Longterm course of neuropsychological symptoms and ME/CFS after SARS-CoV-2-infection: a prospective registry study.

A significant proportion of patients after SARS-CoV-2 infection suffer from long-lasting symptoms. Although many different symptoms are described, the majority of patients complains about neuropsychological symptoms. Additionally, a subgroup of patients fulfills diagnostic criteria for ME/CFS. We analyzed a registry of all patients presenting in the out-patients clinic at a German university center. For patients with more than one visit, changes in reported symptoms from first to second visit were analyzed. A total of 1022 patients were included in the study, 411 of them had more than one visit. 95.5% of the patients reported a polysymptomatic disease. At the first visit 31.3% of the patients fulfilled ME/CFS criteria after a median time of 255 days post infection and and at the second visit after a median of 402 days, 19.4% still suffered from ME/CFS. Self-reported fatigue (83.7-72.7%) and concentration impairment (66.2-57.9%) decreased from first to second visit contrasting non-significant changes in the structured screening. A significant proportion of SARS-CoV-2 survivors presenting with ongoing symptoms present with ME/CFS. Although the proportion of subjective reported symptoms and their severity reduce over time, a significant proportion of patients suffer from long-lasting symptoms necessitating new therapeutic concepts.

[German S1 Guideline Long-/Post-COVID]. / S1-Leitlinie Long-/Post-COVID.

The German Society of Pneumology initiated 2021 the AWMF S1 guideline Long COVID/Post-COVID. In a broad interdisciplinary approach, this S1 guideline was designed based on the current state of knowledge.The clinical recommendations describe current Long COVID/Post-COVID symptoms, diagnostic approaches, and therapies.In addition to the general and consensus introduction, a subject-specific approach was taken to summarize the current state of knowledge.The guideline has an explicit practical claim and will be developed and adapted by the author team based on the current increase in knowledge.

[Aspects of pulmonary involvement in inflammatory bowel disease]. / Lungenbeteiligung bei chronisch-entzündlichen Darmerkrankungen.

The incidence of pulmonary manifestations of inflammatory bowel disease (IBD) appears to be much higher than previously assumed. In prospective studies, subclinical pulmonary interstitial infiltrates or pathological lung function were found in 40%-60% of IBD patients, both in children and adults. Pulmonary disorders can affect any part of the respiratory system, the most frequent pattern being inflammation of the large airways often associated with bronchiectasis. The differential diagnosis should include drug-related pulmonary disease and infectious causes when receiving immunosuppressive therapy. The diagnostic approach consists of a thorough history and clinical status as well as lung function tests including body plethysmography and high-resolution computed tomography of the thorax. Bronchoscopy with broncheoalveolar lavage and sample collection for histology as well as exclusion of pulmonary embolism may be indicated. Pulmonary disease in association with IBD can develop at any time during the course of IBD: in rare cases, symptoms can evolve even before gastrointestinal symptoms appear. On the other hand, there are frequent reports on the occurrence of pulmonary inflammation after proctocolectomy in patients with ulcerative colitis. The pathophysiologic background is largely unknown, but there seems to be an interaction between gastrointestinal and pulmonary inflammation. The mainstay of therapy are inhaled or systemic corticosteroids. Most patterns of pulmonary involvement in IBD respond well to corticosteroid therapy. Rarely, serious and persisting complications occur, such as strictures or stenosis of the large airways.

[Controlled evaluation of a high-resolution three-dimensional magnetic detector system (3D-MAGMA) as a proof of concept - examination of healthy volunteers before and after application of Metoclopramide (MCP)]. / Kontrollierte Evaluierung des 3-dimensionalen, magnetischen Markermonitorings (3D-MAGMA) in einer Proof-of-Concept-Studie - Untersuchungen vor und nach Gabe von Metoclopramid (MCP) bei gesunden Probanden.

