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Original article

Correlation of clinical, endoscopic, and histological findings with virulence factors in children with Helicobacter pylori gastritis Mukadder A. Selimoglua, Hamza Karabibera, Baris Otlub, Ozge Yildirimb, ¨ zerc and Emine Samdancid Ali O Background and goals As there are limited data regarding the correlation between virulence factors and clinical, endoscopic, and histological findings in children with Helicobacter pylori gastritis, we aimed to evaluate that probable relationship in pediatric cases. Study One hundred and fifty-nine children with chronic abdominal pain or dyspepsia were included in this study. Upper gastrointestinal endoscopy was performed and multiple biopsy samples were taken from the esophagus, the antrum, and the duodenum. PCR was used for the determination of virulence factors. Results According to PCR analysis, 98 (61.6%) children were positive for H. pylori. Using histopathological examination and culture, H. pylori was detected in 65 (40.9%) and 51 (32.1%) children, respectively. Peptic ulcer prevalence and histopathological features were not different among cagA, cagE, or iceA1 positive and negative groups (P > 0.05). Peptic ulcer prevalence and histopathological findings were more common in iceA2positive patients (P < 0.05). Antral nodularity was more common in cagA-positive patients (P < 0.05). Endoscopic

Introduction Helicobacter pylori is capable of colonizing the gastric mucosa, leading to chronic active gastritis and peptic ulcer. It is known that approximately half of the world’s population is infected with H. pylori, and the infection is generally acquired during childhood. The prevalence in developing countries is between 60 and 85%, although it is different between asymptomatic and symptomatic individuals [1,2]. Whereas some strains of H. pylori cause gastritis, peptic ulcer, or carcinoma, some others lead to an asymptomatic course [2,3]. The variability of the clinical course is thought to be due to individual factors of the host and virulence factors of the bacteria [4]. H. pylori genes that are related to pathogenicity include cagA (cytotoxin associated gene), vacA (vacuolating associated cytotoxin), and iceA (induced by contact with the epithelium) [2,3]. It is very well known that cagA is closely related to the development of peptic ulcer and gastric carcinoma, and some strains carrying vacA gene are related to peptic ulcer [3,5,6]. Different genotypes of H. pylori circulate in different geographic areas; the different clinical presentations are c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-691X

and histological features were not different among patients with or without m1 or m2 strains (P > 0.05). S1b positivity was associated with a higher esophagitis rate (P < 0.05). Conclusion Among virulence factors, iceA2 was associated with peptic ulcer and milder histopathological findings, and vacAs1 was associated with milder histopathological findings. Eur J Gastroenterol Hepatol c 2014 Wolters Kluwer Health | Lippincott 26:602–606 Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2014, 26:602–606 Keywords: children, endoscopy, Helicobacter pylori, histopathology, virulence factors a Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Departments of bClinical Microbiology, cPublic Health and dPathology, School of Medicine, Inonu University, Malatya, Turkey

Correspondence to Hamza Karabiber, MD, Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Inonu University, Tip Fakultesi, Cocuk Sagligi ve Hastaliklari AD, 44280 Malatya, Turkey Tel: + 90 422 341 0660; fax: + 90 422 341 0728; e-mail: [email protected] Received 14 January 2014 Accepted 5 March 2014

partly attributed to this high genetic diversity; however, no clinical study has focused on the clinical and endoscopic findings of different genotypes so far. In this study, we aimed to investigate the probable relationship between virulence factors and clinical, endoscopic, and histological findings of children with H. pylori infection.

