Category: Overlapping Illnesses

Long-Term Impairment of Working Ability in Subjects under 60 Years of Age Hospitalised for COVID-19 at 2 Years of Follow-Up: A Cross-Sectional Study

Abstract:

Background: Coronavirus disease 2019 (COVID-19) can lead to persistent and debilitating symptoms referred to as Post-Acute sequelae of SARS-CoV-2 infection (PASC) This broad symptomatology lasts for months after the acute infection and impacts physical and mental health and everyday functioning. In the present study, we aimed to evaluate the prevalence and predictors of long-term impairment of working ability in non-elderly people hospitalised for COVID-19.

Methods: This cross-sectional study involved 322 subjects hospitalised for COVID-19 from 1 March 2020 to 31 December 2022 in the University Hospital of Bari, Apulia, Italy, enrolled at the time of their hospital discharge and followed-up at a median of 731 days since hospitalization (IQR 466-884). Subjects reporting comparable working ability and those reporting impaired working ability were compared using the Mann-Whitney test (continuous data) and Fisher’s test or Chi-Square test (categorical data). Multivariable analysis of impaired working ability was performed using a logistic regression model.

Results: Among the 322 subjects who were interviewed, 184 reported comparable working ability (57.1%) and 134 reported impaired working ability (41.6%) compared to the pre-COVID-19 period. Multivariable analysis identified age at hospital admission (OR 1.02, 95% CI 0.99 to 1.04), female sex (OR 1.90, 95% CI 1.18 to 3.08), diabetes (OR 3.73, 95% CI 1.57 to 9.65), receiving oxygen during hospital stay (OR 1.76, 95% CI 1.01 to 3.06), and severe disease (OR 0.51, 95% CI 0.26 to 1.01) as independent predictors of long-term impaired working ability after being hospitalised for COVID-19.

Conclusions: Our findings suggest that PASC promotes conditions that could result in decreased working ability and unemployment. These results highlight the significant impact of this syndrome on public health and the global economy, and the need to develop clinical pathways and guidelines for long-term care with specific focus on working impairment.

Source: Frallonardo L, Ritacco AI, Amendolara A, Cassano D, Manco Cesari G, Lugli A, Cormio M, De Filippis M, Romita G, Guido G, Piccolomo L, Giliberti V, Cavallin F, Segala FV, Di Gennaro F, Saracino A. Long-Term Impairment of Working Ability in Subjects under 60 Years of Age Hospitalised for COVID-19 at 2 Years of Follow-Up: A Cross-Sectional Study. Viruses. 2024 Apr 26;16(5):688. doi: 10.3390/v16050688. PMID: 38793570; PMCID: PMC11125725. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11125725/ (Full text)

Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome

Abstract:

A substantial number of patients recovering from acute SARS-CoV-2 infection present serious lingering symptoms, often referred to as long COVID (LC). However, a subset of these patients exhibits the most debilitating symptoms characterized by ongoing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS).

We specifically identified and studied ME/CFS patients from two independent LC cohorts, at least 12 months post the onset of acute disease, and compared them to the recovered group (R). ME/CFS patients had relatively increased neutrophils and monocytes but reduced lymphocytes. Selective T cell exhaustion with reduced naïve but increased terminal effector T cells was observed in these patients. LC was associated with elevated levels of plasma pro-inflammatory cytokines, chemokines, Galectin-9 (Gal-9), and artemin (ARTN). A defined threshold of Gal-9 and ARTN concentrations had a strong association with LC.

The expansion of immunosuppressive CD71+ erythroid cells (CECs) was noted. These cells may modulate the immune response and contribute to increased ARTN concentration, which correlated with pain and cognitive impairment. Serology revealed an elevation in a variety of autoantibodies in LC. Intriguingly, we found that the frequency of 2B4+CD160+ and TIM3+CD160+ CD8+ T cells completely separated LC patients from the R group.

Our further analyses using a multiple regression model revealed that the elevated frequency/levels of CD4 terminal effector, ARTN, CEC, Gal-9, CD8 terminal effector, and MCP1 but lower frequency/levels of TGF-β and MAIT cells can distinguish LC from the R group. Our findings provide a new paradigm in the pathogenesis of ME/CFS to identify strategies for its prevention and treatment.

