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For some people who get COVID-19, the acute illness is just the opening act. Nagging symptoms—from fatigue and brain fog to GI symptoms and more—can arise or persist in the weeks or months after their bodies have shed the SARS-CoV-2 infection. But why? And what can be done to help them?
Recognizing the toll of "long COVID," scientists around the globe have been on a mission to tease out answers, hoping to pave the way for effective treatments. A group of researchers reporting in the journal Cell believe they have made some headway.
The study, published January 24, identifies a handful of factors that may help to predict which people are likely to go on to develop long COVID—or what researchers call PASC, post-acute sequelae of COVID-19. The analysis singles out four biologic factors tied to long COVID, specifically, the presence and level of autoantibodies (which are antibodies that attack the body's own healthy tissues), Epstein-Barr virus in the blood, viral load (meaning the amount of SARS-CoV-2 genetic material in the blood), and pre-existing type 2 diabetes.
Though the study doesn't prove that these factors cause chronic symptoms, and larger and longer-term analyses are still needed, the research is still a meaningful step forward for science—and people affected by the condition.
"It's early work, but it's important work," says Nahid Bhadelia, MD, founding director of Boston University's Center for Emerging Infectious Diseases Policy and Research and member of the Infectious Diseases Society of America.
Here's what experts are saying about the significance of the research for those who experience long-COVID symptoms.
How to Submit Your At-Home COVID Test to Your Insurance Company
What is long COVID?
First, let's define the problem. The US Centers for Disease Control and Prevention (CDC) refers to long COVID as "post-COVID conditions." You might also run across terms like post-acute COVID, chronic COVID, long-haul COVID, or PASC. They all refer to the same phenomenon: the new, ongoing, or recurring symptoms that people who've been infected with the SARS-CoV-2 virus (which causes COVID-19) may experience.
The symptoms are wide-ranging and poorly understood, says the CDC. The agency lists nearly two dozen commonly reported ones that linger on, including:
Difficulty breathing
Fatigue
Malaise
Brain fog
Chest pain
Headache
Diarrhea
Insomnia
Rash
Typically, symptoms are present four or more weeks after the viral infection, according to the CDC, although it says that timetable is a rough estimate and subject to change as scientists learn more about COVID's long-term effects.
It's not known exactly how many people go on to develop long COVID; studies present wildly differing estimates. One review of studies published last October in JAMA Open Network finds nearly a third to upwards of two-thirds of COVID patients experience at least one post-COVID symptom, and that more than half of COVID survivors have symptoms that persist six months after their recovery from the virus. Those figures are based on an analysis of studies involving more than 250,000 COVID survivors.
Capturing the true burden of long COVID is complicated by the lack of access to COVID testing, particularly in communities of color, and by the lack of diversity in research studies, Dr. Bhadelia points out. The lack of a standard definition of long COVID across studies, which use different symptom scales and methodologies, is a problem, too, she says.
On top of that, how do you tease apart the effects of long COVID versus the impact of hospitalization after a serious bout of COVID? Or between long COVID and living in the times that we do?
"It's been two years in a global pandemic. We're all fatigued," says Dr. Bhadelia.
Should You Retest After Testing Positive for COVID-19—And, If So, When?
Factors that may predict long COVID
The new study in Cell brings together researchers from Seattle; San Francisco; Stanford, California; and elsewhere. Interestingly, the group didn't set out to investigate long COVID. It was only after these post-COVID symptoms began to emerge that the team pivoted.
"We did this longitudinal study because we wanted to understand how immunity against the virus developed," says James R. Heath, PhD, a coauthor of the study and president and professor at the Seattle-based Institute for Systems Biology, a nonprofit biomedical research organization. "Once we began to appreciate that long COVID was emerging, then we did some slight modifications to the study to understand it more completely," he tells Health.
Researchers studied two "cohorts," or groups of patients. The main cohort of 209 patients with COVID had blood draws and nasal swabs after their initial diagnosis, about a week later (around the peak of their acute disease), and two to three months later. A separate group of 100 patients had testing, too, which served to validate findings in the main cohort.
Using those patient samples, symptom surveys, and other data, the team conducted a "deep immunological analysis" aimed at solving the long-COVID puzzle. For example, a lot of patients were feeling fatigue or flu-like symptoms. So researchers looked into whether they had inflammatory proteins in their blood samples, which could signal ongoing inflammation.
All in all, the study revealed four potential predictors of long COVID. However, the presence of certain autoantibodies was "twofold more important" than any other factor identified in the study, says Heath.
Autoantibodies
Don't confuse autoantibodies with the antibodies your immune system makes to fight off illness. Autoantibodies are immune system proteins that mistakenly attack a person's own tissues. They're found in autoimmune diseases like lupus.
As autoantibodies rise, protective SARS-CoV-2 antibodies decrease, according to a news release describing the findings of the Cell study and the association of these proteins with long COVID.
The presence of detectable autoantibodies is the risk factor, but the level is important, too, says Heath. "Higher levels of autoantibodies do seem to correlate with more severe PASC," he explains.
Other studies have looked at the role of autoimmune antibodies in COVID. One study funded by the National Institutes of Health (NIH), for example, shows autoimmunity against certain parts of the immune response can worsen acute outcomes from SARS-CoV-2.
Does that mean anyone with an autoimmune condition could be at greater risk of developing long COVID? For people with one disease in particular, it certainly appears so: "This is almost certainly true for lupus—those patients have the same autoantibodies as the ones we measured," says Heath.
But Jason S. Knight, MD, PhD, associate professor in the Division of Rheumatology at the University of Michigan, suggests the implications are more nuanced. For people at a "preclinical" stage (meaning those who have autoantibodies in their blood but no symptoms or diagnosis), "I think the study suggests that they are at increased risk of getting long-COVID symptoms."
