Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in Long COVID

Abstract Background Critical COVID-19 disease is accompanied by depletion of plasma tryptophan (TRY) and increases in indoleamine-dioxygenase (IDO)-stimulated production of neuroactive tryptophan catabolites (TRYCATs), including kynurenine (KYN) and quinolinic acid. The TRYCAT pathway has not been studied extensively in association with the physiosomatic and affective symptoms of Long COVID. Methods In the present study, we measured serum tryptophan (TRY), TRYCATs, insulin resistance (using the HOMA2-IR index), C-reactive protein (CRP), physiosomatic, depression and anxiety symptoms in 90 Long COVID patients, 3-10 months after remission of acute infection. Results We were able to construct an endophenotypic class of severe Long COVID (22% of the patients) with very low TRY and oxygen saturation (SpO2, during acute infection), increased kynurenine, KYN/TRY ratio, CRP, and very high ratings on all symptom domains. One factor could be extracted from physiosomatic symptoms (including chronic fatigue-fibromyalgia), depression, and anxiety symptoms, indicating that all domains are manifestations of the common physio-affective phenome. Three Long COVID biomarkers (CRP, KYN/TRY, IR) explained around 40% of the variance in the physio-affective phenome. The latter and the KYN/TRY ratio were significantly predicted by peak body temperature (PBT) and lowered SpO2 during acute infection. One validated latent vector could be extracted from the three symptom domains and a composite based on CRP, KYN/TRY, IR (Long COVID), and PBT and SpO2 (acute COVID-19). Conclusion The physio-affective phenome of Long COVID is a manifestation of inflammatory responses during acute and Long COVID and lowered plasma tryptophan and increased kynurenine may contribute to these effects.