A randomised controlled clinical study of standard triple therapy, bismuth-based quadruple therapy and sequential therapy for Helicobacter pylori infection in children

A randomised controlled clinical study of standard triple therapy, bismuth-based quadruple therapy and sequential therapy for Helicobacter pylori infection in children | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A randomised controlled clinical study of standard triple therapy, bismuth-based quadruple therapy and sequential therapy for Helicobacter pylori infection in children Ruixue Miao, Jing Chen, Shan Gao, Liyuan Wang, Wei Zhou, Chaomin Wan, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4350024/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Aug, 2024 Read the published version in BMC Pediatrics → Version 1 posted 10 You are reading this latest preprint version Abstract Background and aim Bismuth and non-bismuth quadruple therapy are the guideline-recommended first-line therapy in children with Helicobacter pylori infection in areas with high antibiotic resistance. However, their efficacy in children is uncertain and there are few well-designed studies. Here, we evaluated the eradication rates of standard triple therapy, bismuth-based quadruple therapy and sequential therapy in children with H. pylori infection. Methods A randomised controlled trial was conducted in children infected with H. pylori in West China Second Hospital. They were randomly assigned to 14-day standard triple therapy (omeprazole + amoxicillin + clarithromycin), 14-day bismuth quadruple therapy (bismuth + omeprazole + amoxicillin + clarithromycin) and 10-day sequential therapy (omeprazole + amoxicillin for 5 days followed by omeprazole + clarithromycin + metronidazole for 5 days). The eradication rate was assessed by a 13 C-urea breath test 4 to 6 weeks after therapy completion. Symptom improvement and adverse events were compared among the groups. Results In total, 132 patients were enrolled. The eradication rates of 14-day standard triple therapy, 14-day bismuth quadruple therapy and 10-day sequential therapy were 70.0%, 78.9% and 50.0% in per-protocol analysis and 63.6%, 68.2% and 43.2% in intention-to-treat analysis, respectively. Symptom improvement and adverse drug event rates were similar in the three groups. Conclusion The three therapeutic regimens evaluated in this study are equally not recommendable for H. pylori infection treatment due to unsatisfactory eradication rates. The high prevalence of clarithromycin resistance makes the use of clarithromycin-based quadruple therapy not advisable, even in combination with amoxicillin and bismuth salts. children Helicobacter pylori eradication bismuth quadruple therapy sequential therapy Figures Figure 1 Figure 2 1. Background Helicobacter pylori colonises the gastric mucosa and causes chronic gastritis, which is defined as an infectious disease [ 1 , 2 ] , as well as peptic ulcer, gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma [ 3 ] . H. pylori infection may also progress to iron deficiency anaemia, chronic immune thrombocytopenic purpura and inflammatory bowel disease and impair children’s growth [ 4 , 5 ] . The infection is usually acquired in childhood and has an overall prevalence of 30.31% in Chinese children [ 6 ] . Its successful eradication can reduce the recurrence of peptic ulcer in infected children. Currently, the efficacy of the standard triple therapy recommended as first-line treatment is generally decreasing due to increased antibiotic resistance. At the same time, some antibiotics are not licensed for the paediatric population. Thus, the treatment of H. pylori infection in children is a particular challenge in areas with severe antibiotic resistance. Bismuth and non-bismuth quadruple therapies, including concomitant, sequential and hybrid regimens, show higher eradication rates than standard triple therapy in the adult population but have been scarcely studied in children [ 7 ] . Moreover, concomitant and hybrid treatments are rarely used in infected children because of the potential for additive adverse events. A Cochrane review determined that sequential therapy including proton pump inhibitors (PPIs) with amoxicillin (AMO) for 5 days followed by PPIs with clarithromycin (CLR) and metronidazole (MET) for 5 days had better efficacy than triple therapy [ 8 ] . The Chinese consensus [ 9 ] on the diagnosis and treatment of H. pylori infection in children states that sequential therapy can be used as first-line treatment in areas with CLR resistance exceeding 20% and recommends bismuth-based quadruple therapies for rescue therapy. Nonetheless, a contradictory result was reported in one study that found an unacceptable eradication rate of 56.1% for sequential therapy, in which the CLR resistance rate was 25.7% [ 10 ] . The joint ESPGHAN/NASPGHAN guidelines recommend bismuth-based quadruple therapies as first-line treatment in areas of high or unknown CLR resistance for children with H. pylori infection based on the literature and adult studies [ 11 ] . However, well-designed clinical studies of bismuth-based therapy in children are lacking. Therefore, in the present randomised controlled trial, we compared the eradication rate, adverse events and adherence of 14-day bismuth-based quadruple therapy and 10-day sequential therapy with 14-day standard triple therapy in children with H. pylori infection in southwest China. 2. Methods 2.1 Participants Patients were included when they met all of the following four inclusion criteria: 1) outpatients aged from 6 to 14 years who were referred for gastroscopy in West China Second University Hospital; 2) confirmed H. pylori infection; 3) indication for eradication according to the 2015 Chinese consensus on H. pylori infection in children; and 4) treatment-naïve. H. pylori infection was diagnosed by one of the following conditions: 1) a positive culture of H. pylori ; 2) H. pylori gastritis on histopathology and a simultaneous positive rapid urease test (RUT); 3) if the histopathology findings and RUT result were inconsistent, a positive 13 C-urea breath test (UBT); and 4) positive histopathology or 13 C-UBT when children had a bleeding peptic ulcer. The following patients were excluded: 1) patients who had undergone earlier eradication treatment and had received antibiotics, bismuth salt, PPIs or H 2 -receptor antagonists within 4 weeks before treatment; 2) patients who had an allergic history to the drugs being used in the study; and 3) patients who had severe systemic diseases such as liver or kidney failure. 2.2 Randomisation and interventions Eligible patients were randomly assigned to one of three treatment groups according to a computer-generated random number table. The standard triple therapy (STT) group received continuous 14-day therapy comprising a PPI (omeprazole) with two antibiotics (CLR and AMO). The bismuth quadruple therapy (BQT) group received continuous 14-day therapy comprising a bismuth salt (bismuth potassium citrate) with a PPI (omeprazole) plus two antibiotics (CLR and AMO). Finally, the sequential therapy (ST) group received 10-day therapy comprising a PPI (omeprazole) with AMO for 5 days followed by a PPI with CLR and MET for 5 days. The dosages are detailed in Table 1 . All treatments were administered by a professor who received the random number table and corresponding treatment regimens from the statistician. Information on the patient demographics, symptoms and telephone number were recorded by another paediatric resident who was blinded to the group allocation throughout the study. Table 1 Description of the three treatments Therapy Time drugs Daily dose # (twice daily) Maximum does for once STT Day1 to14 omeprazole AMO CLA 0.6-1.0mg/kg 50mg/kg 15-20mg/kg 20 mg 1 g 0.5 g BQT Day1 to14 Bismuth omeprazole AMO CLA 6-8mg/kg 0.6-1.0mg/kg 50mg/kg 15-20mg/kg 220 mg 20 mg 1 g 0.5 g ST Day 1 to 5 Day 6 to 10 omeprazole AMO omeprazole CLA MET 0.6-1.0mg/kg 50mg/kg 0.6-1.0mg/kg 15-20mg/kg 20mg/kg 20 mg 1 g 20 mg 0.5 g 0.5 g CLA: clarithromycin; AMO amoxicillin; MET metronidazole; STT: standard triple therapy; BQT: bismuth quadruple therapy; ST: sequential therapy. # Drugs were given to each child at the appropriate dosage according to the range shown in the table and in conveniently dispensed doses. Telephone follow-ups with the children’s guardians were conducted every 3 days during the therapy period to monitor adherence and record adverse events and symptom changes. After the end of the treatment, telephone follow-ups were performed once a week until 4 weeks after treatment completion to record adverse events and symptom improvement. The eradication condition was then assessed by 13 C-UBT at 4–6 weeks after treatment completion. All follow-ups were conducted by the above-mentioned paediatric resident. The patients and personnel involved in this study were blinded to the group allocation throughout the study. Treatment regimens were unblinded after all patient follow-ups were completed. 