Journal of Pediatric Gastroenterology and Nutrition 31:490497 November 2000 Lippincott Williams & Wilkins, Inc.

, Philadelphia

Medical Position Statement: The North American Society for Pediatric Gastroenterology and Nutrition

Helicobacter pylori Infection in Children: Recommendations for Diagnosis and Treatment

*Benjamin D. Gold, Richard B. Colletti, Myles Abbott, Steven J. Czinn, Yoram Elitsur, Eric Hassall, #Colin Macarthur, **John Snyder, and Philip M. Sherman
Division of *Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; Pediatric Gastroenterology, University of Vermont, Fletcher Allen Health Center, Burlington, Vermont; Berkeley California; Pediatric Gastroenterology, Rainbow Babies and Childrens Hospital, Cleveland, Ohio; Division of Gastroenterology, Marshall University School of Medicine, Huntington, West Virginia; Division of Gastroenterology, BC Childrens Hospital, Vancouver, British Columbia, Canada; Divisions of #General Pediatrics and Gastroenterology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada; and **Pediatric Gastroenterology, University of California San Francisco, San Francisco, California, U.S.A.

Helicobacter pylori infects at least 50% of the worlds human population (1). However, most individuals infected with H. pylori do not experience symptoms or have signs of recognizable disease. In most children, the presence of H. pylori infection does not lead to clinically apparent disease, even when the organism colonizing the gastric mucosa causes chronic active gastritis (2). Knowledge about H. pylori infection is evolving, particularly in the pediatric age group for which there are still large gaps in knowledge. Additional multicenter, randomized, placebocontrolled treatment trials in children infected by H. pylori are critically needed to definitively characterize the effect of H. pylori eradication treatment during childhood on symptoms and gastroduodenal mucosal disease. There is compelling evidence that this organism is associated with a significant proportion of duodenal ulcers and, to a lesser extent, with gastric ulcers in children (3). There are epidemiologic data linking chronic H. pylori infection, probably beginning in childhood, with the development of gastric adenocarcinoma and gastric lymphoma (4). Findings in recently reported animal models support the role of H. pylori in the pathogenesis of gastric cancers (5). There are many studies describing the prevalence of H. pylori infection. Most epidemiologic studies of H. pylori infection have been performed in adults who had
Received and accepted September 8, 2000. Address correspondence and reprint requests to Dr. Benjamin Gold, Emory University School of Medicine, 2040 Ridgewood Drive, NE, Atlanta, GA 30322, U.S.A.; or to Dr. Richard B. Colletti, University of Vermont, Department of Pediatrics, A-121 Given Medical Building, Burlington, VT 05405-5557, U.S.A.

been infected for many years before clinical symptoms appeared (6). The incidence of H. pylori infection in industrialized countries is estimated to be approximately 0.5% of the susceptible population per year. In contrast, there is a significantly higher estimated incidence of H. pylori infection in developing countries of approximately 3% to 10% per year (7). The limited data on the incidence of H. pylori infection in children consist largely of retrospective seroprevalence studies. Humans appear to be the primary natural reservoir of H. pylori infection. Other reservoirs that have been proposed include water, domestic cats, and houseflies (8 10). The risk factors described for acquiring infection include residence in a developing country, poor socioeconomic conditions, family overcrowding, and possibly an ethnic or genetic predisposition. In North America, the prevalence rates of H. pylori among Asian-Americans, African-Americans and Hispanics are similar to those of residents of developing countries (11). The route of transmission of H. pylori in humans is not known but is postulated to be fecal-oral, gastric-oral (in vomitus), or oral-oral (12). Although H. pylori infection may be acquired during childhood, there are limited guidelines regarding its diagnosis and treatment in children and adolescents. Such evidence-based consensus guidelines are needed for both primary care and specialty medical providers to ensure judicious use of diagnostic testing and appropriate therapeutic regimens for the management of children with H. pylori infection. Therefore, the North American Society for Pediatric Gastroenterology and Nutrition (NASPGN) appointed the Helicobacter pylori Infection Guideline Committee to develop a clinical practice guideline for the child with H. pylori infection. 490

