By the time Kristin Hill, an interior designer in Baltimore, was diagnosed with COVID-19, she’d felt lousy for several weeks, but she wasn’t overly worried, though immunizations were not yet readily accessible then, in September 2020. Kristin recalls, “I was 48 and healthy. I believed it wouldn’t be long until I returned to my usual busy life.” (Prevention changed her name to protect her privacy.)
Two years later, she worries whether she’ll ever be well again. “I used to spend hours rehabbing houses,” she recalls. “Now I need to relax for a day or two before and after going to the grocery store, and I have terrible cognitive glitches—I can’t do simple math, and I’ll put food that belongs in the fridge in the pantry. I can’t work at all. I’m seeing a pulmonologist and a cardiologist, but so far no one has been able to help me.” Between 8 million and 23 million persons in the U.S. are now battling with long-term health difficulties after a bout with COVID-19. Their many, baffling symptoms, from rashes to crushing weariness, have evaded explanation. But that may soon change.
In April the Biden administration began a large, all-hands-on-deck interagency research and policy program designed in part to find the causes of and potential therapies for extended COVID (stress, worry, and depression may raise your risk, for example) (stress, anxiety, and depression may increase your risk, for example). Last year the National Institutes of Health began enrolling participants across the country in the Researching COVID to Enhance Recovery Initiative (RECOVER), a multipronged $1.15 billion study that will follow thousands of patients for four years, examine millions of medical records, and scrutinize tissue from people who died of COVID-19 to discover where the virus might linger. “It’s designed to leave no stone unturned in terms of getting to the origin of the problem,” says Walter Koroshetz, M.D., head of the NIH National Institute of Neurological Disorders and Stroke and cochair of the RECOVER Initiative.
“It’s a hopeful moment,” says Akiko Iwasaki, Ph.D., Sterling Professor of Immunobiology and Molecular, Cellular, and Developmental Biology at Yale University. “We’re starting to gain more understanding of what’s driving long COVID and who is most at risk, and the more we understand, the more it will help us get a grip on similar chronic illnesses, like ME/CFS, that have been largely ignored for far too long. People are suffering. Answers can’t come soon enough.” Here’s what we know now:
What are the symptoms of long COVID?
Between 10% and 30% of people have new, returning, or ongoing health problems four or more weeks after a bout with COVID, the Center for Disease Control (CDC)’s definition of long COVID. “It’s a pandemic within the pandemic,” adds Iwasaki.
An online survey of 3,762 people with long COVID conducted by the Patient-Led Research Collaborative (a group of long COVID patients who are also researchers) found that participants experienced an average of 56 symptoms, from difficulty breathing to bulging veins to vibrating sensations. In those who felt ill from post COVID-19 syndrome for at least six months, the most common symptoms were fatigue, cognitive dysfunction, and post-exertional malaise (a triad that besets many people with ME/CFS), according to the study.
Risk factors for long COVID
Being a woman
While women are less likely to have severe COVID-19, we’re more likely to have lingering symptoms, per an April study by Italian researchers. Ironically, our robust immune response to viruses and bacteria may be part of the problem. If long COVID is driven by a hidden reservoir of virus lingering in the body (a leading theory), women’s immune systems could be overreacting to that persistent low-grade infection and causing diverse health issues, Iwasaki says.
Having diabetes
People with the disease may be up to four times as likely to develop long COVID, a team at Emory University Medical School reported in June. “Though the mechanisms are still unknown, it is possible that COVID-19 binds to receptors in the pancreas that play a crucial role in regulating blood sugar and releasing insulin, which could cause elevated blood sugar and put people at increased risk of long COVID,” explains Jessica Harding, Ph.D., the study’s lead author.
Having certain auto antibodies at the time of infection
Researchers followed 309 COVID-19 patients for several months and found autoantibodies (antibodies you produce against something in your own body, as in autoimmune conditions) in about 60% of people who developed long COVID.
Older age
The CDC reported in May that one in four people 65 and older had at least one symptom that could indicate long COVID, compared with one in five among those 18 to 64.
The key theories about long COVID
“One reason long COVID has been so difficult to understand is that it isn’t just one illness,” says Iwasaki. “There are probably subtypes caused by different underlying biological mechanisms.” The key to solving the long COVID puzzle, she adds, is identifying the most common disease pathways, along with their biomarkers, so doctors can treat the underlying causes rather than playing whack-a-mole with disparate symptoms. Here are the key theories:
Lingering virus or viral remnants in the body’s tissues may be causing it
“We’ve found viral RNA or protein in biopsies and autopsies of some long COVID patients,” says Iwasaki. If researchers can discern which patients’ symptoms are caused by a lurking viral reservoir, they could offer targeted treatments, like antivirals (Paxlovid is one), vaccines, or monoclonal antibodies—man-made proteins that mimic the immune system’s ability to fight off pathogens, she adds.
