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Nonstop inflammation and immune problems top the list of potential causes of long COVID, but doctors say it’s growing clear that more than one thing is to blame for the wide swath of often debilitating symptoms that could last months or even years.
“I think that it’s a much more complex picture than just inflammation, or just autoimmunity, or just immune dysregulation. And it’s probably a combination of all three causing a cascade of effects that then manifests itself as brain fog, or shortness of breath, or chronic fatigue,” says Alexander Truong, MD, a pulmonologist and assistant professor at Emory University School of Medicine, who also runs a long COVID clinic.
Long COVID, post-COVID-19 condition, and post-acute sequelae of SARS-CoV-2 (PASC) are among the terms used by the National Institutes of Health to describe the long-term health issues faced by an estimated 10% to 30% of people infected with COVID-19. Symptoms — as many as 200 — can range from inconvenient to crippling, damage multiple organ systems, come and go, and relapse. Long COVID increases the risk of worsening existing health problems and triggering new ones, including cardiovascular disease and type 2 diabetes.
So far, research suggests there is no single cause, condition, or disease that explains why some people have an extensive range of symptoms long after the early COVID-19 infection has cleared up. Many experts believe some combination of biological processes — including the virus hanging around in our bodies, inflammation, autoimmunity, tiny blood clots, immune system problems, and even the reactivation of dormant viruses such as the Epstein-Barr virus — could be the culprit, a theory also supported by a comprehensive and in-depth review of long COVID studies published in January in the journal Nature Reviews Microbiology.
“It’s become clear over the last couple of years that there are different [symptoms] of long COVID…that cannot all be lumped together,” says Michael Peluso, MD, an assistant professor of medicine and an infectious diseases doctor at the University of California, San Francisco.
Inflammation and a Virus that Hangs Around
Multiple studies have shown that the virus or pieces of it can remain in many parts of the body, including the kidneys, brain, heart, and gastrointestinal system, long after the early infection.
“One major question that I think is the area of most intense investigation now is whether there is viral persistence that is driving immune dysregulation and therefore symptoms,” says Peluso.
A small Harvard University study published in September, for example, found evidence that reservoirs of the coronavirus could linger in patients up to a year after they’re first diagnosed.
An earlier German study found that patients with post-COVID-19 symptoms had higher levels of three cytokines — small proteins that tell the body’s immune system what to do and are involved in the growth and activity of immune system cells and blood cells. Researchers said the results supported the theory that there is persistent reprogramming of certain immune cells, and that the uncontrolled “self-fueled hyperinflammation” during the early COVID-19 infection can become continued immune cell disruption that drives long COVID symptoms.
“Long COVID is more likely due to either an inflammatory response by the body or reservoirs of virus that the body is still trying to clear … and the symptoms we’re seeing are a side effect of that,” says Rainu Kaushal, MD, senior associate dean for clinical research at Weill Cornell Medicine in New York.
Australian researchers also found that immune system recovery appeared different, compared with those who were infected with other common coronaviruses.
These findings also support concerns that some experts express over the long-term risks of COVID-19 infections in general, but especially repeat infections.
“Anything that kind of revs up inflammation in the body can boil that pot over and make the symptoms worse. That’s very easily an infection or some other insult to the body. So that’s the generalized hypothesis as to why insults to the body may worsen the symptoms,” says Truong.
An Autoimmune Condition?
But inflammation alone does not fully explain post-COVID-19 problems.
Truong and his team, for example, have been documenting inflammatory markers in patients at the post-COVID clinic he co-founded more than two years ago at Emory Executive Park in Atlanta. When the clinic was first launched, high-dose nonsteroidal anti-inflammatory drugs, known as NSAIDs — including ibuprofen — and prednisone were prescribed to long COVID patients.
“It didn’t make a difference at all for any of these folks,” he says, adding that there are signs that autoimmunity is at play. But he cautions that it is still too early to suggest treating long COVID patients with medications used for other autoimmune conditions.
In autoimmune conditions such as rheumatoid arthritis, lupus, and type 1 diabetes, a person’s immune system doesn’t tell normal cells from foreign pathogens and attacks healthy cells. There is typically no single diagnostic test, and many share similar symptoms, making detection and diagnosis potentially difficult, according to Johns Hopkins Medicine.
A small study published in the journal Science Translational Medicine in December found that among patients who failed to regain their sense of smell long after their initial infection, there was inflammation in the nose tissue where smell nerve cells are found, even though no detectable virus remained. Fewer olfactory sensory neurons were seen, as well — findings that researchers said resembled some kind of “autoimmune-like process.”
