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Long COVID largely remains a mystery, experts say, but a few clues are starting to emerge.
With symptoms ranging from breathlessness to blood clots to lack of smell, what has been called long COVID might actually be a constellation of problems not one overarching condition.
Calling it one thing is like saying someone has “cancer,” rather than specifying “pancreatic cancer” or “skin cancer,” said Dr. Nir Goldstein, a pulmonologist and director for The Center for Post-COVID Care and Recovery at National Jewish Health in Denver.
The more precision experts can add to those diagnoses, the more likely they are to find treatments that will help people with unrelenting headaches, brain fog, trouble breathing and crippling exhaustion, he and others said.
Studies are not definitive but suggest that as many as one-third of people who had symptomatic COVID-19 – and even some who had no symptoms at all – may still suffer more than a month after their infection. A smaller number, but again, it’s not clear how many have symptoms that persist for months or even years.
The problem is global. People report similar symptoms around the world.
And there’s no question those symptoms can be debilitating.
“We have patients who were Olympians who struggle with basic activities of daily life. Patients who are academics and professors who forget what button to push on the washing machine to make it go,” Goldstein said.
The National Institutes of Health is recruiting thousands of Americans with long COVID into a $470 million research study so they can better categorize patients and eventually develop treatments for them.
Understanding long COVID is crucial for clinicians and scientists, said Dr. Onur Boyman, an immunologist at University Hospital Zurich in Switzerland.
“This is going to be a major burden on us and on the people,” he said. “As long as we don’t understand, we will have difficulties finding appropriate treatments.”
But answers won’t come easily.
Many of the symptoms of long COVID, like fatigue, are common among people with a variety of different ailments and even in daily life, particularly over the last two difficult years, said Dr. Michael Edelstein, an epidemiologist at Bar-Ilan University and research director at Ziv Medical Centre, both in northern Israel.
It’s going to take time to even define exactly what long COVID is, he said.
This will be crucial for individual patients, for developing treatments, but also for insurance coverage and disability allowances, he said. “There’s going to be interests beyond the scientific community that are going to have an interest in figuring out exactly what constitutes long COVID.”
Researchers will get there eventually, he said. “But it will take some time and it’s important to manage expectations.”
Two types of long COVID, maybe more
At this point, two distinct categories of long COVID have been identified.
The first occurs among people who were severely ill with COVID-19 and are taking a long time to recover. A study published Monday from the Netherlands found that 74% of patients hospitalized in intensive care reported physical symptoms a year later, while 26% reported lingering mental symptoms and 16% cognitive ones.
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The second group may have barely noticed their initial infection or weren’t sick enough to go to the hospital, but can’t seem to shake symptoms.
While the first group tends to be older people at highest risk for a severe bout of COVID-19, the second group is often healthy and not yet middle-aged, experts said.
Some in this second group might have an overactive immune system that responded too well to COVID-19 and now can’t turn off. Their symptoms may include brain fog, exhaustion, endless headaches, and unusual tingling or sensations.
“It’s sobering to think that you could have something … that’s plaguing you for months,” said Dr. Serena Spudich, a neurology professor at the Yale School of Medicine, who helps run a long-COVID neurology clinic at Yale.
These patients need different treatments than those still recovering from hospitalization, Spudich said, but this group probably needs to be broken down further, too. It’s too soon to tell. A number of studies are underway to test whether different immune therapies can help long-COVID patients.
Spudich co-authored a report earlier this month about the nervous system consequences of COVID-19.
She and others worry about the long-term impacts of this neurological damage.
At NYU Langone Health in New York City, neurologists Thomas Wisniewski, and Jennifer Frontera published a study earlier this month, identifying extremely high levels of toxic proteins in the brains of patients hospitalized for COVID-19. Those who ended up dying had the highest levels, the study found.
Some of the proteins have been linked to Alzheimer’s and it’s possible, Wisniewski said, that some of these patients will end up with Alzheimer’s or another brain disorder. The 1918 flu pandemic led to a marked increase in Parkinson’s Disease and other neurological conditions, he noted.
About half of the patients in the study group continue to have cognitive problems 6- and 12-months after their hospitalizations, Wisniewski said.
“These are very striking changes and indicators of injury and brain inflammation,” he said. “These are all worrisome and striking changes that obviously we need to follow up long-term as to how these patients fare.”
Boyman published a paper Tuesday, providing a risk score for people with COVID who are most likely to develop long-term symptoms.
He and his colleagues looked at two groups, one that had COVID-19 and developed lingering symptoms and one that had COVID-19 and did not.
They found four types of factors increase risk for long COVID: age, a history of asthma, symptoms during infection and immune markers in the blood.
The risk of long COVID increases with age among older people who are still recovering from severe disease as well as among younger adults with healthy, perhaps overactive, immune systems.
Risk for long COVID also increases with the number of symptoms during infection. People with five symptoms are at higher risk than those who had just one or two, Boyman said.
Having asthma increases risk, potentially because those are people with skewed immune systems. They already have a “misguided immune response” affecting their lungs, Boyman said, so COVID-19, which has disproportionately afflicted lungs, might compound existing problems.
