External validation of a treatment decision algorithm for tuberculosis in children living with HIV - a diagnostic cohort study.

IntroductionTuberculosis (TB) is the leading cause of death in children living with HIV (CLHIV) and is challenging to confirm the diagnosis. The PAANTHER treatment decision algorithm (TDA) was developed to improve the diagnosis of TB in CLHIV. We aimed to externally validate the PAANTHER TDA in CLHIV with presumptive TB. MethodsWe conducted a prospective diagnostic cohort study in seven tertiary hospitals across Cote dIvoire, Mozambique, Uganda, and Zambia, implementing the PAANTHER TDA in CLHIV aged between 1 month and 14 years with presumptive TB. TDA assessments included Xpert MTB/RIF Ultra (Ultra) on respiratory and stool samples, history of contact, symptoms (fever >2 weeks, unremitting cough, haemoptysis and/or weight loss in previous 4 weeks, tachycardia), chest radiography and abdominal ultrasound. A positive score (>100) prompted TB treatment initiation. Children were followed-up for 6 months, and retrospectively classified as having confirmed, unconfirmed or unlikely TB. The primary outcome was the proportion of missed TB cases (false negative) among children with negative scores; secondary outcomes included TDA diagnostic accuracy, feasibility, and time to treatment initiation. The TDA was considered validated if the negative predictive value (NPV, 1 - rate of false negative) was superior to a 75% pre-established confidence interval lower limit. FindingsFrom 2 October 2019 to 31 December 2021, we enrolled 277 CLHIV, including 175 (63{middle dot}2%) who were on antiretroviral therapy at inclusion. 272 (98{middle dot}2%) children had a complete TDA evaluation; 215 (75.8%) scored >100, including 24 (8{middle dot}7%) with positive Ultra. 182 (86{middle dot}7%) children who scored [≥]100, and 12 children who scored negative, initiated TB treatment at a median of 1 (IQR: 0-3) and 27 [8{middle dot}2; 64] days after inclusion, respectively. 62/215 children (28{middle dot}8%) who scored [≥]100 were classified as having unlikely TB and 4/12 (33{middle dot}3%) who scored negative were initiated on treatment and were classified as having unconfirmed TB. The proportion of children with TB (confirmed and unconfirmed) was 155/273 (56{middle dot}8%; 95% CI: 50{middle dot}9; 62{middle dot}5). The NPV was 55/67 (93{middle dot}3%; 95% CI: 84{middle dot}1; 97{middle dot}4), reaching protocol-defined validation. The TDA sensitivity was 97{middle dot}4% (95% CI: 93{middle dot}6; 90{middle dot}0) with specificity of 47{middle dot}5 (95% CI: 38{middle dot}7; 56{middle dot}4). InterpretationThe PAANTHER TDA was validated in CLHIV. Its high sensitivity, excellent feasibility, and short turnaround time to treatment initiation, should allow rapid treatment decision-making and could reduce morbidity and mortality in CLHIV. FundingUNITAID