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Aims: Diuretic resistance (i.e., insufficient diuretic and natriuretic response to an appropriate dose of intravenously administered loop diuretic) is a major cause of insufficient decongestion in acute heart failure (AHF). Early assessment of diuretic and natriuretic response already after the first administration of loop diuretic is currently recommended, but few data exist on the prevalence and characteristics of upfront diuretic resistance in AHF. The aim of this sub-study of the P-Value-AHF randomized clinical trial was to investigate the prevalence and characteristics of upfront diuretic resistance in patients presenting with AHF in the emergency department (ED)., Methods: Consecutive patients presenting with a clinical diagnosis of AHF, ≥1 sign of congestion, and NT-proBNP >1000 ng/L between February and June 2024 were prospectively screened. Loop diuretics were administered per protocol: 40 mg furosemide i.v. in diuretic-naïve patients and those on oral torasemide <40 mg, 80 mg furosemide i.v. in patients on oral torasemide ≥40 mg daily. Urine output was measured over the following 2 h and in patients with urine volume <300 mL, urine sodium concentration was additionally measured in a spot sample. Upfront diuretic resistance was defined as urine volume <300 mL in 2 h and urine sodium concentration <70 mmol/L., Results: From a total of 127 screened AHF patients presenting to the ED, 17 subjects were excluded after denial of informed consent and 17 could not be treated according to the protocol due to one or more exclusion criteria. Of the remaining 93 per-protocol-treated patients, 91 showed an adequate diuretic response either in terms of urine volume or urine sodium concentration. Only two of 93 patients (2.2%) met the criteria of upfront diuretic resistance. In a post-hoc analysis, patients with diuretic resistance had higher prevalence of chronic kidney or liver diseases, markedly lower blood pressure and heart rate, markedly higher serum creatinine and potassium levels, and lower serum sodium. Notably, clinical signs of congestion, circulating NT-proBNP, and left-ventricular ejection fraction were similar in both groups., Conclusions: Upfront diuretic resistance in an unselected population of AHF patients presenting to the ED affects only a minority of patients. These data highlight the importance of a standardized, protocolized approach to decongestive treatment in AHF, which includes the rapid administration of loop diuretics in an adequate dose. Pre-existing chronic kidney disease and high creatinine levels were more prevalent in patients with diuretic resistance., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Conestat alfa (ConA), a recombinant human C1 inhibitor, may prevent thromboinflammation., Methods: We conducted a randomized, open-label, multi-national clinical trial in which hospitalized adults at risk for progression to severe COVID-19 were assigned in a 2:1 ratio to receive either 3 days of ConA plus standard of care (SOC) or SOC alone. Primary and secondary endpoints were day 7 disease severity on the WHO Ordinal Scale, time to clinical improvement within 14 days, and safety, respectively., Results: The trial was prematurely terminated because of futility after randomization of 84 patients, 56 in the ConA and 28 in the control arm. At baseline, higher WHO Ordinal Scale scores were more frequently observed in the ConA than in the control arm. On day 7, no relevant differences in the primary outcome were noted between the two arms ( p = 0.11). The median time to defervescence was 3 days, and the median time to clinical improvement was 7 days in both arms ( p = 0.22 and 0.56, respectively). Activation of plasma cascades and endothelial cells over time was similar in both groups. The incidence of adverse events (AEs) was higher in the intervention arm (any AE, 30% with ConA vs. 19% with SOC alone; serious AE, 27% vs. 15%; death, 11% vs. 0%). None of these were judged as being related to the study drug., Conclusion: The study results do not support the use of ConA to prevent COVID-19 progression., Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT04414631., Competing Interests: MT reports receiving grants from the Swiss National Science Foundation, and having research collaborations with Roche, Novartis, and Idorsia outside the submitted work. WA reports receiving fees and research grants from A. Vogel AG, Gilead, and OM Pharma and fees for attendance of advisory boards to Pfizer, MSD Vifor Pharma, GSK, Sanofi, OM Pharma, and Janssen that were paid to his institution outside the submitted work. MO reports receiving grants from the Swiss National Science Foundation, consulting fees from Pharming Biotechnologies B.V. during the conduct of the study and grants from Pharming Biotechnologies B.V. outside the submitted work. LH reports receiving consulting fees from GlaxoSmithKline and Novartis during the conduct of the study but unrelated to this trial. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Pharming Biotechnologies B.V. The funder was involved in the design of the study at an initial stage and in the trial organization of the study in Brazil and Mexico (e.g., shipment of study drug)., (Copyright © 2023 Urwyler, Leimbacher, Charitos, Moser, Heijnen, Trendelenburg, Thoma, Sumer, Camacho-Ortiz, Bacci, Huber, Stüssi-Helbling, Albrich, Sendi and Osthoff.)

