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Background: Metamizole is one of the most used analgesic, antipyretic, and spasmolytic agents in many countries worldwide. While metamizole-induced agranulocytosis is an, albeit seldom, well-known adverse event, metamizole-associated drug-induced liver injury has been reported rarely in the literature and hence often remains unconsidered. Here, we present a unique case where metamizole-induced hepatotoxicity got unmasked by the simultaneous development of characteristic agranulocytosis. Case Report: A 22-year-old woman without known conditions presented with a new onset of fever, jaundice, and maculopapular rash and explicitly denied intake of any new substances. Laboratory tests showed liver injury, granulopenia, and positive anti-nuclear and anti-mitochondrial (AMA-M2) antibodies. Liver biopsy revealed a histological pattern characteristic of drug-induced liver injury and bone marrow biopsy, the classical picture of metamizole-induced agranulocytosis. Indeed the in-depth interview of the patient unveiled metamizole consumption over the last two months. Therefore, we could diagnose metamizole-induced hepato- and myelotoxicity. Accordingly, steroid therapy led to normalization of liver parameters and stimulation with granulocyte colony- stimulating factor to leukocyte recovery. Conclusion: This case report is intended to increase the awareness of metamizole-associated druginduced liver injury which should always be kept in mind due to its occasionally life-threatening course. Diagnosis can be difficult particularly if anamnesis and written records are without hints for prior metamizole intake.

Ulcerative colitis (UC) is characterized by chronic inflammation of the colorectum. Histological remission has emerged as a potential future treatment goal; however, the histopathological assessment of intestinal inflammation in UC remains challenging with a multitude of available scoring systems and the need for a pathologist with expertise in inflammatory bowel disease (IBD). In previous studies, quantitative phase imaging (QPI) including digital holographic microscopy (DHM) was successfully applied as an objective method for stain-free quantification of the degree of inflammation in tissue sections. Here, we evaluated the application of DHM for the quantitative assessment of histopathological inflammation in patients with UC. In our study, endoscopically obtained colonic and rectal mucosal biopsy samples from 21 patients with UC were analyzed by capturing DHM-based QPI images that were subsequently evaluated using the subepithelial refractive index (RI). The retrieved RI data were correlated with established histological scoring systems including the Nancy index (NI) as well as with endoscopic and clinical findings. As a primary endpoint, we found a significant correlation between the DHM-based retrieved RI and the NI (R2 = 0.251, p < 0.001). Furthermore, RI values correlated with the Mayo endoscopic subscore (MES; R2 = 0.176, p < 0.001). An area under the receiver operating characteristics (ROC) curve of 0.820 confirms the subepithelial RI as a reliable parameter to distinguish biopsies with histologically active UC from biopsies without evidence of active disease as determined by conventional histopathological examination. An RI higher than 1.3488 was found to be the most sensitive and specific cut-off value to identify histologically active UC (sensitivity of 84% and specificity of 72%). In conclusion, our data demonstrate DHM to be a reliable tool for the quantitative assessment of mucosal inflammation in patients with UC.

Aims Although coronavirus disease 2019 (COVID-19) and bacterial sepsis are distinct conditions, both are known to trigger endothelial dysfunction with corresponding microcirculatory impairment. The purpose of this study was to compare microvascular injury patterns and proteomic signatures in COVID-19 and bacterial sepsis patients. Methods and results This multi-center, observational study included 22 hospitalized adult COVID-19 patients, 43 hospitalized bacterial sepsis patients, and 10 healthy controls from 4 hospitals. Microcirculation and glycocalyx dimensions were quantified via intravital sublingual microscopy. Plasma proteins were measured using targeted proteomics (Olink). Coregulation and cluster analysis of plasma proteins was performed using a training-set and confirmed in a test-set. An independent external cohort of 219 COVID-19 patients was used for validation and outcome analysis. Microcirculation and plasma proteome analysis found substantial overlap between COVID-19 and bacterial sepsis. Severity, but not disease entity explained most data variation. Unsupervised correlation analysis identified two main coregulated plasma protein signatures in both diseases that strictly counteract each other. They were associated with microvascular dysfunction and several established markers of clinical severity. The signatures were used to derive new composite biomarkers of microvascular injury that allow to predict 28-day mortality or/and intubation (area under the curve 0.90, p Conclusion Our data imply a common biological host response of microvascular injury in both bacterial sepsis and COVID-19. A distinct plasma signature correlates with endothelial health and improved outcomes, while a counteracting response is associated with glycocalyx breakdown and high mortality. Microvascular health biomarkers are powerful predictors of clinical outcomes. Graphical abstract

Patients with cancer are at high risk of severe coronavirus disease 2019 (COVID-19), with high morbidity and mortality. Furthermore, impaired humoral response renders severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines less effective and treatment options are scarce. Randomized trials using convalescent plasma are missing for high-risk patients. Here, we performed a randomized, open-label, multicenter trial (https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001632-10/DE) in hospitalized patients with severe COVID-19 (n = 134) within four risk groups ((1) cancer (n = 56); (2) immunosuppression (n = 16); (3) laboratory-based risk factors (n = 36); and (4) advanced age (n = 26)) randomized to standard of care (control arm) or standard of care plus convalescent/vaccinated anti-SARS-CoV-2 plasma (plasma arm). No serious adverse events were observed related to the plasma treatment. Clinical improvement as the primary outcome was assessed using a seven-point ordinal scale. Secondary outcomes were time to discharge and overall survival. For the four groups combined, those receiving plasma did not improve clinically compared with those in the control arm (hazard ratio (HR) = 1.29; P = 0.205). However, patients with cancer experienced a shortened median time to improvement (HR = 2.50; P = 0.003) and superior survival with plasma treatment versus the control arm (HR = 0.28; P = 0.042). Neutralizing antibody activity increased in the plasma cohort but not in the control cohort of patients with cancer (P = 0.001). Taken together, convalescent/vaccinated plasma may improve COVID-19 outcomes in patients with cancer who are unable to intrinsically generate an adequate immune response.

