MIS-C displays clinical, proteomic heterogeneity, 'outsized' CXCL9 levels
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Multisystem inflammatory syndrome in children demonstrates clinical and proteomic heterogeneity, with signals suggestive of thrombotic microangiopathy and macrophage activation syndrome, according to data presented at ACR Convergence 2021.
Data also suggested that patients with the post-COVID-19 syndrome, also known as MIS-C, are additionally characterized by an “outsized” CXCL9 response to interferon-gamma (IFNg).
“Multisystem inflammatory syndrome in children, or MIS-C, is a post-infectious complication of pediatric SARS-CoV-2, typically occurring 3 to 4 weeks after asymptomatic exposure,” Edward Behrens, MD, of the Children’s Hospital of Philadelphia, told attendees at the virtual meeting. “The symptoms of MIS-C include myocarditis and ventricular dysfunction, significant gastrointestinal inflammation/diarrhea, conjunctivitis, rash, thrombocytopenia and lymphopenia.”
“It was originally recognized as a Kawasaki’s disease-like syndrome, with many patients also having coronary artery aneurisms or dilation,” he added. “MIS-C can certainly be fatal if left untreated, both from the dehydration from the diarrhea in combination with the polar cardiac function and decreased output from the ventricular dysfunction. The etiology and biology of MIS-C is relatively poorly understood.”
To better characterize the biology of MIS-C, Behrens and colleagues analyzed the plasma proteome of more than 1,400 proteins in children with COVID-19. Between April 2020 and October 2020, the researchers enrolled a total 63 hospitalized patients, including 22 with MIS-C, 15 with severe COVID-19 and 26 with asymptomatic or mild COVID-19. They also included remnant plasma samples from 25 healthy patients. Using the Olink Explore 1536/384 protein biomarker platform, Behrens and colleagues interrogated the plasma proteome of all 88 patients.
The researchers created a principal component analysis (PCA) that mapped all proteins and all patients in order to better understand how the overall proteome of patients with MIS-C changes over time. They then PCA transformed data for convalescent samples on that space.
According to the researchers, convalescent samples shifted towards the healthy patients, suggesting that, after treatment, the proteome in MIS-C patients returns to a baseline state. When they analyzed CXCL9 as the key protein associated with IFNg response, they found that all patients with COVID-19 demonstrated a positive CXCL9 response to increasing IFNg. Additionally, Behrens and colleagues reported that patients with MIS-C showed a “disproportionately high” CXCL9 response to IFNg, compared with the other groups.
MIS-C patients also expressed less TRIM21 protein compared to healthy patients, consistent with a derepression of IFNg signaling.
According to Behrens, unsupervised hierarchical clustering revealed two distinct groups of patients with MIS-C demonstrating increases in multiple Macrophage Activation Syndrome (MAS) markers. The two clusters differed primarily in IFNg expression — either high or low.
Through hierarchical clustering, the researchers reported that SC5B9 correlated most highly with PLA2G2A, PDGFC, SELE, CALCA, NOS3, VWA1 and TYMP, suggesting a signature consistent with thrombotic microangiopathy (TMA). Patients with higher MAS or TMA markers were more likely to meet clinical criteria for MAS or TMA, respectively, the researchers wrote.
Patients with MIS-C who demonstrated a low IFNg signature were at higher risk for requiring inotropes.
“MIS-C has both clinical and proteomic heterogeneity, with a mixture of TMA- and MAS-like signals, both in the clinical presentation as well as in the proteome,” Behrens said. “MIS-C patients show a CXCL9 level that is outsized given their interferon-gamma response, suggesting that part of the MIS-C physiology is an interferon-gamma hyper-responsivity. Finally, there are two clusters of MIS-C patients: an interferon-gamma high and an interferon-gamma low, with interferon-gamma high patients having milder cardiac disease.”
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Behrens E. Abstract 0961. Presented at: ACR Convergence 2021; November 5-9, 2021 (virtual meeting).
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