Tag: covid-19

ACE-2-like enzymatic activity is associated with immunoglobulin in COVID-19 patients

Abstract:

Many mechanisms responsible for COVID-19 pathogenesis are well-established, but COVID-19 includes features with unclear pathogenesis, such as autonomic dysregulation, coagulopathies, and high levels of inflammation. The receptor for the SARS-CoV-2 spike protein receptor-binding domain (RBD) is angiotensin-converting enzyme 2 (ACE2). We hypothesized that some COVID-19 patients may develop antibodies that have a negative molecular image of RBD sufficiently similar to ACE2 to yield ACE2-like catalytic activity-ACE2-like abzymes.

To explore this hypothesis, we studied patients hospitalized with COVID-19 who had plasma samples available obtained about 7 days after admission. ACE2 is a metalloprotease that requires Zn2+ for activity. However, we found that the plasma from some patients studied could specifically cleave a synthetic ACE2 peptide substrate, even though the plasma samples were collected using disodium EDTA anticoagulant. When we spiked plasma with synthetic ACE2, no ACE2 substrate cleavage activity was observed unless Zn2+ was added or the plasma was diluted to decrease EDTA concentration.

After processing samples by 100 kDa size exclusion columns and protein A/G adsorption, which depleted immunoglobulin by >99.99%, the plasma samples did not cleave the ACE2 substrate peptide. The data suggest that some patients with COVID-19 develop antibodies with abzyme-like activity capable of cleaving synthetic ACE2 substrate. Since abzymes can exhibit promiscuous substrate specificities compared to the enzyme whose active site image they resemble, and since proteolytic cascades regulate many physiologic processes, anti-RBD abzymes may contribute to some otherwise obscure COVID-19 pathogenesis.

Importance: We provide what we believe to be the first description of angiotensin-converting enzyme 2 (ACE2)-like enzymatic activity associated with immunoglobulin in COVID-19 patients. COVID-19 includes many puzzling clinical features that have unclear pathogenesis, including a hyperinflammatory state, abnormalities of the clotting cascade, and blood pressure instability.

We hypothesized that some patients with COVID-19 patients may produce antibodies against SARS-CoV-2 with enzymatic activity, or abzymes, that target important proteolytic regulatory cascades. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein binds ACE2 on the surface of the future host cell. This means that the RBD has a negative molecular image of ACE2.

We hypothesized that some antibodies produced against the RBD would have, in turn, a negative molecular image of the RBD sufficiently similar to ACE2 to have ACE2-like catalytic activity. In other words, some anti-RBD antibodies would be ACE2-like abzymes. Abzymes elicited by SARS-CoV-2 infection have the potential to affect host physiology.

Source: Song Y, Myers R, Mehl F, Murphy L, Brooks B, Wilson JM, Kadl A, Woodfolk J, Zeichner SL. ACE-2-like enzymatic activity is associated with immunoglobulin in COVID-19 patients. mBio. 2024 Mar 19:e0054124. doi: 10.1128/mbio.00541-24. Epub ahead of print. PMID: 38501835. https://journals.asm.org/doi/10.1128/mbio.00541-24 (Full text)

Bulk RNA sequencing for analysis of post COVID-19 condition in adolescents and young adults

Abstract:

Background: Post COVID-19 condition (PCC) is a complication of SARS-COV-2 infection and can lead to long-term disability.

Methods: The present study was designed to analyse the gene expression patterns of PCC through bulk RNA sequencing of whole blood and to explore the potential molecular mechanisms of PCC. Whole blood was collected from 80 participants enrolled in a prospective cohort study following SARS-CoV-2 infected and non-infected individuals for 6 months after recruitment and was used for bulk RNA sequencing. Identification of differentially expressed genes (DEG), pathway enrichment and immune cell deconvolution was performed to explore potential biological pathways involved in PCC.

Results: We have found 13 differentially expressed genes associated with PCC. Enriched pathways were related to interferon-signalling and anti-viral immune processes.

