Pediatrics International (2007) 49, 220–225 doi: 10.1111/j.1442-200X.2007.02329.x Original Article Long-term aspects of nodular gastritis in children MUSTAFA AKCAM, REHA ARTAN, TEKINALP GELEN,1 AYGEN YILMAZ, ERDAL EREN,3 VEDAT UYGUN2 AND HIKMET CIG2 Medical School, Departments of 1Pathology and 2Pediatrics, Akdeniz University, Antalya, and 3Medical School, Department of Pediatrics, Suleyman Demirel University, Isparta, Turkey Abstract Background: Close association of nodular gastritis and Helicobacter pylori infection has been initially proved by various studies. There have been some studies reporting microscopic and histologic recovery in a short time after eradication therapy. But there is not enough data about the long-term course of this condition. The aim of this study is to document current clinical conditions, presence of H. pylori and results of endoscopic and histologic examination, after a long-term period, in children with endoscopically diagnosed antral nodularity. Methods: A total of 35 patients diagnosed as nodular antral gastritis by upper gastrointestinal endoscopy during a 2 year period, were invited for re-evaluation and re-endoscopy after 3 years. Histopathologically, H. pylori detected ones had been treated with standard triple eradication therapy. In total, 27 patients were accepted for enrollment in the study. Repeated endoscopy could be performed in all 27 patients. Results: The persistence of antral nodularity was detected in 18 of 27 patients. Decrease in symptoms, absence of symptoms and presence of H. pylori infection were detected in 6, 8 and 16 (89%) of them, respectively. There was no statistical significance between the first and last endoscopic biopsies when activity, atrophy, intestinal metaplasia and presence of follicles were regarded. Malt lymphoma could not be detected in any of the patients. Conclusion: There is a strong association between nodular gastritis and H. pylori. Presence of antral nodularity in the long-term period may be related to H. pylori re-infection. New therapeutic approaches are required for treatment and management of the patients diagnosed as nodular gastritis and living in areas endemic for H. pylori infection. Key words childhood, course, Helicobacter pylori, nodular gastritis. Nodular gastritis (NG) is usually characterized as presenting with an endoscopic appearance that has been described as ‘goose flesh’.1 It is also characterized by intense inflammatory cell infiltration consisting mainly of monocytes and by increased numbers of lymphoid follicles with a germinal center, in gastric mucosa.2 It has been known that common and universally distributed Helicobacter pylori infection is the most frequent reason for gastritis and peptic ulcer disease. This infection, predominantly acquired in childhood, has been accepted as directly associat- Correspondence: Mustafa Akcam, Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Akdeniz University, Medical School, Çocuk Sağlığı ve Hastalıkları AD, Antalya 07059, Turkey. Email: makcam@akdeniz.edu.tr Received 11 October 2005; revised 1 December 2005; accepted 26 December 2005. ed with gastric carcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma.3 The inflammation that H. pylori causes in the gastric mucosa is not always observed macroscopically with endoscopy, but it is identified on the histologic examination of gastric biopsies.4 A strong association between endoscopic detection of NG and presence of H. pylori has been established in previous studies.1,2,5–8 There are a few reports mentioning recovery of this nodular appearance after eradication treatment.5,9 There is no definite reason for antral nodularity, and we could not recognize any study about long-term follow up and evaluation of endoscopic and histologic changes after this time in the literature. In the present study, re-evaluation of clinical conditions, presence of H. pylori and results of endoscopic and histologic examination of children diagnosed as NG is aimed after a mean 3 years follow up. Nodular gastritis in children 221 Methods Between January 2001 and December 2002, a total of 263 (143 female, 120 male) upper gastrointestinal endoscopies were performed due to various indications. Antral nodularity was detected endoscopically in 35 of them and 30/35 were detected as infected with H. pylori. All H. pylori-positive patients received standard therapy (omeprazole or lansoprazole + amoxycillin + clarithromycin, for 14 days). All patients were controlled