No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials.

Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients.

Receptor transfer between immune cells by autoantibody-enhanced, CD32-driven trogocytosis is hijacked by HIV-1 to infect resting CD4 T cells.

Immune cell phenotyping frequently detects lineage-unrelated receptors. Here, we report that surface receptors can be transferred from primary macrophages to CD4 T cells and identify the Fcγ receptor CD32 as driver and cargo of this trogocytotic transfer. Filamentous CD32+ nanoprotrusions deposit distinct plasma membrane patches onto target T cells. Transferred receptors confer cell migration and adhesion properties, and macrophage-derived membrane patches render resting CD4 T cells susceptible to infection by serving as hotspots for HIV-1 binding. Antibodies that recognize T cell epitopes enhance CD32-mediated trogocytosis. Such autoreactive anti-HIV-1 envelope antibodies can be found in the blood of HIV-1 patients and, consistently, the percentage of CD32+ CD4 T cells is increased in their blood. This CD32-mediated, antigen-independent cell communication mode transiently expands the receptor repertoire and functionality of immune cells. HIV-1 hijacks this mechanism by triggering the generation of trogocytosis-promoting autoantibodies to gain access to immune cells critical to its persistence.

Smart hospital: achieving interoperability and raw data collection from medical devices in clinical routine.

Introduction: Today, modern technology is used to diagnose and treat cardiovascular disease. These medical devices provide exact measures and raw data such as imaging data or biosignals. So far, the Broad Integration of These Health Data into Hospital Information Technology Structures-Especially in Germany-is Lacking, and if data integration takes place, only non-Evaluable Findings are Usually Integrated into the Hospital Information Technology Structures. A Comprehensive Integration of raw Data and Structured Medical Information has not yet Been Established. The aim of this project was to design and implement an interoperable database (cardio-vascular-information-system, CVIS) for the automated integration of al medical device data (parameters and raw data) in cardio-vascular medicine. Methods: The CVIS serves as a data integration and preparation system at the interface between the various devices and the hospital IT infrastructure. In our project, we were able to establish a database with integration of proprietary device interfaces, which could be integrated into the electronic health record (EHR) with various HL7 and web interfaces. Results: In the period between 1.7.2020 and 30.6.2022, the data integrated into this database were evaluated. During this time, 114,858 patients were automatically included in the database and medical data of 50,295 of them were entered. For technical examinations, more than 4.5 million readings (an average of 28.5 per examination) and 684,696 image data and raw signals (28,935 ECG files, 655,761 structured reports, 91,113 x-ray objects, 559,648 ultrasound objects in 54 different examination types, 5,000 endoscopy objects) were integrated into the database. Over 10.2 million bidirectional HL7 messages (approximately 14,000/day) were successfully processed. 98,458 documents were transferred to the central document management system, 55,154 materials (average 7.77 per order) were recorded and stored in the database, 21,196 diagnoses and 50,353 services/OPS were recorded and transferred. On average, 3.3 examinations per patient were recorded; in addition, there are an average of 13 laboratory examinations. Discussion: Fully automated data integration from medical devices including the raw data is feasible and already creates a comprehensive database for multimodal modern analysis approaches in a short time. This is the basis for national and international projects by extracting research data using FHIR.

Are enterococcal bloodstream infections an independent risk factor for a poorer 5-year survival or just a marker for severity of illness?-The Munich multicentric enterococci cohort.

IMPORTANCE: The present study provides a substantial contribution to literature, showing that patients with enterococcal bloodstream infections (BSI) have a lower survival rate than those with Escherichia coli (E. coli) bloodstream infections after adjusting for 17 limiting prognostic factors and excluding patients with a limited life expectancy [metastatic tumor disease, Charlson Comorbidity Index (CCI) (greater than or equal to) 5]. This difference in the 5-year long-term survival was mainly driven by Enterococcus faecium (ECFM) bloodstream infections, with vancomycin resistance not being a significant contributing factor. Our findings imply that E. faecium bloodstream infections seem to be an independent risk factor for poor long-term outcomes. As such, future research should confirm this relationship and prioritize investigating its causality through prospective studies.

Evaluation of Self-Collected Versus Health Care Professional (HCP)-Performed Sampling and the Potential Impact on the Diagnostic Results of Asymptomatic Sexually Transmitted Infections (STIs) in High-Risk Individuals.

