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Microbiota separation and C-reactive protein elevation in treatment-naive pediatric granulomatous Crohn disease.

ABSTRACT: In patients with inflammatory bowel diseases (IBDs), the presence of noncaseating mucosal granuloma is sufficient for diagnosing Crohn disease (CD) and may represent a specific immune response or microbial-host interaction. The cause of granulomas in CD is unknown and their association with the intestinal microbiota has not been addressed with high-throughput methodologies.The mucosal microbiota from 3 different pediatric centers was studied with 454 pyrosequencing of the bacterial 16S rRNA gene and the fungal small subunit (SSU) ribosomal region in transverse colonic biopsy specimens from 26 controls and 15 treatment-naïve pediatric CD cases. Mycobacterium avium subspecies paratuberculosis (MAP) was tested with real-time polymerase chain reaction. The correlation of granulomatous inflammation with C-reactive protein was expanded to 86 treatment-naïve CD cases.The CD microbiota separated from controls by distance-based redundancy analysis (P = 0.035). Mucosal granulomata found in any portion of the intestinal tract associated with an augmented colonic bacterial microbiota divergence (P = 0.013). The granuloma-based microbiota separation persisted even when research center bias was eliminated (P = 0.04). Decreased Roseburia and Ruminococcus in granulomatous CD were important in this separation; however, principal coordinates analysis did not reveal partitioning of the groups. CRP levels >1 mg/dL predicted the presence of mucosal granulomata (odds ratio 28 [6-134.32]; 73% sensitivity, 91% specificity).Granulomatous CD associates with microbiota separation and C-reactive protein elevation in treatment-naïve children; however, overall dysbiosis in pediatric CD appears rather limited. Geographical/center bias should be accounted for in future multicenter microbiota studies.

SUBMITTER: Kellermayer R

PROVIDER: S-EPMC3812911 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Microbiota separation and C-reactive protein elevation in treatment-naïve pediatric granulomatous Crohn disease.

Kellermayer Richard R Mir Sabina A V SA Nagy-Szakal Dorottya D Cox Stephen B SB Dowd Scot E SE Kaplan Jess L JL Sun Yan Y Reddy Sahna S Bronsky Jiri J Winter Harland S HS

Journal of pediatric gastroenterology and nutrition 20120901 3

<h4>Objectives</h4>In patients with inflammatory bowel diseases (IBDs), the presence of noncaseating mucosal granuloma is sufficient for diagnosing Crohn disease (CD) and may represent a specific immune response or microbial-host interaction. The cause of granulomas in CD is unknown and their association with the intestinal microbiota has not been addressed with high-throughput methodologies.<h4>Methods</h4>The mucosal microbiota from 3 different pediatric centers was studied with 454 pyrosequen ...[more]

PMID: 22699834

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Project description:ObjectivesSubtherapeutic drug concentrations contribute to both primary and secondary nonresponse to infliximab in children with Crohn disease (CD). The aim of this study was to evaluate treatment outcomes and infliximab concentrations at infusions 2 and 3 with an objective to establish infliximab targets during induction for primary responders.MethodsSingle-center, prospective cohort of anti- tumor necrosis factor-alpha naïve CD patients younger than 22 years starting infliximab. Clinical response was defined with the weighted pediatric CD activity index at the fourth infusion. Rates of biological response (>50% improvement in fecal calprotectin) and maintenance concentrations ≥5 μg/mL were secondary outcomes.ResultsWe enrolled 72 patients with CD with 70 of 72 receiving infliximab monotherapy. Clinical response, biological response, and start of maintenance concentrations ≥5 μg/mL were achieved in 64%, 54%, and 22%, respectively. The median (interquartile range) infliximab concentrations at infusion 2 and 3 in clinical responders were 27.8 μg/mL (19.5-40) and 14 μg/mL (8.3-24) compared to 18.8 μg/mL (9.1-23, P < 0.001) and 7.8 μg/mL (4-13.2, P < 0.01) in nonresponders. Receiver operating characteristic analysis determined that an infliximab concentration ≥15.9 μg/mL at infusion 3 was associated with clinical response (area under the curve [AUC] 0.73), whereas an infusion 3 level ≥18 μg/mL was associated with a start of maintenance concentration >5 μg/mL (AUC 0.85). Independent predictors for infusion 3 levels <18 μg/mL included pretreatment prednisone, low body mass index, elevated erythrocyte sedimentation rate and C-reactive protein, hypoalbuminemia, and an infusion 2 infliximab level <29 μg/mL.ConclusionsWe found that infusion 2 (≥29 μg/mL) and infusion 3 (≥18 μg/mL) infliximab concentrations were strongly associated with improved early outcomes and higher first maintenance dose levels.

Dataset Information

Microbiota separation and C-reactive protein elevation in treatment-naive pediatric granulomatous Crohn disease.

Publications

Microbiota separation and C-reactive protein elevation in treatment-naïve pediatric granulomatous Crohn disease.

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