Background Numerous predictive clinical scores with varying discriminatory performance have been developed in the context of the current coronavirus disease 2019 (COVID-19) pandemic. To support clinical application, we test the transferability of the frequently applied 4C mortality score (4C score) to the German prospective Cross-Sectoral Platform (SUEP) of the National Pandemic Cohort Network (NAPKON) compared to the non COVID-19 specific quick sequential organ failure assessment score (qSOFA). Our project aims to externally validate these two scores, stratified for the most prevalent variants of concerns (VOCs) of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) in Germany. Methods A total of 685 adults with polymerase chain reaction (PCR)-detected SARS-CoV-2 infection were included from NAPKON-SUEP. Patients were recruited from 11/2020 to 03/2022 at 34 university and non-university hospitals across Germany. Missing values were complemented using multiple imputation. Predictive performance for in-hospital mortality at day of baseline visit was determined by area under the curve (AUC) with 95%-confidence interval (CI) stratified by VOCs of SARS-CoV-2 (alpha, delta, omicron) (Figure 1). Figure 1:Study flow chart with inclusion criteria and methodological workflow. Results Preliminary results suggest a high predictive performance of the 4C score for in-hospital mortality (Table 1). This applies for the overall cohort (AUC 0.813 (95%CI 0.738-0.888)) as well as the VOC-strata (alpha: AUC 0.859 (95%CI 0.748-0.970); delta: AUC 0.769 (95%CI 0.657-0.882); omicron: AUC 0.866 (95%CI 0.724-1.000)). The overall mortality rates across the defined 4C score risk groups are 0.3% (low), 3.2% (intermediate), 11.6% (high), and 49.5% (very high). The 4C score performs significantly better than the qSOFA (Chi2-test: p=0.001) and the qSOFA does not seem to be a suitable tool in this context. Table 1:Discriminatory performance of the 4C Mortality Score and the qSOFA score within the validation cohort NAPKON-SUEP stratified by the Variant of Concerns of SARS-CoV-2. Conclusion Despite its development in the early phase of the pandemic and improved treatment, external validation of the 4C score in NAPKON-SUEP indicates a high predictive performance for in-hospital mortality across all VOCs. However, since the qSOFA was not specifically designed for this predictive issue, it shows low discriminatory performance, as in other validation studies. Any interpretations regarding the omicron stratum are limited due to the sample size. Disclosures Daniel Pape, Dr., Advanz Pharma Germany: Support for attending meetings and/or travel for ECCMID 2021 Martin Hower, n/a, MSD: Advisor/Consultant|Trogarzo: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant Björn-Erik O. Jensen, Dr. med., GILEAD: Advisor/Consultant|GILEAD: Lectures, Travel|GSK: Lectures, Travel Jörg J. Vehreschild, Univ.-Prof. Dr. med., Ärztekammer Nordrhein: Honoraria|Academy for Infectious Medicine, University Manchester: Honoraria|Astellas Pharma: Grant/Research Support|Astellas Pharma: Honoraria|Back Bay Strategies: Honoraria|Basilea: Grant/Research Support|Basilea: Honoraria|Deutsches Zetrum für Luft- und Raumfahrt (DLR): Grant/Research Support|German Centre for Infection Research (DZIF): Grant/Research Support|German Centre for Infection Research (DZIF): Honoraria|German Federal Ministry of Education and Research (BMBF): Grant/Research Support|German Society for Infectious Diseases (DGI): Honoraria|German Society for Internal Medicine (DGIM): Honoraria|GILEAD: Advisor/Consultant|GILEAD: Grant/Research Support|GILEAD: Honoraria|Janssen: Honoraria|Merck / MSD: Grant/Research Support|Merck / MSD: Honoraria|Molecular Health: Honoraria|Netzwerk Universitätsmedizin: Honoraria|NordForsk: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Rigshospitalet Copenhagen: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Honoraria|University Hospital Aachen: Honoraria|University Hospital Freiburg/ Congress and Communication: Honoraria|University of Bristol: Grant/Research Support.

