Niall Anderson

Rising incidence of pediatric inflammatory bowel disease in Scotland

Background: An accurate indication of the changing incidence of pediatric inflammatory bowel disease (PIBD) within a population is useful in understanding concurrent etiological factors. We aimed to compare the current incidence and other demographic attributes of PIBD in the Scottish population to previous data. Methods: A national cohort of prospectively and retrospectively acquired incident cases of PIBD diagnosed less than 16 years old in pediatric services in Scotland was captured for the period 2003–2008; historical Scottish data were used for comparison (1990–1995). Age/sex‐adjusted incidences were calculated and statistical comparisons made using Poisson regression. Results: During the 2003–2008 study period 436 patients were diagnosed with PIBD in Scotland, giving an adjusted incidence of 7.82/100,000/year. The incidence of Crohns disease (CD) was 4.75/100,000/year, ulcerative colitis (UC) 2.06/100,000/year, and inflammatory bowel disease‐unclassified (IBDU) 1.01/100,000/year. Compared with data from 1990–1995 when 260 IBD patients were diagnosed, significant rises in the incidence of IBD (from 4.45/100,000/year, P < 0.0001), CD (from 2.86/100,000/year, P < 0.0001), and UC (from 1.59/100,000/year, P = 0.023) were seen. There was also a significant reduction in the median age at IBD diagnosis from 12.7 years to 11.9 years between the periods (P = 0.003), with a continued male preponderance. Conclusions: The number of Scottish children diagnosed with IBD continues to rise, with a statistically significant 76% increase since the mid‐1990s. Furthermore, PIBD is now being diagnosed at a younger age. The reason for this continued rise is not yet clear; however, new hypotheses regarding disease pathogenesis and other population trends may provide further insights in future years. (Inflamm Bowel Dis 2012;)

Genotype-phenotype analysis in childhood-onset Crohn's disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease.

Introduction: The incidence of early‐onset CD in Scotland is among the highest worldwide. Three single nucleotide polymorphisms (SNPs) R702W, G908R and Leu1007finsC in the NOD2/CARD15 gene predispose to adult CD. We investigated the contribution of these variants to disease susceptibility and phenotype in the Scottish early‐onset IBD population. Patients and Methods: 906 individuals including 247 Scottish IBD patients aged <16 years at diagnosis, 414 parents and 245 controls were genotyped. Transmission disequilibrium testing (TDT), case‐control analysis and detailed genotype‐phenotype analysis were performed. Results: The Leu1007finsC variant was associated with susceptibility to CD by case‐control (4.2% versus. 1.4%, P = 0.01) and TDT analysis (P = 0.006). The Population Attributable Risk (PAR) for the 3 NOD2/CARD15 mutations was 7.9%. Carriage of NOD2/CARD15 variants was associated with, at diagnosis: decreased albumin (31.0% versus. 9.0%, P = 0.001) and raised CRP (25% versus. 9.5%, P = 0.04) and at follow up: need for surgery (39.5% versus. 12.8%, P = 0.0002) jejunal involvement (50% versus. 18.4%, P = 0.01) jejunal and ileal involvement (50% versus. 10.7%, P = 0.009), raised CRP (57.1% and 12.8%, P = 0.0009), lower weight/height centile (75.0% versus. 20.2%, P = 0.03, 50.0% versus. 16.0%, P = 0.001 respectively) and stricturing disease (45.5% versus. 19.4%, P < 0.05). Multifactorial analysis demonstrated carriage was associated with need for surgery (P = 0.004, OR 4.9 [1.5‐14.7]). Conclusions: These NOD2/CARD 15 variants in the Scottish early onset CD population have a definite, albeit relatively small contribution to CD susceptibility (PAR 7.9%) but a major impact on phenotype. In particular NOD2/CARD15 variants are strongly associated with several markers of disease severity in pediatric CD, notably need for surgery.

