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Influence of Helicobacter pylori Eradication on Gastroesophageal Reflux Symptoms and Epigastric Pain in Children and Adolescents

Arie Levine, MD^*, Tamir Milo, MD, Efrat Broide, MD^¶, Eitan Wine, MD, Ilan Dalal, MD, Mona Boaz, PhD^||, Yona Avni, MD and Haim Shirin, MD

^* Pediatric Gastroenterology Unit
Department of Pediatrics
Gastroenterology Division
^|| Epidemiology Unit, Edith Wolfson Medical Center, Holon, Israel
^¶ Pediatric Gastroenterology Unit, Assaf Harofe Medical Center, Holon, Israel

	ABSTRACT

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Objective. Conflicting reports have noted a possible association linking eradication of Helicobacter pylori with aggravation of gastroesophageal reflux (GER) disease. We prospectively evaluated the effect of eradication of H pylori on GER symptoms and epigastric pain and the association among these 3 parameters in a pediatric cohort.

Methods. Patients who were referred for gastroscopy were evaluated for frequency, severity, and nocturnal presence of symptoms related to GER as well as epigastric pain. Patients who were positive for H pylori received triple antibiotic therapy. The patients were followed for at least 6 months after therapy. Patients with successful eradication had symptoms compared with their pre-eradication state and were compared with a cohort of patients without H pylori or those with persistent H pylori.

Results. Of 119 children and adolescents who were recruited, 95 patients completed the study, with a mean follow-up of 11.2 months. The distribution of outcomes for each GER symptom (better, worse, unchanged) was similar before and after eradication and did not depend on prior H pylori status. Among patients with GER and epigastric pain, improvement in epigastric pain was significantly correlated with the improvement in GER symptoms but not with eradication of H pylori.

Conclusions. Eradication of H pylori is not associated with increased symptoms of GER in children and adolescents. Improvement in epigastric pain in children is significantly correlated with the improvement in GER symptoms but not with eradication of H pylori.

Key Words: gastroesophageal reflux • Helicobacter pylori • child • esophagitis • abdominal pain • dyspepsia

Abbreviations: GER, gastroesophageal reflux

Helicobacter pylori infection has been implicated in the development of gastritis and duodenal and gastric ulcers. In patients with clinical symptoms and endoscopic findings supporting H pylori–related disease, the indication for eradication of the organism by a combination of antibiotics along with a proton pump inhibitor is clear cut.¹ However, a large cohort of patients will be found to have H pylori infection, although it is not the cause of their symptoms. These patients are also at increased risk for developing long-term H pylori–related morbidity such as peptic disease or neoplasia.^2,3 The theoretical benefits involved in decreasing the lifetime risk have to be weighed against drawbacks of trying to eradicate the organism. Aside from increasing resistance to antibiotic therapy, the major concern related to eradication has been the possible emergence of gastroesophageal reflux (GER) and its sequelae.

The hypothesis that eradication of H pylori may be deleterious is based on theoretical grounds as well as epidemiologic and clinical studies. H pylori has been found to be inversely correlated with the prevalence of reflux esophagitis, and certain studies have shown aggravation of esophagitis with eradication.^4–9 Suggested mechanisms include presence of atrophic or significant body gastritis leading to a posteradication increase in acid secretion; decreased buffering as a result of elimination of H pylori, which produces ammonia via bacterial urease; masking of reflux by acid neutralizing medications given for H pylori–related disease; and increased appetite with weight gain–mediated reflux. These observations are controversial, because several studies have not found a correlation between eradication of H pylori and reflux disease.^10–14 The interaction between H pylori and reflux symptoms has not been studied prospectively in children and adolescents.

Abdominal pain in children is often poorly localized or periumbilical and has not been found to be related to H pylori. Studies evaluating the relationship between H pylori or GER and abdominal pain^14,15 in children have not focused specifically on epigastric pain, a true peptic symptom. The relationship between epigastric pain and GER has not been evaluated prospectively in children. To answer these questions, we evaluated the effect of H pylori eradication on GER symptoms and epigastric pain in this age group.

