Long COVID has largely remained a mystery for scientists. Initially only thought to affect very severe cases of COVID-19, patients with mild cases proved otherwise.
Long COVID, also known as post-acute sequelae SARS-CoV-2 infection (PASC) in medicine, can be characterized as an amalgamation of lingering symptoms long after the acute infection has cleared. These symptoms are often respiratory or physical, but there are increasing reports of gastrointestinal and neurological symptoms.
This wide systemic response and ambiguities surrounding the condition have prompted researchers to pinpoint those at higher risk and develop effective treatments for the long-term condition.
In a recent study, researchers from several universities and centers, including the University of Washington, the Institute for Systems Biology (ISB), and Swedish Medical Center in Seattle, discovered that four biological factors might help predict whether a patient goes on to develop long COVID.
The study, which appears in the journal Cell, saw that certain markers that appear early in a COVID-19 infection signaled an increased risk of developing long COVID symptoms weeks later.
“We’ve been carrying out large studies of COVID-19 patients since the start of the pandemic, and so extending those studies to long COVID was a natural extension of that work since many of our patients were experiencing long COVID,” said ISB president Prof. Jim Heath, Ph.D., co-corresponding author of the study.
As part of the study, the researchers followed 309 patients aged 18–89 for 2–3 months after being diagnosed with COVID-19.
Of these patients, 71% were hospitalized, while the remaining were outpatients. The patients were questioned about 20 long covid symptoms.
These were grouped as:
Out of these patients, 37% reported experiencing at least three or more symptoms of long COVID, and 24% said they experienced one or two symptoms.
Researchers then analyzed their blood samples and nasal swabs and found four factors associated with a higher chance of getting long COVID.
These factors were:
Of the patients who had three or more symptoms, 95% had at least one of these four factors.
Female patients or patients with chronic obstructive pulmonary disease (COPD) were more likely to present with at least three long COVID symptoms.
The patients who had a high level of SARS-CoV-2 RNA in their blood early in the infection, which means they had a higher viral load, were more likely to develop long COVID symptoms.
A higher viral load has been linked to more severe COVID-19 and an increased risk of death. The more severe the disease, the more time it takes the body to clear the virus.
The patients who had autoantibodies, or the type of antibodies associated with conditions such as rheumatoid arthritis and lupus where the body mistakenly attacks its own tissues, were also more likely to be diagnosed with long COVID.
The same patients also had low amounts of protective antibodies that neutralized SARS-CoV-2, which the researchers said made them more susceptible to so-called breakthrough infections.
Autoantibodies were seen as the most influential indicator in developing long COVID.
Two-thirds of the patients had autoantibodies, while the other three factors were only present in a third of the patients.
The third factor was the reactivation of the EBV, which is estimated to infect 95% of the healthy population during the early years of life but often lays dormant. The virus can cause infectious mononucleosis and other illnesses.
The researchers said this reactivation was likely triggered by immune dysregulation during COVID-19 infection.
The final factor the study found associated with a higher risk of long COVID was having type 2 diabetes, one of the many chronic health conditions scientists suspect could heighten this risk.
Weighing on the importance of this study, Dr. Donald J. Alcendor, Ph.D., associate professor in microbiology, immunology, and physiology at Meharry Medical College, and associate professor adjunct of infectious diseases at Vanderbilt University Medical Center, said:
“This is the beginning of truly understanding the complexities of long COVID. There is a rationale with some these blood markers, and to take this study to scale would only amplify its significance to the body of knowledge being developed to better understand post-COVID syndrome.”
Dr. Kyle Freese, Ph.D., chief epidemiologist and chief scientific officer at STChealth, said it made sense that a high viral load early in diagnosis was associated with certain PASC outcomes, in particular, memory problems, fatigue, difficulty concentrating, and sputum.
“There is certainly a biologically plausible link between certain biomarkers and/or viral load and the health outcomes associated with long COVID, particularly those associated with organ system dysfunction,” he said.
Dr. Alan Bulbin, director of infectious diseases at Catholic Health’s St. Francis Hospital and Heart Center in Roslyn, New York, who was also not involved in the study, commented:
“The high serum viral load is not surprising. But the finding of EBV by PCR was surprising, with the idea of immune dysregulation as the link.”
Dr. Alcendor pointed out that latent EBV reactivation did not usually occur in immunocompetent individuals, i.e., people with normal functioning immune systems.
