Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post-acute sequelae of COVID-19.

Post-acute sequelae of COVID-19 (PASC) are long-term consequences of SARS-CoV-2 infection that can substantially impair quality of life. Underlying mechanisms ranging from persistent virus to innate and adaptive immune dysregulation have been discussed. Here, we profiled plasma of 181 individuals from the cohort study for digital health research in Germany (DigiHero) including individuals after mild to moderate COVID-19 with or without PASC and uninfected controls. We focused on soluble factors related to monocyte/macrophage biology and on circulating SARS-CoV-2 spike (S1) protein as potential biomarker for persistent viral reservoirs. At a median time of eight months after infection, we found pronounced dysregulation in almost all tested soluble factors including both pro-inflammatory and pro-fibrotic cytokines. These immunological perturbations were remarkably independent of ongoing PASC symptoms per se, but further correlation and regression analyses suggested PASC specific patterns involving CCL2/MCP-1 and IL-8 that either correlated with sCD162, sCD206/MMR, IFN-α2, IL-17A and IL-33, or IL-18 and IL-23. None of the analyzed factors correlated with the detectability or levels of circulating S1 indicating that this represents an independent subset of patients with PASC. This data confirms prior evidence of immune dysregulation and persistence of viral protein in PASC and illustrates its biological heterogeneity that still awaits correlation with clinically defined PASC subtypes. This article is protected by copyright. All rights reserved.

Maturation trajectories and transcriptional landscape of plasmablasts and autoreactive B cells in COVID-19.

In parasite and viral infections, aberrant B cell responses can suppress germinal center reactions thereby blunting long-lived memory and may provoke immunopathology including autoimmunity. Using COVID-19 as model, we set out to identify serological, cellular, and transcriptomic imprints of pathological responses linked to autoreactive B cells at single-cell resolution. We show that excessive plasmablast expansions are prognostically adverse and correlate with autoantibody production but do not hinder the formation of neutralizing antibodies. Although plasmablasts followed interleukin-4 (IL-4) and BAFF-driven developmental trajectories, were polyclonal, and not enriched in autoreactive B cells, we identified two memory populations (CD80+/ISG15+ and CD11c+/SOX5+/T-bet+/-) with immunogenetic and transcriptional signs of autoreactivity that may be the cellular source of autoantibodies in COVID-19 and that may persist beyond recovery. Immunomodulatory interventions discouraging such adverse responses may be useful in selected patients to shift the balance from autoreactivity toward long-term memory.

SARS-CoV-2-specific antibody rearrangements in prepandemic immune repertoires of risk cohorts and patients with COVID-19.

A considerable fraction of B cells recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with germline-encoded elements of their B cell receptor, resulting in the production of neutralizing and nonneutralizing antibodies. We found that antibody sequences from different discovery cohorts shared biochemical properties and could be retrieved across validation cohorts, confirming the stereotyped character of this naive response in coronavirus disease 2019 (COVID-19). While neutralizing antibody sequences were found independently of disease severity, in line with serological data, individual nonneutralizing antibody sequences were associated with fatal clinical courses, suggesting detrimental effects of these antibodies. We mined 200 immune repertoires from healthy individuals and 500 repertoires from patients with blood or solid cancers - all acquired prior to the pandemic - for SARS-CoV-2 antibody sequences. While the largely unmutated B cell rearrangements occurred in a substantial fraction of immune repertoires from young and healthy individuals, these sequences were less likely to be found in individuals over 60 years of age and in those with cancer. This reflects B cell repertoire restriction in aging and cancer, and may to a certain extent explain the different clinical courses of COVID-19 observed in these risk groups. Future studies will have to address if this stereotyped B cell response to SARS-CoV-2 emerging from unmutated antibody rearrangements will create long-lived memory.

[Triage recommendations of the specialist societies : Background, summary and comments]. / "Triage-Empfehlungen" der Fachgesellschaften : Hintergrund, Zusammenfassung und Kommentar.

Triage decisions are concerned with the distribution of limited resources in times of crises, which is why the term is normally used in war and catastrophe scenarios. Under the leadership of the Academy for Ethics in Medicine (AEM) and the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI), intensive care physicians from nine specialist societies together with representatives from medical ethics and jurisprudence elaborated clinical and ethical recommendations on "necision on the allocation of intensive medical care resources in the context of the COVID-19 pandemic". These recommendations were published online in a first version on 26 March 2020 and comments were requested. After a critical consideration of the comments a second version was published on 16 April 2020. In the currently occurring second wave of the COVID-19 pandemic, the question of triage now threatens to become acute.

Decisions on the allocation of intensive care resources in the context of the COVID-19 pandemic : Clinical and ethical recommendations of DIVI, DGINA, DGAI, DGIIN, DGNI, DGP, DGP and AEM.

In view of the globally evolving coronavirus disease (COVID-19) pandemic, German hospitals rapidly expanded their intensive care capacities. However, it is possible that even with an optimal use of the increased resources, these will not suffice for all patients in need. Therefore, recommendations for the allocation of intensive care resources in the context of the COVID-19 pandemic have been developed by a multidisciplinary group of authors with the support of eight scientific medical societies. The recommendations for procedures and criteria for prioritisations in case of resource scarcity are based on scientific evidence, ethicolegal considerations and practical experience. Medical decisions must always be based on the need and the treatment preferences of the individual patient. In addition to this patient-centred approach, prioritisations in case of resource scarcity require a supraindividual perspective. In such situations, prioritisations should be based on the criterion of clinical prospect of success in order to minimize the number of preventable deaths due to resource scarcity and to avoid discrimination based on age, disabilities or social factors. The assessment of the clinical prospect of success should take into account the severity of the current illness, severe comorbidities and the patient's general health status prior to the current illness.

[Decisions on the allocation of intensive care resources in the context of the COVID-19 pandemic : Clinical and ethical recommendations of DIVI, DGINA, DGAI, DGIIN, DGNI, DGP, DGP and AEM. German version]. / Entscheidungen über die Zuteilung intensivmedizinischer Ressourcen im Kontext der COVID-19-Pandemie : Klinisch-ethische Empfehlungen der DIVI, der DGINA, der DGAI, der DGIIN, der DGNI, der DGP, der DGP und der AEM.

In view of the globally evolving Coronavirus Disease (COVID-19) pandemic, German hospitals rapidly expanded their intensive care capacities. However, it is possible that even with an optimal use of the increased resources, these will not suffice for all patients in need. Therefore, recommendations for the allocation of intensive care resources in the context of the COVID-19 pandemic have been developed by a multidisciplinary authors group with support of eight scientific medical societies. The recommendations for procedures and criteria for prioritisations in case of resource scarcity are based on scientific evidence, ethico-legal considerations and practical experience. Medical decisions must always be based on the need and the treatment preferences of the individual patient. In addition to this patient-centred approach, prioritisations in case of resource scarcity require a supra-individual perspective. In such situations, prioritisations should be based on the criterion of clinical prospect of success in order to minimize the number of preventable deaths due to resource scarcity and to avoid discrimination based on age, disabilities or social factors. Assessment of the clinical prospect of success should take into account the severity of the current illness, severe comorbidities and the patient's general health status prior to the current illness.