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. The Limulus amebocyte lysis (LAL) assay, which utilizes extracts of blood cells (amebocytes) of the Limulus polyphemus horseshoe crab, is a highly sensitive and specific test available for the detection of endotoxin (lipopolysaccharide [LPS]) (1). This assay is a reliable method for the detection of infection with Gramnegative (GN) bacteria in body fluids other than blood (1). However, the clinical significance of endotoxin detection in blood as both a diagnostic and a prognostic test is unclear, despite over 100 studies published over 4 decades for a broad range of patient groups (2-45). The interpretation of the literature is confounded by a 100-fold increase in assay sensitivity (3) and substantial differences in patient inclusion criteria among the studies in the literature over this period.Moreover, in the evaluations of endotoxemia therapies over this time period, there has been a substantial and unexplained disconnect between the results of animal models of sepsis and the results of subsequent clinical trials of the same therapies (46).Five factors have prompted a reappraisal of this question of the clinical significance of endotoxin detection. First, new studies and new data from older studies relating to endotoxemia detection have appeared and need to be incorporated (5-7, 15, 24, 32, 37, 43, 44). Second, the relevance of recently defined structural differences in lipid A,...

Increased serum levels of lipopolysaccharide and antiflagellin antibodies in patients with diarrhea‐predominant irritable bowel syndrome

“…The LAL assay results were reported in endotoxin units (EU)/mL. According to the assay data sheet from the lot utilized in these experiments, 1EU LPS Escherichia coli 0111:B4 equals 100 pg/mL LPS . Antibody titers against flagellin and total immunoglobulin G (IgG) levels were assessed by ELISA.…”

Diagnostic Accuracy of Procalcitonin Compared to C-Reactive Protein and Interleukin 6 in Recognizing Gram-Negative Bloodstream Infection: A Meta-Analytic Study

“…In clinical practice, IL-6 has potential in serving together with PCT as markers for GNBSI and researches are needed for comparative effectiveness of IL-6 under different clinical settings [33,39]. Endotoxemia was another widely investigated marker for GNBSI and was also systematically reviewed for prediction of GNBSI [58]. The pooled DORs of endotoxemia were 3.2 and 5.8 in association with GNBSIs with Escherichia coli and those with Pseudomonas aeruginosa, which were both lower than the DORs of PCT, CRP, and IL-6 derived in our study [58].…”

“…Endotoxemia was another widely investigated marker for GNBSI and was also systematically reviewed for prediction of GNBSI [58]. The pooled DORs of endotoxemia were 3.2 and 5.8 in association with GNBSIs with Escherichia coli and those with Pseudomonas aeruginosa, which were both lower than the DORs of PCT, CRP, and IL-6 derived in our study [58]. However, because none of the studies assessed PCT and endotoxemia tests in the same population, direct comparison between PCT and endotoxemia was not feasible.…”

Horseshoe Crab Aquaculture as a Sustainable Endotoxin Testing Source

“…Basal LPS levels are subject to significant variation due to an array of bacterial species and the preparation method used. Nonetheless, they are consistently higher in septic patients (0.96-3.45 EU/ml and 300 pg/ml) when compared to healthy subjects with ranges from 0.04 to 0.36 EU/ml and 5.1 pg/ml (Fleishman and Fowlkes, 1982;Casey et al, 1993;Bates et al, 1998;Ketchum et al, 1997;Strutz et al, 1999;Hurley et al, 2015). For FDA testing protocols, the acceptable safe (non-pyrogenic) endotoxin limit for injected and inhaled pharmaceutical products is ∼0.25-0.50 EU/ml (Williams, 2007;Hynes, 2016), which falls within the expected range of clinical insignificance.…”