Risk Factors for Gastric Disease in Pediatric Helicobacter Pylori (H. Pylori)
Condition: Helicobacter Infections; Gastritis; Peptic Ulcer
MeSH terms: Helicobacter Infections; Gastritis; Peptic Ulcer; Stomach Diseases
Study type: Observational

Summary: 
      Helicobacter pylori (Hp) is a major cause of chronic-active gastritis and primary duodenal
      ulcers, and is strongly linked to gastric cancer. Most Hp infections worldwide are acquired
      in childhood. Why some individuals develop symptomatic disease is unclear and, until
      recently, no studies critically evaluated the role of pediatric Hp strains and/or host
      factors in disease outcomes. Over the past 5 years of National Institutes of Health (NIH)
      funding, 486 children from Atlanta, Cleveland, and Miami were enrolled; 184 (38%) were
      Hp-infected. Race (African American) and younger age, in conjunction with Hp strains
      expressing cagA and vacAs1B, were shown to be risk factors for both esophageal and gastric
      disease, suggesting a different disease paradigm from Hp-infected adults. Using the updated
      Sydney system, the investigators demonstrated a histopathologic spectrum in children, which
      included novel observations of atrophic gastritis with intestinal metaplasia.

      Overall hypothesis for competitive renewal: disease manifestations in Hp-infected children
      are influenced by specific host factors (i.e., race, immune phenotype), environmental
      exposures, and specific virulence factors of infecting Hp strains.

      Specific aims:

        1. Using well defined cases and controls, further characterize specific host factors and
           environmental exposures contributing to symptomatic childhood infection emphasizing
           targeted enrollment in specific age, gender and demographic strata to facilitate
           detection of significant differences not attained previously and follow-up of 2
           established specific cohorts to ascertain immune response natural history.

        2. Utilize gene-array technology for the whole Hp genome assessment and bacterial gene
           expression of specific virulence determinants associated with pediatric Hp strains.

        3. Further characterize the host immunologic and mucosal response in Hp-infected children.

      Hp-infected symptomatic endoscopy cases at the investigators' established 3 clinical centers
      of high, moderate and low Hp prevalence will be compared with age-matched Hp-infected
      asymptomatic and uninfected symptomatic controls. Two geographically and demographically
      distinct centers have been added to provide additional geographic and subject
      representativeness to the patient cohort. The updated Sydney system will be employed to
      assess gastric histopathology severity and phenotype in newly enrolled cases in specific age,
      gender and demographic strata and follow-up of the two "novel" cohorts established in the
      past 5 years: a) atrophic gastritis; and b) esophageal and gastric disease groups enabling a
      comprehensive, multivariate evaluation of the natural history of Hp-infected children in two
      distinct disease paradigms.

      Using molecular methods (multiplex [MP]-PCR, RT-PCR) and a micro ELISPOT assay on peripheral
      blood mononuclear cells (PBMCS), Th1, Th2, Th3 or balanced Th1/Th2 response will be
      determined to further characterize the Hp-infected child's immune response phenotype. The
      investigators propose to further their previous work with critically lacking studies from a
      multivariate approach, leading to a better understanding of the gastroduodenal disease
      sequelae and overall pathobiology of Hp infection in humans.
    

Detailed description: 
      Discovered in 1982 as a cause of gastroduodenal ulceration, Helicobacter pylori (Hp) is the
      major cause of gastritides (e.g. chronic-active) and primary duodenal ulcers in adults and
      children. [Warren, 1983 #1180; Whitney, 2000 #1345; Ashorn, 1995 #1179; Asante, 1997 #1173;
      Drumm, 1987 #355; Czinn, 1986 #101; Drumm, 1988 #1096; Ernst, 2000 #1351; Goggin, 1998 #986;
      Torres, 2000 #1346] Infection with Hp, particularly in susceptible persons, is also strongly
      linked to gastric adenocarcinoma cancer and mucosal-associated lymphoid tissue-type (MALT)
      lymphomas. [Uemura, 2001 #1409; Alexander, 2000 #1232; Alm, 1999 #1038; Blaser, 1995 #757;
      Correa, 1990 #1523; El-Omar, 2000 #1272] The majority of infections worldwide are acquired in
      childhood. In the United States, minority populations (African Americans, Hispanics) have
      increased seroprevalence rates in all age groups. [Fontham, 1995 #139; Gold, 2001 #1422;
      Graham, 1991 #235; Staat, 1996 #190; Smoak, 1994 #618] Consensus guidelines for pediatric Hp
      infection were first published in 1999, yet there remains an overwhelming paucity of
      information regarding both the epidemiology of pediatric Hp infection and associated
      diseases. [Gold, 2000 #1347; Drumm, 2000 #1123; Sherman, 1999 #1129; Hunt, 1998 #353] It is
      not known why some Hp-infected children develop symptoms, and mechanisms accounting for
      differences in the inflammatory response and disease in Hp-infected children are
      uncharacterized. Using a multicenter study approach to test our hypothesis, this proposal
      will provide an in depth examination of the association between host factors, Hp strain
      genotype, and the severity of gastric inflammatory response in children. Variation between
      age, race/ethnicity, medical/environmental exposures, socioeconomic status and geographic
      regions and their effects on disease phenotype in children will be investigated. These
      studies will address unanswered questions about the earliest stages in the pathobiology of Hp
      infection that are essential to improve our ability to manage this infection in children, and
      potentially, identify and understand "at risk groups" to prevent more severe disease sequelae
      in adults. Understanding the evolution of the host response to Hp infection is needed to
      develop prevention strategies or new therapies, and allow a better definition of the
      pathobiology of this human pathogen that causes significant morbidity, suffering, and
      economic impact in our society.

