Chronic fatigue, depression and anxiety symptoms in Long COVID are strongly predicted by neuroimmune and neuro-oxidative pathways which are caused by the inflammation during acute infection

Abstract Background Long-term coronavirus disease 2019 (Long COVID) is associated with physio-somatic (chronic fatigue syndrome and somatic symptoms) and affective (depression and anxiety) symptoms. The severity of the Long COVID physio-affective phenome is largely predicted by peak body temperature (BT) and lowered oxygen saturation (SpO2) during the acute infectious phase. This study aims to delineate whether the association of BT and SpO2 during the acute phase and the Long COVID physio-affective phenome is mediated by neurotoxicity (NT) resulting from activated immune-inflammatory and oxidative stress pathways. Methods We recruited 86 patients with Long COVID (3-4 months after the acute phase) and 39 healthy controls and assessed serum C-reactive protein (CRP), caspase-1, interleukin (IL)-1β, IL-18, IL-10, myeloperoxidase (MPO), advanced oxidation protein products (AOPP), total antioxidant capacity (TAC), and calcium (Ca), as well as peak BT and SpO2 during the acute phase. Results Cluster analysis revealed that a significant part (34.9%) of Long COVID patients (n=30) show a highly elevated NT index computed based on IL-1β, IL-18, Caspase-1, CRP, MPO and AOPP. Partial Least Squares analysis showed that 61.6% of the variance in the physio-affective phenome of Long COVID is explained by the NT index, lowered Ca, peak BT/SpO2 in the acute phase, and prior vaccinations with Astra-Zeneca or Pfizer. The most important predictors of the physio-affective phenome are Ca, CRP, IL-1β, AOPP and MPO. Conclusion The infectious-immune-inflammatory core of acute COVID-19 strongly predicts the development of physio-affective symptoms 3-4 months later, and these effects are partly mediated by neuro-immune and neuro-oxidative pathways.