An unhealthy gut microbiome could contribute
One place the virus hides out is in the gut, where it can disrupt the trillions of microorganisms in the large intestine. “We know gut bacteria affect the immune system and have an effect on overall health,” says Iwasaki. Chinese researchers reported in March that gut bacteria associated with healthy immunity were depleted in long COVID patients, while problematic types of bacteria were flourishing—and were correlated with symptoms like respiratory problems, cognitive issues, and fatigue. The researchers suggested that future studies should investigate whether shifting the balance of the microbiome (which might be accomplished with a high- fibre diet or fecal transplantation) helps long COVID patients get better.
COVID may be triggering an overzealous immune response
“We know that acute respiratory infections can induce auto immune conditions, in which the immune system attacks the body’s own healthy tissue, in some people,” Iwasaki says. In addition, some long COVID patients have auto antibodies, the hallmark of autoimmunity, which means they might respond to treatments for common auto immune illnesses, such as steroids, or to an approach that targets B cells, white blood cells that play a role in autoimmunity.
Reactivated Epstein-Barr virus (EBV) could be connected to long COVID
More than 90% of us harbor latent EBV, a type of herpes virus that can cause mononucleosis, in our bodies. It is usually harmless but has been associated with autoimmunity and cancer, and researchers now suspect that it plays a role in ME/CFS in a subset of genetically susceptible people. If EBV is also causing some cases of long COVID, doctors could try antivirals in combination with other medications that are being studied for EBV-associated ME/CFS.
Inflammation could be to blame
It’s almost certain that inflammation plays a role in long COVID—and contributes to the cognitive issues that at least half of people with it experience. A team of researchers at the University of California San Francisco found elevated levels of protein in the cerebrospinal fluid of people who had cognitive changes associated with long COVID, suggesting brain inflammation. “Many doctors don’t know that viral infections can be associated with cognitive disorders, so they often dismiss these patients,” says Joanna Hellmuth, M.D., a neurologist at UCSF. “But the cognitive issues some long COVID patients are experiencing are a true neurological disorder.”
Here’s what might protect you from long COVID Vaccines
“Getting vaccinated cuts the risk of developing persistent symptoms in half,” says Dr. Koroshetz. (It also may help some people with long COVID feel better; a poll of 2,000 of them conducted by Survivor Corps, a long COVID advocacy and research organization, found that after two vaccine doses, about 40% reported mild to full resolution of their symptoms, while about 14% reported that their symptoms got worse.)
A healthy gut
Having a healthy balance of bacteria in the gut might help as well. When Chinese researchers tracked 106 COVID-19 patients to see which ones developed long COVID, they found that those who had less healthy microbiomes when they were diagnosed were more at risk, leading them to suggest that improving gut health might prevent long-term symptoms.
How to participate in research to help solve the long COVID crisis?
“The real heroes of the effort to understand long COVID are the patients who join medical studies,” says Dr. Koroshetz. Doing so also may enable participants to have access to cutting-edge treatments. Here are three trials looking for participants:
The NIH’S Recover Initiative
“We’re looking for people who are newly infected with COVID so we can follow them over time and hopefully uncover a pattern in those who develop long COVID,” says Dr. Koroshetz.
The Yale COVID Recovery Study
Based on anecdotal accounts of people with long COVID feeling better after receiving immunizations, Yale is working with Survivor Corps, a long-COVID patient and advocate organization, to explore the topic. “We’re measuring symptoms before and after the vaccine and collecting blood and saliva samples to understand how participants’ immune systems respond to it,” says Iwasaki.
The You + Me Registry and Biobank
“We launched this in June 2020 for people with ME/CFS, but when we realized that long COVID causes similar symptoms, we included an additional path for those patients to participate,” says Amitay of Solve ME/CFS. It comprises patient-reported data, a symptom-tracking app, and bio- samples to be utilized in research looking at causes, treatments, and potential cures.
These patient activists are fighting for change
When actress Lili Lim heard accounts of people with long COVID in late 2020, she was angry. Lili, 27, has had myalgic encephalo myelitis/chronic fatigue syndrome (ME/CFS), which can also be triggered by a virus, for five years. “We’ve known for decades that viruses can create long-term health problems, so why do we not understand how it happens or what to do about it?” she wonders.
Now active in the Long Covid Alliance, a network of patient- advocates and scientists, Lili helps raise awareness of post- viral illnesses. “Those of us in the ME/CFS world know how medicine disregards people with unexplained illnesses,” says Oved Amitay, CEO of Solve ME/CFS, which is part of the Alliance. “We wanted to save COVID long-haulers the suffering.” Researchers too are sharing information regarding parallels between the disorders, says Lily Chu, M.D., vice president of the International Association for CFS/ME. “For instance, studies of ME/CFS patients have shown irregularities in the body’s ability to generate energy—a finding we need to investigate in long COVID patients, who struggle with extreme fatigue too.”
In the absence of concrete treatments for either illness, ME/CFS advocates are advising COVID groups on coping with a hallmark of both illnesses: post-exertional malaise. “This isn’t just tiredness after exercise. It’s feeling exhausted and ill, like you’re coming down with the flu, for hours or days—even after mild exertion, like taking a shower,” says Dr. Chu. Doctors often suggest gradually upping exercise—this is dangerous, Dr. Chu adds, as even low- intensity exercise can exacerbate symptoms.