Eric Balestre’s research while affiliated with University of Bordeaux and other places

Objectives Chest x‐ray (CXR) plays an important role in childhood tuberculosis (TB) diagnosis, but access to quality CXR remains a major challenge in resource‐limited settings. Digital CXR (d‐CXR) can solve some image quality issues and facilitate their transfer for quality control. We assess the implementation of introducing d‐CXR in 12 district hospitals (DHs) in 2021–2022 across Cambodia, Cameroon, Ivory Coast, Mozambique, Sierra Leone and Uganda as part of the TB‐speed decentralisation study on childhood TB diagnosis. Methods For digitisation of CXR, digital radiography (DR) plates were setup on existing analogue radiography devices. d‐CXR were transferred to an international server at Bordeaux University and downloaded by sites' clinicians for interpretation. We assessed the uptake and performance of CXR services and health care workers' (HCW) perceptions of d‐CXR implementation. We used a convergent mixed method approach utilising process data, individual interviews with 113 HCWs involved in performing or interpreting d‐CXRs and site support supervision reports. Results Of 3104 children with presumptive TB, 1642 (52.9%) had at least one d‐CXR, including 1505, 136 and 1 children with one, two and three d‐CXRs, respectively, resulting in a total of 1780 d‐CXR. Of them, 1773 (99.6%) were of good quality and 1772/1773 (99.9%) were interpreted by sites' clinicians. One hundred and sixty‐four children had no d‐CXR performed despite attending the radiography department: 126, 37 and 1 with one, two and three attempts, respectively. d‐CXRs were not performed in 21.6% (44/203) due to connectivity problem between the DR plate captor and the computer. HCW reported good perceptions of d‐CXR and of the DR plates provided. The main challenge was the upload to and download from the server of d‐CXRs due to limited internet access. Conclusion d‐CXR using DR plates was feasible at DH level and provided good quality images but required overcoming operational challenges.

Objectives Chest X-ray (CXR) plays an important role in childhood tuberculosis (TB) diagnosis but access to quality CXR remains a major challenge in resource-limited settings. Digital CXR (d-CXR) can solve some image quality issues and facilitate their transfer for quality control. We describe the implementation of introducing d-CXR in twelve district hospitals (DH) in 2021-22 across Cambodia, Cameroon, Ivory Coast, Mozambique, Sierra Leone and Uganda as part of the TB-Speed decentralization study on childhood tuberculosis diagnosis. Methods For digitization of CXR Digital Radiography (DR) plates was set-up on existing analogue radiography machines. D-CXR were transferred to an international server at Bordeaux University and downloaded by sites’ clinicians for interpretation. We assessed the pre-intervention (baseline situation and d-CXR set-up) and per-intervention (uptake, challenges and health care workers’ (HCW) perceptions) of d-CXR implementation. We used a convergent mixed method approach utilizing process data, individual interviews with 113 HCWs involved in performing or interpreting d-CXRs and site support supervision reports. Results Of 3104 children with presumptive TB, 1642 (52.9%) had at least one d-CXR including 1505, 136 and 1 children with one, two and three d-CXR respectively, resulting in a total of 1780 d-CXR. Of them, 1773 (99.6%) were of good quality and 1772/1773 (99.9%) were interpreted by sites’ clinicians. 164 children had no d-CXR performed despite attending the radiography department: 126, 37 and 1 with one, two and three attempts, respectively. D-CXRs were not performed in 21.6% (44/203) due to connectivity problem between the DR plate captor and the computer. HCWs reported good perceptions of d-CXR and of the DR plates provided. The main challenge was the upload to and download from the server of d-CXRs, due to limited internet access. Conclusion D-CXR using DR plates was feasible at district hospital level and provided good quality images but required overcoming operational challenges.