2.3 Outcomes The efficacy of anti- H. pylori therapy can be assessed based on symptom improvement, the eradication rate and adverse events during follow-up. Symptoms were graded according to the score improvement ratio (SIR) of the frequency score and severity score of the main complaints at the first visit before treatment and at 6 weeks after treatment completion [ 12 ] . SIR = (pre-treatment total score − post-treatment total score) / pre-treatment total score × 100% where total score is the sum of the frequency score and severity score. The frequency score was calculated as follows: 0 = no symptoms; 1 = one symptom a week; 2 = two symptoms a week; and 3 = three or more symptoms a week. The severity score was graded as follows: 0 = no symptoms; 1 = symptoms are present but tolerable; 2 = symptoms are present and affect daily activities; and 3 = symptoms are intolerable and severely affect daily life. In our study, the SIR was divided into four levels: grade A (clinical control, SIR ≥ 85%), grade B (markedly effective, SIR = 60%-84.9%), grade C (moderately effective, SIR = 30%-59.9%) and grade D (ineffective, SIR < 30%-59.9%). The eradication rate was measured using 13 C-UBT (Beijing Richen-force Science & Technology Co., Ltd.) at 4–6 weeks after therapy completion. The criterion for successful eradication was a negative 13 C-UBT result of < 4.0. 2.4 Analysis Our initial hypothesis was that the eradication rates of 14-day standard triple therapy, 14-day bismuth quadruple therapy and 10-day sequential therapy in children with H. pylori infection would be significantly different. We assumed that the eradication rates of the three treatment regimens would be 65%, 91.9% and 89.7% based on the literature (with an α of 0.05 and β of 0.2 for a 20% increase in a two-sided test) [ 13 – 15 ] . A minimum sample size of 40 children in each group was thus required. Statistical analysis was performed using SPSS 20.0. A dropout rate including withdrawal and loss to follow-up less than 20% was accepted. The eradication rate was analysed by intention-to-treat and per-protocol analyses. For intention-to-treat, all participants enrolled in the study were analysed, regardless of whether they dropped out. For per-protocol, only children who completed the entire study process were included in the analysis. Measurement and count data are expressed as mean ± standard deviation and percentage, respectively. Comparisons between groups were performed using a t-test or analysis of variance (ANOVA) and chi-square test. The rank data of two groups and three groups were compared by the Mann-Whitney rank-sum test and Kruskal-Wallis rank-sum test, respectively. A P value < 0.05 was considered statistically significant. 3. Results 3.1 Patients’ characteristics A total of 2554 patients underwent upper gastrointestinal endoscopy from June 2018 to December 2019 in West China Second University Hospital. Of these patients, 276 children were diagnosed with H. pylori infection. The overall H. pylori infection rate in children undergoing gastroscopy was 10.81%. The study flow diagram is shown in Fig. 1. 132 patients were enrolled in this study and 44 were allocated to each of the 14-day STT, 14-day BQT and 10-day ST groups. The symptoms included in this study were nonspecific and mainly manifested as abdominal pain, vomiting, nausea and lack of appetite. A symptom frequency of more than 3 times per week was reported by 78.8% patients. In terms of symptom severity, most patients (72.7%) had tolerable symptoms that did not affect daily activities. The frequency score (Z = 1.804, P = 0.801) and severity score (Z = 2.74, P = 0.252) before treatment were similar in the three groups. There were no differences in age (10.25 ± 2.59 years, 10.09 ± 2.87 years and 10.07 ± 2.32 years; F = 0.064, P = 0.938) or sex (males, 31/24/20; females, 13/20/24; χ2 = 5.62, P = 0.064) among the three groups. Four children were withdrawn because they did not receive or complete the therapy. Twelve children were lost to follow-up and were missing data on symptoms and 13 C-UBT due to poor adherence at 6 weeks. These 16 children were excluded from the per-protocol analysis. The dropout rates did not differ among the three treatment groups. 3.2 Treatment outcomes The eradication rates of 14-day standard triple therapy, 14-day bismuth quadruple therapy and 10-day sequential therapy were 70.0% (28 of 40, 95%Cl 55.2%-84.8%), 78.9% (30 of 38, 95%Cl 65.4%-92.5%) and 50.0% (19 of 38, 95%Cl 33.3%%-66.7%) in per-protocol analysis and 63.6% (28 of 44, 95%Cl 48.8%-78.4%), 68.2% (28 of 44, 95%Cl 53.9%-82.5%) and 43.2% (28 of 44, 95%Cl 27.9%-58.4%) in intention-to-treat analysis. The results indicated that there was a significant difference among the three groups, with the efficiency of 10-day sequential therapy significantly lower than that of 14-day standard triple therapy and of 14-day bismuth quadruple therapy. The eradication rate did not differ between the STT and BQT groups. Eradication results are summarised in Fig. 2. The outcomes were similar for per-protocol analysis and intention-to-treat analysis. Symptoms were determined to have improved based on the scores obtained before and after treatment. No significant difference was found among the groups (Table 2 ). Interestingly, we found that the symptom improvement of children with a positive 13 C-UBT was not significantly different from that of children with a negative 13 C-UBT at 4–6 weeks (Z = 1.18, P = 0.80). In this study, 8 children (3 in the STT group, 3 in the BQT group and 2 in the ST group) had mild adverse reactions after taking the drugs, including headache, diarrhoea, stomach discomfort and nausea, but none of them needed to discontinue the treatment due to the adverse events. There were no significant differences in adverse events among the groups. Table 2 Symptom improvements in children with H. pylori infection in the different groups Grade A Grade B Grade C Grade D P-value P-value Groups by therapy STT 21 5 14 0 5.49 0.451 BQT 16 5 16 0 ST 21 5 9 2 Group by UBT in 4 weeks Negative 42 9 26 1 1.18 0.80 Positive 19 6 14 1 STT: standard triple therapy; BQT: bismuth quadruple therapy; ST: sequential therapy; grade A: clinical control, SIR ≥ 85%; grade B: markedly effective, SIR = 60%-84.9%; grade C: effective, SIR = 30%-59.9%; grade D: ineffective, SIR < 30%-59.9%; UBT: urea breath test. Three children had no symptoms in this study. In addition, we conducted H. pylori culture but, unfortunately, no resistance results were obtained due to bacterial purification failure. 4. Discussion Standard triple therapy is still the preferred regimen in areas where the predominant strain is susceptible to CLR. However, studies have reported worrisome levels of resistance to agents such as CLR and MET [ 16 ] . CLR-resistant H. pylori has been designated a high priority by the World Health Organization. The use of standard triple therapy is generally decreasing, and guidelines for children with H. pylori infection recommend that bismuth and non-bismuth quadruple therapy be used as first-line therapy in areas with high antibiotic resistance, based on adult studies. The present randomised controlled study showed unsatisfactory eradication rates (< 80%) of 14-day standard triple therapy (PPI + AMO + CLR), 14-day bismuth quadruple therapy (PPI + AMO + CLR + Bismuth) and sequential therapy (PPI + AMO and PPI + CLA + MET). Eradication success is primarily influenced by good adherence and low antibiotic resistance. The need to take the medication as prescribed was constantly emphasised throughout the treatment process in this study, and the overall drug adherence among children who completed the therapy exceeded 90%. Although we failed to obtain antimicrobial susceptibility testing results, another of our contemporaneous studies determined primary resistance rates in our area of 45.3% for CLR and 73.6% for MET and a dual resistance rate of 28.3% for CLR and MET [ 17 ] . The high rate of resistance to CLR and MET helps to explain the low eradication rates. In our area, CLR-based therapy should not be recommended as the first-line treatment. Bismuth was initially mainly used as a mucosal protective agent for peptic ulcer and gastritis. In vitro, the combination of bismuth and antibiotic has shown a synergistic bacteriostatic and bactericidal effect in H. pylori treatment [ 18 ] . Accordingly, bismuth-containing therapy has become an effective alternative treatment to overcome antimicrobial resistance. In a review of studies conducted in children from 2011 to 2021, Lai et