Eradication of Helicobacter Pylori Improves Dyspepsia Symptoms in Elderly People

Eradication of Helicobacter Pylori Improves Dyspepsia Symptoms in Elderly People | 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 Eradication of Helicobacter Pylori Improves Dyspepsia Symptoms in Elderly People Ikko Tanaka, Shoko Ono, Yoshihiko Shimoda, Masaki Inoue, Sayoko Kinowaki, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-118169/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background Therapy for eradication of Helicobacter pylori ( H. pylori ) improves symptoms of H. pylori -associated dyspepsia (HPD), but the effects of eradication in elderly patients are unclear. Aims To evaluate the outcomes of eradication therapy and effects of eradication on dyspepsia symptoms in elderly patients. Methods This retrospective study included 496 patients who received H. pylori eradication therapy. The patients were divided into a group of elderly patients (group E: ≧ 65 years old) and a group of non-elderly patients (group N: < 65 years old). Abdominal symptoms were evaluated using a questionnaire about 12 abdominal symptoms before eradication and after eradication (1-2 months and more than one year). Dyspepsia was defined as a score of 4 points or more score for at least one of 4 items (postprandial fullness, early satiety, epigastric pain, and hunger pain). Results Succesful H. pylori eradication rate in group E was significantly lower than that in group N (74.7 % vs. 84.4 %, P < 0.05) and it was remarkable in the 3rd-line therapy (59.7 % vs. 76.5 %, P < 0.05). Serious adverse events did not occur in either groups. Successful eradication improved symptoms in patients with dyspepsia in both groups within 2 months (70.3% of the patients in group N, 76.2% of the patients in group E) and decrease of GOS score lasted for more than 1 year. Conclusions H. pylori eradication would be recommend for elderly patients with dyspepsia symptoms. Gastroenterology & Hepatology dyspepsia Helicobacter pylori eradication therapy the elderly Figures Figure 1 Figure 2 Introduction Functional dyspepsia (FD) is defined in the ROMA Ⅳ criteria as one or more of the following symptoms persisting for the past 3 months with symptom onset at least 6 months ago: postprandial fullness, early satiation, epigastric pain and epigastric burning [1]. Helicobacter pylori ( H. pylori ) infection is often associated with dyspepsia symptoms, and it has been reported that eradication of H. pylori improved the symptoms [2- 4]. In the Kyoto Global Consensus Report in 2015, it was stated that all H. pylori -positive individuals worldwide should receive eradication therapy [5] . H. pylori -associated dyspepsia (HPD) is also defined as sustained symptomatic relief for 6 to 12 months after eradication. In Japan, H. pylori infection is one of the major infections, especially in elderly people [6]. Mamori et al. reported that the rate of successful eradication of H. pylori in first-line therapy was lower in patients less than 50 years of age than in patients aged over 50 years [7]. However, Kobayashi et al. reported that age did not affect the efficacy or safety of eradication therapy [8]. There has been no report on the effect of eradication of H. pylori on dyspepsia symptoms in elderly people. We therefore evaluated the outcomes of H. pylori eradication therapy and the effect on dyspepsia symptoms in elderly patients. Methods Patients Consecutive patients who visited our H. pylori -specific out-patient unit and received eradication therapy during the period from January 2009 to December 2017 were retrospectively analyzed. Esophagogastroduodenoscopy revealed no active gastric diseases before eradication in any of the patients. We divided the patients into two groups according to age: an elderly group (group E) of patients who were 65 years of age or older and a non-elderly group (group N) of the patients who were less than 65 years of age. The study was approved by the Ethics Committee of Hokkaido University Hospital (approval number 018-0367). H. pylori test Before eradication, both 13 C-urea breath test (UBT) (Ubit ® , Otsuka Pharmaceutical, Tokyo, Japan) and one or more other H. pylori tests (rapid urease test, serological and urinary anti- H. pylori IgG antibody, culture and microscopic examination) were used. Generally, the patients was defined as positive for H. pylori when in whom one of those tests was positive. Generally, the patients was defined as positive for H. pylori when in whom one of those tests was positive. When the values of UBT were weak positive (2.5 to 5.0‰, cut-off value: 2.5‰), we confirmed that other tests were positive for excluding false positive for UBT tests. Successful eradication was confirmed using UBT at 1 to 2 months after the completion of eradication treatment. Eradication regimen The prescribed regimens during the study period are summarized in Table 1. Vonoprazan (VPZ) has been available since March 2015 in our institution and proton-pump inhibitors (PPIs) were changed to VPZ after it became available. Evaluation of upper gastrointestinal symptoms A questionnaire with a scale from 1 (no problem) to 7 (very severe problem) consisting of 17 items covered Global Overall Systems (GOS) and Gastrointestinal Symptom Rating Scale (GSRS) was used [9, 10]. The questionnaire was filled out by each patient before the urea breath test. For evaluation of upper gastrointestinal (GI) symptoms, that GOS questionnaires are simple and valid outcome measurements to assess the symptoms of FD according to the severity of the following eight symptoms: epigastric pain, heartburn, acid reflux, stomach discomfort, nausea, belching, early satiety and distention [9,11,12]. Patients who had a score of 4 points or more for at least one of 4 items (postprandial fullness, early satiety, epigastric pain, and hunger pain) were defined as patients with dyspepsia. Improvement of dyspepsia was defined as a decrease in the maximum score of abdominal symptoms before eradication by more than 2 points and each GOS item after eradication therapy being less than 3 points. For evaluation of the long-term effects H. pylori eradication on dyspepsia symptoms, a 3rd GOS questionnaire was given to patients for whom more than 1 year had passed after successful eradication. We mailed the questionnaires to the patients who had dyspepsia before eradication. HPD was defined as sustained dyspepsia relief for more than 1 year after successful eradication. Measured outcome parameters The primary endpoint was long-term improvement in the GOS score after successful H. pylori eradication in elderly patients with dyspepsia. Secondary endpoints were successful eradication rates, adverse events, and short-term and long-term improvements of each GOS item in groups E and N. Analysis of H. pylori eradication efficacy was performed on an intention-to-treat (ITT) basis. Compliance with therapy and adverse events were determined by a questionnaire at the time of judgement of H. pylori eradication. Statistical analysis Mean values were calculated for continuous variables and percentages were calculated for categorical data. Categorical data were compared using Fisher's exact test and numerical data were compared using Student’s t test. A P value of < .05 in each analysis was considered statistically significant. Results Outcomes of H. pylori eradication therapy A total of 496 patients received H. pylori eradication therapy during the study period. Fifty-nine patients were excluded for the reason of not meeting our H. pylori diagnosis criteria, finally a total of 437 patients including 275 patients in group N and 162 patients in group E were analyzed. A flow diagram for treatment and characteristics of the patients are shown in Figure 1 and Table 2. Three patients discontinued the eradication therapy due to adverse events (skin eruption) and 6 patients did not visit the hospital for judgement of eradication. According to the questionnaires, compliance with the protocol was 100%. ITT eradication rates were 84.4% (232/ 275) in group N and 74.7% (121/ 162) in group E, and there was a significant difference between the two groups ( P < 0.05). According to the number of eradications, only the success rate for the 3 rd -line eradication in group E was significantly lower than that in group N (59.7% vs 76.5%, P < 0.05) (Table 3). But there were no significant differences in the patients with between 7-days and 14-days regimen in both groups (for 14-days regimen, group E: 19% (12/62), group N: 25% (21/85), P = 