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Research Agenda for Pediatric Gastroenterology, Hepatology and Nutrition: Secretion and Diarrhea: Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation

Lencer, Wayne I.; Barrett, Kim; Colgan, Sean; Cohen, Mitchell B.; Duggan, Christopher P.; Kotelchuck, Milton; Rhoads, J. Marc

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Boston

San Diego

Boston

Cincinnati

Boston

Boston

Chapel Hill

Address requests for reprints to: Executive Director, Children's Digestive Health and Nutrition Foundation, PO Box 6, Flourtown, PA, 19031, U.S.A. (e-mail: NASPGHAN@naspghan.org).

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RATIONALE

The intestine has four fundamental functions: digestion and absorption of nutrients; vectorial transport of water and solutes; barrier function; and host defense. Failure of any one function typically leads to diarrhea. Diarrheal diseases, which are among the most common pediatric disorders, carry the potential for significant morbidity: children with recurrent disease fail to grow, and parents caring for sick children have diminished economic productivity. In children younger than 5 years of age, diarrhea remains a leading cause of death, accounting for nearly 3 million to 5 million deaths each year. This represents the single greatest worldwide cause of loss of human potential due to disease in the pediatric or adult population. A focus on basic, clinical and epidemiologic research is needed to broaden our understanding of diarrheal diseases.

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AREAS OF EMPHASIS: Basic Research

Basic research goals focus on the intestinal epithelial cell and its relation to cellular and noncellular components in the intestinal lumen and subepithelial space. In all transporting organs, such as the intestine, lung and kidney, the epithelial-layer cell defines and maintains a selective barrier separating two physically distinct compartments. The capacity to transport essential solutes, water and cells (such as neutrophils, certain microbes and perhaps macrophages) between these compartments is essential for normal physiologic function of the intestine. Thus, in nearly all instances, the cellular and molecular biology of the polarized epithelium, and its dynamic relationship with the mucosal environment, defines ultimately the physiology and pathophysiology of the intestine.

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Study Membrane and Epithelial-Cell Biology of Salt and Water Transport, Epithelial Barrier Function, Epithelial Polarity, and Regulation of Membrane Structure and Function
Research Goals

Such studies should elucidate down-regulatory mechanisms for apical membrane Cl channels and basolateral K channels; the biology of apical membrane Ca++-dependent Cl channels; mechanisms of membrane organization that dictate specificity in signal transduction; and the biology of intestinal crypt cell-cell, cell-matrix and cell-microbe interactions. In addition, mechanisms that couple solute transport with regulation of the intercellular tight junctions, and novel mechanisms of Na-coupled or HCO3-coupled solute transport (i.e., potential transporters that may be harnessed for oral rehydration therapies) should be studied.

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Research Strategies

In our view, the single most important strategy is to increase the number of people engaged in research on diarrheal diseases and to improve access to, and the quality of, the career path these people will follow. It is hoped that funds can be made available to investigators proposing well-founded and hypothesis-driven basic research. The funding of investigators in the early stages of their career path should be considered a priority.

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Study Mechanisms and Regulation of Signal Transduction Between and Within Cells and Noncellular Components of the Intestinal Mucosa
Research Goals

Studies should define the interactions between microbes, epithelial cells and subepithelial cells. Examples of such interactions are the mechanisms and regulation of microbial pathogenesis; inflammatory diarrhea; mucosal immunology; and the sequelae of infection, including hemolytic uremic syndrome, arthropathy and Guillain-Barre syndrome. In addition, interactions between central or enteric nerves and epithelial cells should be defined. Other objectives of these studies include elucidation of the cross-talk between epithelial cells, the extracellular matrix, rnesenchymal cells and subepithelial immune-competent cells. Finally, cytokine and chemokine actions in the intestinal mucosa should be identified.

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Research Strategies

Research strategies are as stated above. The single most important strategy is to increase the number of people engaged in research on diarrheal diseases and to improve access to, and the quality of, the career path these people will follow. It is hoped that funds can be made available to investigators proposing well-founded and hypothesis-driven basic research. The funding of investigators in the early stages of their career path should be considered a priority.

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Study Mechanisms and Regulation of Macromolecular Transepithelial Transport
Research Goals

An understanding of macromolecular transepithelial antigen transport is important for the development of mucosal vaccines. Knowledge of immunoglobulin transport is helpful in achieving an understanding of host defense mechanisms.

