Peptic Ulcer Clinical Trial
Official title:
Risk Factors for Gastric Disease in Pediatric H. Pylori
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.
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.
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