Patients and methods In this study, 159 2–18-year-old children with dyspeptic symptoms, who were evaluated at a pediatric gastroenterology outpatient clinic and who underwent upper gastrointestinal endoscopy, were included. Of the included children, 60 (37.7%) were boys and 99 (62.3%) were girls. Patients with celiac disease and lactose intolerance were excluded. Symptoms, physical examination and endoscopic findings, and anthropometric measurements were recorded. Endoscopic biopsy samples, which were taken from the antrum and the corpus were placed into sterilized watercontaining tubes and immediately transferred to the laboratory for culture and PCR. Columbia Agar (Oxoid Ltd, Hants, UK), containing H. pylori-selective supplement DOI: 10.1097/MEG.0000000000000095

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Virulence factors in H. pylori gastritis Selimoglu et al. 603

(Oxoid Ltd) and horse blood (Laked horse blood; Oxoid Ltd) was used as the culture medium. The microaerophilic atmosphere (5% O2, 10% CO2, and 85% N2) needed for H. pylori growth was provided with a commercial kit (GENbag microaer; Biomerieux SA, Marcy I’Etoile, France). Samples were incubated at 371C for 72 h. The BioRobot EZ1 system (Qiagen, Hilden, Germany) was used for bacterial DNA isolation. In-house PCR was performed based on predefined primer sequences [7,8]. The Phosphosphatase mutase (glmM) gene was selected as a target to determine H. pylori in gastric samples. For each gene region, a combination of 25 ml of amplification mixture (12.5 ml Top Taq DNA PCR Master Mix; Qiagen), 1 ml of each primer (10 pmol/ml, 8 ml H2O), and 2.5 ml of the extraction product were processed using an automated thermal cycler (Palmcycler Corbett Research, Sydney, New South Wales, Australia) for amplification. After amplification, the product was electrophoresed on 1.5–3% agarose gel and stained within 400 ml ultrapure water containing 5 mg/ml ethidium bromide and examined using a gel imaging system [Gel Logic 2200 imaging system (1708  1280 pixels); Kodak Company, Rochester, New York, USA]. Biopsy samples from the esophagus, the antrum, the corpus, and the duodenum were stained with hematoxylin and eosin. Antrum and corpus samples were stained further with modified Giemsa for H. pylori detection. The updated Sydney classification (inflammation, activation, dysplasia, intestinal metaplasia, atrophy, and H. pylori density) was used for the histologic evaluation [9].

for H. pylori culture were 52, 100, 100, and 56.7%, respectively. When patients were classified according to age group, such as preschool (2–6 years), primary school-aged (7–12 years), and high school-aged (13–18 years), PCR positivity was 11.2, 36.7, and 52%, respectively. Prevalence of H. pylori increased gradually with age, but it was not statistically significant (P > 0.05). Symptoms of the patients, including abdominal pain, vomiting, gastrointestinal bleeding, constipation, diarrhea, dyspepsia, halitosis, and regurgitation, were interrogated. Only the frequency of dyspepsia (P < 0.01) and halitosis was significantly higher (P < 0.05) in H. pylori-positive children compared with H. pylori-negative ones (67.3 vs. 27.9%; and 32.7 vs. 16.4%, respectively). The sensitivity, the specificity, the PPV, and the NPV of halitosis for H. pylori infection were 32.6, 83.6, 76.1, and 43.5%, respectively. The sensitivity, the specificity, the PPV, and the NPV of dyspepsia for H. pylori infection were 67.3, 72.1, 79.5, and 57.8%, respectively. The endoscopic pattern of the gastric mucosa is shown in Table 1. In the H. pylori-positive group, eight (8.2%) children had duodenal ulcer, and in the H. pylori-negative group, two children with a history of NSAID usage had gastric ulcer. Peptic ulcer prevalence was not different between the H. pylori-positive and the H. pylori-negative groups (P > 0.05) (Table 1).

Statistical analyses were performed using SPSS 11.0 (SPSS Inc., Chicago, Illinois, USA). w2, Fisher’s, and Student’s t-tests were used. The study was funded by the ˙Ino¨nu ¨ University Scientific Research Projects Unit (project number: 2010/62). The Inonu University Ethics Committee approved the study (number: 2009/153).

The sensitivity, the specificity, the PPV, and the NPV of antral nodularity for H. pylori infection were 96.1, 6, 70.7, and 40%, respectively. The sensitivity, the specificity, the PPV, and the NPV of antral erythema were 86.9, 6.6, 41.6, and 40%, respectively. The sensitivity, the specificity, the PPV, and the NPV of peptic ulcer presence were 8.1, 96.7, 80, and 39.5%, respectively.