Background Patients with hematological malignancy or other cancers as well as immunosuppression bear a high risk for severe COVID-19. Monoclonal antibodies (mAb) are efficient at early stages of the disease but may lose potency with new variants. Trials on plasma from convalescent donors in unselected patients have not shown clinical benefit. No randomized trials focussing on patients with underlying disease have been published. Methods We conducted an open-label, multicenter, randomized controlled trial to evaluate efficacy of plasma (CVP - convalescent or after vaccination) in patients with COVID-19 at high risk for adverse outcome in Germany. We assessed the effect of high-titer CVP (2 units from different donors, 238-337 ml each, on subsequent days). Patients with hematological or other malignancy (group 1), immunosuppression (group 2), age >50 and ≤75 years and lymphopenia and/or high D-dimers (group 3) or age >75 years (group 4) who were hospitalized with confirmed SARS-CoV-2 infection and with an oxygen saturation ≤94% were included. Primary outcome measure was time to clinical improvement on a seven-point ordinal scale, secondary outcome was mortality (Janssen et al. Trials 2020 Oct 6;21(1):828). Results Overall, 133 patients were randomized, 68 received CVP with an additional 10 patients as a crossover on day 10. Median age (range) was 68 years (39-95) in the CVP group and 70 (38-90) in controls. For the entire cohort, no significant difference was seen in time to improvement (median days: CVP 12.5 vs. control 18; HR 1.24 (95% confidence interval (CI) 0.83-1.85), p=0.29). Subgroup analysis (group 1+2) revealed shortened time to improvement (median days CVP 13 vs. control 32; HR 2.03 (95%CI 1.17-3.6), p=0.01) and mortality was reduced (mortality CVP n=6 (18%) vs. control n=10 (29%). No significant differences in time to improvement were observed in group 3 or 4 (HR 0.72 (95%CI 0.41-1.28), p=0.26). No relevant adverse events were observed. Conclusion CVP improves time to clinical improvement and mortality for COVID-19 patients with underlying hematological disease/cancer or other reasons of impaired immune response. Even with new variants, high-titer CVP may offer a widely available and inexpensive therapy option in high-risk groups. Funding BMBF FKZ 01KI20152; EudraCT 2020-001632-10. Disclosures Uta Merle, MD, Gilead: Sponsored congress travel and accommodation Markus Weigand, MD, Bbraun: Speakers fee/ad boards fee|Biotest: Speakers fee/ad boards fee|Eumedica: Speakers fee/ad boards fee|Gilead: Speakers fee/ad boards fee|MSD: Speakers fee/ad boards fee|Pfizer: Speakers fee/ad boards fee|Shionogi: Speakers fee/ad boards fee|SOBI: Speakers fee/ad boards fee Martin Bornhäuser, MD, Alexion: Honoraria|Jazz Pharmaceuticals: Honoraria|MSD: Honoraria|Novartis: Honoraria Nael Alakel, MD, Amgen: personal fee, travel grant|Gilead: personal fee, travel grant|MSD Sharp and Dohme GmbH: personal fee, travel grant|Pfizer: personal fee, travel grant Timo Wolf, MD, Gilead Sciences: Lecture fee, travel grant|Janssen Pharmaceuticals: Lecture fee, travel grant|Merck Sharp Dome: Lecture fee, travel grant Maria Vehreschild, Prof. Dr., 3M: speaker fee|Astellas: Advisor/Consultant|Astellas: speaker fee|biologische heilmittel heel gmbh: Grant/Research Support|BioNtech: Grant/Research Support|EUMEDICA: Advisor/Consultant|Farmak International Holding: Advisor/Consultant|Ferring: Advisor/Consultant|Ferring: Speaker fee|Gilead Sciences: Advisor/Consultant|Immunic AG: Advisor/Consultant|MaaT: Advisor/Consultant|Merck: Advisor/Consultant|Merck: speaker fee|MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: speaker fees|Pfizer: speaker fee|Roche Molecular Systems: Grant/Research Support|Roche Molecular Systems: speaker fees|SocraRTec R&D GmbH: Advisor/Consultant|Takeda California: Grant/Research Support Hanns-Martin Lorenz, MD, Abbvie: Advisor/Consultant|Abbvie: Honoraria|Actelion: Advisor/Consultant|Actelion: Honoraria|Alexion: Advisor/Consultant|Alexion: Honoraria|Amgen: Advisor/Consultant|Amgen: Grant/Research Support|Astra Zeneca: Advisor/Consultant|Astra Zeneca: Honoraria|Baxter: Advisor/Consultant|Baxter: Advisor/Consultant|Baxter: Honoraria|Baxter: Honoraria|Bayer Vital: Advisor/Consultant|Bayer Vital: Honoraria|Biogen: Advisor/Consultant|Biogen: Honoraria|BMS: Advisor/Consultant|BMS: Honoraria|Boehringer Ingelheim: Advisor/Consultant|Boehringer Ingelheim: Honoraria|Celgene: Advisor/Consultant|Celgene: Honoraria|Fresenius: Advisor/Consultant|Fresenius: Honoraria|Genzyme: Advisor/Consultant|Genzyme: Honoraria|Gilead/Galapagos: Advisor/Consultant|Gilead/Galapagos: Honoraria|GSK: Advisor/Consultant|GSK: Honoraria|Hexal: Advisor/Consultant|Hexal: Honoraria|Janssen-Cilag: Advisor/Consultant|Janssen-Cilag: Honoraria|Lilly: Advisor/Consultant|Lilly: Honoraria|Medac: Advisor/Consultant|Medac: Honoraria|MSD: Advisor/Consultant|MSD: Honoraria|Mundipharm: Advisor/Consultant|Mundipharm: Honoraria|Mylan: Advisor/Consultant|Mylan: Honoraria|Novartis: Advisor/Consultant|Novartis: Honoraria|octapharm: Advisor/Consultant|octapharm: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Roche/Chugai: Advisor/Consultant|Roche/Chugai: Honoraria|Sandoz: Advisor/Consultant|Sandoz: Honoraria|Sanofi: Advisor/Consultant|Sanofi: Honoraria|Shire: Advisor/Consultant|Shire: Honoraria|SOBI: Advisor/Consultant|SOBI: Honoraria|Thermo Fisher: Advisor/Consultant|Thermo Fisher: Honoraria|UCB: Advisor/Consultant|UCB: Honoraria.

