There remains a need to understand the impact of the coronavirus disease 2019 (COVID-19) pandemic on children, especially as new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge. In the United States, there have been over 16.5 million pediatric COVID-19 cases and about 2,000 pediatric deaths as of March 2023.1 Within Colorado, there have been an estimated 334,600 pediatric cases.2 Although children have experienced less morbidity and mortality compared to adults, severe infections occur, more commonly in older adolescents and those with underlying medical conditions.3–5

Pediatric studies are conflicting on whether children experienced more severe illness during the Delta period than the pre-Delta periods.6–8 Preliminary reports comparing the Omicron variant surge to previous variants among children have shown trends toward decreasing severity of disease and younger age groups affected.5,6,8,9 Vaccine effectiveness (VE) in children continues to be studied, with recent data suggesting decreases in VE associated with newer variants.10–12

The objectives of our study were: (1) to compare the clinical characteristics of pediatric patients hospitalized with symptomatic SARS-CoV-2 during different variant periods (wild type vs. Delta vs. Omicron) and (2) to determine VE against COVID-19-associated hospitalization among vaccine-eligible children in Colorado.

METHODS Study Design

This is a retrospective cohort study based at Children’s Hospital Colorado, a large tertiary care referral center, of children with SARS-CoV-2 infection between March 16, 2020 and January 18, 2022.

Time Periods

We defined each variant period based on the SARS-CoV-2 variant that was predominant (>50% of circulating virus) according to the Colorado Department of Public Health & Environment.2 We included patients during the following periods: wild type (March 16, 2020–November 4, 2020); Delta B.1.617.2 (hereafter referred to as Delta, June 6, 2021–October 31, 2021) and Omicron B.1.1.529 (hereafter referred to as Omicron, December 19, 2021–January 18, 2022).

Study Population

The analysis of clinical severity included all symptomatic inpatients admitted with COVID-19 during the time periods described above. We included the first hospitalization for children under 21 years of age with a positive SARS-CoV-2 molecular test performed within −1 to +10 days of the admission date. During the study period, all inpatients were tested for SARS-CoV-2 upon admission. We considered hospitalized children to be symptomatic if medical record documentation attributed specific symptoms to SARS-CoV-2 infection; however, COVID-19 was not always the primary reason for admission. Hospitalized children with SARS-CoV-2 who had no symptoms consistent with COVID-19 were excluded from clinical severity analyses.

Children diagnosed with multisystem inflammatory syndrome in children were excluded because the focus of our analysis was on acute COVID-19 as opposed to postinfectious inflammatory complications.

In our analysis of VE at preventing symptomatic hospital admission, we included all inpatients and outpatients identified with SARS-CoV-2 via molecular testing during the time periods above. We compared symptomatic inpatients to asymptomatic inpatients and all outpatients combined.

This study was approved by the Colorado Multiple Institutional Review Board with a waiver of informed consent.

Data Collection and Management

We received monthly reports from the electronic health record (EHR) for every patient with a positive SARS-CoV-2 molecular result in the Children’s Hospital Colorado system. Demographic and clinical data were abstracted from the EHR and entered into standardized data collection forms developed in REDCap, hosted by the University of Colorado, Denver.13 Race and ethnicity were recorded as documented in the EHR. Body mass index was calculated from the most recent height and weight recorded (which must have been measured within the last 6 months for those 2–5 years, and within the last year for children greater than 5 years of age). The proportion of children with overweight and obesity was determined according to the Centers for Disease Control and Prevention classification system.14 Comorbid conditions were recorded as documented in the EHR and categorized according to the body system. Symptoms at the time of the first positive molecular test were abstracted from the EHR. We collected laboratory data at admission, including hematologic and inflammatory markers. We assigned maximum respiratory support on a scale from lowest to highest: no respiratory support; low flow nasal cannula; high flow nasal cannula; noninvasive positive pressure ventilation; mechanical ventilation and extracorporeal membrane oxygenation. Intensive care unit (ICU) admissions were defined as admissions to the pediatric ICU or cardiac ICU and admissions to the neonatal ICU that required greater than low-flow oxygen respiratory support. Deaths related to COVID-19 infection were included if the patient died within 90 days of diagnosis.

