[What is confirmed in the treatment of chronic inflammatory bowel diseases]. / Was ist gesichert in der Therapie chronisch-entzündlicher Darmerkrankungen.

The prevalence of the chronic inflammatory bowel diseases (CIBD) Crohn's disease (CD) and ulcerative colitis (UC) is on the rise worldwide. In Germany CIBDs are also a significant healthcare problem. The pathogenesis is complex and involves genetic factors, environmental aspects and changes in the immunological constitution. Furthermore, the gut microbiota plays a role in the maintenance of intestinal inflammation. Fortunately, several new drugs, in particular biologicals, have been approved for the treatment of CIBDs. The treatment of UC is mainly based on 5­aminosalicylic acid formulations, preferably as a topical form for distal colitis and proctitis as well as local budesonide formulations. In the case of extensive spread, high disease activity and refractory disease antibodies (biologicals) are successfully used, similar to CD. In addition to anti-tumor necrosis factor antibodies (infliximab, adalimumab, golimumab), vedolizumab, an anti-integrin antibody and the interleukin 12/23 antibody ustekinumab can be successfully used. The intravenous and also subcutaneous administration of antibodies are increasing in importance and are now available for all forms. Furthermore, the Janus kinase inhibitor tofacitinib is an orally administered option for UC. Clinical scores, endoscopy, ultrasound, laboratory parameters and calprotectin determination in stool are employed to evaluate treatment response (treat to target approach). Ultimately, the long-term goal is mucosal healing. Despite advances in the pharmaceutical treatment, a significant number of patients with CIBD still suffer from treatment refractory courses and need surgery at some time during the disease.

Initial therapy affects duration of diarrhoea in critically ill patients with Clostridioides difficile infection (CDI).

BACKGROUND: Critically ill patients in the intensive care unit (ICU) are at high risk for developing Clostridioides difficile infections (CDI). Risk factors predicting their mortality or standardized treatment recommendations have not been defined for this cohort. Our goal is to determine outcome and mortality associated risk factors for patients at the ICU with CDI by evaluating clinical characteristics and therapy regimens. METHODS: A retrospective single-centre cohort study. One hundred forty-four patients (0.4%) with CDI-associated diarrhoea were included (total 36.477 patients admitted to 12 ICUs from January 2010 to September 2015). Eight patients without specific antibiotic therapy were excluded, so 132 patients were analysed regarding mortality, associated risk factors and therapy regimens using univariate and multivariate regression. RESULTS: Twenty-eight-day mortality was high in patients diagnosed with CDI (27.3%) compared to non-infected ICU patients (9%). Patients with non CDI-related sepsis (n = 40/132; 30.3%) showed further increase in 28-day mortality (45%; p = 0.003). Initially, most patients were treated with a single CDI-specific agent (n = 120/132; 90.9%), either metronidazole (orally, 35.6%; or IV, 37.1%) or vancomycin (18.2%), or with a combination of antibiotics (n = 12/132; 9.1%). Patients treated with metronidazole IV showed significantly longer duration of diarrhoea > 5 days (p = 0.006). In a multivariate regression model, metronidazole IV as initial therapy was an independent risk factor for delayed clinical cure. Immunosuppressants (p = 0.007) during ICU stay lead to increased 28-day mortality. CONCLUSION: Treatment of CDI with solely metronidazole IV leads to a prolonged disease course in critically ill patients.

Hepatitis E seroprevalence in the Americas: A systematic review and meta-analysis.

