Table 2 Biomarkers for sepsis, septic shock, and sepsis-associated encephalopathy

Acute-phase proteins

CRP, hsCRP

Plasma and serum

Sepsis = 483

–

–

15–20 mg/dl

–

–

↑ hsCRP hyperinflammatory phenotype

[22]

Mean age mean = 60.5

–

–

–

–

–

↑ hsCRP day 1 to 2, 95.8%

♂ 54.9%

–

–

–

–

–

↑ hsCRP, 23 patients (25.8%) at 3, 26 patients (30.2%) at 6, and 23 patients (25.6%) at 12 months

Plasma

Sepsis = 43

–

–

–

–

0.51, 0.56, and 0.48

CRP, day 1, 3, and 8 to predict 30-day mortality p = 0.836, p = 0.059, and p = 0.819, respectively

[74]

Septic shock n = 93

Age = 26 to 88

Plasma

Sepsis = 17

61.54%

52.17%

9 mg/dl

–

0.684

↑ hsCRP sepsis versus control group, p = 0.008

[103]

Control = 19

Age = 52.18

♂ 63%

Serum

Sepsis = 38

100%

88.40%

8.02 mg/l

–

0.98

↑ CRP in septic patients compared to control group, p = 0.001

[104]

Septic shock = 31 Control = 40

Age = 37 to 95

♂ 57.89%

Serum

Sepsis = 27

75.00%

78.00%

7.4 mg/dl

–

0.825

↑ hsCRP sepsis versus control group, p = 0.001

[105]

Septic shock = 23

–

–

–

–

0.751

↑ hsCRP septic shock versus sepsis, p = 0.002

Control = 20

–

–

–

0.686

–

↑ hs-CRP level versus SOFA, p < 0.001

Age = 85

♂57.89%

Blood

Sepsis = 33

90.70%

98.60%

407 pg/ml

-

0.859

↑ CRP in sepsis patients compared in SIRS group, p < 0.05

[48]

Severe sepsis = 24

Septic shock = 15

SIRS = 23

Normal = 20

Mean age = 62.1

Serum

Sepsis = 119

-

-

-

-

-

↑ CRP and SOFA score in the sepsis group compared to the control group, p < 0.05

[46]

Septic shock = 32

 ↔ Septic shock group when compared with sepsis group, p = 0.086

Control = 20

–

–

–

–

–

 ↔ Diagnosing positive infection culture in patients with sepsis, p = 0.071

–

–

–

–

0.609

Serum

Severe sepsis = 34

–

–

–

–

–

 ↔ CRP did not differentiate septic shock and severe sepsis

[89]

Septic shock = 53

Age = 2 mo to 16 years

Complement

Plasma

Sepsis = 20

–

–

–

–

–

↑ Sepsis (C4d 3.5-fold; Factor Bb 6.1-fold; C3 0.8-fold; C3a 11.6-fold; and C5a 1.8-fold) versus control

[25]

Proteins

Control = 10

↑ C5a ↓ SOFA

Age = 85

–

–

–

0.18

–

♂57.89%

–

PTX-3

Plasma

Sepsis = 73

–

–

–

0.36

–

↑ PTX-3 versus APACHE-II, and SOFA, p = 0.0001

[72]

Control = 77

–

–

31.4 ng/ml

–

–

Sepsis versus SIRS, p > 0.05

Septic Shock = 140

–

–

–

–

–

Sepsis versus septic shock, p = 0.0001

Age = 26 to 88

–

–

–

–

–

↑Sepsis/septic shock versus control, p ≤ 0.001

♂57.89%

–

–

–

–

0.82 and 0.73

Sepsis and septic shock discrimination on day 1

Plasma

Sepsis = 17

–

–

–

–

–

↑ PTX-3 sepsis, septic shock, and post-surgery infection versus control group, p < 0.05

[73]

Septic shock = 26

↑ PTX-3 sepsis shock versus sepsis, p < 0.0001

Post-surg. Inf. = 33

–

–

–

–

0.798

Control = 25

Cytokines and chemokines

IL-10

Plasma

Sepsis = 208 Control = 210

–

–

–

–

− 0.161

↑ miR-126 correlated negatively with IL-10, p = 0.020

[106]

Plasma

Sepsis = 309

–

–

–

–

− 0.166

↑ lncRNA ITSN1-2 correlated negatively with IL-10, p = 0.003

[107]

Mean age = 57,3 ± 9,7

Control = 330

Mean age = 55,8 ± 9,7

MCP-1

Plasma

Sepsis = 43

–

–

–

–

0.64, 0.51, and 0.51

MCP-1, day 1, 3, and 8 to predict 30-day mortality, p = 0.004, p = 0.948, and p = 0.948, respectively

[74]

Septic shock n = 93

Age = 26 to 88

Plasma

Sepsis = 17

–

–

–

–

–

↑ MCP-1 sepsis, septic shock and post-surgery infection versus control group, p < 0.05

[73]

Septic shock = 26

↑ MCP-1 sepsis shock versus sepsis, p = 0.0059

Post-surg. Inf. = 33

–

–

–

–

0.71

Control = 25

TNF-α, IL-1β, IL-6

Serum

Sepsis = 288

–

–

–

–

–

↑ Sepsis TNF-α, IL-1β, IL-6, and IL-8 compared to the control group, p < 0.001

[70]

Mean age = 58.2 ± 11.2

↑ TNF-α, IL-1β, IL-6, and IL-8 were negatively correlated with surviving sepsis patients, p < 0 .001

