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Journal of Pediatric Gastroenterology & Nutrition:
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Research Agenda for Pediatric Gastroenterology, Hepatology and Nutrition: Acid-Peptic Diseases: Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation

Czinn, Steven; Gold, Benjamin D.; Dickinson, Chris J.; Ramakrishna, Jyoti; Orenstein, Susan

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Cleveland

Atlanta

Ann Arbor

Worcester

Pittsburgh

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

Research priorities in acid-peptic diseases encompass clinical studies in children with gastroesophageal reflux disease (GERD) and those with peptic ulcer disease. Gastroesophageal reflux (GER) is the passive retrograde movement of gastric contents into the esophagus above the lower esophageal sphincter (LES). Physiologically, in both children and adults, reflux occurs as a result of transient relaxations of the LES and inhibition of lower esophageal body peristalsis. Reflux is not primarily related, as previously thought, to lower LES pressure. At least one episode of GER occurs daily in two thirds of infants younger than 4 months of age; by 1 year of age, only 5% of infants have daily reflux. It is clear that in addition to more subtle clinical presentations, toddlers will often manifest the classic signs and symptoms of GERD (1). Based on a study by Nelson et al, 7% of children between the ages of 3 and 9 report symptoms such as heartburn, epigastric pain and regurgitation (2). Approximately 35% of adults have heartburn on a regular basis. In a recent study, up to 50% of adults in Canada and the US have self-reported GERD symptoms weekly. In most adults, GERD is a chronic condition that waxes and wanes during their lifetime. Little information is available regarding the relationship between GER that presents during infancy and early childhood and the development of chronic heartburn and esophageal disease, both macroscopic and microscopic, in an adult.

The gold standard for diagnosing and quantitatively assessing the severity of gastroesophageal reflux and GERD in children remains to be determined. Prolonged intraesophageal pH study, performed by placing a pH probe in the distal esophagus, identifies and quantifies acidic gastric fluid within the lumen of the esophagus. This technique determines not only the frequency but also the duration of reflux episodes. Newer approaches, such as impedance techniques, need to be validated in pediatric patients. Ultimately, such studies may provide vital new information to help guide physicians in managing patients with GERD.

Although much progress has been made in understanding GERD in children, many questions remain unanswered. Based on single-center studies of small cohort size, the prevalence of GER in infants under the age of 3 months is estimated to be in excess of 85%. Premature infants, in particular, are susceptible to GER. The overwhelming majority of infants younger than 3 months have physiologic reflux and do not require medical intervention. Approximately 10% have pathologic reflux, with esophageal manifestations (irritability, feeding refusal, arching, crying during feeding) and extraesophageal manifestations (apnea, bradycardia, reactive airways disease/asthma, impaired growth). Additional research is needed to more fully understand the natural history of GERD to enable the identification of children at risk for serious sequelae, including erosive esophagitis, Barrett's esophagus and esophageal carcinoma. Studies also are needed to determine the optimum dosing regimens for currently available acid-suppressive and prokinetic medications.

Peptic ulcer disease affects approximately 4 million people annually, with some estimates as high as 10 million per annum. For much of the past century, it was thought that gastroduodenal ulcers are caused by multiple predisposing factors, the most important being hypersecretion of gastric acid. Based on this paradigm of peptic ulcer disease, mucosal ulceration develops as a result of an imbalance between acid and cytoprotective mechanisms. Factors such as diet, medications toxic to the gastric mucosa and genetic predisposition were also thought to contribute to the development of peptic ulcer disease. Since the discovery of Helicobacter pylori and its relationship to gastritis and peptic ulcers, dramatic changes have occurred in our understanding of the pathobiology, diagnosis and treatment of peptic ulcer disease (3–5).

Since 1983, many studies have confirmed the presence of H pylori in association with antral inflammation. It is now clear that H pylori infection is primarily acquired during childhood. In most children, the infection will persist for most of their lifetime. Ultimately, a subset of H pylori-infected children are at risk for the development of peptic ulcer disease and possibly even gastric cancer in adulthood. However, most individuals infected with H pylori do not experience symptoms or manifest signs of disease and are unaware of the infection over the course of their lives.

The diagnosis of H pylori-associated diseases can be reliably established only through the use of gastroduodenal endoscopy with biopsy. Commercial serologic and other noninvasive tests that are currently available have not been proven sufficiently reliable for use in screening children for the presence of H pylori. Serologic testing is not recommended to diagnose H pylori-associated diseases. Primarily because of a striking paucity of well-controlled studies, eradication therapy is recommended only for infected children with duodenal ulcer, gastric ulcer, gastric lymphoma and atrophic gastritis with intestinal metaplasia. This approach may be too conservative in light of recent data that continue to link gastric carcinoma in adults to the acquisition of H pylori early in childhood. Thus, a number of important study objectives remain.

