scispace - formally typeset
Search or ask a question
Journal ArticleDOI

Biomarkers in sepsis.

01 May 2013-Current Opinion in Pulmonary Medicine (Wolters Kluwer Health)-Vol. 19, Iss: 3, pp 305-309
TL;DR: The potential for novel biomarkers in sepsis will need to be properly realized with considerable funding, academic–industry collaborations, appropriate investigations and validation in heterogenous populations, but these developments do hold the capacity to transform patient care and outcomes.
Abstract: Purpose of reviewThis review discusses the current developments in biomarkers for sepsis.Recent findingsWith quantum leaps in technology, an array of biomarkers will become available within the next decade as point-of-care tools that will likely revolutionize the management of sepsis. These markers
Citations
More filters
Journal ArticleDOI
TL;DR: Biomarkers may be used to help diagnose patients with sepsis, and they may also help to identify patients who would benefit from immunomodulatory therapies.
Abstract: Sepsis is a serious clinical condition that represents a patient’s response to a severe infection and has a very high mortality rate. Normal immune and physiologic responses eradicate pathogens, and the pathophysiology of sepsis is due to the inappropriate regulation of these normal reactions. In an ideal scenario, the first pathogen contact with the inflammatory system should eliminate the microbe and quickly return the host to homeostasis. The septic response may accelerate due to continued activation of neutrophils and macrophages/monocytes. Upregulation of lymphocyte costimulatory molecules and rapid lymphocyte apoptosis, delayed apoptosis of neutrophils, and enhanced necrosis of cells/tissues also contribute to the pathogenesis of sepsis. The coagulation system is closely tied to the inflammatory response, with cross talk between the two systems driving the dysregulated response. Biomarkers may be used to help diagnose patients with sepsis, and they may also help to identify patients who would benefit from immunomodulatory therapies.

662 citations


Cites background from "Biomarkers in sepsis."

  • ...A kinetic study of high mobility group box 1 demonstrated that it remained persistently elevated in the plasma compared with cytokines such as IL-6, IL-8, and TNF, emphasizing this biomarker’s high clinical relevance (90, 92, 116)....

    [...]

  • ...CRP does not play a major role in diagnosis, and prediction of outcome in sepsis due to its low specificity (90, 96)....

    [...]

  • ...The utility of a biomarker for the diagnosis of sepsis should be judged on its ability to shorten the time necessary to make a diagnosis, improve discrimination between infectious and noninfectious causes of inflammation, enhance differentiation of viral from bacterial infections, and assess appropriate control of the infection (90)....

    [...]

  • ...Biomarker-based immunomonitoring offers a versatile approach for various disease and prevention scenarios (90)....

    [...]

  • ...timely information beyond the data generated during routine physiologic evaluation, thereby allowing the prospect of successful intervention before the therapeutic window permanently closes (90)....

    [...]

Journal ArticleDOI
TL;DR: Novel approaches to sepsis promise to transform sePSis from a physiologic syndrome into a group of distinct biochemical disorders and help in the development of better diagnostic tools and effective adjunctive sepsi therapies.
Abstract: SUMMARY Sepsis is among the most common causes of death in hospitals. It arises from the host response to infection. Currently, diagnosis relies on nonspecific physiological criteria and culture-based pathogen detection. This results in diagnostic uncertainty, therapeutic delays, the mis- and overuse of antibiotics, and the failure to identify patients who might benefit from immunomodulatory therapies. There is a need for new sepsis biomarkers that can aid in therapeutic decision making and add information about screening, diagnosis, risk stratification, and monitoring of the response to therapy. The host response involves hundreds of mediators and single molecules, many of which have been proposed as biomarkers. It is, however, unlikely that one single biomarker is able to satisfy all the needs and expectations for sepsis research and management. Among biomarkers that are measurable by assays approved for clinical use, procalcitonin (PCT) has shown some usefulness as an infection marker and for antibiotic stewardship. Other possible new approaches consist of molecular strategies to improve pathogen detection and molecular diagnostics and prognostics based on transcriptomic, proteomic, or metabolic profiling. Novel approaches to sepsis promise to transform sepsis from a physiologic syndrome into a group of distinct biochemical disorders and help in the development of better diagnostic tools and effective adjunctive sepsis therapies.

