[Position paper on reporting of intestinal ultrasound findings in patients with inflammatory bowel disease]. / Positionspapier zur Befunderhebung von Darmultraschallbefunden bei chronisch entzündlichen Darmerkrankungen.

BACKGROUND: Intestinal ultrasound is increasingly used for primary diagnosis, detection of complications and monitoring of patients with Crohn's disease and ulcerative colitis. Standardization of reporting is relevant to ensure quality of the methodology and to improve communication between different specialties. The current manuscript describes the features required for optimized reporting of intestinal ultrasound findings in inflammatory bowel disease (IBD). METHODS: An expert consensus panel of gastroenterologists, radiologists, pathologists, paediatric gastroenterologists and surgeons conducted a systematic literature search. In a Delphi- process members of the Kompetenznetz Darmerkrankungen in collaboration with members of the German Society for Radiology (DRG) voted on relevant criteria for reporting of findings in intestinal ultrasound. Based on the voting results statements were agreed by expert consensus. RESULTS: Clinically relevant aspects of intestinal ultrasound (IUS) findings have been defined to optimize reporting and to standardize terminology. Minimal requirements for standardized reporting are suggested. The statements focus on description of disease activity as well as on complications of IBD. Attributes of intestinal inflammation are described and illustrated by exemplary images. CONCLUSION: The current manuscript provides practical recommendations on how to standardize documentation and reporting from intestinal ultrasound findings in patients with IBD.

ECCO Guidelines on Therapeutics in Ulcerative Colitis: Surgical Treatment.

This is the second of a series of two articles reporting the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of adult patients with ulcerative colitis [UC]. The first article is focused on medical management, and the present article addresses medical treatment of acute severe ulcerative colitis [ASUC] and surgical management of medically refractory UC patients, including preoperative optimisation, surgical strategies, and technical issues. The article provides advice for a variety of common clinical and surgical conditions. Together, the articles represent an update of the evidence-based recommendations of the ECCO for UC.

[Position paper on endoscopic reporting in IBD]. / Positionspapier zur Befunderstellung endoskopischer Untersuchungen bei Patienten mit chronisch-entzündlichen Darmerkrankungen.

The complete and reliable documentation of endoscopic findings make up the crucial foundation for the treatment of patients with inflammatory bowel diseases such as Crohn´s disease and ulcerative colitis. These findings are, on the one hand, a prerequisite for therapeutic decisions and, on the other hand, important as a tool for assessing the response to ongoing treatments. Endoscopic reports should, therefore, be recorded according to standardized criteria to ensure that the findings of different endoscopists can be adequately compared and that changes in the course of the disease can be traced back. In consideration of these necessities, fifteen members of the Imaging Working Group of the German Kompetenznetz Darmerkrankungen have created a position paper proposing a structure and specifications for the documentation of endoscopic exams. In addition to the formal report structure, the recommendations address a large number of attributes of acute and chronic inflammatory alterations as well as endoscopically detectable complications, which are explained in detail and illustrated using exemplary images. In addition, more frequently used endoscopic activity indices are presented and their use in everyday clinical practice is discussed.

Microbiota-associated Risk Factors for Clostridioides difficile Acquisition in Hospitalized Patients: A Prospective, Multicentric Study.

BACKGROUND: Asymptomatic C. difficile colonization is believed to predispose to subsequent C. difficile infection (CDI). While emerging insights into the role of the commensal microbiota in mediating colonization resistance against C. difficile have associated CDI with specific microbial components, corresponding prospectively collected data on colonization with C. difficile are largely unavailable. METHODS: C. difficile status was assessed by GDH EIA and real-time PCR targeting the toxin A (tcdA) and B (tcdB) genes. 16S V3 and V4 gene sequencing results from fecal samples of patients tested positive for C. difficile were analyzed by assessing alpha and beta diversity, LefSe, and the Piphillin functional inference approach to estimate functional capacity. RESULTS: 1506 patients were recruited into a prospective observational study (DRKS00005335) upon admission into one of five academic hospitals. 936 of them provided fecal samples on admission and at discharge and were thus available for longitudinal analysis. Upon hospital admission, 5.5% (83/1506) and 3.7% (56/1506) of patients were colonized with toxigenic (TCD) and non-toxigenic C. difficile (NTCD), respectively. During hospitalization, 1.7% (16/936) acquired TCD. Risk factors for acquisition of TCD included pre-existing lung diseases, lower GI endoscopy and antibiotics. Species protecting against hospital-related C. difficile acquisition included Gemmiger spp., Odoribacter splanchnicus, Ruminococcus bromii and other Ruminococcus spp. Metagenomic pathway analysis identified steroid biosynthesis as the most underrepresented metabolic pathway in patients who later acquire C. difficile colonization. CONCLUSIONS: Gemmiger spp., Odoribacter splanchnicus, Ruminococcus bromii and other Ruminococci were associated with a decreased risk of C. difficile acquisition. CLINICAL TRIALS REGISTRATION: DRKS00005335.

