Immune activation and immune-associated neurotoxicity in Long-COVID: A systematic review and meta-analysis of 82 studies comprising 58 cytokines/chemokines/growth factors. (preprint)

Background: Multiple studies have shown that Long COVID (LC) disease is associated with heightened immune activation, as evidenced by elevated levels of inflammatory mediators. However, there is no comprehensive meta-analysis focusing on activation of the immune inflammatory response system (IRS) and the compensatory immunoregulatory system (CIRS) along with other immune phenotypes in LC patients. Objectives: This meta-analysis is designed to explore the IRS and CIRS profiles in LC patients, the individual cytokines, chemokines, growth factors, along with C-reactive protein (CRP) and immune-associated neurotoxicity. Methods: To gather relevant studies for our research, we conducted a thorough search using databases such as PubMed, Google Scholar, and SciFinder, covering all available literature up to December 20th, 2023. Results: The current meta-analysis encompassed 82 studies that examined multiple immune profiles, C-reactive protein, and 58 cytokines/chemokines/growth factors in 3836 LC patients versus 4537 normal controls (NC). LC patients showed significant increases in IRS/CIRS ratio (standardized mean difference (SMD:0.156, confidence interval (CI): 0.051;0.261), IRS (SMD: 0.345, CI: 0.222;0.468), M1 macrophage (SMD: 0.421, CI: 0.290;0.551), T helper (Th)1 (SMD: 0.353, CI: 0.189;0.517), Th17 (SMD: 0.492, CI: 0.332;0.651) and immune-associated neurotoxicity (SMD: 0.327 CI: 0.205;0.448). In addition, CRP and 19 different cytokines displayed significantly elevated levels in LC patients compared to NC. Conclusion: LC disease is characterized by IRS activation and increased immune-associated neurotoxicity.

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

Background: Some months after the remission of acute COVID-19 infection, some people show depressive symptoms, which are predicted by increased peak body temperature (PBT) and lowered blood oxygen saturation (SpO2). Nevertheless, no data indicate whether Long COVID is associated with increased insulin resistance (IR) in association with depressive symptoms and immune, oxidative, and nitrosative (IO&NS) processes. Methods. We used the homeostasis Model Assessment 2 (HOMA2) calculator to compute beta-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. We examined the associations between the HOMA2 indices and PBT and SpO2 during acute infection, and depression, IO&NS biomarkers (C-reactive protein, NLRP3 activation, myeloperoxidase, and advanced oxidation protein products) 3-4 months after the acute infection. Results. Long COVID is accompanied by increased HOMA2-IR, fasting blood glucose, and insulin levels. We found that 33.7% of the patients versus 0% of the controls had HOMA2-IR values >1.8, suggesting IR. PBT, but not SpO2, during acute infection significantly predicted IR, albeit with a small effect size. Increased IR was significantly associated with depressive symptoms as assessed with the BDI and HAMD above and beyond the effects of IO&NS pathways. There were no significant associations between increased IR and the activated IO&NS pathways during Long COVID. Conclusion. Long COVID is associated with new-onset IR in a subset of patients. Increased IR may contribute to the onset of depressive symptoms due to Long COVID by enhancing overall neurotoxicity.

Lowered quality of life in Long COVID is strongly predicted by affective symptoms and chronic fatigue syndrome which are associated with inflammatory processes during the acute infectious phase and consequent neuroimmunotoxic pathways (preprint)

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 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) 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)-1β, 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 Astra-Zeneca 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.

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. (preprint)

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 (“physio-affective”) symptoms three to four months later. The present study was performed to characterize whether the effects of SpO2 and PBT on the physio-affective phenome of Long COVID are mediated by immune, oxidative and nitrosative stress (IO&NS) pathways. 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 physio-affective phenome 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. Both PBT and SpO2 strongly predict OSTOX/ATIOX during Long COVID. In conclusion, the impact of acute COVID-19 on the physio-affective 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. Post-viral physio-affective symptoms have an inflammatory origin and are partly mediated by neuro-oxidative toxicity.