The Diagnostic Accuracy of Fecal Calprotectin During the Investigation of Suspected Pediatric Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

OBJECTIVES:Fecal calprotectin (FC) is increasingly used during the diagnosis of inflammatory bowel disease (IBD), outperforming blood markers during investigation in children. Tests that reduce endoscopy rates in children with suspected gut inflammation would be beneficial. We aimed to determine the usefulness of FC in children undergoing their primary investigation for suspected IBD by systematic review and meta-analysis.METHODS:An electronic search was performed with keywords relating to IBD and calprotectin in multiple electronic resources from 1946 to May 2012; a hand search was also performed. Inclusion criteria were studies that reported FC levels before the endoscopic investigation of IBD in patients less than 18 years old. Studies were evaluated using the Quality Assessment of Diagnostic Accuracy Studies tool, and a meta-analysis was performed using a hierarchical summary receiver operating curve model.RESULTS:Eight papers met the inclusion criteria (six prospective and two retrospective case–control studies); methodological quality was determined in detail for each study. The 8 studies presented FC levels at presentation in 715 patients, 394 pediatric IBD patients, and 321 non-IBD controls. Pooled sensitivity and specificity for the diagnostic utility of FC during the investigation of suspected pediatric IBD were 0.978 (95% confidence interval (CI), 0.947–0.996) and 0.682 (95% CI, 0.502–0.863), respectively; the positive and negative likelihood ratios were 3.07 and 0.03, respectively.CONCLUSIONS:FC has a high sensitivity and a modest specificity during the diagnosis of suspected pediatric IBD. Further work is required to determine the effect of FC levels on endoscopy rates and its role during the re-evaluation of those with confirmed disease.

Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth indices in early onset inflammatory bowel disease

Background and aims: The OCTN1 (SLC22A4 1672C→T) and OCTN2 (SLC22A5 −207G→C) variants within the IBD5 locus have been associated with susceptibility to adult onset Crohn’s disease (CD), but their contribution in children has not been examined. Methods: These OCTN1/2 variants and IBD5 marker single nucleotide polymorphisms (SNPs) (IGR2096a_1, IGR2198a_1, and IGR2230a_1) were examined in 299 Scottish children (200 with CD, 74 with ulcerative colitis (UC), and 25 with indeterminate colitis (IC)), together with 502 parents (for transmission disequilibrium testing) and 256 controls. Results: All SNPs were in strong linkage disequilibrium (D′ >0.94). TDT analysis showed association of the OCTN1 variant with inflammatory bowel disease (IBD) (p = 0.01) and CD (p = 0.04). Allele frequencies of the OCTN1/2 variants were significantly higher in IBD/CD cases (p<0.04). The homozygous mutant OCTN1/2 haplotype was increased in IBD (24.3% v 16.1%, p = 0.02) and UC (28.2% v 16.1%, p = 0.02) compared with controls. The OCTN1/2 variants were not independent of the background IBD5 risk haplotype in conferring disease susceptibility. Unifactorial analysis in CD patients showed that carriage of the TC haplotype was associated with lower weight, height, and BMI centile (<9th centile) at diagnosis (weight: 87.9% v 67.3% (p = 0.002), odds ratio (OR) = 3.52 (95% confidence interval, 1.51 to 8.22); height: 84.1% v 68.4% (p<0.05), OR = 2.44 (1.00 to 5.99); BMI: 79.6% v 61.1% (p = 0.02), OR = 2.49 (1.14 to 5.44)), and lower weight centile at follow up (87.5% v 64.6% (p = 0.03), OR = 3.83 (1.03 to 14.24)). Multifactorial binary logistic regression analysis confirmed association of the TC haplotype with lower weight centile at diagnosis (p = 0.02, OR = 3.41 (1.20 to 9.66)). Conclusions: These data implicate variants within the IBD5 haplotype, as determinants of disease susceptibility and growth indices in early onset IBD. The OCTN1/2 variants remain potential positional candidate genes, but require further analysis.

