Children with MIS-C have highly activated immune systems, study finds

Taking the first deep dive into immune system behavior in patients with multisystem inflammatory syndrome in children (MIS-C), researchers at the Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania found that children with this disease have highly activated immune systems that, in many ways, are more similar to adults with severe COVID-19.

The results, published today in Scientific immunology, show that a better understanding of immune activation in patients with MIS-C could not only help treat these patients better, but also improve the treatment of adults with severe COVID-19.

“This study shows that children with MIS-C are extremely immune, especially to CD8 T cells, but this activation goes away once patients start to improve clinically,” said Laura Vella, MD, PhD, attending physician of the Division. of Infectious Diseases at CHOP and first author of the study. “Our findings provide a broad immunological basis for understanding the pathogenesis and recovery in this novel inflammatory syndrome associated with SARS-CoV-2, with potential implications for disease in adults.”

Pediatricians first recognized MIS-C in April 2020, when pediatric patients began to experience symptoms of hyperinflammation, including fever, gastrointestinal distress, and cardiogenic shock. The syndrome, thought to be a post-infectious complication of SARS-CoV-2 infection, has clinical presentation similarities to Kawasaki disease, particularly vascular involvement, but differs from Kawasaki disease in key ways including clinical, inflammatory, and autoantibody signatures. The syndrome also does not have the respiratory complications typical of adult and pediatric COVID-19. However, up to this point, the immunological characteristics behind MIS-C have remained poorly understood.

To better understand the immunology behind MIS-C, the researchers collected blood samples from patients admitted to CHOP with COVID-19 or MIS-C between April and June 2020. They analyzed more than 200 immune parameters, including serologic and plasma cytokine data, and compared these data with samples from adult patients with COVID-19, recovered adult COVID-19 subjects, and healthy adults.

The researchers found that children with MIS-C had very high T cells, specifically CD8 T cells and a highly activated vascular patrolling CD8 T cell subset. These vascular patrolling CD8 T cells have a proposed role in controlling the persistence or reactivation of viral infection and have also been implicated in cardiovascular disease, which may be related to the vascular symptoms seen in these patients. . The researchers found that the MIS-C patients, all of whom had elevated vascular patrolling CD8 T cells, also required vasoactive support, had elevated D-dimer, and decreased platelets. The rise in CD8 T cells far exceeded what researchers observed in pediatric patients with acute COVID-19 and most adults with COVID-19, but CD8 T cell counts fell in MIS patients -C in conjunction with clinical improvement.

The study also found an asymmetric B cell response in patients with MIS-C compared to acute pediatric COVID-19 and resolved adult disease. Patients with MIS-C are almost universally seropositive for SARS-CoV-2, which means that enough time has passed since infection for an antiviral antibody to develop and be detected. Pediatric and adult patients with acute COVID-19 were not HIV positive, which is consistent with the belief that MIS-C is a delayed event following infection with SARS-CoV-2. Yet although MIS-C is a delayed event, researchers found that patients with MIS-C had elevated plasmablasts, or immature plasma B cells, while plasmablasts in adults recovering from COVID- 19 return to baseline two to three weeks after symptoms resolve, although a subset of hospitalized adult patients with COVID-19 had sustained elevations in plasmablasts.

The researchers proposed three possible factors of immune pathogenesis in MIS-C: (1) the continued activation of adaptive immune responses, driven by the persistent SARS-CoV-2 antigen; (2) an additional trigger, such as virus localizing to a new tissue type or secondary infection, occurring two to three weeks after the initial infection with SARS-CoV-2; or (3) an autoimmune response. Further research is needed to investigate these potential scenarios.

“Infection with SARS-CoV2 can lead to a wide range of clinical and immunological outcomes,” said E. John Wherry, PhD, director of the Institute of Immunology and lead author of the study. “The use of an ‘Immune Health’ profiling approach for pediatric COVID-19 patients not only identified distinct features of the pediatric MIS-C presentation of the disease, but the knowledge gained from studying MIS-C patients may reveal new therapeutic opportunities for children and children. COVID-19 adult patients. “