Role of Biomarkers Sepsis

Role of Biomarkers in Sepsis(Follow up on Non-Culture Methods for Sepsis)

N. Naidoo

The next slide should define all these terms. Unless the 2nd slide (4) from this one is the one in which you will define the terms!!

Term DefinitionInfection invasion of a host organism's bodily tissues by disease-causing

organisms, their multiplication, and the reaction of host tissues to these organisms and the toxins they produce

Bacteremia The presence of viable bacteria in circulating blood

Systemic Inflammatory Response Syndrome (SIRS)

Temperature > 38°C or < 36°CHeart rate > 90 beats/minRespiratory rate > 20 breaths/min or PaCO2 < 32 mm HgWBC count > 12,000/mm3 , < 4000/mm3 , or > 10% immature (band) forms.

Sepsis The systemic inflammatory response to infection. It should be determined whether they are a direct systemic response to the presence of an infectious process and represent an acute alteration from baseline in the absence of other known causes for such abnormalities.

Wang P, Yang Z, He Y, Shu C. Pitfalls in the rapid diagnosis of positive blood culture. Rev. Med. Microbiol. 21(3), 39–43 (2010).

http://en.wikipedia.org/wiki/Host_(biology)

http://en.wikipedia.org/wiki/Tissue_(biology)

http://en.wikipedia.org/wiki/Disease

http://en.wikipedia.org/wiki/Organism

http://en.wikipedia.org/wiki/Toxin

Severe Sepsis/SIRS. Sepsis (SIRS) associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status.

Refractory (Septic) Shock/SIRS Shock.

A subset of severe sepsis (SIRS) and defined as sepsis (SIRS) induced hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients receiving inotropic or vasopressor agents may no longer be hypotensive by the time they manifest hypoperfusion abnormalities or organ dysfunction, yet they would still be considered to have septic (SIRS) shock.

Multiple Organ Dysfunction Syndrome (MODS).

Presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention.


http://www.ccmtutorials.com/renal/Oligur/oliguria%201.htm

http://www.ccmtutorials.com/renal/Oligur/oliguria%201.htm

TRANSIENT BACTEREMIA

• generally lasting for a few minutes or a few hours, is associated with procedures involving

• anatomic sites colonized by normal microbial flora (i.e., after colonoscopy, percutaneous catheterization, or dental extractions) or with a manipulation of localized infected sites (i.e., furuncles).

INTERMITTENT BACTEREMIA

• typically associated with closed-space infections, such as abscesses, or with focal infections,

• such as pneumonia and osteomyelitis. • It is defined as recurrent episodes of bacteremia due to

the same microorganism intermittently detected in blood because of cyclical clearance and recurrence of the pathogen at the primary site of infection.

CONTINOUS BACTEREMIA

• persistent low-grade bacteremia is commonly• associated with an intravascular focus of infection such

as infective endocarditis (IE) or vascular-graft infections. In all cases the microbial load may be as low as 1 CFU/ml, making the microbiological diagnosis difficult



Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29(7), 1303–1310 (2001).

SIRSsystemic inflammatory response syndrome

– systemic pro-inflammatory mediators (primarily TNF, IL-1, IL-6) predominate over anti-inflammatory mediators.

MARSmixed antagonist response syndrome

– surges of SIRS and CARS

CARSCompensatory anti-inflammatory syndrome

compensatory anti-inflammatory syndrome

– systemic anti-inflammatory mediators (IL-4, IL-10, IL-11, IL-13, soluble TNF receptors, IL-1 receptor antagonists, and others) predominate over pro-inflammatory mediators.

Desmet SS. The problem of sepsis – an expert report of the European-Society-Of-Intensive-Care-Medicine. Intensive Care Med. 20(4), 300–304 (1994).

The Relationships between SIRS, MARS and CARS

What is the Title of the slide?

Desmet SS. The problem of sepsis – an expert report of the European-Society-Of-Intensive-Care-Medicine. Intensive Care Med. 20(4), 300–304 (1994).

FEVER

FEVER • temperature greater than 38.0 .C is considered fever, and fever is typically defined as a pyrogen-mediated rise in body temperature above this temperature.

•• Physiologically, it has been defined as “a state of elevated

core temperature, which is often, but not necessarily,• part of the defensive responses of multicellular organisms

(host) to the invasion of live•• (micro-organisms) or inanimate matter recognized as

pathogenic or alien by the host•• The elevated body temperature during fever should be

distinguished from that occurring in hyperthermia.

Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit. Care 14(1), R15 (2010).

FUNCTION OF FEVER• different studies showing both potentiating and inhibitory effects of the response to infection.

• Phylogenetic studies have shown that fever is widespread within the animal kingdom; as the rise in temperature is metabolically expensive but still is well-preserved in evolution,

• it has been argued that fever has to be an adaptive and beneficial response.

• Animal studies have demonstrated enhanced resistance to infection during experimentally increased temperature.

• In human in vivo studies associations between higher temperatures and better disease outcome have been observed.

• On the contrary, it has been suggested that pyrogenic cytokines such as IL-1, IL-2 and TNF are involved in at least part of the local and systemic response to infection, with higher levels of circulating cytokines correlating with less favorable outcome.

Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit. Care 14(1), R15 (2010).

PYROGENSEndogenous Pyrogens • Most exogenous pyrogens are microbes, toxins or other microbial

products,• either working directly on the hypothalamus or inducing the release of

endogenous pyrogens,• derived form the host’s cells.

Exogenous Pyrogens • Endogenous pyrogens, most importantly IL-1, IL-6, TNF-α and IFN-γ, interact

• with brain microglia and brain endothelial receptors, thus activating the arachidonic acid

• pathway. This in turn results in the production of cyclo-oxygenase derived prostaglandins,

• prostacyclins and thromboxane. Prostaglandin E2, most notably, increases the hypothalamic thermostatic setpoint

FUNGAL BIOMARKERS

Fungal Biomarkers: GM•ELISA for the detection of galactomannan (GM), an Aspergillus sp. cell wall component

•A positive test confirmed with two sequential samples is considered to be a valid index for invasive aspergillosis diagnosis

•Although the detection of GM in serum is easy to perform, a major disadvantage of the serodiagnosis of invasive aspergillosis is the occurrence of false-positive results.

•Several possible causes of false-positive reactions have been reported, including the intake of certain foods, especially if the intestinal barrier is altered; gastrointestinal chronic graft- versus-host disease; solutions containing sodium gluconate; and, in particular, the use of semisynthetic �-lactam treatments, especially piperacillin-tazobactam (Changes in the manufacturing process for this antibiotic, possibly resulting in the reduction of cross- reacting materials, have been suggested).

•Although the GM assay has been designed to be specific for Aspergillus spp. cross-reactivity with other fungal species such as Blastomyces dermatitidis, Penicillium spp., and Fusarium spp. has been reported.

•The increasing clinical impact of non-Aspergillus invasive infections warrants caution when interpreting positive GM results, especially if an infection with a potentially cross- reacting species cannot be clinically excluded.

•Additionally, different studies reported highly variable sensitivities. In a meta-analysis of 27 studies, the overall sensitivity was reported to be 71%, and the specificity was reported to be 89% (155). Even lower sensitivities were reported for high-risk patients, such as recipients of solid-organ transplants

Early Diagnosis of Sepsis Using Serum Biomarkers;Terence Chan; Frank Gu Expert Rev Mol Diagn. 2011;11(5):487-496. © 2011 Expert Reviews Ltd.

Fungal Biomarkers: (133)--D-Glucan•�-Glucan (BG) is another component of the fungal cell wall - present in a wider variety of fungal species, including

Candida spp.

•As for GM, different studies reported variable sensitivities - with a sensitivity of 69.9% being observed for a large multicenter study using just one sample per patient

•For most patients with confirmed invasive fungal infections, BG levels were elevated several days before clinical diagnosis.

•It was suggested that BG detection may be a useful adjunctive tool for promptly guiding preemptive antifungal therapy for neutropenic patients but further studies investigating this aspect are certainly needed.

•The combined use of GM and BG detection has also been proposed. In a retrospective study of 40 neutropenic patients, parallel detection improved the specificity and positive predictive value of each individual test without affecting the sensitivity and negative predictive values. In other words, the combination seems to be useful to identify false-positive reactions for each test. Several studies of animal models seem to confirm this observation, but further clinical studies are needed to evaluate the cost-effectiveness of this approach.

