Prognostic Value of Early Stage Biomarkers on COVID-19 Severity: A Systematic Review and Meta-Analysis

Main Article Content

Rasya Azka Lazuwardi
Zahra Rabiatul Zhafira
Nadira Putri Nastiti
Andiva Nurul Fitri


Background: The surge in morbidity and mortality rate of COVID-19 is happening worldwide. Identifying COVID-19 severity prognosis in patients at an early stage became imperative as it could help to monitor and prevent disease progression towards severe form.

Purpose of Study: To comprehend the variation and profile of specific biomarkers to have the preferred modality to monitor the severity outcomes of COVID-19. Furthermore, this study is expected to help the clinicians to identify the probability of disease progression towards severe in COVID-19 patients on admission.

Methods: This study was reported based on criteria from PRISMA. The literature search was conducted in databases such as MEDLINE, Scopus, and ScienceDirect. RevMan 5.4 were used to provide pooled estimates for standardized mean differences with 95% confidence intervals. Random effect model was used based on heterogeneity level. Risk of Bias was assessed for each study using QUIPS tools.

Results: Fifty studies were included in the qualitative synthesis and twenty three from it were included in the quantitative meta-analysis. These studies consist of a total of 12720 cohort size, 2965 and 9755 for severe patients and non-severe patients respectively. Plasma suPAR (pooled SMD = 1.54, 95% CI = 0.85-2.22, p <0.0001), serum KL-6 (pooled SMD = 1.21, 95% CI = 0.85-1.57, p <0.00001), and SP-D (pooled SMD = 1.75, 95% CI = 0.79-2.70, p = 0.0003) were shown to have significantly high prognostic value for COVID-19 severity.

Conclusion: This study provides evidence that plasma suPAR, serum KL-6, and SP-D can be used as an excellent early stage biomarkers for COVID-19 severity.

Keywords: COVID-19, Biomarker, Severity, Prognosis

Article Details

How to Cite
Lazuwardi, R. A., Zhafira, Z. R., Nastiti, N. P. and Fitri, A. N. (2022) “Prognostic Value of Early Stage Biomarkers on COVID-19 Severity: A Systematic Review and Meta-Analysis”, Journal of Asian Medical Students’ Association. Kuala Lumpur, Malaysia. Available at: (Accessed: 4December2022).
Scientific Papers (EAMSC 2023 Nepal)


Malik P, Patel U, Mehta D, Patel N, Kelkar R, Akrmah M et al. Biomarkers and outcomes of COVID-19 hospitalisations: systematic review and meta-analysis. BMJ Evidence-Based Medicine. 2020;26(3):107-108.

Kermali M, Khalsa R, Pillai K, Ismail Z, Harky A. The role of biomarkers in diagnosis of COVID-19 – A systematic review. Life Sciences. 2020;254:117788.

WHO. Coronavirus disease (COVID-19). Available online: (accessed on 15 November 2021)

WHO. WHO Coronavirus (COVID-19) Dashboard. Available online: (accessed on 15 November 2021

Stauning M, Altintas I, Kallemose T, Eugen-Olsen J, Lindstrøm M, Rasmussen L et al. Soluble Urokinase Plasminogen Activator Receptor as a Decision Marker for Early Discharge of Patients with COVID-19 Symptoms in the Emergency Department. The Journal of Emergency Medicine. 2021;61(3):298-313.

Ozger H, Dizbay M, Corbacioglu S, Aysert P, Demirbas Z, Tunccan O et al. The prognostic role of neopterin in COVID‐19 patients. Journal of Medical Virology. 2020;93(3):1520-1525.Vaquero-Roncero, L. M., Sánchez-Barrado, E., Escobar-Macias, D., Arribas-Pérez, P., González de Castro, R., González-Porras, J. R., & Sánchez-Hernandez, M. V. (2021). C-Reactive protein and SOFA scale: A simple score as early predictor of critical care requirement in patients with COVID-19 pneumonia in Spain. Revista Española de Anestesiología y Reanimación (English Edition).