BACKGROUND & AIMS: While hepatitis E virus infections are a relevant topic in Europe, knowledge about epidemiology of hepatitis E virus infections in the USA and Latin America is still limited. Aim of this study was to estimate anti-hepatitis E virus IgG seroprevalence in the Americas and to assess whether low socioeconomic status is associated with hepatitis E virus exposure. METHODS: We performed a systematic review and meta-analysis. Literature search was performed in PubMed for articles published 01/1994-12/2016. Prevalence was estimated using a mixed-effects model and reported in line with PRISMA reporting guidelines. RESULTS: Seroprevalence was significantly higher in the USA than in Latin America, independently of assay, patient cohort, methodological quality or study year (OR: 1.82 (1.06-3.08), P = .03). Patients in the USA had a more than doubled estimated seroprevalence (up to 9%, confidence interval 5%-15.6%) than those in Brazil (up to 4.2%, confidence interval 2.4%-7.1%; OR: 2.27 (1.25-4.13); P = .007) and Mixed Caribbean (up to 1%, OR: 8.33 (1.15-81.61); P = .04). A comparison with published data from Europe demonstrated that anti-hepatitis E virus seroprevalence in the USA and Europe did not differ significantly (OR: 1.33 (0.81-2.19), P = .25), while rate in South America was significantly lower than that in Europe (OR: 0.67 (0.45-0.98), P = .04). CONCLUSIONS: Hepatitis E virus is common in the USA. Surprisingly, the risk of hepatitis E virus exposure was low in many South American countries. Seroprevalence did not differ significantly between Europe and the USA. Hence, hepatitis E virus is not limited to countries with low sanitary standards, and a higher socioeconomic status does not protect populations from hepatitis E virus exposure.

Trp53 deficiency protects against acute intestinal inflammation.

The p53 protein has not only important tumor suppressor activity but also additional immunological and other functions, whose nature and extent are just beginning to be recognized. In this article, we show that p53 has a novel inflammation-promoting action in the intestinal tract, because loss of p53 or the upstream activating kinase, ATM, protects against acute intestinal inflammation in murine models. Mechanistically, deficiency in p53 leads to increased survival of epithelial cells and lamina propria macrophages, higher IL-6 expression owing to enhanced glucose-dependent NF-κB activation, and increased mucosal STAT3 activation. Blockade or loss of IL-6 signaling reverses the protective effects of p53 deficiency. Conversely, IL-6 treatment protects against acute colitis in a manner dependent on STAT3 signaling and induction of cytoprotective factors in epithelial cells. Together, these results indicate that p53 promotes inflammation in the intestinal tract through suppression of epithelium-protective factors, thus significantly expanding the spectrum of physiological and immunological p53 activities unrelated to cancer formation.

IL-17A promotes protective IgA responses and expression of other potential effectors against the lumen-dwelling enteric parasite Giardia.

Giardia lamblia is a leading protozoan cause of diarrheal disease worldwide. It colonizes the lumen and epithelial surface of the small intestine, but does not invade the mucosa. Acute infection causes only minimal mucosal inflammation. Effective immune defenses exist, yet their identity and mechanisms remain incompletely understood. Interleukin (IL)-17A has emerged as an important cytokine involved in inflammation and antimicrobial defense against bacterial pathogens at mucosal surfaces. In this study, we demonstrate that IL-17A has a crucial function in host defense against Giardia infection. Using murine infection models with G. muris and G. lamblia, we observed marked and selective induction of intestinal IL-17A with peak expression after 2 weeks. Th17 cells in the lamina propria and innate immune cells in the epithelial compartment of the small intestine were responsible for the IL-17A response. Experiments in gene-targeted mice revealed that the cytokine, and its cognate receptor IL-17RA, were required for eradication of the parasite. The actions of the cytokine were mediated by hematopoietic cells, and were required for the transport of IgA into the intestinal lumen, since IL-17A deficiency led to marked reduction of fecal IgA levels, as well as for increased intestinal expression of several other potential effectors, including ß-defensin 1 and resistin-like molecule ß. In contrast, intestinal hypermotility, another major antigiardial defense mechanism, was not impacted by IL-17A loss. Taken together, these findings demonstrate that IL-17A and IL-17 receptor signaling are essential for intestinal defense against the important lumen-dwelling intestinal parasite Giardia.

Indispensable functions of ABL and PDGF receptor kinases in epithelial adherence of attaching/effacing pathogens under physiological conditions.

