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The characteristics of 83 giant peptic ulcers in Chinese children: Evaluation and follow‑up

in aims to the Methods: We analyzed patients at the Patients with GPUs (>2.0 were included in the and the data, pathological characteristics and presence of Helicobacter pylori (H. pylori ) analyzed Results: A total of 19208 children underwent gastroscopic examinations, and 83 patients with GPUs were enrolled. The mean age of onset for GPU patients was 9.7 ± 3.2 years(range, 1-15). The main complaints were abdominal pain (92.7%), anemia (53%), retching (45.8%), hematochezia (21.7%) and hematemesis (16.9%). With respect to the types of GPU, 68 patients (81.9%) had duodenal ulcers, and 15 patients (18.1%) had gastric ulcers. Compared to the group <6 years of age, the group ≥6 years was more susceptible to GPU ( P < 0.05). Among GPU patients, 71.1% of cases were H. pylori (+) (59/83), and 16.9% (14/83) of patients were H. pylori (‑). Compared to the H. pylori (‑) group, the H. pylori (+) group showed inflammatory activity, atrophy and lymphoid follicular formation in the gastric mucosa ( P < 0.05). Conclusions: This study suggests that GPUs are strongly associated with H. pylori infection in Chinese children. Duodenal ulcers are the main type of GPU in patients older than 6 years. Appropriate diagnosis, treatment and follow-up are necessary for children with GPUs. Abstract

rates of morbidity, mortality, and complications compared with standard-sized ulcers. GPUs can impose a substantial socioeconomic burden and can negatively affect patients' quality of life. [5] However, few studies have described GPUs, especially in children. The aim of this study was to analyze the clinical characteristics, presence of Helicobacter pylori (H. pylori) infection, and study the outcome of GPU in Chinese children.

METHODS
This study was approved by the ethics committee of the Children's Hospital of Fudan University. The data were collected from April 2014 to August 2017. GGUs and duodenal ulcers (DUs) ≥ 2 cm in size were defined as GPUs. [6,7] Children admitted with gastrointestinal symptoms were enrolled in this study, and all relevant clinical data were recorded. H. pylori infection was diagnosed based on invasive methods, that is, culture of the biopsy specimens, standard rapid urease test (RUT), histopathology test, or non-invasive test, including the urea breathe test (UBT). [8][9][10] All children underwent upper gastrointestinal system endoscopy due to abdominal pain, hematemesis, anemia, hematochezia, and other findings. Among patients undergoing endoscopy, macroscopic findings were noted, and gastric biopsies (antrum and corpus) were taken for histological diagnosis. The patients were divided into an H. pylori(+) group and an H. pylori (-) group. The H. pylori (+) group received triple therapy with amoxicillin + clarithromycin + omeprazole, or metronidazole + clarithromycin + omeprazole for 14 days.
PUD was defined by the presence of an active, healing, or scar-stage ulcer in the stomach or duodenum. The diagnostic criteria of mild (Hb <90 ~ 120 g/L for children ≥6 years old and <90 ~ 110 g/L for children <6 years old), moderate (Hb: 60 ~ 90 g/L), and severe anemia (Hb: 30 ~ 60 g/L) in children was adopted as per standards of the World Health Organization (WHO), with a slight modification made according to the Chinese children nutrition conditions. The data were gathered from the electronic database, endoscopy records, autopsy records, and radiography. The medical records of all patients were evaluated to determine their characteristics and outcomes. All patients were contacted by phone for long-term follow-up.

Statistical Analysis
Descriptive statistics for continuous variables were calculated and expressed as reported, as the means ± standard deviation (SD). Categorical variables were described using frequency distributions and were reported as numbers (%). The Chi-squared test was used to analyze the categorical variables. Data were analyzed using SPSS Statistics 16.0 (SPSS, Chicago IL) statistical software. A value of P < 0.05 was considered significant.

Location of GPU and Related Symptoms
Fifteen GGUs and 68 GDUs were found in these patients with GPUs via endoscopy or imagological examinations . Abdominal pain, anemia, and retching were the main symptoms in these patients. The symptoms and disease course of GGUs and GDUs are shown in Table 1.

H. pylori infection
Among the GPU patients, 59 (71.1%) had H. pylori infection (51 diagnosed via RUT and 8 diagnosed via histopathology test) and 24 did not have H. pylori infection. In 59 H. pylori infection cases, 39 cases were positive for anti-CIM IgG antibody. The median age at diagnosis of GPU for the H. pylori(+) group was 10.6 ± 2.7 years, which was significantly greater than that of the H. pylori(-) group (7.9 ± 3.8 years) (P < 0.001). In microscopic findings, we found that compared with the H. pylori(-) group, the H. pylori(+) group showed more severe inflammatory activity, atrophy, and lymphoid follicular formation in the gastric mucosa (P < 0.05). The clinical data of the two groups are shown in Table 2.
The patients were divided into two groups according to the age of onset. The numbers of H. pylori(+) children in the different age groups among patients with ulcers located in the duodenal bulb and gastric region are shown in Table 3. Among GPU patients, 75.9% were >6 years old. Furthermore, H. pylori infection was the main cause of GDUs in children aged >6 years (53/70).

