Soluble Urokinase Plasminogen Activator Receptor (suPAR) Levels Are Predictive of COVID-19 Severity: an Italian Experience

Overview

Journal Clin Immunol

Specialty Allergy & Immunology

Date 2022 Aug 9

PMID 35944880

Authors

Maria Infantino

Lorenza Morena

Massimo Antonio Di Pietro

Benedetta Romanin

Barbara Cimolato

Beatrice Anna Luisa Rocca

Silvia Tunnera

Giulia Modi

Marta Tilli

Valentina Grossi

Barbara Lari

Helena Cerutti

Giulia Tesi

Valentina Anro

Alessandra Cartocci

Maurizio Benucci

Francesca Veneziani

Patrizia Casprini

Mariangela Manfredi

Affiliations

Soon will be listed here.

Abstract

Background: The soluble urokinase Plasminogen Activator Receptor (suPAR) has been identified as a reliable marker of COVID-19 severity, helping in personalizing COVID-19 therapy. This study aims to evaluate the correlation between suPAR levels and COVID-19 severity, in relation to the traditional inflammatory markers.

Methods: Sera from 71 COVID-19 patients were tested for suPAR levels using Chorus suPAR assay (Diesse Diagnostica Senese SpA, Italy). suPAR levels were compared with other inflammatory markers: IL-1β, IL-6, TNF-α, circulating calprotectin, neutrophil and lymphocyte counts, and Neutrophil/Lymphocytes Ratio (NLR). Respiratory failure, expressed as P/F ratio, and mortality rate were used as indicators of disease severity.

Results: A positive correlation of suPAR levels with IL-6 (r = 0.479, p = 0.000), TNF-α (r = 0.348, p = 0.003), circulating calprotectin (r = 0.369, p = 0.002), neutrophil counts (r = 0.447, p = 0.001), NLR (r = 0.492, p = 0.001) has been shown. Stratifying COVID-19 population by suPAR concentration above and below 6 ng/mL, we observed higher levels of circulating calprotectin (10.1 μg/mL, SD 7.9 versus 6.4 μg/mL, SD 7.5, p < 0.001), higher levels of P/F ratio (207.5 IQR 188.3 vs 312.0 IQR 127.8, p = 0.013) and higher mortality rate. Median levels of suPAR were increased in all COVID-19 patients requiring additional respiratory support (Nasal Cannula, Venturi Mask, BPAP and CPAP) (6.5 IQR = 4.9) compared to the group at room air (4.6 IQR = 4.2).

Conclusion: suPAR levels correlate with disease severity and survival rate of COVID-19 patients, representing a promising prognostic biomarker for the risk assessment of the disease.

Citing Articles

Hematological, inflammatory, and novel biomarkers assessment as an eminent strategy for clinical management of COVID-19.

Rezaeian S, Razmjooei F, Pourmokhtari M, Abdoli A, Mofazzal Jahromi M, Bagheri K Heliyon. 2023; 9(12):e22896.

PMID: 38076059 PMC: 10703635. DOI: 10.1016/j.heliyon.2023.e22896.

The Association of uPA, uPAR, and suPAR System with Inflammation and Joint Damage in Rheumatoid Arthritis: suPAR as a Biomarker in the Light of a Personalized Medicine Perspective.

Benucci M, Damiani A, Russo E, Guiducci S, Li Gobbi F, Fusi P J Pers Med. 2022; 12(12).

PMID: 36556207 PMC: 9788564. DOI: 10.3390/jpm12121984.

References

Rello J, Belliato M, Dimopoulos M, Giamarellos-Bourboulis E, Jaksic V, Martin-Loeches I . Update in COVID-19 in the intensive care unit from the 2020 HELLENIC Athens International symposium. Anaesth Crit Care Pain Med. 2020; 39(6):723-730. PMC: 7580531. DOI: 10.1016/j.accpm.2020.10.008. View

Pinsky M, Vincent J, Deviere J, Alegre M, KAHN R, Dupont E . Serum cytokine levels in human septic shock. Relation to multiple-system organ failure and mortality. Chest. 1993; 103(2):565-75. DOI: 10.1378/chest.103.2.565. View

Gubernatorova E, Gorshkova E, Polinova A, Drutskaya M . IL-6: Relevance for immunopathology of SARS-CoV-2. Cytokine Growth Factor Rev. 2020; 53:13-24. PMC: 7237916. DOI: 10.1016/j.cytogfr.2020.05.009. View

