Helicobacter pylori has been recognized as an important etiological factor in the development of chronic gastritis and peptic ulcer disease in adults and children (1). All components of the inflammatory response to H pylori observed in adults are present in children (2,3). Host and bacterial factors dictate eventual significant disease phenotypes, and the age of acquisition of the bacteria has been proposed as an important factor for the later adverse outcomes (4,5). Early H pylori infection is associated with a high risk for the development of peptic ulcer and gastric cancer (5–7), probably owing to the severe inflammation and development of atrophic gastritis (8). In most developing countries, the high prevalence of H pylori infection in children contributes to chronic infection in the majority of young adults and elderly adults (4,5).
The histopathological changes associated with H pylori infection are well defined in adults but less conclusive in children (9–11). Children, in general, experience less inflammation than adults and display an inflammatory process whose intensity and type vary depending on their geographic location (11). There are different histological expressions of H pylori–associated inflammation in children compared with adults, which suggest that specific pediatric aspects of H pylori–associated gastritis may be envisaged (9,10).
The most reliable method for diagnosing H pylori infection is directly from endoscopic biopsies (12), and the major reasons for endoscopy referral of children include chronic epigastric or abdominal pain, with or without vomiting (13). Whether H pylori gastritis causes abdominal pain in the absence of peptic ulcer disease is still debatable (14), but studies are required to determine whether subsets of children with abdominal pain can be identified in whom signs and symptoms are caused by H pylori infection.
Therefore, we performed a cross-sectional case-control study on children and adolescents from southern Brazil with chronic nonulcer dyspepsia to investigate the histopathological lesions associated with H pylori infection. The potential associations with clinical findings in the upper gastrointestinal tract were also evaluated.
A total of 471 consecutive children and adolescents with chronic abdominal pain, according to Apley criteria (15), were attended at the Outpatient Pediatric Gastroenterology Clinic of the Department of Pediatrics of Botucatu Medical School, Botucatu, São Paulo, Brazil, from January 2006 to December 2010. Of them, 196 patients, with chronic dyspeptic syndrome (epigastric pain, postprandial fullness, retrosternal pain, early satiety, upper abdominal distention, nausea, retching, belching, and vomiting for at least 2 days/week, for a period of at least 3 months) suggestive of organic underlying disease (16), were submitted to upper gastrointestinal endoscopy. They were between 4 and 17 years old; had normal hematology, urine analysis, and culture; normal plain radiograph of abdomen; and 3 routine stool examination without any ova or cysts. Patients with a history of gastric surgery, active gastrointestinal bleeding, duodenal ulcer, and gastric ulcer were excluded from the study. None of the patients had received antisecretory drugs (H2 receptor blockers and proton pump inhibitors), bismuth compounds, recent use of nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, or immunosuppressive drugs, in the preceding 4 weeks of endoscopy. A standard clinical protocol was applied on the day of the upper gastrointestinal endoscopy. Anthropometric data were assessed according to World Health Organization growth standards.
Endoscopy was performed by 1 of the authors (E.V.P.O.) using an Olympus GIF videoendoscope (Olympus America, Center Valley, PA) combined with biopsy forceps. The endoscopic findings were recorded as normal gross appearance, hyperemia, nodularity, erosions, and ulcers. Tissue samples were collected from the lesions, whenever present. At least 4 biopsy specimens were collected during endoscopy: 1 sample from the distal esophagus, 2 from the gastric antrum, and 1 from the corpus (17). One biopsy sample from the antrum was used for an immediate rapid urease test (Renylab uretest, Barbacena, Brazil).
Definition of H pylori Status
Patients were considered to have H pylori infection if the rapid urease test was positive, and the histological examination of the gastric mucosa confirmed the presence of the bacterium and noninfected when both tests produced negative results. If the patient had only 1 positive test, then the patient was not included in the study.