BACKGROUND: Changes in gastric and small bowel motility are a common clinical problem. Currently diagnostic options are limited because each method harbors certain disadvantages. It has been shown that the high-resolution three-dimensional magnetic detector system 3D-MAGMA is capable of reliably measuring gastric and small intestine motor activity. This system allows precise localization of a small magnetic marker and determination of its three-dimensional orientation inside a human body. The aim of the current study was to determine if 3D-MAGMA is reliably able to detect changes in gastric and small bowel motility under controlled conditions. MCP was used as a well known prokinetic agent to shorten the gastric and small bowel passage. PATIENTS AND METHODS: 8 healthy volunteers (fasting) underwent motility testing of the stomach and small bowel by 3D-MAGMA with and without administration of MCP (10 mg orally). Among other data the time the capsule needed to pass through the stomach and the duodenum and the time the capsule needed to pass through the first 50 cm of the jejunum were recorded. RESULTS: The retention time of the capsule in the stomach under physiological conditions was 49.1 minutes (median; min. 18 min; max. 88.8 min). The median time the capsule needed to pass through the duodenum was 13.8 minutes (median; min. 1.7 min; max. 24.8 min). The time the capsule needed to pass through the first 50 cm of the jejunum under physiological conditions was 33.0 minutes (median; min. 20.2 min; max. 67.2 min). The retention time of the capsule in the stomach decreased significantly after administration of MCP to 20.9 minutes (median; min. 1.7 min; max. 62.8 min; p = 0.008). The time the capsule needed to pass through the duodenum was also reduced to 7.1 minutes (median; min. 3.1 min; max. 18.3 min; p = 0.055). The time the capsule needed to pass through the first 50 cm of the jejunum was also reduced to 21.7 minutes (median; min. 10.7 min; max. 31.2 min; p = 0.069). DISCUSSION: 3D-MAGMA is able to accurately detect changes in gastric and small bowel motility. Its clinical use appears conceivable especially in patients with diseases that have impact on gastric and small bowel motility.

Motivation of patients with inflammatory bowel disease to participate in a clinical trial.

Background: Clinical trials are designed to investigate innovative diagnostic and therapeutic strategies for patients. However, factors that influence patients with inflammatory bowel disease (IBD) and willingness to participate in a clinical trial are unknown. Methods: We developed a questionnaire and asked IBD patients about their willingness to hypothetically participate in a clinical trial and their current health-related quality of life by using the IBDQ. Results: Of 201 distributed questionnaires, 166 were returned and included in the analysis. One-hundred-one (61 %) patients declared their willingness to participate in a clinical trial hypothetically offered in their current situation, whereas 65 (39 %) declined. Among all patients, a trustful relationship between patient and doctor was most important for trial participation. The willingness to help others and to support medical progress were other key issues mentioned. In contrast, those patients inclined to refuse trial participation feared impairment of their current health status, potential side effects, medical examinations, and the expenditure of time and effort. Conclusion: In our cohort of IBD patients, approximately two-thirds were willing to participate in a clinical trial. We were able to identify a number of factors that should help physicians to directly address fears and break down barriers in order to increase the number of patients willing to participate in clinical trials.

Yellow fever vaccination during treatment with infliximab in a patient with ulcerative colitis: A case report.

We report the case of a 59-year-old patient who accidentally underwent live vaccination against yellow fever during continuous treatment with the TNF-α-antibody (AB) infliximab for ulcerative colitis. The clinical course showed fever of short duration and elevation of liver enzymes without further clinical complications. Yellow fever viremia was not detectable and protective antibodies were developed. A primary vaccination against yellow fever under infliximab has not been reported in the literature before, although vaccination is an important topic in IBD. Live vaccinations, like Stamaril(®) against yellow fever, are contraindicated during TNF-α-AB treatment. Treatment regimens containing TNF-α-AB are of growing importance, not only in gastroenterology, but also in rheumatology and dermatology. We discuss this topic by presenting our case and reviewing the current literature.

