Mycobacterium Tuberculosis Blood Stream Infection Prevalence, Diagnosis, and Mortality Hazard in HIV-Positive Adults: A Systematic Review and Meta-Analysis of Individual Patient Data

Background: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis blood stream infection (MTB-BSI) is incompletely understood. We hypothesised that MTB-BSI prevalence has been underestimated, that MTB-BSI independently predicts death, and sputum Xpert has suboptimal diagnostic yield for MTB-BSI. Methods: We conducted a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood-culture (TBBC), including HIV-positive adults aged ≥13-years with suspected tuberculosis. Predicted probabilities of MTB-BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum (Xpert or culture if Xpert unavailable) and urinelipoarabinomannan for MTB-BSI were obtained by two-level random-effect meta-analysis, mortality hazard of MTB-BSI by mixed-effect Cox proportional-hazard modelling, and effect of treatment delay with propensity-score analysis. Findings 5751 patients met inclusion criteria. Predicted probability of MTB-BSI was 45% (95%CI 38-52%) for danger-sign positive tuberculosis inpatients with cohort median CD4 count of 76 cells/μL. Diagnostic yield of sputum was 77% (95%CI 63–87%), rising to 89% (95%CI 80-94%) when combined with urinelipoarabinomannan testing. MTB-BSI increased hazard of death before 30-days (aHR2·5, 95%CI 2·1–3·1). In a propensity-score matched cohort (n=630), mortality increased with treatment delay >4 days in MTB-BSI (OR 3·2, 95%CI 1·1–10·3). Interpretation: In critically-ill adults with HIV-tuberculosis, MTB-BSI is a very frequent manifestation of tuberculosis and strongly predicts mortality. Better diagnostic yield in patients with MTB-BSI can be achieved by parallel use of sputum-Xpert and urine-LAM. Treatment delay may increase mortality hazard. Funding Statement: This study was supported by Wellcome fellowships 109105z/15/a, 105165/Z14/A. Charlotte Schutz was funded by the South African Medical Research Council under the National Health Scholars Programme. Moshi, Tanzania research was supported by an International Studies on AIDS Associated Co-infections (ISAAC) award, a program funded by the US National Institutes of Health (NIH) (U01 AI062563). John A. Crump receives support from US NIH R01AI121378. Elizabeth L. Corbett is supported by a Wellcome trust senior fellowship in clinical science (WT200901). Gary Maartens was supported in part by National Research Fund incentive funding (UID: 85810). Susan E. Dorman was supported by contract #HHSN2722000900050C and grant K24AI104830 (to SED), both from the US National Institutes of Health. Douglas Wilson was supported by BMS Secure the Future. Graeme Meintjes was supported by the Wellcome Trust (098316 and 203135/Z/16/Z), the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787), NRF incentive funding (UID: 85858) and the South African Medical Research Council through its TB and HIV Collaborating Centres Programme with funds received from the National Department of Health (RFA# SAMRC-RFA-CC: TB/HIV/AIDS-01-2014). Declaration of Interests: David Alland is on the Scientific Advisory Board of Specific Technologies and receives a portion of the licensing income paid by Cepheid to Rutgers University for sales of the Xpert Ultra assay. Neil Martinson has received institutional grants for collection of specimens for Roche and Becton Dickinson, and from Pfizer for assessing incident pneumonia. All other authors declare no competing interests. Ethics Approval Statement: PROSPERO registration: CRD42016050022.