Source: Saito S, Shahbaz S, Osman M, Redmond D, Bozorgmehr N, Rosychuk RJ, Lam G, Sligl W, Cohen Tervaert JW, Elahi S. Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome. J Autoimmun. 2024 May 25;147:103267. doi: 10.1016/j.jaut.2024.103267. Epub ahead of print. PMID: 38797051. https://www.sciencedirect.com/science/article/pii/S089684112400101X (Full text)

The long COVID evidence gap in England

Introduction:

The term long COVID, also known as post-COVID-19 condition, was coined in spring, 2020, by individuals with ongoing symptoms following COVID-19 in response to unsatisfactory recognition of this emerging syndrome by health-care practitioners.

In September to November, 2020, clinical codes for persistent post-COVID-19 condition and related referrals were introduced and became available for use by health-care practitioners to record details of clinical encounters in electronic health records (EHRs) in England. EHRs, which cover a large proportion of individuals living in England, are increasingly used to help understand the epidemiology of disease alongside the effectiveness and safety of interventions.
Many factors influence the completeness of information in EHRs, including help-seeking behaviour of patients and the discretion and data-recording behaviour of practitioners. Longitudinal population-based studies often include participant self-reports of illness; hence, these studies might be subject to reporting and participation biases. Comparing reported illness in studies to recorded illness in the EHRs of the same individuals might be helpful in understanding the epidemiology and clinical recognition of emerging conditions such as long COVID.
Source: Knuppel A, Boyd A, Macleod J, Chaturvedi N, Williams DM. The long COVID evidence gap in England. Lancet. 2024 May 6:S0140-6736(24)00744-X. doi: 10.1016/S0140-6736(24)00744-X. Epub ahead of print. PMID: 38729195. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)00744-X/fulltext (Full text)

Examining well-being and cognitive function in people with long Covid and ME/CFS, and age-matched healthy controls: A Case-Case-Control Study

Abstract:

Purpose: Well-being and cognitive function had not previously been compared between people with long COVID and people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Therefore, this study examined well-being and cognitive function in people with long COVID (∼16 months illness duration; n= 17) and ME/CFS (∼16 years illness duration; n=24), versus age-matched healthy controls (n=16).

Methods: Well-being was examined using several questionnaires, namely the Health Visual Analogue Scale (VAS), Fatigue Severity Scale (FSS), Post-exertional malaise (PEM), Pittsburgh Sleep Quality Index (PSQI), European Quality of Life-5 Domains (EQ-5D), MRC Dyspnoea, Self-Efficacy (SELTC), The Edinburgh Neurosymptoms Questionnaire (ENS), General Anxiety Disorder 7 (GAD-7), and Patient Health Questionnaire 9 (PHQ-9). Cognitive function was examined using Single Digit Modalities Test (SDMT), Stroop test, and Trails A and B. These were delivered via a mobile application (app) built specifically for this remote data collection.

Results: The main findings of the present investigation were that people with ME/CFS and people with long COVID were generally comparable on all well-being and cognitive function measures, but self-reported worse values for pain, fatigue, Post-exertional malaise, sleep quality, general well-being in relation to mobility, usual activities, self-care, breathlessness, neurological symptoms, self-efficacy, and other well-being such as anxiety and depression, compared to controls. There was no effect of group for cognitive function measures.

Conclusions: These data suggest that both people with long COVID and people with ME/CFS have similar impairment on well-being measures examined herein. Therefore, interventions that target well-being of people with ME/CFS and long COVID are required.

Source: Sanal-Hayes NEM, Mclaughlin M, Hayes LD, Berry ECJ, Sculthorpe NF. Examining well-being and cognitive function in people with long Covid and ME/CFS, and age-matched healthy controls: A Case-Case-Control Study. Am J Med. 2024 May 13:S0002-9343(24)00273-0. doi: 10.1016/j.amjmed.2024.04.041. Epub ahead of print. PMID: 38750713. https://www.amjmed.com/article/S0002-9343(24)00273-0/fulltext (Full text)

The Role of Heparin in Postural Orthostatic Tachycardia Syndrome and Other Post-Acute Sequelae of COVID-19

Abstract:

The therapeutic management and short-term consequences of the coronavirus disease 2019 (COVID-19) are well known. However, COVID-19 post-acute sequelae are less known and represent a public health problem worldwide. Patients with COVID-19 who present post-acute sequelae may display immune dysregulation, a procoagulant state, and persistent microvascular endotheliopathy that could trigger microvascular thrombosis. These elements have also been implicated in the physiopathology of postural orthostatic tachycardia syndrome, a frequent sequela in post-COVID-19 patients.
These mechanisms, directly associated with post-acute sequelae, might determine the thrombotic consequences of COVID-19 and the need for early anticoagulation therapy. In this context, heparin has several potential benefits, including immunomodulatory, anticoagulant, antiviral, pro-endothelial, and vascular effects, that could be helpful in the treatment of COVID-19 post-acute sequelae. In this article, we review the evidence surrounding the post-acute sequelae of COVID-19 and the potential benefits of the use of heparin, with a special focus on the treatment of postural orthostatic tachycardia syndrome.

