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The complement system (CS) plays a pivotal role in Coronavirus disease 2019 (COVID-19) pathophysiology. The objective of this study was to provide a comparative, prospective data analysis of CS components in an all-comers cohort and COVID-19 patients. Patients with suspected COVID-19 infection admitted to the Emergency department were grouped for definite diagnosis of COVID-19 and no COVID-19 accordingly. Clinical presentation, routine laboratory and von Willebrand factor (vWF) antigen as well as CS components 3, 4 and activated 5 (C5a) were assessed. Also, total complement activity via the classical pathway (CH50) was determined. Levels of calprotectin in serum were measured using an automated quantitative lateral flow assay. We included 80 patients in this prospective trial. Of those 19 (23.7%) were tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with COVID-19 had higher levels of CS components 5a and 4 (54.79 [24.14–88.79] ng/ml vs. 35 [23.15–46.1] ng/ml; p = 0.0433 and 0.3772 [± 0.1056] g/L vs. 0.286 [0.2375–0.3748] g/L; p = 0.0168). COVID-19 patients had significantly higher levels of vWF antigen when compared to the control group (288.3 [± 80.26] % vs. 212 [151–320] %; p = 0.0469). There was a significant correlation between CS C3 and 5a with vWF antigen (rs = 0.5957 [p = 0.0131] and rs = 0.5015 [p = 0.042]) in COVID-19 patients. There was no difference in calprotectin plasma levels (4.786 [± 2.397] µg/ml vs. 4.233 [± 2.142] µg/ml; p = 0.4175) between both groups. This prospective data from a single centre all-comers cohort accentuates altered levels of CS components as a distinct feature of COVID-19 disease. Deregulation of CS component 3 and C5a are associated with increased vWF antigen possibly linking vascular damage to alternative CS activation in COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s11239-021-02617-x.

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.

Increasing evidence suggests that some patients suffer from persistent symptoms for months after recovery from acute COVID-19. However, the clinical phenotype and its pathogenesis remain unclear. We here present data on complaints and results of a diagnostic workup of patients presenting to the post-COVID clinic at the University Medical Center Freiburg. Retrospective data analysis of persistently symptomatic patients presenting to our clinic at least 6 months after onset of acute COVID-19. All patients were assessed by a doctor and routine laboratory analysis was carried out. Quality of life was assessed using SF-36 questionnaire. In case of specific persisting symptoms, further organ-specific diagnostic evaluation was performed, and patients were referred to respective departments/specialists. 132 Patients (58 male, 74 female; mean age 53.8 years) presented to our clinic at least 6 months after COVID-19. 79 (60 %) had been treated as outpatients and 53 (40 %) as inpatients. Most common complaints were persistent fatigue (82 %) and dyspnea on exertion (61 %). Further common complaints were impairments of concentration (54 %), insomnia (43 %), and impairments of smell or taste (35 %). Quality of life was reduced in all sections of the SF-36 questionnaire, yielding a reduced working capacity. Significant pathological findings in laboratory, echocardiographic and radiological work-up were rare. Impairments in lung function tests were more common in previously hospitalized patients. Patients presenting 6 months after onset of acute COVID-19 suffer from a diverse spectrum of symptoms with impaired quality of life, also referred to as Long COVID or Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Further research is needed to determine the frequency of these post-COVID syndromes and their pathogenesis, natural course and treatment options. Evaluation and management should be multi-disciplinary. Fortbestehende Beschwerden und ärztlich validierte Diagnosen nach COVID-19 sind bislang nicht gut definiert. Wir berichten über Symptome und Diagnostik bei Patienten in unserer COVID-19-Nachsorgeambulanz. Es erfolgte eine retrospektive Analyse der Beschwerden und Befunde bei erwachsenen Patienten nach labordiagnostisch gesicherter COVID-19-Erkrankung mit über mindestens 6 Monate fortbestehenden Beschwerden. Neben Anamnese, körperlicher Untersuchung und Labordiagnostik erfolgte eine symptomgeleitete erweiterte apparative Diagnostik. Die Lebensqualität wurde mittels SF-36-Fragebogens erfasst. 132 Patienten mit über mindestens 6 Monate persistierenden Beschwerden wurden in die Auswertung eingeschlossen (58 männlich, 74 weiblich; mittleres Alter 53,8 Jahre). 40 % der Patienten waren in der Akutphase stationär behandelt worden. Die häufigsten Beschwerden waren Fatigue (82 %), Belastungsdyspnoe (61 %), kognitive Beschwerden (54 %), Schlafstörungen (43 %) und Dysgeusie/-osmie (35 %). Die Lebensqualität war in allen im SF-36 abgefragten Bereichen eingeschränkt. Immerhin 23 % der zuvor Berufstätigen waren aus gesundheitlichen Gründen für mindestens 6 Monate arbeitsunfähig. Signifikante Pathologien in der laborchemischen und apparativen Diagnostik waren insbesondere bei ambulant behandelten Patienten dagegen selten; Lungenfunktionsstörungen waren häufiger bei ehemals stationär behandelten Patienten. Patienten nach COVID-19 berichten über vielfältige Symptome, für die häufig kein organpathologisches Korrelat gefunden werden kann. Dies geht mit Einschränkungen der Lebensqualität und Arbeitsfähigkeit, auch 6 Monate nach Akutinfektion, einher. Populationsbasierte Prävalenz, Pathogenese, Langzeitverlauf und Therapiemöglichkeiten dieses vielfach als Long COVID bezeichneten Syndroms sind weitgehend ungeklärt. Aufgrund der vielfältigen Beschwerden sollte die Patientenversorgung interdisziplinär erfolgen und vermehrt Leistungsdiagnostik und systematische neuropsychiatrische Tests beinhalten.

