Detrimental effects of COVID-19 in the brain and therapeutic options for long COVID: The role of Epstein–Barr virus and the gut–brain axis

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(12), P. 4968 - 4976

Published: July 4, 2023

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome 2 (SARS-CoV-2) infection has resulted in a serious public health burden worldwide. In addition to respiratory, heart, and gastrointestinal symptoms, patients infected with SARS-CoV-2 experience number of persistent neurological psychiatric known as long COVID or "brain fog". Studies autopsy samples from who died COVID-19 detected the brain. Furthermore, increasing evidence shows that Epstein-Barr virus (EBV) reactivation after might play role symptoms. Moreover, alterations microbiome contribute this article, author reviews detrimental effects on brain, biological mechanisms (e.g., EBV reactivation, changes gut, nasal, oral, lung microbiomes) underlying COVID. addition, discusses potential therapeutic approaches based gut-brain axis, including plant-based diet, probiotics prebiotics, fecal microbiota transplantation, vagus nerve stimulation, sigma-1 receptor agonist fluvoxamine.

Language: Английский

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Early treatment with fluvoxamine, bromhexine, cyproheptadine, and niclosamide to prevent clinical deterioration in patients with symptomatic COVID-19: a randomized clinical trial

EClinicalMedicine, Journal Year: 2024, Volume and Issue: 70, P. 102517 - 102517

Published: March 14, 2024

Repurposed drugs with host-directed antiviral and immunomodulatory properties have shown promise in the treatment of COVID-19, but few trials studied combinations these agents. The aim this trial was to assess effectiveness affordable, widely available, repurposed used combination for which may be particularly relevant low-resource countries.

Language: Английский

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Overview of the potential use of fluvoxamine for COVID-19 and long COVID

Discover Mental Health, Journal Year: 2023, Volume and Issue: 3(1)

Published: March 21, 2023

Abstract Coronavirus disease 2019 (COVID-19) has presented a serious worldwide threat to public health since its emergence in late 2019. From safety point of view, drug repurposing received particular attention. Several clinical studies have demonstrated that the use fluvoxamine, selective serotonin reuptake inhibitor with potent sigma-1 receptor agonism, early-stage infection might be associated prevention deterioration individuals SARS-CoV-2 infection, although several reports shown low dose fluvoxamine may ineffective. There is increasing evidence can cross blood–brain barrier, resulting number psychiatric and neurologic symptoms COVID-19 survivors. Importantly, about half survivors experience variety long-term sequelae, including symptoms, known as long COVID. In this priority review, author presents an overview potential treatment

Language: Английский

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Association of severe mental illness and septic shock case fatality rate in patients admitted to the intensive care unit: A national population-based cohort study

PLoS Medicine, Journal Year: 2023, Volume and Issue: 20(3), P. e1004202 - e1004202

Published: March 13, 2023

Background Patients with severe mental illness (SMI) (i.e., schizophrenia, bipolar disorder, or major depressive disorder) have been reported to excess mortality rates from infection compared patients without SMI, but whether SMI is associated higher lower case fatality (CFRs) among infected remains unclear. The primary objective was compare the 90-day CFR in septic shock and admitted intensive care unit (ICU), after adjusting for social disadvantage physical health comorbidity. Methods findings We conducted a nationwide, population-based cohort study of all adult ICU France between January 1, 2014, December 31, 2018, using French national hospital database. matched (within hospitals) ratio 1:up 4 (matched-controls) age (5 years range), sex, degree deprivation, year hospitalization. Cox regression models were adjustment smoking, alcohol other substance addiction, overweight obesity, Charlson comorbidity index, presence trauma, surgical intervention, Simplified Acute Physiology Score II score, organ failures, source admission (home, transfer ward), length time admission. outcome CFR. Secondary outcomes 30- 365-day CFRs, clinical profiles patients. A total 187,587 identified, including 3,812 2,258 5,246 disorder. Compared controls, significantly schizophrenia (1,052/3,269 = 32.2% versus 5,000/10,894 45.5%; adjusted hazard (aHR) 0.70, 95% confidence interval (CI) 0.65,0.75, p < 0.001), disorder (632/1,923 32.9% 2,854/6,303 45.3%; aHR CI 0.63,0.76, (1,834/4,432 41.4% 6,798/14,452 47.1%; 0.85, 0.81,0.90, 0.001). Study limitations include inability capture deaths occurring outside hospital, lack data on processes care, problems missing miscoding medico-administrative databases. Conclusions Our suggest that, comorbidity, there are improved without. This finding may be result different immunological exposures psychotropic medications, which should further explored.

