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      Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19

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          Abstract

          The role of adaptive SARS-CoV-2 specific immunity in post-acute sequelae of COVID-19 (PASC) is not well explored, although a growing population of convalescent COVID-19 patients with manifestation of PASC is observed. We analyzed the SARS-CoV-2-specific immune response, via pseudovirus neutralizing assay and multiparametric flow cytometry in 40 post-acute sequelae of COVID-19 patients with non-specific PASC manifestation and 15 COVID-19 convalescent healthy donors. Although frequencies of SARS-CoV-2-reactive CD4+ T cells were similar between the studied cohorts, a stronger SARS-CoV-2 reactive CD8+ T cell response, characterized by IFN γ production and predominant T EMRA phenotype but low functional TCR avidity was detected in PASC patients compared to controls. Of interest, high avidity SARS-CoV-2-reactive CD4+ and CD8+ T cells were comparable between the groups demonstrating sufficient cellular antiviral response in PASC. In line with the cellular immunity, neutralizing capacity in PASC patients was not inferior compared to controls. In conclusion, our data suggest that PASC may be driven by an inflammatory response triggered by an expanded population of low avidity SARS-CoV-2 reactive pro-inflammatory CD8+ T cells. These pro-inflammatory T cells with TEMRA phenotype are known to be activated by a low or even without TCR stimulation and lead to a tissue damage. Further studies including animal models are required for a better understanding of underlying immunopathogensis. Summary: A CD8+ driven persistent inflammatory response triggered by SARS-CoV-2 may be responsible for the observed sequelae in PASC patients.

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          Most cited references53

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          Post-acute COVID-19 syndrome

          Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.
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            Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection

            Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
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              Characterizing long COVID in an international cohort: 7 months of symptoms and their impact

              Background A significant number of patients with COVID-19 experience prolonged symptoms, known as Long COVID. Few systematic studies have investigated this population, particularly in outpatient settings. Hence, relatively little is known about symptom makeup and severity, expected clinical course, impact on daily functioning, and return to baseline health. Methods We conducted an online survey of people with suspected and confirmed COVID-19, distributed via COVID-19 support groups (e.g. Body Politic, Long COVID Support Group, Long Haul COVID Fighters) and social media (e.g. Twitter, Facebook). Data were collected from September 6, 2020 to November 25, 2020. We analyzed responses from 3762 participants with confirmed (diagnostic/antibody positive; 1020) or suspected (diagnostic/antibody negative or untested; 2742) COVID-19, from 56 countries, with illness lasting over 28 days and onset prior to June 2020. We estimated the prevalence of 203 symptoms in 10 organ systems and traced 66 symptoms over seven months. We measured the impact on life, work, and return to baseline health. Findings For the majority of respondents (>91%), the time to recovery exceeded 35 weeks. During their illness, participants experienced an average of 55.9+/- 25.5 (mean+/-STD) symptoms, across an average of 9.1 organ systems. The most frequent symptoms after month 6 were fatigue, post-exertional malaise, and cognitive dysfunction. Symptoms varied in their prevalence over time, and we identified three symptom clusters, each with a characteristic temporal profile. 85.9% of participants (95% CI, 84.8% to 87.0%) experienced relapses, primarily triggered by exercise, physical or mental activity, and stress. 86.7% (85.6% to 92.5%) of unrecovered respondents were experiencing fatigue at the time of survey, compared to 44.7% (38.5% to 50.5%) of recovered respondents. 1700 respondents (45.2%) required a reduced work schedule compared to pre-illness, and an additional 839 (22.3%) were not working at the time of survey due to illness. Cognitive dysfunction or memory issues were common across all age groups (~88%). Except for loss of smell and taste, the prevalence and trajectory of all symptoms were similar between groups with confirmed and suspected COVID-19. Interpretation Patients with Long COVID report prolonged, multisystem involvement and significant disability. By seven months, many patients have not yet recovered (mainly from systemic and neurological/cognitive symptoms), have not returned to previous levels of work, and continue to experience significant symptom burden. Funding All authors contributed to this work in a voluntary capacity. The cost of survey hosting (on Qualtrics) and publication fee was covered by AA's research grant (Wellcome Trust/Gatsby Charity via Sainsbury Wellcome center, UCL).
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                02 June 2023
                2023
                02 June 2023
                : 14
                : 1196721
                Affiliations
                [1] 1Department of Infectious Diseases, West German Centre of Infectious Diseases, University Hospital Essen, University Duisburg-Essen , Essen, Germany
                [2] 2Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum , Bochum, Germany
                [3] 3CellTrend GmbH , Luckenwalde, Germany
                [4] 4Department of Molecular and Medical Virology, Ruhr-University Bochum , Bochum, Germany
                [5] 5Department of Nephrology, University Hospital Essen, University Duisburg-Essen , Essen, Germany
                [6] 6Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum , Herne, Germany
                [7] 7Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Campus Virchow , Berlin, Germany
                [8] 8Berlin Institute of Health at Charité – University Clinic Berlin, BIH Center for Regenerative Therapies (BCRT) Berlin , Berlin, Germany
                Author notes

                Edited by: Svetlana Khaiboullina, University of Nevada, United States

                Reviewed by: Jakob Nilsson, University Hospital Zürich, Switzerland; Rafael B. Polidoro, Indiana University Bloomington, United States

                *Correspondence: Nina Babel, nina.babel@ 123456charite.de

                These authors have contributed equally to this work

                Article
                10.3389/fmicb.2023.1196721
                10272838
                37333646
                5b0899a2-396f-4d93-abc7-7451ed4d4908
                Copyright © 2023 Paniskaki, Konik, Anft, Heidecke, Meister, Pfaender, Krawczyk, Zettler, Jäger, Gaeckler, Dolff, Westhoff, Rohn, Stervbo, Scheibenbogen, Witzke and Babel.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 March 2023
                : 16 May 2023
                Page count
                Figures: 3, Tables: 2, Equations: 0, References: 53, Pages: 9, Words: 6569
                Funding
                Funded by: Mercator Foundation, EFRE grant for COVID.DataNet. NRW, AiF grant for EpiCov, and BMBF for NoChro
                Award ID: FKZ 13GW0338B
                Categories
                Microbiology
                Original Research
                Custom metadata
                Infectious Agents and Disease

                Microbiology & Virology
                post-acute sequelae of covid-19,pasc,long covid,t cells,bmi
                Microbiology & Virology
                post-acute sequelae of covid-19, pasc, long covid, t cells, bmi

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