Debby Waldman
August 09, 2023
After catching COVID-19 for the second time in July 2022, Daniel Lewis suffered persistent headaches, chest pain, and a dangerously high heart rate. He recalls that he was also so exhausted packing for a family wedding that he had to take a break to rest each time he put something into his suitcase.
Instead of attending the wedding, the 30-year-old Washington, DC, data analyst visited his doctor, who diagnosed “some post-viral thing” and prescribed rest. Lewis found a new doctor, went to a long COVID clinic, and saw multiple specialists, but a year later, he’s still sick — and disabled. He meets the federal criteria for long COVID (symptoms that last more than 4 weeks).
He now uses an electric wheelchair whenever he leaves his apartment, a far cry from his pre-COVID life, when he was training for a half marathon.
“Some doctors have genuinely tried to help,” he said. “Most don’t really know what long COVID is, and…since there’s no official guidance on what to do with long COVID patients, they just throw up their hands and say there’s nothing to do.”
That could be changing — at least the part about official guidance. New findings published in JAMA indicate we’re getting closer to unraveling what long COVID is all about and may help refine how it is defined and diagnosed. The study, published in May, identified the 37 most common symptoms of long COVID, an important step toward better understanding and treament of the condition, which affects an estimated 65 million people worldwide.
Although the study, “Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection,” provides a way to systematically identify the condition, the authors were clear that this is significant but that it is only a first step. Naming symptoms is very different from understanding what causes them, and understanding them is critical for developing effective treatments, said pulmonologist Bruce Levy, MD, a study co-author who is interim chair of medicine at Brigham and Women’s Hospital in Boston and a professor of medicine at Harvard Medical School.
Researchers relied on self-reported symptoms from the 9764 participants, all adults who are part of the ongoing Researching COVID to Enhance Recovery (RECOVER) Initiative, a longitudinal study run by the National Institutes of Health. Some patients had long COVID when they signed up for the study, some developed it afterward, and some had never had it, or if they had, they were unaware.
Other studies, most of them involving smaller groups of patients, have examined long COVID biomarkers, risk factors, and specific symptoms. Levy said it’s important to have a symptom-based definition of long COVID that draws from a large cohort of patients who reported on their experiences with symptoms during the aftermath of infection. However, he pointed out that because participants volunteered for the study and were not chosen on the basis of specific criteria, they may not be representative of the more general population of patients with long COVID.
“We need this kind of evidence — it’s important to have self-reported symptoms, because clearly, the patients know what they’re feeling,” Levy said. “But it’s only part of the picture.”
Levy said the definition of long COVID needs to be further refined by ongoing research, including objective assessments of clinical findings, laboratory testing, imaging, and biomarkers.
One of the notable findings in the JAMA study is that certain symptoms tend to occur in clusters. The biostatisticians and analysts who processed the data identified four subgroups of very common symptoms that appeared together in more than 80% of the long COVID patients:
- Loss of or change in smell and taste
- Post-exertional malaise and fatigue
- Brain fog, postexertional malaise, and fatigue
- Fatigue, postexertional malaise, dizziness, brain fog, gastrointestinal issues, and palpitations
Many of those symptoms are also associated with underlying conditions not related to long COVID, which makes an accurate diagnosis a challenge.
“Just the fact that they would cluster into four groups suggests that underlying all this is not just one unifying pathobiology,” Levy said. He stressed that clinicians need to understand what’s causing the symptoms before they can properly treat patients.
He pointed out that two of the possible disease-driving mechanisms are persistence of the virus and prolonged inflammation that is slow to resolve. For patients experiencing inflammation after the virus is gone, an anti-inflammatory therapy would be most appropriate.
But if they have persistent virus, “you would want to treat with an antiviral antibiotic and not quiet down the body’s antiviral inflammatory response,” he said. “How you treat the two potential underlying causes of long COVID could thus be almost diametrically opposed, so that’s part of the importance of figuring out what is the underlying cause of those symptoms, not just identifying the symptoms themselves.”
More studies are needed to determine whether long COVID is a syndrome or is related to a singular pathobiology, experts said.
That’s consistent with the impression of long COVID researcher Harlan Krumholz, MD, the Harold H. Hines, Jr, Professor of Medicine (Cardiology) at Yale School of Medicine.
Krumholz worries that some clinicians might use the JAMA findings to dismiss patients whose symptoms meet the criteria in the scoring system developed for the study.
“It’s important for people who read this paper to know that this is preliminary,” said Krumholz, a principal investigator of another patient-focused study designed to understand long COVID — the “Yale Listen to Immune, Symptom, and Treatment Experiences Now (LISTEN) Study.” “It’s a condition we don’t understand yet.”
Krumholz said he has lost track of the number of patients he knows who, like Daniel Lewis, are ill and are unable to get answers. “There is an intense sense of inadequacy on the clinical side and the research side,” he said. “Every day people ask me, ‘Are there any evidence-based strategies?’ And so far I have to say, every day, ‘No.’ I hate to say it, but it’s kind of like every patient is on their own. They’re trying different things because they can’t wait. There is an imperative to help them.”
At the end of July, the National Institutes of Health launched phase 2 clinical trials to evaluate at least four new treatments for long COVID, all part of the RECOVER initiative. By then, Lewis, who believes his myalgic encephalomyelitis/chronic fatigue syndrome was triggered by the virus, had made plans to try an alternative, experimental therapy.
“My hope is that it will fix me,” he said. “I’m excited about those kinds of hard-hitting infusion, immunological treatment.”
As for the JAMA study, he didn’t allow himself to get excited when it was released, a function of his experience as a data analyst and long COVID patient.
“I don’t think it moves the needle much yet,” he said. “It’s the first study, and we shouldn’t expect much from the first pieces of data to come out of that. If they keep following that cohort and go deeper and deeper, they’re going to find some interesting stuff that will lead to treatments.”
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