Background While the leading symptoms during coronavirus disease 2019 (COVID-19) are acute and the majority of patients fully recover, a significant fraction of patients now increasingly experience long-term health consequences. However, most data available focus on health-related events after severe infection and hospitalisation. We present a longitudinal, prospective analysis of health consequences in patients who initially presented with no or minor symptoms of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. Hence, we focus on mild COVID-19 in non-hospitalised patients. Methods 958 Patients with confirmed SARS-CoV-2 infection were observed from April 6th to December 2nd 2020 for long-term symptoms and SARS-CoV-2 antibodies. We identified anosmia, ageusia, fatigue or shortness of breath as most common, persisting symptoms at month 4 and 7 and summarised presence of such long-term health consequences as post-COVID syndrome (PCS). Predictors of long-term symptoms were assessed using an uni- and multivariable logistic regression model. Findings We observed 442 and 353 patients over four and seven months after symptom onset, respectively. Four months post SARS-CoV-2 infection, 8•6% (38/442) of patients presented with shortness of breath, 12•4% (55/442) with anosmia, 11•1% (49/442) with ageusia and 9•7% (43/442) with fatigue. At least one of these characteristic symptoms was present in 27•8% (123/442) and 34•8% (123/353) at month 4 and 7 post-infection, respectively. A lower baseline level of SARS-CoV-2 IgG, anosmia and diarrhoea during acute COVID-19 were associated with higher risk to develop long-term symptoms. Interpretation The on-going presence of either shortness of breath, anosmia, ageusia or fatigue as long-lasting symptoms even in non-hospitalised patients was observed at four and seven months post-infection and summarised as post-COVID syndrome (PCS). The continued assessment of patients with PCS will become a major task to define and mitigate the socioeconomic and medical long-term effects of COVID-19. Funding COVIM:„NaFoUniMedCovid19“(FKZ: 01KX2021)

Highlights d Low avidity and broad cross-reactivities of pre-existing SARS-CoV-2 memory T cells d Strong CCCoV-specific memory CD4 + T cell responses in all analyzed individuals d SARS-CoV-2-specific CD4 + T cells in COVID-19 patients lack cross-reactivity to CCCoVs d Low avidity and clonality of SARS-CoV-2-specific T cell responses in severe COVID-19

Coronavirus-disease-2019 (COVID-19) caused by the severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) shows a rapid spread over-the-world. Given scarce resources, non-laboratory diagnostics is crucial. In this cross-sectional study, two-thirds of European patients with polymerase chain reaction confirmed COVID-19 reported olfactory and gustatory dysfunction, indicating the significance of this history in the early diagnostics.

Understanding antibody-based SARS-CoV-2 immunity is critical for overcoming the COVID-19 pandemic and informing vaccination strategies. We evaluated SARS-CoV-2 antibody dynamics over 10 months in 963 individuals who predominantly experienced mild COVID-19. Investigating 2,146 samples, we initially detected SARS-CoV-2 antibodies in 94.4% individuals, with 82% and 79% exhibiting serum and IgG neutralization, respectively. Approximately 3% of individuals demonstrated exceptional SARS-CoV-2-neutralization, with these ‘elite neutralizers’ also possessing SARS-CoV-1 cross-neutralizing IgG. Multivariate statistical modeling revealed age, symptomatic infection, disease severity and gender as key factors predicting SARS-CoV-2 neutralizing activity. A loss of reactivity to the virus spike protein was observed in 13% individuals 10 months after infection. Neutralizing activity had half-lives of 14.7 weeks in serum versus 31.4 weeks in purified IgG, indicating a stable long-term IgG antibody response. Our results demonstrate a broad spectrum in the initial SARS-CoV-2-neutralizing antibody response, with sustained antibodies in most individuals for 10 months after mild COVID-19.

