Biomarker predicts severity of SARS-CoV-2 infection in patients

The coronavirus disease 2019 (COVID-19) presents with different levels of severity. A new study published on the preprint server medRxiv* investigates a biomarker to predict the severity of disease in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Soluble angiotensin-converting enzyme 2 as a prognostic biomarker for disease progression in patients infected with SARS-CoV-2. Image Credit: Near D Krasaesom /

COVID-19 disease severity

Infection by SARS-CoV-2 causes COVID-19 with different degrees of severity. Following the entry of SARS-CoV-2 into the host cell through its interaction with the angiotensin-converting enzyme 2 (ACE-2) receptor, an immune response subsequently arises.

If it is a severe SARS-CoV-2 infection, the activated immune system causes a cytokine storm. This local and systemic inflammation subsequently leads to dysfunction and damage of other organ systems.

Markers of inflammation and tissue damage

The molecules of the immune system that are mediators of inflammation are often utilized as biomarkers of immune system activation. Thus, these markers may play a role in the pathology of SARS-CoV-2 infection.

C-reactive protein (CRP), for example, is produced in the acute phase of COVID-19 and is a predictive marker of disease progression in patients with severe SARS-CoV-2 infection. Additionally, the growth/differentiation factor-15 (GDF-15) is a cytokine that shows elevated levels in patients with severe SARS-CoV-2 infection.

Interleukin-6 (IL-6) is a pro-inflammatory cytokine mediator. The cytokine storm in severe COVID-19 is mediated by IL-6 receptors.

Soluble fms-like tyrosine kinase-1 (sFlt-1) is a protein that reduces the growth of new blood vessels. Elevated levels of sFlt-1 correlate with damage to the membrane that lines the inside of the heart and blood vessels, as well as organ failure in COVID-19 patients.

Soluble ACE2 (sACE2)

When the membrane of SARS-CoV-2 is shed after binding to the ACE-2 receptor on the host cell, sACE2 arises. Patients with severe SARS-CoV-2 infection have increased vascular permeability, local tissue injury, and tissue scarring. These pathological changes are associated with a reduction in mACE2 activity due to the binding of SARS-CoV-2.

The current study evaluates the predictive value of sACE2 as a biomarker for disease severity in the context of other biomarkers of inflammation and tissue damage including CRP, GDF-15. IL-6, and sFlt-1. The scientists studied these biomarkers in patients with and without COVID-19 with different clinical outcomes.

A prospective and observational study

The current prospective observational study was conducted at the Vall d’Hebron University Hospital, Barcelona, Spain. This study included 850 adults aged 25-90 years who were tested for SARS-CoV-2 infection by reverse transcription-polymerase chain reaction (RT-PCR) assay using nose and throat swabs. Patients with autoimmune disorders or cardiovascular diseases were excluded from this study.

Patients were classified into 7 groups:

  • Group 1 – Emergency care and home discharge
  • Group 2 – Ward admission for moderate illness
  • Group 3 – Admission to the intensive care unit (ICU)
  • Group 4 – Death associated with SARS-CoV-2 infection
  • Group 5 – Negative RT-PCR result after previous confirmed RT-PCR result with emergency care and home discharge
  • Group 6 – Negative RT-PCR result after previous confirmed RT-PCR result of patients from Group 3.
  • Group 7 – Negative RT-PCR result with no history of SARS-CoV-2 infection. This was the control group.

Blood samples were taken from the patients and different biochemical assays were used to measure the levels of CRP, GDF-15. IL-6, sFlt-1, and sACE2.

Clinical data related to demographics, medical history, and metabolic profile medications were collected from the medical records. Other data related to blood count, platelet count, coagulation (prothrombin time and D-dimer tests), liver function tests, lipids, sugar, kidney function tests, and inflammatory markers were also collected.

The difference between marker levels within the patient groups was assessed for statistical significance.

Levels of biomarkers in patients with SARS-CoV-2

The levels of CRP, GDF-15, IL-6, and sFlt-1 were significantly higher in hospitalized patients with COVID-19 as compared to COVID-19 patients who were discharged.

The sACE2 levels were similar between samples of patients from Group 1 and Group 5. Conversely, sACE2 levels were higher in samples of patients from Group 6 than those of Group 3. The sACE2 levels were higher in samples of patients from Group 5 than those from Group 6.

In conclusion, levels of sACE2 were significantly lower in patients with COVID-19 who had the most severe clinical outcome.

Limitations of the study

This is a single-center study with under-representation of certain groups like the patients infected with SARS-CoV-2 who were discharged and controls. This study did not include samples from patients with mild symptoms who did not require hospital treatment, as public health recommendations advised such cases to stay at home.

The sACE2 levels were measured using a non-commercial kit; therefore, this analytical approach may not be as robust as the assays for other markers used in clinical practice.

The timing of collecting blood samples from a SARS-CoV-2 positive individual may be important for interpreting sACE2 levels. Blood sACE2 levels indicate the circulating levels of sACE2; thus, local sACE2 levels may be a more accurate indicator of SARS-CoV-2 disease severity. Importantly, blood sACE2 levels vary by gender and age, which was a factor that was not taken into consideration in this study.


The current study supports the further investigation of sACE2 as a novel biomarker for disease severity in patients infected with SARS-CoV-2. This approach could therefore be used to complement the predictions based on other biomarkers of inflammation and tissue damage.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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