Type-2 immune responses are associated with less severe COVID-19 in a hospitalized cohort
Journal of Allergy and Clinical Immunology: Global, 2025
Jayavelu N., Qi J., Milliren C., Ozonoff A., Liu S., Levy O., Baden L., Melamed E., McComsey G., Sekaly R., Cairns C., Schaenman J., Shaw A., Hafler D., Corry D., Kheradmand F., Atkinson M., Brakenridge S., Agudelo Higuita N., Metcalf J., Hough C., Messer W., Pulendran B., Nadeau K., Davis M., Geng L., Sesma A., Simon V., Krammer F., Bime C., Calfee C., Bosinger S., Eckalbar W., Steen H., Maecker H., Augustine A., Diray-Arce J., Haddad E., Sekaly R., Kraft M., Woodruff P., Erle D., Ehrlich L., Montgomery R., Becker P., Altman M., Fourati S.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Infectious Diseases | Pathophysiology | Serum |  Olink Target 96 |
Abstract
Background
The novel coronavirus SARS-CoV-2 (COVID-19) spread rapidly after its identification in December 2019 to cause a global pandemic. The respiratory tract is the primary site of infection, and there is a large range in the severity of respiratory illnesses caused by the virus. Defining molecular and cellular factors for protection from severe disease and death has been a goal to better understand and to predict and mitigate the effects of SARS-CoV-2 and future coronaviruses.
Objective
Despite well-known susceptibilities to respiratory viral infections, respiratory allergy and allergic asthma have not been identified as risk factors for severe COVID-19 in most epidemiologic studies and may be protective. We sought to investigate associations between markers of type-2 (T2) immune responses with SARS-CoV-2 clinical outcomes and viral loads in a cohort of 1164 individuals hospitalized for COVID-19 from May 2020 to March 2021 as part of the IMPACC study.
Methods
We characterized the clinical outcomes, as defined by severity trajectory groups reflecting the degree of respiratory support required, viral loads and antibody titers of COVID-19 infections in IMPACC participants in relation to molecular and cellular markers of Type-2 (T2) immune responses through multiple assays, including, 1) IL-4, IL-5, and IL-13 levels in serum Olink data, 2) T2 cellular signatures in blood CyTOF data, 3) relative quantification of T2 signaling gene pathways in airway RNA-sequencing data, and/or 4) T2 pathways in PBMC RNA-sequencing data. We also investigated the outcomes of individuals with self-reported asthma and evidence of T2 immune responses.
Results
The diagnosis of asthma (odd ratio=1.27), elevated serum T2 cytokine levels (median fold-change=1.06) and a higher frequency of Th2 cells (difference=+2%) were associated with less severe clinical disease during hospitalization. Distinct T2-related transcriptomic changes in nasal and blood samples were associated with reduced viral loads. This included the expression of T2-regulated genes implicated in T/B cell activation and apoptosis in nasal samples and the expression of T2-regulated genes implicated in myeloid differentiation and ROS signaling in blood. Among these, several canonical T2-regulated genes that were increased in less severe disease were identified to have antiviral properties in large high-throughput screens.
Conclusion
T2 immune responses were associated with lower viral loads and more favorable clinical outcomes suggesting that T2 inflammation related to asthma and allergic diseases may have a direct protective effect against SARS-CoV2.