Tong, M., Xiong, Y., Zhu, C., Xu, H., Zheng, Q., Jiang, Y., Zou, L., Xiao, X., Chen, F., Yan, X., Hu, C., & Zhu, Y. (2021). Serum surfactant protein D in COVID-19 is elevated and correlated with disease severity. BMC Infectious Diseases, 21(1).

Ozger, H. S., Dizbay, M., Corbacioglu, S. K., Aysert, P., Demirbas, Z., Tunccan, O. G., Hizel, K., Bozdayi, G., & Caglar, K. (2021). The prognostic role of neopterin in COVID‐19 patients. Journal of Medical Virology, 93(3), 1520–1525.

Yang, M., Chen, X., & Xu, Y. (2020). A Retrospective Study of the C-Reactive Protein to Lymphocyte Ratio and Disease Severity in 108 Patients with Early COVID-19 Pneumonia from January to March 2020 in Wuhan, China. Medical Science Monitor, 26, e926393.

Scozzi, D., Cano, M., Ma, L., Zhou, D., Zhu, J. H., O’Halloran, J. A., Goss, C., Rauseo, A. M., Liu, Z., Sahu, S. K., Peritore, V., Rocco, M., Ricci, A., Amodeo, R., Aimati, L., Ibrahim, M., Hachem, R., Kreisel, D., Mudd, P. A., … Gelman, A. E. (2021). Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19. JCI Insight, 6(4).

Jin, M., Shi, N., Wang, M., Shi, C., Lu, S., Chang, Q., Sha, S., Lin, Y., Chen, Y., Zhou, H., Liang, K., Huang, X., Shi, Y., & Huang, G. (2020). CD45: a critical regulator in immune cells to predict severe and non-severe COVID-19 patients. Aging, 12(20), 19867–19879.

Rovina, N., Akinosoglou, K., Eugen-Olsen, J., Hayek, S., Reiser, J., & Giamarellos-Bourboulis, E. J. (2020). Soluble urokinase plasminogen activator receptor (suPAR) as an early predictor of severe respiratory failure in patients with COVID-19 pneumonia. Critical Care, 24(1), 187.

Conca, W., Alabdely, M., Albaiz, F., Foster, M. W., Alamri, M., Alkaff, M., Al-Mohanna, F., Nagelkerke, N., & Almaghrabi, R. S. (2021). Serum β2-microglobulin levels in Coronavirus disease 2019 (Covid-19): Another prognosticator of disease severity? PLOS ONE, 16(3), e0247758.

Zingaropoli, M. A., Nijhawan, P., Carraro, A., Pasculli, P., Zuccalà, P., Perri, V., Marocco, R., Kertusha, B., Siccardi, G., Del Borgo, C., Curtolo, A., Ajassa, C., Iannetta, M., Ciardi, M. R., Mastroianni, C. M., & Lichtner, M. (2021). Increased sCD163 and sCD14 Plasmatic Levels and Depletion of Peripheral Blood Pro-Inflammatory Monocytes, Myeloid and Plasmacytoid Dendritic Cells in Patients With Severe COVID-19 Pneumonia. Frontiers in Immunology, 12, 627548.

Gandini, O., Criniti, A., Ballesio, L., Giglio, S., Galardo, G., Gianni, W., Santoro, L., Angeloni, A., & Lubrano, C. (2020). Serum Ferritin is an independent risk factor for Acute Respiratory Distress Syndrome in COVID-19. Journal of Infection, 81(6), 979–997.

Bergantini, L., Bargagli, E., d’Alessandro, M., Refini, R. M., Cameli, P., Galasso, L., Scapellato, C., Montagnani, F., Scolletta, S., Franchi, F., Valente, S., Bennett, D., Sebastiani, G., Frediani, B., & Dotta, F. (2021). Prognostic bioindicators in severe COVID-19 patients. Cytokine, 141, 155455.

