Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity

Innate lymphoid cells (ILCs) are critical for maintaining epithelial barrier integrity at mucosal surfaces; however, the tissue-specific factors that regulate ILC responses remain poorly characterized. Using mice with intestinal epithelial cell (IEC)-specific deletions in either inhibitor of κB kinase (IKK)α or IKKβ, two critical regulators of NFκB activation, we demonstrate that IEC-intrinsic IKKα expression selectively regulates group 3 ILC (ILC3)-dependent antibacterial immunity in the intestine. Although IKKβ(ΔIEC) mice efficiently controlled Citrobacter rodentium infection, IKKα(ΔIEC) mice exhibited severe intestinal inflammation, increased bacterial dissemination to peripheral organs, and increased host mortality. Consistent with weakened innate immunity to C. rodentium, IKKα(ΔIEC) mice displayed impaired IL-22 production by RORγt(+) ILC3s, and therapeutic delivery of rIL-22 or transfer of sort-purified IL-22-competent ILCs from control mice could protect IKKα(ΔIEC) mice from C. rodentium-induced morbidity. Defective ILC3 responses in IKKα(ΔIEC) mice were associated with overproduction of thymic stromal lymphopoietin (TSLP) by IECs, which negatively regulated IL-22 production by ILC3s and impaired innate immunity to C. rodentium. IEC-intrinsic IKKα expression was similarly critical for regulation of intestinal inflammation after chemically induced intestinal damage and colitis. Collectively, these data identify a previously unrecognized role for epithelial cell-intrinsic IKKα expression and TSLP in regulating ILC3 responses required to maintain intestinal barrier immunity.

Chronological Order of Appearance of Extraintestinal Manifestations Relative to the Time of IBD Diagnosis in the Swiss Inflammatory Bowel Disease Cohort.

BACKGROUND Data evaluating the chronological order of appearance of extraintestinal manifestations (EIMs) relative to the time of inflammatory bowel disease (IBD) diagnosis is currently lacking. We aimed to assess the type, frequency, and chronological order of appearance of EIMs in patients with IBD. METHODS Data from the Swiss Inflammatory Bowel Disease Cohort Study were analyzed. RESULTS The data on 1249 patients were analyzed (49.8% female, median age: 40 [interquartile range, 30-51 yr], 735 [58.8%] with Crohn's disease, 483 [38.7%] with ulcerative colitis, and 31 [2.5%] with indeterminate colitis). A total of 366 patients presented with EIMs (29.3%). Of those, 63.4% presented with 1, 26.5% with 2, 4.9% with 3, 2.5% with 4, and 2.7% with 5 EIMs during their lifetime. Patients presented with the following diseases as first EIMs: peripheral arthritis 70.0%, aphthous stomatitis 21.6%, axial arthropathy/ankylosing spondylitis 16.4%, uveitis 13.7%, erythema nodosum 12.6%, primary sclerosing cholangitis 6.6%, pyoderma gangrenosum 4.9%, and psoriasis 2.7%. In 25.8% of cases, patients presented with their first EIM before IBD was diagnosed (median time 5 mo before IBD diagnosis: range, 0-25 mo), and in 74.2% of cases, the first EIM manifested itself after IBD diagnosis (median: 92 mo; range, 29-183 mo). CONCLUSIONS In one quarter of patients with IBD, EIMs appeared before the time of IBD diagnosis. Occurrence of EIMs should prompt physicians to look for potential underlying IBD.

High Rates of Smoking Especially in Female Crohn's Disease Patients and Low Use of Supportive Measures to Achieve Smoking Cessation--Data from the Swiss IBD Cohort Study

BACKGROUND AND AIMS Smoking is a crucial environmental factor in inflammatory bowel disease [IBD]. However, knowledge on patient characteristics associated with smoking, time trends of smoking rates, gender differences and supportive measures to cease smoking provided by physicians is scarce. We aimed to address these questions in Swiss IBD patients. METHODS Prospectively obtained data from patients participating in the Swiss IBD Cohort Study was analysed and compared with the general Swiss population [GSP] matched by age, sex and year. RESULTS Among a total of 1770 IBD patients analysed [49.1% male], 29% are current smokers. More than twice as many patients with Crohn's disease [CD] are active smokers compared with ulcerative colitis [UC] [UC, 39.6% vs CD 15.3%, p < 0.001]. In striking contrast to the GSP, significantly more women than men with CD smoke [42.8% vs 35.8%, p = 0.025], with also an overall significantly increased smoking rate compared with the GSP in women but not men. The vast majority of smoking IBD patients [90.5%] claim to never have received any support to achieve smoking cessation, significantly more in UC compared with CD. We identify a significantly negative association of smoking and primary sclerosing cholangitis, indicative of a protective effect. Psychological distress in CD is significantly higher in smokers compared with non-smokers, but does not differ in UC. CONCLUSIONS Despite well-established detrimental effects, smoking rates in CD are alarmingly high with persistent and stagnating elevations compared with the GSP, especially in female patients. Importantly, there appears to be an unacceptable underuse of supportive measures to achieve smoking cessation.

