The most common symptoms of post-COVID syndrome are chronic fatigue, shortness of breath, anxiety, depression, memory and concentration problems. About a third of patients suffer from neuropsychiatric symptoms, including insomnia and depression, within six months after COVID-19.
Post-COVID syndrome is associated with inflammatory processes that begin in the acute phase of COVID-19, accompanied by decreased blood oxygen levels and increased body temperature. Additionally, post-COVID syndrome is linked to neuro-oxidative stress and reduced antioxidant defenses in the body. Indicators of inflammation include elevated CRP levels and increased insulin resistance, assessed by the HOMA2-IR index.
A critical role in post-COVID syndrome is played by tryptophan depletion and increased synthesis of neurotoxic tryptophan catabolites (TRYCAT). TRYCAT leads to oxidative damage to cells. Tryptophan deficiency is characteristic of severe depression, schizophrenia, and cognitive deficits. Increased production of neurotoxic TRYCAT may contribute to the development of depression, bipolar disorder, schizophrenia, anxiety, chronic fatigue syndrome, and neurocognitive impairments.
Study on the Association of Post-COVID Syndrome with the TRYCAT Pathway
The study involved 60 patients with post-COVID syndrome, with a control group of 30 individuals. A psychiatrist assessed symptoms of chronic fatigue, anxiety, and depression. Other symptoms were also considered, including muscle pain, tension, fatigue, gastrointestinal symptoms, headaches, and flu-like malaise. Blood samples were collected from participants to assess serum levels of tryptophan, kynurenine, and other tryptophan catabolites, CRP, insulin, and glucose. From medical records, the lowest SpO2 levels and peak body temperature (PBT) during acute COVID-19 were obtained.
Analysis Results
Patients with severe post-COVID syndrome had significantly higher levels of CRP, KYN/TRY, IR, PBT, and the lowest SpO2 compared to patients with less severe post-COVID syndrome and the control group. The control group had the lowest CRP, KYN/TRY, IR, and PBT levels. More detailed data:
- Fasting glucose levels were significantly higher in the severe post-COVID syndrome group compared to the control group.
- Tryptophan was significantly lower in the severe post-COVID syndrome group compared to the mild post-COVID syndrome group.
- Insulin levels were higher in patients with post-COVID syndrome compared to the control group.
- The KYN/TRY ratio was higher in severe post-COVID syndrome than in other groups.
Correlation Between Laboratory Indicators and Post-COVID Syndrome Symptoms
- Low tryptophan levels and a high KYN/TRY ratio were associated with fatigue, anxiety, and physiosomatic symptoms—physical symptoms linked to emotional states—but were not related to pure depressive symptoms.
- The severity of acute COVID-19 correlated with KYN/TRY, CRP, and IR.
- The duration of acute COVID-19 correlated with fatigue, anxiety, and physiosomatic symptoms.
Conclusions
Physical and Emotional Symptoms in Post-COVID Syndrome Are Driven by the Same Mechanism
These results align with previous studies that identified similar associations between rheumatoid arthritis and depression. 31% of COVID-19 patients experienced moderate to severe depressive symptoms, often progressing to clinical depression. In addition to depression, many also developed anxiety disorders and mild chronic fatigue syndrome (CFS). Symptoms persisted in patients for 3 to 12 months after acute COVID-19. This data suggests that viral infections can trigger both depression and CFS, as well as related comorbidities. Severe COVID-19 was associated with more severe post-COVID syndrome, confirming that inflammation drives post-COVID syndrome symptoms.
TRYCAT and Post-COVID Syndrome
Patients with post-COVID syndrome show decreased tryptophan levels and an increased kynurenine-to-tryptophan ratio (KYN/TRY). These changes are linked to anxiety, chronic fatigue syndrome, and physiosomatic symptoms. Tryptophan depletion has previously been associated with physical and psychological symptoms, which is confirmed in the case of post-COVID syndrome. Tryptophan is essential for serotonin production. Decreased tryptophan levels can weaken the brain’s defense mechanisms, exacerbating symptoms. In acute inflammatory and infectious conditions, tryptophan starvation due to tryptophan depletion is essential to the innate immune response, protecting against invasive infections and hyperinflammation. Increased production of tryptophan catabolites is a hallmark of acute inflammatory states, including acute COVID-19. Therefore, the inflammatory response during acute COVID-19 can predict an increase in KYN/TRY and the development of post-COVID syndrome symptoms. Elevated levels of neurotoxic TRYCAT, other than kynurenine, do not play a significant role in the development of post-COVID syndrome.
Biomarkers of Post-COVID Syndrome
Three biomarkers—CRP, the KYN/TRY ratio, and the insulin resistance index (IR)—play a key role in developing post-COVID syndrome. Together, these indicators explain up to 41% of the symptoms related to physical and emotional conditions after COVID-19. Inflammatory processes that began during acute COVID-19 and their continuation as immune-inflammatory reactions significantly impact the development of long-term consequences of coronavirus. Decreased SpO2 during acute COVID-19 is associated with more severe manifestations of post-COVID syndrome. The most severe post-COVID syndrome is observed in patients with extremely low SpO2, elevated kynurenine levels, deficient tryptophan levels (and consequently, an increased KYN/TRY ratio), very high CRP levels, and moderate IR elevation. Therefore, early control of inflammatory processes can reduce the risk of severe post-COVID syndrome.
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