Enterobacter cloacae complex (ECC) represent globally important nosocomial pathogens. A three-year study of ECC in Germany identified Enterobacter xiangfangensis as the most common species (65.5%) detected, a result replicated by examining a global pool of 3246 isolates. Antibiotic resistance profiling revealed widespread resistance and heteroresistance to the antibiotic colistin and detected the mobile colistin resistance (mcr)-9 gene in 19.2% of all isolates. We show that resistance and heteroresistance properties depend on the chromosomal arnBCADTEF gene cassette whose products catalyze transfer of L-Ara4N to lipid A. Using comparative genomics, mutational analysis, and quantitative lipid A profiling we demonstrate that intrinsic lipid A modification levels are genospecies-dependent and governed by allelic variations in phoPQ and mgrB, that encode a two-component sensor-activator system and specific inhibitor peptide. By generating phoPQ chimeras and combining them with mgrB alleles, we show that interactions at the pH-sensing interface of the sensory histidine kinase phoQ dictate arnBCADTEF expression levels. To minimize therapeutic failures, we developed an assay that accurately detects colistin resistance levels for any ECC isolate.

The new pandemic coronavirus SARS-CoV-2 causing coronavirus disease-2019 (COVID-19) poses immense challenges to health care systems worldwide. In the current manuscript we summarize the strategies, organisational approaches and actions of the Task-force Coronavirus at the University Medical Center Freiburg. We also report on experiences with implementation of these approaches and treatment outcomes in the first 115 COVID patients.Retrospective, narrative process description and analysis of the time period between end of January and beginning of April 2020, performed by representatives of the involved departments and institutes. Additionally a retrospective observational cohort study with descriptive analysis of epidemiological and clinical data of COVID patients admitted until March 31st was performed.A multidisciplinary Task-force Coronavirus initiated measures concerning outpatient testing and counseling, reorganisation and separation of patient flow processes alongside with substantial escalation of inpatient capacities on regular wards and intensive care units. Within the framework of the resulting dynamic care model, 115 patients suffering from COVID could be treated without shortages in staff or bed capacities.In the upcoming pandemic, adequate COVID management and care could be secured by a collaborative approach with inclusion of administrative departments, clinical disciplines and theoretical institutes of the University Medical Center Freiburg.Das neue, pandemische Coronavirus SARS-CoV-2 und die damit einhergehende Erkrankung COVID-19 (Coronavirus Disease 2019) stellt die medizinischen Versorgungssysteme vor große Herausforderungen. Die vorliegende Arbeit fasst die Strategie, Organisation und Maßnahmen der COVID-Taskforce des Universitätsklinikums Freiburg zusammen und berichtet über Erfahrungen und Behandlungsergebnisse von der Versorgung der ersten 115 COVID-19-Patienten.Retrospektive, narrative Prozessbeschreibung und -analyse des Zeitraums Ende Januar bis Anfang April 2020, durchgeführt unter Mitwirken der beteiligten Departments, Kliniken und Institute des Universitätsklinikums Freiburg. Ergänzend erfolgte eine retrospektive Beobachtungsstudie mit deskriptiver statistischer Auswertung der epidemiologischen und klinischen Daten aller bis 31. März 2020 hospitalisierten COVID-19-Patienten.Durch eine interdisziplinär zusammengesetzte Taskforce Coronavirus wurden Maßnahmen in den Bereichen ambulante Testung und Beratung, Separierung der Patientenströme sowie Eskalation der Versorgungskapazitäten auf Normal- und Intensivstationen im Sinne eines dynamischen Stufenmodells angeregt und umgesetzt. Die Versorgung der ersten 115 Patienten gelang somit ohne Entstehung von Engpässen.Durch Zusammenwirken sämtlicher Disziplinen und Abteilungen des Universitätsklinikums Freiburg konnte eine adäquate Versorgung von COVID-19-Patienten sichergestellt und die Handlungsfähigkeit des Klinikums in der aktuellen Ausbruchsituation erhalten werden.

