Determinants of tuberculosis disease development in children in central Ethiopia: A matched case-control study.

BACKGROUND: The risk factors for tuberculosis (TB) disease development in children remained understudied, particularly in low-income countries like Ethiopia. The objective of this study was to identify determinants of TB disease development in general and in relation to BCG vaccination in children in central Ethiopia. METHODS: We employed a 1:1 age-matched case-control design to compare the characteristics of children who developed TB (cases) with those who did not (controls). Data were collected in healthcare facilities in Addis Ababa city, Adama, and Bishoftu towns between September 25, 2021, and June 24, 2022. Two hundred and fifty-six cases were drawn at random from a list of childhood TB patients entered into SPSS software, and 256 controls were selected sequentially at triage from the same healthcare facilities where the cases were treated. A bivariate conditional logistic regression analysis was performed first to select candidate variables with p-values less than or equal to 0.20 for the multivariable model. Finally, variables with a p-value less than 0.05 for a matched adjusted odds ratio (mORadj) were reported as independent determinants of TB disease development. RESULTS: The mean age of the cases was nine years, while that of the controls was 10 years. Males comprised 126 cases (49.2%) and 119 controls (46.5%), with the remainder being females. Ninety-nine (38.7%) of the cases were not BCG-vaccinated, compared to 58 (22.7%) of the controls. Household TB contact was experienced by 43 (16.8%) of the cases and 10 (3.9%) of the controls. Twenty-two (8.6%) of the cases and six (2.3%) of the controls were exposed to a cigarette smoker in their household. Twenty-two (8.6%) of the cases and three (1.2%) of the controls were positive for HIV. Children who were not vaccinated with BCG at birth or within two weeks of birth had more than twice the odds (mORadj = 2.11, 95% CI = 1.28-3.48) of developing TB compared to those who were. Children who ever lived with a TB-sick family member (mORadj = 4.28, 95% CI = 1.95-9.39), smoking family members (mORadj = 3.15, 95% CI = 1.07-9.27), and HIV-infected children (mORadj = 8.71, 95% CI = 1.96-38.66) also had higher odds of developing TB disease than their counterparts. CONCLUSIONS: Being BCG-unvaccinated, having household TB contact, having a smoker in the household, and being HIV-infected were found to be independent determinants of TB disease development among children.

Management of the infant born to a mother with tuberculosis: a systematic review and consensus practice guideline.

Infants born to mothers with tuberculosis disease are at increased risk of developing tuberculosis disease themselves. We reviewed published studies and guidelines on the management of these infants to inform the development of a consensus practice guideline. We searched MEDLINE, CINAHL, and Cochrane Library from database inception to Dec 1, 2022, for original studies reporting the management and outcome of infants born to mothers with tuberculosis. Of the 521 published papers identified, only three met inclusion criteria and no evidence-based conclusions could be drawn from these studies, given their narrow scope, variable aims, descriptive nature, inconsistent data collection, and high attrition rates. We also assessed a collection of national and international guidelines to inform a consensus practice guideline developed by an international panel of experts from different epidemiological contexts. The 16 guidelines reviewed had consistent features to inform the expert consultation process. Two management algorithms were developed-one for infants born to mothers considered potentially infectious at the time of delivery and another for mothers not considered infectious at the time of delivery-with different guidance for high and low tuberculosis incidence settings. This systematic review and consensus practice guideline should facilitate more consistent clinical management, support the collection of better data, and encourage the development of more studies to improve evidence-based care.

The magnitude of unfavorable tuberculosis treatment outcomes and their relation with baseline undernutrition and sustained undernutrition among children receiving tuberculosis treatment in central Ethiopia.

