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Elevated Biomarkers Offer Early Indicator of Severe COVID-19, Study Says

May 16, 2022

Elevated biomarkers can reveal whether a patient with COVID-19 is likely to develop severe disease and need care in the ICU, Yale researchers have found.

When patients with COVID-19 arrive in emergency rooms, there are relatively few ways for doctors to predict which ones are more likely to become critically ill and require intensive care and which ones are more likely to enjoy a quick recovery.

Recent Yale research could help them identify important early clues that foretell severe cases of COVID-19.

Elevated Neutrophil Biomarkers Associated with Severe COVID-19

In a recent study published in Blood Advances, researchers report that a series of biomarkers, or biological signals, associated with white blood cell activation and obesity can predict severe outcomes in COVID-19 patients.

“Patients with high levels of these markers were much more likely to require care in the intensive care unit, require ventilation, or die due to their COVID-19,” said Hyung Chun, MD, the lead author, associate professor of medicine in cardiovascular medicine and pathology, and director of translational research at the Yale Pulmonary Vascular Disease Program.

Previously, a few laboratory studies had identified possible indicators of severe COVID-19, including D-dimer levels, a measure of blood coagulation, levels of proteins known as cytokines, which are released as part of inflammatory responses in the body, and low levels of renalase, an enzyme that might help reduce the damaging immune system response. However, until now, no laboratory marker could predict which patients with COVID-19 would eventually become critically ill prior to showing clinical signs and symptoms of severe disease.

For the more recent study, Yale researchers used proteomic profiling — a screen for multiple proteins within the blood — to analyze samples taken from 100 patients who would go on to experience different levels of COVID-19 severity. In all cases, the blood samples were collected on the patients’ first day of admission. The researchers also analyzed clinical data for over 3,000 additional patients with COVID-19 within the Yale New Haven Hospital system.

They found that five proteins (resistin, lipocalin-2, HGF, IL-8, and G-CSF) that are associated with neutrophils, a type of white blood cell, were elevated in the COVID-19 patients who later became critically ill. Many of these proteins had previously been associated with obesity but not with COVID-19 or other viral illnesses.

Notably, the elevated neutrophil biomarkers for patients who would go on to experience more serious symptoms were evident before those symptoms appeared. All COVID-19 patients who were admitted or transferred to the ICU had elevated neutrophil activation markers, while these biomarkers remained low for patients who never developed severe illness. None of the patients with lower neutrophil biomarker levels died.

“This is one of the first demonstrations that a set of biomarkers in the blood of COVID patients can predict eventual ICU admission, even before such patients become critically ill,” said study author Alfred Lee, MD, PhD, associate professor of medicine in hematology, director of the Yale Medical Oncology-Hematology Fellowship Program, and a member of the Yale Cancer Center.

Neutrophils: The Connector Between COVID-19 and Obesity

The study also underscores the connection between COVID-19 and obesity, researchers said. The Centers for Disease Control and Prevention notes that obesity and severe obesity increase risk of severe illness from COVID-19. Obesity triples the risk of hospitalization from COVID-19, and body mass index has been found to correlate with the risk of death from COVID-19.

Neutrophils are inflammatory cells, said Lee, so it makes sense that they would be elevated in the context of both obesity — which involves chronic, low-grade inflammation — and COVID-19, which causes hyperinflammation in the most severe cases, leading to tissue damage and organ failure.

“There are also signs that neutrophils might participate in thrombosis or blood clotting,” said Lee, another troubling hallmark of COVID-19.

“We are hoping these findings motivate other groups to look at their own patient populations,” said Chun, adding that they’ll need additional validation studies that would support developing diagnostic tests for these biomarkers.

The research involved collaborators from across many different Yale departments, including Matthew L. Meizlish, an M.D./Ph.D. student; Alex Pine, MD, PhD, assistant professor of medicine in hematology and staff physician at the VA Medical Center in West Haven; Jason Bishai, a graduate student; Hanming Zhang, PhD, and C-Hong Chang, postdoctoral fellows; and David van Dijk, PhD, assistant professor of medicine in cardiology.

Other Biomarkers Can Identify Patients at Risk of Severe COVID-19

These findings followed earlier COVID-19 research that also involved collaboration among researchers and experts across several medical specialties at Yale. This research, published in The Lancet Haematology, sought to identify a leading mechanism behind the pathophysiology and COVID-19 and pinpoint a biological marker for the mechanism that could aid in treating these patients.

“While many forms of illness can generate blood clots, the endothelial cells that line the inside of blood vessels play a surprisingly large role in COVID-19 clotting,” said Lee, who was co-senior author on this research. “Endothelial damage is a central component in the entire spectrum of COVID-19 disease. Our study is the first to demonstrate that this process of endothelial damage is present in a wide range of COVID-19 patients, particularly as people become critically ill.”

The clinical study examined the blood of 68 patients with COVID-19, 48 of them critically ill in an ICU and 20 receiving care in a non-ICU hospital unit, along with 13 disease-free volunteers who acted as a control arm. Several markers of endothelial cell and blood platelet activation were about twice as high in the ICU group than in the non-ICU group, and also higher in the non-ICU group than in the control group.

One of the biomarkers, a soluble form of a protein on the surface of endothelial cells called thrombomodulin, was highly correlated with survival among all COVID-19 patients. This finding suggests that measuring thrombomodulin levels might aid in managing patients. “If we have a marker to identify which patients are most likely to progress towards critical illness and possibly death, that would be hugely helpful, as these patients might benefit from closer monitoring and possibly earlier intervention,” said Lee.

“As terrible as it is, COVID-19 brought people together who almost never would have the chance to intersect, so that we could all exchange amazing ideas and learn from each other and accomplish great science,” Lee added.

The study was supported by a gift from Jack Levin to Yale’s Benign Hematology program and by the National Institutes of Health.

Originally published February 26, 2021; updated Mat 16, 2022.

Submitted by Anne Doerr on June 30, 2020