[Clostridium difficile infection : What is currently available for treatment?] / Clostridium-difficile-Infektion : Was ist gesichert in der Therapie?

Clostridium difficile (C. difficile) is an anaerobic, Gram-positive, spore-forming, toxin-secreting bacillus. It is transmitted via a fecal-oral route and can be found in 1-3 % of the healthy population. Symptoms caused by C. difficile range from uncomplicated diarrhea to a toxic megacolon. The incidence, frequency of recurrence, and mortality rate of C. difficile infections (CDIs) have increased significantly over the past few decades. The most important risk factor is antibiotic treatment in elderly patients and patients with severe comorbidities. There is a screening test available to detect C. difficile-specific glutamate dehydrogenase (GDH), which is produced by both toxigenic and non-toxigenic strains. To confirm CDIs, it is necessary to test for toxins in a fresh, liquid stool sample via polymerase chain reaction or an enzyme-coupled immune adsorption test. If CDIs are diagnosed, then ongoing antibiotic treatment should be ended. Metronidazole is used to treat mild cases, and vancomycin is recommended for severe cases. Vancomycin or fidaxomicin should be used to treat recurrences (10-25 % of patients). In cases with several recurrences, a treatment option is fecal microbiome transfer (FMT). The cure rate following FMT is approximately 80 %. The treatment of severe and complicated CDI with a threatening toxic megacolon remains problematic. The degree of evidence of medicated treatment in this situation is low; the significance of metronidazole i. v. as an additional therapeutic measure is controversial. Tigecycline i. v. is an alternative option. Surgical treatment must be considered in patients with a toxic megacolon or an acute abdomen.

[Drug delivery strategies for targeted treatment of inflammatory bowel disease]. / Drug-Delivery-Strategien zur gezielten Behandlung von chronisch-entzündlichen Darmerkrankungen.

Inflammatory bowel disease (IBD) is a frequently occurring disease in young people, which is characterized by chronic inflammation of the gastrointestinal tract. The therapy of IBD is dominated by the administration of anti-inflammatory and immunosuppressive agents, which suppress the intestinal inflammatory burden and improve the disease-related symptoms. Present treatment strategies are characterized by a limited therapeutical efficacy and the occurrence of adverse drug reactions. The development of novel disease-targeted drug delivery strategies is preferable for a more effective therapy and thus demonstrates the potential to address unmet medical needs. This review gives an overview about drug delivery strategies for the treatment of IBD. Therefore, established intestine-targeting strategies for a selective drug release into the diseased part of the gastrointestinal tract will be presented, including prodrugs, and dosage forms with pH-/time-dependent drug release. Furthermore future-oriented disease-targeting strategies for a selective drug release into the intestinal inflammation will be described, including micro-/nanosized synthetic and biologic drug carriers. This novel therapeutic approach may enable a more effective anti-inflammatory treatment of IBD with reduced risks of adverse reactions.

[Jejunal ulcerations - a diagnostic challenge in a patient with coeliac disease]. / Jejunale Ulzerationen - eine diagnostische Herausforderung bei einem Patienten mit Zöliakie.

A subset of patients with coeliac disease (CD) suffers persistent or recurrent complaints despite a strict adherence to a gluten-free diet (GFD) that can be caused by refractory coeliac disease (RCD). We present a patient with weight loss and signs of malassimilation secondary to villous atrophy and jejunal ulcerations complicating known CD. We demonstrate a stepwise approach to the diagnosis and subtyping of RCD and to rule out important alternative causes of jejunal ulcerations. RCD can be classified as type I based on the absence or as type II based on the presence of an aberrant intestinal mucosal lymphocyte population. RCD type I shows a more benign course as these patients usually improve on a treatment consisting of nutritional support and immunosuppressive therapies such as budesonide or azathioprine. In contrast, clinical response to standard therapies in RCD type II is less certain and the prognosis is poor. Several groups suggest that RCD type II should be regarded as low-grade intraepithelial lymphoma which frequently transforms into an aggressive enteropathy associated T-cell lymphoma with a high mortality rate. Therefore, a rapid differentiation of RCD type I and RCD type II is a major clinical challenge to early initiate appropriate treatment modalities.