Background: One of the global key indicators for monitoring the implementation of the World Health Organization's End Tuberculosis (TB) Strategy is the treatment outcome rate. Objective: This study aims to assess the magnitude of unfavorable treatment outcomes and estimate their relationship with baseline undernutrition and sustained undernutrition among children receiving TB treatment in central Ethiopia. Methods: This retrospective cohort study included children treated for drug-susceptible TB between June 2014 and February 2022. The study comprised children aged 16 and younger who were treated in 32 randomly selected healthcare facilities. A log-binomial model was used to compute adjusted risk ratios (aRR) with 95% confidence intervals (CIs). Results: Of 640 children, 42 (6.6%; 95% CI = 4.8-8.8%) had an unfavorable TB treatment outcomes, with 31 (73.8%; 95% CI = 58.0-86.1%) occurring during the continuation phase of TB treatment. We confirmed that baseline undernutrition (aRR = 2.68; 95% CI = 1.53-4.71), age less than 10 years (aRR = 2.69; 95% CI = 1.56-4.61), HIV infection (aRR = 2.62; 95% CI = 1.50-4.59), and relapsed TB (aRR = 3.19; 95% CI = 1.79-4.71) were independent predictors of unfavorable TB treatment outcomes. When we looked separately at children who had been on TB treatment for two months or more, we found that sustained undernutrition (aRR = 3.76; 95% CI = 1.90-7.43), age below ten years (aRR = 2.60; 95% CI = 1.31-5.15), and HIV infection (aRR = 2.26; 95% CI = 1.11-4.59) remained predictors of unfavorable outcomes, just as they had in the first two months. However, the effect of relapsed TB became insignificant (aRR = 2.81; 95% CI = 0.96-8.22) after the first two months TB treatment. Conclusions: The magnitude of unfavorable TB treatment outcomes among children in central Ethiopia met the World Health Organization's 2025 milestone. Nearly three-quarters of unfavorable TB treatment outcomes occurred during the continuation phase of TB treatment. Baseline undernutrition, sustained undernutrition, younger age, HIV infection, and relapsed TB were found to be independent predictors of unfavorable TB treatment outcomes among children receiving TB treatment in central Ethiopia.

Predicted Pharmacokinetic Interactions Between Hormonal Contraception and Single or Intermittently Dosed Rifampicin.

The scale-up of rifampicin-based prevention regimens is an essential part of the global leprosy strategy. Daily rifampicin may reduce the effectiveness of the oral contraceptive pill (OCP), but little is known about the effects of rifampicin at the less frequent dosing intervals used for leprosy prophylaxis. As many women of reproductive age rely on OCP for family planning, evaluating the interaction with less-than-daily rifampicin regimens would enhance the scalability and acceptability of leprosy prophylaxis. Using a semi-mechanistic pharmacokinetic model of rifampicin induction, we simulated predicted changes in OCP clearance when coadministered with varying rifampicin dosing schedules. Rifampicin given as a single dose (600 or 1200 mg) or 600 mg every 4 weeks was not predicted to result in a clinically relevant interaction with OCP, defined as a >25% increase in clearance. Simulations of daily rifampicin were predicted to increase OCP clearance within the range of observed changes previously reported in the literature. Therefore, our findings suggest that OCP efficacy will be maintained when coadministered with rifampicin-based leprosy prophylaxis regimens of 600 mg once, 1200 mg once, and 600 mg every 4 weeks. This work provides reassurance to stakeholders that leprosy prophylaxis can be used with OCP without any additional recommendations for contraception prevention.

Epidemiology of childhood tuberculosis and predictors of death among children on tuberculosis treatment in central Ethiopia: an extended Cox model challenged survival analysis.

BACKGROUND: Childhood tuberculosis (TB) was poorly studied in Ethiopia. This study aimed to describe the epidemiology of childhood TB and identify predictors of death among children on TB treatment. METHODS: This is a retrospective cohort study of children aged 16 and younger who were treated for TB between 2014 and 2022. Data were extracted from TB registers of 32 healthcare facilities in central Ethiopia. Phone interview was also conducted to measure variables without a space and not recorded in the registers. Frequency tables and a graph were used to describe the epidemiology of childhood TB. To perform survival analysis, we used a Cox proportional hazards model, which was then challenged with an extended Cox model. RESULTS: We enrolled 640 children with TB, 80 (12.5%) of whom were under the age of two. Five hundred and fifty-seven (87.0%) of the enrolled children had not had known household TB contact. Thirty-six (5.6%) children died while being treated for TB. Nine (25%) of those who died were under the age of two. HIV infection (aHR = 4.2; 95% CI = 1.9-9.3), under nutrition (aHR = 4.2; 95% CI = 2.2-10.48), being under 10 years old (aHR = 4.1; 95% CI = 1.7-9.7), and relapsed TB (aHR = 3.7; 95% CI = 1.1-13.1) were all independent predictors of death. Children who were found to be still undernourished two months after starting TB treatment also had a higher risk of death (aHR = 5.64, 95% CI = 2.42-13.14) than normally nourished children. CONCLUSIONS: The majority of children had no known pulmonary TB household contact implying that they contracted TB from the community. The death rate among children on TB treatment was unacceptably high, with children under the age of two being disproportionately impacted. HIV infection, baseline as well as persistent under nutrition, age < 10 years, and relapsed TB all increased the risk of death in children undergoing TB treatment.