al. demonstrated that bismuth-based therapy had higher eradication rates [ 19 ] . A paediatric population study in Shanghai showed eradication rates of 89.8% for bismuth-based quadruple therapy and of 74.1% for standard triple therapy, in a population with CLR resistance in 18.5% and dual CLR and MET resistance in 18.5% [ 20 ] . However, the present study indicated that bismuth-based quadruple therapy had comparable efficacy to standard triple therapy (78.9% vs. 70%), which is inconsistent with the results of other studies. We believe that the unsatisfactory eradication rate for bismuth-based quadruple therapy may be related to the resistance. It is unclear whether higher antibiotic resistance has a greater impact on the eradication rate of bismuth-based quadruple therapy. Several adult studies have also reported that CLR and MET resistance are risk factors for failure of bismuth-based quadruple therapy and suggested that bismuth regimens not be recommended when the strains develop dual CLR/MET resistance or when there is a high level of metronidazole resistance with a minimum inhibitory concentration MIC > 32 µg/mL [ 21 – 23 ] . Currently, the impact of antibiotic resistance on the efficiency of bismuth in children is unclear, and further multicentre clinical studies should be performed. In most studies, 10-day sequential therapy eradication appeared to be superior to 14-day standard triple therapy [ 19 ] . The Chinese consensus on H. pylori infection recommends sequential therapy as first-line therapy in areas where CLR resistance exceeds 20%. However, it remains controversial whether 10-day sequential therapy is better than 14-day standard triple therapy because a growing number of studies reached inconsistent conclusions, finding a similar or even inferior efficacy for sequential therapy [ 20 , 24 , 25 ] . In the present study, we found a shocking eradication rate of 50% in 10-day sequential therapy. An unacceptably low efficacy of 56.1% was also reported in a Turkish study with 25.7% CLR resistance [ 10 ] . The reasons for the results are unknown. Bontems et al. identified a lower eradication rate in children with CLR resistance than in those without resistance [ 26 ] . In addition, sequential therapy exposes children to three different antibiotics, and the ESPGHAN/NASPGHAN guidelines recommend against the use of sequential therapy in treatment-naïve children when the strain is CLR resistant or susceptibility testing is not available. Several adult studies have proposed that the efficacy of sequential therapy can be improved by extending the duration and have reported that 14-day sequential treatment is better than 14-day triple therapy [ 27 ] . A retrospective study in children also concluded that 14-day sequential therapy tended to be better than 14-day triple treatment. Moreover, a novel 14-day bismuth-based sequential therapy has been reported in Turkish children with H. pylori infection; it achieved a high eradication rate of 92% [ 28 ] . However, the efficacy and practicality of the above-mentioned new regimens and adverse antibiotic events need to be further explored based on antibiotic sensitivity testing. The latest 2022 Chinese expert consensus on children with H. pylori infection [ 29 ] no longer recommends sequential therapy as the first-line treatment, which is consistent with our current results. In this study, we also evaluated symptoms in the children with H. pylori infection. It is worth mentioning that there was no significant difference in symptom improvement between the two groups of children with or without H. pylori eradication. A similar result was also reported in a randomised controlled study [ 30 ] . This suggests that H. pylori infection may not be the main cause of these symptoms. Therefore, nonspecific clinical manifestations should not be an indication for H. pylori testing and eradication therapy in children. This opinion is also supported by a meta-analysis indicating that the prevalence of abdominal symptoms was not different between H. pylori -positive and -negative children [ 31 ] . The updated JSPGHAN 2020 guidelines recommend testing for H. pylori in children with alarm signs rather than in children diagnosed with functional abdominal pain. The guidelines also propose that a paediatrician discuss the advantages and disadvantages of eradication therapy before treatment, in contrast to the ‘test and treat’ principle used in adults. A limitation of this study is that antibiotic susceptibility testing was not conducted and that the relationship between antibiotic resistance and the eradication regimen was absent. Nevertheless, another of our studies performed in the same hospital has provided useful information on the antibiotic resistance of H. pylori strains. Despite the aforementioned limitation, this study comprises a randomised controlled trial with few biases that compared standard triple therapy, bismuth-based quadruple therapy and sequential therapy in children with H. pylori infection. Conclusion 10-day sequential therapy is not recommendable in children with high antibiotic resistance to CLR and MET. At the same time, the eradication rate of bismuth-based quadruple therapy was not always superior to that of standard triple therapy. The risk factors for bismuth failure in children undergoing H. pylori eradication treatment need further exploration. Abbreviations MALT: mucosa-associated lymphoid tissue; PPIs: proton pump inhibitors; AMO: amoxicillin; CLR: clarithromycin; MET: metronidazole; RUT: rapid urease test; UBT: C-urea breath test; STT: standard triple therapy; BQT: bismuth quadruple therapy; ST: sequential therapy; SIR: score improvement ratio Declarations Ethics approval and consents to participate This randomised controlled study was approved by the Ethical Committee of West China Second Hospital, Sichuan University, and has been registered in the China Clinical Trial Center (ChiCTR1900027450, the date of first trail registration 13/11/2019). Informed consent was obtained from the guardian of each child. Consent for publication Not applicable Availability of date and materials The authors confirm that the data supporting the findings of this study are available within the article Competing interests No conflict of interest. Funding This study was supported by the Research Development Project of Sichuan Provincial Science and Technology Department (No. 2018SZ0130) and the Clinical Research Project of West China Second Hospital, Sichuan University (No. KL039). Authors’ contributions Drs Ruixue Miao designed the study, followed-up, analyzed data, carried out the data analyses, drafted the initial manuscript. Shan Gao, Liyuan Wang and Jing Chen performed gastroscopy, collected specimens, conducted histopathology examination and made 13C-urea breath test. Wei Zhou cultured H pylori and tested. Zhiling Wang and Professor Wan designed the study, guided process and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Acknowledgements We thank all of the children and their parents for their participation in this study. References Sugano K, Tack J, Kuipers EJ, et al. 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Supplementary Files CONSORT2010Checklist.doc Cite Share Download PDF Status: Published Journal Publication published 23 Aug, 2024 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Revision requested 08 Jul, 2024 Reviews received at journal 07 Jul, 2024 Reviewers agreed at journal 17 Jun, 2024 Reviews received at journal 16 Jun, 2024 Reviewers agreed at journal 16 Jun, 2024 Reviewers invited by journal 15 Jun, 2024 Editor invited by journal 13 Jun, 2024 Submission checks completed at journal 04 Jun, 2024 Editor assigned by journal 04 Jun, 2024 First submitted to journal 30 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4350024","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":315590884,"identity":"03c358b3-1d64-4efa-bf35-6aaa558dd5cd","order_by":0,"name":"Ruixue Miao","email":"","orcid":"","institution":"Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Ruixue","middleName":"","lastName":"Miao","suffix":""},{"id":315590885,"identity":"06b0af0e-e115-4601-852d-35c0683ff080","order_by":1,"name":"Jing Chen","email":"","orcid":"","institution":"Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Chen","suffix":""},{"id":315590886,"identity":"e5b47fd9-c2e8-4d12-af83-92ba5d68c186","order_by":2,"name":"Shan Gao","email":"","orcid":"","institution":"Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Shan","middleName":"","lastName":"Gao","suffix":""},{"id":315590887,"identity":"1e92bea6-bc5e-4b44-be25-75a4fd044afb","order_by":3,"name":"Liyuan Wang","email":"","orcid":"","institution":"Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Liyuan","middleName":"","lastName":"Wang","suffix":""},{"id":315590888,"identity":"a486ceb7-538d-45e6-871b-e9e676e46acb","order_by":4,"name":"Wei