Results

Findings of the histopathological evaluation according to the updated Sydney classification are shown in Table 2.

According to PCR analysis, 98 (61.6%) children were positive for H. pylori. Using histopathological examination and culture, H. pylori was detected in 65 (40.9%) and 51 (32.1%) children, respectively. H. pylori infection was detected in 60 (61.2%) girls and 38 (38.8%) boys by PCR. H. pylori culture was positive in 31 (60.8%) girls and 20 (39.2%) boys. Because PCR is the most sensitive test for detecting H. pylori, statistical analyses were performed on the basis of PCR results. Prevalence of H. pylori infection was not different between girls and boys (P > 0.5). Mean age and BMI values of children with H. pylori infection were not different from those of H. pylori-negative ones (P > 0.05). The sensitivity, the specificity, the positive predictive value (PPV), and the negative predictive value (NPV) of histopatological examination for H. pylori detection were 66.3, 100, 100, and 64.8%, respectively. Relevant values

Of 98 children with H. pylori infection, 100, 51, 70.4, 49, 34.7, and 25.5% were positive for vacA, cagA, cagE, babA, iceA1, and iceA2. The most common subtype of vacA was s1am2 (32.7%). Three patients had mutational multivacA (s1am1/m2, s1c/s2m2, and s2m1/m2). Of eight children with peptic ulcer, five (62.5%) were positive for cagA; Table 1 Endoscopic pattern of the gastric mucosa in children with or without Helicobacter pylori infection Helicobacter pylori [n (%)]

Endoscopic pattern Gastric mucosa Normal Antral nodularity Peptic ulcer (gastric or duodenal)

Positive (n = 98)

Negative (n = 61)

Total (n = 159) [n (%)]

3 (3.1) 75 (76.5) 8 (8.2)

2 (3.3) 31 (50.8) 2 (3.3)

5 (3.1) 106 (66.7) 10 (6.3)

P 0.003 0.217

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604 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 6

Table 2 Histopathological findings of patients with or without Helicobacter pylori infection

Some histopathological findings with respect to different vacA subtypes

Table 4

PCR [n (%)] Positive (n = 98) H. pylori density Absent Present Lymphoid aggregates Absent Present Activation Absent Present Inflammation Absent Present Histopathologic gastritis

n (%)

Negative (n = 61)

P

33 (33.7) 65 (66.3)

56 (91.8) 3 (4.9)

0.001

41 (41.8) 57 (58.2)

45 (73.8) 12 (19.7)

0.001

38 (38.8) 60 (61.2)

47 (77) 11 (18)

0.001

24 (24.5) 74 (75.5) 75 (76.5)

31 (50.8) 23 (37.7) 33 (54.1)

0.001 0.001

Table 3 Some histopathological findings with respect to iceA2 positivity

Mild

Lymphoid aggregates IceA2 Negative 28 (38.4) 10 (13.7) Positive 13 (52) 8 (32) Inflammation IceA2 Negative 14 (19.2) 15 (20.5) Positive 10 (40) 7 (28) Helicobacter pylori density IceA2 Negative 19 (26) 17 (23.3) Positive 14 (56) 6 (24)

Moderate

Severe

Total

Mild

Moderate

Severe

Total

P

(28) (41.7)

5 (10) 12 (25)

5 (10) 4 (8.3)

50 (100) 48 (100)

0.02

(37.8) (18.8)

17 (20.7) 0 (0)

6 (7.3) 3 (18.8)

82 (100) 16 (100)

0.02

(14.6) (37.5)

23 (28) 1 (6.3)

11 (13.4) 4 (25)

82 (100) 16 (100)

0.04

(17.1) (50)

34 (41.5) 3 (18.8)

12 (14.6) 3 (18.8)

82 (100) 16 (100)