Pragmatic cluster-randomized trial of home-based preventive treatment for TB in Ethiopia and South Africa (CHIP-TB).

BACKGROUND: Each year, 1 million children develop TB resulting in over 200,000 child deaths. TB preventive treatment (TPT) is highly effective in preventing TB but remains poorly implemented for household child contacts. Home-based child contact management and TPT services may improve access to care. In this study, we aim to evaluate the effectiveness and cost-effectiveness of home-based contact management with TPT initiation in two TB high-burden African countries, Ethiopia and South Africa. METHODS: This pragmatic cluster randomized trial compares home-based versus facility-based care delivery models for contact management. Thirty-six clinics with decentralized TB services (18 in Ethiopia and 18 in South Africa) were randomized in a 1:1 ratio to conduct either home-based or facility-based contact management. The study will attempt to enroll all eligible close child contacts of infectious drug-sensitive TB index patients diagnosed and treated for TB by one of the study clinics. Child TB contact management, including contact tracing, child evaluation, and TPT initiation and follow-up, will take place in the child's home for the intervention arm and at the clinic for the control arm. The primary outcome is the cluster-level ratio of the number of household child contacts less than 15 years of age in Ethiopia and less than 5 years of age in South Africa initiated on TPT per index patient, comparing the intervention to the control arm. Secondary outcomes include child contact identification and the TB prevention continuum of care. Other implementation outcomes include acceptability, feasibility, fidelity, cost, and cost-effectiveness of the intervention. DISCUSSION: This implementation research trial will determine whether home-based contact management identifies and initiates more household child contacts on TPT than facility-based contact management. TRIAL REGISTRATION: NCT04369326 . Registered on April 30, 2020.

Number Needed to Screen for Tuberculosis Disease Among Children: A Systematic Review.

CONTEXT: Improving detection of pediatric tuberculosis (TB) is critical to reducing morbidity and mortality among children. OBJECTIVE: We conducted a systematic review to estimate the number of children needed to screen (NNS) to detect a single case of active TB using different active case finding (ACF) screening approaches and across different settings. DATA SOURCES: We searched 4 databases (PubMed, Embase, Scopus, and the Cochrane Library) for articles published from November 2010 to February 2020. STUDY SELECTION: We included studies of TB ACF in children using symptom-based screening, clinical indicators, chest x-ray, and Xpert. DATA EXTRACTION: We indirectly estimated the weighted mean NNS for a given modality, location, and population using the inverse of the weighted prevalence. We assessed risk of bias using a modified AXIS tool. RESULTS: We screened 27 221 titles and abstracts, of which we included 31 studies of ACF in children < 15 years old. Symptom-based screening was the most common screening modality (weighted mean NNS: 257 [range, 5-undefined], 19 studies). The weighted mean NNS was lower in both inpatient (216 [18-241]) and outpatient (67 [5-undefined]) settings (107 [5-undefined]) compared with community (1117 [28-5146]) and school settings (464 [118-665]). Risk of bias was low. LIMITATIONS: Heterogeneity in the screening modalities and populations make it difficult to draw conclusions. CONCLUSIONS: We identified a potential opportunity to increase TB detection by screening children presenting in health care settings. Pediatric TB case finding interventions should incorporate evidence-based interventions and local contextual information in an effort to detect as many children with TB as possible.

Preventive Treatment for Household Contacts of Drug-Susceptible Tuberculosis Patients.

People who live in the household of someone with infectious pulmonary tuberculosis are at a high risk of tuberculosis infection and subsequent progression to tuberculosis disease. These individuals are prioritized for contact investigation and tuberculosis preventive treatment (TPT). The treatment of TB infection is critical to prevent the progression of infection to disease and is prioritized in household contacts. Despite the availability of TPT, uptake in household contacts is poor. Multiple barriers prevent the optimal implementation of these policies. This manuscript lays out potential next steps for closing the policy-to-implementation gap in household contacts of all ages.

Tuberculosis in Children.

Tuberculosis (TB) is one of the leading causes of mortality in children worldwide, but there remain significant challenges in diagnosing and treating TB infection and disease. Treatment of TB infection in children and adolescents is critical to prevent progression to TB disease and to prevent them from becoming the future reservoir for TB transmission. This article reviews the clinical approach to diagnosing and treating latent TB infection and pulmonary and extrapulmonary TB disease in children. Also discussed are emerging diagnostics and therapeutic regimens that aim to improve pediatric TB detection and outcomes.

Plasma Kynurenine-to-Tryptophan Ratio, a Highly Sensitive Blood-Based Diagnostic Tool for Tuberculosis in Pregnant Women Living With Human Immunodeficiency Virus (HIV).

