged 5 years or older were screened for TB. Of these contacts, 1652 (83.3%) did not know their HIV status, 1457 (88.2%) accepted HIV testing, and 1439 (98.8%) received testing. HIV testing acceptance was lower among adults than children [adjusted odds ratio (aOR) = 0.35, 95% confidence interval (CI): 0.22 to 0.55], those living in household of an HIV-positive vs HIV-negative index case (aOR = 0.56, 95% CI: 0.38 to 0.83), and contacts requiring a reassessment visit after the initial TB screening visit vs asymptomatic contacts (aOR = 0.20, 95% CI: 0.06 to 0.67) and was higher if living in Uganda vs Cameroon (aOR = 4.54, 95% CI: 1.17 to 17.62) or if another contact of the same index case was tested for HIV (aOR = 9.22, 95% CI: 5.25 to 16.18). CONCLUSION: HIV testing can be integrated into community-based household TB contact screening and is well-accepted.

Cost-effectiveness of community-based household tuberculosis contact management for children in Cameroon and Uganda: a modelling analysis of a cluster-randomised trial.

BACKGROUND: WHO recommends household contact management (HCM) including contact screening and tuberculosis-preventive treatment (TPT) for eligible children. The CONTACT trial found increased TPT initiation and completion rates when community health workers were used for HCM in Cameroon and Uganda. METHODS: We did a cost-utility analysis of the CONTACT trial using a health-system perspective to estimate the health impact, health-system costs, and cost-effectiveness of community-based versus facility-based HCM models of care. A decision-analytical modelling approach was used to evaluate the cost-effectiveness of the intervention compared with the standard of care using trial data on cascade of care, intervention effects, and resource use. Health outcomes were based on modelled progression to tuberculosis, mortality, and discounted disability-adjusted life-years (DALYs) averted. Health-care resource use, outcomes, costs (2021 US$), and cost-effectiveness are presented. FINDINGS: For every 1000 index patients diagnosed with tuberculosis, the intervention increased the number of TPT courses by 1110 (95% uncertainty interval 894 to 1227) in Cameroon and by 1078 (796 to 1220) in Uganda compared with the control model. The intervention prevented 15 (-3 to 49) tuberculosis deaths in Cameroon and 10 (-20 to 33) in Uganda. The incremental cost-effectiveness ratio was $620 per DALY averted in Cameroon and $970 per DALY averted in Uganda. INTERPRETATION: Community-based HCM approaches can substantially reduce child tuberculosis deaths and in our case would be considered cost-effective at willingness-to-pay thresholds of $1000 per DALY averted. Their impact and cost-effectiveness are likely to be greatest where baseline HCM coverage is lowest. FUNDING: Unitaid and UK Medical Research Council.

Effectiveness of a community-based approach for the investigation and management of children with household tuberculosis contact in Cameroon and Uganda: a cluster-randomised trial.

BACKGROUND: Globally, the uptake of tuberculosis-preventive treatment (TPT) among children with household tuberculosis contact remains low, partly due to the necessity of bringing children to health facilities for investigations. This study aimed to evaluate the effect on TPT initiation and completion of community-based approaches to tuberculosis contact investigations in Cameroon and Uganda. METHODS: We did a parallel, cluster-randomised, controlled trial across 20 clusters (consisting of 25 district hospitals and primary health centres) in Cameroon and Uganda, which were randomised (1:1) to receive a community-based approach (intervention group) or standard-of-care facility-based approach to contact screening and management (control group). The community-based approach consisted of symptom-based tuberculosis screening of all household contacts by community health workers at the household, with referral of symptomatic contacts to local facilities for investigations. Initiation of TPT (3-month course of rifampicin-isoniazid) was done by a nurse in the household, and home visits for TPT follow-up were done by community health workers. Index patients were people aged 15 years or older with bacteriologically confirmed, drug-susceptible, pulmonary tuberculosis diagnosed less than 1 month before inclusion and who declared at least one child or young adolescent (aged 0-14 years) household contact. The primary endpoint was the proportion of declared child contacts in the TPT target group (those aged <5 years irrespective of HIV status, and children aged 5-14 years living with HIV) who commenced and completed TPT, assessed in the modified intention-to-treat population (excluding enrolled index patients and their contacts who did not fit the eligibility criteria). Descriptive cascade of care assessment and generalised linear mixed modelling were used for comparison. This study is registered with ClinicalTrials.gov (NCT03832023). FINDINGS: The study included nine clusters in the intervention group (after excluding one cluster that did not enrol any index patients for >2 months) and ten in the control group. Between Oct 14, 2019 and Jan 13, 2022, 2894 child contacts were declared by 899 index patients with bacteriologically confirmed tuberculosis. Among all child contacts declared, 1548 (81·9%) of 1889 in the intervention group and 475 (47·3%) of 1005 in the control group were screened for tuberculosis. 1400 (48·4%) child contacts were considered to be in the TPT target group: 941 (49·8%) of 1889 in the intervention group and 459 (45·7%) of 1005 in the control group. In the TPT target group, TPT was commenced and completed in 752 (79·9%) of 941 child contacts in the intervention group and 283 (61·7%) of 459 in the control group (odds ratio 3·06 [95% CI 1·24-7·53]). INTERPRETATION: A community-based approach using community health workers can significantly increase contact investigation coverage and TPT completion among eligible child contacts in a tuberculosis-endemic setting. FUNDING: Unitaid. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Mortality and Cause of Death in Children With Presumptive Disseminated Tuberculosis.

