Tag: long Covid

A systematic review of quantitative EEG findings in Long COVID, Fibromyalgia and Chronic Fatigue Syndrome

Abstract:

Long COVID (LC) is a multisymptom clinical syndrome with similarities to Fibromyalgia Syndrome (FMS) and Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). All these conditions are believed to be associated with centrally driven mechanisms such as central sensitisation.

There is a lack of consensus on quantitative EEG (qEEG) changes observed in these conditions. This review aims to synthesise and appraise the literature on resting-state qEEG in LC, FMS and CFS/ME, to help uncover possible mechanisms of central sensitisation in these similar clinical syndromes.

A systematic search of MEDLINE, Embase, CINHAL, PsycINFO and Web of Science databases for articles published between December 1994 and September 2023 was performed. Following screening for predetermined selection criteria and out of the initial 2510 studies identified, 17 articles were retrieved that met all the inclusion criteria, particularly of assessing qEEG changes in one of the three conditions compared to healthy controls. All studies scored moderate to high quality on the Newcastle-Ottawa scale.

There was a general trend for decreased low frequency EEG band activity (delta, theta, and alpha) and increased high-frequency EEG beta activity in FMS, whereas an opposite trend was found in CFS/ME. The limited LC studies included in this review focused mainly on cognitive impairments and showed mixed findings not consistent with patterns seen in FMS and CFS/ME.

Further research is required to explore whether there are phenotypes within LC that have EEG signatures similar to FMS or CFS/ME. This could inform identification of reliable diagnostic markers and possible targets for neuromodulation therapies.

Source: Bárbara Silva-Passadouro, Arnas Tamasauskas, Omar Khoja, Alexander J. Casson, Ioannis Delis, Christopher Brown, Manoj Sivan. A systematic review of quantitative EEG findings in Long COVID, Fibromyalgia and Chronic Fatigue Syndrome. medRxiv [Preprint] https://www.medrxiv.org/content/10.1101/2023.11.06.23298171v1.full-text (Full text)

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

Abstract:

Background Autoimmune responses contribute to the pathophysiology of Long COVID, affective symptoms and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Objectives To 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.

Methods IgA/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.

Results Long 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.

Conclusion Brain-targeted autoimmunity contributes significantly to the pathogenesis of Long COVID and the severity of its physio-affective phenome.

Source: Abbas F. Almulla, Michael Maes, Bo Zhou, Hussein K. Al-Hakeim, Aristo Vojdani. Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms. medRxiv [Preprint] https://www.medrxiv.org/content/10.1101/2023.10.04.23296554v1 (Full text available as PDF file)

Post Viral Pain, Fatigue, and Sleep Disturbance Syndromes: Current knowledge and Future Directions

Abstract:

Post-viral pain syndrome, also known as post-viral syndrome (PVS), is a complex condition characterized by persistent pain, fatigue, musculoskeletal pain, neuropathic pain, neurocognitive difficulties, and sleep disturbances1,2 that can occur after an individual has recovered from a viral infection. Much remains unknown regarding the pathophysiology of post-viral syndromes and few studies have provided a comprehensive summary of the condition, agents that cause it, and successful treatment modalities.

With the COVID-19 pandemic continuing to affect millions of people worldwide, the need for understanding the etiology of post-viral illness and how to help individuals cope with the sequalae is paramount.2 This narrative review provides a summary of the sequelae of post-viral syndromes, viral agents that cause it, the pathophysiology, treatment, and future considerations for research and targeted therapies.

Source: Caleb Tackey, P. Maxwell Slepian, Hance Clarke & Nimish Mittal (2023) Post Viral Pain, Fatigue, and Sleep Disturbance Syndromes: Current knowledge and Future Directions, Canadian Journal of Pain, DOI: 10.1080/24740527.2023.2272999 https://www.tandfonline.com/doi/full/10.1080/24740527.2023.2272999 (Full text)

Blood T cell phenotypes correlate with fatigue severity in post-acute sequelae of COVID-19

Abstract:

Purpose: Post-acute sequelae of COVID-19 (PASC) affect approximately 10% of convalescent patients. The spectrum of symptoms is broad and heterogeneous with fatigue being the most often reported sequela. Easily accessible blood biomarkers to determine PASC severity are lacking. Thus, our study aimed to correlate immune phenotypes with PASC across the severity spectrum of COVID-19.