Sexually transmitted infections (STIs) are increasing among men who have sex with men (MSM). Screening can improve the detection and outcome of asymptomatic STIs in high-risk populations. Self-sampling may be a resource-optimized strategy; however, its diagnostic reliability compared to testing by healthcare professionals (HCPs) requires further investigation. In this prospective, multicenter cohort study in a high-income country, asymptomatic MSM with a sexual risk profile for STIs were included. Sequential swabs for STI nucleic acid-based diagnosis of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) were performed after randomization, either through self-sampling or HCP-performed sampling. Baseline demographic information, sexual risk behavior, and acceptance and feedback on self-sampling were recorded using an electronic questionnaire. Out of 236 asymptomatic MSM, 47 individuals (19.9%) tested positive for CT and/or NG through self- or HCP-performed sampling. For CT, the sensitivity was 93.3% for both sampling methods, while for NG, it was 90.0% for self-sampling and 95.0% for HCP-performed sampling. Our study demonstrates that self-sampling for asymptomatic STIs has a comparable diagnostic outcome to HCP-performed sampling, with high acceptance in high-risk MSM.

[Measures and Recommendations for Ensuring Adequate Inpatient Care Capacities for Pandemic Management within a Region: Results of a Hybrid Delphi Method]. / Maßnahmen und Empfehlungen für die Sicherstellung adäquater stationärer Versorgungskapazitäten für das Pandemiemanagement innerhalb einer Region ­ Ergebnisse eines hybriden Delphi-Verfahrens.

INTRODUCTION: Since the beginning of the pandemic in spring 2020, inpatient healthcare has been under enormous burden, which is reflected especially in overworked staff, imprecise bed planning and/or data transfer. According to the recommendation of the Science Council, university clinics should play a controlling role in regional healthcare and act in conjunction with surrounding hospitals and practices. METHODS: In September 2021, 31 representatives from 18 university hospitals were invited to a hybrid Delphi study with a total of 4 survey rounds to discuss criteria for effective inpatient care in a pandemic situation, which were extracted from previous expert interviews. Criteria that were classified as very important/relevant by≥75% of the participants in the first round of the survey (consensus definition) were then further summarized in 4 different small groups. In a third Delphi round, all participants came together again to discuss the results of the small group discussions. Subsequently, these were prioritized as Optional ("can"), Desirable ("should") or Necessary ("must") recommendations. RESULTS: Of the invited clinical experts, 21 (67.7%) participated in at least one Delphi round. In an online survey (1st Delphi round), 233 criteria were agreed upon and reduced to 84 criteria for future pandemic management in four thematic small group discussions (2nd Delphi round) and divided into the small groups as follows: "Crisis Management and Crisis Plans" (n=20), "Human Resources Management and Internal Communication" (n=16), "Regional Integration and External Communication" (n=24) and "Capacity Management and Case & Care" (n=24). In the following group discussion (3rd Delphi round), the criteria were further modified and agreed upon by the experts, so that in the end result, there were 23 essential requirements and recommendations for effective inpatient care in a pandemic situation. CONCLUSION: The results draw attention to key demands of clinical representatives, for example, comprehensive digitization, standardization of processes and better (supra) regional networking in order to be able to guarantee needs-based care even under pandemic conditions. The present consensus recommendations can serve as guidelines for future pandemic management in the inpatient care sector.

Seroconversion rate of SARS-CoV-2 IgG antibodies and dating behaviour in HIV-PrEP users in a German metropolis during the COVID-19 pandemic.

BACKGROUND: At the beginning of the COVID-19 pandemic, when mortality was high, social distance was the only option to prevent transmission of SARS-CoV-2 and prohibit uncontrolled spreading. As the impact of social distancing on sexual behavior was unclear, we aimed to assess the influence of sexual risk behavior on SARS-CoV-2 seroconversion in HIV pre-exposition prophylaxis (PrEP) users after declaration of the pandemic. METHODS: Prospective study on SARS-CoV-2 IgG-antibody seroconversion rate over time in men having sex with men (MSM) using PrEP at a single tertiary university hospital in Munich, Germany, during quarterly (Q) routine HIV-PrEP visits over 1 year per participant (May 2020 - September 2021). Seroconversion was defined as at least one positive anti-nucleocapsid (anti-N) SARS-CoV-2 IgG antibody test as surrogate for past infection. In addition, sexually transmitted infections (STIs), personal estimated risk behavior and sexual contacts were assessed. RESULTS: Seroconversion rate during the full observation period was 7.3% (9/124 subjects) by September 2021. Percentage of subjects with symptomatic STIs (T. pallidum, N. gonorrhoeae, C. trachomatis and M. genitalium) was 18.7% in Q3-20, 8.1% in Q4-20, 11.1% in Q1-21, 11.6% in Q2-21 and 9.5% in Q3-21. Perception of subjective threat of SARS-CoV-2 infection and adequacy of preventive measures decreased during the observation period. However, self-reported sex behavior remained stable during the observation period. CONCLUSIONS: Our cohort showed low proportion of PrEP-users with anti-N IgG by September 2021, comparable to the local incidence. Sexual behavior in this cohort did not change, despite local recommendations for social distancing.

