By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

SYNOPSIS: SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) can be severe and life-threatening. New data suggest that the degree of elevation of spike protein receptor-binding domain antibodies could serve as a diagnostic marker of MIS-C as well as point to potential pathogenic processes.

SOURCE: Rostad CA, Chahroudi A, Mantus G, et al. Quantitative SARS-CoV-2 serology in children with multisystem inflammatory syndrome (MIS-C). Pediatrics 2020;146:e2020018242.

SARS-CoV-2 infection often is asymptomatic or mild in children. However, some children go on to develop a Kawasaki disease-like condition with hemodynamic instability, cardiac dysfunction, and respiratory failure. The clinical features of this condition, now commonly termed multisystem inflammatory syndrome in children (MIS-C), have been described, but serologic correlates had not been described.

Thus, Rostad and colleagues measured various SARS-CoV-2-related antibodies in the serum of 10 children hospitalized with MIS-C, 10 children with symptomatic COVID-19 who did not meet Centers for Disease Control and Prevention criteria for having MIS-C, five children with Kawasaki disease (three with complete and two with incomplete Kawasaki disease), and four hospitalized control children in Atlanta from March to May 2020.

The median age of studied children was 8.5 years (interquartile range 6.5-12 years). The children with MIS-C were mostly boys, Black, previously healthy, and of normal body mass index. By contrast, most children with COVID-19 without MIS-C had an underlying medical comorbidity, and three of the 10 were immunocompromised due to chemotherapy for malignant disease.

Laboratory test features linked to having MIS-C included elevated D-dimer levels, lymphopenia, and thrombocytopenia. Gastrointestinal (GI) symptoms predominated at the time of diagnosis, but some children also had respiratory symptoms. Children with MIS-C were more likely than the others to require intensive care and to require vasodilator therapy for shock. All of the children with MIS-C survived with improvement in health, but two of the children with COVID-19 and cancer died of presumed bacterial sepsis.

All 10 children with MIS-C and nine of the 10 with COVID-19 had detectable immunoglobulin G (IgG) antibodies to SARS-CoV-2 spike protein receptor-binding domain (RBD). Children with Kawasaki disease and the control children did not have marked antibody elevations. RBD IgG levels were significantly higher in children with MIS-C than in the others (P < 0.001 for each group). RBD immunoglobulin M (IgM) levels were higher in MIS-C patients than in hospitalized controls but not in comparison to COVID-19 patients.

Neutralization titers to SARS-CoV-2 were found in 100% of MIS-C patients and in 30% of COVID-19 patients. SARS-CoV-2 full length spike and nucleocapsid antibody titers also were higher in children with MIS-C than in children with COVID-19 (and also higher than in Kawasaki and control patients).

RBD IgG antibody titers in children with MIS-C were positively correlated with erythrocyte sedimentation rates (but not peak C-reactive protein levels), total length of hospitalizations, and the duration of intensive care unit stays.

Rightly, the authors concluded that RBD IgG serological testing might helpfully differentiate patients with MIS-C from those with COVID-19 or Kawasaki disease. The degree of elevation of these antibody titers also was linked with an inflammatory marker and the duration of hospitalization and, thus, might be a predictive measure of disease severity and prognosis.

Interestingly, none of the MIS-C patients had a recent history of a respiratory and/or febrile illness (despite having SARS-CoV-2 antibodies), but two had positive polymerase chain reaction (PCR) tests for SARS-CoV-2 when they presented with MIS-C. It seems that MIS-C follows or is concurrent to SARS-CoV-2 infection, whether or not that infection caused symptoms prior to the onset of MIS-C.

COMMENTARY

The pathophysiology of COVID-19-related MIS-C is poorly understood, and it often is clinically challenging to differentiate this condition from “simple” COVID-19 and Kawasaki disease. The new data from Rostad and colleagues give clues to a possible pathophysiologic mechanism and provide potential help with diagnostic testing. In addition, these data raise hypothetical concern about the safety of some COVID-19 vaccines in children.

The pathophysiology of MIS-C is not clear, but the condition does seem to represent a hyperinflammatory response to SARS-CoV-2 infection. It could be that the development of higher RBD antibody titers with the initial SARS-CoV-2 infection could put some patients at greater risk of developing MIS-C. If this is the case, one might want to screen convalescent serum, when that is used therapeutically, to give serum with higher neutralizing antibody levels and lower RBD antibody levels.

Clinicians might want to measure RBD antibody titers in patients presenting with severe multisystem problems. This might help clarify whether the patient actually has MIS-C or not, and this might help prognosticate the severity of illness in those who do have MIS-C.

Various COVID-19 vaccines are being deployed around the world, but currently more for adults than for children. It is possible that children would be adequately protected and less at risk of MIS-C if the vaccine(s) used for children do not provoke strong anti-RBD responses.