David G. Binion

Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.

Clostridium difficile infection (CDI) is a leading cause of hospital-associated gastrointestinal illness and places a high burden on our health-care system. Patients with CDI typically have extended lengths-of-stay in hospitals, and CDI is a frequent cause of large hospital outbreaks of disease. This guideline provides recommendations for the diagnosis and management of patients with CDI as well as for the prevention and control of outbreaks while supplementing previously published guidelines. New molecular diagnostic stool tests will likely replace current enzyme immunoassay tests. We suggest treatment of patients be stratified depending on whether they have mild-to-moderate, severe, or complicated disease. Therapy with metronidazole remains the choice for mild-to-moderate disease but may not be adequate for patients with severe or complicated disease. We propose a classification of disease severity to guide therapy that is useful for clinicians. We review current treatment options for patients with recurrent CDI and recommendations for the control and prevention of outbreaks of CDI.

EPIDEMIOLOGIC AND CLINICAL CHARACTERISTICS OF CHILDREN WITH NEWLY DIAGNOSED INFLAMMATORY BOWEL DISEASE IN WISCONSIN: A STATEWIDE POPULATION-BASED STUDY

OBJECTIVE To define epidemiologic and clinical characteristics of newly diagnosed pediatric inflammatory bowel disease (IBD) in a large population-based model. STUDY DESIGN All pediatric gastroenterologists providing care for Wisconsin children voluntarily identified all new cases of IBD during a 2-year period. Demographic and clinical data were sent to a central registry prospectively for analysis. RESULTS The incidence of IBD in Wisconsin children was 7.05 per 100,000, whereas the incidence for Crohns disease was 4.56, more than twice the rate of ulcerative colitis (2.14). An equal IBD incidence occurred among all ethnic groups, and children from sparsely and densely populated counties were equally affected. The majority (89%) of new IBD diagnoses were nonfamilial. CONCLUSIONS This study provides novel, prospective, and comprehensive information on pediatric IBD incidence within the United States. The surprisingly high incidence of pediatric IBD, the predominance of Crohns disease over ulcerative colitis, the low frequency of patients with a family history, the equal distribution of IBD among all racial and ethnic groups, and the lack of a modulatory effect of urbanization on IBD incidence collectively suggest that the clinical spectrum of IBD is still evolving and point to environmental factors contributing to the pathogenesis.

Excess hospitalisation burden associated with Clostridium difficile in patients with inflammatory bowel disease

Background: Clostridium difficile is an important cause of diarrhoea in hospitalised patients. An increasing number of cases of C difficile colitis occur in patients with inflammatory bowel disease (IBD)—Crohn’s disease (CD), ulcerative colitis (UC). Objective: To estimate the potential excess morbidity and mortality associated with C difficile in hospitalised patients with IBD. Methods: Data from the Nationwide Inpatient Sample (2003) were analysed and outcomes were examined of patients hospitalised with both C difficile colitis and IBD compared with those hospitalised for either condition alone. The primary outcome was in-hospital mortality. A subgroup analysis was also performed comparing outcomes of C difficile infection in patients with CD and UC. Results: 2804 discharges were diagnosed as having both C difficile and IBD, 44 400 as having C difficile alone, and 77 366 as having IBD alone. On multivariate analysis, patients in the C difficile–IBD group had a four times greater mortality than patients admitted to hospital for IBD alone (aOR = 4.7, 95% CI 2.9 to 7.9) or C difficile alone (aOR = 2.2, 95% CI 1.4 to 3.4), and stayed in the hospital for three days longer (95% CI 2.3 to 3.7 days). Significantly higher mortality, endoscopy and surgery rates were found in patients with UC compared with CD (p<0.05), but no significant difference in length of stay or median hospital charge between the two groups was seen. Conclusions: C difficile colitis is associated with a significant healthcare burden in hospitalised patients with IBD and carries a higher mortality than in patients with C difficile without underlying IBD.

Intentional infliximab use during pregnancy for induction or maintenance of remission in Crohn's disease

Aim:  To study the effects of infliximab on pregnancy and foetal outcome.