0.02

histological features were not different between patients with or without m1 or m2 strains (P > 0.05).

n (%) Absent

Absent

Histopathological activation S1a Negative 26 (52) 14 Positive 12 (25) 20 S1b Negative 28 (34.1) 31 Positive 10 (62.5) 3 Lymphoid aggregate S1c Negative 36 (43.9) 12 Positive 5 (31.3) 6 Inflammation S1c Negative 22 (26.8) 14 Positive 2 (12.4) 8

P

Discussion 22 (30.1) 2 (8)

13 (17.8) 2 (8)

73 (100) 25 (100)

0.02

33 (45.2) 4 (16)

11 (15.1) 4 (16)

73 (100) 25 (100)

0.04

19 (26) 4 (16)

18 (24.7) 1 (4)

73 (100) 25 (100)

0.02

however, peptic ulcer prevalence between the cagA-positive and the cagA-negative groups was not different (P > 0.05). Histopathological features were not different either (P > 0.05). Endoscopically, antral nodularity was more common in cagA-positive patients (P < 0.05). The sensitivity, the specificity, the PPV, and the NPV of antral nodularity for cagA positivity were 58.6, 6, 97.7, and 6%, respectively. Of eight children with peptic ulcer, seven (87.5%) were positive for cagE, five (62.5%) were positive for babA, and five (62.5%) were positive for iceA. Peptic ulcer prevalence and endoscopic or histological features in the positive and the negative groups were not different (P > 0.05). Six of eight children (75%) with peptic ulcer were iceA2 positive (P < 0.05). The sensitivity, the specificity, the PPV, and the NPV of the presence of peptic ulcer for iceA2 positivity were 75, 78.8, 24, and 97.2%, respectively. The relationship between histopathological features and iceA2 positivity is shown in Table 3. The frequency of esophagitis was lower in children with VacAs1b-positive H. pylori infection (P < 0.05). Whereas 20 of 28 patients (71.4%) with histological esophagitis were negative for s1b, 8 (28.6%) were positive (P < 0.05). Some histopathological findings were different with respect to the vacA subtypes (Table 4). Endoscopic and

The relationship between recurrent abdominal pain and H. pylori infection is controversial. Some studies from different countries [10–15] showed that H. pylori prevalence was higher in those with recurrent abdominal pain compared with asymptomatic children. In contrast, in a systematic review including 38 studies, no association between recurrent abdominal pain and H. pylori infection was found [16]. However, in the same study, authors found evidence for an association between H. pylori and undetermined abdominal pain, not fulfilling Apley’s criteria [16]. In our series, among the children who underwent upper gastrointestinal endoscopy because of gastrointestinal symptoms including recurrent abdominal pain and dyspepsia, 64.9% were found to have H. pylori infection. No specific symptom of H. pylori infection has been described so far; however, epigastric pain, dyspepsia, halitosis, nausea, vomiting, and retrosternal pain may accompany H. pylori infection [17]. Although the most common symptom was abdominal pain (87.8%), followed by dyspepsia (67.3%), regurgitation (36.7%), and halitosis (32.7%) among our patients with H. pylori infection, only dyspepsia and halitosis were statistically more common in those with H. pylori infection when compared with H. pylori-negative children. These results emphasize the mismatch between recurrent abdominal pain and H. pylori gastritis. It could be argued that many symptoms were not reliably reported by younger children; only two of our patients were below 2 years and four patients were 5 years old. Some studies revealed that H. pylori infection was more prevalent in patients with halitosis [18,19]. The specificity of halitosis for H. pylori infection was found to be 83.6% in our study. It is known that the most common endoscopic finding of H. pylori infection in children is antral nodularity [20].

