Copyright ©The Author(s) 2023.
World J Crit Care Med. Sep 9, 2023; 12(4): 188-203
Published online Sep 9, 2023. doi: 10.5492/wjccm.v12.i4.188
Table 1 Biomarkers in sepsis
ProcalcitoninPrecursor of hormone calcitonin secreted by C cells of thyroid gland
C-reactive protein Acute phase protein secreted by hepatocytes in response to pathogen or tissue damage
IL6 A cytokine, mainly produced by macrophages and lymphocytes in response to infection and it can affect the activation of B and T lymphocytes
suPARA protein derived from cleavage and release of cell membrane bound urokinase plasminogen activator receptor
sTREM1Mainly expressed on the surface of polymorphonuclear cells and mature monocytes
Presepsin (sCD14-ST)sCD14 is cleaved by proteases during inflammation, to form an N terminal fragment-the sCD14 subtype (sCD14-ST)
AdrenomedullinA 52 amino acid peptide initially isolated from phaeochromocytomas. It is secreted by mammalian tissues and endothelial cells in response to various stimuli such as hypoxia, angiotensin 2, inflammatory cytokine such as TNF-α, IL-1β, etc.
Mid regional Proadrenomedullin (MR-proADM)A peptide secreted by multiple tissues in order to stabilize the microcirculation and protect against endothelial permeability
Table 2 Biomarkers for diagnosis of sepsis
Ref.Study characteristics
Results and inference
Study type
Patient characteristics
Tan et al[5], 2019Meta-Analysis; 9 studiesPooled data. Total: 1368 patients. Sepsis: 495. Non sepsis: 873CRP; PCT0.73 (95%CI: 0.69-0.77), 0.85 (95% CI: 0.82-0.88)Sensitivity 0.80 (95%CI: 0.63-0.90); spec: 0.61 (95%CI: 0.50-0.72) DOR: 6.89 (95%CI: 3.86-12.31); sensitivity 0.80 (95%CI: 0.69-0.87); specificity: 0.77 (95%CI: 0.60-0.88) DOR: 12.50 (95%CI: 3.65-42.80)Diagnosis accuracy and specificity of PCT are higher than those of CRP
Thomas-Rüddel et al[9], 2018Randomised control trial, Prospective, Secondary analysisGram negative vs Gram positive bacteremia and candidemiaPCT (Gram negative bacteremia)0.72 (95%CI: 0.71-0.74)Value was 10 ng/mL sensitivity 69%, specificity 35% for Gram negative bacteraemiaStreptococci, E. coli and other Enterobacteriaceae detected from BC were associated with three times higher PCT values. Urogenital or abdominal foci of infection were associated with twofold increased PCT
Lai et al[7], 2020Meta-Analysis; 25 studiesGNBSICRP0.85 (0.81–0.87)Sens: 0.75 (0.56–0.87); Spec: 0.80 (0.68–0.88)PCT was helpful in recognizing GNBSI, but the test results should be interpreted carefully with knowledge of patients' medical condition and should not serve as the only criterion for GNBSI
PCT0.87 (0.84–0.90)Sens: 0.80 (0.60–0.91); Spec: 0.82 (0.72–0.89)
IL60.83 (0.80-0.86)Sens: 0.76 (0.58–0.88); Spec: 0.79 (0.71-0.85)
Zhao et al[29], 2014Prospective; Observational, single centreTotal: 652; Sepsis: 452; Non sepsis SIRS: 200PCT0.803Sens: 75.2%, Spec: 80.0%, PPV: 89.5%, NPV: 58.8%Combination of PCT, IL6 and D-dimer enhances the diagnostic ability for sepsis and severe sepsis
IL60.770Sens: 81.0%, Spec: 61.0%, PPV: 82.4%, NPV: 58.7%
D-Dimer(0.737)Sens: 79.9%, Spec: 59.0%, PPV: 81.5%, NPV: 56.5%
PCT + IL6 + D-Dimer0.866Sens: 81.6%, Spec: 73.6%, PPV: 56.0%, NPV: 90.6%
Kondo et al[14], 2019Meta-Analysis; 19 studiesAdult. Tot: 3012Presepsin0.87Sens: 0.84 (95% 0.80-0.88); Spec: 0.73 (0.61-0.82)Diagnostic accuracy of procalcitonin and presepsin in detecting infection was similar
PCT0.84Sens: 0.80 (0.75-0.84); spec 0.75 (0.67-0.81)
Kang et al[16], 2019AdultInfected trauma: 89; Non infected trauma: 68; Healthy controls: 60Presepsin0.853 (0.784-0.922)321.5 pg/mL; Sens: 67.2%; Spec: 91.9; PPV: 87.5; NPV: 78.2; LR+: 4.89; LR-: 0.39Presepsin might be a superior biomarker for early differentiation of infection in trauma patients