TREATMENT RECOMMENDATIONS FOR HELICOBACTER INFECTION These clinical practice guidelines are designed to assist primary care physicians, nurse practitioners, physician assistants, and pediatric gastroenterologists in the evaluation and treatment of suspected or diagnosed H. pyloriassociated disease. The desired outcomes of these recommendations are the detection of children and adolescents with H. pylori who need treatment. These recommendations are applicable to children in developed countries where the prevalence of infection is low but may not be directly relevant to children living in communities where there is a higher frequency of gastric colonization by H. pylori. These recommendations have been endorsed by the Executive Council of NASPGN and by the American Academy of Pediatrics. They are general guidelines to assist medical care providers in the diagnosis and treatment of H. pylori infection in children. They are not intended as a substitute for clinical judgment or as a protocol for the management of all patients. In its deliberations, the committee addressed four issues about H. pylori infection in children: How reliable are tests to detect H. pylori? When is testing for H. pylori indicated? When is treatment of H. pylori infection indicated? What is the preferred treatment of H. pylori? A summary of the recommendations of the H. pylori Infection Guideline Committee is presented in Table 1. METHODS
The H. pylori Infection Guideline Committee consisted of a primary care pediatrician, a clinical epidemiologist, and seven pediatric gastroenterologists. To develop evidence-based guidelines, articles published in English from January 1966 through May 1999 on H. pylori in children were searched. Articles on diagnosis and treatment were sought separately. Letters, editorials, case reports, abstracts, and reviews were excluded. Evidence tables were prepared based on 16 articles on clinical presentation, 9 articles on diagnostic studies, and 30 articles on therapy. Subsequently, additional articles were identified and reviewed. When the pediatric literature was insufficient, the adult literature was also considered. Articles were evaluated using published criteria (13). The Committee based its recommendations on an integration of a review of the medical literature and expert opinion. Consensus was achieved by using the nominal group technique, a structured quantitative method, as described previously (14,15). By using the methods of the Canadian Preventive Services Task Force (16), the quality of evidence of each of the recommendations made by the committee was determined and is summarized (Table 1).

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TABLE 1. Summary of recommendations and the quality of the supporting evidence

Recommendations Quality of evidencea

How reliable are tests for H. pylori infection? Currently, the diagnosis of H. pylori-mediated disease can be made reliably only through the use of endoscopy with biopsy. II, III Presently available commercial serologic tests are frequently unreliable for screening children for the presence of H. pylori infection. II Urea breath testing, although promising, has not been studied sufficiently in children. II When is testing indicated? It is recommended that testing be performed in children with endoscopically diagnosed, or radiographically definitive, duodenal or gastric ulcers. I It is recommended that children with recurrent abdominal pain, in the absence of documented ulcer disease, not be tested for H. pylori infection. II Testing for H. pylori infection is not recommended in asymptomatic children. II Routine screening of children with a family history of gastric cancer or recurrent peptic ulcer disease is not recommended. II Testing following treatment of documented H. pylori is recommended, especially with complicated peptic ulcer disease (i.e., bleeding, perforation, or obstruction). For patients who remain symptomatic after treatment, it is recommended that endoscopy and biopsy be performed to evaluate for the persistence of H. pylori-associated peptic ulcer disease. I, II If pathological evidence of MALT lymphoma is documented, then testing for H. pylori is recommended. II When is treatment of H. pylori infection indicated? Eradication treatment is recommended for children who have a duodenal ulcer or gastric ulcer identified at endoscopy and H. pylori detected on histology. I A prior history of documented duodenal or gastric ulcer disease is an indication for treatment if active H. pylori infection is documented. I There is no compelling evidence for treating children with H. pylori infection and non-ulcer dyspepsia or functional recurrent abdominal pain. III Treatment is not recommended for H. pylori-infected children residing in chronic care facilities; children with unexplained short stature; or children at increased risk for acquisition of infection, including asymptomatic children who have a family member with either peptic ulcer disease or gastric cancer. III What is the preferred treatment of H. pylori infections in children? It is recommended that treatment consist of three or four medications, given once or twice daily, for one to two weeks. I
a Categories of the quallity of evidence: I Evidence obtained from at least one properly designed randomized controlled study. II-1 Evidence obtained from well-designed cohort or case-controlled trials without randomization. II-2 Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group. II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence. III Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

HOW RELIABLE ARE TESTS FOR H. PYLORI INFECTION? Several invasive and noninvasive tests are available to detect H. pylori infection (Table 2). An ideal test for H. pylori is noninvasive or minimally invasive, highly accurate, inexpensive, and readily available and enables differentiation between active or past infection with the

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TABLE 2. Tests for Helicobacter pylori and Helicobacter-related disorders
Invasive tests requiring endoscopy Biopsies and histology Rapid urease testing Bacterial culture Polymerase chain reaction of bacterial DNA Non-invasive tests Serum and whole blood antibody Saliva antibody Urine antibody Stool antigen Urea breath testing

