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

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). The TRYCAT pathway has not been studied extensively in association with the physiosomatic and affective symptoms of Long COVID. In the present study, we measured serum TRY, TRYCATs, insulin resistance (using the Homeostatic Model Assessment Index 2-insulin resistance, HOMA2-IR), C-reactive protein (CRP), physiosomatic, depression, and anxiety symptoms in 90 Long COVID patients, 3-10 months after remission of acute infection. 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, and 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, and IR (Long COVID), and PBT and SpO2 (acute COVID-19). In 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.

Increased insulin resistance due to Long COVID is associated with depressive symptoms and partly predicted by the inflammatory response during acute infection.

BACKGROUND: Some months after the remission of acute COVID-19, some individuals show depressive symptoms, which are predicted by increased peak body temperature (PBT) and decreased blood oxygen saturation (SpO2). No data indicate whether Long COVID is associated with increased insulin resistance (IR) in association with neuroimmune and oxidative (NIO) processes. METHODS: This case control and retrospective cohort study used the homeostasis Model Assessment 2 (HOMA2) calculator© to compute ß-cell function, insulin sensitivity and resistance (HOMA2-IR) and measured the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HAMD) in 86 Long COVID patients and 39 controls. RESULTS: Long COVID (3-4 months after the acute infection) is accompanied by increased HOMA2-IR, fasting blood glucose, and insulin levels; 33.7% of the patients versus 0% of the controls had HOMA2-IR values >1.8, suggesting IR. Increased IR was predicted by PBT during acute infection, and associated with depressive symptoms above and beyond the effects of NIO pathways (NLRP3 inflamasome, myeloperoxidase, protein oxidation). There were no significant associations between increased IR and the activated NIO pathways during Long COVID. CONCLUSION: Long COVID is associated with new-onset IR which may contribute to the onset of depressive symptoms due to Long COVID by enhancing overall neurotoxicity.

Lowered oxygen saturation and increased body temperature in acute COVID-19 largely predict chronic fatigue syndrome and affective symptoms due to Long COVID: A precision nomothetic approach.

BACKGROUND: Long coronavirus disease 2019 (LC) is a chronic sequel of acute COVID-19. The exact pathophysiology of the affective, chronic fatigue and physiosomatic symptoms (labelled as "physio-affective phenome") of LC has remained elusive. OBJECTIVE: The current study aims to delineate the effects of oxygen saturation (SpO2) and body temperature during the acute phase on the physio-affective phenome of LC. METHOD: We recruited 120 LC patients and 36 controls. For all participants, we assessed the lowest SpO2 and peak body temperature during acute COVID-19, and the Hamilton Depression and Anxiety Rating Scale (HAMD/HAMA) and Fibro Fatigue (FF) scales 3-4 months later. RESULTS: Lowered SpO2 and increased body temperature during the acute phase and female sex predict 60.7% of the variance in the physio-affective phenome of LC. Using unsupervised learning techniques, we were able to delineate a new endophenotype class, which comprises around 26.7% of the LC patients and is characterised by very low SpO2 and very high body temperature, and depression, anxiety, chronic fatigue, and autonomic and gastro-intestinal symptoms scores. Single latent vectors could be extracted from both biomarkers, depression, anxiety and FF symptoms or from both biomarkers, insomnia, chronic fatigue, gastro-intestinal and autonomic symptoms. CONCLUSION: The newly constructed endophenotype class and pathway phenotypes indicate that the physio-affective phenome of LC is at least in part the consequence of the pathophysiology of acute COVID-19, namely the combined effects of lowered SpO2, increased body temperature and the associated immune-inflammatory processes and lung lesions.

Long-COVID post-viral chronic fatigue and affective symptoms are associated with oxidative damage, lowered antioxidant defenses and inflammation: a proof of concept and mechanism study.