Vaccination data were collected for all eligible children, including doses given throughout the state of Colorado if documented in the Colorado Immunization Information System. Children were defined as fully vaccinated 14 days after receiving their second dose of a messenger ribonucleic acid (mRNA) vaccine (Pfizer or Moderna) or 14 days after a single Johnson & Johnson/Janssen vaccine. We considered the first date at which specific age groups became eligible for any vaccine and were able to calculate VE for children ≥12 years of age during the Delta period, and for children ≥5 years of age during the Omicron period.

Statistical Analysis

We described demographic characteristics using summary statistics. Characteristics were compared between variant periods using Kruskal–Wallis tests for continuous variables and generalized Fisher exact tests for categorical variables. If the 3-way test was significant at the P ≤ 0.05 level, further evaluation was carried out using Wilcoxon rank sum tests or Fisher exact tests to determine where differences existed in the 2-way comparisons. When comparing symptoms reported during the variant periods, we first analyzed the cohort as a whole and then performed subgroup analyses of children <5 and 5–<21 years of age. We used univariable and multivariable logistic regression to estimate the odds ratio of COVID-19-associated hospitalization among vaccinated compared with unvaccinated children. Multivariable models included age, race/ethnicity and sex. VE was defined as 1 minus the odds ratio times 100. All analyses were performed in SAS 9.4.

RESULTS

A total of 8,802 children were identified with SARS-CoV-2 during the study period. Of these, 2,279 (26%) were during the wild-type period, 2,558 (29%) during the Delta period and 3,965 (45%) during the Omicron period (Fig. 1). Fewer than 10% of children with SARS-CoV-2 were hospitalized during any time period. Among hospitalized children with SARS-CoV-2, the proportion who were symptomatic over time was: 72% during the wild-type period, 83% during the Delta period and 89% during the Omicron period.

FIGURE 1.:

Children <21 years old diagnosed with COVID-19 based on the first positive SARS-CoV-2 molecular test during different variant periods. COVID-19, Coronavirus disease 19; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2 *Includes symptomatic and asymptomatic inpatients. Includes only first hospitalization for patients hospitalized more than once.

Characteristics of Symptomatic Hospitalized Patients

Table 1 describes the demographic and clinical characteristics of 115 hospitalized children during the wild-type period, 194 during the Delta period and 226 during the Omicron period. Differences among included characteristics are compared overall (between all 3 time periods) and between time periods as pairwise comparisons. The median age of children decreased with each variant period, from 12.2 years [interquartile range (IQR): 1.5–16.9], to 5.9 years (IQR: 1.0–13.8), to 1.3 years (IQR: 0.4–7.2) in the wild type, Delta, and Omicron periods, respectively (overall P < 0.0001). This trend is further demonstrated by the substantial increase in the proportion of hospitalized children under the age of 5 years, which was 36% during the wild type period, 46% during the Delta period and almost 70% during the Omicron period (overall P < 0.0001). There was a Hispanic predominance during the wild-type period compared to the Delta and Omicron periods (P < 0.001 overall and for wild type vs. Delta and wild type vs. Omicron periods), whereas the proportion of Hispanic patients was lower and did not differ significantly between the Delta and Omicron periods (P = 0.61).

