Analysis of risk factors for ulcer recurrence and upper gastrointestinal bleeding in children with peptic ulcer treated with Helicobacter pylori eradication therapy

Introduction

Peptic ulcer disease (PUD), a common disease of the upper gastrointestinal tract, is a mucosal rupture larger than 3–5 mm and visible in depth in the stomach or duodenum (1). It is mainly caused by an imbalance between endogenous protective factors of the gastric mucosa (mucus and bicarbonate, prostaglandin E₂, nitric oxide, sulfhydryl compounds, and antioxidant enzymes) and invasive factors (acid and pepsin secretion) (2). PUD often leads to complications of bleeding, perforation, and pyloric obstruction if not diagnosed and treated in a timely manner, thus increasing the risk of death and socioeconomic burden on patients (3).

Currently, the prevalence of PUD remains high and is increasing year by year in the adolescent population. According to previous studies, the current prevalence of PUD is about 0.2% to 0.5% in Western countries, 2% to 3% in Asian countries (4), and 24–28% in sub-Saharan African populations (5-7). It is estimated that 15,000 people die from PUD each year, which indicates that PUD still affects human health to a large extent. Helicobacter pylori (H. pylori) infection and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) are recognized to be the main causes of PUD (8). It has been shown that about 80–90% of patients with gastric and duodenal ulcers have a cause related to H. pylori infection (9), and the lifetime risk of developing PUD is 3–10 times higher in H. pylori-positive individuals than in negative individuals (10). A study showed that 4.4 billion people (57.9% of the global population at that time) were infected with H. pylori in 2017 (11). and global reports show that the prevalence of H. pylori infection in patients with PUD is 14–21% in the United States, 60–70% in Asia, and 70–90% in sub-Saharan Africa (12,13). Therefore, worldwide consensus guidelines recommend mandatory H. pylori eradication in patients with PUD (14). Since this mandate, anti-H. pylori treatment has become an important part of the peptic ulcer treatment process and is widely used in clinical practice. A study found that by eradicating or suppressing H. pylori infection, the possibility of bleeding could be reduced (15). Subsequent studies have also confirmed that H. pylori eradication promotes healing and reduces the occurrence of rebleeding (16). In addition, it was also revealed that the annual recurrence rate of peptic ulcer patients with eradicated H. pylori is significantly lower than that of patients who fail to successfully eradicate H. pylori (17). The annual recurrence rate of peptic ulcers after H. pylori eradication has been reported to be 6.45%, while the annual recurrence rate of H. pylori–positive PUD can reach 23.3% (18). All of the above studies indicate that H. pylori eradication therapy significantly improves the prognosis of patients. However, there is less analysis of the factors influencing the occurrence of ulcer recurrence and bleeding even after anti-H. pylori treatment. Therefore, the aim of this study was to analyze the risk factors for ulcer recurrence and upper gastrointestinal bleeding after anti-H. pylori treatment for peptic ulcer in adolescents. We hope our findings can help clinicians identify the relevant clinical features as early as possible and provide a reference basis for reducing the occurrence of ulcer recurrence and upper gastrointestinal bleeding, thus improving the quality of life of adolescent patients. We present the following article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-23-155/rc).

Methods

Research participants

A total of 536 adolescent patients who developed PUD and received H. pylori eradication therapy at the Affiliated Hospital of Jiangnan University between June 2016 and July 2021 were included in this study.

The included participants were (I) adolescent patients who were 12–18 years old, (II) who met the diagnosis (19) of PUD and received H. pylori eradication therapy between June 2016 and July 2021, and (III) who had complete clinicopathological data.

The exclusion criteria were as follows: (I) upper gastrointestinal bleeding due to other factors such as gastric cancer, (II) combination of other gastrointestinal diseases, (III) associated with impaired consciousness or psychiatric disorders that prevented cooperation with this study, and (IV) incomplete clinicopathological data (Figure 1).

Figure 1 Flowchart of patient selection. PUD, peptic ulcer disease; H. pylori, Heliobacter pylori.

The formula N=(Z_1-α/2/δ)²P(1-P) was used to calculate the sample size. In this study, the incidence of recurrence and bleeding was used as the main outcome index. According to the previous study of our group, the incidence of bleeding after H. pylori eradication was 10%, δ was 3%, α was 0.05(bilateral), and 10% sample loss rate was taken into account. Finally, N=423 cases were obtained. After H. pylori eradication, the incidence of ulcer recurrence (P) was 5%, δ was 3%, α was 0.05(bilateral), and 10% sample loss rate was taken into account. Finally, N=223 cases were obtained. Therefore, the sample size of the study population planned for this study was 560 cases. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Affiliated Hospital of Jiangnan University ethics board (No. KYLC2016113) and informed consent was taken from all the patients’ guardians.