Neue ABS-Leitlinien und strukturelle Empfehlungen Neue Leitlinien fur „Antibiotic Stewardship“ (ABS) und EU-Empfehlungen raten zur Einrichtung von ABS-Teams an Krankenhausern. Mit einer personellen Ausstattung von (mindestens) einer Vollkraft pro 500 Betten scheint damit ein Basisbundel von ABS-Masnahmen kostenneutral durchfuhrbar. Empfohlen werden nun, je nach Versorgungschwerpunkt, ein bis drei Vollkrafte pro 500 Betten, darunter Infektiologiefacharzte und Apotheker, um eine verbesserte Versorgung von Patienten mit Infektionskrankheiten zu erreichen. Antiinfektivavisiten als wichtiges ABS-Instrument Wichtiges Instrument fur eine optimierte Antibiotikaverordnungsqualitat und die Vermeidung von Medikationsfehlern sind spezielle Infektionsvisiten. Mit diesen kann meistens auch eine Verkurzung der Therapie sowie eine Reduktion des Verbrauchs von Antibiotika erreicht werden. Antibiotikaverbrauch in deutschen Akutkrankenhausern Nach einer aktualisierten Querschnittsanalyse des Antibiotikaeinsatzes in mehr als 100 Akutkrankenhausern zeigte der Gesamtverbrauch 2013/2014 mit rund 40 Tagesdosen/100 Pflegetage wenige Anderungen gegenuber dem Vorjahr. Cephalosporine wurden im Vergleich zu anderen europaischen Landern immer noch relativ viel eingesetzt. Beispiele fur eine sinnvolle Reduktion des Antibiotikaverbrauchs im Krankenhaus Neue Studien unterstreichen die Empfehlungen, nach denen eine perioperative Antibiotikaprophylaxe nicht langer als 24 Stunden durchgefuhrt werden soll – dies gilt auch fur ICD- und Schrittmacherimplantationen. Antibiotika zur Pneumonieprophylaxe bei Schlaganfall sind nicht wirksam. Bisherige Studien zur kritischen Indikationsstellung fur Cephalosporine und zum reduzierten Verbrauch von Fluorchinolonen zeigen masige Effekte auf die Haufigkeit multiresistenter gramnegativer Bakterien.

Introduction Pseudomonas aeruginosa (PA) has historically been one of the major causes of severe sepsis and death among neutropenic cancer patients. There has been a recent increase of multidrug-resistant PA (MDRPA) isolates that may determine a worse prognosis, particularly in immunosuppressed patients. The aim of this study is to establish the impact of antibiotic resistance on the outcome of neutropenic onco-haematological patients with PA bacteraemia, and to identify the risk factors for MDRPA bacteraemia and mortality. Methods and analysis This is a retrospective, observational, multicentre, international study. All episodes of PA bacteraemia occurring in neutropenic onco-haematological patients followed up at the participating centres from 1 January 2006 to 31 May 2018 will be retrospectively reviewed. The primary end point will be overall case-fatality rate within 30 days of onset of PA bacteraemia. The secondary end points will be to describe the following: the incidence and risk factors for multidrug-resistant and extremely drug-resistant PA bacteraemia (by comparing the episodes due to susceptible PA with those produced by MDRPA), the efficacy of ceftolozane/tazobactam, the rates of persistent bacteraemia and bacteraemia relapse and the risk factors for very early (48 hours), early (7 days) and overall (30 days) case-fatality rates. Ethics and dissemination The Clinical Research Ethics Committee of Bellvitge University Hospital approved the protocol of the study at the primary site. To protect personal privacy, identifying information of each patient in the electronic database will be encrypted. The processing of the patients’ personal data collected in the study will comply with the Spanish Data Protection Act of 1998 and with the European Directive on the privacy of data. All data collected, stored and processed will be anonymised. Results will be reported at conferences and in peer-reviewed publications.

Few guidelines for health care of refugees exist in Germany. Screening as a part of initial health checks as well as general organisation of early health care for refugees is very heterogenous across different regions. Current experience will be relevant to develop integrated health care models. Prevention and care of infectious diseases are an important part of early health care for refugees, even if non-communicable diseases and mental health conditions should also be considered in every effort to design early health care models. We are presenting a pragmatic review of current evidence for prevention and care of tuberculosis, HIV, chronic viral hepatitis and other infectious diseases. More evidence is needed to assess morbidity and efficacy of early health care interventions and integrated care models in refugees.

