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      The IL-1β, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19

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          Abstract

          Post-acute sequelae of COVID-19 (PASC) is emerging as global problem with unknown molecular drivers. Using a digital epidemiology approach, we recruited 8,077 individuals to the cohort study for digital health research in Germany (DigiHero) to respond to a basic questionnaire followed by a PASC-focused survey and blood sampling. We report the first 318 participants, the majority thereof after mild infections. Of those, 67.8% report PASC, predominantly consisting of fatigue, dyspnea, and concentration deficit, which persists in 60% over the mean 8-month follow-up period and resolves independently of post-infection vaccination. PASC is not associated with autoantibodies, but with elevated IL-1β, IL-6, and TNF plasma levels, which we confirm in a validation cohort with 333 additional participants and a longer time from infection of 10 months. Blood profiling and single-cell data from early infection suggest the induction of these cytokines in COVID-19 lung pro-inflammatory macrophages creating a self-sustaining feedback loop.

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          Abstract

          By using a digital epidemiology approach including blood sampling, Schultheiβ et al. report post-acute sequelae persisting up to 24 months in 60% of patients after mild COVID-19. Plasma cytokine analysis reveals association with elevated levels of IL-1β, IL-6, and TNF potentially secreted from overactivated monocytes/macrophages.

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          Fast, sensitive, and accurate integration of single cell data with Harmony

          The emerging diversity of single cell RNAseq datasets allows for the full transcriptional characterization of cell types across a wide variety of biological and clinical conditions. However, it is challenging to analyze them together, particularly when datasets are assayed with different technologies. Here, real biological differences are interspersed with technical differences. We present Harmony, an algorithm that projects cells into a shared embedding in which cells group by cell type rather than dataset-specific conditions. Harmony simultaneously accounts for multiple experimental and biological factors. In six analyses, we demonstrate the superior performance of Harmony to previously published algorithms. We show that Harmony requires dramatically fewer computational resources. It is the only currently available algorithm that makes the integration of ~106 cells feasible on a personal computer. We apply Harmony to PBMCs from datasets with large experimental differences, 5 studies of pancreatic islet cells, mouse embryogenesis datasets, and cross-modality spatial integration.
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            6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

            Background The long-term health consequences of COVID-19 remain largely unclear. The aim of this study was to describe the long-term health consequences of patients with COVID-19 who have been discharged from hospital and investigate the associated risk factors, in particular disease severity. Methods We did an ambidirectional cohort study of patients with confirmed COVID-19 who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7, 2020, and May 29, 2020. Patients who died before follow-up, patients for whom follow-up would be difficult because of psychotic disorders, dementia, or re-admission to hospital, those who were unable to move freely due to concomitant osteoarthropathy or immobile before or after discharge due to diseases such as stroke or pulmonary embolism, those who declined to participate, those who could not be contacted, and those living outside of Wuhan or in nursing or welfare homes were all excluded. All patients were interviewed with a series of questionnaires for evaluation of symptoms and health-related quality of life, underwent physical examinations and a 6-min walking test, and received blood tests. A stratified sampling procedure was used to sample patients according to their highest seven-category scale during their hospital stay as 3, 4, and 5–6, to receive pulmonary function test, high resolution CT of the chest, and ultrasonography. Enrolled patients who had participated in the Lopinavir Trial for Suppression of SARS-CoV-2 in China received severe acute respiratory syndrome coronavirus 2 antibody tests. Multivariable adjusted linear or logistic regression models were used to evaluate the association between disease severity and long-term health consequences. Findings In total, 1733 of 2469 discharged patients with COVID-19 were enrolled after 736 were excluded. Patients had a median age of 57·0 (IQR 47·0–65·0) years and 897 (52%) were men. The follow-up study was done from June 16, to Sept 3, 2020, and the median follow-up time after symptom onset was 186·0 (175·0–199·0) days. Fatigue or muscle weakness (63%, 1038 of 1655) and sleep difficulties (26%, 437 of 1655) were the most common symptoms. Anxiety or depression was reported among 23% (367 of 1617) of patients. The proportions of median 6-min walking distance less than the lower limit of the normal range were 24% for those at severity scale 3, 22% for severity scale 4, and 29% for severity scale 5–6. The corresponding proportions of patients with diffusion impairment were 22% for severity scale 3, 29% for scale 4, and 56% for scale 5–6, and median CT scores were 3·0 (IQR 2·0–5·0) for severity scale 3, 4·0 (3·0–5·0) for scale 4, and 5·0 (4·0–6·0) for scale 5–6. After multivariable adjustment, patients showed an odds ratio (OR) 1·61 (95% CI 0·80–3·25) for scale 4 versus scale 3 and 4·60 (1·85–11·48) for scale 5–6 versus scale 3 for diffusion impairment; OR 0·88 (0·66–1·17) for scale 4 versus scale 3 and OR 1·77 (1·05–2·97) for scale 5–6 versus scale 3 for anxiety or depression, and OR 0·74 (0·58–0·96) for scale 4 versus scale 3 and 2·69 (1·46–4·96) for scale 5–6 versus scale 3 for fatigue or muscle weakness. Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with estimated glomerular filtration rate (eGFR) 90 mL/min per 1·73 m2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m2 at follow-up. Interpretation At 6 months after acute infection, COVID-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression. Patients who were more severely ill during their hospital stay had more severe impaired pulmonary diffusion capacities and abnormal chest imaging manifestations, and are the main target population for intervention of long-term recovery. Funding National Natural Science Foundation of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Key Research and Development Program of China, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, and Peking Union Medical College Foundation.
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              Persistent Symptoms in Patients After Acute COVID-19

              This case series describes COVID-19 symptoms persisting a mean of 60 days after onset among Italian patients previously discharged from COVID-19 hospitalization.
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                Author and article information

                Journal
                Cell Rep Med
                Cell Rep Med
                Cell Reports Medicine
                The Author(s).
                2666-3791
                21 June 2022
                21 June 2022
                21 June 2022
                : 3
                : 6
                : 100663
                Affiliations
                [1 ]Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany
                [2 ]Institute for Medical Epidemiology, Biometrics and Informatics (IMEBI), Interdisciplinary Center for Health Sciences, Medical School of the Martin-Luther University Halle-Wittenberg, Magdeburger Strasse 8, 06097 Halle (Saale), Germany
                [3 ]I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany
                [4 ]Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Bernhard Nocht Strasse 74, 20359 Hamburg, Germany
                [5 ]Mid-German Heart Center, Department of Cardiology and Intensive Care Medicine, University Hospital, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany
                [6 ]Institute of General Practice and Family Medicine, Martin-Luther-University Halle-Wittenberg, Magdeburger Str. 8, 06112 Halle (Saale), Germany
                [7 ]Department of Internal Medicine II, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany
                [8 ]Pediatric Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany
                [9 ]Julius Bernstein-Institute of Physiology, Faculty of Medicine, Martin-Luther-University Halle-Wittenberg, Magdeburger Str. 6, 06110 Halle (Saale), Germany
                Author notes
                []Corresponding author
                [10]

                Twitter: @lab_binder

                [11]

                Lead contact

                Article
                S2666-3791(22)00195-1 100663
                10.1016/j.xcrm.2022.100663
                9214726
                35732153
                b68d8d30-0ee1-4124-b816-12f858ea0232
                © 2022 The Author(s)

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 11 January 2022
                : 28 March 2022
                : 25 May 2022
                Categories
                Article

                sars-cov-2,covid-19,post-acute sequelae of covid-19,pasc,long covid,cytokine,macrophage,tnf,il-1β,il-6

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