Experts urge caution in rushing to define long COVID

This is a MedPage Today story.

While long COVID is a rapidly emerging health crisis across the U.S. and abroad, there is not a practical medical definition for it -- and that may not be a bad thing, experts said.

There are overarching definitions for long COVID, like those from the Centers for Disease Control and Prevention, which states that long COVID can first be identified "at least four weeks after infection," and the World Health Organization, which says that it occurs "usually within three months from the onset of COVID-19, with symptoms and effects that last for at least two months."

Medical societies have taken a more clinical swing at defining long COVID in an effort to improve patient care. The American Academy of Physical Medicine and Rehabilitation has listed 50 different symptoms that could be related to long COVID.

Scrolling through patient-driven forums, like the Reddit channel called r/covidlonghaulers, reveals an even more extensive list of symptoms.

Still, researchers and clinicians working to understand long COVID are no closer to identifying clear definitions for diagnosing or treating the condition. The absence of a clearly outlined algorithm for long COVID might be frustrating for physicians and their patients, but experts agree that rushing to define long COVID could present a slew of new challenges.

Building blocks of a definition

According to Dr. Lawrence Kleinman of the department of pediatrics at Rutgers Robert Wood Johnson Medical School in New Jersey, we need to take our time in defining long COVID, whether it's with a checklist, an algorithm, or an entry for the medical dictionary.

"If we defined it a certain way and we missed something in that initial definition, then there will be silence on that until someone comes around and does a postmortem on our analysis," Kleinman, who is also the lead researcher in the Rutgers pediatric hub of the NIH's nationwide RECOVER study, told MedPage Today. "We want to avoid that to the extent that's possible."

He said more research and data collection are needed before the work of defining long COVID is possible in a clinically meaningful way. At the moment, he noted, there isn't even clear criteria for where to start.

For example, should researchers focus on setting a specific number of days a person experiences fatigue after an acute COVID infection? If so, what should those ranges look like -- fatigue after 30 days? As he pointed out, there is not enough data to develop the foundational elements needed for researchers to piece together a practical definition just yet.

Without those building blocks of data, such as the mechanism of fatigue related to long COVID, researchers can't begin to create definitions that might help clinicians diagnose and treat patients with those symptoms.

And they probably shouldn't even try, Dr. Sally Hodder of West Virginia University Health Sciences Center told MedPage Today.

"I think the worst thing, particularly when an entity is not understood, is to start making definitions that are not well based in the science and preclude things that may actually be very important," said Hodder, who is the lead researcher in her university's adult hub of the RECOVER study.

Researchers know far more about long COVID now, but they also agree that it's not the right time to rush to a specific clinical definition, in part because they are still in the discovery phase -- but that is not the only reason.

More complex than 1 definition

Another emerging insight into long COVID is the probability that it is more than just one syndrome. Dr. Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, emphasized that even the name for long COVID, "post-acute sequelae of SARS-CoV-2," suggests plurality.

In fact, the experts who spoke with MedPage Today agreed that it has multiple different phenotypes and endotypes. As such, researchers will need to focus on developing not just one definition, but multiple definitions, each with clinically relevant algorithms and guidelines to help clinicians work through each version of long COVID.

"They're all important, but they're all different," Koroshetz, who is also the co-chair of the RECOVER Senior Oversight Committee, said.

According to Dr. David Putrino, the director of rehabilitation innovation at Mount Sinai Health System in New York City, the focus should be on identifying the endotypes of long COVID, including an immune-mediated type, a viral persistence-mediated type, and a chronic inflammation-mediated type.

Furthermore, he said he believes there are probably 10 to 15 different causes of long COVID, which is why waiting to develop clinically meaningful definitions is critical for the sake of long COVID patients.

"I think that given how hard it is to access adequate care right now, it is imperative that we keep the working definition of long COVID necessarily broad," Putrino told MedPage Today.

He noted that more specific definitions -- that lack foundational evidence -- could lead to overemphasis on patient presentation that could harm efforts to diagnose and treat as many patients as possible.

For example, using positive PCR tests or antibody tests to identify long COVID cases would likely lead to health inequities, since people from historically underserved groups do not have equal access to those tests.

Putrino also noted that antibody tests have not performed as well as expected and that some patients did not experience seroconversion with COVID-19. The bottom line is that a specific definition for even one endotype of long COVID would likely mean that large groups of patients will be left out of any guidelines or algorithms in the future, he said.

"Until we have a handle on all of the endotypes, narrowing the scope of a definition would be an unmitigated disaster," he added.

Treatment without definition

While Putrino, along with several others, expressed concern about defining long COVID, they also pushed for more data collection.

This is one area where physicians and their patients can contribute meaningfully to building the knowledge base needed to eventually develop clinical definitions for long COVID, Putrino said, acknowledging that this has not been an easy task so far. One of his main concerns is time.

"The first interaction that most people with long COVID have with medical professionals is with their primary care provider; their primary care provider has 15 minutes to work with them, which is just not nearly enough time," he noted.

Putrino said that he thinks in order to get long COVID patients the care they need, and to improve broad data collection, primary care providers should be given more time -- an hour for initial evaluations of long COVID patients, instead of the standard 15 minutes.

Diana Berrent, the founder of Survivor Corps, a COVID patient advocacy and research organization, sees similar obstacles to improving the treatment options for long COVID. She noted that the current status of research won't allow for a patient-focused definition of these conditions, and that the medical community still might not be aware of all the potential symptoms of long COVID.

Like Putrino, Berrent said the focus at this time needs to be on working with long COVID patients.

"I think there needs to be an increased urgency focused on how to provide relief, while we are simultaneously searching for a definition and identifying the mechanisms of the upstream causes of these issues," she said. "People are losing hope."

Putrino emphasized that the risks from narrowing the definition would be entirely placed on patients who struggle to get the proper care to treat their unique symptoms. A definition that excludes even a small number of patients would be a critical mistake in the effort to address this crisis, he said.

"What we should be doing right now, given how hard it is to receive care, is we should be keeping the definition necessarily broad," he stressed. "We should be counting everybody, and we should be saying this is the number of people nationwide who have persistent symptoms.