Current Evidence and Limitation of Biomarkers for Detecting Sepsis and Systemic Infection
Abstract
:1. Introduction
2. Categories of Biomarkers
3. Six Promising Biomarkers
3.1. C-Reactive Protein
3.2. Procalcitonin
3.3. Interleukin-6
3.4. CD64
3.5. Presepsin
3.6. Soluble TREM-1 (sTREM-1)
4. Risk of Bias
5. Future Directions
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Assay | Study Inclusion Criteria | Study Exclusion Criteria | Reference Standard | Included Studies/Total Patient Number | Risk of Bias | Outcome (Sensitivity; Specificity; AUROC); Heterogeneity (I2) % | Cutoff | Publication Bias | |
---|---|---|---|---|---|---|---|---|---|
CRP | |||||||||
Liu 2016 | nil | Evaluate the diagnostic accuracy of CRP for distinguishing patients with sepsis from those with non-infectious SIRS | Lacked non-infectious SIRS patients as a control group; Immunocompromised, hematologic and pediatric patients; Not provide sufficient data to build a 2 × 2 contingency table | Culture positive or clinically diagnosed with ACCP/SCCM pre-sepsis 3 definition | 45/5654 | Most studies were not fulfilled or with unclear representative spectrum of patients | 0.75 [0.69, 0.79]; 86.6; 0.67 [0.58, 0.74]; 89.3; 0.77 [0.73, 0.81] | IQR 38–140 mg/L Median 84 mg/L | p = 0.71 |
Tan 2018 | nil | English and Chinese article; Clinical trial studies; Adult patients diagnosed with sepsis, severe sepsis, or septic shock in the experience group; noninfectious origin with SIRS in control group; Provide sufficient data to build a 2 × 2 contingency table | Repeat published articles; Data had obvious mistakes; Case report, theoretical research, conference report, systematic review, meta-analysis, expert comment, economic analysis | Clinically diagnosed with ACCP/SCCM pre-sepsis 3 definition | 9/1368 | No QUADAS assessment | 0.80 [0.63, 0.90]; 88.7; 0.61 [0.50, 0.72]; 81.7; 0.73 [0.69, 0.77] | 12.00 to 90.00 mg/L | p = 0.32 |
PCT | |||||||||
Wacker 2013 | PCT-Q; PCT-Kryptor; PCT-LIA | English, German and French; Differentiate between sepsis patients and SIRS without infection; | Studies that involved healthy people; Studies involving neonates (<28 days); Animal experiments, reviews, correspondences, case reports, expert opinions, editorials | Culture positive or clinically diagnosed with ACCP/SCCM pre-sepsis 3 definition or German Sepsis Society definition | 30/3244 | Most studies were not fulfilled representative spectrum of patients; Most studies were not fulfilled or with unclear description of reference standard | 0.77 [0.72, 0.81]; 77.8; 0.79 [0.74, 0.84]; 78.1; 0.85 [0.81, 0.88] | IQR 0.5-2.0 ng/mL Median 1.1 ng/mL | p < 0.0005 |
IL-6 | |||||||||
Ma 2016 | ECL; ELISA; CLIA | English articles; Comparing sepsis patients with SIRS without infection; Provide sufficient data to build a 2 × 2 contingency table; Studies including at least 10 patients | Studies involving neonates (<28 days); Animal studies, abstracts, review articles, case reports, letters, editorials, comments, conference proceedings | Culture positive or clinically diagnosed with ACCP/SCCM pre-sepsis 3 definition | 22/2680 | Most studies with unclear risk of bias for index test, flow and timing | 0.68 [0.65, 0.70] 91.6; 0.73 [0.71, 0.76] 77.6; 0.80 [Q*=0.73] | 18 to 423.5 pg/mL | p = 0.68 |