BACKGROUND: For pregnant women living with human immunodeficiency virus (HIV), concurrent active tuberculosis (TB) disease increases the risk of maternal mortality and poor pregnancy outcomes. Plasma indoleamine 2,3-dioxygenase (IDO) activity measured by kynurenine-to-tryptophan (K/T) ratio has been proposed as a blood-based TB biomarker. We investigated whether plasma K/T ratio could be used to diagnose active TB among pregnant women with HIV. METHODS: Using an enzyme-linked immunosorbent assay (ELISA), we measured K/T ratio in 72 pregnant women with and active TB and compared them to 117 pregnant women with HIB but without TB, matched by age and gestational age. RESULTS: Plasma K/T ratio was significantly elevated during pregnancy compared to sampling done after pregnancy (P < .0001). Pregnant women who had received isoniazid preventive therapy (IPT) before enrollment had decreased plasma K/T ratio compared to those who had not received IPT (P = .0174). Plasma K/T ratio was elevated in women with active TB at time of diagnosis compared to those without TB (P < .0001). Using a cutoff of 0.100, plasma K/T ratio gave a diagnostic sensitivity of 94% (95% confidence interval [CI]: 82-95), specificity of 90% (95% CI: 80-91), positive predictive value (PPV) 85% and negative predictive value (NPV) 98%. A receiver operating characteristic curve (ROC) gave an area under the curve of 0.95 (95% CI: .92-.97, P < .0001).In conclusion, plasma K/T ratio is a sensitive blood-based diagnostic test for active TB disease in pregnant women living with HIV. Plasma K/T ratio should be further evaluated as an initial TB diagnostic test to determine its impact on patient care.

Cost-effectiveness of scaling up short course preventive therapy for tuberculosis among children across 12 countries.

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).

Post-trial perceptions of a symptom-based TB screening intervention in South Africa: implementation insights and future directions for TB preventive healthcare services.

BACKGROUND: Tuberculosis is a top-10 cause of under-5 mortality, despite policies promoting tuberculosis preventive therapy (TPT). We previously conducted a cluster randomized trial to evaluate the effectiveness of symptom-based versus tuberculin skin-based screening on child TPT uptake. Symptom-based screening did not improve TPT uptake and nearly two-thirds of child contacts were not identified or not linked to care. Here we qualitatively explored healthcare provider perceptions of factors that impacted TPT uptake among child contacts. METHODS: Sixteen in-depth interviews were conducted with key informants including healthcare providers and administrators who participated in the trial in Matlosana, South Africa. The participants' experience with symptom-based screening, study implementation strategies, and ongoing challenges with child contact identification and linkage to care were explored. Interviews were systematically coded and thematic content analysis was conducted. RESULTS: Participants' had mixed opinions about symptom-based screening and high acceptability of the study implementation strategies. A key barrier to optimizing child contact screening and evaluation was the supervision and training of community health workers. CONCLUSIONS: Symptom screening is a simple and effective strategy to evaluate child contacts, but additional pediatric training is needed to provide comfort with decision making. New clinic-based child contact files were highly valued by providers who continued to use them after trial completion. Future interventions to improve child contact management will need to address how to best utilize community health workers in identifying and linking child contacts to care. TRIAL REGISTRATION: The results presented here were from research related to NCT03074799 , retrospectively registered on 9 March 2017.

Child Contact Case Management-A Major Policy-Practice Gap in High-Burden Countries.

The 2021 Global Tuberculosis (TB) report shows slow progress towards closing the pediatric TB detection gap and improving the TB preventive treatment (TPT) coverage among child and adolescent contacts. This review presents the current knowledge around contact case management (CCM) in low-resource settings, with a focus on child contacts, which represents a key priority population for CCM and TPT. Compelling evidence demonstrates that CCM interventions are a key gateway for both TB case finding and identification of those in need of TPT, and their yield and effectiveness should provide a strong rationale for prioritization by national TB programs. A growing body of evidence is now showing that innovative models of care focused on community-based and patient-centered approaches to household contact investigation can help narrow down the CCM implementation gaps that we are currently facing. The availability of shorter and child-friendly TPT regimens for child contacts provide an additional important opportunity to improve TPT acceptability and adherence. Prioritization of TB CCM implementation and adequate resource mobilization by ministries of health, donors and implementing agencies is needed to timely close the gap.

Coronavirus Disease 2019 (COVID-19) Pharmacologic Treatments for Children: Research Priorities and Approach to Pediatric Studies.

