A child’s positive COVID-19 test may come as a surprise to parents, given that a SARS-CoV-2 infection may cause very mild, or even no, symptoms in children. While many children do not suffer severe COVID-19 disease, a subset experience the serious complication known as Multisystem Inflammatory Syndrome in Children (MIS-C), which sends many pediatric patients to intensive care. Presenting 4–6 weeks after infection, the inflammatory condition is marked by abdominal pain, headaches, rashes, and vomiting, and shares many clinical features with the pre-pandemic syndrome of Kawasaki disease (KD).

Kawasaki disease has puzzled pediatricians for more than 50 years. MIS-C and KD share many symptoms though KD disease can also lead to coronary artery aneurysms and heart attack. Unlike MIS-C, which is associated with a specific virus, KD may be triggered by a variety of infectious and environmental stimuli.

To better understand how these inflammatory syndromes compare, researchers collected blood and tissue samples from MIS-C and KD patients. Using artificial intelligence tools, they analyzed patterns of gene expression in both conditions and compared them to gene expression markers of COVID-19.

The study reveals that MIS-C and KD are on the same immune response continuum as COVID-19, with MIS-C being a more severe version of the response than KD. Despite these underlying similarities, the conditions diverge in several laboratory and clinical parameters. The authors said the findings could improve disease diagnosis, monitoring, and treatment in pediatric patients.

This work is published in Nature Communications in the article, “An artificial intelligence-guided signature reveals the shared host immune response in MIS-C and Kawasaki disease.

“We want our immune system to protect us from harmful stimuli, but some children are genetically predisposed to respond more intensely, leading to inflammation and unwanted symptoms across the body,” said Jane C. Burns, MD, a pediatrician at Rady Children’s Hospital-San Diego and director of the Kawasaki Disease Research Center at University of California, San Diego (UCSD), School of Medicine. “The sooner we can identify and understand the child’s inflammatory condition, the better we can tailor our delivery of life-saving support.”

This study was led by University of California, San Diego, School of Medicine researchers Pradipta Ghosh, MD, (left), Jane C. Burns, MD, (center), and Debashis Sahoo, PhD (right). [UC San Diego Health Sciences]
The research team previously identified a set of 166 genes expressed in viral respiratory diseases—including COVID-19—a subset of which also corresponded to disease severity. Researchers found that this same “gene signature” also applied to both MIS-C and KD, suggesting the conditions all stem from a similar underlying mechanism, which involves the rapid release of IL15/IL15RA cytokines.

In this work, they used a computational toolbox of two gene signatures that were developed in the context of SARS-CoV-2 infection. The first was a viral pandemic (ViP) signature and the second was a 13-transcript signature previously demonstrated to be diagnostic for KD.

The team found that a computer program trained to look for this genetic signature could not tell the KD and MIS-C samples apart and that KD and MIS-C are on the same continuum of the host immune response as COVID-19.

“We were not expecting that,” said Pradipta Ghosh, MD, professor of medicine and cellular and molecular medicine at UCSD School of Medicine. “We analyzed MIS-C and KD through the lens of two distinct gene signatures, and both experiments told us these diseases are closely related.”

Ghosh said the two gene signatures likely represent different parts of the same broader immune response.

More specifically, they showed that both of the pediatric syndromes (KD and MIS-C) “converge upon an IL15/IL15RA-centric cytokine storm, suggestive of shared proximal pathways of immunopathogenesis; however, they diverge in other laboratory parameters and cardiac phenotypes.”

UCSD researchers summarize the similarities and differences between COVID-19, MIS-C, and Kawasaki disease, three conditions unified by the same immune-associated gene signature. [UCSD Health Sciences]
While the study provides a new unifying framework for these diseases, it also identifies a few subtle differences. For example, MIS-C patients had lower blood platelet and eosinophil counts, two features that can be measured from routine blood tests. And, while many serum cytokines were similarly elevated in both conditions, a select few were more elevated in MIS-C than in KD samples.

Therapeutics targeting some of these cytokines, including TNFα and IL1β, have already been approved by the FDA and are being tested as novel treatments for MIS-C.

“We believe our findings have a high potential to impact clinical trial planning immediately, and also shape clinical guidelines and patient care down the line,” said Debashis Sahoo, PhD, associate professor of pediatrics and computer science at UCSD School of Medicine and UCSD Jacobs School of Engineering.