Conclusion: The PCC transcriptome is characterized by a modest overexpression of interferon-stimulated genes, pointing to a subtle ongoing inflammatory response.

Source: Sommen SL, Zhao Z, Segtnan S, Stiansen-Sonerud T, Selvakumar J, Beier Havdal L, Gjerstad J, Wyller VBB, Lund Berven L. Bulk RNA sequencing for analysis of post COVID-19 condition in adolescents and young adults. J Transl Med. 2024 Mar 26;22(1):312. doi: 10.1186/s12967-024-05117-7. PMID: 38532465. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05117-7 (Full text)

SARS-CoV2 evokes structural brain changes resulting in declined executive function

Abstract:

Background: Several research has underlined the multi-system character of COVID-19. Though effects on the Central Nervous System are mainly discussed as disease-specific affections due to the virus’ neurotropism, no comprehensive disease model of COVID-19 exists on a neurofunctional base by now. We aimed to investigate neuroplastic grey- and white matter changes related to COVID-19 and to link these changes to neurocognitive testings leading towards a multi-dimensional disease model.

Methods: Groups of acutely ill COVID-19 patients (n = 16), recovered COVID-19 patients (n = 21) and healthy controls (n = 13) were prospectively included into this study. MR-imaging included T1-weighted sequences for analysis of grey matter using voxel-based morphometry and diffusion-weighted sequences to investigate white matter tracts using probabilistic tractography. Comprehensive neurocognitive testing for verbal and non-verbal domains was performed.

Results: Alterations strongly focused on grey matter of the frontal-basal ganglia-thalamus network and temporal areas, as well as fiber tracts connecting these areas. In acute COVID-19 patients, a decline of grey matter volume was found with an accompanying diminution of white matter tracts. A decline in executive function and especially verbal fluency was found in acute patients, partially persisting in recovered.

Conclusion: Changes in gray matter volume and white matter tracts included mainly areas involved in networks of executive control and language. Deeper understanding of these alterations is necessary especially with respect to long-term impairments, often referred to as ‘Post-COVID’.

Source: Deuter D, Hense K, Kunkel K, Vollmayr J, Schachinger S, Wendl C, Schicho A, Fellner C, Salzberger B, Hitzenbichler F, Zeller J, Vielsmeier V, Dodoo-Schittko F, Schmidt NO, Rosengarth K. SARS-CoV2 evokes structural brain changes resulting in declined executive function. PLoS One. 2024 Mar 12;19(3):e0298837. doi: 10.1371/journal.pone.0298837. PMID: 38470899; PMCID: PMC10931481. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10931481/ (Full text)

Role of the complement system in Long COVID

Abstract:

Long COVID, or Post-Acute COVID Syndrome (PACS), may develop following SARS-CoV-2 infection, posing a substantial burden to society. Recently, PACS has been linked to a persistent activation of the complement system (CS), offering hope for both a diagnostic tool and targeted therapy. However, our findings indicate that, after adjusting proteomics data for age, body mass index and sex imbalances, the evidence of complement system activation disappears.

Furthermore, proteomic analysis of two orthogonal cohorts—one addressing PACS following severe acute phase and another after a mild acute phase—fails to support the notion of persistent CS activation. Instead, we identify a proteomic signature indicative of either ongoing infections or sustained immune activation similar to that observed in acute COVID-19, particularly within the mild-PACS cohort.

