The plasma metabolome of long COVID-19 patients two years after infection, 2023, Yamille Lopez-Hernandez et al

[Mij]

Abstract
Background: 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. The World Health Organization (WHO) recognized long COVID as a distinct clinical entity in 2021. It is estimated that at least 30% of patients who have had COVID-19 will develop long COVID. This has put a tremendous strain on still-overstretched healthcare systems around the world.

Methods: In this study, our goal was to assess the plasma metabolome in a total of 108 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 concentrations were measured in long COVID patients by immunoenzymatic assay.

Results: The comparison of paired COVID-19/post-COVID-19 samples revealed 53 metabolites that were statistically different (FDR < 0.05). Compared to controls, 29 metabolites remained dysregulated even after two years. Notably, glucose, kynurenine, and certain acylcarnitines continued to exhibit altered concentrations similar to the COVID-19 phase, while sphingomyelins and long saturated and monounsaturated LysoPCs, phenylalanine, butyric acid, and propionic acid levels normalized. Post-COVID-19 patients displayed a heterogeneous metabolic profile, with some showing no symptoms while others exhibiting a variable number of symptoms. Lactic acid, lactate/pyruvate ratio, ornithine/citrulline ratio, sarcosine, 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.

Conclusions: 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.

https://www.medrxiv.org/content/10.1101/2023.05.03.23289456v1

 

[Hutan]

Currently, a preprint. The abstract is a bit confusing; it's hard to know what is happening in various subsets.

15 hospitalised Covid survivors from one hospital; 33 hospitalised survivors from another hospital.
18 of these people reported no persistent symptoms.
17 reported 1 to 4 persistent symptoms (Class A Long Covid)
13 reported 5 or more persistent symptoms (Class B Long Covid)

There doesn't seem to have been a requirement that the symptoms are having a significant effect on daily life, a requirement of the WHO definition of Long Covid, soo it is pretty loose. However, the Class B Long Covid probably meets that requirement. Because the participants are hospitalised survivors, it's likely that there are various causes of the symptoms. So, I think it's a pretty small sample of the people we are most interested in, and a sample with a lot of noise from various pathologies.

 

[Hutan]

Six patients were reinfected during the study period.

The most predominant symptoms were loss of memory (73.3%), sleep disorders, arthralgia, fatigue, exercise intolerance, myalgia (66.7%), and anxiety (60.0%).

There are more women in the Long covid group, and the average age is different, so these factors could be affecting metabolite differences in small samples.

The lactate/pyruvate ratio (adjusted p value = 5.8 x 10-7), lactate (adjusted p value = 4.8 x 10-6), arginine (1.8 x 10-3), ornithine/citrulline ratio (adjusted p value 5. x 10-3), and sarcosine (adjusted p value = 0.02) were the variables best able to differentiate long COVID patients with more than five symptoms from patients with less than five symptoms. Arginine and sarcosine negatively correlated with the number of symptoms.

For differentiating class B long COVID patients from all other post-COVID-19
patients, the lactate/pyruvate ratio had the best performance (AUC: 0.95 (0.92 -0.97),sensitivity: 0.92 (0.87-0.97), specificity: 0.94 (0.91-0.98)), followed by the combination of the ornithine/citrulline ratio and uric acid (AUC: 0.92 (0.89-0.95), sensitivity: 0.83 (0.77- 0.90), specificity: 0.84 (0.79-0.90)).

When comparing class B patients with those recovered, the top five metabolic pathways (FDR<0.05) were: pyruvate metabolism, gluconeogenesis, glycine and serine metabolism, urea cycle metabolism, and the Warburg effect.

IL-17 was significantly increased in class B patients relative to class A patients (Mann-Whitney
test, p = 0.0073) and recovered patients (Mann-Whitney test, p = 0.002).

Interesting comment on the possible impact of Covid treatments on glucose regulation:

Montefusco et al. [23] reported glycemic abnormalities in recovered patients two months after the onset of disease. The hyperglycemic state has been reported to be even worse in hospitalized patients, pointing to a possible causal role of administered drug regimens, including remdesivir and corticosteroids. These drugs stimulate hepatic gluconeogenesis from amino acids released from muscles, which then inhibits glucose uptake [24].

Some more comments from the discussion that are interesting, although I haven't checked out the data behind them, and the various issues with the study mean that the findings should be taken with a pinch of salt.

