Characteristics, Outcomes, and Severity Risk Factors Associated With SARS-CoV-2 Infection Among Children in the US National COVID Cohort Collaborative

Abstract

Importance: Understanding of SARS-CoV-2 infection in US children has been limited by the lack of large, multicenter studies with granular data.

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

Design, setting, and participants: A prospective cohort study of encounters with end dates before September 24, 2021, was conducted at 56 N3C facilities throughout the US. Participants included children younger than 19 years 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 multisystem inflammatory syndrome in children (MIS-C), and Delta vs pre-Delta variant differences for children with SARS-CoV-2.

Results: A total of 1 068 410 children were tested for SARS-CoV-2 and 167 262 test results (15.6%) were positive (82 882 [49.6%] girls; median age, 11.9 [IQR, 6.0-16.1] years). Among the 10 245 children (6.1%) who were hospitalized, 1423 (13.9%) met the criteria for severe disease: mechanical ventilation (796 [7.8%]), vasopressor-inotropic support (868 [8.5%]), extracorporeal membrane oxygenation (42 [0.4%]), or death (131 [1.3%]). Male sex (odds ratio [OR], 1.37; 95% CI, 1.21-1.56), Black/African American race (OR, 1.25; 95% CI, 1.06-1.47), obesity (OR, 1.19; 95% CI, 1.01-1.41), and several pediatric complex chronic condition (PCCC) subcategories were associated with higher severity disease. Vital signs and many laboratory test values from the day of admission were predictive of peak disease severity. Variables associated with increased odds for MIS-C vs acute COVID-19 included male sex (OR, 1.59; 95% CI, 1.33-1.90), Black/African American race (OR, 1.44; 95% CI, 1.17-1.77), younger than 12 years (OR, 1.81; 95% CI, 1.51-2.18), obesity (OR, 1.76; 95% CI, 1.40-2.22), and not having a pediatric complex chronic condition (OR, 0.72; 95% CI, 0.65-0.80). The children with MIS-C had a more inflammatory laboratory profile and severe clinical phenotype, with higher rates of invasive ventilation (117 of 707 [16.5%] vs 514 of 8241 [6.2%]; P < .001) and need for vasoactive-inotropic support (191 of 707 [27.0%] vs 426 of 8241 [5.2%]; P < .001) compared with those who had acute COVID-19. Comparing children during the Delta vs pre-Delta eras, there was no significant change in hospitalization rate (1738 [6.0%] vs 8507 [6.2%]; P = .18) and lower odds for severe disease (179 [10.3%] vs 1242 [14.6%]) (decreased by a factor of 0.67; 95% CI, 0.57-0.79; P < .001).

Conclusions and relevance: In this cohort study of US children with SARS-CoV-2, there were observed differences in demographic characteristics, preexisting comorbidities, and initial vital sign and laboratory 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.. Age and Maximum Clinical Severity Distributions Over Time for Children With SARS-CoV-2

(A) Distribution of relative maximum clinical severity (by adapted World Health Organization Clinical Progression Scale categories) by month during the study period compared with adults in the National COVID Cohort Collaborative database. Severe indicates hospital mortality, invasive ventilation, vasoactive-inotropic support, or extracorporeal membrane oxygenation; moderate, hospitalized without any of the severe factors; mild ED, emergency department visit; and mild, outpatient visit. March 2020 data not shown given because there were less than 20 pediatric patients in the severe subgroup. (B) Age category distribution of children with SARS-CoV-2 infection by month during the study period stratified by test type (polymerase chain reaction [PCR]/antigen [Ag]-positive with negative or no antibody [Ab] testing vs Ab-positive regardless of PCR/Ag testing results). The light blue trendline represents monthly positive test incidence.

Figure 2.. In-Hospital 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 compared with National COVID Cohort Collaborative adult values. For each day of hospitalization, the median (IQR) for patients with a given vital sign or laboratory value available on that day were calculated. The vertical bars represent the IQR for measurements of that specific vital sign or laboratory value on that day of hospitalization. SpO₂ indicates oxygen saturation as measured by pulse oximetry. To convert brain-type natriuretic peptide (BNP) to nanograms per liter, multiply by 1; C-reactive protein to milligrams per liter, multiply by 10; hemoglobin to grams per liter, multiply by 10; and lymphocytes to ×10⁹ per liter, multiply by 0.001.

Figure 3.. Characteristics and Outcomes of Children Hospitalized With Multisystem Inflammatory Syndrome in Children (MIS-C) vs Acute COVID-19

Comparison of the percentage of hospitalized children with MIS-C (identified via the presence of qualifying International Statistical Classification of Diseases, 10th Revision code) and acute COVID-19 (positive SARS-CoV-2 PCR/Ag but no positive antibody test or MIS-C International Statistical Classification of Diseases, 10th Revision code) with a given demographic characteristic, preexisting comorbidity, abnormal laboratory test value (during hospitalization), or clinical outcome. eTable 7 in the Supplement provides the absolute number of patients in each corresponding category. Per National COVID Cohort Collaborative policy, groups with fewer than 20 patient encounters were censored and are reported as 0%. ALC indicates absolute lymphocyte count; ALT, alanine aminotransferase; ANC, absolute neutrophil count; BNP, brain-type natriuretic peptide; ECMO, extracorporeal membrane oxygenation; ESR, erythrocyte sedimentation rate; IL-6, interleukin 6; Na, sodium; NT-Pro-BnP, N-terminal pro b-type natriuretic peptide; PCCC, pediatric complex chronic condition; PCR/Ag, polymerase chain reaction/antigen; and WBC, white blood cell. To convert ALC to ×10⁹ per liter, multiply by 0.001; ALT to microkatals per liter, multiply by 0.0167; ANC to ×10⁹ per liter, multiply by 0.001; BNP to nanograms per liter, multiply by 1; ferritin to micrograms per liter, multiply by 1; and Na to millimoles per liter, multiply by 1. ^aThe percentage of children with obesity was calculated by dividing the number of children aged 2 years or older with a body mass index (for age and sex) greater than or equal to the 95th percentile by the number of children in that subgroup who were aged 2 years or older and had a body mass index measurement available.

Figure 4.. Characteristics and Outcomes of Children in the Pre-Delta and Delta Eras

Comparison of the percent of children in the pre-Delta era (before June 26, 2021) to the Delta era with a given demographic characteristic, comorbidity, abnormal laboratory value during hospitalization, or clinical outcome. eTable 8 in the Supplement reports the absolute number of patients in each corresponding category. Per National COVID Cohort Collaborative policy, groups with less than 20 patient encounters were censored and are reported as 0%. ^aThe percentage of children with obesity was calculated by dividing the number of children aged 2 years or older with a body mass index (for age and sex) greater than or equal to the 95th percentile by the number of children in that subgroup who were aged 2 years or older and had a body mass index measurement available.