Source: Vadim Farztdinov, Boris Zühlke, Franziska Sotzny, Fridolin Steinbeis, Martina Seifert, Claudia Kedor, Kirsten Wittke, Pinkus Tober-Lau, Thomas Zoller, Kathrin Textoris-Taube, Daniela Ludwig, Clemens Dierks, Dominik Bierbaum, Leif Erik Sander, Leif G Hanitsch, Martin Witzenrath, Florian Kurth, Michael Mülleder, Carmen Scheibenbogen, Markus Ralser. Role of the complement system in Long COVID. medRxiv 2024.03.14.24304224; doi: https://doi.org/10.1101/2024.03.14.24304224 https://www.medrxiv.org/content/10.1101/2024.03.14.24304224v1.full-text (Full text)

An exploration of the experiences and self-generated strategies used when navigating everyday life with Long Covid

Abstract:

Background: Around one in ten people who contract Covid-19 report ongoing symptoms or ‘Long Covid’. Without any known interventions to cure the condition, forms of self-management are routinely prescribed by healthcare professionals and described by people with the condition. However, there is limited research exploring what strategies are used to navigate everyday life with Long Covid, and experiences that initiate development of these strategies. Our study aimed to explore the range and influence of self-generated strategies used by people with Long Covid to navigate everyday life within the context of their own condition.

Methods: Forming part of the Long Covid Personalised Self-managemenT support co-design and EvaluatioN (LISTEN) project, we conducted a qualitative study using narrative interviews with adults who were not hospitalised with Covid-19. Participants aged over 18 years, who self-identified with Long Covid, were recruited from England and Wales. Data were analysed with patient contributors using a reflexive thematic analysis.

Results: Eighteen participants (mean age = 44 years, SD = 13 years) took part in interviews held between December 2021 and February 2022. Themes were constructed which depicted 1) the landscape behind the Long Covid experience and 2) the everyday experience of participants’ Long Covid. The everyday experience comprised a combination of physical, emotional, and social factors, forming three sub-themes: centrality of physical symptoms, navigating ‘experts’ and the ‘true colour’ of personal communities, and a rollercoaster of psychological ambiguity). The third theme, personal strategies to manage everyday life was constructed from participants’ unique presentations and self-generated solutions to manage everyday life. This comprised five sub-themes: seeking reassurance and knowledge, developing greater self-awareness through monitoring, trial and error of ‘safe’ ideas, building in pleasure and comfort, and prioritising ‘me’.

Conclusions: Among this sample of adults with Long Covid, their experiences highlighted the unpredictable nature of the condition but also the use of creative and wide ranging self-generated strategies. The results offer people with Long Covid, and healthcare professionals supporting them, an overview of the collective evidence relating to individuals’ self-management which can enable ways to live ‘better’ and regain some sense of identity whilst facing the impact of a debilitating, episodic condition.

Trial registration: LISTEN ISRCTN36407216.

Source: Leggat FJ, Heaton-Shrestha C, Fish J, Siriwardena AN, Domeney A, Rowe C, Patel I, Parsons J, Blair J, Jones F. An exploration of the experiences and self-generated strategies used when navigating everyday life with Long Covid. BMC Public Health. 2024 Mar 13;24(1):789. doi: 10.1186/s12889-024-18267-6. PMID: 38481230; PMCID: PMC10938753. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10938753/ (Full text)

Comparison of the muscle oxygenation during submaximal and maximal exercise tests in patients post-coronavirus disease 2019 syndrome with pulmonary involvement

Abstract:

Introduction: Pulmonary involvement is prevalent in patients with coronavirus disease 2019 (COVID-19). Arterial hypoxemia may reduce oxygen transferred to the skeletal muscles, possibly leading to impaired exercise capacity. Oxygen uptake may vary depending on the increased oxygen demand of the muscles during submaximal and maximal exercise.

Objective: This study aimed to compare muscle oxygenation during submaximal and maximal exercise tests in patients with post-COVID-19 syndrome with pulmonary involvement.

Methods: Thirty-nine patients were included. Pulmonary function (spirometry), peripheral muscle strength (dynamometer), quadriceps femoris (QF) muscle oxygenation (Moxy® device), and submaximal exercise capacity (six-minute walk test (6-MWT)) were tested on the first day, maximal exercise capacity (cardiopulmonary exercise test (CPET)) was tested on the second day. Physical activity level was evaluated using an activity monitor worn for five consecutive days. Cardiopulmonary responses and muscle oxygenation were compared during 6-MWT and CPET.

