Long COVID Is Real, and Many Real Questions Remain

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Jan. 28, 2022 — Long story short, we still have a lot to learn about long COVID-19.

But it is a real phenomenon with real long-term health effects for people recovering from coronavirus infections. And diagnosing and managing it can get tricky, as some symptoms of long COVID-19 overlap with those of other conditions — and what many people have as they recover from any challenging stay in the intensive care unit.

Risk factors remain largely unknown as well: What makes one person more likely to have symptoms like fatigue, “brain fog,” or headaches vs. someone else? Researchers are just starting to offer some intriguing answers, but the evidence is preliminary at this point, experts said at a media briefing sponsored by the Infectious Diseases Society of America.

Unanswered questions include: Does an autoimmune reaction drive long COVID? Does the coronavirus linger in reservoirs within the body and reactivate later? What protection against long COVID do vaccines and treatments offer, if any?

To get a handle on these and other questions, nailing down a standard definition of long COVID would be a good start.

“Studies so far have used different definitions of long COVID,” Nahid Bhadelia, MD, founding director of the Boston University Center for Emerging Infectious Diseases Policy and Research, said during the briefing.

Fatigue is the most common symptom of long COVID in research so far, said Bhadelia, who is also an associate professor of medicine at Boston University.

“What’s difficult in this situation is it’s been 2 years in a global pandemic. We’re all fatigued. How do you tease this apart?” she asked.

Other common symptoms are a hard time thinking quickly — also known as “brain fog” — and the feeling that, despite normal oxygen levels, breathing is difficult, said Kathleen Bell, MD.

Headache, joint and muscle pain, and persistent loss of smell and taste are also widely reported, said Bell, a professor and chair of the Department of Physical Medicine and Rehabilitation at the University of Texas Southwestern Medical Center in Dallas.

Not all the symptoms are physical either.

“Pretty prominent things that we’re seeing are very high levels of anxiety, depression, and insomnia,” Bell said. These “actually seem to be associated independently with the virus as opposed to just being a completely reactive component.”

More research will be needed to distinguish the causes of these conditions.

A Difficult Diagnosis

Without a standard definition, the wide range of symptoms, and the lack of specific guidance on how to manage them, contribute to making it more challenging to distinguish long COVID from other conditions, the experts said.

“We are starting to see some interesting features of inaccurate attributions to COVID, both on the part of perhaps the person with long COVID symptoms and health care providers,” Bell said.

“It’s sometimes a little difficult to sort it out,” she said.

Bell said she was not suggesting misdiagnoses are common, “but it is difficult for physicians that don’t see a lot of people with long COVID.”

The advice is to consider other conditions. “You can have both a long COVID syndrome and other syndromes as well,” she said. “As one of my teachers used to say: ‘You can have both ticks and fleas.'”

Predicting Long COVID

In a study getting attention, researchers identified four early things linked to greater chances that someone with COVID-19 will have long-term effects: type 2 diabetes at the time of diagnosis, the presence of specific autoantibodies, unusual levels of SARS-CoV-2 RNA in the blood, and signs of the Epstein-Barr virus in the blood.

The study, published online Monday in the journal Cell, followed 309 people 2 to 3 months after COVID-19.

“That’s important work, but it’s early work,” Bhadelia said. “I think we still have a while to go in terms of understanding the mechanism of long COVID.”

Unexpected Patients Getting Long COVID Care

“We are seeing different populations than we all expected to see when this pandemic first started,” Bell said.

Instead of seeing primarily patients who had severe COVID-19, “the preponderance of people that we’re seeing in long COVID clinics are people who are enabled, were never hospitalized, and have what people might call mild to moderate cases of coronavirus infection,” she said.

Also, instead of just older patients, people of all ages are seeking long COVID care.

One thing that appears more certain is a lack of diversity in people seeking care at long COVID clinics nationwide.

“Many of us who have long COVID specialty clinics will tell you that we are tending to see fairly educated, socioeconomically stable population in these clinics,” Bell said. “We know that based on the early statistics of who’s getting COVID and having significant COVID that we may not be seeing those populations for follow-up.”

Is an Autoinflammatory Process to Blame?

It remains unclear if a hyperinflammatory response is driving persistent post-COVID-19 symptoms. Children and some adults have developed multi-system inflammatory conditions associated with COVID-19, for example.

There is a signal, and “I think there is enough data now to show something does happen,” Bhadelia said. “The question is, how often does it happen?”

Spending time in critical care, even without COVID-19, can result in persistent symptoms after a hospital stay, such as acute respiratory distress syndrome. Recovery can take time because being in an ICU is “basically the physiologically equivalent of a car crash,” Bhadelia said. “So you’re recovering from that, too.”

Bell agreed. “You’re not only recovering from the virus itself, you’re recovering from intubation, secondary infections, secondary lung conditions, perhaps other organ failure, and prolonged bed rest. There are so many things that go into that, that it’s a little bit hard to sort that out from what long COVID is and what the direct effects of the virus are.”

Also a Research Opportunity

“I hate to call it this, but we’ve never had an opportunity [where] we have so many people in such a short amount of time with the same viral disorder,” Bell said. “We also have the technology to investigate it. This has never happened.”

“SARS-CoV-2 is not the only virus. This is just the only one we’ve gotten whacked with in such a huge quantity at one time,” she said.

What researchers learn now about COVID-19 and long COVID “is a model that’s going to be able to be applied in the future to infectious diseases in general,” Bell predicted.

How Long Will Long COVID Last?

The vast majority of people with long COVID will get better over time, given enough support and relief of their symptoms, Bell said.

Type 2 diabetes, pre-existing pulmonary disease, and other things could affect how long it takes to recover from long COVID, she said, although more evidence is needed.

“I don’t think at this point that anyone can say how long this long COVID will last because there are a variety of factors,” Bell said.

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