Infectious Agents in Pediatric Crohn's
Condition: Crohn's Disease; Inflammatory Bowel Disease
MeSH terms: Communicable Diseases; Infections; Crohn Disease; Intestinal Diseases; Inflammatory Bowel Diseases
Study type: Observational

Summary: 
      Six sites of the Pediatric Inflammatory Bowel Disease Consortium (plus 2 additional sites)
      will participate in this study. The participating sites will be that of the Principal
      Investigator (PI), Emory University School of Medicine, Atlanta, GA (Benjamin D. Gold, MD);
      Texas Children's Hospital / Baylor College of Medicine (George Ferry, MD and Tony Olive, MD);
      Children's Hospital of Philadelphia, Philadelphia, PA (Bob Baldassano, MD); University of
      Chicago Children's Hospital, Chicago, IL (Barbara Kirschner, MD); University of California,
      San Francisco (Mel Heyman, MD); Mass General Hospital / Harvard University (Harland Winter,
      MD); V.A. Stanford University School of Medicine, Stanford, CA (David Relman, MD); Children's
      Center For Digestive Healthcare, Atlanta, GA (Stanley Cohen, MD); and Centers for Disease
      Control and Prevention, Atlanta, GA (Drs. Jeannette Guarner, Siobhan O'Connor and Thomas
      Shinnick)

      The duration of study is 2 yrs.

      Objectives:

        1. Improve the methods to collect biopsies from the colon and ileum, tissue storage
           techniques and best methods to detect specific infections in children with Crohn's
           disease;

        2. Determine if there are specific infectious agents that are more common in children with
           Crohn's disease, and;

        3. Determine if there are types of children with Crohn's disease (e.g., children living in
           Boston, African American children) who may be more at risk for getting the infections.

      The study design involves children ages 6 months through 17 11/12 years of age who are
      undergoing a clinically-indicated colonoscopy. Subjects will be grouped into cases and
      controls.

        -  Any child ages 6 mos through 17 11/12 years of age, undergoing a clinically-indicated
           colonoscopy as determined by the treating physician, is eligible for enrollment. About
           500 patients will be enrolled in this study.

        -  Cases will consist of those children within the defined age group, who are undergoing
           diagnostic colonoscopy and have the definitive diagnosis of Crohn's disease.

        -  Children who have the diagnosis of indeterminate colitis or ulcerative colitis for the
           purpose of this R03, will be excluded as cases and from initial analysis, but will have
           tissue specimens banked for subsequent evaluation for infectious agents.

        -  Controls will consists of children within the defined age group, undergoing clinically
           indicated colonoscopy and who are not diagnosed with Crohn's disease, ulcerative colitis
           or indeterminate colitis (e.g., juvenile polyps, irritable bowel syndrome or functional
           bowel disease).

        -  Stool specimen (5ml/1 tsp) will be collected to test for different types of bacteria

        -  A questionnaire will be administered to each research volunteer.

        -  Each subject's medical information (i.e. diagnosis, disease stage, and laboratory
           results) will be stored electronically in a separate access-based database. A unique
           identifier will be assigned to each patient entered into the study and will also be used
           for blinding of the specimens analyzed by the pathologist and by molecular assays for
           infectious agents.

        -  Colonoscopy will be performed by the treating pediatric gastroenterologist and biopsies
           obtained in the usual standard of care.

        -  Clinical biopsies from the rectum, left, right, transverse colon and cecum will be
           placed in formalin containing vials as per standard of care for the clinical pathologist
           and diagnostic evaluation.
    

Detailed description: 
      Inflammatory bowel disease (IBD), which includes CD and ulcerative colitis (UC), is estimated
      to affect approximately 1 - 2 million Americans. Recent studies strongly suggest that these
      disorders are increasing in prevalence in developed and developing countries, and in first
      generation immigrants to industrialized nations. Changing epidemiology of IBD implies that,
      in addition to a genetic susceptibility for disease, an environmental trigger or exposure
      likely impacts disease expression. However, the specific pathobiology and etiology of IBD
      remain unclear. Knowledge of the host genetic basis of IBD has advanced, including
      characterization of a novel susceptibility gene in adult and adolescent CD (NOD2/CARD-15)
      located on the pericentromeric region of chromosome 16. Recent studies not only implicate
      NOD2/CARD-15 in susceptibility to CD, but also suggest a link between the innate immune
      response to bacterial components and development of disease. Thus, well-designed
      investigations of infectious etiologies of CD, with sufficient power to detect differences in
      infection between IBD and non-IBD patients, are critically needed. Yet, deficiencies in the
      methods and tools for such studies still exist.