Source: Gómez-Moyano E, Pavón-Morón J, Rodríguez-Capitán J, Bardán-Rebollar D, Ramos-Carrera T, Villalobos-Sánchez A, Pérez de Pedro I, Ruiz-García FJ, Mora-Robles J, López-Sampalo A, et al. The Role of Heparin in Postural Orthostatic Tachycardia Syndrome and Other Post-Acute Sequelae of COVID-19. Journal of Clinical Medicine. 2024; 13(8):2405. https://doi.org/10.3390/jcm13082405 https://www.mdpi.com/2077-0383/13/8/2405 (Full text)

An amyloidogenic fragment of the SARS CoV-2 envelope protein promotes serum amyloid A misfolding and fibrillization

Abstract:

SARS CoV-2 infection can affect a surprising number of organs in the body and cause symptoms such as abnormal blood coagulation, fibrinolytic disturbances, and neurodegeneration. Our study delves into the intricate pathogenic potential of a SARS-CoV-2 envelope protein peptide, shedding light on its implications for multi-organ effects and amyloid formation. Specifically, we focus on the peptide SK9 or 54SFYVYSRVK62 derived from the C-terminus of human SARS coronavirus 2 envelope protein.

We demonstrate that SK9 containing peptides readily form classic amyloid structures consistent with predictions of amyloid aggregation algorithms. In vivo, overexpression of proteases such as neutrophil elastase during inflammation can potentially lead to C-terminal peptides containing SK9. We also demonstrate that SK9 can promote the fibrillization of SAA, a protein marker of acute inflammation.

Our investigations reveal that the aromatic residues Phe2 and Tyr3 of SK9 play a pivotal role in its amyloidogenic function. We show that the primary sites of SK9-SAA binding lie in the amyloidogenic hotspots of SAA itself. Our results highlight two possible complications of SARS CoV-2 infection in individuals with hyper-inflammation either due to amyloids arising from SK9 containing peptides or SK9-induced AA amyloidosis.

Source: Asal Nady, Sean E. Reichheld, Simon Sharpe. An amyloidogenic fragment of the SARS CoV-2 envelope protein promotes serum amyloid A misfolding and fibrillization. bioRxiv 2024.04.25.591137; doi: https://doi.org/10.1101/2024.04.25.591137 https://www.biorxiv.org/content/10.1101/2024.04.25.591137v1.full (Full text)

Persistence of SARS-CoV-2 in Platelets and Megakaryocytes in Long COVID

Abstract:

Background: We have shown that acute COVID-19 pathophysiology is profoundly altered by infection of lung megakaryocytes (MKs) and platelets by SARS‑CoV‑2 (Zhu et al, 2022). A significant proportion of COVID-19 patients have symptoms persisting for > 3 months after initial infection with SARS-CoV-2, referred to as Long COVID or Post-acute Sequelae of SARS-CoV-2 (PASC) patients. Persistent or re-emerging symptoms are varied, with a predominance of asthenia, neuro-cognitive impairment and cardio-vascular symptoms. The pathophysiology underlying long-onset COVID remains poorly understood.

Methods: Blood was collected from patients with Long COVID with symptoms duration > 3 months (LC) (n=30), previously infected by SARS-CoV-2 but without persistent symptoms (resolved COVID-19 (CR), n=10), or healthy donor (n=20). MK frequency in blood was quantified by flow cytometry. Platelets and blood MKs were analysed for microclots, the presence of Spike protein and SARS-CoV-2 RNA by in situ hybridization and immunodetection visualized by confocal microscopy. Spike and serotonin were quantified in plasma.

Results: The frequency of CD41+ MKs in peripheral blood mononucleated cells (PBMCs) was significantly higher than healthy donors (0.28±0.05 versus 0.03±0.02) as a sign of MK infection, as we previously shown in acutely infected individuals with SARS-CoV-2 in platelets. Accordingly, in all samples analyzed, circulating MK in Long COVID sheltered both Spike and SARS-CoV-2 ssRNA, but also dsRNA suggestive of viral replication. These infected MKs produced blood platelets that contain also P Spike and SARS-CoV-2 ssRNA. Platelets microclots were detected in all tested Long COVID patients. Spike protein was detected at the pg level in 30 % of analyzed plasma from Long COVID but not CR individuals. The level of serotonin in platelet and of tryptophan hydroxylase-1 (TPH-1), the enzyme that regulates serotonin synthesis decreased significantly (p<0.0001) in blood of Long COVID patients compared to CR individuals.

