The influence of prenatal and intrapartum antibiotics on intestinal microbiota colonisation in infants: A systematic review.

OBJECTIVES: The intestinal microbiota develops in early infancy and is essential for health status early and later in life. In this review we focus on the effect of prenatal and intrapartum maternally administered antibiotics on the infant intestinal microbiota. METHODS: A systematic literature search was conducted in PubMed and EMBASE. All studies reporting effect on diversity or microbiota profiles were included. RESULTS: A total of 4.030 records were encountered. A total of 24 articles were included in the final analysis. Infants from mothers exposed to antibiotics during delivery showed a decreased microbial diversity compared to non-exposed infants. The microbiota of infants exposed to antibiotics was characterised by a decreased abundance of Bacteriodetes and Bifidobacteria, with a concurrent increase of Proteobacteria. These effects were most pronounced in term vaginally born infants. CONCLUSION: Maternal administration of antibiotics seems to have profound effects on the infant gut microbiota colonisation. Interpretation of microbiota aberrations in specific populations, such as preterm and caesarean born infants, is complicated by multiple confounding factors and by lack of high quality studies and high heterogeneity in study design. Further research is needed to investigate the potential short- and long-term clinical consequences of these microbial alterations.

Phenotypic Variation in Paediatric Inflammatory Bowel Disease by Age: A Multicentre Prospective Inception Cohort Study of the Canadian Children IBD Network.

BACKGROUND AND AIMS: Incidence of paediatric inflammatory bowel disease [IBD] in Canada is among the highest worldwide, and age of onset may be decreasing. In a multicentre nationwide inception cohort study, we examined variation in phenotype of IBD throughout the paediatric age spectrum. METHODS: Children aged ≥2 years [y] and <17y [A1 age at diagnosis], with new onset IBD, were systematically evaluated at sites of the Canadian Children IBD Network. Prospectively recorded phenotypic data were compared between age groups. RESULTS: Among 1092 children (70% Caucasian; 64% Crohn's disease [CD], 36% ulcerative colitis/inflammatory bowel disease unclassified [UC/IBD-U]; median age 13 y, interquartile range [IQR] 11-15 y), 210 [19%] were diagnosed before the age of age 10 y [Paris A1a] and 43 [4%] before age 6 y (very-early-onset [VEO-IBD]). CD was less common in younger children [42%, 56%, 66%, respectively, of VEO-IBD, A1a; A1b]. Colon-only IBD [UC/IBDU or CD-colon] was present in 81% of VEO-IBD and 65% of A1a; ileal disease increased progressively, reaching plateau at age 10 y. CD location was ileocolonic [L3] in 53% overall. Ileitis [L1] increased with age [6% of VEO-IBD; 13% of A1a; 21% of A1b], as did stricturing/penetrating CD [4% of A1a; 11% of A1b]. At all ages UC was extensive [E3/E4] in >85%, and disease activity moderate to severe according to Physician's Global Assessment [PGA] and weighted Paediatric Crohn's Disease Activity Index/Paediatric Ulcerative Colitis Activity Index [wPCDAI/PUCAI] in >70%. Heights were modestly reduced in CD [mean height z score -0.30 ± 1.23], but normal in UC/IBD-U. CONCLUSIONS: Paris classification of age at diagnosis is supported by age-related increases in ileal disease until age 10 years. Other phenotypic features, including severity, are similar across all ages. Linear growth is less impaired in CD than in historical cohorts, reflecting earlier diagnosis.

Autophagy: from basic science to clinical application.

Autophagy is a cellular pathway involved in protein and organelle degradation, which is likely to represent an innate adaptation to starvation. In times of nutrient deficiency, the cell can self-digest and recycle some nonessential components through nonselective autophagy, thus sustaining minimal growth requirements until a food source becomes available. Over recent years, autophagy has been implicated in an increasing number of clinical scenarios, notably infectious diseases, cancer, neurodegenerative diseases, and autoimmunity. The recent identification of the importance of autophagy genes in the genetic susceptibility to Crohn's disease suggests that a selective autophagic response may play a crucial role in the pathogenesis of common complex immune-mediated diseases. In this review, we discuss the autophagic mechanisms, their molecular regulation, and summarize their clinical relevance. This progress has led to great interest in the therapeutic potential of manipulation of both selective and nonselective autophagy in established disease.

Filaggrin loss-of-function variants are associated with atopic comorbidity in pediatric inflammatory bowel disease.

BACKGROUND: Pediatric inflammatory bowel disease (IBD) has a high prevalence of coexistent atopy. Filaggrin (FLG) loss-of-function variants (null-alleles) are associated with eczema and asthma in association with eczema. The aim was to assess the contribution of FLG null-alleles to pediatric IBD susceptibility and to coexistent atopy (eczema, asthma, allergic rhinitis, or food allergy). METHODS: FLG variants (R501X and 2282del4) were genotyped in 403 children with IBD, 683 parents, and 996 population controls. RESULTS: In all, 11% of IBD patients carried at least 1 FLG null-allele compared to 11% of population controls (P > 0.4). Carriage of 1 or more null-alleles in patients with atopy (present in 52% of IBD patients) differed from IBD patients without atopy (14% versus 6%, P = 0.01; odds ratio [OR] 2.4, 95% confidence interval [CI] 1.2-5.1). The effect of FLG null-alleles was strongest for eczema (19% versus 7%, P = 0.0003; OR 3.3, 95% CI 1.7-6.6) and food allergy (28% versus 8%, P = 0.0001; OR 4.5, 95% CI 2.0-10.0). The presence of more than 1 atopic disease tended to increase the associated OR: eczema + asthma (23% versus 7%, P = 0.001; OR 3.9, 95% CI 1.6-9.1), eczema + asthma + allergic rhinitis (29% versus 7%, P = 0.0006; OR 5.4, 95% CI 1.9-15.4) and eczema + asthma + allergic rhinitis + food allergy (45% versus 6%, P < 10(-4); OR 12.2, 95% CI 3.2-46.3). Logistic regression analysis of IBD cases confirmed the association of carriage of an FLG null-allele with atopy (P = 0.01; OR 2.4, 95% CI 1.2-5.1) and co-occurrence of different forms of atopy (P = 0.003; OR 3.5, 95% CI 1.5-8.1). CONCLUSIONS: Filaggrin null-alleles have no effect on IBD susceptibility but contribute to coexistent eczema and food allergy.

