Recurrence Rate and Influencing Factors of Helicobacter Pylori Infection After Successful Eradication in Southern Coastal China

Introduction

Helicobacter pylori (H. pylori) is a microaerobic Gram-negative bacterium that colonizes the human stomach and duodenum. It is considered a pathogenic bacterium closely associated with the development of chronic gastritis, peptic ulcer, and gastric cancer.^1–3 In fact, the International Agency for Research on Cancer (IARC) classified H. pylori as a definitive gastric cancer carcinogen in 1994.⁴ H. pylori infection is highly prevalent, with nearly 50% of the global population being infected in China, in particular, has a significantly high rate of H. pylori infection, with 46.7% of the population affected. Moreover, familial H. pylori infection is also common in China, with a prevalence of 71.2% and notable familial clustering.^5,6 According to authoritative domestic and international guidelines, eradication therapy is recommended when H. pylori infection is detected unless contraindicating factors such as age (children under 14), severe heart, liver, or kidney insufficiency, or drug allergies/intolerances exist.⁷ However, despite eradication therapy, there is still a possibility of recurrence, leading to a reemergence of associated diseases and increased medical costs for subsequent treatment. Recurrence can occur through relapse or reinfection, with the former generally happening within 1 year after eradication and the latter referring to reinfection with a different strain after a longer period.^8,9 Relapse is characterized by the return of H. pylori and related symptoms within a year of initial eradication treatment. It signifies that the bacterium was not completely eliminated and reactivates and multiplies after a latent period in the host.^10,11 On the other hand, reinfection refers to a new infection with a different strain of H. pylori after the complete eradication of the original strain.¹¹ To distinguish between relapse and reinfection, DNA fingerprinting can be employed, although its complexity and cost have limited its clinical implementation. Previous studies suggest that recurrence within one year of successful eradication is usually relapse, while recurrence after one year is more likely to be reinfection.^11–14 Hu et al reported global annual rates of H. pylori recurrence, reinfection, and relapse as 4.3%, 3.1%, and 2.2%, respectively.¹⁵ It is important to note that published reinfection rates and associated factors vary considerably across different countries, regions, populations, sample sizes, socio-economic conditions, and investigation methods.^10,15,16

Currently, there is a lack of large-scale studies on H. pylori recurrence in the coastal provinces of southern China.

Methods

Eradication Therapy and Follow-Up: Study Overview and Patient Demographics

From August 2021 to December 2022, our study included patients who had received successful H. pylori eradication therapy for the first time. The data for this study was partly from our previous study¹⁷ and partly from data collected in city and county outpatient clinics. The clinics included 21 different health service stations across five cities in Hainan province: Haikou, Sanya, Qionghai, Dongfang, and Wuzhishan. The inclusion criteria for this study were patients aged 14 years and older who had upper digestive tract symptoms and were diagnosed with H. pylori infection using either the 13C or 14C-UBT. The study was approved by the institutional ethics committee of the Second Hospital of Hainan Medical University (reference number: 2023-KJY-02), and all participants provided signed informed consent. For patients under 18 years of age, a parent or legal guardian provided the informed consent. The exclusion criteria included patients who had previously received eradication therapy, those who had used proton pump inhibitors, H2 receptor antagonists, bismuth, antibiotics, or other medications that could affect test results within the last four weeks, patients with a history of gastrointestinal tract cancer, gastric or esophageal surgery, Zollinger-Ellison syndrome, serious disorders of the liver, kidneys, cardiovascular, respiratory, hematological, neuropsychiatric, or endocrine system, individuals who had allergies to drugs used for treatment, pregnant or breastfeeding women, and patients with alcohol abuse or any other clinical condition that may increase the risk of treatment side effects.

A total of 975 H. pylori-infected patients received eradication therapy. The 13C-UBT or 14C-UBT was performed 8 to 12 weeks after therapy, and eradication was considered successful if the test result was negative. Out of these patients, a total of 824 succeeded in eradication and were followed up. From this group, 734 patients provided full information and were enrolled in the subsequent study, as shown in Figure 1. At one year after the eradication of H. pylori infection, patients were followed up using the 13C-UBT or 14C-UBT (Figure 1). We calculated the one-year eradication rates and compared the differences between recurrent patients and other patients in terms of basic data, sociological characteristics, lifestyle, and medical history.

Figure 1 The Flow Chart of this Study.

Comprehensive Data Collection Methods for H. pylori Survey

The questionnaire included gathering basic information such as the individuals’ level of education. It also collected data on various aspects of their lifestyle, including their source of drinking water and their meal patterns. Additionally, the survey aimed to identify any contact the participants may have had with other individuals infected with H. pylori. The survey process was conducted directly by the researcher or under the supervision of a highly trained investigator.

