suPAR as a biomarker for infectious diseases
The suPAR level is elevated in patients with infectious diseases compared with healthy individuals, and an elevated level is associated with:
- Advanced disease
- Poor prognosis
This applies to various infectious diseases, among others:
- Hepatitis B12
- Hepatitis C13-14
In general, the suPAR level is slightly elevated in patients with infectious diseases, and in all infectious diseases studied, an elevated suPAR level is associated with a poorer prognosis. In infectious diseases, the diagnostic value of suPAR is weak, but instead it has a prognostic value.
“It has become clear that suPAR is a very strong prognostic marker, exceeding the prognostic value of all other routinely measured biomarkers in our hospital.”
Prof. Ove Andersen,
MD, PhD, DmSc, Copenhagen University Hospital Hvidovre, Denmark
suPAR News Vol. 3, June 2020
In patients with HIV infection, it was demonstrated that the suPAR level is slightly elevated and increases with the disease stage (WHO criteria). The first study of suPAR in HIV showed that suPAR was at least as strong a prognostic marker of the natural progression of HIV as CD4 and viral load1. Antiretroviral therapy (ART) causes a decrease in suPAR of about 17%2. However, after 5 years of treatment, the patients’ suPAR level is still higher than in healthy controls2. Side effects of treatment are associated with higher suPAR levels3. In addition to the correlation with virological and immunological effects of the infection, the suPAR level correlates with age, metabolic syndrome, smoking, and low muscle mass4. In HIV patients with ARTinduced viral suppression, suPAR is a superior and independent predictor of non-AIDS events comorbidities (e.g. cardiovascular and renal diseases).
In patients with sepsis5-7, it has been found that the suPAR level is of some diagnostic value, as it increases with seriousness of sepsis and is frequently above 10 ng/mL in patients with impaired organ function8,9. However, most studies show that CRP and procalcitonin (PCT) are better diagnostic markers of bacterial sepsis, whereas suPAR is the best prognostic marker6,10. In a later cohort it was shown and validated that suPAR in combination with the APACHE score can improve the risk stratification of patients with sepsis11.
The suPAR level is elevated in hepatitis B patients with hepatic fibrosis compared to patients with no or mild fibrosis. Thus, suPAR may be useful for identification of hepatitis B patients with significant fibrosis12.
In hepatitis C patients the suPAR level is elevated, and the level increases with the severity of fibrosis. Because hepatic disease and fibrosis affect the suPAR level, the prognostic value and the reflection of disease severity are probably a result of the liver condition rather than the hepatitis C infection13. This is supported by data demonstrating that suPAR is also associated with seriousness and prognosis in patients with non-alcoholic fatty liver disease14.
Active tuberculosis (TB) causes a substantial increase in suPAR level, typically to about 6-7 ng/mL – the higher, the worse15,16. A study from Guinea-Bissau has shown that the suPAR level measured upon initiation of treatment for TB is a prognostic marker of mortality during treatment. Measurement of suPAR following one month of treatment demonstrated that the change in suPAR level was also associated with mortality; patients experiencing no decrease – or even an increase – in suPAR level have a poorer prognosis than patients experiencing a decrease following one month of treatment17.
In malaria, suPAR has been studied in children, adults, and pregnant women. In children, a doubling of the suPAR level is observed, which decreases back to a normal level following 14 days of effective treatment18. In adult patients with malaria and acute renal damage, suPAR was associated with severity of the renal damage and was higher in patients who subsequently needed dialysis19. In pregnant women infected with malaria, a high suPAR level is associated with low birth weight of the baby20.
An elevated suPAR level in the cerebrospinal fluid (CSF) in children and adults with meningitis is associated with increased mortality21,22.
In children with pneumonia, suPAR is associated with the severity of the infection and length of hospital stay23. In adults with sepsis and ventilator-associated pneumonia, the suPAR level is strongly and independently associated with a negative prognosis24.
1. Sidenius N, Sier CF, Ullum H et al. Serum level of soluble urokinase-type plasminogen activator receptor is a strong and independent predictor of survival in human immunodeficiency virus infection. Blood 2000;96(13):4091-4095.
2. Ostrowski SR, Katzenstein TL, Pedersen M et al. Plasma levels of intact and cleaved urokinase receptor decrease in HIV-1-infected patients initiating highly active antiretroviral therapy. Scand J Immunol 2006;63(6):478-486.
3. Andersen O, Eugen-Olsen J, Kofoed K, Iversen J, Haugaard SB. Soluble urokinase plasminogen activator receptor is a marker of dysmetabolism in HIV-infected patients receiving highly active antiretroviral therapy. J Med Virol 2008;80(2):209-216.
