Helicobacter pylori Infection in Children and Adolescents: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition

Abstract

I. SUMMARY OF THE PROBLEM Helicobacter pylori–induced gastritis causing mucosal ulceration either in the stomach or the proximal duodenum is a relatively uncommon event in children compared with adults. When H. pylori–associated ulcers occur in children, duodenal ulceration is much more frequently identified than gastric ulcers. In children younger than 6 to 10 years of age, peptic ulcers are usually due to noxious agents (such as corticosteroids and nonsteroidal antiinflammatory agents) or after major stresses (for example, burns, head injury, systemic illness). In these settings, upper gastrointestinal tract hemorrhage, vomiting, or perforation are frequent presenting features. The ulcers tend not to recur after healing if either the offending agent or underlying disease predisposing to mucosal ulceration can be removed. In older children and adolescents, the clinical presentation and natural history of peptic ulcers are more comparable to those observed in adults. The ulcers present as epigastric and nocturnal abdominal pain in teenagers with a positive family history of peptic ulceration. In this setting, despite healing of the acute ulceration, the natural history is for the ulcer to recur. It is now clear that such ulcers are not related to a genetic predisposition to hyperpepsinogenemia but to infection of the stomach with the pathogen H. pylori. Recurrences of H. pylori–associated peptic ulceration are markedly reduced by treatment directed at eradicating the gastric infection. For example, duodenal ulcer recurrence rates in H. pylori–infected children have been reported to be reduced from 65% recurrence at 1 year of follow-up if ulcers are healed with acid suppressive agents alone compared with 1-year ulcer recurrence rates below 5% if the gastric pathogen is eradicated. This intervention therefore results in reduced global health care costs. Historical Perspective Peptic ulcer disease has been considered to arise as a result of an imbalance between mucosal defenses and aggressive factors, including acid and pepsin. Mucosal defenses against acid and pepsin include mucus and bicarbonate, mucosal blood flow, prostaglandins, trefoil peptides, and epidermal growth factor. Primary peptic ulcers are usually duodenal, chronic, and related to H. pylori, whereas secondary ulcers are gastric, acute, and unrelated to infection status. It is clear that marked overproduction of gastric acid, such as occurs in the Zollinger-Ellison syndrome and, more commonly in children, antral G cell hyperplasia (also referred to as pseudo-Zollinger Ellison syndrome) can cause duodenal ulceration. However, excess acid production does not account for the overwhelming majority of peptic ulcers in children. It has been known for many years that recurrent peptic ulcer disease in humans is accompanied by a chronic-active gastritis. In 1983, Drs. Barry Marshall and Robin Warren in Perth, Australia provided the explanation for the cause of the gastritis and accompanying peptic ulcer disease when they successfully cultured H. pylori from the gastric antrum of humans. Subsequent studies in children confirmed the findings first reported in adults. There is specificity to the infection, the infection is associated with previously unexplained recurrent peptic ulcers, and both gastritis and ulcers resolve when the infection is successfully eradicated (1). Although there is general consensus worldwide to treat H. pylori infection when there is endoscopic evidence of peptic ulceration, whether to intervene in other more frequently encountered clinical settings remains uncertain. Increasing knowledge of the natural history of the infection, routes of transmission in human populations, and potential environmental reservoirs will help to clearly define why, when, and in whom to treat H. pylori. II. MAJOR ISSUES IN NEED OF INVESTIGATION OR IMPLEMENTATION A. Epidemiology of H. pylori Infection in Children No environmental reservoir for H. pylori has been identified. Although nonhuman primates and domestic cats have been reported to harbor the infection, it appears that this is due to transmission of the infection from people to nonhumans. It is now clear that H. pylori infection is usually acquired in childhood. In developing countries, H. pylori is acquired early in infancy, with up to two thirds of children infected by 2 years of age. The prevalence of infection appears to be lower amongst breast-fed infants whose mothers are infected with the organism. A reduced rate of infection could relate to the presence of specific H. pylori immunoglobulin A antibodies present in the milk. In contrast, in developed nations only 10% of all children will be infected with H. pylori at 10 years of age. There are higher prevalence rates observed in certain childhood populations, such as the clustering of infection among family members and in children living in institutions. Such epidemiologic features suggest that the infection is spread amongst humans. Person-to-person transmission could occur via oral transmission because the organism has been detected in the oral cavity and in vomitus (2). Alternatively the route of transmission of infection could be fecal to oral because the organism has, on a few occasions, been cultured from feces, and bacterial antigens are detected in human feces of those harboring the organism in the stomach. Moreover, fecal-to-oral transmission has been demonstrated convincingly in animal models of Helicobacter infection (such as H. mustelae infection of ferrets). The prevalence of H. pylori