In 1983, Warren and Marshall reported an association between the presence of Helicobacter pylori in the gastric mucosa and antral gastritis in adults (1). H pylori is a Gram-negative, spiral, flagellated bacterium that colonizes the gastric mucosa in the infected host. H pylori infection has been implicated in the development of gastritis and peptic ulcer disease, as well as chronic atrophic gastritis (2). H pylori infection increases the risk of gastric malignancies such as adenocarcinoma and mucosal-associated lymphoid tissue lymphoma (3). Antral gastritis and duodenal ulcer have been described as common presenting features of H pylori infection in the pediatric population (4,5). It is well known that H pylori infection is acquired in childhood, often before the age of 5 years, through fecal–oral, oral–oral, or gastro–oral transmission (6). The infection may be lifelong in the absence of treatment. Children with symptomatic H pylori infection associated with duodenal and gastric ulcers, lymphoma, or atrophic gastritis with intestinal metaplasia require treatment to eradicate the bacterium (7).
The relation between H pylori and gastroesophageal reflux disease (GERD) has been controversial in published literature in the past decade (8–20). H pylori infection has been associated with a significantly reduced risk of developing GERD, Barrett esophagus, and esophageal adenocarcinoma in contrast to its increased risk for peptic ulcer disease and gastric cancer (8–10). Labenz et al (11,12), who first reported in 1997 that there was an increased risk of development of GERD after H pylori eradication, postulated a possible protective role of H pylori infection. Subsequently, McColl and others (13–17) suggested that H pylori infection may protect against GERD in infected patients who had atrophic gastritis and reduced gastric acid secretion. The regional distribution and severity of gastritis appeared to be a more important risk factor than the mere presence of H pylori in the gastric mucosa (14). However, several papers contradicted Labenz's findings showing that H pylori eradication may not induce GERD symptoms in adults, and in fact the infection may have no association (18–20).
There are limited data regarding the relation between H pylori infection and GERD in the pediatric population (21–24). Levine et al (21) reported that eradication of H pylori was not associated with increased symptoms of GERD in children. Pollet et al (22) found that H pylori eradication did not provoke or worsen GERD in neurologically impaired children. Özçay et al (23) found no significant difference in reflux esophgitis (RE) between children with and without H pylori infection, whereas Daugule et al (24) showed a significantly higher prevalence of H pylori in children with RE compared with children with hyperemic gastropathy.
The aim of this study was to evaluate potential relations between H pylori infection and GERD in pediatric patients on the basis of a retrospective examination of biopsy specimens in conjunction with clinical and demographic characteristics.
PATIENTS AND METHODS
A retrospective chart review of 562 patients who underwent EGD between January 2000 and April 2006 was carried out. One hundred forty-two patients were excluded from the study: 87 patients were eliminated for the absence of either an esophageal or gastric biopsy; 11 were eliminated because their biopsies were unavailable for review by the pathologist; and 44 were eliminated because they had had more than 1 procedure during the time period. A detailed characterization and analysis of the remaining 420 patients (M:F = 214:206) was conducted. The mean age of the study population was 8.2 years (range 0–20 years). The prevalence of GERD in H pylori–positive and H pylori–negative groups was further analyzed on the basis of sex and age (<1 year, 1–10 years, >10 years). In addition, the histologic severity of GERD in both groups was compared using the χ2 test. The indication for the procedures in order of prevalence was as follows: recurrent abdominal pain (n = 186, 44%), malabsorption (n = 80, 19%), persistent vomiting (n = 80, 19%), suspected eosinophilic gastrointestinal disorders (n = 63, 15%), and others such as upper gastrointestinal bleeding or inflammatory bowel disease surveillance (n = 11, 3%) (Table 1).