0.55). Furthermore, there were no significant differences of adverse events associated with eradication therapy between the two groups. Upper GI symptoms before and after eradication therapy Forty-six participants did not fill out the questionnaire, and data for 391 patients including 350 patients in whom eradication was successful and 41 patients in whom eradication therapy failed were analysed. In the patients in whom eradication therapy failed, there was no significant difference of GOS scores before and after eradication therapy: 1.80 ± 1.11 before and 1.82 ± 0.80 after in group E (n = 20) ( P = 0.94) and 2.13 ± 1.15 before and 1.84 ± 0.94 after in group N (n = 21) ( P = 0.06). Before eradication, there were no significant differences between the two groups in total GOS score and score of each item. Successful eradication significantly improved all upper GI symptoms regardless of age (supplement 1). According to our definition of dyspepsia, 84 (36.1%) of the patients in group N and 37 (31.6%) of the patients in group E had dyspepsia before eradication. Within 2 months after successful eradication, 76.2% (64/ 84) of the patients in group N and 70.3% (26/ 37) of the patients in group E had improvement in dyspepsia ( P = 0.48) (Table 4). Long-term effects of H. pylori eradication on dyspepsia for long term Responses to questionnaire were obtained from 40 patients in group N and 20 patients in group E (supplement 2). Mean periods from successful eradication were 52.4 months in group N and 54.8 months in group E ( P = 0.51). GOS scores at more than 1 year after successful eradication were significantly decreased compared to those before eradication in both groups (Figure 2). 32 patients (80%) in group N and 12 patients (60%) in group E had long-term improvement in HPD after eradication ( P = 0.13). Short-term and long-term effects of eradication on dyspepsia symptoms were different in 35.0% of the patients in group N and 50.0% of the patients in group E (supplement 3). Discussion This is the first report on the effects of H. pylori eradication on dyspepsia in elderly patients. Dyspepsia symptoms often occur in H. pylori -positive individuals. Shimatani et al. reported that the prevalence of patients with dyspeptic symptoms was significantly higher in H. pylori -positive patients than in H. pylori -negative patients (28.7% vs 6.5%) [13]. Kawamura et al. also reported that 46.3% of H. pylori -positive patients had dyspepsia symptoms [14]. Approximately 30% of our patients had dyspepsia symptoms, and the percentage is similar to that in previous studies. It has been reported that H. pylori eradication therapy improved dyspepsia symptoms in 24-53% of patients [2, 15-18]. In our study, dyspepsia symptoms after successful eradication improved in about 73% of the patients in the long term, and the percentage of patients was slightly higher that in the previous studies (supplement 3). Unfortunately, the definitions of improvement of dyspepsia were different in some studies, and further research is needed to compare the symptoms using the same methods at same timing after eradication. Tsuda et al. reported that a questionnaire within 2 months after H. pylori eradication might be useful for diagnosis in 70% of patients with HPD [19]. Similarly, questionnaires in the short term after eradication was predicted HPD in 60% of elderly patients. However, the symptoms in 40% of the patients with dyspepsia changed in the long term and HPD could not be predicted. According to Kyoto Global Consensus Report, it is necessary to follow symptoms for more than 6 months after successful eradication to determine HPD as was indicated by our results [5]. There have been a few studies on outcomes of eradication therapy for the elderly, but the outcomes investigated in those studies were for 1 st -line and 2 nd -line therapy [7, 8, 20, 21]. In our study, there was a significant difference in eradication rates only in 3 rd -line therapy. There were no significant differences in rates of eradication using PPIs and VPZ, and Kusunoki et al. and Nishida et al. reported that the effect of VPZ was unclear in elderly patients [20, 21]. Resistance to clarithromycin (CAM) might be the main reason for failure of 3 rd -line therapy, but that was unfortunately not checked in our subjects [22, 23]. Recently, Furuta et al. reported that autoimmune gastritis (AIG) patients were often misdiagnosed as refractory to eradication therapy [24]. Because, AIG causes achlorhydria and non H. pylori urease-positive bacteria overgrowth. Although patients with suspected false positive for UBT were excluded from this study, 4 of them were positive for anti‐parietal cell antibody (APCA) and/ or anti‐intrinsic factor antibody. Adverse events of eradication therapy are one of the concerns for the elderly. We have not experienced serious adverse events in eradication therapy, but there has been a report of death in an elderly patient [25]. Therefore, it is necessary to pay attention to drug interaction, hepatorenal function and co-morbidities in eradication, especially for the elderly. The present study has several limitations. This was a retrospective study with a small sample size at a single institution. And antibiotic resistance was not tested. In conclusion, eradication of H. pylori would improve dyspepsia for long term in elderly patients with dyspepsia symptoms. Declarations Acknowledgements Not applicable. Funding There is no funding for the study. Availability of data and materials The datasets generated and/or analyzed during the current study are not publicly available due [secondary use of data was not approved by our IRB] but are available from the corresponding author on reasonable request. Authors' contributions All authors read and approved the final version of the manuscript, including the authorship. IT, SO and MK designed the study; IT, SO and MT performed the research; YS, SK, MI, MO, KY andYS analyzed the data; IT and SO wrote the paper; and NS revised the manuscript for final submission. Ethics approval and consent to participate This study was performed in accordance with the ethical standards detailed in the Declaration of Helsinki. The study was reviewed and approved by the Hokkaido University Hospital Review Board 018-0367. Competing interests The authors declare that have no competing interests. References Stanghellini V, Chan FK, Hasler WL, et al. Gastroduodenal Disorders. 2016;150(6):1380-1392. Du LJ, Chen BR, Kim JJ, Kim S, Shen JH, Dai N. Helicobacter pylori eradication therapy for functional dyspepsia: Systematic review and meta-analysis. World J Gastroenterol. 2016;22(12):3486-3495. Zhao B, Zhao J, Cheng WF, et al. Efficacy of Helicobacter pylori eradication therapy on functional dyspepsia: a meta-analysis of randomized controlled studies with 12-month follow-up. J Clin Gastroenterol. 2014;48(3):241-247. Armstrong D. Helicobacter pylori infection and dyspepsia. Scand J Gastroenterol Suppl. 1996;215:38-47. Sugano K, Tack J, Kuipers EJ, et al. Kyoto global consensus report on Helicobacter pylori gastritis. 2015;64(9):1353-1367. Kamada T, Haruma K, Ito M, et al. Time Trends in Helicobacter pylori Infection and Atrophic Gastritis Over 40 Years in Japan. 2015;20(3):192-198. Mamori S, Higashida A, Kawara F, et al. Age-dependent eradication of Helicobacter pylori in Japanese patients. World J Gastroenterol. 2010;16(33):4176-4179. Kobayashi S, Joshita S, Yamamoto C, et al. Efficacy and safety of eradication therapy for elderly patients with helicobacter pylori infection. Medicine (Baltimore). 2019;98(30):e16619. Veldhuyzen van Zanten SJ, Chiba N, Armstrong D, et al. Validation of a 7-point Global Overall Symptom scale to measure the severity of dyspepsia symptoms in clinical trials. Aliment Pharmacol Ther. 2006;23(4):521-529. Svedlund, J., I. Sjodin, G. Dotevall et al. GSRS--a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig Dis Sci. 1988;33 (2):129-134. van Zanten SV, Armstrong D, Chiba N, et al. Esomeprazole 40 mg once a day in patients with functional dyspepsia: the randomized, placebo-controlled "ENTER" trial. Am J Gastroenterol. 2006;101(9):2096-2106. Sakurai K, Nagahara A, Inoue K, et al. Efficacy of omeprazole, famotidine, mosapride and teprenone in patients with upper gastrointestinal symptoms: an omeprazole-controlled randomized study (J-FOCUS). BMC Gastroenterol. 2012;12:42. Shimatani T, Inoue M, Iwamoto K, et al. Prevalence of Helicobacter pylori infection, endoscopic gastric findings and dyspeptic symptoms among a young Japanese population born in the 1970s. J Gastroenterol Hepatol. 