Inflammatory Cutaneous Lesions in Inflammatory Bowel Disease Treated With Vedolizumab or Ustekinumab: An ECCO CONFER Multicentre Case Series.

This was a multicentre case series supported by the European Crohn's and Colitis Organisation [ECCO] and performed as part of the Collaborative Network of Exceptionally Rare case reports [CONFER] project. The aim was to report on whether cutaneous lesions associated with inflammatory bowel disease [IBD] and refractory to standard medical therapy including anti-tumour necrosis factors [anti-TNFs], would respond to the newer biologic agents ustekinumab [UST] or vedolizumab [VDZ]. This report includes 28 patients with cutaneous lesions from 14 centres, all of whom had failed immunomodulator and anti-TNF therapy. Metastatic Crohn's disease [MCD] was diagnosed in 10 patients: UST led to remission in five cases and partial response in four cases, with a single report of VDZ inducing remission. All cases of MCD treated with UST responded after the first or second dose, and the median time for the five cases that attained remission was 5 months. Pyoderma gangrenosum [PG] was diagnosed in four cases: three of these attained remission with UST [median time to remission 4 months] and one case did not respond to VDZ. There were seven cases of erythema nodosum [EN]: UST led to remission in four cases and partial response in 1 case whilst VDZ had partial response in 2 cases and non-response in two cases. There were seven single cases of other inflammatory lesions. In summary, UST appears to be useful for different cutaneous lesions including MCD, PG, and EN, whereas VDZ does not appear to be useful for lesions that are independent of disease activity.

ECCO Guidelines on Therapeutics in Crohn's Disease: Surgical Treatment.

This article is the second in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohn's disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohn's disease and an update of previous guidelines.

Quality of Life Is Associated With Wearable-Based Physical Activity in Patients With Inflammatory Bowel Disease: A Prospective, Observational Study.

OBJECTIVES: Patient-reported outcomes such as quality of life are gaining importance in the assessment of patients suffering from inflammatory bowel disease (IBD). The association of objectively measured physical activity and quality of life in patients with IBD has not been studied in depth. To investigate the association of disease-specific quality of life and physical activity as well as clinical and biochemical disease activity in patients with IBD. METHODS: A total of 91 patients with IBD were stratified into 4 groups (Crohn's disease and ulcerative colitis, in remission and with moderate-severe activity, respectively) and evaluated in terms of disease-specific quality of life (Inflammatory Bowel Disease Questionnaire [IBDQ]), physical activity (accelerometry), body composition (bioelectrical impedance analysis), as well as clinical (Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index) and biochemical (C-reactive protein and fecal calprotectin) parameters of disease activity. RESULTS: In patients with moderate-severe disease activity, the IBDQ was significantly lower as compared to patients in remission (Mann-Whitney U test and Kruskal-Wallis test, P < 0.001). The physical activity level was higher in remission than in active disease (Mann-Whitney U test, P < 0.05). The IBDQ was significantly correlated with the duration of strenuous physical activity per day (P = 0.029178, r = 0.235), skeletal muscle mass (P = 0.033829, r = 0.229), and biomarkers of inflammation (C-reactive protein: P < 0.005, r = -0.335 and fecal calprotectin: P < 0.005, r = -0.385). DISCUSSION: In this prospective, cross-sectional study, disease-specific quality of life was significantly associated with accelerometrically determined physical activity and disease activity in patients with IBD. This may be related to a reciprocal impact of these factors (DRKS00011370).

The impact of technical and clinical factors on fecal microbiota transfer outcomes for the treatment of recurrent Clostridioides difficile infections in Germany.

