Table 4 Risk ratios for ARDS mortality in the ARDS population
| Â | Reference | Biomarker role in ARDS | Sample size | Risk ratio (95% CI) | Cut-off | Comment |
|---|---|---|---|---|---|---|
Biomarkers in plasma | Â | Â | Â | Â | Â | Â |
 Activin-A | Kim 2019 [76] | Pro-fibrotic | 97 | 2.64 (1.04–6.70) |  |  |
 Angiopoietin-1/angiopoietin-2 ratio | Ong 2010 [90] | Modulates endothelial permeability | 24 | 5.52 (1.22–24.9) |  |  |
 Angiopoietin-2 | Calfee 2012 [65] | Increased endothelial permeability | 931 | 0.92 (0.73–1.16) | Per log10 | Infection-related ALI |
 Angiopoietin-2 | Calfee 2012 [65] | Increased endothelial permeability | 931 | 1.94 (1.15–3.25) | Per log10 | Noninfection-related ALI |
 Angiopoietin-2 | Calfee 2015 [66] | Increased endothelial permeability | 100 | 2.54 (1.38–4.68) | Per log10 | Single centre |
 Angiopoietin-2 | Calfee 2015 [66] | Increased endothelial permeability | 853 | 1.43 (1.19–1.73) | per log10 | Multicentre |
 Angiotensin 1–9 | Reddy 2019 [95] | Pro-fibrotic | 39 | 2.24 (1.15–4.39) | Concentration doubled (in Ln) |  |
 Angiotensin 1–10 | Reddy 2019 [95] | Pro-fibrotic | 39 | 0.36 (0.18–0.72) | Concentration doubled (in Ln) |  |
 Angiotensin converting enzyme | Tsantes 2013 [103] | Endothelial permeability, pro-fibrotic | 69 | 1.06 (1.02–1.10) | Per 1 unit increase | 28-day mortality |
 Angiotensin converting enzyme | Tsantes 2013 [103] | Endothelial permeability, pro-fibrotic | 69 | 1.04 (1.01–1.07) | Per 1 unit increase | 90-day mortality |
 NT-pro brain natriuretic peptide | Bajwa 2008 [59] | Myocardial strain | 177 | 2.36 (1.11–4.99) | ≥ 6813 ng/L |  |
 NT-pro brain natriuretic peptide | Lin 2012 [81] | Myocardial strain | 87 | 2.18 (1.54–4.46) | Per unit |  |
 Club cell secretory protein | Cartin-Ceba 2015 [67] | Alveolar epithelial injury | 100 | 1.09 (0.60–2.02) | Per log10 |  |
 Club cell secretory protein | Lesur 2006 [78] | Alveolar epithelial injury | 78 | 1.37 (1.25–1.83) | Increments of 0.5 |  |
 Copeptin | Lin 2012 [81] | Osmo-regulatory | 87 | 4.72 (2.48–7.16) | Per unit |  |
 C-reactive protein (CRP) | Adamzik 2013 [58] | Inflammation | 47 | 1.01 (0.9–1.1) | Per log10 |  |
 C-reactive protein (CRP) | Bajwa 2009 [60] | Inflammation | 177 | 0.67 (0.52–0.87) | Per log10 |  |
 C-reactive protein (CRP) | Lin 2010 [80] | Inflammation | 63 | 2.316 (0.652–8.226) |  |  |
 C-reactive protein (CRP) | Tseng 2014 [104] | Inflammation | 56 | 1.265 (0.798–2.005) |  | Day 3 |
 D-dimer | Tseng 2014 [104] | Coagulation | 56 | 1.211 (0.818–1.793) |  |  |
 Decoy receptor 3 | Chen 2009 [68] | Immunomodulation | 59 | 4.02 (1.20–13.52) | > 1 ng/mL | Validation cohort |
 Endocan | Tang 2014 [100] | Leukocyte adhesion inhibition | 42 | 1.374 (1.150–1.641) | > 4.96 ng/mL |  |
 Endocan | Tsangaris 2017 [102] | Leukocyte adhesion inhibition | 53 | 3.36 (0.74–15.31) | > 13 ng/mL |  |
 Galectin 3 | Xu 2017 [108] | Pro-fibrotic | 63 | 1.002 (0.978–1.029) | Per 1 ng/mL |  |
 Granulocyte colony stimulating factor | Suratt 2009 [99] | Inflammation | 645 | 1.70 (1.06–2.75) | Quartile 4 vs quartile 2 |  |
 Growth differentiation factor-15 | Clark 2013 [70] | Pro-fibrotic | 400 | 2.86 (1.84–4.54) | Per log10 |  |