2005;20(9):1352-1357. Kawamura Y, Funaki Y, Yoshimine T, et al. Characteristics and Predictive Factor of Helicobacter pylori-Associated Functional Dyspepsia in Japanese Patients. 2019;100(4):277-285. Mazzoleni LE, Sander GB, Francesconi CF, et al. Helicobacter pylori eradication in functional dyspepsia: HEROES trial. Arch Intern Med. 2011;171(21):1929-1936. Khan MQ. Helicobacter pylori Eradication Therapy in Nonulcer Dyspepsia is Beneficial. Saudi J Gastroenterol. 2008;14(2):96-100. Allison JE, Hurley LB, Hiatt RA, Levin TR, Ackerson LM, Lieu TA. A randomized controlled trial of test-and-treat strategy for Helicobacter pylori: clinical outcomes and health care costs in a managed care population receiving long-term acid suppression therapy for physician-diagnosed peptic ulcer disease. Arch Intern Med. 2003;163(10):1165-1171. Gwee KA, Teng L, Wong RK, Ho KY, Sutedja DS, Yeoh KG. The response of Asian patients with functional dyspepsia to eradication of Helicobacter pylori infection. Eur J Gastroenterol Hepatol. 2009;21(4):417-424. Tsuda M, Kato M, Ono S, et al. Changes of Dyspeptic Symptom after Successful Eradication in Helicobacter pylori-Associated Dyspepsia. 2019:1-9. Kusunoki M, Yuki M, Ishitobi H, et al. Effect of Age on Effectiveness of Vonoprazan in Triple Therapy for Helicobacter pylori Eradication. Intern Med. 2019;58(11):1549-1555. Nishida T, Tsujii Y, Okamoto A, et al. A Triple-Drug Blister-Packaged Drug with Vonoprazan Improves First-Line Eradication of Helicobacter pylori in Elderly Patients: A Retrospective Propensity Score-Matched Cohort Study. 2019:1-7. Graham DY, Shiotani A. New concepts of resistance in the treatment of Helicobacter pylori infections. Nat Clin Pract Gastroenterol Hepatol. 2008;5(6):321-331. Kato M, Ota H, Okuda M, et al. Guidelines for the management of Helicobacter pylori infection in Japan: 2016 Revised Edition. 2019;24(4):e12597. Furuta T, Baba S, Yamade M, et al. High incidenceof autoimmunegastritis in patients misdiagnosed with two or more failures of H. pylori eradication. Aliment Pharmacol Ther . 2018;48(3):370-377. Nei T, Hagiwara J, Takiguchi T, et al. Fatal fulminant Clostridioides difficile colitis caused by Helicobacter pylori eradication therapy; a case report. J Infect Chemother. 20120; 26(3):305-308. Tables Table 1. Regimens of Helicobacter pylori eradication. Eradication Antibiotics Antacids 1st and 2nd lines AMPC 750mg and CAM 200mg, b.i.d. 7days RPZ 20mg or LPZ 30mg or VPZ 20mg, b.i.d. AMPC 750mg and MNZ 250mg, b.i.d. 7days 3rd line AMPC 500mg q.i.d. and STFX 100mg, b.i.d. 7 or 14days 4th line STFX 100mg and MINO 250mg b.i.d. 7 days and AMPC 500mg q.i.d. 14 days For penicillin allergy CAM 200mg and MNZ 250mg b.i.d.7 days MNZ 250mg and STFX 100mg b.i.d. 7 days RPZ: rabeprazole, LPZ: lansoprazole, VPZ: vonoprazan, AMPC: amoxicillin, CAM: clarithromaycin, MNZ: metronidazole, STFX: sitafloxacin, MINO: minomycin, b.i.d: bis in die, q.i.d: quarte in die Table 2. Characteristics of patients. Group N (n = 275) Group E (n = 162) Male: female, n 116: 159 61: 101 Mean age at H. pylori eradication, years (range) 51.7 (17-64) 70.6 (65-87) Gastric disease, n (%) Chronic gastritis 164 (59.6) 100 (61.7) Peptic ulcer scar 43 (15.6) 13 (8.0) Gastric cancer post treatment 9 (3.3) 13 (8.0) Eradication therapy, n (%) 1 st -line 160 (58.1) 80 (49.4) 2 nd -line 25 (9.1) 13 (8.0) 3 rd -line 85 (30.9) 62 (38.3) 4 th -line 5 (1.8) 7 (4.3) Penicillin allergy, n (%) 69 (25.1) 35 (21.6) PPI-based regimen 186 (67.6) 104 (64.2) PCAB-based regimen 89 (32.4) 58 (35.8) PPI: proton-pump inhibitors, PCAB: potassium competitive acid blocker Table 3. Outcomes and adverse events of Helicobacter pylori eradication therapy. Group N (n = 275) Group E (n = 162) P Eradication rates, % (n) 84.4 (232/ 275) 74.7 (121/ 162) < 0.05 1 st -line 88.8 (142/ 160) 87.5 (70/ 80) 0.83 2 nd -line 90.1 (23/ 25) 84.6 (11 /13) 0.59 3 rd -line 76.5 (65/ 85) 59.7 (37/ 62) < 0.05 4 th -line 40.0 (2/ 5) 42.9 (3/ 7) 1.00 PPI-based regimen 84.9 (158/ 186) 77.9 (81/ 104) 0.15 PCAB-based regimen 83.1 (74/ 89) 69.0 (40/ 58) 0.07 Adverse events, n (%) 48 (17.5%) 23 (14.2%) 0.42 Diarrhea 25 (9.1%) 10 (6.2%) 0.36 Skin rash 7 (2.5%) 7 (4.3%) 0.40 Others 16 (5.8 %) 6 (3.7 %) 0.37 PPI: proton-pump inhibitors, PCAB: potassium competitive acid blocker Table 4. Dyspepsia before and after successful eradication. Group N (n = 233) Group E (n = 117) P Mean age at H. pylori eradication, years ± SD 51.3 ± 9.9 70.5 ± 4.89 － Gender (male/ female) 99/ 134 43/ 74 N.S Patients with dyspepsia before eradication, n (%) 84 (36.1) 37 (31.6) N.S Improvement in dyspepsia after eradication, n (%) 64/ 84 (76.2) 26/ 37 (70.3) N.S Supplementary Files supplementmodify1.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 10 May, 2021 Review # 2 received at journal 09 May, 2021 Review # 3 received at journal 02 May, 2021 Review # 1 received at journal 29 Apr, 2021 Reviewer # 3 agreed at journal 26 Apr, 2021 Reviewer # 2 agreed at journal 24 Apr, 2021 Reviewer # 1 agreed at journal 21 Apr, 2021 Reviewers invited by journal 15 Feb, 2021 Editor assigned by journal 16 Nov, 2020 Submission checks completed at journal 16 Nov, 2020 Editor invited by journal 16 Nov, 2020 First submitted to journal 14 Nov, 2020 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. 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15:30:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-118169/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-118169/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":4020519,"identity":"3659644e-0495-4421-962b-6525e8d878b0","added_by":"auto","created_at":"2020-12-04 16:51:58","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":174879,"visible":true,"origin":"","legend":"A flow diagram for treatment and characteristics of the patients are shown in Figure 1","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-118169/v1/c9ed817761e823c490cd41dd.jpg"},{"id":4020520,"identity":"c79c6e89-c4e9-4f6f-b6e4-ace1432c2b2a","added_by":"auto","created_at":"2020-12-04 16:51:58","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":128313,"visible":true,"origin":"","legend":"GOS scores at more than 1 year after successful eradication were significantly decreased compared to those before eradication in both groups (Figure 2). ","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-118169/v1/27950b839a6e4655f2b0cc40.jpg"},{"id":13624954,"identity":"7e0036fb-7eba-47b1-8e17-05f323cbeb7e","added_by":"auto","created_at":"2021-09-17 07:24:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":360416,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-118169/v1/37904725-2719-45e3-b8f1-914c71c71d60.pdf"},{"id":4020521,"identity":"9d4b6948-b373-48a6-9307-2bb0b4baddb9","added_by":"auto","created_at":"2020-12-04 16:51:58","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":77116,"visible":true,"origin":"","legend":"","description":"","filename":"supplementmodify1.docx","url":"https://assets-eu.researchsquare.com/files/rs-118169/v1/9f095efcd29417dd00bdc586.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eEradication of Helicobacter Pylori Improves Dyspepsia Symptoms in Elderly People\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFunctional dyspepsia (FD) is defined in the ROMA Ⅳ criteria as one or more of the following symptoms persisting for the past 3 months with symptom onset at least 6 months ago: postprandial fullness, early satiation, epigastric pain and epigastric burning [1]. \u003cem\u003eHelicobacter pylori\u003c/em\u003e (\u003cem\u003eH. pylori\u003c/em\u003e) infection is often associated with dyspepsia symptoms, and it has been reported that eradication of \u003cem\u003eH. pylori\u003c/em\u003e improved the symptoms [2- 4]. In the Kyoto Global Consensus Report in 2015, it was stated that \u003cstrong\u003eall \u003c/strong\u003e\u003cem\u003eH. pylori\u003c/em\u003e\u003cstrong\u003e-positive individuals worldwide should receive eradication therapy \u003c/strong\u003e[5]\u003cstrong\u003e. \u003c/strong\u003e\u003cem\u003eH. pylori\u003c/em\u003e-associated dyspepsia (HPD) is also defined as sustained symptomatic relief for 6 to 12 months after eradication.