Control = 290

–

–

–

–

− 0.270,

Mean age = 56.8 ± 12.1

− 0.310,

− 0.254, and

− 0.256

Plasma

Sepsis = 483

–

–

10² pg/dl

–

–

↑ IL-6, 72 patients (74.2%) at 3 months, 62 (70.5%) at 6 months, and 59 (66.3%) at 12 months

[22]

Age mean = 60.5

♂ 54.9%

Serum

Sepsis = 43

–

–

–

–

0.69, 0.70, and 0.68

↑ IL-6, day 1, 3, and 8 to predict 30-day mortality, p = 0.0001, p = 0.0001, and p = 0.012, respectively

[74]

Septic shock n = 93

Age = 26 to 88

Serum

Sepsis = 39

–

–

12,704—111,372

–

–

↑ IL-6 septic patients with DIC, p = 0.01

[34]

Control = 15

pg/ml

Age ≥ 18 years

DAMPs

Calprotectin

Plasma

Sepsis = 77

56%

81%

1.3 mg/l

–

–

↑ Calprotectin, sepsis versus trauma patients, p < 0.001

[28]

Trauma = 32

–

–

–

–

–

↑ Calprotectin at admission was ↑ in non-survivors than in survivors at day 30, p < 0.01

HMGB-1

Serum

Sepsis = 247

–

–

3.6 ng/ml

–

–

↑ HMGB-1 sepsis versus control, p < 0.001

[75]

–

–

–

–

0.51 and 0.53

HMGB-1, day 0 and 3, survivor = non-survivor

–

–

–

–

–

HMGB-1 does not have predictive value for organ failure and outcome

Endothelial cells and BBB markers

Syndecan-1

Serum

Sepsis = 39

–

–

–

–

–

↑ Syndecan-1 in sepsis versus control, p < 0.0001

[34]

Control = 15

–

–

–

–

–

↑ Syndecan-1 non-survivors on days 1, 2, and 4

Age

–

–

–

–

0.54 and 0.59

↑ Syndecan-1 versus DIC on day 1 and 2, p = 0.0004 and p = 0.0002, subsequently

Age ≥ 18 years

–

–

189–1301 ng/ml

–

–

↑ Syndecan-1 in septic patient with DIC, p < 0.01

VLA-3 (a3β1)

Neutrophil

SIRS = 9

–

–

–

–

–

↑ α3β1 (VLA-3, CD49c/CD29) on neutrophils of septic patients, p < 0.05

[77]

Sepsis = 15

Control = 7

Sepsis = 6

–

–

–

–

–

↑ β1 (CD29), on neutrophils of sepsis patients, p < 0.05

[78]

Control = 5

Ang-1

Serum

Severe sepsis = 48

–

–

–

–

–

↑ Ang-1 severe sepsis compared with shock septic, p < 0.01

[79]

Septic shock = 54

↓ Ang-1/Tie-2 in non-survivors, p < 0.001

Age ≥ 18 years

–

–

3.81–16.1 ng/ml

–

–

Plasma

SIRS = 943

–

–

–

–

–

↑ Ang-1 was associated with a reduced risk of shock. OR: 0.77

[81]

Sepsis = 330

↑ Ang-1 was higher in survivor versus non-survivor, p < 0.001

Shock = 216

–

–

5719 pg/ml

–

–

Pneumonia = 169

Others = 152

Age = 55.1 ± 16.1

♂ 63.9%

Ang-2

Serum

Severe sepsis = 48

–

–

–

–

–

↑ Ang-2 severe sepsis compared with shock septic, p < 0.02

[79]

Septic shock = 54

↓ Ang-2/Ang-1 in non-survivors, p < 0.001

Age ≥ 18 years

–

–

–

–

–

Plasma

SIRS = 943

–

–

–

–

–

↑ Ang-2 was associated with an increased risk of shock, OR: 1.63

[81]

Sepsis = 330

–

–

42.063 pg/ml

–

–

↑ Ang-2 non-survivor, p < 0.001

Shock = 216

Pneumonia = 169

Others = 152

Age = 55.1 ± 16.1

♂ 63.9%

CLDN-5

Serum

Sepsis = 11

–

–

–

–

–

↑ CLDN-5 was not associated with MODS and the non-MODS group

[31]

Severe sepsis = 18

–

–

–

–

0.157 and 0.087

↑ CLDN-5 was not correlated with SOFA or APACHE score, p = 0.270, p = 0.542

Septic shock = 22

–

–

–

–

–

Did not predict mortality

Serum

Sepsis = 11

–

–

–

–

–

CLDN-5 was absent from the endothelium

[32]

Severe sepsis = 18

Septic shock = 22

OCLN

Serum

Sepsis = 11

–

–

–

–

–

↑ OCLN in severe sepsis and septic shock than in sepsis, p < 0.05

[31]

Severe sepsis = 18

–

–

–

–

–

↑ OCLN in non-survivors compared with survivors, p < 0.01

Septic shock = 22

–

–

–

–

0.337

↑ OCLN positively correlated with SOFA, p < 0.016

–

–

–

–

0.224

 ↔ OCLN levels were not correlated with the APACHE-II, p < 0.085

Brain tissue autopsies

Sepsis = 47

–

–

–

–

–

↓ OCLN, cerebellar endothelium damage, ↑ CRP ≥ 100 mg/l

[32]

