Discovery explains Long COVID breathing problems
University of Virginia Health System
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UVA Health researchers have made a discovery about the immune system that explains breathing problems in Long COVID. From left: Alexandra Kadl MD; Sepideh Dolatshahi, PhD; Lyndsey Muehling, PhD; Judith Woodfolk, MBChB, PhD; Glenda Canderan, PhD; and Shay Ladd, BS.
view moreCredit: UVA Health
Groundbreaking research from the University of Virginia School of Medicine has revealed crucial new insights into the immune systems of COVID-19 survivors, particularly those struggling with persistent breathing issues. The study shows that these patients have distinct changes in their immune system that link to the severity of their lung damage. This discovery holds promise for developing targeted treatments for the lung complications of Long COVID.
The researchers were struck by the diversity of immune patterns they discovered, and they say the findings highlight how varied the underlying drivers of Long COVID can be, even among patients with the same symptom.
A key innovation of the study was its ability to connect immune data from the blood with lung injury. For the first time, the team was able to differentiate immune patterns in patients suffering from more severe lung injury, offering a path toward more personalized and effective treatments.
“Long COVID is complex, with a variety of potential underlying causes. For this reason, understanding the immune response in patients with lung disease has been especially difficult,” said UVA Health’s Judith A. Woodfolk, MBChB, PhD, part of the Department of Medicine’s Division of Asthma, Allergy and Immunology. “Our findings reveal crucial differences in the blood that reflect the extent of lung damage. By analyzing many different immune measures, we can pinpoint potential targets that may not only predict who might experience worse outcomes but also help guide more tailored and effective treatments in the future.”
Understanding Long COVID
To dive deeper into the persistent respiratory symptoms of Long COVID, Woodfolk and her team examined extensive clinical and immune datasets from 110 patients at UVA Health’s Long COVID Clinic. Most had been hospitalized with severe COVID-19 before vaccines were available, and many had been on ventilators during their hospital stay.
Researchers used a form of artificial intelligence called machine learning to study long-term changes in patients’ T cells, a type of immune cell. Their analysis found marked differences in the numbers and types of T cells according to the severity of lung disease. After analyzing hundreds of additional cellular and molecular features, the team was able to link these changes in T cells to other important components of the immune system. This approach revealed strikingly different “immune landscapes” in patients with milder lung disease compared with more severe cases hallmarked by lung fibrosis (scarring).
“By uncovering distinct immune patterns in patients who have different types of restrictive lung disease after infection, we can better understand the immune drivers of lung injury and how these patterns may reflect different stages of the same disease process,” Woodfolk said. “Our ability to distinguish immune changes linked to lung disease from those linked to other disorders typical of Long COVID also adds a new dimension to our understanding of this complex illness.”
“Our ultimate goal is to help patients by guiding new treatments that could stop or even reverse lung damage caused by COVID-19,” Woodfolk added “This study simply would not have been possible without the dedication of an exceptional team of physicians and scientists and the participation of patient volunteers. We’re excited to broaden our strategy into new areas so we can gain insight into other types of chronic lung diseases and inflammatory conditions.”
Findings Published
The researchers have published their findings in the scientific journal Nature Immunology. The research team consisted of Glenda Canderan, Lyndsey M. Muehling, Alexandra Kadl, Shay Ladd, Catherine Bonham, Claire E. Cross, Sierra M. Lima, Xihui Yin, Jeffrey M. Sturek, Jeffrey M. Wilson, Behnam Keshavarz, Kyle B. Enfield, Chintan Ramani, Naomi Bryant, Deborah D. Murphy, In Su Cheon, Michael Solga, Patcharin Pramoonjago, Coleen A. McNamara, Jie Sun, Paul J. Utz, Sepideh Dolatshahi, Jonathan M. Irish and Woodfolk.
The study was supported by the National Institutes of Health, grants U01 AI100799, R21 AI138077, R56 AI178669, T32 AI007496, T32 GM145443, CA226833, AG069264, AI147394, HL170961, AI176171 and AG090337; Vanderbilt-Ingram Cancer Center, grant P30 CA68485; the University of Virginia School of Medicine; UVA’s Global Infectious Diseases Institute; the UVA Manning COVID-19 Research Fund; the Henry Gustav Floren Trust; the Stanford Department of Medicine Team Science Program; and the Stanford Medicine Office of the Dean.