Inflammatory Articular Disease in Patients with Inflammatory Bowel Disease: Result of the Swiss IBD Cohort Study

BACKGROUND Inflammatory bowel diseases (IBD) are systemic conditions that commonly display extraintestinal manifestations. Inflammatory articular disease (IAD: axial or peripheral) is the most common extraintestinal manifestation. The aim of this study was to evaluate the prevalence and the clinical characteristics associated with IAD in patients with IBD. METHODS We analyzed patients enrolled in the Swiss IBD cohort study. IAD was defined as persistent or recurrent joint pain with an inflammatory pattern (night pain, progressive relief during the day, morning stiffness lasting at least 30 minutes) or the presence of arthritis as diagnosed by the physicians. A multivariate logistic regression was performed to analyze which disease characteristics were independently associated with the presence of IAD. RESULTS A total of 2353 patients with IBD, 1359 with Crohn's disease, and 994 with ulcerative colitis (UC) were included. Forty-four percent of patients fulfilled the criteria for IAD, whereas 14.5% presented with other extraintestinal manifestations. IAD was associated with Crohn's disease, with female sex, with older age, and generally in patients with more active intestinal disease. Only in UC, IAD was further associated with tobacco smoking and with increasing body mass index. CONCLUSIONS This population of patients with IBD displays a high prevalence of IAD. IAD was more strongly associated with Crohn's disease than UC. Other risk factors for IAD were female sex, advanced age, active digestive disease, and tobacco consumption in patients with UC, which is interesting given the established association between smoking and other inflammatory arthritides.

[Smoking and digestive tract: a complex relationship. Part 1: Inflammatory bowel disease and cigarette smoking]

Little is known about the effects of smoking on inflammatory bowel diseases (IBD). However the co-occurrence of smoking and IBD often happens in ambulatory care. Smokers have a doubled risk of developing a Crohn's disease with a more active disease course. After quitting, a decrease in risk can be observed after only one year. An inverse relationship is found between smoking and ulcerative colitis. Smoking seems protective for the development of the disease and its course is less active among smokers. Smoking cessation transitorily increases the risk of developing ulcerative colitis. Nevertheless, continuing smoking cannot be justified among those patients given the risks of long-term extra-digestive effects. It is thus important to counsel all smokers with an IBD to quit smoking.

The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease

Trying to conceive and being pregnant is an emotional period for those involved. In the majority of patients suffering from inflammatory bowel disease, maintenance therapy is required during pregnancy to control the disease, and disease control might necessitate introduction of new drugs during a vulnerable period. In this updated consensus on the reproduction and pregnancy in inflammatory bowel disease reproductive issues including fertility, the safety of drugs during pregnancy and lactation are discussed.

Quality of Life in Swiss Paediatric Inflammatory Bowel Disease Patients: Do Patients and Their Parents Experience Disease in the Same Way?

BACKGROUND AND AIMS Inflammatory bowel diseases (IBDs) may impair quality of life (QoL) in paediatric patients. We aimed to evaluate in a nationwide cohort whether patients experience QoL in a different way when compared with their parents. METHODS Sociodemographic and psychosocial characteristics were prospectively acquired from paediatric patients and their parents included in the Swiss IBD Cohort Study. Disease activity was evaluated by the Paediatric Crohn's Disease Activity Index (PCDAI) and the Paediatric Ulcerative Colitis Activity Index (PUCAI). We assessed QoL using the KIDSCREEN questionnaire. The QoL domains were analysed and compared between children and parents according to type of disease, parents' age, origin, education and marital status. RESULTS We included 110 children and parents (59 Crohn's disease [CD], 45 ulcerative colitis [UC], 6 IBD unclassified [IBDU]). There was no significant difference in QoL between CD and UC/IBDU, whether the disease was active or in remission. Parents perceived overall QoL, as well as 'mood', 'family' and 'friends' domains, lower than the children themselves, independently of their place of birth and education. However, better concordance was found on 'school performance' and 'physical activity' domains. Marital status and age of parents significantly influenced the evaluation of QoL. Mothers and fathers being married or cohabiting perceived significantly lower mood, family and friends domains than their children, whereas mothers living alone had a lower perception of the friends domain; fathers living alone had a lower perception of family and mood subscores. CONCLUSION Parents of Swiss paediatric IBD patients significantly underestimate overall QoL and domains of QoL of their children independently of origin and education.

