Hyperinflammatory State and Low T1 Adaptive Immune Response in Severe and Critical Acute COVID-19 Patients

Mercedes Garcia-Gasalla; María Berman-Riu; Jaime Pons; Adrián Rodríguez; Amanda Iglesias; Natalia Martínez-Pomar; Isabel Llompart-Alabern; Melchor Riera; Adrián Ferré Beltrán; Albert Figueras-Castilla; Javier Murillas; Joana M Ferrer

doi:10.3389/fmed.2022.828678

Hyperinflammatory State and Low T1 Adaptive Immune Response in Severe and Critical Acute COVID-19 Patients

Front Med (Lausanne). 2022 Mar 29:9:828678. doi: 10.3389/fmed.2022.828678. eCollection 2022.

Authors

Mercedes Garcia-Gasalla^{1

2}, María Berman-Riu², Jaime Pons^{2

3

4}, Adrián Rodríguez^{2

5}, Amanda Iglesias^{2

4}, Natalia Martínez-Pomar^{2

3}, Isabel Llompart-Alabern^{2

6}, Melchor Riera^{1

2}, Adrián Ferré Beltrán¹, Albert Figueras-Castilla⁷, Javier Murillas^{1

2}, Joana M Ferrer^{2

3

4}

Affiliations

¹ Department of Internal Medicine, Hospital Universitari Son Espases, Palma, Spain.
² Balearic Islands Health Research Institute (IdISBa), Palma, Spain.
³ Department of Immunology, Hospital Universitari Son Espases, Palma, Spain.
⁴ Centro de Investigación Biomedica en Red (CIBER) de Enfermedades Respiratorias, Hospital Universitari Son Espases, Palma, Spain.
⁵ Department of Internal Medicine, Hospital Universitari Son Llàtzer, Palma, Spain.
⁶ Análisis Clínicos, Hospital Universitari Son Espases, Palma, Spain.
⁷ Intensive Care Unit, Hospital Universitari Son Espases, Palma, Spain.

Abstract

Background: A better understanding of COVID-19 immunopathology is needed to identify the most vulnerable patients and improve treatment options.

Objective: We aimed to identify immune system cell populations, cytokines, and inflammatory markers related to severity in COVID-19.

Methods: 139 hospitalized patients with COVID-19-58 mild/moderate and 81 severe/critical-and 74 recovered patients were included in a prospective longitudinal study. Clinical data and blood samples were obtained on admission for laboratory markers, cytokines, and lymphocyte subsets study. In the recovered patients, lymphocyte subsets were analyzed 8-12 weeks after discharge.

Results: A National Early Warning Score 2 >2 (OR:41.4; CI:10.38-167.0), ferritin >583 pg/mL (OR:16.3; CI: 3.88-69.9), neutrophil/lymphocyte ratio >3 (OR: 3.5; CI: 1.08-12.0), sIL-2rα (sCD25) >512 pg/mL (OR: 3.3; CI: 1.48-7.9), IL-1Ra >94 pg/mL (OR: 3.2; IC: 1.4-7.3), and IL-18 >125 pg/mL (OR: 2.4; CI: 1.1-5.0) were associated with severe/critical COVID-19 in the multivariate models used. Lower absolute values of CD3, CD4, CD8, and CD19 lymphocytes together with higher frequencies of NK cells, a CD4 and CD8 activated (CD38+HLA-DR+) memory T cell and effector memory CD45RA+ (EMRA) phenotype, and lower T regulatory cell frequencies were found in severe/critical patients relative to mild/moderate and recovered COVID-19 patients. A significant reduction in Th1, Tfh1, and Tc1 with higher Th2, Tfh2, Tc2, and plasma cell frequencies was found in the most severe cases.

Conclusion: A characteristic hyperinflammatory state with significantly elevated neutrophil/lymphocyte ratio and ferritin, IL-1Ra, sIL-2rα, and IL-18 levels together with a "low T1 lymphocyte signature" was found in severe/critical COVID-19 patients.

Keywords: COVID-19 severity; EMRA phenotype; IL-18; IL-1Ra; T regulatory cell; T1 cells; activated memory T cell; sIL-2rα.