Results: Patients’ minimum and recovery muscle oxygen saturation were significantly decreased; maximum total hemoglobin increased, heart rate, blood pressure, breathing frequency, dyspnea, fatigue, and leg fatigue at the end-of-test and recovery increased in CPET compared to 6-MWT (p < .050). Peak oxygen consumption (VO2peak) was 18.15 ± 4.75 ml/min/kg, VO2peak; percent predicted < 80% was measured in 51.28% patients. Six-MWT distance and QF muscle strength were less than 80% predicted in 58.9% and 76.9% patients, respectively.

Conclusions: In patients with post-COVID-19 syndrome with pulmonary involvement, muscle deoxygenation of QF is greater during maximal exercise than during submaximal exercise. Specifically, patients with lung impairment should be evaluated for deoxygenation and should be taken into consideration during pulmonary rehabilitation.

Source: Kavalcı Kol B, Boşnak Güçlü M, Baytok E, Yılmaz Demirci N. Comparison of the muscle oxygenation during submaximal and maximal exercise tests in patients post-coronavirus disease 2019 syndrome with pulmonary involvement. Physiother Theory Pract. 2024 Mar 12:1-14. doi: 10.1080/09593985.2024.2327534. Epub ahead of print. PMID: 38469863. https://pubmed.ncbi.nlm.nih.gov/38469863/

Impaired Sleep in Patients with Post-COVID-19 Syndrome Compared to Healthy Controls: A Cross-Sectional Trial

Abstract:

Introduction: To objectify self-reported sleep disorders in individuals with post-COVID-syndrome (PCS), we aimed to investigate the prevalence and nature of sleep disturbances by polysomnography (PSG) in PCS compared to healthy individuals.

Methods: People with PCS (n = 21) and healthy controls (CON, n = 10) were included in this prospective trial. At baseline, clinical and social anamnesis, lung function, 1 min sit-to-stand test (STST) and Pittsburgh Sleep Quality Index (PSQI) were assessed. For a single-night, sleep health was evaluated by video-PSG. The apnoea/hypopnea index (AHI) was used as the primary outcome.

Results: Twenty patients with PCS (50 ± 11 y, BMI 27.1 m2/kg, SARS-CoV-2 infection 8.5 ± 4.5 months ago) and 10 CON participants (46 ± 10 y, BMI 23.0 m2/kg, no SARS-CoV-2 infection in the history) completed the study. Forced vital capacity (p = 0.018), STST repetitions (p &lt; 0.001), and symptoms of dyspnoea (at rest: p = 0.002, exertion: p &lt; 0.001) were worse in PCS compared to CON. PSQI score (PCS: 7.5 ± 4.7 points) was higher in PCS compared to CON (Δ = 3.7 points, 95% CI [0.4-7.1] p = 0.015), indicating poor sleep in 80% of patients with PCS. Although PSG showed comparable sleep stage distributions in both groups, AHI (Δ = 9.0 n/h, 95% CI [3.3-14.8], p = 0.002), PLM index (Δ = 5.1 n/h, 95% CI [0.4-9.8], p = 0.017), and the prevalence of sleep apnoea (60% vs. 10%, p = 0.028) was significantly higher in PCS compared to CON.

Conclusion: Quantifiable subjective limitations of sleep have been revealed by PSG data in this PCS cohort. More than half of PCS patients had signs of sleep apnoea, highlighting the importance of sleep screening in PCS.

Source: Jarosch I, Schneeberger T, Stegemann A, Gloeckl R, Leitl D, Dennis C, Hitzl W, Schoen C, Koczulla AR. Impaired Sleep in Patients with Post-COVID-19 Syndrome Compared to Healthy Controls: A Cross-Sectional Trial. Respiration. 2024 Mar 1:1-5. doi: 10.1159/000536272. Epub ahead of print. PMID: 38432219. https://karger.com/res/article/doi/10.1159/000536272/896169/Impaired-Sleep-in-Patients-with-Post-COVID-19 (Full text)

Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19

Abstract:

Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one year from COVID-19 symptom onset to determine the early correlates of PASC.