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Study Mechanisms of Epithelial Differentiation, Proliferation, Restitution and Repair
Research Goals

Studies should define the determinants, maintenance and development of the crypt/villus axis. What factors regulate and account for the developmental programs of each major cell lineage? A second research goal is an understanding of the regulation of epithelial restitution after infections and ischemic and toxic injuries. Finally, mechanisms of epithelial adaptation should be studied: how epithelial cells respond to hypoxia, nutrient deficiency or excess, and an altered microbial flora.

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Delineate the Developmental Biology of the Gastrointestinal (GI) Tract
Research Goals

Studies should search for epithelial stem cells and define the influence of gut flora.

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Study the Pathophysiology of Specific Disease States
Research Goals

Studies should characterize the molecular and cellular pathophysiology of congenital diarrheal diseases, including microvillus inclusion disease and tufting enteropathy; autoimmune enteropathy; and congenital transport defects. In cystic fibrosis patients, intestinal consequences should be studied, including effects on the epithelium of secretory defects, malabsorption and pancreatitis. Additionally, the pathophysiology of meconium ileus should be investigated, as well as approaches for overcoming the secretory defect. Finally, the molecular and cellular pathophysiology of intestinal allergy should be characterized.

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Focus on Vaccine Development
Research Goals

Studies should characterize vaccines against infections by rotavirus, Vibrio cholerae, Salmonella, Shigella,Campylobacter, pathogenic strains of Escherichia coli, parasites and human immunodeficiency virus (HIV). Research goals include orally administered vaccines that target other mucosal surfaces, such as the respiratory and genitourinary tracts.

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AREAS OF EMPHASIS: Clinical Research

Evaluate Promising New Technologies and Medications
Research Goals

Emerging modalities with high therapeutic potential include prebiotics, probiotics and small and macromolecules exhibiting potent antidiarrheal or anti-inflammatory activity. The treatment of E. coli O157:H7 colitis and prevention of the hemolytic uremic syndrome are high priority. Novel nutritional or hormonal therapies for the short-gut syndrome should be targeted.

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Research Strategies

Multicenter networks need to be developed well as for information-sharing.

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Conduct Outcomes Research on Existing Technologies
Research Goals

Outcome research should evaluate access to, and use of, available health services in the management of acute and chronic diarrheas. The impact of managed care is an important research goal. In addition, studies should determine the value of available therapeutic approaches, such as improved oral rehydration solutions and non-antimicrobial therapy for diarrheal disease. Finally, cost-effectiveness studies to be considered in specific diseases include the treatment of diarrhea in patients with HIV infection and nutritional management of necrotizing enterocolitis.

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Research Strategies

Multicenter networks need to be developed to ensure adequate pediatric study populations as well as for information-sharing.

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AREAS OF EMPHASIS: Epidemiologic Research

Epidemiologic research goals focus on disease surveillance and assessment of the health and economic impact of existing technologies and delivery systems.

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Measure the Distribution of Disease (Surveillance) to Detect Emerging Pathologies and Determine the Economic Burden of Diarrheal Diseases on Children and Their Families
Research Goals

These studies provide surveillance of diseases not addressed by the Centers for Disease Control and Prevention (CDC), which cover infectious diseases only if they are “reportable.”

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Projected Timetable and Funding Requirements

Studies are ongoing.

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HEALTH AND ECONOMIC OUTCOMES

Diarrheal disease is a major cause of morbidity, with incidence rates ranging from 2 to 12 or more illnesses per person per year in developed and developing countries. GI and nutritional diseases are among the most common causes of death worldwide, causing an estimated 3 million to 5 million deaths each year. Most of these fatalities occur in children younger than 5 years of age (1). An estimated 12,600 children die each day in Africa, Asia and Latin America due to diarrheal diseases (2).

