Helicobacter pylori reinfection and its risk factors after initial eradication

Abstract Background: Helicobacter pylori (H pylori) infection is a common health problem, which is closely related to peptic ulcers, gastric cancer, and extragastric diseases. Drugs can successfully eradicate it. However, the recurrence of H pylori often occurs after initial eradication. To confirm the global incidence of H pylori reinfection and systematically evaluate its risk factors. Methods: We will search for the relevant literature through Chinese and English databases, with the retrieval deadline being November 2021. Databases include PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database, Wanfang Database, and China Biomedical Literature Database. Stata14.0 will be used to conduct this systematic review. The preferred reporting items for systematic reviews and meta-analysis protocols statements are followed in this protocol, and the PRISMA statement will be followed in the completed systematic review. Results: The results will be published in a peer-reviewed journal. Conclusions: This systematic review will provide evidence regarding the rate of H pylori reinfection and its risk factors after successful eradication. It can guide the management of patients with H pylori infection.


Introduction
Helicobacter pylori (H pylori), as we all know, is a notorious gastrointestinal microorganism, which can lead to chronic gastritis, peptic ulcer, and even evolve into gastric cancer. [1] Besides, H pylori infection is also associated with extragastric diseases, especially cardiovascular, metabolic, and neurologic disorders. [2,3] In the world, more than half of the human population is infected with H pylori. [4] A meta-analysis [5] found that a wide variation in the prevalence of H pylori for countries ranges from 18.9% (Switzerland) to 87.7% (Nigeria). Therefore, the eradication of H pylori has attracted much attention. Kyoto Global Consensus Report [6] had stated that H pylori gastritis recommends eradication therapy for H pylori-infected individuals, except in the case of competing considerations. And it can effectively decrease the risk of gastric cancer by eradicating H pylori. [7] The recurrence of H pylori infection can be classified into 2 distinct mechanisms: recrudescence and reinfection. [8] The recrudescence is the reappearance of the original strain after initial eradication; it is considered to be a failure of eradication. The reinfection is infected with a new strain after initial eradication. The identification of H pylori strain requires the application of some molecular fingerprinting techniques. These techniques have very complicated procedures and require high personnel and facilities. So, at present, it cannot be widely used in clinical and scientific research. Some investigators believe that the recurrence of H pylori infection less than 1 year after eradication is classified as recrudescence, while reinfection if it was more than 1 year. [9,10] Other researchers think that the change of H pylori from negative to positive at 1 year after initial eradication may be caused by recurrence or reinfection, and reinfection was the leading cause of recurrence at 3 years after successful eradication. [11] Hu et al [12] revealed that the global annual recurrence, reinfection, and recrudescence rate of H pylori were 4.3%, 3.1%, and 2.2%, respectively. In recent years, many studies have studied the mechanism and influencing factors of the recurrence of H pylori. There are significant differences in the rate of H pylori reinfection and recrudescence and risk factors in different countries and regions. Thus, this review intends to analyze the risk effects of H pylori reinfection by evidence-based medicine.

Protocol and registration
This protocol has been registered on the INPLASY website, and its registration number is INPLASY202140121, which could be accessed on https://inplasy.com/inplasy-2021-4-0121/.

Literature search
This systematic review and meta-analysis will be performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. [13] We will search the following databases from their inception to November 2021: PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database, Wanfang Database, and China Biomedical Literature Database. The following phrase: Helicobacter pylori, Campylobacter pylori, H pylori, HP, and recurrence, recurrences, recrudescence, recrudescences, relapse, relapses, recurrent, recurred, reinfection, re-infect * , relapse * will be used for each electronic search. The search was restricted to human studies and literature written in English and Chinese. A strategy details for PubMed are shown in Table 1, and the Chinese databases will use these items translated by Chinese. At the same time, we will supplement and obtain the relevant literature, though searching manually the references included in the study. The electronic search will be conducted by 2 reviews (YY, LC) independently.

