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Purpose Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course. Methods A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed. Results Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10–1.37, p p p Conclusions Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19.

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathogenesis, and it remains unclear if T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and proteomics with mechanistic studies assessing pathogenic T cell functions and inducing signals. We identified activated, CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Age-dependent generation of C3a in severe COVID-19 induced activated CD16 + cytotoxic T cells. The proportion of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a correlated with clinical outcome, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19. Funding: This work was supported by the German Research Foundation (DFG): SA1383/3-1 to B.S.; SFB-TR84 114933180 to L.E.S., S.B., P.G., S.H. and W.M.K. INST 37/1049-1, INST 216/981- 1, INST 257/605-1, INST 269/768-1, INST 217/988-1, INST 217/577-1, and EXC2151- 390873048 to J.L.S.; GRK 2168 – 272482170, ERA CVD (00160389 to J.L.S.; SFB 1454 – 432325352 to A.C.A. and J.L.S.; SFB TR57 and SPP1937 to J.N.; GRK2157 to A.-E.S.; and ME 3644/5-1 to H.E.M.; RTG2424 to N.B.; SFB-TRR219 322900939, BO3755/13-1 Project- ID 454024652 to P.B.; the Berlin University Alliance (BUA) (PreEP-Corona grant to L.E.S. and V.M.C.); the Berlin Institute of Health (BIH) (to L.E.S., V.M.C.,B.S. and W.M.K.); Helmholtz- Gemeinschaft Deutscher Forschungszentren, Germany (sparse2big to J.L.S.), EU projects SYSCID (733100 to J.L.S.); European Research Council Horizon 2020 (grant agreement No 101001791 to P.B.); the DZIF, Germany (TTU 04.816 and 04.817 to J.N.); the Hector Foundation (M89 to J.N.); the EU projects ONE STUDY (260687), BIO-DrIM (305147) and INsTRuCT (860003) to B.S.); German Registry of COVID-19 Autopsies through Federal Ministry of Health (ZMVI1-2520COR201 to P.B.); Federal Ministry of Education and Research (DEFEAT PANDEMICs, 01KX2021 and STOP-FSGS-01GM1901A to P.B.); the Berlin Senate to German Rheumatism Research Centre (DRFZ); the Berlin Brandenburg School for regenerative Therapies (BSRT) to C.B.; the German Federal Ministry of Education and Research (BMBF) projects RECAST (01KI20337) to B.S., V.M.C., L.E.S and M.R.; VARIPath (01KI2021) to V.M.C.; NUM COVIM (01KX2021) to L.E.S., V.M.C., F.K., J.L.S., J.N. and B.S.; RAPID to and S.H.,; SYMPATH to N.S. and W.M.K.; PROVID to S.H. and W.M.K.; ZissTrans (02NUK047E) to N.B; National Research Node ‘Mass spectrometry in Systems Medicine (MSCoresys) (031L0220A) to M.R. and N.B.; Diet–Body–Brain (DietBB) (01EA1809A) to J.L.S.; the UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC), the Francis Crick Institute through the Cancer Research UK (FC001134), the UK Medical Research Council (FC001134), the Wellcome Trust (FC001134 and IA 200829/Z/16/Z) to M.R.; a Charite 3R project (to B.S., S.H., W.M.K.); and an intramural grant from the Department of Genomics & Immunoregulation at the LIMES Institute to A.C.A. We are grateful to the patients and donors volunteering to participate in this study making this research possible in the first place and wish for a speedy and full recovery. Conflict of Interest: V.M.C. is named together with Euroimmun GmbH on a patent application filed recently regarding SARS-CoV-2 diagnostics via antibody testing. A.R.S. and H.E.M. are listed as inventors on a patent application by the DRFZ Berlin in the field of mass cytometry. Ethical Approval: The study was approved by the Institutional Review board of Charite (EA2/066/20).

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. There is an urgent need for predictive markers that can guide clinical decision-making, inform about the effect of experimental therapies, and point to novel therapeutic targets. Here, we characterize the time-dependent progression of COVID-19 through different stages of the disease, by measuring 86 accredited diagnostic parameters and plasma proteomes at 687 sampling points, in a cohort of 139 patients during hospitalization. We report that the time-resolved patient molecular phenotypes reflect an initial spike in the systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution and immunomodulation. Further, we show that the early host response is predictive for the disease trajectory and gives rise to proteomic and diagnostic marker signatures that classify the need for supplemental oxygen therapy and mechanical ventilation, and that predict the time to recovery of mildly ill patients. In severely ill patients, the molecular phenotype of the early host response predicts survival, in two independent cohorts and weeks before outcome. We also identify age-specific molecular response to COVID-19, which involves increased inflammation and lipoprotein dysregulation in older patients. Our study provides a deep and time resolved molecular characterization of COVID-19 disease progression, and reports biomarkers for risk-adapted treatment strategies and molecular disease monitoring. Our study demonstrates accurate prognosis of COVID-19 outcome from proteomic signatures recorded weeks earlier.

