The protective effect of tumor necrosis factor-alpha inhibitors in COVID-19 in patients with inflammatory rheumatic diseases compared to the general population-A comparison of two German registries.

Objectives: To investigate, whether inflammatory rheumatic diseases (IRD) inpatients are at higher risk to develop a severe course of SARS-CoV-2 infections compared to the general population, data from the German COVID-19 registry for IRD patients and data from the Lean European Survey on SARS-CoV-2 (LEOSS) infected patients covering inpatients from the general population with SARS-CoV-2 infections were compared. Methods: 4310 (LEOSS registry) and 1139 cases (IRD registry) were collected in general. Data were matched for age and gender. From both registries, 732 matched inpatients (LEOSS registry: n = 366 and IRD registry: n = 366) were included for analyses in total. Results: Regarding the COVID-19 associated lethality, no significant difference between both registries was observed. Age > 65°years, chronic obstructive pulmonary disease, diabetes mellitus, rheumatoid arthritis, spondyloarthritis and the use of rituximab were associated with more severe courses of COVID-19. Female gender and the use of tumor necrosis factor-alpha inhibitors (TNF-I) were associated with a better outcome of COVID-19. Conclusion: Inflammatory rheumatic diseases (IRD) patients have the same risk factors for severe COVID-19 regarding comorbidities compared to the general population without any immune-mediated disease or immunomodulation. The use of rituximab was associated with an increased risk for severe COVID-19. On the other hand, the use of TNF-I was associated with less severe COVID-19 compared to the general population, which might indicate a protective effect of TNF-I against severe COVID-19 disease.

Quality, availability and suitability of antimicrobial stewardship guidance: a multinational qualitative study.

Background: Antimicrobial stewardship (AMS) programmes are established across the world to treat infections efficiently, prioritize patient safety, and reduce the emergence of antimicrobial resistance. One of the core elements of AMS programmes is guidance to support and direct physicians in making efficient, safe and optimal decisions when prescribing antibiotics. To optimize and tailor AMS, we need a better understanding of prescribing physicians' experience with AMS guidance. Objectives: To explore the prescribing physicians' user experience, needs and targeted improvements of AMS guidance in hospital settings. Methods: Semi-structured interviews were conducted with 36 prescribing physicians/AMS guidance users from hospital settings in Canada, Germany, Israel, Latvia, Norway and Sweden as a part of the international PILGRIM trial. A socioecological model was applied as an overarching conceptual framework for the study. Results: Research participants were seeking more AMS guidance than is currently available to them. The most important aspects and targets for improvement of AMS guidance were: (i) quality of guidelines; (ii) availability of infectious diseases specialists; and (iii) suitability of AMS guidance to department context. Conclusions: Achieving prudent antibiotic use not only depends on individual and collective levels of commitment to follow AMS guidance but also on the quality, availability and suitability of the guidance itself. More substantial commitment from stakeholders is needed to allocate the required resources for delivering high-quality, available and relevant AMS guidance to make sure that the prescribers' AMS needs are met.

Vaccine-derived yellow fever in an immunocompromised patient on anti-CD20-antibody therapy and its treatment with sofosbuvir.

Yellow fever (YF) is a potentially lethal viral hemorrhagic fever that can be prevented with the 17D live attenuated YF vaccine. However, this vaccination can cause severe adverse reactions including vaccine-associated YF. Here, we describe the case of a 32-year-old female who was permanently immunosuppressed with an anti-CD20 antibody due to multiple sclerosis. Following YF vaccination, the patient developed a variety of symptoms such as febrile temperatures, muscle and joint pain, headaches, and dysuria. A vaccine-associated YF with viremia was diagnosed. To avoid a potentially severe course of the disease, sofosbuvir was used as antiviral treatment followed by the resolution of symptoms and serological response. As travelers with chronic diseases and immunosuppression will increasingly engage in long distance travel, this case demonstrates the importance of assessing patient history prior to the administration of live vaccines and points towards a possible therapeutic approach in those suffering from vaccine-associated YF.

Prevalence of infectious diseases, immunity to vaccine-preventable diseases and chronic medical conditions among Ukrainian refugees in Germany - A cross sectional study from the German Network University Medicine (NUM).

