Development of tuberculosis treatment decision algorithms in children below 5 years hospitalised with severe acute malnutrition in Zambia and Uganda: a prospective diagnostic cohort study.

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.

Viral load suppression after intensive adherence counselling among adult people living with HIV at Kiswa health centre, Kampala: a retrospective cohort study. Secondary data analysis.

BACKGROUND: The Joint United Nations Programme on HIV/AIDS through the 95-95-95 target requires 95% of people living with HIV (PLHIV) on antiretroviral treatment (ART) to be virally suppressed. Viral Load (VL) non-suppression has been found to be associated with suboptimal ART adherence, and Intensive Adherence Counselling (IAC) has been shown to lead to VL re-suppression by over 70% in PLHIV on ART. Currently, there is data paucity on VL suppression after IAC in adult PLHIV in Uganda. This study aimed to evaluate the proportion of VL suppression after IAC and associated factors among adult PLHIV on ART at Kiswa Health Centre in Kampala, Uganda. METHODS: Study was a retrospective cohort design and employed secondary data analysis to review routine program data. Medical records of adult PLHIV on ART for at least six months with VL non-suppression from January 2018 to June 2020 at Kiswa HIV clinic were examined in May 2021. Descriptive statistics were applied to determine sample characteristics and study outcome proportions. Multivariable modified Poisson regression analysis was employed to assess predictors of VL suppression after IAC. RESULTS: Analysis included 323 study participants of whom 204 (63.2%) were female, 137 (42.4%) were between the age of 30 and 39 years; and median age was 35 years (interquartile range [IQR] 29-42). Participant linkage to IAC was 100%. Participants who received the first IAC session within 30 days or less after unsuppressed VL result were 48.6% (157/323). Participants who received recommended three or more IAC sessions and achieved VL suppression were 66.4% (202/304). The percentage of participants who completed three IAC sessions in recommended 12 weeks was 34%. Receipt of three IAC sessions (ARR = 1.33, 95%CI: 1.15-1.53, p < 0.001), having baseline VL of 1,000-4,999 copies/ml (ARR = 1.47, 95%CI: 1.25-1.73, p < 0.001) and taking Dolutegravir containing ART regimen were factors significantly associated with VL suppression after IAC. CONCLUSION: VL suppression proportion of 66.4% after IAC in this population was comparable to 70%, the percentage over which adherence interventions have been shown to cause VL re-suppression. However, timely IAC intervention is needed from receipt of unsuppressed VL results to IAC process completion.

Effect of systematic tuberculosis detection on mortality in young children with severe pneumonia in countries with high incidence of tuberculosis: a stepped-wedge cluster-randomised trial.

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.