Background: Two-dose COVID-19 vaccination often results in poor humoral response rates in patients with hematologic malignancies (HMs); yet responses to COVID-19 booster vaccines and the risk of COVID-19 infection post-booster are mostly uncertain. Methods: We included 200 outpatients with HMs and predominantly lymphoid neoplasms (96%, 191/200) in our academic center and reported on the humoral responses, which were assessed by measurement of anti-spike IgG antibodies in peripheral blood as early as 14 days after mRNA-based prime-boost vaccination, as well as factors hampering booster efficacy. Previous basic (double) immunization was applied according to the local recommendations with mRNA- and/or vector-based vaccines. We also report on post-booster COVID-19 breakthrough infections that emerged in the Omicron era and the prophylaxis strategies that were applied to poor and non-responders to booster vaccines. Results: A total of 55% (110/200) of the patients achieved seroconversion (i.e., anti-spike protein IgG antibody titer > 100 AU/mL assessed in median 48 days after prime-boost vaccination) after prime-boost vaccination. Multivariable analyses revealed age, lymphocytopenia, ongoing treatment and prior anti-CD20 B-cell depletion to be independent predictors for booster failure. With each month between anti-CD20-mediated B-cell depletion and booster vaccination, the probability of seroconversion increased by approximately 4% (p < 0.001) and serum–antibody titer (S-AbT) levels increased by 90 AU/mL (p = 0.011). Notably, obinutuzumab treatment was associated with an 85% lower probability for seroconversion after prime-boost vaccination compared to rituximab (p = 0.002). Of poor or non-responders to prime-boost vaccination, 41% (47/114) underwent a second booster and 73% (83/114) underwent passive immunization. COVID-19 breakthrough infections were observed in 15% (29/200) of patients after prime-boost vaccination with predominantly mild courses (93%). Next to seroconversion, passive immunization was associated with a significantly lower risk of COVID-19 breakthrough infections after booster, even in vaccine non-responders (all p < 0.05). In a small proportion of analyzed patients with myeloid neoplasms (9/200), the seroconversion rate was higher compared to those with lymphoid ones (78% vs. 54%, accordingly), while the incidence rate of COVID-19 breakthrough infections was similar (22% vs. 14%, respectively). Following the low frequency of myeloid neoplasms in this study, the results may not be automatically applied to a larger cohort. Conclusions: Patients with HMs are at a high risk of COVID-19 booster vaccine failure; yet COVID-19 breakthrough infections after prime-boost vaccination are predominantly mild. Booster failure can likely be overcome by passive immunization, thereby providing immune protection against COVID-19 and attenuating the severity of COVID-19 courses. Further sophistication of clinical algorithms for preventing post-vaccination COVID-19 breakthrough infections is urgently needed.

Two-dose COVID-19 vaccination often results in poor humoral response rates in patients with hematologic malignancies (HMs); yet responses to COVID-19 booster vaccines and the risk of COVID-19 infection post-booster are mostly uncertain.We included 200 outpatients with HMs and predominantly lymphoid neoplasms (96%, 191/200) in our academic center and reported on the humoral responses, which were assessed by measurement of anti-spike IgG antibodies in peripheral blood as early as 14 days after mRNA-based prime-boost vaccination, as well as factors hampering booster efficacy. Previous basic (double) immunization was applied according to the local recommendations with mRNA- and/or vector-based vaccines. We also report on post-booster COVID-19 breakthrough infections that emerged in the Omicron era and the prophylaxis strategies that were applied to poor and non-responders to booster vaccines.A total of 55% (110/200) of the patients achieved seroconversion (i.e., anti-spike protein IgG antibody titergt; 100 AU/mL assessed in median 48 days after prime-boost vaccination) after prime-boost vaccination. Multivariable analyses revealed age, lymphocytopenia, ongoing treatment and prior anti-CD20 B-cell depletion to be independent predictors for booster failure. With each month between anti-CD20-mediated B-cell depletion and booster vaccination, the probability of seroconversion increased by approximately 4% (Patients with HMs are at a high risk of COVID-19 booster vaccine failure; yet COVID-19 breakthrough infections after prime-boost vaccination are predominantly mild. Booster failure can likely be overcome by passive immunization, thereby providing immune protection against COVID-19 and attenuating the severity of COVID-19 courses. Further sophistication of clinical algorithms for preventing post-vaccination COVID-19 breakthrough infections is urgently needed.

With increasing numbers of patients recovering from COVID-19, there is increasing evidence for persistent symptoms and the need for follow-up studies. This retrospective study included patients without comorbidities, who recovered from COVID-19 and attended an outpatient clinic at a university hospital for follow-up care and potential convalescent plasma donation. Network analysis was applied to visualize symptom combinations and persistent symptoms. Comprehensive lab-testing was ascertained at each follow-up to analyze differences regarding patients with vs without persistent symptoms. 116 patients were included, age range was 18–69 years (median: 41) with follow-ups ranging from 22 to 102 days. The three most frequent persistent symptoms were Fatigue (54%), Dyspnea (29%) and Anosmia (25%). Lymphopenia was present in 13 of 112 (12%) cases. Five of 35 cases (14%) had Lymphopenia in the later follow-up range of 80–102 days. Serum IgA concentration was the only lab parameter with significant difference between patients with vs without persistent symptoms with reduced serum IgA concentrations in the patient cohort of persistent symptoms (p = 0.0219). Moreover, subgroup analyses showed that patients with lymphopenia experienced more frequently persistent symptoms. In conclusion, lymphopenia persisted in a noticeable percentage of recovered patients. Patients with persistent symptoms had significantly lower serum IgA levels. Furthermore, our data provides evidence that lymphopenia is associated with persistence of COVID-19 symptoms.