both clinically and via stool antigen test (Cromatest, Linear Chemicals, S.L. Barcelona, Spain) 6 weeks after initiation of treatment. Six cases that were positive for stool antigen received second line eradication therapy (ranitidine bismuth-citrate + tetracycline + amoxicillin 14 days, per oral). At 4 weeks after termination of therapy, stool antigen was still positive in three cases, although they were asymptomatic. A total of 35 patients diagnosed as NG were recalled approximately 3 years after treatment for the purpose of clinical, endoscopical and histopathological evaluation. In total, 28 of them came to control, and only one refused endoscopy. The data of the 27 eligible patients is shown in Figure 1. Four of them were not infected with H. pylori at the first evaluation. Four of 35 patients with NG were diagnosed with celiac disease during the first biopsy (pts 15, 16, 23, and 24). The other two patients were followed up with the diagnosis of chronic liver disease (chronic autoimmune hepatitis in pt. 17 and unknown origin in pt. 26). Mediastinal non-Hodgkin lymphoma developed during follow up of one patient (pt.2). All of these patients were also among the group that was investigated for a second time. Endoscopy was performed by one of the authors. Endoscopy was done using the Olympus EVIS CV-240 video endoscopes (outer diameter = 9.5 mm; biopsy channel diameter = 2.8 mm) with FB-24K-1 biopsy forceps. During endoscopy, all abnormalities seen are noted in a standardized report. The macroscopic aspect of the antrum is noted separately with special attention for nodularity. The definition of endoscopic nodularity was made when the mucosa had an irregular appearance resembling a cobblestone pavement (Fig. 2). During endoscopy, two antral biopsies were taken in addition to biopsies obtained from esophagus, corpus and duodenum. One of the antral biopsy specimens were embedded in the rapid urease test (CLO test duo; Ballard Medical Products, Draper, UT, USA) which consist urea agar and pH indicator. Other specimens were placed directly in 10% formalin without a paper filter, for histologic examination. One of the authors, blinded to the patients’ endoscopic or clinical findings, examined the biopsies (stained with hematoxylin–eosin, and Diff-Quick) for H. pylori and gastritis. H. pylori infection was characterized by bacteria found with histologic examination, and density of organisms was rated low, moderate or high. The diagnosis of gastritis was based on the histopatho- Fig. 1 Election algorithm of the 27 patients. logic findings of inflammation, activity, metaplasia, and atrophy. Each of these findings was scored as normal (−), mild (+), moderate (++), or marked (+++) following the updated Sydney System and using visual analog scales.10 Symptoms and clinical findings of 27 patients, who could be contacted 3 years after treatment, were recorded. Patients were classified as H. pylori positive when histological investigation was positive, as the gold standard tool for H. pylori infection. Exclusion criteria were a history of gastric surgery; or the use of antacids, H2-receptor antagonists, proton pump inhibitors, antibiotics, steroids, or nonsteroidal anti-inflammatory drugs within 1 month before endoscopy. Statistical analysis was made with statistical software program SPSS for Windows version 11.00 (SPSS, Chicago, IL, USA), using the McNemar, ␹2 and Mann–Whitney tests. The results were given as the mean ± SD. Statistical significance was set at the 0.05 level. Informed parental consent was obtained from all patients prior to entry into the study. 222 M Akcam et al. Fig. 2 Endoscopic nodular appearance of the antral mucosa. Results A total of 263 patients underwent upper gastrointestinal examination because of various indications; 107 of them (41%) were H. pylori positive and 35 of them were diagnosed as (21 female, 14 male) NG. The prevalence of NG in children who underwent endoscopy was 13% (35/263). NG showed a female predominance (odds ratio = 1.3; 95% confidence interval, 0.63–2.69). H. pylori infection rate in NG patients was 86% (30/35). CLO test were positive in 22 of 30 patients who were infected with H.pylori, and one of five patients who weren’t infected. At initial endoscopic examination, mean age of 27 patients who accepted control endoscopy was 11.2 ± 3.8 (range, 2– 16). H. pylori had been detected in 23 of them (85%) in the first endoscopy. The median between the first and the last endoscopy was 33 (24–46) months. According to last endoscopy, antral nodularity was found in 18 (66%) and H. pylori were positive in 22 (81%) of the total 27 patients. All the H. pylori-negative patients were confirmed by a stool antigen test. H. pylori stool antigens were negative in five patients with H. pylori histologically negative. H. pylori were positive in 16 of 18 (89%) and in 6 of 9 (67%) patients who had antral nodularity or no nodularity, respectively. When H. pylori density was scored from 0 to 3, mean densities were 1.43 ± 0.6 and 1 ± 0 in patients with nodularity and no nodularity, respectively (P = 0.08, Mann–Whitney test). Last endoscopy of five H. pylori-negative patients revealed that two patients (40%) had nodular appearance. NG was seen in 14 (61%) and H. pylori was positive in 19 (83%) of 23 patients who had H. pylori and received eradication therapy after the first endoscopy. Duodenal ulcer was seen in one patient without NG. Lymphoid follicles were detected in 11 of 27 (41%) patients during the first endoscopy, and were found in six of 18 (33%) NG patients during second endoscopy. There was no statistical significance between the first and last endoscopic biopsies when histopathologic activity, atrophy, intestinal metaplasia and presence of follicles were regarded (P > 0.05 for all). In the last evaluation there was no atrophic gastritis in three patients who had it initially. NG was detected in two and was absent in four of six patients who had atrophy in the second endoscopy. MALT lymphoma was detected in none of the patients. Although all 27 patients were symptomatic initially, only 15 of them (55%) were symptomatic in the last control. A total of 13 of 23 patients (57%) who received eradication therapy before, were symptomatic in the last control. Four of these 13 patients were symptomatic in spite of recovery of nodularity. In total, 10 of 18 (55%) NG detected patients in the last control were symptomatic whereas the remaining eight (45%) were asymptomatic. The characteristics of the patients are given in Table 1. Discussion The initial infection of H. pylori occurs more frequently during childhood, and endoscopic antral nodularity also occurs more frequently in children than in adults.5 Antral nodularity is the only sign with a high positive predictive value for the presence of H. pylori infection.6,11 This finding may identify patients in whom gastritis is more severe and associated with marked bacterial colonization.5 Our study also establishes the importance of endoscopic antral nodularity for suggesting H. pylori infection in children. The almost 3:1 female predominance in NG was reported in an adult study.1 We also found a slight female predominance (3:2). A pattern of male predominance has been reported for duodenal ulcer, whereas H. pylori infection shows no gender predilection.12 This condition underlines the importance of host factors for the formation of NG when H. pylori infection is present. Nodular gastritis in children 223 Table 1 The characteristics of the patients Patient No 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Age (year)/ gender 10/F 16/M§ 12/F 10/F 15/F 6/M 15/F 15/F 14/F 13/F 10/F 14/F 15/F 10/F 2/M* 8/M* 5/F# 8/M 14/F 14/F 12/M 16/F 5/F* 7/M* 15/M 12/M# 10/F Initial symptoms RAP,V He, B, He, RAP RAP N, He, B, V V, RAP RAP RAP,V RAP RAP, V, Hea RAP He RAP,V RAP, Hea, He An RAP, He RAP Anemia He, B, RAP He, Hea RAP RAP An, D,RAP, V An RAP An, RAP RAP, An, Na, He, D Initial H. pylori density Type of Gastritis Symptom of 4–6 weeks after eradication therapy¶ Current symptoms − − − − + + ++ ++ + + + + ++ + + + + + ++ ++ ++ ++ ++ + + ++ + C C C C CL‡ C CL‡ CL‡ C CL‡ CL CL‡ C CL‡ C C CL‡ CA C CL‡ CL‡ CA CL‡ CL‡ CA CL C NS NS Decrease NS Decrease Decrease NS NS NS RAP Decrease NS Decrease NS NS NS NS NS Decrease Decrease NS NS NS NS NS NS Decrease RAP NS Decrease NS Decrease Decrease RAP RAP NS RAP Decrease He D RAP, He NS NS Decrease NS Decrease NS NS Decrease NS NS NS NS RAP, Ha 3 years later Endoscopic H.pylori finding density H, E, DU NG NG NG H NG NG NG N NG DGR H NG N H,E N NG N NG NG NG NG NG NG NG NG NG + − + + − ++ + + − − – + ++ + + + + + ++ + ++ + + +++ + ++ + Type of Gastritis C N CL C C CL‡ CA CA CA C C CA CL‡ CA CL‡ CA CL‡ C CL C CL‡ C CL‡ CL‡ C CL C § Non Hodgkin lymphoma; *Celiac disease; #Chronic Liver Disease; ¶Only H.pylori-positive patients were treated; ‡ having lymphoid follicle; –, normal; +, mild; ++, moderate; +++, marked. An, anorexia with failure to