Helicobacter pylori recrudescence and its influencing factors

Abstract Helicobacter pylori (H pylori) is known as one of the most common infectious pathogens, with high infection and recurrence rates worldwide. The prevalence of H pylori is up to 90% in developing countries, while the annual recurrence rate is much higher than that in developed countries. Recurrence can occur either by recrudescence or reinfection. Compared with reinfection, the time window for recrudescence is generally shorter, followed by the recurrence of H pylori–associated diseases in the short‐term. Many factors are involved in the H pylori reinfection, such as the prevalence of H pylori infection, living conditions and economic development, health conditions and so forth. Previous studies focused less on H pylori recrudescence. Therefore, the influencing factors for H pylori recrudescence needed further exploration. This study reviewed the recrudescence of H pylori infection and its influencing factors.


| INTRODUC TI ON
Helicobacter pylori (H pylori) is a microaerobic Gram-negative bacterium that colonizes the human stomach and duodenum. 1 It can cause lifelong infection without eradication. Many studies showed 2,3 that H pylori led to some important gastrointestinal diseases, such as chronic gastritis, peptic ulcer, gastric adenocarcinoma and mucosaassociated lymphoid tissue lymphoma, and was associated with a variety of parenteral diseases such as idiopathic thrombocytopenic purpura. H pylori eradication significantly alleviated stomach inflammation, promoted ulcer healing and prevented gastric cancer. 2 In 1994, H pylori was listed as Group I carcinogen. The 2015 Tokyo Global Consensus Report 4 defines H pylori gastritis as an infectious disease and recommends eradication therapy for H pylori-infected individuals, except in the case of competing considerations. However, H pylori infection can still recur after eradication therapy. Recurrence can occur by either recrudescence or reinfection. 5 Compared with reinfection, the time window for recrudescence is generally shorter. Recrudescence is generally considered as H pylori recurrence within 1 year after eradication, followed by the recurrence of H pylori-associated diseases in the short-term. 6,7 Patients with short-term recurrence suffer from the risk of recurrence of these diseases. The economic pressure, psychological burden and potential adverse drug reactions have increased dramatically. Therefore, exploring the factors related to H pylori recrudescence is important. In this study, the recrudescence of H pylori and its influencing factors were discussed.