General information questionnaire

A general information questionnaire was used to collect demographic data, such as gender, age, body mass index, and clinical data (history of PUD, history of smoking, history of alcohol consumption, family history of upper gastrointestinal ulcer, number of ulcers, ulcer location, ulcer diameter, ulcer stage, dietary habits, compliance with medication, regular exercise, negative emotions, complications, gastrointestinal symptoms, and laboratory indexes, etc.).

Diagnosis of H. pylori infection, eradication regimens and Eradication criteria after H. pylori treatment

All of our included patients were confirmed to be Hp positive by gastroscopy or ¹⁴C-urea breath test.

Patients were administered with amoxicillin capsules 25 mg/kg per time, 2 times/d; clarithromycin extended-release tablets 10 mg/kg per time, 2 times/d; colloidal bismuth capsules 2–3 mg/kg per time, 4 times/d; all patients were treated for 2 weeks, and the eradication effect was observed.

Eradication criteria: Gastroscopic review was requested in all cases 4 weeks after the end of the treatment course, and antibiotics, proton pump inhibitors (PPIs) and H₂ receptor inhibitors were not allowed to be used within 4 weeks after the review. If the patient refused to repeat gastroscopy, ¹⁴C-urea breath test was performed.

Evaluation of efficacy

We classified the efficacy of therapy in patients into 4 classes: (I) recovery—clinical symptoms and signs disappear, the endoscopic ulcer disappears, and the surrounding inflammation disappears, or the ulcer turns into the scarring stage; (II) marked effective—clinical symptoms and signs improve significantly, and the endoscopic ulcer area is reduced by ≥50%; (III) moderately effective—clinical symptoms and signs improve, the endoscopic ulcer area or the number of ulcers is reduced by <50%, or the ulcer enters the healing stage; and (IV) ineffective—clinical symptoms and signs do not change significantly after treatment, the endoscopic ulcer is still in the active stage, and the ulcer area does not decrease. The total efficacy was calculated as follows: total efficacy = recovery + marked effective + moderately effective.

The last follow-up was in July 2022.

Recurrence

All enrolled patients were followed up for 1 year by telephone, internet, or outpatient appointment. Immediate hospital visits were encouraged if there was any discomfort, and endoscopy was conducted as necessary to determine if the peptic ulcer had recurred. The last follow-up visit was in July 2022.

Statistical analysis

The data of each scale were entered into a computer for score conversion, and statistical analysis was performed using SPSS 26 (IBM Corp.), with measured data expressed as mean and standard deviation and count data expressed as frequency and percentage. Statistical analysis between groups was performed using a t-test and chi-squared test, and factors influencing the occurrence of bleeding and ulcer recurrence were analyzed using binary logistic regression. A P value <0.05 was considered statistically significant.