PCT0.771 (0.682-0.859)0.923 ng/mL; Sens: 61.1%; Spec: 88.2%; PPV: 79.1; NPV: 74.7; LR+: 5.21; LR-: 0.47
Presepsin + ISS0.939 (0.9-0.977)
Liu et al[15], 2013Prospective, adult consecutive, emergency departmentTotal: 859; Control: 100; SIRS: 372; Sepsis: 372; Severe sepsis: 210; Septic shock: 98Presepsin0.820 (0.784-0.856)317 pg/mL; Sens: 70.8%; Spec: 85.8%; PPV: 93.2%; NPV: 51.6%; LR+: 4.99; LR-: 0.34Presepsin is a valuable biomarker for early diagnosis of sepsis. trauma stress elevates PCT, CRP, and WBCs even in the absence of infection
PCT0.724 (0.680 to 0.769)0.25 ng/mL; Sens: 60%; Spec: 77.7%; PPV: 93.2%; NPV: 28.4%; LR+: 2.69; LR-: 0.51
Cong et al[20], 2021Meta-AnalysisAdult 20 studiesCD 640.94 (0.91-0.96)Sens: 0.88 (0.81-0.92); Spec: 0.88 (0.83-0.91); LR+: 7.2; LR-: 0.14; DOR-51 (25-101)Neutrophil CD64 test has a high sensitivity and specificity in adult sepsis patients, and was superior to the traditional biomarkers PCT and IL6
PCT0.87 (0.83-0.89)Sens: 0.82 (0.78-0.85); Spec-: 0.78 (0.74-0.82); LR+: 3.7; LR-: 0.23; DOR-16 (11-23)
IL60.77 (0.73-0.80)Sens: 0.72 (0.65-0.78); Spec: 0.70 (0.62-0.76); LR+: 2.4; LR-: 0.40; DOR-6 (4-9)
Gámez-Díaz et al[25], 2011Prospective, cohortEmergency, total 631 pts; based on expert consensus, Sepsis- 416nCD-64NASens: 65.8% (95%CI: 61.1%-70.3%); Spec: 64.6% (95%CI: 57.8%-70.8%); LR+: 1.85 (95%CI: 1.52-2.26); LR-: 0.52 (95%CI: 0.44-0.62)Patients suspected of having any infection in the ED, the accuracy of nCD64, sTREM1, and HMGB-1 was not significantly sensitive or specific for diagnosis of sepsis
HMGB-1Sens: 57.5% (95%CI: 52.7%-62.3%); Spec: 57.8% (95%CI: 51.1%-64.3%); LR+: 1.36 (95%CI: 1.14-1.63); LR-: 0.73 (95%CI: 0.62-0.86)
s-TREM-1Sens: 60% (95%CI: 55.2%-64.7%). Spec: 59.2% (95%CI: 52.5%-65.6%). LR+: 1.47 (95%CI: 1.22-1.76). LR-: 0.67 (95%CI: 0.57-0.79)
Yeh et al[19], 2019Metaanalysis. 14 studiesAdult, pooled data: Total: 2471; Control: 1167; Sepsis: 1304Neutrophilic CD 640.89 (0.87–0.92)Sens: 0.87 (0.80-0.92); spec 0.89 (0.82-0.93)Neutrophil CD64 levels are an excellent biomarker with moderate accuracy outperforming both CRP and PCT determinations
PCT0.84 (0.79–0.89)Sens: 0.76 (0.61-0.86); spec 0.79 (0.70-0.86)
CRP0.84 (0.80–0.88)Sens: 0.83 (0.78-0.86); spec 0.71 (0.56-0.85)
Dimoula et al[22], 2014Prospective observational study548 adult ICU patients. Sepsis: 103; Non sepsis: 445nCD64NR230 MFI. sens: 89% (81%-94%); spec: 87% (83%-90%).Combining CRP and nCD64 expression, an abnormal result for both was associated with a 92% probability of sepsis, whereas sepsis was ruled out with a probability of 99% if both were normal. In nonseptic patients, an increase in nCD64 expression ≥ 40 MFI predicted ICU-acquired infection (n = 29) with a sensitivity of 88% and specificity of 65%
Wang et al[23], 2021Metaanalysis: 7 articlesNeonatal, paediatric and adultsIL270.88 (0.84-0.90)Sens: 0.85 (95%CI: 0.72-0.93); Spec: 0.72 (95%CI: 0.42-0.90); DOR-15 (95%CI: 3-72)IL27 is a reliable diagnostic biomarker for sepsis and should be evaluated with other clinical tests
Wong et al[24], 2013ProspectiveAdults, infective (n = 145) and non-infective (n = 125) critically illIL270.68 (0.62-0.75)IL27 inferior to PCT in sepsis diagnosis
PCT0.84 (0.79-0.89)
Uusitalo-Seppälä et al[27], 2012Prospective cohort525 adult patients in emergency. Severe sepsis: 49; Sepsis: 302; SIRS: 58. Sirs with no bacterial infection: 53. Bacterial infection no SIRS: 63PLA(2)GIIANAOR: 1.48 (1.20-1.81, P < 0.001)Differences in AUC between these parameters were not significant. On multivariate logistic regression analysis only PLA(2)GIIA could differentiate patients with severe sepsis from others (OR: 1.37, 95%CI: 1.05-1.78, P = 0.019
BPIOR: 2.66 (1.54-4.60, P = 0.001)
CRPOR: 1.35 (1.02-1.77, P = 0.036)