–

–

–

–

–

38% of patients (18/47) had no expression of OCLN in the BMVECs

–

–

–

–

–

34% of patients (16/47) had MOFs

–

–

–

–

–

74.5% of patients (35/47) had septic shock

–

–

–

–

–

The deceased with BBB damage had SOFA scores six versus 14, p = 0.04

PAI-1

Plasma

Sepsis = 63

–

–

–

–

0.85

↑ PAI-1 to predict mortality, p < 0.05

[33]

Severe sepsis = 61

–

–

–

0.45

–

↑ PAI-1 correlated with the SOFA score at 24 h, p < 0.0001

Septic shock = 42

–

–

–

0.58

–

↑ PAI-1 correlation with APACHE-II score, p < 0.0001

Age = 60 ± 17

–

–

–

–

–

↑ Severe sepsis ↑ sFlt-1, p < 0.0001

Serum

Sepsis = 39

–

–

15.5–49.9

–

–

↑ PAI-1 in patients with DIC, p = 0.016

[34]

Control = 15

ng/ml

Age ≥ 18 years

sICAM-1

Plasma

Sepsis = 63

–

–

–

–

–

↑ Severe sepsis ↑ sICAM-1, p < 0.001

[33]

Severe sepsis = 61

–

–

–

0.15

–

↑ sICAM-1 correlated with SOFA score at 24 h, p < 0.03

Septic shock = 42

–

↑ sICAM-1 correlate with APACHE-II score, p < 0.05

Age = 60 ± 17

–

–

–

0.17

–

Serum

Severe sepsis = 48

–

–

1.297–1787 ng/ml

-

–

↑ sICAM-1 in non-survivors, p < 0.001

[79]

Septic shock = 54

–

–

–

–

–

↑ sICAM-1, predictor of 90 day-mortality, p < 0.0001

Age ≥ 18 years

–

–

–

–

–

↑ sICAM-1, septic shock compared to severe sepsis p < 0.01

S100B

Serum

Septic shock = 22

–

–

 > 0.15 μg/l

–

–

↑ Delirium was present in 10/22 of the patients (45.5%)

[37]

–

–

–

–

–

OR: 18.0, for risk of developing delirium S-100β > 0.15 μg/l

–

–

–

–

0.489

↑ S100 β correlate positively with and IL-6 p = 0.021

Serum

Sepsis = 104

80.0% and

66.1 and

0.226 and

–

–

↑ S100B cut-of value for day 1 and 3

[36]

Sepsis-associated encephalopathy = 59

84.44%

69.49%

0.144 μg/l

–

–

↑ S100B in sepsis-associated encephalopathy day 1 to day 3 compared with non- sepsis-associated encephalopathy, p < 0.001

non- sepsis-associated encephalopathy = 45

–

–

–

–

0.728 and 0.819

↑ S100B on days 1 and 3 to predict sepsis-associated encephalopathy

–

–

–

–

0.61

↑ S100B on day 1 to predict 180 day-mortality

84.44%

69.49%

0.529 μg/l

–

0.731

↑ S100B on day 3 to predict 180 day-mortality

93.33%

50.00%

0.266 μg/l

Serum

Sepsis = 21

–

–

–

–

0.082, 0.082,

↑ S100B did not correlate with GCS, EEG pattern, or SOFA scores

[108]

Age = 68.7

and 0.124

E-selectin

Plasma

Sepsis = 63

–

–

–

–

0.77

↑ Predict mortality

[33]

Severe sepsis = 61

–

–

–

–

–

↑ Severe sepsis ↑ sE-selectin, p < 0.001

Septic shock = 42

–

–

–

0.27

–

↑ sE-selectin correlated with SOFA score at 24 h, p < 0.0001

Age = 60 ± 17

–

–

–

0.31

–

↑ sE-selectin correlated with APACHE-II score, p < 0.0001

sFlt-1

Plasma

Sepsis = 63

–

–

–

-

0.85

↑ sFlt-1 to predict mortality, p < 0.05

[33]

Severe sepsis = 61

–

–

–

0.36

–

↑ sFlt-1 associated with organ dysfunction

Septic shock = 42

–

–

–

0.63

–

↑ sFlt-1 correlation with ↑ IL-6, p < 0.0001

Age = 60 ± 17

–

–

–

0.6

–

↑ sFlt-1 correlated with SOFA score at 24 h, p < 0.0001

–

–

–

0.64

–

↑ sFlt-1 correlated with APACHE-II score, p < 0.0001

sVCAM-1

Plasma

Sepsis = 63

–

–

–

–

0.78

↑ Predict mortality

[33]

Severe sepsis = 61

–

–

–

–

–

↑ Severe sepsis ↑ sVCAM-1, p < 0.002

Septic shock = 42

–

–

–

0.45

–

↑ sE-selectin correlated with SOFA at 24 h, p < 0.0001

Age = 60 ± 17

–

–

–

0.38

–

↑ sVCAM-1 correlated with APACHE-II s, p < 0.0001

Serum

Severe sepsis = 48

–

–

369–467 µg/l

–

–

↑ sVCAM in non-survivors, p < 0.001

[79]

Septic shock = 54

–

–

–

–

–

↑ sVCAM, predictor of 90 day-mortality, p < 0.0001

Age ≥ 18 years

–

–

–

–

–

↑ sVCAM, septic shock compared to severe sepsis, p < 0.01

Plasma

SIRS = 943

–

–

–

–

–

↑ s-VCAM was associated with an increased risk of shock. OR: 1.63

[81]

