J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website https://www.jocmr.org

Review

Volume 13, Number 4, April 2021, pages 195-203

Do Certain Biomarkers Predict Adverse Outcomes in Coronavirus Disease 2019?

**Table 1.** Summary of Biomarkers That May Help Predict Adverse Outcomes in COVID-19
Biomarker	Outcome	Strength of association	References
COVID-19: coronavirus disease 2019; OR: odds ratio; CI: confidence interval; PLR: platelet-lymphocyte ratio; hs-cTnI: high-sensitivity cardiac troponin I; NT-proBNP: N-terminal pro-brain natriuretic peptide; CK-MB: creatine kinase-myocardial band; ICU: intensive care unit; LDH: lactate dehydrogenase; ROC: receiving operator characteristics; CRP: C-reactive protein; PPV: positive prediction value; NPV: negative prediction value; ESR: erythrocyte sedimentation rate; IL-6: interleukin-6; GFR: glomerular filtration rate; AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: gamma-glutamyl transferase; INR: international normalized ratio.
Hematological/coagulation markers
Platelet count	Thrombocytopenia (defined as a platelet count of < 150,000/mm³) was associated with over five-fold enhanced risk of severe COVID-19.	OR: 5.1; 95% CI: 1.8 - 14.6	Lippe et al [11]
Lymphocyte count	Lymphocytopenia (defined as a lymphocyte count of < 1,500/mm³) was associated with poor outcomes.	Mean difference: -361.06 µL (-439.18, -282.95), P < 0.001	Huang et al [12]
ΔPLR (the difference between PLR at admission and the highest PLR during hospitalization)	The average ΔPLR in severe cases was 466.24 ± 471.86, while in non-severe cases was 19.61 ± 130.40.	At a cut-off value of > 126.7, ΔPLR had a sensitivity of 100%, and the specificity is 81.5% (P = 0.014).	Qu et al [15]
Serum ferritin	Elevated in severe cases and non-survivors	Univariable OR: 9.10; CI: 2.04 - 40.58; P = 0.0038	Zhou et al [10]
D-dimer	D-dimer level > 1.0 µg/mL at admission was associated with higher in-hospital mortality.	OR: 18.42; CI: 2.64 - 128.55; P = 0.0033	Zhou et al [10]
Cardiac biomarkers
hs-cTnI, NT-proBNP, CK-MB	Hs-cTnI level > 28 pg/dL was associated with ICU admission, severe disease, more frequent complications, increased in-hospital mortality. Elevated hs-cTnI levels were associated with elevated NT-proBNP and CK-MB levels. NT-proBNP concentrations of 800 pg/mL were seen in those who died compared to 72 pg/mL in those who recovered.	Univariable OR for in-hospital mortality: 80.07; 95% CI: 10.34 - 620.36; P < 0.0001 Standardized mean difference (between severe and mild cases): 25.6 ng/L; 95% CI: 6.8 - 44.5 ng/L	Zhou et al [10] Huang et al [16] Lippi et al [17] Wang et al [18] Guo et al [19] Shi et al [20] Chen et al [21]
Inflammatory indices
Serum LDH	Accurately predicts disease severity when serum levels above 344.5 U/L.	Sensitivity of 96.9% and a specificity of 68.8% on the area under ROC curve	Han et al [13]
CRP	Elevated CRP levels could reflect larger lung lesions and severe disease in early cases of COVID-19 infection	CRP levels had strong positive correlation with the diameter of lung lesions (correlation coefficient = 0.873, 0.734, P < 0.001) A CRP value of 20.42 mg/L has a sensitivity, specificity, PPV and NPV of 83%, 91%, 71% and 95%, respectively, for severe COVID-19	Wang [25] Tan et al [14]
ESR	Elevated ESR levels were associated with greater disease severity.	An ESR value of 19.50 mm/h has sensitivity, specificity, PPV and NPV of 83%, 81%, 56% and 94%, respectively for severe COVID-19.	Tan et al [14]
IL-6	Elevations strongly associated with mortality and the need for mechanical ventilation	IL-6 levels of ≥ 80 pg/mL had a 22-fold higher risk of respiratory failure compared to patients with lower IL-6 levels.	Ulhaq et al [26] Coomes et al [27] Herold et al [28]
Procalcitonin	Elevated levels are seen in severe infection.	Procalcitonin levels > 0.5 µg/L corresponded with an almost five times higher risk of severe infection (OR: 4.76; 95% CI: 2.74 - 8.29).	Lippi et al [29]
Renal function indices
GFR	Patients with kidney dysfunction had higher rates of sepsis, respiratory failure and in-hospital mortality.	P < 0.001	Cheng et al [22] Xiang et al [23] Uribarri et al [24]
Liver function indices
AST, ALT, total bilirubin, GGT, LDH and INR	Patients with severe disease had significantly elevated levels of these biomarkers compared to patients with mild disease.	Logistic regression analysis did not show an independent association between the above biomarkers and severe COVID-19.	Zhang et al [30]
Serum albumin	Hypoalbuminemia was an independent predictor for mortality.	OR: 6.394; 95% CI: 1.315 - 31.092	Huang et al [31]