Introduction: Fecal microbiota transfer (FMT) is highly effective in the treatment and prevention of recurrent Clostridioides difficile infection (rCDI) with cure rates of about 80% after a single treatment. Nevertheless, the reasons for failure in the remaining 20% remain largely elusive. The aim of the present study was to investigate different potential clinical predictors of response to FMT in Germany. Methods: Information was extracted from the MicroTrans Registry (NCT02681068), a retrospective observational multicenter study, collecting data from patients undergoing FMT for recurrent or refractory CDI in Germany. We performed binary logistic regression with the following covariates: age, gender, ribotype 027, Eastern Co-operative Oncology Group score, immunosuppression, preparation for FMT by use of proton pump inhibitor, antimotility agents and bowel lavage, previous recurrences, severity of CDI, antibiotic induction treatment, fresh or frozen FMT preparation, and route of application. Results: Treatment response was achieved in 191/240 evaluable cases (79.6%) at day 30 (D30) post FMT and 78.1% at day 90 (D90) post FMT. Assessment of clinical predictors for FMT failure by forward and confirmatory backward-stepwise regression analysis yielded higher age as an independent predictor of FMT failure (p = 0.001; OR 1.060; 95%CI 1.025-1.097). Conclusion: FMT in Germany is associated with high cure rates at D30 and D90. No specific pre-treatment, preparation or application strategy had an impact on FMT success. Only higher age was identified as an independent risk factor for treatment failure. Based on these and external findings, future studies should focus on the assessment of microbiota and microbiota-associated metabolites as factors determining FMT success.

Fecal calprotectin is significantly linked to azathioprine metabolite concentrations in Crohn's disease.

BACKGROUND: The value of therapeutic drug monitoring during azathioprine (AZA) therapy with respect to clinical outcomes has been convincingly demonstrated in recent meta-analyses. However, the association between AZA metabolites and the mucosal state in inflammatory bowel disease is largely unclear. AIMS: We investigated the association between AZA's active metabolite 6-thioguanine nucleotides (6-TGN) and fecal calprotectin (FC) as a well-validated surrogate marker of mucosal inflammation in patients with Crohn's disease (CD) on AZA monotherapy. PATIENTS AND METHODS: Of 443 6-TGN measurements, 140 values from 88 patients with CD on AZA monotherapy visiting the inflammatory bowel disease outpatient clinic between 2009 and 2016 were retrospectively analyzed. In a subcohort with serial 6-TGN measurements, longitudinal FC measurements in patients with versus without intervention (dose increase, allopurinol, and education) were assessed. RESULTS: In patients with 6-TGN concentrations within a predefined range (250-450 pmol/8×10 red blood cells), FC was significantly lower (median: 119.5 vs. 327.2 mg/kg, P=0.003), and hemoglobin as well as serum protein concentrations were significantly higher than in patients with 6-TGN outside of this range. C-reactive protein and transferrin saturation were not different. In the longitudinal cohort, 6-TGN increased in the intervention group, but only a minority reached the defined range; no significant change in FC was observed. CONCLUSION: This study is the first to show that in patients with CD receiving AZA monotherapy, 6-TGN concentrations within a defined range (250-450 pmol/8×10 red blood cells) are associated with significantly lower FC. A treat-to-target concept directed by 6-TGN to reach mucosal healing may thus be a promising approach (DRKS00013246).

Non-celiac gluten/wheat sensitivity (NCGS)-a currently undefined disorder without validated diagnostic criteria and of unknown prevalence: Position statement of the task force on food allergy of the German Society of Allergology and Clinical Immunology (DGAKI).

Within the last decade, non-celiac gluten/wheat sensitivity (NCGS) has been increasingly discussed not only in the media but also among medical specialties. The existence and the possible triggers of NCGS are controversial. Three international expert meetings which proposed recommendations for NCGS were not independently organized and only partially transparent regarding potential conflicts of interest of the participants. The present position statement reflects the following aspects about NCGS from an allergist's and nutritionist's point of view: (A) Validated diagnostic criteria and/or reliable biomarkers are still required. Currently, this condition is frequently self-diagnosed, of unknown prevalence and non-validated etiology. (B) Gluten has not been reliably identified as an elicitor of NCGS because of high nocebo and placebo effects. Double-blind, placebo-controlled provocation tests are of limited value for the diagnosis of NCGS and should be performed in a modified manner (changed relation of placebo and active substance). (C) Several confounders hamper the assessment of subjective symptoms during gluten-reduced or gluten-free diets. Depending on the selection of food items, e.g., an increased vegetable intake with soluble fibers, diets may induce physiological digestive effects and can modify gastrointestinal transit times independent from the avoidance of gluten. (D) A gluten-free diet is mandatory in celiac disease based on scientific evidence. However, a medically unjustified avoidance of gluten may bear potential disadvantages and risks. (E) Due to a lack of diagnostic criteria, a thorough differential diagnostic work-up is recommended when NCGS is suspected. This includes a careful patient history together with a food-intake and symptom diary, if necessary an allergy diagnostic workup and a reliable exclusion of celiac disease. We recommend such a structured procedure since a medically proven diagnosis is required before considering the avoidance of gluten.

BaiCD gene cluster abundance is negatively correlated with Clostridium difficile infection.

