COVID-19 : suPAR protein in blood samples could be a new biomarker to predict who will develop severe respiratory failure

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A very high level of a protein known as suPAR in the blood of patients with COVID-19 may be a predictor of severe respiratory failure, according to new research published in the Journal of Critical Care on April 30.

The findings by researchers at Rush University Medical Center and other institutions suggest suPAR could be a potential predictor for which patients with COVID-19 will need to be put on ventilators to help them breathe.

“This is the first report in the world to show that suPAR is elevated in COVID-19 and is predictive. Since suPAR is a reactant of the innate immune system, it’s an indicator of disease severity,” said Jochen Reiser, MD, PhD, the Ralph C. Brown, MD, Professor of Internal Medicine, chairperson of the Department of Internal Medicine at Rush.

“These results show that the higher the plasma suPAR level, the worse the outcome will be in the lungs of these patients,” said Reiser, who is co-correspondent author of the study. “The higher the suPAR level, the shorter the time before patients needed intubation.”

Reiser’s research team tested suPAR levels in 15 Rush patients when they were admitted or tested for COVID-19.

The University of Athens Medical School measured 57 patients for suPAR and followed them in their clinical course. Time to intubation was followed and found to be shorter in patients with a higher plasma suPAR.

“There is a body of literature that suPAR is associated with poor outcomes from acute respiratory distress syndrome (a condition in many patients with severe COVID-19) and poor lung functioning in critically ill patients,” Reiser said.

Reiser also mentions that the link between suPAR and respiratory failure suggests a way to help manage patients with COVID-19.

“If we measure suPAR as part of diagnosing COVID-19, we may know whom to watch more and whom to send home,” he said. “Plasma suPAR levels give us a window into the course of the disease, allowing for an improved monitoring and applying new and supportive treatments early.”

The findings of the present research raise additional new questions about a role for suPAR in COVID-19-associated organ dysfunction.

Soluble urokinase plasminogen activator receptor, aka suPAR, is produced in the endobronchial tree in the lungs and by immune cells in the bone marrow and repeatedly has been shown to harm kidneys.

In two publications in the New England Journal of Medicine, Reiser’s research showed that chronically elevated blood levels are linked to development of chronic kidney disease, yet a high plasma suPAR also increases the risk for acute kidney injury – a sudden decline in kidney function that can be a severe side effect of general medical procedures.

Reportedly, an increasing number of patients with severe COVID-19 also develop kidney problems, which is leading researchers to investigate the connection between COVID-19, suPAR and kidney disease.

“Our research on suPAR and COVID-19 associated lung injury is based on a small sample size, and we will need more data, but the findings support a concept that suPAR is harmful in COVID-19. It may therefore play a prognostic and a causal role in COVID-19 associated kidney disease, Reiser said.”

Funding: Funding for this work was provided by unrestricted educational grants by the Hellenic Institute for the Study of Sepsis. Funds were also provided by Rush University Medical Center.


As of April 1, 2020, 885,689 cases of infections by the novel coronavirus SARS-CoV-2 (COVID-19) have been recorded worldwide; 44,217 of them have died (https://www.worldometers.info/coronavirus). At the beginning of the illness, patients may experience low-degree fever or flu-like symptoms, but suddenly, severe respiratory failure (SRF) emerges [1].

Increased circulating levels of D-dimers [1, 2] suggest endothelial activation. Urokinase plasminogen activator receptor (uPAR) that is bound on the endothelium may be cleaved early during the disease course leading to an increase of its soluble counterpart, namely suPAR [3].

If this holds true, then suPAR may be used as an early predictor of the risk of SRF.

The Hellenic Sepsis Study Group (HSSG, www.sepsis.gr) is collecting clinical information and serum samples within the first 24 h of admission from patients with infections and at least two signs of the systemic inflammatory response syndrome.

Since March 1, 2020, 57 patients with community-acquired pneumonia and molecular documentation of SARS-CoV-2 in respiratory secretions were enrolled. Patients were followed up daily for 14 days; the development of SRF defined as PO2/FiO2 ratio less than 150 requiring mechanical ventilation (MV) or continuous positive airway pressure treatment (CPAP) was recorded. suPAR was measured by an enzyme immunoassay in duplicate (suPARnostic™, ViroGates, Lyngby, Denmark); the lower detection limit was 1.1 ng/ml. Measurements were performed and reported by one technician who was blinded to clinical information.

The study endpoint was the prognostic performance of suPAR admission levels for the development of SRF within 14 days. Measured levels were compared to those collected from 15 patients with COVID-19 from the emergency department (ED) of Rush University Medical Center.