Zhou","email":"","orcid":"","institution":"Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Zhou","suffix":""},{"id":315590889,"identity":"b3c959b9-844d-4669-b047-604386cb2d20","order_by":5,"name":"Chaomin Wan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtklEQVRIiWNgGAWjYJCCAx8qJOTY2JsPEK2D8eGMMzbGfDzHEojWwmzM25aWOE8iR4E49QbHT6dJ8LAdTm9jyGFg+FGxjQgtZ3K3SUjwHM5tYzh7gLHnzG3CWsxu8G6TMJAAamHsS2BmbCNWS4LB4XQ2Zh4DorVsNjiQkJbAxkasFvszuRsfNhywMWzjYUs4SJRfJNvPbjj895+EvPz8xwcf/KggQgsKOECi+lEwCkbBKBgFuAAAtWg9978+Mg0AAAAASUVORK5CYII=","orcid":"","institution":"Sichuan University","correspondingAuthor":true,"prefix":"","firstName":"Chaomin","middleName":"","lastName":"Wan","suffix":""},{"id":315590890,"identity":"d8e255ae-140c-42fd-86a8-e984264971bf","order_by":6,"name":"Zhiling Wang","email":"","orcid":"","institution":"Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Zhiling","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-04-30 15:14:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4350024/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4350024/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12887-024-05020-6","type":"published","date":"2024-08-23T15:57:20+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":58760344,"identity":"8db7c769-ef09-450d-96eb-67d060d73c7b","added_by":"auto","created_at":"2024-06-20 18:49:36","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":103991,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the patient selection and allocation process.\u003c/p\u003e\n\u003cp\u003eSTT: standard triple therapy; BQT: bismuth quadruple therapy; ST:sequential therapy\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4350024/v1/7852e495caadcabe72f298e3.jpg"},{"id":58760343,"identity":"ed13e364-0876-4e68-8334-af6e96bb9067","added_by":"auto","created_at":"2024-06-20 18:49:36","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":97859,"visible":true,"origin":"","legend":"\u003cp\u003eThe eradication rate of three group\u003c/p\u003e\n\u003cp\u003eSTT: standard triple therapy; BQT: bismuth quadruple therapy; ST:sequential therapy\u003c/p\u003e\n\u003cp\u003ePP: per-protocol; ITT: intention-to-treat\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4350024/v1/c4ae2775199624013ac48f79.jpg"},{"id":63300199,"identity":"ef43b750-fcaf-46af-90af-b8d711a20291","added_by":"auto","created_at":"2024-08-26 16:12:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":693758,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4350024/v1/4b79210a-3bc9-46c3-8b38-07159a2050c7.pdf"},{"id":58760342,"identity":"33849bfb-4685-4149-ae02-45f6995c4b2a","added_by":"auto","created_at":"2024-06-20 18:49:36","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":221184,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORT2010Checklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-4350024/v1/ad0f3891a11dfb84aa510305.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"A randomised controlled clinical study of standard triple therapy, bismuth-based quadruple therapy and sequential therapy for Helicobacter pylori infection in children","fulltext":[{"header":"1. Background","content":"\u003cp\u003e \u003cem\u003eHelicobacter pylori\u003c/em\u003e colonises the gastric mucosa and causes chronic gastritis, which is defined as an infectious disease \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e, as well as peptic ulcer, gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. \u003cem\u003eH. pylori\u003c/em\u003e infection may also progress to iron deficiency anaemia, chronic immune thrombocytopenic purpura and inflammatory bowel disease and impair children\u0026rsquo;s growth \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. The infection is usually acquired in childhood and has an overall prevalence of 30.31% in Chinese children \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Its successful eradication can reduce the recurrence of peptic ulcer in infected children. Currently, the efficacy of the standard triple therapy recommended as first-line treatment is generally decreasing due to increased antibiotic resistance. At the same time, some antibiotics are not licensed for the paediatric population. Thus, the treatment of \u003cem\u003eH. pylori\u003c/em\u003e infection in children is a particular challenge in areas with severe antibiotic resistance.\u003c/p\u003e \u003cp\u003eBismuth and non-bismuth quadruple therapies, including concomitant, sequential and hybrid regimens, show higher eradication rates than standard triple therapy in the adult population but have been scarcely studied in children \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Moreover, concomitant and hybrid treatments are rarely used in infected children because of the potential for additive adverse events. A Cochrane review determined that sequential therapy including proton pump inhibitors (PPIs) with amoxicillin (AMO) for 5 days followed by PPIs with clarithromycin (CLR) and metronidazole (MET) for 5 days had better efficacy than triple therapy \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. The Chinese consensus \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e on the diagnosis and treatment of \u003cem\u003eH. pylori\u003c/em\u003e infection in children states that sequential therapy can be used as first-line treatment in areas with CLR resistance exceeding 20% and recommends bismuth-based quadruple therapies for rescue therapy. Nonetheless, a contradictory result was reported in one study that found an unacceptable eradication rate of 56.1% for sequential therapy, in which the CLR resistance rate was 25.7% \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. The joint ESPGHAN/NASPGHAN guidelines recommend bismuth-based quadruple therapies as first-line treatment in areas of high or unknown CLR resistance for children with \u003cem\u003eH. pylori\u003c/em\u003e infection based on the literature and adult studies \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. However, well-designed clinical studies of bismuth-based therapy in children are lacking. Therefore, in the present randomised controlled trial, we compared the eradication rate, adverse events and adherence of 14-day bismuth-based quadruple therapy and 10-day sequential therapy with 14-day standard triple therapy in children with \u003cem\u003eH. pylori\u003c/em\u003e infection in southwest China.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Participants\u003c/h2\u003e \u003cp\u003ePatients were included when they met all of the following four inclusion criteria: 1) outpatients aged from 6 to 14 years who were referred for gastroscopy in West China Second University Hospital; 2) confirmed \u003cem\u003eH. pylori\u003c/em\u003e infection; 3) indication for eradication according to the 2015 Chinese consensus on \u003cem\u003eH. pylori\u003c/em\u003e infection in children; and 4) treatment-na\u0026iuml;ve.\u003c/p\u003e \u003cp\u003e \u003cem\u003eH. pylori\u003c/em\u003e infection was diagnosed by one of the following conditions: 1) a positive culture of \u003cem\u003eH. pylori\u003c/em\u003e; 2) \u003cem\u003eH. pylori\u003c/em\u003e gastritis on histopathology and a simultaneous positive rapid urease test (RUT); 3) if the histopathology findings and RUT result were inconsistent, a positive \u003csup\u003e13\u003c/sup\u003eC-urea breath test (UBT); and 4) positive histopathology or \u003csup\u003e13\u003c/sup\u003eC-UBT when children had a bleeding peptic ulcer.\u003c/p\u003e \u003cp\u003eThe following patients were excluded: 1) patients who had undergone earlier eradication treatment and had received antibiotics, bismuth salt, PPIs or H\u003csub\u003e2\u003c/sub\u003e-receptor antagonists within 4 weeks before treatment; 2) patients who had an allergic history to the drugs being used in the study; and 3) patients who had severe systemic diseases such as liver or kidney failure.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Randomisation and interventions\u003c/h2\u003e \u003cp\u003eEligible patients were randomly assigned to one of three treatment groups according to a computer-generated random number table. The standard triple therapy (STT) group received continuous 14-day therapy comprising a PPI (omeprazole) with two antibiotics (CLR and AMO). The bismuth quadruple therapy (BQT) group received continuous 14-day therapy comprising a bismuth salt (bismuth potassium citrate) with a PPI (omeprazole) plus two antibiotics (CLR and AMO). Finally, the sequential therapy (ST) group received 10-day therapy comprising a PPI (omeprazole) with AMO for 5 days followed by a PPI with CLR and MET for 5 days. The dosages are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. All treatments were administered by a professor who received the random number table and corresponding treatment regimens from the statistician. Information on the patient demographics, symptoms and telephone number were recorded by another paediatric resident who was blinded to the group allocation throughout the study.