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

SARS-CoV-2 can cause severe pediatric disease, including acute COVID-19 and multisystem inflammatory syndrome.¹ Published reports associating SARS-CoV-2 with upper airway infection (UAI), such as laryngotracheobronchitis (croup), have been limited to small case series.² Although noncoronaviruses, including parainfluenza and respiratory syncytial virus, most frequently cause UAI, coronaviruses (eg, type NL63) are also commonly implicated. Young children are especially vulnerable to UAI given their small and relatively collapsible airways.

The Omicron (B.1.1.529) strain of SARS-CoV-2 became dominant in the US the week ending December 25, 2021.³ Omicron is known to cause lower severity disease than the Delta (B.1.617.2) variant. This may be because Omicron replicates less efficiently in lung parenchyma and more efficiently in the conducting airways.⁴ We conducted this retrospective cohort study to determine if cases of UAI among children increased when Omicron became the dominant SARS-CoV-2 variant in the US.

We leveraged the US National COVID Cohort Collaborative (N3C)⁵ and a pipeline we built for a National Institutes of Health–funded pediatric COVID-19 dashboard⁶ to conduct this study. Among children in N3C younger than 19 years with a positive SARS-CoV-2 test result (polymerase chain reaction, antigen, or antibody), we identified those with a UAI diagnosis (eTable in the Supplement). We included bacterial tracheitis because it can be difficult to distinguish from and can be a complication of viral croup. We compared demographic, comorbidity, and clinical outcome variables between patients from the pre-Omicron (March 1, 2020, to December 25, 2021) and Omicron (December 26, 2021, to February 17, 2022) periods. We used χ² 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. The N3C Data Enclave, data transfer from sites to N3C, and this analysis were approved under separate institutional review board protocols as documented elsewhere.¹ The N3C Data Enclave is approved under the authority of the National Institutes of Health Institutional Review Board. Each participating N3C site maintains an institutional review board–approved 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.

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-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), 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).

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, helium-oxygen 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.

Accepted for Publication: March 9, 2022.

Published Online: April 15, 2022. doi:10.1001/jamapediatrics.2022.1110

Correction: This article was corrected on November 7, 2022, to add funding information.

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Martin B et al. JAMA Pediatrics.

Corresponding Author: Blake Martin, MD, Section of Critical Care Medicine, Department of Pediatrics, University of Colorado School of Medicine, 13123 E 16th Ave, Aurora, CO 80045 (blake.martin@cuanschutz.edu).

Author Contributions: Dr Martin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Martin, Haendel, Bennett.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Martin, DeWitt, Bennett.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Martin, DeWitt, Russell, Bennett.

Obtained funding: Haendel, Bennett.

Administrative, technical, or material support: Russell.

Supervision: Martin, Sanchez-Pinto, Moffitt, Bennett.

Conflict of Interest Disclosures: Dr Martin reports grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development during the conduct of the study and from Thrasher Research Fund Early Career Award outside the submitted work. Drs Sanchez-Pinto and Moffitt report grants from National Institutes of Health during the conduct of the study. Dr Bennett reports grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development during the conduct of the study and grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Heart, Lung, and Blood Institute, and the National Center for Advancing Translational Sciences outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD105939-01S1) and through the National Institutes of Health RECOVER Initiative (OT2HL161847). 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.