Co-morbidities as predictors of mortality in Clostridium difficile infection and derivation of the ARC predictive score.

Clostridium difficile associated diarrhoea (CDAD) has increased significantly in the last 15 years, but predictors of outcome are inadequately understood. This was a cohort study of 2761 patients in North East England between 2002 and 2009, with the end-point of mortality at 30 days. The role of age, gender and co-morbidities was examined by binary logistic regression. Rounded odds ratios were used to develop a predictive score. A predictive score based on age, renal disease and cancer (ARC score) differentiated groups with differing risk of 30-day mortality (risk for score of 0-3 was 9-21%, score of 4-7 was 31-48% and score of 8 was 66%). Co-morbidities were shown to be important predictors of outcome in CDAD, and can be combined with age in the ARC score to assess the likelihood of survival. This requires further validation in other populations, but has important implications for clinical and research practice.

Impact of deprivation on short- and long-term outcomes after colorectal cancer surgery.

BACKGROUND: The aim of the study was to determine the association between short- and long-term outcomes and deprivation for patients undergoing operative treatment for colorectal cancer in the Northern Region of England. METHODS: This was a retrospective analytical study based on the Northern Region Colorectal Cancer Audit Group database for the period 1998-2002. The Index of Multiple Deprivation 2004, an area-based measure, was recalibrated and used to quantify deprivation. Patients were ranked based on their postcode of residence and grouped into five categories. RESULTS: Of 8159 patients in total, 7352 (90·1 per cent) had surgery; 6953 (94·6 per cent) of the 7352 patients underwent tumour resection and 4935 (67·7 per cent) of 7294 had a margin-negative (R0) resection. Deprivation was not associated with age, sex, tumour site, stage or other tumour-related factors. Compared with the most affluent group, the most deprived patients had fewer elective operations (72·9 versus 76·4 per cent; P = 0·014), more adverse co-morbidity (P < 0·001) and fewer curative resections (65·5 versus 71·2 per cent; P < 0·001). In multivariable analysis, deprivation was not an independent predictor of postoperative death (odds ratio (OR) 0·72, 95 per cent confidence interval 0·48 to 1·06; P = 0·101) but it was a predictor of curative resection (OR 1·24, 1·01 to 1·52; P = 0·042), overall survival (HR 0·83, 0·73 to 0·95; P = 0·006) and relative survival (HR 0·74, 0·58 to 0·95; P = 0·023). CONCLUSION: Deprivation, both independently and by influencing other surgical predictors, impacts on short- and long-term outcomes of patients with colorectal cancer.

Thirty-day mortality of Clostridium difficile infection in a UK National Health Service Foundation Trust between 2002 and 2008.

Few standardised data are available on mortality rates in patients with Clostridium difficile infection (CDI). The literature often reports 'attributable' mortality or cannot be universally applied. We aimed to investigate the pattern and trends in all-cause mortality in a large unselected cohort of patients affected by CDI. This was done by means of a retrospective cohort study between 2002 and 2008 of all patients with positive stool toxin tests indicating CDI in one National Health Service (NHS) Trust, comprising three general hospitals and seven community hospitals. Vital status of the patients was determined from two sources. In total, 2571 patients with a first episode of CDI were identified (1638 females; median age 82.1 years). Cumulative mortality at 7 days, 14 days, 30 days and 1 year was 13.4%, 20.8%, 32.5% and 58.7%, respectively. There was no significant difference in mortality between sex, year of diagnosis or hospital site. Mortality at 30 days increased incrementally from 3.4% in those aged <40 years to 41% in those >90 years. Mortality rates were significantly higher than reported by previous studies but were remarkably consistent over the time period and between different hospitals within the Trust. Prognosis falls with increasing age, and the age of this cohort may explain the high 30-day absolute mortality. CDI infection is associated with high early mortality. To reduce mortality, new interventions need to be introduced soon after diagnosis. There is a need for standardised outcome data for CDI.

Postinfectious irritable bowel syndrome may occur after non-gastrointestinal and intestinal infection.