Endoscopy and Biopsy
All of the endoscopies were performed using videogastroscopes (Pentax, Japan) EG1840, EG2430, or EG2731. Biopsy specimens were taken from the gastric antrum and distal esophagus during the procedure. The specimens were immediately fixed in 10% buffered formalin solution, embedded in paraffin, cut at 4- to 6-μm thick, and stained with hematoxylin-eosin (H&E) for histologic evaluation. All of the biopsies with inflammation were also stained with a modified Diff-Quik stain to identify H pylori. H pylori infection was defined as histologic identification of bacillary forms and gastritis on H&E stain and/or modified Diff-Quik stain. A diagnosis of chronic active gastritis was made on the basis of a stromal lymphoplasmacytic infiltrate in combination with neutrophilic infiltration of the glandular epithelium. The updated Sydney system was used to assess the severity of H pylori gastritis (25). A diagnosis of RE was based on histologic findings of basal cell hyperplasia with eosinophilic exocytosis (in the absence of such findings in the upper esophagus). All esophageal biopsy slides were re-evaluated by a single pathologist for grading of the esophagitis using a modification of the scale suggested by Zentilin et al (26). Biopsy specimens were graded on a 4-point scale; 0/3 = normal, no basal cell hyperplasia, minimal (<3 eosinophils/high-power field (HPF) exocytosis; 1/3 = mild (up to 1/3 of epithelial thickness) basal cell hyperplasia, minimal to mild (between 2 and 8 eosinophils/HPF) exocytosis (mild active esophagitis); 2/3 = moderate (from 1/3 to 2/3 of epithelial thickness) basal cell hyperplasia, moderate (between 10 and 15 eosinophils/HPF) exocytosis (moderate active esophagitis); 3/3 = marked (2/3 to full thickness) basal cell hyperplasia, marked (>20 eosinophils/HPF) exocytosis (severe active esophagitis) (Fig. 1). The study was approved by the institutional review board of Weill Medical College of Cornell University.
The χ2 test and Fisher exact test were used to evaluate the association among patients' demographic characteristics, H pylori status, and RE status. Multivariate logistical regression analysis predicting RE status was used to estimate the odds ratios, 95% confidence intervals, and P value of H pylori status and demographic characteristics. All statistical tests were 2-sided and P < 0.05 was considered statistically significant. Analyses were performed in SAS version 9.1 (SAS Institute, Inc, Cary, NC).
Among the 420 patients (M:F = 214:206), 16 patients had H pylori infection and 167 patients had histologic evidence of RE. The prevalence of H pylori in the entire patient population was 3.8%, and the prevalence of RE was 39.8% (Table 1).
All 16 patients with H pylori had chronic active gastritis in the antrum. The biopsies were graded on the basis of cell infiltration and H pylori density using the updated Sydney system. One patient had mild neutrophilic or mononuclear cell infiltration (grade 1 of 3), 10 had moderate cellular infiltration (grade 2 of 3), and 5 had marked cell infiltration (grade 3 of 3). Nine patients had a mild density of H pylori (grade 1 of 3), 4 had a moderate density (grade 2 of 3), and 3 showed a marked density (grade 3 of 3) (Table 2). No patients had intestinal metaplasia or atrophy in either the antrum or corpus. There was no correlation between the updated Sydney grade of gastritis and the severity of esophagitis.
A total of 13 patients with H pylori had histologic evidence of RE (Table 3). The prevalence of RE in the H pylori–positive patients was 81.3% compared with 38.1% in the H pylori–negative patients (P ≤ 0.05) (Table 4). Among 13 patients with H pylori, 76.9% had grade 1 RE, 15.4% had grade 2 RE, and 7.7% had grade 3 RE (Table 5). Among 154 patients without H pylori, 76.6% had grade 1 RE, 15.6% had grade 2 RE and 7.8% had grade 3 RE. Thus, most of the patients in both groups were found to have grade 1 RE (Table 5).
Nine male patients were positive for H pylori, whereas 7 female patients were positive for H pylori with a prevalence of 4.2% and 3.4%, respectively (Table 3). Ninety-nine male patients had RE (prevalence of 46.3%), whereas 68 female patients had RE (prevalence of 33.0%) (P ≤ 0.05) (Table 4). Both male and female patients with H pylori had a higher prevalence of RE, 77.8% and 85.7%, respectively, compared with those without H pylori (Table 6).