Thirty-four (59.6%) patients were male and 23 (40.1%) female; the mean ± SD age was 64.0 ± 10.3 years, and the Charlson’s comorbidity index was 2.70 ± 1.80. The mean ± SD admission total neutrophil count was 4414.1 ± 2526.5/mm3; the total lymphocyte count was 1149.1 ± 1131.4/mm3; the C-reactive protein was 73.1 ± 76.4 mg/l. Admission levels of suPAR were significantly greater among patients who eventually developed SRF (Fig. 1a).

Circulating levels of suPAR were of the same range as those of the US cohort (Fig. 1b). Receiver operator characteristics curve analysis identified levels ≥ 6 ng/ml as the best predictor for SRF. At that cutoff point, the sensitivity, specificity, positive predictive value, and negative predictive value for the prediction of SRF was 85.7%, 91.7%, 85.7%, and 91.7%, respectively.

The time to SRF was much shorter among patients with suPAR ≥ 6 ng/ml (Fig. 1c). The only admission variables that were independently associated with the development of SRF were male gender and suPAR ≥ 6 ng/ml (Table 1). A positive association was found between admission suPAR and D-dimers (rs = + 0.777, p < 0.0001).

figure1
suPAR as an early predictor of the development of severe respiratory failure (SRF). a Admission levels of suPAR among Greek patients who eventually developed or not SRF. The p value of comparisons by the Mann-Whitney U test is provided. b Levels of suPAR in patients with COVID-19 and controls. The p value of comparisons by the Mann-Whitney U test is provided. c Time to SRF of Greek patients in relation to the admission levels of suPAR. CI, confidence interval; HR, hazard ratio

Table 1 Independent variables at admission associated with the development of severe respiratory failure

 No need for MV or CPAP, n (%)Need for MV or CPAP, n (%)Univariate analysisForward Cox regression analysis
OR (95%CIs)p valueHR (95%CIs)p value
Male gender15 (41.7)19 (90.5)0.07 (0.02–0.37)< 0.00017.80 (1.75–34.76)0.007
CCI > 217 (48.6)17 (77.3)7.00 (2.11–24.25)0.002 ns
suPAR ≥ 6 ng/ml3 (8.3)18 (85.7)66.00 (12.05–361.35)< 0.000116.43 (4.56–59.19)< 0.0001
Neutrophils ≥ 4200/mm38 (22.2)16 (72.2)11.20 (3.13–40.08)< 0.0001 ns
CRP ≥ 58 mg/l7 (19.4)13 (61.9)6.73 (2.01–22.51)0.002 ns
  1. CCI Charlson’s comorbidity index, CRP C-reactive protein, CI confidence interval, HR hazard ratio, OR odds ratio

suPAR has been proposed as a biomarker for the risk of death. An analysis of the TRIAGE III trial in 4420 patients admitted at the ED in Denmark revealed that suPAR ranged between 2.6 and 4.7 ng/ml in 30-day survivors and between 6.7 and 11.8 ng/ml in 30-day non-survivors [4].

Early increase of suPAR has also been reported to be a prediction of 28-day outcome in sepsis [5]. uPAR is bound to the endothelial membrane and functions for the differential signaling between the cleaved and uncleaved forms of kininogen [3].

The positive association between D-dimers and suPAR suggest early complex kininogen and uPAR interactions at the endothelial level of early stages of COVID-19. Higher plasma levels of suPAR are predictive of and potentially causally involved in kidney disease [6] which can be a feature of severe COVID-19 infection.

Findings suggest that suPAR may early trace patients who need intensified management probably in need of anti-inflammatory treatment [6]. Whether modification of circulating suPAR is a useful therapeutic option will require further study.

References

  1. Guan W, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020. https://doi.org/10.1056/NEJMoa2002032.
  2. Pixley RA, Espinola RG, Ghebrehiwet B, Joseph K, Kao A, Bdeir K, et al. Interaction of high-molecular-weight kininogen with endothelial cell binding proteins suPAR, gC1qR and cytokeratin 1 determined by surface plasmon resonance (BiaCore). Thromb Haemost. 2011;105:1053–9.
  3. Schultz M, Rasmussen LJH, Høi-Hansen T, Kjøller E, Jensen BN, Lind MN, et al. Early discharge from the emergency department based on soluble urokinase plasminogen activator receptor (suPAR) levels: a TRIAGE III substudy. Dis Markers. 2019;2019:3403549.
  4. Hayek SS, Leaf DE, Samman Tahhan A, Raad M, Sharma S, et al. Soluble urokinase receptor and acute kidney injury. N Engl J Med. 2020;382:416–26.
  5. Giamarellos-Bourboulis EJ, Norrby-Teglund A, Mylona V, Savva A, Tsangaris I, Dimopoulou I, et al. Risk assessment in sepsis: a new prognostication score by APACHE II score and serum soluble urokinase plasminogen activator receptor. Crit Care. 2012;16:R149.
  6. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, et al., 2020. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet https://doi.org/10.1016/S0140-6736(20)30628-0.


Source:
Rush University

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