Biopsy specimens were fixed in 10% neutral buffered formalin solution, processed for histology, and embedded in paraffin. Serial longitudinal 4-μm sections were stained with hematoxylin-eosin and giemsa for assessment of H pylori colonization. The histopathological slides were analyzed by 2 authors (M.A.M.R. and M.A.C.), who were unaware of the clinical and endoscopic findings and jointly reached a consensus on the score of the histological variables. Only cases with 2 adequately sized biopsies and with at least 1 gastric biopsy were accepted for histological assessment. Gastric biopsies were analyzed separately from esophageal biopsies.
Gastritis Scores, Topographic Distribution, and Grading
The diagnosis of gastritis was based on the histopathological findings of inflammation and activity scored according to the updated Sydney system (18), using a visual-analogue scale: acute inflammation (0–3), chronic inflammation (0–3), atrophy (0–3), and intestinal metaplasia (0–3). Density of H pylori colonization was analyzed histologically using a visual-analogue scale, proposed by the Sydney system guidelines to quantify the amount of bacteria on the histological sections of the gastric mucosa. Additionally, lymphoid aggregates and surface epithelial damage, such as erosions, were noted.
The phenotypic pattern of pangastritis was defined if inflammation was distributed throughout the stomach, with little or no difference between antrum and corpus. Antral-predominant gastritis was defined if there was a moderate to severe inflammation in the antrum and a normal to mild inflammation in the corpus. Corpus-predominant gastritis was considered if there was moderate to severe inflammation in the corpus and normal to mild inflammation in the antrum.
A semiquantitative assessment of the combined severity of polymorphonuclear and mononuclear cell inflammation scored in both antral and corpus biopsy samples was performed (19). Grades ranged from 0 (absence of inflammatory cells in any of the specimens) to IV (an extremely dense infiltrate in all biopsy samples).
The histopathological diagnosis of esophagitis was performed by 2 methods (20,21) as recommended by ESPGHAN (22). The scores were graded 0, Ia, Ib, Ic, II, III, IV, and V. To simplify the comparison between the methods, hyperplasia of basal cells (Ia), lengthening of the papillae (Ib), and dilatation of intraepithelial vessels (Ic), were grouped and defined as grade I.
The statistical analysis was performed using GraphPad Prism version 4.0 (LaJolla, CA). Calculation of the mean, standard deviation, median, and 95% confidence interval was performed for all quantitative variables. Qualitative variables were described by counts and percentages. The nonparametric Mann-Whitney test was used for statistical comparisons between quantitative variables; the chi-square test or Fisher exact test was used for statistical comparisons between categorical variables. Tests of association between different variables were performed using the Spearman rank correlation test. All statistical tests were 2-sided and values of P < 0.05 were considered statistically significant.
The study was approved by the local hospital ethical committee. Informed consent was obtained from the parents of all enrolled subjects and assent was obtained from subjects aged 10 years and older.
Patients’ Characteristics and Clinical Data
A total of 196 symptomatic children and adolescents with chronic abdominal pain and clinical criteria for chronic dyspeptic syndrome (age range 4–17 years, mean age 9.5 ± 2.7 years) were considered eligible for the study. Eleven patients were not included because of disagreement between the results on the urease test and the histological examination of the gastric mucosa. Of the 185 patients analyzed, 96 (51.8%) presented H pylori infection and 89 (48.2%) were noninfected. All of the patients were from the same geographical area of southern Brazil and 117 (63.2%) were girls. The groups were homogeneous, except for age at endoscopy. Patients with H pylori infection were significantly older than noninfected subjects (9.9 ± 2.8 vs 9.0 ± 2.6 years). The results of demographics and clinical characteristics are summarized in Table 1.
