Aetiology of sepsis in adults living with HIV in East Africa: a secondary analysis of an open-label, multicentre, randomised, controlled phase 3 trial.

Abstract

Sepsis in people living with HIV (PLWH) in East Africa has high mortality. Regionally, the etiology of sepsis is incompletely understood. We performed a planned analysis of the microbiological data obtained from a randomised clinical trial of early empiric anti-<i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) therapy for sepsis (ATLAS) in Tanzania and Uganda. We present a prespecified, secondary analysis of a phase three, open-label, multicentre, randomised, controlled trial conducted at four regional referral hospitals in Tanzania and Uganda. Participants were adults living with HIV admitted with concern for infection and a modified quick sepsis-related organ failure assessment (qSOFA) ≥2. Participants were randomised to (1) immediate or diagnosis-dependent antituberculosis therapy and to (2) high-dose or conventional-dose antituberculosis therapy. Tests for sepsis etiology included bacterial blood and urine cultures, multi-pathogen qPCR from blood, GeneXpert MTB/RIF Ultra from sputum and urine, urine lipoarabinomannan (LF-LAM), and <i>Mtb</i> cultures from sputum and blood. We used multivariable logistic regression analysis and random forest analysis to determine variables that predicted <i>Mtb</i> as the sepsis etiology. The trial is registered with ClinicalTrials.gov, NCT04618198. From January 5, 2022 through December 9, 2024, we randomised 437 participants to receive immediate and/or high dose antituberculosis therapy. <i>Mtb</i> was the most common pathogen, detected in 229 (52%) of 437 participants, and in 54 (50%) of 108 participants with a bloodstream infection. Combined urine LF-LAM and sputum GeneXpert MTB/RIF testing missed 17 (32%) of 54 <i>Mtb</i> bloodstream infections. The most frequent non-mycobacterial bacteria were <i>Klebsiella</i> species and <i>Escherichia coli</i>, which were identified in 39 (9%) and 33 (8%) of 437 participants, respectively. We detected ceftriaxone resistance in 21 (64%) of 33 bacterial isolates. In a random forest prediction model (accuracy: 0.6; precision: 0.5; recall: 0.6; F1-score: 0.5), the best indicators of <i>Mtb</i> as a sepsis pathogen were a greater number of ill-days before presentation (mean decrease in accuracy [MDA] 10.1), younger age (MDA 8.7), a longer duration of cough (MDA 7.7), and low CD4+ T-cell concentration (MDA 3.7). <i>Mtb</i> was the most common pathogen causing sepsis and bloodstream infection and was frequently missed by conventional rapid diagnostics. We also identified a high prevalence of non-mycobacterial pathogens resistant to ceftriaxone in blood and urine cultures. Limitations of our study included exclusion of cryptococcal antigen positive participants, non-systematic drug susceptibility testing, and potential regional differences in sepsis etiology and resistance patterns. NIH.