| DEFINITI ON AND D IAG NOS IS OF H PYLORI RECRUDE SCEN CE
Helicobacter pylori recurrence is generally divided into recrudescence and reinfection. 5 Recrudescence is defined as the reappearance of the original infection following an initially false-negative post-eradication test result. 2 A small amount of H pylori that has not been eradicated (H pylori was hidden in the deep part of the stomach or the gastric epithelial metaplasia of the duodenum) or is in dormancy (eg H pylori coccoid forms) is recolonized, reproduced and eventually detected. Therefore, the recrudescence strain is generally the original infectious strain. Reinfection is defined as infection with a new strain or a strain homologous to the original strain of H pylori.
So far, relevant studies have shown that recrudescence is generally considered as H pylori recurrence within 1 year after eradication. 6,7 Gisbert et al 8 suggested that the cumulative annual recurrence rate after H pylori eradication was 5.3% after 1 year, 6.8% after 2 years, 7% after 3 years, 7.6% after 4 years and 9.3% after 5 years. The present study found that recurrence decreased with time and declined sharply after the first year. Kim et al 9 performed a 2-year follow-up of patients with H pylori eradication. They found that, regardless of first-line or second-line therapy, the recurrence rate in the first year was significantly different (9.3% vs 4.5%) and the recurrence rate in the second year was similar (2.0% vs 2.9%).
If the recurrence after H pylori eradication is reinfection, the annual reinfection rate should be stable. 8,9 However, the annual recurrence rate of H pylori increases at a steady rate, which is contrary to the conclusions of the aforementioned studies. It is generally believed that the recurrence of H pylori in the first year after eradication is mainly based on recrudescence. However, Raymond et al 10 performed a strain typing study on three patients with repeated recurrence after H pylori eradication. The time interval between the first recrudescence of two patients was 2 years, and the recrudescence interval was 1-3 years. One patient's first reinfection interval was up to 8 years and the reinfection interval was 1-2 years. Accordingly, Raymond et al believed that the recurrence interval was not a reliable clinical marker for recrudescence. However, the number of specimens in the aforementioned study was extremely small, with some contingency in the conclusion. Further large-sample H pylori strain typing follow-up studies are needed to confirm this view.
To distinguish whether H pylori recurrence is recrudescence or reinfection, genotyping methods are used to judge the H pylori strain type before and after recurrence. H pylori genotyping methods include 11 multi-locus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), random amplification of polymorphic DNA (RAPD), amplified fragment length polymorphism (AFLP), whole-genome sequencing (WGS) and so on. Multi-locus sequence typing analyses strain variation by polymerase chain reaction (PCR) amplification of multiple housekeeping genes (such as atpA, efp, mutY and so on) and determination of their nucleic acid sequences. 12 Multi-locus sequence typing has the advantages of high repeatability and high resolution and can provide more detailed information on human migration than human genetic analysis to a certain extent. 12 However, MLST only reflects the variability of several housekeeping genes. Pulsed-field gel electrophoresis is to detect some large fragments of linear DNA and is considered as the gold standard for bacterial typing. 13 But it has not been widely used in H pylori typing. It is very crucial of restriction enzymes choice and enzyme digestion condition control, which still needs further exploration in exploration in H pylori typing. 13 Random amplification of polymorphic DNA is a typing technique based on PCR that can perform polymorphism analysis on the entire unknown sequence genome. Even trace amounts of DNA can also be analysed. But there still exist some limitations. Random amplification of polymorphic DNA cannot provide any information about strain virulence factors and genetic evolution information. 14 Meanwhile, it depends highly on the quality and quantity of the template. 14 Amplified fragment length polymorphism is a molecular marker technology developed on the basis of PCR, which has the advantages of high repeatability and high resolution. 15 However, it also has high-quality requirements for DNA template and it is a non-rapid detection method. 15 Whole-genome sequencing masters the entire genomic sequence of the microorganism. In theory, any microorganism can be typed with a resolution of a single base. 13 However, at the same time, the experiment cost is large and the cycle is long. Therefore, the aforementioned gene detection methods have not been widely carried out clinically. In addition, some studies pointed out that even if the same H pylori strain was identified before and after recurrence, still the patient might be reinfected by the same strain in the environment. 16 Therefore, how to quickly and effectively identify H pylori recurrence and recrudescence is a hot issue worthy of further study.

| INFLUEN CING FAC TOR S OF H PYLORI RECRUDE SCEN CE
The rates varied widely among countries and areas from a high of 21.3% to a low of 0.2%. 5 In recent years, more attention has been paid to H pylori and its diseases at home and abroad. However, Hu et al 17 performed a systematic review with meta-analysis of H pylori recurrence rates worldwide. They suggested no change in the recurrence rates over the past 27 years. 17 These findings showed that the studies on the prevention and treatment of H pylori recurrence might not have achieved great results.
The global annual recurrence rate of H pylori was 4.3%. 17 The annual recurrence rate of H pylori in developing countries (13%) is much higher than that in developed countries (2.7%). 18 Among studies on

| Selection of therapeutic scheme and treatment time window
Many studies have reported that the therapeutic scheme is closely related to H pylori recurrence within 1 year. 8,9 A therapeutic scheme with low H pylori-eradication rate is temporary clearance rather than complete eradication, leading to H pylori recrudescence. Therefore, the rate of H pylori recrudescence negatively correlates with the eradication rate. The lower the H pylori-eradication rate, the higher the H pylori recrudescence rate. Gisbert et al 8 performed a prospective study involving 1000 patients, selecting two therapeutic schemes with low eradication rates (omeprazole plus amoxicillin, 32%; omeprazole plus amoxicillin and metronidazole, 56%) and two therapeutic schemes with high eradication rates (omeprazole plus clarithromycin and either amoxicillin or metronidazole, 85%; bismuth subcitrate, tetracycline chlorhydrate and metronidazole, 77%). The review results after 1 year showed that the former H pylori recrudescence rate was significantly higher than the latter (11.3% vs 4.7%, P = .006). A similar study was conducted in Korea, in which a standard triple therapy (eradication rate was 79.9%) and a barium-containing quadruple therapy (eradication rate was 90.4%) were used for H pylori eradication. 9 A follow-up showed that H pylori recrudescence rates were 9.3% and 4.5% (P < .05) within 1 year. 9 However, due to the geographical variation in H pylori resistance to antibiotics, even in the same treatment programme, H pylori-eradication rates were different in different areas and countries. 19,20 Therefore, to increase the H pylori eradication and reduce its recurrence, different countries should use drugs as a first-line treatment based on the epidemiological study of local H pylori antibiotic resistance.
In addition to therapeutic schemes, selecting an appropriate treatment time window is also important for the H pylori eradica-