Background: Several autoimmune features occur during coronavirus disease 2019 (COVID-19), with possible implications for disease course, immunity, and autoimmune pathology. In this study, we longitudinally screened for clinically relevant systemic autoantibodies to assess their prevalence, temporal trajectory, and association with immunity, comorbidities, and severity of COVID-19., Methods: We performed highly sensitive indirect immunofluorescence assays to detect antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA), along with serum proteomics and virome-wide serological profiling in a multicentric cohort of 175 COVID-19 patients followed up to 1 year after infection, eleven vaccinated individuals, and 41 unexposed controls., Results: Compared with healthy controls, similar prevalence and patterns of ANA were present in patients during acute COVID-19 and recovery. However, the paired analysis revealed a subgroup of patients with transient presence of certain ANA patterns during acute COVID-19. Furthermore, patients with severe COVID-19 exhibited a high prevalence of ANCA during acute disease. These autoantibodies were quantitatively associated with higher SARS-CoV-2-specific antibody titers in COVID-19 patients and in vaccinated individuals, thus linking autoantibody production to increased antigen-specific humoral responses. Notably, the qualitative breadth of antibodies cross-reactive with other coronaviruses was comparable in ANA-positive and ANA-negative individuals during acute COVID-19. In autoantibody-positive patients, multiparametric characterization demonstrated an inflammatory signature during acute COVID-19 and alterations of the B-cell compartment after recovery., Conclusion: Highly sensitive indirect immunofluorescence assays revealed transient autoantibody production during acute SARS-CoV-2 infection, while the presence of autoantibodies in COVID-19 patients correlated with increased antiviral humoral immune responses and inflammatory immune signatures., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: T-cell lymphopenia and functional impairment is a hallmark of severe acute coronavirus disease 2019 (COVID-19). How T-cell numbers and function evolve at later timepoints after clinical recovery remains poorly investigated., Methods: We prospectively enrolled and longitudinally sampled 173 individuals with asymptomatic to critical COVID-19 and analyzed phenotypic and functional characteristics of T cells using flow cytometry, 40-parameter mass cytometry, targeted proteomics, and functional assays., Results: The extensive T-cell lymphopenia observed particularly in patients with severe COVID-19 during acute infection had recovered 6 months after infection, which was accompanied by a normalization of functional T-cell responses to common viral antigens. We detected persisting CD4 + and CD8 + T-cell activation up to 12 months after infection, in patients with mild and severe COVID-19, as measured by increased HLA-DR and CD38 expression on these cells. Persistent T-cell activation after COVID-19 was independent of administration of a COVID-19 vaccine post-infection. Furthermore, we identified a subgroup of patients with severe COVID-19 that presented with persistently low CD8 + T-cell counts at follow-up and exhibited a distinct phenotype during acute infection consisting of a dysfunctional T-cell response and signs of excessive pro-inflammatory cytokine production., Conclusion: Our study suggests that T-cell numbers and function recover in most patients after COVID-19. However, we find evidence of persistent T-cell activation up to 12 months after infection and describe a subgroup of severe COVID-19 patients with persistently low CD8 + T-cell counts exhibiting a dysregulated immune response during acute infection., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Among people infected with SARS-CoV-2, the determination of clinical features associated with poor outcome is essential to identify those at high risk of deterioration. Here, we aimed to investigate clinical phenotypes of patients hospitalized due to COVID-19 and to examine the predictive value of the neutrophil-to-lymphocyte ratio (NLR) in a representative patient collective of the Swiss population. We conducted a retrospective monocentriccohort study with patients hospitalized due to COVID-19 between 27 February and 31 December 2020. Data were analyzed descriptively, using the binary logistic regression model, proportional odds logistic regression model, competing risk analysis, and summary measure analysis. A total of 454 patients were included in our study. Dyspnea, elevated respiratory rate, low oxygen saturation at baseline, age, and presence of multiple comorbidities were associated with a more severe course of the disease. A high NLR at baseline was significantly associated with disease severity, unfavorable outcome, and mortality. In non-survivors, NLR further increased during hospital stay, whereas in survivors, NLR decreased. In conclusion, our data emphasize the importance of accurate history taking and clinical examination upon admission and confirm the role of baseline NLR as a surrogate marker for increased disease severity, unfavorable outcome, and mortality in patients hospitalized due to infection with SARS-CoV-2.

