Acute Upper Airway Disease in Children With the Omicron (B.1.1.529) Variant of SARS-CoV-2—A Report From the US National COVID Cohort Collaborative

This cohort study uses data from the US National COVID Cohort Collaborative to evaluate upper airway infections in children during the surge of the Omicron (B.1.1.529) variant of SARS-CoV-2 in the US.

, with 178 of 384 cases (46%) occurring during the Omicron period.Children with UAIs during the Omicron period were more likely to be younger and Hispanic or Latino and less likely to receive dexamethasone or develop severe disease compared with those in the pre-Omicron period.Lastly, the proportion of children with a pediatric complex chronic condition was not significantly different in the pre-Omicron period compared with the Omicron period (74 of 206 [36%] vs 39 of 178 [22%], respectively; P = 0.54).
Discussion | SARS-CoV-2-positive pediatric UAI rates increased during the Omicron surge.More than one-fifth of children hospitalized with SARS-CoV-2 and UAI developed severe disease.Given the high proportion of UAI cases during the Omicron period, these results appear to support recent mechanistic reports.A limitation of this analysis is that diagnosis codes will only be present for completed encounters; as such, children who are still hospitalized are not represented, and the frequency of severe disease observed in the Omicron period may be an underestimate.
Children with severe UAI are at risk of cardiac arrest from rapid-onset upper airway obstruction.They may require therapies typically provided in intensive care units, including frequent administration of nebulized racemic epinephrine, heliumoxygen mixtures, and intubation.While the rate of SARS-CoV-2 pediatric UAI is not overwhelmingly high, understanding this new clinical phenotype and the potential for acute upper airway obstruction may help guide therapeutic decision-making.).Additionally, the analyses described in this publication were conducted with data or tools accessed through the NCATS N3C Data Enclave (covid.cd2h.org/enclave)and supported by NCATS U24 TR002306.This research was possible because of the patients whose information is included within the data from participating organizations (covid.cd2h.org/dtas)and the organizations and scientists (covid.cd2h.org/duas) who have contributed to the ongoing development of this community resource (https://doi.org/10.1093/jamia/ocaa196).

Role of the Funder/Sponsor:
The Eunice Kennedy Shriver National Institute of Child Health and Human Development provided support for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.We aimed to estimate the risk of MIS-C after SARS-CoV-2 infection in vaccinated and unvaccinated individuals during the Omicron wave.Further, we aimed to compare the risk and clinical characteristics of MIS-C with the pre-Omicron waves.
Methods | This population-based cohort study prospectively included patients aged 0 to 17 years with MIS-C from all 18 Danish pediatric departments.Patients were diagnosed from January 1, 2022, to March 15, 2022, after SARS-CoV-2 infection between January 1 and February 1, 2022, when Omicron constituted more than 95% of variants.We followed the STROBE reporting guidelines for cohort studies.We used previously re-ported data to compare MIS-C during Omicron with the pre-Omicron waves. 1,2e calculated the risk of MIS-C per 1 million estimated SARS-CoV-2 infections in children and adolescents.We estimated the number of infections by applying multipliers of 1.5 to 2.1 to laboratory-confirmed infections obtained from the Danish COVID-19 surveillance registries (Table 1).All 95% CIs were calculated using an exact method for binomial proportions.We compared risks of MIS-C in risk ratios (RRs) using Fisher exact test.Two-tailed Mann-Whitney U or χ 2 tests were used to compare patient characteristics.Permission to disclose patient data was obtained by oral and written parental consent or by a waiver of requirement.
Results | We identified 1 vaccinated and 11 unvaccinated patients with MIS-C among 583 618 estimated infected children and adolescents, including 267 086 vaccinated individuals (Table 1).No MIS-C cases occurred among 31 516 estimated individuals with reinfections.
Discussion | We found the risk of MIS-C after SARS-CoV-2 infection during the Omicron wave substantially lower compared with previous SARS-CoV-2 variants.This could be explained by a reduced ability of Omicron to trigger hyperinflammation as it is phylogenetically different and associated with an increased immune escape. 3The lower risk could also partly be explained by a reduced risk after reinfection, although only 6% of our included infected individuals had confirmed reinfection, and such a reduced risk after reinfection has not yet been reported.
The risk of MIS-C during the Omicron wave was found to be significantly lower after breakthrough infection in vaccinated compared with unvaccinated children and adolescents.A high vaccine effectiveness against MIS-C has previously been found during the Delta wave, primarily explained by a high effectiveness against the Delta variant. 1,4,5The present study suggests a direct vaccine effectiveness against MIS-C after breakthrough infection.This may be caused by vaccine-induced modulation of the immune system rendering it less prone to cause hyperinflammation after SARS-CoV-2 infection.
The main limitation of this study was the small population size resulting in few MIS-C cases, making our estimates vulnerable to fluctuations.The multipliers of 1.5 to 2.1 used to estimate the true number of infected individuals were encumbered with uncertainty and lower than those previously used for the US population 6 ; our multipliers were low owing to thorough test capacity in Denmark with biweekly screening tests in schools.In this Danish population-based cohort study, we found a substantially decreased risk of MIS-C after infection with Omicron compared with pre-Omicron variants and a lower risk of MIS-C after breakthrough infections in vaccinated individuals.

