Researchers Are Getting Closer to Understanding Long COVID. But Treatments Are Likely Still a Ways Off

Long COVID remains a mystery two years after the COVID-19 pandemic. Why do some people develop long-lasting symptoms—often after a mild case of COVID-19, sometimes even after being vaccinated—while others fully recover from their brushes with the SARS-CoV-2 virus? What is the reason Long COVID seems to be more common in women than it does for men? One condition can affect multiple body systems. This causes symptoms such as brain fog, joint pain and exhaustion. Long COVID can be referred to as a single diagnosis. Or is it more like a umbrella term that refers to a wide range of illnesses caused by different biologically distinct effects of the virus. It could be one of many post-viral ailments that have existed for years.
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Many studies have recently been published in peer-reviewed journals. Others are going through the same process. They aim to help explain Long COVID, which affects millions. Every one of these studies contributes to the greater research puzzle and helps to improve scientific understanding of Long COVID.

However, Long COVID continues to grow in prevalence and research has not yet provided any treatment. “Patients are pushing for an answer. They’re pushing for the one treatment,” says Christina Martin, a nurse practitioner who helps run Dartmouth-Hitchcock Medical Center’s Post-Acute COVID Syndrome Clinic in New Hampshire. “They’re looking for the Holy Grail, and it’s just not out there.”

What causes long-term COVID?

In the last few months, dozens of researches on Long COVID were published. Many of these studies can broadly be divided into two groups. While one group investigates how Long COVID is caused, the other focuses on identifying individuals most likely to develop the condition.

In the latest version Nature on March 7, suggests that SARS-CoV-2, the virus that causes COVID-19, can damage the brain—even among people who experienced mild cases. The authors warn that this could cause long-term problems such as cognitive decline, loss of smell, inflammation, and damage to the nervous system.

In a similar vein, research set to be presented at the European Congress of Clinical Microbiology and Infectious Diseases in April suggests that damage to the vagus nerve—which extends from the brain down the torso—is behind many Long COVID symptoms. Researchers studied almost 350 Long COVID sufferers and discovered that 66% showed symptoms of damage to the vagus nerve. This includes abnormal heartbeat, dizziness, and other gastrointestinal issues. A second study was published in March by the journal. Neurology: Neuroimmunology & NeuroinflammationThis suggests that nerve damage is a possible cause for many of the symptoms.

But for a condition as complex as Long COVID, which is linked to more than 200 different symptoms, there will likely not be a single cause, says Dr. Gemma Lladós, an infectious disease physician at Hospital Germans Trias i Pujol in Spain and one of the researchers behind the vagus nerve study. Nerve damage may explain many cases, but it almost certainly can’t explain them all, she says.

Research has also been drawn to the area of the vascular systems. In a study, Biochemical Journal in February argues that tiny “microclots” in the blood may cause many Long COVID symptoms by preventing oxygen from reaching the body’s tissues. A paper in the same journal also published this argument. Chest One hallmark of Long COVID is intolerance for exercise. This may have been linked to inadequate oxygen delivery in January.

Others believe that the SARS-CoV-2 viruses may still be present in some people, possibly causing long-lasting effects. It’s also possible that, for some people, COVID-19 pushes the immune system into a hyperactive state, essentially causing it to attack itself.

The hypothesis corresponds to a paper that was published in the journal. Cell in January, which tried to explain why some people develop Long COVID and others don’t. Researchers identified four risk factors that are associated with Long COVID.

  • a type 2 diabetes diagnosis
  • SARS-CoV-2 viruses genetic material found in the blood
  • Evidence of Epsteinbarr virus in blood
  • the presence of autoantibodies—molecules that attack the body’s own tissues, instead of foreign pathogens like a virus

Co-author James Heath, president of Seattle’s Institute for Systems Biology, says the autoantibody finding was the most important, in part because it showed a possible similarity between Long COVID and the autoimmune disease lupus. While there’s no cure for lupus, “there are treatments out there that can be effective,” Heath says. “So those would be a line of things that are worth looking at” for Long COVID patients.

His research has shown that some COVID cases can be predicted by Epstein-Barr and SARS-CoV-2 virus levels in the blood. He also says that antivirals should be taken as soon as possible after receiving a COVID-19 diagnosis.

The Treatment Gap

They are currently hypotheses. At least until more research is done, knowing about risk factors does little to help people who already have Long COVID, says Martin from Dartmouth-Hitchcock—especially since most people have no idea whether they have something like autoantibodies in their systems.