Probiotic Yogurt for the Treatment of Minimal Hepatic Encephalopathy

OBJECTIVES:Minimal hepatic encephalopathy (MHE), the preclinical stage of overt hepatic encephalopathy (OHE), is a significant condition affecting up to 60% of cirrhotics. All MHE therapies modify gut microflora, but consensus regarding MHE treatment and long-term adherence studies is lacking. The aim was to determine the effect of probiotic supplementation in the form of a food item, probiotic yogurt, on MHE reversal and adherence.METHODS:Nonalcoholic MHE cirrhotics (defined by a standard psychometric battery) were randomized with unblinded allocation to receive probiotic yogurt (with proven culture stability) or no treatment (no Rx) for 60 days in a 2:1 ratio. Quality of life (short form [SF]-36), adherence, venous ammonia, model of end-stage liver disease (MELD) scores, and inflammatory markers (tumor necrosis factor [TNF]-α, interleukin [IL]-6) were also measured. Outcomes were MHE reversal using blinded scoring, OHE development, and adherence.RESULTS:Twenty-five patients (17 yogurt, 8 no Rx; 84% Child class A) were enrolled. A significantly higher percentage of yogurt patients reversed MHE compared to no Rx patients (71% vs 0%, P= 0.003, intention-to-treat). Yogurt patients demonstrated a significant improvement in number connection test-A (NCT-A), block design test (BDT), and digit symbol test (DST) compared to baseline/no Rx group. Twenty-five percent of no Rx versus 0% of yogurt patients developed OHE during the trial. Eighty-eight percent of yogurt patients were adherent. No adverse effects or change in covariates were observed. All patients who completed the yogurt arm were agreeable to continue yogurt for 6 months if needed.CONCLUSIONS:This trial demonstrated a significant rate of MHE reversal and excellent adherence in cirrhotics after probiotic yogurt supplementation with potential for long-term adherence.

Clostridium difficile and inflammatory bowel disease.

Clostridium difficile colitis has doubled in North America over the past 5 years and recent reports have demonstrated an increase in incidence and severity of these infections in patients with inflammatory bowel disease (IBD; Crohns disease, ulcerative colitis). Studies from single institutions as well as trends identified in nationwide inpatient databases have shown that IBD patients with concomitant C. difficile infection experience increased morbidity and mortality. Results from our center have shown that over half of C. difficile-infected IBD patients will require hospitalization and the colectomy rate may approach 20%. Because C. difficile colitis will both mimic and precipitate an IBD flare, it is essential that clinicians be vigilant to identify and address this infectious complication, as empiric treatment with corticosteroids without appropriate antibiotics may precipitate deterioration. The majority of IBD patients appear to contract C. difficile as outpatients, and a prior history of colitis appears to be the most significant risk factor for acquiring this infection. In addition to C. difficile colitis, IBD patients are now known to be at risk for C. difficile enteritis as well as infections in reconstructed ileoanal pouches. An additional challenge facing C. difficile infections in IBD patients is the decreased efficacy of metronidazole, and the need for oral vancomycin in patients requiring hospitalization. In this review we summarize the present knowledge regarding C. difficile infection in the setting of IBD, including unique clinical scenarios facing IBD patients, diagnostic algorithms, and treatment approaches.

Vitamin D deficiency in patients with inflammatory bowel disease: association with disease activity and quality of life.

BACKGROUND Vitamin D deficiency is common in inflammatory bowel disease (IBD). The aim of the study was to determine the prevalence and predictors of vitamin D deficiency in an IBD cohort. It was hypothesized that vitamin D deficiency is associated with increased disease activity and lower health-related quality of life (HRQOL). METHODS This was a retrospective cohort study. Harvey-Bradshaw index and ulcerative colitis disease activity index were used to assess disease activity. Short Inflammatory Bowel Disease Questionnaire scores were used to assess HRQOL. Multivariate logistic regression was used to identify independent predictors of vitamin D deficiency and its association with disease activity and HRQOL. RESULTS The study included 504 IBD patients (403 Crohns disease [CD] and 101 ulcerative colitis [UC]) who had a mean disease duration of 15.5 years in CD patients and 10.9 years in UC patients; 49.8% were vitamin D deficient, with 10.9% having severe deficiency. Vitamin D deficiency was associated with older age (P = .004) and older age at diagnosis (P = .03). Vitamin D deficiency was associated with lower HRQOL (regression coefficient -2.21, 95% confidence interval [CI], -4.10 to -0.33) in CD but not UC (regression coefficient 0.41, 95% CI, -2.91 to 3.73). Vitamin D deficiency was also associated with increased disease activity in CD (regression coefficient 1.07, 95% CI, 0.43 to 1.71). CONCLUSIONS Vitamin D deficiency is common in IBD and is independently associated with lower HRQOL and greater disease activity in CD. There is a need for prospective studies to assess this correlation and examine the impact of vitamin D supplementation on disease course.