Statistical Analysis Methods for Investigating H. pylori Infection Recurrence

Data analysis was performed using SPSS 26.0 software. Continuous variables were presented as mean ± standard deviation (SD), and the comparison between groups was conducted using an independent sample t-test. Categorical variables were described as frequencies and percentages [n(%)], and chi-square tests or trend chi-square tests were utilized to compare the groups. Variables with a p-value < 0.05 in the univariate analysis were included in the multifactorial logistic regression analysis to investigate the potential relationship of H. pylori infection recurrence. The results were reported as odds ratios (OR) with 95% confidence intervals (CI). Statistical significance was established at a p-value less than 0.05.

Results

Demographic Characteristics of Participants in Follow-Up Study

A total of 734 patients, comprising 263 males and 471 females, with ages ranging from 14 to 70 years, completed the follow-up tests 1 year after eradication therapy and provided valid questionnaires (Table 1).

Table 1 The General Factors of the Recurrence and Non-Recurrence Patients with H. pylori Infection

H. pylori Infection Recurrence Rates Among Participants in Follow-Up Study

Among the 734 patients who completed the follow-up tests 1 year after eradication therapy, 26 individuals (3.5% of the total) experienced a recurrence of H. pylori infection.

Significant Risk Factors for H. pylori Infection Recurrence

The analysis of variance revealed several significant risk factors for H. pylori infection recurrence. Exposure to other H. pylori-infected individuals (χ²=12.852, P<0.001), poor hygiene condition of dining out places (χ²=6.839, P=0.009), frequency of dining out (χ²=24.315, P<0.001), smoking (χ²=7.510, P=0.006), consumption of non-purified water (χ²=16.437, P<0.001), consumption of pickles (χ²=5.682, P=0.017), irregular meals (χ²=16.877, P<0.001), and age (χ²=9.195, P=0.010) were identified as significant risk factors (Table 2). Moreover, the results indicated that exposure to other H. pylori-infected individuals, poor hygiene condition of dining out places, consumption of non-purified water, frequency of dining out, and irregular meals were independent influential factors for H. pylori recurrence (P=0.022, 0.016, 0.002, <0.001,<0.001, 95% CI 0.146–0.861, 0.121–0.806, 1.715–10.845, 0.085–0.521, 2.291–14.556) (Table 3).

Table 2 Univariate Analysis of the Factors Affecting the Recurrence of H. pylori Infection

Table 3 Multivariate Analysis of Factors Affecting the Recurrence of H. pylori Infection

Discussion

The effective eradication of H. pylori plays a crucial role in reducing the risk of gastric cancer.¹⁸ However, recurrence of H. pylori infection remains a major concern worldwide, particularly in underdeveloped regions with a high prevalence of H. pylori infection or gastric cancer.¹⁸

Various studies have indicated significant variation in the recurrence rates of H. pylori infection across different countries and regions. A meta-analysis conducted by Yan et al based on 77 studies and including 1226 patients (equivalent to 43,525 patient-years) found that the average annual recurrence rate of H. pylori infection globally was 2.82 ± 1.16%.¹⁹

Developed countries such as the United States, Germany, Norway, and Japan exhibit lower recurrence rates of H. pylori infection, ranging from 0.2% to 6.2%.^15,20,21 Conversely, developing countries such as Peru, Turkey, Mexico, and India have higher recurrence rates, ranging from 2.2% to 73%.^15,20,21 Niv et al observed a significantly higher recurrence rate of H. pylori infection in developing countries compared to developed countries (13.0% vs 2.7%) and found a negative correlation with the Human Development Index (HDI) proposed by Yan et al^19,21 In our study, the 1-year recurrence rate was 3.2%, which is relatively high and could be attributed to factors such as Hainan’s socio-economic level, poor sanitary conditions, sample size, and regional differences. It’s important to note that our study was retrospective and lacked regular follow-up of patients, which may have influenced the accuracy of the recurrence rate statistics. Furthermore, some patients who had undergone successful radical treatment were not followed up due to lack of symptoms or insufficient attention, suggesting that the actual recurrence rate may be lower.

Several studies have indicated that smokers and alcohol drinkers have a higher risk of H. pylori infection. Interestingly, some studies have also suggested that alcohol consumption may actually reduce the rate of H. pylori infection. However, our study’s findings contradict these assertions, as we found no evidence that smoking and alcohol consumption increase the recurrence rate of H. pylori infection.²² It is well-established that the effectiveness of initial H. pylori treatment is negatively correlated with the recurrence rate of the infection. The higher the eradication rate of H. pylori achieved during treatment, the lower the chance of recurrence.²³ However, our study encountered limitations in terms of the wide variation in the number of cases for each treatment regimen, as well as the lack of data on the eradication rate associated with each regimen. Consequently, further large-scale, prospective clinical follow-up studies are necessary to investigate the relationship between H. pylori eradication rates and recurrence rates for different treatment regimens.