 Heparin binding protein | Lin 2013 [82] | Inflammation, endothelial permeability | 78 | 1.52 (1.12–2.85) | Per log10 |  |
 High mobility group protein B1 | Tseng 2014 [104] | Pro-inflammatory | 56 | 1.002 (1.000–1.004) |  | Day 1 |
 High mobility group protein B1 | Tseng 2014 [104] | Pro-inflammatory | 56 | 0.990 (0.968–1.013) |  | Day 3 |
 Insulin-like growth factor | Ahasic 2012 [24] | Pro-fibrotic | 175 | 0.70 (0.51–0.95) | Per log10 |  |
 IGF binding protein 3 | Ahasic 2012 [24] | Pro-fibrotic | 175 | 0.69 (0.50–0.94) | Per log10 |  |
 Intercellular adhesion molecule-1 | Calfee 2009 [63] | Pro-inflammatory | 778 | 1.22 (0.99–1.49) | Per log10 |  |
 Intercellular adhesion molecule-1 | Calfee 2011 [64] | Pro-inflammatory | 547 | 0.74 (0.59–0.95) | Per natural log |  |
 Intercellular adhesion molecule-1 | McClintock 2008 [86] | Pro-inflammatory | 50 | 5.8 (1.1–30.0) | Per natural log |  |
 Interleukin-1 beta | Lin 2010 [80] | Pro-inflammatory | 63 | 1.355 (0.357–5.140) | Per log 10 |  |
 Interleukin-6 | Calfee 2015 [66] | Pro-inflammatory | 100 | 1.81 (1.34–2.45) | Per log10 | Single centre |
 Interleukin-6 | Calfee 2015 [66] | Pro-inflammatory | 853 | 1.24 (1.14–1.35) | Per log10 | Multicentre |
 Interleukin-6 | Parsons 2005 [92] | Pro-inflammatory | 781 | 1.18 (0.93–1.49) | Per log10 |  |
 Interleukin-8 | Amat 2000 [26] | Pro-inflammatory | 21 | 0.09 (0.01–1.35) | > 150 pg/mL |  |
 Interleukin-8 | Calfee 2011 [64] | Pro-inflammatory | 547 | 1.36 (1.15–1.62) | Per natural log |  |
 Interleukin-8 | Calfee 2015 [66] | Pro-inflammatory | 100 | 1.65 (1.25–2.17) | Per log10 | Single centre |
 Interleukin-8 | Calfee 2015 [66] | Pro-inflammatory | 853 | 1.41 (1.27–1.57) | Per log10 | Multicentre |
 Interleukin-8 | Cartin-Ceba 2015 [67] | Pro-inflammatory | 100 | 1.08 (0.72–1.61) | Per log10 |  |
 Interleukin-8 | Lin 2010 [80] | Pro-inflammatory | 63 | 0.935 (0.280–3.114) | Per log 10 |  |
 Interleukin-8 | McClintock 2008 [86] | Pro-inflammatory | 50 | 2.0 (1.1–4.0) | Per natural log |  |
 Interleukin-8 | Parsons 2005 [92] | Pro-inflammatory | 780 | 1.73 (1.28–2.34) | Per log10 |  |
 Interleukin-8 | Tseng 2014 [104] | Pro-inflammatory | 56 | 1.039 (0.955–1.130) |  | Day 1 |
 Interleukin-8 | Tseng 2014 [104] | Pro-inflammatory | 56 | 1.075 (0.940–1.229) |  | Day 3 |
 Interleukin-10 | Parsons 2005 [92] | Anti-inflammatory | 593 | 1.23 (0.86–1.76) | Per log10 |  |
 Interleukin-18 | Dolinay 2012 [71] | Pro-inflammatory | 28 | 1.60 (1.17–2.20) | Per 500 pg/mL increase |  |
 Interleukin-18 | Rogers 2019 [97] | Pro-inflammatory | 683 | 2.2 (1.5–3.1) | ≥ 800 pg/mL |  |
 Leukocyte microparticles | Guervilly 2011 [75] | Immunomodulation | 52 | 5.26 (1.10–24.99) | < 60 elements/μL |  |
 Leukotriene B4 | Amat 2000 [26] | Pro-inflammatory | 21 | 22.5 (1.1–460.5) | > 14 pmol/mL |  |
 Neutrophil elastase | Wang 2017 [105] | Pro-inflammatory | 167 | 1.76 (p value 0.002) | 1 SD change | Day 1 |
 Neutrophil elastase | Wang 2017 [105] | Pro-inflammatory | 167 | 1.58 (p value 0.06) | 1 SD change | Day 3 |
 Neutrophil elastase | Wang 2017 [105] | Pro-inflammatory | 167 | 1.70 (p value 0.001) | 1 SD change | Day 7 |