BACKGROUND: Vulnerability to infectious diseases in refugees is dependent on country of origin, flight routes, and conditions. Information on specific medical needs of different groups of refugees is lacking. We assessed the prevalence of infectious diseases, immunity to vaccine-preventable diseases, and chronic medical conditions in children, adolescents, and adult refugees from Ukraine who arrived in Germany in 2022. METHODS: Using different media, we recruited Ukrainian refugees at 13 sites between 9-12/2022. An antigen test for acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, serologies for a range of vaccine-preventable diseases, as well as interferon gamma release assays (IGRAs) for tuberculosis (TB), and SARS-CoV-2 were performed. We assessed personal and family history of chronic medical conditions, infectious diseases, vaccination status, and conditions during migration. RESULTS: Overall, 1793 refugees (1401 adults and 392 children/adolescents) were included. Most participants were females (n = 1307; 72·3%) and from Eastern or Southern Ukraine. TB IGRA was positive in 13% (n = 184) of the adults and in 2% (n = 7) of the children. Serology-based immunological response was insufficient in approximately 21% (360/1793) of the participants for measles, 32% (572/1793) for diphtheria, and 74% (1289/1793) for hepatitis B. CONCLUSIONS: We show evidence of low serological response to vaccine-preventable infections and increased LTBI prevalence in Ukrainian refugees. These findings should be integrated into guidelines for screening and treatment of infectious diseases in migrants and refugees in Germany and Europe. Furthermore, low immunity for vaccine-preventable diseases in Ukrainians independent of their refugee status, calls for tailor-made communication efforts.

[Infectious Diseases - a new specialty for postgraduate training in Germany]. / Infektiologie ­ eine neue Facharztdisziplin in Deutschland.

Medicine in Germany is currently facing major structural and economic challenges. Infectious Diseases, with the recent introduction of a new specialty in "Internal Medicine and Infectious Diseases" and with the existing additional training for almost all specializations, will make an important contribution to overcoming these challenges. Expertise in infectious diseases has to be very broad and requires high interdisciplinarity, which makes infectious diseases an attractive and demanding specialty. The complex fundamentals of infectious diseases must now be quickly conveyed to as many physicians as possible in a short period of time, as part of their specialization or as additional training. Until this is achieved, transitional solutions will be necessary for some time. The adaptation of the current billing and reimbursement system for infectious diseases services and improved intersectoral cooperation are of the utmost importance for the further development of the specialty.

Regulatory workshop on challenge strain development and GMP manufacture - A stakeholder meeting report.

Within the Innovative Health Initiative (IHI) Inno4Vac CHIMICHURRI project, a regulatory workshop was organised on the development and manufacture of challenge agent strains for Controlled Human Infection Model (CHIM) studies. Developers are often uncertain about which GMP requirements or regulatory guidelines apply but should be guided by the 2022 technical white paper "Considerations on the Principles of Development and Manufacturing Qualities of Challenge Agents for Use in Human Infection Models" (published by hVIVO, Wellcome Trust, HIC-Vac consortium members). Where those recommendations cannot be met, regulators advise following the "Principles of GMP" until definitive guidelines are available. Sourcing wild-type virus isolates is a significant challenge for developers. Still, it is preferred over reverse genetics challenge strains for several reasons, including implications and regulations around genetically modified organisms (GMOs). Official informed consent guidelines for collecting isolates are needed, and the characterisation of these isolates still presents risks and uncertainty. Workshop topics included ethics, liability, standardised clinical endpoints, selection criteria, sharing of challenge agents, and addressing population heterogeneity concerning vaccine response and clinical course. The organisers are confident that the workshop discussions will contribute to advancing ethical, safe, and high-quality CHIM studies of influenza, RSV and C. difficile, including adequate regulatory frameworks.

Flucloxacillin and cefazolin for treatment of Staphylococcus aureus bloodstream infection.

