Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Gastroenterology
Positive Association Between Helicobacter pylori and Gastroesophageal Reflux Disease in Children
Moon, Aeri*; Solomon, Aliza*; Beneck, Debra†; Cunningham-Rundles, Susanna‡
*Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, USA
†Department of Pathology, USA
‡Department of Pediatrics, Division of Hematology/Oncology, Host Defenses Program, Weill Medical College, Cornell University, New York, NY, USA
Received 26 April, 2007
Accepted 21 September, 2008
Address correspondence and reprint requests to Aeri Moon, MD, Weill Medical College of Cornell University, 505 East 70th St, 3rd Floor, New York, NY 10021 (e-mail: firstname.lastname@example.org).
Dr Solomon is the recipient of an NIH NCIR25 fellowship. The study was supported in part by NIH NCI P30 CA29502, NIH NCI R25 105012, and the Children's Cancer and Blood Foundation.
The authors report no conflicts of interest.
Objectives: The role of Helicobacter pylori (H pylori) in gastroesophageal reflux disease (GERD) remains controversial, particularly in children, because there are limited published data. Adult studies suggested that H pylori infection may protect against GERD by causing atrophic gastritis, which leads to reduced gastric acid secretion. The objective of our study was to determine the role of H pylori infection in the development of GERD in a pediatric population.
Patients and Methods: A retrospective analysis of 420 patients (M:F = 214:206) who underwent esophagogastroduodenoscopy (EGD) with biopsies between January 2000 and April 2006 was conducted. Patient demographics, clinical indications for EGD and the prevalence of reflux esophagitis (RE), the biomarker for GERD, in 2 groups, H pylori positive and H pylori negative, were reviewed. The prevalence of RE in the 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). The mean age of the study population was 8.2 years (range 0–20 years). The clinical indications for EGD were 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%). Statistical analysis was performed by using χ2 test, Fisher exact test, and multivariate logistical regression analysis.
Results: Among the 420 patients, 16 patients (3.8%) were positive for H pylori and 167 patients (39.8%) were found to have RE. Thirteen patients with H pylori were found to have histologic evidence of RE. The prevalence of RE in the H pylori–positive population was 81.3% compared with 38.1% in the H pylori–negative population (P ≤ 0.05). There were no patients with H pylori in the youngest age group. In the second age group (1–10 years), 100% of the H pylori–positive patients had RE, whereas 44.6% of the H pylori–negative patients had RE (P ≤ 0.05). Both male and female patients with H pylori had a higher prevalence of RE, 77.8% and 85.7%, respectively. On a multivariate logistical regression, for the overall study cohort, H pylori–positive patients had an odds ratio of 5.79 of developing RE compared with H pylori–negative patients (P ≤ 0.05).
Conclusions: Our study results indicate that there is a significantly higher prevalence of RE in an H pylori–infected cohort independent of age or sex. The findings suggest that H pylori infection in children is positively associated with RE.
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.
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