Panel of Five Serum Biomarkers Identifies COVID-19 Patients at High Risk to Develop Serious Complications

Based on early Chinese COVID-19 studies showing that certain biomarkers were associated with bad outcomes, investigators at George Washington University (Washington, DC, USA) determined levels of five serum biomarkers in samples obtained from 299 patients diagnosed with COVID-19 admitted to George Washington Hospital between March 12 and May 9, 2020.

The five biomarkers measured were:

1) D-dimer, a fibrin degradation product present in the blood after a blood clot has been degraded by fibrinolysis. It was so named because it contains two D fragments of the fibrin protein joined by a cross-link. D-dimer concentration may be determined by a blood test to help diagnose thrombosis. Since its introduction in the 1990s, it has become an important test performed in patients with suspected thrombotic disorders. A four-fold increase in the protein is a strong indicator of mortality in those suffering from COVID-19.

2) C-reactive protein (CRP) is a ring-shaped, pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T-cells.

3) IL-6 (interleukin-6) is an important mediator of fever and of the acute phase response. There is some early evidence that IL-6 can be used as an inflammatory marker for severe COVID-19 infection with poor prognosis, in the context of the wider coronavirus pandemic.

4). Lactate dehydrogenase (LDH) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of lactate to pyruvate and back, as it converts NAD+ to NADH and back. LDH is expressed extensively in body tissues, such as blood cells and heart muscle. Since it is released during tissue damage, LDH is a marker of common injuries and disease such as heart failure.

5) Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. Plasma ferritin is an indirect marker of the total amount of iron stored in the body and is used as a diagnostic test for iron-deficiency anemia.

For each patient, age, sex, BMI, comorbidities, and medications were recorded. Laboratory tests were performed either in the emergency room prior to admission or after the admission orders, and patients were placed in one of the special COVID-19 units. In addition to routine admission laboratory studies, CRP, D-dimer, IL-6, ferritin, and LDH were recorded. Further, the maximum oxygen requirements prior to transfer to ICU, transfer to the ICU, necessity for mechanical ventilation, and discharge status were noted.

Results revealed that elevated levels of these biomarkers were associated with inflammation and bleeding disorder, showing an independent increased risk for ICU admission, invasive ventilatory support, and death. The highest odds of death occurred when the LDH level was greater than 1200 units/liter and a D-dimer level was greater than 3 microgram/milliliter.

"When we first started treating COVID-19 patients, we watched them get better or get worse, but we did not know why," said contributing authour Dr. Juan Reyes, assistant professor of medicine at the George Washington University. "Some initial studies had come out of China showing certain biomarkers were associated with bad outcomes. There was a desire to see if that was true for our patients here in the U.S."

"We hope these biomarkers help physicians determine how aggressively they need to treat patients, whether a patient should be discharged, and how to monitor patients who are going home, among other clinical decisions," said first author Dr. Shant Ayanian, assistant professor of medicine at George Washington University.

The study was published in the July 17, 2020, online edition of the journal Future Medicine.

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