Long COVID symptoms may have causes other than SARS-CoV-2

A French study finds that, of 20 persistent physical symptoms reported by adults who said they had recovered from COVID-19, only 1 was linked to SARS-CoV-2 infection, as indicated by the presence of antibodies to the virus.

The researchers, however, said that the results don't discount the presence of symptoms but rather underscore the importance of considering all possible causes in addition to COVID-19, such as other diseases, anxiety, or deconditioning related to the pandemic but not the virus itself.

The study, published yesterday in JAMA Internal Medicine, involved analysis of blood samples from 26,823 adult participants who reported recovering from COVID-19.

The participants were provided self-sampling dried-blood spot cards from May to November 2020. And from December 2020 to January 2021 they completed questionnaires about COVID-19 infection, symptoms lasting longer than 8 weeks, and whether they thought the two were correlated.

Participants were aware of their serology results when they indicated whether they thought they had COVID-19. Average age was 49.4 years, and 51.2% were women.

Only loss of smell tied to previous COVID-19

The prevalence of persistent symptoms was 0.5% (146 participants with loss of smell) to 10.2% (2,729 participants with sleep problems). Of all participants, 1,091 tested positive for SARS-CoV-2 antibodies, including 453 participants (41.5%) who later reported having had COVID-19. A total of 914 participants said they had COVID-19 before the serology test, including the 453 (49.6%) with a positive serologic test result.

Self-reported COVID-19 infection was positively associated with lingering symptoms (odds ratios [ORs], 1.39 to 16.37), except for impaired hearing (OR, 1.45) and sleep problems (OR, 1.14).

A positive serology test result was positively linked with only a persistent loss of smell (OR, 2.72), even when the researchers considered only participants who attributed their symptoms to SARS-CoV-2 infection. An adjusted analysis for self-rated health or depressive symptoms showed similar results, and the interaction between beliefs and serology results was not significant.

Similarly, confirmation of the COVID-19 diagnosis by a laboratory test or a physician (versus the belief the participant had it and excluding participants who said they didn't know if they had it) was also associated only with an impaired sense of smell (OR, 4.29).

The researchers noted that most previous studies of long COVID-19 included only patients with confirmed COVID-19 infection and therefore lacked a control group.

"Indeed, our results showed that the persistent physical symptoms observed after COVID-19 infection were quite frequent in the general population," they wrote.

"Although our study did not assess long COVID per se because we also included participants without COVID-19 infection, these specific analyses may be more representative of the long COVID clinical issue in real-life settings than the picture provided by cohorts of patients with a laboratory-confirmed or physician-documented COVID-19 infection."

Possible belief-related maladaptive health behaviors

The authors said that the study results could be explained by two main mechanisms, the first of which was that having lingering symptoms may have led participants to believe that they had COVID-19.

Diseases other than COVID-19 may have caused the symptoms, they said, or the belief in having had a SARS-CoV-2 infection may have led to maladaptive health behaviors such as reduced physical activity. "These mechanisms are thought to contribute to the long-described persistence of physical symptoms after acute infections," they wrote.

In an audio interview with Mitch Katz, MD, JAMA Internal Medicine deputy editor, senior study author Cedric Lemongne, MD, PhD, of the Universite de Paris, said, "The persistent symptoms may also be due to the acute symptoms that you may have experienced due to the coronavirus or to another disease. But in this sense, the persistence of the symptoms because of hypervigilance or because of the health behaviors or the new health behaviors that are caused by the concerns or beliefs about the symptoms may have contributed to perpetuate the symptoms."

Katz also pointed out that many patients with lab-confirmed COVID-19 have lingering heart, kidney, and other damage that has been demonstrated via medical tests, and Lemongne agreed that this is an important point.

The authors said in the study that the results suggest that further research into lingering physical symptoms after COVID-19 infection should also consider mechanisms that may not be specific to the SARS-CoV-2 virus. "From a clinical perspective, patients in this situation should be offered a medical evaluation to prevent their symptoms being erroneously attributed to COVID-19 infection and to identify cognitive and behavioral mechanisms that may be targeted to relieve the symptoms," they concluded.

In the interview, Lemongne said the results were unlikely to have been influenced by insufficiently sensitive antibody tests.

"If our results would have been explained to some extent by particular subsets of participants, let's say, for those with negative serology, but having actually been infected by SARS-CoV-2, we should have expected a significant statistical interaction, and we found none," Lemongne said.

His hospital, he said, addresses these patients' symptoms through a series of consultations with an internist, a psychiatrist, and a physician specialized in physical activity to address possible physical deconditioning and refer the patient to rehabilitation services, if needed.

"We only started this program 3 months ago, so we are far from, I think, quantitative data to draw some conclusion about the relevance of this management," he said. "But we're quite confident that it helps many, many of these patients."

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