Tag: covid-19

From COVID-19 to long COVID; the forms of the neurological manifestations

Abstract:

Ever since the SARS-CoV-2 infection was declared a global pandemic in 2020, numerous multisystemic manifestations have been discovered. The COVID-19 is known to cause a wide spectrum of neurological symptoms like fatigue, headache, brain fog, stroke, smell and taste disorders, encephalopathy and neurodegenerative disorders. The neurological manifestations are more prevalent in the post-COVID syndrome or long COVID. The National Institute for Health and Care Excellence and WHO defined Ongoing Symptomatic COVID as 4-12 weeks post infection and post COVID-19 syndrome as persistence of symptoms beyond 12 weeks.

So far there are limited data available regarding the pathophysiology of neurological symptoms of prolonged COVID, although neuroinflammation and oxidative damage have been implicated. In this review article, we have highlighted the transition from COVID to long-term COVID, focusing the discussion particularly on neurological complications.

Source: Ahuja, Sana and Zaheer, Sufian (2023) “From COVID-19 to long COVID; the forms of the neurological manifestations,” Journal of Mind and Medical Sciences: Vol. 10: Iss. 2, Article 5.
DOI: https://doi.org/10.22543/2392-7674.1403
Download available at: https://scholar.valpo.edu/jmms/vol10/iss2/5

Treatment of 95 post-Covid patients with SSRIs

Abstract:

After Covid-19 infection, 12.5% develops post-Covid-syndrome (PCS). Symptoms indicate numerous affected organ systems. After a year, chronic fatigue, dysautonomia and neurological and neuropsychiatric complaints predominate. In this study, 95 PCS patients were treated with selective serotonin reuptake inhibitors (SSRIs). This study used an exploratory questionnaire and found that two-thirds of patients had a reasonably good to strong response on SSRIs, over a quarter of patients had moderate response, while 10% reported no response.

Overall, patients experienced substantial improved well-being. Brainfog and sensory overload decreased most, followed by chronic fatigue and dysautonomia. Outcomes were measured with three different measures that correlated strongly with each other. The response to SSRIs in PCS conditions was explained by seven possible neurobiological mechanisms based on recent literature on PCS integrated with already existing knowledge.

Important for understanding these mechanisms is the underlying biochemical interaction between various neurotransmitter systems and parts of the immune system, and their dysregulation in PCS. The main link appears to be with the metabolic kynurenine pathway (KP) which interacts extensively with the immune system. The KP uses the same precursor as serotonin: tryptophan. The KP is overactive in PCS which maintains inflammation and which causes a lack of tryptophan. Finally, potential avenues for future research to advance this line of clinical research are discussed.

Source: Rus CP, de Vries BEK, de Vries IEJ, Nutma I, Kooij JJS. Treatment of 95 post-Covid patients with SSRIs. Sci Rep. 2023 Nov 2;13(1):18599. doi: 10.1038/s41598-023-45072-9. PMID: 37919310; PMCID: PMC10622561. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10622561/ (Full text)

Characterization of neurocognitive deficits in patients with post-COVID-19 syndrome: persistence, patients’ complaints, and clinical predictors.

Abstract:

Introduction: Cognitive symptoms persisting beyond 3 months following COVID-19 present a considerable disease burden. We aimed to establish a domain-specific cognitive profile of post-COVID-19 syndrome (PCS). We examined the deficits’ persistence, relationships with subjective cognitive complaints, and clinical variables, to identify the most relevant cognitive deficits and their predictors.

Methods: This cross-sectional study examined cognitive performance and patient-reported and clinical predictors of cognitive deficits in PCS patients (n = 282) and socio-demographically comparable healthy controls (n = 52).

Results: On the Oxford Cognitive Screen-Plus, the patient group scored significantly lower in delayed verbal memory, attention, and executive functioning than the healthy group. In each affected domain, 10 to 20% of patients performed more than 1.5 SD below the control mean. Delayed memory was particularly affected, with a small effect of hospitalization and age. Attention scores were predicted by hospitalization and fatigue.

Discussion: Thus, PCS is associated with long-term cognitive dysfunction, particularly in delayed memory, attention, and executive functioning. Memory deficits seem to be of particular relevance to patients’ experience of subjective impairment. Hospitalization, fatigue, and age seem to predict cognitive deficits, while time since infection, depression, and pre-existing conditions do not.