Stauning, M. A., Altintas, I., Kallemose, T., Eugen-Olsen, J., Lindstrøm, M. B., Rasmussen, L. J. H., Gamst-Jensen, H., Nehlin, J. O., Andersen, O., & Tingleff, J. (2021). Soluble Urokinase Plasminogen Activator Receptor as a Decision Marker for Early Discharge of Patients with COVID-19 Symptoms in the Emergency Department. The Journal of Emergency Medicine, 61(3), 298–313.

Xue, G., Gan, X., Wu, Z., Xie, D., Xiong, Y., Hua, L., Zhou, B., Zhou, N., Xiang, J., & Li, J. (2020). Novel serological biomarkers for inflammation in predicting disease severity in patients with COVID-19. International Immunopharmacology, 89, 107065.

Myhre, P. L., Prebensen, C., Strand, H., Røysland, R., Jonassen, C. M., Rangberg, A., Sørensen, V., Søvik, S., Røsjø, H., Svensson, M., Erik Berdal, J., & Omland, T. (2020). Growth Differentiation Factor 15 Provides Prognostic Information Superior to Established Cardiovascular and Inflammatory Biomarkers in Unselected Patients Hospitalized With COVID-19. Circulation, 142(22), 2128–2137.

Lorè, N. I., De Lorenzo, R., Rancoita, P. M. V, Cugnata, F., Agresti, A., Benedetti, F., Bianchi, M. E., Bonini, C., Capobianco, A., Conte, C., Corti, A., Furlan, R., Mantegani, P., Maugeri, N., Sciorati, C., Saliu, F., Silvestri, L., Tresoldi, C., Farina, N., … Manfredi, A. A. (2021). CXCL10 levels at hospital admission predict COVID-19 outcome: hierarchical assessment of 53 putative inflammatory biomarkers in an observational study. Molecular Medicine, 27(1), 129.

Ding, M., Zhang, Q., Li, Q., Wu, T., & Huang, Y.-Z. (2020). Correlation analysis of the severity and clinical prognosis of 32 cases of patients with COVID-19. Respiratory Medicine, 167, 105981.

Wang, G., Wu, C., Zhang, Q., Wu, F., Yu, B., Lv, J., Li, Y., Li, T., Zhang, S., Wu, C., Wu, G., & Zhong, Y. (2020). C-Reactive Protein Level May Predict the Risk of COVID-19 Aggravation. Open Forum Infectious Diseases, 7(5), ofaa153.

Fromonot, J., Gette, M., Ben Lassoued, A., Guéant, J.-L., Guéant-Rodriguez, R.-M., & Guieu, R. (2021). Hypozincemia in the early stage of COVID-19 is associated with an increased risk of severe COVID-19. Clinical Nutrition (Edinburgh, Scotland).

Ahnach, M., Zbiri, S., Nejjari, S., Ousti, F., & Elkettani, C. (2020). C-reactive protein as an early predictor of COVID-19 severity. Journal of Medical Biochemistry, 39(4), 500–507.

García de Guadiana‐Romualdo, L., Calvo Nieves, M. D., Rodríguez Mulero, M. D., Calcerrada Alises, I., Hernández Olivo, M., Trapiello Fernández, W., González Morales, M., Bolado Jiménez, C., Albaladejo‐Otón, M. D., Fernández Ovalle, H., Conesa Hernández, A., Azpeleta Manrique, E., Consuegra‐Sánchez, L., Nogales Martín, L., Conesa Zamora, P., & Andaluz‐Ojeda, D. (2021). MR‐proADM as marker of endotheliitis predicts COVID‐19 severity. European Journal of Clinical Investigation, 51(5), e13511.

Karakoyun, I., Colak, A., Turken, M., Altin, Z., Arslan, F. D., Iyilikci, V., Yilmaz, N., & Kose, S. (2021). Diagnostic utility of C-reactive protein to albumin ratio as an early warning sign in hospitalized severe COVID-19 patients. International Immunopharmacology, 91, 107285.