All of the patients had chronic abdominal pain and chronic dyspepsia as including criteria. The most common presenting symptoms were epigastric pain, nonepigastric abdominal pain, vomiting, retrosternal pain, and anorexia, respectively, 87%, 13%, 39%, 53%, and 40% for the group with H pylori infection, and 85%, 15%, 52%, 54%, and 32% for the noninfected group. There was no difference among the proportion of symptoms between H pylori–infected and noninfected groups. The main endoscopic finding was nodularity in the gastric antrum, identified in 45 (46.8%) children with H pylori infection. From the 89 patients in the noninfected group, 69 (77.5%) had a final diagnosis of gastroesophageal reflux disease, 18 (20.2%) functional dyspepsia, and 2 (2.3%) eosinophilic gastroenteropathy.
H pylori Infection and Histopathology
The histopathological analysis was performed in all of the 185 cases. Biopsy samples from the antrum were available in 183 patients, from the corpus in 171, from antrum and corpus in 169, and from esophagus in 181 patients. There was no difference for number of gastric and esophageal biopsies among H pylori–infected and noninfected groups.
The scores for the histopathological parameters analyzed in samples from the antrum and corpus considering polymorphonuclear, mononuclear cell inflammation, H pylori density, intestinal metaplasia, and atrophy in the H pylori–infected and noninfected groups are summarized in Table 2 Moderate to severe chronic active antral gastritis and chronic active gastritis in the corpus were significantly more prevalent in patients with H pylori infection than in noninfected subjects (P < 0.0001).
The comparison of histopathological parameters between the antrum and corpus in the group with H pylori infection according to the updated Sydney system is presented in Table 3. The infiltration of the lamina propria by polymorphonuclear cells was significantly higher in the antrum than in corpus (P = 0.0005). The intensity of mononuclear infiltration in the lamina propria was significantly higher in the antrum than in corpus (P = 0.0007). Moderate to severe chronic active gastritis was present in 66/95 (69.5%) of antral biopsies and in 36/85 (42.2%) of corpus biopsies, with significantly higher grading in antrum than in corpus (P = 0.0005). The scores for H pylori density were significantly higher in the antrum than in corpus (P = 0.0075). Moderate to severe scores for H pylori density were present in 64/95 (67.3%) of antral biopsies and in 46/85 (54.1%) biopsies from the corpus. Six patients (7.0 %) presented mild to severe atrophy in the gastric corpus and 2 (2.1%) mild atrophy in the antrum. In the noninfected group, infiltration of the lamina propria by polymorphonuclear cells was absent in all of the patients in both antrum and corpus and mild infiltration by mononuclear cells was found in 8/86 (9.3%) children in antrum and 4/86 (4.6%) in corpus.
The topographic distribution of gastritis on the 84 patients from the H pylori–infected group, with both antral and corpus biopsies, was 52 (61.9%) with pangastritis, 27 (32.1%) antral-predominant, and 5 (5.9%) corpus-predominant gastritis. The topographic distribution of gastritis did not differ between the younger and older children in the H pylori–infected group (≤9.7 vs >9.7 years, P = 0.4).
Lymphoid aggregates were found in 29/95 (30%) of antral biopsies and 16/85 (18%) of corpus biopsies in children with H pylori infection, and were present in 8/88 (9%) patients in the antrum and 4/86 (4.6%) in the corpus in the noninfected group. Lymphoid aggregates were significantly more prevalent in biopsies from H pylori–infected children both in antrum and corpus (P < 0.05). Intestinal metaplasia was not found in any child in the present series of patients.
Overall Gastritis Grading
The combined scores of gastric inflammation (grades) obtained with both antral and corpus biopsies in the group with H pylori infection were, respectively, 23.8% (grade I), 22.6% (grade II), 21.4% (grade III), and 32.2% (grade IV). Considering that the median age of the H pylori–infected group was 9.7 years old and the median duration of dyspepsia was 1 year, there was no difference in gastritis grading according to younger or older age at endoscopy (≤9.7 vs >9.7 years old, P = 0.0730) nor to the duration of dyspepsia (≤1 vs >1 year, P = 0.07) in the H pylori–infected patients; however, when considering the overall scores of gastritis grading, there was a significant negative association with the scores of esophagitis (P = 0.007, r = −0.29).
