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

Abstract

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.

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

“…These results indicate that the physio-affective core during acute and Long COVID is largely the consequence of infection-immuneinflammatory pathways. The results confirm that physio-somatic symptoms including chronic fatigue, physio-somatic symptoms including pain, GIS, malaise, and autonomic symptoms and affective symptoms share common immune-inflammatory pathways as reviewed in the introduction.In accordance with our previous study(Al-Hakeim, Al-Rubaye et al 2022), we found that AstraZeneca (viral vector, genetically engineered virus) and Pfizer (mRNA) vaccination, but not administration of the Sinopharm vaccine (inactivated virus), may exacerbate the physio-affective phenome of Long COVID. Those SARS-CoV-2 vaccinations were reported in a few studies to be associated with Long COVID-like symptoms, including sadness, anxiety, exhaustion, and immune disoders, including increased synthesis of spike protein, T cell activation, deficits in type 1 interferon signaling, and autoimmune responses(Couzin-Frankel and Vogel 2022, Seneff, Nigh et al.…”

“…confirm the results of another study conducted on an independent study sample of Iraqi COVID-19 patients and controls(Al-Hakeim, Al-Rubaye et al 2022). Moreover, both the latter and the current study reported that the physio-affective core of Long COVID was strongly predicted by the combined effects of increased peak BT and lowered SpO2 during the acute phase of disease.…”

“…Ca levels are necessary to maintain normal mood and cognition by affecting neuronal signaling pathways and protecting neuroplasticity processes (Toescu and Verkhratsky 2007, Hurst 2010, Grützner, Listunova et al 2018. Moreover, the lowered Ca levels in acute COVID-19 are part of the infection-immune-inflammatory core (Al-Jassas, Al-Hakeim et al 2022), which also appears to determine lower Ca levels during Long COVID. Thus, it is safe to hypothesize that in patients with Long COVID, abnormal Ca which accompanies the immune-inflammatory response during the acute phase of illness, contributes mechanistically to the physio-affective phenome of both acute and Long COVID.…”

“…Moreover, elevated peak BT and lowered SpO2 during the acute phase of infection predict the physio-affective phenome of Long COVID (Al-Hadrawi, Al-Rubaye et al 2022). In Long COVID, the severity of the physio-affective phenome was also predicted by increased oxidative toxicity as indicated by increased levels of malondialdehyde (MDA), protein carbonyls (PCs), myeloperoxidase (MPO), and nitric oxide (NO), and lowered antioxidant defenses as indicated by lowered zinc and glutathione peroxidase (Gpx) (Al-Hakeim, Al-Rubaye et al 2022). Moreover, the oxidative toxicity / antioxidant ratio was significantly predicted by increased peak BT and lowered SpO2 (Al-Hakeim, Al-Rubaye et al 2022).…”

“…In acute COVID-19, this physio-affective phenome was largely explained by the cumulative effects of increased pro-inflammatory cytokines, including IL-6, soluble advanced glycation products (sRAGEs), changes in acute phase proteins, including C-reactive protein (CRP) and albumin, lowered calcium (Ca), pneumonia as indicated by chest computerized tomography scan abnormalities (CCTAs), and diminished SpO2 (Al-Jassas, Al-Hakeim et al 2022). Moreover, elevated peak BT and lowered SpO2 during the acute phase of infection predict the physio-affective phenome of Long COVID (Al-Hadrawi, Al-Rubaye et al 2022).…”