Objectives Dexamethasone has become the standard of care for severe coronavirus disease 2019 (COVID-19), but its virological impact is poorly understood. The objectives of this work were to characterize the kinetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) concentration in the upper respiratory tract (URT) and the antibody response in patients with (D+) and without (D–) dexamethasone treatment. Methods Data and biosamples from hospitalized patients with severe COVID-19, enrolled between 4th March and 11th December 2020 in a prospective observational study, were analysed. SARS-CoV-2 virus concentration in serial URT samples was measured using RT-PCR. SARS-CoV-2-specific immunoglobulins A and G (IgA and IgG) were measured in serum samples using S1-ELISA. Results We compared 101 immunocompetent patients who received dexamethasone (according to the inclusion criteria and dosage determined in the RECOVERY trial) to 93 immunocompetent patients with comparable disease severity from the first months of the pandemic, who had not been treated with dexamethasone or other glucocorticoids. We found no inter-group differences in virus concentration kinetics, duration of presence of viral loads >106 viral copies/mL (D+ median 17 days (IQR 13–24), D– 19 days (IQR 13–29)), or time from symptom onset until seroconversion (IgA: D+ median 11.5 days (IQR 11–12), D– 14 days (IQR 11.5–15.75); IgG: D+ 13 days (IQR 12–14.5), D– 12 days (IQR 11–15)). Conclusion Dexamethasone does not appear to lead to a change in virus clearance or a delay in antibody response in immunocompetent patients hospitalized with severe COVID-19.

49 patients (22 women, 27 men, mean age 43.7 [21-65] years) with Hodgkin's disease were examined by Doppler echocardiography a median of 5.37 (2-10) years after the end of chemotherapy (given according to the COPP/ABVD scheme, with or without mediastinal irradiation) for possible chronic changes in myocardium, pericardium or cardiac valves, as well as for any haemodynamic sequelae. Maximal and integrated early (E, Ei) and late (A, Ai) diastolic flow velocities and their ratio (E/A, Ei/Ai) were measured by pulsed Doppler over the mitral and tricuspid valves. Although on two-dimensional echo 21 patients (42.9%) were found to have valvar thickening, 19 (38.8%) pericardial thickening and 9 (18.4%) a reduced fibre shortening fraction, the Doppler indices were statistically not significantly different from those in 25 controls with normal hearts. These echocardiographic data of functional and morphological parameters indicate that there was no effect on various measurements of diastolic function after chemotherapy with or without mediastinal radiation. In successfully treated patients with Hodgkin's disease the described changes are of minor significance.

Acute kidney injury (AKI) occurs in 7% of hospitalized and 66% of Intensive Care Unit (ICU) patients. It increases mortality, hospital length of stay, and costs. The aim of this study was to investigate, whether there is an association between adherence to guidelines (standard operating procedures (SOP)) for potentially nephrotoxic antibiotics and the occurrence of AKI. This study was carried out as a prospective, clinical, non-interventional, observational study. Data collection was performed over a total of 170 days in three ICUs at Charite – Universitaetsmedizin Berlin. A total of 675 patients were included; 163 of these had therapy with vancomycin, gentamicin, or tobramycin; were >18 years; and treated in the ICU for >24 hours. Patients with an adherence to SOP >70% were classified into the high adherence group (HAG) and patients with an adherence of

The net effects of acute changes in pre- and afterload on left ventricular filling, were examined by altering loading conditions in normal subjects. The specific purpose of this study was to investigate whether Doppler-derived transmitral flow patterns are able to differentiate the type of loading conditions. In 24 normal subjects (13 females, 11 males, mean age 44.1 +/- 11.5 years), the following Doppler variables were determined at baseline, after rapid volume infusion (preload increase), after nitroglycerin administration (preload decrease), during isometric exercise (afterload increase), and after application of a converting enzyme inhibitor (afterload decrease): the peak and integrated early (E, Ei) and late (A, Ai) diastolic flow velocities, their ratios (E/A, Ei/Ai), the percentage of atrial contribution (ACON), and the acceleration and deceleration times (Ac, Dc) of early filling. Reduced preload and increased afterload led to similar filling patterns characterized by a significant E and Ei decrease (p0.05, compared to baseline) accompanied by an A and Ai increase with a resultant reduction of E/A and Ei/Ai. Both changes increased the atrial contribution to filling and reduced Ac and Dc. Increased preload only significantly increased E and Ei, while reduced afterload did not induce any significant changes. Different loading conditions alter Doppler-derived diastolic filling patterns. However, the transmitral flow profile is not specific enough to distinguish the manner in which loading conditions have been altered.