The histopathological analysis of the esophageal mucosa was performed in 93/96 patients from the group with H pylori infection and in 88/89 patients from the noninfected group. The mean value for the esophagitis score was significantly higher (P = 0.006) in the noninfected group (1.43 ± 0.84) than in the H pylori–infected group (1.07 ± 0.91), as presented in Table 4. The proportion of patients with retrosternal pain and the worst esophagitis score (score 2) was significantly higher in the noninfected group (P = 0.0426) when compared with the H pylori–infected group.
Relation Between Clinical Data and the Topographic Distribution of Gastritis
The duration of dyspepsia symptoms did not differ among antral predominant, corpus predominant, or pangastritis (P = 0.1924). Also, there was no significant association between the duration of dyspepsia and the age of the patients.
Correlation Between H pylori Density and Gastric Histopathological Findings
There was a significant positive association between density of H pylori colonization and the degree of active/chronic inflammation in both antral and corpus biopsies (P < 0.0001).
Correlation Between Esophagitis Scores and Gastric Histopathological Findings
A significant negative relation was observed between the esophagitis scores and the gastric histopathological findings such as mononuclear cell infiltrate in antrum (r = –0.28; P = 0.007) and in corpus (r = –0.24; P = 0.029) and with the overall gastritis grading (r = −0.294; P = 0.007). No correlation was observed between the esophagitis scores and H pylori density in both antrum and corpus.
This study evaluated the potential associations among H pylori infection and clinical and histological findings in the upper gastrointestinal tract of Brazilian children and adolescents submitted to upper gastrointestinal endoscopy for chronic dyspeptic syndrome.
The recently published guidelines from ESPGHAN and NASPGHAN (14) for H pylori infection in children had highlighted large gaps in knowledge regarding H pylori infection and abdominal pain in children and emphasized that there are no convincing data to support H pylori as a cause of abdominal pain; however, whether H pylori gastritis causes abdominal pain in the absence of peptic ulcer disease is still debatable (14). In studies from countries where the prevalence of H pylori infection is high, it has been reported that H pylori infection is a causative agent of various gastrointestinal symptoms such as chronic abdominal pain (23,24). Therefore, we have chosen to study a subset of children with chronic abdominal pain with dyspeptic syndrome suggestive of organic underlying disease; however, in the present study the dyspeptic symptoms did not discriminate between the H pylori–infected and noninfected groups, as found by Kalach et al (25).
In a meta-analysis of 18 studies involving endoscopy and biopsy evaluations in children with recurrent abdominal pain, H pylori infection was detected in 2% to 63% of the patients (26). In studies from the Czech Republic (27), Turkey (24), and Poland (28) approximately half of the children with upper gastrointestinal symptoms had active H pylori infection, which indirectly points to the role of the bacterium in the development of symptoms, although causality is not proven. In Brazil, studies performed on dyspeptic children from 3 different geographic regions showed an H pylori prevalence of 34% to 77%, using serological, histological, and culture analysis (29–31). In our series of 185 dyspeptic children submitted to upper gastrointestinal endoscopy we have observed a high prevalence of patients infected with H pylori (51.8%), probably owing to regional characteristics of the population studied and to the inclusion criteria adopted, which considered eligible for the analyses only children who had dyspeptic symptoms suggestive of organic disease.
We have observed a high prevalence of pangastritis in both younger and older children infected with H pylori. This suggests that H pylori tends to colonize the vast majority of the gastric mucosa after the initial antral infection (10). In almost two-thirds of the cases in our study, features of gastritis had spread out beyond the antrum and involved the gastric corpus. Our data are in agreement with the Chilean study (32) but contrasts with previous results that have reported preponderance of antral-predominant gastritis in children infected with H pylori(33). These differences may be related to the virulence of H pylori strains and/or to a massive exposure to H pylori earlier in life and to prolonged duration of the infection (32).