Woodfolk receives support for unrelated research from Regeneron. All the other scientists declared no financial interest in the work.
To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog at http://makingofmedicine.virginia.edu.
Journal
Nature Immunology
Article Title
Distinct type 1 immune networks underlie the severity of restrictive lung disease after COVID-19
Study shows large improvements in Long COVID symptoms and return to work
San Francisco, May 5, 2025 – Researchers at the University of Alabama at Birmingham (UAB) have identified what is believed to be the first intervention found in a randomized controlled trial to show large and very large improvements in multiple symptoms associated with Long COVID, and to result in people debilitated by those symptoms returning to work. The study deployed progressively challenging computerized brain exercises alongside a progressively challenging coaching approach. The brain exercise used in the study is commercially-available only in the brain exercise app, BrainHQ made by Posit Science.
While estimates of those still coping with Long COVID vary, some 20 million Americans have been diagnosed with Long Covid, and an estimated 9-10 million still report symptoms, with nearly 14% reporting an inability to return to work even 90 days after infection.
The UAB study showed that the intervention resulted in statistically significant and very large benefits on its primary measures of performance and satisfaction with daily activities.
It also showed significant benefits in many secondary measures, including large to very large benefits on depressive, fatigue, and brain fog symptoms, as well as a significant benefit in brain processing speed, and a trend toward large benefits on anxiety symptoms. No significant change was noted in a measure of global cognition.
Perhaps, most strikingly, the researchers reported that eighty percent of the non-retired participants in the intervention group returned to work, and none in the control group.
This was a modest-sized study designed primarily to assess feasibility and to help scope follow-on studies. The researchers enrolled 16 community residents, who were three or more months past COVID infection, with mild cognitive impairment and with dysfunction in the performance of instrumental activities of daily living. Participants were randomly assigned to the intervention or to a wait-list control.
The intervention is based on the science of neuroplasticity, which has established that intensive, repetitive, and progressively challenging activities can drive beneficial changes to the brain. The approach is based on the seminal work of Dr. Michael Merzenich, who upended the field of brain science four decades ago, by showing that brains remain plastic — capable of chemical, physical and functional change — at any age.
After discovering lifelong plasticity, Dr. Merzenich first harnessed plasticity in his co-invention of the cochlear implant to restore hearing to hundreds of thousands of people. For the past three decades, he has focused on creating computerized brain exercises to improve brain health and function. He is the Co-Founder and Chief Scientific Officer of the company that makes the BrainHQ exercises.
The intervention in this study reflects further work in plasticity of two distinguished UAB faculty members. Dr. Karlene Ball pioneered plasticity-based exercises to address age-related cognitive decline. Her UAB colleague, Dr. Edward Taub, developed plasticity-based, constraint-induced movement therapy to address movement disorders. His supportive and progressively challenging coaching inspired the coaching used in this study.
Prior studies of BrainHQ exercises in older adults, and in patients with various health conditions, (cancer, heart failure, multiple sclerosis, schizophrenia, mild cognitive impairment) suggested the kind of improvements seen in this study (in cognition, daily activities, depressive symptoms, stress, fatigue, and employment status). However, the magnitude of the improvements in this study were quite large as compared to some prior studies.
“That may be because this study population had substantial deficits with room for substantial improvement, or it may be there is extra benefit from combining the exercises with this type of coaching,” commented Dr. Henry Mahncke, CEO of Posit Science. “Either way, it suggests that brain training is a promising approach to helping people with Long COVID.”
“It’s been a long road to address Long COVID,” observed Dr. Mahncke. “We hope this will be a turning point in identifying tools to address a condition that is often quite debilitating.”
BrainHQ exercises have shown benefits in more than 300 studies. Such benefits include gains in cognition (attention, speed, memory, decision-making), in quality of life (depressive symptoms, confidence and control, health-related quality of life) and in real-world activities (health outcomes, balance, driving, workplace activities). BrainHQ is offered by leading health and Medicare Advantage plans, by leading medical centers, clinics, and communities, and by sports, military, and other organizations focused on peak performance. Consumers can try a BrainHQ exercise for free daily at https://www.brainhq.com.
Journal
Rehabilitation Psychology
Method of Research
Randomized controlled/clinical trial
Subject of Research
People
Article Title
Long COVID brain fog treatment: An early-phase randomized controlled trial of constraint-induced cognitive therapy signals go.
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