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Virulence factors in H. pylori gastritis Selimoglu et al. 605

The frequency of antral nodularity in H. pylori infection was found to be 76.5%, a figure similar to that revealed in other studies [21,22]. The sensitivity and the PPV of antral nodularity for H. pylori infection were 96.1 and 70.7%, respectively. The sensitivity of antral erythema was 86.9% and the specificity of peptic ulcer was 96.7%. These figures suggest that antral nodularity and duodenal ulceration are significant predictors of H. pylori infection, although they are not specific. When the detection of H. pylori by PCR is considered as the gold standard for diagnosis, histopathological and microbiological positivity were 66.3 and 52%, respectively. It was reported that the culture was positive in only 21–55% of children with histopathologically proven H. pylori infection [22,23]. We found a higher ratio when the histopathological examination was taken as a reference: 78.4%. In 33.9% of PCR-positive children, histopathological examination could not detect H. pylori infection. Severe complications such as peptic ulcer and malignancy develop in only 10–15% of patients who are infected with H. pylori, a situation that can be attributed to the virulence factors of H. pylori [24]. That is why we investigated the relationship between virulence factors and endoscopic and histopathological findings. In adults, the severity of H. pylori infection was found to be related to virulence factors such as vacA (s1a, s1b, s1c, s2, m1, and m2), cagA, cagE, babA, iceA1, and iceA2, which might all interfere with inflammatory and immunological mechanisms and accelerate the development of ulcer and malignancy. In children, cagA was shown to be related to the pathogenicity [25,26]. Subtypes of H. pylori may vary in different geographic locations and ethnic groups [27]. In two other Turkish pediatric studies, the positivity rate of cagA was reported as 55.6% [28] and 74.4% [29], respectively. Neither of them had data on other virulence factors, but they both concluded that there was no relationship between gastrointestinal symptoms and virulence factors. The VacA gene (vacuolating cytotoxin gene A: vacA) was reported to be associated with peptic ulcer and gastric carcinoma. Although all H. pylori strains have the vacA gene, capabilities of cytotoxin production are different; the m1 strain is more toxic than m2, the s1a strain is more toxic than s1b, and s1 is more toxic than s2 [7,26,30]. Whereas vacAs1 and vacAs1/m1 genotypes are related to peptic ulcer and carcinoma, s2/m2 and s2/m1 genotypes are not [30]. In our study, we could not find any difference in terms of symptomatology and endoscopic and histological findings between children with different genotypes. In western populations, it was reported that cagA, cagE, and babA were related to more severe presentations such as atrophic gastritis, peptic ulcer, and gastric carcinoma [7,26,30], and 90–95% of the patients with peptic ulcer were cagA positive [31]. In their study, So¨ku ¨cu ¨ et al. [29]

found that antral nodularity was more common, but esophagitis was less common in children with cagApositive H. pylori infection. We could not find any relationship between cagA or babA positivity and endoscopic or histopathological findings, a result that may be explained by the small number of patients with peptic ulcer or atrophic gastritis. IceA (induced by contact with the epithelium) is a newly defined gene, which has two different alleles: iceA1 and iceA2. Their role in the pathogenicity is not clear yet [7,24,26,30]. Of our eight patients with peptic ulcer, six were iceA2 positive (P < 0.05). Antral nodularity and histopathological findings were not different other than the milder lymphoid aggregate, inflammation, and H. pylori density, which are more common in iceA2-positive patients (P < 0.05). These findings together may be interpreted as follows: iceA2 might facilitate ulcer formation, but does not lead to the development of gastric carcinoma because it does not cause severe chronic inflammation. Conclusion

H. pylori infection presents mostly with gastritis in the pediatric population and not related to recurrent abdominal pain, and antral nodularity is an important predictor of H. pylori infection. Among virulence factors, iceA2 is associated with peptic ulcer and milder histopathological findings, and vacAs1 is correlated with some histopathological findings, including esophagitis.

Acknowledgements This study was funded by the Inonu University Scientific Research Projects Unit with the project number of 2010/62. Conflicts of interest

There are no conflicts of interest.

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Correlation of clinical, endoscopic, and histological findings with virulence factors in children with Helicobacter pylori gastritis.

As there are limited data regarding the correlation between virulence factors and clinical, endoscopic, and histological findings in children with Hel...
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