IL23R Arg381Gln is associated with childhood onset inflammatory bowel disease in Scotland

The discovery of NOD2/CARD15 as the first susceptibility gene in Crohn’s disease has contributed significantly to a fundamental change in the direction of basic research in inflammatory bowel disease (IBD), triggering renewed interest in the integrity of the innate immune response in IBD and appropriate orchestration of a subsequent adaptive immune response.1,2 More widely, in all complex diseases this finding in 2001 provided a much welcomed and needed proof of principle for non-parametric linkage analysis. Another study with major implications for the pathogenesis of Crohn’s disease as well as for investigation of all complex disorders has recently been published.3 The North American consortium performed an association study testing 308 332 markers spanning the entire genome in 567 patients with ileal Crohn’s disease and 571 controls of non-Jewish European ancestry. Of the three markers reported to retain significance after stringent Bonferroni correction, two were located in the NOD2/CARD15 gene. The third marker (rs11209026) was a non-synonymous variant in the interleukin-23 receptor (IL23R) gene on chromosome 1p31. Replication was obtained in the index paper in a Jewish ancestry case-control analysis of patients with Crohn’s disease by transmission disequilibrium testing in 883 families with offspring affected by IBD and in a combined case-control analysis …

Does cigarette smoking influence the phenotype of Crohn's disease? Analysis using the Montreal classification.

OBJECTIVES:The clinical subclassification of Crohns disease by phenotype has recently been reevaluated. We have investigated the relationships between smoking habit, age at diagnosis, disease location, and progression to stricturing or penetrating complications using the Montreal classification.METHODS:408 patients (157 male, median age 29.4 yr) were assessed. Data were collected on smoking habit, age at diagnosis, anatomical distribution, and disease behavior. Follow-up data were available on all patients (median 10 yr).RESULTS:At diagnosis, ex-smokers (N = 53) were older than nonsmokers (N = 177) or current smokers (N = 178, medians 43.2 vs 28.3 or 28.9 yr, respectively, P < 0.001). Disease location differed according to smoking habit at diagnosis (χ2 = 24.1, P = 0.02) as current smokers had less colonic (L2) disease than nonsmokers or ex-smokers (30% vs 45%, 50%, respectively). In univariate Kaplan–Meier survival analysis, smoking habit at diagnosis was not associated with time to development of stricturing disease, internal penetrating disease, perianal penetrating disease, or time to first surgery. Patients with isolated colonic (L2) disease were slower to develop strictures (P < 0.001) or internal penetrating disease (P = 0.001) and to require surgery (P < 0.001). Cox models with smoking habit as time-dependent covariates showed that, relative to ileal (L1) location of disease, progression to stricturing disease was less rapid for patients with colonic (L2) disease (HR 0.140, P < 0.001), but not independently affected by smoking habit. Progression to surgery was also slower for colonic (L2) than ileal (L1) disease location (HR 0.273, P < 0.001), but was independent of smoking habit.CONCLUSIONS:Smoking habit was associated with age at diagnosis and disease location in Crohns disease, while disease location was associated with the rate of development of stricturing complications and requirement for surgery. The pathogenic basis of these observations needs to be explained.

Diagnostic importance of pulmonary interleukin-1β and interleukin-8 in ventilator-associated pneumonia

Background Ventilator-associated pneumonia (VAP) is the most commonly fatal nosocomial infection. Clinical diagnosis of VAP remains notoriously inaccurate. The hypothesis was tested that significantly augmented inflammatory markers distinguish VAP from conditions closely mimicking VAP. Methods A prospective, observational cohort study was carried out in two university hospital intensive care units recruiting 73 patients with clinically suspected VAP, and a semi-urban primary care practice recruiting a reference group of 21 age- and sex-matched volunteers. Growth of pathogens at >104 colony-forming units (cfu)/ml of bronchoalveolar lavage fluid (BALF) distinguished VAP from “non-VAP”. Inflammatory mediators were quantified in BALF and serum. Mediators showing significant differences between patients with and without VAP were analysed for diagnostic utility by receiver operator characteristic (ROC) curves. Results Seventy-two patients had recoverable lavage—24% had VAP. BALF interleukin-1β (IL-1β), IL-8, granulocyte colony-stimulating factor and macrophage inflammatory protein-1α were significantly higher in the VAP group (all p<0.005). Using a cut-off of 10 pg/ml, BALF IL-1β generated negative likelihood ratios for VAP of 0.09. In patients with BALF IL-1β <10 pg/ml the post-test probability of VAP was 2.8%. Using a cut-off value for IL-8 of 2 ng/ml, the positive likelihood ratio was 5.03. There was no difference in cytokine levels between patients with sterile BALF and those with growth of <104 cfu/ml. Conclusions BALF IL-1β and IL-8 are amongst the strongest markers yet identified for accurately demarcating VAP within the larger population of patients with suspected VAP. These findings have potential implications for reduction in unnecessary antibiotic use but require further validation in larger populations.