PURPOSE: Antistaphylococcal penicillins and cefazolin have been used as first line therapy in Methicillin-susceptible Staphylococcus aureus bloodstream infection. While efficacy of both regimens seems to be similar, the compounds may differ with regard to tolerability. This study aims to describe the clinical use of cefazolin and flucloxacillin, focussing on discontinuation or change of anti-infective agent due to adverse events. METHODS: This observational prospective study was conducted at two German tertiary care centres with an internal recommendation of flucloxacillin for MSSA-BSI in one, and of cefazolin in the other centre. Adverse events were registered weekly under treatment and at a 90-day follow-up. Descriptive analysis was complemented by a propensity score analysis comparing adverse events (stratified rank-based test applied to the sum of Common Terminology Criteria for adverse events ratings per patient). RESULTS: Of 71 patients included, therapy was initiated with flucloxacillin in 56 (79%), and with cefazolin in 15 (21%). The propensity score analysis indicates a statistically significant difference concerning the severity of adverse events between the treatment groups in favour of cefazolin (p = 0.019). Adverse events led to discontinuation of flucloxacillin in 7 individuals (13% of all patients receiving flucloxacillin). Clinical outcome was not different among treatment groups. CONCLUSION: Using cefazolin rather than flucloxacillin as a first line agent for treatment of MSSA-BSI is supported by these clinical data.

Dataset of single nucleotide polymorphisms of immune-associated genes in patients with SARS-CoV-2 infection.

The SARS-CoV-2 pandemic has affected nations globally leading to illness, death, and economic downturn. Why disease severity, ranging from no symptoms to the requirement for extracorporeal membrane oxygenation, varies between patients is still incompletely understood. Consequently, we aimed at understanding the impact of genetic factors on disease severity in infection with SARS-CoV-2. Here, we provide data on demographics, ABO blood group, human leukocyte antigen (HLA) type, as well as next-generation sequencing data of genes in the natural killer cell receptor family, the renin-angiotensin-aldosterone and kallikrein-kinin systems and others in 159 patients with SARS-CoV-2 infection, stratified into seven categories of disease severity. We provide single-nucleotide polymorphism (SNP) data on the patients and a protein structural analysis as a case study on a SNP in the SIGLEC7 gene, which was significantly associated with the clinical score. Our data represent a resource for correlation analyses involving genetic factors and disease severity and may help predict outcomes in infections with future SARS-CoV-2 variants and aid vaccine adaptation.

Analysis of Mould Exposure of Immunosuppressed Patients at a German University Hospital.

Moulds are ubiquitous components of outdoor and indoor air and local conditions, temperature, humidity and season can influence their concentration in the air. The impact of these factors on mould exposure in hospitals and the resulting risk of infection for low to moderately immunocompromised patients is unclear. In the present retrospective analysis for the years 2018 to 2022, the monthly determined mould contamination of the outdoor and indoor air at the University Hospital Frankfurt am Main is compared with the average air temperature and the relative humidity. Mould infections (Aspergillus spp., Mucorales) of low to moderately immunosuppressed patients of a haematological-oncological normal ward were determined clinically according to the criteria of the European Organisation for Research and Treatment of Cancer (EORTC, Brussels, Belgium) and of the National Reference Centre for Surveillance of Nosocomial Infections (NRC-NI, Berlin, Germany). The data revealed that in the summer months (May-October), increased mould contamination was detectable in the outdoor and indoor air compared to the winter months (November-April). The mould levels in the patient rooms followed the detection rates of the outdoor air. Two nosocomial Aspergillus infections, one nosocomial Mucorales (Rhizopus spp.) infection (according to both NRC-NI and EORTC criteria) and five Aspergillus spp. infections (according to EORTC criteria) occurred in 4299 treated patients (resulting in 41,500 patient days). In our study, the incidence density rate of contracting a nosocomial mould infection (n = 3) was approximately 0.07 per 1000 patient days and appears to be negligible.

TIGIT+ NK cells in combination with specific gut microbiota features predict response to checkpoint inhibitor therapy in melanoma patients.

