New BIDMC Study Reveals Persistent Immune Activation and Paths to Treatment
BOSTON — A new study from investigators at Beth Israel Deaconess Medical Center (BIDMC) sheds light on why some people never fully recover from COVID-19.
In a study analyzing blood samples from more than 140 participants, scientists led by Dan H. Barouch, MD, PhD and colleagues tracked the immunologic and inflammatory responses over time in patients who developed long COVID as compared with patients who fully recovered from COVID-19. The team found key differences in patients who developed long COVID and evidence of persistent chronic inflammation long after acute COVID-19. 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 BIDMC. "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. People with long COVID may struggle with a wide array of symptoms including 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, 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 that 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 COVID-19 infection, and again more than six months after initial infection.
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 first author, Malika Aid, PhD. "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 team has initiated a phase 2a clinical trial of a drug that has been approved for atopic dermatitis — the JAK1 inhibitor abrocitinib (NCT06597396) — to evaluate the therapeutic efficacy of targeting one of the top pathways identified in this study.
Co-authors included Malika Aid, Valentin Boero-Teyssier, Katherine McMahan, Nazim Belabbaci, Erica Borducchi, Ai-Ris Y. Collier of the Center for Virology and Vaccine Research at BIDMC; Rammy Dong, Michael Doyle and Janet Mullington of the Division of Sleep Medicine at BIDMC.
This work was supported by the Massachusetts Consortium for Pathogen Readiness; the Gates Foundation (INV-027406, INV-041469), and the National Institutes of Health (grant CA260476 to D.H.B.). Next-generation sequencing services were provided by the Emory NPRC Genomics Core (grants NIH P51 OD011132, S10 OD026799). Proteomics data were generated by the Beth Israel Deaconess Medical Center Proteomics Core.
The authors report no conflict of interest.