TABLE 1. - Demographics and Comorbidities of Symptomatic Inpatients Wild type, N (%) = 115 Delta, N (%) = 194 Omicron, N (%) = 226 Overall P value P value wild type vs. Delta P value wild type vs. Omicron P value Delta vs. Omicron Sex  Male 63 (54.8) 112 (57.7) 128 (56.6) 0.88  Female 52 (45.2) 82 (42.3) 98 (43.4) Age (years); median (IQR) 12.2 (1.5–16.9) 5.9 (1.0–13.8) 1.3 (0.4–7.2) <0.0001 0.006 <0.001 <0.001 Age category (years)  0–4 41 (35.7) 90 (46.4) 158 (69.9) <0.0001 0.001 <0.001 <0.001  5–9 10 (8.7) 31 (16.0) 21 (9.3)  10–15 22 (19.1) 40 (20.6) 25 (11.1)  15–20 44 (36.5) 33 (17.0) 22 (9.7) Race/ethnicity  Hispanic 67 (61.5) 65 (38.2) 81 (38.4) <0.001 <0.001 <0.001 0.69  Non-Hispanic white 24 (22.0) 75 (44.1) 86 (40.8)  Non-Hispanic other 18 (16.5) 30 (17.7) 44 (20.7)  Unknown 6 24 15 Language  English 78 (67.8) 177 (91.2) 200 (88.5) <0.001 <0.001 <0.001 0.54  Spanish 33 (28.7) 14 (7.2) 20 (8.9)  Other 4 (3.5) 3 (1.6) 6 (2.6) Comorbidities  Any comorbidity 83 (72.2) 123 (63.4) 125 (55.3) 0.009 0.13 0.003 0.11  Cardiac 9 (7.8) 12 (6.2) 31 (13.7) 0.025 0.64 0.15 0.01  Endocrine 17 (14.8) 21 (10.8) 7 (3.1) 0.0004 0.37 <0.001 0.003  Gastrointestinal 25 (21.7) 25 (12.9) 35 (15.5) 0.12  Genetic/metabolic 4 (3.5) 17 (8.8) 19 (8.4) 0.18  Immunocompromised 18 (15.7) 10 (5.2) 15 (6.6) 0.003 0.003 0.01 0.54  Neurologic 18 (15.7) 22 (11.3) 35 (15.5) 0.40  Preterm birth 7 (6.1) 10 (5.1) 15 (6.6) 0.81  Psychiatric 17 (14.8) 12 (6.2) 19 (8.4) 0.035 0.01 0.09 0.46  Pulmonary 33 (28.7) 51 (26.3) 46 (20.4) 0.17 BMI* N = 78 N = 123 N = 101 0.0003 0.77 <0.001 <0.001 Overweight 39 (50.0) 58 (47.1) 25 (24.7) 0.0004 0.76 <0.001 <0.001 Obese† 29 (37.2) 43 (35.0) 15 (14.9)

*Data not available for all patients, total numbers evaluated are shown. BMI calculated only for those patients ≥2 years-old.

†Obese is a subset of overweight.

Significant p-values are bolded.

BMI, body mass index; IQR, interquartile range.

While over half of children hospitalized with COVID-19 had underlying comorbidities, these became less common over time with 72% of admitted children in the wild-type period having any comorbidity, decreasing to 55% in the Omicron period (P = 0.003). Immunocompromising conditions were less common during the Delta (P = 0.003) and Omicron (P = 0.01) periods compared to the wild-type period. Endocrine conditions, which include diabetes, were less common during the Omicron period compared to the wild type (P < 0.001) or Delta (P = 0.003) periods. The proportion of children with overweight or obesity was lower in the Omicron period compared to the wild type (P < 0.001) or Delta (P < 0.001) periods. The one exception to this trend was for underlying cardiac conditions, which were infrequent but more common during the Omicron compared to the Delta period (P = 0.01). The rates of underlying neurological and pulmonary conditions (which include asthma) and preterm birth remained stable over the 3 periods.

Symptoms and Laboratory Values at Presentation

At admission, the most common symptoms (present in more than 20% of children) during all time periods included fever, cough, congestion, shortness of breath, vomiting and fatigue (Table 2). Cough and congestion were more common during the Delta and Omicron periods, and loss of taste was less common during the Delta and Omicron periods, compared to the wild-type period. Chest pain, headaches, myalgias and abdominal pain occurred less frequently during the Omicron period among the entire cohort. However, when comparing symptoms over time in children <5 and 5 to <21 years of age, only the decrease in reporting of abdominal pain remained significant (Tables, Supplemental Digital Content 1 and 2, https://links.lww.com/INF/F26). There were no significant differences in admission labs between the 3 time periods, with the exception of median platelet count, which demonstrated a nonclinically significant increase during later variant periods (data not shown).