BACKGROUND: Composition of the intestinal microbiota has been correlated to therapeutic efficacy of immune checkpoint inhibitors (ICI) in various cancer entities including melanoma. Prediction of the outcome of such therapy, however, is still unavailable. This prospective, non-interventional study was conducted in order to achieve an integrated assessment of the connection between a specific intestinal microbiota profile and antitumor immune response to immune checkpoint inhibitor therapy (anti-PD-1 and/or anti-CTLA-4) in melanoma patients. METHODS: We assessed blood and stool samples of 29 cutaneous melanoma patients who received immune checkpoint inhibitor therapy. For functional and phenotypical immune analysis, 12-color flow cytometry and FluoroSpot assays were conducted. Gut microbiome was analyzed with shotgun metagenomics sequencing. To combine clinical, microbiome and immune variables, we applied the Random Forest algorithm. RESULTS: A total of 29 patients was analyzed in this study, among whom 51.7% (n = 15) reached a durable clinical benefit. The Immune receptor TIGIT is significantly upregulated in T cells (p = 0.0139) and CD56high NK cells (p = 0.0037) of responders. Several bacterial taxa were associated with response (e.g. Ruminococcus torques) or failure (e.g. Barnesiella intestinihominis) to immune therapy. A combination of two microbiome features (Barnesiella intestinihominis and the Enterobacteriaceae family) and one immune feature (TIGIT+ CD56high NK cells) was able to predict response to ICI already at baseline (AUC = 0.85; 95% CI: 0.841-0.853). CONCLUSIONS: Our results reconfirm a link between intestinal microbiota and response to ICI therapy in melanoma patients and furthermore point to TIGIT as a promising target for future immunotherapies.

Coinfections and antimicrobial treatment in a cohort of falciparum malaria in a non-endemic country: a 10-year experience.

INTRODUCTION: Falciparum malaria remains one of the deadliest infectious diseases worldwide. In Germany, it is mainly an imported infection among travellers. Rates of coinfection are often unknown, and a clinical rationale for the beneficial use of calculated antibiotic therapy in patients with malaria and suspected coinfection is lacking. METHODS: We conducted an analysis of all in-patients treated with falciparum malaria at a German infectious diseases centre in vicinity to one of Europe's major airports for 2010-2019. Logistic regression and time-to-event analysis were used to evaluate predictors for bacterial coinfection, the use of antibacterial substances, as well as their influence on clinical course. RESULTS: In total, 264 patients were included. Of those, 64% received an additional antibacterial therapy (n = 169). Twenty-nine patients (11.0%) were found to have suffered from a relevant bacterial coinfection, while only a small fraction had relevant bacteremia (n = 3, 1.4%). However, patients with severe malaria did not suffer from coinfections more frequently (p = 0.283). CRP levels were not a reliable predictor for a bacterial coinfection (OR 0.99, 95% CI 0.94-1.06, p = 0.850), while another clinical focus of infection was positively associated (OR 3.86, 95% CI 1.45-11.55, p = 0.010). CONCLUSION: Although bacterial coinfections were rare in patients with malaria at our centre, the risk does not seem negligible. These data point rather towards individual risk assessment in respective patients than to general empiric antibiotic use.

The KINETIC phase 2 randomized controlled trial of oral pamapimod-pioglitazone in non-critically ill COVID-19 inpatients.

The combination of pamapimod and pioglitazone (KIN001) has a synergetic antiviral, anti-inflammatory, and antifibrotic activity, which may prevent evolution toward COVID-19-associated severe respiratory failure. In a randomized, placebo-controlled, double-blind, phase 2, multicenter trial, 128 non-critically ill hospitalized patients with confirmed COVID-19 were treated with KIN001 or a placebo for 28 days. The proportion of patients alive and free of oxygen or respiratory support at the end of the therapy was lower than anticipated but not different in the two groups (KIN001 n = 19, 29%, placebo n = 21, 33%). 85 participants had at least one adverse event, with no difference in the number and distribution of events between the two groups. The clinical trial was stopped for futility, mainly due to a lower-than-expected incidence of the primary endpoint. KIN001 was safe and well-tolerated but had no significant effect on clinical outcome.

Pooled allogeneic faecal microbiota MaaT013 for steroid-resistant gastrointestinal acute graft-versus-host disease: a single-arm, multicentre phase 2 trial.