GOLD ET AL. study. The optimal staining of biopsy sections is best determined by local expert pathologists. Endoscopic examination of and specimens obtained in the esophagus, stomach, and duodenum also provide information about other upper gastrointestinal disorders that may be the cause of clinical symptoms including, for example, esophagitis and peptic ulcer disease that is not due to H. pylori. There are drawbacks to diagnostic gastrointestinal endoscopy. It is a relatively invasive procedure requiring sedation or anesthesia. Furthermore, the test remains relatively expensive in many centers, and access to an endoscopist with specific pediatric expertise is limited in many geographic areas. Rapid Urease Testing of Biopsy Tissues Urease testing (CLO, TriMed, Kansas City, MO; HpFast, GI Supply, Division of ChekMed Systems Inc., Camphill, PA; PyloriTek, Horizons International, Aguadilla, Puerto Rico) provides indirect identification of H. pylori infection within a few hours of endoscopy (20). However, these tests have a poor positive predictive value (as low as 50%) in children, even though the negative predictive value is high (9798%) (20,21). The accuracy of the test is dependent on the number of tissue specimens tested, the location of biopsy sites, bacterial load, and previous usage of antibiotics and proton pump inhibitors, as well as the prevalence of H. pylori in the population tested. Bacterial Culture Culture of H. pylori from the gastric mucosa provides an opportunity to obtain a profile of antibiotic sensitivity that could identify potential treatment failure due to antibiotic resistance (22). Culture also provides a bacterial strain for use in epidemiologic studies to examine associations of virulence characteristics with disease outcome. However, bacterial culture for H. pylori is relatively expensive and success rates for recovery of the organism in many clinical laboratories are low (23). Currently, standardization of culture procedures has not been established, and bacterial cultures are only obtained routinely in research settings. Polymerase Chain Reaction Polymerase chain reaction (PCR) is a highly sensitive technique that can be used to detect the presence of H. pylori in body fluids (e.g., gastric juice and stool), tissues (e.g., gastric mucosa), and water (24). Testing of H. pylori genomic DNA by PCR can be used to advance knowledge at the molecular levelfor example, by providing information about point mutations conferring resistance to antibiotics and about putative bacterial virulence factors. However, PCR is expensive, the assay

organism. In addition, such a test enables discrimination between the presence of H. pylori infection and H. pyloriassociated disease. Because no such ideal test currently exists, the advantages and drawbacks of tests that are available require critical appraisal and must be assessed for their suitability for use in children. Failure to reach an accurate diagnosis carries considerable financial and social costs including the expense of more tests, repeated visits to health care providers, inappropriate treatment, and missed school or work. A definitive test, even if it is expensive, may result in overall cost savings (17). It is important to emphasize that the accuracy of a diagnostic test is greatly impacted by the prevalence of H. pylori in the population tested. There is a need for studies to assess the accuracy and potential utility of various noninvasive diagnostic tests in populations in North America that differ in demographic factors that may influence the prevalence and natural history of H. pylori infection (18). Invasive Testing Through Endoscopy Biopsies and Histopathology The definitive diagnosis of H. pylori and the evidence of the consequences of infection can be made reliably only by endoscopy with multiple biopsy specimens obtained in one or more regions of the stomach including antrum, body, and transition zones (i.e., cardia and incisura). Histology provides information regarding the presence of H. pylori and the severity and topographic distribution of gastritis including the presence of atrophic gastritis, intestinal metaplasia, and mucosa-associated lymphoid tissue (MALT) lymphoma (3). As in adults, biopsy specimens obtained in the prepyloric antrum have the highest yield in H. pylori infection. Tissue specimens often are also obtained from the body and the transition zones of the stomach, particularly if the patient has recently taken acid-suppressing medication (19). It is recommended that multiple biopsies be performed in children with endoscopically documented peptic ulcer disease or peptic ulcer suspected as a result of radiographic
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TREATMENT RECOMMENDATIONS FOR HELICOBACTER INFECTION is difficult to set up, specificity may be compromised by inadvertent contamination, and it is not widely available outside the research laboratory. Noninvasive Testing Immunoassay Tests to Detect H. pylori Antibodies Enzyme-linked immunosorbent assays (ELISAs) to detect H. pylori antibodies are relatively inexpensive and easy to implement in the clinical setting. Many tests are available for use to test whole blood, plasma, or serum. However, compared with histology, the sensitivity and specificity of serologic assays are poor in both adults and children unless used in the populations in which they were initially developed (25). In general, the accuracy of serum-based immunoassays and whole-blood tests for use in the physicians office in symptomatic children in developed countries is poor, with a range of sensitivity of only 60% to 70% (2628). Furthermore, age-related cutoff values for commercial immunologic tests have not been established for children. One immunoassay developed in a research center to detect H. pylorispecific immunoglobulin (Ig)G in children was 91% sensitive compared with sensitivity of less than 70% in three commercially available assays (28). In areas with low prevalence of H. pylori infection, such as in developed countries, testing of serum and whole blood is not sufficiently accurate to diagnose H. pylori infection in children. Accordingly, treatment regimens based on the results of these tests cannot be recommended. Serologic tests may not be used reliably to verify eradication of H. pylori, because antibody titers can remain positive for months, despite resolution of infection. Saliva and Urine Tests for H. pylori Antibodies Similar to serologic tests, saliva-based tests also detect the presence of H. pylorispecific IgG antibodies. The tests are easy to perform, painless, and inexpensive. Saliva tests are less sensitive than assays of serum or whole blood (29). The protein concentration of saliva appears to affect the accuracy of test results. Urine-based assays are easy to perform, require minimal labor for collection, and are painless (30). However, these assays are highly variable and are not yet commercially available. Therefore, saliva and urine assays for the detection of H. pylori antibodies cannot be recommended. Stool Test for H. pylori Antigens Testing of H. pylori antigens in stools has shown promising results in adults for the noninvasive diagnosis of gastric infection using a commercially available kit (31). Testing for H. pylori antigens in feces also appears to be accurate for use in monitoring the success of eradi-