Treatment, Follow-Up and Prognosis
Among the 83 patients, four were lost to follow-up (one had Langerhans cell histiocytosis, and the other three patients were transferred to other hospitals and could not be contacted). Seventy patients received formal treatment, including one patient who underwent hemostasis under endoscopy. The average follow-up time of the 70 patients was 23.0 ± 11.2 months. Sixty-six patients were re-examined under endoscopy, and the average time until re-examination was 4.9 ± 2.9 weeks. Fifty-seven patients exhibited remission, and 54 patients required hospitalization. Fourteen of 83 patients had recurrence of peptic ulcers (16.9%), and two patients exhibited duodenal stenosis and underwent surgery.

DISCUSSION
The history of GDU dates back to 1931, when Brdiczka first described these exceptionally large ulcers. [11] A GPU is an emergency for the gastroenterologist, especially in children, because of their higher rates of perforation, massive hemorrhage, severe anemia, and other serious complications. [12] For adults, PUDs present with various symptoms, such as epigastric pain, dyspepsia, nausea, and anorexia. However, serious complications such as bleeding or perforation may be the first sign of a problem without any other warning symptom, and these complications occur in approximately 25% of PUD patients. [13] Reports of GPUs in children are uncommon. Unlike the adult population, symptoms cannot be used to diagnose PUD in children. [14] For children with GPUs, abdominal pain is the main symptom, which occurs mainly in the upper abdomen. However, other patients experience pain in the periumbilical region or other abdominal regions, and some experience involvement of the right hypochondrium, which is difficult to locate. For the pediatric gastroenterologist, a PUD should be considered when the patients have abdominal pain. Biliary and pancreatic diseases should be included in the differential diagnosis, and the appropriate examinations   Since the introduction of endoscopy, the diagnostic accuracy has markedly improved. The other obvious benefit of endoscopy is the ability to perform a biopsy. [11] The radiographic diagnosis rate of barium meal and CT is difficult to determine because this method is used only as a second-line method for the diagnosis of peptic ulcers. [16] In this study, all the GPUs were diagnosed by endoscopy, and it is essential to examine the location of the GPUs and evaluate the size of the ulcer.
This study revealed that GPUs occurred most often in children older than 6 years. Consistent with the findings from another group, H. pylori infection is the main etiologic factor for PUD. [17] In this study, 66.7% of patients, 40% of GGU patients, and 71.4% of GDU patients had H. pylori infections. The development of H2 blockers and proton pump inhibitors (PPIs) and the discovery of a standard treatment for H. pylori infection have increased the trend toward increased medical and decreased surgical therapy.
Compared with GGU, GDU has the following characteristics: (1) GDU has a higher H. pylori infection rate; (2) exhibits more severe pathological inflammation; (3) has a longer disease course; (4) is characterized by abdominal pain and is often accompanied by moderate anemia; and (5) occurs more often in older children and more in males than in females.
In adult PUD, the course of treatment for DU lasts 4 weeks, and that for GU lasts 6 to 8 weeks; additionally, the ulcer healing rate is greater than 90% according to gastroscopy results. However, data on the treatment of GPUs in children are scarce. In this study, we found great differences between children and adults. We suggest that the treatment course for GDU should be 6 to 8 weeks and that for GGU should be 2 weeks. For H. pylori-infected patients, the treatment course for GGU should include H. pylori eradication therapy plus an additional course of an ulcer-healing drug to reduce the recurrence of GPU. [18] After H. pylori eradication therapy or omeprazole treatment, an active peptic ulcer may be present, or the ulcer may recur. The CYP2C19 gene mutation of the P450 enzyme, which is involved in PPI metabolism, may influence the acid-inhibitory effects. [19] Compared with adults, our patients had a more favorable prognosis. In this study, only eight patients experienced GPU recurrence, and one patient underwent surgery. This suggests that the GPU patients in this study did not have severe illnesses, such as cardiovascular, pulmonary, renal, and metabolic diseases, and this lack of illness resulted in better outcomes. [20,21] Furthermore, the GGUs healed with no recurrence; one of the main reasons for this finding may be the low number of GGU patients. For adults, recurrence of PUD is more common in the elderly, males, and those with comorbid chronic kidney disease and this finding differed from those in our pediatric patients. [22] The recurrence of GDU may be associated with H. pylori eradication failure.
In conclusion, this study showed that children with GPUs more commonly had GDUs. Children older than 6 years have a high risk of GPU. H. pylori infection was the most important risk factor for GPU. Effective medical interventions could cure or improve these patients' clinical symptoms.

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Conflicts of interest
There are no conflicts of interest.