Acquired microvascular dysfunction in inflammatory bowel disease: loss of nitric oxide-mediated vasodilation

BACKGROUND & AIMS Inflammatory bowel disease (IBD; i.e., Crohns disease, ulcerative colitis) is characterized by refractory inflammatory ulceration and damage to the intestine. Mechanisms underlying impaired healing are not defined. Because microvascular dysfunction resulting in diminished vasodilatory capacity and tissue hypoperfusion is associated with impaired wound healing, we hypothesized that microvascular dysfunction may also occur in chronic IBD. METHODS Intact submucosal arterioles from control, involved, and uninvolved IBD specimens were assessed using in vitro videomicroscopy to assess endothelium-dependent vasodilation in response to acetylcholine (Ach) and fluorescence microscopy to detect oxyradicals. RESULTS Normal microvessels dilated in a dose-dependent and endothelium-dependent manner to Ach (maximum, 82% +/- 2%; n = 34). Inhibition of nitric oxide synthase with N(G)-nitro-L-arginine methyl ester (L-NAME) reduced maximal dilation to 54% +/- 6% (P < 0.05, n = 7), and further reduction was observed after inhibiting cyclooxygenase (indomethacin; 23% +/- 10%, n = 6). Chronically inflamed IBD microvessels showed significantly reduced Ach-induced vasodilation (maximum, 15% +/- 2%; n = 33), with no effect of L-NAME. Indomethacin eliminated the remaining Ach-induced vasodilation, resulting in frank vasoconstriction (-54% +/- 9%, n = 6). Uninvolved IBD gut vessels and non-IBD inflammatory controls responded in a fashion similar to normal vessels. IBD-involved microvessels generated significantly higher levels of reactive oxygen species compared with control and uninvolved IBD vessels (P < 0.01). CONCLUSIONS Human intestinal microvessels from chronically inflamed IBD show microvascular endothelial dysfunction, characterized by loss of NO-dependent dilation that may contribute to reduced perfusion, poor wound healing, and maintenance of chronic inflammation.

Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease

Background and aims: Crohn’s disease is a life-long form of inflammatory bowel disease (IBD) mediated by mucosal immune abnormalities. Understanding of the pathogenesis is limited because it is based on data from adults with chronic Crohn’s disease. We investigated mucosal T-cell immunoregulatory events in children with early Crohn’s disease. Methods: Mucosal biopsies and T-cell clones were derived from children experiencing the first attack of Crohn’s disease, children with long-standing Crohn’s disease, infectious colitis, and children without gut inflammation. Results: As in acute infectious colitis, interleukin (IL) 12 induced T cells from early Crohn’s disease to acquire a strongly polarised T helper (Th) type 1 response characterised by high IFN-γ production and IL12Rβ2 chain expression. Th1 polarisation was not induced in clones from late Crohn’s disease. Mucosal levels of IL12p40 and IL12Rβ2 messenger RNA were significantly higher in children with early than late Crohn’s disease. These results demonstrate that susceptibility to IL12-mediated modulation is strongly dependent on the stage of Crohn’s disease. Conclusions: At the onset of Crohn’s disease mucosal T cells appear to mount a typical Th1 response that resembles an acute infectious process, and is lost with progression to late Crohn’s disease. This suggests that mucosal T-cell immunoregulation varies with the course of human IBD. Patients with the initial manifestations of IBD may represent an ideal population in which immunomodulation may have optimal therapeutic efficacy.

Inflammatory bowel disease in the elderly is associated with worse outcomes: A national study of hospitalizations

Background: Inflammatory bowel disease (IBD) has a bimodal peak of incidence with ≈15% of the cases manifesting after 65 years. Previous reports on the outcomes of IBD in the elderly have been single‐center studies or have predated the use of biologics. The aim of our study was to compare outcomes of IBD‐related hospitalizations in a nationwide representative cohort of patients 65 years and older with younger patients. Methods: This was a cross‐sectional study utilizing data from the Nationwide Inpatient Sample (NIS) for the year 2004. We identified all IBD‐related hospitalizations through the presence of the appropriate ICD‐9‐CM codes for Crohns disease, ulcerative colitis, or associated complications. We compared the differences in disease presentation as well the frequency of utilization of different interventions. We calculated the adjusted odds of mortality in older compared to the younger IBD patients using multivariate logistic regression. Results: Patients older than 65 years accounted for ≈25% of all IBD‐related hospitalizations in 2004. They were less likely to be hospitalized with fistulizing (4.0 versus 8.8%, P < 0.001) or stricturing disease (4.0 versus 5.8%, P = 0.001). Even after adjusting for comorbidity, they had higher in‐hospital mortality (odds ratio [OR] 3.91, 95% confidence interval [CI] 2.50–6.11). Older patients with fistulizing disease are more likely to undergo surgery (OR 1.55, 95% CI 1.00–2.40). Among IBD patients who underwent surgery, older patients also had a longer postoperative stay (1.73 days, 95% CI 1.04–2.21). Conclusions: Older patients with IBD‐related hospitalizations have substantial morbidity and higher mortality than younger patients. Further research is needed to better characterize the natural history and treatment outcomes in this cohort.