Postinfectious functional gastrointestinal disorders (FGIDs) may not be specific to gastroenteritis. This pilot study aimed to ascertain the 3- and 6-month incidence of functional gut disorders in people with non-gastrointestinal (GI) infection, gastroenteritis and healthy controls. This was a prospective study of three cohorts recruited from hospital (non-GI infections) and the community (others). FGIDs were diagnosed using self-completed Rome II modular questionnaires administered at baseline, 3 and 6 months. Thirty-six subjects with non-GI infection, 219 healthy subjects and 108 with bacterial gastroenteritis participated. No difference in incidence of FGID was detected between the GI and non-GI infection cohorts. Any FGID was more frequent in people who had a non-GI infection than in controls at both 3 [odds ratio: 4.34 (95% CI: 3.60-16.45)] and 6 months [4.76 (4.42-27.92)]. Irritable bowel syndrome (IBS) alone was more frequent in people with non-GI infections than in controls at 3 months (6.12 [1.30-29.12]) but did not quite reach statistical significance at 6 months (4.58 [0.79-26.46]). Our findings were unexpected. Postinfectious FGIDs may be related to non-GI and GI infection, although not all potential biases were controlled in study design. Further studies need to explore these preliminary findings and, if confirmed, the underlying mechanisms.

Influence of dietary factors on the clinical course of ulcerative colitis: a prospective cohort study.

BACKGROUND AND AIMS: The causes of relapses of ulcerative colitis (UC) are unknown. Dietary factors have been implicated in the pathogenesis of UC. The aim of this study was to determine which dietary factors are associated with an increased risk of relapse of UC. METHODS: A prospective cohort study was performed with UC patients in remission, recruited from two district general hospitals, who were followed for one year to determine the effect of habitual diet on relapse. Relapse was defined using a validated disease activity index. Nutrient intake was assessed using a food frequency questionnaire and categorised into tertiles. Adjusted odds ratios for relapse were determined using multivariate logistic regression, controlling for non-dietary factors. RESULTS: A total of 191 patients were recruited and 96% completed the study. Fifty two per cent of patients relapsed. Consumption of meat (odds ratio (OR) 3.2 (95% confidence intervals (CI) 1.3-7.8)), particularly red and processed meat (OR 5.19 (95% CI 2.1-12.9)), protein (OR 3.00 (95% CI 1.25-7.19)), and alcohol (OR 2.71 (95% CI 1.1-6.67)) in the top tertile of intake increased the likelihood of relapse compared with the bottom tertile of intake. High sulphur (OR 2.76 (95% CI 1.19-6.4)) or sulphate (OR 2.6 (95% CI 1.08-6.3)) intakes were also associated with relapse and may offer an explanation for the observed increased likelihood of relapse. CONCLUSIONS: Potentially modifiable dietary factors, such as a high meat or alcoholic beverage intake, have been identified that are associated with an increased likelihood of relapse for UC patients. Further studies are needed to determine if it is the sulphur compounds within these foods that mediates the likelihood of relapse and if reducing their intake would reduce relapse frequency.

A comparison of the discriminatory power of the Inflammatory Bowel Disease Questionnaire and the SF-36 in people with ulcerative colitis.

The aim of this study was to compare the discriminatory power of a generic and a condition-specific quality of life measure (the Medical Outcomes Study Short-Form 36 (SF-36) and the Inflammatory Bowel Disease Questionnaire (IBDQ)) with respect to sub-groups defined by disease-related and other factors, in a sample of patients with ulcerative colitis. Disease activity was generally more highly correlated with IBDQ scores than with SF-36 scores. The only significant differences with respect to disease extent were in the SF-36 energy/vitality and social function domains. Age was negatively and weakly to moderately correlated with the physical domains of the SF-36 but positively though weakly correlated with scores on the IBDQ emotional domain and those domains of the SF-36 related to mental well-being. Co-existing chronic illness, even on controlling for age, was associated with significantly poorer scores on the generic measure, but had little influence on IBDQ scores. In conclusion, generic and disease-specific measures of quality of life appear to be complementary rather than interchangeable. We recommend the use of both types of measure in parallel.

Defining relapse of ulcerative colitis using a symptom-based activity index.