COVID-19 vaccines have become an integral element in the protection of cancer patients against SARS-CoV-2. To date, there are no direct comparisons of the course of COVID-19 infection in cancer patients between the pre- and post-vaccine era. We analyzed SARS-CoV-2 infections and their impact on cancer in COVID-19 vaccinated and non-vaccinated patients from three German cancer centers. Overall, 133 patients with SARS-CoV-2 were enrolled in pre- and post-vaccine eras: 84 non-vaccinated and 49 vaccinated, respectively. A mild course of COVID-19 was documented more frequently in vaccinated patients (49% vs. 29%), while the frequency of severe and critical courses occurred in approximately one-half of the non-vaccinated patients (22% vs. 42%, p = 0.023). Particularly, patients with hematologic neoplasms benefited from vaccination in this context (p = 0.031). Admissions to intermediate- and intensive-care units and the necessity of non-invasive and invasive respiratory support were reduced by 71% and 50% among vaccinated patients, respectively. The median length of admission was 11 days for non-vaccinated and 5 days for vaccinated patients (p = 0.002). COVID-19 mortality was reduced by 83% in vaccinated patients (p = 0.046). Finally, the median time from SARS-CoV-2 infection to restarting cancer therapy was 12 and 26 days among vaccinated and non-vaccinated groups, respectively (p = 0.002). Although this study does not have enough power to perform multivariate analyses to account for confounders, it provides data on COVID-19 in non-vaccinated and vaccinated cancer patients and illustrates the potential benefits of COVID-19 vaccines for these patients.

Rationale Pre-clinical and autopsy studies have fueled the hypothesis that a dysregulated vascular endothelium might play a central role in the pathogenesis of ARDS and multi-organ failure in COVID-19. Objectives To comprehensively characterize and quantify microvascular alterations in patients with COVID-19. Methods Hospitalized adult patients with moderate-to-severe or critical COVID-19 (n = 23) were enrolled non-consecutively in this prospective, observational, cross-sectional, multi-center study. Fifteen healthy volunteers served as controls. All participants underwent intravital microscopy by sidestream dark field imaging to quantify vascular density, red blood cell velocity (VRBC), and glycocalyx dimensions (perfused boundary region, PBR) in sublingual microvessels. Circulating levels of endothelial and glycocalyx-associated markers were measured by multiplex proximity extension assay and enzyme-linked immunosorbent assay. Measurements and main results COVID-19 patients showed an up to 90% reduction in vascular density, almost exclusively limited to small capillaries (diameter 4–6 µm), and also significant reductions of VRBC. Especially, patients on mechanical ventilation showed severe glycocalyx damage as indicated by higher PBR values (i.e., thinner glycocalyx) and increased blood levels of shed glycocalyx constituents. Several markers of endothelial dysfunction were increased and correlated with disease severity in COVID-19. PBR (AUC 0.75, p = 0.01), ADAMTS13 (von Willebrand factor-cleaving protease; AUC 0.74, p = 0.02), and vascular endothelial growth factor A (VEGF-A; AUC 0.73, p = 0.04) showed the best discriminatory ability to predict 60-day in-hospital mortality. Conclusions Our data clearly show severe alterations of the microcirculation and the endothelial glycocalyx in patients with COVID-19. Future therapeutic approaches should consider the importance of systemic vascular involvement in COVID-19.

SARS-CoV-2 infection can cause severe pneumonia (COVID-19). There is evidence that patients with comorbidities are at higher risk of a severe disease course. The role of immunosuppression in the disease course is not clear. In the present report, we first describe two cases of persisting SARS-CoV-2 viraemia with fatal outcome in patients after rituximab therapy.

(1) Background: Angiotensin-converting enzyme 2 (ACE2) is a functional receptor of SARS-CoV-2 and counter-balances ACE in the renin–angiotensin system (RAS). An imbalance of the RAS could be associated with severe COVID-19 progression. (2) Methods: Activities of serum proteases angiotensin-converting enzyme (ACE) and carboxypeptidase N (CPN) for 45 hospitalized and 26 convalescent COVID-19 patients were investigated vs. healthy controls using labeled bradykinin (DBK) degradation with and without inhibition by captopril as a read-out. Data were correlated to clinical parameters. (3) Results: DBK degradation and CPN activity were significantly reduced gender-independently in COVID-19 and returned to normal during convalescence. ACE activity was over-active in severe disease progression; product DBK1-5 was significantly increased in critically ill patients and strongly correlated with clinical heart and liver parameters. ACE inhibitors seemed to be protective, as DBK1-5 levels were normal in moderately ill patients in contrast to critically ill patients. (4) Conclusions: CPN and ACE serum activity correlated with disease severity. The RAS is affected in COVID-19, and ACE could be a therapeutic target. Further proof from dedicated studies is needed.

