Ignite Creation Date:
2024-05-05 @ 12:01 PM
Last Modification Date:
2024-10-26 @ 9:18 AM
Study NCT ID:
NCT00212225
Status:
COMPLETED
Last Update Posted:
2010-01-13
First Post:
2005-09-20
Brief Title:
Risk Factors for Gastric Disease in Pediatric Helicobacter Pylori H Pylori
Sponsor:
National Institute of Diabetes and Digestive and Kidney Diseases NIDDK
Organization:
National Institute of Diabetes and Digestive and Kidney Diseases NIDDK
Study Overview
Official Title:
Risk Factors for Gastric Disease in Pediatric H Pylori
Status:
COMPLETED
Status Verified Date:
2010-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 andor 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 ie 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 Th1Th2 response will be determined to further characterize the Hp-infected childs 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
Overall hypothesis for competitive renewal disease manifestations in Hp-infected children are influenced by specific host factors ie 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 Th1Th2 response will be determined to further characterize the Hp-infected childs 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 eg 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 raceethnicity medicalenvironmental 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 genotypedisease phenotype relationships and disease paradigms not previously described in the pediatric population ie atrophic gastritis and intestinal metaplasia associated with Hp infection Overall hypothesis for competitive renewal gastroduodenal disease eg duodenal ulcer in Hp-infected children is associated with specific host factors ie raceethnicity 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 ie ulcer disease or a Th1 response resulting in a more chronic corpus-predominant inflammatory infiltrate ie 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 ie 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 Th1Th2 response will be used to further characterize the Hp-infected childs immune phenotype During the latter 2 years of the proposed studies PBMC chemokine response will then be compared to the mucosalcellular 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 inflammatoryimmune response These studies are critical to understand and better predict the gastroduodenal disease sequelae and overall pathobiology of Hp infection in humans
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 genotypedisease phenotype relationships and disease paradigms not previously described in the pediatric population ie atrophic gastritis and intestinal metaplasia associated with Hp infection Overall hypothesis for competitive renewal gastroduodenal disease eg duodenal ulcer in Hp-infected children is associated with specific host factors ie raceethnicity 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 ie ulcer disease or a Th1 response resulting in a more chronic corpus-predominant inflammatory infiltrate ie 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 ie 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 Th1Th2 response will be used to further characterize the Hp-infected childs immune phenotype During the latter 2 years of the proposed studies PBMC chemokine response will then be compared to the mucosalcellular 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 inflammatoryimmune response These studies are critical to understand and better predict the gastroduodenal disease sequelae and overall pathobiology of Hp infection in humans
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None