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. . 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.There are key structural differences between the lipid A components of the endotoxin molecule (lipopolysaccharide) of different gram-negative (GN) bacteria. Members of the Enterobacteriaceae characteristically have a lipid A structure with a hexa-acyl structure, whereas other lipid A structures are present for non-Enterobacteriaceae (45). These differences in lipid A structure are now known to be critically important for the recognition of GN bacteremia by the host immune system (45) by the MD-2-Toll-like receptor 4 receptor but not for sensing by the clotting proteins of the blood cells of the Limulus polyphemus horseshoe crab, from which the Limulus amebocyte lysate assay is derived (56). If the recognition of hexaacyl lipid A by the host immune system has a role in the pathogenesis of bacteremia, it might be expected that the proportion with detectable endotoxemia among patients with GN bacteremia might depend on the lipid A structure of the isolate.Attempts to define the concordance between GN bacteremia and endotoxemia in patients with sepsis have been elusive. Indeed, two of those studies (15, 54), with over a hundred patients each, concluded that there is no concordance. The purpose of this review is to attempt to reconcile the disparate findings from studies of clinically detected sepsis by examining the proportion with endotoxemia detected by using the Limulus assay for patients with different types of GN bacteremia for which the lipid A structures are known. Of particular interest is the proportion with endotoxemia among cases of bacteremia caused by commensal Enterobacteriaceae versus non-Enterobacteriaceae. The statistical techniques of meta-analysis are used to derive study-specific and summary estimates of these proportions expressed as an OR and more so to obtain estimates of the consistency in these ORs across the panel of studies (24). MATERIALS AND METHODS Data sources.A comprehensive search of the literature from 1966 to April 2009 was performed by using...

Endotoxemia and mortality prediction in ICU and other settings: underlying risk and co-detection of gram negative bacteremia are confounders

“…The reciprocal distribution is a consequence of differences in endotoxemia detection rates, being more common for GN bacteremias with P. aeruginosa versus E. coli . This reciprocal distribution for different GN bacteremia species types is apparent among a broader collection of studies that used the limulus assay [43]. Likewise, among 57 GN bacteremias found in a therapeutic trial in patients with septic shock selected on the basis of a positive detection of endotoxemia using the limulus assay, 15 versus only 12 of the GN bacteremias were P. aeruginosa versus E. coli , respectively [58].…”

“…This search was supplemented by a hand-search for studies reporting mortality outcome data in relation to endotoxemia detection and detection of GN bacteremia with blood culture for patient groups at risk of GN bacteremia. This search has been performed repeatedly over two decades [44] up to April 2012 as detailed previously [43,44]. A call for data was published [53] and authors were contacted for additional data to enable inclusion.…”

“…Less than two thirds of patients with GN bacteremia have endotoxemia detected and vice versa [42]. The concordance with GN bacteremia varies with GN bacteremia species type [43]. The structure function activity of lipid-A, the biologically active component of endotoxin differs for different GN bacteria [45].…”

Prognostic Value of Endotoxemia in Patients with Gram-Negative Bacteremia Is Bacterial Species Dependent

“…From this, it could be hypothesized that the differences in relative frequency of detection of concomitant endotoxemia with GN bacteremia on the one hand [30,53,54], or the known differences in the structure activity relationship of the lipid A component of the endotoxin molecule on the other [1,22,27,28], might account for differences in mortality between bacteremias with Enterobacteriaceae versus other GN bacteria. However, the findings here were unexpectedly otherwise.…”

Meta-analysis of Clinical Studies of Diagnostic Tests: Developments in How the Receiver Operating Characteristic “Works”

“…35 Here, the question was whether the type of gram-negative bacteremia detected, either an Enterobacteriaceae type or not, was an important factor in the ability of the assay to detect endotoxemia, a question that no single study had been large enough to address. All 46 studies used the limulus assay method, but the sensitivity limits of that method differed by up to a 1000-fold.…”