Detailed assessment of NOD2/CARD15 exonic variation in inflammatory bowel disease in Scotland: implications for disease pathogenesis.

The high incidence of Scottish Crohn's disease (CD) is not explained by the common three NOD2/CARD15 variants. We aimed to identify population-specific NOD2/CARD15 coding variants. A total of 1478 (320 inflammatory bowel disease patients <16 years, 343 adult CD patients, 542 parents and 273 controls). All NOD2/CARD15 exons were sequenced in 24 CD patients. Sequencing identified 18 single-nucleotide polymorphisms (SNPs) including 4 non-synonymous coding SNPs altering the structure of the Leucine-rich region--two were well established (1007-/C and 908G/R). Two other variants, valine955isoleucine (955V/I) and methionine863valine (863M/V), were genotyped in all subjects. 863M/V carriage was not significantly higher in CD patients vs controls (1.35 vs 0.37%, P=0.27). 955V/I carriage was no higher in CD or ulcerative colitis patients (12.8 and 15.8%, respectively) compared to controls (16.2%). Transmission disequilibrium test analysis was negative. 955V/I carriage was higher in indeterminate colitis patients (n=29) compared to controls (41.4 vs 16.2%, P=0.001, OR=3.6 (1.6-8.2)). Population-specific NOD2/CARD15 exonic variants do not account for the high-CD prevalence in Scotland.

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 Crohn's 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.

Contribution of the NOD1/CARD4 insertion/deletion polymorphism +32656 to inflammatory bowel disease in Northern Europe.

BACKGROUND: NOD1/CARD4 and NOD2/CARD15 are both intracellular pattern-recognition receptors. The NOD1/CARD4 gene lies within a previously described inflammatory bowel disease (IBD) locus (7p14). An association has been suggested between the NOD1/CARD4+32656 deletion*1 variant of a complex deletion*1/insertion*2 polymorphism and IBD in 1 recent study in Europe. Our aim was to assess the influence of NOD1/CARD4+32656 on disease susceptibility and phenotype in the Scottish and Swedish IBD populations. METHODS: A total of 3,962 individuals (1,791 IBD patients, 522 parents, 1,649 healthy controls) from 2 independent populations (Scotland and Sweden) were genotyped for NOD1/CARD4+32656 A/C by TaqMan and direct sequencing. Case-control, Transmission Disequilibrium Testing (TDT) and detailed genotype-phenotype (Montreal) analyses were performed. The case-control analysis had 80% power to detect an effect size of odds ratio (OR) 1.21 for IBD. RESULTS: In case-control analyses in Scottish and Swedish patients, none of the genotypes studied in IBD, Crohn's disease (CD) or ulcerative colitis (UC), differed significantly from controls (deletion*1 allelic frequency 73.9%, 73.6%, 73.9%, and 73.6%, respectively: all P > 0.8). No epistatic interaction with NOD2/CARD15 was seen for CD susceptibility. TDT analysis in our Scottish early onset cohort was negative. CONCLUSIONS: This variant allele of NOD1/CARD4+32656 is not associated with a strong effect on susceptibility to IBD in children and adults in Northern Europe. A gene-wide haplotype-based approach may be preferable to analysis of individual variants to assess the contribution of the NOD1/CARD4 gene to IBD.

Streptococcus A in paediatric accident and emergency: are rapid streptococcal tests and clinical examination of any help?

BACKGROUND: Rapid streptococcal tests (RSTs) for streptococcal pharyngitis have made diagnosis at once simpler and more complicated. The American Academy of Pediatrics recommends that all RSTs be confirmed by a follow up throat culture unless local validation has proved the RST to be equally sensitive. AIMS: To evaluate (a) RST as a single diagnostic tool, compared with RST with or without throat culture; (b) clinical diagnosis and the relative contribution of different symptoms. METHODS: The study included 213 patients with clinical signs of pharyngitis. Throat swabs were analysed using Quickvue+ Strep A Test; negative RSTs were backed up by throat culture. Thirteen clinical features commonly associated with strep throat were analysed using backward stepwise logistic regression. RESULTS: Positive results (RST or throat culture) were obtained in 33 patients; RST correctly identified 21. Eleven samples were false negative on RST. At a strep throat prevalence of 15.9%, sensitivity of RST was 65.6% (95% CI 46.8% to 81.4%) and specificity 99.4% (96.7% to 99.9%). Sensitivity of clinical diagnosis alone was 57% (34% to 78%) and specificity 71% (61% to 80%). Clinically, only history of sore throat, rash, and pyrexia contributed to the diagnosis of strep throat (p<0.05). CONCLUSION: The high specificity of RST facilitates early diagnosis of strep throat. However, the low sensitivity of RST does not support its use as a single diagnostic tool. The sensitivity in the present study is markedly different from that reported by the manufacturer. Clinical examination is of limited value in the diagnosis of strep throat. It is important to audit the performance of new diagnostic tests, previously validated in different settings.