There is no agreement about the frequency of nosocomial infections and infections caused by multidrug resistant organisms (MDRO) in Germany. The aim of this review is to generate updated estimates of the national burden of these infections and to discuss them in an international context. The most important sources of this analysis are the data of the national prevalence studies conducted in various European countries and in the U.S. It can be assumed that there are between 400,000 and 600,000 patients with nosocomial infections each year in Germany. The mortality attributable to them is between 6000 and 15,000 patients. About 30,000 to 35,000 patients develop nosocomial infections caused by MDRO. Currently there are no robust data how many patients die each year because of MDRO infections. According to the best available estimate, the annual number may be between 1000 and 4000 cases. The problems of nosocomial infections and the increase of antimicrobial resistance are highly relevant and should not be belittled. However, an overestimation of this dangerous trend may lead to inappropriate use of limited resources.

In der Akutmedizin, insbesondere bei schweren Erkrankungen, die eine Behandlung auf der Intensivstation notwendig machen, ist in vielen Fallen eine empirische Initialtherapie, d. h. eine Behandlung mit Antiinfektiva vor Erregersicherung notwendig. Die Antiinfektivawahl in dieser Situation richtet sich nach dem erwarteten Erregerspektrum und der erwarteten Erregerempfindlichkeit (»kalkulierte«Therapie). Nach Erregersicherung kann und sollte in den meisten Fallen auf eine gezielte Therapie umgestellt werden. Dabei spielen die Aspekte Wirksamkeit, Nebenwirkungen, Resistenzentwicklung und Kosten eine Rolle.

Resin-containing aerobic and anaerobic blood culture media (NR 16A and NR 17A) for use with the new BACTEC infrared blood cultures system were compared with standard BACTEC media (NR 6A and NR 7A) in their efficacy to detect bacteremia in febrile granulocytopenic patients receiving antimicrobial treatment. A total of 1185 sets of blood cultures obtained from 341 patients during a 12-month period were evaluated. There were 109 positive cultures (9.2%) with 128 pathogenic organisms isolated from 52 patients (15.2%). Statistically significant differences were found between aerobic media, but not between anaerobic media. Aerobic resin bottles (NR 16A) were more often positive (90 versus 78, p less than 0.05) than standard aerobic bottles (NR 6A). They yielded a higher number of microorganismS (98 versus 80, p less than 0.05) per culture and per culture-positive patient (53 versus 42, p less than 0.01). NR 16A cultures also were more often positive after 1-day incubation (44% versus 21%, p less than 0.01) than NR 6A cultures and allowed earlier subcultivation. The use of NR 16A medium instead of resin-free aerobic NR 6A medium may enhance the detection of bacteremia in selected groups of patients receiving antimicrobial treatment, and can shorten the time until detection of bacteremia.

Morbidity and mortality in patients with malignancies, especially leukemia and lymphoma, are increased by invasive fungal infections. Since diagnosis of invasive fungal infection is often delayed, antifungal prophylaxis is an attractive approach for patients expecting prolonged neutropenia. Antifungal prophylaxis has obviously attracted much interest resulting in dozens of clinical trials since the late 1970s. The non-absorbable polyenes are probably ineffective in preventing invasive fungal infections, but may reduce superficial mycoses. Intravenous amphotericin B and the newer azoles were used in clinical trials, but their role in antifungal prophylaxis is still not well defined. Allogeneic stem cell transplant recipients are at particularly high risk for invasive fungal infections. Other well described risk factors are neutropenia10 days, corticosteroid therapy, sustained immunosuppression, graft versus host disease, and concomitant viral infections. The enormous study efforts are contrasted by a scarcity of risk stratified evidence based recommendations for clinical decision making. The objective of this review accumulating information on about 10.000 patients is to assess evidence based criteria primarily regarding the efficacy of antifungal prophylaxis in neutropenic cancer patients.

This study describes neuropsychiatric side effects in patients after treatment with mefloquine. Reactions consisted mainly of seizures, acute psychoses, anxiety neurosis, and major disturbances of sleep-wake rhythm. Side effects occurred after both therapeutic and prophylactic intake and were graded from moderate to severe. In a risk analysis of neuropsychiatric side effects in Germany, it is estimated that one of 8,000 mefloquine users suffers from such reactions. The incidence calculation revealed that one of 215 therapeutic users had reactions, compared with one of 13,000 in the prophylaxis group, making the risk of neuropsychiatric reactions after mefloquine treatment 60 times higher than after prophylaxis. Therefore, certain limitations for malaria prophylaxis and treatment with mefloquine are recommended.