Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22–2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified ‘Age, RNAemia’ and ‘Age, PTX3’ as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.

The COVID-19 pandemic has been the primary global health issue since its outbreak in December 2019. Patients with metabolic syndrome suffer from severe complications and a higher mortality rate due to SARS-CoV-2 infection. We recently proposed that SARS-CoV-2 can hijack host mitochondrial function and manipulate metabolic pathways for their own advantage. The aim of the current study was to investigate functional mitochondrial changes in live peripheral blood mononuclear cells (PBMCs) from COVID-19 patients, decipher the pathways of substrate utilization in these cells and corresponding changes in the inflammatory pathways. We demonstrate mitochondrial dysfunction, metabolic alterations with an increase in glycolysis and high levels of mitokine in PBMCs from COVID-19 patients. Interestingly, we found that levels of FGF-21 mitokine correlate with COVID-19 disease severity and mortality. These data suggest that COVID-19 patients have compromised mitochondrial function and an energy deficit which is compensated by a metabolic switch to glycolysis. This metabolic manipulation by SARS-CoV-2 triggers an enhanced inflammatory response which contributes to severity of symptoms in COVID-19. Targeting mitochondrial metabolic pathway(s) can help define novel strategies for COVID-19.

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The extracellular matrix (ECM) plays an important role in the regulation of the tissue microenvironment and in the maintenance of cellular homeostasis. Several proteins with a proteolytic activity toward several ECM components are involved in the regulation and remodeling of the ECM. Among these, Matrix Metalloproteinases (MMPs) are a class of peptidase able to remodel the ECM by favoring the tumor invasive processes. Of these peptidases, MMP-9 is the most involved in the development of cancer, including that of melanoma. Dysregulations of the MAPKs and PI3K/Akt signaling pathways can lead to an aberrant overexpression of MMP-9. Even ncRNAs are implicated in the aberrant production of MMP-9 protein, as well as other proteins responsible for the activation or inhibition of MMP-9, such as Osteopontin and Tissue Inhibitors of Metalloproteinases. Currently, there are different therapeutic approaches for melanoma, including targeted therapies and immunotherapies. However, no biomarkers are available for the prediction of the therapeutic response. In this context, several studies have tried to understand the diagnostic, prognostic and therapeutic potential of MMP-9 in melanoma patients by performing clinical trials with synthetic MMPs inhibitors. Therefore, MMP-9 may be considered a promising molecule for the management of melanoma patients due to its role as a biomarker and therapeutic target.

Background: Most studies of anti-transglutaminase (anti-tTG) assays have considered preselected groups of patients. This study compared the sensitivity, specificity, and predictive value of an immunofluorescence method for anti-endomysial antibodies (EmAs) and two anti-tTG ELISAs, one using guinea pig tTG (gp-tTG) and the other human tTG (h-tTG) as antigen, in consecutive patients investigated for suspected celiac disease (CD). Methods: We studied 207 consecutive patients (99 men, 108 women; age range, 17–84 years) who underwent intestinal biopsy for suspected CD. Patients presented with one or more of the following: weight loss, anemia, chronic diarrhea, abdominal pain, dyspepsia, alternating bowel habits, constipation, pain in the joints, and dermatitis. At entry to the study, an intestinal biopsy was performed and a serum sample was taken for IgA EmAs, anti-gp-tTG, and anti-h-tTG. Results: Intestinal histology showed that 24 patients had partial or total villous atrophy; in these patients the diagnosis of CD was confirmed by follow-up. The remaining 183 patients had villous/crypt ratios that were within our laboratory’s reference values and were considered controls. Serum EmAs, anti-gp-tTG, and anti-h-tTG were positive in all 24 CD patients; in the control group, none were positive for serum EmAs, but 15 of 183 (8.2%) were positive for anti-gp-tTG, and 6 of 183 (3.3%) were positive for anti-h-tTG. Sensitivity was 100% for all assays, whereas specificity was 100% for the EmA, 92% for the anti-gp-tTG, and 97% for the anti-h-tTG assay. The negative predictive value was 100% for all assays; the positive predictive value was 100% for the EmA, 80% [95% confidence interval (CI), 65–95%] for the anti-h-tTG (P = 0.03 vs EmA) and 60% (95% CI, 44–76%) for the anti-gp-tTG assay (P = 0.0002 vs EmA). Areas (95% CIs) under the ROC curves were 0.987 (0.97–1.0) for anti-h-tTG and 0.965 (0.94–0.99) for anti-gp-tTG. Most of the patients testing false positive for anti-tTG had Crohn disease or chronic liver disease. Conclusions: Although both anti-tTG ELISAs showed optimum sensitivity, their lack of specificity yielded positive predictive values significantly lower than those for the EmA assay.

Aims Coronavirus disease 2019 (COVID-19) can lead to multiorgan damage. MicroRNAs (miRNAs) in blood reflect cell activation and tissue injury. We aimed to determine the association of circulating miRNAs with COVID-19 severity and 28-day intensive care unit (ICU) mortality. Methods and results We performed RNA-Seq in plasma of healthy controls (n = 11), non-severe (n = 18) and severe (n = 18) COVID-19 patients and selected 14 miRNAs according to cell- and tissue origin for measurement by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in a separate cohort of mild (n = 6), moderate (n = 39) and severe (n = 16) patients. Candidates were then measured by RT-qPCR in longitudinal samples of ICU COVID-19 patients (n = 240 samples from n = 65 patients). 60 miRNAs, including platelet-, endothelial-, hepatocyte- and cardiomyocyte-derived miRNAs, were differentially expressed depending on severity, with increased miR-133a and reduced miR-122 also being associated with 28-day mortality. We leveraged mass spectrometry-based proteomics data for corresponding protein trajectories. Myocyte-derived (myomiR) miR-133a was inversely associated with neutrophil counts and positively with proteins related to neutrophil degranulation, such as myeloperoxidase. In contrast, levels of hepatocyte-derived miR-122 correlated to liver parameters and to liver-derived positive (inverse association) and negative acute phase proteins (positive association). Finally, we compared miRNAs to established markers of COVID-19 severity and outcome, i.e. SARS-CoV-2 RNAemia, age, BMI, D-dimer and troponin. Whilst RNAemia, age and troponin were better predictors of mortality, miR-133a and miR-122 showed superior classification performance for severity. In binary and triplet combinations, miRNAs improved classification performance of established markers for severity and mortality. Conclusion Circulating miRNAs of different tissue origin, including several known cardiometabolic biomarkers, rise with COVID-19 severity. MyomiR miR-133a and liver-derived miR-122 also relate to 28-day mortality. MiR-133a reflects inflammation-induced myocyte damage, whilst miR-122 reflects the hepatic acute phase response. Translational perspective Adding biomarkers to conventional scores for illness severity and mortality could improve prognostic performance in COVID-19 patients. Circulating miRNAs are emerging as promising biomarkers with tissue specific origins but have only sparsely been investigated in COVID-19. We quantified circulating miRNAs of different tissue origin in COVID-19 patients, identifying several miRNAs of the cardiometabolic system to be associated with severity. Myocyte-derived miR-133a and liver-derived miR-122 also associated with mortality. Through longitudinal proteomics measurements, we related myomiR miR-133a release to neutrophil activation and miR-122 release to the hepatic acute phase response. Our findings highlight key pathophysiological changes and provide first evidence on the performance of miRNA biomarkers in COVID-19.

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