The impact of valvular, myocardial and pericardial abnormalities on cardiac haemodynamics in patients treated for Hodgkin's disease with COPP/ABVD with and without mediastinal irradiation was determined in 49 patients 2-10 years after induction therapy. Diagnostic procedures to evaluate cardiac function consisted of history, physical examination, exercise bicycle stress test, M-mode two-dimensional and pulsed Doppler echocardiography. No patient reported symptoms related to cardiomyopathy, and only one of the 49 had evidence of coronary heart disease. Pericardial thickening was seen on echocardiograms in 19/49 patients (38.8%), valvular thickening in 21/49 (42.9%), and reduced fractional shortening in 9/49 (18.4%). The Doppler-derived mean E and A (+/- SD) of transmitral flow were 0.75 +/- 0.14 m/s and 0.56 +/- 0.09 m/s, respectively, in patients receiving chemotherapy and 0.81 +/- 0.19 m/s and 0.63 +/- 0.20 m/s in those with additional mediastinal irradiation. There was no statistically significant difference between mean E and A in transmitral flow in patients treated for Hodgkin's disease and control subjects. Furthermore, the transtricuspid and hepatic vein flow velocities did not differ significantly. Although the present study demonstrates high frequencies of pericardial and valvular thickening in patients treated for Hodgkin's disease with the COPP/ABVD regimen with or without mediastinal irradiation, it showed no impact on cardiac flow velocities. The abnormalities might thus be of minor clinical relevance in these patients.

There is still controversy as to the manner in which Doppler-derived transmitral filling patterns change because of myocardial ischemia. To evaluate the effects of exercise-induced ischemia on Doppler-derived filling patterns, 28 patients were examined at rest and during three stages of supine bicycle exercise (0.5, 1.0, and 1.5 W/kg). The peak early (E) and integrated early (Ei) and peak late (A) and integrated late (Ai) diastolic flow velocities, as well as their ratios (E/A, Ei/Ai), were compared between patients with exercise-induced ischemia but no wall-motion abnormalities at rest (ischemia group, n = 13) and those with akinetic scars from previous infarction but no exercise ischemia (scar group, n = 15). Normal subjects with no evidence of heart disease served as a control group (n = 11). At maximal workload the ischemia group showed a significantly lower peak flow velocity at atrial contraction than the control and scar group (0.74 +/- 0.18 vs 1.08 +/- 0.25 and 0.89 +/- 0.19 m/sec, respectively; p0.05) and also a significantly lower flow velocity integral at atrial contraction (8.24 +/- 2.2 vs 12.81 +/- 4.8 and 11.32 +/- 3.6 cm, respectively; p0.05). Therefore, the atrial contribution to filling was diminished during ischemia (36.2% +/- 9.2% vs 47.3% +/- 6.4% and 48.4% +/- 13.8%, respectively; p0.05). By maintaining the early filling rate during ischemia, the reduced atrial contribution resulted in a significantly higher E/A ratio (1.48 +/- 0.31 vs 1.05 +/- 0.15 and 1.16 +/- 0.44, respectively) and Ei/Ai ratio (2.0 +/- 1.06 vs 1.09 +/- 0.26 and 1.24 +/- 0.79, respectively). The assessment of Doppler-derived transmitral filling during exercise-induced ischemia shows mainly early diastolic filling, which is in contrast to the profile of impaired relaxation usually associated with ischemia. Evidence of exercise-induced ischemia leading to greater increases in left atrial pressure suggests that transmitral filling patterns are more closely related to hemodynamic status than to diastolic function.

Dependence of left heart opacification on ventricular function was evaluated for the new transpulmonary echo enhancing agent (SH U 508-A). The contrast agent was injected intravenously in 5 patients with normal cardiac function (ejection fraction [EF] greater than 60% and echocardiographic left ventricular end-diastolic diameter [LVED] less than 56 mm) and in five patients with pathological ventricular function (EF less than 40%, LVED greater than 65 mm). A concentration of 400 mg/mL with dosages of 5, 9, and 16 mL was used in all patients. The visually assessed signal enhancement as well as the videodensitometrically determined peak intensity and duration of signal enhancement did not differ significantly between the two patient groups, while the transit times were markedly prolonged in patients with impaired ventricular function. No significant alteration was found for systemic blood pressure and heart rate. Side effects were transitory and dose related. The noninvasive nature of the procedure and the absence of hemodynamic effects make repeated studies of left ventricular performance with SH U 508-A in patients with varied hemodynamic status possible.