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDescription of the three treatments\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTherapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTime\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003edrugs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDaily dose\u003csup\u003e#\u003c/sup\u003e (twice daily)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMaximum does for once\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSTT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDay1 to14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eomeprazole AMO\u003c/p\u003e \u003cp\u003eCLA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.6-1.0mg/kg\u003c/p\u003e \u003cp\u003e50mg/kg\u003c/p\u003e \u003cp\u003e15-20mg/kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20 mg\u003c/p\u003e \u003cp\u003e1 g\u003c/p\u003e \u003cp\u003e0.5 g\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBQT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDay1 to14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBismuth\u003c/p\u003e \u003cp\u003eomeprazole AMO\u003c/p\u003e \u003cp\u003eCLA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6-8mg/kg\u003c/p\u003e \u003cp\u003e0.6-1.0mg/kg\u003c/p\u003e \u003cp\u003e50mg/kg\u003c/p\u003e \u003cp\u003e15-20mg/kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e220 mg\u003c/p\u003e \u003cp\u003e20 mg\u003c/p\u003e \u003cp\u003e1 g\u003c/p\u003e \u003cp\u003e0.5 g\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDay 1 to 5\u003c/p\u003e \u003cp\u003eDay 6 to 10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eomeprazole AMO\u003c/p\u003e \u003cp\u003eomeprazole CLA\u003c/p\u003e \u003cp\u003eMET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.6-1.0mg/kg\u003c/p\u003e \u003cp\u003e50mg/kg\u003c/p\u003e \u003cp\u003e0.6-1.0mg/kg\u003c/p\u003e \u003cp\u003e15-20mg/kg\u003c/p\u003e \u003cp\u003e20mg/kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20 mg\u003c/p\u003e \u003cp\u003e1 g\u003c/p\u003e \u003cp\u003e20 mg\u003c/p\u003e \u003cp\u003e0.5 g\u003c/p\u003e \u003cp\u003e0.5 g\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eCLA: clarithromycin; AMO amoxicillin; MET metronidazole; STT: standard triple therapy; BQT: bismuth quadruple therapy; ST: sequential therapy.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e#\u003c/sup\u003e Drugs were given to each child at the appropriate dosage according to the range shown in the table and in conveniently dispensed doses.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTelephone follow-ups with the children\u0026rsquo;s guardians were conducted every 3 days during the therapy period to monitor adherence and record adverse events and symptom changes. After the end of the treatment, telephone follow-ups were performed once a week until 4 weeks after treatment completion to record adverse events and symptom improvement. The eradication condition was then assessed by \u003csup\u003e13\u003c/sup\u003eC-UBT at 4\u0026ndash;6 weeks after treatment completion. All follow-ups were conducted by the above-mentioned paediatric resident. The patients and personnel involved in this study were blinded to the group allocation throughout the study. Treatment regimens were unblinded after all patient follow-ups were completed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Outcomes\u003c/h2\u003e \u003cp\u003eThe efficacy of anti-\u003cem\u003eH. pylori\u003c/em\u003e therapy can be assessed based on symptom improvement, the eradication rate and adverse events during follow-up. Symptoms were graded according to the score improvement ratio (SIR) of the frequency score and severity score of the main complaints at the first visit before treatment and at 6 weeks after treatment completion \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSIR = (pre-treatment total score\u0026thinsp;\u0026minus;\u0026thinsp;post-treatment total score) / pre-treatment total score \u0026times; 100%\u003c/p\u003e \u003cp\u003ewhere total score is the sum of the frequency score and severity score. The frequency score was calculated as follows: 0\u0026thinsp;=\u0026thinsp;no symptoms; 1\u0026thinsp;=\u0026thinsp;one symptom a week; 2\u0026thinsp;=\u0026thinsp;two symptoms a week; and 3\u0026thinsp;=\u0026thinsp;three or more symptoms a week. The severity score was graded as follows: 0\u0026thinsp;=\u0026thinsp;no symptoms; 1\u0026thinsp;=\u0026thinsp;symptoms are present but tolerable; 2\u0026thinsp;=\u0026thinsp;symptoms are present and affect daily activities; and 3\u0026thinsp;=\u0026thinsp;symptoms are intolerable and severely affect daily life. In our study, the SIR was divided into four levels: grade A (clinical control, SIR\u0026thinsp;\u0026ge;\u0026thinsp;85%), grade B (markedly effective, SIR\u0026thinsp;=\u0026thinsp;60%-84.9%), grade C (moderately effective, SIR\u0026thinsp;=\u0026thinsp;30%-59.9%) and grade D (ineffective, SIR\u0026thinsp;\u0026lt;\u0026thinsp;30%-59.9%).\u003c/p\u003e \u003cp\u003eThe eradication rate was measured using \u003csup\u003e13\u003c/sup\u003eC-UBT (Beijing Richen-force Science \u0026amp; Technology Co., Ltd.) at 4\u0026ndash;6 weeks after therapy completion. The criterion for successful eradication was a negative \u003csup\u003e13\u003c/sup\u003eC-UBT result of \u0026lt;\u0026thinsp;4.0.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Analysis\u003c/h2\u003e \u003cp\u003eOur initial hypothesis was that the eradication rates of 14-day standard triple therapy, 14-day bismuth quadruple therapy and 10-day sequential therapy in children with \u003cem\u003eH. pylori\u003c/em\u003e infection would be significantly different. We assumed that the eradication rates of the three treatment regimens would be 65%, 91.9% and 89.7% based on the literature (with an α of 0.05 and β of 0.2 for a 20% increase in a two-sided test) \u003csup\u003e[\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. A minimum sample size of 40 children in each group was thus required. Statistical analysis was performed using SPSS 20.0.\u003c/p\u003e \u003cp\u003eA dropout rate including withdrawal and loss to follow-up less than 20% was accepted. The eradication rate was analysed by intention-to-treat and per-protocol analyses. For intention-to-treat, all participants enrolled in the study were analysed, regardless of whether they dropped out. For per-protocol, only children who completed the entire study process were included in the analysis.\u003c/p\u003e \u003cp\u003eMeasurement and count data are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation and percentage, respectively. Comparisons between groups were performed using a t-test or analysis of variance (ANOVA) and chi-square test. The rank data of two groups and three groups were compared by the Mann-Whitney rank-sum test and Kruskal-Wallis rank-sum test, respectively. A P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Patients\u0026rsquo; characteristics\u003c/h2\u003e \u003cp\u003eA total of 2554 patients underwent upper gastrointestinal endoscopy from June 2018 to December 2019 in West China Second University Hospital. Of these patients, 276 children were diagnosed with \u003cem\u003eH. pylori\u003c/em\u003e infection. The overall \u003cem\u003eH. pylori\u003c/em\u003e infection rate in children undergoing gastroscopy was 10.81%. The study flow diagram is shown in Fig.\u0026nbsp;1. 