Conclusions: In patients developing Long COVID, SARS-CoV-2 persists and replicates in MKs producing virus-containing platelets. The presence of spike in plasma might be an additional sign of viral persistence that could be used as a Long COVID biomarker. The presence of the virus could lead to abnormal platelet activation and the formation of microclots, which would contribute to the various symptoms and to deregulation of serotonin uptake, contributing to the neurocognitive symptoms observed in long-onset COVID.

Source: Feifan He, Boxin Huang, Andrea Cottignies-Calamarte, Wiem Bouchneb, Agathe Goubard, Faroudy Boufassa, Jacques Callebert, Dominique Salmon, Morgane Bomsel. Persistence of SARS-CoV-2 in Platelets and Megakaryocytes in Long COVID. The Conference on Retroviruses and Opportunistic Infections (CROI), March 3-6, 2024 | Denver, Colorado. https://www.croiconference.org/abstract/persistence-of-sars-cov-2-in-platelets-and-megakaryocytes-in-long-covid/ 

Cognitive profile in multiple sclerosis and post-COVID condition: a comparative study using a unified taxonomy

Abstract:

Post-COVID condition (PCC) and multiple sclerosis (MS) share some clinical and demographic features, including cognitive symptoms and fatigue. Some pathophysiological mechanisms well-known in MS, such as autoimmunity, neuroinflammation and myelin damage, have also been implicated in PCC. In this study, we aimed to compare the cognitive phenotypes of two large cohorts of patients with PCC and MS, and to evaluate the relationship between fatigue and cognitive performance.

Cross-sectional study including 218 patients with PCC and 218 with MS matched by age, sex, and years of education. Patients were evaluated with a comprehensive neuropsychological protocol and were categorized according to the International Classification of Cognitive Disorders system. Fatigue and depression were also assessed.

Cognitive profiles of PCC and MS largely overlapped, with a greater impairment in episodic memory in MS, but with small effect sizes. The most salient deficits in both disorders were in attention and processing speed. The severity of fatigue was greater in patients with PCC. Still, the correlations between fatigue severity and neuropsychological tests were more prominent in the case of MS. There were no differences in the severity of depression among groups. Our study found similar cognitive profiles in PCC and MS. Fatigue was more severe in PCC, but was more associated with cognitive performance in MS. Further comparative studies addressing the mechanisms related to cognitive dysfunction and fatigue may be of interest to advance the knowledge of these disorders and develop new therapies.

Source: Delgado-Alonso C, Delgado-Alvarez A, Díez-Cirarda M, Oliver-Mas S, Cuevas C, Montero-Escribano P, Ramos-Leví AM, Gil-Moreno MJ, López-Carbonero JI, Hermann BP, Matias-Guiu J, Matias-Guiu JA. Cognitive profile in multiple sclerosis and post-COVID condition: a comparative study using a unified taxonomy. Sci Rep. 2024 Apr 29;14(1):9806. doi: 10.1038/s41598-024-60368-0. PMID: 38684843; PMCID: PMC11059260. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11059260/ (Full text)

PASC (Post Acute Sequelae of COVID-19) is associated with decreased neutralizing antibody titers in both biological sexes and increased ANG-2 and GM-CSF in females

Abstract:

Post-acute sequelae of COVID-19 (PASC) or the continuation of COVID-19 (Coronavirus disease 2019) symptoms past 12 weeks may affect as many as 30% of people recovering from a SARS-CoV-2 (severe acute respiratory coronavirus 2) infection. The mechanisms regulating the development of PASC are currently not known; however, hypotheses include virus reservoirs, pre-existing conditions, microblood clots, immune dysregulation, as well as poor antibody responses. Importantly, virus neutralizing antibodies are essential for COVID-19 recovery and protection from reinfection but there is currently limited information on these immune regulators and associated cytokines in PASC patients. Understanding the key drivers of general and specific symptoms associated with Long COVID and the presence of virus neutralizing antibodies in PASC will aid in the development of therapeutics, diagnostics, and vaccines which currently do not exist.

We designed a cross-sectional study to investigate systemic antibody and cytokine responses during COVID-19 recovery and PASC. In total, 195 participants were recruited in one of four groups: (1) Those who never had COVID-19 (No COVID); (2) Those in acute COVID-19 recovery (Acute Recovery) (4–12 weeks post infection); (3) Those who recovered from COVID-19 (Recovered) (+ 12 weeks from infection); and (4) those who had PASC (PASC) (+ 12 weeks from infection). Participants completed a questionnaire on health history, sex, gender, demographics, experiences with COVID-19 acute and COVID-19 recovery/continuing symptoms. Serum samples collected were evaluated for antibody binding to viral proteins, virus neutralizing antibody titers, and serum cytokine levels using Ella SimplePlex Immunoassay™ panels.