Results

Baseline data

Baseline characteristics of the patients are shown in Table 1. Due to 24 cases of actual loss and lost to follow-up, therefore, 536 adolescent patients with PUD treated with H. pylori eradication therapy were included in this study, of whom 51 (9.5%) had bleeding and 25 (4.7%) had ulcer recurrence, with a mean age of 15.35±1.99 years. There were 33 males (64.7%) in the bleeding group and 237 males (48.9%) in the nonbleeding group, and there was a significant difference between the bleeding and nonbleeding groups in prevalence of male patients (P<0.05). In the bleeding group, 3 patients (12.0%) had a history of smoking, while 9 patients (1.8%) in the nonbleeding group had a history of smoking. In the ulcer recurrence group, 3 patients (5.9%) had a history of smoking, while in the nonrecurrence group, 9 patients (1.9%) had a history of smoking. Smoking history was significantly different between both the nonrecurrence and recurrence groups (P<0.05). In the recurrence group, 7 patients (28.0%) had a family history, while in the nonrecurrence group, 43 patients (8.4%) had a family history of upper gastrointestinal ulcer, representing a statistically significant between the 2 groups (P<0.05). History of ulcers, number and size of ulcers, and application of NSAIDs were significantly different between groups which did and did not experience bleeding and recurrence (P<0.05). In the bleeding group, there were 5 (9.8%) patients with ulcer history, 16 (31.4%) with multiple ulcers, 6 (11.8%) with ulcer size ≥2 cm, and 4 (7.8%) treated with NSAIDs. In the nonbleeding group, there were 10 (2.1%) patients with ulcer history, 67 (13.8%) with multiple ulcers, 18 (3.7%) with ulcer size ≥2 cm, and 12 (2.5%) treated with NSAIDs. In the relapse group, there were 3 (12.0%) patients with a history of ulcers, 9 (36.0%) with multiple ulcers, 4 (16.0%) with ulcers ≥2 cm in size, and 3 (12.0%) with NSAIDs. In the nonrecurrence group, there were 12 (2.3%) patients with a history of ulcers, 74 (14.5%) with multiple ulcers, 20 (3.9%) with ulcers ≥2 cm in size, and 13 (2.5%) treated with NSAIDs. In the bleeding group, 5 (9.8%) cases were compound ulcers, while in the nonbleeding group, 18 (3.7%) cases were compound ulcers, representing a significant difference (P<0.05). In the bleeding group, 26 (51.0%) ulcers were in the active stage, while in the nonbleeding group, 175 (36.1%) ulcers were in the active stage; 5 (9.8%) coagulation abnormalities were found in the bleeding group and only 7 (1.4%) coagulation abnormalities were found in the nonbleeding group. There was a significant difference between ulcer stage and the presence of coagulation abnormalities in the presence or absence of bleeding and nonbleeding (P<0.05). In the recurrence group, 13 (52.0%) patients preferred spicy food, 16 (64.0%) followed medical advice on medication, and 5 (20.0%) had negative emotions; in the nonrecurrence group, 155 (30.3%) patients preferred spicy food, 416 (81.4%) took medication as prescribed, and 37 (7.2%) had negative emotions. There was a significant difference (P<0.05) in dietary habits, compliance with medication, and negative emotions between the recurrence and nonrecurrence groups.

Patient complications

Of all adolescent patients receiving anti-H. pylori treatment for PUD, 51 (9.5%) had gastrointestinal bleeding, 22 (4.1%) had gastrointestinal perforation, 18 (3.4%) had gastrointestinal obstruction, and none (0.0%) had cancer (Table 2).

Comparison of gastrointestinal symptoms between the patient groups

In the bleeding group, 26 (51.0%) patients had abdominal pain, 14 (27.5%) had bloating, 13 (25.5%) had nausea, 12 (23.5%) had vomiting, 23 (45.1%) had acid reflux, and 21 (41.2%) ate less food than before. The symptoms of abdominal pain, vomiting, acid reflux, and reduced food intake were significantly different between the bleeding and nonbleeding groups (P<0.05).

In the recurrence group, 10 (40.0%) patients had abdominal pain, 4 (16.0%) had bloating, 2 (8.0%) had nausea, 9 (36.0%) had vomiting, 8 (32.0%) had acid reflux, and 8 (32.0%) ate less food than before. The symptoms of vomiting was significantly different between the recurrence and nonrecurrence groups (P<0.05; Table 3).

Comparison of laboratory metrics between the patient groups

In the bleeding group, the mean laboratory metrics were as follows: platelet count (PLT) (161.53±61.89)×10⁹/L, prostaglandin E₂ (PGE2) 226.27±68.91 pg/mL, hemoglobin (Hb) 107.90±13.81 g/L, albumin (Alb) 38.41±8.62 g/L, interleukin-6 (IL-6) 40.38±7.07 pg/mL, IL-8 29.97±4.88 µg/L, C-reactive protein (CRP) 20.66±9.01 mg/L, and the tumor necrosis factor alpha (TNF-α) was 20.86±4.72 ng/L. In the nonbleeding group, the mean laboratory metrics were as follows: PLT (187.35±59.47)×10⁹/L, PGE2 302.85±40.67 pg/mL, Hb 128.41±13.39 g/L, Alb 41.89±8.83 g/L, IL-6 41.71±7.53 pg/mL, IL-8 30.07±5.50 µg/L, CRP 16.75±5.80 mg/L, and TNF-α 20.27±4.66 ng/L. Among these, the differences in PLT, PGE2, Hb, Alb, and CRP levels were statistically significant between the bleeding and nonbleeding groups (P<0.05).