A multivariate signature detected beyond two weeks of disease, encompassing unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression and emerging stress erythropoiesis; differentiated those who reported PASC months later, irrespective of COVID-19 severity. A whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1-3 post onset, coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis reported iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes.

Thus, defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction due to COVID-19 possibly contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology, and may be therapeutically tractable.

Source: Hanson AL, Mulè MP, Ruffieux H, Mescia F, Bergamaschi L, Pelly VS, Turner L, Kotagiri P; Cambridge Institute of Therapeutic Immunology and Infectious Disease–National Institute for Health Research (CITIID–NIHR) COVID BioResource Collaboration; Göttgens B, Hess C, Gleadall N, Bradley JR, Nathan JA, Lyons PA, Drakesmith H, Smith KGC. Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19. Nat Immunol. 2024 Mar;25(3):471-482. doi: 10.1038/s41590-024-01754-8. Epub 2024 Mar 1. PMID: 38429458; PMCID: PMC10907301. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10907301/ (Full text)

Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment

Abstract:

Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood–brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog.

Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog.

Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers.

Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.

Source: Greene C, Connolly R, Brennan D, Laffan A, O’Keeffe E, Zaporojan L, O’Callaghan J, Thomson B, Connolly E, Argue R, Martin-Loeches I, Long A, Cheallaigh CN, Conlon N, Doherty CP, Campbell M. Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci. 2024 Mar;27(3):421-432. doi: 10.1038/s41593-024-01576-9. Epub 2024 Feb 22. PMID: 38388736; PMCID: PMC10917679. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917679/ (Full text)

What is the impact of long-term COVID-19 on workers in healthcare settings? A rapid systematic review of current evidence

Abstract:

Background: Long COVID is a devastating, long-term, debilitating illness which disproportionately affects healthcare workers, due to the nature of their work. There is currently limited evidence specific to healthcare workers about the experience of living with Long COVID, or its prevalence, pattern of recovery or impact on healthcare.

Objective: Our objective was to assess the effects of Long COVID among healthcare workers and its impact on health status, working lives, personal circumstances, and use of health service resources.

Methods: We conducted a systematic rapid review according to current methodological standards and reported it in adherence to the PRISMA 2020 and ENTREQ statements.

Results: We searched relevant electronic databases and identified 3770 articles of which two studies providing qualitative evidence and 28 survey studies providing quantitative evidence were eligible. Thematic analysis of the two qualitative studies identified five themes: uncertainty about symptoms, difficulty accessing services, importance of being listened to and supported, patient versus professional identity and suggestions to improve communication and services for people with Long COVID. Common long-term symptoms in the survey studies included fatigue, headache, loss of taste and/or smell, breathlessness, dyspnoea, difficulty concentrating, depression and anxiety.

Conclusion: Healthcare workers struggled with their dual identity (patient/doctor) and felt dismissed or not taken seriously by their doctors. Our findings are in line with those in the literature showing that there are barriers to healthcare professionals accessing healthcare and highlighting the challenges of receiving care due to their professional role. A more representative approach in Long COVID research is needed to reflect the diverse nature of healthcare staff and their occupations. This rapid review was conducted using robust methods with the codicil that the pace of research into Long COVID may mean relevant evidence was not identified.

Source: Cruickshank M, Brazzelli M, Manson P, Torrance N, Grant A. What is the impact of long-term COVID-19 on workers in healthcare settings? A rapid systematic review of current evidence. PLoS One. 2024 Mar 5;19(3):e0299743. doi: 10.1371/journal.pone.0299743. PMID: 38442116; PMCID: PMC10914278. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10914278/ (Full text)