New associations of classic acute macular neuroretinopathy

PURPOSE: To describe novel underlying associations of classic acute macular neuroretinopathy (AMN). METHODS: Multimodal imaging case series evaluating patients with classic AMN lesions and previously unreported underlying aetiologies. RESULTS: Six patients were included (five women, one man, mean age 30±7 years). Mean distance best corrected visual acuity at initial presentation was 0.21±0.3 logMAR (mean Snellen acuity: 20/30, range 20/15-20/100) and at last follow-up visit 0.09±0.17 logMAR (Snellen acuity: 20/20, range 20/15-20/60). All cases but one had bilateral lesions and showed typical parafoveal hyporeflective lesions on infrared imaging, which corresponded to the hyper-reflectivity in the Henle's layer with attenuation of the external limiting membrane, the ellipsoid zone and interdigitation zone. Underlying diseases included thrombocytopenia and anaemia associated with dengue fever, acute lymphoblastic leukaemia, chronic kidney disease and ulcerative colitis, while Valsalva-like manoeuvre was found to be a potential trigger. Other novel associations included the use of lisdexamphetamine. CONCLUSIONS: Classic AMN may be associated with leukaemia, dengue fever, ulcerative colitis and chronic kidney disease, probably as a result of chorioretinal hypoxia in the setting of thrombocytopenia and anaemia. Adrenergic agonists such as lisdexamphetamine may also contribute to the manifestation of AMN.

Risk factors for Clostridium difficile nosocomial diarrhea in patients at the Michael E. Debakey Veterans Affairs Medical Center, Houston, Texas

Background. Clostridium difficile is the leading cause of hospital associated infectious diarrhea and colitis. About 3 million cases of Clostridium difficile diarrhea occur each year with an annual cost of $1 billion. ^ About 20% of patients acquire C. difficile during hospitalization. Infection with Clostridium difficile can result in serious complications, posing a threat to the patient's life. ^ Purpose. The aim of this research was to demonstrate the uniqueness in the characteristics of C. difficile positive nosocomial diarrhea cases compared with C. difficile negative nosocomial diarrhea controls admitted to a local hospital. ^ Methods. One hundred and ninety patients with a positive test and one hundred and ninety with a negative test for Clostridium difficile nosocomial diarrhea, selected from patients tested between January 1, 2002 and December 31, 2003, comprised the study population. Demographic and clinical data were collected from medical records. Logistic regression analyses were conducted to determine the associated odds between selected variables and the outcome of Clostridium difficile nosocomial diarrhea. ^ Results. For the antibiotic classes, cephalosporins (OR, 1.87; CI 95, 1.23 to 2.85), penicillins (OR, 1.57; CI 95, 1.04 to 2.37), fluoroquinolones (OR, 1.65; CI 95, 1.09 to 2.48) and antifungals (OR, 2.17; CI 95, 1.20 to 3.94), were significantly associated with Clostridium difficile nosocomial diarrhea Ceftazidime (OR, 1.95; CI 95, 1.25 to 3.03, p=0.003), gatifloxacin (OR, 1.97; CI 95, 1.31 to 2.97, p=0.001), clindamycin (OR, 3.13; CI 95, 1.99 to 4.93, p<0.001) and vancomycin (OR, 1.77; CI 95, 1.18 to 2.66, p=0.006, were also significantly associated with the disease. Vancomycin was not statistically significant when analyzed in a multivariable model. Other significantly associated drugs were, antacids, laxatives, narcotics and ranitidine. Prolong use of antibiotics and an increased number of comorbid conditions were also associated with C. difficile nosocomial diarrhea. ^ Conclusion. The etiology for C. difficile diarrhea is multifactorial. Exposure to antibiotics and other drugs, prolonged antibiotic usage, the presence and severity of comorbid conditions and prolonged hospital stay were shown to contribute to the development of the disease. It is imperative that any attempt to prevent the disease, or contain its spread, be done on several fronts. ^

Relationship between Clostridium difficile toxin type and clinical features, severity and outcome in patients with C. difficile diarrhea (CDAD)