BACKGROUND: Several tools exist to assess disease activity in patients with ulcerative colitis (UC), but a definition of relapse does not exist. The aim of the study was to determine the score in the Simple Clinical Colitis Activity Index (SCCAI) that defined relapse. The reliability and validity of the SCCAI when self-administered was also examined. METHODS: Patients with UC routinely attending hospital completed the SCCAI questionnaire, which was later administered by their clinician blinded to the scoring process. In the absence of a gold standard definition of relapse, a subjective global assessment of disease status was made by the clinician. The SCCAI was evaluated in a separate cohort of patients. RESULTS: Seventy-one presentations were analysed; mean age 48 years, 49% male, 37% relapse rate. The mean patient score was 4.2 (range 0-14) and mean physician score 3.8 (0-14). A score of 5 or more defined relapse with 92% sensitivity, 93% specificity, 88% positive predictive value and 95% negative predictive value. The difference between the scores obtained by the patient and clinician (0.35, 95% CI 0.09-0.62) was small. Correlation with a more complex symptom and laboratory-based activity index was very high (r = 0.79, P < 0.01). The index was quick to use and comparative results for sensitivity and specificity were recorded in the second cohort of patients. CONCLUSIONS: The SCCAI is a simple tool that can be accurately and quickly self-administered, correlates well with a more complex disease activity index, and can be used to define relapse of UC with high specificity and sensitivity.

Absence of a genetic association between IL-1RN and IL-1B gene polymorphisms in ulcerative colitis and Crohn disease in multiple populations from northeast England.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract of unknown aetiology, phenotypically categorized into ulcerative colitis (UC) and Crohn disease (CD). Genetic factors are of considerable importance in both. The genetic relationship between IBD and the interleukin-1 receptor antagonist and interleukin-1beta genes (IL-1RN, and IL-1B, respectively) has been extensively studied. However, the quality and outcome of the genetic association studies, in particular the association with IL-1RN*2, have been variable and these associations remain controversial. The aim of the present study was to re-investigate these two candidate genes in a large series of IBD patients from a genetically homogeneous population with low levels of population admixture, and provide a definitive answer to this question. METHODS: A total of 529 northern European Caucasoid patients with IBD (347 UC, 182 CD) and 289 racially and geographically matched healthy controls were studied. The IL-1RN and IL-1B genotypes, allele frequencies and most probable haplotypes were determined by standard PCR protocols. RESULTS: There were no significant differences in the distributions of the IL-1RN and IL-1B genotypes, allele frequencies or haplotypes in either patient series compared to healthy controls or between clinical subsets. Genotype distribution and frequency data for allele 2 (IL-1RN*2) in particular showed no significant differences across all patient groups for all three series. CONCLUSION: The findings of this study lead us to reject the IL-1RN*2 association with IBD.

The short inflammatory bowel disease questionnaire is reliable and responsive to clinically important change in ulcerative colitis.

OBJECTIVE: The Short Inflammatory Bowel Disease Questionnaire (SIBDQ) is a health-related quality of life (HRQoL) tool measuring physical, social, and emotional status (score 10-70, poor to good HRQoL). The SIBDQ has been predominantly used in trials for Crohn's disease, and further validation of the SIBDQ is desirable in ulcerative colitis (UC) patients. The primary objective was to further validate the SIBDQ by examining discriminant ability against measures of disease activity. The secondary objectives were to examine reliability and responsiveness to change. METHODS: UC patients attending hospital completed the SIBDQ and two activity indices. Patients' disease status (remission, mild, moderate, or severe relapse) was determined subjectively by the patients and their physician. RESULTS: Scores were obtained for 69 events in 61 patients. mean age 47.8 yr (range 16-79). All classes of disease extent were represented. The mean SIBDQ score was 48.4 (13-70). The difference between mean score in patients in remission and relapse was -20.1 (95% CI = -25.1 to -15.1). The difference for remission and mild relapse was -14.6 (95% CI = -8.9 to -20.2). The correlation between SIBDQ and the activity indices were good, r = -0.83 and r = -0.61. Eight patients presented twice. Those with unchanged disease status showed no significant difference in the mean SIBDQ score. Patients whose disease status had deteriorated from remission to mild relapse, or from mild to moderate relapse demonstrated a mean reduction of 11.8 points (95% CI = 20.1-3.4). CONCLUSIONS: This study contributes to the validation of the SIBDQ as a HRQoL tool in UC. It is reproducible and responsive to changes in disease activity.

Esophageal mucin: an adherent mucus gel barrier is absent in the normal esophagus but present in columnar-lined Barrett's esophagus.