infection increases with advancing chronologic age due to a cohort effect. Prevalence rates are higher in developing nations and amongst children living in lower socioeconomic groups in developed countries. Previous reports of ethnic and genetic susceptibilities to H. pylori likely reflect insufficient consideration of the confounding effects of socioeconomic deprivation as an independent risk factor. There is controversy regarding the natural history of H. pylori infection in children. Recent reports highlight the changes in histology in the stomach over time. In one study, children followed over a period of 2 years demonstrated increasing mucosal inflammation in the stomach without evidence of changes in bacterial density. These interesting findings need to be confirmed by researchers evaluating children longitudinally in other clinical and geographic settings. Several recent reports also indicate that the acute inflammatory response in the gastric mucosa is less pronounced in children compared with adults. These findings could indicate that the host humoral and cellular responses differ depending on the age at which the gastric infection is first acquired and might serve to explain varying rates of disease outcome (ulcer, cancers) evident in different parts of the world. At least four studies, using indirect markers of gastric infection, report spontaneous clearing and re-acquisition of the gastric infection in preschoolers. These interesting findings need to be confirmed using highly accurate methods to definitively establish the presence or absence of infection. If confirmed, the findings would indicate marked differences in the natural history of infection in young children compared with the rest of the human population because spontaneous eradication of infection does not appear to occur in adults. Re-acquisition of H. pylori after successful therapy in adolescents and adults is an exceedingly uncommon event; at least amongst those individuals living in developed nations. It has been considered that re-infections are, in reality, recrudescences after treatment failure. B. Consequences of H. pylori Infection Gastritis:H. pylori infection fulfills each of Koch's postulates and all of Hill's criteria for causation as a cause of chronic-active pangastritis in humans. Therefore, there is no doubt that the organism is a human pathogen. Questions remaining at this time relate to the clinical consequences of the infection and the accompanying mucosal inflammation in the stomach. Duodenal ulcer: The evidence in support of H. pylori infection as a cause of duodenal ulceration is convincing. Ulcers heal faster when anti-helicobacter therapy is used compared with acid suppression therapy alone. More importantly, duodenal ulcers do not recur when H. pylori infection is successfully eradicated. Gastric ulcer: The natural history of non-NSAID–associated gastric ulceration in adults is changed by eradication of H. pylori infection. However, the causative role of H. pylori in causing gastric ulcers in children and adolescents is less certain. In some, but not all, reports in children with gastric ulceration the presence of H. pylori infection is uncommon and no more frequent than in age-matched reference populations of asymptomatic individuals. This finding may simply reflect the fact that a large proportion of gastric ulcers is secondary in nature in children. Gastric adenocarcinoma: There is accumulating evidence supporting long-standing H. pylori infection, gastric atrophy, and intestinal metaplasia with the development of intestinal-type and undifferentiated adenocarcinomas in the antrum and body of the stomach in adults. To date, H. pylori-induced gastric cancer has not been reported in children. Epidemiologic studies associating H. pylori infection with gastric cancers were judged to be sufficiently compelling by the World Health Organization for the organism to be the first bacterium classified as a human carcinogen. Adenocarcinomas developing in the stomach of animals infected with helicobacter species (H. pylori infection of Mongolian gerbils, and H. mustelae infection of ferrets in conjunction with oral delivery of a chemical carcinogen) provide strong support for the role of the organism as a carcinogen. Whether the possible progression of childhood H. pylori infection to gastric carcinoma in adult life is sufficient reason to advocate eradication of the organism as soon as it is encountered is currently a highly contentious issue. Additional research is required to clarify current controversies. Gastric lymphoma and MALToma: Seroepidemiologic studies support an association between long-standing H. pylori infection and both lymphoma and B cell monoclonal proliferative responses—also referred to as MALTomas. H. pylori-associated MALTomas have been reported only very occasionally in children. Studies in adults suggest that at least a proportion of MALTomas appear to demonstrate regression after eradication of the gastric infection. C. Helicobacter pylori Infection and Abdominal Pain The link between H. pylori infection and the development of recurrent abdominal pain is controversial. A recent meta-analysis of a large number of controlled studies in adults with epigastric abdominal pain in the absence of endoscopic evidence of peptic ulceration provides support for the contention that H. pylori-induced gastritis may well be a risk factor in non-ulcer dypepsia (3). The meta-analysis indicated that the presence of H. pylori was associated with symptoms of non-ulcer dyspepsia (odds ratio 1.6, 95% confidence intervals: 1.4–1.8), and symptoms improve when the organism is successfully eradicated (1.9, 