Background. Clostridium difficile infection is one of the major causes of antibiotic associated diarrhea and colitis in the United States. Currently, there is a dearth of literature on the risk factors and outcomes differences between the patients with infection due to the hypervirulent strain vs. the non-hypervirulent strains. The objective of this study was to determine the relationship between C. difficile toxin type and clinical features, severity and outcome in patients with C. difficile diarrhea. ^ Methods. The case group included 37 patients who had infections due to hypervirulent strain (tcdC deletion) and the control group included 55 patients with other toxin types (toxin A, B, binary toxin). A univariate analysis was performed followed by a multivariable logistic regression analysis to assess the differences between cases and controls. ^ Results. In the multivariate analyses, we found out that being a male was a protective factor for developing the infection due to the hypervirulent strain [OR 0.33; 95% CI 0.12-0.90]. Also, the hypervirulent group has worse clinical and economic outcomes, although the differences were small and nonsignificant. ^ Conclusions. There may likely be no predictive risk factor for acquiring infection due to the hypervirulent strain and the acquisition may be more linked to the infection control practices of the individual hospitals or location of patients. Hence, better infection control practices may prove helpful in decreasing the overall disease burden and thus improve patient outcomes. ^

Risk factors and inflammatory markers in pouchitis

Individuals who do not respond to medical therapy for ulcerative colitis (UC) often undergo proctocolectomy followed by ileal-pouch anal anastomosis (IPAA) in hopes of resolving symptoms associated with UC. Inflammation of the ileal pouch, better known as pouchitis, is the most common complication of the IPAA procedure. The causes and development of pouchitis is not well understood. To better understand pathogenesis of pouchitis, pouch aspirates of patients having undergone IPAA were quantitatively analyzed for fecal IL-8, IL-17, and IL-23 levels. According to published literature IL-8 has been linked to pouchitis whereas IL-17 and IL-23 are associated with intestinal inflammation. The study had 80 participants, 33 patients diagnosed with Crohn's Disease (CD) of the pouch, 19 patients diagnosed with pouchitis, and 28 diagnosed with having normal pouches. Patient characteristics and histopathological findings for all patients were noted and statistically compared in addition to fecal cytokine levels. This study supported previous literature that IL-8 production was associated with pouch inflammation. However, IL-17 and IL-23 levels in both CD of the pouch and pouchitis were not significantly different to the levels noted in normal pouch.^

A systematic review of clostridium difficile infection in patients with iatrogenic immunesuppression

Background: Incidence of C. difficile infection (CDI) has increased dramatically in the past decade and is the most frequent cause of nosocomial infectious diarrhea. The outcome of infection may range from mild diarrhea to life-threatening pseudomembranous colitis depending on the immunological response of the host, which is highly compromised in this special population that includes bone marrow transplant (BMT), solid organ transplant (SOT) and cancer patients on cytotoxic chemotherapy. ^ Objectives: We conducted a meta-analysis to assess the incidence rates of CDI and the time to onset of infection in patients with iatrogenic immune suppression. ^ Methods: Original studies were identified through an extensive search of electronic databases including PubMed, Ovid Medline (R), RefWorks and Biological Abstracts and their references. The overall incidence rate of CDI in the immune suppressed population was calculated using random effects model and their 95% confidence interval was derived. Differences in the incidence of CDI and time to onset of infection were calculated between the groups and within the groups. Publication bias was assessed using a funnel plot. Results: Twenty nine published articles involving 7,424 patients met the eligibility requirements. The overall incidence of CDI in the immune suppressed population is 11.1% (95% Confidence Interval (CI): 9.2–13.4%). The incidence of CDI was higher in SOT patients (14.2%, 95% CI: 6.8–21.5%); (p-value-0.022) and in cancer patients on cytotoxic chemotherapy (11.4%, 95% CI: 8.4–15.4%); (p = 0.042) than in BMT patients (10.5%, 95% CI: 7.9–13.1%). In a subgroup analysis of BMT population, the incidence of CDI is significantly higher in patients who received allogeneic BMT (15.1%, 95% CI: 11.2–20.0%; p value <0.0001). Similarly, in the SOT population, the incidence of CDI was higher in patients who underwent liver transplantation (11.0%, 95% CI: 5.6–20.3%); (p= 0.0672). The median time to onset of infection was shorter in BMT patients (p=0.0025). ^ Conclusions: It is evident from the combined analysis of these 29 published studies that the incidence of CDI in the immune suppressed population is higher. However, early diagnosis and treatment of CDI will help reduce the morbidity and mortality due to CDI in this special population.^