Patients often ask about studies they’ve read about risk factors and all Martin can tell them is that, “‘it’s not changing how we manage your symptoms,’” she says. “‘What might make you at risk for it, it doesn’t change things. You have it.’”

Even symptom management is, at this point, a sophisticated game of trial and error, says Dr. Jeffrey Parsonnet, an infectious disease physician who also works in Dartmouth-Hitchcock’s clinic. Some of the interventions that seem to work best for patients in his clinic—like occupational therapy and mental health support—have little to do with the basic science described in studies. “One of the biggest things we have to offer is a knowledgeable and sympathetic ear,” Parsonnet says.

Dr. Brad Nieset, who runs the Benefis Health System Post-COVID-19 Recovery Program in Montana, says his approach hinges on meeting each patient’s recovery goals, whether that’s feeling well enough to sing in church or getting back to an outdoor activity. While his team stays up-to-date on the latest research, Nieset says it sometimes feels that “people are grasping at zebras [rather than looking for horses]. It’s not as complex once you break it down” and focus on what could actually help each individual patient. Often, that means applying long-used treatments—like respiratory therapies or neurologic support—to a new disease, he says.

Nieset suggests that it would help to have a better understanding about risk factors if those who test positive for COVID-19 could access care immediately. But, again, many risk factors identified by studies, such as autoantibodies or viral load in the blood, aren’t something the average individual would know they have.

As such, “there’s no direct implications of that,” as far as developing screening standards or patient treatments, Parsonnet says.

Onur Boyman (a University of Zurich clinician immunologist) disagrees. A recent paper by Dr. Onur Boyman on Long COVID Risk Factors was also published. Nature Communications. His group found that people older than 50, with asthma history, as well as people with low immunoglobulin levels (which is a type antibody), were more likely to develop Long COVID. A higher rate of Long COVID was seen in people who suffered multiple symptoms from their COVID-19 acute infections than those with fewer symptoms.

While most people don’t know much about their immunoglobulin levels, Boyman says that testing is fairly easy and inexpensive to do. “If you have patients who are of older age and/or have a history of asthma, then you could measure their immunoglobulin levels. If those are also relatively low, then you would know this individual has a particularly high risk of developing Long COVID,” he says.

Armed with that knowledge, he says, “you can make sure that individual is very well vaccinated,” perhaps getting more regular booster shots than the average person, Boyman says. Long COVID is half the risk for people who have been vaccinated than those who are not.

The Long CoVID

Even if studies don’t immediately translate to treatments, it’s important to understand how a disease works and who is affected. That’s especially true for a condition as complicated as Long COVID; if studies begin to suggest that there are actually different subtypes of Long COVID, that could lead to more personalized patient care, Boyman says.

A wider range of chronic diseases includes Long COVID. It seems to overlap especially significantly with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—a condition that can follow viral illnesses and leads to debilitating exhaustion—to the point that some Long COVID patients meet the diagnostic criteria for ME/CFS.

Complex chronic conditions like ME/CFS and chronic Lyme disease have existed since before COVID-19 was created. They affect millions of Americans, yet they are not receiving much funding for research or attention from mainstream medicine. “ME has a 40-year history that’s defined by neglect and abandonment,” says patient advocate Rivka Solomon, who has had ME/CFS for 32 years.

While Solomon says she’s thrilled by the amount of attention given to Long COVID and stresses that there is no “us versus them” in the chronic disease world, she wishes other complex illnesses received the same amount of attention and funding—like the $1.15 billion over four years Congress gave the National Institutes of Health in 2020 to support research into the long-term effects of COVID-19.

The scale and urgency of Long COVID may be a part of this imbalance. Experts believe there may be as many as 15 million Long-COVID patients living in America and around the globe, most of them having been sick for the past two years. The United States has 2.5 million patients with ME/CFS. Solomon suggests that researchers could find better treatments for patients with Long COVID if they had started investing in ME/CFS, Solomon states.

Heath believes that Long COVID’s attention could help other diseases. He believes that if researchers are able to learn more about chronic diseases, this could lead over time to better care for patients with multiple conditions. Research is “not really just about Long COVID. It’s about the triggers that can lead to the development of chronic diseases.” (Solomon says she’d like to see more studies focus specifically on conditions like ME/CFS, rather than assuming Long COVID findings will translate to other diagnoses.)

While science is improving, the pace of progress can seem slow for patients with Long COVID and others who have been affected by other viruses. It can take years for hypotheses to turn into solutions—years patients will never get back.


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