In the recurrence group, the mean laboratory metrics were as follows: PLT (186.48±58.04)×10⁹/L, PGE2 286.92±48.39 pg/mL, Hb 121.12±18.21 g/L, Alb 40.44±8.11 g/L, IL-6 52.77±10.93 pg/mL, IL-8 32.56±5.50 µg/L, CRP 21.51±9.43 mg/L, and TNF-α 24.17±7.68 ng/L. In the nonrecurrence group, the mean laboratory metrics were as follows: PLT (184.82±60.28)×10⁹/L, PGE2 295.98±49.52 pg/mL, Hb 126.72±14.48 g/L, Alb 41.62±8.90 g/L, IL-6 41.04±6.84 pg/mL, IL-8 29.94±5.41 µg/L, CRP 16.91±6.01 mg/L, and TNF-α 20.14±4.39 ng/L. Among these, the differences in IL-6, IL-8, CRP, and TNF-α levels were statistically significant between the recurrence and nonrecurrence groups (P<0.05; Table 4).

Comparison of treatment efficacy between the patient groups

According to the results of the chi-squared analysis, in the bleeding group, 7 (13.7%) patients were classified as recovery, 16 (31.4%) as effective, 11 (21.6%) as moderately effective, 8 (15.7%) as ineffective, and 9 patients (17.6%) as recurrence, for a total efficacy rate of 66.7%. In the nonbleeding group, 77 (15.9%) patients were classified as recovery, 185 (38.1%) as effective, 184 (37.9%) as moderately effective, 23 (4.7%) as ineffective, and 16 (3.3%) as recurrence, for a total efficacy rate of 92.0%. The treatment efficacy in the nonbleeding group was significantly higher than that of the bleeding group, and the total efficacy rate was also significantly higher than that of the nonbleeding group (P<0.05), as shown in Table 5.

Treatment associated with recurrence in 1 year

In the relapse group, 4 (16.0%) were treated with surgery, 21 (84.0%) were treated with PPIs, 8 (32.0%) were treated with H₂ antagonists, and 2 (8.0%) were treated with antacids. PPI, H₂ antagonist, and antacid treatment had a significant effect on whether relapse occurred (P<0.05; Table 6).

Risk factors of bleeding and recurrence analyzed with binary logistic regression models

Binary logistic regression analysis showed that gender, ulcer history, number and location of ulcers, abnormal coagulation, vomiting, PGE2, Hb, Alb, and CRP were independent risk factors for the occurrence of bleeding in patients (Table 7). Bleeding, number and size of ulcers, dietary habits, compliance with medication, vomiting, IL-6, and TNF-α were independent risk factors for the occurrence of ulcer recurrence in patients (Table 8).

Discussion

PUD is a common medical condition with severe symptoms and a complex etiology, but the most important cause remains H. pylori infection (20). It has been shown that H. pylori is present in up to 85% of patients with PUD (21). Because of the high prevalence of H. pylori, there is now a consensus to treat with H. pylori eradication therapy. There are various clinical manifestations of PUD, and one of the hallmark symptoms is abdominal pain (22). Patients with abdominal pain in this study had the highest proportion of all symptoms, which is consistent with the results of the previous studies. Upper gastrointestinal bleeding is a common comorbidity of PUD, and the percentage of PUD complicated by upper gastrointestinal bleeding can be 20% to 30% (23,24). Melena is the most common first symptom of upper gastrointestinal bleeding, followed by vomiting blood, with abdominal pain, fever, anemia, and hypovolemic manifestations all being concomitant symptoms (25). To sum up, peptic ulcer, as one of the most common chronic diseases of the digestive system, seriously reduces the quality of life of patients and brings great troubles to patients. Therefore, it is important to analyze the risk factors for peptic ulcer bleeding and recurrence after anti-H. pylori treatment to prevent peptic ulcer recurrence and improve patients’ prognosis (26-28).