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cation therapy. However, patients may be reluctant to collect stool specimens. In addition, refrigerated stools are more difficult to test. Additional pediatric studies evaluating the accuracy of stool antigen testing for both initial diagnosis and posttreatment follow-up are required before specific recommendations can be considered (32). Urea Breath Testing Urea breath tests are noninvasive and have high sensitivity and specificity (>95%) both in adults (33) and children (34,35). The test requires the ingestion of either radiolabeled 14C-urea or urea tagged with the stable isotope 13C. Test results may be influenced by concurrent use of antibiotics and acid-suppressing medications and by the presence of other urease-producing organisms present in the oral cavity. Test parameters are currently laboratory-specific (e.g., dosages for differing ages of children, cutoff values, duration of fasting, use of a test meal, times of sampling, and timing of posttherapy testing) and have not been well standardized for children (36). In addition, urea breath testing is technically more difficult to perform in small children and infants, with failure rates in collection up to 10%, especially outside the clinical research setting (34). In summary, the diagnosis of H. pyloriassociated diseases currently can be made reliably only by endoscopy with biopsies. The most commonly used noninvasive test to screen adults for H. pylori infection is serology. Unfortunately, currently available commercial serologic tests are frequently unreliable for screening children for the presence of H. pylori infection. Current whole-blood, saliva, and urinary immunoassays are insufficiently sensitive or specific to be effective as diagnostic tools. Insufficient data are available in children to confirm the accuracy of the recently approved H. pylori stool antigen test. The urea breath test has the promise to provide noninvasive and accurate diagnosis of H. pylori infection; but currently, there is insufficient evidence that it can be used to reliably diagnose or exclude H. pylori associated diseases.

WHEN IS TESTING INDICATED? The primary goal of testing is to diagnose the cause of clinical symptoms and not simply to detect the presence of H. pylori infection. Testing is not helpful unless it will alter the management of the disease. A variety of invasive and noninvasive tests exist for the detection of H. pylori infection, but their degree of sensitivity and specificity vary, as do their suitability for clinical use in children. Thus, there is potential for inappropriate testing or misuse of tests in children.
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GOLD ET AL. dicates that there is a link between gastric cancers (both adenocarcinoma and lymphoma) and H. pylori infection. However, no studies have shown that H. pylori eradication during childhood prevents subsequent development of gastric malignancies. Until evidence is available to better define the role of H. pylori in a variety of gastric cancers and the role of H. pylori eradication in disease prevention, routine screening of children with a family history of gastric cancer or recurrent peptic ulcer disease is not recommended. Histologic Evidence of Lymphoma Abdominal Pain Unrelated to Peptic Ulcers In the rare circumstance in which histopathologic evidence of MALT lymphoma is documented in a child, testing for H. pylori is recommended. Follow-up of Therapy for H. pylori Infection Testing to confirm eradication of infection and the resolution of associated symptoms and disease sequelae is advisable in selected children. Guidelines in adults recommend testing after treatment of complicated peptic ulcer (52), but studies in children are limited. As such, few data are available on the effectiveness of therapy in children, testing after treatment is recommended in those with complicated peptic ulcer disease (i.e., bleeding, perforation, or obstruction) or lymphoma. For patients who remain symptomatic, it is recommended that endoscopy and biopsy be performed to evaluate for the persistence of H. pylori-associated peptic ulcer disease. For patients with an uncomplicated ulcer who are asymptomatic after completion of eradication therapy, testing for persistence of infection is not necessary. However, some physicians advocate the use of urea breath testing in this clinical setting. WHEN IS TREATMENT OF H. PYLORI INFECTION INDICATED? Eradication therapy is recommended for children who have both known active H. pylori infection and symptomatic gastrointestinal disease. Known active H. pylori infection is defined as identification of the organisms by histopathologic examination or as a positive culture from endoscopic gastric biopsy. Serology is not a reliable test for active disease, because it may indicate past but not current infection with H. pylori. There are no randomized controlled trials in children that determine the precise clinical settings in which eradication therapy is indicated. Although additional studies in children are needed (53), the available evidence supports the following recommendations.

Endoscopically Diagnosed or Radiographically Definitive Peptic Ulcer The causal relationship between H. pylori infection and primary duodenal ulcers is compelling (37). Therefore, it is recommended that testing for the presence of H. pylori infection be performed in children with endoscopically diagnosed or radiographically definitive duodenal ulcer. Although the data in children are less complete, evidence from studies in adults (38) supports the recommendation that testing for H. pylori also be performed in subjects with a documented gastric ulcer.