Background: Failure of gastrointestinal acute graft-versus-host disease (GI-aGvHD) to respond to steroid therapy is associated with limited further therapeutic options. We aimed to assess the safety and efficacy of the first-in-human use of the pooled allogeneic faecal microbiota, MaaT013, for the treatment of steroid-refractory GI-aGvHD. Methods: This prospective, international, single-arm, phase 2a study reports clinical outcomes from a 24-patient cohort with grade III-IV, steroid refractory GI-aGvHD treated with the pooled allogeneic faecal microbiota MaaT013. MaaT013 involved pooling faecal matter from 3 to 8 screened donors then transplanting the pooled batches into patients to treat GI-aGVHD. The 24 patients were treated in the HERACLES study (Aug 2018 to Nov 2020) at 26 sites in Europe and an additional 52 patients were treated in a compassionate use/expanded access program (EAP) in France (July 2018 to April 2021). The primary endpoint was GI response at day 28, defined as the proportion of patients with GI-aGvHD who had a complete response (CR) or very good partial response (VGPR). GvHD grading and staging were assessed according to the revised Glucksberg criteria. Adverse events and severe adverse events were monitored for 6 months and 12 months, respectively. The HERACLES study was registered with ClinicalTrials.gov (NCT03359980). Findings: Compared with single donors, MaaT013 is characterised by higher microbial richness and reduced variability across batches. At day 28 (D28), the GI-overall response rate (ORR) was 38% in the prospective population, including 5 complete responses (CR), 2 very good partial responses (VGPR) and 2 partial responses (PR). In the EAP, the GI-ORR was 58% (17 CR, 9 VGPR and 4 PR). The 12-month overall survival (OS) was 25% in the prospective study and 38% in the EAP. Regarding safety, five infectious complications, including 3 sepsis, could not be excluded from being related to the study procedure in HERACLES. Shotgun sequencing analyses of the identified strains suggest that none were found in MaaT013. In the EAP, 18 pharmacovigilance cases were reported among 52 treated patients, including 11 bacteraemia/sepsis. In HERACLES, we observed in stools from responding patients at D28 a higher microbiota richness and increased levels of beneficial bacteria, in particular butyrate producers, along with increased levels of short-chain fatty acid and bile acids. In contrast, stools from non-responding (NR) patients displayed increased levels of pathogenic pro-inflammatory bacteria along with increased systemic inflammatory parameters. Interpretation: Overall, MaaT013 was safe in this population of highly immunocompromised patients and was associated with responses in some patients with GI-aGvHD and deserves further investigation. Funding: MaaT Pharma.

Torque teno virus-DNA load as individual cytomegalovirus risk assessment parameter upon allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Immune recovery following allogeneic hematopoietic stem cell transplantation (allo-HSCT) decisively influences the occurrence of opportunistic infections, one of the leading causes of death among this group of patients. Yet, today, there are no laboratory parameters mirroring immune function sufficiently. Torque teno virus (TTV) has already proven itself as a functional immune marker in other settings. AIMS: In this analysis, we investigated whether monitoring of TTV-DNA load in whole blood is able to provide additional information on the capacity of the immune system to control cytomegalovirus (CMV) replication in allo-HSCT recipients. METHODS: Whole blood samples from 59 patients were collected upon allo-HSCT (between Day -7 and +10), on Day +14, +21, +28, +56, +90, and +365 post-transplant. TTV-DNA loads and other relevant clinical information were correlated with the risk of CMV infections or reactivations, defined by evidence of viral replication in blood. RESULTS: CMV serostatus of the recipient and a TTV load below 1000 copies/mL upon allo-HSCT were significantly associated with an increased incidence of CMV infection or reactivation. CONCLUSIONS: Quantification of TTV load in the early phase of allo-HSCT procedure could provide additional information in order to identify patients at risk for CMV infection or reactivation.

Bacillus velezensis DSM 33864 reduces Clostridioides difficile colonization without disturbing commensal gut microbiota composition.