TABLE 2. - Symptoms present on date of first positive molecular SARS-CoV-2 test for hospitalized children Wild type, N = 115 (%) Delta, N = 194 (%) Omicron, N = 226 (%) Overall P value P Value Wild Type vs. Delta P Value Wild Type vs. Omicron P Value Delta vs. Omicron Fever >100.4 F 65 (56.5) 124 (63.9) 136 (60.2) 0.42 Chills 8 (7.0) 8 (4.1) 8 (3.5) 0.35 Cough 48 (41.7) 139 (71.6) 147 (65.0) <0.001 <0.001 <0.001 0.17 Congestion 30 (26.1) 111 (57.2) 130 (57.5) <0.001 <0.001 <0.001 1.0 Shortness of breath 28 (24.4) 56 (28.9) 46 (20.4) 0.13 Chest pain 15 (13.0) 14 (7.2) 7 (3.1) 0.002 0.11 0.001 0.07 Loss of taste 8 (7.0) 1 (0.5) 0 (0.0) <0.001 0.002 <0.001 0.46 Headache 22 (19.1) 24 (12.4) 15 (6.6) 0.002 0.14 <0.001 0.06 Myalgia 16 (13.9) 19 (9.8) 13 (5.7) 0.039 0.27 0.01 0.14 Sore throat 15 (13.0) 18 (9.3) 15 (6.6) 0.14 Wheezing 4 (3.5) 11 (5.7) 8 (3.5) 0.50 Cyanosis 2 (1.7) 2 (1.0) 6 (2.6) 0.47 Hypoxia 20 (17.4) 37 (19.1) 41 (18.1) 0.93 Diarrhea 15 (13.0) 29 (15.0) 20 (8.9) 0.15 Abdominal pain 20 (17.4) 26 (13.4) 18 (8.0) 0.027 0.41 0.01 0.06 Vomiting 22 (19.1) 54 (27.8) 55 (24.3) 0.23 Seizure 3 (2.6) 3 (1.6) 7 (3.1) 0.58 Rash 4 (3.5) 9 (4.6) 12 (5.3) 0.75 Altered mental status 3 (2.6) 3 (1.6) 4 (1.8) 0.84 Other 43 (37.4) 67 (34.5) 65 (28.8) 0.21 Fatigue 25 (21.7) 36 (18.6) 29 (12.8) 0.08

Significant p-values are bolded.

Hospital Outcomes

A higher proportion of children required ICU care during the Delta period (32.5%) compared with the wild type (20.9%, P = 0.036) and Omicron (25.0%, P = 0.08) periods (Table 3). The proportion of children who required any respiratory support was also highest during the Delta period (61.9%) compared to the wild type (47.8%, P = 0.02) and Omicron (56.5%, P = 0.32) periods. The highest level of respiratory support required did not differ between the 3 variant periods, with the majority of children in all variant periods requiring low-flow oxygen. Overall, 29 (5.4%) children required mechanical ventilation and 7 (1.3%) required extracorporeal membrane oxygenation across all 3 variant periods. The median length of stay for all hospitalized children was 2 days (IQR: 1–3) during the Omicron period compared to 3 days during the wild type (IQR: 1–6) and Delta periods (IQR: 2–5) (overall P = 0.003). A total of 6 deaths occurred within 90 days of a COVID-19 diagnosis, 3 during wild type, 3 during Delta and none during Omicron periods (overall P = 0.07).

TABLE 3. - Admission Outcomes of the First Hospitalization for Symptomatic Inpatients Wild Type, N (%) = 115 Delta, N (%) = 194 Omicron, N (%) = 226 Overall P-value P-value wild type vs. Delta P-value wild type vs. Omicron P-value Delta vs. Omicron Required critical care 24 (20.9) 63 (32.5) 56 (25.0) 0.05 0.036 0.50 0.08 Required any respiratory support 55 (47.8) 120 (61.9) 128 (56.6) 0.05 0.02 0.12 0.32 Maximum respiratory support require  Low flow oxygen 35 (63.6) 68 (56.7) 80 (62.5) 0.21  High flow oxygen 4 (7.3) 19 (15.8) 20 (15.6)  Non-invasive PPV 6 (10.9) 23 (19.2) 12 (9.4)  Mechanical 8 (14.5) 8 (6.7) 13 (10.2)  Ventilation  ECMO 2 (3.6) 2 (1.7) 3 (2.3) Length of stay (days), median (IQR) 3 (1-6) 3 (2-5) 2 (1-3) 0.003 0.53 0.005 0.004 Death 3 (2.5) 3 (1.0) 0 (0.0) 0.07

ECMO indicates extracorporeal membrane oxygenation; IQR, inter