Front Immunol. 2023;14:1110874.

Different degree of cytokinemia and T-cell activation according to serum IL-6 levels in critical COVID-19.

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제1저자 이찬미, 김민지 · 교신저자 박완범, 김항래, 신현무

PMID 37081872 PMC10110916 DOI 10.3389/fimmu.2023.1110874 IF 7 감염내과

소속 (7)

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Anatomy & Cell Biology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea.
Research and development team 2, Molecular Diagnostics Division, Quantamatrix Inc., Seoul, Republic of Korea.
Wide River Institute of Immunology, Seoul National University, Hongcheon, Republic of Korea.
Medical Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

Abstract

INTRODUCTION Tocilizumab, a humanized anti-interleukin-6 receptor (IL-6R) antibody, is recommended for the treatment of severe to critical coronavirus diseases 2019 (COVID-19). However, there were conflicting results on the efficacy of tocilizumab. Therefore, we hypothesized that the differences in tocilizumab efficacy may stem from the different immune responses of critical COVID-19 patients. In this study, we described two groups of immunologically distinct COVID-19 patients, based on their IL-6 response.

METHODS We prospectively enrolled critical COVID-19 patients, requiring oxygen support with a high flow nasal cannula or a mechanical ventilator, and analyzed their serial samples. An enzyme-linked immunosorbent assay and flow cytometry were used to evaluate the cytokine kinetics and cellular immune responses, respectively.

RESULTS A total of nine patients with critical COVID-19 were included. The high (n = 5) and low IL-6 (n = 4) groups were distinguished by their peak serum IL-6 levels, using 400 pg/mL as the cut-off value. Although the difference of flow cytometric data did not reach the level of statistical significance, the levels of pro-inflammatory cytokines and the frequencies of intermediate monocytes (CD14⁺CD16⁺), IFN-γ⁺ CD4⁺ or CD8⁺ T cells, and HLA-DR⁺PD-1⁺ CD4⁺ T cells were higher in the high IL-6 group than in the low IL-6 group.

CONCLUSION There were distinctive two groups of critical COVID-19 according to serum IL-6 levels having different degrees of cytokinemia and T-cell responses. Our results indicate that the use of immune modulators should be more tailored in patients with critical COVID-19.

Keywords

IL-6T cellcritical COVID-19cytokineimmune response

Figures

**Figure 1** Levels of cytokines and inflammatory marker in patients with critical COVID-19. **(A)** The levels of interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α in the high IL-6 (n = 5) and low IL-6 (n = 4) groups. **(B)** Levels of C-reactive protein (CRP) in the high IL-6 and low IL-6 groups. Vertical and horizontal lines indicate the median with the interquartile range. The cytokine and CRP levels at the closest point to the onset of critical illness (within 0–5 days of high flow nasal cannula oxygen therapy initiation) are shown.

**Figure 2** Proportion of monocyte subpopulation and expression levels of cytokine and activation markers in T cells. **(A)** Representative flow cytometry dot plots showing the identification of intermediate monocytes (CD14⁺CD16⁺) in the high IL-6 (n = 5) and low IL-6 (n = 4) groups. **(B)** Representative flow cytometry dot plots showing the identification of IFN-γ⁺ CD4⁺ T cells and CD8⁺ T cells in the high IL-6 and low IL-6 groups. **(C)** Representative flow cytometry dot plots showing the identification of HLA-DR⁺PD-1⁺ CD4⁺ T cells and CD8⁺ T cells in the high IL-6 and low IL-6 groups. Numbers indicate population frequencies as the median with interquartile range.

그림 출처: PubMed Central 공개 논문 (PMC10110916)

Conflict of interest statement

Author HB and TC are employed by QuantaMatrix. The remaining 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.

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