Sepsis = 330

↑ sVCAM-1 non-survivor, p < 0.001

Shock = 216

–

–

819 pg/ml

–

–

Pneumonia = 169

Others = 152

Age = 55.1 ± 16.1

♂ 63.9%

ZO-1

Serum

Sepsis = 11

–

–

–

–

–

↑ ZO-1 in severe sepsis and septic shock compared to sepsis, p < 0.05

[31]

Severe sepsis = 18

–

–

–

–

–

↑ ZO-1 in non-survivors compared with survivors, p < 0.01

Septic shock = 22

–

–

–

–

–

↑ ZO-1 in MODs group

–

–

–

–

0.502 and 0.380

↑ ZO-1 was positively correlated with SOFA and APACHE-II scores, p < 0.001 and p < 0.006

Brain tissue autopsies

Sepsis = 47

–

–

–

–

–

ZO-1 is absent from the endothelial cells in the cerebrum and endothelium

[32]

Gut permeability markers

Citrulline

Plasma

Septic shock = 16

–

–

–

–

–

Citrulline was positively correlated with plasma arginine (r² = 0.85) and glutamine (r² = 0.90) concentrations in both groups, and significantly inversely correlated with CRP (r² = 0.10)

[109]

(Survivors = 8

↓ Citrulline in patients with digestive bacterial translocation

Age = 60 ± 16.5

Non-survivor = 8

Age = 62.9 ± 18.5

–

–

–

–

–

Plasma

Sepsis/ARDS = 44

–

–

–

–

–

↓ Citrulline in all patients

[83]

Sepsis/NO ARDS = 91

–

–

6 and 10.1 uM

–

–

↓ ARDS compared to the no ARDS group, p = 0.002

Age = 55 ± 16

–

–

–

–

–

Citrulline levels were associated with ARDS

I-FABP

Serum

Sepsis = 30

–

–

27.46 and 36.95 μg/l

–

–

↑ I-FABP sepsis and septic shock group, p < 0.01

[40]

Septic shock = 30

–

↑ I-FABP no difference between survivors and non-survivors

Control = 20

–

–

–

–

Zonulin

Plasma

Sepsis = 25

–

–

6.61 ng/ml

–

–

↑ Zonulin sepsis compared to post-surgical and control groups, p = 0.008

[39]

Post-surgical = 18

–

–

–

–

–

No difference between survivors and non-survivors, p = 0.305

Control = 20

–

–

–

–

0.01, − 0.46, − 0.19, and 0.10

↑ Zonulin, no correlation with CRP, APACHE-II, SAPSII, SOFA, p = 0.997, p = 0.077, p = 0.491, and p = 0.671, subsequently

D-lactic acid

Serum

Sepsis = 30

–

–

15.32 and 27.95 mg/l

–

–

↑ D-lactic acid sepsis and septic shock groups, p < 0.01

[40]

Septic shock = 30

–

–

–

–

↑ D-lactic acid is no different between survivors and non-survivors

Control = 20

Non-coding RNAs

Lnc-MALAT1

Plasma

Sepsis = 196

–

–

–

–

0.866

↑ Lnc‐MALAT1/miR‐125a axis in sepsis patients

[41]

Age = 58.2 ± 11.2

–

–

–

–

–

↑ Lnc‐MALAT1 relative expression in sepsis patients

Control = 196

–

–

–

–

–

Lnc-MALAT1/miRNA-125a axis discriminates sepsis patients from healthy controls and exhibits a positive association with general disease severity, organ injury, inflammation level, and mortality in sepsis patients

Age = 57.1 ± 12.1

Plasma

Sepsis = 152

68.50%

65.90%

–

–

0,674 (ARDS

↑ lnc-MALAT1 correlates with raised ARDS risk, disease severity, and increased mortality in septic patients

[42]

Age = 59.7 ± 11.2

38.30%

88.60%

–

–

0.651

High mortality in sepsis patients

–

–

–

–

–

Lnc-MALAT1 expression was positively correlated with inflammatory factor levels (CRP, PCT, TNF-α, IL-1β, IL-6, and IL-17) in septic patients

Plasma

Sepsis = 120

–

–

–

–

0.91

↑ lnc-MALAT1 in septic patients, distinguishing patients with sepsis from control

[110]

Control = 60

–

–

–

–

0.836

Septic shock patients compared to patients without septic shock

–

–

–

–

0.886

Non-survivors compared to surviving patients

–

–

–

–

–

↑ Lnc-MALAT1 expression was an independent risk factor for sepsis, septic shock, and poor prognosis

lnc-MEG3

Plasma

Sepsis = 219

–

–

–

–

0,887

↑ lnc‐MEG3 expression predicting elevated sepsis risk

[43]

Control = 219

–

–

–

–

0.934

lnc-MEG3/miR-21 axis predicting elevated sepsis risk

Age = 56.5 ± 10.3

–

–

–

–

0.801

miR-21 was predicting reduced sepsis risk

–

–

–

–

0.704

lnc‐MEG3 predicting 28‐day mortality risk

–

–

–

–

0.669

lnc‐MEG3/miR‐21 axis predicting 28‐day mortality risk

–

–

–

–

–

↑ lnc-MEG3/miR-21 axis, while ↓ miR-21 expression was decreased in sepsis patients

-

lnc-MEG3 expression and lnc‐MEG3/miR‐21 axis positively correlated, whereas miR‐21 expression negatively correlated with APACHE-II, SOFA, and inflammatory molecules in sepsis patients

