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. 2022 Mar 29:9:828678.
doi: 10.3389/fmed.2022.828678. eCollection 2022.

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

Mercedes Garcia-Gasalla  1   2 , María Berman-Riu  2 , 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 Beltrán  1 , Albert Figueras-Castilla  7 , Javier Murillas  1   2 , Joana M Ferrer  2   3   4
Affiliations

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

Mercedes Garcia-Gasalla et al. Front Med (Lausanne). .

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.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Lower lymphocytes absolute number and frequency and higher NK frequency in severe/critical COVID-19 patients. Absolute numbers (A) and frequency (B) of peripheral blood cell populations (CD3, CD4, CDS, CD19 and NK) in mild/moderate (light gray circles), severe/critical (dark gray circles) and recovered (white circles) groups of patients. Each dot represents an individual patient. Data are given as mean (Kruskal–Wallis test P-values: **P < 0.01; ***P < 0.001).
Figure 2
Figure 2
Lower regulatory T cells and higher activated (CD38+HlA-DR+) and EMRA phenotype CD4 and CDS frequency in severe/critical COVID-19 patients. Frequency of selected peripheral blood T cell populations (A,B) in mild/moderate (light gray circles), severe/critical (dark gray circles) and recovered (white circles) groups of patients. Each dot represents an individual patient. Data are given as mean (Kruskal–Wallis test P-values: *P < 0.05; **P < 0.01; ***P < 0.001). TEM, T effector memory; TCM, T central memory; EMRA, terminally differentiated effector memory cells re-expressingCD45RA.
Figure 3
Figure 3
Lower Tfhl, Thl, and Tel and higher Tfh2, Th2, and Tc2 cells frequency in severe/critical COVID-19 patients. Frequency of T follicular helper cells (A), T helper cells (B) and T cytotoxic cells (C) in mild/moderate (light gray circles), severe/critical (dark gray circles) and recovered (white circles) groups of patients. Each dot represents an individual patient. Data are given as mean (Kruskal–Wallis test P-values: *P < 0.05; **P < 0.01; ***P < 0.001). Tfh, T follicular helper; Th, T helper; Tc, T cytotoxic.
Figure 4
Figure 4
Lower memory and “double negative” and higher naive and plasma B cells frequency in severe/critical COVID-19 patients. Frequency of peripheral blood B cell populations in mild/moderate (light gray circles), severe/critical (dark gray circles) and recovered (white circles) groups of patients. Each dot represents an individual patient. Data are given as mean (Kruskal–Wallis test P-values: *P < 0.05; **P < 0.01; ***P < 0.001). nsm B, non-switch memory B; smB, switch memory B.
Figure 5
Figure 5
Performance of ROC curves in predicting severe/critical COVID-19 disease for News-2, Ferritin, NLR and CRP (A), sCD25s, 111Ra, and IL1S (B) and activated CD4 and CDS, NK, Tc2 and EMRA CDS (C).
See this image and copyright information in PMC

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