Meanwhile, scientists in Canada found signs of autoimmunity in blood samples taken from patients who still had fatigue and shortness of breath after their initial COVID-19 infection. Two specific proteins were present a year after infection in up to 30% of patients, many of whom still had shortness of breath and fatigue, the researchers reported in the Jan. 1 issue of European Respiratory Journal. These patients had been healthy and had no autoimmune condition or other diseases before they were infected.
Immune System Problems
A number of studies have suggested that a problematic immune response could also explain why symptoms persist for some people.
Researchers in France, for example, found that the immune response problems in those with severe COVID-19 infections caused exaggerated or uncontrolled formation of a type of bug-fighting defense mechanism called a neutrophil extracellular trap (NET), which in turn triggers harmful inflammation that can result in multi-organ damage. These traps are net-like structures made from fibers composed mostly of DNA strings that bind, or trap, pathogens.
Long COVID is not like an acute infectious disease, says Alexander Charney, MD, PhD, the lead principal investigator of the RECOVER adult cohort at Mount Sinai in New York City, and an associate professor at Icahn School of Medicine at Mount Sinai. It is more similar to other complex chronic diseases that have taken decades to understand, such as heart disease, mental illness, and rheumatological diseases, he says.
Biomarkers and Blood Clots
Scientists are homing in on biomarkers, or detectable and measurable traits — in this case, molecular indicators — that can make diagnosing long COVID easier and give better direction for treatment. These biomarkers are also key to helping sort out the complex biology of long COVID.
In one study, data from blood samples taken from hundreds of hospitalized COVID-19 patients suggests changes are happening at the molecular level during initial severe infections. These changes may be tied to the development of longer-term symptoms, according to the study published in December by Charney and his team at Mount Sinai.
Blood clotting issues have also been detected in long COVID patients. At least one study found signs that long COVID patients had higher levels of a type of auto-antibody linked to the abnormal formation of clots. Researchers suspect that tiny, persistent microclots — undetectable via regular pathology tests — may be cutting off oxygen flow to tissue by blocking capillaries — billions of tiny, delicate blood vessels throughout the body — and could explain many of the post-COVID symptoms described by patients.
While enormous progress has been made toward understanding long COVID, the research is still considered early and faces many challenges, including varying criteria used to define the condition, the types and quality of data used, differences in how patients are defined and recruited, and the small size of many studies. Some research also appears to conflict with others. And while there are specialized tools for diagnosing some aspects of the condition, standard tests often don’t detect many of the signs seen in long COVID patients. But given the urgency and global scale of the problem, experts say more funding and support should be prioritized.
“People are suffering now, and they want answers now…it’s not like with COVID, where the path towards a great and meaningful solution to this unbelievable problem was clear — we need a vaccine,” says Charney.
“It’s going to be a long haul to figure out what is going on.”
Sources:
Alexander Truong, MD, pulmonologist, assistant professor, Emory University School of Medicine, Atlanta.
Alexander Charney, MD, PhD, lead principal investigator, RECOVER adult cohort, associate professor of psychiatry, genetics and genomic sciences, neuroscience, and neurosurgery, Icahn School of Medicine at Mount Sinai, New York.
Michael Peluso, MD, assistant professor of medicine, infectious diseases doctor, University of California, San Francisco.
Rainu Kaushal, MD, senior associate dean for clinical research, Weill Cornell Medicine, New York.
The Lancet eClinicalMedicine: “Characterizing long COVID in an international cohort: 7 months of symptoms and their impact.”
Nature Reviews Microbiology: “Long COVID: major findings, mechanisms and recommendations.”
Immunity, Inflammation and Disease: “COVID-19 associated EBV reactivation and effects of ganciclovir treatment.”
Clinical Infectious Diseases: “Persistent Circulating Severe Acute Respiratory Syndrome Coronavirus 2 Spike Is Associated With Post-acute Coronavirus Disease 2019 Sequelae.”
Cell Reports Medicine: “The IL-1β, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19.”
Nature Medicine: “Data-driven identification of post-acute SARS-CoV-2 infection subphenotypes,” “Molecular states during acute COVID-19 reveal distinct etiologies of long-term sequelae.”
Nature Immunology: “Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection.”
Science Translational Medicine: “Persistent post—COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium.”
European Respiratory Journal: “Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long COVID symptoms.”
Journal of Medical Virology: “Persistence of neutrophil extracellular traps and anticardiolipin auto-antibodies in post-acute phase COVID-19 patients.”
Johns Hopkins Medicine: “What are common symptoms of autoimmune disease?”
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