Lung disease and ulcerative colitis--mesalazine-induced bronchiolitis obliterans with organizing pneumonia or pulmonary manifestation of inflammatory bowel disease?

Ulcerative colitis can be associated with numerous extraintestinal organ manifestations. Pulmonary disease in inflammatory bowel disease (IBD) is supposed to be a rare entity and has to be distinguished from infectious complications and side-effects of medications used in the treatment of IBD. We present the case of a 20-year-old male patient with ulcerative colitis and a 4-week history of respiratory symptoms, malaise, fever and respiratory insufficiency under a medication with mesalazine. Computed tomography showed bilateral subpleural consolidations, bronchoscopy revealed signs of acute bronchitis. The diagnostic work-up ruled out an infectious cause. Under the tentative diagnosis of a mesalazine-induced bronchiolitis obliterans with organizing pneumonia (BOOP) the medication with mesalazine was withdrawn and the patient received a corticosteroid trial. The symptoms quickly improved and prednisone was tapered and stopped after 6 months. Unexpectedly, lung function after complete resolution of respiratory symptoms revealed a residual obstructive ventilatory defect that might be due to an asymptomatic pulmonary manifestation of ulcerative colitis. A review of the literature shows that pulmonary manifestations in IBD as well as pulmonary toxicity of mesalazine might not be as rare as expected and should be included as differential diagnoses in the work-up of respiratory symptoms in patients with IBD. A pragmatic therapeutic approach is reasonable in critically ill patients as it is not always easy to distinguish both entities.

[Morbus Behçet or inflammatory bowel disease--a diagnostic and therapeutic dilemma]. / Morbus Behçet oder chronisch-entzündliche Darmerkrankung--ein diagnostisches und therapeutisches Dilemma.

We present the case of a 43-year old caucasian male suffering from a condition initially diagnosed as colitis ulcerosa. For 2 years Azathioprine and anti-TNF-alpha antibodies were used for treatment without convincing benefit but with serious adverse events. After the first occurrence of complex accompanying symptoms like oral and scrotal ulcerations, arthritis and scratch-induced skin lesions the differential diagnosis of a Morbus Adamantiades-Behçet with intestinal evolvement was considered. After introduction of a parenteral Ciclosporin medication, which was later switched to Tacrolimus and Azathioprin, a remission could be achieved that lasted for several months. When a drug-induced acute kidney injury occurred, the regime was changed to Golimumab and a delayed but significant improvement was achieved. To separate Morbus Adamantiades-Behçet from inflammatory bowel disease is of some difficulty, demands interdisciplinary cooperation and is the basis for a successful therapy.

[Economic burden of Clostridium difficile enterocolitis in German hospitals based on routine DRG data]. / Ökonomische Auswirkungen einer Clostridium-difficile-Enterokolitis in deutschen Krankenhäusern auf der Basis von DRG-Kostendaten.

