Scientists at Massachusetts General Hospital (MGH) and Brigham and Women’s Hospital (BWH) have identified a promising drug candidate for the treatment of multi-inflammatory syndrome in children (MIS-C), they report in Clinical Care Explorations. MIS-C is a rare but severe and potentially life-threatening condition that usually develops in children, weeks to months after they have experienced a mild or even asymptomatic case of COVID-19.
MIS-C occurs mainly in children and leads to high fevers and a hyperinflammatory response that can affect multiple organs, including the heart, brain, and gastrointestinal organs. Symptoms include stomach pain, diarrhea, vomiting, dizziness, and rash. Fifty-five of the 6,431 children diagnosed with MIS-C have died since May 2020, according to the Centers for Disease Control and Prevention.
A previous study by researchers from MGH and BWH showed that in cases of MIS-C, the SARS-CoV-2 virus, which causes COVID-19, can remain in the gut for weeks to months after the infection. When SARS-CoV-2 is present in the gut, an impaired mucosal barrier can allow small viral particles, such as the spike protein, to enter the bloodstream, leading to infections such as COVID-19 and in rare cases, the hyperinflammatory response that triggers MIS-C.
“Working collaboratively, we’ve been able to demonstrate that viral particles that remain in the gut long after COVID-19 infection can instigate MIS-C,” says co-senior author David Walt, PhD, principal investigator of the Walt Laboratory in the Brigham’s Department of Pathology. “Building on this important discovery, we wanted to see if treatment with a drug developed for another condition — celiac disease — could help resolve symptoms in children experiencing MIS-C.”
Based on these findings, the team administered the drug larazotide acetate to four extremely ill children ages 3 to 17 being treated for MIS-C at MGH. Larazotide decreases the release of zonulin, a molecule that can lead to increased gut permeability and an impaired mucosal barrier. The researchers compared the clinical outcomes of the four children who received larazotide plus steroids and intravenous immune globulin (IVIG) to 22 children who received only steroids and IVIG.
The children who received four daily oral doses of larazotide acetate had a significantly faster resolution of gastrointestinal symptoms and a slightly shorter hospital stay. Serum levels of the highly inflammatory spike protein associated with the SARS-CoV-2 virus dropped much more quickly in children treated with larazotide, clearing from the blood within one day, versus 10 days for children not treated with larazotide.
“These findings suggest that larazotide may provide a safe and beneficial adjuvant therapy for the treatment of MIS-C,” state the authors in the new paper. Adds lead author Lael Yonker, MD, pediatric pulmonologist and director of the Cystic Fibrosis Center at MassGeneral Hospital for Children (MGHfC): “Our results demonstrate the urgent need for the development of diagnostic and prognostic tools to advance our understanding and treatment of this devastating disease.”
“What makes our approach unique is that we have been able to identify the zonulin-dependent leak of the spike protein from the gut lumen into the circulatory system. This provides us not only with a diagnostic tool by searching for the spike protein in blood but also with a therapeutic target of blocking zonulin-dependent increased gut permeability to treat this serious complication of COVID-19 infection,” says Alessio Fasano, MD, director of the Mucosal Immunology and Biology Research Center and chief of the Division of Pediatric Gastroenterology and Nutrition at MGHfC.