Table 1. Summary of Biomarkers That May Help Predict Adverse Outcomes in COVID-19

Biomarker

Outcome

Strength of association

References

COVID-19: coronavirus disease 2019; OR: odds ratio; CI: confidence interval; PLR: platelet-lymphocyte ratio; hs-cTnI: high-sensitivity cardiac troponin I; NT-proBNP: N-terminal pro-brain natriuretic peptide; CK-MB: creatine kinase-myocardial band; ICU: intensive care unit; LDH: lactate dehydrogenase; ROC: receiving operator characteristics; CRP: C-reactive protein; PPV: positive prediction value; NPV: negative prediction value; ESR: erythrocyte sedimentation rate; IL-6: interleukin-6; GFR: glomerular filtration rate; AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: gamma-glutamyl transferase; INR: international normalized ratio.

Hematological/coagulation markers

Platelet count

Thrombocytopenia (defined as a platelet count of < 150,000/mm³) was associated with over five-fold enhanced risk of severe COVID-19.

OR: 5.1; 95% CI: 1.8 - 14.6

Lippe et al [11]

Lymphocyte count

Lymphocytopenia (defined as a lymphocyte count of < 1,500/mm³) was associated with poor outcomes.

Mean difference: -361.06 µL (-439.18, -282.95), P < 0.001

Huang et al [12]

ΔPLR (the difference between PLR at admission and the highest PLR during hospitalization)

The average ΔPLR in severe cases was 466.24 ± 471.86, while in non-severe cases was 19.61 ± 130.40.

At a cut-off value of > 126.7, ΔPLR had a sensitivity of 100%, and the specificity is 81.5% (P = 0.014).

Qu et al [15]

Serum ferritin

Elevated in severe cases and non-survivors

Univariable OR: 9.10; CI: 2.04 - 40.58; P = 0.0038

Zhou et al [10]

D-dimer

D-dimer level > 1.0 µg/mL at admission was associated with higher in-hospital mortality.

OR: 18.42; CI: 2.64 - 128.55; P = 0.0033

Zhou et al [10]

Cardiac biomarkers

hs-cTnI, NT-proBNP, CK-MB

Hs-cTnI level > 28 pg/dL was associated with ICU admission, severe disease, more frequent complications, increased in-hospital mortality.
Elevated hs-cTnI levels were associated with elevated NT-proBNP and CK-MB levels.
NT-proBNP concentrations of 800 pg/mL were seen in those who died compared to 72 pg/mL in those who recovered.

Univariable OR for in-hospital mortality: 80.07; 95% CI: 10.34 - 620.36; P < 0.0001
Standardized mean difference (between severe and mild cases): 25.6 ng/L; 95% CI: 6.8 - 44.5 ng/L

Zhou et al [10]
Huang et al [16]
Lippi et al [17]
Wang et al [18]
Guo et al [19]
Shi et al [20]
Chen et al [21]

Inflammatory indices

Serum LDH

Accurately predicts disease severity when serum levels above 344.5 U/L.

Sensitivity of 96.9% and a specificity of 68.8% on the area under ROC curve

Han et al [13]

CRP

Elevated CRP levels could reflect larger lung lesions and severe disease in early cases of COVID-19 infection

CRP levels had strong positive correlation with the diameter of lung lesions (correlation coefficient = 0.873, 0.734, P < 0.001)
A CRP value of 20.42 mg/L has a sensitivity, specificity, PPV and NPV of 83%, 91%, 71% and 95%, respectively, for severe COVID-19

Wang [25]
Tan et al [14]

ESR

Elevated ESR levels were associated with greater disease severity.

An ESR value of 19.50 mm/h has sensitivity, specificity, PPV and NPV of 83%, 81%, 56% and 94%, respectively for severe COVID-19.

Tan et al [14]

IL-6

Elevations strongly associated with mortality and the need for mechanical ventilation

IL-6 levels of ≥ 80 pg/mL had a 22-fold higher risk of respiratory failure compared to patients with lower IL-6 levels.

Ulhaq et al [26]
Coomes et al [27]
Herold et al [28]

Procalcitonin

Elevated levels are seen in severe infection.

Procalcitonin levels > 0.5 µg/L corresponded with an almost five times higher risk of severe infection (OR: 4.76; 95% CI: 2.74 - 8.29).

Lippi et al [29]

Renal function indices

GFR

Patients with kidney dysfunction had higher rates of sepsis, respiratory failure and in-hospital mortality.

P < 0.001

Cheng et al [22]
Xiang et al [23]
Uribarri et al [24]

Liver function indices

AST, ALT, total bilirubin, GGT, LDH and INR

Patients with severe disease had significantly elevated levels of these biomarkers compared to patients with mild disease.

Logistic regression analysis did not show an independent association between the above biomarkers and severe COVID-19.

Zhang et al [30]

Serum albumin

Hypoalbuminemia was an independent predictor for mortality.

OR: 6.394; 95% CI: 1.315 - 31.092

Huang et al [31]