Up to 25% of the US population harbor Clostridioides difficile in the gut. Following antibiotic disruption of the gut microbiota, C. difficile can act as an opportunistic pathogen and induce potentially lethal infections. Consequently, reducing the colonization of C. difficile in at-risk populations is warranted, prompting us to identify and characterize a probiotic candidate specifically targeting C. difficile colonization. We identified Bacillus velezensis DSM 33864 as a promising strain to reduce C. difficile levels in vitro. We further investigated the effects of B. velezensis DSM 33864 in an assay including human fecal medium and in healthy or clindamycin-treated mouse models of C. difficile colonization. The addition of B. velezensis DSM 33864 to human fecal samples was shown to reduce the colonization of C. difficile in vitro. This was supported in vivo where orally administered B. velezensis DSM 33864 spores reduced C. difficile levels in clindamycin-treated mice. The commensal microbiota composition or post-antibiotic reconstitution was not impacted by B. velezensis DSM 33864 in human fecal samples, short-, or long-term administration in mice. In conclusion, oral administration of B. velezensis DSM 33864 specifically reduced C. difficile colonization in vitro and in vivo without adversely impacting the commensal gut microbiota composition.

Association of ward-level antibiotic consumption with healthcare-associated Clostridioides difficile infections: an ecological study in five German university hospitals, 2017-2019.

OBJECTIVES: To analyse the influence of antibiotic consumption on healthcare-associated healthcare onset (HAHO) Clostridioides difficile infection (CDI) in a German university hospital setting. METHODS: Monthly ward-level antibiotic consumption measured in DDD/100 patient days (pd) and CDI surveillance data from five university hospitals in the period 2017 through 2019 were analysed. Uni- and multivariable analyses were performed with generalized estimating equation models. RESULTS: A total of 225 wards with 7347 surveillance months and 4 036 602 pd participated. With 1184 HAHO-CDI cases, there was a median incidence density of 0.17/1000 pd (IQR 0.03-0.43) across all specialties, with substantial differences among specialties. Haematology-oncology wards showed the highest median incidence density (0.67/1000 pd, IQR 0.44-1.01), followed by medical ICUs (0.45/1000 pd, IQR 0.27-0.73) and medical general wards (0.32/1000 pd, IQR 0.18-0.53). Multivariable analysis revealed carbapenem (mostly meropenem) consumption to be the only antibiotic class associated with increased HAHO-CDI incidence density. Each carbapenem DDD/100 pd administered increased the HAHO-CDI incidence density by 1.3% [incidence rate ratio (IRR) 1.013; 95% CI 1.006-1.019]. Specialty-specific analyses showed this influence only to be valid for haematological-oncological wards. Overall, factors like ward specialty (e.g. haematology-oncology ward IRR 2.961, 95% CI 2.203-3.980) or other CDI cases on ward had a stronger influence on HAHO-CDI incidence density (e.g. community-associated CDI or unknown association case in same month IRR 1.476, 95% CI 1.242-1.755) than antibiotic consumption. CONCLUSIONS: In the German university hospital setting, monthly ward-level carbapenem consumption seems to increase the HAHO-CDI incidence density predominantly on haematological-oncological wards. Furthermore, other patient-specific factors seem to be equally important to control HAHO-CDI.

Fighting Post-COVID and ME/CFS - development of curative therapies.

The sequela of COVID-19 include a broad spectrum of symptoms that fall under the umbrella term post-COVID-19 condition or syndrome (PCS). Immune dysregulation, autoimmunity, endothelial dysfunction, viral persistence, and viral reactivation have been identified as potential mechanisms. However, there is heterogeneity in expression of biomarkers, and it is unknown yet whether these distinguish different clinical subgroups of PCS. There is an overlap of symptoms and pathomechanisms of PCS with postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). No curative therapies are available for ME/CFS or PCS. The mechanisms identified so far provide targets for therapeutic interventions. To accelerate the development of therapies, we propose evaluating drugs targeting different mechanisms in clinical trial networks using harmonized diagnostic and outcome criteria and subgrouping patients based on a thorough clinical profiling including a comprehensive diagnostic and biomarker phenotyping.

Pathogenetic mechanisms and therapeutic approaches of acute-to-chronic liver failure.

