Chronic fatigue and affective symptoms in acute and long <scp>COVID</scp> are attributable to immune‐inflammatory pathways

Almulla, Abbas F.; Al‐Hakeim, Hussein Kadhem; Maes, Michaël

doi:10.1111/pcn.13514

Cited by 19 publications

(22 citation statements)

References 10 publications

(45 reference statements)

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“…The first major finding of this study is that a common core (latent vector) could be extracted from physiosomatic, depressive, and anxiety symptoms, demonstrating that these symptom domains are highly interrelated expressions of the physio-affective phenome of Long COVID. These findings are consistent with our prior findings that a single component drives both physiosomatic and affective symptoms in individuals with Long COVID (Al-Hadrawi, Al-Rubaye et al 2022, Al-Hakeim, Al-Rubaye et al 2023, Almulla, Al-Hakeim et al 2023). In the present investigation, however, the relationships were calculated in patients who had all suffered from acute COVID-19 infection, while in our prior studies, the connections were calculated in healthy controls and participants with long-term COVID.…”

Section: Discussionsupporting

confidence: 93%

“…In recent meta-analyses, no notable changes in TRYCAT production have been observed in depression and schizophrenia, even though low tryptophan levels are a characteristic of both diseases (Almulla, Thipakorn et al 2022. Increased production of TRYCATs appears to be a characteristic of acute inflammatory conditions, such as critical acute COVID-19 infection (Almulla, Al-Hakeim et al 2023) and interferon-induced depression (Bonaccorso, Marino et al 2002), as opposed to mild chronic inflammatory conditions, such as depression, schizophrenia, and Alzheimer's disease , Almulla, Thipakorn et al 2022. Reduced blood albumin, which binds tryptophan, is likely the most significant mechanism leading to decreased tryptophan in moderate chronic inflammatory diseases (such as depression and schizophrenia) (McMenamy and Oncley 1958, Yuwiler, Oldendorf et al 1977, Maes, Minner et al 1991, Maes, Wauters et al 1996, Maes, Verkerk et al 1997.…”

Section: The Trycat Pathway and Long Covidmentioning

confidence: 99%

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

Al‐Hakeim

Abed

Moustafa

et al. 2023

Preprint

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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.

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Section: Discussionsupporting

confidence: 93%

Section: The Trycat Pathway and Long Covidmentioning

confidence: 99%

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

Al‐Hakeim

Abed

Moustafa

et al. 2023

Preprint

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“…However, there is still much debate on what causes Long COVID disease and the severity of CFS, depression and anxiety symptoms due to Long COVID. In this context, in yet another study, some of the same authors have identified molecular pathways implicated in the onset of symptoms in individuals with Long COVID disease, including activation of immune-inflammatory processes with oxidative and nitrosative stress reactions (Al-Hakeim, Al-Rubaye et al 2022, Al-Hakeim, Al-Rubaye et al 2022), increased insulin resistance (Al-Hakeim, Al-Rubaye et al 2023, Maes, Almulla et al 2023), decreased tryptophan levels and increased tryptophan catabolites, such as kynurenine (Al-Hakeim, Abed et al 2023, Al-Hakeim, Khairi Abed et al 2023). Moreover, a recent meta-analysis reported that Long COVID disease is accompanied by increased C-reactive protein (CRP), D-dimer, lactate dehydrogenase, leukocytes, lymphocytes, and interleukin (IL)-6 (Yong, Halim et al 2023).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, Vojdani et al discovered that Long COVID patients show elevated levels of immunoglobulins (Ig) IgG/IgM directed against Severe Acute Respiratory Syndrome Coronavirus 2 (IgG/IgM-SARS-CoV-2), human Herpesvirus type 6 (HHV-6) and its deoxyuridine 5′-triphosphate nucleotidohydrolase (HHV-6-duTPase) along with IgA/IgM at activin-A (a self-antigen) (Vojdani, Almulla et al 2023). These findings confirmed previous studies which indicated that Long COVID disease is accompanied by persistence of SARS-CoV-2, reactivation of dormant viruses, and autoimmune reactions against self-proteins (Acosta-Ampudia, Monsalve et al 2022, Rojas, Rodríguez et al 2022, Su, Yuan et al 2022, Vojdani, Vojdani et al 2023).…”

