Macrophage Migration Inhibitory Factor (MIF) Plasma Concentration in Critically Ill COVID-19 Patients: A Prospective Observational Study

Christian Bleilevens, Josefin Soppert, Adrian Hoffmann, Thomas Breuer, Jürgen Bernhagen, Lukas Martin, Lara Stiehler, Gernot Marx, Michael Dreher, Christian Stoppe, Tim-Philipp Simon, Christian Bleilevens, Josefin Soppert, Adrian Hoffmann, Thomas Breuer, Jürgen Bernhagen, Lukas Martin, Lara Stiehler, Gernot Marx, Michael Dreher, Christian Stoppe, Tim-Philipp Simon

Abstract

Mortality in critically ill coronavirus disease 2019 (COVID-19) patients is high and pharmacological treatment strategies remain limited. Early-stage predictive biomarkers are needed to identify patients with a high risk of severe clinical courses and to stratify treatment strategies. Macrophage migration inhibitory factor (MIF) was previously described as a potential predictor for the outcome of critically ill patients and for acute respiratory distress syndrome (ARDS), a hallmark of severe COVID-19 disease. This prospective observational study evaluates the predictive potential of MIF for the clinical outcome after severe COVID-19 infection. Plasma MIF concentrations were measured in 36 mechanically ventilated COVID-19 patients over three days after intensive care unit (ICU) admission. Increased compared to decreased MIF was significantly associated with aggravated organ function and a significantly lower 28-day survival (sequential organ failure assessment (SOFA) score; 8.2 ± 4.5 to 14.3 ± 3, p = 0.009 vs. 8.9 ± 1.9 to 12 ± 2, p = 0.296; survival: 56% vs. 93%; p = 0.003). Arterial hypertension was the predominant comorbidity in 85% of patients with increasing MIF concentrations (vs. decreasing MIF: 39%; p = 0.015). Without reaching significance, more patients with decreasing MIF were able to improve their ARDS status (p = 0.142). The identified association between an early MIF response, aggravation of organ function and 28-day survival may open future perspectives for biomarker-based diagnostic approaches for ICU management of COVID-19 patients.

Keywords: COVID-19; Horowitz Quotient; ICU treatment; Macrophage Migration Inhibitory Factor (MIF); SOFA Score; acute respiratory distress syndrome (ARDS).

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Plasma concentrations of macrophage migration inhibitory factor (MIF) on day 1 and day 3 of Intensive Care Unit (ICU) admission in 36 patients (day 1 vs. day 3, p = 0.307).
Figure 2
Figure 2
Plasma concentration of macrophage migration inhibitory factor (MIF) on day 1 (black circles) and day 3 (white circles) of intensive care unit (ICU) admission for each of the 36 coronavirus disease 2019 (COVID-19) patients. Patients showing decreasing MIF concentrations between day 1 and day 3 were summarized as “Responder” and those with increasing MIF concentrations were summarized as “Non-Responder” *** p < 0.001 vs. day 1 Non-Responder; ###p < 0.001 vs. day 3 Non-Responder; §§§p < 0.001 day 1 vs. day 3.
Figure 3
Figure 3
In both groups, an equal number of patients showed an improved sequential organ failure assessment sequential organ failure assessment (SOFA) score, respectively improved organ function after 14 days (green), as well as an aggravated (red), or unchanged (grey) organ function. SOFA score on day 14 was significantly different between improved- and aggravated organ function, independent from the groups (Responder vs. Non-Responder). Within the Non- Responder group, the SOFA score increase was significant from day 1 to day 14 for patients with aggravated organ function.
Figure 4
Figure 4
The number of patients changing their acute respiratory distress syndrome (ARDS) status from improved (green), aggravated (red) or equal (grey) from day 1 to day 14 was not significantly different between the groups (Responder vs. Non-Responder p = 0.142). Within the groups, the number of patients changing their ARDS status was not significantly different (p = 0.146 vs. p = 0.370). In both groups, a significant increase of HQ in patients showing improvement from day 1 to day 14 could be shown (p < 0.05).
Figure 5
Figure 5
No changes of plasma interleukin 6 (IL-6) (A), procalcitonin (PCT) (B) and C-reactive protein (CRP) (C) from day 1 to day 14 were detected within or between the groups (IL-6: p = 0.587; PCT: p = 0.228; CRP: p = 0.955).
Figure 6
Figure 6
Significantly more COVID-19 patients survived the 28 days ICU treatment in the Responder group (A, p = 0.003). Within the Non-Responder group, the MIF concentration on day 3 was significantly increased in patients who died compared to survivors (p = 0.026) (B). There was no significant difference in gender- (p = 0.137) and age-distribution (p = 0.924), but none of the female patients (n = 3) died in the Responder group, whereas 2 of 7 female patients in the Non-Responder group died during the observational period (p = 0.0159) (C).

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