Table 2.
Biomarkers for sepsis, septic shock, and sepsis-associated encephalopathy
| Biomarker | Sample | Demographic | Specificity (%) | Sensitivity (%) | Cut-off | R2 | AUC | Clinical relevance | References |
|---|---|---|---|---|---|---|---|---|---|
| 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] |
Ang-1 angiopoietin-1, Ang-2 angiopoietin-2, APACHE-II acute physiology and chronic health evaluation II, ARDS acute respiratory distress syndrome, AUC area under the curve, BBB blood–brain barrier, BMVEC brain microvascular endothelial cells, CD cluster of differentiation, CLDN-5 claudin-5, CRP C reactive protein, CSF cerebrospinal fluid, DAMPs damage-associated molecular patterns, DIC disseminated intravascular coagulation, EEG electroencephalography, GCS Glasgow coma scale, HDL high-density lipoprotein, HLA-DR human leukocyte antigen, HMGB1 high mobility group box 1, hsCRP high-sensitivity C reactive protein, I-FABP intestinal fatty acid binding protein, IL interleukin, LDL low-density lipoprotein, lnc-ANRIL long non-coding antisense non-coding RNA in the INK4 locus, lnc-MALAT1 long non-coding metastasis-associated lung adenocarcinoma transcript 1, lnc-MEG3 long non-coding RNA maternally expressed gene 3, lncRNA long non-coding RNA, MCP-1 monocyte chemoattractant protein-1, miR-125a micro RNA-125a, miR-125b micro RNA-125b, MODS multiple organ dysfunction syndrome, MOF multiple organ failure, MPO myeloperoxidase, MR-proADM mid-regional pro adrenomedullin, NFL neurofilament light, NfH neurofilament heavy, NSE neuron specific enolase, NT-proBNP N-terminal pro-brain natriuretic peptide, OCLN occludin, OR odds ratio, PAI-1 plasminogen activator inhibitor 1, PCT procalcitonin, PTX-3 pentraxin-3, RNA ribonucleic acid, S100B calcium-binding protein B, sE-Selectin soluble E-selectin, sFlt-1 soluble fms-like tyrosine kinase 1, sICAM-1 soluble intercellular adhesion molecule 1, SIRS systemic inflammatory response syndrome, SOFA sequential organ failure assessment, sPD-1 soluble programmed death protein 1, sPD-L1 soluble programmed death ligand 1, SPPB short physical performance battery, sTNFR1 soluble tumor necrosis factor receptor type 1, sTNFR2 soluble tumor necrosis factor receptor type 2, sTREM-1 soluble triggering receptor expressed on myeloid cells 1, suPAR soluble form of the urokinase plasminogen activator receptor, sVCAM-1 soluble vascular cell adhesion molecule 1, T-chol total cholesterol, TNF-α tumour necrosis factor alpha, TREM-1 triggering receptor expressed on myeloid cells-1, VLA-3/a3β1 integrin alpha 3 beta 1, ZO-1 zonula-occluden 1). ↑ increase, ↓ decrease, ↔ no difference