Iwase 2019 | Roche Diagnostics; BosterBiological Technology; Biosource; Medgenics Diagnostics; DPC Biermann; R&D System | Provide sufficient data to build a 2 × 2 contingency table | Did not investigate the diagnostic accuracy of blood IL-6 level; Animal experiments, case reports, commentaries, letters, meta-analyses, reviews, editorials, meeting abstracts, poster presentations, correspondence | Culture positive or clinically diagnosed with ACCP/SCCM mixed sepsis definition, CDC/NHSN or ISF definition | 6/527 | Most studies with unclear risk of bias for index test and reference standard | 0.73 [0.61, 0.82]; 0.76 [0.61, 0.87]; 0.81 [0.78, 0.85] | 35 to 620 pg/mL Median 176 pg/mL | nil |
CD64 | |||||||||
Wang 2015 | FCM; Hematology analyzer; Leuko64 kit | English articles; Provide sufficient data to build a 2 × 2 contingency table | Studies involving neonates (<28 days); Included patients did not have SIRS or were not critically ill | Culture positive or clinically diagnosed with ACCP/SCCM pre sepsis-3 definition | 8/1986 | QUADAS score between 8-11 | 0.76 [0.73, 0.78] 92.7; 0.85 [0.82, 0.87] 91.3; 0.95 [Q*=0.89] | nil | p = 0.02 |
Yeh 2019 | In-house; Leuko64 kit | English articles Original article; Adult patients; | Duplicated study; Prognosis based on the prediction of mortality from sepsis; Not provide sufficient data to build a 2 × 2 contingency table | Culture positive or clinically diagnosed with ACCP/SCCM pre sepsis-3 definition | 14/2471 | Most studies with high risk of bias for index test; Most studies with high or unclear risk of bias for patient selection | 0.87 [0.80, 0.92] 94.3; 0.89 [0.82, 0.93] 92.0; 0.94 [0.92, 0.96] | nil | p = 0.05 |
sTREM-1 | |||||||||
Wu 2012 | ELISA; Luminex multiplex assay | Studies assessed the accuracy of plasma sTREM-1 for sepsis diagnosis in adult patients with SIRS; Provided sufficient information to construct a 2 × 2 contingency table; | Studies involving neonates (<28 days); Review article, conference paper, or case report; Did not investigate the diagnostic accuracyof blood sTREM-1 level | Culture positive or clinically diagnosed with ACCP/SCCM pre-sepsis 3 definition | 11/1795 | Most studies with unclear risk of disease progression bias provided | 0.79 [0.65, 0.89] 95.0; 0.80 [0.69, 0.88] 92.7; 0.87 [0.84, 0.89] | 40 to 755 pg/mL | p = 0.02 |
Chang 2020 | ELISA; Quantitative sandwich enzyme immunoassay; Homemadeenzyme immunosorbent assay; Immunoblots; Luminex multiplex assay; DuoSet enzyme-linked immunosorbent assay | Clinical trials of adult patients (> 18-year-old) with suspected sepsis; Serum or plasma sTREM-1 protein expression; Provide sufficient data to build a 2 × 2 contingency table | Review article, animal study, in vitro study; Prognostic study; Pediatric study;Non-serum sample | Culture positive or clinically diagnosed with ACCP/SCCM pre-sepsis 3 definition | 19/2418 | Most studies with high or unclear risk of reference standard and patient selection; All studies with unclear risk of index test | 0.82 [0.73, 0.89] 93.6; 0.81 [0.75, 0.86] 89.6; 0.88 [0.85, 0.91] | 30 to 60,000 pg/mL | p = 0.002 |
Presepsin | |||||||||
Zheng 2015 | PATHFAST | Provided the presepsin concentrations of sepsis patients and non-sepsis patients; Provide sufficient data to build a 2 × 2 contingency table; | Reviews, correspondence, editorials, conference abstracts Studies limited to restrictive subgroups | Clinically diagnosed with ACCP/SCCM pre-sepsis 3 definition | 8/1757 | Most studies with high risk of bias for index test; Most studies with unclear risk of biasfor reference standard, flow and timing | 0.77 [0.75, 0.80] 85.2; 0.73 [0.69, 0.77] 80.6; 0.86 [Q* = 0.79] | 317 to 729 pg/mL | p = 0.755 |