Table .
Characteristics and Outcomes of Hospitalized Children With Upper Airway Infection (UAI) and SARS-CoV-2 During the Pre-Omicron and Omicron Periods

Reprinted) JAMA Pediatrics August 2022 Volume 176, Number 8 819 Downloaded From: https://jamanetwork.com/ on 10/08/2023 and
The N3C Data Enclave, data transfer from sites to N3C, and this analysis were approved under separate institutional review board protocols as documented elsewhere.1TheN3C Data Enclave is approved under the authority of the National Institutes of Health Institutional Review Board.Each participating N3C site maintains an institutional review boardapproved data transfer agreement.The analyses in this article were approved by the institutional review boards of the study investigators with data access, which includes a waiver of informed consent.-CoV-2-positive UAI rates have increased with progression from the pre-Omicron to Omicron periods (206 of 14 473 [1.5%] vs 178 of 4376 [4.1%], respectively; P < .001)(Figure Omicron (December 26, 2021, to February 17, 2022)periods.We used χ 2 and Fisher exact tests for categorical variable comparisons and the Mood median and t tests for continuous variable comparisons.Race and ethnicity were identified from N3C site electronic health record data and included to aid with identification of variables associated with increased risk of UAI among children with SARS-CoV-2.Each N3C site determines race and ethnicity at its discretion.We used linear regression to determine the change over time in percentage of children with UAI among children hospitalized with SARS-CoV-2.Results | The February 17, 2022, N3C data release contains 18 849 children hospitalized with SARS-CoV-2, 384 of whom (2.0%) had UAIs (Table).Severe disease (defined as requiring invasive ventilation, vasopressors, or extracorporeal membrane oxygenation or death) occurred in 81 children (21%).SARS SARS-CoV-2 cases per month among inpatient (solid line) and outpatient/emergency department (dotted line) encounters with a diagnosis of UAI within the National COVID Cohort Collaborative (N3C) February 17, 2022, data release.Per N3C policy, only data points in which the group (inpatient or outpatient and emergency department [ED]) had at least 20 patients are shown to prevent exposure of patient counts fewer than 20.Prior months are not shown given patient counts of fewer than 20 per month within the inpatient group before September 2021.Hospitalizations in February 2022 were fewer than 20 and are not shown.
aThe percentage of sequenced SARS-CoV-2 samples found to be the Omicron strain among samples from weekly variant testing by the US Centers for Disease Control and Prevention COVID-19 Data Tracker 3 increased from 0.6% during the week ending December 4, 2021, to 89.2% during the week ending January 1, 2022.b Linear regression identified the rate of change per month in SARS-CoV-2positive children with a UAI diagnosis as 0.6% (standard error, 0.1%; P = .008)among hospitalized cases (solid line) and 0.2% (standard error, 0.03%; P = .005)among outpatient and emergency department cases (dotted line).Shaded regions indicate 95% CIs.Initiative (OT2HL161847