Study uncovers the drivers of lingering symptoms in COVID-19 long-haulers

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

Since the first few months of the pandemic, scientists have been trying to find out why some patients experience symptoms such as shortness of breath, cough, fever, fatigue, or chest pain weeks to months after their initial infection with COVID-19. What drives or predicts the persistence of long-term symptoms, also known as “post-acute consequences of COVID-19”, is still poorly understood. A study published June 10 in JCI Insight magazine may provide answers to this mysterious disease.

The study, led by Hyung J. Chun, MD, Associate Professor of Cardiovascular Medicine and Pathology and Co-Director of the Yale Cardiovascular Research Center, examined the predictors of persistent disease.

“We wanted to better understand what drives the disease process in patients who have had persistent symptoms after their COVID-19 infection,” said Chun.

The researchers used patient data collected at the post-COVID-19 clinics to analyze whether the severity of COVID-19 illness could affect the likelihood of later persistent symptoms – particularly deterioration in lung function – and whether proteins in the blood were associated with an increased likelihood of symptoms in post-COVID-19 patients.

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

The results showed that nearly 70 percent of patients continued to report persistent breathing difficulties during their follow-up visits. The data also confirmed that those who were more severely ill during their acute COVID infection were more likely to have impaired lung function at the time of follow-up.

Next, the team analyzed blood samples from patients to identify biomarkers, or biological markers, that could be linked to 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 for the activation of a certain type of immune cell called neutrophils, as well as factors that can promote lung damage in the event of increased lung damage. While we previously found that they are 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 results support a study published Feb. 26 in Blood Advances, in which Chun and colleagues found that lipocalin 2 and hepatocyte growth factors were predictive of which patients were more likely to have severe COVID-19 illness and critical care need. Chun believes these biomarkers may not only be linked to the severity of COVID-19 symptoms, but also fuel the disease process – which future therapies may target.

Co-authors of the study 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 from the Duke University School of Medicine.

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