Xin Zhang 2015 | PATHFAST | Comparing sepsis patients with SIRS without infection; Adult patient; Provide sufficient data to build a 2 × 2 contingency table | Reviews, letters, commentaries, correspondence, case reports, conference abstracts, expert opinions, animal experiments; Pediatric study | Clinically diagnosed with ACCP/SCCM pre-sepsis 3 definition | 8/1815 | Most studies not fulfilled blinding of investigators to index test; All studies were not fulfilled with uninterpretable test results reported | 0.86 [0.79, 0.91] 90.5; 0.78 [0.68, 0.85] 91.8; 0.89 [0.86, 0.92] | IQR 317–729 pg/mL Median 560 pg/mL | p = 0.31 |
Jing Zhang 2015 | PATHFAST ELISA | Provide sufficient data to build a 2 × 2 contingency table | Duplicate studies; Non-English publications; Conference abstracts; Studies involving asepsis or control sample size <10 | Clinically diagnosed with ACCP/SCCM pre-sepsis 3 definition, ABA, IPSCG or ISF definition | 11/3052 | Most studies with high or unclear risk of bias for patient selection and index test | 0.83 [0.77, 0.88] 84.3; 0.78 [0.72, 0.83] 86.0; 0.88 [0.84, 0.90] | 317 to 729 pg/mL | p = 0.12 |
Wu 2017 | PATHFAST | English articles; Sepsis related studies including Diagnostic studies | Non-sepsis related studies; Non-diagnostic studies; Studies with no performance parameters given; Non-original studies; Non-blood specimen | Culture positive or clinically diagnosed with ACCP/SCCM mixed sepsis definition, ABA, or SEIMC definition | 18/3470 | All studies with high risk of index test | 0.84 [0.80, 0.87] 82.0; 0.76 [0.67, 0.82] 90.2; 0.88 [0.85, 0.90] | IQR 439–664 pg/mL Median 600 pg/mL | p = 0.68 |
Kondo 2019 | Sepsis 3, severe sepsis or septic shock with Sepsis 1,2 definition; Cross-sectional, cohort, case-control and randomized controlled trials; Plasma or serum study | Predominantly comprising neonates or perioperative patients; Comprising healthy participants as controls; Not provide sufficient data to build a 2 × 2 contingency table; Animal study | Culture positive or clinically diagnosed with ACCP/SCCM mixed sepsis definition | 19/3012 | Most studies with high or unclear risk of bias for index test; Most studies with unclear risk of reference standard | 0.84 [0.80, 0.88] 62.4; 0.73 [0.61, 0.82] 86.7; 0.87 [0.84, 0.90] | 106.1–907 pg/mL | p = 0.35 |
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Hung, S.-K.; Lan, H.-M.; Han, S.-T.; Wu, C.-C.; Chen, K.-F. Current Evidence and Limitation of Biomarkers for Detecting Sepsis and Systemic Infection. Biomedicines 2020, 8, 494. https://doi.org/10.3390/biomedicines8110494
Hung S-K, Lan H-M, Han S-T, Wu C-C, Chen K-F. Current Evidence and Limitation of Biomarkers for Detecting Sepsis and Systemic Infection. Biomedicines. 2020; 8(11):494. https://doi.org/10.3390/biomedicines8110494
Chicago/Turabian StyleHung, Shang-Kai, Hao-Min Lan, Shih-Tsung Han, Chin-Chieh Wu, and Kuan-Fu Chen. 2020. "Current Evidence and Limitation of Biomarkers for Detecting Sepsis and Systemic Infection" Biomedicines 8, no. 11: 494. https://doi.org/10.3390/biomedicines8110494