The immune-inflammatory response during the acute phase of COVID-19, as assessed using peak body temperature (PBT) and peripheral oxygen saturation (SpO2), predicts the severity of chronic fatigue, depression and anxiety symptoms 3-4 months later. The present study was performed to examine the effects of SpO2 and PBT during acute infection on immune, oxidative and nitrosative stress (IO&NS) pathways and neuropsychiatric symptoms of Long COVID. This study assayed SpO2 and PBT during acute COVID-19, and C-reactive protein (CRP), malondialdehyde (MDA), protein carbonyls (PCs), myeloperoxidase (MPO), nitric oxide (NO), zinc, and glutathione peroxidase (Gpx) in 120 Long COVID individuals and 36 controls. Cluster analysis showed that 31.7% of the Long COVID patients had severe abnormalities in SpO2, body temperature, increased oxidative toxicity (OSTOX) and lowered antioxidant defenses (ANTIOX), and increased total Hamilton Depression (HAMD) and Anxiety (HAMA) and Fibromylagia-Fatigue (FF) scores. Around 60% of the variance in the neuropsychiatric symptoms of Long COVID (a factor extracted from HAMD, HAMA and FF scores) was explained by OSTOX/ANTIOX ratio, PBT and SpO2. Increased PBT predicted increased CRP and lowered ANTIOX and zinc levels, while lowered SpO2 predicted lowered Gpx and increased NO production. Lowered SpO2 strongly predicts OSTOX/ANTIOX during Long COVID. In conclusion, the impact of acute COVID-19 on the symptoms of Long COVID is partly mediated by OSTOX/ANTIOX, especially lowered Gpx and zinc, increased MPO and NO production and lipid peroxidation-associated aldehyde formation. The results suggest that post-viral somatic and mental symptoms have a neuroimmune and neuro-oxidative origin.

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.

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 increased 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) 1ß, IL-18, IL-10, myeloperoxidase (MPO), advanced oxidation protein products (AOPPs), 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 as computed based on IL-1ß, IL-18, caspase 1, CRP, MPO, and AOPPs. Partial least squares analysis showed that 61.6% of the variance in the physio-affective phenome of long COVID could be explained by the NT index, lowered Ca, and peak BT/SpO2 in the acute phase and prior vaccinations with AstraZeneca or Pfizer. The most important predictors of the physio-affective phenome are Ca, CRP, IL-1ß, AOPPs, and MPO. CONCLUSION: The infection-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.

Lowered Quality of Life in Long COVID Is Predicted by Affective Symptoms, Chronic Fatigue Syndrome, Inflammation and Neuroimmunotoxic Pathways.

The physio-affective phenome of Long COVID-19 is predicted by (a) immune-inflammatory biomarkers of the acute infectious phase, including peak body temperature (PBT) and oxygen saturation (SpO2), and (b) the subsequent activation of immune and oxidative stress pathways during Long COVID. The purpose of this study was to delineate the effects of PBT and SpO2 during acute infection, as well as the increased neurotoxicity on the physical, psychological, social and environmental domains of health-related quality of life (HR-QoL) in people with Long COVID. We recruited 86 participants with Long COVID and 39 normal controls, assessed the WHO-QoL-BREF (World Health Organization Quality of Life Instrument-Abridged Version, Geneva, Switzerland) and the physio-affective phenome of Long COVID (comprising depression, anxiety and fibromyalgia-fatigue rating scales) and measured PBT and SpO2 during acute infection, and neurotoxicity (NT, comprising serum interleukin (IL)-1ß, IL-18 and caspase-1, advanced oxidation protein products and myeloperoxidase, calcium and insulin resistance) in Long COVID. We found that 70.3% of the variance in HR-QoL was explained by the regression on the physio-affective phenome, lowered calcium and increased NT, whilst 61.5% of the variance in the physio-affective phenome was explained by calcium, NT, increased PBT, lowered SpO2, female sex and vaccination with AstraZeneca and Pfizer. The effects of PBT and SpO2 on lowered HR-QoL were mediated by increased NT and lowered calcium yielding increased severity of the physio-affective phenome which largely affects HR-QoL. In conclusion, lowered HR-Qol in Long COVID is largely predicted by the severity of neuro-immune and neuro-oxidative pathways during acute and Long COVID.

Increased ACE2, sRAGE, and immune activation, but lowered calcium and magnesium in COVID-19.

BACKGROUND: The characterization of new biomarkers that could help to externally validate the diagnosis of COVID-19 and to optimize treatments is extremely important. Many studies established changes in immune-inflammatory and antibody levels, but few studies measured the soluble receptor for advanced glycation end product (sRAGE), angiotensin-converting enzyme 2 (ACE2), calcium and magnesium in COVID-19. OBJECTIVE: To evaluate serum advanced glycation end-product receptor (sRAGE) and angiotensin converting enzyme (ACE)2 and peripheral oxygen saturation (SpO2) and chest CT scan abnormalities (CCTA) in COVID-19. METHODS: sRAGE, ACE2, interleukin (IL)-6, IL-10, C-reactive protein (CRP), calcium, magnesium, and albumin were measured in 60 COVID-19 patients and 30 healthy controls. RESULTS: COVID-19 is characterized by significantly increased IL-6, CRP, IL-10, sRAGE, ACE2, and lowered SpO2, albumin, magnesium and calcium. COVID-19 with CCTAs showed lower SpO2 and albumin. SpO2 was significantly inversely correlated with IL-6, IL-10, CRP, sRAGE, and ACE2, and positively with albumin, magnesium and calcium. Neural networks showed that a combination of calcium, IL-6, CRP, and sRAGE yielded an accuracy of 100% in detecting COVID-19 patients with calcium being the most important predicter followed by IL-6, and CRP. Patients with positive IgG results showed a significant elevation in the serum level of IL-6, sRAGE, and ACE2 compared to the negatively IgG patient subgroup. CONCLUSION: The results show that immune-inflammatory and RAGE pathways biomarkers may be used as external validating criterion for the diagnosis COVID-19. Those pathways coupled with lowered SpO2, calcium and magnesium are drug targets that may help to reduce the consequences of COVID-19.