A fraction of COVID-19 convalescent individuals mount a potent antibody response to SARS-CoV-2 with cross-reactivity to SARS-CoV-1. To uncover their humoral response in detail, we performed single B-cell analysis from 10 SARS-CoV-2 elite neutralizers. We isolated and analyzed 126 monoclonal antibodies, many of which were sarbecovirus cross-reactive, with some displaying merbecovirus- and embecovirus-reactivity. Several isolated broadly neutralizing antibodies were effective against B.1.1.7, B1.351, B.1.429, B.1.617, B.1.617.2 variants and 19 prominent potential escape sites. Furthermore, assembly of 716,806 SARS-CoV-2 sequences predicted emerging escape variants, which were also effectively neutralized. One of these broadly neutralizing potent antibodies, R40-1G8, is a IGHV3-53 RBD-Class-1 antibody. Remarkably, Cryo-EM analysis revealed that R40-1G8 has a flexible binding mode, targeting both ‘up’ and ‘down’ conformations of the RBD. Given the threat of emerging SARS-CoV-2 variants, we demonstrate that elite neutralizers are a valuable source for isolating ultrapotent antibody candidates to prevent and treat SARS-CoV-2 infection.

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On July 1, 2009, the German Network for Health Services Research [Deutsches Netzwerk Versorgungsforschung e. V. (DNVF e. V.)] approved the Memorandum III "Methods for Health Services Research", supported by the member societies mentioned as authors and published in this Journal (Gesundheitswesen 2009; 71: 505-510). This is an in-depth publication on the "epidemiological methods for health services research". Legal, political and economic steps of intervention in the medical care system modify the health services structures and processes but the impact of such interventions on the medical care users has, so far and in general, not been examined scientifically. Due to this lack of evaluation, there is, also with regard to the economic situation within the health system, no transparency of potentially severe effects on healthy and, particularly, on ill people. For this very reason, the main questions and focuses of medical care research deal with prevalence, causes and effects of over, under and inappropriate supply of health services, the interaction between diagnostics and therapy, the processes across different sectors and the complex interdependences of health services. This part of the Memorandum of Deutsches Netzwerk für Versorgungsforschung e. V. (DNVF e. V., German Network for Health Services Research) will enumerate the methods and instruments that will be used for planned studies and that have been applied for finished studies of health services research and for the evaluation of its quality and value. Health services research takes advantage of the theories and the methods of the disciplines that are involved in its studies. It does not need a specific research methodology; its methods are adapted to the specific research question. It is rather to be expected that certain issues of this research branch and its access to data will lead to the development of new methods.

Objectives To evaluate ocular symptoms in European non-hospitalized patients with severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and to investigate associations with the demographic data as well as nasal and general physical symptoms. Methods In this prospective, observational study, 108 non-hospitalized patients with PCR-confirmed SARS-CoV-2 infection not requiring intensive care were asked about disease-associated ocular symptoms, demographic data, as well as general physical and nasal symptoms using a standardized questionnaire. Total ocular symptom score (TOSS) was evaluated during and, retrospectively, before development of coronavirus disease 2019 (COVID-19). Associations between TOSS and demographic data as well as general and nasal symptoms were evaluated. Results Seventy-five of the 108 COVID-19 patients (69.4%) had at least one ocular symptom during COVID-19. The most common symptoms included burning sensations in 39 (36.1%), epiphora in 37 (34.3%) and redness in 28 (25.9%), compatible with conjunctivitis. These symptoms occurred 1.96 ± 3.17 days after the beginning of COVID-19 and were mild. TOSS was significantly higher during COVID-19 (1.27 ± 1.85) than before the infection (0.33 ± 1.04; p < 0.001). There were no significant associations between TOSS and gender (β coefficient –0.108; p 0.302), age (–0.024; p 0.816), rhinorrhoea (–0.127; p 0.353), nasal itching (–0.026; p 0.803), sneezing (0.099; p 0.470), nasal congestion (–0.012; p 0.930), cough (–0.079; p 0.450), headache (0.102; p 0.325), sore throat (0.208; p 0.052), or fever (0.094; p 0.361). Conclusions Ocular involvement in European non-hospitalized individuals with COVID-19 seems to be highly underestimated. Overall, these ocular symptoms, including burning sensations, epiphora and redness, seem to be mild and to not need treatment.