Long COVID-19 News: German Study Finds That Dysregulated Metabolism And Inflammation Contributes To Ongoing Symptoms In Long COVID

Long COVID-19 News: A new study by German researchers have found that that dysregulated metabolism and Inflammation contributes to many ongoing symptoms found in individuals with Long COVID.


 
The study team comprised scientists from University of Tübingen--Germany and the University Hospital Tübingen-Germany.
 
Numerous past studies and Long COVID-19 News coverages indicate that about 20-30% of individuals infected with the SARS-CoV-2 virus regardless of hospitalization status experience long-COVID-19 symptoms.
 
 It is catastrophic for millions of people worldwide and hardly anything is known about why some individuals experience these symptoms even after 3 to 12 months after the acute phase.
 
The study team attempted to understand whether dysregulated metabolism and inflammation could be contributing factors to the ongoing symptoms in Long COVID.
 
The study findings showed that total blood triglycerides and the Cory cycle metabolites (lactate and pyruvate) were significantly higher, lipoproteins (Apo-A1 and A2) were drastically lower in Long COVID individuals compared to healthy controls.
 
Correlation analysis revealed that either age or gender are positively correlated with several metabolites (citrate, glutamate, 3-hydroxybutyrate, glucose) and lipoproteins (Apo-A1, HDL Apo-A1, LDL triglycerides) in Long COVID individuals.
 
 Also, several cytokines and chemokines were positively correlated with metabolites and lipoproteins thus, dysregulation in metabolism and inflammation could be a potential contributory factor for Long COVID symptoms.
 
To date, deep metabolomic, proteomic and immunologic phenotyping of SARS-CoV-2 patients have matched a wide diversity of clinical symptoms with potential biomarkers for coronavirus disease 2019 (COVID-19). Within here, several studies described the role of metabolites, lipoproteins and inflammation markers during infection and in recovered patients.
 
So far, how these small biomolecules such as metabolites, lipoprotein, cytokines and chemokines altogether govern pathophysiology is largely underexplored.
 
A proper understanding how these parameters into an integrated fashion could predict the disease course may help to stratify Long COVID patients from acute COVID-19 or recovered specimen and would help to elucidate a potential mechanistic role of these biomolecules during the disease course.
 
The study reported an integrated analysis of blood serum and plasma by in vitro diagnostics research NMR spectroscopy and flow cytometry-based cytokine quantification in a total of 125 individuals (healthy controls (HC; n=73), recovered (Recov, n=12), acute (n=7) and Long COVID (n=33)).
 
Importantly, it was found that in Long COVID individuals, lactate and pyruvate were significantly different from either healthy controls or acute COVID-19 patients.
 
Subsequent correlational analysis of cytokines and metabolites indicated that creatine, glutamine, and high-density lipoprotein (HDL) phospholipids were distributed differentially amongst patients or indi viduals.
 
Significantly, triglycerides and several lipoproteins (apolipoproteins Apo-A1 and A2) in Long COVID individuals demonstrate COVID-19-like alterations compared to HC.
 
Long COVID and acute COVID-19 samples were distinguished mostly by their creatinine, phenylalanine, succinate, 3-hydroxybutyrate (3-HB) and glucose concentrations, illustrating an imbalanced energy metabolism.
 
It was also found that most of the cytokines and chemokines were present at low levels in Long COVID individuals compared with HC except IL-18 chemokine, which tended to be higher in Long COVID individuals and correlated positively with several amino acids (creatine, histidine, leucine, and valine), metabolites (lactate and 3-HB) and lipoproteins.
 
The identification of these persisting plasma metabolites, lipoprotein and inflammation alterations will help to better stratify Long COVID patients from other diseases and could help to predict ongoing severity of Long COVID patients.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2023.01.13.523998v1
 
This is the first study to identify several metabolites and lipoprotein and cytokines which are dysregulated in Long COVID individuals compared with either HC, Recov or acute COVID-19 patients.
 
The key findings revealed that lactate and pyruvate were highly upregulated in Long COVID individuals compared with HC and similar metabolites were also upregulated in Recov patients.
 
This could be due to dysregulated oxidative phosphorylation in Recov or Long COVID patients.
 
Furthermore, phenylalanine, glycine, acetate, Gln/Glu ratio, glutamine, and creatinine were downregulated in Long COVID patients compared with HC or Recov which may be indicative of the Long COVID symptom.
 
A sign of a greater long COVID-related severity state could be demonstrated by phenylalanine, ketone bodies (acetoacetate, acetone, and 3-hydroxybutyrate), formate, creatine, and pyruvate blood levels.
 