The results of this study showed that smoking history, ulcer history, number and size of ulcers, and application of NSAIDs were significantly different between groups that did and did not experience bleeding or recurrence. Smoking was found to be an independent risk factor for the development of peptic ulcers. Smoking inhibits bile secretion, and nicotine relaxes the sphincter, causing bile reflux and increasing the rate of H. pylori infection, which leads to PUD (29). Larger ulcers heal more slowly and form larger scars during treatment, resulting in degeneration of the local peptic mucosa and reduced resistance to erosion via gastric acid or proteases, which in turn causes the recurrence of the ulcer and an increased chance of bleeding. In addition, NSAID drugs can accumulate in high concentrations in cells in an acidic environment, thereby damaging mucosal cells and increasing the risk of ulcers complicated by gastrointestinal bleeding. At the same time, NSAID drugs can inhibit the effect of COX-1, leading to a decrease in PGE synthesis and vasoconstriction, which affects the blood supply to the gastric mucosa and its cell regeneration and repair, reduces the secretion of pancreatic and bile content, weakens the ability to neutralize gastric acid, and destroys the gastric protection function, which also leads to an increased probability of PUD complicated by upper gastrointestinal bleeding (30). This study demonstrated that the differences in PLT, PGE2, Hb, Alb and CRP levels were statistically different between the ulcer bleeding and nonbleeding groups, while IL-6, IL-8, CRP, and TNF-α levels were significantly different between the recurrence and nonrecurrence groups. Among these, PGE2 can inhibit gastric acid secretion, synthesize gastric mucosal protective substances, and maintain good blood circulation in gastric mucosa, thus playing a protective role against peptic ulcer bleeding (31). In contrast, H. pylori mainly colonizes the gastric-type epithelium and contains strong urease, which promotes the hydrolysis of urea to produce ammonia, causing gastric epithelial cells to secrete transmembrane ammonia gradients that disrupt gastric mucosal barrier function, interfere with gastric mucosal hydrophobicity, reduce antacid effects, and thus decrease prostaglandin content. In addition, acute neutrophils infiltrate the gastric mucosal surface to varying degrees after H. pylori infection (32). Neutrophils and monocytes activated by H. pylori and its products infiltrate the H. pylori-infected gastric mucosa and stimulate the transcription and synthesis of several proinflammatory cytokines, such as interleukins IL-1β, IL-6, IL-8, TNF-α, and anti-inflammatory cytokines (e.g., IL-4 and IL-10) (33). One study reported that the increased production of inflammatory cytokines after H. pylori infection leads to enhanced inflammation of the gastric mucosa via the binding to specific receptors on target cells, which does not heal easily and thus increases the risk of bleeding and recurrence (34). This finding is consistent with our study in which IL-6 and TNF-α were independent risk factors for the development of ulcer recurrence in patients.

The prevalence of peptic ulcer is high in China, and it tends to occur in those who are younger. A large amount of clinical research indicates that patients mostly develop peptic ulcer due to H. pylori infection. H. pylori is resistant to most antimicrobial drugs, making eradication difficult and treatment generally ineffective (35). The results of this study showed that the efficacy found in the bleeding group was also significantly lower than that in the nonbleeding group. The reason for this may be that the bleeding group had a greater number of ulcers, larger ulcer diameters, and more compound ulcers. Their gastric and duodenal mucosal wounds healed relatively poorly, or because H. pylori eradication was not complete, which could have resulted in a significantly lower treatment effect than that in the nonbleeding group; meanwhile, their recurrence rate was higher than that of the nonbleeding group.

In conclusion, there are many factors that influence bleeding and ulcer recurrence after H. pylori eradication therapy of peptic ulcer in adolescents. In clinical work, great attention should be paid to the relevant clinical characteristics of patients, and sequential therapy should be used for patients with H. pylori-positive peptic ulcer to improve clinical efficacy and reduce the risk of bleeding and recurrence. This type of therapy can improve the clinical symptoms of patients and promote the recovery of patients’ health.

The main drawback of this study is the relatively short follow-up period due to limited time and manpower. In addition, we used a retrospective design, and although the study indicators were all from the same hospital, the impact of laboratory tests and treatments on the data at different time periods was not studied due to the large time span of collection. Furthermore, ulcer recurrence was only defined clinically in this study, not endoscopically, which may have caused some errors.

Conclusions

In the clinical treatment of adolescent patients, it is important to pay particular attention to clinical characteristics of patients and to adopt individualized treatment methods in response to the risk factors of ulcer bleeding and recurrence after H. pylori eradication therapy, which can effectively reduce the harmfulness of the disease by decreasing the occurrence of complications and thus improve the prognosis of patients.

Acknowledgments

Funding: This study was supported by funds from the Wuxi Taihu Talent Plan High-Level Talent Training Project (Grant No. HB2020038).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-23-155/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-23-155/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-23-155/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-155/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Affiliated Hospital of Jiangnan University ethics board (No. KYLC2016113) and informed consent was taken from all the patients’ guardians.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Gray)