      Both infectious and noninfectious mechanisms of pathogenesis remain plausible but
      unconfirmed. To date, scientific evidence cannot conclude whether one or more infectious
      pathogens triggers or determines the development and outcomes of CD or UC. Persistent
      exposure to "normal resident flora" in an abnormally permeable gut might also conceivably
      determine disease. Thus carefully designed investigations that apply systematically
      evaluated, reliable and reproducible detection assays are needed to confirm or disprove
      infectious hypotheses of causation. The first step is a pilot study that validates study
      design and complementary assays (morphology-, molecular- and culture-based) and uniformly
      applies these to target patient and control tissues (i.e., pediatric endoscopic biopsies). It
      must focus on newly diagnosed CD (surrogate for "incident" CD) in a well-characterized group
      of patients and appropriate, well-selected controls who meet uniform case and control
      definitions. It must develop reproducible methods to ensure that results from different
      studies can be compared and appropriate clinical interpretations made in order to translate
      research results into treatment and prevention strategies that decrease the burden of CD. At
      this time, deficiencies in both methodology and laboratory technology impede successful
      conduct and interpretation of the needed studies on causality.

      Based on age of onset, newly diagnosed children with IBD, may be closer to triggering
      immunopathogenic events that initiate the inflammatory response than adults. They may also
      represent a unique population for the study of environmental factors (e.g., infection), i.e.,
      younger age usually brings shorter and less complicated exposure histories to confound
      analyses. It is reasonable to postulate that a single agent or polymicrobial insults, in the
      genetically susceptible host, may determine the development or course of CD and it may be
      easier to identify some infectious determinants in childhood CD. We hypothesize that adequate
      collection of intestinal tissue biopsies from uniformly defined pediatric CD cases and
      controls and validation of sensitive and specific laboratory tools to detect potential
      infectious triggers of CD in these particular specimen types are needed to test causality for
      infection in CD. The Pedi IBDC, 6 large, geographically diverse U.S. centers represents an
      excellent platform to investigate potential infectious factors in CD, annually evaluating and
      recording clinical and epidemiologic data on ~288 newly diagnosed pediatric CD cases in a
      comprehensive data repository. The Pedi IBDC has a system to assess the safety and efficacy
      of its research. The Consortium also provides a pool of cases and controls in which to
      implement standardized specimen collection techniques under a well-conceived algorithm. The
      R03 assembled research team draws on a wide range of expertise and institutional resources in
      epidemiology, infectious disease pathology, molecular microbiology, mycobacteriology and
      virology, and the conduct of clinical trials. The multi-disciplinary expertise of this
      proposal can test and validate in small endoscopic biopsies the histopathology and molecular
      microbial detection assays previously validated in alternative paraffin-embedded or frozen
      tissues.

      The R03 funding mechanism will facilitate tissue collection and banking techniques and
      evaluations of a panel of assays to detect select infectious agents ranging from those
      thought not to cause CD to those speculated as etiologic, from non-pathogenic commensals to
      known and undetermined pathogens. Therefore, our specific study aims are to:

        1. standardize the collection (e.g., anatomic site of biopsy origin, biopsy number and
           collection technique), processing and banking of gastrointestinal tissue biopsies
           obtained during clinically-indicated endoscopy of well-characterized children with CD
           followed by the Pedi IBDC;

        2. verify and standardize the definition of appropriate controls, evaluating both
           "non-diseased" biopsies from cases and clinically-indicated biopsies from children
           without IBD (e.g., juvenile polyposis, Hirschsprung's disease) to improve the design of
           future studies;

        3. standardize and validate in pediatric biopsies detection methods to identify potential
           infectious risk factors for CD through parallel, paired and complementary
           pathology-based (IHC), broad range amplification-based molecular (PCR) and
           organism-specific (e.g., MAP) molecular analysis, and primary culture of tissue
           specimens taken from well-defined cases and controls.

      Additionally, molecular characterization of microbiota in the feces from cases and controls
      will be compared to microbial detection in their respective tissue biopsies. Successful
      completion of these goals will provide a platform for imminent comprehensive investigations
      that characterize clinically relevant microbial risk factors for CD in the child and quite
      possibly the adult patient.
    

Time perspective: Prospective
Keywords: Children; Crohn's disease; Inflammatory bowel disease; Infectious agents; Colonoscopy