thrive; B, belching; C, chronic; CA, chronic atrophic; CL, chronic lymphocytic; D, diarrhea; DGR, duodenogastric reflux; DU, duodenal ulcus; E, epigastric burning/pain; E, erosion; Ha, halitosis; He, heartburn; Hea, hematemesis; H, hyperemia; Na, nausea; RAP, recurrent abdominal pain; V, vomiting; N, normal; NG, nodular gastritis; NS, no symptom. NG appears to be a reversible sign of active H. pylori infection. After successful eradication of the bacterium, the antrum becomes macroscopically normal.5–9 Sbeih et al. also reported that the successful eradication for H. pylori led to regression of NG in five cases.9 There is no specific symptom of H. pylori infection except ulcer-related disease. Most studies on the evolution of symptoms after eradication of infection have failed to show any difference in symptoms between children in whom the infection had or had not been eradicated.13,14 We also found that the patients with H. pylori-positive NG became less symptomatic following standard H. pylori eradication therapy, in a short-term follow up. But in some of them, symptoms relapsed over time and when they came to the last control, 13 of 23 (57%) patients were symptomatic. Four of them were symptomatic even when recovery of nodular appearance was detected. Among 17 patients with nodularity in the last control, 10 were symptomatic (59%) while seven were asymptomatic (41%). Problems with antibiotic resistance in this age group are increasing because of the frequent use of amoxycillin, clarithromycin and metronidazole for respiratory and gastrointestinal infections.15 We could not be informed about the intake of antibiotics which could be related to the evolution of NG. The eradication success rate with the combination of metronidazole, clarithromycin and omeprazole was 53.2% in a previous study, performed in Turkey in which resistance to metronidazole was reported at 36.4%.16 The eradication rate and clarithromycin resistance was reported as 75.5% and 18.2%, respectively.17 224 M Akcam et al. It is reported that 70–80% of the adult population in Turkey is infected with H. pylori,18 whereas this ratio was reported as 44.5% in children.19 Our aim was to answer what is the destiny of patients with antral gastritis in the long-term follow up. But patients could be followed at most 46 months in this study. During this time MALT lymphoma did not develop in any of the patients but persistence of nodularity in 61% of patients is a disturbing condition. Persistence of nodular appearance in 61% and positivity of H. pylori in 83% of patients after eradication treatment brings to mind probability of relapse or re-infection. Although reinfection rates have been uncommon in adults, it varies from 2.4 to 20% for children.20–22 Multivariate analysis revealed that only age at primary infection correlates with an increased risk of re-infection.12 Additionally, early infection represents a critical factor in the future development of complications later in life.23 Success of eradication was confirmed only with stool antigen test in our study. If we prove this test true, it is necessary to evaluate the high rate of positivity of H. pylori (81%) during the second endoscopy as re-infection. We could not explain such a high re-infection rate in these patients group. There was no association between histologic findings of chronic gastritis and persistence of NG. The relation between NG and histopathologic atrophy must be evaluated by using a larger patient population. Diagnosis of celiac disease in four patients during first endoscopy, presence of chronic liver disease in two patients, and emergence of lymphoma during follow up in one patient are interesting conditions which brings to mind a special immune status in the host which may play a role for NG development. Finally, a strong correlation between NG disease and H. pylori infection was determined, as in previous studies. After 3 years follow up, most H. pylori-negative patients (60%) did not have nodular appearance, endoscopically. There seems to be a positive relation between eradication and endoscopic recovery. Only 19% of patients were bacteria free, 3 years after successfull eradication treatment. Since NG patients have a high re-infection rate, they have to be followed closely and treated appropriately, by second and may be third line eradication treatments. It is very important and necessary to prevent more serious problems probable in the future. 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