LONG COVID News: Decreased Plasma Tryptophan And Increased Kynurenine Levels May Be Contributing Factors To Long COVID Symptoms

LONG COVID News: A new study by researchers based in Iraq and Thailand has found that decreased plasma Tryptophan and increased Kynurenine levels may be contributing factors to Long COVID symptoms.


 
Already, severe cases of COVID-19 have been linked to reduced levels of tryptophan (TRY) in the blood and an increase in indoleamine-dioxygenase (IDO)-triggered production of neuroactive tryptophan metabolites (TRYCATs), such as kynurenine (KYN) and quinolinic acid.
 
However, the relationship between the TRYCAT pathway and the physical and emotional symptoms of Long COVID has not been thoroughly investigated.
 
The study team assessed serum tryptophan levels, TRYCATs, insulin resistance (using the HOMA2-IR index), C-reactive protein (CRP), and symptoms related to physical health, depression, and anxiety in 90 Long COVID patients who had recovered from acute infection 3-10 months prior.
 
The study identified a subset of severe Long COVID patients (22%) with extremely low TRY and oxygen saturation (SpO2, during acute infection), elevated kynurenine, KYN/TRY ratio, CRP, and severe symptoms across all domains.
 
A single factor encompassing physical symptoms (including chronic fatigue-fibromyalgia), depression, and anxiety symptoms emerged, suggesting that all these domains are expressions of a shared physio-emotional phenotype.
 
Three Long COVID biomarkers (CRP, KYN/TRY, and IR) accounted for around 40% of the variation in this physio-emotional phenotype. Both the phenotype and the KYN/TRY ratio were significantly influenced by peak body temperature (PBT) and decreased SpO2 during acute infection.
 
The study findings extracted a single validated latent vector from the three symptom domains and a composite based on CRP, KYN/TRY, IR (Long COVID), and PBT and SpO2 (acute COVID-19).
 
The study findings lead to the conclusion that the physio-emotional phenotype of Long COVID reflects inflammatory responses during both acute and Long COVID, with reduced plasma tryptophan levels and increased kynurenine playing a role in these effects.
 
The study finings were published on a preprint server and are currently being peer reviewed.
https://www.medrxiv.org/content/10.1101/2023.03.11.23287152v1
 
Long COVID's physio-affective phenome, including physiosomatic and affective symptoms, is believed to be influenced by multiple factors. Reduced oxygen saturation and elevated peak body temperature during acute infection suggest immune-inflammatory processes play a role. Additionally, Long COVID is associated with neurooxidative stress toxicity, decreased antioxidant defenses, inflammation indicated by increased C-reactive protein levels, and insulin resistance.
 
A recent meta-analysis found that acute infection triggers indoleamine-2,3-dioxygenase (IDO), leading to tryptophan depletion and increased synthesis of tryptophan catabolites (TRYCATs), which are linked to critical illness and higher mortality.
https://www.mdp i.com/2073-4409/11/19/3112/review_report
 
TRYCATs include neurotoxic metabolites such as kynurenine, 3-hydroxykynurenine, and quinolinic acid, as well as protective ones like kynurenic acid. Neurotoxic TRYCATs can cause oxidative cell damage and contribute to neuropsychiatric symptoms in various disorders.
 
However, the association between Long COVID's physio-affective phenome and IDO activation has not been investigated.
 
This is the first study to examine the relationship between Long COVID and TRYCAT pathway activity, assess the association between TRYCATs and inflammation during acute infection, and determine the effects of TRYCATs beyond inflammation and insulin resistance.
 
The first major finding of this study reveals that a common core, or latent vector, can be extracted from the interrelated physiosomatic, depressive, and anxiety symptoms. This demonstrates that these symptom domains are highly intertwined expressions of the physio-affective phenome of Long COVID.
 
These findings align with previous discoveries, which indicated that a single component drives both physiosomatic and affective symptoms in individuals suffering from Long COVID.
 