“It would be interesting to know if there is a reaction of other latent viruses in patients with post-COVID syndrome,” he said.
He added that he was surprised that cytomegalovirus (CMV), another virus related to the herpes virus that causes cold sores and chickenpox, was not detected in the bloods of long COVID patients.
Dr. Bulbin said more confirmation was needed to establish whether EBV was a cause of long COVID or just an associated marker.
Meanwhile, Dr. Heath said the relatively small number of PASC factors they found that could anticipate long COVID was surprising. Another interesting finding was that the PASC factors are also associated with different symptoms of long COVID, including neurological or gastrointestinal symptoms.
“The relative importance of those PASC factors, and the fact that they don’t necessarily associate with COVID-19 severity, also surprised us,” he said.
Dr. Heath said that the link between PASC and systemic lupus erythematosus (SLE), the most common form of lupus, was also unexpected.
“This relation is evident from the immunology, even in patients who had no previous reports of lupus or other autoimmune diseases,” he explained.
Dr. Freese pointed out that only 6% of those with detectable autoantibodies had a confirmed history of autoimmune disorder.
“It is possible that this is a sign of subclinical disease and could explain why there is an association between these markers and PASC,” he said.
The identification of these four major indicators could help scientists design interventions to help people with long-haul COVID-19. However, more research will be needed to confirm them.
Dr. Bulbin said it would be interesting to see if the same results were obtained with Omicron.
Dr. Heath noted the study suggested that administering antivirals very early in the disease course could reduce long COVID cases, as well as reduce infection severity.
“Any profile of predictable markers [is] always useful prognostically for any illness, but here suggests early intervention such as antiviral treatment might impact the outcome in a subset of patients with these markers.”
– Dr. Alan Bulbin
The researchers also hypothesized that antivirals could also help with conditions linked to EBV, such as multiple sclerosis (MS) and chronic fatigue syndrome, which produce symptoms similar to some long COVID cases.
The study also suggests that other treatments may also alleviate long COVID symptoms in certain cases.
One such treatment could be cortisol replacement therapy.
The researchers found that patients with lingering respiratory problems had low levels of the stress hormone cortisol.
Dr. Alcendor said that low cortisol levels could be attributable to steroids used to treat COVID-19 but that it returns to normal after recovery.
“It is likely that a more thorough investigation of how the autoantibodies interfere with normal immune responses may also lead to treatment possibilities,” Dr. Heath added.
Dr. Heath said that although a large number of patients was studied on the whole, the number of patients with specific symptoms and specific PASC factors was relatively small.
“This means that for certain PASC, such as cardiac-related, we can’t say much. Also, we are looking at relatively early PASC, so we didn’t look at patients who were experiencing long-term PASC,” he said.
Dr. Alcendor said the study’s biggest limitations were that children and pregnant women were excluded, and it was not clear if it included a significant number of African-American or Hispanic patients, which could help address health disparities.
“[Symptoms] were self-reported by the patients. The timing of SARS-COV-2 infection is not uniform among patients,” he added.
Dr. Heath also said that research around autoantibodies could be expanded.
“We only looked at a few autoantibodies, and so, we might be missing some critical ones,” he said.
Dr. Bulbin agreed.
“I like the idea of trying to predict future problems with a profile as described in the report, but I think we would need more corroborating studies to confirm the specificity of these markers,” he said.
Dr. Freese said future research could focus on whether the severity of long COVID persists over time and whether one’s health at infection, whether mild or not, impacts the likelihood of developing long COVID.
The study has brought scientists closer to unraveling the biological mechanism behind long COVID.
It has found four key indicators that are associated with a higher risk of developing long COVID and an array of lingering symptoms.
They are viral load in the blood, the presence of certain autoantibodies, the reactivation of EBV, and having pre-existing type 2 diabetes. However, it is important to remember that this study does not show a direct cause-and-effect relationship.
“The clinical implications would suggest that patients that have COVID-19 or are recovering should be screened for these biomarkers that may be linked to the development of [long COVID],” Dr. Alcendor told Medical News Today.
Although the research remains largely exploratory and more evidence is needed to confirm the findings, the study could inspire better treatment for COVID-19 long haulers.
“These biomarkers may also provide information for the development of innovative therapeutic interventions for the treatment of post-COVID syndrome. Identifying the immune signature of patients that develop [long COVID] could lead to the development of specific therapies designed for specific patients.”
– Dr. Donald J. Alcendor, Ph.D.