Eradication of Helicobacter Pylori Improves Dyspepsia Symptoms in Elderly People

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 dened 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). vs. and it was remarkable vs. P < 0.05). Serious improved in patients with dyspepsia in both within 2 (70.3% of the in of the in and GOS more than 1 year. H.


Introduction
Functional dyspepsia (FD) is de ned in the ROMA 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][3][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 de ned 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 rst-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 e cacy 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.

Patients
Consecutive patients who visited our H. pylori-speci c 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 de ned as positive for H. pylori when in whom one of those tests was positive. Generally, the patients was de ned 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 con rmed that other tests were positive for excluding false positive for UBT tests.
Successful eradication was con rmed 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 lled 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 re ux, 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 de ned as patients with dyspepsia. Improvement of dyspepsia was de ned 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 de ned 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 signi cant.

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, nally a total of 437 patients including 275 patients in group N and 162 patients in group E were analyzed. A ow 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 signi cant 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 signi cantly lower than that in group N (59.7% vs 76.5%, P < 0.05) ( Table 3). But there were no signi cant 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 signi cant 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 ll 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 signi cant 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 signi cant differences between the two groups in total GOS score and score of each item. Successful eradication signi cantly improved all upper GI symptoms regardless of age (supplement 1). According to our de nition 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 signi cantly 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 rst 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 signi cantly 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][16][17][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 de nitions 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 signi cant difference in eradication rates only in 3 rd -line therapy. There were no signi cant 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 ureasepositive 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.  A ow diagram for treatment and characteristics of the patients are shown in Figure 1