↑ lnc‐MEG3 relative expression and lnc‐MEG3/miR‐21 axis in deaths than that in survivor

miRNA

miR-125a, miR-125b

Plasma

Sepsis = 120

–

–

–

–

0.557

 ↔ miR‐125a expression between groups of patients and not differentiate sepsis patients from controls

[84]

Control = 120

–

–

–

–

0.658

↑ miR-125b in sepsis patients and can distinguish sepsis patients from control healths

59.1 ± 12.1

–

–

–

–

–

Positive correlation between miR‐125a and miR‐125b in sepsis patients and controls

–

–

–

–

–

miR-125a was not correlated with APACHE-II or SOFA score, while miR-125b was positively associated with both scores

–

–

–

–

–

↓ miR-125b in survivors compared with non‐survivors

–

–

–

–

–

↑ miR-125b, but not miR‐125a, is correlated with ↑ disease severity, inflammation, and ↑ mortality in sepsis patients

Plasma

Sepsis = 126

–

–

–

–

0.817

↓ miR-125a good predictive values for sepsis risk

[85]

Control = 125

–

–

–

–

0.843

↑ lnc‐ANRIL/miR‐125a axis for sepsis risk

Age = 56.6 ± 13

–

–

–

–

0.745

↓ miR‐125a expression in deaths than those in survivors

–

–

–

–

0.785

↑ lnc‐ANRIL/miR‐125a differentiating deaths from survivors

–

–

–

–

–

lnc-ANRIL/miR-125a axis positively correlated, and miR-125a was negatively associated with disease severity and inflammation in sepsis patients

Plasma

Sepsis = 150

–

–

–

–

0.749 and 0.839

↑ miR-125a and miR-125b distinguish sepsis patients from controls

[111]

Age = 56.9 ± 10.3

–

–

–

–

0.588

miR-125a to predict 28-day mortality risk

Control = 150

–

–

–

–

0.699

miR-125b had a potential value in predicting elevated 28-day mortality risk

Age = 55.1 ± 11.4

–

–

–

–

–

miR-125a failed to predict the 28-day mortality risk in sepsis patients

–

–

–

–

–

1. The predictive value of miR‐125b for sepsis risk

–

–

–

–

miR‐125a and miR‐125b relative expressions were positively associated with disease severity in sepsis patients

Plasma

Sepsis = 196

–

–

–

–

–

↑ lnc‐MALAT1/miR‐125a axis in sepsis patients, p < 0.001

[41]

Age = 58.2 ± 11.2

–

–

–

–

0.931

lnc-MALAT1/miRNA-125a axis discriminates sepsis patients from control

Control = 196

–

–

–

–

0.866

lnc-MALAT1 discriminates sepsis patients from control

Age = 57.1 ± 12.1

Membrane receptors, cell proteins, and metabolites

CD64

Blood

Sepsis = 119

–

–

–

–

–

↑ nCD64 and SOFA score in the sepsis compared to control p < 0.05

[46]

Septic shock = 32

–

–

4.1, 9, and 2.2 MFI

–

–

↑ Sepsis and septic shock compared to control p < 0.001

Control = 20

–

–

–

–

0.879

nCD64 in bacterial infection

–

–

–

–

0.888

↑ AUC of nCD64 combined with SOFA than that of any other parameter alone or in combination

–

–

–

–

0.85

CD64 for predicting death

–

–

–

–

0.916

Combination of nCD64 and SOFA score

–

–

4.1 versus 8.9 MFI

–

–

↑ nCD64 survivors versus non-survivors p < 0.001

Blood

Sepsis = 20

0.82, 0.67 and 0.67

0.67, 0.76, and 0.76

 < 90.40, < 3.01, and < 0.825

–

0.843, 0.824, and 0.804

↑ CD64, ↓CD13, and ↓HLA-DR predict mortality in septic patients

[45]

Age = 54.35 ± 17.97

Control = 20

Age = 51.55 ± 13.37

CD68

Brain

Septic shock = 16

–

–

–

–

–

↑CD68 in the hippocampus (1.5 fold), putamen (2.2 fold), and cerebellum (2.5 fold) in patients with sepsis than control patients

[86]

Age = 8.9–71.7

Control = 15

Age = 65.2–87.4

NFL

CSF and plasma

Sepsis = 20

–

–

1723.4, 1905.2

–

–

Day 1 – sepsis versus control p > 0.05

[87]

Age = 66.7 ± 14.0

–

–

2753.1, 2208.0

–

–

Day 3 – sepsis versus control p > 0.05

Control = 5

–

–

5309.6, 3701.3 pg/ml

–

–

Day 7 – sepsis versus control p > 0.05

Age = 61.2 ± 24.7

–

–

–

–

–

↑ NFL in patient septic compared to control from day 1 p = 0.0063

–

–

–

–

–

↑ NFL patients with sepsis-associated encephalopathy p = 0.011

–

–

–

–

–

↑ NFL correlated with the severity of sepsis-associated encephalopathy p = 0.022

–

–

–

–

↑ NFL at CSF in non-survivors compared to survivors p = 0.012

NFH

CSF and plasma

Sepsis = 20

–

–

17.6, 100.3

-

-

Day 1 – sepsis versus control p > 0.05

[87]