 Neutrophil to lymphocyte ratio | Li 2019 [79] | Pro-inflammatory | 224 | 5.815 (1.824–18.533) | First–fourth quartile |  |
 Neutrophil to lymphocyte ratio | Wang 2018 [106] | Pro-inflammatory | 247 | 1.011 (1.004–1.017) | Per 1% increase |  |
 Neutrophil to lymphocyte ratio | Wang 2018 [106] | Pro-inflammatory | 247 | 1.532 (1.095–2.143) | > 14 |  |
 Nucleated red blood cells | Menk 2018 [87] | Erythrocyte progenitor cell, pro-inflammatory | 404 | 3.21 (1.93–5.35) | > 220/μL |  |
 Peptidase inhibitor 3 | Wang 2017 [105] | Anti-inflammatory | 167 | 0.50 (p value 0.003) | 1 SD change | Day 1 |
 Peptidase inhibitor 3 | Wang 2017 [105] | Anti-inflammatory | 167 | 0.43 (p value 0.001) | 1 SD change | Day 3 |
 Peptidase inhibitor 3 | Wang 2017 [105] | Anti-inflammatory | 167 | 0.70 (p value 0.18) | 1 SD change | Day 7 |
 Plasminogen activator inhibitor 1 | Cartin-Ceba 2015 [67] | Coagulation | 100 | 0.96 (0.62–1.47) | Per log10 |  |
 Plasminogen activator inhibitor 1 (activity) | Tsangaris 2009 [101] | Coagulation | 52 | 1.30 (0.84–1.99) | Per 1 unit increase |  |
 Procalcitonin | Adamzik 2013 [58] | Inflammation | 47 | 1.01 (0.025–1.2) | Per log10 |  |
 Procalcitonin | Rahmel 2018 [94] | Inflammation | 119 | 0.999 (0.998–1.001) |  |  |
 Protein C | McClintock 2008 [86] | Coagulation | 50 | 0.5 (0.2–1.0) | Per natural log |  |
 Protein C | Tsangaris 2017 [102] | Coagulation | 53 | 3.58 (0.73–15.54) | < 41.5 mg/dL |  |
 Receptor for advanced glycation end products | Calfee 2008 [62] | Alveolar epithelial injury | 676 | 1.41 (1.12–1.78) | Per log10 | Tidal volume 12 mL/kg |
 Receptor for advanced glycation end products | Calfee 2008 [62] | Alveolar epithelial injury | 676 | 1.03 (0.81–1.31) | Per log10 | Tidal volume 6 mL/kg |
 Receptor for advanced glycation end products | Calfee 2015 [66] | Alveolar epithelial injury | 100 | 1.98 (1.18–3.33) | Per log10 | Single centre |
 Receptor for advanced glycation end products | Calfee 2015 [66] | Alveolar epithelial injury | 853 | 1.16 (1.003–1.34) | Per log10 | Multicentre |
 Receptor for advanced glycation end products | Cartin-Ceba 2015 [67] | Alveolar epithelial injury | 100 | 0.81 (0.50–1.30) | Per log10 |  |
 Receptor for advanced glycation end products | Mrozek 2016 [89] | Alveolar epithelial injury | 119 | 3.1 (1.1–8.9) | – |  |
 Soluble suppression of tumourigenicity-2 | Bajwa 2013 [61] | Myocardial strain and inflammation | 826 | 1.47 (0.99–2.20) | ≥ 534 ng/mL (day 0) | Day 0 |
 Soluble suppression of tumourigenicity-2 | Bajwa 2013 [61] | Myocardial strain and inflammation | 826 | 2.94 (2.00–4.33) | ≥ 296 ng/mL (day 3) | Day 3 |
 Soluble triggering receptor expressed on myeloid cells-1 | Lin 2010 [80] | Pro-inflammatory | 63 | 6.338 (1.607–24.998) | Per log 10 |  |
 Surfactant protein-A | Eisner 2003 [72] | Alveolar epithelial injury | 565 | 0.92 (0.68–1.27) | Per 100 ng/mL increment |  |
 Surfactant protein D | Calfee 2011 [64] | Alveolar epithelial injury | 547 | 1.55 (1.27–1.88) | Per natural log |  |
 Surfactant protein D | Calfee 2015 [66] | Alveolar epithelial injury | 100 | 1.33 (0.82–2.14) | Per log10 | Single centre |
 Surfactant protein D | Calfee 2015 [66] | Alveolar epithelial injury | 853 | 1.09 (0.95–1.24) | Per log10 | Multicentre |