We found participants with PASC reported more pre-existing conditions (e.g. such as hypertension, asthma, and obesity), and PASC symptoms (e.g. fatigue, brain fog, headaches, and shortness of breath) following COVID-19 than COVID-19 Recovered individuals. Importantly, we found PASC individuals to have significantly decreased levels of neutralizing antibodies toward both SARS-CoV-2 and the Omicron BA.1 variant. Sex analysis indicated that female PASC study participants had sustained antibody levels as well as levels of the inflammatory cytokines GM-CSF and ANG-2 over time following COVID-19.

Our study reports people experiencing PASC had lower levels of virus neutralizing antibodies; however, the results are limited by the collection time post-COVID-19 and post-vaccination. Moreover, we found females experiencing PASC had sustained levels of GM-CSF and ANG-2. With lower levels of virus neutralizing antibodies, this data suggests that PASC individuals not only have had a suboptimal antibody response during acute SARS-CoV-2 infection but may also have increased susceptibility to subsequent infections which may exacerbate or prolong current PASC illnesses. We also provide evidence suggesting GM-CSF and ANG-2 to play a role in the sex-bias of PASC. Taken together, our findings maybe important for understanding immune molecular drivers of PASC and PASC subgroups.

Source: Jansen EB, Ostadgavahi AT, Hewins B, Buchanan R, Thivierge BM, Sganzerla Martinez G, Goncin U, Francis ME, Swan CL, Scruten E, Bell J, Darbellay J, Facciuolo A, Falzarano D, Gerdts V, Fenton ME, Hedlin P, Kelvin DJ, Kelvin AA. PASC (Post Acute Sequelae of COVID-19) is associated with decreased neutralizing antibody titers in both biological sexes and increased ANG-2 and GM-CSF in females. Sci Rep. 2024 Apr 29;14(1):9854. doi: 10.1038/s41598-024-60089-4. PMID: 38684819; PMCID: PMC11058778. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11058778/ (Full text)

Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection

Abstract:

Crimean-Congo hemorrhagic fever (CCHF) caused by CCHF virus (CCHFV) is one of the epidemic-prone diseases prioritized by the World Health Organisation as public health emergency with an urgent need for accelerated research. The trajectory of host response against CCHFV is multifarious and remains unknown. Here, we reported the temporal spectrum of pathogenesis following the CCHFV infection using genome-wide blood transcriptomics analysis followed by advanced systems biology analysis, temporal immune-pathogenic alterations, and context-specific progressive and postinfection genome-scale metabolic models (GSMM) on samples collected during the acute (T0), early convalescent (T1), and convalescent-phase (T2).

The interplay between the retinoic acid-inducible gene-I-like/nucleotide-binding oligomerization domain-like receptor and tumor necrosis factor signaling governed the trajectory of antiviral immune responses. The rearrangement of intracellular metabolic fluxes toward the amino acid metabolism and metabolic shift toward oxidative phosphorylation and fatty acid oxidation during acute CCHFV infection determine the pathogenicity. The upregulation of the tricarboxylic acid cycle during CCHFV infection, compared to the noninfected healthy control and between the severity groups, indicated an increased energy demand and cellular stress. The upregulation of glycolysis and pyruvate metabolism potentiated energy generation through alternative pathways associated with the severity of the infection.

The downregulation of metabolic processes at the convalescent phase identified by blood cell transcriptomics and single-cell type proteomics of five immune cells (CD4+ and CD8+ T cells, CD14+ monocytes, B cells, and NK cells) potentially leads to metabolic rewiring through the recovery due to hyperactivity during the acute phase leading to post-viral fatigue syndrome.

Source: Ambikan AT, Elaldi N, Svensson-Akusjärvi S, Bagci B, Pektas AN, Hewson R, Bagci G, Arasli M, Appelberg S, Mardinoglu A, Sood V, Végvári Á, Benfeitas R, Gupta S, Cetin I, Mirazimi A, Neogi U. Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection. Proc Natl Acad Sci U S A. 2023 Sep 12;120(37):e2304722120. doi: 10.1073/pnas.2304722120. Epub 2023 Sep 5. PMID: 37669378; PMCID: PMC10500270. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10500270/ (Full text)