BACKGROUND: Clostridium difficile infection (CDI) is a major cause of hospital-acquired diarrhea. Secondary bile acids were shown to confer resistance to colonization by C. difficile. 7α-dehydroxylation is a key step in transformation of primary to secondary bile acids and required genes have been located in a single bile acid-inducible (bai) operon in C. scindens as well as in C. hiranonis, two Clostridium sp. recently reported to protect against C. difficile colonization. AIM: To analyze baiCD gene abundance in C. difficile positive and negative fecal samples. MATERIAL & METHODS: A species-specific qPCR for detecting baiCD genes was established. Fecal samples of patients with CDI, asymptomatic toxigenic C. difficile colonization (TCD), non-toxigenic C. difficile colonization (NTCD), of C. difficile negative (NC) patients, and of two patients before and after fecal microbiota transplantation (FMT) for recurrent CDI (rCDI) were tested for the presence of the baiCD genes. RESULTS: The prevalence of the baiCD gene cluster was significantly higher in C. difficile negative fecal samples than in samples of patients diagnosed with CDI (72.5% (100/138) vs. 35.9% (23/64; p<0.0001). No differences in baiCD gene cluster prevalence were seen between NC and NTCD or NC and TCD samples. Both rCDI patients were baiCD-negative at baseline, but one of the two patients turned positive after successful FMT from a baiCD-positive donor. CONCLUSION: Fecal samples of CDI patients are less frequently baiCD-positive than samples from asymptomatic carriers or C. difficile-negative individuals. Furthermore, we present a case of baiCD positivity observed after successful FMT for rCDI.

Alcohol, microbiome, and their effect on psychiatric disorders.

There is accumulating evidence that alcohol consumption and especially alcohol withdrawal increase brain levels of known innate immune signaling molecules and cause neuroinflammation. It has been shown that microbiota play a pivotal role in this process and affect central neurochemistry and behavior. Disruption of or alterations in the intimate cross-talk between microbiome and brain may be a significant factor in many psychiatric disorders. Alterations in the composition of the microbiome, so called dysbiosis, may result in detrimental distortion of microbe-host homeostasis modulating the hypothalamic-pituitary-adrenal axis. A variety of pathologies are associated with changes in the community structure and function of the gut microbiota, suggesting a link between dysbiosis and disease etiology, including irritable bowel syndrome depression, anxiety disorders, schizophrenia, and alcoholism. Despite a paucity of clinical studies in alcohol-dependent humans, emerging data suggests that alcohol induced alterations of the microbiome may explain reward-seeking behaviors as well as anxiety, depression, and craving in withdrawal and increase the risk of developing psychiatric disorders.

A Randomised, Double-blind, Placebo-controlled Trial of Trichuris suis ova in Active Crohn's Disease.

BACKGROUND AND AIMS: To investigate the efficacy and safety of three different dosages of embryonated, viable eggs of Trichuris suis [TSO] versus placebo for induction of remission in mildly-to-moderately active ileocolonic, uncomplicated Crohn's disease [CD]. METHODS: Adults with active CD [n = 252] randomly received six fortnightly doses of 250, 2500, or 7500 TSO/15 ml suspension/day [TSO 250, TSO 2500, TSO 7500], or 15 ml placebo solution/day, in a double-blind fashion, with 4 weeks' follow-up. Primary endpoint was the rate of clinical remission [Crohn's Disease Activity Index [CDAI] < 150] at end of treatment, ie at Week 12 or withdrawal. Secondary endpoints included the course of clinical remission, rate of clinical response, change in CDAI, change in markers of inflammation, mucosal healing, and Physician's Global Assessment. RESULTS: Clinical remission at Week 12 occurred in 38.5%, 35.2%, and 47.2% of TSO 250, TSO 2500, and TSO 7500 patients, respectively, and in 42.9% of placebo recipients. TSO induced a dose-dependent immunological response. There was no response regarding laboratory markers of inflammation. Other secondary efficacy variables also showed no advantage of TSO over placebo for treatment of active CD. Administration of TSO did not result in any serious adverse drug reaction. Review of non-serious suspected adverse drug reactions following TSO did not reveal any safety concerns. CONCLUSIONS: Administration of 250-7500 TSO fortnightly over 12 weeks was safe and showed a dose-dependent immunological response, but no TSO dose showed a clinically relevant effect over placebo for induction of clinical remission or response in mildly-to-moderately active, ileocolonic CD.

Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy.