| Re-examination means and time
The detection methods for H pylori are of two types: invasive and non-invasive. Invasive detection methods include rapid urease test, HE staining, Giemsa stain, bacterial culture and so on. The non-invasive detection methods include a 13C-urea breath test, 14C-urea breath test, stool antigen test and so on. However, if only one of the aforementioned means is used to evaluate the efficacy, sensitivity and specificity are reduced. If a patient has used a PPI 2 months before re-examination or an antibiotic 1 month before re-examination, the breath test may be false negative because of the urease activity suppressed by these drugs. Especially, when the result is at a critical value, whether to use eradication therapy is difficult to determine. 20 In addition, due to the drugs such as PPI, the H pylori distribution in the stomach changes (eg H pylori in the antrum is moved up to the corpus ventriculi). H pylori rejuvenates and multiplies due to the reduction or loss of drug efficacy after a period of eradication therapy.
When H pylori is detected again, the result becomes positive again, which is H pylori recrudescence. Therefore, to reduce diagnostic error, it is best to use two or more different diagnostic techniques for H pylori recurrence detection.
In addition to H pylori detection methods, the evaluation time for H pylori eradication is also related to H pylori recrudescence.
At present, the clinical evaluation of H pylori eradication is carried out at least 4 weeks after the therapy completion. Neil et al 23 also believed that 1 month after eradication therapy was sufficient to evaluate the effect of H pylori eradication. Some studies 16,24 postponed the re-examination means to 2 months to reduce the falsenegative rate. However, H pylori can be recrudesced within a few months after therapy. Ishizuka et al 25 found that H pylori could reappear within 3 months after eradication therapy. When a patient is examined within 2-3 months after eradication, it is difficult for the investigators to distinguish between eradication failure and recrudescence. Therefore, the selection of a time node for re-examination influences the evaluation of H pylori recrudescence. However, a few studies currently define an evaluation period for H pylori eradication failure and recrudescence.

| Helicobacter pylori oral colonization
Helicobacter pylori is mainly transmitted through multiple routes between humans, including faecal-oral transmission, oral-oral transmission, gastric-oral transmission and iatrogenic transmission.
It can also be transmitted to humans through water, environment and animals. 26  However, the conclusion may not be applicable to all populations because the studies involved a small sample size, some were limited to people of certain areas, and some involved different material parts of obtaining oral H pylori (such as dental plaque and saliva).
Therefore, multi-centre and large-sample studies are needed to confirm the effect of oral H pylori treatment on reducing gastric H pylori recrudescence in the future.

| H pylori biofilm formation
Biofilms can be defined as adherent aggregates of microorganisms encased with an extracellular polymeric substance. Growing evidence indicates that H pylori can also establish biofilms. 39,40 Moreover, a study found that the H pylori-eradication rate in the N-acetylcysteine (NAC)-treated group (which can eliminate and prevent biofilm establishment) before the traditional eradication therapy was significantly higher than that in the NAC-free group (65% vs 20%, P = .005). 41  increase the reliability of evidence in the future. The aim should be to disrupt the protection mechanism of H pylori in a harsh environment, prevent its transformation into coccoid forms and biofilm formation and improve the H pylori detection rate under the protection mechanism.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no conflicts of interest concerning this study.