Helicobacter pylori in Childhood: New Insights Into the Immunopathogenesis of Gastric Disease and Implications for Managing Infection in Children

Helicobacter pylori has become recognized as a pathogen that causes gastritis, peptic ulcer, and some forms of gastric cancer. Although most of the more severe clinical manifestations of this infection appear in adults, epidemiologic studies show that the acquisition of infection usually occurs in childhood. Our understanding of the pathogenesis of the various gastric diseases associated with this infection suggests that the gastric mucosal damage resulting from the infection is progressive. The notion that infection in children progresses to disease in adulthood raises the possibility that the prevention or treatment of childhood infection may be indicated. However, a "screen-and-treat" policy has not been universally adopted, because a minority of infected people actually experience development of peptic ulcers or gastric cancer, and the treatment itself has risks and favors the potential development of antibiotic resistance. One of the impediments to planning when to intervene in the pediatric population has been the paucity of information regarding the nature of the interaction between different strains of H. pylori and the various host responses in the gastric mucosa of infected children. Although the host response includes processes such as changes in hormone or acid production, epithelial cell restitution, and inflammation, this review focuses on the current views regarding the immunopathogenesis of gastric disease associated with H. pylori infection. Finally, the gastric immune response that may be induced by H. pylori vaccines currently under development is briefly described and compared with the changes observed during natural infection. MICROBIOLOGY H. pylori is a gram-negative organism that resides under microaerobic conditions in a neutral microenvironment between the mucus and the superficial epithelium. Two primary morphologic shapes, bacillary and coccoid, have been described for this organism (1). Although the bacillary forms are clearly the predominant, viable type of H. pylori, the coccoid morphology is easily observed in culture and in some patients (1). The biologic relevance of each morphologic form is not clearly understood, although it is thought that the bacillary morphology is the more virulent form, whereas the coccoid morphology is either nonviable or a form that protects the organisms in dormancy. This organism is highly motile with multiple unipolar flagella. Biochemically, H. pylori produces enzymes including catalase, oxidase, and urease. It is the urease that allows this organism to metabolize urea to help neutralize luminal acid during colonization. The H. pylori urease enzyme also provides a useful, rapid diagnostic tool for invasive (upper endoscopy) and noninvasive (breath analysis) tests. (2). In addition to detecting urease, other diagnostic techniques such as serology, bacterial culture, and direct histologic visualization have been used in characterizing the epidemiology of this infection in humans. EPIDEMIOLOGY OF H. PYLORI INFECTION IN HUMANS Patterns of Transmission Our understanding of the epidemiology of pediatric H. pylori infection is somewhat limited, because most epidemiologic studies of gastric infection have been performed in adults. Nonetheless, much has been learned from the descriptions of the prevalence of H. pylori infection and its association with gastroduodenal disease, even though there is a notable lack of investigations focused on the incidence of this infection. The paucity of information on the prevalence of infection is attributable to the difficulty in determining when the infection is initially acquired. Unlike other enteric infections such as Escherichia coli, Salmonella, and Shigella, in which the onset of easily recognized symptoms is invariably associated with the initial infection, acute, natural H. pylori infection is not known to be associated with specific clinical signs. The risk factors for infection of children include familial overcrowding, endemic country of origin, poor socioeconomic circumstances, and certain ethnic backgrounds. Thus, the incidence of H. pylori infection is estimated to be between 3% and 10% per year in countries with emerging economies in contrast to approximately 1% per year in wealthier countries. For example, incidence rates in Bolivian children appear very high, particularly in the 2- to 4-year-old age group, with more than 70% of 10-year-old children infected (Ben Gold et al., unpublished observations, May 1998). Conversely, incidence in children living in the southeastern United States is just over 1.2% per year, with 12% to 15% of 10-year-old children infected. The prevalence rates among African-Americans and Hispanics in the United States are notably similar to those of people residing in developing countries (3), although this may be largely attributable to socioeconomic status (4,5). Humans seem to be the primary natural reservoir of H. pylori infection, although other putative sources include water (6,7), domestic cats (8), and houseflies (9,10). The route of transmission of H. pylori is postulated to be fecal-oral or oral-oral (11). This is supported in studies in which H. pylori DNA has been identified in the dental plaque and saliva of adults and children, by using polymerase chain reaction to amplify bacterial DNA to levels that permit detection (12). The mouth may be a reservoir for this infection or an initial site of colonization before seeding of the stomach and colonization of the gastric epithelia. Water was first proposed as an environmental source of H. pylori infection in a study of Peruvian infants. Using 13C breath testing to detect infection in these young patients, an epidemiologic association was observed between contaminated water and the high prevalence of this infection. Evidence for the presence of H. pylori in water has been based on various techniques (immunomagnetic beads, fluorescent microscopy, and polymerase chain reaction) that do not identify viable organisms. Detection of H. pylori with these techniques, combined with the epidemiologic evidence that associates contaminated water and the presence of infection in humans, suggests that water may be one mode of transmission (13). However, direct evidence that this organism can survive in water has not been found. Despite the variety of postulated reservoirs, the actual impact of each one of these potential environmental sources for human infection with H. pylori has not been determined. Thus, it is difficult to prevent infection through the manipulation of the host's environment, given that the different putative reservoirs, the mode of person-to-person transmission, and the specific pediatric population at risk are poorly understood. Gastritis and Peptic Ulcer Associated With H. pylori Infection in Childhood Soon after Marshall and Warren (14) reported an association between the presence of H. pylori in the gastric mucosa and antral gastritis in adults, this association was also noted in children (15). However, critics of the conclusions that H. pylori plays a role in gastritis have argued that the bacteria are colonizing inflamed tissue rather than causing the inflammation (16). Gastritis is a less frequent finding in children, thereby allowing investigations of pediatric H. pylori as a cause of gastritis, rather than an opportunistic infection of inflamed tissue. Although the bacteria are not a common finding on the gastric mucosa of children with secondary causes of gastritis (e.g., eosinophilic gastroenteritis and Crohn's disease) (17), H. pylori is present in most children with gastritis (15). This observation implicates H. pylori as a cause of chronic antral gastritis. However, the observation that eradication of H. pylori from the gastric mucosa resolves antral gastritis provides the most compelling evidence in favor of H. pylori as the cause of primary gastritis in children (18). In addition to chronic gastritis, H. pylori has been identified as a cause of recurrent peptic ulcers (19,20). It is now estimated that the lifetime risk for development of peptic ulcer disease in H. pylori-infected people is approximately 10% (21). The recurrence rate of duodenal ulcers is markedly reduced after successful treatment of H. pylori infection (22,23). Almost all peptic ulcers in children are located in the duodenum, and gastric ulcers are extremely rare (24). Similar to findings in adults, duodenal ulcers in the absence of H. pylori are uncommon in children unless they are receiving nonsteroidal anti-inflammatory drugs (25,26). Moreover, it has been demonstrated that duodenal ulcer disease in children also does not relapse if infection with H. pylori is cleared from the gastric mucosa (24). However, because the prevalence of this infection in developed countries continues to decrease, the relative proportion of peptic ulcers not associated with H. pylori increases, unless other risk factors are avoided. H. pylori and Gastric Cancer Gastric adenocarcinoma is more common in developing nations and lower socioeconomic classes of the industrialized world (27). In many countries of Latin America and Asia, gastric adenocarcinoma remains the most common malignancy among men and the second most common among women. Incidence rates are as high as 80 per 100,000 people in regions of Colombia and Japan. By contrast, gastric cancer afflicts fewer than 10 per 100,000 people per year in the United States and western Europe. Within low-risk countries, there are ethnic groups with increased risk. 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