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The long-term sequelae of COVID-19, collectively known as post-acute COVID-19 syndrome, are rapidly emerging across the globe. Symptoms include lingering fatigue, pain, impaired cognition, and loss of taste and smell.

SARS-CoV-2 infects human epithelium and can be detected in anal swabs, which can remain positive long after nasopharyngeal swabs are negative. Initially dismissed by many, post-acute COVID-19 syndrome is now recognized as a multi-organ disease that poses a growing

Against this backdrop, Herbert Tilg, MD, and Timon E. Adolph, MD, PhD, of the Medical University of Innsbruck in Austria, and colleagues investigated whether severe acute SARS-CoV-2 antigen persistence could be the underlying driver of post-acute COVID-19 syndrome in patients with inflammatory bowel disease (IBD).

Tilg and Adolph discussed their study, recently published in , with the Reading Room.

What was the impetus for undertaking this study? What questions did you want to answer?

Tilg/Adolph: We wanted to understand the potential mechanisms of post-acute COVID-19 syndrome that reflect heterogenous long-term sequelae that are not necessarily related to initial disease severity. Specifically, we asked whether SARS-CoV-2 antigen persistence that frequently occurs in the gut, and possibly other organs, after an acute infection could be a cause of post-acute COVID-19 syndrome.

What was the makeup of the cohort of patients you examined?

Tilg/Adolph: We studied gut mucosal antigen persistence of SARS-CoV-2 in 46 patients with active or inactive IBD who underwent disease evaluation or colorectal cancer screening at our IBD outpatient clinic by upper and lower endoscopy. SARS-CoV-2 antigen persistence was analyzed in biopsy specimens and stool with quantitative PCR and immunofluorescence, and we related viral antigen persistence with symptoms compatible with post-acute COVID-19 syndrome.

What were your main findings?

Tilg/Adolph: First, we found SARS-CoV-2 RNA and viral antigens in the gut mucosa approximately 7 months after mild acute COVID-19 in around two-thirds of patients with IBD. Expression of SARS-CoV-2 antigens was not detectable in stool, however, and viral antigen persistence was unrelated to severity of acute COVID-19, immunosuppressive therapy, and gut inflammation.

The second major finding was that post-acute sequelae of COVID-19 were reported by the majority of patients with viral antigen persistence but not by patients without it. This was surprising to us, but these associations strongly suggest that viral antigen persistence could serve as a basis for post-acute COVID-19 syndrome.

Do the results have any immediate clinical implications for IBD patients?

Tilg/Adolph: They indicate that SARS-CoV-2 antigen persistence is not related to the severity of gut inflammation in IBD. Moreover, viral antigen persistence could be an originator of immune dysregulation or symptoms reported by patients with post-acute COVID-19 syndrome. It is important to note that no direct causality between viral antigen persistence and this emerging syndrome has been established. This needs to be corroborated in controlled clinical trials.

Do your findings align with any other recent research in this area?

Tilg/Adolph: Recent research has reported immune dysregulation in patients with post-acute COVID-19 syndrome, while the origin for such dysregulation is unclear. Again, our data suggest that continuous viral antigen persistence is a likely basis for immune dysregulation, which could be a driver of symptoms in a genetically susceptible host.

Is further research in IBD patients warranted?

Tilg/Adolph: Further studies in and beyond IBD should delineate whether viral antigen persistence indeed elicits the immune perturbation that has been described in post-acute COVID-19 syndrome patients. Moreover, it is tempting to speculate that drugs that facilitate antigen removal could be therapeutically useful for these patients.

What is the next question that needs to be answered?

Tilg/Adolph: Why do some patients exhibit antigen persistence in the gut while others don't? This difference could not be explained by immunosuppressive therapy in our cohort, and so could possibly be related to genetic variation and highly individual immune responses to pathogens.

What is the take-home message for gastroenterologists?

Tilg/Adolph: SARS-CoV-2 viral antigen persistence frequently occurs about 7 months after an acute mild infection in patients with IBD. This does not appear to affect disease course in IBD, but this observation could provide a mechanistic understanding of how post-acute COVID-19 syndrome develops.

You can read the abstract of the study here.