Intersections between pneumonia, lowered oxygen saturation percentage and immune activation mediate depression, anxiety, and chronic fatigue syndrome-like symptoms due to COVID-19: A nomothetic network approach.

BACKGROUND: COVID-19 is associated with neuropsychiatric symptoms including increased depressive, anxiety and chronic fatigue-syndrome (CFS)-like and physiosomatic symptoms. AIMS: To delineate the associations between affective and CFS-like symptoms in COVID-19 and chest computed tomography scan anomalies (CCTAs), oxygen saturation (SpO2), interleukin (IL)-6, IL-10, C-Reactive Protein (CRP), albumin, calcium, magnesium, soluble angiotensin converting enzyme (ACE2) and soluble advanced glycation products (sRAGEs). METHOD: The above biomarkers were assessed in 60 COVID-19 patients and 30 healthy controls who had measurements of the Hamilton Depression (HDRS) and Anxiety (HAM-A) and the Fibromyalgia and Chronic Fatigue (FF) Rating Scales. RESULTS: Partial Least Squares-SEM analysis showed that reliable latent vectors could be extracted from a) key depressive and anxiety and physiosomatic symptoms (the physio-affective or PA-core), b) IL-6, IL-10, CRP, albumin, calcium, and sRAGEs (the immune response core); and c) different CCTAs (including ground glass opacities, consolidation, and crazy paving) and lowered SpO2% (lung lesions). PLS showed that 70.0% of the variance in the PA-core was explained by the regression on the immune response and lung lesions latent vectors. One common "infection-immune-inflammatory (III) core" underpins pneumonia-associated CCTAs, lowered SpO2 and immune activation, and this III core explains 70% of the variance in the PA core, and a relevant part of the variance in melancholia, insomnia, and neurocognitive symptoms. DISCUSSION: Acute SARS-CoV-2 infection is accompanied by lung lesions and lowered SpO2 which may cause activated immune-inflammatory pathways, which mediate the effects of the former on the PA-core and other neuropsychiatric symptoms due to SARS-CoV-2 infection.

Increased Serum Thromboxane A2 and Prostacyclin but Lower Complement C3 and C4 Levels in COVID-19: Associations with Chest CT Scan Anomalies and Lowered Peripheral Oxygen Saturation

COVID-19 patients suffer from hypercoagulation and activated immune-inflammatory pathways. The current study examined the relationship between specific complements and coagulation abnormalities associated with chest CT scan anomalies (CCTAs) and peripheral oxygen saturation (SpO2) in COVID-19 patients. Serum levels of complement C3 and C4, and thromboxane A2 (TxA2) and prostacyclin (PGI2) were measured using an ELISA and albumin, calcium, and magnesium by using the spectrophotometric method in 60 COVID-19 patients and 30 controls. C3 and C4 were significantly decreased (p <0.001), and TxA2 and PGI2 significantly increased (p <0.001) in the COVID-19 patients compared with the controls with the highest levels in the CCTA patients’ group. Neural networks showed that a combination of C3, albumin, and TxA2 yielded a predictive accuracy of 100% in detecting COVID-19 patients. SpO2 was significantly decreased in the COVID-19 patients and was inversely associated with TxA2 and PGI2, and positively with C3, C4, albumin, and calcium. Patients with positive IgG results show significantly higher SpO2, TxA2, PGI2, and C4 levels than IgG-negative patients. CCTAs were accompanied by lower SpO2 and albumin and increased PGI2 and TxA2 levels, suggesting that interactions between immune-inflammatory pathways and platelet hyperactivity participate in the pathophysiology of COVID-19 and, consequently, may play a role in an enhanced risk of hypercoagulability and venous thromboembolism. These mechanisms are aggravated by lowered calcium and magnesium levels.