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Table 4 Risk ratios for ARDS mortality in the ARDS population

From: A systematic review of biomarkers multivariately associated with acute respiratory distress syndrome development and mortality

  Reference Biomarker role in ARDS Sample size Risk ratio (95% CI) Cut-off Comment
Biomarkers in plasma       
 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  
  1. Abbreviations: ALI acute lung injury, BALF bronchoalveolar lavage fluid, SD standard deviation