Source: Kozik V, Reuken P, Utech I, Gramlich J, Stallmach Z, Demeyere N, Rakers F, Schwab M, Stallmach A, Finke K. Characterization of neurocognitive deficits in patients with post-COVID-19 syndrome: persistence, patients’ complaints, and clinical predictors. Front Psychol. 2023 Oct 17;14:1233144. doi: 10.3389/fpsyg.2023.1233144. PMID: 37915528; PMCID: PMC10616256. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10616256/ (Full text)

Children and Young People with Long COVID—Comparing Those Seen in Post-COVID Services with a Non-Hospitalised National Cohort: A Descriptive Study

Abstract:

Background: Post-COVID services have been set up in England to treat children with ongoing symptoms of Long COVID. To date, the characteristics of children seeking treatment from these services has not been described.
Purpose: (1) to describe the characteristics of children aged 11–17 referred to the Pan-London Post-COVID service and (2) to compare characteristics of these children with those taking part in the United Kingdom’s largest research study of Long COVID in children (CLoCk).
Design: Data from 95 children seeking treatment from the Post-COVID service between May 2021 and August 2022 were included in the study. Their demographic characteristics, symptom burden and the impact of infection are described and compared to children from CLoCk.
Results: A high proportion of children from the Post-COVID service and CLoCk reported experiencing health problems prior to the pandemic. Almost all Post-COVID service children met the research Delphi definition of Long COVID (94.6%), having multiple symptoms that impacted their lives. Symptoms were notably more severe than the participants in CLoCk.
Conclusions: This study describes the characteristics of children seeking treatment for Long COVID compared to those identified in the largest longitudinal observational study to date. Post-COVID service children have more symptoms and are more severely affected by their symptoms following infection with COVID-19 than children in the CLoCk study. Research to understand predisposing factors for severity and prognostic indicators is essential to prevent this debilitating condition. Evaluation of short- and long-term outcomes of interventions by clinical services can help direct future therapy for this group.
Source: Newlands F, Goddings A-L, Juste M, Boyd H, Nugawela MD, Pinto Pereira SM, Whelan E, Whittaker E, Stephenson T, Heyman I, et al. Children and Young People with Long COVID—Comparing Those Seen in Post-COVID Services with a Non-Hospitalised National Cohort: A Descriptive Study. Children. 2023; 10(11):1750. https://doi.org/10.3390/children10111750 https://www.mdpi.com/2227-9067/10/11/1750 (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)

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)

Senolytic drugs: from discovery to translation

Abstract:

Senolytics are a class of drugs that selectively clear senescent cells (SC). The first senolytic drugs Dasatinib, Quercetin, Fisetin and Navitoclax were discovered using a hypothesis-driven approach.

SC accumulate with ageing and at causal sites of multiple chronic disorders, including diseases accounting for the bulk of morbidity, mortality and health expenditures. The most deleterious SC are resistant to apoptosis and have up-regulation of anti-apoptotic pathways which defend SC against their own inflammatory senescence-associated secretory phenotype (SASP), allowing them to survive, despite killing neighbouring cells. Senolytics transiently disable these SCAPs, causing apoptosis of those SC with a tissue-destructive SASP.

Because SC take weeks to reaccumulate, senolytics can be administered intermittently – a ‘hit-and-run’ approach. In preclinical models, senolytics delay, prevent or alleviate frailty, cancers and cardiovascular, neuropsychiatric, liver, kidney, musculoskeletal, lung, eye, haematological, metabolic and skin disorders as well as complications of organ transplantation, radiation and cancer treatment.

As anticipated for agents targeting the fundamental ageing mechanisms that are ‘root cause’ contributors to multiple disorders, potential uses of senolytics are protean, potentially alleviating over 40 conditions in preclinical studies, opening a new route for treating age-related dysfunction and diseases. Early pilot trials of senolytics suggest they decrease senescent cells, reduce inflammation and alleviate frailty in humans.

Clinical trials for diabetes, idiopathic pulmonary fibrosis, Alzheimer’s disease, COVID-19, osteoarthritis, osteoporosis, eye diseases and bone marrow transplant and childhood cancer survivors are underway or beginning. Until such studies are done, it is too early for senolytics to be used outside of clinical trials.

Source: Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020 Nov;288(5):518-536. doi: 10.1111/joim.13141. Epub 2020 Aug 4. PMID: 32686219; PMCID: PMC7405395. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395/ (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)