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Study Uncovers Drivers of Lingering Symptoms in COVID-19 Long-haulers

June 10, 2021
by Elisabeth Reitman

A Yale-Duke collaborative research team may have identified some of the first biomarkers linked to impaired lung function in long-term COVID-19 patients.

Since the early months of the pandemic, scientists have tried to determine why some patients experience symptoms such as shortness of breath, cough, fever, fatigue, or chest pain weeks to months after their initial COVID-19 infection. What may drive or predict the persistence of long-term symptoms, also known as “post-acute sequelae of COVID-19,” remains poorly understood. A study published June 10 in the journal JCI Insight may provide answers about this mysterious condition.

The study, led by Hyung J. Chun, MD, an associate professor of cardiovascular medicine and pathology and co-director of the Yale Cardiovascular Research Center, examined the predictors of persistent illness.

“We wanted to get a better understanding of what is driving the disease process in patients who had persistent symptoms after their COVID-19 infection,” said Chun.

The researchers used patient data collected from the post-COVID-19 clinics to analyze whether the severity of the COVID-19 illness could impact the likelihood of persistent symptoms later — specifically worsening lung function — and if proteins in the blood were linked to increased likelihood of symptoms in post-COVID-19 patients.

Chun and the Yale team partnered with colleagues at Duke University School of Medicine for the study. The team enrolled 61 participants from post-COVID-19 clinics. The researchers used a pulmonary function test to track two key parameters for lung function, including the amount of air a person could exhale after taking a deep breath, and the ability to transfer inhaled oxygen from the lungs to the red blood cells.

We wanted to get a better understanding of what is driving the disease process in patients who had persistent symptoms after their COVID-19 infection.

Hyung J. Chun, MD

The results showed that almost 70 percent of patients continued to report persistent difficulty breathing during their follow-up visits. The data also confirmed that those with more severe illness during their acute COVID infection were more likely to have impaired lung function at the time of the follow up.

Next, the team analyzed patients’ blood samples to identify biomarkers or biological markers that may be associated with persistent lung symptoms. They identified three proteins (lipocalin 2, matrix metalloproteinase 7, and hepatocyte growth factor) that were strongly associated with impaired lung function.

“These are markers of activation of a specific immune cell type called neutrophils, as well as factors that may promote lung injury when elevated. While we previously found them to be strongly associated with severe illness during acute COVID-19 illness, it is interesting that they appear to remain elevated in those who continue to have poor lung function during their recovery,” said Chun.

The findings support a Feb. 26 study published in the journal Blood Advances, where Chun and his colleagues discovered that lipocalin 2 and hepatocyte growth factors predicted which patients were more likely to suffer severe COVID-19 illness and require intensive care. Chun believes that these biomarkers may not only be associated with the severity of COVID-19 symptoms, but may also be driving the disease process — which could be targeted by future therapies.

The study’s co-authors are Alexander Pine, Alfred I. Lee, Vanessa Yu, and Marcus Shallow from the Yale School of Medicine, and Elias Coutavas, Coral X. Giovacchini, Anne Mathews, Brian Stephenson, Loretta G. Que, and Bryan D. Kraft of the Duke University School of Medicine.

Submitted by Elisabeth Reitman on June 10, 2021