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

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.

SARS-CoV-2 infects human adipose tissue and elicits an inflammatory response consistent with severe COVID-19

“…Across multiple experiments, at both the RNA and protein level, we saw increased expression of cytokines, ISGs and other molecules related to inflammation and antiviral pathways 24 hours after SVC infection. Many of the molecules we found upregulated upon SARS-CoV-2 infection are associated with COVID-19 severity: IP-10, PDGFAA, PDGFAB/BB, IL-4, and MCSF all have been reported to be elevated in the serum of critically ill COVID-19 patients (49,51,52), MIF has been described as a predictor of poor outcome on mechanically ventilated COVID-19 patients (62), and VEGF may play a crucial role in COVID-19 related brain inflammation (60). Further, we detected increased type I interferon transcripts and ISG15 in SVC of both SAT and VAT 72 and 96 hpi, indicative of a persistent antiviral response during viral replication.…”

“…The copyright holder for this preprint this version posted October 25, 2021. ; https://doi.org /10.1101/2021.10.24.465626 doi: bioRxiv preprint severity: IP-10, PDGFAA, PDGFAB/BB, IL-4, and MCSF all have been reported to be elevated in the serum of critically ill COVID-19 patients (49,51,52), MIF has been described as a predictor of poor outcome on mechanically ventilated COVID-19 patients (62), and VEGF may play a crucial role in COVID-19 related brain inflammation (60). Further, we detected increased type I interferon transcripts and ISG15 in SVC of both SAT and VAT 72 and 96 hpi, indicative of a persistent antiviral response during viral replication.…”

Predominance of Distinct Autoantibodies in Response to SARS-CoV-2 Infection

“…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 (40). VEGF is identified as a principal proangiogenic factor that enhances the production of new blood vessels from existing vascular network.…”

“…We analyzed samples from our primary cohort of 177 previously SARS-CoV-2 infected HCW individuals in addition to the comparator cohorts comprising 54 HCs blood donors and 6 SLE patients. The median age of the primary cohort was 35 [IQR: [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44]] years, including 62 (35%) men with 38% of the total with a self-reported formal diagnosis of COVID-19 (Supplemental Table 1). Twenty-one COVID-19 related symptoms were scored based on their frequency of report by participants of the HCW survey.…”

Redox-dependent Structure and Dynamics of Macrophage Migration Inhibitory Factor Reveal Sites of Latent Allostery

“…[4][5][6] Circulating levels are reported in the low µM range in healthy humans, [7][8][9] but MIF is overexpressed under inflammatory conditions and has been linked to glucocorticoid overriding activity, 10 asthma, 7,11 rheumatoid arthritis, 12 colitis, 13 pancreatitis, 14 acute respiratory distress syndrome (ARDS), 15 and cancer [16][17][18][19][20] as well as complications from COVID-19. 21 Efforts to elucidate the pathogenic mechanism of MIF have attempted to connect its disease state to cellular redox properties, 11 most recently by investigating its cysteine residues as conformational switches. 22 Mutation of either C56 or C59 in a canonical 56 CXXC 59 (XX = AL in MIF) motif modulates the enzymatic and macrophage activation functions of MIF.…”