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; In Japan, \u003cem\u003eH. pylori\u003c/em\u003e infection is one of the major infections, especially in elderly people [6]. Mamori et al. reported that the rate of successful eradication of \u003cem\u003eH. pylori\u003c/em\u003e in first-line therapy was lower in patients less than 50 years of age than in patients aged over 50 years [7]. However, Kobayashi et al. reported that age did not affect the efficacy or safety of eradication therapy [8]. There has been no report on the effect of eradication of \u003cem\u003eH. pylori\u003c/em\u003e on dyspepsia symptoms in elderly people. We therefore evaluated the outcomes of \u003cem\u003eH. pylori\u003c/em\u003e eradication therapy and the effect on dyspepsia symptoms in elderly patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003ePatients\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eConsecutive patients who visited our \u003cem\u003eH. pylori\u003c/em\u003e-specific out-patient unit and received eradication therapy during the period from January 2009 to December 2017 were retrospectively analyzed. Esophagogastroduodenoscopy revealed no active gastric diseases before eradication in any of the patients. We divided the patients into two groups according to age: an elderly group (group E) of patients who were 65 years of age or older and a non-elderly group (group N) of the patients who were less than 65 years of age. The study was approved by the Ethics Committee of Hokkaido University Hospital (approval number 018-0367).\u003c/p\u003e\n \u003cem\u003eH. pylori test\u003c/em\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eBefore eradication, both \u003csup\u003e13\u003c/sup\u003eC-urea breath test (UBT) (Ubit\u003csup\u003e\u0026reg;\u003c/sup\u003e, Otsuka Pharmaceutical, Tokyo, Japan) and one or more other \u003cem\u003eH. pylori\u003c/em\u003e tests (rapid urease test, serological and urinary anti-\u003cem\u003eH. pylori \u003c/em\u003eIgG antibody, culture and microscopic examination) were used. Generally, the patients was defined as positive for \u003cem\u003eH. pylori\u003c/em\u003e when in whom one of those tests was positive. Generally, the patients was defined as positive for \u003cem\u003eH. pylori\u003c/em\u003e when in whom one of those tests was positive. When the values of UBT were weak positive (2.5 to 5.0\u0026permil;, cut-off value: 2.5\u0026permil;), we confirmed that other tests were positive for excluding false positive for UBT tests.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Successful eradication was confirmed using UBT at 1 to 2 months after the completion of eradication treatment.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEradication regimen\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe prescribed regimens during the study period are summarized in Table 1. Vonoprazan (VPZ) has been available since March 2015 in our institution and proton-pump inhibitors (PPIs) were changed to VPZ after it became available.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEvaluation of upper gastrointestinal symptoms\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA questionnaire with a scale from 1 (no problem) to 7 (very severe problem) consisting of 17 items covered Global Overall Systems (GOS) and Gastrointestinal Symptom Rating Scale (GSRS) was used [9, 10]. The questionnaire was filled out by each patient before the urea breath test. For evaluation of upper gastrointestinal (GI) symptoms, that GOS questionnaires are simple and valid outcome measurements to assess the symptoms of FD according to the severity of the following eight symptoms: epigastric pain, heartburn, acid reflux, stomach discomfort, nausea, belching, early satiety and distention [9,11,12]. Patients who had a score of 4 points or more for at least one of 4 items (postprandial fullness, early satiety, epigastric pain, and hunger pain) were defined as patients with dyspepsia. Improvement of dyspepsia was defined as a decrease in the maximum score of abdominal symptoms before eradication by more than 2 points and each GOS item after eradication therapy being less than 3 points.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; For evaluation of the long-term effects \u003cem\u003eH. pylori\u003c/em\u003e eradication on dyspepsia symptoms, a 3rd GOS questionnaire was given to patients for whom more than 1 year had passed after successful eradication. We mailed the questionnaires to the patients who had dyspepsia before eradication. HPD was defined as sustained dyspepsia relief for more than 1 year after successful eradication.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMeasured outcome parameters\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint was long-term improvement in the GOS score after successful \u003cem\u003eH. pylori\u003c/em\u003e eradication in elderly patients with dyspepsia. Secondary endpoints were successful eradication rates, adverse events, and short-term and long-term improvements of each GOS item in groups E and N.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Analysis of \u003cem\u003eH. pylori \u003c/em\u003eeradication efficacy was performed on an intention-to-treat (ITT) basis. Compliance with therapy and adverse events were determined by a questionnaire at the time of judgement of \u003cem\u003eH. pylori \u003c/em\u003eeradication.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eMean values were calculated for continuous variables and percentages were calculated for categorical data. Categorical data were compared using Fisher's exact test and numerical data were compared using Student\u0026rsquo;s\u003cem\u003e t\u003c/em\u003e test. A \u003cem\u003eP\u003c/em\u003e value of \u0026lt; .05 in each analysis was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eOutcomes of H. pylori eradication therapy\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA total of 496 patients received \u003cem\u003eH. pylori \u003c/em\u003eeradication therapy during the study period. Fifty-nine patients were excluded for the reason of not meeting our \u003cem\u003eH. pylori\u003c/em\u003e diagnosis criteria, finally a total of 437 patients including 275 patients in group N and 162 patients in group E were analyzed. A flow diagram for treatment and characteristics of the patients are shown in Figure 1 and Table 2. Three patients discontinued the eradication therapy due to adverse events (skin eruption) and 6 patients did not visit the hospital for judgement of eradication. According to the questionnaires, compliance with the protocol was 100%. ITT eradication rates were 84.4% (232/ 275) in group N and 74.7% (121/ 162) in group E, and there was a significant difference between the two groups (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05). According to the number of eradications, only the success rate for the 3\u003csup\u003erd\u003c/sup\u003e-line eradication in group E was significantly lower than that in group N (59.7% vs 76.5%, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05) (Table 3). But there were no significant differences in the patients with between 7-days and 14-days regimen in both groups (for 14-days regimen, group E: 19% (12/62), group N: 25% (21/85), \u003cem\u003eP \u003c/em\u003e= 0.55).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Furthermore, there were no significant differences of adverse events associated with eradication therapy between the two groups.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUpper GI symptoms before and after eradication therapy\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eForty-six participants did not fill out the questionnaire, and data for 391 patients including 350 patients in whom eradication was successful and 41 patients in whom eradication therapy failed were analysed.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; In the patients in whom eradication therapy failed, there was no significant difference of GOS scores before and after eradication therapy: 1.80 \u0026plusmn; 1.11 before and 1.82 \u0026plusmn; 0.80 after in group E (n = 20) (\u003cem\u003eP \u003c/em\u003e= 0.94) and 2.13 \u0026plusmn; 1.15 before and 1.84 \u0026plusmn; 0.94 after in group N (n = 21) (\u003cem\u003eP \u003c/em\u003e= 0.06).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Before eradication, there were no significant differences between the two groups in total GOS score and score of each item. Successful eradication significantly improved all upper GI symptoms regardless of age (supplement 1). According to our definition of dyspepsia, 84 (36.1%) of the patients in group N and 37 (31.6%) of the patients in group E had dyspepsia before eradication. Within 2 months after successful eradication, 76.2% (64/ 84) of the patients in group N and 70.3% (26/ 37) of the patients in group E had improvement in dyspepsia (\u003cem\u003eP\u003c/em\u003e = 0.48) (Table 4).