Since the beginning of the COVID-19 pandemic, SARS-CoV-2 has caused a global burden for health care systems due to high morbidity and mortality rates, leading to caseloads that episodically surpass hospital resources. Due to different disease manifestations, the triage of patients at high risk for a poor outcome continues to be a major challenge for clinicians. The AIFELL score was developed as a simple decision instrument for emergency rooms to distinguish COVID-19 patients in severe disease stages from less severe COVID-19 and non-COVID-19 cases. In the present study, we aimed to evaluate the AIFELL score as a prediction tool for clinical deterioration and disease severity in hospitalized COVID-19 patients. During the second wave of the COVID-19 pandemic in Switzerland, we analyzed consecutively hospitalized patients at the Triemli Hospital Zurich from the end of November 2020 until mid-February 2021. Statistical analyses were performed for group comparisons and to evaluate significance. AIFELL scores of patients developing severe COVID-19 stages IIb and III during hospitalization were significantly higher upon admission compared to those patients not surpassing stages I and IIa. Group comparisons indicated significantly different AIFELL scores between each stage. In conclusion, the AIFELL score at admission was useful to predict the disease severity and progression in hospitalized COVID-19 patients.

Following acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a significant proportion of individuals develop prolonged symptoms, a serious condition termed post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) or long COVID. Predictors of PACS are needed. In a prospective multicentric cohort study of 215 individuals, we study COVID-19 patients during primary infection and up to one year later, compared to healthy subjects. We discover an immunoglobulin (Ig) signature, based on total IgM and IgG3 levels, which - combined with age, history of asthma bronchiale, and five symptoms during primary infection - is able to predict the risk of PACS independently of timepoint of blood sampling. We validate the score in an independent cohort of 395 individuals with COVID-19. Our results highlight the benefit of measuring Igs for the early identification of patients at high risk for PACS, which facilitates the study of targeted treatment and pathomechanisms of PACS., (© 2022. The Author(s).)

Background: We aimed to longitudinally monitor the recovery in breathlessness, symptom burden, health-related quality-of-life, and mental health status in individuals hospitalised due to SARS-CoV-2 associated respiratory failure. Methods: Individuals hospitalised due to SARS-CoV-2 associated respiratory failure were recruited at hospital discharge in three participating centres. During the 90 day follow-up, European Quality of Life-5 Dimensions-5 Levels Instrument (EQ-5D-5L), modified Medical Research Council (mMRC) Dyspnoea Scale, COPD Assessment Test (CAT), and weekly Hospital Anxiety and Depression Scale (HADS) questionnaires were assessed using a smartphone application. The results were presented using descriptive statistics and graphics. Linear mixed models with random intercept were fitted to analyse differences of intensive-care unit status on the recovery course in each outcome. Results: We included 58 participants, 40 completed the study. From hospital discharge until 90 days post-discharge, EQ-5D-5L index changed from 0.83 (0.66, 0.92) to 0.96 (0.82, 1.0), VAS rating on general health status changed from 62 (50, 75) % to 80 (74, 94) %, CAT changed from 13 (10, 21) to 7 (3, 11) points, mMRC changed from 1 (0, 2) to 0 (0, 1) points, HADS depression subscale changed from 6 (4, 9) to 5 (1, 6) points, HADS anxiety subscale changed from 7 (3, 9) to 2 (1, 8) points. Differences in the recovery courses were observed between intensive-care and ward participants. Participants that were admitted to an intensive-care unit during their hospitalisation ( n = 16) showed increases in CAT, mMRC, HADS scores, and decreases in EQ-5D-5L 30 days after hospital discharge. Conclusion: Being admitted to an ICU led to statistically significant reductions in recovery in the EQ-5D-5L and the CAT. Furthermore, the flare-up in symptom burden and depression scores, accompanied by an attenuated recovery in HrQoL and general health status in the ICU-group suggests that a clinical follow-up 1 month after hospital discharge can be recommended, evaluating further treatments. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT04365595]., Competing Interests: YN is cofounder and Chief Medical Officer of docdok.health with a financial interest in commercialisation of the docdok.health platform. MS received fees for lectures/talks, participation in advisory boards, and travel/accommodation/meeting reimbursements from Boehringer, GSK, OM Pharma, and KAIA Breathe within the last 36 months. All outside the submitted work. CC received fees for lectures/talks, development of educational materials, participation in advisory boards, and travel/accommodation/meeting reimbursements from Roche, Novartis, Boehringer, GSK, Astra Zeneca, Sanofi, Vifor, OM Pharma, and Mundipharma within the last 36 months. All outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kohlbrenner, Kuhn, Stüssi-Helbling, Nordmann, Spielmanns and Clarenbach.)