Background In children with severe acute malnutrition (SAM) tuberculosis is common, challenging to diagnose, and often fatal. We developed tuberculosis treatment decision algorithms (TDAs) for children under the age of 5 years with SAM. Methods In this prospective diagnostic study, we enrolled and followed up children aged <60 months hospitalised with SAM at three tertiary hospitals in Zambia and Uganda from 4 November 2019 to 20 June 2022. We included children aged 2–59 months with SAM as defined by WHO and hospitalised following the WHO clinical criteria. We excluded children with current or history of antituberculosis treatment within the preceding 3 months. They underwent tuberculosis symptom screening, clinical assessment, chest X-ray, abdominal ultrasound, Xpert MTB/RIF Ultra (Ultra) and culture on respiratory and stool samples with 6 months follow-up. Tuberculosis was retrospectively defined using the 2015 standard case definition for childhood tuberculosis. We used logistic regression to develop diagnostic prediction models for a one-step diagnosis and a two-step screening and diagnostic approaches. We derived scores from models using WHO-recommended thresholds for sensitivity and proposed TDAs. This study is registered with ClinicalTrials.gov, NCT04240990. Findings Of 1906 children hospitalised with SAM during the study period, 1230 were screened, 1152 were eligible and 603 were enrolled. Of the 603 children enrolled–median age 15 (inter-quartile range (IQR): 11–20) months and 65 (11.0%) living with HIV–114 (18.9%) were diagnosed with tuberculosis, including 51 (8.5%) with microbiological confirmation and 104 (17.2%) initiated treatment at a median of 6(IQR: 2–10) days after inclusion. 108 children were retrospectively classified as having tuberculosis resulting in a prevalence of 17.9% (95% confidence intervals (CI): 15.1; 21.2). 75 (69.4%) children with tuberculosis reported cough of any duration, 32 (29.6%) cough ≥2 weeks and 11 (10.2%) tuberculosis contact history. 535 children had complete data and were included in the diagnostic prediction model. The one-step diagnostic model had 15 predictors, including Ultra, clinical, radiographic, and abdominal features, an area under the receiving operating curve (AUROC) of 0.910, and derived TDA sensitivity of 86.14% (95% CI: 78.07–91.56) and specificity of 80.88% (95% CI: 76.91–84.30). The two-step model had AUROCs of 0.750 and 0.912 for screening and diagnosis, respectively, and derived combined TDA sensitivity of 79.21% (95% CI: 70.30–85.98) and a specificity of 83.64% (95% CI: 79.87–86.82). Interpretation Tuberculosis prevalence was high among hospitalised children with SAM, with atypical clinical features. TDAs achieved satisfactory diagnostic accuracy and could be used to improve diagnosis in this vulnerable group. Funding Unitaid.

Background The burden of childhood tuberculosis remains high globally, largely due to under-diagnosis. Decentralising childhood tuberculosis diagnosis services to lower health system levels could improve case detection, but there is little empirically based evidence on cost-effectiveness or budget impact. Methods In this mathematical modelling study, we assessed the cost-effectiveness and budget impact of decentralising a comprehensive diagnosis package for childhood tuberculosis to district hospitals (DH-focused) or primary health centres (PHC-focused) compared to standard of care (SOC). The project was conducted in Cambodia, Cameroon, Côte d’Ivoire, Mozambique, Sierra Leone, and Uganda between August 1st, 2018 and September 30th, 2021. A mathematical model was developed to assess the health and economic outcomes of the intervention from a health system perspective. Estimated outcomes were tuberculosis cases, deaths, disability-adjusted life years (DALYs) and incremental cost-effectiveness ratios (ICERs). We also calculated the budget impact of nationwide implementation. The TB-Speed Decentralization study is registered with ClinicalTrials.gov, NCT04038632. Findings For the DH-focused strategy versus SOC, ICERs ranged between $263 (Cambodia) and$342 (Côte d’Ivoire) per DALY averted. For the PHC-focused strategy versus SOC, ICERs ranged between $477 (Cambodia) and$599 (Côte d’Ivoire) per DALY averted. Results were sensitive to TB prevalence and the discount rate used. The additional costs of implementing the DH-focused strategy ranged between $12.8 M (range 10.8–16.4) (Cambodia) and$50.4 M (36.5–74.4) (Mozambique), and between $13.9 M (12.6–15.6) (Sierra Leone) and$134.6 M (127.1–143.0) (Uganda) for the PHC-focused strategy. Interpretation The DH-focused strategy may be cost-effective in some countries, depending on the cost-effectiveness threshold used for policy making. Either intervention would require substantial early investment. Funding Unitaid.

