A new study from investigators at Harvard and Beth Israel Deaconess Medical Center sheds light on why some people never fully recover from COVID-19.

In research that analyzed blood samples from more than 140 participants, scientists led by Dan H. Barouch tracked immunologic and inflammatory responses over time in patients who developed long COVID as compared with patients who fully recovered from COVID. The team found key differences in patients who developed long COVID and evidence of persistent chronic inflammation long after acute illness. The team’s findings, published in Nature Immunology, open the door to new treatment strategies for people with long COVID.

“There is currently no specific treatment for long COVID, which affects millions of people in the United States, and most clinical trials to date for this condition have focused on testing antiviral agents to clear potential residual virus,” said Barouch, director of the Center for Virology and Vaccine Research at Beth Israel and the William Bosworth Castle Professor of Medicine at Harvard Medical School. “In contrast, our findings show that long COVID in humans is characterized by persistent activation of chronic inflammatory pathways, which defines new potential therapeutic targets.”

Long COVID affects an estimated 15 million Americans, according to recent data from the U.S. Department of Health and Human Services. Symptoms include fatigue, brain fog, shortness of breath, exercise intolerance, and cognitive decline for months or even years. Doctors and scientists don’t fully understand why some people develop long COVID while others don’t.

Barouch and colleagues took a comprehensive approach in their new study, integrating data on immune responses, viral markers, gene expression (transcriptomics), and plasma proteins (proteomics) to develop a detailed profile of the immune system during long COVID. This “multi-omic” technique allowed the investigators to compare immune and inflammatory responses in patients living with long COVID to those of people never infected with SARS-CoV-2, those acutely infected, and individuals who fully recovered.

The team studied two cohorts of patients, one group from 2020-2021 and a second group from 2023-2024. Blood samples were analyzed three to six months after initial infection, and again more than six months later.

Analysis revealed clear differences in specific signaling pathways — series of chemical reactions that regulate all the body’s functions and activities — that appear to be the hallmarks of long COVID. Patients with long COVID demonstrated signs of chronic inflammation, immune system depletion, and disruptions in cellular metabolism not seen in patients who had fully recovered from COVID-19.

Those whose immune systems showed the greatest inflammation at the start of infection were also more likely to face lingering symptoms later, a sign that the body’s early fight against the virus may, in some cases, set the stage for long COVID.

“Integrating multi-omic data gave us a unified view of long COVID’s immune landscape, enabling us to identify key pathways that can be therapeutically targeted,” said the study’s first author, Malika Aid Boudries, an assistant professor of medicine at Harvard Medical School. “This bridge between data and clinical action is essential for advancing patient care.”

Barouch and colleagues further identified specific immune and inflammatory proteins and molecular signatures that could serve as potential targets for therapies aimed at calming chronic inflammation and restoring healthy immune function.

The research described in this article received funding from the National Institutes of Health.