## 4 Discussion
### Metabolomic Changes
Patients forced to lie in bed for a sustained period lack spontaneous movement utilising muscle energy, which is probably the reason for the increase of plasma creatine. BCAAs (branched chain amino acids), including leucine, isoleucine, and valine, share a common pattern of extrahepatic metabolism, and their relative plasma concentrations were represented similarly in both groups of patients. In Figure 3, we show only the dynamics of leucine since isoleucine and valine behaved almost identically. As a representative of ketoacids derived from BCAAs, we show only the course of ketoleucine, as the dynamics was repeated for the other two ketoacids: ketovaline and ketoisoleucine. Increased leucine in COVID-19 patients was reported by [PERSON]  
Figure 3: Relative concentrations of selected metabolites in blood plasma for patient Groups A and B on Day 1, Day 3, and Day 7. Values are relativised to the median of controls set to 1.  
established association between elevated circulating BCAAs and their deleterious effects, as their increased concentration may promote oxidative stress and inflammation [35], having also a neurological impact [36; 37]. By monitoring dynamic changes for two different patient subgroups, we observed that initially increased plasma levels of BCAAs in both groups slowly decreased in Group A but not in Group B (Figure 3). Interestingly, the mean values of BCAAs in Group B obviously follow the course of the plasma glucose levels. The increase of BCAAs at time of impaired glycolysis and increased use of fatty acids were very recently discussed in a comprehensive review by [PERSON] [38], showing the important role of BCAAs in energy metabolism. Taking the above discussed results together, severe inflammation induced by COVID-19 caused changes in energy metabolism, where we observed increased blood glucose that implies lowered glucose utilisation (the influence of dexamethasone treatment cannot be omitted). In balance, the body, including immune cells, uses ketone bodies (observed increased 3-hydroxybutyrate together with decreased triacylglycerlycerides) as an energy source, and, alternatively also amino acids released by accelerated protein catabolism (increased levels of essential amino acids BCAAs). Interestingly, although all patients in both groups received the dexamethasone treatment during the follow-up period, the above mentioned changes normalised only in patients with a positive outcome; however, they persisted in patients with a negative outcome (more than half of them had died at the time of writing). This course was independent of the patients' diet (Figure S2 in Supplement). In acute inflammatory conditions, the demand on glutamine increases [39] which may lead to its plasma decrease if the endogenous synthesis of glutamine does not fulfil the requirements of the body [39]. Glutamine serves besides others as a fuel for immune cells--lymphocytes, neutrophils, and macrophages [39; 40; 41; 42]--and plays a crucial role in cytokine production [42]. In our study, we noticed a decrease in the glutamine plasma level in COVID-19 patients on Day 1, observed to a lower extent in Group A, which is in accordance with another study where glutamine deficiency may have contributed to disease severity [43]. The glutamine plasma level normalised in both groups, but this was faster in Group A (Figure 4). On Day 7, both groups of patients showed plasma glutamine levels very similar to the level in control subjects, where probably the balance between glutamine production and utilisation had stabilised (Figure 4). Accelerated spontaneous stabilisation of glutamine levels in patients with better outcome supports the results from another study, where the administration of glutamine in the early period of infection suggested a shortened hospital stay and decreased the need for ICU stay [40]. Another significant metabolic parameter associated with immune activation and inflammation is the Phe/Tyr ratio [44; 45].