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLong-term effects of H. pylori eradication on dyspepsia for long term\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eResponses to questionnaire were obtained from 40 patients in group N and 20 patients in group E (supplement 2). Mean periods from successful eradication were 52.4 months in group N and 54.8 months in group E (\u003cem\u003eP \u003c/em\u003e= 0.51).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; GOS scores at more than 1 year after successful eradication were significantly decreased compared to those before eradication in both groups (Figure 2). 32 patients (80%) in group N and 12 patients (60%) in group E had long-term improvement in HPD after eradication (\u003cem\u003eP\u003c/em\u003e = 0.13). Short-term and long-term effects of eradication on dyspepsia symptoms were different in 35.0% of the patients in group N and 50.0% of the patients in group E (supplement 3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first report on the effects of \u003cem\u003eH. pylori\u003c/em\u003e eradication on dyspepsia in elderly patients.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Dyspepsia symptoms often occur in \u003cem\u003eH. pylori\u003c/em\u003e-positive individuals. Shimatani et al. reported that the prevalence of patients with dyspeptic symptoms was significantly higher in \u003cem\u003eH. pylori\u003c/em\u003e-positive patients than in \u003cem\u003eH. pylori\u003c/em\u003e-negative patients (28.7% vs 6.5%) [13]. Kawamura et al. also reported that 46.3% of \u003cem\u003eH. pylori\u003c/em\u003e-positive patients had dyspepsia symptoms [14]. Approximately 30% of our patients had dyspepsia symptoms, and the percentage is similar to that in previous studies.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; It has been reported that \u003cem\u003eH. pylori\u003c/em\u003e eradication therapy improved dyspepsia symptoms in 24-53% of patients [2, 15-18]. In our study, dyspepsia symptoms after successful eradication improved in about 73% of the patients in the long term, and the percentage of patients was slightly higher that in the previous studies (supplement 3). Unfortunately, the definitions of improvement of dyspepsia were different in some studies, and further research is needed to compare the symptoms using the same methods at same timing after eradication.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Tsuda et al. reported that a questionnaire within 2 months after \u003cem\u003eH. pylori \u003c/em\u003eeradication might be useful for diagnosis in 70% of patients with HPD [19]. Similarly, questionnaires in the short term after eradication was predicted HPD in 60% of elderly patients. However, the symptoms in 40% of the patients with dyspepsia changed in the long term and HPD could not be predicted. According to Kyoto Global Consensus Report, it is necessary to follow symptoms for more than 6 months after successful eradication to determine HPD as was indicated by our results [5].\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; There have been a few studies on outcomes of eradication therapy for the elderly, but the outcomes investigated in those studies were for 1\u003csup\u003est\u003c/sup\u003e-line and 2\u003csup\u003end\u003c/sup\u003e-line therapy [7, 8, 20, 21]. In our study, there was a significant difference in eradication rates only in 3\u003csup\u003erd\u003c/sup\u003e-line therapy. There were no significant differences in rates of eradication using PPIs and VPZ, and Kusunoki et al. and Nishida et al. reported that the effect of VPZ was unclear in elderly patients [20, 21]. Resistance to clarithromycin (CAM) might be the main reason for failure of 3\u003csup\u003erd\u003c/sup\u003e-line therapy, but that was unfortunately not checked in our subjects [22, 23].\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Recently, Furuta et al. reported that autoimmune gastritis (AIG) patients were often misdiagnosed as refractory to eradication therapy [24]. Because, AIG causes achlorhydria and non \u003cem\u003eH. pylori\u003c/em\u003e urease-positive bacteria overgrowth. Although patients with suspected false positive for UBT were excluded from this study, 4 of them were positive for anti‐parietal cell antibody (APCA) and/ or anti‐intrinsic factor antibody.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; Adverse events of eradication therapy are one of the concerns for the elderly. We have not experienced serious adverse events in eradication therapy, but there has been a report of death in an elderly patient [25]. Therefore, it is necessary to pay attention to drug interaction, hepatorenal function and co-morbidities in eradication, especially for the elderly.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; The present study has several limitations. This was a retrospective study with a small sample size at a single institution. And antibiotic resistance was not tested.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; In conclusion, eradication of \u003cem\u003eH. pylori \u003c/em\u003ewould improve dyspepsia for long term in elderly patients with dyspepsia symptoms.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is no funding for the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due [secondary use of data was not approved by our IRB] but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final version of the manuscript, including the authorship. IT, SO and MK designed the study; IT, SO and MT performed the research; YS, SK, MI, MO, KY andYS analyzed the data; IT and SO wrote the paper; and NS revised the manuscript for final submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in accordance with the ethical standards detailed in the Declaration of Helsinki. The study was reviewed and approved by the Hokkaido University Hospital Review Board 018-0367.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eStanghellini V, Chan FK, Hasler WL, et al. Gastroduodenal Disorders. 2016;150(6):1380-1392.\u003c/li\u003e\n\u003cli\u003eDu LJ, Chen BR, Kim JJ, Kim S, Shen JH, Dai N. Helicobacter pylori eradication therapy for functional dyspepsia: Systematic review and meta-analysis. \u003cem\u003eWorld J Gastroenterol. \u003c/em\u003e2016;22(12):3486-3495.\u003c/li\u003e\n\u003cli\u003eZhao B, Zhao J, Cheng WF, et al. Efficacy of Helicobacter pylori eradication therapy on functional dyspepsia: a meta-analysis of randomized controlled studies with 12-month follow-up. \u003cem\u003eJ Clin Gastroenterol. \u003c/em\u003e2014;48(3):241-247.\u003c/li\u003e\n\u003cli\u003eArmstrong D. Helicobacter pylori infection and dyspepsia. \u003cem\u003eScand J Gastroenterol Suppl. \u003c/em\u003e1996;215:38-47.\u003c/li\u003e\n\u003cli\u003eSugano K, Tack J, Kuipers EJ, et al. Kyoto global consensus report on Helicobacter pylori gastritis. 2015;64(9):1353-1367.\u003c/li\u003e\n\u003cli\u003eKamada T, Haruma K, Ito M, et al. Time Trends in Helicobacter pylori Infection and Atrophic Gastritis Over 40 Years in Japan. 2015;20(3):192-198.\u003c/li\u003e\n\u003cli\u003eMamori S, Higashida A, Kawara F, et al. Age-dependent eradication of Helicobacter pylori in Japanese patients. \u003cem\u003eWorld J Gastroenterol. \u003c/em\u003e2010;16(33):4176-4179.\u003c/li\u003e\n\u003cli\u003eKobayashi S, Joshita S, Yamamoto C, et al. Efficacy and safety of eradication therapy for elderly patients with helicobacter pylori infection. \u003cem\u003eMedicine (Baltimore). \u003c/em\u003e2019;98(30):e16619.\u003c/li\u003e\n\u003cli\u003eVeldhuyzen van Zanten SJ, Chiba N, Armstrong D, et al. Validation of a 7-point Global Overall Symptom scale to measure the severity of dyspepsia symptoms in clinical trials. \u003cem\u003eAliment Pharmacol Ther. \u003c/em\u003e2006;23(4):521-529.\u003c/li\u003e\n\u003cli\u003eSvedlund, J., I. Sjodin, G. Dotevall et al. GSRS--a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig Dis Sci. 1988;33 (2):129-134.\u003c/li\u003e\n\u003cli\u003evan Zanten SV, Armstrong D, Chiba N, et al. Esomeprazole 40 mg once a day in patients with functional dyspepsia: the randomized, placebo-controlled \"ENTER\" trial. \u003cem\u003eAm J Gastroenterol. \u003c/em\u003e2006;101(9):2096-2106.\u003c/li\u003e\n\u003cli\u003eSakurai K, Nagahara A, Inoue K, et al. Efficacy of omeprazole, famotidine, mosapride and teprenone in patients with upper gastrointestinal symptoms: an omeprazole-controlled randomized study (J-FOCUS). \u003cem\u003eBMC Gastroenterol. \u003c/em\u003e2012;12:42.