Age = 66.7 ± 14

–

–

18.9, 163.1

–

–

Day 3 – sepsis versus control p > 0.05

Control = 5

–

–

164.3, 519.9

–

–

Day 7 – sepsis versus control p = 0.016

Age = 61.2 ± 24.7

–

–

ng/ml

–

–

↑ NFH from day 1 in septic patients p = 0.043

NSE

Serum

Sepsis/ sepsis-associated encephalopathy = 48

–

–

24.87 and 15.49 ng/ml

–

–

↑ NSE in sepsis-associated encephalopathy group versus no- sepsis-associated encephalopathy group p = 0.003

[80]

Age = 56 ± 16 Sepsis/non- sepsis-associated encephalopathy = 64

24.15 ng/ml

Diagnostic of sepsis-associated encephalopathy

Age = 52 ± 17

82.80%

54.20%

–

–

0.664

 ↔ NSE, sepsis-survivors versus sepsis-non-survivors p = 0.108

–

–

–

–

Plasma

Sepsis = 124

–

–

 > 12.5 ug/l

–

–

23.3%, increased risk of 30-day mortality, p = 0.006, and a 29.3% increased risk of delirium p = 0.005

[88]

Mean age = 52–71

–

–

–

–

–

↑ NSE is associated with mortality p = 0.003, and delirium in critically ill septic patients p < 0.001

CSF and plasma

Sepsis/ sepsis-associated encephalopathy = 12

–

–

Eight versus 3.8 ng/ml

–

–

↑ CSF NSE in sepsis group compared to controls p < 0.05

[112]

Control = 21

 ↔ Plasma NSE sepsis group versus control group

Mean age = 67.8 ± 1 2.1

–

–

–

–

–

Presepsin

Blood

Sepsis = 33

90.70%

98.60%

407 pg/ml

–

0.954

↑ Presepsin in sepsis patients compared to SIRS group p < 0.05

[48]

Severe sepsis = 24

↑ Presepsin and APACHE-II score in severe sepsis group than sepsis group p < 0.05

Septic shock = 15

–

–

–

–

–

↑ Presepsin and  APACHE-II score in septic shock group compared to severe sepsis group p < 0.05

SIRS = 23

Normal = 20

–

–

–

–

–

Mean age = 62.1

TREM-1

Serum

Severe sepsis = 34

–

–

129 pg/ml versus 105 pg/ml

–

–

↑ TREM-1 levels in septic shock compared to severe sepsis

[89]

Septic shock = 53

–

–

–

–

–

 ↔ TREM-1 did not differentiate between septic shock and severe sepsis

Age = 2 mo to 16 years

56%

60%

116.47 pg/ml

–

0.62

Predict septic shock

52%

71%

116.47 pg/ml

–

0.63

Predict mortality

–

–

–

–

–

 ↔ TREM-1 non-survivors versus survivors

Serum

SIRS = 38

73.30%

71.10%

 ≥ 133 pg/ml

–

–

sTREM-1 cut-off for sepsis

[113]

Sepsis = 52

–

–

–

–

–

↑ sTREM-1 in sepsis group p = 0.001

Age = 20 to 92

–

–

–

–

–

↑ sTREM-1 in the patients with positive blood culture p = 0.002

Plasma and leukocytes

Septic shock = 60 Postoperative = 30

100%

98.30%

30.0 pg/ml

–

–

↑ sTREM-1 plasma in septic shock compared to control and postoperative groups p < 0.05

[91]

Control = 30

–

–

–

–

–

↑ sTREM-1 compared with postoperative group p < 0.05

–

–

–

–

0.955

↑ TREM-1 expression on human monocytes of a septic shock compared to control and postoperative groups p < 0.05

Peptide precursor of the hormone and hormone

MR-proADM

Plasma

Sepsis/bacterial isolate = 39

78%

74.20%

 ≥ 1.5

–

0.82

↑ MR-proADM sepsis versus control p < 0.0001

[92]

Sepsis w/bacterial isolate = 23

80%

89.36%

 ≥ 1.70

–

0.92

↑ MR-proADM septic shock versus control p < 0.0001

Septic shock = 47

77.40%

59.60%

 > 3.00

–

0.7

↑ MR-proADM septic shock versus sepsis p < 0.0001

Control = 50

–

–

4.37 versus 2.34 nmol/l

–

–

↑ MR-proADM, non-survivor versus survivor p < 0.0001

Bio-ADM

Sepsis = 632

–

–

–

–

Median sepsis patients = 74 pg/mL; septic shock = 107 pg/mL, and 29 pg/mL in non-septic patients

[53]

Septic shock = 267

–

–

–

Mortality in sepsis patients OR of 1.23

Non-septic = 1235

–

–

–

–

↑ Dialysis: OR 1.97 in sepsis patients

–

–

70 pg/mL

↑ bio-ADM ↑ Use of vasopressors, OR 1.33

–

–

108 pg/mL

–

Survivors and non-survivors in sepsis

–

–

–

Youden’s index derived threshold of performed better

–

–

–

↑ bio-ADM non-survivors

–

–

–

PCT

Serum

Sepsis = 59

–

–

–

–

–

↑ PCT p < 0.0005

[66]

Severe sepsis/septic shock = 71

–

–

0.67 versus 3.81

–

–

Survivor versus non-survivor at seven days

Mean age = 80

–

–

0.48 versus 1.82 ng/mL

–

–

Survivor versus non-survivor at 30 days

Serum

SIRS = 38

65.79%

67.33%

1.57 ng/ml

–

–

PCT cut-off for sepsis

[113]

