Protein present in blood of COVID-19 patients can indicate progress and severity of the disease

Brazilian researchers discovered that sTREM-1 protein in immunoglobulin family could be a very useful biomarker to help medical teams make clinical decisions.

By Maria Fernanda Ziegler  |  Agência FAPESP – A protein present in the bloodstream of COVID-19 patients could be an important biomarker of the severity of the inflammation triggered by the novel coronavirus SARS-CoV-2.

Researchers at the University of São Paulo (USP) and the Federal University of São Carlos (UFSCar) in Brazil found that measuring the level of a protein called sTREM-1 as soon as the first symptoms appear could be a way of helping medical teams make clinical decisions and also serve as a predictor of disease severity and outcome.

The study was reported in an article posted to medRxiv, a preprint platform for new medical research that has not yet been peer-reviewed.

“The inflammatory response to SARS-CoV-2 varies considerably from one patient to another, and we don’t yet know exactly why. However, we believe that monitoring this protein by means of simple laboratory bloodwork [immunoenzymatic test] can be of help in treating patients. Decisions by medical teams will be supported by a biomarker that is a predictor of severity if the level rises,” said Carlos Sorgi, a professor in the Chemistry Department of the University of São Paulo’s Ribeirão Preto School of Philosophy, Sciences and Letters (FFCLRP-USP).

The study was supported by FAPESP as part of a project dedicated to investigating biomarkers of severe COVID-19 and targets for its clinical management.

The research is being conducted as a contribution to ImunoCovid, a multidisciplinary initiative involving 11 researchers affiliated with USP and UFSCar. Sharing data and samples, they collaborate under the leadership of Lúcia Helena Faccioli, a professor at the University of São Paulo’s Ribeirão Preto School of Pharmaceutical Sciences (FCFRP-USP).

Degrees of severity

TREM-1 stands for triggering receptor expressed on myeloid cells 1. The protein is a member of the immunoglobulin superfamily expressed in myeloid and epithelial cells. It is present in macrophages, monocytes, neutrophils, and other defense cells in the innate immune system (non-specific defense mechanisms triggered as soon as an antigen is detected in the body). As a membrane receptor, when activated it makes the cell emit signals warning that inflammation is in progress. The soluble form found in the bloodstream is sTREM-1.

“We don’t yet know what the soluble form does,” Sorgi said. “Previous studies found a correlation between death from sepsis and high levels of sTREM-1.”

Before the pandemic, Sorgi’s main research interest was how cancer correlated with augmented levels of sTREM-1, and this was the focus for the PhD thesis of his student Pedro da Silva-Neto.

In this latest study, the group measured levels of the protein in blood serum from 91 COVID-19 patients; 44 were isolated at home and 47 were hospitalized. They were classified as mild, moderate, severe, and critical. A control group was also recruited with 30 healthy subjects who tested negative for the disease.

“We observed a strong correlation between levels of the protein and degrees of disease severity,” Faccioli said. “The level of sTREM-1 in COVID-19 patients rose significantly as their condition became more severe. This variation indicates activation of the immune response to infection by SARS-CoV-2.”

Ever since the first cases of COVID-19 were reported in Wuhan, China, researchers all over the world have noted the importance of inflammatory markers such as a low lymphocyte count (lymphopenia) and high levels of neutrophils, C-reactive protein and cytokines IL-6 and IL-10, as well as elevated D-dimer (blood clotting).

“However, none of these markers is as accurate as sTREM-1 for stratifying degrees of severity and predicting the progress of the disease,” Faccioli said.

Point of no return

In the study, the researchers also set out to see if levels of the protein correlated with outcomes of the disease. “We found there’s a ‘point of no return’ when the inflammatory situation becomes so critical that it’s no longer possible to help the patient get better,” Sorgi said. “This second major finding confirmed the hypothesis that monitoring sTREM-1 is extremely important to ensure treatment at an early stage is successful.”

The patients in the study who progressed to the moderate, severe and critical stages also displayed augmented levels of sTREM-1. “Levels of the protein stabilized or fell slightly in most patients whose inflammation was treated with corticosteroids, for example,” Sorgi said. “However, we observed that after a certain point in the treatment, although there was no rise in blood serum levels of sTREM-1 this wasn’t reflected in recovery of the patient.”

Recovery reflected control of sTREM-1 only when the initial level was not very high, he added. The study, therefore, suggests that the beneficial effect of steroids in severe patients depends not only on the right dose but also on using the drug at the right time with regard to the stages of the disease.

“If the inflammation is very bad, the damage is so severe for the patient that they eventually die even if steroids are administered,” Sorgi said. “Patients who don’t reach the ‘point of no return’ are able to recover even if their condition is very serious.”

The ImunoCovid researchers collected data and biological samples relating to 500 patients infected by SARS-CoV-2 and from 100 subjects who tested negative for the virus. “We’re anxious to find a biomarker that helps treat the disease, so we completed the study with data for 91 patients, but our aim now is to extend the analysis not only to a larger number of subjects but also to more factors associated with the disease,” Faccioli said.

The group has collaborated for some time with scientists at Emory University in Atlanta, Georgia, who have a large repository of serological data for US patients.

The article “Prognostic value of sTREM-1 in COVID-19 patients: a biomarker for disease severity and mortality” can be retrieved from: www.medrxiv.org/content/10.1101/2020.09.22.20199703v2.