Smoking Habit and Load Influence Age at Diagnosis and Disease Extent in Ulcerative Colitis

INTRODUCTION:Cigarette smoking affects susceptibility to ulcerative colitis (UC), but its effects on age at diagnosis, disease extent, and need for surgery are less well defined. We examined these parameters in a detailed retrospective analysis of a large cohort of well-characterized UC patients.METHODS:499 UC patients (254 male, median age 34.3 yr) were studied. Data were collected on smoking habits, smoking load (pack-years), age at recruitment, age at diagnosis, surgery, and disease extent. Colonoscopic and histological data at both diagnosis and follow-up (median follow-up time 4.6 yr) were available on 349 patients.RESULTS:Ex-smokers were older at diagnosis than current or nonsmokers, (46.5 yr vs 31.1 or 29.4 yr, respectively, P < 0.001). Before diagnosis, ex-smokers had a higher smoking load than current smokers (13.0 vs 6.94 pack-years, P < 0.001). A Cox model for age at diagnosis, with smoking as a time-dependent covariate, showed that at any age, ex-smokers were significantly more likely to develop UC than current smokers (hazard ratio 1.8, 95% CI 1.41–2.44, P < 0.001). For current smokers at latest colonoscopy, those with extensive disease were the lightest smokers (median 0.320 pack-years), whereas those with healthy colons were the heaviest smokers (median 9.18 pack-years, P = 0.006). At 5 yr, regression of extensive disease was more frequent in current than ex-smokers or nonsmokers (30% current smokers vs 8% nonsmokers and 5% ex-smokers, χ2 = 30.4, P < 0.001) but these differences were not maintained over a longer time period.CONCLUSIONS:Smoking habit influences the age at diagnosis and changes in disease extent in UC. Mechanisms are likely to be complex and require further investigation.

Autophagy Gene ATG16L1 Influences Susceptibility and Disease Location but Not Childhood-Onset in Crohn's Disease in Northern Europe

Background: The rs2241880A/G variant of the ATG16L1 gene has been associated with susceptibility to ileal Crohns disease (CD) in adults. Our aim was to assess whether germline variation of ATG16L1 acts as an independent determinant of susceptibility to childhood‐onset CD in the high‐incidence Scottish population. Methods: In all, 2195 subjects (361 children (inflammatory bowel disease [IBD] diagnosis <17 years), their parents (n = 634), 855 adult IBD patients, and 345 controls were genotyped. Case‐control analysis was powered to detect effect sizes with an odds ratio (OR) >1.39 in pediatric CD. Case‐control analysis, transmission disequilibrium testing (TDT), analysis of variance (ANOVA) of growth parameter z‐scores, Kruskal–Wallis test (age at diagnosis), and multifactorial genotype–phenotype analysis (Montreal classification) were performed. 7.8% of pediatric CD patients and 37.2% of adult CD patients had pure ileal disease. Results: We confirmed the association of the rs2241880G‐allele with adult‐onset CD (60.7% versus controls 53.9%, P = 0.01, OR 1.32, 95% confidence interval [CI] 1.07–1.63) in contrast to childhood‐onset CD (54.1% versus controls, P = 0.95, OR 1.01, 95% CI 0.80–1.26). TDT analysis was negative. Genotype–phenotype analysis demonstrated an association of pure ileal disease with the rs2241880G‐allele (P = 0.02, OR 1.34, 95% CI 1.03–1.74). Using binary logistic regression analysis we confirmed the effect of rs2241880 genotype (GG) on ileal disease versus colonic disease (P = 0.03, OR 2.43, 95% CI 1.05–5.65). ATG16L1 genotype did not influence age at CD diagnosis. ANOVA of z‐scores of height, weight, and body mass index (BMI) at CD diagnosis in children showed no association with genotype. Conclusions: The ATG16L1 variant is associated with susceptibility to adult CD in Scotland, but not early‐onset disease. These contrasting effects are primarily driven by differences in disease location between early‐onset and adult‐onset disease.

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients

Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3Kδ. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P = .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P = .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection.