Alessio Fasano, MD: W. Allan Walker Chair in Pediatric Gastroenterology and Nutrition, Director, Mucosal Immunology & Biology Research Center, Harvard Medical School/ MGH
Lael Yonker, MD: Assistant Professor of Pediatrics Center & Director of the MGH Cystic Fibrosis Center, Harvard Medical School/ MGH
This study will test the hypothesis that Long COVID in children is associated with chronic reservoirs of the SARS-CoV-2 virus in the gut, increased gut epithelial barrier permeability (“leaky gut”), and leakage of viral spike protein into the bloodstream. To test this hypothesis, the project team will measure SARS-CoV-2 spike protein and cytokines in blood with very sensitive methods. They will also use targeted proteomics to measure zonulin – a biomarker of intestinal permeability discovered and characterized by project team member Dr. Alessio Fasano. The project team will additionally work to develop strategies to collect blood and test for SARS-CoV-2 spike protein in a manner that can best be performed rapidly in a clinical setting.
A second part of the project will establish a proof-of-concept clinical trial to determine if treatment with the medication lorazotide can improve the symptoms of children with Long COVID. Lorazotide is a zonulin antagonist that targets breakdown of gut barrier tight junctions, thereby preventing the potential trafficking of SARS-CoV-2 spike protein from the gut into blood. There is precedence that lorazotide may be able to benefit children with Long COVID. The project team has successfully treated five children with multisystem inflammatory syndrome (MIS-C, a SARS-CoV-2 illness with parallels to Long COVID) with lorazotide with positive effects. These positive effects included more rapid improvement of gastrointestinal symptoms and improved time to SARS-CoV-2 spike protein clearance in blood as compared to untreated controls.
Additional project information:
While children were initially thought to be spared from COVID-19, nearly 14.5 million children have been reported as being infected with the SARS-CoV-2 virus to date. Children are also not spared from Long COVID: a recent systematic review reported that 25% of infected children develop Long COVID, with common debilitating symptoms including fatigue, sleep disorders, persistent dyspnea, and mood symptoms. However, these children are often excluded from large Long COVID studies based on age, so mechanisms driving Long COVID in children have not been well-characterized.
Multisystem inflammatory syndrome in children (MIS-C) is a severe SARS-CoV-2-related inflammatory disorder that has been defined as part of the Long COVID spectrum. In an important study, the current project’s team demonstrated that children with MIS-C harbored SARS-CoV-2 RNA in stool weeks after initial infection. This was accompanied by significantly increased release of zonulin (a biomarker of intestinal permeability) and SARS-CoV-2 spike protein in blood. Overall, the findings suggest that in MIS-C, prolonged persistence of the SARS-CoV-2 virus in the gut drives zonulin-instigated permeability of the mucosal barrier, with subsequent increased trafficking of SARS-CoV-2 antigen from the gut into the bloodstream, leading to hyperinflammation.
A similar phenomenon might occur in pediatric patients with Long COVID. Multiple studies have now identified SARS-CoV-2 genetic material or protein in gut tissue or stool samples obtained months after acute COVID-19, suggesting that the gut may be a common site of a SARS-CoV-2 reservoir in Long COVID individuals. A study by project team collaborators at Harvard Medical School also identified high levels of SARS-CoV-2 spike protein in the blood of adult study participants with Long COVID. Increased levels of zonulin have additionally been documented in adult individuals with Long COVID. The current project will be the first in the world to analyze and connect these factors in children with Long COVID, so that children may directly benefit from diagnostics and treatment options derived from the scientific findings.