In the US and other industrialized countries, deaths from GI diseases are less common, but the morbidity associated with both acute and chronic intestinal diseases remains substantial. All children are infected with rotavirus during the first few years of life. Rotavirus infections account for 30% to 50% of hospitalizations for diarrhea in children younger than 5 years of age and for 40% to 77% of hospitalizations in those aged 5 years and older in Europe and the US (3). Each year, rotavirus infections result in more than 3 million cases of diarrhea, 400,000 outpatient visits, 160,000 emergency department visits, 50,000 to 70,000 hospitalizations, and 120 to 200 deaths (4,5). Rotavirus admissions at one referral hospital were associated with outlays of $1.5 million annually (6) and $289 per rotavirus episode for outpatient management. More than half of this expense was due to lost productivity of the parents of sick children. Altogether, the annual cost of rotavirus infections in the US alone has been estimated at $352 million for inpatient care (not including lost productivity at work) (6) and up to $1.08 billion for outpatient care (7).

The economic impact of diarrhea due to other intestinal infections is less well documented. One analysis based on community surveys and national interviews placed the annual incidence of acute diarrhea at almost 100 million episodes, with 50% leading to at least one day of restricted activity or missed work (8). Associated medical costs were estimated at $1.25 billion, with an additional $19 billion in lost productivity at the workplace (8). Food-borne infections also exert a significant impact on heath care expenditures. The total cost for an outbreak of hepatitis A has been projected at more than $800,000 (9). Direct medical expenditures during food-borne epidemics are often dwarfed by the additional cost to society of disease prevention efforts, public health responses, insurance and legal expenses.

With respect to chronic diarrheal diseases, the lifetime cost of medical care for a person with Crohn's disease was estimated recently at $39,000 to $125,000 (10). Total direct and indirect costs for all patients in the US with inflammatory bowel disease (IBD) may reach $2 billion dollars annually (11), with nearly 10% to 25% of adults with IBD unable to work full time.

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CONCLUSIONS

Of the recommendations in basic research, selected priorities include studies of a) microbe-epithelial-subepithelial interactions; b) the mechanism and regulation of vectorial solute transport and barrier function, including epithelial restitution after injury; and c) the pathobiology of, and potential therapies for, disease caused by E. coli O157:H7.

Of the clinical research recommendations, selected priorities include a) clinical trials of probiotic therapies and other antidiarrheal or anti-inflammatory agents, and b) vaccine development for enteric pathogens.

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REFERENCES

1. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: global burden of disease study. Lancet 1997; 349:1269–76.

2. Guerrant RL, Hughes JM, Lima NL, Crane J. Diarrhea in developed and developing countries: magnitude, specific settings, and etiologies. Rev Infect Dis 1990; 12(suppl 1):S41–50.

3. Glass RI, Bresee JS, Parashar UD, Holman RC, Gentsch JR. First rotavirus vaccine licensed: is there really a need? Acta Paediatr Suppl 1999; 88:2–8.

4. Glass RI, Lew JF, Gangarosa RE, LeBaron CW, Ho MS. Estimates of morbidity and mortality rates for diarrheal diseases in American children. J Pediatr 1991; 118(4pt2):S27–33.

5. Tucker AW, Haddix AC, Bresee JS, Holman RC, Parashar UD, Glass RI. Cost-effectiveness analysis of a rotavirus immunization program for the United States. JAMA 1998; 279:1371–6.

6. Matson DO, Estes MK. Impact of rotavirus infection at a large pediatric hospital. J Infect Dis 1990; 162:598–604.

7. Avendano P, Matson DO, Long J, Whitney S, Matson CC, Pickering LK. Costs associated with office visits for diarrhea in infants and toddlers. Pediatr Infect Dis J 1993; 12:897–902.

8. Garthright WE, Archer DL, Kvenberg JE. Estimates of incidence and costs of intestinal infectious diseases in the United States. Public Health Rep 1988; 103:107–15.

9. Dalton CB, Haddix A, Hoffman RE, Mast EE. The cost of a food-borne outbreak of hepatitis A in Denver, Colo. Arch Intern Med 1996; 156:1013–6.

10. Silverstein MD, Loftus EV, Sandborn WJ, et al. Clinical course and costs of care for Crohn's disease: Markov model analysis of a population-based cohort. Gastroenterology 1999; 117:49–57.

11. Ward FM, Bodger K, Daly MJ, Heatley RV. Clinical economics review: medical management of inflammatory bowel disease. Aliment Pharmacol Ther 1999; 13:15–25.

© 2002 Lippincott Williams & Wilkins, Inc.

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