Section: Introductionmentioning

confidence: 99%

“…These findings confirmed previous studies which indicated that Long COVID disease is accompanied by persistence of SARS-CoV-2, reactivation of dormant viruses, and autoimmune reactions against self-proteins (Acosta-Ampudia, Monsalve et al 2022, Rojas, Rodríguez et al 2022, Su, Yuan et al 2022, Vojdani, Vojdani et al 2023). Importantly, Vojdani et al were able to predict the Long COVID diagnosis with high sensitivity (78.9%) and specificity (81.8%) based on elevated levels of IgA-activin-A, IgG-HHV-6, IgM-HHV-6-duTPase, IgG-SARS-CoV-2, and IgM-HHV-6, and a factor extracted from all IgA levels to all viral antigens (Vojdani, Almulla et al 2023).…”

Section: Introductionmentioning

confidence: 99%

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Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms

Almulla,

Maes,

Zhou

et al. 2023

Preprint

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BackgroundAutoimmune responses contribute to the pathophysiology of Long COVID, affective symptoms and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).ObjectivesTo examine whether Long COVID, and its accompanying affective symptoms and CFS are associated with immunoglobulin (Ig)A/IgM/IgG directed at neuronal proteins including myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), synapsin, α+β-tubulin, neurofilament protein (NFP), cerebellar protein-2 (CP2), and the blood-brain-barrier-brain-damage (BBD) proteins claudin-5 and S100B.MethodsIgA/IgM/IgG to the above neuronal proteins, human herpes virus-6 (HHV-6) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were measured in 90 Long COVID patients and 90 healthy controls, while C-reactive protein (CRP), and advanced oxidation protein products (AOPP) in association with affective and CFS ratings were additionally assessed in a subgroup thereof.ResultsLong COVID is associated with significant increases in IgG directed at tubulin (IgG-tubulin), MBP, MOG and synapsin; IgM-MBP, MOG, CP2, synapsin and BBD; and IgA-CP2 and synapsin. IgM-SARS-CoV-2 and IgM-HHV-6 antibody titers were significantly correlated with IgA/IgG/IgM-tubulin and -CP2, IgG/IgM-BBD, IgM-MOG, IgA/IgM-NFP, and IgG/IgM-synapsin. Binary logistic regression analysis shows that IgM-MBP and IgG-MBP are the best predictors of Long COVID. Multiple regression analysis shows that IgG-MOG, CRP and AOPP explain together 41.7% of the variance in the severity of CFS. Neural network analysis shows that IgM-synapsin, IgA-MBP, IgG-MOG, IgA-synapsin, IgA-CP2, IgG-MBP and CRP are the most important predictors of affective symptoms due to Long COVID with a predictive accuracy of r=0.801.ConclusionBrain-targeted autoimmunity contributes significantly to the pathogenesis of Long COVID and the severity of its physio-affective phenome.

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Multi-target drugs for the treatment of cognitive impairment and fatigue in post-COVID syndrome: focus on Ginkgo biloba and Rhodiola rosea

Mueller,

Müller

2024

J Neural Transm

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Cognitive impairment, depression and (mental) fatigue represent the most frequent neuropsychiatric symptoms of the post-COVID syndrome. Neuroinflammation, oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological mechanisms underlying these symptoms. Attempts to treat post-COVID-associated cognitive impairment and fatigue with different drugs available for other diseases have not yet been successful. One probable explanation could be that these drugs work by one specific mechanism of action only and not in a broad multi-target way. Therefore, they will not address the broad pathophysiological spectrum possibly responsible for cognitive impairment, depression and fatigue in post-COVID syndrome. Notably, nearly all drugs currently under investigation for fatigue in post-COVID syndrome are rather addressing one single target instead of the several pathomechanisms underlying this condition. Contrary to this approach, herbal drugs often consist of many different ingredients with different pharmacological properties and pharmacological targets. Therefore, these drugs might be a promising approach for the treatment of the broad symptomatic presentation and the pathophysiological mechanisms of cognitive impairment and fatigue following a SARS-CoV-2 infection. Of these herbal drugs, extracts of Ginkgo biloba and Rhodiola rosea probably are the best investigated candidates. Their broad pharmacological spectrum in vitro and in vivo includes anti-oxidative, anti-inflammatory, antidepressant as well as properties reducing cognitive impairment and fatigue. In several studies, both drugs showed positive effects on physical and mental fatigue and impaired cognition. Moreover, depressive symptoms were also reduced in some studies. However, even if these results are promising, the data are still preliminary and require additional proof by further studies.

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Chronic fatigue and affective symptoms in acute and long COVID are attributable to immune‐inflammatory pathways

Cited by 19 publications

References 10 publications

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

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

Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms

Multi-target drugs for the treatment of cognitive impairment and fatigue in post-COVID syndrome: focus on Ginkgo biloba and Rhodiola rosea

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