Kerget, B., Kerget, F., Aksakal, A., Aşkın, S., Uçar, E. Y., & Sağlam, L. (2021). Evaluation of the relationship between KIM‐1 and suPAR levels and clinical severity in COVID‐19 patients: A different perspective on suPAR. Journal of Medical Virology, 93(9), 5568–5573.

Bennouar, S., Bachir Cherif, A., Kessira, A., Hamel, H., Boudahdir, A., Bouamra, A., Bennouar, D., & Abdi, S. (2020). Usefulness of biological markers in the early prediction of corona virus disease-2019 severity. Scandinavian Journal of Clinical and Laboratory Investigation, 80(8), 611–618.

Zeng, Z., Hong, X.-Y., Li, Y., Chen, W., Ye, G., Li, Y., & Luo, Y. (2020). Serum-soluble ST2 as a novel biomarker reflecting inflammatory status and illness severity in patients with COVID-19. Biomarkers in Medicine, 14(17), 1619–1629.

Lin, S., Mao, W., Zou, Q., Lu, S., & Zheng, S. (2021). Associations between hematological parameters and disease severity in patients with SARS-CoV-2 infection. Journal of Clinical Laboratory Analysis, 35(1).

Yamaya, T., Hagiwara, E., Baba, T., Kitayama, T., Murohashi, K., Higa, K., Sato, Y., Otoshi, R., Tabata, E., Shintani, R., Okabayashi, H., Ikeda, S., Niwa, T., Nakazawa, A., Oda, T., Okuda, R., Sekine, A., Kitamura, H., Komatsu, S., & Ogura, T. (2021). Serum Krebs von den Lungen-6 levels are associated with mortality and severity in patients with coronavirus disease 2019. Respiratory Investigation, 59(5), 596–601.

Xiao, L.-N., Ran, X., Zhong, Y.-X., & Li, S.-S. (2021). Clinical value of blood markers to assess the severity of coronavirus disease 2019. BMC Infectious Diseases, 21(1).

Borgne, P. L., Vuillaume, L. A., Alamé, K., Lefebvre, F., Chabrier, S., Bérard, L., Haessler, P., Gennai, S., Bilbault, P., & Lavoignet, C.-E. (2021). Do blood eosinophils predict in-hospital mortality or severity of disease in SARS-CoV-2 infection? A retrospective multicenter study. Microorganisms, 9(2), 1–12.

Koç, D. O., Sipahi, H., Sürmeli, C. D., Çallk, M., Bireroǧlu, N., Öksüz, S., Baydar, T., & Şahin, G. (2020). Serum Neopterin Levels and the Clinical Presentation of COVID-19. Pteridines, 31(1), 185–192.

Asan, A., Üstündağ, Y., Koca, N., Şimşek, A., Sayan, H. E., Parildar, H., Cilo, B. D., & Huysal, K. (2021). Do initial hematologic indices predict the severity of covid-19 patients? Turkish Journal of Medical Sciences, 51(1), 39–44.

Leulseged, T. W., Hassen, I. S., Ayele, B. T., Tsegay, Y. G., Abebe, D. S., Edo, M. G., Maru, E. H., Zewde, W. C., Naylor, L. K., Semane, D. F., Dresse, M. T., & Tezera, B. B. (2021). Laboratory biomarkers of covid-19 disease severity and outcome: Findings from a developing country. PLoS ONE, 16(3 March).

Ruetsch, C., Brglez, V., Crémoni, M., Zorzi, K., Fernandez, C., Boyer-Suavet, S., Benzaken, S., Demonchy, E., Risso, K., Courjon, J., Cua, E., Ichai, C., Dellamonica, J., Passeron, T., & Seitz-Polski, B. (2021). Functional Exhaustion of Type I and II Interferons Production in Severe COVID-19 Patients. Frontiers in Medicine, 7.