In the current investigation, the relationships were calculated in patients who had all experienced acute COVID-19 infection, while in earlier studies, the connections were calculated in healthy controls and participants with long-term COVID. Prior research, including meta-analyses, has generally corroborated that Long COVID is characterized by physiosomatic and affective symptoms.
 
In other illnesses, such as rheumatoid arthritis, major depressive disorder, and schizophrenia, we have previously established intertwined associations between high physiosomatic and affective symptom levels. It has also been shown that the acute infectious phase of COVID-19 was characterized by increases in physiosomatic and affective symptoms and that a common core could be identified from these.
 
Consequently, both acute COVID-19 and Long COVID are linked with significant increases in the physio-affective phenome, suggesting that comparable pathways may be responsible for the physio-affective phenome of both acute COVID-19 and Long COVID.
 
The study team found that 31.1% of COVID-19 patients experienced moderate to severe symptoms of depression consistent with major depression when a cutoff value of 23 on the BDI-II was used. The mean HAMD, HAMA, and FF scores (23.6 ±5.6; 25.4 ±8.6 and 30.9 ±10.1, respectively) for the group of patients with severe COVID indicate that they also suffer from moderate to severe anxiety and mild chronic fatigue syndrome. It is essential to note that blood samples were collected between 3 and 12 months (mean: 7.3 ±2.6 months) after remission from the acute phase, and all participants exhibited symptoms that persisted beyond the acute phase of illness. This indicates that some Long COVID patients developed chronic depressive symptoms, chronic major depression, chronic anxiety disorders, and chronic fatigue syndrome.
 
The study findings suggest that chronic fatigue and affective symptoms belong to the same symptom spectrum.
 
 In addition, the exclusion of patients with premorbid major depression, anxiety disorders, and chronic fatigue syndrome from the study implies that some individuals with COVID-19 develop de novo physiosomatic and affective symptoms, as well as major depression and chronic fatigue syndrome, some months later.
 
These study findings indicate that both major depression and chronic fatigue syndrome, along with their comorbidities, may be induced by viral infections. There is now evidence that viral infections are related to the development of chronic fatigue syndrome, severe depression, and anxiety.
 
Similar to earlier studies, the severity of the acute phase inflammatory response (as measured by PBT and SpO2) was substantially linked with the physiosomatic and affective symptoms of acute COVID-19 and Long COVID, indicating that common pathways underlie the acute and long-term COVID phenomes.
 
The current study findings suggest that inflammatory pathways modulate the effects of SARS-CoV-2 infection on the acute and Long COVID physio-affective phenome.
 
The TRYCAT Pathway and Long COVID
 
The second primary conclusion of this research is that severe Long COVID is associated with significantly decreased blood levels of tryptophan and a higher KYN/TRY ratio, both of which are linked to anxiety, chronic fatigue, and physiosomatic symptoms.
 
The study team successfully identified a specific subgroup of severe Long COVID patients (22% of all cases) characterized by extremely low SpO2 levels during the initial infection and Long COVID biomarkers such as reduced tryptophan, increased kynurenine, elevated KYN/TRY ratio, higher CRP, and notably high scores in areas of physical symptoms, chronic fatigue, depression, and anxiety.
 
These aspects collectively represent the interconnected physio-affective characteristics of Long COVID. Approximately 40% of the variation in these characteristics can be attributed to the Long COVID biomarkers, including CRP, KYN/TRY, and IR. The physio-affective features of Long COVID result from inflammatory responses during the acute and long-term phases of the illness, alongside decreased tryptophan levels in the blood, while heightened kynurenine levels may also contribute to these effects.
 
The study team commented, “In conclusion, the physical-emotional phenome of Long COVID is a result of inflammatory responses during both acute and Long COVID phases. Decreased plasma tryptophan and increased kynurenine levels may contribute to these effects.”
 
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