The hypothesis is gathering momentum, ‘but we still have a lot of work to do’, says an international expert.
While long covid remains a significant, but poorly understood health crisis around the world, a US rheumatologist, immunologist and researcher has told ACR Convergence 2024 that there is growing evidence a dysregulated immune system may be a possible driver for the condition.
Long covid is known to affect tens of millions of people globally, and the complex disease has been associated with more than 200 symptoms, including autoimmune disorders such as lupus, rheumatoid arthritis and Sjogren’s syndrome.
Professor Leonard Calabrese is a professor of medicine, vice chair of the Cleveland Clinic’s Department of Rheumatic and Immunologic Diseases and the co-director of the Centre for Vasculitis Care and Research.
He also serves as director of the RJ Fasenmyer Centre for Clinical Immunology at the Cleveland Clinic. He also holds appointments in the Department of Infectious Diseases and the Wellness Institute.
Professor Calabrese’s clinical and research interests include vascular inflammatory disease of the central nervous system, primary and secondary immunodeficiency states and the intersection of infections and autoimmunity.
He said he believed the rheumatology community had a key role to play in understanding the connection between autoimmune dysregulation and long covid.
“This hypothesis has profound clinical implications, suggesting that treatments often used by rheumatologists could potentially have a role in treating or preventing post-infectious consequences of covid-19, including long covid,” said Professor Calabrese.
“Given that the scientific research in this field changes on a daily basis, it is important for clinicians to be aware of data that might affect treatment for patients with autoimmune disorders.”
In June 2024, the National Academies of Sciences, Engineering and Medicine issued a broad, new definition of long covid, stating that any unexplained symptom lasting for more than three months after covid infection could be diagnosed as long covid.
It also suggests that many common conditions can fall under this definition, including autoimmune disorders such as lupus, Sjogren’s disease and rheumatoid arthritis (RA).
Professor Calabrese expressed significant concerns over the wording and interpretation of the new case definition, especially its inclusion of immune-mediated rheumatic disorders as qualifying conditions for its diagnosis.
He said he believed it would take more time and critical appraisal of additional data to more accurately assess its utility in both clinical care and research.
“As of August 2024, the data are far from clear as to whether autoimmunity is a driver of all or even part of the long covid clinical spectrum,” he said.
It is already clear covid infection generates autoantibodies like those seen in autoimmune diseases. But it is less clear what role these antibodies play in long covid, in part because cases can present very differently from patient to patient.
Normally, in an autoimmune disorder like RA, antibodies all have the same target. Healthy people can also have autoantibodies, or they can appear when there is an infection and then disappear without causing harm.
Recent animal studies make a stronger case for autoimmunity as a driver of long covid. In these studies, researchers transferred antibodies from the blood of human patients with long covid to mice. Most of the mice subsequently developed symptoms like those of the human donors, especially an increased sensitivity to pain.
However, more work needed to be done, said Professor Calabrese. Some researchers think there is a trigger before autoantibodies are activated, such as lingering bits of virus – another common explanation for long covid.
“The establishment of a small animal model of long covid could potentially be a breakthrough for both understanding the cause of the disorder and testing new therapies,” said Professor Calabrese.
“The role of autoimmunity in covid-19 and long covid is clearly a work in progress, and the rheumatology community has much to add based on their vast experience with immune-mediated inflammatory diseases and autoimmunity.”
Professor Calabrese told ACR he believed that long covid was not a “single disease”.
“I love this quote by Professor Iwasaki from Yale that she said, that long covid likely represents a disease with many subtypes, each having its own risk factors and biologic mechanisms and disease trajectories and may respond differently to different therapies because they may be caused by different pathogenic mechanisms,” he said.
“There is incontrovertible data that there is persistence of protein of this virus several years after the infection. What that means is unclear, but this has given light to new potential therapies.”
Even though long covid remained poorly understood, researchers around the world were scrambling to find answers.
“The bibliometrics of long covid are insane,” he said.
“There’s over 20,000 articles written just in the past few years. The vast majority of them have an immunologic bent. There is not a single person on the planet that is in control of these data.”
In conclusion – Professor Calabrese said there was still much work to be done.
“At the moment, I think covid-19 is strongly associated with an array of auto antibodies, but the role in pathogenesis of long covid right now is unclear,” he said.
“Secondly, the risk of established image in this disease is quite possible, but I think at the present time, I think that the prudent tack is that this is clinically uncertain at the present time, and that we must be vigilant.
“There are numerous anecdotes that people tell me about all the time, of people have developed weird things after covid-19. Be vigilant for new nosological entities. But we still have a lot of work to do.”
A modelling study published earlier this year in the Medical Journal of Australia indicated up to 872,799 people would have long covid symptoms by the end of 2024.
“Our modelling indicates that hundreds of thousands of Australians are likely to be living with long covid after a single infection; 0.7–3.4% of all Australians have long covid and have not recovered twelve months after SARS-CoV-2 infection,” the authors wrote.
“By way of comparison, 3% of Australians aged 20 years or older were living with ischaemic heart disease in 2023, the leading cause of the global disease burden.
“The prevalence of ischaemic heart disease is highest among people aged 75 years and older, but our modelled proportion of those with long covid was largest for people aged 30–49 years, and the estimated mean loss in labour supply for people aged 10–69 years during 2022 was 102.4 million hours.”
The authors concluded that further research into the population impact of expanded access to covid vaccine boosters and antiviral medications was needed.
“Our model suggests health and economic burdens of long covid comparable with those of the leading causes of the burden of disease in Australia, but, unlike cardiovascular disease and cancer, the burden of long covid is highest among working age adults, a key difference that results in major economic losses,” they wrote.
“The focus of public policy on covid-19 must shift from solely preventing hospitalisations and deaths during the acute disease to encompassing the prevention of long covid.”