1.3–2.6). A comparable evaluation of published studies available in the pediatric literature does not provide support for H. pylori gastritis as an etiologic factor in recurrent abdominal pain of childhood; at least, as defined by Apley (4). The role of H. pylori as a cause of uninvestigated dyspepsia (that is, epigastric pain before diagnostic upper endoscopy has been performed) and non-ulcer dyspepsia (epigastric symptoms in the absence of mucosal ulceration at esophagogastroduodenseopy) in children and adolescents is an important unanswered question. There are no definitive recommendations for universal testing or treatment of H. pylori in children with either recurrent pain referable to the epigastrium or recurrent periumbilical abdominal pain. It remains to be determined whether H. pylori–induced gastritis is responsible for clinical symptoms in at least a subgroup of infected children and adolescents. D. Extraintestinal Features of H. pylori Infection H. pylori has been associated with a wide variety of neurologic, dermatologic, and cardiac manifestations. Current critical reviews of the literature comment on the poor quality of the available evidence and the need for additional carefully conducted, high-quality studies with appropriate control groups (5). There are also reports from some centers associating H. pylori infection in children with short stature and diarrheal disease, but this finding has not been confirmed in studies by other investigators. Additional studies in this important but contentious area are awaited with interest. A few case reports describe sideropenic refractory anemia, occurring both in adults and in children, that respond to the eradication of H. pylori with an increase in hemoglobin and ferritin levels. These findings are of particular interest because case-control studies describe lower body iron stores in H. pylori–infected children compared to age-matched controls without evidence of gastric colonization. E. Methods to Diagnose Peptic Ulcers and H. pylori 1. Invasive Methods Endoscopy is the only method to accurately diagnose peptic ulceration in children. At the time of diagnostic upper endoscopy, nodularity in the antrum of the stomach is a specific (but not sensitive) feature indicative of active H. pylori infection in children. Biopsy specimens taken from the stomach can be tested for the presence of H. pylori by a variety of complementary techniques. These approaches include staining of biopsy sections (silver, Giemsa, Genta, acridine orange) and microscopic evaluation, culture, and testing for the presence of urease activity. Staining with silver and microscopic evaluation by an expert pathologist is the most accurate invasive method of diagnosis of H. pylori infection in pediatric populations. Giemsa staining is a reasonable alternative because it is easy to perform, less susceptible to technical artifacts, and is relatively inexpensive. Much less commonly than H. pylori, a morphologically distinct helicobacter also has been associated with gastritis in humans, including children (6). Currently referred to as “Helicobacter heilrnaneii” (previously called “Gastrospirillum horn mis”), the nonculturable organism has not been associated with other complication such as peptic ulcer disease or gastric cancers. Culture of gastric biopsy specimens is less sensitive and more expensive, but it offers the opportunity to test for antimicrobial resistance that may be relevant for those children failing to respond to traditional therapeutic regimens. Polymerase chain reaction using appropriate specific primers can be employed to successfully detect bacterial genomic DNA in gastric biopsy specimens, as well as in feces and in saliva. The technology can be employed to differentiate between recrudescence and re-infection and to detect point mutations in genes accounting for bacterial resistance to antibiotics, including nitroimidazoles and macrolides. In children and teenagers receiving concurrent therapy with a proton pump inhibitor, biopsies should be performed on the body and cardia (and, possibly, transition zones) of the stomach as well as from the antrum to reduce the chances of false-negative results. Follow-up endoscopy is rarely necessary in pediatric populations, except in the setting of peptic ulceration associated with complications (for example, massive hemorrhage or perforation). If repeat diagnostic upper endoscopy is undertaken, biopsies from antrum, body, cardia, and transition zones are recommended in adults. However, published data supporting similar recommendations in children and adolescents are currently lacking. 2. Noninvasive Methods Infection with H. pylori induces a vigorous immune response resulting in the presence of local and systemic antibodies. H. pylori–specific immunoglobulin G antibodies present in serum, plasma, whole blood, saliva, gastric juice, and urine have each been used to successfully detect the presence of infection in adults. The humoral immune response is less vigorous in children. Therefore, the cutoff values established for use in adults to determine the presence or absence of H. pylori infection are not appropriate for use in young children. Increasing concerns have been raised about the utility of testing for antibodies in low-prevalence settings such as is the case for children and adolescents living in developed nations (7). Although immunoassays are relatively inexpensive and technically easy to perform, those employed in children must first be validated in each country or region, using serum samples obtained from relevant populations. Office-based tests using whole blood or saliva have been advocated for use in