429 citations


Cites background from "Biomarkers in sepsis."

  • ...TNF-treated patients at higher levels of IL-6 monoclonal antibody (170)....

    [...]

  • ...The potential of biomarkers in the field of sepsis was first addressed systematically in the context of a colloquium convened by the International Sepsis Forum in 2005 (170)....

    [...]

  • ...size physiologic changes in vital parameters that are common to a number of disparate processes,” and that “biomarkers promise to transform sepsis from a physiologic syndrome to a group of distinct biochemical disorders” (170)....

    [...]

  • ...Furthermore, it is important to note that an adequate evaluation of clinical utility is possible only if the assays that are used in this context for biomarker measurement provide reliable and reproducible results (170)....

    [...]

Journal ArticleDOI
TL;DR: Copeptin showed promising diagnostic and prognostic role in the management of sepsis, together with its possible role in monitoring the response to treatment, and no significant differences were found in copeptin temporal profile among different subgroups.
Abstract: The diagnostic and prognostic usefulness of copeptin were evaluated in septic patients, as compared to procalcitonin assessment. In this single centre and observational study 105 patients were enrolled: 24 with sepsis, 25 with severe sepsis, 15 with septic shock, and 41 controls, divided in two subgroups (15 patients with gastrointestinal bleeding and 26 with suspected SIRS secondary to trauma, acute coronary syndrome, and pulmonary embolism). Biomarkers were determined at the first medical evaluation and thereafter 24, 48, and 72 hours after admission. Definitive diagnosis and in-hospital survival rates at 30 days were obtained through analysis of medical records. At entry, copeptin proved to be able to distinguish cases from controls and also sepsis group from septic shock group, while procalcitonin could distinguish also severe sepsis from septic shock group. Areas under the ROC curve for copeptin and procalcitonin were 0.845 and 0.861, respectively. Noteworthy, patients with copeptin concentrations higher than the threshold value (23.2 pmol/L), calculated from the ROC curve, at admission presented higher 30-day mortality. No significant differences were found in copeptin temporal profile among different subgroups. Copeptin showed promising diagnostic and prognostic role in the management of sepsis, together with its possible role in monitoring the response to treatment.

391 citations


Cites background from "Biomarkers in sepsis."

  • ...The use of biomarkers may be useful in the detection of infection and in the management of the septic patient; despite the fact that more than 100molecules have been evaluated in sepsis [6], an ideal biomarker, that is to say a molecule which, at the same time, allows early diagnosis, risk stratification, monitoring of clinical response to therapy, and prediction of outcome [7], is still missing....

    [...]

Journal ArticleDOI
TL;DR: The MSS reliably predicts disease progression and mortality in an animal model of polymicrobial sepsis, and may be used to assess and compare outcomes among various experimental models of sepsi, and serve as an ethically acceptable alternative to death as an endpoint.
Abstract: The lack of a reliable scoring system that predicts the development of septic shock and death precludes comparison of disease and/or treatment outcomes in animal models of sepsis. We developed a murine sepsis score (MSS) that evaluates seven clinical variables, and sought to assess its validity and reliability in an experimental mouse model of polymicrobial sepsis. Stool collected from the cecum of C57BL/6 (B6) mice was dissolved in 0.9% normal saline (NS) and filtered, resulting in a fecal solution (FS) which was injected intraperitoneally into B6 mice. Disease severity was monitored by MSS during the experimental timeline. Blood and tissue samples were harvested for the evaluation of inflammatory changes after sepsis induction. The correlation between pro-inflammatory markers and MSS was assessed by the Spearman rank correlation coefficient. Mice injected with FS at a concentration of 90 mg/mL developed polymicrobial sepsis with a 75% mortality rate at 24 hours. The MSS was highly predictive of sepsis progression and mortality, with excellent discriminatory power, high internal consistency (Cronbach alpha coefficient = 0.92), and excellent inter-rater reliability (intra-class coefficient = 0.96). An MSS of 3 had a specificity of 100% for predicting onset of septic shock and death within 24 hours. Hepatic dysfunction and systemic pro-inflammatory responses were confirmed by biochemical and cytokine analyses where the latter correlated well with the MSS. Significant bacterial dissemination was noted in multiple organs. Furthermore, the liver, spleen, and intestine demonstrated histopathological evidence of injury. The MSS reliably predicts disease progression and mortality in an animal model of polymicrobial sepsis. More importantly, it may be used to assess and compare outcomes among various experimental models of sepsis, and serve as an ethically acceptable alternative to death as an endpoint.