T-Cell-Dominated Immune Response Resolves Protracted SARS-CoV-2 Infection in the Absence of Neutralizing Antibodies in an Immunocompromised Individual.

Immunocompromised individuals are at higher risk of developing protracted and severe COVID-19, and understanding individual disease courses and SARS-CoV-2 immune responses in these individuals is of the utmost importance. For more than two years, we followed an immunocompromised individual with a protracted SARS-CoV-2 infection that was eventually cleared in the absence of a humoral neutralizing SARS-CoV-2 antibody response. By conducting an in-depth examination of this individual's immune response and comparing it to a large cohort of convalescents who spontaneously cleared a SARS-CoV-2 infection, we shed light on the interplay between B- and T-cell immunity and how they interact in clearing SARS-CoV-2 infection.

Differentiation of Spontaneous Bacterial Peritonitis from Secondary Peritonitis in Patients with Liver Cirrhosis: Retrospective Multicentre Study.

Ascitic fluid infection is a serious complication of liver cirrhosis. The distinction between the more common spontaneous bacterial peritonitis (SBP) and the less common secondary peritonitis in patients with liver cirrhosis is crucial due to the varying treatment approaches. This retrospective multicentre study was conducted in three German hospitals and analysed 532 SBP episodes and 37 secondary peritonitis episodes. Overall, >30 clinical, microbiological, and laboratory parameters were evaluated to identify key differentiation criteria. Microbiological characteristics in ascites followed by severity of illness and clinicopathological parameters in ascites were the most important predictors identified by a random forest model to distinguish between SBP and secondary peritonitis. To establish a point-score model, a least absolute shrinkage and selection operator (LASSO) regression model selected the ten most promising discriminatory features. By aiming at a sensitivity of 95% either to rule out or rule in SBP episodes, two cut-off scores were defined, dividing patients with infected ascites into a low-risk (score ≥ 45) and high-risk group (score < 25) for secondary peritonitis. Overall, the discrimination of secondary peritonitis from SBP remains challenging. Our univariable analyses, random forest model, and LASSO point score may help clinicians with the crucial differentiation between SBP and secondary peritonitis.

Disease severity in hospitalized COVID-19 patients: comparing routine surveillance with cohort data from the LEOSS study in 2020 in Germany.

INTRODUCTION: Studies investigating risk factors for severe COVID-19 often lack information on the representativeness of the study population. Here, we investigate factors associated with severe COVID-19 and compare the representativeness of the dataset to the general population. METHODS: We used data from the Lean European Open Survey on SARS-CoV-2 infected patients (LEOSS) of hospitalized COVID-19 patients diagnosed in 2020 in Germany to identify associated factors for severe COVID-19, defined as progressing to a critical disease stage or death. To assess the representativeness, we compared the LEOSS cohort to cases of hospitalized patients in the German statutory notification data of the same time period. Descriptive methods and Poisson regression models were used. RESULTS: Overall, 6672 hospitalized patients from LEOSS and 132,943 hospitalized cases from the German statutory notification data were included. In LEOSS, patients above 76 years were less likely represented (34.3% vs. 44.1%). Moreover, mortality was lower (14.3% vs. 21.5%) especially among age groups above 66 years. Factors associated with a severe COVID-19 disease course in LEOSS included increasing age, male sex (adjusted risk ratio (aRR) 1.69, 95% confidence interval (CI) 1.53-1.86), prior stem cell transplantation (aRR 2.27, 95% CI 1.53-3.38), and an elevated C-reactive protein at day of diagnosis (aRR 2.30, 95% CI 2.03-2.62). CONCLUSION: We identified a broad range of factors associated with severe COVID-19 progression. However, the results may be less applicable for persons above 66 years since they experienced lower mortality in the LEOSS dataset compared to the statutory notification data.