WBCOR: 2.81 (1.48-5.34, P = 0.002)
Aksaray et al[26], 2016ProspectiveICU, Adult, Sepsis (52), SIRS (38)STREM10.78 (0.69–0.86)sTREM1 cut-off value ≥ 133 pg/mL. Sens: 71.1%; Spec: 67.33%; PPV: 80.43; NPV: 65.91 sTREM1, APACHES II higher in patients with positive culture than negative cultures. sTREM1, PCT and CRP levels, or WBC count performed equally to differentiate
PCT0.65 (95%CI: 0.53–0.76)PCT cut-off value of 1.57 ng/mL. Sens: 67.31; Spec: 65.79%; PPV: 72.92; NPV: 70
Table 3 Biomarkers for diagnosis of sepsis-current understanding in diagnosis of sepsis
Diagnosis of sepsis
Differentiating sepsis and SIRS
Guiding antibiotic initiation
Organism identification
ProcalcitoninBetter than CRP; cannot be used independently; diagnosis based on clinical contextBetter than CRP; cannot be used independently; diagnosis based on clinical contextDelays antibiotic administration; No short term mortality benefitHigher in Gram negative bacteremia than Gram positive. Higher in bacteremia than in candidemia. No defined cutoffs. Treatment to be based on clinical judgement
PresepsinPossible rolePossible roleNo significant dataNo significant data
nCD64Possible role; when combined with CRP, higher diagnostic accuracy and high negative predictive valueNo significant dataNo significant dataIncreased in bacterial and viral infection more than fungal
suPARPossible rolePerformed poorlyNo significant dataNo significant data
IL6Inferior to PCT, CRPInferior to PCT, CRPNo significant dataNo significant data
Table 4 Procalcitonin for prognosis of sepsis
Type of study
Patient population
No. of patients/studies
Conclusion of study
Ryu et al[52], 2015ObservationalAdultsTo compare changes in PCT and CRP concentration in critically ill septic patients to determine which marker better predicts outcome 157 patients; 171 episodesCPCTc and CRPc are significantly associated with treatment failure (P = 0.027 and P = 0.03 respectively) and marginally significant with 28 d mortality (P = 0.064 and 0.062 respectively). AUC for prediction of treatment success-PCTc-0.71 (95%CI: 0.61-0.81); CRPc-0.71 (95%CI: 0.61-0.81); AUC for survival prediction-PCTc-0.77 (95%CI: 0.66-0.88); CRPc-0.77 (95%CI: 0.67-0.88)Changes in PCT and CRP concentrations were associated with outcomes of critically ill septic patients. CRP may not be inferior to PCT in predicting outcomes in these patients
Patnaik et al[32], 2020Meta-AnalysisAdults To evaluate the results of all non-clearance of serial PCT as a mortality predictor10 studies, 1974 patients AUC varied between the studies between 0.52 and 0.86. Overall AUC-0.711 (95%CI: 0.662-0.760) under fixed effect model and 0.708 (95%CI: 0.648-0.769) under random effect model. Overall proportion of mortality-37.54%PCT non clearance is a marker for increased mortality. Optimal cut off points for PCT non clearance in septic patients admitted to ICU are not known
Park et al[53], 2013ObservationalAdults To evaluate the value of PCT in women with APN at ED 240AUC for predicting 28 d mortality for PCT-0.68. For predicting mortality, a cut off value of 0.42 ng/mL, sensitivity was 80% and specificity was 50%. Disease classification systems were predicted to be superior to PCT in predicting 28 d mortalityBy distinguishing the severity of sepsis related to APN mortality, PCT levels help clinicians in disease severity classification and treatment decisions at ED
Oberhoffer et al[54], 1999ObservationalAdults To predict outcome with traditional and new inflammatory markers in septic patients242AUC for PCT was 0.878 which was highest as compared to other markersPCT may be a better marker than other inflammatory markers, CRP, leukocyte count, body temperature to identify patients endangered by severe infection or sepsis