	METHODS

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This was a prospective study conducted from 1999 to 2002 in symptomatic children and adolescents who were aged 8 to 19 and referred for gastroscopy because of upper abdominal pain, reflux symptoms, vomiting, hematemesis, and abdominal pain with weight loss. It was performed at 2 hospitals in central Israel. These hospitals serve a mostly lower socioeconomic region of central Israel, with a high prevalence of H pylori infection. Patients were interviewed by participating physicians and filled out a questionnaire that was compiled from a simplified modification of the questionnaire evaluated by Locke et al¹⁶ in adults that addresses both presence and severity of GER disease. We chose this method in the absence of a validated pediatric severity scale for older children. Physicians evaluated the presence of 2 key symptoms, heartburn and regurgitation, reported to be the most specific symptoms and used for assessment in multiple studies,¹¹ as well as 3 different measures of disease activity: severity of heartburn, frequency, and nocturnal presence of the symptom. Nocturnal presence was defined as a symptom that awakened a patient from sleep. We also evaluated epigastric pain (as opposed to abdominal pain), usually considered a dyspeptic symptom, using the same method, to assess the association among epigastric pain, H pylori, and GER.

After consent was obtained, patients and parents received clarification by a participating physician about grading and symptoms, including examples. The same physician reviewed the form with the patients. There were 4 possible answers for frequency of symptoms: less than once a week, once a week, several times a week, or daily. Severity was analyzed by an analog scale from 1 to 10, where 1 is the mildest and 10 is the severest. The severity scale was explained in simple terms with examples. Symptoms off therapy were reevaluated at each visit.

Patients who were positive for H pylori infection by histology from an antral biopsy and a rapid urease test (CUTest; Temmler Pharma, Marburg, Germany) were treated with a combination of omeprazole and 2 antibiotics (clarithromycin and amoxicillin, or metronidazole if penicillin allergy was reported) for 7 days. Patients with gastritis, duodenitis, or an ulcer received omeprazole for an additional month, whereas patients with esophagitis received omeprazole for 2 months. Patients with evidence of H pylori were invited back for a ¹³C urea breath test to evaluate eradication at least 6 weeks after completion of therapy. The same symptom assessment was performed at 6 months and at continued follow-up visits until termination of the study. Patients who were still positive for H pylori after the initial treatment were offered a second course of the alternative treatment regimen. Patients who refused or did not take the therapy were not excluded and served as a noneradicated control group.

Patients were considered to have possible GER when they had erosive esophagitis (LA grading system), the presence of heartburn, or regurgitation and vomiting at least once a week for >1 month at entry. GER was considered to be worse at follow-up when the frequency of a symptom was both greater than once a week and had increased or when the severity had increased by at least 3 points or new nocturnal symptoms were present. A decrease in the same criteria (disappearance of symptom, decreased frequency, decreased severity, or disappearance of nocturnal symptoms) were used to define improvement.

Patients were excluded at entry when they could not understand or fill out the form; had an eating disorder, gastrostomy tube, or gastric outlet obstruction; had a history of gastric surgery or fundoplication; or H pylori status was not ascertained at gastroscopy from 2 antral biopsies and a rapid urease test. Biopsies were also taken from abnormal-appearing tissue. Patients were excluded when they did not perform a follow-up breath test, did not have at least 6 months of follow-up, or had received antibiotics or antireflux medication for 7 days before the breath test or gastroscopy.

For judging the effect of eradication on reflux symptoms and epigastric pain, patients with eradicated H pylori had symptoms compared with baseline and were also compared with a group without H pylori and with patients with H pylori that was not eradicated. Patients who were negative for H pylori were classified as group 1, those with H pylori and successful eradication by breath test were defined as group 2, and patients with unaltered status (continued H pylori infection) were defined as group 3. This study was authorized by an institutional review board.

