Experts discuss the data on post-COVID-19 symptoms

Christine Laine, MD, MPH, FACP, began the ninth ACP and Annals of Internal Medicine COVID-19 forum by describing the difficulty postacute sequelae of COVID-19 (PASC) pose for internists.

“The current limited understanding of the pathophysiology, epidemiology, and course of this condition makes caring for these patients a vexing challenge,” said Dr. Laine, Editor-in-Chief of Annals and coauthor of a subsequent Annals article summarizing the online forum.

The day of the forum, May 24, brought an additional step toward better understanding of persistent symptoms after SARS-CoV-2 infection—the release, in Annals, of baseline results from an NIH-funded longitudinal study of COVID-19 sequelae.

The senior author of that study, H. Clifford Lane, MD, MACP, led off the forum's panel discussion with an explanation of the methods and results of the research.

“This study was initially conceived shortly after the pandemic began, and we were fortunate to be able to begin enrollment early in June of 2020, so the first participants in this cohort have now been followed for close to two years,” said Dr. Lane, director for clinical research and special projects at the National Institute of Allergy and Infectious Diseases in Bethesda, Md.

The study included 189 self-referred patients with a history of COVID-19, 104 of them with a persistent or new symptom since infection, and a control group of 120 patients with no antibodies to SARS-CoV-2.

One major finding of the study was apparent from a simple breakdown of the groups by sex. Both the COVID-19 and control groups were 55% to 56% female, explained Dr. Lane. “However, if you looked at the COVID group split into no PASC or with PASC, you saw there was an increased percentage of women in the group with PASC, at 64%, versus 43% in the no-PASC group,” he said.

Overall, persistent symptoms were reported by 55% of the COVID-19 group, based on a structured questionnaire that asked about 17 different symptoms. Those found at higher rates in the COVID-19 group than in controls included fatigue, dyspnea, headache, and memory impairment.

Researchers also performed lab tests on participants, including C-reactive protein, D-dimer, and autoantibodies. “No differences were noted among the groups in these measurements,” Dr. Lane said. “There was a difference in the six-minute walk test such that those in the COVID-19 group had a shorter six-minute walk test, but this did not distinguish PASC versus non-PASC.”

Besides female gender, there was only one predisposing factor identified with PASC: anxiety. Those with a history of anxiety were more likely to have PASC, and those with PASC scored higher on measures of anxiety. “We also saw lower quality of life [in PASC patients], certainly not to be unexpected,” said Dr. Lane.

He noted several limitations to the study, including that most included patients had mild to moderate acute illness, the sample size was relatively small, and the patients were all self-referred.

There was also the limitation of how much actionable information can be drawn from the findings. “In summary, PASC is a significant clinical entity that has yet to be precisely defined,” Dr. Lane concluded in his summary.

The solution, for both individual patients and society, is more research, noted panelist Carlos del Rio, MD, FACP, a distinguished professor in the division of infectious diseases at Emory University School of Medicine in Atlanta.

Specifically, he pointed internists to the NIH's RECOVER Initiative (Researching COVID to Enhance Recovery). “If you have the opportunity to refer your patient into the RECOVER cohort, I think it's a good opportunity. Not only will they get good care, but we really have a lot of questions to be answered,” said Dr. del Rio.

There may already be data that can help explain PASC, said panelist Aluko Hope, MD, MSCE, associate professor in the division of pulmonary and critical care at Oregon Health & Science University in Portland and medical director of the university's Long COVID-19 Program.

“I wish that we would go back to the studies on chronic fatigue, because the immunologic fatigue syndromes that happen after viral illnesses have been around for longer than most of us—since the beginning of the last century,” he said. “The postviral fatigue, the cognitive impairment, the changes in sleep … It looks very similar to the chronic fatigue syndrome literature.”

Some patients with symptoms after COVID-19 do have specific diagnosable conditions, including cryptogenic organizing pneumonia and reactive airway disease, Dr. Hope noted. “It's all being lumped into long COVID, and I think that that's a challenge. But I do think the core of what we're seeing in these clinics is a postviral fatigue syndrome,” he said.

Differentiating these patients is one of the main challenges of treating PASC, Dr. del Rio noted. “Please listen to the patient and strive to understand the symptoms. But most importantly, let's make sure they don't have another illness. I've seen plenty of people referred to me as long COVID patients who happen to have something else,” he said.

It's reasonable to ask the experts for help on tough cases, noted panelist Lindsay Lief, MD, associate professor of clinical medicine at Weill Cornell Medicine/NewYork-Presbyterian Hospital and director of the Weill Cornell Post-ICU Recovery Clinic.

Dr. Lief and the other experts discussed clinical vignettes related to PASC during the forum, including one about a patient who was still unable to work eight months after an ICU stay for COVID-19. For patients like this, “I think referral to a post-COVID center is appropriate,” Dr. Lief said.

Forum moderator Elisa I. Choi, MD, FACP, followed up on that point during the Q&A portion of the forum. “Until we know more about PASC, is it best to refer all patients with persistent symptoms to a specialty setting to get evaluation and treatment?” asked Dr. Choi, who is Chair of ACP's Board of Governors and a practicing physician and educator who is board-certified in internal medicine and infectious diseases.

“The issue is we have what, 80 million, 90 million, 100 million Americans that have been infected? If 10% of them get PASC … there's no referral place that can take all the patients,” answered Dr. del Rio. “We have all set up clinics, and our clinics are full very quickly.”

Thus, the care is going to fall to general internists, he continued. “In the early years of HIV, some of the people that are now called experts … became experts because they saw the patients. I think something similar is happening here. None of us are experts; we're all learning as we go,” Dr. del Rio said. “You have to be a thorough internist. I think you have to be open to inquiry, to reading the literature and to understanding science and to really staying up to date.”

Finally, the experts also delved briefly into potential therapeutics, noting that vaccines, antivirals, steroids, and more unlikely therapies have all been discussed but not yet proven to alleviate PASC.

“There's such appetite for intervention that sometimes we have to be careful with the politics at the moment. A lot of those things are coming from the movements that are not particularly scientific,” said Dr. Hope, who recommended using medications when appropriate, but more often “trying to help the patient understand where less might be better than more.”