Methods: A total of 176 originally immunonaïve, convalescent COVID-19 patients from a prospective cohort during the first pandemic phase were stratified by initial disease severity and underwent clinical, psychosocial, and immune phenotyping around 10 weeks after first COVID-19 symptoms. COVID-19-associated fatigue dynamics were assessed and related to clinical and immune phenotypes.

Results: Fatigue and severe fatigue were commonly reported irrespective of initial COVID-19 severity or organ-specific PASC. A clinically relevant increase in fatigue severity after COVID-19 was detected in all groups. Neutralizing antibody titers were higher in patients with severe acute disease, but no association was found between antibody titers and PASC. While absolute peripheral blood immune cell counts in originally immunonaïve PASC patients did not differ from unexposed controls, peripheral CD3+CD4+ T cell counts were independently correlated with fatigue severity across all strata in multivariable analysis.

Conclusions: Patients were at similar risk of self-reported PASC irrespective of initial disease severity. The independent correlation between fatigue severity and blood T cell phenotypes indicates a possible role of CD4+ T cells in the pathogenesis of post-COVID-19 fatigue, which might serve as a blood biomarker.

Source: Pink, I., Hennigs, J.K., Ruhl, L. et al. Blood T cell phenotypes correlate with fatigue severity in post-acute sequelae of COVID-19. Infection (2023). https://doi.org/10.1007/s15010-023-02114-8 https://link.springer.com/article/10.1007/s15010-023-02114-8 (Full text)

First-in-human immunoPET imaging of COVID-19 convalescent patients using dynamic total-body PET and a CD8-targeted minibody

Abstract:

With most of the T cells residing in the tissue, not the blood, developing noninvasive methods for in vivo quantification of their biodistribution and kinetics is important for studying their role in immune response and memory. This study presents the first use of dynamic positron emission tomography (PET) and kinetic modeling for in vivo measurement of CD8+ T cell biodistribution in humans. A 89Zr-labeled CD8-targeted minibody (89Zr-Df-Crefmirlimab) was used with total-body PET in healthy individuals (N = 3) and coronavirus disease 2019 (COVID-19) convalescent patients (N = 5).
Kinetic modeling results aligned with T cell–trafficking effects expected in lymphoid organs. Tissue-to-blood ratios from the first 7 hours of imaging were higher in bone marrow of COVID-19 convalescent patients compared to controls, with an increasing trend between 2 and 6 months after infection, consistent with modeled net influx rates and peripheral blood flow cytometry analysis. These results provide a promising platform for using dynamic PET to study the total-body immune response and memory.
Source: Omidvari N, Jones T, Price PM, Ferre AL, Lu J, Abdelhafez YG, Sen F, Cohen SH, Schmiedehausen K, Badawi RD, Shacklett BL, Wilson I, Cherry SR. First-in-human immunoPET imaging of COVID-19 convalescent patients using dynamic total-body PET and a CD8-targeted minibody. Sci Adv. 2023 Oct 13;9(41):eadh7968. doi: 10.1126/sciadv.adh7968. Epub 2023 Oct 12. PMID: 37824612; PMCID: PMC10569706. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10569706/ (Full text)

Mast Cells in the Autonomic Nervous System and Potential Role in Disorders with Dysautonomia and Neuroinflammation

Abstract:

Mast cells (MC) are ubiquitous in the body and are critical for allergic diseases, but also in immunity and inflammation, as well as potential involvement in the pathophysiology of dysautonomias and neuroinflammatory disorders. MC are located perivascularly close to nerve endings and sites such as the carotid bodies, heart, hypothalamus, the pineal and the adrenal glands that would allow them to regulate, but also be affected by the autonomic nervous system (ANS).

MC are stimulated not only by allergens, but also many other triggers including some from the ANS that can affect MC release of neurosensitizing, proinflammatory and vasoactive mediators. Hence MC may be able to regulate homeostatic functions that appear to be dysfunctional in many conditions, such as postural orthostatic hypertension syndrome (POTS), autism spectrum disorder (ASD), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long-COVID syndrome.

The evidence indicates that there is a possible association between these conditions and diseases associated with mast cell activation, There is no effective treatment for any form of these conditions other than minimizing symptoms. Given the many ways MC could be activated and the numerous mediators released, it would be important to develop ways to inhibit stimulation of MC and the release of ANS-relevant mediators.