Study selection 2.3.1. Definitions.
Successful eradication: Negative H pylori status in a previously H pylori-infected patient at least 4 weeks after initial eradication. H pylori recrudescence: A recrudescence, with the same strain occurred, during the 6 to 12 months period immediately after successful eradication. [14] H pylori reinfection: A recurrence with a new strain, which was negative for 12 months after successful eradication, becomes positive again at a later stage, based on both clinical and molecular evidence previously reported. [15] 2.3.2. Inclusion criteria. The study is considered qualified when the following criteria are met.

Data extraction and management
Two authors (HZ and PZ) search and screen the literature independently. Provided that the 2 reviewers have different opinions, whether or not the literature should be included, it is advisable for them to resolve by discussion. We manage the search results through NoteExpress 3.3.0 software. The selection will be performed according to the PRISMA flow chart shown in Figure 1. The content of the data extraction: author's name, year of publication, title, country, The enforcement time of the study, study design, sample size, follow-up, eradication treatment, annual reinfection rate, multivariable adjusted hazard ratio or risk ratio, with their corresponding 95% confidence interval, and adjustment for confounding factors.

Risk of bias assessment
Newcastle-Ottawa Scale was applied to examine the methodological quality of the included studies. [16] Newcastle-Ottawa Scale had: 4 items for study subjects (4 points), 1 item for intergroup comparability (2 points), and 3 items for result measurement (3 points), with a total score of 9 (http://www.ohri. ca/programs/clinical_epidemiology/oxford.asp).

Statistical analysis
This meta-analysis will be conducted using STATA 14.0. A random-effects model will be used to estimate the pooled reinfection rate and its risk factors with 95% confidence interval. Heterogeneity will be assessed using a chi-square test and I 2 statistics (P value <.10 or I 2 over 50% were defined as substantial heterogeneity). Publication bias will be estimated by the Begg test [17] and Egger test, [18] with P < .1 indicating statistically significant.

Sensitivity analysis
We will use the leave-one-out method for sensitivity analysis to judge the stability of outcome indicators.

Subgroup analysis
If the source of heterogeneity cannot be found after sensitivity analysis, we will do further subgroup analysis.

Ethics and dissemination
In this study, no individual data from participants will be involved, so ethics approval is not required.

Discussion
H pylori is a pathogen that can cause chronic and progressive gastric mucosal damage and is closely related to peptic ulcer, gastric cancer, gastric atrophy, gastric mucosa-associated tissue lymphoma, proliferative gastric polyp, and idiopathic thrombocytopenic purpura. [6,19,20] It has been confirmed that H pylori eradication after treatment reduced the risk of gastric cancer. [21] Recurrence either as recrudescence (inadequate treatment) and reinfection eliminates the benefits of H pylori eradication. The recurrence of H pylori is related to lousy family personal living habits and re-exposure caused by exposure to H pylori infection. H pylori are transmitted through oral-oral, fecal-oral, www.md-journal.com and gastro-oral. [8] H pylori infection has familial aggregation. In daily life, those who were successful in H pylori eradication had close contact with family members infected with H pylori, shared meals, shared dental brushing tools, and came into contact with contaminated water and food. Any re-exposure of H pylori will cause recurrence. Zhou et al [22] discovered that exposure to H pylori infectors, peptic ulcer, and hospitalization were its risk factors. In China, the annual H pylori reinfection rate was 1.5% per person-year and independently associated with the following risk factors: minority groups, the education at lower levels, a family history of gastric cancer, and the residence located in Western and Centra China. [14] In developing countries, with a large population and high H pylori infection rates, it is essential to prevent H pylori infectious diseases, that is, to remain H pylori-negative for a long time. The purpose of this article is to analyze the risk factors of reinfection after H pylori successful eradication, to provide suggestions for clinical H pylori eradication treatment and management of recurrence after initial eradication.