George B Sigal1, Tanya Novak2, Anu Mathew1, Janet Chou3, Yubo Zhang4, Navaratnam Manjula1, Pradeepthi Bathala1, Jessica Joe1, Nikhil Padmanabhan1, Daniel Romero1, Gabriella Allegri-Machado5, Jill Joerger5, Laura L Loftis6, Stephanie P Schwartz7, Tracie C Walker7, Julie C Fitzgerald8, Keiko M Tarquinio9, Matt S Zinter10, Jennifer E Schuster11, Natasha B Halasa12, Melissa L Cullimore13, Aline B Maddux14, Mary A Staat15, Katherine Irby16, Heidi R Flori17, Bria M Coates18, Hillary Crandall19, Shira J Gertz20, Adrienne G Randolph2, Nira R Pollock21. 1. Meso Scale Diagnostics, LLC, Rockville, Maryland, USA. 2. Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, and Department of Anesthesia, Harvard Medical School, Boston, Massachusetts, USA. 3. Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA. 4. Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, Massachusetts, USA. 5. Department of Laboratory Medicine, Boston Children's Hospital, Boston, Massachusetts, USA. 6. Division of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA. 7. Department of Pediatrics, University of North Carolina at Chapel Hill Children's Hospital, Chapel Hill, North Carolina, USA. 8. Division of Critical Care, Department of Anesthesiology and Critical Care, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. 9. Division of Critical Care Medicine, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA. 10. Divisions of Critical Care and Bone Marrow Transplantation, Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA. 11. Division of Pediatric Infectious Diseases, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, Missouri, USA. 12. Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA. 13. Department of Pediatrics, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA. 14. Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA. 15. Department of Pediatrics, University of Cincinnati, Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. 16. Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Children's Hospital, Little Rock, Arkansas, USA. 17. Division of Pediatric Critical Care Medicine, Department of Pediatrics, Mott Children's Hospital and University of Michigan, Ann Arbor, Michigan, USA. 18. Division of Critical Care Medicine, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA. 19. Division of Pediatric Critical Care, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA. 20. Division of Pediatric Critical Care, Department of Pediatrics, Saint Barnabas Medical Center, Livingston, New Jersey, USA. 21. Department of Laboratory Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
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.
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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