132 patients were enrolled in this study and 44 were allocated to each of the 14-day STT, 14-day BQT and 10-day ST groups. The symptoms included in this study were nonspecific and mainly manifested as abdominal pain, vomiting, nausea and lack of appetite. A symptom frequency of more than 3 times per week was reported by 78.8% patients. In terms of symptom severity, most patients (72.7%) had tolerable symptoms that did not affect daily activities. The frequency score (Z\u0026thinsp;=\u0026thinsp;1.804, P\u0026thinsp;=\u0026thinsp;0.801) and severity score (Z\u0026thinsp;=\u0026thinsp;2.74, P\u0026thinsp;=\u0026thinsp;0.252) before treatment were similar in the three groups. There were no differences in age (10.25\u0026thinsp;\u0026plusmn;\u0026thinsp;2.59 years, 10.09\u0026thinsp;\u0026plusmn;\u0026thinsp;2.87 years and 10.07\u0026thinsp;\u0026plusmn;\u0026thinsp;2.32 years; F\u0026thinsp;=\u0026thinsp;0.064, P\u0026thinsp;=\u0026thinsp;0.938) or sex (males, 31/24/20; females, 13/20/24; χ2\u0026thinsp;=\u0026thinsp;5.62, P\u0026thinsp;=\u0026thinsp;0.064) among the three groups. Four children were withdrawn because they did not receive or complete the therapy. Twelve children were lost to follow-up and were missing data on symptoms and \u003csup\u003e13\u003c/sup\u003eC-UBT due to poor adherence at 6 weeks. These 16 children were excluded from the per-protocol analysis. The dropout rates did not differ among the three treatment groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Treatment outcomes\u003c/h2\u003e \u003cp\u003eThe eradication rates of 14-day standard triple therapy, 14-day bismuth quadruple therapy and 10-day sequential therapy were 70.0% (28 of 40, 95%Cl 55.2%-84.8%), 78.9% (30 of 38, 95%Cl 65.4%-92.5%) and 50.0% (19 of 38, 95%Cl 33.3%%-66.7%) in per-protocol analysis and 63.6% (28 of 44, 95%Cl 48.8%-78.4%), 68.2% (28 of 44, 95%Cl 53.9%-82.5%) and 43.2% (28 of 44, 95%Cl 27.9%-58.4%) in intention-to-treat analysis. The results indicated that there was a significant difference among the three groups, with the efficiency of 10-day sequential therapy significantly lower than that of 14-day standard triple therapy and of 14-day bismuth quadruple therapy. The eradication rate did not differ between the STT and BQT groups. Eradication results are summarised in Fig.\u0026nbsp;2. The outcomes were similar for per-protocol analysis and intention-to-treat analysis.\u003c/p\u003e \u003cp\u003eSymptoms were determined to have improved based on the scores obtained before and after treatment. No significant difference was found among the groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Interestingly, we found that the symptom improvement of children with a positive \u003csup\u003e13\u003c/sup\u003eC-UBT was not significantly different from that of children with a negative \u003csup\u003e13\u003c/sup\u003eC-UBT at 4\u0026ndash;6 weeks (Z\u0026thinsp;=\u0026thinsp;1.18, P\u0026thinsp;=\u0026thinsp;0.80). In this study, 8 children (3 in the STT group, 3 in the BQT group and 2 in the ST group) had mild adverse reactions after taking the drugs, including headache, diarrhoea, stomach discomfort and nausea, but none of them needed to discontinue the treatment due to the adverse events. There were no significant differences in adverse events among the groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSymptom improvements in children with \u003cem\u003eH. pylori\u003c/em\u003e infection in the different groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrade A\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade B\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGrade C\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGrade D\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroups by therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSTT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e5.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.451\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBQT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup by UBT in 4 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eSTT: standard triple therapy; BQT: bismuth quadruple therapy; ST: sequential therapy; grade A: clinical control, SIR\u0026thinsp;\u0026ge;\u0026thinsp;85%; grade B: markedly effective, SIR\u0026thinsp;=\u0026thinsp;60%-84.9%; grade C: effective, SIR\u0026thinsp;=\u0026thinsp;30%-59.9%; grade D: ineffective, SIR\u0026thinsp;\u0026lt;\u0026thinsp;30%-59.9%; UBT: urea breath test.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eThree children had no symptoms in this study.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn addition, we conducted \u003cem\u003eH. pylori\u003c/em\u003e culture but, unfortunately, no resistance results were obtained due to bacterial purification failure.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eStandard triple therapy is still the preferred regimen in areas where the predominant strain is susceptible to CLR. However, studies have reported worrisome levels of resistance to agents such as CLR and MET \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. CLR-resistant \u003cem\u003eH. pylori\u003c/em\u003e has been designated a high priority by the World Health Organization. The use of standard triple therapy is generally decreasing, and guidelines for children with \u003cem\u003eH. pylori\u003c/em\u003e infection recommend that bismuth and non-bismuth quadruple therapy be used as first-line therapy in areas with high antibiotic resistance, based on adult studies. The present randomised controlled study showed unsatisfactory eradication rates (\u0026lt; 80%) of 14-day standard triple therapy (PPI + AMO + CLR), 14-day bismuth quadruple therapy (PPI + AMO + CLR + Bismuth) and sequential therapy (PPI + AMO and PPI + CLA + MET). Eradication success is primarily influenced by good adherence and low antibiotic resistance. The need to take the medication as prescribed was constantly emphasised throughout the treatment process in this study, and the overall drug adherence among children who completed the therapy exceeded 90%. Although we failed to obtain antimicrobial susceptibility testing results, another of our contemporaneous studies determined primary resistance rates in our area of 45.3% for CLR and 73.6% for MET and a dual resistance rate of 28.3% for CLR and MET \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. The high rate of resistance to CLR and MET helps to explain the low eradication rates. In our area, CLR-based therapy should not be recommended as the first-line treatment.\u003c/p\u003e \u003cp\u003eBismuth was initially mainly used as a mucosal protective agent for peptic ulcer and gastritis. In vitro, the combination of bismuth and antibiotic has shown a synergistic bacteriostatic and bactericidal effect in \u003cem\u003eH. pylori\u003c/em\u003e treatment \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Accordingly, bismuth-containing therapy has become an effective alternative treatment to overcome antimicrobial resistance. In a review of studies conducted in children from 2011 to 2021, Lai et al. demonstrated that bismuth-based therapy had higher eradication rates \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. A paediatric population study in Shanghai showed eradication rates of 89.8% for bismuth-based quadruple therapy and of 74.1% for standard triple therapy, in a population with CLR resistance in 18.5% and dual CLR and MET resistance in 18.5% \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. However, the present study indicated that bismuth-based quadruple therapy had comparable efficacy to standard triple therapy (78.9% vs. 70%), which is inconsistent with the results of other studies. We believe that the unsatisfactory eradication rate for bismuth-based quadruple therapy may be related to the resistance. It is unclear whether higher antibiotic resistance has a greater impact on the eradication rate of bismuth-based quadruple therapy. Several adult studies have also reported that CLR and MET resistance are risk factors for failure of bismuth-based quadruple therapy and suggested that bismuth regimens not be recommended when the strains develop dual CLR/MET resistance or when there is a high level of metronidazole resistance with a minimum inhibitory concentration MIC \u0026gt; 32 µg/mL \u003csup\u003e[\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e–\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. Currently, the impact of antibiotic resistance on the efficiency of bismuth in children is unclear, and further multicentre clinical studies should be performed.