      In our 5 years of NIH funding, we enrolled a cohort of 486 children from 3 sites (Atlanta,
      Cleveland, Miami); 184 (38%) were Hp-infected. We made novel observations regarding
      environmental exposures, pilot validation of a symptom assessment instrument, pediatric Hp
      strain genotype/disease phenotype relationships, and disease paradigms not previously
      described in the pediatric population; i.e., atrophic gastritis and intestinal metaplasia
      associated with Hp infection. Overall hypothesis for competitive renewal: gastroduodenal
      disease (e.g., duodenal ulcer) in Hp-infected children is associated with specific host
      factors (i.e., race/ethnicity), environmental exposures, and infection by Hp strains carrying
      specific virulence genes contained within the cag pathogenicity island. These combined
      factors drive either a predominant Th2 gastric mucosal response with antral predominant
      severe mucosal inflammation (i.e., ulcer disease) or a Th1 response resulting in a more
      chronic, corpus-predominant inflammatory infiltrate (i.e., atrophy).

      Specific aims:

      Aim 1: Further characterize specific host factors and environmental exposures contributing to
      symptomatic childhood infection by emphasizing targeted enrollment of patients from multiple
      centers in specific age, gender and demographic strata to facilitate detection of significant
      differences in symptomatic and asymptomatic Hp-infected children not attained previously and
      follow-up of 2 established specific cohorts to ascertain immune response natural history.

      Aim 2: Utilize gene-array technology for whole genome assessment of bacterial virulence genes
      and specific bacterial gene expression to allow characterization of virulence proteins
      associated with pediatric Hp infection. The Hp isolated from the prospectively enrolled
      infected children (cases) in Aim 1, Hp strains obtained in follow-up of the two established
      cohorts who remain infected, as well as a retrospective analysis of 125 banked pediatric
      isolates linked to clinical, demographic and epidemiological data will be characterized.
      Specific emphasis will be on the analysis of isolates found in the following three disease
      categories: ulcers, gastritis, atrophic gastritis.

      Aim 3: Further characterize the gastric mucosal host inflammatory response in Hp-infected
      children.

      The Updated Sydney system will be applied to assess severity of gastric histopathology, and
      immunohistochemistry performed on formalin-fixed, paraffin embedded tissues to phenotype
      mucosal disease (i.e., character, severity) in newly enrolled cases in specific age, gender
      and demographic strata and the two "novel" cohorts established in our previous studies; i)
      atrophic gastritis cohort; ii) esophageal and gastric disease cohort, affording insight into
      the natural history of the immune response in Hp-infected children in two different disease
      paradigms. Both molecular methods and a novel micro ELISPOT performed on PBMCS and gastric
      T-cells to determine Th1, Th2 or balanced Th1/Th2 response will be used to further
      characterize the Hp-infected child's immune phenotype. During the latter 2 years of the
      proposed studies, PBMC chemokine response will then be compared to the mucosal/cellular
      response using RT-PCR and gene array. The data obtained from aims 1 and 3 will be integrated
      with that obtained in aim 2 (Hp-strain genotype) in order to develop a model to predict
      disease outcome based on host demographics, strain type and inflammatory/immune response.
      These studies are critical to understand and better predict the gastroduodenal disease
      sequelae and overall pathobiology of Hp infection in humans.
    

Keywords: gastric disease; H. pylori; children; Helicobacter pylori; child; epidemiology