Contradictory results have been reported on the intensity and type of inflammatory response and density of H pylori colonization in children. Most studies have reported a mild inflammatory response (11,32,34). Our findings are in agreement with the studies from Peru (35), Colombia (6), Japan (8), and Greece (36), which have reported a high prevalence of H pylori infection associated with an intense inflammatory response in the gastric mucosa. Our children probably come from populations infected with more virulent H pylori strains and with a higher risk of gastric cancer, which is related to greater degrees of gastric mucosal damage and higher density of H pylori colonization (6).
Some studies have reported that mononuclear but not polymorphonuclear inflammation is higher in antrum than in corpus (11,34). In the present study, both mononuclear and polymorphonuclear inflammations were higher in the antrum than in corpus, in agreement with previous results (6,8,35). The association of high degrees of H pylori colonization with a more severe inflammation in the antrum, but not in the corpus, emphasizes the antrum as the primary site of H pylori colonization in children.
The updated Sydney system remains essential for the recognition of gastric inflammatory disease; however, most pathologists find it too cumbersome to use in their routine diagnostic activities. Rugge and Genta (19) proposed a reporting system for chronic gastritis in grading by combining the severity of both mononuclear and polymorphonuclear inflammation to offer a more immediate perception of the overall condition of the gastric mucosa. This is the first time that this protocol of staging and grading of chronic gastritis was applied in children. The analysis of grading for the H pylori–infected group revealed a great number of cases with the highest overall grade of gastritis (score IV), although not statistically significant. Interestingly, there was no significant atrophy nor intestinal metaplasia, in spite of the degree of inflammation, which is in agreement with previous studies (32,37). The presence of gastric mucosal atrophy associated with H pylori gastritis is still controversial in children, with prevalence varying between 0% and 72% according to different studies (38,39).
In adults, the majority of data suggest a negative association between H pylori infection and reflux esophagitis (40,41) and with Barrett esophagus (42). In the present study we observed a significant negative correlation between H pylori infection and esophagitis, and also a significantly higher prevalence of esophagitis in the noninfected group. This topic is still controversial in the pediatric population, with few studies, some demonstrating similar inverse correlation in children (43), others a positive correlation (44,45), and others no relationship (46).
In conclusion, the results of the present study showed high prevalence of H pylori infection among Brazilian dyspeptic children and adolescents, with significant degrees of inflammation of the gastric mucosa associated with high density of H pylori colonization involving both antrum and corpus. Also, the high scores of esophagitis in the noninfected group points to 2 distinct groups of pathological conditions sharing similar clinical patterns.
1. NIH Consensus Conference. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. Helicobacter pylori in peptic ulcer disease. JAMA 1994;272:65–9.
2. Drumm B, Sherman P, Cutz E, et al. Association of Campylobacter pylori on the gastric mucosa with antral gastritis in children. N Engl J Med 1987; 316:1557–1561.
3. Go MF. Review article: natural history and epidemiology of Helicobacter pylori infection. Aliment Pharmacol Ther 2002; 16:3–15.
4. Rothenbacher D, Inceoglu J, Bode G, et al. Acquisition of Helicobacter pylori infection in a high-risk population occurs within the first 2 years of life. J Pediatr 2000; 136:744–748.
5. Torres J, Perez-Perez G, Goodman KJ, et al. A comprehensive review of the natural history of Helicobacter pylori infection in children. Arch Med Res 2000; 31:431–469.
6. Bedoya A, Garay J, Sanzón F, et al. Histopathology of gastritis in Helicobacter pylori-infected children from populations at high and low gastric cancer risk. Hum Pathol 2003; 34:206–213.
7. Munoz L, Carmolinga R, Hernandez S, et al. Immune and proliferative cellular responses to Helicobacter pylori infection in the gastric mucosa of Mexican children. Helicobacter 2007; 12:224–230.