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AREAS OF EMPHASIS: GERD

Clarify further the pathophysiology of GERD

Refine our understanding of the natural history and epidemiology of GERD to allow for the identification of children predisposed to developing significant GERD as an adult

Identify cost-effective methods for the diagnosis of GERD

Perform studies of upper GI motility and gastric acid physiology and establish correlations with reflux signs and symptoms. Determine whether there is a correlation between endoscopic and histologic evidence of GERD.

Establish clinical correlates for signs and symptoms of GERD

Determine appropriate and efficacious therapies for GERD

Evaluate the role of lifestyle therapies at various ages. Determine optimal dosages of acid-suppressive and prokinetic medications for use in children.

Establish the role of, and appropriate indications for, antireflux surgery

Evaluate long-term outcomes of antireflux surgical procedures.

Determine the relationship in children between H. pylori infection, gastritis and GERD

Determine whether eradication therapy alters the natural history of gastric and esophageal mucosal disease, as well as reflux signs and symptoms.

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Research Goals

The pathophysiology, natural history and management of GERD in children have not been well studied (6). Investigations focusing on upper GI tract motility and gastric acid secretion will enhance our understanding of pediatric GERD. Longitudinal and cross-sectional studies are needed to determine which children with physiologic reflux go on to develop significant sequelae as teenagers and adults. Clinical trials are needed to determine pediatric dosing requirements for antacids, histamine-2 (H2) receptor antagonists and proton pump inhibitors for the successful resolution of GER symptoms and disease. Objective criteria need to be established for when to recommend an antireflux surgical procedure in children. Finally, it is critical to determine if H pylori eradication in children influences the signs and symptoms as well as natural history of GERD.

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Research Strategies

To address these critical questions, a number of methodologies must first be developed and validated for use in children. These include a) a method for localization of the LES; b) standardization of diagnostic testing, using either noninvasive methods, 24-hour pH studies or endoscopy with biopsy; and c) an instrument to assess the severity of GERD symptoms. All these methodologies are to have reproducible results. The symptom severity instrument should assess signs and symptoms related to a) regurgitation or vomiting and b) pain, as well as include endoscopic and histologic findings. As part of this methodology, subjective assessments may be correlated to results of a validated 24-hour pH probe analysis.

A multicenter collaborative approach would be most appropriate for ensuring that thorough longitudinal and cross-sectional studies are performed. Family cohort studies and population-based epidemiologic studies may also be useful in answering the above questions.

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Projected Timetable and Funding Requirements

These studies may be funded by industry; the National Institutes of Health (NIH), in particular the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), National Institute of Child Health and Human Development (NICHD), and National Institute of Allergy and Infectious Diseases (NIAID); and private foundations. Partnerships with companies currently marketing H2-receptor antagonists, proton pump inhibitors and prokinetic agents are to be considered.

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AREAS OF EMPHASIS: H pylori

Determine whether H pylori eradication is effective in resolving upper gastrointestinal (GI) symptoms (e.g., chronic or recurrent abdominal pain) in infected children

Determine the relationship between H pylori infection and esophageal disease

Identify specific patient groups at increased risk for infection and serious sequelae

Determine the mode of transmission of H pylori

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Research Goals

Well-controlled studies can expand the therapeutic options for a number of prevalent pediatric conditions, including upper GI symptoms (e.g., chronic or recurrent abdominal pain), extragastrointestinal manifestations (e.g., short stature, growth disturbances, co-infection by other enteric microorganisms such as Salmonella) and esophageal symptoms.

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Research Strategies

Multicenter, randomized, placebo-controlled trials are recommended for the first two questions. The treatment trial in abdominal pain will evaluate infected children with gastritis and abdominal pain with or without associated peptic ulceration. Follow-up is to include both endoscopy and urea breath testing at 3 months and breath testing at 1 year.

To study the role of H pylori infection in esophageal disorders, the recommended protocol will enroll children with gastric and esophageal disease and compare them with children having only gastric disease. Initial follow-up is to include endoscopy and urea breath testing at 3 months. Subsequent follow-up with breath testing at 1 and 2 years in conjunction with esophagogastroduodenoscopy will assess the development or resolution of esophageal disease.