BACKGROUND: Clostridium difficile associated diarrhea (CDAD) is not only a increasing medical but also economical problem. METHODS: Data from the DRG project group of the German society for digestive and metabolic diseases (DGVS) were analyzed for CDAD. Out of 430,875 cases from 37 German hospitals 2,767 cases were grouped by having CDAD either as primary (PD) or secondary diagnosis (SD; likely to be from a hospital source) in an initial or recurring hospital stay (RD). For comparison non-CDAD cases from the same hospitals from that year where matched using propensity score matching. As endpoints we defined LOS (length of stay), difference of LOS to national average LOS, total costs per case and difference between costs and revenue for all three groups. RESULTS: Patients from the PD group (n = 817) showed a mean LOS of 11.2 days compared to 8.5 days for the control group, 4,132 € mean cost per case (536 € more than control) and a mean loss of -1,064 € per case compared to -636 €. In the SD group (n = 1,840) patients stayed in the hospital for 28.8 days (control: 18.1 days), had costs of 19,381 € (control: 13,082 €) and a loss of -3,442 € compared to -849 € in the control group. Recurring cases (RD; n = 110) showed a LOS of 37.3 days (control: 21.3 days), had even higher costs (20.755 € vs. 13,101 €) and higher losses (-4,196 € vs. -1,109 €). CONCLUSION: By extrapolating these findings CDAD not only harms patients but generates a yearly cost burden of 464 million € for the German healthcare system including a loss of 197 million € for German hospitals. To the authors' opinion sufficient measures against CDAD should include pre hospital risk reduction programs, introduction of effective therapeutic and hygienic strategies in hospitals as well as improvements in documentation for these cases to support further developments of the German DRG system.

[Current position on Vedolizumab for ulcerative colitis and Crohn's disease]. / Vedolizumab bei Colitis ulcerosa und Morbus Crohn: eine Standortbestimmung.

Vedolizumab, the first drug in the class of anti-integrin molecules, is newly approved for ulcerative colitis and Crohn's disease and can be prescribed in Germany since mid-2014. By a specific receptor binding a relatively gut-selective mode of action was achieved without the known side effects of the systemic immunosuppression of the anti-TNF-alpha antibodies. According to the present data the safety profile of Vedolizumab appears to be more favorable than that of the anti-TNF- alpha therapy. Vedolizumab is suitable for induction therapy in patients with ulcerative colitis and Crohn's disease, however the kinetic of response compared with the anti-TNF-alpha antibodies seems to be slower. For maintenance therapy the Vedolizumab data show a deep and sustained remission in patients initially responding to induction therapy with a lower loss of efficacy in the long-term treatment known from the anti-TNF-alpha therapy. On the basis of currently available data the efficacy of Vedolizumab in ulcerative colitis appears to be slightly better than in Crohn's disease.

MALDI imaging-based classification of hepatocellular carcinoma and non-malignant lesions in fibrotic liver tissue.

Histopathologic differentiation of nodular lesions in cirrhotic liver is difficult even for experienced hepatopathologists especially regarding diagnosis of hepatocellular carcinoma (HCC) in biopsies. For this reason, new tissue markers are needed to reinforce histopathologic decision-making. With advances in molecular techniques, proteomic analysis may help to confirm the diagnosis of HCC. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is a powerful technology which allows to determine and to localize proteins directly in tissue sections. Using MALDI IMS proteomic patterns of cryosections with lesions of HCC (n = 15) and non-malignant fibrotic liver tissue (n = 11) were investigated to establish a classification model of HCC, which was validated in an independent set of tissue to distinguish HCC (n = 10) from regenerative nodules (n = 8). By correlating generated mass spectrometric images with the histology of the tissue sections we found that the expression of 4 proteins as indicated by m/z 6274, m/z 6647, m/z 6222 and m/z 6853 was significantly higher in HCC tissue than in non-tumorous liver tissue. The generated classification model based on the most significant 3 differentially expressed proteins allowed a reliable prediction of benign and malignant lesions in fibrotic liver tissue with a sensitivity and specificity of 90 % in the validation set. The identified MALDI IMS proteomic signature can be diagnostically helpful to allow simplifying the diagnostic process and minimize the risks of delays in establishing the objective final diagnosis and initiating treatment of patients with HCC.

[Multiresistant Organisms]. / Multiresistente Erreger.

Infections caused by multidrug resistant (MDR) organisms are becoming more frequently in daily practice and are associated with an increase in duration of treatment and mortality. During the past decades, particular attention in the field of MDR pathogens was paid to methicillin-resistant staphylococcus aureus (MRSA). For the last years, MDR gram-negative organisms, with e.g., "extended-spectrum beta-lactamases" (ESBL), have been gaining a growing significance. Currently, treatment of infections with these organisms displays a greater challenge for the clinician compared to MRSA infections. This review illustrates the emergence of antibiotic resistance, provides information on the most important gram-negative and gram-positive bacteria, Clostridium difficile and measures to prevent their further spread.

