Impact of the Innate Inflammatory Response on ICU Admission and Death in Hospitalized Patients with COVID-19

Jorge Monserrat, Angel Asunsolo, Ana Gómez-Lahoz, Miguel A Ortega, Jose Maria Gasalla, Óscar Gasulla, Jordi Fortuny-Profitós, Ferran A Mazaira-Font, Miguel Teixidó Román, Alberto Arranz, José Sanz, Benjamin Muñoz, Juan Arévalo-Serrano, José Miguel Rodríguez, Carlos Martínez-A, Dimitri Balomenos, Melchor Álvarez-Mon, Jorge Monserrat, Angel Asunsolo, Ana Gómez-Lahoz, Miguel A Ortega, Jose Maria Gasalla, Óscar Gasulla, Jordi Fortuny-Profitós, Ferran A Mazaira-Font, Miguel Teixidó Román, Alberto Arranz, José Sanz, Benjamin Muñoz, Juan Arévalo-Serrano, José Miguel Rodríguez, Carlos Martínez-A, Dimitri Balomenos, Melchor Álvarez-Mon

Abstract

Objective: To describe the capacity of a broad spectrum of cytokines and growth factors to predict ICU admission and/or death in patients with severe COVID-19.

Design: An observational, analytical, retrospective cohort study with longitudinal follow-up.

Setting: Hospital Universitario Príncipe de Asturias (HUPA).

Participants: 287 patients diagnosed with COVID-19 admitted to our hospital from 24 March to 8 May 2020, followed until 31 August 2020.

Main outcome measures: Profiles of immune response (IR) mediators were determined using the Luminex Multiplex technique in hospitalized patients within six days of admission by examining serum levels of 62 soluble molecules classified into the three groups: adaptive IR-related cytokines (n = 19), innate inflammatory IR-related cytokines (n = 27), and growth factors (n = 16).

Results: A statistically robust link with ICU admission and/or death was detected for increased serum levels of interleukin (IL)-6, IL-15, soluble (s) RAGE, IP10, MCP3, sIL1RII, IL-8, GCSF and MCSF and IL-10. The greatest prognostic value was observed for the marker combination IL-10, IL-6 and GCSF.

Conclusions: When severe COVID-19 progresses to ICU admission and/or death there is a marked increase in serum levels of several cytokines and chemokines, mainly related to the patient's inflammatory IR. Serum levels of IL-10, IL-6 and GCSF were most prognostic of the outcome measure.

Keywords: COVID-19; ICU; SARS-CoV-2; cytokines; innate inflammatory response.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Serum levels of cytokines and growth factors in COVID-19 patients and HC. Y axes indicate the ratios of concentrations of each cytokine in the COVID-19 patients to those in HC. Ratios for adaptive IR-related cytokines (A), innate inflammatory-related IR cytokines (B) and growth factors (C). The vertical bars represent the mean of the COVID-19:HC ratios for the indicated molecule. The intensity of color denotes significant differences between serum levels of each cytokine in the COVID-19 patients and HC.
Figure 1
Figure 1
Serum levels of cytokines and growth factors in COVID-19 patients and HC. Y axes indicate the ratios of concentrations of each cytokine in the COVID-19 patients to those in HC. Ratios for adaptive IR-related cytokines (A), innate inflammatory-related IR cytokines (B) and growth factors (C). The vertical bars represent the mean of the COVID-19:HC ratios for the indicated molecule. The intensity of color denotes significant differences between serum levels of each cytokine in the COVID-19 patients and HC.
Figure 2
Figure 2
Odds ratios for ICU/Exitus of serum levels of adaptive IR-related cytokines (A), innate inflammatory IR-related cytokines (B) and growth factors (C) in COVID-19 patients. Y axes show the odds ratio of increased concentrations of each marker for ICU/Exitus. The intensity of the color grades the level of the significance of the odds ratio.
Figure 2
Figure 2
Odds ratios for ICU/Exitus of serum levels of adaptive IR-related cytokines (A), innate inflammatory IR-related cytokines (B) and growth factors (C) in COVID-19 patients. Y axes show the odds ratio of increased concentrations of each marker for ICU/Exitus. The intensity of the color grades the level of the significance of the odds ratio.
Figure 3
Figure 3
Contributions of the selected molecules to the final models of prediction of ICU admission and/or death in COVID-19 patients. In addition to the different combinations of molecules included in the three models, the AUC of the prognostic value of clinical score (age, sex, comorbidities and blood oxygen saturation) was calculated. Percentages represent the relative importance of the four different components of variables in each model estimated using SHAP values.

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