(1) Background: Angiotensin-converting enzyme 2 (ACE2) is a functional receptor of SARS-CoV-2 and counter-balances ACE in the renin-angiotensin system (RAS). An imbalance of the RAS could be associated with severe COVID-19 progression. (2) Methods: Activities of serum proteases angiotensin-converting enzyme (ACE) and carboxypeptidase N (CPN) for 45 hospitalized and 26 convalescent COVID-19 patients were investigated vs. healthy controls using labeled bradykinin (DBK) degradation with and without inhibition by captopril as a read-out. Data were correlated to clinical parameters. (3) Results: DBK degradation and CPN activity were significantly reduced gender-independently in COVID-19 and returned to normal during convalescence. ACE activity was over-active in severe disease progression; product DBK1-5 was significantly increased in critically ill patients and strongly correlated with clinical heart and liver parameters. ACE inhibitors seemed to be protective, as DBK1-5 levels were normal in moderately ill patients in contrast to critically ill patients. (4) Conclusions: CPN and ACE serum activity correlated with disease severity. The RAS is affected in COVID-19, and ACE could be a therapeutic target. Further proof from dedicated studies is needed.

Crohn’s disease and ulcerative colitis are chronic inflammatory bowel diseases (IBDs). Immunosuppressive medication is the main therapeutic approach to reducing inflammation of the gastrointestinal tract. Immunocompromised patients are more vulnerable to severe courses of illness after infection with common pathogens. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the pathogen of the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 leads to acute respiratory distress syndrome (ARDS) following severe pulmonal damage in a significant number of cases. The worldwide circulation of SARS-CoV-2 has led to major concerns about the management of IBD patients during the pandemic, as these patients are expected to be at greater risk of complications because of their underlying altered immunological condition and immunosuppressive therapies. Vaccination against SARS-CoV-2 is considered the main approach in containing the pandemic. Today, several vaccines have been shown to be highly effective in the prevention of SARS-CoV-2 infection and severe disease course in subjects without underlying conditions in respective registration studies. Patients with underlying conditions such as IBD and/or immunosuppressive therapies were not included in the registration studies, so little is known about effectiveness and safety of SARS-CoV-2 vaccination in immunocompromised IBD patients. This review provides an overview of the recent knowledge about vaccine response in IBD patients after vaccination against SARS-CoV-2.

Background. Following COVID-19, patients often present with ongoing symptoms comparable to chronic fatigue and subjective deterioration of exercise capacity (EC), which has been recently described as postacute COVID-19 syndrome. Objective. To objectify the reduced EC after COVID-19 and to evaluate for pathologic limitations. Methods. Thirty patients with subjective limitation of EC performed cardiopulmonary exercise testing (CPET). If objectively limited in EC or deteriorated in oxygen pulse, we offered cardiac stress magnetic resonance imaging (MRI) and a follow-up CPET. Results. Eighteen male and 12 female patients were included. Limited relative EC was detected in 11/30 (36.7%) patients. Limitation correlated with reduced body weight-indexed peak oxygen (O2) uptake (peakV̇O2/kg) (mean 74.7 (±7.1) % vs. 103.6 (±14.9) %, p < 0.001 ). Reduced peakV̇O2/kg was found in 18/30 (60.0%) patients with limited EC. Patients with reduced EC widely presented an impaired maximum O2 pulse (75.7% (±5.6) vs. 106.8% (±13.9), p < 0.001 ). Abnormal gas exchange was absent in all limited EC patients. Moreover, no patient showed signs of reduced pulmonary perfusion. Using cardiac MRI, diminished biventricular ejection fraction was ruled out in 16 patients as a possible cause for reduced O2 pulse. Despite noncontrolled training exercises, follow-up CPET did not reveal any exercise improvements. Conclusions. Deterioration of EC was not associated with ventilatory or pulmonary vascular limitation. Exercise limitation was related to both reduced O2 pulse and peakV̇O2/kg, which, however, did not correlate with the initial severity of COVID-19. We hypothesize that impaired microcirculation or limited peripheral O2 utilization might be causative for prolonged deterioration of EC following acute COVID-19 infection.

Infection with the novel coronavirus SARS-CoV-2 triggers severe illness with high mortality in a subgroup of patients. Such a critical course of COVID-19 is thought to be associated with the development of cytokine storm, a condition seen in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH). However, specific data demonstrating a clear association of cytokine storm with severe COVID-19 are still lacking. The aim of this study was to directly address whether immune activation in COVID-19 does indeed mimic the conditions found in these classic cytokine storm syndromes.Levels of 22 biomarkers were quantified in serum samples from patients with COVID-19 (n = 30 patients, n = 83 longitudinal samples in total), patients with secondary HLH/MAS (n = 50), and healthy controls (n = 9). Measurements were performed using bead array assays and single-marker enzyme-linked immunosorbent assay. Serum biomarker levels were assessed for correlations with disease outcome.In patients with secondary HLH/MAS, we observed pronounced activation of the interleukin-18 (IL-18)-interferon-γ axis, increased serum levels of IL-1 receptor antagonist, intercellular adhesion molecule 1, and IL-8, and strongly reduced levels of soluble Fas ligand in the course of SARS-CoV-2 infection. These observations appeared to discriminate immune dysregulation in critical COVID-19 from the well-recognized characteristics of other cytokine storm syndromes.Serum biomarker profiles clearly separate COVID-19 from MAS or secondary HLH in terms of distinguishing the severe systemic hyperinflammation that occurs following SARS-CoV-2 infection. These findings could be useful in determining the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions in the treatment of COVID-19.