Sepsis = 52

–

–

–

–

–

↑ PCT in sepsis group, p = 0.01

Age = 20 to 92

Serum

Sepsis = 79

–

–

–

–

–

↑ PCT concentrations in patients with sepsis and infection

[114]

Age = newborn to 12

↓ PCT concentrations with antibiotic treatment

Control = 21

–

–

–

–

Age = newborn to 10

Blood

Sepsis = 119

–

–

17.1, 1.8, and 0.04 ng/ml

–

–

↑ PCT septic shock and sepsis compared to the control group p < 0.001

[46]

Septic shock = 32

–

–

1.8 and 9.2 ng/ml

–

–

↑ PCT levels in survivors versus non-survivors p > 0.001

Control = 20

Blood

Sepsis = 33

90.70%

98.60%

407 pg/ml

–

0.874

↑ PCT sepsis patients compared to SIRS group p < 0.05

[48]

Severe sepsis = 24

–

–

–

–

–

↑ PCT and APACHEII score in severe sepsis group compared to sepsis group p < 0.05

Septic shock = 15

SIRS = 23

Normal = 20

Mean age = 62.1

Plasma

Sepsis and shock septic = 1089

 ↔ There was no statistic difference in the primary outcome regarding PCT-guidance 27.9% versus no PCT-guidance 22.9% to predict mortality p = 0.18

[61]

PCT-guidance n = 279

 ↔ PCT-guidance versus no PCT-guidance there was no statistic difference in 28-day mortality, 25.6% versus 28.2% p = 0.34

No PCT-guidance n = 267

Serum

Severe sepsis = 34

–

–

129 pg/ml versus 105 pg/ml

–

–

 ↔ PCT did not differentiate septic shock from severe sepsis

[89]

Septic shock = 53

Age = 2 mo to 16 years

NT-proBNP

Serum

Sepsis = 60

–

–

1.209 ng/l

–

–

↑ NT-proBNP level at 24 h after sepsis diagnosis

[55]

Severe sepsis = 89

–

–

–

–

–

↑ NT-proBNP levels at 24 h after sepsis onset were associated with ↓ SPPB scores at 12 months p < 0.05, and ↓ handgrip strength at six and 12-month follow-up p < 0.001

Septic shock = 47

Age = 59.1 ± 15.1

Plasma

Sepsis = 142

4 (2.6–8.8) versus 8.2 nmol/L (5.2–12.6)

-

↑ NT-proBNP levels in non-survivors compared with survivors p < 0.01. ↔ CRP did not change in survivors and non-survivors

[52]

Septic shock = 947

-

↑ NT-proBNP prediction of 28-day mortality in total population, sepsis group, and shock septic group, respectively

0.73, 0.73, and 0.72

Neutrophil, cells, and related biomarkers

Lactate

Plasma

Sepsis = 59

–

–

–

–

↑ Lactate p < 0.0005

[66]

Severe sepsis/septic shock = 71

–

–

1.7 versus 3.4

–

Survivor versus non-survivor at seven days

Mean age = 80

–

–

1.6 versus 2.2

–

Survivor versus non-survivor at 30 days

–

–

mmol/l

0.79 and 0.77

Predictors of mortality at 7 and 30 days p = 0.001

Serum

Non- sepsis-associated encephalopathy = 2513 Sepsis-associated encephalopathy = 2474

–

–

–

–

–

↑ Lactate predicted 30-day mortality of patients with sepsis-associated encephalopathy, OR: 1.19 p < 0.0005

[93]

Blood

Sepsis = 33

90.70%

98.60%

407 pg/ml

–

0.859 and 0.723

↑ Lactate and APACHE-II score in severe sepsis group compared to sepsis group p < 0.05

[48]

Severe sepsis = 24

–

–

–

–

–

↑ APACHE-II score and lactate in septic shock group when compared with severe sepsis group p < 0.05

Septic shock = 15

SIRS = 23

Normal = 20

Mean age = 62.1

Serum

Severe sepsis = 34

–

–

–

–

–

 ↔ Lactate did not differentiate septic shock from severe sepsis

[89]

Septic shock = 53

Age = 2 mo to 16 years

MPO

Plasma

Sepsis = 957

–

–

128.1 ng/ml

–

–

↑ MPO day 1 and progressively decreased until day 7

[94]

–

–

–

–

–

↑ MPO increase on days on days 1, 2, and 7 in 90-day non-survivors p < 0.003, p = 0.03, and p = 0.001

Septic shock = 55

–

–

–

–

–

↑ MPO-DNA and cf-DNA in patients with septic shock on day 1 p < 0.01

[95]

Control = 13

–

–

–

–

–

↑ MPO-DNA on days 3 and 7 of sepsis was associated with 28-day mortality p < 0.01

Mean age = 68

–

–

–

0.303 and 0.434

–

↑ MPO-DNA on day 3 and 7 positive correlation with SOFA score p = 0.04 and p = 0.03, subsequently

♂ = 71%

Resistin

Plasma

Sepsis = 957

–

–

192.9 ng/ml

–

–

↑ Resistin on day one and progressively decreased until day 7

[94]

Mean age = 70

–

–

–

–

–

↑ Resistin increase on days 1, 2, and 7 in 90-day non-survivors p < 0.001

♂ = 60%

Serum

Sepsis = 50

72%, 80%, and 100%

82%, 95%, and 100%

5.2, 6.1, and 7,5 ng/ml

–

–

↑ Resistin levels on day 1, 4, and 7

[115]