\u003c/li\u003e\n\u003cli\u003eShimatani T, Inoue M, Iwamoto K, et al. Prevalence of Helicobacter pylori infection, endoscopic gastric findings and dyspeptic symptoms among a young Japanese population born in the 1970s. \u003cem\u003eJ Gastroenterol Hepatol. \u003c/em\u003e2005;20(9):1352-1357.\u003c/li\u003e\n\u003cli\u003eKawamura Y, Funaki Y, Yoshimine T, et al. Characteristics and Predictive Factor of Helicobacter pylori-Associated Functional Dyspepsia in Japanese Patients. 2019;100(4):277-285.\u003c/li\u003e\n\u003cli\u003eMazzoleni LE, Sander GB, Francesconi CF, et al. Helicobacter pylori eradication in functional dyspepsia: HEROES trial. \u003cem\u003eArch Intern Med. \u003c/em\u003e2011;171(21):1929-1936.\u003c/li\u003e\n\u003cli\u003eKhan MQ. Helicobacter pylori Eradication Therapy in Nonulcer Dyspepsia is Beneficial. \u003cem\u003eSaudi J Gastroenterol. \u003c/em\u003e2008;14(2):96-100.\u003c/li\u003e\n\u003cli\u003eAllison JE, Hurley LB, Hiatt RA, Levin TR, Ackerson LM, Lieu TA. A randomized controlled trial of test-and-treat strategy for Helicobacter pylori: clinical outcomes and health care costs in a managed care population receiving long-term acid suppression therapy for physician-diagnosed peptic ulcer disease. \u003cem\u003eArch Intern Med. \u003c/em\u003e2003;163(10):1165-1171.\u003c/li\u003e\n\u003cli\u003eGwee KA, Teng L, Wong RK, Ho KY, Sutedja DS, Yeoh KG. The response of Asian patients with functional dyspepsia to eradication of Helicobacter pylori infection. \u003cem\u003eEur J Gastroenterol Hepatol. \u003c/em\u003e2009;21(4):417-424.\u003c/li\u003e\n\u003cli\u003eTsuda M, Kato M, Ono S, et al. Changes of Dyspeptic Symptom after Successful Eradication in Helicobacter pylori-Associated Dyspepsia. 2019:1-9.\u003c/li\u003e\n\u003cli\u003eKusunoki M, Yuki M, Ishitobi H, et al. Effect of Age on Effectiveness of Vonoprazan in Triple Therapy for Helicobacter pylori Eradication. \u003cem\u003eIntern Med. \u003c/em\u003e2019;58(11):1549-1555.\u003c/li\u003e\n\u003cli\u003eNishida T, Tsujii Y, Okamoto A, et al. A Triple-Drug Blister-Packaged Drug with Vonoprazan Improves First-Line Eradication of Helicobacter pylori in Elderly Patients: A Retrospective Propensity Score-Matched Cohort Study. 2019:1-7.\u003c/li\u003e\n\u003cli\u003eGraham DY, Shiotani A. New concepts of resistance in the treatment of Helicobacter pylori infections. \u003cem\u003eNat Clin Pract Gastroenterol Hepatol. \u003c/em\u003e2008;5(6):321-331.\u003c/li\u003e\n\u003cli\u003eKato M, Ota H, Okuda M, et al. Guidelines for the management of Helicobacter pylori infection in Japan: 2016 Revised Edition. 2019;24(4):e12597.\u003c/li\u003e\n\u003cli\u003eFuruta T, Baba S, Yamade M, et al. High incidenceof\u0026nbsp;autoimmunegastritis\u0026nbsp;in patients misdiagnosed with two or more failures of H. pylori eradication. \u003cem\u003eAliment Pharmacol Ther\u003c/em\u003e. 2018;48(3):370-377.\u003c/li\u003e\n\u003cli\u003eNei T, Hagiwara J, Takiguchi T, et al. Fatal fulminant Clostridioides difficile colitis caused by Helicobacter pylori eradication therapy; a case report. \u003cem\u003eJ Infect Chemother. \u003c/em\u003e20120; 26(3):305-308.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u0026nbsp;Table 1. Regimens of \u003cem\u003eHelicobacter pylori\u003c/em\u003e eradication.\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"123\"\u003e\n\u003cp\u003eEradication\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"387\"\u003e\n\u003cp\u003eAntibiotics\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"104\"\u003e\n\u003cp\u003eAntacids\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"123\"\u003e\n\u003cp\u003e1st and 2nd lines\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"387\"\u003e\n\u003cp\u003eAMPC 750mg and CAM 200mg, b.i.d. 7days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 212px;\" rowspan=\"5\" width=\"104\"\u003e\n\u003cp\u003eRPZ 20mg\u003c/p\u003e\n\u003cp\u003eor\u003c/p\u003e\n\u003cp\u003eLPZ 30mg\u003c/p\u003e\n\u003cp\u003eor\u003c/p\u003e\n\u003cp\u003eVPZ 20mg, b.i.d.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"123\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"387\"\u003e\n\u003cp\u003eAMPC 750mg and MNZ 250mg, b.i.d. 7days\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"123\"\u003e\n\u003cp\u003e3rd line\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"387\"\u003e\n\u003cp\u003eAMPC 500mg q.i.d. and STFX 100mg, b.i.d. 7 or 14days\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 48px;\"\u003e\n\u003ctd style=\"height: 48px;\" width=\"123\"\u003e\n\u003cp\u003e4th line\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 48px;\" width=\"387\"\u003e\n\u003cp\u003eSTFX 100mg and MINO 250mg b.i.d. 7 days and AMPC 500mg q.i.d. 14 days\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 59px;\"\u003e\n\u003ctd style=\"height: 59px;\" width=\"123\"\u003e\n\u003cp\u003eFor penicillin allergy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 59px;\" width=\"387\"\u003e\n\u003cp\u003eCAM 200mg and MNZ 250mg b.i.d.7 days\u003c/p\u003e\n\u003cp\u003eMNZ 250mg and STFX 100mg b.i.d. 7 days\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eRPZ: rabeprazole, LPZ: lansoprazole, VPZ: vonoprazan, AMPC: amoxicillin, CAM: clarithromaycin, MNZ: metronidazole, STFX: sitafloxacin, MINO: minomycin, b.i.d: bis in die, q.i.d: quarte in die\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Characteristics of patients.\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003eGroup N (n = 275)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003eGroup E (n = 162)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003eMale: female, n\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003e116: 159\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e61: 101\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003eMean age at \u003cem\u003eH. pylori\u003c/em\u003e eradication, years (range)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003e51.7 (17-64)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e70.6 (65-87)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003eGastric disease, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003e\u0026nbsp; Chronic gastritis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003e164 (59.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e100 (61.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003e\u0026nbsp; Peptic ulcer scar\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003e43 (15.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e13 (8.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003e\u0026nbsp; Gastric cancer post treatment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003e9 (3.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e13 (8.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003eEradication therapy, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003e\u0026nbsp; 1\u003csup\u003est\u003c/sup\u003e-line\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003e160 (58.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e80 (49.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003e\u0026nbsp; 2\u003csup\u003end\u003c/sup\u003e-line\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003e25 (9.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e13 (8.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003e\u0026nbsp; 3\u003csup\u003erd\u003c/sup\u003e-line\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003e85 (30.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e62 (38.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003e\u0026nbsp; 4\u003csup\u003eth\u003c/sup\u003e-line\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003e5 (1.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e7 (4.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003ePenicillin allergy, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003e69 (25.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e35 (21.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003ePPI-based regimen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003e186 (67.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e104 (64.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"222\"\u003e\n\u003cp\u003ePCAB-based regimen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"181\"\u003e\n\u003cp\u003e89 (32.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e58 (35.