The plasma metabolome of long COVID patients two years after infection

Abstract

One of the major challenges currently faced by global health systems is the prolonged COVID-19 syndrome (also known as “long COVID”) which has emerged as a consequence of the SARS-CoV-2 epidemic. It is estimated that at least 30% of patients who have had COVID-19 will develop long COVID. In this study, our goal was to assess the plasma metabolome in a total of 100 samples collected from healthy controls, COVID-19 patients, and long COVID patients recruited in Mexico between 2020 and 2022. A targeted metabolomics approach using a combination of LC–MS/MS and FIA MS/MS was performed to quantify 108 metabolites. IL-17 and leptin were measured in long COVID patients by immunoenzymatic assay. The comparison of paired COVID-19/long COVID-19 samples revealed 53 metabolites that were statistically different. Compared to controls, 27 metabolites remained dysregulated even after two years. Post-COVID-19 patients displayed a heterogeneous metabolic profile. Lactic acid, lactate/pyruvate ratio, ornithine/citrulline ratio, and arginine were identified as the most relevant metabolites for distinguishing patients with more complicated long COVID evolution. Additionally, IL-17 levels were significantly increased in these patients. Mitochondrial dysfunction, redox state imbalance, impaired energy metabolism, and chronic immune dysregulation are likely to be the main hallmarks of long COVID even two years after acute COVID-19 infection.

Reinforcing the Evidence of Mitochondrial Dysfunction in Long COVID Patients Using a Multiplatform Mass Spectrometry-Based Metabolomics Approach

“…In our case, no difference between the two studied groups was observed regarding the CAR subclass, and even though a decrease in those LPCs was observed in our study, as shown in Table S3, there were no significant differences in Long COVID vs recovered individuals. Similarly to previous studies, no significant changes were observed in SM in Long COVID patients.…”

“…Even though little is known about lipidomic in Long COVID, an increase of CAR levels along with decreased levels of specific LPCs has been previously reported, LPC(16:0), LPC(17:0), LPC(18:0), and LPC (20:4), in Long COVID patients when compared to healthy controls. 6 In our case, no difference between the two studied groups was observed regarding the CAR subclass, and even though a decrease in those LPCs was observed in our study, as shown in Table S3, there were no significant differences in Long COVID vs recovered individuals. Similarly to previous studies, 6 From all the lipid subclasses analyzed, the main one that resulted to be significantly altered in our comparison was ceramides, which were significantly decreased when comparing Long COVID to fully recovered individuals.…”

“…In addition to the methodology used for the present study, the high level of annotations of metabolites and lipids achieved is remarkable, surpassing the findings of previously reported articles. , …”

“…In addition to the methodology used for the present study, the high level of annotations of metabolites and lipids achieved is remarkable, surpassing the findings of previously reported articles. 6,7 To understand the interconnection among all relevant metabolites identified in each analytical platform listed in Figure 4, we conducted a comprehensive scheme, illustrated in Figure 7, where the alteration of amino acids, TCA cycle, and ceramides observed is related.…”

“…Emerging studies have been working to work out the complexities of the syndrome and to try to understand why some individuals develop these persistent symptoms. 6−9 Several targeted 6 and untargeted 7 metabolomics approaches have proven that one of the major dysregulations of the metabolic pathways described in Long COVID syndrome is that of the TCA cycle (tricarboxylic acid cycle), which is critical for cellular metabolism. 6,10 Alterations in the TCA cycle lead to profound changes in energy production and cellular function and consequently result in mitochondrial dysregulation.…”