Liver cirrhosis is the end stage of all chronic liver diseases and contributes significantly to overall mortality of 2% globally. The age-standardized mortality from liver cirrhosis in Europe is between 10 and 20% and can be explained by not only the development of liver cancer but also the acute deterioration in the patient's overall condition. The development of complications including accumulation of fluid in the abdomen (ascites), bleeding in the gastrointestinal tract (variceal bleeding), bacterial infections, or a decrease in brain function (hepatic encephalopathy) define an acute decompensation that requires therapy and often leads to acute-on-chronic liver failure (ACLF) by different precipitating events. However, due to its complexity and organ-spanning nature, the pathogenesis of ACLF is poorly understood, and the common underlying mechanisms leading to the development of organ dysfunction or failure in ACLF are still elusive. Apart from general intensive care interventions, there are no specific therapy options for ACLF. Liver transplantation is often not possible in these patients due to contraindications and a lack of prioritization. In this review, we describe the framework of the ACLF-I project consortium funded by the Hessian Ministry of Higher Education, Research and the Arts (HMWK) based on existing findings and will provide answers to these open questions.

[Fecal Microbiota Transfer (FMT) in Germany - Status and Perspective]. / Fäkaler Mikrobiota-Transfer (FMT) in Deutschland ­ Status und Perspektive.

INTRODUCTION: Fecal microbiota transfer (FMT) is a treatment to modulate the gastrointestinal microbiota. Its use in recurrent Clostridioides difficile infection (rCDI) is established throughout Europe and recommended in national and international guidelines. In Germany, the FMT is codeable in the hospital reimbursement system. A comprehensive survey on the frequency of use based on this coding is missing so far. MATERIAL AND METHODOLOGY: Reports of the Institute for Hospital Remuneration (InEK), the Federal Statistical Office (DESTATIS), and hospital quality reports 2015-2021 were examined for FMT coding and evaluated in a structured expert consultation. RESULTS: Between 2015 and 2021, 1,645 FMT procedures were coded by 175 hospitals. From 2016 to 2018, this was a median of 293 (274-313) FMT annually, followed by a steady decline in subsequent years to 119 FMT in 2021. Patients with FMT were 57.7% female, median age 74 years, and FMT was applied colonoscopically in 72.2%. CDI was the primary diagnosis in 86.8% of cases, followed by ulcerative colitis in 7.6%. DISCUSSION: In Germany, FMT is used less frequently than in the European comparison. One application hurdle is the regulatory classification of FMT as a non-approved drug, which leads to significantly higher costs in manufacturing and administration and makes reimbursement difficult. The European Commission recently proposed a regulation to classify FMT as a transplant. This could prospectively change the regulatory situation of FMT in Germany and thus contribute to a nationwide offer of a therapeutic procedure recommended in guidelines.

Is Autologous Fecal Microbiota Transfer after Exclusive Enteral Nutrition in Pediatric Crohn's Disease Patients Rational and Feasible? Data from a Feasibility Test.

BACKGROUND: Exclusive enteral nutrition (EEN) is a highly effective therapy for remission induction in pediatric Crohn's disease (CD), but relapse rates after return to a regular diet are high. Autologous fecal microbiota transfer (FMT) using stool collected during EEN-induced clinical remission might represent a novel approach to maintaining the benefits of EEN. METHODS: Pediatric CD patients provided fecal material at home, which was shipped at 4 °C to an FMT laboratory for FMT capsule generation and extensive pathogen safety screening. The microbial community composition of samples taken before and after shipment and after encapsulation was characterized using 16S rRNA amplicon sequencing. RESULTS: Seven pediatric patients provided fecal material for nine test runs after at least three weeks of nutritional therapy. FMT capsules were successfully generated in 6/8 deliveries, but stool weight and consistency varied widely. Transport and processing of fecal material into FMT capsules did not fundamentally change microbial composition, but microbial richness was <30 genera in 3/9 samples. Stool safety screening was positive for potential pathogens or drug resistance genes in 8/9 test runs. CONCLUSIONS: A high pathogen burden, low-diversity microbiota, and practical deficiencies of EEN-conditioned fecal material might render autologous capsule-FMT an unsuitable approach as maintenance therapy for pediatric CD patients.