People with allergies don’t seem to have the same vulnerability, he said, perhaps because their immune skewing is less pronounced or different.
Certain antibodies, called immunoglobulins, detectable with a simple blood test also boost risk.
If he’s right, this list of risk factors might also suggest treatment options. For people with low levels of key antibodies, boosting those with drugs might help improve symptoms or even help people avoid developing long COVID in the first place.
Goldstein said he thinks another explanation for long COVID might be found in mitochondria. These cellular energy factories may get damaged by COVID-19, explaining why so many people feel crushing fatigue and can’t manage exercise. He published a study on the subject earlier this month.
Damaged mitochondria might also make it harder for people to think, because the brain requires so much energy to function well, Goldstein said.
“It’s one of the hypotheses to add to the others,” he said.
Vaccination can prevent long COVID
In a rare bit of good news, two shots of COVID-19 vaccine appears to almost completely prevent symptoms associated with long COVID, at least for a period of time, said Edelstein, who found this in a study, posted online earlier this month, though not yet peer reviewed.
Edelstein and his team compared people who had been vaccinated twice and infected with COVID-19 and found they were no more likely to have symptoms like fatigue and headaches than people who’d never had COVID-19.
What the ongoing study can’t yet answer, Edelstein said, is whether this benefit is sustained. “Are people who’ve received at least two doses, will they continue to report these lower level of symptoms or are they going to rise? Do you need a third dose?”
They also couldn’t answer definitively whether vaccination prevented these long COVID symptoms or cleared up lingering symptoms from an infection, Edelstein said, though early evidence suggests it’s more likely preventing the symptoms in most people.
Skipping vaccination puts people at higher risk for long COVID, Boyman said, comparing it to climbing a very high mountain without any training or special gear.
“You can do that and everything can go well if you are lucky,” he said, reaching the top without developing altitude sickness or falling.
Getting vaccinated is like climbing the same mountain after training and gearing up properly, Boyman said. “Your chances of going to the top and coming back safely are so much bigger.”
Whether different variants cause different amounts of long COVID or different symptoms remains to be seen.
Omicron hasn’t been around long enough to note any differences, Spudich said.
She’d like to believe that because it’s milder, it’s less likely to trigger an immune over-reaction. But since the majority of her clinic’s patients had a mild illness from earlier strains, “I think we really don’t know,” whether omicron will cause less long COVID, she said.
Edelstein said he’s particularly interested in looking at whether vaccination is equally good at preventing long COVID across all variants. Because omicron has more differences from the original variant, it’s possible the original vaccine won’t be as protective, he said.
“There is some kind of theoretically plausible reasons why they may be, especially with omicron being more likely to escape the vaccine immunity,” he said. “I don’t think anyone has the answer to this yet.”
Spudich said one small silver lining to long COVID may be that it helps researchers better understand the role the immune system plays in a host of conditions.
She said she saw one patient suffering from psychosis who didn’t respond to typical medications, but who improved after immune therapy.
“It may be that this is just the tip of the iceberg of these types of conditions,” Spudich said, with the immune system playing a much larger role than has previously been understood. Maybe a variety of underlying conditions are triggered or worsened when the immune system is turned on by an infection, she said.
COVID has also broken down some of the silos that normally exist in medical research, promoting collaborations among specialties and with patients.
“If nothing else, the focus on understanding COVID and the complications of COVID and the fact that the whole world has been galvanized to study this may have some benefits for other conditions,” she said.
In the meantime, she and others said, the best thing people with long COVID can do is take care of themselves. “Focus on things one can control,” Spudich said, like getting enough sleep and appropriate exercise.
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Wisniewski said keeping cognitively active is important, too, as is eating a Mediterranean diet, and treating diabetes, hypertension, high cholesterol and other risk factors for heart and brain disease.
People with long COVID should also consider volunteering for a clinical trial, Spudich said. It might not help them, she said, but “that’s a real way to contribute and actually also a way to get additional personal attention and be involved in developing cutting-edge kinds of treatments.”
Although many people recover with time, for some, long COVID symptoms seem to have become a way of life – unfortunately, a miserable one.
SurvivorCorps, a group of long COVID advocates led by Diana Berrent, has been tracking symptoms among its more than 100,000 members.
Ronald Rushing Sr., who turns 47 later this month, still has crushing headaches that leave him bedridden most days. Two years ago, he was running marathons. Now, he walks slowly and deliberately with a cane.
Rushing, of Southern Pines, North Carolina, hasn’t worked since July 2020, when he caught COVID-19 and had to take time off from his job as a grocery store manager, but his disability claim has been repeatedly denied.
“As of today I haven’t received any money or pay since January 11th 2021,” Rushing wrote in a Monday email. He can’t afford the $3,000 he’s expected to pay out of pocket for insurance, so he expects to lose his coverage in April.
He’s applied for financial aid to continue to get help from a long-hauler clinic at the University of North Carolina and can no longer afford to see his therapist, at $65 a visit.
“Things are not good but could be much worse I’m sure,” he wrote. “I handle things 5 minutes at a time to get through issues. I’m lost, sad and in pain but still fighting on!!!”
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