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

Hurley, James C.; Opal, Steven M.

doi:10.1159/000347172

Cited by 11 publications

(12 citation statements)

References 56 publications

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“…Likewise, endotoxemia should not be regarded as a single entity given the recently described differences in the lipid-A structures among the different GN bacteremia types. Also, the relationship between endotoxemia versus GN bacteremia both with respect to their mutual concordance and as predictors of outcome among patients with suspected sepsis is not simple [ 76 , 77 , 78 ].…”

Section: Endotoxemia As a Therapeutic Target In Sepsismentioning

confidence: 99%

“…This has been examined in a series of meta-analyses and L’Abbé plots using data derived from 100 studies of patients with sepsis in various settings. The most recent analyses examined the relative strength of endotoxemia and GN bacteremia as independent predictors of increased mortality risk [ 77 ] and the confounding relationship with the GN bacteremia type [ 78 ].…”

Section: Endotoxemia As a Therapeutic Target In Sepsismentioning

confidence: 99%

“…A further analysis of the individual patient data from studies of patients derived from eight ICU studies and small numbers from an additional 6 non-ICU studies had been undertaken [ 78 ]. These patients were identified to have GN bacteremia with or without endotoxemia ( i.e.…”

Section: Endotoxemia As a Therapeutic Target In Sepsismentioning

confidence: 99%

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Towards Clinical Applications of Anti-endotoxin Antibodies; A Re-appraisal of the Disconnect

Hurley

2013

Toxins

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Endotoxin is a potent mediator of a broad range of patho-physiological effects in humans. It is present in all Gram negative (GN) bacteria. It would be expected that anti-endotoxin therapies, whether antibody based or not, would have an important adjuvant therapeutic role along with antibiotics and other supportive therapies for GN infections. Indeed there is an extensive literature relating to both pre-clinical and clinical studies of anti-endotoxin antibodies. However, the extent of disconnect between the generally successful pre-clinical studies versus the failures of the numerous large clinical trials of antibody based and other anti-endotoxin therapies is under-appreciated and unexplained. Seeking a reconciliation of this disconnect is not an abstract academic question as clinical trials of interventions to reduce levels of endotoxemia levels are ongoing. The aim of this review is to examine new insights into the complex relationship between endotoxemia and sepsis in an attempt to bridge this disconnect. Several new factors to consider in this reappraisal include the frequency and types of GN bacteremia and the underlying mortality risk in the various study populations. For a range of reasons, endotoxemia can no longer be considered as a single entity. There are old clinical trials which warrant a re-appraisal in light of these recent advances in the understanding of the structure-function relationship of endotoxin. Fundamentally however, the disconnect not only remains, it has enlarged.

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Section: Endotoxemia As a Therapeutic Target In Sepsismentioning

confidence: 99%

Section: Endotoxemia As a Therapeutic Target In Sepsismentioning

confidence: 99%

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Towards Clinical Applications of Anti-endotoxin Antibodies; A Re-appraisal of the Disconnect

Hurley

2013

Toxins

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“…Moreover, the prognostic significance of endotoxemia is dependent on the copresence of GN bacteremia and is unequal for GN bacteremias of different types. For example, endotoxemia with E. coli bacteremia has no prognostic significance (55). The somewhat surprising finding here is that the concordance between endotoxemia and GN bacteremia was lower within studies that used sepsis criteria for patient inclusion versus studies that selected patients more broadly, despite the fact that the studies of a Abbreviations: TP, true positive, the number of patients with endotoxemia and Gram-negative bacteremia; FP, false positive, the number of patients with endotoxemia and without Gram-negative bacteremia; FN, false negative, the number of patients without endotoxemia and with Gram-negative bacteremia; TN, true negative, the number of patients with neither endotoxemia nor Gram-negative bacteremia.…”

Section: Figmentioning

confidence: 99%

Endotoxemia as a Diagnostic Tool for Patients with Suspected Bacteremia Caused by Gram-Negative Organisms: a Meta-Analysis of 4 Decades of Studies

et al. 2015

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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,...

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“…For example, while animal model studies commonly use ( E. coli ) endotoxin, it is possible that this may have been the wrong endotoxin to study. We recently found that endotoxemia detected in association with Gram-negative sepsis with E. coli bacteremia does not have a significant association with mortality [ 8 , 9 ] although endotoxemia with non- E. coli bacteremia does.…”

mentioning

confidence: 99%

Response to John G. Brock-Utne. Comment on Hurley, J.C. Towards Clinical Application of Anti-endotoxin Antibodies; A Re-Appraisal of the Disconnect

Hurley

2014

Toxins

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

Cited by 11 publications

References 56 publications

Towards Clinical Applications of Anti-endotoxin Antibodies; A Re-appraisal of the Disconnect

Towards Clinical Applications of Anti-endotoxin Antibodies; A Re-appraisal of the Disconnect

Endotoxemia as a Diagnostic Tool for Patients with Suspected Bacteremia Caused by Gram-Negative Organisms: a Meta-Analysis of 4 Decades of Studies

Response to John G. Brock-Utne. Comment on Hurley, J.C. Towards Clinical Application of Anti-endotoxin Antibodies; A Re-Appraisal of the Disconnect

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