Enteropathogenic Escherichia coli (EPEC) and Citrobacter rodentium are attaching-and-effacing (A/E) pathogens that cause intestinal inflammation and diarrhea. The bacteria adhere to the intestinal epithelium, destroy microvilli, and induce actin-filled membranous pedestals but do not invade the mucosa. Adherence leads to activation of several host cell kinases, including FYN, n-SRC, YES, ABL, and ARG, phosphorylation of the bacterial translocated intimin receptor, and actin polymerization and pedestal formation in cultured cells. However, marked functional redundancy appears to exist between kinases, and their physiological importance in A/E pathogen infections has remained unclear. To address this question, we employed a novel dynamic in vitro infection model that mimics transient and short-term interactions in the intestinal tract. Screening of a kinase inhibitor library and RNA interference experiments in vitro revealed that ABL and platelet-derived growth factor (PDGF) receptor (PDGFR) kinases, as well as p38 MAP kinase, have unique, indispensable roles in early attachment of EPEC to epithelial cells under dynamic infection conditions. Studies with mutant EPEC showed that the attachment functions of ABL and PDGFR were independent of the intimin receptor but required bacterial bundle-forming pili. Furthermore, inhibition of ABL and PDGFR with imatinib protected against infection of mice with modest loads of C. rodentium, whereas the kinases were dispensable for high inocula or late after infection. These results indicate that ABL and PDGFR have indispensable roles in early A/E pathogen attachment to intestinal epithelial cells and for in vivo infection with limiting inocula but are not required for late intimate bacterial attachment or high inoculum infections.

Human milk oligosaccharides protect against enteropathogenic Escherichia coli attachment in vitro and EPEC colonization in suckling mice.

Breast-feeding reduces the risk of enteric bacterial infections in newborns in part because of human milk oligosaccharides (HMOs), complex glycans that are present in human milk, but not in infant formula. Enteropathogenic Escherichia coli (EPEC) are attaching/effacing pathogens that cause serious diarrheal illness with potentially high mortality in infants. We isolated HMOs from pooled human milk and found that they significantly reduce EPEC attachment to cultured epithelial cells. In suckling mice, administration of HMOs significantly reduced colonization with EPEC compared with untreated controls. These data suggest an essential role for HMOs in the prevention of EPEC infections in human infants.

[The new guideline for gastrointestinal infections]. / Die neue Leitlinie für gastrointestinale Infektionen.

Gastrointestinal infections are still responsible for around 60% of the infectious diseases that must be reported in Germany and are probably among the most common gastroenterological diseases. The main therapy for gastrointestinal infections remains oral fluid replacement. The recommendations for Clostridioides difficile infections (CDI) have been adapted according to the current data and based on international guidelines; vancomycin or, especially if there is an increased risk of recurrence, fidaxomicin should now be used primarily in CDI. In the case of febrile diarrhea and/or bloody diarrhea, malaria diagnosis should be carried out immediately.

Clinical Presentation and Outcome of Critically Ill Patients with Inflammatory Bowel Disease.

Introduction: Admission to the intensive care unit severely affects inflammatory bowel disease (IBD) patients. This study aimed to determine factors associated with mortality in IBD patients admitted to the intensive care unit. Methods: A retrospective cohort study was performed, analyzing data of all IBD patients admitted to the Department of Intensive Care Medicine at the University Medical Center Hamburg-Eppendorf between 2013 and 2022. Bivariate comparisons and multivariate regression analyses were performed to identify factors associated with mortality. Results: Overall, 439 IBD patients were admitted to the intensive care unit, representing 0.56% of total admissions. In 98 of these patients, IBD-associated complications were accountable for admission (22.3%). In detail, 39 (40.8%) patients were admitted after IBD-related surgery, 36 (35.7%) due to infections, and 23 (23.5%) due to medical conditions such as bleeding or electrolyte derangement. A total of 16 (16.3%) of these patients died within 90 days after admission. Parameters associated with increased mortality were age (p < 0.001), later age at diagnosis (p 0.026), catecholamine therapy (p 0.003), mechanical ventilation (p < 0.001), renal replacement therapy (p < 0.001), and parenteral nutrition (p 0.002). Prior treatment with anti-TNF therapy was associated with a higher chance of survival (p 0.018). There was no association between prior immunosuppressant therapy and admission because of infections (p 0.294). Conclusions: 16.3% of IBD patients admitted to the intensive care unit died within 90 days after admission. Prior treatment with anti-TNF therapy was associated with a higher chance of survival.

Myeloid Cell-Specific Deletion of PDGFR-α Promotes Dysbiotic Intestinal Microbiota and thus Increased Colitis Susceptibility.