8. Kato S, Nakajima S, Nishino Y, et al. Association between gastric atrophy and Helicobacter pylori infection in Japanese children: a retrospective multicenter study. Dig Dis Sci 2006; 51:99–104.
9. Meining A, Behrens R, Lehn N, et al. Different expression of Helicobacter pylori gastritis in children: evidence for a specific pediatric disease? Helicobacter 1996; 1:92–97.
10. Riddell RH. Pathobiology of Helicobacter pylori infection in children. Can J Gastroenterol 1999; 3:599–603.
11. Jaramillo-Rodriguez Y, Nares-Cisneros J, Martínez-Ordaz VA, et al. Chronic gastritis associated with Helicobacter pylori in Mexican children: histopathological patterns. Pediatr Dev Pathol 2011; 14:93–98.
12. Guarner J, Kalach N, Elitsur Y, et al. Helicobacter pylori diagnostic tests in children: review of the literature from 1999 to 2009. Eur J Pediatr 2010; 169:15–25.
13. Thakkar K, Chen L, Tatevian N, et al. Diagnostic yield of oesophagogastroduodenoscopy in children with abdominal pain. Aliment Pharmacol Ther 2009; 30:662–669.
14. Koletzko S, Jones NL, Goodman KJ, et al. Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children. J Pediatr Gastroenterol Nutr 2011; 53:230–243.
15. Apley J, Naish N. Recurrent abdominal pains: a field survey of 1,000 school children. Arch Dis Child 1958; 33:165–170.
16. Chelimsky G, Czinn SJ. Techniques for the evaluation of dyspepsia in children. J Clin Gastroenterol 2001; 33:11–13.
17. Elitsur Y, Lawrence Z, Triest WE. Distribution of Helicobacter pylori organisms in the stomachs of children with H pylori infection. Hum Pathol 2002; 33:1133–1135.
18. Dixon MF, Genta RM, Yardley JH, et al. Classification and grading of gastritis. The updated Sydney System. Am J Surg Pathol 1996; 20:1161–1181.
19. Rugge M, Genta RM. Staging and grading of chronic gastritis. Hum Pathol 2005; 36:22–33.
20. Knuff TE, Benjamin SB, Worsham GF, et al. Histologic evaluation of chronic gastroesophageal reflux. An evaluation of biopsy methods and diagnostic criteria. Dig Dis Sci 1984; 29:194–201.
21. Leape LL, Bhan I, Ramenofsky ML. Esophageal biopsy in the diagnosis of reflux esophagitis. J Pediatr Surg 1981; 16:379–384.
22. Vandenplas Y. Reflux esophagitis in infants and children: a report from the Working Group on Gastro-oesophageal Reflux Disease of the European Society of Paediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 1994; 18:413–422.
23. Shamaly H, Berkowitz D, Rosenthal E, et al. Efficacy of bismuth based triple therapy in children with abdominal pain and Helicobacter pylori gastritis. J Pediatr Gastroenterol Nutr 2000; 30:198–200.
24. Ozen H, Dinler G, Akyon Y, et al. Helicobacter pylori infection and recurrent abdominal pain in Turkish children. Helicobacter 2001; 6:234–238.
25. Kalach N, Mention K, Guimber D, et al. Helicobacter pylori infection is not associated with specific symptoms in nonulcer-dyspeptic children. Pediatrics 2005; 115:17–21.
26. Thakkar K, Gilger MA, Shulman RJ, et al. EGD in children with abdominal pain: a systematic review. Am J Gastroenterol 2007; 102:654–661.
27. Sedlackova M, Malaty H, Volf V, et al. Helicobacter pylori infection in a group of symptomatic and asymptomatic children and adolescents in Czech Republic. Cas Lek Cesk 2003; 142:102–105.
28. Gzyl A, Dzierzanowska D, Rozynek E, et al. PCR based diagnosis of Helicobacter pylori infection in Polish children and adults. J Med Microbiol 1999; 48:349–356.