Background Childhood tuberculosis (TB) remains underdiagnosed largely because of limited awareness and poor access to all or any of specimen collection, molecular testing, clinical evaluation, and chest radiography at low levels of care. Decentralising childhood TB diagnostics to district hospitals (DH) and primary health centres (PHC) could improve case detection. Methods We conducted an operational research study using a pre-post intervention cross-sectional study design in 12 DHs and 47 PHCs of 12 districts across Cambodia, Cameroon, Côte d’Ivoire, Mozambique, Sierra Leone and Uganda. The intervention included 1) a comprehensive diagnosis package at patient-level with tuberculosis screening for all sick children and young adolescents <15 years, and clinical evaluation, Xpert Ultra-testing on respiratory and stool samples, and chest radiography for children with presumptive TB, and 2) two decentralisation approaches (PHC-focused or DH-focused) to which districts were randomly allocated at country level. We collected aggregated and individual data. We compared the proportion of tuberculosis detection in children and young adolescents <15 years pre-intervention (01 August 2018–30 November 2019) versus during intervention (07 March 2020–30 September 2021), overall and by decentralisation approach. This study is registered with ClinicalTrials.gov, NCT04038632. Findings TB was diagnosed in 217/255,512 (0.08%) children and young adolescent <15 years attending care pre-intervention versus 411/179,581 (0.23%) during intervention, (OR: 3.59 [95% CI 1.99–6.46], p-value<0.0001; p-value = 0.055 after correcting for over-dispersion). In DH-focused districts, TB diagnosis was 80/122,570 (0.07%) versus 302/86,186 (0.35%) (OR: 4.07 [1.86–8.90]; p-value = 0.0005; p-value = 0.12 after correcting for over-dispersion); and 137/132,942 (0.10%) versus 109/93,395 (0.11%) in PHC-focused districts, respectively (OR: 2.92 [1.25–6.81; p-value = 0.013; p-value = 0.26 after correcting for over-dispersion). Interpretation Decentralising and strengthening childhood TB diagnosis at lower levels of care increases tuberculosis case detection but the difference was not statistically significant. Funding source Unitaid, Grant number 2017-15-UBx-TB-SPEED

Background Tuberculosis diagnosis might be delayed or missed in children with severe pneumonia because this diagnosis is usually only considered in cases of prolonged symptoms or antibiotic failure. Systematic tuberculosis detection at hospital admission could increase case detection and reduce mortality. Methods We did a stepped-wedge cluster-randomised trial in 16 hospitals from six countries (Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Uganda, and Zambia) with high incidence of tuberculosis. Children younger than 5 years with WHO-defined severe pneumonia received either the standard of care (control group) or standard of care plus Xpert MTB/RIF Ultra (Xpert Ultra; Cepheid, Sunnyvale, CA, USA) on nasopharyngeal aspirate and stool samples (intervention group). Clusters (hospitals) were progressively switched from control to intervention at 5-week intervals, using a computer-generated random sequence, stratified on incidence rate of tuberculosis at country level, and masked to teams until 5 weeks before switch. We assessed the effect of the intervention on primary (12-week all-cause mortality) and secondary (including tuberculosis diagnosis) outcomes, using generalised linear mixed models. The primary analysis was by intention to treat. We described outcomes in children with severe acute malnutrition in a post hoc analysis. This study is registered with ClinicalTrials.gov (NCT03831906) and the Pan African Clinical Trial Registry (PACTR202101615120643). Findings From March 21, 2019, to March 30, 2021, we enrolled 1401 children in the control group and 1169 children in the intervention group. In the intervention group, 1140 (97·5%) children had nasopharyngeal aspirates and 942 (80·6%) had their stool collected; 24 (2·1%) had positive Xpert Ultra. At 12 weeks, 110 (7·9%) children in the control group and 91 (7·8%) children in the intervention group had died (adjusted odds ratio [OR] 0·986, 95% CI 0·597–1·630, p=0·957), and 74 (5·3%) children in the control group and 88 (7·5%) children in the intervention group had tuberculosis diagnosed (adjusted OR 1·238, 95% CI 0·696–2·202, p=0·467). In children with severe acute malnutrition, 57 (23·8%) of 240 children in the control group and 53 (17·8%) of 297 children in the intervention group died, and 36 (15·0%) of 240 children in the control group and 56 (18·9%) of 297 children in the intervention group were diagnosed with tuberculosis. The main adverse events associated with nasopharyngeal aspirates were samples with blood in 312 (27·3%) of 1147 children with nasopharyngeal aspirates attempted, dyspnoea or SpO2 less than 95% in 134 (11·4%) of children, and transient respiratory distress or SpO2 less than 90% in 59 (5·2%) children. There was no serious adverse event related to nasopharyngeal aspirates reported during the trial. Interpretation Systematic molecular tuberculosis detection at hospital admission did not reduce mortality in children with severe pneumonia. High treatment and microbiological confirmation rates support more systematic use of Xpert Ultra in this group, notably in children with severe acute malnutrition. Funding Unitaid and L'Initiative. Translation For the French translation of the abstract see Supplementary Materials section.