There were no patients with H pylori in the youngest age group (<1 year). In the next age group (1–10 years), the prevalence of H pylori was 3.8%, equal to the prevalence in the entire study population, whereas in the oldest age group (>10 years), the prevalence of H pylori was 5.2% (Table 3). The prevalence of RE in both the second (1–10 years) and the third (>10 years) age groups was 46.7% and 43%, respectively, compared with a lower prevalence of 10.9% in the youngest age group (<1 year) (P ≤ 0.05) (Table 4).
In the second age group (1–10 years), 100% of H pylori–positive patients had RE, whereas 44.6% of H pylori–negative patients had RE (P ≤ 0.05). In the third age group (>10 years), 66.7% of H pylori–positive patients had RE, whereas 41.7% of H pylori–negative patients had RE (Table 6).
On a multivariate logistical regression analysis, H pylori–positive patients had an odds ratio of 5.79 (95% confidence interval 1.6–20.1) for having RE compared with H pylori–negative patients (P ≤ 0.05). Patients between 1 and 10 years and patients older than 10 years had odds ratios of 7.00 (95% confidence interval 3.0–16.3) and 5.99 (95% confidence interval 2.6–14.0), respectively, of having RE compared with patients younger than 1 year (P ≤ 0.05). Furthermore, male patients had an odds ratio of 1.84 (95% confidence interval 1.2–2.8) of having RE compared with female patients (P ≤ 0.05) (Table 6).
Abdominal pain was the most common indication for EGD, 44.3% of all of the indications. Among 186 patients with abdominal pain, only 5.9% of patients had H pylori (P ≤ 0.05), whereas 43% had biopsy proven RE (Tables 1, 3, and 4).
In this study, we report that the prevalence of RE, the biomarker for GERD, among H pylori–positive patients regardless of their age and sex was twice as high as among H pylori–negative patients (81.3% vs 38.1%). On the basis of a multivariate logistical regression analysis, H pylori–positive patients were 6 times more likely to have RE compared with H pylori–negative patients. There was no difference in the apparent severity of RE between H pylori–positive and H pylori–negative patients.
The overall prevalence of H pylori infection in our cohort was 3.8%. Although this is lower than that of some previously published studies (27–31), it is consistent with the reported prevalence of less than 10% in children in developed countries (5,32–35). For example, Mourad-Baars et al (34) reported a low seroprevalence (1.2%) of H pylori infection in young Dutch children. The overall prevalence of H pylori is declining in developed countries (5,32–35) and the rate of infection is largely influenced by several factors, such as socioeconomic status and living conditions (27,36). The low prevalence of H pylori in our study may be attributed to demographic factors in our population. H pylori infection rates among 200 adults in New York City were highest in African Americans (43%), followed by Hispanics (20%), and whites (11%) (37). Our hospital serves a predominantly upper-middle socioeconomic class population. Our pediatric patient population consists of approximately 50% white, 39% African American or Hispanic, and 17% Asian; 70% have private insurance. Furthermore, we speculate that the low prevalence of H pylori, in part, may be explained by the frequent use of antibiotic treatment of other types of infection in children. Monotherapies with common antibiotics such as amoxicillin and clarithromycin can suppress or potentially eradicate H pylori in 10% to 50% of treated subjects (38,39).
Similar to our findings of an increased prevalence of RE in H pylori–positive patients, Daugule et al (24) showed that the prevalence of H pylori was significantly higher among children with RE than in children with hyperemic gastropathy. We also found that H pylori infection was more closely associated with RE in younger children (0–10 years) than in older children (>10 years), although this may be related to an age-specific distribution of H pylori gastritis. Antral predominant nonatrophic gastritis is more common in children, whereas corpus predominant gastritis is more common in adults. Antral predominant nonatrophic gastritis causes increased acid secretion and in turn increases the risk of developing GERD and related complications including RE. All 16 patients with H pylori in our study had antral nonatrophic gastritis. Because this retrospective study did not include biopsy specimens from the corpus, an age-specific distribution of H pylori gastritis was not evaluated.