•Finally, it is important that neither the BG nor GM assay detects zygomycetes, a rare but emerging cause of invasive fungal mycosis


Non-microbiological, Nonspecific Sentinel Markers in Sepsis Patients

The Ideal Biomarker

To be considered clinically relevant, a biomarker must have a high DA;[32] that is, it must have high sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) (Table 1). Many studies also calculate the likelihood ratio to determine if test results are truly indicative of disease or due to random chance

These values are commonly graphed for multiple cutoff values (CVs) as a receiver operating characteristic curve. The area under the curve value is used to determine the best diagnostically relevant CV. At a CV where area under the curve is equal to 1, an ideal biomarker would possess 100% sensitivity, specificity, PPV and NPV.


Biomarker Cutoff value Diagnostic accuracy values (%) Ref.Sensitivity Specificity PPV NPV

CRP 1.56–110 mg/l 30–97.2 75–100 31–100 81–97 [5,20,27,28,34,37–40]

PCT 0.3–8.05 ng/ml 74.8–100 70–100 55–100 56.3–100 [4,9,21,34,37,38,40,53]

SAA 8–68 mg/l 76.4–98.4 92.3–100 85–100 58–99 [4,28,40]M 0.1–1 ng/ml 67–78 73–100 58–100 72.7–87 [29,45]

M and AM0.1–0.25 ng/ml; 2.6–4

AU/ml† 73–100 73.9–80 36–80 95–100 [29,70]

IP-10 260–1700 pg/ml 67–93 59.4–89 77‡ 97‡ [52,72,73]


IL-6• The release of inflammatory cytokines such as tumor necrosis factor alpha (TNF-), IL-1b, IL-8, and IL-6 in

response to infectious pathogens and host injury may lead to SIRS.

• In particular, IL-6 is induced by TNF- and can be measured reliably in blood, having a long half-life.

• IL-6 - an important mediator in septic shock, has been acknowledged to predict severity and clinical outcome under this condition

• However, it is relatively nonspecific as a marker of infection, and it was observed that IL-6 levels are elevated under a variety of conditions, such as in the acute-phase response to injury, in acute pancreatitis, and in renal transplant patients with an increased risk of acute rejection or graft failure

• From a clinical point of view, IL-6 may be regarded principally as an early predictor of downstream effects, such as organ dysfunction, due to its initial role in the cytokine response


CRP• CRP is an acute-phase protein synthesized predominantly in hepatocytes and alveolar

macrophages in response to a variety of cytokines, including IL-6. CRP also plays a role in immunomodulation. I

• CRP modulates the complement cascade and regulates bacterial opsonisation and phagocytosis

• Increases in CRP levels have been documented under a variety of noninfectious conditions, including postmyocardial infarction settings and rheumatologic diseases

• The kinetics of serum CRP are characterized by a rapid response to inflammation and a short half-life (approximately 19 h).

• Finally, the assay is inexpensive and widely available. Although several studies demonstrated elevated CRP levels in sepsis, its nonspecific dynamics cannot support a major diagnostic role for this biomarker in sepsis.


PCT• Procalcitonin (PCT) is a propeptide of calcitonin that is ubiquitously expressed as part of the host’s inflammatory response to a

variety of insults

• Although calcitonin is a hormone classically produced in the parathyroids and involved in calcium homeostasis, PCT (one of the calcitonin precursors) has effects on a variety of inflammatory conditions, including cardiogenic shock, trauma, necrotizing pancreatitis, burns, surgery, and infection

• A growing body of evidence suggests that PCT is a marker of severe bacterial infection and can distinguish patients who have sepsis from patients who have SIRS

• In particular, PCT levels in plasma have been correlated with sepsis-related organ failure scores and may be useful in risk assessment

• High and persistent elevations in PCT levels have been associated with poor outcomes for ICU patients

• There seems to be particular value of PCT in risk assessment for pediatric patients

• Although several studies suggested that PCT is among the most promising biomarkers for sepsis, considerable controversy surrounding its clinical usefulness still remains.

• A recent meta-analysis indicated that PCT cannot reliably differentiate sepsis from other noninfectious causes of SIRS in critically ill adult patients.

• However, the U.S. Food and Drug Administration (FDA) has approved the use of PCT in conjunction with other laboratory findings to aid the risk assessment of critically ill patients.

Pierrakos and Vincent: Sepsis biomarkers: a review. Critical Care 2010 14:R15.