OBJECTIVES: The presence of a protective adherent mucus gel barrier against gastric reflux in the healthy esophagus is uncertain. The aim was to characterize the surface mucin composition and determine the extent of any adherent mucus gel layer on the normal esophagus, and compare this with that in Barrett's esophagus. METHODS: Isolated surface mucins were characterized by density centrifugation, gel filtration chromatography, and chemical composition. Adherent surface mucus was visualized in situ on unfixed and cryostat sections of mucosa and biopsies using a method that preserves mucus layer thickness. RESULTS: There was a complete absence of adherent mucus gel layers on normal human, pig, and rat esophagi. This was in contrast to the thick adherent mucous layer (median thickness = 100-200 microm) seen on the corresponding gastric mucosa. Small quantities of glycoprotein with a composition characteristic of a secretory mucin were isolated from the pig esophagus surface. The mucin, density range between 1.44 and 1.48 g x ml(-1), contained 80% carbohydrate and was rich in serine, threonine, and proline. The mucin fragmented into smaller glycoprotein units on proteolysis and partially on reduction. Cryostat sections from columnar-lined esophageal biopsies had a substantial adherent surface mucous layer (median thickness = 90 microm, interquartile range = 84-94 microm) staining for neutral mucins (gastric-type epithelium) and acidic mucins (intestinal metaplasia). CONCLUSIONS: A secretory mucin, with an analysis distinct from that of gastric or salivary mucin, is present in very small quantities on the esophageal mucosa and in amounts insufficient to form an adherent gel layer. It is unlikely that mucus has a role in protecting the normal esophagus against reflux. However, an adherent mucous layer was observed over columnar-lined esophagus, and this may protect against reflux.

Role of polymorphisms in the interleukin-10 gene in determining disease susceptibility and phenotype in inflamatory bowel disease.

Interleukin-10 (IL-10) has a key role in regulating mucosal inflammation. The role of functional polymorphisms at positions -627 and -1117 in the IL-10 gene as candidate susceptibility loci in inflammatory bowel disease and their importance in determining disease extent were evaluated in 159 patients with ulcerative colitis (83 left-sided; 76 extensive), 90 patients with Crohn's disease (22 small bowel; 29 large bowel; 39 both), and 227 controls. Genotyping was performed either by PCR-RFLP assays (-627 site) or SSCP analysis (-1117 site). An excess of -627A allele was observed in patients with left-sided colitis (52%) compared with controls (33%; P = 0.004) suggesting that IL-10 may influence the extent of the disease. These results were not replicated in a newly recruited group (N = 100) of patients with UC. We conclude that polymorphisms at -627 and -1117 sites in the IL-10 gene do not contribute to the susceptibility to IBD or determining the extent of the disease in our population.

The CC chemokine receptor 5 delta32 mutation is not associated with inflammatory bowel disease (IBD) in NE England.

Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases of the gastrointestinal tract of unknown aetiology. Evidence of abnormalities in immune regulation and cytokine production in patients with IBD has led to investigations of various immuno-regulatory genes as potential candidate susceptibility loci. Studies using whole genome scanning have highlighted chromosomes 3, 7, 12 and 16. A 32 base-pair deletion in the CC-chemokine receptor-5 gene (CCR5-A32, chromosome 3p21.3) has been associated with susceptibility to IBD. We have investigated CCR5 as a candidate susceptibility gene in 350 patients (251 with ulcerative colitis and 99 with Crohn's disease) and 103 controls using polymerase chain reaction. There were no significant differences in the distribution of CCR5 genotypes or frequencies comparing patients and controls, or associations with extent of colitis. In contrast to preliminary data, these findings suggest no evidence for involvement of this mutation in susceptibility/resistance or disease progression in IBD.

The effect of NAT2 genotype and gender on the metabolism of caffeine in nonsmoking subjects.

AIMS: To establish whether gender or N-acetyltransferase 2 (NAT2) genotype influence the urinary 17 U+17X/137X ratio after dosing with caffeine. METHODS: Ninety-two nonsmoking individuals underwent caffeine phenotyping. NAT2 genotype was determined by the polymerase chain reaction followed by a restriction digest (PCR-RFLP). RESULTS: The median ratio for urinary 17 U+17X/137X was 6.7 (range 1.45-18. 65). 55% of subjects were slow acetylators. Gender did not affect the metabolic ratio or NAT2 genotype. Mean 17 U+17X/137X ratio differed between fast (6.75) and slow (8.69) acetylators (95% CI for the difference, 0.32-3.56). CONCLUSIONS: The findings are further evidence that the 17 U+17X/137X urinary ratio is not a robust measure of CYP1A2 activity. A possible mechanism by which the ratio might be influenced by NAT2 genotype is suggested.