Objectives To assess the efficacy of inhaled ciclesonide in reducing the risk of adverse outcomes in COVID-19 outpatients at risk of developing severe illness. Methods COVERAGE is an open-label, randomised controlled trial. Outpatients with documented COVID-19, risk factors for aggravation, symptoms <7 days and absence of criteria for hospitalisation are randomly allocated to either a control arm or one of several experimental arms, including inhaled ciclesonide. The primary efficacy endpoint is COVID-19 worsening (hospitalisation, oxygen therapy at home, or death) by Day 14. Other endpoints are adverse events, maximal follow-up score on the WHO OSCI, sustained alleviation of symptoms, cure, and RT-PCR and blood parameter evolution at Day 7. The trial’s Safety Monitoring Board reviewed the first interim analysis of the ciclesonide arm and recommended halting it for futility. The results of this analysis are reported here. Results The analysis involved 217 participants (control 107, ciclesonide 110), including 111 women and 106 men. Their median age was 63 years [Interquartile range (IQR) 59-68]. 157/217 (72.4%) had at least one comorbidity. The median time since first symptom was 4 days [IQR 3-5]. During the 28-day follow-up, 2 participants died (control 2/107 [1.9%], ciclesonide 0), 4 received oxygen therapy at home and were not hospitalized (control 2/107 [1.9%], ciclesonide 2/110 [1.8%]) and 24 were hospitalised (control 10/107 [9.3%], ciclesonide 14/110 [12.7%]). In intent-to-treat analysis of observed data, 26 participants reached the composite primary endpoint by Day14, including 12/106 (11. 3%, 95% CI 6.0 to 18.9%) in the control arm and 14/106 (13.2%; 95% CI 7.4 to 21.2%) in the ciclesonide arm. Secondary outcomes were similar for both arms. Conclusions Our findings are consistent with the European Medicines Agency’s COVID-19 taskforce statement that there is currently insufficient evidence that inhaled corticosteroids are beneficial for people with COVID-19.

Introduction: Sex differences have already been reported in sub-Saharan Africa for attrition and immunological response after antiretroviral therapy (ART) initiation, but follow-up was usually limited to the first two to three years after ART initiation. We evaluated sex differences on the same outcomes in the 10 years following ART initiation in West African adults. Methods: We used cohort data of patients included in the IeDEA West Africa collaboration, who initiated ART between 2002 and 2014. We modelled no-follow-up and 10-year attrition risks, and immunological response by sex using logistic regression analysis, survival analysis with random effect and linear mixed models respectively. Results: A total of 71,283 patients (65.8% women) contributed to 310,007 person-years of follow-up in 16 clinics in eight West African countries. The cumulative attrition incidence at 10-year after ART initiation reached 75% and 68% for men and women respectively. Being male was associated with an increased risk of no follow-up after starting ART (5.1% vs. 4.0%, adjusted Odds Ratio: 1.25 [95% CI: 1.15 to 1.35]) and of 10-year attrition throughout the 10-year period following ART initiation: adjusted Hazard Ratios were 1.22 [95% CI: 1.17 to 1.27], 1.08 [95% CI: 1.04 to 1.12] and 1.04 [95% CI: 1.01 to 1.08] during year 1, years 2 to 4 and 5 to 10 respectively. A better immunological response was achieved by women than men: monthly CD4 gain was 30.2 and 28.3 cells/mL in the first four months and 2.6 and 1.9 cells/μL thereafter. Ultimately, women reached the average threshold of 500 CD4 cells/μL in their sixth year of follow-up, whereas men failed to reach it even at the end of the 10-year follow-up period. The proportion of patients reaching the threshold was much higher in women than in men after 10 years since ART initiation (65% vs. 44%). Conclusions: In West Africa, attrition is unacceptably high in both sexes. Men are more vulnerable than women on both attrition and immunological response to ART in the 10 years following ART initiation. Innovative tracing strategies that are sex-adapted are needed for patients in care to monitor attrition, detect early high-risk groups so that they can stay in care with a durably controlled infection.