Language: Английский

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De-black-boxing health AI: demonstrating reproducible machine learning computable phenotypes using the N3C-RECOVER Long COVID model in the All of Us data repository

Journal of the American Medical Informatics Association, Journal Year: 2023, Volume and Issue: 30(7), P. 1305 - 1312

Published: May 22, 2023

Abstract Machine learning (ML)-driven computable phenotypes are among the most challenging to share and reproduce. Despite this difficulty, urgent public health considerations around Long COVID make it especially important ensure rigor reproducibility of phenotyping algorithms such that they can be made available a broad audience researchers. As part NIH Researching Enhance Recovery (RECOVER) Initiative, researchers with National Cohort Collaborative (N3C) devised trained an ML-based phenotype identify patients highly probable have COVID. Supported by RECOVER, N3C NIH’s All Us study partnered reproduce output N3C’s model in data enclave, demonstrating extensibility multiple environments. This case reuse illustrates how open-source software best practices cross-site collaboration de-black-box algorithms, prevent unnecessary rework, promote open science informatics.

Language: Английский

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Positionspapier zum Post-COVID-Syndrom

Deleted Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

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A systematic review and meta-analysis, investigating dose and time of fluvoxamine treatment efficacy for COVID-19 clinical deterioration, death, and Long-COVID complications

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: June 12, 2024

Abstract There have been 774,075,242 cases of COVID-19 and 7,012,986 deaths worldwide as January 2024. In the early stages pandemic, there was an urgent need to reduce severity disease prevent for hospitalization avoid stress on healthcare systems worldwide. The repurposing drugs clinical deterioration patients trialed in many studies using different drugs. Fluvoxamine (an SSRI sigma-1 receptor agonist) initially identified potentially provide beneficial effects COVID-19-infected patients, preventing hospitalization. Fourteen carried out date, with seven those being randomized placebo-controlled studies. This systematic review meta-analysis covers literature from outbreak SARS-CoV-2 late 2019 until Search terms related fluvoxamine, such its trade names chemical names, along words COVID-19, coronavirus, were used databases including PubMed, Google Scholar, Scopus, ClinicalTrials.gov database NIH, identify trials subsequent analysis. Clinical death data extracted these where available meta-analysis. A total 7153 studied across 14 (both open-label double-blind placebo-controlled). 681 3553 (19.17%) standard care group 255 3600 (7.08%) fluvoxamine-treated experienced deterioration. estimated average log odds ratio 1.087 (95% CI 0.200 1.973), which differed significantly zero (z = 2.402, p 0.016). resulted a 0.359 0.1111 0.5294), 3.103, 0.002). results this study fluvoxamine effective deterioration, subgrouping analysis suggests that earlier treatment dose 200 mg or above provides best outcomes. We hope outcomes can help design future into respiratory viral infections improve

Language: Английский

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From intestinal metabolites to the brain: Investigating the mysteries of Long COVID

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(3)