 Surfactant protein D | Eisner 2003 [72] | Alveolar epithelial injury | 565 | 1.21 (1.08–1.35) | Per 100 ng/mL increment |  |
 Thrombin–antithrombin III complex | Cartin-Ceba 2015 [67] | Coagulation | 100 | 1.05 (0.53–2.05) | Per log10 |  |
 High sensitivity troponin I | Metkus 2017 [88] | Myocardial injury | 1057 | 0.94 (0.64–1.39) | 1st, 5th quintile |  |
 Cardiac troponin T | Rivara 2012 [96] | Myocardial injury | 177 | 1.44 (1.14–1.81) | Per 1 ng/mL increase |  |
 Trombomodulin | Sapru 2015 [98] | Coagulation | 449 | 2.40 (1.52–3.83) | Per log10 | Day 0 |
 Trombomodulin | Sapru 2015 [98] | Coagulation | 449 | 2.80 (1.69–4.66) | Per log10 | Day 3 |
 Tumour necrosis factor alpha | Lin 2010 [80] | Pro-inflammatory | 63 | 3.691 (0.668–20.998) | Per log 10 |  |
 Tumour necrosis factor receptor-1 | Calfee 2011 [64] | Pro-inflammatory | 547 | 1.58 (1.20–2.09) | Per natural log |  |
 Tumour necrosis factor receptor-1 | Parsons 2005 [91] | Pro-inflammatory | 562 | 5.76 (2.63–12.6) | Per log10 |  |
 Tumour necrosis factor receptor-2 | Parsons 2005 [91] | Pro-inflammatory | 376 | 2.58 (1.05–6.31) | Per log10 |  |
 Uric acid | Lee 2019 [77] | Antioxidant | 237 | 0.549 (0.293–1030) | ≥ 3.00 mg/dL |  |
 Von Willebrand factor | Calfee 2011 [64] | Endothelial activation, coagulation | 547 | 1.57 (1.16–2.12) | Per natural log |  |
 Von Willebrand factor | Calfee 2012 [65] | Endothelial activation, coagulation | 931 | 1.51 (1.20–1.90) | Per log10 |  |
 Von Willebrand factor | Calfee 2015 [66] | Endothelial activation, coagulation | 853 | 1.83 (1.46–2.30) | Per log10 | Multicentre |
 Von Willebrand factor | Cartin-Ceba 2015 [67] | Endothelial activation, coagulation | 100 | 2.93 (0.90–10.7) | Per log10 |  |
 Von Willebrand factor | Ware 2004 [107] | Endothelial activation, coagulation | 559 | 1.6 (1.4–2.1) | Per SD increment |  |
Biomarkers in BALF | ||||||
 Angiopoietin-2 | Tsangaris 2017 [102] | Increased endothelial permeability | 53 | 11.18 (1.06–117.48) | > 705 pg/mL |  |
 Fibrocyte percentage | Quesnel 2012 [93] | Pro-fibrotic | 92 | 6.15 (2.78–13.64) | > 6% |  |
 Plasminogen activator inhibitor 1 (activity) | Tsangaris 2009 [101] | Coagulation | 52 | 0.37 (0.06–2.35) | Per 1 unit increase |  |
 Procollagen III | Clark 1995 [69] | Pro-fibrotic | 117 | 3.6 (1.2–10.7) | ≥ 1.75 U/mL |  |
 Procollagen III | Forel 2015 [73] | Pro-fibrotic | 51 | 5.02 (2.06–12.25) | ≥ 9 μg/L |  |
 Transforming growth factor alpha | Madtes 1998 [83] | Pro-fibrotic | 74 | 2.3 (0.7–7.0) | > 1.08 pg/mL |  |
 Transforming growth factor beta 1 | Forel 2018 [74] | Pro-fibrotic | 62 | 1003 (0.986–1.019) |  |  |
 T regulatory cell/CD4+ lymphocyte ratio | Adamzik 2013 [58] | Immunomodulation | 47 | 6.5 (1.7–25) | ≥ 7.4% |  |
Biomarkers in urine | ||||||
 Desmosine-to-creatinine ratio | McClintock 2006 [84] | Alveolar epithelial injury (elastin breakdown) | 579 | 1.36 (1.02–1.82) | Per log10 |  |
 Nitric oxide | McClintock 2007 [85] | Oxidative injury | 576 | 0.33 (0.20–0.54) | Per log10 |  |
 Nitric oxide-to-creatinine ratio | McClintock 2007 [85] | Oxidative injury | 576 | 0.43 (0.28–0.66) | Per log10 |  |