\u003c/p\u003e \u003cp\u003eIn most studies, 10-day sequential therapy eradication appeared to be superior to 14-day standard triple therapy \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. The Chinese consensus on \u003cem\u003eH. pylori\u003c/em\u003e infection recommends sequential therapy as first-line therapy in areas where CLR resistance exceeds 20%. However, it remains controversial whether 10-day sequential therapy is better than 14-day standard triple therapy because a growing number of studies reached inconsistent conclusions, finding a similar or even inferior efficacy for sequential therapy \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. In the present study, we found a shocking eradication rate of 50% in 10-day sequential therapy. An unacceptably low efficacy of 56.1% was also reported in a Turkish study with 25.7% CLR resistance \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. The reasons for the results are unknown. Bontems et al. identified a lower eradication rate in children with CLR resistance than in those without resistance \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. In addition, sequential therapy exposes children to three different antibiotics, and the ESPGHAN/NASPGHAN guidelines recommend against the use of sequential therapy in treatment-naïve children when the strain is CLR resistant or susceptibility testing is not available. Several adult studies have proposed that the efficacy of sequential therapy can be improved by extending the duration and have reported that 14-day sequential treatment is better than 14-day triple therapy \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. A retrospective study in children also concluded that 14-day sequential therapy tended to be better than 14-day triple treatment. Moreover, a novel 14-day bismuth-based sequential therapy has been reported in Turkish children with \u003cem\u003eH. pylori\u003c/em\u003e infection; it achieved a high eradication rate of 92% \u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. However, the efficacy and practicality of the above-mentioned new regimens and adverse antibiotic events need to be further explored based on antibiotic sensitivity testing. The latest 2022 Chinese expert consensus on children with \u003cem\u003eH. pylori\u003c/em\u003e infection \u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e no longer recommends sequential therapy as the first-line treatment, which is consistent with our current results.\u003c/p\u003e \u003cp\u003eIn this study, we also evaluated symptoms in the children with \u003cem\u003eH. pylori\u003c/em\u003e infection. It is worth mentioning that there was no significant difference in symptom improvement between the two groups of children with or without \u003cem\u003eH. pylori\u003c/em\u003e eradication. A similar result was also reported in a randomised controlled study \u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. This suggests that \u003cem\u003eH. pylori\u003c/em\u003e infection may not be the main cause of these symptoms. Therefore, nonspecific clinical manifestations should not be an indication for \u003cem\u003eH. pylori\u003c/em\u003e testing and eradication therapy in children. This opinion is also supported by a meta-analysis indicating that the prevalence of abdominal symptoms was not different between \u003cem\u003eH. pylori\u003c/em\u003e-positive and -negative children \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. The updated JSPGHAN 2020 guidelines recommend testing for \u003cem\u003eH. pylori\u003c/em\u003e in children with alarm signs rather than in children diagnosed with functional abdominal pain. The guidelines also propose that a paediatrician discuss the advantages and disadvantages of eradication therapy before treatment, in contrast to the ‘test and treat’ principle used in adults.\u003c/p\u003e \u003cp\u003eA limitation of this study is that antibiotic susceptibility testing was not conducted and that the relationship between antibiotic resistance and the eradication regimen was absent. Nevertheless, another of our studies performed in the same hospital has provided useful information on the antibiotic resistance of \u003cem\u003eH. pylori\u003c/em\u003e strains. Despite the aforementioned limitation, this study comprises a randomised controlled trial with few biases that compared standard triple therapy, bismuth-based quadruple therapy and sequential therapy in children with \u003cem\u003eH. pylori\u003c/em\u003e infection.\u003c/p\u003e "},{"header":"Conclusion","content":"\u003cp\u003e10-day sequential therapy is not recommendable in children with high antibiotic resistance to CLR and MET. At the same time, the eradication rate of bismuth-based quadruple therapy was not always superior to that of standard triple therapy. The risk factors for bismuth failure in children undergoing \u003cem\u003eH. pylori\u003c/em\u003e eradication treatment need further exploration.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eMALT: mucosa-associated lymphoid tissue; PPIs: proton pump inhibitors; AMO: amoxicillin; CLR: clarithromycin; MET: metronidazole; RUT: \u0026nbsp;rapid urease test; UBT:\u003csup\u003e\u0026nbsp;\u003c/sup\u003eC-urea breath test; STT: standard triple therapy; BQT: bismuth quadruple therapy; ST: sequential therapy; SIR: score improvement ratio\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consents to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis randomised controlled study was approved by the Ethical Committee of West China Second Hospital, Sichuan University, and has been registered in the China Clinical Trial Center (ChiCTR1900027450, the date of first trail registration 13/11/2019). Informed consent was obtained from the guardian of each child.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of date and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors confirm that the data supporting the findings of this study are available within the article\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Research Development Project of Sichuan Provincial Science and Technology Department (No. 2018SZ0130) and the Clinical Research Project of West China Second Hospital, Sichuan University (No. KL039).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDrs Ruixue Miao designed the study, followed-up, analyzed data, carried out the data analyses, drafted the initial manuscript. Shan Gao, Liyuan Wang and Jing Chen performed gastroscopy, collected specimens, conducted histopathology examination and made 13C-urea breath test. Wei Zhou cultured\u0026nbsp;\u003cem\u003eH pylori\u0026nbsp;\u003c/em\u003eand tested. Zhiling Wang and Professor Wan designed the study, guided process and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all of the children and their parents for their participation in this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSugano K, Tack J, Kuipers EJ, et al. Kyoto global consensus report on Helicobacter pylori gastritis. Gut 2015;64:1353\u0026ndash;67.\u003c/li\u003e\n \u003cli\u003eMalfertheiner P, Megraud F, Rokkas T On behalf of the European Helicobacter and Microbiota Study group, et al. Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus reportGut 2022;71:1724-1762.\u003c/li\u003e\n \u003cli\u003eVakil N, Malfertheiner P, Chey W D. Helicobacter pylori infection. The New England journal of medicine, 2010, 363(6): 595-596.Kato S, Shimizu T, Toyoda S, et al. The updated JSPGHAN guidelines for the management of Helicobacter pylori infection in childhood. Pediatrics International, 2020, 62(12): 1315-1331.\u003c/li\u003e\n \u003cli\u003eDror G, Muhsen K. Helicobacter pylori infection and children\u0026apos;s growth: an overview. Journal of pediatric gastroenterology and nutrition, 2016, 62(6): e48-e59.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRoka, K.; Roubani, A.; Stefanaki, K.; Panayotou, I.; Roma, E.; Chouliaras, G. The prevalence of Helicobacter pylori gastritis in newly diagnosed children with inflammatory bowel disease. Helicobacter, 2014, 19, 400\u0026ndash;405.\u003c/li\u003e\n \u003cli\u003eWenhong L I, Ziwei L I, Na W, et al. Prevalence of Helicobacter Pylori Infection and Associated Risk Factors among Chinese Children: a Meta-analysis. Chinese General Practice, 2022, 25(28): 3569.\u003c/li\u003e\n \u003cli\u003eNyssen OP, Bordin D, Tepes B, et al. European Registry on Helicobacter pylori management (Hp-EuReg): patterns and trends in first-line empirical eradication prescription and outcomes of 5 years and 21 533 patients. Gut, 2021;70:40\u0026ndash;54.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNyssen O P, McNicholl A G, Megraud F, et al. Sequential versus standard triple first‐line therapy for Helicobacter pylori eradication. Cochrane Database of Systematic Reviews, 2016 (6).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHuang Y, Zhou Y. Standardized treatment of Helicobacter pylori infection in children [J]. Chinese Journal of Practical Pediatrics,2016,31(07):505-509. (in Chinese)\u003c/li\u003e\n \u003cli\u003eKutluk G, Tutar E, Bayrak A, et al. Sequential therapy versus standard triple therapy for Helicobacter pylori eradication in children: any advantage in clarithromycin-resistant strains?. European journal of gastroenterology \u0026amp; hepatology, 2014, 26(11): 1202-1208.\u003c/li\u003e\n \u003cli\u003eJones N L , Koletzko S , Goodman K , et al. Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016). Journal of Pediatric Gastroenterology \u0026amp; Nutrition, 2017:991.\u003c/li\u003e\n \u003cli\u003eKato S, Shimizu T, Toyoda S, et al. The updated JSPGHAN guidelines for the management of Helicobacter pylori infection in childhood. Pediatrics International, 2020, 62(12): 1315-1331.\u003c/li\u003e\n \u003cli\u003eKhurana R, Fischbach L, Chiba N, et al. Meta‐analysis: Helicobacter pylori eradication treatment efficacy in children. Alimentary pharmacology \u0026amp; therapeutics, 2007, 25(5): 523-536.