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ePPI: proton-pump inhibitors, PCAB: potassium competitive acid blocker\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3. Outcomes and adverse events of \u003cem\u003eHelicobacter pylori\u003c/em\u003e eradication therapy.\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"198\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003eGroup N (n = 275)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003eGroup E (n = 162)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003eEradication rates, % (n)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e84.4 (232/ 275)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e74.7 (121/ 162)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026lt; 0.05\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e 1\u003csup\u003est\u003c/sup\u003e-line\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e88.8 (142/ 160)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e87.5 (70/ 80)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.83\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e 2\u003csup\u003end\u003c/sup\u003e-line\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e90.1 (23/ 25)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e84.6 (11 /13)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.59\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e 3\u003csup\u003erd\u003c/sup\u003e-line\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e76.5 (65/ 85)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e59.7 (37/ 62)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e\u0026lt; 0.05\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e 4\u003csup\u003eth\u003c/sup\u003e-line\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e40.0 (2/ 5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e42.9 (3/ 7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e PPI-based regimen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e84.9 (158/ 186)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e77.9 (81/ 104)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.15\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e PCAB-based regimen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e83.1 (74/ 89)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e69.0 (40/ 58)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.07\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003eAdverse events, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e48 (17.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e23 (14.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.42\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; Diarrhea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e25 (9.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e10 (6.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.36\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; Skin rash\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e7 (2.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e7 (4.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.40\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp; Others\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e16 (5.8 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003e6 (3.7 %)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"76\"\u003e\n\u003cp\u003e0.37\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ePPI: proton-pump inhibitors, PCAB: potassium competitive acid blocker\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 4. Dyspepsia before and after successful eradication.\u003c/p\u003e\n\u003ctable border=\"1\" width=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003eGroup N (n = 233)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003eGroup E (n = 117)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eMean age at \u003cem\u003eH. pylori\u003c/em\u003e eradication, years \u0026plusmn; SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e51.3 \u0026plusmn; 9.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e70.5 \u0026plusmn; 4.89\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e－\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eGender (male/ female)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e99/ 134\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e43/ 74\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003eN.S\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003ePatients with dyspepsia before eradication, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e84 (36.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e37 (31.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003eN.S\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"189\"\u003e\n\u003cp\u003eImprovement in dyspepsia after eradication, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"151\"\u003e\n\u003cp\u003e64/ 84 (76.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e26/ 37 (70.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003eN.S\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"dyspepsia, Helicobacter pylori, eradication therapy, the elderly","lastPublishedDoi":"10.21203/rs.3.rs-118169/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-118169/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eTherapy for eradication of \u003cem\u003eHelicobacter pylori\u003c/em\u003e (\u003cem\u003eH. pylori\u003c/em\u003e) improves symptoms of \u003cem\u003eH. pylori\u003c/em\u003e-associated dyspepsia (HPD), but the effects of eradication in elderly patients are unclear. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAims\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eTo\u003cstrong\u003e \u003c/strong\u003eevaluate the outcomes of eradication therapy and effects of eradication on dyspepsia symptoms in elderly patients.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThis retrospective study included 496 patients who received \u003cem\u003eH. pylori \u003c/em\u003eeradication therapy. The patients were divided into a group of elderly patients (group E: ≧ 65 years old) and a group of non-elderly patients (group N: \u0026lt; 65 years old). Abdominal symptoms were evaluated using a questionnaire about 12 abdominal symptoms before eradication and after eradication (1-2 months and more than one year). Dyspepsia was defined as a score of 4 points or more score for at least one of 4 items (postprandial fullness, early satiety, epigastric pain, and hunger pain).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eSuccesful \u003cem\u003eH. pylori\u003c/em\u003e eradication rate in group E was significantly lower than that in group N (74.7 % vs. 84.4 %, \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.05) and it was remarkable in the 3rd-line therapy (59.7 % vs. 76.5 %, \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.05). Serious adverse events did not occur in either groups. Successful eradication improved symptoms in patients with dyspepsia in both groups within 2 months (70.3% of the patients in group N, 76.2% of the patients in group E) and decrease of GOS score lasted for more than 1 year.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eH. pylori\u003c/em\u003e eradication would be recommend for elderly patients with dyspepsia symptoms.\u003c/p\u003e","manuscriptTitle":"Eradication of Helicobacter Pylori Improves Dyspepsia Symptoms in Elderly People","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-12-04 16:31:33","doi":"10.21203/rs.3.rs-118169/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-05-11T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-05-10T00:00:00+00:00","index":2,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nReview on BMGE-D-20-01383 by Tanaka I et al., entitled \"Eradication of Helicobacter pylori improves dyspepsia symptoms in elderly people\"\nThis study evaluated the outcomes and effect of H. pylori eradication on dyspepsia in elderly patients. \nThe following comments are for the reference of authors:\n\nMajor comments\n1. In Introduction, the last sentence of the first paraphrase, \"H. pylori-associated dyspepsia (HPD) is also defined as sustained symptomatic relief for 6 to 12 months after eradication,\" is not clear. Why was \"relief\" defined as HPD?\n2. Please give p values of comparisons between the two groups for each variables in Table 2.\n3. The authors should calculate the sample size to show the results about long-term improvement in HPD after eradication between the group N (80%) and the group E (60%) did not have a type II error.