Arora et al[31], 2015 Meta-Analysis Adults To study the procalcitonin levels in survivors and non survivors of sepsis 25 studies; 2353 patients Mean difference in procalcitonin levels between survivors and non survivors on day 1 (P = 0.02) and day 3 (P = 0.03) was statistically significantSignificantly lower levels of procalcitonin were observed in survivors as compared to non survivors in early stages of sepsis
Table 5 Presepsin for prognosis of sepsis
Type of study
Patient population
No. of studies/patients
Conclusion of study
Masson et al[33], 2015Retrospective case control studyAdults To evaluate the prognostic value of presepsin and comparison with procalcitonin100Presepsin levels at day 1 were higher in decedents (2269 pg/mL, median-1171 to 4300 pg/mL) than in survivors (1184 pg/mL, median-875 to 2113 pg/ml); P = 0.002) whereas PCT was not different (18.5 mcg/L, median 3.4 to 45.2) and 10.8 mcg/L (2,7 to 41.9 mcg/L) P = 0.13). The evolution of presepsin levels over time was significantly different in survivors compared to non survivors (P for time-survival interaction-0.03)Presepsin showed better prognostic accuracy than procalcitonin in the range of SOFA. (AUC: 0.64-0.75 vs AUC: 0.53-0.65)
Behnes et al[55], 2014Prospective cohort studyAdults Evaluation of diagnostic and prognostic value of presepsin in sepsis and septic shock patients during the 1st wk of ICU treatment116 AUC- 0.64 TO 0.71; Presepsin cut off values-Sepsis-530 pg/mL; Severe sepsis-600 pg/mL; Septic shock-700 pg/mLPresepsin has good prognostic value in terms of prognosis for 30 d and 6 mo all cause mortality throughout the 1st wk of ICU stay and its prognostic value for all cause mortality is comparable to that of IL6 and better than that of PCT, CRP or WBC
Yang et al[56], 2018Meta-Analysis Adults To evaluate the mortality prediction value of presepsin in septic patients10 studies; 1617 patients Initial prespesin levels (within 24 h) were significantly lower in survivors as compared to non survivors. Pooled SMD (standardized mean difference) between survivors and non survivors-0.92 (95%CI: 0.62–1.22)Some mortality prediction of presepsin; further studies may be needed to define optimal cut off points for presepsin to predict mortality in sepsis
Wang et al[57], 2020Observational Elderly patients To investigate the prognostic value of presepsin for elderly septic patients in ICU142Presepsin levels were significantly higher in infected patients. Day 3 presepsin levels showed a significant prognostic value for 30 d mortality but was not found to be superior to other biomarkersEarly diagnostic ability comparable to that of PCT; however not a perfect biomarker for prognosis of 30 d mortality in elderly patients
Koh et al[58], 2021ObservationalAdults Estimation of prognostic value of presepsin in septic patients153AUC for presepsin- 0.656; Presepsin levels > 1176 pg/mL (odds ratio 3.352, P < 0.001) was a risk factor for in hospital mortality Non survivors had higher presepsin levels; presepsin may have prognostic value
Endo et al[59], 2014Prospective study Adults To compare presepsin with other conventional biomarkers (PCT, CRP, IL6) for evaluating the severity of sepsis 103In patients with unfavorable prognosis: (1) Presepsin levels did not decrease significantly during follow up; (2) Higher duration of antibiotic therapy was used (P < 0.05); and (3) Higher 28 day mortality (P < 0.05)Presepsin levels correlated with severity during follow up as compared to other conventional biomarkers