the diagnosis of H. pylori infection in adults. The accuracy of these methodologies in varying pediatric populations should be the subject of carefully controlled studies before they are employed in the clinical testing using the or as as an alternative to diagnose H. pylori infection Although the of is very are for use in children and years in some nations. testing appears to be highly accurate in children older than years of age, the specific of the testing need to be between Whether the test will to have sufficiently positive and values in is a of current At least in older than years of age, the presence of other in the oral cavity and in the do not provide confounding results. A test has been reported to be highly accurate as a diagnostic test for use in adults. In to in which may for after successful eradication of the the test is reported to a after of H. pylori. The accuracy of the test when used in pediatric populations in a variety of clinical settings testing of Ulcers and H. pylori Infection The of H. pylori has changed the of with peptic ulcers. of the organism recurrence of ulcer Therefore, treatment should now on the eradication of H. pylori. therapeutic agents that heal peptic ulcers including and have no on H. pylori and the accompanying chronic-active antral gastritis. Although proton pump have anti-helicobacter in the agents are not in eradicating the organism in when employed alone as In to antimicrobial agents are not an of response to therapy in the clinical setting Current treatment advocated in a variety of consensus as include a proton pump two two of the or indicate successful eradication in more than of when on an Although controlled studies in children are not available in the case suggest comparable rates of when using the treatment in children may be obtained when treatment provide for a period of is an important consideration because it is a major of the of H. pylori to either or more to In this setting, the use of which can include a treatment may It should be that the use of is not in some (for example, in some for the use of in to H. pylori infection has not been by the appropriate of H. pylori Infection H. pylori two important criteria that it for there is infection in both developing and in adults living in more developed nations. the infection a of in developed nations that sufficient should be to be to support the necessary research required for Moreover, increasing rates of resistance to and with provide additional for Studies in animals indicate that there is potential for the development of a to both H. pylori infection and to bacterial in the stomach. In models of Helicobacter infection, a variety of and are in a the cellular and humoral immune responses that result in successful therapeutic To date, all of the the use of of either or as mucosal The development of that can be employed successfully in animals and humans without the need for the is a for the of the both in the and in the clinical is required to clearly define the of transmission of the organism. Such studies should resolve the reports regarding potential environmental reservoir for H. pylori. The of of the and potential role as a for transmission research and appropriate animal models of infection are required to clearly the natural history of infection. Studies in young children, using validated and highly accurate diagnostic are to clarify the of spontaneous eradication of infection and host responses to gastric by the The if of other than H. pylori, for example, Helicobacter in gastrointestinal and in humans The of gastritis by helicobacter infection to mucosal and intestinal metaplasia in childhood populations in the of gastric cancers in life should be over time. Such studies will to potential confounding including other environmental that on The role of and treatment for H. pylori infection For in children the potential role of as anti-helicobacter therapy in the clinical research setting or with the use of appropriate animal and not simply on data in in the The development of an oral for use in humans, without the need for mucosal is studies and at eradication of established infection in children likely should studies 1 and 2 in nonhuman primates and adult humans to establish and provide evidence of potential The potential for H. pylori to cause clinical symptoms in the absence of mucosal ulceration additional These clinical the use of to definitively establish whether there are of infected children and adolescents have clinical symptoms from gastric infection and the resulting chronic-active non-ulcer and recurrent abdominal pain must be as such studies the use of appropriate age-matched Such research will help to define current regarding appropriate for the diagnosis and treatment of H. pylori infection in children. reports and reports of case will to current in the Additional important clinical research in children. These research include the of accurate indirect diagnostic tests for use in children years of age, a clear of the of in young children after eradication the and of diagnostic tests for use in follow-up of children receiving eradication and the of treatment including the role of testing in this for the research in the identified should be and subject to the of the of to support the necessary research should include traditional the World Health appropriate and with These should be to more support research in this and with of the health children should be in this research of these could be by the development of and should be to the quality research that research In this research can critical in the care setting as well as in children living in a variety of socioeconomic