CHICAGO—About 400 million people are experiencing long COVID around the world, including, as of last year, about 5% of adults in the U.S., so the syndrome remains a serious clinical challenge, experts said in a session at ACR Convergence 2025.
Progress has been made in clarifying the clinical picture in an effort to make long COVID more easily identified, and in pinpointing the mechanisms underlying it. But so far no long-COVID-specific therapies have emerged, although steps continue in this direction.
Zhaoqi Yan, PhD, a scientist and researcher at the San Francisco-based Gladstone Institute for Neurological Disease, discussed the progress that has been made to understand the role of fibrin in long-COVID-induced inflammation and suggested that an antibody already being studied in other diseases could be useful in long COVID.
This therapeutic avenue would be a significant step, he said.
Complex Biological Mechanisms
“The biological mechanisms of long COVID are still very complex—there’s been a lot of study to find the mechanism,” Dr. Yan said. “There are multiple hypotheses, including acute infection, virus persistence, post-acute infection, autoimmunity thrombosis, latent virus reactivation, dysbiosis and gut microbes finding their way into other tissues.” But up until now, he said, “there’s not a lot of medications that can actually reverse the course of long COVID.”
In the lab of Katerina Akassoglou, PhD, where he works, he has focused on the role of fibrin, the key component of the body’s natural blood clotting process, because clotting has come to be recognized as a common feature of COVID-19, and fibrinogen, a protein closely related to fibrin, has been associated with cognitive deficits after infection with the SARS-CoV-2 virus.1
Role of Fibrin
In a mouse model, Dr. Yan has found that fibrin is required for SARS-CoV-2 inflammation and suppresses the natural killer cells that have a role in viral clearance. Dr. Yan said that experiments in mice have found that the 5B8 antibody, which targets an inflammatory fibrin domain that is only expressed on pathogenic fibrin, is able to target the inflammatory function of fibrin without having adverse anticoagulant effects.
A humanized version of this antibody, known as THN391, is now in phase 1b studies in Alzheimer’s disease and diabetic macular edema.2 Dr. Yan said it has been found to suppress brain inflammation in non-neuroinvasive and in neuroinvasive COVID-19.
“Our data shed new light on the enigmatic coagulopathy found in COVID-19, revealing a causal role for fibrinogen in thromboinflammation,” Dr. Yan said. “Fibrin-targeting immunotherapy may represent an approach to selectively suppress COVID-19 pathogenesis in the brain or other organs without adverse effects on normal hemostasis.”
Complexity of Long COVID
Linda Geng, MD, PhD, co-director of the Stanford Long COVID Collaborative in Palo Alto, Calif., a multidisciplinary clinical and research program, said long COVID is likely underdiagnosed because of its complexity. “It is difficult to diagnose and that’s partially because the definition has evolved.”
More than 200 symptoms fall under the umbrella of long COVID, but research has found 12 that are the most common, including loss of taste and smell; post-exertional malaise, which refers to social and emotional exertion and cognitive exertion, as well as physical; and brain fog, a term that includes cognitive impairment, attention problems and language problems.
Symptoms come in many forms including organ damage, complications from hospitalization and known autoimmune conditions, making long COVID a “syndrome of syndromes,” Dr. Geng said. “That’s what makes it challenging as well, as we think about the pathogenesis,” she said, because it can be difficult to distinguish one category from another.
Viral particle persistence, immune dysregulation, persistent inflammation and imbalance in the microbiome have all been implicated in bringing on long COVID symptoms. “They’re not mutually exclusive,” she said. “Any given patient may have a combination of any of these, and they may be interacting to different degrees.”
The Search for Therapies
Trials studying a 15-day trial of nirmatrelvir-ritonavir, an antiviral used to treat acute COVID, have not found this approach to be effective in long COVID, although a 25-day trial by the long COVID study group RECOVER is underway, with results expected soon, Dr. Geng said.3
Researchers have identified intriguing markers that seem to be involved in long COVID, including translocator protein binding in key brain regions of patients with depressive and cognitive symptoms after COVID, increased levels of interleukin-6 and tumor necrosis factor alpha in long COVID patients, and antineuronal autoantibodies in the cerebrospinal fluid of patients with post-COVID cognitive symptoms.4
The top priority regarding the study of long COVID at this point, Dr. Geng said, are randomized, controlled trials, to more definitely understand the role of these potential markers. “What I think is a confusing aspect of a lot of the emerging biomarkers is, are they pathogenic?” she said. “And if they are, such as viral reservoirs, then if we can target them with the appropriate therapy and show that they actually change clinical outcomes that correlate with these biomarkers, that would be the holy grail.”
In a discussion at the end of the session, Dr. Geng was asked about viral particle persistence with regard to vaccines, particularly in a period of growing vaccine hesitancy.
“When we talk about viral persistence, presumably there’s more than just the antigen. But it’s possible that it plays a role; we just don’t fully understand or know about that as of yet,” Dr. Geng responded. “What I try to emphasize also is the huge amount of data, including meta-analyses, that have shown the benefit of vaccines, not just for acute COVID, but for long COVID as well, in terms of prevention.”
Thomas Collins is a freelance medical writer based in Florida.
References
- Ryu JK, Yan Z, Montano M, et al. Fibrin drives thromboinflammation and neuropathology in COVID-19. Nature. 2024 Sep;633(8031):905–913.
- Kantor AB, Akassoglou K, Stavenhagen JB. Fibrin-targeting immunotherapy for dementia. J Prev Alzheimers Dis. 2023;10(4):647–660.
- Geng LN, Bonilla H, Hedlin H, et al. Nirmatrelvir-ritonavir and symptoms in adults with postacute sequelae of SARS-CoV-2 infection: The STOP-PASC randomized clinical trial. JAMA Intern Med. 2024 Sep 1;184(9):1024–1034.
- Monje M, Iwasaki A. The neurobiology of long COVID. Neuron. 2022 Nov 2;110(21):3484–3496.