Masson et al[33], 2015ObservationalAdults Evaluating the relationship between presepsin levels and host response, appropriateness of antibiotics, and mortality in severe sepsis patients997 patients with severe sepsis or septic shock in ALBIOS trialBaseline Presepsin concentrations increased with SOFA score, number of organ failures, and incidence of new organ failures; An increasing concentration of presepsin from day 1 to day 2 predicted higher ICU (P < 0.0001) and 90 d mortality (P < 0.01)Presepsin is an early predictor of host response and mortality in patients with sepsis
Table 6 Adrenomedullin and pro adrenomedullin for prognosis of sepsis
Type of study
Patient population
No. of patients
Conclusion of study
Christ-Crain et al[34], 2006 Prospective observational Adult patients with CAP To evaluate the value of Pro ADM levels for severity assessment and outcome prediction in CAP302 Pro ADM levels (as compared to CRP and leukocyte count) increased with increasing severity of CAP (calculated through PSI score). Pro ADM levels at admission significantly higher 2.1 (1.5 to 3) nmol/L compared to survivors 1 (0.6 to 1.6) nmol/L; P < 0.001. AUC for proADM was 0.76 (95%CI: 0.71–0.81)-significantly higher than PCT, CRP, TLCPro ADM is a useful biomarker for risk stratification in patients with CAP
Charles et al[60], 2017Prospective cohort Adults To assess the prognostic value of PCT, MR pro ADM, copeptin and CT proendothelin1 concentrations173Day 1 MR-ProADM levels significantly higher in non survivors [8.6 (5.9) vs 4.4 (3.9)] nmol/L; P < 0.0001Day 1 MR-ProADM is a good predictor of short term clinical outcome as compared with others
Li et al[36], 2018Meta-Analysis Adults To evaluate the ability of adrenomedullin and Pro Adm to predict mortality in septic patients 13 studies; 2556 patients Increased AM or Pro ADM levels are associated with increased mortality (pooled RR = 3.31; 95%CI: 2.31-4.75); AUC 0.8 (95%CI: 0.77-0.84)AM and Pro ADM may be used as prognostic markers in sepsis
Chen and Li[61], 2013 ObservationalAdultsTo evaluate the prognostic value of adrenomedullin in septic patients and compare it with PCT and MEDS837Mean levels (at admission of AM were 28.66 ± 6.05 ng/L in 100 healthy controls, 31.65 ± 6.47 ng/L in 153 systemic inflammatory response syndrome patients, 33.24 ± 8.59 ng/L in 376 sepsis patients, 34.81 ± 8.33 ng/L in 210 severe sepsis patients, and 45.15 ± 9.87 ng/L in 98 septic shock patients. The differences between the 2 groups were significant. ADM levels significantly higher in non survivors; AUC for in hospital mortality-AM-0.773; PCT-0.701; MEDS-0.721Adrenomedullin is valuable prognostic biomarker for septic patients in ED
Caironi et al[62], 2017Observational AdultsTo evaluate the role of Bio ADM 956Plasma bio ADM (day 1) was higher in and associated with higher 90 d mortality, multi organ failures, extent of haemodynamic support and serum lactate time course over the 1st wk. Bio ADM trajectory during the 1st wk of treatment predicted 90 d mortality; Reduction to levels below 110 pg/ml at day 7 was associated with reduction in 90 d mortalityBio ADM levels may help individualize haemodynamic support therapy in septic patients
Elke et al[63], 2018Secondary analysis of RCT Adults To evaluate role of MR Pro Adm compared to conventional biomarkers (PCT, CRP, lactate) and clinical scores to identify disease severity in sepsis1089 MR Pro Adm had strongest association with mortality and high disease severity; A decreasing concentration of PCT by ≥ 20 % from baseline to day 1 or ≥ 50 % from baseline to day 4 but a persisting high level of Pro Adm had significantly increased mortality risk [HR (95%CI)-19 (8-45.9) and 43.1 (10.1-184)]MR Pro Adm assesses disease severity and treatment response more accurately than conventional biomarkers and scores
Table 7 Soluble urokinase plasminogen activator receptor for prognosis of sepsis
Type of study
Patient population
No. of patients
Conclusion of study
