Study reveals complex immunology behind MIS-C in children with COVID-19

In a recent paper published in the prestigious journal Cell, researchers from Sweden and Italy show that inflammatory response in Multisystem Inflammatory Syndrome in Children associated with coronavirus disease (COVID-19) differs from the cytokine storm found in severe acute illness, involving autoantibodies at the same time and sharing several features with Kawasaki disease.

The infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is usually relatively mild and very often asymptomatic in children. Still, this view is challenged by recent reports describing children that have developed rare but quite severe hyperinflammatory syndrome in the United Kingdom, Spain, Italy, and New York City.

The complication is known as the rare Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19, which develops approximately 4-6 weeks after infection. The condition is characterized by high fever, organ dysfunction, and elevated inflammatory markers.

Albeit the exact pathogenesis is not clear, MIS-C has overlapping features with Kawasaki disease indicative of vasculitis with a plausible autoimmune etiology. This is also coupled with an imbalance of cytokines and T cells that produce interleukin-17.

Taking into account the severity of MIS-C associated with COVID-19, as well as the uncertain evolution of the ongoing pandemic, there is a pressing need to fully comprehend the pathogenesis of this condition, as well as its resemblances and differences with Kawasaki disease in order to devise optimal treatment strategies.

As a result, a group of researchers from Sweden and Italy (led by Dr. Camila Rosat Consiglio from Karolinska Institute in Stockholm) have utilized several high-dimensional analysis methods to unveil multiple aspects of the hyperinflammatory response in children with MIS-C.

MIS-C has overlapping features with Kawasaki disease
MIS-C has overlapping features with Kawasaki disease

A methodological tour de force

This study employed complex, systems-level analyses of blood immune cells, cytokine levels, and autoantibodies in four distinct groups: healthy children, children with Kawasaki disease enrolled before COVID-19, children infected with SARS-CoV-2, as well as children presenting with MIS-C.

In order to better understand the hyperinflammation present in MIS-C and Kawasaki disease, the researchers assessed peripheral blood mononuclear cell phenotypes with the use of flow cytometry. Furthermore, Olink assays (based on the proprietary proximity extension assay technology) on plasma samples were also performed.

Additionally, to appraise the complex interaction among different components of the immune system and their co-regulation, the scientists applied Multiomics Factor Analysis to integrate T-cell subset frequencies and plasma protein concentrations.

Immunopathology of all stripes

"We find similarities with the inflammatory response seen in children with Kawasaki disease, but also important differences, such as the interleukin-17A mediated hyperinflammation in Kawasaki disease, but not MIS-C", explain study authors in their Cell paper.

In addition, this study found differences in T-cell subsets and cytokine mediators, which place MIS-C at the junction of Kawasaki disease and immune states of acute SARS-CoV-2 infection in children on the one hand, and the hyperinflammation observed in adults with severe forms of COVID-19 on the other one.

"We also find higher levels of biomarkers associated with arteritis and coronary artery disease in Kawasaki disease than in MIS-C, suggesting a more diffuse endothelial involvement and immunopathology in MIS-C than in Kawasaki disease", further say study authors.

Finally, there was clear evidence of autoantibodies bound to proteins involved in specific immune cell signaling, structural proteins of the heart, and blood vessels. This indicates possible targets of autoimmune attack.

Tailoring the treatment

"Collectively, our findings show that MIS-C is a hyperinflammatory disease with a qualitatively different inflammatory response as compared to what is seen in acute SARS-CoV-2 infection and also different from the hyperinflammation in children with Kawasaki disease", summarize study authors.

Overall, the paper opens the door for a more mechanistic understanding of immune pathology found in MIS-C, underlying immune perturbations, as well as the development of targeted immunomodulatory therapies for alleviating the hyperinflammatory disease and long-term tissue harm in those rare children that are severely affected by COVID-19.

Therapy regimens for MIS-C have thus far primarily followed protocols utilized in atypical Kawasaki disease due to the aforementioned overlap in presentation between these groups of patients. However, these findings paint a much more complex picture with a juxtaposition of shared features and stark differences – with serious treatment consequences.

Hence, more work is warranted in the future. Some argue there is a possibility of a 'second hit' of viral replication or viral reservoirs driving hyperinflammatory state; in the meantime, a number of candidate autoantibodies have already been identified for further research of MIS-C pathogenesis.

Journal reference:
Dr. Tomislav Meštrović

Written by

Dr. Tomislav Meštrović

Dr. Tomislav Meštrović is a medical doctor (MD) with a Ph.D. in biomedical and health sciences, specialist in the field of clinical microbiology, and an Assistant Professor at Croatia's youngest university - University North. In addition to his interest in clinical, research and lecturing activities, his immense passion for medical writing and scientific communication goes back to his student days. He enjoys contributing back to the community. In his spare time, Tomislav is a movie buff and an avid traveler.

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