Children with SARS-CoV-2 in the National COVID Cohort Collaborative (N3C)

Abstract

Importance: SARS-CoV-2.

Objective: To determine the characteristics, changes over time, outcomes, and severity risk factors of SARS-CoV-2 affected children within the National COVID Cohort Collaborative (N3C).

Design: Prospective cohort study of patient encounters with end dates before May 27th, 2021.

Setting: 45 N3C institutions.

Participants: Children <19-years-old at initial SARS-CoV-2 testing.

Main outcomes and measures: Case incidence and severity over time, demographic and comorbidity severity risk factors, vital sign and laboratory trajectories, clinical outcomes, and acute COVID-19 vs MIS-C contrasts for children infected with SARS-CoV-2.

Results: 728,047 children in the N3C were tested for SARS-CoV-2; of these, 91,865 (12.6%) were positive. Among the 5,213 (6%) hospitalized children, 685 (13%) met criteria for severe disease: mechanical ventilation (7%), vasopressor/inotropic support (7%), ECMO (0.6%), or death/discharge to hospice (1.1%). Male gender, African American race, older age, and several pediatric complex chronic condition (PCCC) subcategories were associated with higher clinical severity (p ≤ 0.05). Vital signs (all p≤0.002) and many laboratory tests from the first day of hospitalization were predictive of peak disease severity. Children with severe (vs moderate) disease were more likely to receive antimicrobials (71% vs 32%, p<0.001) and immunomodulatory medications (53% vs 16%, p<0.001). Compared to those with acute COVID-19, children with MIS-C were more likely to be male, Black/African American, 1-to-12-years-old, and less likely to have asthma, diabetes, or a PCCC (p < 0.04). MIS-C cases demonstrated a more inflammatory laboratory profile and more severe clinical phenotype with higher rates of invasive ventilation (12% vs 6%) and need for vasoactive-inotropic support (31% vs 6%) compared to acute COVID-19 cases, respectively (p<0.03).

Conclusions: In the largest U.S. SARS-CoV-2-positive pediatric cohort to date, we observed differences in demographics, pre-existing comorbidities, and initial vital sign and laboratory test values between severity subgroups. Taken together, these results suggest that early identification of children likely to progress to severe disease could be achieved using readily available data elements from the day of admission. Further work is needed to translate this knowledge into improved outcomes.

Figure 1:. Geographic distribution and case incidence over time for SARS-CoV-2 positive patients.

Figure 1a shows the geographic distribution of all pediatric N3C patients (N = 728,047). Figure 1b shows the geographic distribution of the positive pediatric cases only (N = 91,865). Figure 1c shows the monthly trends for positive pediatric SARS-CoV-2 testing by subregion and test type. Figure 1d shows the monthly trends for SARS-CoV-2 positive children by test type along with overall adult positive PCR/Ag cases (N = 609,734) for comparison.

Figure 2:. Age, maximum clinical severity, and antimicrobial and immunomodulatory medication use over time for SARS-CoV-2 positive children

Figure 2a illustrates changes in the distribution of maximum clinical severity (by WHO CPS score) by month during the study period compared to N3C positive adults. Red = hospital mortality, discharge to hospice, or invasive ventilation, vasoactive-inotropic support, or ECMO. Yellow = Hospitalized without any of those. Dark Green = Emergency Department visit. Light Green = Outpatient visit. March, 2020 censored given <20 pediatric patients in the severe subgroup. Figure 2b shows the age category distribution of infected children by month during the study period stratified by test type (PCR/Ag+ with negative or no Ab testing vs Ab+ regardless of PCR/Ag testing results). The trendline demonstrates the monthly positive test incidence. Figure 1c shows the evolution in use of selected antimicrobial and immunomodulatory medications by quarter (Apr 2020 – Mar 2021) among hospitalized children with SARS-CoV-2 compared to hospitalized N3C adult cases: Q1 = Apr 2020 – Jun 2020, Q2 = Jul 2020 – Sep 2020, Q3 = Oct 2020 – Dec 2020, and Q4 = Jan 2021 – Mar 2021

Figure 3:. Vital sign and laboratory value trajectories.

Trajectories of selected vital sign (a-e) and laboratory (f-i) median values by day of hospitalization during pediatric hospital encounters as compared to N3C adult values, stratified my maximum clinical severity

Figure 4:. Characteristics and outcomes of children with MIS-C versus acute COVID-19

Heatmap comparing the percent of children in the MIS-C and acute COVID-19 subgroups with a given demographic characteristic, pre-existing comorbidity, abnormal lab value during hospitalization, or clinical outcome. See Supplemental Table 6 for the absolute number of patients in each corresponding category. *The percent of children with obesity was calculated by dividing the number of children ≥2-years-old who had a BMI for age and sex that was ≥95th percentile by the number of children in that subgroup who were ≥2 years old who had a BMI measurement available.