An important finding of our investigation was the significant correlation between residential drinking water sources and H. pylori infection. This suggests that local drinking water contamination may be a factor contributing to H. pylori infection.²⁴ Previous literature has reported that consuming non-purified water increases the risk of H. pylori infection. Additionally, consumption of vegetables contaminated with feces has also been identified as a risk factor for H. pylori infection.²⁵

In our study, we discovered that individuals who frequently dined out under poor hygienic conditions had a higher likelihood of experiencing a recurrence of H. pylori infection. Previous research by XIA et al²⁶ has shown that H. pylori infection primarily occurs through the digestive tract via fecal-oral transmission. Additionally, H. pylori can survive in various foods such as milk, vegetables, and meats, leading to the transmission of infections.²⁷ Consequently, food contamination has been identified as a potential cause for the recurrence of H. pylori infections. Further studies by Lili Zhang²⁸ on the population in Baoshan District, Shanghai, revealed that people who frequently dined out were more susceptible to H. pylori infection. Meirong Wang²⁹ also found that sharing tableware while eating out increases the risk of cross-infection of H. pylori. Another study conducted by Li³⁰ in Xi’an, which followed up with 422 patients who had received H. pylori eradication treatment, confirmed that poor hygiene in restaurants was a risk factor for H. pylori recurrence. From a sociological and public health perspective, it is crucial to improve people’s income and health awareness in order to prevent the recurrence of H. pylori infection.

A nationwide, large-scale, household-based cross-sectional survey conducted previously indicated that the overall household H. pylori infection rate ranged from 50.27% to 85.06%, with a mean infection rate of 71.21%, while the mean individual-based H. pylori infection rate was 40.66%.⁶ Family members who carry H. pylori bacteria and come into contact with infected family members may serve as the primary source of its transmission. Our study further revealed that exposure to other individuals infected with H. pylori was an independent, influential factor for the recurrence of H. pylori. This suggests that H. pylori can be transmitted from one family member to another through the gastrointestinal tract.^15,31

Our study revealed that irregular meal patterns are significant risk factors for the recurrence of H. pylori infections. Skipping meals leads to low-grade inflammation, increased fat oxidation, and higher postprandial insulin concentrations, which are associated with the development of type 2 diabetes.^32,33 In diabetic patients, dysfunction of glucose metabolism leads to immune dysfunction. This results in reduced adhesion and phagocytosis of granulocytes in the body, weakening the immune cell response to bacterial, viral, and chemical toxin invasions.³⁴ Consequently, H. pylori is more likely to occur or recur in diabetic patients, and the degree of infection tends to be more severe compared to non-diabetic patients.³⁴ One of the key factors that make diabetic patients more susceptible to H. pylori infections is delayed gastric emptying.^35,36 Inflammation and immune responses in diabetic patients can impact the metabolism of peripheral nerves, leading to antrum pyloric motor incoordination and delayed gastric emptying, and in some cases, even gastroparesis caused by gastrointestinal motor neuropathy.^35,36 These conditions weaken the ability of the gastric wall to resist various invasions, making it easier for H. pylori to settle and significantly increasing the infection rate of H. pylori in diabetic patients with gastroparesis.

Our study has several limitations that need to be acknowledged. Firstly, it is important to note that this study was retrospective in nature, which means that there may have been inconsistencies in follow-up and the timing of eradication treatment. Additionally, some patients tested positive for H. pylori even after receiving multiple medications and undergoing multiple follow-up reviews throughout the 1-year follow-up period. This may have introduced some bias into our results. Secondly, the number of cases of H. pylori recurrence was relatively small, resulting in limited representation and potentially affecting the generalizability of our findings. Thirdly, we failed to consider certain important risk factors in our study, such as antibiotic resistance, hand hygiene practices before meals and after using the restroom, the specific regimen used for eradication treatment, and whether the patients were hospitalized after undergoing eradication therapy.

In conclusion, our study found that the recurrence rate of H. pylori in Hainan, China, was comparable to that observed in developing countries. We identified several independent risk factors for H. pylori recurrence, including exposure to other individuals infected with H. pylori, poor hygiene conditions at dining establishments, consumption of non-purified water, frequent dining out, and irregular meal patterns. Given these findings, regular surveillance of high-risk groups for H. pylori infection is necessary.