	Statistics

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Descriptive statistics for continuous data were determined and are reported as mean ± standard deviation. All data were visually scanned for normalcy of distribution. Means of normally distributed data were compared using the t test for independent samples entering patient group (eradicated for H pylori vs others) as the categorical variable. Frequency counts were conducted for nominal data and are reported as absolute value (%). These values were cross-tabbed and compared by patient group using the ² test. In addition, in the group eradicated for H pylori only, frequency and severity of symptoms (epigastric pain, heartburn, vomiting) were compared before and after eradication using the Wilcoxon signed rank test. Nocturnal symptoms, a dichotomous variable, were compared before and after H pylori eradication using the McNemar test. The correlation between epigastric pain and heartburn at follow-up was performed with Spearman rho. The difference in outcome of epigastric pain by absence or presence of heartburn was calculated by Fisher exact test. Univariate general linear modeling was used to evaluate whether eradication of H pylori or improvement in heartburn or reflux symptoms best predict improvement in epigastric pain. All tests were considered significant at P < .05.

	RESULTS

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Patient Data
During the study, 119 patients were enrolled. Twenty-two patients (16 H pylori positive, 6 H pylori negative, 2 patients with nodular gastritis) were lost to follow-up, and 2 patients were excluded because of breath test exclusion criteria. The remaining 95 patients served as the study population. There were 58 girls and 37 boys (mean age: 14.2 ± 3.3 years). The mean follow-up for all patients was 11.2 months. Fifty-five patients were positive for H pylori at gastroscopy. Pathologic endoscopic findings at gastroscopy among patients who were included in the study were erosive esophagitis in 7 (5 H pylori positive), antral or body gastritis in 13 (11 H pylori positive), duodenitis in 4 (all H pylori positive), and duodenal ulcer in 3 (all H pylori positive). These patients had evidence of microscopic inflammation as well. Mild atrophic gastritis was found only in 1 patient with collagenous gastritis. Eradication was offered in all 55 patients. Four patients declined or did not take the therapy. Of the remaining 51 patients, 42 underwent successful H pylori eradication, an initial rate of 82.4%. Nine patients were retreated, and 2 of these patients’ H pylori was eradicated by retreatment (overall eradication rate 86.3%). Altogether, we divided our patients into 3 groups. Patients without H pylori were designated group 1 (N = 40), patients with successful eradication were defined as group 2 (N = 44), and patients with persistent H pylori were designated group 3 (N = 11). Entry data for these groups (Table 1) indicate that they were similar in age, severity of epigastric pain, and GER symptoms at baseline.

Effect of Eradication on Reflux Symptoms
The effect on overall reflux, as manifested by worsening of any symptom (the endpoint), was not different between any of the groups. There was no significant deterioration or improvement for any specific reflux symptom or for overall reflux state between baseline or after treatment in patients whose H pylori was eradicated. This was true for both frequency and severity analysis. Data regarding effect of H pylori eradication on GER symptoms (any change) and comparison between groups are presented in Fig 1.

View larger version (29K): [in this window] [in a new window]   Fig 1. Overall change in reflux symptoms by H pylori status at follow-up (mean follow-up: 11.2 months). Group 1, H pylori negative; group 2, H pylori positive after eradication; group 3, H pylori positive, eradication failure.

View larger version (23K): [in this window] [in a new window]   Fig 2. Change in specific reflux symptoms over time by group. Group 1, H pylori negative; group 2, H pylori positive after eradication; group 3, H pylori positive, eradication failure.

Reflux Symptoms and Epigastric pain
Epigastric pain was present in 29 of 35 patients with frequent heartburn (at least twice a week for >1 month) at baseline. Univariate general linear modeling demonstrated that improvement in epigastric pain during follow-up was significantly correlated with improvement in reflux symptoms (P < .01) but not with H pylori eradication. Presence of epigastric pain at follow-up was found to be significantly correlated with the presence of heartburn (correlation coefficient: 0.837).