Procalcitonin for the Guidance of Antibiotic Therapy inLower Respiratory Tract Infections

• Numerous studies have evaluated PCT as a biomarker to guide initiation of antibiotic therapy in patients suspected of LRTIs

• A meta-analysis published in 2011 with 8 studies (3431 patients) showed a reduction in antibiotic prescription in the PCT-guided antibiotic treatment groups by 30%

• As PCT levels increase upon bacterial infection and decrease upon recovery, it can be used to guide antibiotic therapy in individual patients as a surrogate biomarker.

• Two low PCT measurements, over the first 4 to 6 hours of hospital admission, resulted in fewer patients started on empirical antibacterials. Low PCT levels over the first 4 hours of inpatient care have an excellent negative predictive value for bacterial infection

• A Cochrane review published in 2012 with 14 studies (4221 participants) showed that PCT guidance was not associated with increased mortality (5.7% versus 6.3%, or treatment failure (19.1% versus 21.9%). Total antibiotic exposure was significantly reduced overall.

• To date, numerous studies (including meta-analysis) have been published and provide consistent results that withhold antibiotic prescription can be done with low levels of PCT


Procalcitonin for Antibiotic Guidance in Other Infections

• Procalcitonin has been studied in febrile neutropenic patients, fungal infections, postoperative fever, arthritis, endocarditis, meningitis, and suspected bloodstream infections

• The majority of published studies were observational and it remains uncertain whether PCT can be safely used for antibiotic guidance in different settings.

• For some infections, PCT may not be sensitive enough for routine clinical use.

• In a recent meta-analysis with 6 trials (1006 episodes of suspected endocarditis), the global measures of accuracy of CRP were higher than PCT showing that current evidence does not support the routine use of serum PCT or CRP to rule in or rule out endocarditis


Procalcitonin for Identification of Sepsis• Procalcitonin has been studied to differentiate between sepsis and SIRS of noninfectious origin.

• Numerous studies have investigated the diagnostic usefulness of PCT, comparing it with CRP. Initially, PCT was found more sensitive and specific than CRP for bacterial infection

• In a meta-analysis of Uzzan et al. (publication date:2006), 33 studies published between April, 1996, and October, 2004, were included, with 3,943 patients (1,825 patients with sepsis, severe sepsis, or septic shock and 1,545 with only SIRS). This meta-analysis showed that the ROC for PCT was higher than for CRP for identification of sepsis (0.78 versus 0.71, �� = 0.02). However, the investigators restricted the population to surgery or trauma patients. Therefore, no conclusion can be drawn for patients other than surgical

• A posterior meta-analysis (2007) looking at the diagnostic accuracy of PCT in sepsis diagnosis in critically ill patients included 18 studies published between April, 1996, and November, 2005, with very restrictive inclusion criteria, including evidence of infection by any microbiological test. Uzzan et al. concluded that PCT was not able to discriminate between sepsis and SIRS. The diagnostic accuracy of PCT was low, mean sensitivity and specificity were both 71% (95% CI 67–76), and AUROC was 0.78 (95% CI 0.73–83).

• However, their findings were heavily biased because of their selection criteria. The rejection of such studies has been raised as a major criticism of their conclusion that PCT cannot accurately distinguish sepsis from SIRS in critically ill patients

• The most recent meta-analysis published by Tang et al. included 30 studies (3244 patients) until February 2012.They concluded that accuracy of PCT to discriminate sepsis and SIRS was low, mean sensitivity 77% (95% 72–81), and specificity 79% (95% CI 74–84).

• Although PCT has been shown to correlate closely with infection, it has some limitations. It rises transiently in patients with nonseptic conditions and SIRS (e.g., trauma, surgery, and heatstroke) and is not detectable in certain cases of sepsis



TREM-1• Neutrophils and monocytes/macrophages are the primary mediators of the innate immune response to bacterial infection, promoting the

release of proinflammatory cytokines such as TNF- and IL-1b, which, when produced in excess, contribute to end-organ dysfunction and overwhelming sepsis.

• The so-called triggering receptor expressed on myeloid cells 1 (TREM-1) is part of the immunoglobulin superfamily and is upregulated in response to bacteria or fungi.

• When bound to ligand, TREM-1 stimulates the release of cytokines.

• In contrast to infections, TREM-1 is not upregulated in noninfectious inflammatory disorders such as inflammatory bowel • disease and SIRS

• A soluble form of TREM-1 (sTREM-1) is shed from the membranes of activated phagocytic cells and can be quantified in human body fluids.