Background Syndecan-1 (Sdc1) is a heparin sulfate proteoglycan expressed in intestinal epithelium, which plays a crucial role in inflammation and epithelial repair. Sdc1-knockout mice have a deteriorated course of dextran sulfate sodium-induced colitis as compared to controls. Syndecan-1 is also shed into the serum during inflammation of the epithelium. We hypothesized that an increased serum level of soluble Sdc1 is a biomarker of intestinal inflammation in ulcerative colitis (UC). Objectives To evaluate serum soluble Sdc1 as a biomarker of intestinal inflammation in UC. Material and methods This is a proof-of-concept study. Patients were recruited by the University Hospital Munster and HELIOS Albert Schweitzer Klinik Northeim (Germany). Blood samples were collected from UC patients actively suffering from this condition and those in remission. The levels of Sdc1 were measured with Diaclone CD 138 ELISA kit (Diaclone Research, Besancon, France) and routine clinical data were collected (C-reactive protein (CRP) levels, calprotectin in stool samples). Data were analyzed using SPSS software. Results Soluble Sdc1 levels were significantly elevated in the active UC group as compared to the inactive UC group (94.5 ±68.1 ng/mL compared to 28.3 ±12.6 ng/mL, p = 0.0020). The levels of Sdc1 also significantly correlated with the severity of UC as measured with the Mayo score (p = 0.0248). Receiver operating characteristic (ROC) analysis showed a good correlation of Sdc1 with an endoscopic Mayo score ≥2, with a value of 0.7747 (95% confidence interval (95% CI) = 0.5775-0.9718). A cutoff value of 37.1 ng/mL of Sdc1 showed a sensitivity of 78% and a specificity of 77%. A panel of biomarkers including CRP, hemoglobin, hematocrit, and Sdc1 was able to precisely predict active UC with an area under the curve (AUC) = 0.9395 (95% CI = 0.8509-1.0000). Conclusions Serum soluble Sdc1 correlates significantly with mucosa inflammation and Mayo score in UC. Clinical trials No. NCT02333526.

COVID-19 is a pandemic disease that causes severe pulmonary damage and hyperinflammation. Vitamin A is a crucial factor in the development of immune functions and is known to be reduced in cases of acute inflammation. This prospective, multicenter observational cross-sectional study analyzed vitamin A plasma levels in SARS-CoV-2 infected individuals, and 40 hospitalized patients were included. Of these, 22 developed critical disease (Acute Respiratory Distress Syndrome [ARDS]/Extracorporeal membrane oxygenation [ECMO]), 9 developed severe disease (oxygen supplementation), and 9 developed moderate disease (no oxygen supplementation). A total of 47 age-matched convalescent persons that had been earlier infected with SARS-CoV-2 were included as the control group. Vitamin A plasma levels were determined by high-performance liquid chromatography. Reduced vitamin A plasma levels correlated significantly with increased levels of inflammatory markers (CRP, ferritin) and with markers of acute SARS-CoV-2 infection (reduced lymphocyte count, LDH). Vitamin A levels were significantly lower in hospitalized patients than in convalescent persons (p &lt, 0.01). Of the hospitalized patients, those who were critically ill showed significantly lower vitamin A levels than those who were moderately ill (p &lt, 0.05). Vitamin A plasma levels below 0.2 mg/L were significantly associated with the development of ARDS (OR = 5.54 [1.01–30.26], p = 0.048) and mortality (OR 5.21 [1.06–25.5], p = 0.042). Taken together, we conclude that vitamin A plasma levels in COVID-19 patients are reduced during acute inflammation and that severely reduced plasma levels of vitamin A are significantly associated with ARDS and mortality.

Background: The prone position (PP) is increasingly used in mechanically ventilated coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) patients. However, studies investigating the influence of the PP are currently lacking in these patients. This is the first study to investigate the influence of the PP on the oxygenation and decarboxylation in COVID-19 patients. Methods: A prospective bicentric study design was used, and in mechanically ventilated COVID-19 patients, PP was indicated from a partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FIO2) ratio of &lt, 200. Patients were left prone for 16 h each. Pressure levels, FIO2, were adjusted to ensure a PaO2 greater than 60 mmHg. Blood gas analyses were performed before (baseline 0.5 h), during (1/2/5.5/9.5/13 h), and after being in the PP (1 h), the circulatory/ventilation parameters were continuously monitored, and lung compliance (LC) was roughly calculated. Responders were defined compared to the baseline value (PaO2/FIO2 ratio increase of ≥15%, partial pressure of carbon dioxide (PaCO2) decrease of ≥2%). Results: 13 patients were included and 36 PP sessions were conducted. Overall, PaO2/FIO2 increased significantly in the PP (p &lt, 0.001). Most PaO2/FIO2 responders (29/36 PP sessions, 77%) were identified 9.5 h after turning prone (14% slow responders), while most PaCO2 responders (15/36 PP sessions, 42%) were identified 13 h after turning prone. A subgroup of patients (interval intubation to PP ≥3 days) showed less PaO2/FIO2 responders (16% vs. 77%). An increase in PaCO2 and minute ventilation in the PP showed a significant negative correlation (p &lt, 0.001). LC (median before the PP = 38 mL/cm H2O, two patients with LC &gt, 80 mL/cm H2O) showed a significant positive correlation with the 28 day survival of patients (p = 0.01). Conclusion: The PP significantly improves oxygenation in COVID-19 ARDS patients. The data suggest that they also benefit most from an early PP. A decrease in minute ventilation may result in fewer PaCO2 responders. LC may be a predictive outcome parameter in COVID-19 patients. Trial registration: Retrospectively registered.

