Endotoxemia as a diagnostic tool for patients with suspected bacteremia caused by gram-negative organisms: a meta-analysis of 4 decades of studies

Abstract

The clinical significance of endotoxin detection in blood has been evaluated for a broad range of patient groups in over 40 studies published over 4 decades. The influences of Gram-negative (GN) bacteremia species type and patient inclusion criteria on endotoxemia detection rates in published studies remain unclear. Studies were identified after a literature search and manual reviews of article bibliographies, together with a direct approach to authors of potentially eligible studies for data clarifications. The concordance between GN bacteremia and endotoxemia expressed as the summary diagnostic odds ratios (DORs) was derived for three GN bacteremia categories across eligible studies by using a hierarchical summary receiver operating characteristic (HSROC) method. Forty-two studies met broad inclusion criteria, with between 2 and 173 GN bacteremias in each study. Among all 42 studies, the DORs (95% confidence interval) were 3.2 (1.7 to 6.0) and 5.8 (2.4 to 13.7) in association with GN bacteremias with Escherichia coli and those with Pseudomonas aeruginosa, respectively. Among 12 studies of patients with sepsis, the proportion of endotoxemia positivity (95% confidence interval) among patients with P. aeruginosa bacteremia (69% [57 to 79%]; P=0.004) or with Proteus bacteremia (76% [51 to 91%]; P=0.04) was significantly higher than that among patients without GN bacteremia (49% [33 to 64%]), but this was not so for patients bacteremic with E. coli (57% [40 to 73%]; P=0.55). Among studies of the sepsis patient group, the concordance of endotoxemia with GN bacteremia was surprisingly weak, especially for E. coli GN bacteremia.

FIG 1

Flow chart of our literature search strategy and study accrual. C-limulus and G-limulus refer to the chromogenic and gelation versions of the LAL assay, respectively. Note that studies may have been excluded for more than one reason but have been counted only once.

FIG 2

Plot of sensitivity versus specificity from 37 studies for all patients populations (39 groups; top plot) and for patients with sepsis (14 groups; bottom plot) for the detection of endotoxemia using the Limulus assay versus E. coli bacteremia, together with the fitted HSROC curve and the bivariate summary estimate (solid square) for sensitivity and specificity together with the corresponding 95% confidence ellipse (inner broken line) and 95% prediction ellipse (outer dotted line). The symbol size for each study is proportional to the study size.

FIG 3

Plot of sensitivity versus specificity for 31 studies for all patient populations (33 groups; top plot) and for patients with sepsis (11 groups; bottom plot) for the detection of endotoxemia using the Limulus assay versus Pseudomonas aeruginosa GN bacteremia together with the fitted HSROC curve and the bivariate summary estimate (solid square) for sensitivity and specificity, together with the corresponding 95% confidence ellipse (inner broken line) and 95% prediction ellipse (outer dotted line). The symbol size for each study is proportional to the study size.