Recognizing the toll of "long COVID," scientists around the globe have been on a mission to tease out answers, hoping to pave the way for effective treatments. A group of researchers reporting in the journal Cell believe they have made some headway.
The study, published January 24, identifies a handful of factors that may help to predict which people are likely to go on to develop long COVID—or what researchers call PASC, post-acute sequelae of COVID-19. The analysis singles out four biologic factors tied to long COVID, specifically, the presence and level of autoantibodies (which are antibodies that attack the body's own healthy tissues), Epstein-Barr virus in the blood, viral load (meaning the amount of SARS-CoV-2 genetic material in the blood), and pre-existing type 2 diabetes.
Though the study doesn't prove that these factors cause chronic symptoms, and larger and longer-term analyses are still needed, the research is still a meaningful step forward for science—and people affected by the condition.
"It's early work, but it's important work," says Nahid Bhadelia, MD, founding director of Boston University's Center for Emerging Infectious Diseases Policy and Research and member of the Infectious Diseases Society of America.
Here's what experts are saying about the significance of the research for those who experience long-COVID symptoms.
How to Submit Your At-Home COVID Test to Your Insurance Company
What is long COVID?
First, let's define the problem. The US Centers for Disease Control and Prevention (CDC) refers to long COVID as "post-COVID conditions." You might also run across terms like post-acute COVID, chronic COVID, long-haul COVID, or PASC. They all refer to the same phenomenon: the new, ongoing, or recurring symptoms that people who've been infected with the SARS-CoV-2 virus (which causes COVID-19) may experience.
The symptoms are wide-ranging and poorly understood, says the CDC. The agency lists nearly two dozen commonly reported ones that linger on, including:
Difficulty breathing
Fatigue
Malaise
Brain fog
Chest pain
Headache
Diarrhea
Insomnia
Rash
Typically, symptoms are present four or more weeks after the viral infection, according to the CDC, although it says that timetable is a rough estimate and subject to change as scientists learn more about COVID's long-term effects.
It's not known exactly how many people go on to develop long COVID; studies present wildly differing estimates. One review of studies published last October in JAMA Open Network finds nearly a third to upwards of two-thirds of COVID patients experience at least one post-COVID symptom, and that more than half of COVID survivors have symptoms that persist six months after their recovery from the virus. Those figures are based on an analysis of studies involving more than 250,000 COVID survivors.
Capturing the true burden of long COVID is complicated by the lack of access to COVID testing, particularly in communities of color, and by the lack of diversity in research studies, Dr. Bhadelia points out. The lack of a standard definition of long COVID across studies, which use different symptom scales and methodologies, is a problem, too, she says.
On top of that, how do you tease apart the effects of long COVID versus the impact of hospitalization after a serious bout of COVID? Or between long COVID and living in the times that we do?
"It's been two years in a global pandemic. We're all fatigued," says Dr. Bhadelia.
Should You Retest After Testing Positive for COVID-19—And, If So, When?
Factors that may predict long COVID
The new study in Cell brings together researchers from Seattle; San Francisco; Stanford, California; and elsewhere. Interestingly, the group didn't set out to investigate long COVID. It was only after these post-COVID symptoms began to emerge that the team pivoted.
"We did this longitudinal study because we wanted to understand how immunity against the virus developed," says James R. Heath, PhD, a coauthor of the study and president and professor at the Seattle-based Institute for Systems Biology, a nonprofit biomedical research organization. "Once we began to appreciate that long COVID was emerging, then we did some slight modifications to the study to understand it more completely," he tells Health.
Researchers studied two "cohorts," or groups of patients. The main cohort of 209 patients with COVID had blood draws and nasal swabs after their initial diagnosis, about a week later (around the peak of their acute disease), and two to three months later. A separate group of 100 patients had testing, too, which served to validate findings in the main cohort.
Using those patient samples, symptom surveys, and other data, the team conducted a "deep immunological analysis" aimed at solving the long-COVID puzzle. For example, a lot of patients were feeling fatigue or flu-like symptoms. So researchers looked into whether they had inflammatory proteins in their blood samples, which could signal ongoing inflammation.
All in all, the study revealed four potential predictors of long COVID. However, the presence of certain autoantibodies was "twofold more important" than any other factor identified in the study, says Heath.
Autoantibodies
Don't confuse autoantibodies with the antibodies your immune system makes to fight off illness. Autoantibodies are immune system proteins that mistakenly attack a person's own tissues. They're found in autoimmune diseases like lupus.
As autoantibodies rise, protective SARS-CoV-2 antibodies decrease, according to a news release describing the findings of the Cell study and the association of these proteins with long COVID.
The presence of detectable autoantibodies is the risk factor, but the level is important, too, says Heath. "Higher levels of autoantibodies do seem to correlate with more severe PASC," he explains.
Other studies have looked at the role of autoimmune antibodies in COVID. One study funded by the National Institutes of Health (NIH), for example, shows autoimmunity against certain parts of the immune response can worsen acute outcomes from SARS-CoV-2.
Does that mean anyone with an autoimmune condition could be at greater risk of developing long COVID? For people with one disease in particular, it certainly appears so: "This is almost certainly true for lupus—those patients have the same autoantibodies as the ones we measured," says Heath.
But Jason S. Knight, MD, PhD, associate professor in the Division of Rheumatology at the University of Michigan, suggests the implications are more nuanced. For people at a "preclinical" stage (meaning those who have autoantibodies in their blood but no symptoms or diagnosis), "I think the study suggests that they are at increased risk of getting long-COVID symptoms."
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