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Cytokine Elevation in Severe COVID-19 From Longitudinal Proteomics Analysis: Comparison With Sepsis
Takeshi Ebihara1, Hisatake Matsumoto1, Tsunehiro Matsubara1
1Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
Insights
Growth differentiation factor (GDF)-15 and interleukin (IL)-6 are key cytokines in COVID-19 and sepsis. GDF-15 levels in intensive care unit (ICU) patients predict recovery and mechanical ventilation weaning time.
Area of Science:
- Proteomics and immunology
- Critical care medicine
- Infectious disease research
Background:
- Cytokine storm, an uncontrolled inflammatory response, is implicated in COVID-19 and sepsis pathogenesis.
- Understanding specific cytokine involvement is crucial for managing severe disease.
Purpose of the Study:
- To identify and validate cytokines associated with COVID-19 severity and prognosis using proteomics.
- To compare cytokine profiles between COVID-19 and sepsis patients.
Main Methods:
- Proteomic analysis of 1463 plasma proteins in a COVID-19 cohort.
- Validation of identified cytokines in COVID-19 and sepsis patients in intensive care units (ICUs).
- Prognostic evaluation including time to mechanical ventilation weaning.
Main Results:
- Interleukin (IL)-6 and growth differentiation factor (GDF)-15 were identified as key cytokines linked to COVID-19 severity.
- IL-6 and GDF-15 levels were higher in sepsis than in COVID-19 patients.
- GDF-15 levels at ICU admission predicted time to mechanical ventilation weaning and late recovery in COVID-19 patients.
Conclusions:
- GDF-15 and IL-6 are significant in COVID-19 pathogenesis and prognosis.
- Elevated GDF-15 is a predictor of outcomes in critically ill COVID-19 patients.
- Cytokine profiles differ between COVID-19 and sepsis, with implications for treatment strategies.
Introduction:
Coronavirus disease 2019 (COVID-19) is a new viral disease. Uncontrolled inflammation called "cytokine storm" is reported to contribute to disease pathogenesis as well as sepsis. We aimed to identify cytokines related to the pathogenesis of COVID-19 through a proteomics analysis of 1463 plasma proteins, validate these cytokines, and compare them with sepsis.
Materials And Methods:
In a derivation cohort of 306 patients with COVID-19, 1463 unique plasma proteins were measured on days 1, 4, and 8. Cytokines associated with disease severity and prognosis were derived. In a validation cohort of 62 COVID-19 patients and 38 sepsis patients treated in the intensive care unit [ICU], these derived cytokines were measured on days 1 (day of ICU admission), 2-3, and 6-8 (maximum: 3 time points/patient). Derived cytokines were compared with healthy controls and between COVID-19 and sepsis patients, and the associations with prognosis were evaluated. The time to wean off mechanical ventilation (MV) was evaluated only for COVID-19.
Results:
IL-6, amphiregulin, and growth differentiation factor (GDF)-15 were associated with disease severity and prognosis in the derivation cohort. In the validation cohort, IL-6 and GDF-15 were elevated in COVID-19 and sepsis on day 1, and the levels of these cytokines were higher in sepsis than in COVID-19. IL-6 and GDF-15 were associated with prognosis in sepsis. Cox proportional hazards model with time as a dependent covariate showed a significant relationship between plasma GDF-15 level and time to wean off MV (hazard ratio, 0.549 [95% confidence level, 0.382-0.789]). The GDF-15 level at ICU admission predicted late recovery.
Conclusion:
GDF-15 and IL-6 derived from proteomics analysis were related with disease severity of COVID-19. Their values were higher in sepsis than in COVID-19 and were associated with prognosis in sepsis. In COVID-19 patients treated in the ICU, GDF-15 was associated with the time to wean off MV and better predicted late recovery.
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