Backes et al[64], 2012Systematic reviewAdultsTo assess the usefulness of suPAR levels in critically ill patients with sepsis, SIRS, bacteraemia, focusing (diagnostic and prognostic value)10 studies Little diagnostic value in critically ill septic patients. Superior prognostic value in such patients as compared to other markers. Improved mortality prediction by combining suPAR with other markers or disease severity classifications. suPAR levels correlate positively with markers of organ dysfunction and severity of disease classification system scoressuPAR has a low diagnostic value for septic patients. It may add to prognostication with other markers and organ dysfunction scores
Huang et al[18], 2020Systematic review Adults To evaluate the value of suPAR for diagnosis and prognosis of sepsis30 studies, 6906 patients Pooled sensitivity and specifity for predicting mortality-0.74 (95%CI: 0.67-0.8) and 0.7 (95%CI: 0.63-0.76) with AUC of 0.78 (95%CI: 0.74-0.82)suPAR is a good maker for prognostication of sepsis
Pregernig et al[65], 2019Meta-Analysis Adults To assess the prognostic value of suPAR and 6 other biomarkers in predicting mortality in adult septic patients28 studies included Pooled mean differences in marker concentrations (survivors-non survivors) at onset of sepsis for suPAR-5.2 ng/mL; 95%CI: 4.5-6; P < 0.01)suPAR can provide prognostication information about mortality in adult septic patients
Ni et al[66], 2016Meta-Analysis Adults To evaluate the usefulness of suPAR for diagnosis and prognosis of bacterial infections17 studies includedHigh suPAR levels were related with a significantly increased risk of death with a pooled risk ratio of 3.37 (95%CI: 2.6-4.38). Pooled sensitivity and specificity for predicting mortality were 0.7 and 0.72 respectively, with AUC of 0.77suPAR can be used for prognosis of bacterial infection
Table 8 Soluble triggering receptor expressed on myeloid cells 1 for prognosis of sepsis
Type of study
Patient population
No. of patients/studies
Conclusion of study
Su et al[67], 2016Systematic review AdultsTo determine prognostic value of sTREM1 in predicting mortality at the initial stage of infection9 studiesHigh sTREM1 level was associated with higher risk of death in infection, with pooled RR 2.54 (95%CI: 0.61-0.86) using a random effects model; Pooled sensitivity and specificity of sTREM1 to predict mortality in infection were 0.75 (95%CI: 0.61-0.86) and 0.66 (95%CI: 0.54-0.75), respectivelyHigher sTREM1 levels had a moderate prognostic significance in assessing the mortality of infection in adult patients; however sTREM1 alone is not sufficient to predict mortality as a marker
Su et al[68], 2012ObservationalAdults To study the association of sepsis prognosis with dynamic changes in sTREM1 and its polymorphisms160sTREM1 levels were significantly raised in non survivors than in survivors (P < 0.001); Logistic regression showed that sTREM1, APACHE 2, and rs2234237 polymorphisms are risk factors for prognosisDynamic changes in sTREM1 and rs2234237 polymorphism could be used for prognostication in septic patients
Wang et al[69], 2011ObservationalAdults To observe dynamic changes in plasma sTREM1 levels and to study its effect on predicting outcome of septic patients combined with SOFA score57Non survivors-sTREM1 levels were highest on Day 1 and a gradual elevation was seen over days 1, 3 and 7). Survivor-sTREM levels were highest on day 1 and then showed a gradual reduction over days 1, 3 and 7. sTREM levels were significantly higher in non survivors as compared to survivors (P < 0.01)High plasma levels of sTREM1 are detected at initial stages in septic patients and sTREM1 level combined with SOFA score may be helpful in predicting outcomes in septic patients