Several lines of evidence, including serologic surveys, endoscopic evaluations, and treatment trials indicate that H. pylori is not a frequent cause of recurrent abdominal pain in children. There have been six studies performed in North America, Europe, and Australia, with 2715 children evaluated by esophagogastroduodenoscopy and biopsy, serology, or urea breath test (3944). Although 5% to 17% of children with abdominal pain had evidence of infection with H. pylori, 5% to 29% of children without abdominal pain were also infected with H. pylori. There are no convincing data to support routine testing of children with recurrent abdominal pain (3945). Investigators have also looked for specific symptom patterns in H. pyloriinfected children, but none so far has been detected (4650). Future studies are needed to determine whether subsets of children with abdominal pain can be identified in whom signs and symptoms are caused by H. pylori infection. It is recommended that children with recurrent abdominal pain, in the absence of documented ulcer disease, not be tested for H. pylori infection. Asymptomatic Children, Including Those at Increased Risk of Acquiring H. pylori Infection There are no compelling data to support routine testing in asymptomatic children. Testing for H. pylori infection is not recommended in children without clinical symptoms, including those residing in long-term care facilities, children with short stature, and those at increased risk of acquiring H. pylori infection. In addition, purported extraintestinal manifestations of H. pylori infection have not been demonstrated in a convincing fashion (51). Accordingly, a test-and-treat approach is not recommended in these circumstances. Family History of Gastric Cancer or Recurrent Peptic Ulcer Disease No currently available data support routine testing in children with a positive family history of diseases related to H. pylori infection (52). Epidemiologic evidence inJ Pediatr Gastroenterol Nutr, Vol. 31, No. 5, November 2000

TREATMENT RECOMMENDATIONS FOR HELICOBACTER INFECTION Duodenal and Gastric Ulcers Eradication treatment is recommended for children who have a duodenal ulcer or gastric ulcer identified at endoscopy and H. pylori documented by histopathology. A prior history of duodenal or gastric ulcer disease is also an indication for treatment if active H. pylori infection is documented. If a definitive ulcer is present on contrast radiography (e.g., an ulcer crater is present), eradication therapy is indicated if either a noninvasive or invasive test result is positive for H. pylori. Lymphoma The rare child with pathologic evidence of MALT lymphoma and H. pylori infection should be treated with eradication therapy. Further studies of pediatric patients with lymphoma should be performed to monitor the recurrence, progression, or remission of the tumor after therapy. Atrophic Gastritis With Intestinal Metaplasia Eradication treatment is recommended for the rare child who has pathologically proven atrophic gastritis with intestinal metaplasia, according to the updated Sydney classification of gastritis (54), plus coexisting H. pylori infection. Because of the preneoplastic nature of these pathologic changes, follow-up endoscopy is recommended to confirm that the H. pylori infection has been eradicated and to ensure that there is no subsequent progression of gastric mucosal disease. Gastritis Without Peptic Ulcer Disease The finding of H. pyloriassociated gastritis in the absence of peptic ulcer disease during diagnostic endoscopy poses a dilemma for the endoscopist. The decision to treat H. pyloriassociated gastritis without duodenal or gastric ulcer in this situation is subject to the judgment of the clinician and deliberations with the patient and family. Studies in adults on the effect of eradication treatment on abdominal symptoms have produced conflicting results (5558). There are no randomized controlled trials in children. The long-term impact of the eradication of H. pylori and the healing of gastritis on the subsequent development of peptic ulcer disease, adenocarcinoma, or lymphoma is uncertain. Although there is a small lifetime risk of development of peptic ulcer disease associated with H. pylori gastritis, there are no randomized controlled trials demonstrating that eradication of H. pylori results in prevention of peptic ulcer disease. In addition, there are no data showing that eradication therapy influences the long-term risk for development of gastric cancers. Antibiotic treatment can result in adverse drug reactions, promote antibiotic resistance, and increase the

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cost of care. Therefore, the H. pylori Infection Guideline Committee concludes that there is insufficient evidence to support either initiating or withholding eradication treatment in this situation.

Recurrent Abdominal Pain and Asymptomatic Children There is no compelling evidence, at the present time, for treating children with H. pylori infection and either nonulcer dyspepsia or functional recurrent abdominal pain. There is also no convincing evidence currently available that asymptomatic children who have a family member with H. pylori infection, peptic ulcer, or gastric cancer need treatment.