252 citations


Cites background from "Biomarkers in sepsis."

  • ...Discussion The development of a reliable, sensitive, and specific scoring system can effectively facilitate comparison of disease outcomes and therapeutic regimens [5,7,21] across multiple models of sepsis, and improve the clinical relevance of novel diagnostic biomarkers [21]....

    [...]

Journal ArticleDOI
TL;DR: TLR-targeted therapies have a strong potential for prevention and intervention in infectious diseases, notably sepsis and agonists of endosomal TLRs are very promising for treating chronic viral infections.
Abstract: Toll-like receptors (TLRs) are pattern recognition receptors playing a fundamental role in sensing microbial invasion and initiating innate and adaptive immune responses. TLRs are also triggered by danger signals released by injured or stressed cells during sepsis. Here we focus on studies developing TLR agonists and antagonists for the treatment of infectious diseases and sepsis. Positioned at the cell surface, TLR4 is essential for sensing lipopolysaccharide of Gram-negative bacteria, TLR2 is involved in the recognition of a large panel of microbial ligands, while TLR5 recognizes flagellin. Endosomal TLR3, TLR7, TLR8, TLR9 are specialized in the sensing of nucleic acids produced notably during viral infections. TLR4 and TLR2 are favorite targets for developing anti-sepsis drugs, and antagonistic compounds have shown efficient protection from septic shock in preclinical models. Results from clinical trials evaluating anti-TLR4 and anti-TLR2 approaches are presented, discussing the challenges of study design in sepsis and future exploitation of these agents in infectious diseases. We also report results from studies suggesting that the TLR5 agonist flagellin may protect from infections of the gastrointestinal tract and that agonists of endosomal TLRs are very promising for treating chronic viral infections. Altogether, TLR-targeted therapies have a strong potential for prevention and intervention in infectious diseases, notably sepsis.

240 citations


Cites background from "Biomarkers in sepsis."

  • ...Ideally, sepsis studies should use specific biomarkers to help patient enrollment and weigh treatment efficacy in realistic conditions (155)....

    [...]

References
More filters
Journal ArticleDOI
21 Aug 2002-JAMA
TL;DR: In this trial, a 7-day treatment with low doses of hydrocortisone and fludrocort isone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events.
Abstract: ContextSeptic shock may be associated with relative adrenal insufficiency. Thus, a replacement therapy of low doses of corticosteroids has been proposed to treat septic shock.ObjectiveTo assess whether low doses of corticosteroids improve 28-day survival in patients with septic shock and relative adrenal insufficiency.Design and SettingPlacebo-controlled, randomized, double-blind, parallel-group trial performed in 19 intensive care units in France from October 9, 1995, to February 23, 1999.PatientsThree hundred adult patients who fulfilled usual criteria for septic shock were enrolled after undergoing a short corticotropin test.InterventionPatients were randomly assigned to receive either hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50-µg tablet once daily) (n = 151) or matching placebos (n = 149) for 7 days.Main Outcome MeasureTwenty-eight-day survival distribution in patients with relative adrenal insufficiency (nonresponders to the corticotropin test).ResultsOne patient from the corticosteroid group was excluded from analyses because of consent withdrawal. There were 229 nonresponders to the corticotropin test (placebo, 115; corticosteroids, 114) and 70 responders to the corticotropin test (placebo, 34; corticosteroids, 36). In nonresponders, there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the corticosteroid group (hazard ratio, 0.67; 95% confidence interval, 0.47-0.95; P = .02). Vasopressor therapy was withdrawn within 28 days in 46 patients (40%) in the placebo group and in 65 patients (57%) in the corticosteroid group (hazard ratio, 1.91; 95% confidence interval, 1.29-2.84; P = .001). There was no significant difference between groups in responders. Adverse events rates were similar in the 2 groups.ConclusionIn our trial, a 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events.