Giamarellos-Bourboulis E, Norrby-Teglund A, Mylona V, Savva A, Tsangaris I, Dimopoulou I . Risk assessment in sepsis: a new prognostication rule by APACHE II score and serum soluble urokinase plasminogen activator receptor. Crit Care. 2012; 16(4):R149. PMC: 3580738. DOI: 10.1186/cc11463. View

Koshelnick Y, Ehart M, Stockinger H, Binder B . Mechanisms of signaling through urokinase receptor and the cellular response. Thromb Haemost. 1999; 82(2):305-11. View

Immovilli P, Morelli N, Antonucci E, Radaelli G, Barbera M, Guidetti D . COVID-19 mortality and ICU admission: the Italian experience. Crit Care. 2020; 24(1):228. PMC: 7228672. DOI: 10.1186/s13054-020-02957-9. View

Fu L, Wang B, Yuan T, Chen X, Ao Y, Fitzpatrick T . Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: A systematic review and meta-analysis. J Infect. 2020; 80(6):656-665. PMC: 7151416. DOI: 10.1016/j.jinf.2020.03.041. View

Mahler M, Meroni P, Infantino M, Buhler K, Fritzler M . Circulating Calprotectin as a Biomarker of COVID-19 Severity. Expert Rev Clin Immunol. 2021; 17(5):431-443. PMC: 8054493. DOI: 10.1080/1744666X.2021.1905526. View

Bivona G, Agnello L, Ciaccio M . Biomarkers for Prognosis and Treatment Response in COVID-19 Patients. Ann Lab Med. 2021; 41(6):540-548. PMC: 8203437. DOI: 10.3343/alm.2021.41.6.540. View

10.

Borges do Nascimento I, von Groote T, OMathuna D, Abdulazeem H, Henderson C, Jayarajah U . Clinical, laboratory and radiological characteristics and outcomes of novel coronavirus (SARS-CoV-2) infection in humans: A systematic review and series of meta-analyses. PLoS One. 2020; 15(9):e0239235. PMC: 7498028. DOI: 10.1371/journal.pone.0239235. View

11.

Ponti G, Maccaferri M, Ruini C, Tomasi A, Ozben T . Biomarkers associated with COVID-19 disease progression. Crit Rev Clin Lab Sci. 2020; 57(6):389-399. PMC: 7284147. DOI: 10.1080/10408363.2020.1770685. View

12.

Maciejewska-Rodrigues H, Al-Shamisi M, Hemmatazad H, Ospelt C, Bouton M, Jager D . Functional autoantibodies against serpin E2 in rheumatoid arthritis. Arthritis Rheum. 2009; 62(1):93-104. DOI: 10.1002/art.25038. View

13.

Schindler R, Mancilla J, Endres S, Ghorbani R, Clark S, Dinarello C . Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood. 1990; 75(1):40-7. View

14.

Hayek S, Leaf D, Tahhan A, Raad M, Sharma S, Waikar S . Soluble Urokinase Receptor and Acute Kidney Injury. N Engl J Med. 2020; 382(5):416-426. PMC: 7065830. DOI: 10.1056/NEJMoa1911481. View

15.

Grasselli G, Greco M, Zanella A, Albano G, Antonelli M, Bellani G . Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy. JAMA Intern Med. 2020; 180(10):1345-1355. PMC: 7364371. DOI: 10.1001/jamainternmed.2020.3539. View

16.

Lagunas-Rangel F . Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis. J Med Virol. 2020; 92(10):1733-1734. PMC: 7228336. DOI: 10.1002/jmv.25819. View

17.

Enocsson H, Lukic T, Ziegelasch M, Kastbom A . Serum levels of the soluble urokinase plasminogen activator receptor (suPAR) correlates with disease activity in early rheumatoid arthritis and reflects joint damage over time. Transl Res. 2021; 232:142-149. DOI: 10.1016/j.trsl.2021.02.007. View

18.

Plesner T, Behrendt N, Ploug M . Structure, function and expression on blood and bone marrow cells of the urokinase-type plasminogen activator receptor, uPAR. Stem Cells. 1997; 15(6):398-408. DOI: 10.1002/stem.150398. View

19.

Haugaard S, Andersen O, Hansen T, Eugen-Olsen J, Linneberg A, Madsbad S . The immune marker soluble urokinase plasminogen activator receptor is associated with new-onset diabetes in non-smoking women and men. Diabet Med. 2011; 29(4):479-87. DOI: 10.1111/j.1464-5491.2011.03513.x. View

20.

Johnson K, Harris C, Cain J, Hummer C, Goyal H, Perisetti A . Pulmonary and Extra-Pulmonary Clinical Manifestations of COVID-19. Front Med (Lausanne). 2020; 7:526. PMC: 7438449. DOI: 10.3389/fmed.2020.00526. View