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Optimal use of hospital resources and intervention using suPAR for improving prognosis and care for patients with COVID-19

Periodic Reporting for period 1 - RISCinCOVID (Optimal use of hospital resources and intervention using suPAR for improving prognosis and care for patients with COVID-19)

Reporting period: 2020-08-01 to 2021-07-31

The issue being addressed in this project is to provide tool for better handling of COVID-19: How we can improve prognosis and care for patients with COVID-19 and, at the same time, optimize hospital resources.

In the original project submission, we wrote the following:

"To optimize hospital resources, it is necessary to test which patients that can be sent home (mild outcome of infection) and which patients that should be admitted to hospital (high risk patients).
This will deliver on the tasks: 1) Identify patients that can safely cope with the infection at home and 2) Identify high risk patients early in the disease and 3) Select high-risk patients that may benefit of therapy.

But how can we identify low- or high-risk patients?
The suPARnostic test developed by ViroGates and CE/IVD approved for clinical use is highly prognostic marker for 30-day mortality. Some hospitals have suPAR in routine clinical assessment of patient risk, and preliminary data support that suPAR levels can triage whether patients with COVID-19 will have a mild or a severe outcome of COVID-19 and thereby select which patients that could be discharged or admitted.
We aim to transfer manufacturing, upscale and implement the suPARnostic technology across hospitals in Europe to improve the risk stratification of COVID-19 patients and optimize hospital resources. We furthermore provide a test method that can identify high-risk patients that may benefit from experimental therapeutic interventions that may impact on outcome. The identification of patients in high risk of mortality (patients with high suPAR) provide a possibility to intervene."

Since this appication, which was an emergency application with a 4-day deadline in March 2020, the pandemic have impacted on lives and societies worldwide. Our work in 3 of the 4 WP's has been successful this far and we have developed a tool for improved handling of COVID-19 patients, that impact on both patient prognosis, treatment, and outcome, and on hospital resources. We also still expect to be successful in the last WP, WP4.
WP1: REDcap database was build and patients with symptoms of COVID-19 included in study. All centers obtained ethical approval for the study. One publication has been published and another submitted. Work package completed.

WP2: The ethical applications for ESCAPE/SAVE have been approved and uploaded. suPAR measurement training courses were held with suPAR measuring sites. Patients has been included and final results for ESCAPE has just been accepted for publication in Journal of Innate Immunity. The publication will be uploaded when the publication has been proofed and officially published. For SAVE study, first part of study has been published, Enrollment of patients is still ongoing. The first part puiblication can be found here: https://pubmed.ncbi.nlm.nih.gov/33682678/ and uploaded under publications. The positive results of the open label SAVE study lead to a double blinded randomised controlled study entitled SAVE MORE. The positive results of the SAVE study was reproduced in the SAVE MORE study. Results from the study has been accepted in Nature medicine (in press) and an application of suPAR guided anakinra treatment in COVID-19 has been submitted to EMA with anticipated approval autumn 2021.

WP3: Structured interviews of medical doctors working with suPAR has been carried out and a manuscript has been drafted and await coauthors approval. Based on this, guidelines for suPAR in the Emergency Department has been created. Implementation of guidelines done. Work package completed.

WP4: The transfer and development of technologies from East to Europe is progressing and validation is in progress. During the first two quarters of 2021 a deep knowhow of the technology has been acquired. The recipe optimization is progressing with challenges of requiring reproducible results. Several issues have been addressed to identify the high risk failure points in both materials and processes. Final optimization to processes are being investigate and implemented to acquire reproducible results. A plan for which requirements for equipment, infrastructure and raw material has been stated. Latex coupling with antibodies has been performed with promising results. The performance of the conjugation is within the set specifications, though the process is not reproducible and currently in the optimization phase. Several factors are being investigated which possibly contribute to the variation and the lack of reproducibility. The validation process has yet to be initiated. The actual upscaling process has not been executed at this stage.
This project has resulted in several findings that have progressed beyond state of the art. The collaborative effort to determine the possible prognostic value of suPAR in COVID-19 identified a cut-off of below 4 ng/ml for low-risk of negative outcome COVID-19 patients. This can lead to quick discharge of COVID-19 patients for home-isolation and thereby save hospital staff and hospital resources (beds etc.). Furthermore, a high risk level of suPAR above 6 ng/ml, identified a subgroup of patients in high risk of developing respiratory failure (https://pubmed.ncbi.nlm.nih.gov/32354367/). Thus, a cut-of of 6 ng/ml can identify patients that are at high risk of severe progression and whom may benefit from therapeutic intervention. We used this cut-of in the SAVE study and compared patients with suPAR above 6 ng/ml who received Anakinra (IL-1 receptor blocker) to patients with suPAR above 6 ng/ml who received standard of care. The save study showed a 70% risk reduction among patients who received Anakinra (Link to manuscript: https://pubmed.ncbi.nlm.nih.gov/33682678/). This lead to the SAVE MORE study, a similar study but using a double blinded randomized controlled protocol. The protocol was written in collaboration with the COVID-19 task force of EMA. The study results were made available in April 2021, and the manufactor of Anakinra, SOBI (Sweden) has in July 2021 applied for approval of Anakinra in the treatment of COVID-19. The manuscript has been published in Nature medicine (https://pubmed.ncbi.nlm.nih.gov/34480127/)

The results will impact on the outcome of patients infected with the corona virus. The early identification of risk of progression by measuring suPAR is superior to any other biomarkers (manuscript submitted), and we have shown that the early identification of high risk patients (who present in the emergency department with a suPAR above 6 ng/ml) identifies patients that will benefit from early initiation of treatment e.g. with Anakinra. This lowers the risk of disease progression almost 3-fold compared to patients who receives standard of care (e.g. dexamethasone and remdesivir). We also show that patients with suPAR above 6 ng/ml who receive anakinra had shorter hospital stay and significantly more were negative for coronavirus and without symptoms 28-days after arrival in the emergency department, thereby also lowering hospital costs.
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