2,698 citations

Journal ArticleDOI
TL;DR: Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydroc Cortisone hastened reversal ofshock in patients in whom shock was reversed.
Abstract: Background Hydrocortisone is widely used in patients with septic shock even though a survival benefit has been reported only in patients who remained hypotensive after fluid and vasopressor resuscitation and whose plasma cortisol levels did not rise appropriately after the administration of corticotropin. Methods In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned 251 patients to receive 50 mg of intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days; the dose was then tapered during a 6-day period. At 28 days, the primary outcome was death among patients who did not have a response to a corticotropin test. Results Of the 499 patients in the study, 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P = 0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P = 1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P = 0.51). In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock. Conclusions Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed. (ClinicalTrials.gov number, NCT00147004.)

1,797 citations

Journal ArticleDOI
TL;DR: In septic patients, an association between nitric oxide overproduction, antioxidant depletion, mitochondrial dysfunction, and decreased ATP concentrations that relate to organ failure and eventual outcome is found.

1,290 citations

Journal ArticleDOI
TL;DR: DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock, and rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death.
Abstract: A b s t r ac t Results At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% con - fidence interval (CI), 0.92 to 1.28; P = 0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P = 0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P = 0.54). Similarly, rates of death at 28 and 90 days were not signifi - cantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P = 0.81). Conclusions DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock. (Funded by Eli Lilly; PROWESS-SHOCK ClinicalTrials.gov number, NCT00604214.)

1,123 citations

Journal ArticleDOI
TL;DR: Recovery of monocyte function resulted in clearance of sepsis in eight of nine patients and suggests that IFN-γ treatment in carefully selected septic patients is a novel therapeutic strategy worth pursuing.
Abstract: Neutralization of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) or interleukin-1 (IL-1), decreases mortality in several animal models of sepsis. However, recent clinical trials did not show an unequivocal improvement in survival. In contrast to animals, which succumb to shock during the first 72 hours, we found that many patients die much later with signs of opportunistic infections accompanied by downregulation of their monocytic HLA-DR expression and reduced ability to produce lipopolysaccharide (LPS)-induced TNF-α in vitro1–3. This phenomenon of monocyte deactivation in septic patients with fatal outcome shows similarities to experimental monocytic refractoriness induced by LPS desensitization or by pretreatment with its endogenous mediators IL-10 and transforming growth factor-β (TGF-β)4. In order to strengthen their antimicrobial defense, here we tested whether interferon-γ (IFN-γ) can improve monocytic functions in these patients and in experimental monocytic deactivation. The considerably lowered in vitro levels of LPS-induced TNF-α in these situations were significantly enhanced by IFN-γ, but did not reach the extremely high levels of IFN-γ primed naive cells from healthy donors. Moreover, IFN-γ applied to septic patients with low monocytic HLA-DR expression restored the deficient HLA-DR expression and in vitro LPS-induced TNF-α secretion. Recovery of monocyte function resulted in clearance of sepsis in eight of nine patients. These data suggest that IFN-γ treatment in carefully selected septic patients is a novel therapeutic strategy worth pursuing.

1,086 citations

Related Papers (5)