NIH Scientists Advance Understanding of Pediatric Immune Responses to COVID-19 and Rare Inflammatory Syndrome

NIAID Now | February 18, 2022

Colorized scanning electron micrograph of an apoptotic cell (blue) infected with SARS-COV-2 virus particles (red), isolated from a patient sample. The patient sample is not from the study described in this blog post. Image captured at the NIAID Integrated Research Facility in Fort Detrick, Maryland.

Credit: NIAID

NIH Scientists Advance Understanding of Pediatric Immune Responses to COVID-19 and Rare Inflammatory Syndrome

A comprehensive analysis evaluating immune responses in children with SARS-CoV-2 infection and in those with a rare post-infection inflammatory syndrome has revealed distinct immunopathological signatures associated with each condition. The new findings, recently published in Nature Medicine, may help guide optimal treatment for multisystem inflammatory syndrome in children (MIS-C), a rare and severe condition associated with COVID-19 in which different body parts can become inflamed. The research was conducted by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and collaborators. The report first appeared on a preprint server in September 2021 in advance of peer-review.

MIS-C symptoms—fever, stomach pain, diarrhea, vomiting, skin rash, bloodshot eyes and dizziness or lightheadedness—usually appear two to six weeks following SARS-CoV-2 infection and can often occur in children who have had no or few symptoms of COVID-19, according to the Centers for Disease Control and Prevention (CDC). No clear data indicates which children may be at higher risk of developing MIS-C, and no specific therapies exist for the condition. Supportive treatment usually requires hospitalization, where doctors typically recommend intravenous immunoglobulin, which contains infection-fighting antibodies, and drugs that can reduce inflammation, including corticosteroids. The CDC notes that although MIS-C can be deadly, most children improve with medical care.

Investigators analyzed blood samples from 262 children ages 1 to 12 years residing in Chile, Italy, Israel and the United States. 110 children had confirmed COVID-19, 76 were diagnosed with MIS-C and 76 were healthy children who served as case controls. The analysis sought to understand the dynamics of various immune markers of inflammation among children with COVID-19 and in those with MIS-C. Investigators used a “multi-omics” approach, which involves using large data sets to characterize and measure various complex biological processes in a systematic way. 

Investigators detected important differences in how children’s immune systems respond to COVID-19 versus the response observed in adults. In particular, they demonstrated that children have stronger innate immune responses to SARS-CoV-2 compared to adults. They also detected early increased levels of several inflammatory biomarkers in children with MIS-C, with the level of activation being generally higher than and qualitatively distinct from children with COVID-19. Children with MIS-C showed a reduction in certain inflammatory markers over time, which could be due to corticosteroid treatment, according to the authors. Of note, children with MIS-C had increased levels of SARS-CoV-2 fragments in blood samples even if they no longer tested positive for infection via a polymerase chain reaction (PCR) nasal swab test, which indicates that these increased levels were not due to persistent infection in the respiratory tract. Investigators also validated previous findings indicating that some children may be genetically susceptible to MIS-C.
“This study explains why children tend to experience a milder clinical course of COVID-19 compared to adults,” said Luigi D. Notarangelo, M.D., chief of NIAID’s Laboratory of Clinical Immunology and Microbiology and senior author of the paper. “It also demonstrates that prompt intervention with steroids and high-dose immunoglobulins is effective in dampening inflammation and allowing clinical improvement in children with MIS-C.”

Reference: K Sacco et al. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nature Medicine DOI: 10.1038/s41591-022-01724-3 (2022).

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