	DISCUSSION

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In our study, the change in GER symptoms after H pylori eradication was not worse than the initial baseline symptoms or the rate found in an age- and reflux-matched control group that did not have a change in H pylori status. Indeed, worsening of symptoms may not be the proper outcome to measure, as patients can also improve. In fact, a larger group (34%) of patients whose H pylori was eradicated showed improvement in reflux symptoms, although this was not statistically significant. The final outcome, as measured by the distribution of any outcome (reflux symptoms worse, same, or better) in both groups, was not significant between groups or within groups. This was also true for the individual symptoms, when evaluated for both frequency and severity, and in patients with esophagitis at entry. Although the cohort was not large, these data indicate that H pylori eradication does not seem to aggravate GER. The similar distribution of symptom outcomes in groups 1 and 2 argues against a protective or a harmful role of H pylori in reflux symptoms in this age group, at least in the short term. Because we did not evaluate the presence of esophagitis after therapy, we cannot directly compare our results with the previously mentioned adult studies.^4,8

Most studies aimed at evaluating the effect of H pylori eradication on reflux in adults have used selected populations such as with duodenal ulcer or patients with GER before eradication.^4,10–12 The spectrum of risk factors found in adults, such as atrophic gastritis, duodenal ulcer, or significant esophagitis, may influence the outcome of the study. These factors are less common in children and do not reflect the patient population that has to be addressed in making the decision to eradicate H pylori when found.

Dent¹⁷ proposed that the outcome of H pylori eradication on gastroesophageal reflux is most likely determined by the population studied. Acid secretion in predominant antral gastritis with preserved body mucosa is hyperresponsive, thus enabling increased duodenal or esophageal injury. In these patients, eradication should improve or not affect reflux. This hypothesis is consistent with the results of other studies^1–12,18 that showed improvement in reflux symptoms in patients with duodenal ulcer. However, in patients with atrophic gastritis or severe body gastritis, H pylori eradication may result in increased acid secretion. Children and adolescents are more likely to behave like the first group, with predominant antral gastritis. In our study, we did not attempt to evaluate any connection between H pylori and the pathophysiology of reflux.

Any study evaluating reflux as an outcome is hampered by the absence of a single uniform valid scale for outcome.^10,16,19 Many of the symptoms that are present in questionnaires for adults would be overrepresented in the pediatric age group, making comparisons difficult. Heartburn and acid regurgitation are considered the most specific symptoms of GER in adults.^20,21 These data are not available in older children. We attempted to evaluate clinically relevant key symptoms that are prevalent in childhood,^14,22 which included the most specific aforementioned symptoms.

In our study, nearly two thirds of patients who had GER and were referred for gastroscopy had epigastric pain. Among patients with heartburn and epigastric pain, H pylori eradication was not associated with improvement in pain. Improvement in reflux symptoms, however, was significantly correlated and a strong predictor of improvement in epigastric pain. These findings suggest that epigastric pain is associated with and parallels GER in children. Children who present with epigastric pain may not initially have reflux symptoms, and the diagnosis of GER will not be entertained. Physicians may tend to focus on the presence of H pylori instead of the presence of a reflux symptom as being the clue to the cause of epigastric pain.

	CONCLUSION

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We have found that eradication of H pylori is not associated with increased symptoms of GER in children and adolescents. However, improvement in epigastric pain in children is significantly correlated with improvement in GER symptoms but not with eradication of H pylori.

	FOOTNOTES

 
Received for publication Feb 18, 2003; Accepted May 15, 2003.

Reprint requests to (A.L.) Pediatric Gastroenterology Unit, Edith Wolfson Medical Center, POB 5 Holon 58100, Israel. E-mail a-levine{at}inter.net.il

	REFERENCES

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