Does gram-negative bacteraemia occur without endotoxaemia? A meta-analysis using hierarchical summary ROC curves

The limulus assay for endotoxin has been studied as a method for the rapid identification of gram-negative (GN) bacteraemia. The chromogenic (C-limulus) version is 100-fold more sensitive to an internal endotoxin standard than the earlier gelation version (G-limulus). The objective of this analysis is to compare the concordance between GN bacteraemia and endotoxaemia as determined in clinical studies using either version of the limulus assay. The summary results for the diagnostic odds ratio (DOR), sensitivity and specificity were derived using a hierarchical summary receiver operating characteristic (HSROC) method of meta-analysis. Fifty-eight studies (25 G-limulus and 33 C-limulus) were included. Surprisingly, the mean DOR (4.9; 3-7.9 versus 10.7; 5.2-21.8) was inferior for studies using the C-limulus versus the original G-limulus version of the assay. Moreover, among studies limited to sepsis syndrome patients, the mean DOR remains poor at 4.2 (1.8-9.5). The proportion of GN bacteraemic patients for whom endotoxaemia is not detectable with either version of the limulus assay is >20% among the 58 studies overall, but >30% after the exclusion of studies with <25 patients and >20% among studies of patients with sepsis syndrome. These findings help to reconcile seemingly disparate study results.