Source: Theoharides TC, Twahir A, Kempuraj D. Mast Cells in the Autonomic Nervous System and Potential Role in Disorders with Dysautonomia and Neuroinflammation. Ann Allergy Asthma Immunol. 2023 Nov 9:S1081-1206(23)01397-2. doi: 10.1016/j.anai.2023.10.032. Epub ahead of print. PMID: 37951572. https://pubmed.ncbi.nlm.nih.gov/37951572/

Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Abstract:

Aging is a major risk factor for neurodegenerative diseases, and coronavirus disease 2019 (COVID-19) is linked to severe neurological manifestations. Senescent cells contribute to brain aging, but the impact of virus-induced senescence on neuropathologies is unknown. Here we show that senescent cells accumulate in aged human brain organoids and that senolytics reduce age-related inflammation and rejuvenate transcriptomic aging clocks.

In postmortem brains of patients with severe COVID-19 we observed increased senescent cell accumulation compared with age-matched controls. Exposure of human brain organoids to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced cellular senescence, and transcriptomic analysis revealed a unique SARS-CoV-2 inflammatory signature. Senolytic treatment of infected brain organoids blocked viral replication and prevented senescence in distinct neuronal populations. In human-ACE2-overexpressing mice, senolytics improved COVID-19 clinical outcomes, promoted dopaminergic neuron survival and alleviated viral and proinflammatory gene expression.

Collectively our results demonstrate an important role for cellular senescence in driving brain aging and SARS-CoV-2-induced neuropathology, and a therapeutic benefit of senolytic treatments.

Source:Aguado, J., Amarilla, A.A., Taherian Fard, A. et al. Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology. Nat Aging (2023). https://doi.org/10.1038/s43587-023-00519-6 https://www.nature.com/articles/s43587-023-00519-6 (Full text)

Post-Vaccination Syndrome: A Descriptive Analysis of Reported Symptoms and Patient Experiences After Covid-19 Immunization

Abstract:

Introduction: A chronic post-vaccination syndrome (PVS) after covid-19 vaccination has been reported but has yet to be well characterized.

Methods: We included 241 individuals aged 18 and older who self-reported PVS after covid-19 vaccination and who joined the online Yale Listen to Immune, Symptom and Treatment Experiences Now (LISTEN) Study from May 2022 to July 2023. We summarized their demographics, health status, symptoms, treatments tried, and overall experience.

Results: The median age of participants was 46 years (interquartile range [IQR]: 38 to 56), with 192 (80%) identifying as female, 209 (87%) as non-Hispanic White, and 211 (88%) from the United States. Among these participants with PVS, 127 (55%) had received the BNT162b2 [Pfizer-BioNTech] vaccine, and 86 (37%) received the mRNA-1273 [Moderna] vaccine. The median time from the day of index vaccination to symptom onset was three days (IQR: 1 day to 8 days). The time from vaccination to symptom survey completion was 595 days (IQR: 417 to 661 days). The median Euro-QoL visual analogue scale score was 50 (IQR: 39 to 70). The five most common symptoms were exercise intolerance (71%), excessive fatigue (69%), numbness (63%), brain fog (63%), and neuropathy (63%). In the week before survey completion, participants reported feeling unease (93%), fearfulness (82%), and overwhelmed by worries (81%), as well as feelings of helplessness (80%), anxiety (76%), depression (76%), hopelessness (72%), and worthlessness (49%) at least once. Participants reported a median of 20 (IQR: 13 to 30) interventions to treat their condition.

Conclusions: In this study, individuals who reported PVS after covid-19 vaccination had low health status, high symptom burden, and high psychosocial stress despite trying many treatments. There is a need for continued investigation to understand and treat this condition.

Source: Harlan M Krumholz, Yilun Wu, Mitsuaki Sawano, Rishi Shah, Tianna Zhou, Adith S Arun, Pavan Khosla, Shayaan Kaleem, Anushree Vashist, Bornali Bhattacharjee, Qinglan Ding, Yuan Lu, Cesar Caraballo, Frederick Warner, Chenxi Huang, Jeph Herrin, David Putrino, Danice Hertz, Brianne Dressen, Akiko Iwasaki. Post-Vaccination Syndrome: A Descriptive Analysis of Reported Symptoms and Patient Experiences After Covid-19 Immunization. medRxiv 2023.11.09.23298266; doi: https://doi.org/10.1101/2023.11.09.23298266 https://www.medrxiv.org/content/10.1101/2023.11.09.23298266v1 (Full text available as PDF file)

Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses

Abstract:

Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health emergency. Although SARS-CoV-2 is primarily a respiratory pathogen, extra-respiratory organs, including the CNS, can also be affected. Neurologic symptoms have been observed not only during acute SARS-CoV-2 infection, but also at distance from respiratory disease, also known as long-COVID or neurological post-acute sequelae of COVID-19 (neuroPASC). The pathogenesis of neuroPASC is not well understood, but hypotheses include SARS-CoV-2-induced immune dysfunctions, hormonal dysregulations and persistence of SARS-CoV-2 reservoirs.