BACKGROUND AND AIMS: The incidence of inflammatory bowel diseases [IBD] is steadily increasing, and thus the identification of new targets to improve therapy is a major goal. Growth factors of the PDGF family and their receptors are expressed early in intestinal development and are found in mononuclear cells and macrophages in adult tissues. Macrophages play a distinct role in the pathogenesis of IBD since their function is crucial to maintaining tolerance. METHODS: We aimed to study the role of myeloid expression of PDGFR-α in mediating intestinal homeostasis in mouse IBD and infectious models. RESULTS: Our results show that loss of myeloid PDGFR-α increases susceptibility to dextran saline sulphate-induced colitis. Accordingly, LysM-PDGFR-α-/- mice showed higher colitis scores, and reduced levels of anti-inflammatory macrophages compared to control mice. This effect was mediated via a pro-colitogenic microbiota, which developed in the absence of myeloid PDGFR-α and caused increased colitis susceptibility in gnotobiotic mice upon faecal microbiota transplantation compared to controls. Furthermore, LysM-PDGFR-α-/- mice had a leaky gut, accompanied by impaired phagocytosis, resulting in a severe barrier defect. CONCLUSIONS: Taken together, our results indicate a protective role for myeloid PDGFR-α in maintaining gut homeostasis by promoting a protective intestinal microbiota and providing an anti-inflammatory macrophage phenotype.

Comparison of the integrin α4ß7 expression pattern of memory T cell subsets in HIV infection and ulcerative colitis.

Anti-α4ß7 therapy with vedolizumab (VDZ) has been suggested as possible immune intervention in HIV. Relatively little is known about the α4ß7-integrin (α4ß7) expression of different T-cell subsets in different anatomical compartments of healthy individuals, patients with HIV or inflammatory bowel disease (IBD). Surface expression of α4ß7 as well as the frequency of activation, homing and exhaustion markers of T cells were assessed by multicolour flow cytometry in healthy volunteers (n = 15) compared to HIV infected patients (n = 52) or patients diagnosed with ulcerative colitis (UC) (n = 14), 6 of whom treated with vedolizumab. In addition, lymph nodal cells (n = 6), gut-derived cells of healthy volunteers (n = 5) and patients with UC (n = 6) were analysed. Additionally, we studied longitudinal PBMC samples of an HIV patient who was treated with vedolizumab for concomitant UC. Overall, only minor variations of the frequency of α4ß7 on total CD4+ T cells were detectable regardless of the disease status or (VDZ) treatment status in peripheral blood and the studied tissues. Peripheral α4ß7+ CD4+ T cells of healthy individuals and patients with UC showed a higher activation status and were more frequently CCR5+ than their α4ß7- counterparts. Also, the frequency of α4ß7+ cells was significantly lower in peripheral blood CD4+ effector memory T cells of HIV-infected compared to healthy individuals and this reduced frequency did not recover in HIV patients on ART. Conversely, the frequency of peripheral blood naïve α4ß7+ CD4+ T cells was significantly reduced under VDZ treatment. The results of the current study will contribute to the understanding of the dynamics of α4ß7 expression pattern on T cells in HIV and UC and will be useful for future studies investigating VDZ as possible HIV cure strategy.

Stool cultures at the ICU: get rid of it!

BACKGROUND: Stool cultures for Campylobacter, Salmonella and Shigella and/or Yersinia spp. are frequently ordered in critically ill patients with diarrhea. The aim of this study is to analyze the diagnostic yield in a large cohort of critically ill patients. Therefore, we performed a cohort study at the Department of Intensive Care Medicine of a University Hospital (11 ICUs). RESULTS: From all patients who were admitted to the ICU between 2010 and 2015, stool cultures were taken from 2.189/36.477 (6%) patients due to diarrhea. Results of all stool cultures tested for Campylobacter, Salmonella and Shigella and/or Yersinia spp. were analyzed. Overall, 5.747 tests were performed; only six were positive (0.1%). In four of these, Campylobacter spp. were detected; diarrhea started within 48 h after ICU admission. Two patients with Salmonella spp. detection were chronic shedders. On the contrary, testing for Clostridium difficile via GDH- and toxin A/B-EIA yielded positive results in 179/2209 (8.1%) tests and revealed 144/2.189 (6.6%) patients with clinically relevant C. difficile infection. CONCLUSIONS: Stool testing for enteric pathogens other than C. difficile should be avoided in ICU patients and is only reasonable when diarrhea commenced less than 48 h after hospital admission.