29. Oliveira AMR, Queiroz DMM, Rocha GA, et al. Seroprevalence of Helicobacter pylori infection in children of low socioeconomic level in Belo Horizonte, Brazil. Am J Gastroenterol 1994; 89:2201–2204.
30. Solari CA, Araruna RPN, Reis EMF, et al. Helicobacter pylori in dyspeptic children and adults: endoscopic, bacteriologic and histologic correlation's. Mem Inst Oswaldo Cruz 1994; 89:581–586.
31. Souto FJD, Fontes CJF, Rocha GA, et al. Prevalence of Helicobacter pylori infection in a rural area of the state of Mato Grosso. Brazil Mem Inst Oswaldo Cruz 1998; 93:171–174.
32. Guiraldes E, Peña A, Duarte I, et al. Nature and extent of gastric lesions in symptomatic Chilean children with Helicobacter pylori-associated gastritis. Acta Paediatr 2002; 91:39–44.
33. Cohen H, Gramisu M, Fitzgibbons P, et al. Campylobacter pylori: associations with antral and fundic mucosal histology and diagnosis by serology in patients with upper gastrointestinal symptoms. Am J Gastroenterol 1989; 84:367–371.
34. Ozawa K, Kato S, Sekine H, et al. Gastric epithelial cell turnover and mucosal protection in Japanese children with Helicobacter pylori infection. J Gastroenterol 2005; 40:236–246.
35. Recavarren-Arce S, León-Barúa R, Rodríguez C, et al. Helicobacter pylori-associated chronic gastritis in Peruvian adolescents is very common and severe. J Clin Gastroenterol 1995; 20:335–337.
36. Sgouras DN, Panayotopoulou EG, Papadakos K, et al. CagA and VacA polymorphisms do not correlate with severity of histopathological lesions in Helicobacter pylori-infected Greek children. J Clin Microbiol 2009; 47:2426–2434.
37. Campbell DI, Warren BF, Thomas JE, et al. The African enigma: low prevalence of gastric atrophy, high prevalence of chronic inflammation in West African adults and children. Helicobacter 2001; 6:263–267.
38. Ricuarte O, Gutierrez O, Cardona H, et al. Atrophic gastritis in young children and adolescents. J Clin Pathol 2005; 58:1189–1193.
39. Dimitrov G, Gottrand F. Does gastric atrophy exist in children? World J Gastroenterol 2006; 12:6274–6279.
40. Raghunath A, Hungin AP, Wooff D, et al. Prevalence of Helicobacter pylori in patients with gastro-oesophageal reflux disease. BMJ 2003; 326:737–743.
41. Cremonini F, Di Caro S, Delgado-Aros S, et al. Meta-analysis: the relationship between Helicobacter pylori infection and gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2003; 18:279–289.
42. Sonnenberg A, Lash RH, Genta RM. A national study of Helicobacter pylori infection in gastric biopsy specimens. Gastroenterology 2010; 139:1894–1901.
43. Abdollahi A, Morteza A, Khalilzadeh O, et al. The role of Helicobacter pylori infection in gastro-oesophageal reflux in Iranian children. Ann Trop Paediatr 2011; 31:53–57.
44. Daugule I, Rumba I, Alksnis J. Helicobacter pylori infection among children with gastrointestinal symptoms: a higher prevalence of infection among patients with reflux oesophagitis. Acta Paediatr 2007; 96:1047–1049.
45. Moon A, Solomon A, Beneck D, et al. Positive association between Helicobacter pylori and gastroesophageal reflux disease in children. J Pediatr Gastroenterol Nutr 2009; 49:283–288.
46. Emiroglu HH, Sokucu S, Suoglu OD, et al. Is there a relationship between Helicobacter pylori infection and erosive reflux disease in children? Acta Paediatr 2010; 99:121–125.