WHAT IS THE PREFERRED TREATMENT OF H. PYLORI INFECTION IN CHILDREN? The optimum treatment regimen for eradicating H. pylori in children has not been determined (59). Effective therapy in adults is defined as successful eradication of H. pylori infection in a minimum of 80% of treated subjects (60). Although it appears that treatment options that have been effective in adults will also be efficacious in children, controlled studies in pediatric populations are needed to confirm or refute this supposition. Unfortunately, the limited data currently available in children are open-label, case series and uncontrolled, anecdotal observations that do not meet the minimum criteria for determining efficacy. In vitro sensitivity of H. pylori to a specific drug does not guarantee that the bacterium will be effectively eradicated from the human stomach. Therefore, current treatment strategies to eradicate H. pylori have been developed primarily by trial-and-error methodology (61). The single most important determinant of successful eradication therapy is compliance with the prescribed combination treatment regimen (62). There are welldescribed treatment failures due to suboptimal compliance. To enhance adherence to the treatment regimen, the number of medications prescribed, the frequency of administration, and the duration of therapy are best kept to the minimum required for successful treatment. It is recommended that initial treatment consist of three medications, administered twice daily, for 1 to 2 weeks (63). Specifically, as shown in Table 3, three firstline therapy options are recommended for use in children and adolescents. For patients in whom initial treatment has failed, two other options are recommended, including one option with four medications. It is recommended that monotherapy and two-drug regimens be avoided, because they are ineffective and increase the likelihood
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GOLD ET AL. pump inhibitor also reduces the effectiveness of eradication treatment protocols. Studies are needed to determine the relative importance of these risk factors in pediatric populations. REFERENCES
1. Ernst PB, Gold BD. Helicobacter pylori in childhood: new insights into the immunopathogenesis of gastric disease and implications for managing infection in children. J Pediatr Gastroenterol Nutr. 1999;28:46273. 2. Drumm B. Helicobacter pylori in the pediatric patient. Gastroenterol Clin North Am. 1993;22:16982. 3. Dohil R, Hassall E, Jevon G, et al. Gastritis and gastropathy of childhood. J Pediatr Gastroenterol Nutr. 1999;29:37894. 4. Huang J-Q, Sridhars CY, Hunt RH. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology. 1998;114:116979. 5. Watanabe T, Tada M, Nagai H, et al. Helicobacter pylori infection induces gastric cancer in Mongolian gerbils. Gastroenterology. 1998;115:6428. 6. Webb PM, Knight T, Greaves S, et al. Relation between infection with Helicobacter pylori and living conditions in childhood: evidence for person to person transmission in early life. BMJ. 1994; 308:7503. 7. Parsonnet J. The incidence of Helicobacter pylori infection. Aliment Pharmacol Ther. 1995;9:4551. 8. Handt LK, Fox JG, Stalis IH, et al. Characterization of feline Helicobacter pylori strains and associated gastritis in a colony of domestic cats. J Clin Microbiol. 1995;33:22809. 9. Grubel P, Hoffman JS, Chong FK, et al. Vector potential of houseflies (Musca domestica) for Helicobacter pylori. J Clin Microbiol. 1997;35:13003. 10. Klein PD, Graham DY, Gaillour A, et al. Water source as a risk factor for Helicobacter pylori infection in Peruvian children. Lancet. 1991;337:15036. 11. Staat MA, Kruszon-Moran D, McQuillan GM, et al. A populationbased serologic survey of Helicobacter pylori infection in children and adolescents in the United States. J Infect Dis. 1996;174: 11203. 12. Goodman KJ, Correa P. The transmission of Helicobacter pylori: a critical review of the evidence. Int J Epidemiol. 1995;24:87587. 13. Sackett DL, Richardson WS, Rosenberg W, et al. Evidence-based Medicine: How to Practice and Teach EBM. Edinburgh: Churchill Livingston; 1998. 14. McMurray AR. Three decision-making aids: brainstorming, nominal group, and Delphi technique. J Nurs Staff Dev. 1994;10:625. 15. Cockeram AW. Clinical practice guidelines: help or hindrance? J Pediatr Gastroenterol Nutr. 1999;28:3623. 16. Canadian Task Force on the Periodic Health Examination: the periodic health examination. Can Med Assoc J. 1979;121:1193 254. 17. Olson AD, Fendrick AM, Deutsch D, et al. Evaluation of initial noninvasive therapy in pediatric patients presenting with suspected ulcer disease. Gastrointest Endosc. 1996;44:5541. 18. Rothman KJ, Greenland S. Modern Epidemiology. 2nd ed. Philadelphia: LippincottRaven; 1998. 19. Genta RM, Graham DY. Comparison of biopsy sites for the histopathologic diagnosis of Helicobacter pylori: a topographic study of H. pylori density and distribution. Gastroenterology. 1997;112: 210810. 20. Elitsur Y, Neace C. Detection of Helicobacter pylori organisms by Hp-fast in children. Dig Dis Sci. 1999;44:116972. 21. Elitsur Y, Hill I, Lichtman SN, et al. Prospective comparison of rapid urease tests (Pyloritek, CLO test) for the diagnosis of Helicobacter pylori infection in symptomatic children: a pediatric multicenter study. Am J Gastroenterol. 1998;93:2179.