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5. Hoenigl M et al and the ACTG NWCS 411 study team. Soluble Urokinase Plasminogen Activator Receptor (suPAR) is predictive of Non-AIDS Events during Antiretroviral Therapy-mediated Viral Suppression. Clin Infect Dis. 2018 ciy966
6. Donadello K, Scolletta S, Covajes C, Vincent JL. suPAR as a prognostic biomarker in sepsis. BMC Med 2012;10:2. doi: 10.1186/1741-7015-10-2.:2-10.
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8. Koch A, Voigt S, Kruschinski C et al. Circulating soluble urokinase plasminogen activator receptor is stably elevated during the first week of treatment in the intensive care unit and predicts mortality in critically ill patients. Crit Care 2011;15(1):R63.
9. Suberviola B, Castellanos-Ortega A, Ruiz RA, Lopez-Hoyos M, Santibanez M. Hospital mortality prognostication in sepsis using the new biomarkers suPAR and proADM in a single determination on ICU admission. Intensive Care Med 2013;39(11):1945-1952.
10. Giamarellos-Bourboulis EJ, Georgitsi M. Host response biomarker in sepsis: suPAR detection. Methods Mol Biol 2015;1237:241-6. doi: 10.1007/978-1-4939-1776-1_18.:241- 246.
11. Giamarellos-Bourboulis EJ, Norrby-Teglund A, Mylona V et al. 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.
12. Sevgi DY, Bayraktar B, Gunduz A et al. Serum soluble urokinase-type plasminogen activator receptor and interferon-gamma-induced protein 10 levels correlate with significant fibrosis in chronic hepatitis B. Wien Klin Wochenschr 2015.
13. Berres ML, Schlosser B, Berg T, Trautwein C, Wasmuth HE. Soluble urokinase plasminogen activator receptor is associated with progressive liver fibrosis in hepatitis C infection. J Clin Gastroenterol 2012;46(4):334-338.
14. Sjowall C, Martinsson K, Cardell K, Ekstedt M, Kechagias S. Soluble urokinase plasminogen activator receptor levels are associated with severity of fibrosis in nonalcoholic fatty liver disease. Transl Res 2015;165(6):658-666.
15. Eugen-Olsen J, Gustafson P, Sidenius N et al. The serum level of soluble urokinase receptor is elevated in tuberculosis patients and predicts mortality during treatment: a community study from Guinea-Bissau. Int J Tuberc Lung Dis 2002;6(8):686-692.
16. Rabna P, Andersen A, Wejse C et al. High mortality risk among individuals assumed to be TB-negative can be predicted using a simple test. Trop Med Int Health 2009;14(9):986-994.
17. Rabna P, Andersen A, Wejse C et al. Utility of the plasma level of suPAR in monitoring risk of mortality during TB treatment. PLoS One 2012;7(8):e43933.
18. Perch M, Kofoed P, Fischer TK et al. Serum levels of soluble urokinase plasminogen activator receptor is associated with parasitemia in children with acute Plasmodium falciparum malaria infection. Parasite Immunol 2004;26(5):207-211.
19. Plewes K, Royakkers AA, Hanson J et al. Correlation of biomarkers for parasite burden and immune activation with acute kidney injury in severe falciparum malaria. Malar J 2014;13:91. doi: 10.1186/1475-2875-13-91.:91-13.
20. Ostrowski SR, Ullum H, Goka BQ et al. Plasma concentrations of soluble urokinase-type plasminogen activator receptor are increased in patients with malaria and are associated with a poor clinical or a fatal outcome. J Infect Dis 2005;191(8):1331-1341.
21. Tzanakaki G, Paparoupa M, Kyprianou M, Barbouni A, Eugen-Olsen J, Kourea- Kremastinou J. Elevated soluble urokinase receptor values in CSF, age and bacterial meningitis infection are independent and additive risk factors of fatal outcome. Eur J Clin Microbiol Infect Dis 2012;31(6):1157-1162.
22. Ostergaard C, Benfield T, Lundgren JD, Eugen-Olsen J. Soluble urokinase receptor is elevated in cerebrospinal fluid from patients with purulent meningitis and is associated with fatal outcome. Scand J Infect Dis 2004;36(1):14-19.
23. Wrotek A, Jackowska T. The role of the soluble urokinase plasminogen activator (suPAR) in children with pneumonia. Respir Physiol Neurobiol 2015;209:120-3. doi: 10.1016/j.resp.2014.12.018. Epub;%2015 Jan 17.:120-123.
24. Savva A, Raftogiannis M, Baziaka F et al. Soluble urokinase plasminogen activator receptor (suPAR) for assessment of disease severity in ventilator-associated pneumonia and sepsis. J Infect 2011;63(5):344-350.
25. Oliveira I, Andersen A, Furtado A et al. Assessment of simple risk markers for early mortality among HIV-infected patients in Guinea-Bissau: a cohort study. BMJ Open 2012;2(6):e001587.