Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data

Abstract

Background: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI.

Methods: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022.

Findings: We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per μL (the median for the cohort) was 45% (95% CI 38-52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63-87), increasing to 89% (80-94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05-3·08) but not after 30 days (1·25, 0·84-2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16-8·84).

Interpretation: In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients.

Funding: This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A.

Figure 1

Study selection IPD=individual patient data. *Some studies met more than one exclusion criterion.

Figure 2

Predicted probability of Mycobacterium tuberculosis BSI in patients with HIV-associated tuberculosis All predictions assume that two tuberculosis blood cultures had been done before the start of anti-tuberculous therapy. (A) Simulated probability of positive tuberculosis blood culture for people with HIV diagnosed with tuberculosis at varying covariate levels; the solid line represents the mean predicted probabilities and the shading represents the 95% CI. (B) Predicted probability (squares) with 95% CI (whiskers) of a positive tuberculosis blood culture in inpatients with HIV-associated tuberculosis and WHO danger signs, with a CD4 count of 76 cells per μL (the median across datasets); the size of the square is proportional to the number of hospital inpatients in each study. The vertical dashed line indicates the population mean (all datasets combined) and the blue diamond the 95% CI around that mean; the 95% prediction interval for the mean predicted probability of M tuberculosis BSI in a new, unobserved dataset is shown by whiskers around the diamond. Also shown for comparison are the tuberculosis blood culture positivity rates originally reported for each primary study (blue circles). BSI=bloodstream infection.

Figure 3

Pooled Kaplan-Meier curves (solid lines) and 95% CIs (shaded areas) for all patients with tuberculosis diagnosed by any means (n=2497), stratified by presence (red) or absence (blue) of Mycobacterium tuberculosis BSI Plot generated using a simple pooling of all data, without imputation of missing data. BSI=bloodstream infection.