New Study Points to 4 Potential Long COVID Risk Factors

Until now, the mechanisms behind long COVID have yet to be understood. Now, a new study is helping us understand who may be at risk for these prolonged symptoms a bit more.

In this recent study published in Cell, researchers executed a longitudinal investigation of more than 300 COVID-19 patients to study biomarkers that may signal an increased risk of developing long COVID later on.

They found four factors that may be linked to a higher likelihood of lingering symptoms, which include:

• A high viral load early in the infection
• The reactivation of the Epstein-Barr virus
• Having type 2 diabetes
• The presence of specific autoantibodies

The study is largely exploratory and more research is needed to verify the association of these factors to long COVID. However, they are biologically plausible, and the findings of the study can help bring us closer to some answers.

High Viral Load

According to the researchers, one of the potential risk factors for long COVID is the level of coronavirus RNA in the blood early on in the disease, which indicates the viral load.

“The amount of viremia reflects the extent of the uncontrolled viral infection,” Martin J. Blaser, MD, Henry Rutgers Chair of the Human Microbiome and Director of the Center for Advanced Biotechnology and Medicine at Rutgers University, told Verywell. “The higher the level, the more out of control by host immune mechanisms. Even if things later settle down, there has been a big perturbation.”

At present, we have antiviral pills like molnupiravir and Paxlovid that inhibit the replication of the virus, which reduces the viral load in the body.

“We know that a higher viral load has been linked to more severe COVID-19 and a higher risk of death,” Beth Oller, MD, a family physician at Solomon Valley Family Medicine, told Verywell. “It makes sense that a higher viral load can equal more symptoms. If you have a more severe infection, it is going to take the body longer to clear the virus, which is one thought as to why a higher viral load is correlating with a higher risk of long COVID.”

If a high viral load does increase the risk of long COVID, it would mean that we can potentially prevent it by reducing viral loads early in the course of the disease, like with antiviral medications, Oller said.

Type 2 Diabetes

The study suggests that type 2 diabetes may predict long COVID at the time of initial diagnosis. About 1 in 10 Americans have diabetes, and approximately 90-95% have type 2 diabetes.

“Patients with type 2 diabetes were more likely to experience fatigue, cough, and other respiratory long-COVID symptoms,” Oller said. “We have known that those with type 2 diabetes are more likely to have serious complications or die from COVID-19, so it is not entirely surprising that long-COVID would also be more likely.”

COVID-19 likely makes glucose control more difficult for people with diabetes. The two are also found to affect each other. Severe COVID-19 can make hyperglycemia worse, which, in turn, causes worse COVID-19 outcomes. 

“High blood sugar or poorly controlled diabetes can weaken the immune system making it less able to fight off infection, so well-controlled diabetes can lessen the risk,” Oller said. “It has been theorized that the pre-existing low-grade inflammatory state seen in type 2 diabetes may be worsened and remain elevated post-COVID, which can cause increased symptoms.”

Reactivation of the Epstein-Barr Virus

According to the study, the reactivation of the Epstein-Barr virus (EBV)—a member of the herpes virus family—may be associated with long COVID. Most people get infected with EBV as a child, and after the course of illness, the virus becomes latent in the body.

“After [the] initial EBV infection, the virus goes dormant and thus individuals carry the virus in an inactivated form,” Bryan Lau, PhD, an epidemiologist at the Johns Hopkins Bloomberg School of Public Health and one of the researchers leading the Johns Hopkins COVID Long Study, told Verywell. “Reactivation of EBV has been linked to stress and therefore prior studies have suggested that COVID-19 may lead to EBV reactivation.”

A small 2021 study found that 55.2% of hospitalized patients with a confirmed COVID-19 case had an EBV infection. A different study reported that among patients with COVID-19, those whose EBV reactivated had higher mortality rates and required more immuno-supportive treatment than those without EBV reactivation.

Although studies suggest that long COVID symptoms may be caused by EBV reactivation induced by the inflammation from COVID-19, we still need more research to know for sure.

“Of note, EBV itself has been associated with some of the symptoms that have been reported by those with long COVID,” Lau said. “Past studies have linked reactivation of EBV to cardiomyopathy and myocarditis as well as tinnitus and hearing loss, each of which have been reported among those with long COVID. So, it is possible that some of long COVID may be due to EBV reactivation, but we really don’t know at this point.” 

Presence of Certain Autoantibodies

Based on the researchers' analysis, the most influential indicator is the presence of certain autoantibodies, which was observed in two-thirds of the patients.

The immune system produces autoantibodies, which react against a protein that the body naturally makes instead of a foreign element like a virus or bacteria. Simply put, it means that the body makes an immune response and mistakenly attacks its own tissues. Some examples of autoimmune disorders include lupus, multiple sclerosis, and rheumatoid arthritis.

The body’s immune response is like a sharp knife—it can cut both ways, Blaser said. It defends against invaders like pathogenic bacteria and viruses, but it can be too exuberant and attack the body’s own tissues, triggered by the immune response to the pathogen. 

“Depending on the particular target, they can cause particular damage,” he added. “Some of the autoantibodies affect immune cells themselves, and could prolong the fight with the virus.”

A study published in the Journal of Translational Medicine found that COVID-19 can trigger a wide variety of autoantibodies up to six months after the initial course of the illness, irrespective of illness severity. Another study found that a subset of hospitalized COVID-19 patients develops autoantibodies over the course of their illness.

“The idea that long COVID may be the result of autoimmunity has been a prominent hypothesis,” Lau said. The question is whether COVID-19 increases the risk of developing sustained antibodies that don’t decrease over time and potentially lead to the development of an autoimmune disease. However, we need more studies to determine this, he added.

“It is not clear yet whether the six autoantibodies that were tested for in the study are the cause of the long-COVID symptoms, directly damage cells, or whether they are just markers of disease,” Oller said. “Patients with autoantibodies also had low amounts of protective antibodies that neutralize the virus, which could make patients more susceptible to lingering symptoms.”

More Research Is Needed

Long COVID is still poorly understood, and studies like this are important in determining if there are ways to predict risk to prevent its development and symptoms, experts said. It’s possible that the condition is caused by a combination of many factors, but there are no definite answers yet.

“The wide range of symptoms that people are reporting in long COVID suggests the different phenotypes may have different underlying biological mechanisms including interaction between different factors,” Lau said.

It’s important to keep investigating the mechanisms behind long COVID to figure out the factors at play, understand how they can be prevented from occurring, and better learn how to treat them.

“The response of the body’s immune system to an infection is an incredibly complex interaction between host and pathogen,” Lau said. “By studying immunological mechanisms we gain better understanding of what is occurring and what can go wrong in the immune system’s response to SARS-CoV-2. Understanding these mechanisms helps us to identify potential targets for intervention that may help prevent or mitigate development of long COVID.”

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