Use and effectiveness of remdesivir for the treatment of patients with covid-19 using data from the Lean European Open Survey on SARS-CoV-2 infected patients (LEOSS): a multicentre cohort study.

OBJECTIVES: The use of remdesivir (RDV) as the first drug approved for coronavirus disease 2019 (COVID-19) remains controversial. Based on the Lean European Open Survey on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected patients (LEOSS), we aim to contribute timing-focused complementary real-world insights to its evaluation. METHODS: SARS-CoV-2 infected patients between January 2020 and December 2021 treated with RDV were matched 1:1 to controls considering sociodemographics, comorbidities and clinical status. Multiple imputations were used to account for missing data. Effects on fatal outcome were estimated using uni- and multivariable Cox regression models. RESULTS: We included 9,687 patients. For those starting RDV administration in the complicated phase, Cox regression for fatal outcome showed an adjusted hazard ratio (aHR) of 0.59 (95%CI 0.41-0.83). Positive trends could be obtained for further scenarios: an aHR of 0.51 (95%CI 0.16-1.68) when RDV was initiated in uncomplicated and of 0.76 (95% CI 0.55-1.04) in a critical phase of disease. Patients receiving RDV with concomitant steroids exhibited a further reduction in aHR in both, the complicated (aHR 0.50, 95%CI 0.29-0.88) and critical phase (aHR 0.63, 95%CI 0.39-1.02). CONCLUSION: Our study results elucidate that RDV use, in particular when initiated in the complicated phase and accompanied by steroids is associated with improved mortality. However, given the limitations of non-randomized trials in estimating the magnitude of the benefit of an intervention, further randomized trials focusing on the timing of therapy initiation seem warranted.

Sofosbuvir plus velpatasvir for 8 weeks in patients with acute hepatitis C: The HepNet acute HCV-V study.

Background & Aims: EASL guidelines recommend 8 weeks of treatment with sofosbuvir plus velpatasvir (SOF/VEL) for the treatment of acute or recently acquired HCV infection, but only 6- and 12-week data are available. Therefore, the aim of this study was to evaluate the safety and efficacy of a shortened 8-week SOF/VEL treatment for acute HCV monoinfection. Methods: In this investigator-initiated, prospective, multicentre, single-arm study, we recruited 20 adult patients with acute HCV monoinfection from nine centers in Germany. Patients received SOF/VEL (400/100 mg) as a fixed-dose combination tablet once daily for 8 weeks. The primary efficacy endpoint was the proportion of patients with sustained virological response 12 weeks after the end of treatment (SVR12). Results: The median HCV RNA viral load at baseline was 104,307 IU/ml; the distribution of HCV genotypes was as follows: GT1a/1b/2/3/4: n = 12/1/1/3/3. Thirteen (65%) of the 20 patients were taking medication for HIV pre-exposure prophylaxis. SVR12 was achieved in all patients who complied with the study protocol (n = 18/18 [100%], per protocol analysis), but the primary endpoint was not met in the intention-to-treat analysis (n = 18/20 [90%]) because two patients were lost to follow-up. One serious adverse event (unrelated to study drug) occurred during 12 weeks of post-treatment follow-up. Conclusions: The 8-week treatment with SOF/VEL was well tolerated and highly effective in all adherent patients with acute HCV monoinfection. Early treatment of hepatitis C might effectively prevent the spread of HCV in high-risk groups. Clinical Trial Number: NCT03818308. Impact and implications: The HepNet acute HCV-V study (NCT03818308), an investigator-initiated, single-arm, multicenter pilot study, demonstrates the efficacy and safety of 8 weeks of daily treatment with the fixed-dose combination sofosbuvir/velpatasvir (400/100 mg) in patients with acute hepatitis C virus (HCV) infection. All patients who completed therapy and were followed-up achieved sustained virologic response. Thus, early treatment with SOF/VEL which might effectively prevent the spread of HCV in high-risk groups can be recommended for patients with acute HCV monoinfection.

[Development and validation of potential structure indicators for clinical infectious disease (ID) care in German hospitals during the COVID-19 pandemic]. / Entwicklung und Validierung potenzieller Strukturindikatoren zur Evaluierung des klinisch-infektiologischen Versorgungsangebots in deutschen Krankenhäusern während der COVID-19-Pandemie.