\n4. In Figure 1, please add the information about how many patients who did not fill out the questionnaire. Thus, the readers would be easy to follow up and understand the case number in Table 4.\n5. May consider to change supplement 3 to be a formal figure in the manuscript because it showed the results of the primary endpoint.\n6. The primary endpoint was long-term improvement in the GOS score after successful eradication in elderly patients with dyspepsia. Please focus on this in the \"Discussion\" part.\n7. What was the evidence to support the conclusion, \"eradication of H. pylori would improve dyspepsia for long term in elderly patients with dyspepsia symptoms\"? Please revise the conclusion if the evidence was weak.\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons after the final decision on the manuscript has been made. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **No**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"editorInvitedReview","content":"","date":"2021-05-03T00:00:00+00:00","index":3,"fulltext":"Recommendation: Accept after minor essential revisions\nForm responses:\n---\n\nComments to Author:\n---\nI read with interest the report on the effect of eradication therapy on dyspeptic symptoms in elderly patients. The study is nicely designed and conducted. Please find here below my comments:\n\nAbstract: the conclusion is too reductive with respect to what the authors did and somewhat misleading, as Hp eradication is recommend beyond presence of dyspepsia, especially in Japan with a very high prevalence of GC, as correctly stated in the Introduction.\nIintroduction: lines 33-36: this sentence is written twice.\nMethods: As correctly stated, accurate diagnosis of Hp infection requires at least two diagnostic methods. The authors state also that efficacy of eradication treatment was verified by UBT. I would have been more correct to verify successful eradication by the same tests which were positive pre-treatment. This may be especially true in those patients with borderline UBT values.\nDiscussion: In contrast to the declarative title chosen by the authors, the discussion section is not really contextualized on this topic, is it is general and not tailored to elderly patients who are the target subjects of the study population. Further, arguments should be commented (for example autoimmune gastritis very common in elderly subjects...)\n\n\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons after the final decision on the manuscript has been made. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **None**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"editorInvitedReview","content":"","date":"2021-04-30T00:00:00+00:00","index":1,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nThe topic explored by the authors is interesting, but some sentences and conclusion could be not completely supported. Dyspepsia in Helicobacter pylori infected subjects is frequent and Maasticht and Kyoto reccomendations are in favour of H.p. eradication to improve dyspepsia. For elderly people, no specific recomendation are present in literature. The relationship beetwen Hp infection and upper GI diseases in elderly has been recognized in the past in several papers:\n\nA Pilotto 1, M Franceschi, G Leandro, M Rassu, L Bozzola, G Valerio, F Di Mario Influence of Helicobacter pylori infection on severity of oesophagitis and response to therapy in the elderly Dig Liver Dis . 2002 May;34(5):328-31.\nAliment Pharmacol Ther\n\nA Pilotto 1, M Franceschi, G Leandro, L Bozzola, M Rassu, G Soffiati, F Di Mario, G Valerio Cure of Helicobacter pylori infection in elderly patients: comparison of low versus high doses of clarithromycin in combination with amoxicillin and pantoprazole 2001 Jul;15(7):1031-6.\nAliment Pharmacol Ther\n\nA Pilotto 1, F Di Mario, M Franceschi, G Leandro, G Battaglia, B Germanà, R Marin, G Valerio Pantoprazole versus one-week Helicobacter pylori eradication therapy for the prevention of acute NSAID-related gastroduodenal damage in elderly subjects. Aliment Pharmacol Ther\n. 2000 Aug;14(8):1077-82.\n\n.A Pilotto, M Franceschi, G Valerio, F Di Mario, G Leandro Helicobacter pylori infection in elderly patients with peptic ulcer Age Ageing, 1999 Jul;28(4):412-4.\n\nA Pilotto 1, F Rumor, M Franceschi, G Leandro, R Novello, G Soffiati, M Scagnelli, F Di Mario, G Valerio Lack of association between Helicobacter pylori infection and extracardiac atherosclerosis in dyspeptic elderly subjects PMID: 10459790 DOI: 10.1093/ageing/28.4.367\nJ Gastroenterol Hepatol\n\n\nA Pilotto 1, M Franceschi, G Leandro, L Bozzola, A Fortunato, M Rassu, S Meli, G Soffiati, M Scagnelli, F Di Mario, G Valerio . Efficacy of 7 day lansoprazole-based triple therapy for Helicobacter pylori infection in elderly patients 1999 May;14(5):468-75. doi: 10.1046/j.1440-1746.1999.01893.x.\n\n\nA Pilotto 1, M Franceschi, F Di Mario, G Leandro, L Bozzola, G Valerio The long-term clinical outcome of elderly patients with Helicobacter pylori-associated peptic ulcer disease. 1998;44(3):153-8. doi: 10.1159/000022000.\nJ Clin Gastroenterol\n\n\nA Pilotto 1, M Rassu, L Bozzola, G Leandro, M Franceschi, F Furlan, S Meli, M Scagnelli, F Di Mario, G Valerio Cytotoxin-associated gene A-positive Helicobacter pylori infection in the elderly. Association with gastric atrophy and intestinal metaplasia . 1998 Jan;26(1):18-22. doi: 10.1097/00004836-199801000-00006.\n\n\nThe effect of Helicobacter pylori infection on NSAID-related gastroduodenal damage in the elderly. Eur J Gastroenterol Hepatol . 1997 Oct;9(10):951-6. doi: 10.1097/00042737-199710000-00006.\nA Pilotto 1, M Franceschi, G Leandro, F Di Mario, G Valerio\n\n\nA Pilotto 1, M Franceschi, G Leandro, F Di Mario, G Valerio The effect of Helicobacter pylori infection on NSAID-related gastroduodenal damage in the elderly Eur J Gastroenterol Hepatol . 1997 Oct;9(10):951-6.\n\n\nA Pilotto 1, F Di Mario, M Franceschi, G Leandro, G Soffiati, M Scagnelli, L Bozzola, G Valerio Cure of Helicobacter pylori infection in the elderly: effects of eradication on gastritis and serological markers. Aliment Pharmacol Ther . 1996 Dec;10(6):1021-7.\n\n\nA Pilotto 1, R Fabrello, M Franceschi, M Scagnelli, F Soffiati, F Di Mario, A Fortunato, G Valerio Helicobacter pylori infection in asymptomatic elderly subjects living at home or in a nursing home: effects on gastric function and nutritional status. Age Ageing . 1996 May;25(3):245-9.\n\n\nWe suggest to include in bibliography some on these papers. In particular, the sentence opening the discussion: \"This is the first report.....\" appears inadeguate. I suggest to include in both background and discussion papers related with Hp eradication schedules in elderly as well as Hp infection and dyspepsia and Hp eradication and dyspepsia.\nDyspepsia is closely influenced by fluttuation lasting the time and this is true also for the relationship beetwen Hp eradication and improvement of dyspepsia, as reported in this paper: Francesco di Mario 1, Nicoletta Stefani, Nadia Dal Bò, Massimo Rugge, Alberto Pilotto, Giulia Martina Cavestro, Lucas Giovanni Cavallaro, Angelo Franzé, Gioacchino Leandro Natural course of functional dyspepsia after Helicobacter pylori eradication: a seven-year survey. Dig Dis Sci . 2005 Dec;50(12):2286-95.\nThe study lasting a period of 7 years after Hp eradication showed a fluttuation in dyspeptic symptoms after Hp eradication.\nOn this subject, the authors reported that in a subgroup of elderly patients the answers to the questionaire have been obtained after 54.8 months, but aonly results after one year were reported in the paper. I suggest to clarify.\n\nOther comments and suggestion\n\nWe suggest to detail which symptoms improved and possible related mechanisms\nIn elderly, atrophic gastritis is increasing. We suggest to report data on the frequency of atrophic gastritis in studied population beside the autoimmune gastritis correctly mentioned.\nWe believe that the control group (N) is not appropriate for the aims of the study. A proper control group, to me, could be an elderly Hp positive population not treated and with an adeguate follow-up. At present the study is consistent only with the demonstartion that younger people have a better response to eradication teraphy in comparison with elderly.\n\n\n\n\n\n\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons after the final decision on the manuscript has been made. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. 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Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. 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