Diagnosis of endotoxemia with gram-negative bacteremia is bacterial species dependent: a meta-analysis of clinical studies

Abstract

Endotoxemia is undetectable for up to 60% of cases of bacteremia caused by gram-negative (GN) species, a discordance attributed to the limitations of the Limulus assay for endotoxemia. The lipid A structure of the endotoxin molecule is critical for the sensing of GN bacteria by the host immune system although not so for sensing by the Limulus assay. The lipid A structure of commensal Enterobacteriaceae is hexa-acyl, whereas non-Enterobacteriaceae have a broader range of structures. By using a previously published classification of lipid A structures (R. S. Munford, Infect. Immun. 76:454-465, 2008), the association of endotoxemia with bacteremia caused by GN organisms is reexamined for 580 GN bacteremic patients from 46 studies. Endotoxemia was less commonly detected for cases of bacteremia caused by Salmonella enterica serovar Typhi (four studies; 15 of 55 cases of bacteremia [27%]) than for cases of bacteremia caused by Neisseria meningitidis (five studies; 69 of 84 cases [82%]) and Pseudomonas pseudomallei (one study; 38 of 41 cases [93%]) among studies restricted to those with specified cases of bacteremia caused by GN organisms. Among 23 unrestricted studies, endotoxemia was less commonly detected for cases of bacteremia with a commensal member of the Enterobacteriaceae (104 of 240 cases [43%]) than with non-Enterobacteriaceae (59 of 100 cases [59%]) (summary odds ratio, 0.53 [90% confidence interval, 0.33 to 0.85]). This finding is consistent across all the unrestricted studies, even including studies with seemingly contrary results for endotoxemia diagnosis among cases of bacteremia caused by GN bacteria overall. Surprisingly, with bacteremia caused by commensal Enterobacteriaceae, the diagnosis of endotoxemia appears to be unrelated to the Limulus assay sensitivity. Across these 45 studies, the association of endotoxemia with GN bacteremia is variable but consistent for different types of GN bacteremia.

FIG. 1.

Forest plot of ORs for endotoxemia with different types of GN bacteremia. The proportions of positive Limulus assay tests (limulus +) for patients with commensal Enterobacteriaceae versus non-Enterobacteriaceae GN bacteremia are presented as study-specific ORs and summary ORs (and 90% CIs) derived from all 23 unrestricted studies without missing data from Table 1, with studies ranked by order of Limulus assay sensitivity. Summary ORs for each subcategory of assay band are also displayed. Arrowheads indicate 90% CIs that extend out of range; limulus + E < nonE indicates the range in ORs for which positive Limulus tests are less common for bacteremia caused by Enterobacteriaceae than non-Enterobacteriaceae; limulus + E > nonE indicates the range in ORs for which positive Limulus tests are more common for bacteremia caused by Enterobacteriaceae than non-Enterobacteriaceae.