Background: Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and shows a broad clinical presentation ranging from asymptomatic infection to fatal disease. A very prominent feature associated with severe COVID-19 is T cell lymphopenia. However, homeostatic and functional properties of T cells are ill-defined in COVID-19., Methods: We prospectively enrolled individuals with mild and severe COVID-19 into our multicenter cohort and performed a cross-sectional analysis of phenotypic and functional characteristics of T cells using 40-parameter mass cytometry, flow cytometry, targeted proteomics, and functional assays., Results: Compared with mild disease, we observed strong perturbations of peripheral T cell homeostasis and function in severe COVID-19. Individuals with severe COVID-19 showed T cell lymphopenia and redistribution of T cell populations, including loss of naïve T cells, skewing toward CD4 + T follicular helper cells and cytotoxic CD4 + T cells, and expansion of activated and exhausted T cells. Extensive T cell apoptosis was particularly evident with severe disease and T cell lymphopenia, which in turn was accompanied by impaired T cell responses to several common viral antigens. Patients with severe disease showed elevated interleukin-7 and increased T cell proliferation. Furthermore, patients sampled at late time points after symptom onset had higher T cell counts and improved antiviral T cell responses., Conclusion: Our study suggests that severe COVID-19 is characterized by extensive T cell dysfunction and T cell apoptosis, which is associated with signs of homeostatic T cell proliferation and T cell recovery., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley and Sons Ltd.)

Background: Whereas severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody tests are increasingly being used to estimate the prevalence of SARS-CoV-2 infection, the determinants of these antibody responses remain unclear., Objectives: Our aim was to evaluate systemic and mucosal antibody responses toward SARS-CoV-2 in mild versus severe coronavirus disease 2019 (COVID-19) cases., Methods: Using immunoassays specific for SARS-CoV-2 spike proteins, we determined SARS-CoV-2-specific IgA and IgG in sera and mucosal fluids of 2 cohorts, including SARS-CoV-2 PCR-positive patients (n = 64) and PCR-positive and PCR-negtive health care workers (n = 109)., Results: SARS-CoV-2-specific serum IgA titers in patients with mild COVID-19 were often transiently positive, whereas serum IgG titers remained negative or became positive 12 to 14 days after symptom onset. Conversely, patients with severe COVID-19 showed a highly significant increase of SARS-CoV-2-specific serum IgA and IgG titers after symptom onset. Very high titers of SARS-CoV-2-specific serum IgA were correlated with severe acute respiratory distress syndrome. Interestingly, some health care workers with negative SARS-CoV-2-specific serum antibody titers showed SARS-CoV-2-specific IgA in mucosal fluids with virus-neutralizing capacity in some cases. SARS-CoV-2-specific IgA titers in nasal fluids were inversely correlated with age., Conclusions: Systemic antibody production against SARS-CoV-2 develops mainly in patients with severe COVID-19, with very high IgA titers seen in patients with severe acute respiratory distress syndrome, whereas mild disease may be associated with transient production of SARS-CoV-2-specific antibodies but may stimulate mucosal SARS-CoV-2-specific IgA secretion., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Coronavirus disease 2019 (COVID-19) manifests with a range of severities, but immune signatures of mild and severe disease are still not fully understood. Here, we use mass cytometry and targeted proteomics to profile the innate immune response of patients with mild or severe COVID-19 and of healthy individuals. Sampling at different stages allows us to reconstruct a pseudo-temporal trajectory of the innate response. A surge of CD169 + monocytes associated with an IFN-γ + MCP-2 + signature rapidly follows symptom onset. At later stages, we observe a persistent inflammatory phenotype in patients with severe disease, dominated by high CCL3 and CCL4 abundance correlating with the re-appearance of CD16 + monocytes, whereas the response of mild COVID-19 patients normalizes. Our data provide insights into the dynamic nature of inflammatory responses in COVID-19 patients and identify sustained innate immune responses as a likely mechanism in severe patients, thus supporting the investigation of targeted interventions in severe COVID-19., Competing Interests: The authors declare no competing interests., (© 2020 The Authors.)

Significant improvement has been achieved in diagnostic accuracy, validation of probability scores, and standardized treatment algorithms for patients with suspected acute pulmonary embolism. These developments have provided the tools for a safe and cost-effective management for most of these patients. In our experience, however, the presence of medical myths and ongoing controversies seem to hinder the implementation of these tools in everyday clinical practice. This review provides a selection of such dilemmas and controversies and discusses the published evidence beyond them. By doing so, we try to overcome these dilemmas and suggest pragmatic approaches guided by the available evidence and current guidelines., (Copyright © 2019 Elsevier Inc. All rights reserved.)