Patient without sepsis = 22

–

–

–

–

0.864, 0.987, and 0.987

↑ Resistin levels on days 1, 4, and 7 were associated with sepsis

Control = 25

Age ≤ 12

Serum

Sepsis = 60

–

–

36.45

–

–

↑ Resistin in sepsis/septic shock groups p = 0.001

[96]

Septic shock = 42

–

–

48.13 versus 31.58

–

–

↑ Resistin levels in non-survivors versus Survivors on day 1 and 7 p < 0.001 and p < 0.001

Control = 102

–

–

46.20 versus 25.22

–

–

↑ Resistin septic shock versus sepsis on day 1 and 3 p < 0.001 and p < 0.001

40.8 versus 33.4

37.1 versus 27.4

µg/l

Soluble receptors

sPD-L1

Serum

Sepsis = 483

–

–

0.16 ng/ml

–

–

↑ sPD-L1 immunosuppression phenotype, ↑ risk of hospital readmission and mortality, OR = 8.26

[22]

Mean age = 60.5

↑ sPD-L1, 45 (46.4%) at 3 months, 40 (44.9%) at 6 months, and 44 (49.4%) at 12 months

♂ 54.9%

–

–

–

–

–

↑ sPD-L1 to predict 28-day mortality ≅ APACHE-II and SOFA scores

–

–

–

–

–

Serum

Sepsis = 91

–

–

2.09 ng/ml

–

–

↑ sPD-L1 and sPD-1 in septic patients p = 0.0001

[68]

Control = 29

–

–

–

–

–

↑ sPD-L1 increased in non-survivors p < 0.05

–

–

–

–

0.71

↑ sPD-L1 level to predict 28-day mortality

suPAR

Serum

Sepsis = 59

–

–

–

–

–

↑ suPAR, p < 0.0005

[66]

Severe sepsis/septic shock = 71

–

–

6.9 versus 9.8

–

–

Survivor versus non-survivor at seven days

Mean age = 80

–

–

6.4 versus 9.3

–

–

Survivor versus non-survivor at 30 days

–

–

ng/ml

0.72 and 0.77

Predictors of mortality at 7 and 30 days p = 0.006

–

–

–

–

–

↓ suPAR from day 1 to day seven sepsis and severe sepsis/septic shock p < 0.0005

Serum

Sepsis = 60

–

–

13

–

–

↑ suPAR in sepsis and septic shock

[96]

Septic shock = 42

–

–

10.5 versus 14.1

–

–

↑ suPAR in septic shock compared with sepsis on day one but not on day 7 p < 0.04 and p = 0.68, subsequently

Control = 102

11.3 versus 12.9 μg/l

sTNFR-1

Plasma

SIRS = 943

–

–

7719 versus 18,197

–

–

↑ sTNFR-1 in non-survivor versus survivor, p < 0.001

[81]

Sepsis = 330

–

–

pg/ml

–

–

↑ sTNFR-1 sepsis compared to SIRS p < 0.001

Shock = 216

Pneumonia = 169

Others = 152

Age = 55.1 ± 16.1

♂ 63.9%

Plasma

No delirium = 47

–

–

3.843 and 10.250 pg/ml

–

–

↑ sTNFR1 and sTNFR2 delirium cutoff p = 0.005

[98]

Delirium = 31

–

–

–

–

–

↑ sTNFR1 and sTNFR2 in delirium group compared with non-delirium p = 0.005, and p = 0.003, subsequently

OR: 18 to sTNFR1, p = 0.004 and OR: 51 to

STNFR2, p = 0.006

–

–

–

–

–

Lipoproteins

LDL

Serum

Sepsis = 594

–

–

–

–

–

Risk of sepsis, OR, 0.86, p = 0.001and admission to the ICU, OR, 0.85; p = 0.008; but not hospital mortality, OR,

[99]

↓Quartile greater risk of sepsis; OR, 1.48; and admission to the ICU, OR, 1.45, versus highest quartile

 ↔ When comorbidities were considered

HDL

Serum

Sepsis = 63

–

–

–

–

–

↓ HDL in non-survivors on days 1 to 4

[100]

Mean age = 72

–

–

–

–

0.84

Predicts mortality within 30 days

80%

92%

20 mg/dl

–

–

83% accuracy to predict 30-day overall mortality

–

–

–

–

–

HDL < 20 mg/dl increases attributable mortality, risk of prolonged ICU stay, and hospital-acquired infection rate

Plasma

Suspected sepsis = 200

0.690

0.716

30.9 mg/dl

–

0,749

MODS predictor

[101]

0.699

0.857

25,1 mg/dl

–

0,818

Mortality in 28 days

–

–

 < 25.1 mg/dl

–

–

↑ Mortality, p < 0.0001 in 28 days and p = 0.0007 in 90 days

–

–

–

–

–

74% of patients with HDL < 25.1 mg/dl required ICU compared to 35% above cutoff; development of severe acute renal dysfunction was 47% versus 21%, respectively; multiple organ dysfunction was 60% versus 25%; and mechanical ventilation was 53% versus 21%

–

–

–

–

–

↓ HD, the 28-day mortality is more than ten-fold higher (17.6% versus 1.5%) and a mean of 6.2 fewer days without mechanical ventilation and vasopressor support

T-chol

Serum

Sepsis = 136

–

–

–

–

–

↓ T-chol associated with risk of death in septic patients p < 0.05

[102]