[Diagnostic workup and therapy of infectious diarrhea. Current standards]. / Diagnostik und Therapie infektiöser Durchfallerkrankungen. Was ist gesichert?

Infectious diarrhea is very common; its severity ranges from uncomplicated, self-limiting courses to potentially life-threatening disease. A rapid diagnostic workup providing detailed information on the suspected pathogen should be performed only in patients at risk, analyzing one single stool sample for Salmonella, Shigella, Campylobacter, and Norovirus. In the presence of risk factors, such as a history of antibiotic exposure within the last 3 months, testing for Clostridium difficile should be performed. Immunocompetent patients do not require specific antibiotic therapy. Exceptions exist in patients with severe comorbidities, immunodeficiency, fever/SIRS, and in patients with Shigella or C. difficile infection. Empirical antibiotic treatment should be considered in patients with fever and/or bloody diarrhea and in patients at risk. In patients with traveler's diarrhea, microbiological diagnosis is required only in patients with fever, bloody diarrhea, prolonged course of disease (more than 5 days), severe clinical course with hypotension or dehydration, and during outbreaks. In these patients one single fecal sample should be collected for stool cultures of Campylobacter, Shigella, and Salmonella, as well as microscopic examination for amoebiasis and Giardiasis. The main therapeutic measure for infectious diarrhea is sufficient oral rehydration. As in community-acquired diarrhea, azithromycin or ciprofloxacin are recommended-taking into account local antimicrobial resistance in the country of travel and possible side effects.

Discrimination and classification of liver cancer cells and proliferation states by Raman spectroscopic imaging.

Discrimination of nodular lesions in cirrhotic liver is a challenge in the histopathologic diagnostics. For this reason, there is an urgent need for new detection methods to improve the accuracy of the diagnosis of liver cancer. Raman imaging allows to determine the spatial distribution of a variety of molecules in cells or tissue label-free and to correlate this molecular information with the morphological structures at the same sample location. This study reports investigations of two liver cancer cell lines, - HepG2 and SK-Hep1, - as well as HepG2 cells in different cellular growth phases using Raman micro-spectroscopic imaging. Spectral data of all cells were recorded as a color-coded image and subsequentially analyzed by hierarchical cluster and principal component analysis. A support vector machine-based classification algorithm reliably predicts previously unknown cancer cells and cell cycle phases. By including selectively the Raman spectra of the cytoplasmic lipids in the classifier, the accuracy has been improved. The main spectral differences that were found in the comparative analysis can be attributed to a higher expression of unsaturated fatty acids in the hepatocellular carcinoma cells and during the proliferation phase. This corresponds to the already examined de novo lipogenesis in cells of liver cancer.

[Azathioprine in Crohn's disease therapy--guidance against the background of recent studies]. / Azathioprin in der Therapie des Morbus Crohn--eine Standortbestimmung vor dem Hintergrund aktueller Studien.

Thiopurines (azathioprine and 6-mercaptopurine) are the most frequently used drugs in the treatment of patients with Crohn's disease. In current guidelines published by the German Society of Gastroenterology, Nutritional and Metabolic Diseases (DGVS) in 2014 and by the European Crohn´s and Colitis Organisation (ECCO) in 2010 different indications have been suggested. However, efficacy of azathioprine has been substantially questioned by recent publications in adults as well as in children examining the efficacy of early initiation of this treatment. These articles were published after release of the aforementioned guidelines. Therefore, in this survey recently published data are discussed on the background of our knowledge on the efficacy of azathioprine and 6-mercaptopurine developed in many years, and suggestions for the future use of these substances in the treatment of patients with Crohn's disease will be provided.