TABLE 3. Recommended eradication therapies for H. pylori disease in children

First-line options 1 Medications amoxicillin clarithromycin proton pump inhibitor: omeprazole (or comparable acid inhibitory doses of another PPI) amoxicillin metronidazole proton pump inhibitor: omeprazole (or comparable acid inhibitory doses of another PPI) clarithromycin metronidazole proton pump inhibitor: omeprazole (or comparable acid inhibitory doses of another PPI) Second-line options 4 bismuth subsalicylate metronidazole proteon pump inhibitor: omeprazole (or comparable acid inhibitory doses of another PPI) pus, an additional antibiotic: amoxicillin or tetracyclinea or clarithromycin 5 ranitidine bismuth-citrate clarithromycin metronidazole Dosage 50 mg/kg/day up to 1 g bid 15 mg/kg/day up to 500 mg bid 1 mg/kg/day up to 20 mg bid 50 mg/kg/day up to 1 g bid 20 mg/kg/day500 mg bid 1 mg/kg/day up to 20 mg bid 15 mg/kg/day up to 500 mg bid 20 mg/kg/day up to 500 mg bid 1 mg/kg/day up to 20 mg bid

1 tablet (262 mg) qid or 15 ml (17.6 mg/mL qid) 20 mg/kg/day500 mg bid 1 mg/kg/day up to 20 mg bid 50 mg/kg/day up to 1 g bid 50 mg/kg/day up to 1 g bid 15 mg/kg/day500 mg bid 1 tablet qid 15 mg/kg/day500 mg bid 20 mg/kg/day500 mg bid

Initial treatment should be provided in a twice daily regimen (to enhance compliance) for 7 to 14 days. a Only for children 12 years of age or older. bid, twice daily; qid, four times daily.

of acquired antibiotic resistance (64). Primary antimicrobial resistance also can result in treatment failure even when a three- or four-drug regimen is used. Resistance of H. pylori to nitroimidazoles causes an increase in the rate of treatment failures in regimens using metronidazole. An increasing prevalence of resistance to clarithromycin, documented in the past few years, particularly in Europe, could eventually impair the therapeutic effectiveness of this antibiotic in H. pylori treatment regimens. Results in some studies suggest that prior therapy with a proton
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22. van der Hulst RW, van der Ende A, Homan A, et al. Influence of metronidazole resistance on efficacy of quadruple therapy for Helicobacter pylori eradication. Gut. 1998;42:1669. 23. Holton J. Clinical relevance of culture: why, how, and when. Helicobacter. 1997;2(suppl 1):S2533. 24. Westblom TU. Molecular diagnosis of Helicobacter pylori. Immunol Invest. 1997;26:16374. 25. Breslin NP, OMorain CA. Noninvasive diagnosis of Helicobacter pylori: a review. Helicobacter. 1997;2:1117. 26. De Oliveira AMR, Rocha GA, Queiroz DMM, et al. Evaluation of enzyme-linked immunosorbent assay for the diagnosis of Helicobacter pylori infection in 157 children from different age groups with and without duodenal ulcer. J Pediatr Gastroenterol Nutr. 1999;28:15761. 27. Czinn SJ. Serodiagnosis of Helicobacter pylori in pediatric patients. J Pediatr Gastroenterol Nutr. 1999;28:1324. 28. Khanna B, Cutler A, Israel NR, et al. Use caution with serologic testing for Helicobacter pylori infection in children. J Infect Dis. 1998;178:4605. 29. Fallone CA, Elizov M, Cleland P, et al. Detection of Helicobacter pylori infection by saliva IgG testing. Am J Gastroenterol. 1996; 91:11459. 30. Alemohammad MM, Foley TJ, Cohen H. Detection of immunoglobulin G antibodies to Helicobacter pylori in urine by an enzyme immunoassay method. J Clin Microbiol. 1993;31:21747. 31. Vaira D, Malfertheiner P, Megraud F, et al. Diagnosis of Helicobacter pylori with a new non-invasive antigen-based assay. Lancet. 1999;354:303. 32. Oderda G, Rapa A, Ronchi B, et al. Detection of Helicobacter pylori in stool specimens by non-invasive antigen enzyme immunoassay in children: multicentre Italian study. BMJ. 2000;320: 3478. 33. Cutler AF, Havstad S, Ma CK, et al. Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology. 1995;109:13641. 34. Rowland M, Lambert I, Gormally S, et al. Carbon 13-labeled urea breath test for the diagnosis of Helicobacter pylori infection in children. J Pediatr. 1997;131:81520. 35. Bode G, Rothenbacher D, Brenner H, et al. Variation in the 13Curea breath test value by nationality in Helicobacter pylori-infected children. Scand J Gastroenterol. 1998;33:46872. 36. Jones NL, Bourke B, Sherman PM. Breath testing for Helicobacter pylori infection in children: a breath of fresh air? J Pediatr. 1997; 131:7913. 37. Sherman PM, Hassall E, Hunt RH, et al. Canadian Helicobacter study group consensus conference on the approach to Helicobacter pylori infection in children and adolescents. Can J Gastroenterol. 1999;13:5539. 38. Hunt R, Thomson AB. Canadian Helicobacter pylori consensus conference. Can J Gastroenterol. 1998;12:3141. 39. Van der Meer SB, Forget PP, et al. The prevalence of Helicobacter pylori serum antibodies in children with recurrent abdominal pain. Eur J Pediatr. 1992;151:799801. 40. McCallion WA, Bailie AG, Ardill JE, et al. Helicobacter pylori, hypergastrinemia, and recurrent abdominal pain in children. J Pediatr Surg. 1995;30:4279. 41. Chong SK, Lou Q, Asnicar MA, et al. Helicobacter pylori infection in recurrent abdominal pain in childhood: comparison of diagnostic tests and therapy. Pediatrics. 1995;96:2115. 42. Bode G, Rothenbacher D, Brenner H, et al. Helicobacter pylori and abdominal symptoms: a population based study among preschool children in southern Germany. Pediatrics. 1998;101:6347. 43. ODonahoe JM, Sullivan PB, Scott R, et al. Recurrent abdominal