Published: March 1, 2024

To date, more than 770 million individuals have been infected with SARS-CoV-2 worldwide.1 Postacute sequelae of COVID-19 (PASC), commonly called 'Long COVID', constitute a primary public health concern. Long COVID involves symptoms that emerge, persist, or relapse over 30 days after acute infection. The PASC span wide range organs and are heterogeneous among patients. A recent study aimed at developing comprehensive definition based on in prospective cohort involving 9764 patients.2 Given the intricacies PASC, underlying etiology remains poorly understood, posing an urgent global challenge necessitates resolution. We recently conducted may shed new light one possible biological causes PASC.3 This began exploring metabolite profiles distinct Among most significantly depleted metabolites observed postacute patients, compared to recovered was serotonin (5-hydroxytryptamine, 5-HT). Mouse models viral infection intestinal organoids model were employed elucidate molecular mechanisms this phenotype. found RNA triggered type I interferon (IFN) signalling, which turn suppressed levels by affecting production, storage degradation. Beyond establishing association between 5-HT elucidating potential connection, our further suggests decrease peripheral can lead impaired hippocampal responses memory impeding activity vagus nerve. findings investigation contribute understanding involved suggest predictive biomarkers therapeutic targets for intervention. reduction plasma identified through metabolomics analysis 58 symptom-free recovery 60 COVID-19. Consistent these human cohorts, SARS-CoV-2-infected K18-ACE2 mouse model, expresses ACE2. By using synthetic double-stranded polyinosinic:polycytidylic acid (poly(I:C)) infection, additionally revealed mediated viral-induced response TLR3- STAT1-dependent manner. next investigated inflammation leads (Figure 1). Notably, tryptophan, precursor is used as substrate synthesis enterochromaffin cells gastrointestinal tract, also diminished Using epithelial cells, we uncovered viral-driven inhibits tryptophan absorption suppressing expression amino uptake genes, such (Slc6a19), encodes neutral transporter B0AT1, its chaperone In addition suppression turnover. Following platelets store transport MAO enzymes rapidly free serotonin. platelet counts decreased following poly(I:C) treatment, suggesting carrying capacity systemic circulation diminished. could not be rescued supplementation, indicating independent reduced uptake. Lastly, transcription Maoa 5-hydroxyindoleacetic (5-HIAA), degradation product, increased virally poly (I:C)-treated mice. characterised spectrum including fatigue, cognitive difficulties, headaches, endurance loss, sleep disturbances, anxiety lapses. crucial role central nervous system function, sought explore physiological consequences depletion neurocognitive 2). Utilising exposed chronic infections, novel object recognition paradigm assess ability. treatment test. selective reuptake inhibitor (SSRI) fluoxetine restored function mice injected poly(I:C). Furthermore, supplementation 5-hydroxytryptophan (5-HTP) only reinstated but demonstrated reversal impairment. None interventions tested altered brain amidst inflammation, pivotal regulating function. How does communicate brain? neuronal brainstem poly(I:C)-treated during novelty exposure, involvement sensory neurons terminate region brain. impairment induced successfully reversed administration capsaicin, Trpv1 ligand potent stimulant neurons. Consistently, when chemogenetics selectively activate Phox2b-expressing vagal restoration neuron Further validation came from experiment pharmacological agonist receptors neurons, emphasised importance signalling nerve cognition. These results important nerve, key mediator sickness behaviour has implicated pathophysiology fatigue syndrome.4, 5 However, unravelling precise circuitry relay explored future research. Understanding complexities holds promise refining approaches address challenges SARS-CoV-2, low documented other conditions high interferons, lupus erythematosus multiple sclerosis, broader implications findings.6-8 Our eliminating trigger chronically elevated levels, restoring activation might clinical utility prevention COVID. efficiency approaches, however, first requires detailed evaluation. Dutch 95 patients showed significant SSRIs; randomised controlled trial.9 preprint detailing multicentre retrospective 17 933 National Cohort Collaborative (N3C) 26% relative risk who received SSRI unexposed controls.10 Extensive, double-blind, studies needed establish whether SSRIs targeting play managing long-term disease burden Serotonin alternative avenue, demanding rigorous formulation testing safety efficacy. Overall, proposes pathway linking persistence, sustained responses, dysfunction potentially postviral syndromes. emphasise necessity extensive investigations into PASC. Directly connection reservoirs inflammatory manifestations gap field, calling initiation large-scale investigate conditions. SL ASD performed literature research wrote manuscript. ML guided edited All authors contributed article approved submitted version. thank members Levy laboratory discussions input. supported NIH Director's New Innovator Award (DP2-AG-067511), American Cancer Society Scholar Award, , Searle Scholars Program, Edward Mallinckrodt, Jr. Foundation, W. Smith Charitable Trust, Burroughs Wellcome Fund, grants Abramson Center (P30-CA- 016420), PennCHOP microbiome program, Penn Nutritional Science Medicine, Coronavirus Center, Institute Immunology, Molecular Studies Digestive Liver Diseases (P30-DK- 050306), Precision Aging, Colton Excellence Environmental Toxicology (P30-ES 013508), Borrelli Family Pilot Grant Lynch Syndrome. Figures created BioRender.com. declare they no conflicts interest. Not applicable

Language: Английский

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Die Bedeutung von Antidepressiva bei COVID-19 und Long-COVID – Ein Scoping-Review Update

Fortschritte der Neurologie · Psychiatrie, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 23, 2024

Introduction Preclinically, fluvoxamine and other antidepressants (AD) exerted antiviral anti-inflammatory properties also against SARS-COV-2. Therfore, It makes sense to test the clinical effect of AD COVID-19 Long COVID.

Language: Английский

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No reduced serum serotonin levels in patients with post-acute sequelae of COVID-19

Infection, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 2, 2024

Language: Английский

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