In this prospective cohort study, we used a high throughput systems serology approach to dissect the humoral response to SARS-CoV-2 (and other common coronaviruses: 229E, HKU1, NL63 and OC43) in the serum and CSF from 112 infected individuals who developed (n = 18) or did not develop (n = 94) neuroPASC. Unique SARS-CoV-2 humoral profiles were observed in the CSF of neuroPASC compared with serum responses. All antibody isotypes (IgG, IgM, IgA) and subclasses (IgA1-2, IgG1-4) were detected in serum, whereas CSF was characterized by focused IgG1 (and absence of IgM).

These data argue in favour of compartmentalized brain-specific responses against SARS-CoV-2 through selective transfer of antibodies from the serum to the CSF across the blood-brain barrier, rather than intrathecal synthesis, where more diversity in antibody classes/subclasses would be expected.

Compared to individuals who did not develop post-acute complications following infection, individuals with neuroPASC had similar demographic features (median age 65 versus 66.5 years, respectively, P = 0.55; females 33% versus 44%, P = 0.52) but exhibited attenuated systemic antibody responses against SARS-CoV-2, characterized by decreased capacity to activate antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and to bind Fcγ receptors. However, surprisingly, neuroPASC individuals showed significantly expanded antibody responses to other common coronaviruses, including 229E, HKU1, NL63 and OC43.

This biased humoral activation across coronaviruses was particularly enriched in neuroPASC individuals with poor outcome, suggesting an ‘original antigenic sin’ (or immunologic imprinting), where pre-existing immune responses against related viruses shape the response to the current infection, as a key prognostic marker of neuroPASC disease.

Overall, these findings point to a pathogenic role for compromised anti-SARS-CoV-2 responses in the CSF, likely resulting in incomplete virus clearance from the brain and persistent neuroinflammation, in the development of post-acute neurologic complications of SARS-CoV-2 infection.

Source: Spatola M, Nziza N, Jung W, Deng Y, Yuan D, Dinoto A, Bozzetti S, Chiodega V, Ferrari S, Lauffenburger DA, Mariotto S, Alter G. Neurologic sequelae of COVID-19 are determined by immunologic imprinting from previous coronaviruses. Brain. 2023 Oct 3;146(10):4292-4305. doi: 10.1093/brain/awad155. PMID: 37161609. https://academic.oup.com/brain/article/146/10/4292/7158783 (Full text)

Sequential multi-omics analysis identifies clinical phenotypes and predictive biomarkers for long COVID

Abstract:

The post-acute sequelae of COVID-19 (PASC), also known as long COVID, is often associated with debilitating symptoms and adverse multisystem consequences. We obtain plasma samples from 117 individuals during and 6 months following their acute phase of infection to comprehensively profile and assess changes in cytokines, proteome, and metabolome.

Network analysis reveals sustained inflammatory response, platelet degranulation, and cellular activation during convalescence accompanied by dysregulation in arginine biosynthesis, methionine metabolism, taurine metabolism, and tricarboxylic acid (TCA) cycle processes.

Furthermore, we develop a prognostic model composed of 20 molecules involved in regulating T cell exhaustion and energy metabolism that can reliably predict adverse clinical outcomes following discharge from acute infection with 83% accuracy and an area under the curve (AUC) of 0.96.

Our study reveals pertinent biological processes during convalescence that differ from acute infection, and it supports the development of specific therapies and biomarkers for patients suffering from long COVID.

Source: Wang K, Khoramjoo M, Srinivasan K, Gordon PMK, Mandal R, Jackson D, Sligl W, Grant MB, Penninger JM, Borchers CH, Wishart DS, Prasad V, Oudit GY. Sequential multi-omics analysis identifies clinical phenotypes and predictive biomarkers for long COVID. Cell Rep Med. 2023 Oct 18:101254. doi: 10.1016/j.xcrm.2023.101254. Epub ahead of print. PMID: 37890487. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(23)00431-7 (Full text)