• Several studies have investigated the use of TREM-1 as a diagnostic biomarker and have shown it to be more sensitive and specific than CRP and PCT

• Although TREM-1 may be a promising diagnostic marker for sepsis, less is presently known about its use in risk assessment and prognosis for patients with known sepsis.

• Overall, the present data suggest that IL-6 and CRP are sentinel markers of inflammation and infection but are too nonspecific for further clinical use. PCT will likely enhance clinicians’ risk assessments for critically ill patients with sepsis.

• Furthermore, TREM-1 is an additional promising candidate. Given the high complexity and variability of the disease, biomarker panels or composite markers may prove most useful in examining a particular immunological pathway, predicting organ- specific responses, and, ideally, identifying at-risk individuals


suPAR• The soluble form of urokinase-type plasminogen activator receptor (suPAR) is a new biological marker of immunologic

activation Urokinase-type plasminogen activator receptor (uPAR) is expressed on various cell types and participates in numerous immunologic functions including migration, adhesion, angiogenesis, fibrinolysis, and cell proliferation.

• uPAR/uPA system participated in migration of inflammatory cells from the bloodstream into tissues against infection. During inflammatory stimulation, uPAR is cleaved from the cell surface by proteases to create the soluble form of the receptor, suPAR, which can be detected in blood, urine, and cerebrospinal fluid

• Measurements can be obtained from commercial ELISA kits; suPAR measurements also are included in multiplex assays together with cytokines.

• High serum suPAR concentrations have also been found to predict mortality in patients with active tuberculosis and other diseases associated with an inflammatory response

• Some studies have showed that suPAR levels were elevated in acutely ill patients but that their diagnostic value was not superior to other biomarkers such as CRP, PCT, or sTREM-1

• Recently, two studies evaluating diagnostic accuracy of suPAR have shown specificity from 64–77%


Pro-ADM• Adrenomedullin (ADM) is a 52-amino-acid peptide with immune modulating, metabolic, and vasodilator activity.

• Its widespread production in the tissues helps to maintain a blood supply in every organ. Moreover, ADM has a bactericidal activity and could be helpful in the evaluation of sepsis diagnosis and prognosis and in monitoring such conditions

• Prohormone fragments (pro-ADM) are more stable than the complete peptide and their levels can be measured in biological fluids - it has been detected in plasma of patients with septic shock as a consequence of the ADM active peptide degradation

• Pro-ADM is a biomarker of prognostic value and could be used to identify more severe patients with pneumonia and/or needing ICU care

• In a recent single prospective observational study conducted in a Spanish adult intensive care unit (137 patients), pro-ADM showed a significant dose-response trends to predict hospital mortality (OR = 3.00, 95% CI 1.06–8.46) compared to PCT and CRP.

• However, the prognostic accuracy was better for severity scores than for any biomarker

• In an Italian study comparing PCT and MR-pro-ADM • in 200 septic patients, 90 patients with SIRS, and 30 healthy individuals, the pro-ADM distinguished septic patients.

• Moreover, the combined use of PCT and MR-pro-ADM gave a posttest probability of 0.998 in the cohort of all septic patients. The combination of biomarkers may substantially improve the early diagnosis of sepsis


Presepsin. • CD14 is a glycoprotein expressed on the membrane surface of monocytes and macrophages and serves as a receptor for

(LPSs) and LPS-binding proteins (LPBs).

• By activating a proinflammatory signaling cascade on contact with infectious agents, CD14 has a role as a recognition molecule in the innate immune response against microorganisms.

• During inflammation, plasma protease activity generates soluble CD14 (sCD14) fragments. One of them is called presepsin, and is normally present in very low concentrations in the serum of healthy individuals and has been shown to be increased in response to bacterial infections

• In a multicenter prospective study (106 patients with • suspected sepsis or septic shock were included and 83 SIRS patients without infection), elevated concentrations of preseason

were observed in septic patients compared to control patients. • The best diagnostic cutoff for presepsin was • 600 pg/mL with sensitivity of 78.95% (95% CI, 69.4 to 86.6) • and specificity of 61.90% (95% CI, 50.7 to 72.3).

• There was no difference between levels of presepsin and sepsis severity.

