Measurement of Severe Acute Respiratory Syndrome Coronavirus 2 Antigens in Plasma of Pediatric Patients With Acute Coronavirus Disease 2019 or Multisystem Inflammatory Syndrome in Children Using an Ultrasensitive and Quantitative Immunoassay

Abstract

Background Detection of SARS-CoV-2 antigens in blood has high sensitivity in adults with acute COVID-19, but sensitivity in pediatric patients is unclear. Recent data suggest that persistent SARS-CoV-2 spike antigenemia may contribute to multisystem inflammatory syndrome in children (MIS-C). We quantified SARS-CoV-2 nucleocapsid (N) and spike (S) antigens in blood of pediatric patients with either acute COVID-19 or MIS-C using ultrasensitive immunoassays (Meso Scale Discovery). Methods Plasma was collected from inpatients (<21 years) enrolled across 15 hospitals in 15 US states. Acute COVID-19 patients (n=36) had a range of disease severity and positive nasopharyngeal SARS-CoV-2 RT-PCR within 24 hours of blood collection. Patients with MIS-C (n=53) met CDC criteria and tested positive for SARS-CoV-2 (RT-PCR or serology). Controls were patients pre-COVID-19 (n=67) or within 24h of negative RT-PCR (n=43). Results Specificities of N and S assays were 95-97% and 100%, respectively. In acute COVID-19 patients, N/S plasma assays had 89%/64% sensitivity, respectively; sensitivity in patients with concurrent nasopharyngeal swab cycle threshold (Ct) < 35 were 93%/63%. Antigen concentrations ranged from 1.28-3,844 pg/mL (N) and 1.65-1,071 pg/mL (S) and correlated with disease severity. In MIS-C, antigens were detected in 3/53 (5.7%) samples (3 N-positive: 1.7, 1.9, 121.1 pg/mL; 1 S-positive: 2.3 pg/mL); the patient with highest N had positive nasopharyngeal RT-PCR (Ct 22.3) concurrent with blood draw. Conclusions Ultrasensitive blood SARS-CoV-2 antigen measurement has high diagnostic yield in children with acute COVID-19. Antigens were undetectable in most MIS-C patients, suggesting that persistent antigenemia is not a common contributor to MIS-C pathogenesis.

SARS-CoV-2 Antigenemia is Associated With Pneumonia in Children But Lacks Sensitivity to Diagnose Acute Infection

“…[3][4][5] Spike protein antigenemia has also been inconsistently observed in children with SARS-CoV-2 associated multisystem inflammatory syndrome (MIS-C). 6,7 Due to limited evidence, the clinical utility of detecting and quantifying SARS-CoV-2 proteins in peripheral blood from children with SARS-CoV-2 is uncertain. We, therefore, sought to determine whether antigenemia is a marker of acute SARS-CoV-2 infection or is associated with disease severity or clinical manifestations in children.…”

Evaluation of Autoantibody Binding to Cardiac Tissue in Multisystem Inflammatory Syndrome in Children and COVID-19 Vaccination–Induced Myocarditis

“…Alternatively, it is plausible that the presence of both viral antigens and antibodies may be required for a direct antibody-mediated cardiac pathology, which is supported by findings of 2 studies from Yonker et al showing viral antigenemia in patients with MIS-C and vaccine myocarditis . However, this is contrary to the findings of another study showing that most patients with MIS-C have undetectable levels of SARS-CoV-2 nucleocapsid and spike antigens in their blood …”

“…23 However, this is contrary to the findings of another study showing that most patients with MIS-C have undetectable levels of SARS-CoV-2 nucleocapsid and spike antigens in their blood. 24 As the clinical profile, cardiac involvement, and disease severity of MIS-C and vaccine myocarditis are very different, these 2 conditions could potentially be caused by different dysregulated immune responses. MIS-C is associated with a systemic hyperinflammatory response and excessive cytokine release, which, along with rapid severe cardiac dysfunction that reverses quickly with immunomodulation, suggests that increased pro-inflammatory cytokines (eg, interlukin 6, interferon γ, tumor necrosis factor α) could be contributing to the cardiac dysfunction.…”

Nutraceuticals for Complementary Treatment of Multisystem Inflammatory Syndrome in Children: A Perspective from Their Use in COVID-19

“…However, N and S antigens in acute COVID-19 did not correlate strongly with RT-PCR [ 29 ]. On the other hand, the use of a novel method (MSD S-PLEX CoV-2 N and S assays) demonstrated that, during the early hospital course, SARS-CoV-2 N and S antigens are detectable in blood in most pediatric patients with acute COVID-19, but in few cases of MIS-C [ 30 ]. Therefore, the RT-PCR method for COVID-19 detection is not exclusive to MIS-C diagnosis, and serology and epidemiological linkage are also considered.…”