As there is a demand for the amino acid and its further pathway products, phenylalanine levels go down in COVID recovery phase patients as reported in a previous study, similarly to currently investigated Long COVID group versus convalescent comparison.
https://pubmed.ncbi.nlm.nih.gov/34878333/
 
A slight change of acetoacetate could be an indicator of dietary habits changes or in combination with other statistically significant parameters could predict COVID-19 disease severity.
https://www.mdpi.com/2076-393X/10/1/79
 
https://europepmc.org/article/med/34489601
 
The study team was able to determine that correlations of creatine, glutamine, lysine, and 3-HB were stronger to the cytokine data in the Long COVID group and these metabolites can provide an insight which metabolic shifts could be persisting and represent a continuous risk to the patients’ health.
 
Recov and Long COVID patients showed very similar types of metabolic dysregulations.
 
The study findings identified some difference between the groups especially for the formate, acetate, creatinine, HDL-4 triglycerides and HDL-4 Apo-A1 apolipoprotein levels, however no significance level was achieved.
 
The study team also investigated a correlation between groups of Recov and LTCS. The findings therefore suggest a contrastingly higher role of creatine to IL-1b, INF-g, TNF-a (predominantly), IL-8/10/18 cytokines positive correlations among the LTCS individuals.


 Graphical Abstract
 
The study findings were similar to the previously reported association of mild/acute COVID-19 patients metabolomic analysis and its classification to the cytokine panel data.
https://europepmc.org/article/pmc/pmc7948172
 
The study findings also identified a Long COVID-specific positive correlation between HDL phospholipids and IL-1b, INF-g, IL-6, IL-12p70, IL-23/33. This evidence could be complemented with finding of HDL phospholipids among other NMR-defined lipoprotein variables in COVID-19 patients.
https://pubs.acs.org/doi/10.1021/acs.jproteome.1c00458
 
The study findings further identified an elevation of citrate and pyruvate in blood of the Long COVID patient group compared with HC. This is in line with another study which identified higher levels of pyruvic acid are accumulated in the bloodstream of COVID-19 patients and which could be used to prognose disease severity.
https://www.frontiersin.org/articles/10.3389/fimmu.2022.912579/full
 
Also, higher levels of lactate in COVID-19 patients are an already established finding.
https://pubmed.ncbi.nlm.nih.gov/34856090/
 
Hence the study team speculates that glycolysis/gluconeogenesis and Krebs cycle metabolic pathways will lead to the elevated consumption of glucose to produce citric acid into the blood plasma.
 
It is interesting to note that the citrate levels did not significantly correlate to any of the chemokine or cytokines as yet it was only connected to the gender factor. Therefore, gender based metabolic dysregulation could play an important role to understand the disease severity. This is especially important as certain Long COVID symptoms have been reported more for female or male patients.
 
Also, maintained triglycerides and other lipoproteins changes indicate that COVID-19 like features still exist in Long COVID patients when comparisons were made with HC.
 
Elevated apolipoproteins ratio B100 to A1 and overall blood triglycerides could be attributed to the disease group.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805607/
 
Though, in the current study, only triglycerides showed negative correlations to IFN-a2, IL-17A, and IL-23. IFN-alpha 2 is connected to the innate inflammatory reaction and this could portray the ongoing need of Long COVID patients to lower down SARS-CoV-2 induced dysregulation of innate immune system.
https://pubmed.ncbi.nlm.nih.gov/32929061/
 
The study findings are prompting to speculate that a core change in cytokine levels as well as high number of triglycerides were in present in the bloodstream of Long COVID patients. This could be result of dysregulated innate immune response which could lead to a higher severity of COVID-19 like symptoms.
 
Similarly, an increase of COVID-19 severity is increased with diabetes and as a result of lowered amounts of HDL cholesterol in COVID-19 patients.
https://pubmed.ncbi.nlm.nih.gov/32416321/
 
The study findings imply that HDL cholesterol (HDCH) is lowered in Long COVID together with correlating INF-g, IL-6, and IL-23.
 
In the past, it was identified that severe immunosuppression is key for the severity of COVID-19 rather than the cytokine storm.
https://pubmed.ncbi.nlm.nih.gov/32687484/
 
Hence, it is plausible that lower level of lipids and inflammatory cytokines may be important for further disease symptoms in Long COVID patients.
 
Another likeliness of the Long COVID group to acute COVID-19 patients is noticed via lowered apolipoproteins A1 & A2 levels, among other close structures they had been lowered in ill subjects.
https://pubmed.ncbi.nlm.nih.gov/32492406/
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264033/
 
The study findings provide a large set of quantitative NMR data on metabolites and lipoproteins and inflammation parameters in LTCS patients and highlights that formate, acetate, creatinine, citrate, lactate, pyruvate, histidine, ornithine, HDL and total blood triglycerides, HDL apolipoproteins Apo-A1, IL-18, TNF-a, IL-23, IL-8, MCP-1 could be key parameters in the pathophysiology of maintained disease symptoms and even progression.
 
The study findings show novel insights into persisting altered blood metabolome, lipoproteome and inflammation parameters when comparing healthy controls with Long COVID individuals.
 
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