497

44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55.

56. 57.

58. 59. 60. 61. 62. 63. 64.

pain and Helicobacter pylori in a community-based sample of London children. Acta Paediatr. 1996;85:9614. Hardikar W, Feekery C, Smith A, et al. Helicobacter pylori and recurrent abdominal pain in children. J Pediatr Gastroenterol Nutr. 1996;22:14852. Macarthur C, Saunder N, Feldman W. Helicobacter pylori, gastroduodenal disease, and recurrent abdominal pain in children. JAMA. 1995;273:72934. Gormally SM, Prakash N, Durnin MT, et al. Association of symptoms with Helicobacter pylori infection in children. J Pediatr. 1995;126:7536. Hardikar W, Davidson PM, Cameron DJ, et al. Helicobacter pylori infection in children. J Gastroenterol Hepatol. 1991;6:4504. Glassman MS, Schwarz Sm, Medow MS, et al. Campylobacter pylori-related gastrointestinal disease in children. Incidence and clinical findings. Dig Dis Sci. 1989;34:15014. Reifen R, Rasooly I, Drumm B, et al. Helicobacter pylori infection in children: is there specific symptomatology. Dig Dis Sci. 1994; 39:148892. Snyder JD, Hardy SC, Thorne GM, et al. Primary antral gastritis in young American children: low prevalence of Helicobacter pylori. Dig Dis Sci. 1994;39:185963. Leontiadis GI, Sharma VK, Howden CW. Non-gastrointestinal tract associations of Helicobacter pylori infection. What is the evidence? Arch Intern Med. 1999;159:92540. Howden CW. For what conditions is there evidence-based justification for treatment of Helicobacter pylori infection? Gastroenterology. 1997;113:S107112. Sherman PM, Hunt RH. Why guidelines are required for treatment of Helicobacter pylori infection in children. Clin Invest Med. 1996; 19:3627. Dixon MF, Genta RM, Yardley JH, et al. Classification and grading of gastritis: the updated Sydney system. Am J Surg Pathol. 1994;20:116181. Blum AL, Talley NJ, OMorain C, et al. Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia: omeprazole plus clarithromycin and amoxicillin effect one year after treatment (OCAY) study group. N Engl J Med. 1998;339: 187581. McColl K, Murray L, El-Omar E, et al. Symptomatic benefit from eradicating Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl J Med. 1998;339:186974. Talley NJ, Janssens J, Lauritsen K, et al. Eradication of Helicobacter pylori in functional dyspepsia: randomized double blind placebo controlled trial with 12 months follow up. The Optimal Regimen Cures Helicobacter Induced Dyspepsia (ORCHID) study group. BMJ. 1999;318:8337. Talley NJ, Vakil N, Ballard D, et al. Absence of benefit from eradicating Helicobacter pylori in patients with nonulcer dyspepsia. N Engl J Med. 1999;3412:15:110611. Blecker U, Gold BD. Treatment of Helicobacter pylori infection: a review. Pediatr Infect Dis J. 1997;16:3919. Harris A. Current regimens for treatment of Helicobacter pylori infection. Br Med Bull. 1998;54:195205. Peura D. Helicobacter pylori: rational management options. Am J Med. 1998;105:42430. Huang H-Q, Hunt RH. Treatment after failure: the problem of non-responders. Gut. 1999;45:1405. Rowland M, Imrie C, Bourke B, et al. How should Helicobacter pylori infected children be managed? Gut. 1999;45:13369. Behrens R, Lang T, Keller KM, et al. Dual versus triple therapy of Helicobacter pylori infection: results of a multicentre trial. Arch Dis Child. 1999;81:6870.

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