By: Jesper Eugen-Olsen, PhD, Copenhagen University Hospital Hvidovre, Denmark The corona virus SARS-CoV-2 pandemic puts tremendous pressure on hospital resources and capacity. Clinical markers of progression are urgently needed in order to quickly discharge patients, who will not develop severe disease, to own home isolation. They are also needed to identify those who will develop more severe symptoms and should be admitted to the medical ward, or to the ICU. A biomarker or a combination of biomarkers that can predict the disease progression may be useful for discharging patients. At the same time it would be valuable to detect the patients with a moderate disease risk and where further progression is low. There has been reports on hyper-immune activation and cytokine storm in patients with a severe response to infection with the SARS-CoV-2 virus.1 However, cytokines are unstable and fluctuating according to sample handling, making them unsuitable for routine clinical decision making. Several routine biomarkers have been shown to be associated with severe illness and mortality in patients with COVID-19. These include increased white blood cell count, decreased lymphocyte and platelet counts, alanine aminotransferase, creatinine kinase, lactate dehydrogenase, ferritin, C-reactive protein, Interleukin-6, and D-dimer.2 "It is expected that suPAR is a strong biomarker of disease severity and progression in patients with COVID-19." Dr. Jesper Eugen-Olsen We speculate that suPAR, a stable biomarker of immune activation, is a strong biomarker for development of severe disease and respiratory failure in patients with COVID-19 symptoms (Fig. 1). There are at least five reasons why suPAR may be a suitable marker for this purpose: \tsuPAR is a marker of chronic inflammation. Patients with high suPAR have a chronically activated immune system that is not capable of fighting disease. \tsuPAR is elevated in elderly with comorbidities and capture the most fragile patients. In acute medical patients in general, suPAR is a strong marker of 30- day readmission and mortality.3,4 \tsuPAR has been investigated in several viral infections, including HIV, HCV, Crimean-Congo hemorrhagic fever, and hantavirus. In all cases, suPAR is associated with clinical severity and mortality.5,6,7,8 \tsuPAR is elevated and associate to disease severity in patients with respiratory diseases including pneumonia9 and COPD10, and predicts risk of acute respiratory distress syndrome in patients with sepsis.11 \tThe SARS-CoV-2 viral infection is likely to induce highly elevated suPAR in the most severe cases. This may cause acute kidney injury12,13, a disease often observed in COVID-19 patients in the intensive care department. https:\/\/www.virogates.com\/wp-content\/uploads\/2020\/08\/suPAR-news-vol-3-Hypothesis-the-baseline-plasma-suPAR-level-can-differentiate-whether-patients-with-COVID-19-will-have-a-mild-or-a-severe-outcome-of-the-infection.png Fig. 1. Hypothesis: the baseline plasma suPAR level can differentiate whether patients with COVID-19 will have a mild or a severe outcome of the infection. In summary, it is expected that suPAR is a strong biomarker of disease severity and progression in patients with COVID-19 and may provide an important tool for the managing of patients suspected of having this virus. Clinical studies documenting this are warranted. 1. Pedersen SF et al. SARS-CoV-2: a storm is raging. J Clin Invest 130;5;2202-2205 (2020). 2. Henry BM et al. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a metaanalysis. Clin Chem Lab Med 58;7;1021-1028 (2020). 3. Rasmussen LJH et al. Soluble urokinase plasminogen activator receptor (suPAR) in acute care: a strong marker of disease presence and severity, readmission and mortality. A retrospective cohort study. Emerg Med J 33;11;769-775 (2016). 4. Rasmussen LJH et al. Combining national early warning score with soluble urokinase plasminogen activator receptor (suPAR) improves risk prediction in acute medical patients: a registry-based cohort study. Crit Care Med 46;12;1961-1968 (2018). 5. Hoenigl M et al. Soluble urokinase plasminogen activator receptor is predictive of non-AIDS events during antiretroviral therapy-mediated viral suppression. Clin Infect Dis 69;4;676-686 (2019). 6. Oliveira I et al. Assessment of simple risk markers for early mortality among HIV-infected patients in Guinea-Bissau: a cohort study. BMJ Open 14;2;6 (2012). 7. Yilmaz G et al. The diagnostic and prognostic significance of soluble urokinase plasminogen activator receptor in Crimean-Congo hemorrhagic fever. J Clin Virol. 50;3;:209-11 (2011). 8. Outinen TK et al. Plasma levels of soluble urokinase-type plasminogen activator receptor associate with the clinical severity of acute Puumala hantavirus infection. PLoS One 8;8; (2013). 9. \u00c7itlenbik H et al. Levels of Soluble Urokinase Plasminogen Activator Receptor in Pediatric Lower Respiratory Tract Infections. Pediatr Allergy Immunol Pulmonol 32;3;121-127 (2019). 10. H\u00e5kansson KEJ et al. High suPAR and Low Blood Eosinophil Count are Risk Factors for Hospital Readmission and Mortality in Patients with COPD. Int J Chron Obstruct Pulmon Dis 15;733-743 (2020). 11. Chen D et al. Serum plasminogen activator urokinase receptor predicts elevated risk of acute respiratory distress syndrome in patients with sepsis and is positively associated with disease severity, inflammation and mortality. Exp Ther Med 18;4;2984-2992 (2019). 12. Hayek SS et al. Soluble Urokinase Receptor and Acute Kidney Injury. N Engl J Med 382;5;416-426 (2020). 13. Yang X et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med pii: S2213-2600;20;30079-5 (2020).