Increased level of the lactate/pyruvate ratio in class B patients is another important indicator of mitochondrial dysfunction. The lactate/pyruvate ratio has been proposed as a marker for mitochondrial disorders since it indirectly reflects the NADH/NAD+ redox state[45], lipid metabolism (fat oxidation), and ATP generation. In our study, both markers (lactate and the lactate/pyruvate ratio) were found positively correlated with fatigue, myalgia and arthralgias (Spearman correlation, R> 0.6, p< 0.05) (Supplementary Figure 3).

The increased ornithine/citrulline ratio level in class B patients reflects abnormal metabolic activity in the urea cycle. It is notable that Yamano et al. [46] reported a similarly increased ornithine/citrulline ratio in CFS patients. An adequate balance of citrulline and ornithine is vital for the clearance of ammonia via urea cycle [47]. If ammonia accumulates intracellularly, the aerobic utilization of pyruvate to feed the TCA cycle is inhibited, resulting in lactate production, which further contributes to fatigue.

In addition, class B patients had decreased levels of arginine. The reduced bioavailability of arginine to produce adequate levels of NO in endothelial cells and vascular tissues leads to the impairment of multiple physiological functions of skeletal muscles, including contractile functions, and muscle repair. This decreased level is not a residual effect of COVID-19, as the paired study (COVID-19/post-COVID-19) showed normal arginine levels. Arginine is also a substrate for ornithine production by arginase. It is well known that under certain inflammatory conditions, arginase activity is increased producing an excess of ornithine and an imbalance in the urea cycle.

Sarcosine was found decreased in class B patients. Previously, Fraser et al. [49] found that sarcosine was depressed in COVID-19 patients. Sarcosine plays a vital role in immune functions, as it activates autophagy and the removal of damaged cells. A reduced amount of plasma sarcosine could in part lead to a sustained inflammatory process.

Previous studies have pointed to the persistent immune dysregulation following COVID-19 infection [50]. We found increased levels of monocytes in class B patients. Nuber-Champier et al. [51]found that monocyte percentage in the acute phase of the disease allowed them to distinguish between patients with anosognosia for memory deficits in the chronic phase (6–9 months after SARS-CoV-2 infection) and nosognosic patients.

IL-17 is a proinflammatory cytokine mainly produced by T helper type 17 cells, playing a vital role in the regulation of host immune response against SARS-CoV-2. IL-17-induced dysregulated immune responses have been shown to potentially cause hyperinflammatory COVID-19 disease [53]. It has been reported that IL-17
downregulates protein phosphatase 6, resulting in increased arginase-1 expression in psoriatic keratinocytes [54]. IL-17A has been found to be associated with neurological sequelae and pulmonary fibrosis in post-COVID-19 patients [55, 56]. Fluctuations in IL-17 have been associated with fatigue and fatigue severity in ME/CFS patients [57].

 

[Mij]

 

[Mij]

 

[EndME]

The study has now been published in Nature https://www.nature.com/articles/s41598-023-39049-x.

 

[Kalliope]

CIDRAP Long-COVID patients have altered metabolite levels 2 years after infection

quote:

"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," the study authors wrote.

They said metabolic information may partially explain the differences in disease presentation among long-COVID patients. "Metabolomics is not only useful in providing a snapshot of transient physiological or pathophysiological processes taking place in a living organism, but it has also proven to be a powerful tool for proposing and monitoring therapeutic interventions," they wrote.

 

[rvallee]

So what does it say that those are all pretty much the same old hypotheses that never seem to produce actionable results.

They do seem like the explanations, all of them, some of them, one of them, varying between people, but it's a comment we see often on the forum, that it's always the same hypotheses, and they sure do make sense, but it never leads anywhere in terms of changing outcomes, finding biomarkers and therapeutic targets.

We seem to be waiting on basic research to catch up, except basic research is a crapshoot, rarely seems to target specific conditions. Like there's a disconnect between observation/hypothesis and actually working back what it fundamentally means. Especially as those come up pretty much in hundreds of diseases and conditions.

It looks like there are so many clues but no one with the kind of mandate that can work out the full picture of the puzzle and hone in on it. Which is what the $1.15 NIH funding should have done, but they don't seem capable of even thinking this way.