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

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 (physio-affective) symptoms three to four months later. The present study was performed to characterize whether the effects of SpO2 and PBT on the physio-affective phenome of Long COVID are mediated by immune, oxidative and nitrosative stress (IO&NS) pathways. 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 physio-affective phenome 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. Both PBT and SpO2 strongly predict OSTOX/ATIOX during Long COVID. In conclusion, the impact of acute COVID-19 on the physio-affective 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. Post-viral physio-affective symptoms have an inflammatory origin and are partly mediated by neuro-oxidative toxicity.

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 (preprint)

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 (labeled 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 to 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 characterized 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.

The tryptophan catabolite or kynurenine pathway in COVID-19 and critical COVID-19: a systematic review and meta-analysis (preprint)

Coronavirus disease 2019 (COVID-19) is accompanied by activated immune-inflammatory pathways and oxidative stress, which both may induce indoleamine-2,3- dioxygenase (IDO), a key enzyme of the tryptophan (TRP) catabolite (TRYCAT) pathway. The aim of the current study was to systematically review and meta-analyze the TRYCAT pathway status including levels of TRP and kynurenine (KYN) and IDO activity, as assessed using the KYN/TRP ratio. This systematic review was performed in December 2021 and searched data in PubMed, Google Scholar, and Web of sciences. In our meta-analysis we included 14 articles which examine TRP and TRYCATs in COVID-19 patients versus non-COVID-19 controls, and severe/critical versus mild/moderate COVID-19. Overall, the analysis was performed on 1269 individuals, namely 794 COVID-19 patients and 475 controls. The results show a significant (p <0.0001) increase in the KYN/TRP ratio (standardized mean difference, SMD=1.099, 95% confidence interval, CI: 0.714; 1.484) and KYN (SMD= 1.123, 95% CI: 0.730;1.516) and significantly lower TRP ((SMD= - 1.002, 95%CI: -1.738; -0.266) in COVID-19 versus controls. The KYN/TRP ratio (SMD= 0.945, 95%CI: 0.629; 1.262) and KYN (SMD= 0.806, 95%CI: 0.462; 1.149) were also significantly (p <0.001) higher and TRP lower (SMD= -0.909, 95% CI: -1.569; -0.249) in severe/critical versus mild/moderate COVID-19. No significant difference was detected in the kynurenic acid (KA)/KYN ratio and KA between COVID-19 patients and controls. Our results indicate increased activity of the IDO enzyme in COVID-19 and in severe/critical patients. The TRYCAT pathway is probably implicated in the pathophysiology and progression of COVID-19 and may signal a worse outcome of the disease. One-sentence summary The current meta-analysis study revealed a significant increase in peripheral blood IDO activity and kynurenine levels and a significant reduction in tryptophan in COVID-19 versus controls and in severe/critical COVID-19 versus mild/moderate COVID-19.

Proposing a health audit model for evaluating the health policy to confront the COVID-19 pandemic for nursing professionals in Saudi hospitals

This study aims to discover the role of health audit in evaluating the health policy adopted to confront the Coronavirus (Covid 19) and to know the side effects of diseases and epidemics, especially on nurses working in Saudi hospitals. Which include the costs of quarantine, as well as developing and implementing a plan of absorptive capacity, monitoring measures and modifying them according to the level of response in hospitals and regions, determining the reference hospitals to receive cases of Covid-19, evaluating their readiness and capacity at the beginning of the pandemic, and preparing other hospitals after that to receive and treat cases, and count the numbers of isolation and care rooms Focusing and monitoring respiratory care consumables and consumables, ECMO devices, and the workforce to escalate and take the necessary measures as needed. The researchers concluded that the health audit contributes to predicting, precaution and taking the necessary measures to get out of the pandemic crisis with the least possible human losses, in addition to the costs of human lives and health risks of epidemics and pandemics, and that health audits have an important role in evaluating health policy in general to reduce health crises, so this type of scrutiny must be strengthened at the level of the Saudi health system, whether at the level of the government or the level of health institutions, and this is to build an early system to confront future health crises. The experience of the Covid-19 pandemic crisis will be beneficial for supervisors and workers in the health sector, especially nurses in Saudi hospitals because health crises are It is sudden and requires preparation and integration in procedures and politics to reduce its negative social and economic effects. [ABSTRACT FROM AUTHOR] Copyright of Journal of Cardiovascular Disease Research (Journal of Cardiovascular Disease Research) is the property of Journal of Cardiovascular Disease Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)