The limitations of our study include the fact that the data reflect a single clinical center with a low prevalence of H pylori. We did not take account of possible effects of antisecretory agents at the time of endoscopy in evaluating the degree of RE and chronic active gastritis in our study population. In addition, we did not address cytotoxin-associated gene status in H pylori–positive patients in the study.
In conclusion, our study showed that H pylori infection was positively associated with RE. Thus, in the study cohort, H pylori appeared to be a risk factor for this biomarker of GERD. In light of these results, H pylori eradication therapy may be beneficial, especially in younger children.
The authors thank Dr Nirav Patel and Dr Eleanor Tripp for their important work in collecting data.
1. Warren JR, Marshall BJ. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984; 1:1311–1315.
2. Blaser MJ. The role of Helicobacter pylori
in gastritis and its progression to peptic ulcer disease. Aliment Pharmacol Ther 1995; 9(suppl 1):27–30.
3. Palli D, Masala G, Del Giudice G, et al
. CagA+ Helicobacter pylori
infection and gastric cancer risk in the EPIC-EURGAST study. Int J Cancer 2007; 120:859–867.
4. Uc A, Chong SK. Treatment of Helicobacter pylori
gastritis improves dyspeptic symptoms in children. J Pediatr Gastroenterol Nutr 2002; 34:281–285.
5. Wallis-Crespo MC, Crespo A. Helicobacter pylori
infection in pediatric population: epidemiology, pathophysiology, and therapy. Fetal Pediatr Pathol 2004; 23:11–28.
6. Ma JL, You WC, Gail MH, et al
. Helicobacter pylori
infection and mode of transmission in a population at high risk of stomach cancer. Int J Epidemiol 1998; 27:570–573.
7. Gold BD, Colletti RB, Abbott M, et al
. Helicobacter pylori
infection in children: recommendations for diagnosis and treatment. J Pediatr Gastroenterol Nutr 2000; 31:490–497.
8. Celinski K, Slomka M, Kasztelan-Szczerbinska B, et al
. Helicobacter pylori
infection and the risk of adenocarcinoma of the esophagus. Ann Univmariae Curie Sklodowska 2004; 59:424–427.
9. Ahmed N, Sechi LA. Helicobacter pylori
and gastroduodenal pathology: new threats of the old friend. Ann Clin Microbiol Antimicrob 2005; 4:1.
10. Delaney B, McColl K. Review article: Helicobacter pylori
and gastroesophageal reflux disease. Aliment Pharmacol Ther 2005; 22(suppl 1):32–40.
11. Labenz J, Blum AL, Bayerdorffor E, et al
. Curing Helicobacter pylori
infection patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology 1997; 112:1442–1447.
12. Labenz J, Malfertheiner P. Helicobacter pylori
in gastroesophageal reflux disease: causal agent, independent or protective factor? Gut 1997; 41:277–280.
13. McColl KE. Review article: Helicobacter pylori
and gastroesophageal reflux disease – the European perspective. Aliment Pharmacol Ther 2004; 20:36–39.
14. El Serag HB, Sonnenberg A, Jamal MM, et al
. Corpus gastritis is protective against reflux gastrirtis. Gut 1999; 45:181–185.
15. Manes G, Mosca S, Laccetti M, et al
. Helicobacter pylori
infection, patterns of gastritis, and symptoms in erosive and non erosive gastroesophageal reflux disease. Scand J Gastroenterol 1999; 34:658–662.
16. Koike T, Ohara S, Sekine H, et al
. Helicobacter pylori
infection inhibits reflux esophagitis by inducing atrophic gastritis. Am J Gastroenterol 1999; 94:3268–3272.
17. Fallone CA, Barkun AN, Friedman G, et al
. Is Helicobacter pylori
eradication associated with gastroesophageal reflux disease? Am J Gastroenterol 2000; 95:914–920.
18. Schwizer W, Thumshirn M, Dent J, et al
. Helicobacter pylori
and symptomatic relapse of gastroesophageal reflux disease; a randomized controlled trial. Lancet 2001; 357:1738–1742.