INTRODUCTION: This study describes the development and validation of structure indicators for clinical infectious disease (ID) care in German hospitals, which is important to adequately face the future challenges in ID medicine. METHODS: A team of experts developed the structure indicators in a three-stage, multicriteria decision-making process: (1) identification of potential structure indicators based on a literature review, (2) written assessment process, and (3) face-to-face discussion to reach consensus and final selection of appropriate structure indicators. A field study was conducted to assess the developed structure indicators. A score based on the structure indicators was determined for each hospital and validated via receiver operator characteristic (ROC) curves using externally validated ID expertise (German Society of ID (DGI) Centre). RESULTS: Based on a list of 45 potential structure indicators, 18 suitable indicators were developed for clinical ID care structures in German hospitals. Out of these, ten key indicators were defined for the general and coronavirus disease 2019- (COVID-19-) specific clinical ID care structures. In the field survey of clinical ID care provision for COVID-19 patients in 40 German hospitals, the participating facilities achieved 0 to 9 points (median 4) in the determined score. The area under the ROC curve was 0.893 (95% CI: 0.797, 0.988; p < 0.001). DISCUSSION/CONCLUSION: The structure indicators developed within the framework of a transparent and established development process can be used in the future to both capture the current state and future developments of ID care quality in Germany and enable comparisons.

Clinical and virological features of first human monkeypox cases in Germany.

BACKGROUND: Monkeypox is a zoonotic orthopoxvirus infection endemic in central and western Africa. In May 2022, human monkeypox infections including human-to-human transmission were reported in a multi-country outbreak in Europe and North America. CASE PRESENTATIONS: Here we present the first two cases of monkeypox infection in humans diagnosed in Germany. We present clinical and virological findings, including the detection of monkeypox virus DNA in blood and semen. The clinical presentation and medical history of our patients suggest close physical contact during sexual interactions as the route of infection. CONCLUSION: Monkeypox requires rapid diagnosis and prompt public health response. The disease should be considered in the current situation especially the differential diagnosis of vesicular or pustular rash, particularly in patients with frequent sexual contacts. Most importantly, it is essential to raise awareness among all health professionals for the rapid and correct recognition and diagnosis of this disease, which is probably still underreported in Europe (Adler et al. in Lancet Infect Dis https://doi.org/10.1016/s1473-3099(22)00228-6 , 2022).

Low Spontaneous Clearance Rates of Recently Acquired Hepatitis C Virus in Human Immunodeficiency Virus-Positive Men Who Have Sex With Men (PROBE-C Study).

BACKGROUND: Using direct-acting antivirals (DAAs) for recently acquired hepatitis C virus (RAHCV) infections, particularly in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM), dramatically reduced the incidence of hepatitis C. However, implementation into clinical practice is challenging. The aim of this study was to analyze spontaneous clearance (SC) rates of RAHCV and to identify predictors of SC. METHODS: The PROBE-C study is an observational European cohort on RAHCV infections in HIV-positive MSM. Between 2007 and 2017, RAHCV infections were documented with ≥12 months of follow-up. Fisher exact, χ2, and Mann-Whitney U tests were used for statistical analysis. RESULTS: A total of 464 RAHCV infections were documented; 457 of 464 patients (98%) were male, and the median age (interquartile range [IQR]) was 41 (38-46) years. The main risk group for hepatitis C virus (HCV) transmission was MSM (98.9%). Most participants were infected with HCV genotype 1 (78.3%). The median baseline HCV RNA level (IQR) was 230 000 (135 000-474 432) IU/mL, and the median CD4+ T-cell count was 574/µL (547-604/µL. Of all cases, 92% received combination antiretroviral therapy, with 91% showing suppressed HIV RNA levels (<200 copies/mL). The median maximum alanine aminotransferase level (IQR) was 445 (402-522) U/L. SC of RAHCV infection occurred in 55 of 464 cases (11.9%). A >2-log decline in HCV RNA levels 4 weeks after diagnosis of RAHCV infection was the strongest predictor of SC (P < .001; sensitivity, 96.4%; specificity, 97.5%; positive predictive value, 84.1%; negative predictive value, 99.5%). CONCLUSIONS: SC of RAHCV in HIV-positive MSM is found in only 11.9% of cases and a <2-log drop in HCV RNA level at week 4 after diagnosis should prompt early DAA-based treatment. However, immediate DAA treatment for RAHCV infection may also be favored in patients with ongoing transmission risk behavior.