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
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Abstract
Background
Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in blood has high sensitivity in adults with acute coronavirus disease 2019 (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 24 hours 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; sensitivities in patients with concurrent nasopharyngeal swab cycle threshold (Ct) ≤35 were 93%/63%. Antigen concentrations ranged from 1.28–3844 pg/mL (N) and 1.65–1071 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.
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SciScore for 10.1101/2021.12.08.21267502: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Sites relied on the Boston Children’s Hospital IRB; informed consent was obtained from at least one parent or legal guardian. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources All samples were also tested using an MSD multiplexed serologic assay that measured IgG antibodies against SARS-CoV-2 N, S, and the spike receptor binding domain (RBD) and N-terminal domain (NTD), as well as antibodies against S from SARS-CoV-1 and common circulating coronaviruses (229E, HKU1, NL63 and OC43). N-terminal domain (NTD)suggested: (Leinco Technologies Cat# LT2000, RRID:AB_2893936)HKU1sugges…SciScore for 10.1101/2021.12.08.21267502: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Sites relied on the Boston Children’s Hospital IRB; informed consent was obtained from at least one parent or legal guardian. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources All samples were also tested using an MSD multiplexed serologic assay that measured IgG antibodies against SARS-CoV-2 N, S, and the spike receptor binding domain (RBD) and N-terminal domain (NTD), as well as antibodies against S from SARS-CoV-1 and common circulating coronaviruses (229E, HKU1, NL63 and OC43). N-terminal domain (NTD)suggested: (Leinco Technologies Cat# LT2000, RRID:AB_2893936)HKU1suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study also had several limitations. First, all acute COVID-19 patient samples were from hospitalized patients, and thus our results may or may not overestimate the sensitivity of the assay in children with mild COVID-19. Second, 75% of MIS-C patients received IVIG prior to collection of the blood sample used in this analysis, raising the question of whether IVIG may have interfered with antigen detection. However, we did not detect N or S antigens in any of the 13 MIS-C patients who had pre-IVIG sampling, and the two acute COVID-19 patients who received IVIG prior to blood collection both had high blood antigen concentrations. Moreover, the presence of SARS-CoV-2-specific antibodies did not appear to inhibit antigen detection in acute COVID-19 patients. The Yonker et al study similarly included many post-IVIG samples, and concluded that IVIG initiation did not seem to have an impact on S antigen levels measured on serial samples in the few patients who had pre-IVIG measurements [9]. In conclusion, in this multicenter representative cohort of U.S. children with acute COVID-19 or MIS-C, we demonstrate that blood SARS-CoV-2 antigen measurement may be useful for diagnosing hospitalized children with acute COVID-19. Our findings do not support the hypothesis that ongoing SARS-CoV-2 spike antigenemia is a major contributor to MIS-C pathogenesis.
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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Results from scite Reference Check: We found no unreliable references.
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