• Although presepsin showed a significant prognostic value and initial values were significantly correlated with in-hospital mortality of patients affected by sepsis, severe sepsis, or septic shock, two recent studies have shown that presepsin is an useful biomarker for early diagnosis of sepsis and evaluation of prognosis in septic patients (sensitivity: 71-72%, specificity: 70–86%, and NPV: 52–71%)


Serum Amyloid A

Serum amyloid A (SAA) is an apolipoprotein reported to have potential for diagnosing sepsis.[4,28] SAA is expressed at levels up to 1000-times higher after 8–24 h from the onset of sepsis.[4,69] Compared with CRP levels, SAA levels are reported to rise faster and higher after the onset of sepsis and remain at higher relative elevations.[28] Similar to PCT and CRP, studies using SAA have reported various DA values and CVs (Table 2), likely a result of the different assays used, as well as the development of assays with lower detection limits. Serum SAA levels of less than 15 mg/l for the elderly over 65 years and less than 10 mg/l for adults and newborns aged 3–7 days are indicative of healthy states

Although SAA is mainly studied as a biomarker for bacterial infection, a recent study by Kajiya et al. on patients with viral infections reported elevated SAA levels above the healthy cutoff of 10 mg/l among the infected patients.[47] However, SAA may not be clinically useful because it may be too sensitive, as it has been reported to increase during minor viral infections and in patients not presenting symptoms.[47]


Conclusions

• (1) Bloodstream infection is a serious life-threatening condition with high mortality. In some cases, the diagnosis is challenging. An early diagnosis of sepsis helps to enable rapid treatment, improve outcomes, and reduce unnecessary antibiotic therapy.

• (2) Choosing the correct empiric therapy is sometimes a difficult process. The emergence of resistant pathogens is consequence of irrational use of antibiotics.

• (3) PCT and PCR are widely used in clinical practice and are more useful to rule out infection. PCT is the most studied biomarker that guides early stopping of antibiotic therapy in adults.

• (4) New biomarkers are being evaluated in different clinical scenarios, although none of them have shown sufficient sensitivity or specificity to rule out infection.

• (5) Presepsin appears to be the most promising new biomarker for early diagnosis of sepsis and better prognostic performance than procalcitonin.

Conclusions

The main challenge facing future biomarker research, and in reviewing biomarker studies, is the lack of standard operating protocols for each specific biomarker. There is high variability in study designs, including small sample sizes,[16,21,27,34,37–40,43–46,48,62,73] heterogeneous population types,[27,33,34,46] population type specificity[21,37,39,45,46,62] and high variation in assay equipment. Several studies also suffer from poor presentation and/or application of statistical analysis of data,[4,16,21,27,33,34,37,38,40,41,43–45,48,53,62] which may lead to improper interpretation of results by the readers. Many studies are single-centre studies involving small sample sizes, which may result in incorrect representation of the general population, but this restriction is a result of the high costs of running studies in the clinical setting and incorporating multiple centres. However, other issues pertaining to study design require the establishment of standardization among biomarker research studies.[17,22,58] Efforts have already been made to establish reporting and analysis standards, such as Standards for Reporting of Diagnostic Accuracy[81,82] and Grading of Recommendations Assessment, Development and Evaluation,[83,84] and the research community should endeavour to adopt these standards on a global scale for all future studies.

Conclusions

Key Issues

• C-reactive protein, procalcitonin and serum amyloid A are promising diagnostic biomarkers of bacterial infection requiring further in-depth research to verify their diagnostic relevancies.

• Mannan and antimannan antibodies are potentially useful biomarkers of fungal infection but their assays are prone to false-positives and -negatives, requiring combination with other assays.

• IFN-γ-inducible protein 10 is a relatively new, promising diagnostic and prognostic biomarker of several different viral infections, needing more studies on its relevancy.

• Many other potential biomarkers of sepsis have been identified; effort should be made to conduct thorough research on existing biomarkers instead of searching for one 'perfect' biomarker.

• No singular 'ideal' biomarker of sepsis has been identified; a more effective, alternative strategy may be to combine multiple markers.

• Assays for current sepsis biomarkers, especially procalcitonin, are too varied and lack the detection limits to produce consistent, accurate results.

• Future sepsis biomarker research requires multicentre studies, methodology standardization and more rigorous assays.

• Development of a multiplex point-of-care testing kit may help overcome many of the existing issues of current studies.

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Role of Biomarkers Sepsis