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDehghani SM，Ergaee A，Imanieh MH，et al. Efficacy of the standard quadruple therapy versus triple therapies containing proton pump inhibitor plus amoxicillin and clarithromycin or amoxicillin- clavulanic acid and metronidazole for Helicobacter pylori eradication in children. Dig Dis Sci，2009，54\u0026nbsp;（8）：1720-1724.\u003c/li\u003e\n \u003cli\u003eHuang J, Zhou L, Geng L, et al. Randomised controlled trial: sequential vs. standard triple therapy for Helicobacter pylori infection in Chinese children\u0026ndash;a multicentre, open‐labelled study. Alimentary pharmacology \u0026amp; therapeutics, 2013, 38(10): 1230-1235.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSavoldi A, Carrara E, Graham D Y, et al. Prevalence of antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis in World Health Organization regions. Gastroenterology, 2018, 155(5): 1372-1382. e17.\u003c/li\u003e\n \u003cli\u003eLi J, Deng J, Wang Z, et al. Antibiotic resistance of Helicobacter pylori strains isolated from pediatric patients in southwest China. Frontiers in Microbiology, 2021, 11: 621791.\u003c/li\u003e\n \u003cli\u003eCheng H, LI J, Jiang H. Vitro activity of bismuth potassium citrate against clinical isolates of antibiotic-resistant Helicobacter pylori. Chin J Gastroenterol Hepatol, 2008, 17(7): 543-546. [in Chinese].\u003c/li\u003e\n \u003cli\u003eLai H H, Lai M W. Treatment of Pediatric Helicobacter pylori Infection. Antibiotics, 2022, 11(6): 757.\u003c/li\u003e\n \u003cli\u003eZhou Y, Ye Z, Wang Y, et al. Comparison of four different regimens against Helicobacter pylori as a first‐line treatment: A prospective, cross‐sectional, comparative, open trial in Chinese children. Helicobacter, 2020, 25(2): e12679.\u003c/li\u003e\n \u003cli\u003eHwang J Y, Kim C, Kwon Y H, et al. Dual clarithromycin and Metronidazole Resistance Is the Main Cause of Failure in Ultimate Helicobacter pylori Eradication. Digestive Diseases, 2021, 39(5): 451-461.\u003c/li\u003e\n \u003cli\u003eLee J W, Kim N, Nam R H, et al. Risk factors of rescue bismuth quadruple therapy failure for Helicobacter pylori eradication. Journal of Gastroenterology and Hepatology, 2019, 34(4): 666-672.\u003c/li\u003e\n \u003cli\u003ePan J, Shi Z, Lin D, et al. Is tailored therapy based on antibiotic susceptibility effective? A multicenter, open-label, randomized trial. Frontiers of Medicine, 2020, 14(1): 43-50.\u003c/li\u003e\n \u003cli\u003eG\u0026Uuml;RAKAN F, \u0026Ouml;ZEN H, AKY\u0026Ouml;N Y, et al. Ornidazole-based sequential therapy is not effective in Helicobacter pylori eradication in children. Turk J Gastroenterol, 2013, 24(5): 382-386.\u003c/li\u003e\n \u003cli\u003eHorvath A, Dziechciarz P, Szajewska H. Meta-analysis: sequential therapy for Helicobacter pylori eradication in children. Aliment Pharmacol Ther 2012;36:534\u0026ndash;41.\u003c/li\u003e\n \u003cli\u003eBontems P, Kalach N, Oderda G, et al. Sequential therapy versus tailored triple therapies for Helicobacter pylori infection in children. Journal of pediatric gastroenterology and nutrition, 2011, 53(6): 646-650.\u003c/li\u003e\n \u003cli\u003eLiou J M, Chen C C, Chen M J, et al. Sequential versus triple therapy for the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial. The Lancet, 2013, 381(9862): 205-213.\u003c/li\u003e\n \u003cli\u003eArslan M, Balamtekin N, G\u0026uuml;nal A. Efficacy of a novel sequential treatment regimen containing bismuth for Helicobacter pylori eradication in Turkish children. Helicobacter, 2020, 25(6): e12757.\u003c/li\u003e\n \u003cli\u003eExpert consensus on the diagnosis and management of Helicobacter pylori infection in Chinese children (2022). Chinese Journal of Pediatrics,2015,53(7):496-498\u003c/li\u003e\n \u003cli\u003eAshorn M, R\u0026auml;g\u0026ouml; T, Kokkonen J, et al. Symptomatic Response to Helicobacter Pylori Eradication in Children With Recurrent Abdominal Pain:: Double Blind Randomized Placebo-controlled Trial. Journal of clinical gastroenterology, 2004, 38(8): 646-650.\u003c/li\u003e\n \u003cli\u003eFukuda Y, Shinozaki K, Sasaki T, et al. Acute gastric mucosal lesions caused by acute Helicobacter pylori infection-clinical outcomes of six cases and problems in the diagnosis of H. pylori infection. Nihon Shokakibyo Gakkai Zasshi The Japanese Journal of Gastro-enterology, 2014, 111(5): 899-908.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"children, Helicobacter pylori, eradication, bismuth quadruple therapy, sequential therapy","lastPublishedDoi":"10.21203/rs.3.rs-4350024/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4350024/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground and aim\u003c/h2\u003e \u003cp\u003eBismuth and non-bismuth quadruple therapy are the guideline-recommended first-line therapy in children with \u003cem\u003eHelicobacter pylori\u003c/em\u003e infection in areas with high antibiotic resistance. However, their efficacy in children is uncertain and there are few well-designed studies. Here, we evaluated the eradication rates of standard triple therapy, bismuth-based quadruple therapy and sequential therapy in children with \u003cem\u003eH. pylori\u003c/em\u003e infection.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA randomised controlled trial was conducted in children infected with \u003cem\u003eH. pylori\u003c/em\u003e in West China Second Hospital. They were randomly assigned to 14-day standard triple therapy (omeprazole\u0026thinsp;+\u0026thinsp;amoxicillin\u0026thinsp;+\u0026thinsp;clarithromycin), 14-day bismuth quadruple therapy (bismuth\u0026thinsp;+\u0026thinsp;omeprazole\u0026thinsp;+\u0026thinsp;amoxicillin\u0026thinsp;+\u0026thinsp;clarithromycin) and 10-day sequential therapy (omeprazole\u0026thinsp;+\u0026thinsp;amoxicillin for 5 days followed by omeprazole\u0026thinsp;+\u0026thinsp;clarithromycin\u0026thinsp;+\u0026thinsp;metronidazole for 5 days). The eradication rate was assessed by a \u003csup\u003e13\u003c/sup\u003eC-urea breath test 4 to 6 weeks after therapy completion. Symptom improvement and adverse events were compared among the groups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn total, 132 patients were enrolled. The eradication rates of 14-day standard triple therapy, 14-day bismuth quadruple therapy and 10-day sequential therapy were 70.0%, 78.9% and 50.0% in per-protocol analysis and 63.6%, 68.2% and 43.2% in intention-to-treat analysis, respectively. Symptom improvement and adverse drug event rates were similar in the three groups.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe three therapeutic regimens evaluated in this study are equally not recommendable for \u003cem\u003eH. pylori\u003c/em\u003e infection treatment due to unsatisfactory eradication rates. The high prevalence of clarithromycin resistance makes the use of clarithromycin-based quadruple therapy not advisable, even in combination with amoxicillin and bismuth salts.\u003c/p\u003e","manuscriptTitle":"A randomised controlled clinical study of standard triple therapy, bismuth-based quadruple therapy and sequential therapy for Helicobacter pylori infection in children","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-20 18:49:30","doi":"10.21203/rs.3.rs-4350024/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-08T15:20:19+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-07T21:22:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"192725318159925631029193253485359226878","date":"2024-06-17T20:23:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-16T10:57:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294363047536290913852037296545628415152","date":"2024-06-16T07:47:10+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-15T14:27:32+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-13T08:52:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-04T08:41:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-04T08:41:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2024-04-30T15:12:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e3744346-1e7f-4aa5-88ca-6f9523728b6d","owner":[],"postedDate":"June 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-26T16:01:32+00:00","versionOfRecord":{"articleIdentity":"rs-4350024","link":"https://doi.org/10.1186/s12887-024-05020-6","journal":{"identity":"bmc-pediatrics","isVorOnly":false,"title":"BMC Pediatrics"},"publishedOn":"2024-08-23 15:57:20","publishedOnDateReadable":"August 23rd, 2024"},"versionCreatedAt":"2024-06-20 18:49:30","video":"","vorDoi":"10.1186/s12887-024-05020-6","vorDoiUrl":"https://doi.org/10.1186/s12887-024-05020-6","workflowStages":[]},"version":"v1","identity":"rs-4350024","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4350024","identity":"rs-4350024","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}