The SIBDQ: further validation in ulcerative colitis patients.

OBJECTIVE: The Inflammatory Bowel Disease Questionnaire (IBDQ) is an instrument that assesses quality of life in patients with inflammatory bowel disease. It has 32 items in four domains. The short form of the IBDQ (SIBDQ) was developed in Canadian Crohn's disease patients for use in clinical practice. Patients with ulcerative colitis might require a different form of the SIBDQ. Our aim was to design and validate a SIBDQ for patients with ulcerative colitis and to compare this to the Crohn's SIBDQ. METHODS: We recruited 122 patients with colitis as an initial sample. Using linear regression modeling, the 10 items that best predicted the total IBDQ score were identified. The colitis and Crohn's versions of the SIBDQ were compared by univariate linear regression with the total IBDQ score in two other cohorts of colitis patients. RESULTS: Ten items explained 97% of the variance of the total IBDQ score in our first cohort. These were items 1 and 9 (bowel); 7, 11, 21, 30 (emotional); 2 and 10 (systemic); and 12 and 28 (social). Only three items were shared with the Crohn's SIBDQ. The R2 for both SIBDQs with the total IBDQ score in the other cohorts were very high (> or =0.95), although the Colitis SIBDQ showed better internal consistency. CONCLUSIONS: The development of a SIBDQ for patients with ulcerative colitis did not reveal any clear advantage over the original version of the SIBDQ. Further studies are required to determine the role of the SIBDQ in routine clinical practice.

Detailed modelling of caffeine metabolism and examination of the CYP1A2 gene: lack of a polymorphism in CYP1A2 in Caucasians.

The cytochrome P450 CYP1A2 is important in the metabolism of both drugs and procarcinogens such as heterocyclic amines. We aimed to clarify the existence of a phenotypic polymorphism and explore the molecular basis of such a polymorphism. Ninety-two non-smoking individuals underwent caffeine phenotyping. The distribution of the 1,7-dimethylxanthine + 1,7-dimethyluracil/caffeine (17U + 17X/137X) ratio and log-transformed data were determined. Probit plots were constructed and the distribution fitted using maximum likelihood method. The CYP1A2 gene, including upstream regulatory regions, was examined for sequence polymorphisms using the single-strand conformation polymorphism technique in 19 individuals and by complete DNA sequencing in two individuals from the extremes of the distribution. We found a similar range (1.45-18.65) and median (6.7) for the 17U + 17X/137X ratio to that found in previous studies of non-smoking Caucasians and no effect of sex. The 17U + 17X/137X ratio gave a normal distribution when log-transformed. Maximum likelihood analysis showed that the log-normal and bimodal distributions had similar deviances but the log-normal distribution was favoured because it has fewer parameters. There was no evidence for significant DNA sequence differences between fast and slow metabolizers, although some differences from published sequences including a silent polymorhpism in exon 7 which were unlikely to be of functional significance were found. We therefore conclude that CYP1A2 does not show functionally significant polymorphism but that the wide interindividual variation in activity may be due to environmental factors.

Polymorphisms in GSTP1, GSTM1, and GSTT1 and susceptibility to colorectal cancer.

Polymorphisms in glutathione S-transferase (GSTs) may predispose to colorectal cancer through deficient detoxification of environmental carcinogens, although previous results are conflicting. A study with 178 matched case-control pairs was conducted to determine the effect of the GSTT1 and GSTM1 null genotypes and polymorphisms in GSTP1 on colorectal cancer susceptibility. In a secondary analysis, we examined interactions between genotypes and with the N-acetyltransferase 2 (NAT2) genotype. Heterogeneity by age, sex, site, and stage of cancer was also examined. No effect of any genotype for GSTM1, GSTT1, or GSTP1 on colorectal cancer susceptibility was detected. Secondary end points showed that individuals with both the GSTT1 null and NAT2 slow genotypes combined appeared to be at increased risk of colorectal cancer (odds ratio = 2.33; 95% confidence interval, 1.1-5.0). We conclude that GST polymorphisms alone do not predispose to colorectal cancer in northeast England. We also observed possible effects of the GSTT1 null genotype on the age and stage at presentation, and these, together with the findings of an apparent interaction with NAT2 genotypes, need to be confirmed in further studies.