BACKGROUND AND OBJECTIVES: Children experience high tuberculosis (TB)-related mortality but causes of death among those with presumptive TB are poorly documented. We describe the mortality, likely causes of death, and associated risk factors among vulnerable children admitted with presumptive TB in rural Uganda. METHODS: We conducted a prospective study of vulnerable children, defined as <2 years of age, HIV-positive, or severely malnourished, with a clinical suspicion of TB. Children were assessed for TB and followed for 24 weeks. TB classification and likely cause of death were assessed by an expert endpoint review committee, including insight gained from minimally invasive autopsies, when possible. RESULTS: Of the 219 children included, 157 (71.7%) were <2 years of age, 72 (32.9%) were HIV-positive, and 184 (84.0%) were severely malnourished. Seventy-one (32.4%) were classified as "likely tuberculosis" (15 confirmed and 56 unconfirmed), and 72 (32.9%) died. The median time to death was 12 days. The most frequent causes of death, ascertained for 59 children (81.9%), including 23 cases with autopsy results, were severe pneumonia excluding confirmed TB (23.7%), hypovolemic shock due to diarrhea (20.3%), cardiac failure (13.6%), severe sepsis (13.6%), and confirmed TB (10.2%). Mortality risk factors were confirmed TB (adjusted hazard ratio [aHR] = 2.84 [95% confidence interval (CI): 1.19-6.77]), being HIV-positive (aHR = 2.45 [95% CI: 1.37-4.38]), and severe clinical state on admission (aHR = 2.45 [95% CI: 1.29-4.66]). CONCLUSIONS: Vulnerable children hospitalized with presumptive TB experienced high mortality. A better understanding of the likely causes of death in this group is important to guide empirical management.

The Association Between Social Network Characteristics and Tuberculosis Infection Among Adults in 9 Rural Ugandan Communities.

BACKGROUND: Social network analysis can elucidate tuberculosis transmission dynamics outside the home and may inform novel network-based case-finding strategies. METHODS: We assessed the association between social network characteristics and prevalent tuberculosis infection among residents (aged ≥15 years) of 9 rural communities in Eastern Uganda. Social contacts named during a census were used to create community-specific nonhousehold social networks. We evaluated whether social network structure and characteristics of first-degree contacts (sex, human immunodeficiency virus [HIV] status, tuberculosis infection) were associated with revalent tuberculosis infection (positive tuberculin skin test [TST] result) after adjusting for individual-level risk factors (age, sex, HIV status, tuberculosis contact, wealth, occupation, and Bacillus Calmette-Guérin [BCG] vaccination) with targeted maximum likelihood estimation. RESULTS: Among 3 335 residents sampled for TST, 32% had a positive TST results and 4% reported a tuberculosis contact. The social network contained 15 328 first-degree contacts. Persons with the most network centrality (top 10%) (adjusted risk ratio, 1.3 [95% confidence interval, 1.1-1.1]) and the most (top 10%) male contacts (1.5 [1.3-1.9]) had a higher risk of prevalent tuberculosis, than those in the remaining 90%. People with ≥1 contact with HIV (adjusted risk ratio, 1.3 [95% confidence interval, 1.1-1.6]) and ≥2 contacts with tuberculosis infection were more likely to have tuberculosis themselves (2.6 [ 95% confidence interval: 2.2-2.9]). CONCLUSIONS: Social networks with higher centrality, more men, contacts with HIV, and tuberculosis infection were positively associated with tuberculosis infection. Tuberculosis transmission within measurable social networks may explain prevalent tuberculosis not associated with a household contact. Further study on network-informed tuberculosis case finding interventions is warranted.

Feasibility of a randomized clinical trial evaluating a community intervention for household tuberculosis child contact management in Cameroon and Uganda.

BACKGROUND: One of the main barriers of the management of household tuberculosis child contacts is the necessity for parents to bring healthy children to the facility. We assessed the feasibility of a community intervention for tuberculosis (TB) household child contact management and the conditions for its evaluation in a cluster randomized controlled trial in Cameroon and Uganda. METHODS: We assessed three dimensions of feasibility using a mixed method approach: (1) recruitment capability using retrospective aggregated data from facility registers; (2) acceptability of the intervention using focus group discussions with TB patients and in-depth interviews with healthcare providers and community leaders; and (3) adaptation, integration, and resources of the intervention in existing TB services using a survey and discussions with stakeholders. RESULTS: Reaching the sample size is feasible in all clusters in 15 months with the condition of regrouping 2 facilities in the same cluster in Uganda due to decentralization of TB services. Community health worker (CHW) selection and training and simplified tools for contact screening, tolerability, and adherence of preventive therapy were key elements for the implementation of the community intervention. Healthcare providers and patients found the intervention of child contact investigations and TB preventive treatment management in the household acceptable in both countries due to its benefits (competing priorities, transport cost) as compared to facility-based management. TB stigma was present, but not a barrier for the community intervention. Visit schedule and team conduct were identified as key facilitators for the intervention. CONCLUSIONS: This study shows that evaluating a community intervention for TB child contact management in a cluster randomized trial is feasible in Cameroon and Uganda. TRIAL REGISTRATION: Clini calTr ials. gov NCT03832023 . Registered on February 6th 2019.