Helicobacter pylori Infection in Children: Recommendations for Diagnosis and Treatment

Abstract

Helicobacter pylori infects at least 50% of the world's 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, placebo-controlled 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 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. 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. pylori–associated 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.TABLE 1: Summary of recommendations and the quality of the supporting evidenceMETHODS 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). HOW RELIABLE ARE TESTS FOR H. PYLORIINFECTION? 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 organism. In addition, such a test enables discrimination between the presence of H. pylori infection and H. pylori–associated 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.TABLE 2: Tests for Helicobacter pylori and Helicobacter -related disordersFailure 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 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;Hp-Fast, 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 (97–98%) (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 level—for example, by providing information about point mutations conferring resistance to antibiotics and about putative bacterial virulence factors. However, PCR is expensive, the assay 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 physician's office in symptomatic children in developed countries is poor, with a range of sensitivity of only 60% to 70%(26–28). 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. pylori–specific 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. pylori–specific 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 eradication 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. pylori–associated 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. Endoscopically or The between H. pylori infection and primary duodenal ulcers is compelling Therefore, it is recommended that testing for the presence of H. pylori infection be performed in children with endoscopically diagnosed or definitive duodenal Although the data in children are less evidence from studies in adults the that testing for H. pylori also be performed in with a documented gastric to Several of including serologic and treatment trials that H. pylori is not a cause of in children. There have been studies performed in North America, and with children evaluated by and or urea breath test Although to of children with had evidence of infection with H. pylori, to of children were also infected with H. pylori. There are no data to support testing of children with have also for specific in H. children, but has been studies are needed to of children with can be identified in signs and symptoms are by H. pylori infection. It is recommended that children with in the of documented ulcer disease, not be for H. pylori infection. at of H. There are no compelling data to support testing in children. Testing for H. pylori infection is not recommended in children clinical including those in care children with and those at risk of acquiring H. pylori infection. In addition, of H. pylori infection have not been in a Accordingly, a is not recommended in these of or currently available data support testing in children with a positive family history of diseases to H. pylori infection evidence that there is a between gastric cancers adenocarcinoma and and H. pylori infection. However, no studies have shown that H. pylori eradication during childhood development of gastric evidence is available to the role of H. pylori in a variety of gastric cancers and the role of H. pylori eradication in disease screening of children with a family history of gastric or peptic ulcer disease is not recommended. Evidence of In the in which evidence of lymphoma is documented in a testing for H. pylori is recommended. of for H. Testing to confirm eradication of infection and the resolution of associated symptoms and disease is in children. in adults testing treatment of peptic ulcer but studies in children are As few data are available on the of in children, testing treatment is recommended in those with peptic ulcer disease (i.e., or or patients who remain it is recommended that endoscopy and biopsy be performed to for the of H. peptic ulcer disease. patients with an ulcer who are of eradication testing for of infection is not However, the use of urea breath testing in this clinical setting. WHEN IS H. INDICATED? is recommended for children who have both known active H. pylori infection and symptomatic gastrointestinal disease. active H. pylori infection is as identification of the organisms by examination or as a positive culture from gastric is not a reliable test for active disease, because it may past but not infection with H. pylori. There are no trials in children that the clinical in which eradication is Although additional studies in children are needed the available evidence the and treatment is recommended for children who have a duodenal ulcer or gastric ulcer identified at endoscopy and H. pylori documented by A history of duodenal or gastric ulcer disease is also an for treatment if active H. pylori infection is a definitive ulcer is present on (e.g., an ulcer is eradication is if either a noninvasive or invasive test result is positive for H. pylori. The child with evidence of lymphoma and H. pylori infection be with eradication therapy. studies of pediatric patients with lymphoma be performed to the or of the therapy. treatment is recommended for the child who has atrophic gastritis with intestinal metaplasia, to the of gastritis H. pylori infection. Because of the of these follow-up endoscopy is recommended to confirm that the H. pylori infection has been and to ensure that there is no of gastric mucosal disease. The of H. pylori–associated gastritis in the of peptic ulcer disease during diagnostic endoscopy a for the The to H. pylori–associated gastritis duodenal or gastric ulcer in this is to the judgment of the and with the patient and in adults on the effect of eradication treatment on symptoms have results There are no trials in children. The of the eradication of H. pylori and the of gastritis on the development of peptic ulcer disease, or lymphoma is Although there is a small risk of development of peptic ulcer disease associated with H. pylori gastritis, there are no trials that eradication of H. pylori results in of peptic ulcer disease. In addition, there are no data that eradication the risk for development of gastric treatment can result in antibiotic and the cost of Therefore, the H. pylori Infection Guideline Committee that there is insufficient evidence to support either or eradication treatment in this and There is no compelling at the present for children with H. pylori infection and either or There is also no evidence currently available that children who have a family with H. pylori infection, peptic or gastric need treatment. IS H. The treatment for H. pylori in children has not been determined in adults is as eradication of H. pylori infection in a of of Although it appears that treatment that have been effective in adults will also be in children, studies in pediatric populations are needed to confirm or this Unfortunately, the limited data currently available in children are case and that do not the criteria for In sensitivity of H. pylori to a specific does not that the will be from the human Therefore, treatment to H. pylori have been developed by The most important of eradication is with the treatment There are treatment due to To to the treatment the number of medications the frequency of and the duration of are best to the required for treatment. It is recommended that initial treatment consist of three for to as shown in Table three are recommended for use in children and adolescents. patients in initial treatment has other are including one with four It is recommended that and regimens be because they are and the of acquired antibiotic resistance resistance also can result in treatment failure even when a is of H. pylori to causes an in the of treatment in regimens using An prevalence of resistance to documented in the past few particularly in could the therapeutic of this antibiotic in H. pylori treatment in studies that with a proton pump also the of eradication treatment are needed to the of these risk factors in pediatric eradication for H. pylori disease in children