Since the early reports of a severe COVID-19–related condition called multisystem inflammatory syndrome in children a few months into the pandemic, doctors and scientists have joined efforts to understand it, but its cause is still uncertain. According to a study published in The Journal of Clinical Investigation on May 25, researchers propose that it is brought on when viral particles in the gut of these patients make their way into the blood. They found that weeks after an initial SARS-CoV-2 infection, kids had viral RNA in their stool and antigens in their blood along with markers of a leaky gut, suggesting that the trafficking of antigens—specifically, the SARS-CoV-2 spike protein—from the gut to the bloodstream might be driving MIS-C.

This work “adds an additional perspective on the pathogenesis” of this syndrome, says Petter Brodin, a pediatric immunologist at the Karolinska Institute and the Karolinska...

In adults, severe COVID-19 disease is associated with the presence of the virus in the blood, says Lael Yonker, a pediatric pulmonologist at Massachusetts General Hospital and a coauthor of the study. Although doctors have looked, they hadn’t detected the virus in the blood of kids with MIS-C, a rare and severe hyperinflammatory condition that is responsible for 35 children’s deaths in the US. If there are no whole viruses in the blood, maybe there could be viral particles, Yonker says her team reasoned. So they decided to look for antigens in the blood.

The study involved 100 children (19 with MIS-C, 26 with acute COVID-19, and 55 healthy controls). They found significantly higher levels of viral antigens in the blood of MIS-C patients than in the rest of the kids.

[This] debunks the idea that there is no virus and that this is totally post-viral.

—Anne Rowley, Northwestern University and the Ann & Robert H. Lurie Children’s Hospital of Chicago

The researchers had previously been unable to detect notable viral particles in respiratory secretions from most children with MIS-C, so the antigens in the blood must have come from somewhere else. The predominance of gastrointestinal symptoms—diarrhea, vomiting, no appetite—in MIS-C motivated the team to look in the gut. They analyzed the stool of these kids and found evidence of viral RNA. SARS-CoV-2, apparently, had found a niche.

The team also found that MIS-C patients showed significantly higher levels of zonulin, a protein that modulates intercellular tight junctions, than did the other kids in the study. High levels of zonulin are associated with increased permeability of the gut, and have been implicated in several disorders, including celiac disease.

According to the authors, the prolonged presence of the virus in the gut might disrupt its microbiome, stimulating zonulin release. The subsequent loss of the gastrointestinal mucosal barrier’s integrity leads to the leakage of the spike protein into the blood, they speculate. Previous work—some involving the authors of this study—have proposed that a subunit of the spike acts as a superantigen, triggering the hyperinflammatory response observed in MIS-C patients. The spike protein leaking from the gut into the blood could complete the model of how the condition comes about.

See “Kids’ Severe COVID-19 Reaction Bears Unique Immune Signature

Anne Rowley, a pediatric infectious disease specialist at Northwestern University and the Ann & Robert H. Lurie Children’s Hospital of Chicago, says that the highlight of this paper is the viral load detected in the gut during the course of MIS-C. Everyone in the field refers to MIS-C as a post-viral event, she says, but that is all based on analyses of SARS-CoV-2 in the respiratory tract. If these data are correct, she says, this “debunks the idea that there is no virus and that this is totally post-viral.”

Rowley adds that she has some concerns regarding different aspects of the data. For instance, she is puzzled by the levels of spike antigen detected in the blood of healthy controls, and she questions whether the antibodies used to detect it are reliable. In a follow-up email to The Scientist, the authors write that this is likely explained by the cross-reactivity of the antibodies with other coronaviruses that cause common colds, and that is why they compared the MIS-C patients to a cohort of healthy controls. Given her various concerns, Rowley says that these results “would need to be confirmed by a totally independent group of investigators before I would feel confident that this explains MIS-C.”

Brodin notes that it is not yet possible to state that a leaky gut is driving MIS-C. “There are many conditions associated with increased gut permeability,” and these analyses cannot tell “whether this is a cause or a consequence of the disease.”

Blocking zonulin as a potential treatment for MIS-C

Encouraged by their findings, Yonker and her colleagues asked the US Food and Drug Administration for compassionate use of larazotide, a zonulin antagonist, in a 17-month-old MIS-C patient with a complex medical history. The toddler was not improving with standard treatment, which included steroids and intravenous antibodies. Larazotide was found to be safe in clinical testing to treat celiac disease and is currently in a Phase 3 clinical trial. Following the treatment, Yonker’s patient showed clinical improvement related to his MIS-C symptoms, and his plasma spike antigen levels decreased.

Alessio Fasano, a pediatric gastroenterologist at Massachusetts General Hospital and a coauthor of the study, says that this achievement, derived from stopping the leakage of antigens from the gut into the bloodstream, is an indication that the leaky gut is a cause and not a consequence of MIS-C. Fasano, who discovered zonulin in 2000, is a cofounder of Alba Therapeutics, a company that was in charge of earlier clinical trials to test larazotide for celiac disease. He makes clear that he won’t be involved in any trial using zonulin to treat MIS-C.

Rowley says that results obtained from one patient do not prove anything. “Most [MIS-C] patients do eventually get better, no matter what you do,” she says. “It theoretically could support the idea, but when it’s just one patient, it could be chance.”

See “Severe Symptoms of MIS-C Typically Clear Within Six Months: Study

According to Yonker, the team has treated four other patients with larazotide, following the FDA’s permission for compassionate use. The analysis of their outcomes has not been completed, but anecdotally, she says, these kids have responded very rapidly to the treatment, particularly in their gastrointestinal symptoms. Yonker acknowledges that without a placebo control, it is not possible to know how the patients would have done otherwise, so the team is planning a clinical trial to test this further.

“What we see is very promising, but we need to do the placebo-controlled study to really know its efficacy. We hope to do that this fall,” says Yonker. 

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