PD-1 checkpoint inhibitors are associated with a specific spectrum of immune-related adverse events. This spectrum is different from toxicities known for kinase inhibitors or cytotoxic drugs. Since PD-1 directed therapies show effectivity in an increasing number of malignant diseases, their clinical usage will increase rapidly. Therefore clinicians from different specialities such as medical oncology, internal medicine, family doctors and emergency unit staff should be aware of the adverse effects of PD-1 checkpoint inhibitors to avoid delays in diagnosis and treatment. Based on pooled data from pivotal trials as reported by the European Medicines Agency, the present paper reviews incidences and kinetics of onset and resolution of immune-mediated "adverse events of specific interest" (AEOSI) of both approved PD-1 inhibitors nivolumab and pembrolizumab. In general, the severity of AEOSI is mild to moderate (grade 1-2); the frequency of immune-mediated but also idiopathic grade 3-4 adverse drug reactions is ⩽2% for any event term. Recommendations for the diagnosis, monitoring and management of the relevant dermatological, gastrointestinal, pulmonary, endocrine, renal and hepatic toxicities are convened by an expert panel that consolidated and clarified treatment recommendations after the onset of AEOSI. Although the time of onset is not predictable - the medians range from 1 to 6months - the huge majority of events is reversible, with no impact of the time of onset. By the systemic use of glucocorticoids, notably methylprednisolone or equivalents, most AEOSI are well manageable. Non-steroidal immunosuppressants may be used in certain cases of refractory/recalcitrant, long-lasting immune toxicities. With regard to the outstanding clinical activity of the anti-PD-1 antibodies, therapy restart is the principal therapeutic option after recovery of grade 2 AEOSI, or diminution of higher grade skin or endocrine events to mild severity. Early diagnosis and close clinical monitoring are essential for successful management of immune-related adverse events.

Regional differences in health care of patients with inflammatory bowel disease in Germany.

BACKGROUND: The regional availability of specialized physicians is an important aspect in healthcare of patients with IBD. The association between physician density and healthcare is not yet clear. Most studies did not consider district type, which reflects population density. Our research question was, "Do specialist density and district type influence the healthcare of IBD patients in Germany?" METHODS: We combined a claims dataset from a German health insurance fund with population and physician data. Four main aspects were investigated: regular specialist visits, drug therapies, surveillance colonoscopy, and IBD-related hospitalizations. Various regression analyses were performed. RESULTS: The study cohort was comprised of 21,771 individuals, including 9282 patients with Crohn disease and 12,489 patients with ulcerative colitis. Patients who were living in districts with higher specialist densities were more likely to attend specialist visits on a regular basis. No difference in the frequencies of TNF-alpha inhibitor therapies was found. However, individuals from urban areas were more likely to receive a permanent immunosuppressive therapy with continuous specialist support. CONCLUSIONS: The results revealed that some aspects had positive effects on the probability of implementing healthcare in accordance with pathways and guidelines. No clear evidence of a general healthcare undersupply in rural areas was found.

Evidence for a causal link between adaptor protein PDZK1 downregulation and Na⁺/H⁺ exchanger NHE3 dysfunction in human and murine colitis.

A dysfunction of the Na(+)/H(+) exchanger isoform 3 (NHE3) significantly contributes to the reduced salt absorptive capacity of the inflamed intestine. We previously reported a strong decrease in the NHERF family member PDZK1 (NHERF3), which binds to NHE3 and regulates its function in a mouse model of colitis. The present study investigates whether a causal relationship exists between the decreased PDZK1 expression and the NHE3 dysfunction in human and murine intestinal inflammation. Biopsies from the colon of patients with ulcerative colitis, murine inflamed ileal and colonic mucosa, NHE3-transfected Caco-2BBe colonic cells with short hairpin RNA (shRNA) knockdown of PDZK1, and Pdzk1-gene-deleted mice were studied. PDZK1 mRNA and protein expression was strongly decreased in inflamed human and murine intestinal tissue as compared to inactive disease or control tissue, whereas that of NHE3 or NHERF1 was not. Inflamed human and murine intestinal tissues displayed correct brush border localization of NHE3 but reduced acid-activated NHE3 transport activity. A similar NHE3 transport defect was observed when PDZK1 protein content was decreased by shRNA knockdown in Caco-2BBe cells or when enterocyte PDZK1 protein content was decreased to similar levels as found in inflamed mucosa by heterozygote breeding of Pdzk1-gene-deleted and WT mice. We conclude that a decrease in PDZK1 expression, whether induced by inflammation, shRNA-mediated knockdown, or heterozygous breeding, is associated with a decreased NHE3 transport rate in human and murine enterocytes. We therefore hypothesize that inflammation-induced loss of PDZK1 expression may contribute to the NHE3 dysfunction observed in the inflamed intestine.