## 4 Discussion
### Metabolomic Changes  
Patients hospitalised due to a severe course of COVID-19 showed a significantly increased glucose level on Day 1. All patients were equally treated over the whole time period with dexamethasone, which is known to impair glucose metabolism [21] via the stimulation of gluconeogenesis from amino acids released from muscles, and even one dose of 10 mg dexamethasone may lead to a temporarily increased blood glucose level [22]. The hyperglyaemia in COVID-19 patients treated with dexamethasone is presumably caused by 'triple insult': dexamethasone-induced impaired glucose metabolism, COVID-19-induced insulin resistance, and COVID-19 impaired insulin production [23]. Prolonged uncontrolled hyperglyaemia, regardless of diabetes mellitus, seems to be important in the pathogenesis of COVID-19 [24]. In our study, the hyperglyaemia normalised in Group A, but not in patients with unfavourable outcome included in Group B (Figure 3). This observed result is in line with general knowledge that hyperglyaemia is an unfavourable state in many clinical conditions, i.a., in severe inflammation [25], and is one of the important risk factors of COVID-19 disease progression [26]. The plasma levels of glycolytic products pyruvate and, eventually, lactate were not significantly changed in any group of patients. The relative plasma level of alanine, a metabolite that contributes significantly to liver gluconeogenesis, was decreased on Day 1 in both groups but normalised in patients with a positive outcome on Days 3 and 7; however, it stayed decreased in Group B (figure not shown). Figure 2: ROC curve with AUC values for systems of COVID-19 patients on Day 1 vs. controls, determined by random forest algorithm with relative concentrations of metabolites in blood plasma as input variables; analysis run in metaboanalyst [16]. In the blood plasma of COVID-19 patients, we observed a significantly increased level of 3-hydroxybutyrate, a ketone bodies representative. Besides serving as an energy source for the brain, heart, and skeletal muscle, ketone bodies play pivotal roles as signalling mediators, drivers of protein post-translational modification, and modulators of inflammation and oxidative stress [27]. 3-hydroxybutyrate exerts a predominantly anti-inflammatory response [28; 29; 30], but can also be pro-inflammatory [31]. A recent study on COVID-19 patients already showed dysbalance in ketone bodies [32]. In our study, the initially increased plasma level of 3-hydroxybutyrate decreased over Day 3 and Day 7 in Group A, but it stayed at an elevated level in Group B on the third and seventh days (Figure 3). Interestingly, the glucose level in this patient group also remained high. As we did not analyse the level of C peptide as a representative of the insulin level, we can hypothesise that the proposed glucose resistance or insufficient glucose utilisation is compensated by ketone bodies. The increase in the 3-hydroxybutyrate level in COVID-19 patients is accompanied by a decreased amount of lipoprotein fraction in blood plasma in patients suffering from COVID-19, containing up to one-third of triacylglyceroles [18] as one of the additional substrates for ketone body synthesis (boxplot not shown). We observed a decreased citrate level in the blood plasma in COVID-19 patients, suggesting alteration of the TCA cycle (Figure 3), similar to the results of a recent study by [PERSON] et al. [11]. Besides including \(\alpha\)-ketoglutarate, an essential substrate for endogenous glutamate/glutamine synthesis, there is evidence that TCA cycle intermediates also have an epigenetic impact by influencing DNA and histone methylation, including immune cells [33]. Further, the metabolite creatine, a part of muscle energy metabolism, was significantly increased in the blood plasma of COVID-19 patients compared with controls in both groups, rising with the time of hospitalisation (Figure 3).