From the Journals

IBD study hints at cause of postacute COVID

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Better understanding of urgent research priority

Understanding the cause and risk factors for the postacute COVID-19 condition is an urgent research priority. The study by Zollner et al. found new clues about the cause of the post–COVID-19 condition in intestinal tissues of patients with IBD. The first important finding was that most adult patients with IBD have persistent viral antigen in their intestine months after even mild acute COVID-19. Importantly, researchers could not recover replicating virus from these tissues, indicating there was unlikely persistent active infection or viral transmissibility. The second major finding was that the presence of persistent viral antigen in intestinal tissue was strongly associated with postacute COVID-19 symptoms. This suggests that persistence of SARS‑CoV‑2 antigen after acute infection could perpetuate an ongoing inflammatory response that causes the postacute COVID-19 condition.

Michael J. Rosen, MD, MSCI, is Endowed Professor for Pediatric IBD & Celiac Disease and director for the Center for Pediatric IBD & Celiac Disease at Stanford (Calif.) University.

Dr. Michael J. Rosen

Since the researchers studied only IBD patients, we do not know if the findings are generalizable to healthy patients after mild acute COVID-19. Although they found some impairment of T-cell responses to the virus in patients on anti-tumor necrosis factor therapy, there was no association of immunosuppressive therapy and either viral antigen persistence or postacute COVID-19 symptoms. Therefore, it is not clear whether IBD or IBD treatment delays viral antigen clearance.

Zollner et al. used the intestine as a window onto how this virus may lead to long-lasting symptoms in IBD patients. However, it does not change our understanding that corticosteroids, poorly controlled IBD, and comorbidities, and not biologic or immunomodulator therapy, increase the risk of severe illness and mortality related to acute COVID-19 in IBD patients.

Michael J. Rosen, MD, MSCI, is Endowed Professor for Pediatric IBD & Celiac Disease and director for the Center for Pediatric IBD & Celiac Disease at Stanford (Calif.) University. Dr. Rosen served on an advisory board for Pfizer.



A new study among patients with inflammatory bowel disease (IBD) suggests that viral antigen persistence in the gut may contribute to post-acute COVID-19 syndrome.

Postacute COVID-19 syndrome is now understood to be a multiorgan condition with symptoms that may include fatigue, cognitive dysfunction, and pain. Poor baseline health and severe acute infection are risk factors for the condition, but nonhospitalized illness can also lead to persistent symptoms.

Researchers found that nearly two-thirds of IBD patients had persistence of the antigen in infected tissues up to 8 months after a mild (nonhospitalized) acute COVID-19 infection. The study is the first to tie gut antigen persistence to post-acute COVID symptoms, and the results imply that the antigen may lead to immune perturbation and ongoing symptoms.

The study was published online in Gastroenterology.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the membrane-bound angiotensin-converting enzyme 2 to gain entry into cells, which is expressed in the brush border enterocytes, as well as elsewhere in the body.

Previous research using intestinal epithelial organoids confirmed that SARS-CoV-2 is capable of infecting the human epithelium and that the virus can be detected in anal swabs long after it is cleared from nasal passages.

One potential explanation is viral immune perturbation or inflammatory tissue injury. Supporting evidence includes neural accumulation of memory T cells in patients with neuropsychiatric symptoms such as malaise and depression, and similar changes are seen with age-related immune senescence and tissue injury. Hyperactivated B and T cells, as well as other innate immune cells, have also been linked to postacute COVID-19, as has heightened expression of proinflammatory cytokines.

To explore the potential role of persistent viral antigens, the researchers gathered biopsies during upper- and lower-gastrointestinal endoscopy in 46 patients with IBD whose prior COVID-19 infection (mean, 7.3 months previous) had been confirmed by polymerase chain reaction and who were seen at the IBD outpatient unit of the investigators’ institution. In all, 43.5% of patients were female, and the average age was 44.67 years. Overall, 67.4% had been diagnosed with Crohn’s disease, 28.3% with ulcerative colitis, and 4.3% had unclassified IBD; 23.9% had a history of exposure to anti–tumor necrosis factor therapy. Among patients in the study, 32 of the patients tested positive for mucosal SARS-CoV-2 RNA, and there was no association between the presence of viral RNA and IBD type.

The researchers found that 52%-70% of patients had antigen persistence in any gut segment, as measured by nucleocapsid immunofluorescence or expression of one of four viral transcripts. They detected persistence of the nucleocapsid in epithelial cells and CD8+ T cells. Viral antigens persisted in patients with and without exposure to immunosuppressive therapy, and there was no association with antigen persistence and severity of acute COVID-19 infection or the presence of inflammation at the time of the endoscopy.

The researchers believed that the persistent viral antigen reflects incomplete clearance from the original infection rather than a latent or persistent infection because they could not replicate the virus in biopsy samples. Most biopsies within a patient produced some, but not all, of the viral transcripts tested. The authors suggest that immunosuppressive therapy may lead to incomplete viral clearance. Some patients lacked humoral nucleocapsid IgG antibodies, especially among those with gut antigen persistence.

In fact, only patients with gut viral RNA persistence had symptoms of postacute COVID. “This observation strongly argues for a role of viral antigen persistence in postacute COVID-19 and it appears plausible that SARS-CoV-2 antigen persistence, possibly in infected tissues beyond the gut, could impact host immune responses underlying the postacute COVID-19 syndrome,” the researchers wrote.

There is precedent for such a phenomenon in influenza. Mouse models have shown that ineffective clearance can influence adaptive immune responses and memory T-cell formation in lymph nodes of the lung. Another report found that COVID-19 pneumonia survivors have persistent changes to pulmonary CD8+ T cells.

The study is limited by its small sample size and a lack of a replication cohort. The study was also conducted in IBD patients because the researchers believed they were at higher risk of COVID-19 infection, although the researchers note that viral antigen persistence has been observed 2 months after recovery from COVID-19 in patients without IBD or exposure to immunosuppressants.

The researchers call for studies in patients without IBD to determine whether viral antigen persistence is a key mechanism in postacute COVID-19.

The researchers have no relevant financial disclosures.

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