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.
