Small Study Finds No Obvious Physical Causes for Long COVID Small Study Finds No Obvious Physical Causes for Long COVID

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Participants with long COVID, or postacute sequelae of SARS-CoV-2 infection (PASC), in a small, prospective study showed no evidence of abnormal systemic immune activation or persistent viral infection, according to a report published today in Annals of Internal Medicine.

The study included 189 people with laboratory-documented COVID-19 and a control group of people with no history of COVID or serologic evidence of SARS-CoV-2 infection. Both groups were enrolled at the same time from the same geographic area.

Participants with COVID were self-referred adults who were at least 6 weeks from their first symptoms, regardless of whether they had PASC.

All participants had an extensive assessment, including medical history, a questionnaire about whether they had 17 symptoms, a neurocognitive assessment, screening for depression and anxiety, and measured health-related quality of life.

At enrollment, symptoms consistent with long COVID were reported by 55% of the COVID-19 group and 13% of controls.

“Exploratory studies found no evidence of persistent viral infection, autoimmunity, or abnormal immune activation in participants with PASC,” write the authors, led by Michael C. Sneller, MD, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.

They say the condition mirrors a swath of other illnesses that are hard to easily define.

“The constellation of subjective symptoms in the absence of objective abnormalities on diagnostic evaluation resembles what has been described with other illnesses, including chronic fatigue syndrome/myalgic encephalomyelitis, postinfection syndromes described after resolution of certain viral and bacterial infections, and mental health disorders such as depression and anxiety,” they write.

Words of Caution

But some caution against interpreting these findings as evidence that long COVID lacks objective criteria and relies on patient reports.

“[The study] is quite small, the controls poorly matched, and the results are blatantly contradicted by an extensive body of literature that documents presence of auto-antibodies and persistent virus or viral remnants in many affected individuals. We obviously need more extensive, large, controlled studies,” Eric Topol, MD, founder and director of the Scripps Research Translational Institute and Medscape’s editor-in-chief, said when asked to comment.

In an accompanying editorial, Aluko A. Hope, MD, Oregon Health & Science University, Portland, writes that the study findings should not be interpreted as evidence that long COVID symptoms have no objective basis.

“This is a small study of a group of highly motivated participants, and these findings should not lead to changes in clinical care,” he writes. 

Hope pointed out some of the limitations, agreeing with Topol’s point that the controls were not well matched and were not matched in age or gender. Other limitations included:

  • Investigators conducting the physical exams were not blinded to study group

  • Investigators’ approach to identifying comorbid conditions, such as anxiety, in the study group “likely overrepresented this diagnosis in patients with PASC given that central or peripheral autonomic impairment is a common feature of many postviral fatigue syndromes and is often misdiagnosed as an anxiety syndrome”

  • Findings may not be generalizable to a population of fully vaccinated adults, as most of the study enrollment occurred before COVID-19 vaccines

Hope told Medscape Medical News that studying long COVID will take more atypical research methods over time. 

Long COVID, he said, not only involves multiple symptoms, but those symptoms can get worse after physical or cognitive exertion. Patients experience ups and downs based on the level of stress, and it can be emotional or social as well.

“I think that sort of construct is very difficult to study in a static way where you focus on doing a physical exam at one timepoint and doing a set of labs based on the viral response of a patient in one time point,” Hope said.

Changes Over Time

As someone who has followed hundreds of patients with COVID over time, Hope describes a diffuse set of symptoms that reflect a change in the body’s set point.

“This has been consistent with post-viral fatigue syndromes since the last century,” he said.

To better understand causes, Hope said, researchers will need to assess symptoms over time in the same patient and ask patients about triggers and relapses and ups and downs at times of exertion and also during rest periods to see how their immune systems change over time.

“Those are the kinds of things that would be more relevant and more interesting in the context of long COVID symptoms to understand the pathophysiology,” he said.

What the study does do, he said, is “it lays to rest the notion that if we just exhaust the static assessment, somehow we will uncover some objective understanding of what’s going on. These detailed assessments are not necessarily going to be more informative if we just keep doing more.”

Hope gave an example of patients describing their narcolepsy — another condition that may not have lab values to match symptoms.

“If you did a physical exam in those patients, the findings would all be normal. But that doesn’t mean the person doesn’t have a sleep issue,” he said. “There’s a lot of work to be done around fatigue, immunologic fatigue in particular, when people recover from viral illnesses.”

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