19. Guliter S, Kandilci U. The effect of Helicobacter pylori
eradication on gastroesophageal reflux disease. J Clin Gastronterol 2004; 38:750–755.
20. Raghunath AS, Hungin AP, Mason J, et al
. Systematic review: the effect of Helicobacter pylori
and its eradication on gastroesophageal reflux disease in patients with duodenal ulcers or reflux oesophagitis. Aliment Pharmacol Ther 2004; 20:733–744.
21. Levine A, Milo T, Broide E, et al
. Influence of Helicobacter pylori
eradication on gastroesophageal reflux symptoms and epigastric pain in children and adolescents. Pediatrics 2004; 113:54–58.
22. Pollet S, Gottrand F, Vincent P, et al
. Gastroesophageal reflux disease and Helicobacter pylori
infection in neurologically impaired children: inter-relations and therapeutic implications. J Pediatr Gastroenterol Nutr 2004; 38:70–74.
23. Őzçay F, Güraken F, Demir H, et al
. Helicobacter pylori infection and reflux esophagitis in children. Helicobacter 2002; 7:328–329.
24. Daugule I, Rumba I, Alksnis J. Helicobacter pylori infection among children with gastrointestinal symptoms: a higher prevlance of infection among patients with reflux oesophagitis. Acta Paediatrica 2007; 96:1047–1049.
25. Dixon MF, Genta RM, Yardley JM, et al
. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 1996; 20:1161–1181.
26. Zentilin P, Salvarino V, Mastracci L, et al
. Reassessment of the diagnostic value of histology in patients with GERD, using multiple biopsy sites and an appropriate control group. Am J Gastroenterol 2005; 100:2299–2306.
27. Opekun AR, Gilger MA, Denyes SM, et al
. Helicobacter pylori
infection in children of Texas. J Pediatr Gastroenterol Nutr 2000; 31:405–410.
28. Chong SKF, Lou Q, Zollinger TW, et al
. The seroprevalence of Helicobacter pylori
in a referral population of children in the United States. Am J Gastroenterol 2003; 98:2162–2168.
29. Gold BD. Helicobacter pylori
infection in children. Curr Probl Pediatr Adolesc Health Care 2001; 31:247–266.
30. Raymond J, Bergeret M, Benhamou PH, et al
. A 2 year study of H. pylori
in children. J Clin Microbiol 1994; 32:461–463.
31. Rosioru C, Glassman MS, Halata MS, et al
. Esophagitis and Helicobacter pylori
in children: incidence and therapeutic implications. Am J Gastroenterol 1993; 88:510–513.
32. Ashorn M, Maki M, Hallstrom M. H. pylori
infection in Finnish children and adolescents. Scand J Gastroenterol 1995; 30:876–877.
33. Blecker U, Hauser B, Lanciers S, et al
. The prevalence of H. pylori
positive serology in asymptomatic children. J Pediatr Gastroenterol Nutr 1993; 16:252–256.
34. Mourad-Baars PE, Verspaget HW, Mertens BJ, et al
. Low prevalence of Helicobacter pylori
infection in young children in the Netherlands. Eur J Gastroenterol Hepatol 2007; 19:213–216.
35. Chen Y, Blaser M. Helicobacter pylori
colonization is inversely associated with childhood asthma. J Infect Dis 2008; 198:553–560.
36. Jacobson K. The changing prevalence of Helicobacter pylori
infection in Canadian children: should screening be performed in high risk children? Can J Gastroenterol 2005; 19:412–414.
37. Straus EW, Patel H, Chang J, et al
. H. pylori
infection and genotyping in patients undergoing upper endoscopy at inner city hospitals. Dig Dis Sci 2002; 47:1575–1581.
38. Israel DM, Hassall E. Treatment and long-term follow-up of Helicobacter pylori
-associated duodenal ulcer disease in children. J Pediatr 1993; 123:53–58.
39. Peterson WL, Graham DY, Marshall B, et al
. Clarithromycin as monotherapy for eradication of Helicobacter pylori
: a randomized, double-blind trial. Am J Gastroenterol 1993; 88:1860–1864.