The coronavirus disease 2019 (COVID-19) pandemic was widely understood to spare children, both in terms of the number of infections and severity of disease. Nevertheless, children continue to be infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with a significant minority of patients experiencing severe symptoms in the form of multisystem inflammatory syndrome in children (MIS-C).

A new study posted to the medRxiv* preprint server explores the distinguishing features of MIS-C as compared to other inflammatory-infectious syndromes in children.

Study: Plasma protein biomarkers distinguish Multisystem Inflammatory Syndrome in Children (MIS-C) from other pediatric infectious and inflammatory diseases. Image Credit: RomanR / Shutterstock.com

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Introduction

While MIS-C is established as a clinical diagnosis, there remains a lack of information on the pathogenesis of this condition. Also known as pediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS), MIS-C typically arises two to six weeks following SARS-CoV-2 infection in children.

Overlapping features of MIS-C often make it difficult for healthcare providers to differentiate between this and other conditions such as Kawasaki Disease (KD) or other severe infections that result in acute respiratory distress syndrome (ARDS) or systemic inflammation leading to multiorgan failure.

MIS-C often presents with persistent fever, skin rash, conjunctivitis, inflammation, gastrointestinal symptoms, or cardiovascular symptoms. In over 70% of children with MIS-C, the illness is critically severe and often accompanied by features of multisystem organ dysfunction and shock.

About 40% of children with MIS-C exhibit symptoms that closely resemble those associated with KD, which is due to acute inflammation of the systemic blood vessels. The cause remains unknown, and no specific diagnostic test has been developed. Importantly, KD responds rapidly to high doses of intravenous immunoglobulin (IVIG), unlike MIS-C, which is mitigated by corticosteroids.

About the study

To develop guidelines that will discriminate between these conditions, the researchers of the current study analyzed a set of different plasma proteins to identify those that could be used as biomarkers of MIS-C but not other similar illnesses.

Previous studies have reported that proteins associated with inflammation, endothelial damage, dysregulation of mucosal immunity, cardiac function, and septic shock have been reported to be present at high levels in MIS-C.

The selected biomarkers have been documented in the literature and have been reported to be raised in patients with MIS-C and other diseases. For the current study, plasma arginase 1 (ARG1), cysteine-cysteine motif chemokine ligand 20 (CCL20), CD163, atrial natriuretic peptide-converting enzyme (CORIN), C-X-C motif chemokine ligands 9 (CXCL9), proprotein convertase subtilisin/kexin type 9 (PCSK9), and a disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS2) levels were analyzed. Quantitative measurements of these proteins were used to determine their utility as discriminatory markers, either alone or in combination.

What did the study show?

Of the 108 plasma samples obtained from children with MIS-C, KD, definite bacterial, or definite viral infections, CD163, CXCL9, and PCSK9 were present at significantly higher levels in the plasma of patients with MIS-C.

Using these three biomarkers, the researchers successfully distinguished seven out of eight cases of MIS-C from other similar conditions. This combination was optimal for this purpose as compared to the use of any two markers.

The incorporation of C-reactive protein (CRP) into this panel increased the ability to distinguish between MIS-C and KD by almost 10%. However, the utilization of CRP did not improve the ability to distinguish between MIS-C and bacterial infections.

Given the overlap in clinical features between MIS-C and KD, especially incomplete KD cases, these findings could be clinically useful.”

Declining plasma concentrations of ARG1 and CORIN were associated with an increased likelihood of severe MIS-C. This indicates a greater likelihood of requiring oxygen and/or inotropic drugs in cardiac failure or of going into shock, respectively.

CD163, which is a scavenger protein that is found in its soluble form when shed during inflammation, is often raised in SARS-CoV-2 infection in children. Likewise, CD163 levels also rise with macrophage activation, thus corroborating its assigned value as an indicator of critically severe MIS-C.

CXCL3 is expressed by white blood cells, especially macrophages, and is involved in the migration and activation of immune cells during inflammation. CXCL3 levels also rise in response to interferon γ (IFN-γ).

PCSK9 is key to cholesterol metabolism, as it regulates the removal of low-density lipoprotein (LDL) from plasma by modulating the number of LDL receptors. Increased levels of PCSK9 are associated with higher plasma LDL levels, thus favoring increased SARS-CoV-2 binding to host target cells. Importantly, SARS-CoV-2 binds to the angiotensin converting enzyme 2 (ACE2) molecules that are attached to cholesterol on the cell membrane.  

PCSK9 also promotes the expression of tumor necrosis factor α (TNF-α), thereby promoting inflammation. PCSK9 inhibitors have been used to treat severe COVID-19 in adults; however, the current study was the first to identify the presence of high PCSK9 levels in children with MIS-C .

ARG-1 mediates the final catabolism of arginine to urea and is often found in the liver. ARG-1 also actively participates in the immune response by modulating inflammatory damage and inhibiting T-cell proliferation. The dysregulation of ARG-1 is associated with multiple inflammatory processes, including cardiovascular, immunological, and cancerous diseases.

Conversely, patients with COVID-19 who have high viral loads have been reported to have high ARG1, which is reduced only as PCSK9 levels rise with severe disease.

CORIN is responsible for the production of atrial natriuretic peptide (ANP) and, as a result, contributes to the regulation of water-electrolyte balance, blood pressure, and blood volume. Previous research suggests that an increased level of the pro-peptide pro-ANP could be a marker of higher mortality risk in children with septic shock or severe sepsis, perhaps because it is the result of low CORIN levels. Likewise, in MIS-C, these changes could be, in part, responsible for hypertension, inflammation, and cardiac weakness.

What are the implications?

This study reports the first protein-based diagnostic signature to discriminate MIS-C from KD and other common bacterial and viral infections.”

Further studies are needed to validate the study findings, which could support the development of more accurate diagnostics for MIS-C, as well as guidelines for its treatment.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.