Pediatric Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): Clinical Presentation, Infectivity, and Immune Responses

Abstract

Objectives: As schools plan for re-opening, understanding the potential role children play in the coronavirus infectious disease 2019 (COVID-19) pandemic and the factors that drive severe illness in children is critical.

Study design: Children ages 0-22 years with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection presenting to urgent care clinics or being hospitalized for confirmed/suspected SARS-CoV-2 infection or multisystem inflammatory syndrome in children (MIS-C) at Massachusetts General Hospital were offered enrollment in the Massachusetts General Hospital Pediatric COVID-19 Biorepository. Enrolled children provided nasopharyngeal, oropharyngeal, and/or blood specimens. SARS-CoV-2 viral load, ACE2 RNA levels, and serology for SARS-CoV-2 were quantified.

Results: A total of 192 children (mean age, 10.2 ± 7.0 years) were enrolled. Forty-nine children (26%) were diagnosed with acute SARS-CoV-2 infection; an additional 18 children (9%) met the criteria for MIS-C. Only 25 children (51%) with acute SARS-CoV-2 infection presented with fever; symptoms of SARS-CoV-2 infection, if present, were nonspecific. Nasopharyngeal viral load was highest in children in the first 2 days of symptoms, significantly higher than hospitalized adults with severe disease (P = .002). Age did not impact viral load, but younger children had lower angiotensin-converting enzyme 2 expression (P = .004). Immunoglobulin M (IgM) and Immunoglobulin G (IgG) to the receptor binding domain of the SARS-CoV-2 spike protein were increased in severe MIS-C (P < .001), with dysregulated humoral responses observed.

Conclusions: This study reveals that children may be a potential source of contagion in the SARS-CoV-2 pandemic despite having milder disease or a lack of symptoms; immune dysregulation is implicated in severe postinfectious MIS-C.

Figure 1

Presenting symptoms of enrolled patients. Darker color intensity depicts increased prevalence of a symptom within each cohort. Patients were grouped by SARS-CoV-2 qPCR results (positive or negative) or diagnosis of MIS-C.

Figure 2

Infective SARS-CoV-2 viral load in children. A, Viral loads from nasopharyngeal, oropharyngeal, and blood were quantified within SARS-CoV-2 (+), MIS-C, and SARS-CoV-2 (−) cohorts. Viral load in nasopharyngeal and oropharyngeal specimens from SARS-CoV-2 (+) children were compared with the Mann-Whitney U test, median presented. B, SARS-CoV-2 viral loads were categorized by symptom duration, including asymptomatic period to day 2 of symptoms, days 3-7 of symptoms, and days 7-26 of symptoms. The median is presented and comparisons are by the Kruskal-Wallis test. Nasopharyngeal viral load was correlated with, C, days of symptoms and, D, age; Spearman correlation. NP, nasopharyngeal; OP, oropharyngeal.

Figure 3

ACE2 expression in the upper airways of children. A, Relative expression of ACE2 (log₁₀) categorized by SARS-CoV-2 infection, median presented, and significance tested by Mann-Whitney U test. B, Correlation of relative ACE2 expression and viral load (log₁₀ RNA copies/mL); Spearman correlation. C, Relative expression of ACE2 (log₁₀) categorized by age <10 years or ≥10 years, median presented, and significance tested by Mann-Whitney U test. D, Correlation of ACE2 expression with age; Spearman correlation.

Figure 4

SARS-CoV-2 antibody response in children infected with SARS-CoV-2. A, Peak IgM and IgG to the RBD component of SARS-CoV-2 were quantified for children acutely infected with SARS-CoV-2 and children presenting with MIS-C. Comparison by Mann-Whitney U tests; median presented. B, IgM and IgG responses in acute SARS-CoV-2 infection were correlated with days of symptoms; Spearman correlation. C, Percent of children mild vs severe MIS-C with elevated IgM or IgG (above a threshold of 0.5 μg/mL) were compared by Fisher exact test. D, Peak IgM and IgG levels were compared between mild and severe MIS-C, Mann-Whitney U tests; median presented. Dotted line represents 0.5 μg/mL threshold for defining high or low antibody response, E, IgM and IgG responses in acute SARS-CoV-2 infection were correlated with days of symptoms; Spearman correlation. F, Heat map depicts relative IgG responses to SARS-CoV-2 RBD and SARS-CoV-2 N capsid protein, other coronaviruses (strains 229E, NL63, HKU1, and OC43), RSV, and influenza (flu). In addition to showing antibody response for children with acute SARS-CoV-2 infection and mild and severe MIS-C, antibody levels from adults with acute SARS-CoV-2 and adults recovered from SARS-CoV-2 infection are displayed.

Figure 5

Violin plot of IgM antibodies to SARS-CoV-2 RBD and SARS-CoV-2 N capsid protein, other coronaviruses (strains 229E, NL63, HKU1, and OC43), and RSV and influenza.

Figure 6

Violin plot of IgG antibodies to SARS-CoV-2 RBD and SARS-CoV-2 N capsid protein, other coronaviruses (strains 229E, NL63, HKU1, and OC4), RSV, and influenza.

Figure 7

Correlation of inflammatory markers and SARS-CoV-2 antibody responses in MIS-C. IgM and IgG SARS-CoV-2 (RBD component) were correlated with A and B, C-reactive protein (CRP), respectively; C and D, ferritin, respectively; and E and F, NT-proBNP, respectively. Spearman correlation.