Clinical trials of pharmacologic treatments of coronavirus disease 2019 (COVID-19) are being rapidly designed and implemented in adults. Children are often not considered during development of novel treatments for infectious diseases until very late. Although children appear to have a lower risk compared with adults of severe COVID-19 disease, a substantial number of children globally will benefit from pharmacologic treatments. It will be reasonable to extrapolate efficacy of most treatments from adult trials to children. Pediatric trials should focus on characterizing a treatment's pharmacokinetics, optimal dose, and safety across the age spectrum. These trials should use an adaptive design to efficiently add or remove arms in what will be a rapidly evolving treatment landscape, and should involve a large number of sites across the globe in a collaborative effort to facilitate efficient implementation. All stakeholders must commit to equitable access to any effective, safe treatment for children everywhere.

Improving Tuberculosis Preventive Therapy Uptake: A Cluster-randomized Trial of Symptom-based Versus Tuberculin Skin Test-based Screening of Household Tuberculosis Contacts Less Than 5 Years of Age.

BACKGROUND: Tuberculosis preventive therapy (TPT) is highly effective at preventing tuberculosis disease in household child contacts (<5 years), but is poorly implemented worldwide. In 2006, the World Health Organization recommended symptom-based screening as a replacement for tuberculin skin testing (TST) to simplify contact evaluation and improve implementation. We aimed to determine the effectiveness of this recommendation. METHODS: We conducted a pragmatic, cluster-randomized trial to determine whether contact evaluation using symptom screening improved the proportion of identified child contacts who initiated TPT, compared to TST-based screening, in Matlosana, South Africa. We randomized 16 clinics to either symptom-based or TST-based contact evaluations. Outcome data were abstracted from customized child contact management files. RESULTS: Contact tracing identified 550 and 467 child contacts in the symptom and TST arms, respectively (0.39 vs 0.32 per case, respectively; P = .27). There was no significant difference by arm in the adjusted proportion of identified child contacts who were screened (52% in symptom arm vs 60% in TST arm; P = .39). The adjusted proportion of identified child contacts who initiated TPT or tuberculosis treatment was 51.5% in the symptom clinics and 57.1% in the TST clinics (difference -5.6%, 95% confidence interval -23.7 to 12.6; P = .52). Based on the district's historic average of 0.7 child contacts per index case, 14% and 15% of child contacts completed 6 months of TPT in the symptom and TST arms, respectively (P = .89). CONCLUSIONS: Symptom-based screening did not improve the proportion of identified child contacts evaluated or initiated on TPT, compared to TST-based screening. Further research is needed to identify bottlenecks and evaluate interventions to ensure all child contacts receive TPT. CLINICAL TRIALS REGISTRATION: NCT03074799.

Isoniazid Preventive Therapy and Pregnancy Outcomes in Women Living With Human Immunodeficiency Virus in the Tshepiso Cohort.

BACKGROUND: Both pregnancy and human immunodeficiency virus (HIV) increase the risk of tuberculosis disease, which results in poor maternal, pregnancy, and infant outcomes. Isoniazid preventive therapy (IPT) reduces mortality among individuals living with HIV in high-burden settings but has recently been associated with adverse pregnancy outcomes when initiated during pregnancy. METHODS: In this secondary analysis, we used multivariable logistic regression to evaluate the association between IPT exposure and adverse pregnancy outcomes (fetal demise, prematurity, low birth weight, congenital anomaly) in pregnant women living with HIV enrolled as controls in the Tshepiso study, a prospective observational cohort of pregnant women living with HIV with and without tuberculosis disease in Soweto, South Africa, from 2011-2014. RESULTS: There were 151 women enrolled with known pregnancy outcomes; 69 (46%) reported IPT initiation during pregnancy. Of the 69 IPT-exposed women, 11 (16%) had an adverse pregnancy outcome compared with 23 (28%) IPT-unexposed women. The adjusted odds of having an adverse pregnancy outcome was 2.5 (95% confidence interval, 1.0-6.5; P = .048) times higher in IPT-unexposed women compared with IPT-exposed women after controlling for maternal age, CD4 count, viral load, antiretroviral regimen, body mass index, and anemia. CONCLUSIONS: IPT exposure during pregnancy was not negatively associated with pregnancy outcomes after controlling for demographic, clinical, and HIV-related factors. These results provide some reassurance that IPT can be safely used in the second or third trimester of pregnancy. Additional research is needed to evaluate the safety of IPT and new short-course tuberculosis preventive therapies during pregnancy.