The clinical course of COVID-19 is very heterogeneous: Most infected individuals can be managed in an outpatient setting, but a substantial proportion of patients requires intensive care, resulting in a high rate of fatalities. Recently, an association between contact to small children and mild course of COVID-19 was reported. We performed an observational study to assess the impact of previous infections with seasonal coronaviruses on COVID-19 severity. 60 patients with confirmed COVID-19 infections were included (age 30 - 82 years; 52 males, 8 females): 19 inpatients with critical disease, 16 inpatients with severe or moderate disease and 25 outpatients (age and gender matched to inpatients). Patients with critical disease had significantly lower levels of HCoV OC43- (p=0.016) and HCoV HKU1-specific (p=0.023) antibodies at the first encounter compared to other COVID-19 patients. Our results indicate that previous infections with seasonal coronaviruses might protect against a severe course of disease. This finding should be validated in other settings and could contribute to identify persons at risk before an infection.

It is known that severe COVID-19 cases in small children are rare. If a childhood-related infection would be protective against severe course of COVID-19, it would be expected that adults with intensive and regular contact to small children also may have a mild course of COVID-19 more frequently. To test this hypothesis, a survey among 4,010 recovered COVID-19 patients was conducted in Germany. 1,186 complete answers were collected. 6.9% of these patients reported frequent and regular job-related contact to children below 10 years of age and 23.2% had own small children, which is higher than expected. In the relatively small subgroup with intensive care treatment (n=19), patients without contact to small children were overrepresented. These findings are not well explained by age, gender or BMI distribution of those patients and should be validated in other settings.

The SARS-CoV-2 virus is the causative agent of the COVID-19 pandemic. The disease causes respiratory failure in some individuals accompanied by marked hyperinflammation. Vitamin A (syn. retinol) can exist in the body in the storage form as retinyl ester, or in the transcriptionally active form as retinoic acid. The main function of retinol binding protein 4 (RBP4), synthesized in the liver, is to transport hydrophobic vitamin A to various tissues. Vitamin A has an important role in the innate and acquired immune system. In particular, it is involved in the repair of lung tissue after infections. In viral respiratory diseases such as influenza pneumonia, vitamin A supplementation has been shown to reduce mortality in animal models. In critically ill COVID-19 patients, a significant decrease in plasma vitamin A levels and an association with increased mortality have been observed. However, there is no evidence on RBP4 in relation to COVID-19. This prospective, multicenter, observational, cross-sectional study examined RBP4 (enzyme-linked immunosorbent assay) and vitamin A plasma levels (high-performance liquid chromatography) in COVID-19 patients, including 59 hospitalized patients. Of these, 19 developed critical illness (ARDS/ECMO), 20 developed severe illness (oxygenation disorder), and 20 developed moderate illness (no oxygenation disorder). Twenty age-matched convalescent patients following SARS-CoV-2 infection, were used as a control group. Reduced RBP4 plasma levels significantly correlated with impaired liver function and elevated inflammatory markers (CRP, lymphocytopenia). RBP4 levels were decreased in hospitalized patients with critical illness compared to nonpatients (p < 0.01). In comparison, significantly lower vitamin A levels were detected in hospitalized patients regardless of disease severity. Overall, we conclude that RBP4 plasma levels are significantly reduced in critically ill COVID-19 patients during acute inflammation, and vitamin A levels are significantly reduced in patients with moderate/severe/critical illness during the acute phase of illness.

Background The vast majority of COVID-19 patients experience a mild disease. However, a minority suffers from critical disease with substantial morbidity and mortality. Objectives To identify individuals at risk of critical COVID-19, the relevance of a seroreactivity against seasonal human coronaviruses was analyzed. Methods We conducted a multi-center non-interventional study comprising 296 patients with confirmed SARS-CoV-2 infections from four tertiary care referral centers in Germany and France. The ICU group comprised more males, whereas the outpatient group contained a higher percentage of females. For each patient, the serum or plasma sample obtained closest after symptom onset was examined by immunoblot regarding IgG antibodies against the nucleocapsid protein (NP) of HCoV 229E, NL63, OC43 and HKU1. Results Median age was 60 years (range 18-96). Patients with critical disease (n=106) had significantly lower levels of anti-HCoV OC43 nucleocapsid protein (NP)-specific antibodies compared to other COVID-19 inpatients (p=0.007). In multivariate analysis (adjusted for age, sex and BMI), OC43 negative inpatients had an increased risk of critical disease (adjusted odds ratio (AOR) 2.68 [95% CI 1.09 - 7.05]), higher than the risk by increased age or BMI, and lower than the risk by male sex. A risk stratification based on sex and OC43 serostatus was derived from this analysis. Conclusions Our results suggest that prior infections with seasonal human coronaviruses can protect against a severe course of COVID-19. Therefore, anti-OC43 antibodies should be measured for COVID-19 inpatients and considered as part of the risk assessment for each patient. Hence, we expect individuals tested negative for anti-OC43 antibodies to particularly benefit from vaccination against SARS-CoV-2, especially with other risk factors prevailing.