The question of transmission may be studied by means of a family cohort protocol utilizing an infected child as the index case and then evaluating immediate family members. A randomized controlled trial could then be initiated with treatment of family cohorts and just index cases and then reinfection rates evaluated by urea breath testing. It is recommended that the study involve multiple centers in different countries, thereby enhancing catchment of populations with different prevalence rates for H pylori infection.

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Projected Timetable and Funding Requirements

As with investigations in GERD, these studies may be funded by industry, the NIH (in particular, NIDDK, NICHD and NIAID), and private foundations. Partnerships with companies currently marketing H2-receptor antagonists, proton pump inhibitors and prokinetic agents are to be considered.

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HEALTH AND ECONOMIC OUTCOMES

The economic consequences of acid-related disorders in infants and children have not been well studied. While health care costs for adult patients with acid-related disorders cannot be extrapolated to children, the adult experience nevertheless provides a framework for assessment. In adults with GERD, a prospective study reported that open antireflux surgery accounted for >90% of direct medical costs (7). In this 1998 cost analysis from Scandinavia, direct medical costs represented 53% of the total cost, with loss of productivity and other indirect costs accounting for the remainder. In a retrospective analysis of 1,550 adults enrolled in a US managed care organization, health care costs associated with peptic ulcer disease were reported to be higher than costs for GERD, with inpatient charges representing a significant cost factor (8).

In the pediatric population, uncomplicated GER is associated with a benign course and favorable prognosis. However, GER in infants may lead to apparent life-threatening events (ALTE), and there is a high association with apnea, feeding intolerance and chronic respiratory disorders. Indeed, pediatric GERD exerts a significant impact on health care in Canada and the US, and fully 10% of all pediatric hospital admissions are related to GERD. US hospital data for 1997 estimated that 77,560 patients aged 17 years or younger were discharged with a diagnosis of esophageal reflux (representing 22% of all discharges for esophageal reflux), after a mean hospital stay of 3.9 to 5.7 days and accumulating a mean charge of $7,032 to $13,507 per person (9).

In the same US survey, a total of 51,871 patients aged 1 to 17 years were discharged in 1997 for gastroduodenal ulcer (except hemorrhage) (9). In that year, pediatric patients accounted for only 1% of all hospital discharges for gastroduodenal ulcer (except hemorrhage). However, when hospitalization was required, the mean hospital stay was 6.3 days and mean charges totaled $15,899 per person.

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REFERENCES

1. Nelson SP, Chen EH, Syniar GM, et al. Prevalence of symptoms of gastroesophageal reflux during infancy: a pediatric practice-based survey. Arch Pediatr Adolesc Med 1997; 151:569–72.

2. Nelson SP, Chen EH, Syniar GM, et al. Prevalence of symptoms of gastroesophageal reflux during childhood: a pediatric practice-based survey. Arch Pediatr Adolesc Med 2000; 154:150–4.

3. Drumm B, Koletzko S, Oderda G. Helicobacter pylori infection in children: a consensus statement. J Pediatr Gastroenterol Nutr 2000; 30:207–13.

4. Sherman P, Hassall E, Hunt RH, Fallone CA, Veldhuyzen van Zanten S, Thomson AB. Canadian Helicobacter study group consensus conference on the approach to Helicobacter pylori infection in children and adolescents. Can J Gastroenterol 1999; 13:553–9.

5. Gold BD, Colletti RB, Abbott M, et al. Helicobacter pylori infection in children: recommendations for diagnosis and treatment. J Pediatr Gastroenterol Nutr 2000; 31:490–7.

6. Rudolph C, Mazur LJ, Liptak GS, Baker R, Boyle JT, Colletti RB, Gerson W, Werlin S. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2001; 32:S1–31.

7. Lundell L, Dalenback J, Janatuinen E, Hattlebakk J, Levander K, Miettinen P, Myrvold HE, Pedersen SA, Thor K, Andersson A, Stalhammar NO. Comprehensive 1-year cost analysis of open antireflux surgery in Nordic countries: Nordic GORD study group, gastro-oesophageal reflux disease. Br J Surg 1998; 85:1002–5.

8. Levin TR, Schmittdiel JA, Kunz K, Henning JM, Henke CJ, Colby CJ, Selby JV. Costs of acid-related disorders to a health maintenance organization. Am J Med 1997; 103:520–8.

9. HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD. http://ww.ahrq.gov/data/hcup/hcupnet.htm.

© 2002 Lippincott Williams & Wilkins, Inc.

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