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. 2023 Jan 5;33(1):1–7. doi: 10.2188/jea.JE20200618

Long-term Response of Helicobacter pylori Antibody Titer After Eradication Treatment in Middle-aged Japanese: JPHC-NEXT Study

Shiori Tanaka 1, Atsushi Goto 1,2, Kazumasa Yamagishi 3,4, Motoki Iwasaki 1, Taiki Yamaji 1, Taichi Shimazu 1, Hiroyasu Iso 3,5, Isao Muraki 5, Nobufumi Yasuda 6, Isao Saito 7, Tadahiro Kato 8, Kiyoshi Aoyagi 9, Kazuhiko Arima 9, Kiyomi Sakata 10, Kozo Tanno 10, Manami Inoue 1, Norie Sawada 1, Shoichiro Tsugane 1, for the Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT) Study Group
PMCID: PMC9727212  PMID: 33907066

Abstract

Background

Helicobacter pylori (H. pylori) is an established causative factor of gastric cancer. Although the expansion of insurance coverage has led to an increase in the number of patients treated for H. pylori, the population impact of eradication treatment for H. pylori has been scarcely investigated. This study aimed to clarify the long-term responses of H. pylori antibody titer after eradication treatment using large scale cross-sectional data from the Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT Study).

Methods

A total of 55,282 Japanese participants aged 40 to 74 years residing in 16 areas provided blood samples from 2011 through 2016. From these, treated (n = 6,276) and untreated subjects who were seropositive for H. pylori or had serological atrophy (n = 22,420) formed the study population (n = 28,696). Seropositivity was defined as an anti-H. pylori IgG titer of ≥10 U/mL. Antibody level was compared among subjects according to self-reported treatment history as untreated, and treated for less than 1 year (<1Y), 1 through 5 years (1–5Y), and 6 or more years ago (6Y+).

Results

Median serum antibody titer was 34.0 U/mL, 7.9 U/mL, 4.0 U/mL, and 2.9 U/mL for the untreated, <1Y, 1–5Y, and 6Y+ groups, respectively. While those treated for H. pylori within the previous year had a 76.8% lower antibody titer compared to untreated subjects, approximately 41% of subjects were still seropositive.

Conclusion

A significant reduction in H. pylori antibody titer occurs within 1 year after eradication treatment, but that a long period is needed to achieve complete negative conversion.

Key words: Helicobacter pylori, antibody, eradication treatment, cohort, Japan

INTRODUCTION

Gastric cancer is the fifth-most common cancer globally, and approximately 89% of cases are attributable to H. pylori infection.1 Japan is one of the countries with a high incidence of gastric cancer, as well as a high prevalence of H. pylori infection.2 Although improvements in public hygiene and environmental conditions have led to a significant decline in H. pylori infection,3,4 gastric cancer remains a major public health challenge in Japan.5,6

Previous reports have suggested that the eradication of H. pylori reduces the risk of gastric cancer.7–14 Accordingly, the Japanese government approved coverage of eradication treatment for H. pylori gastritis under the public health insurance in 2013, resulting in a dramatic increase in the number of patients receiving H. pylori eradication treatment.15,16 Although the population impact of eradication treatment may affect the future incidence of gastric cancer, chronological change in H. pylori antibody titer after eradication using large-scale population data has been scarcely investigated. Of note, antibody titer levels after eradication may be a potential predictor of post-eradication gastric cancer, with substantial impact on population health.

Here, to investigate the long-term response of H. pylori antibody titers following eradication, we conducted a cross-sectional analysis of baseline data from a large cohort study by comparing the history of eradication treatment in middle-aged and elderly Japanese.

METHODS

Study participants

The study was conducted using the baseline survey in The Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT Study). The details of the study design have been described elsewhere.17 The purpose and human rights regarding blood collection were informed to each participant in person, and written consent was obtained. A total of 55,282 Japanese participants aged 40 to 74 years residing in 16 municipalities (2 in Iwate, 1 in Akita, 7 in Nagano, 1 in Ibaraki, 2 in Kochi, 1 in Ehime, and 2 in Nagasaki prefectures) in Japan provided blood samples between 2011 and 2016. At the same time, the participants were surveyed using a self-administered questionnaire on their history of gastric cancer, as well as receipt of H. pylori eradication treatment as follows: (1) no history; and (2) receipt less than 1 year; (3) 1 to 5 years ago; and (4) 6 or more years ago. The study protocol was approved by the Institutional Review Board of the National Cancer Center Japan (Approval number: 2011-186).

Blood collection

We used sera that were derived from biospecimens obtained in the health examinations or sera especially collected for this study. Immunoglobulin (IgG) antibody titer against H. pylori was measured using enzyme immunoassay (EIA) (E Plate “Eiken” HP Antibody; Eiken Chemical Co., Ltd., Tokyo, Japan), while pepsinogen (PG) concentration was measured using latex agglutination (LA) (LSI Medience Co., Tokyo, Japan). This commercial kit, which is widely used to measure anti-H. pylori IgG titer in Japan, has a lower limit of detection of 3 U/mL. Sensitivity and specificity are approximately 91% and 97%, respectively.18 Seropositivity was defined as an anti-H. pylori IgG titer of ≥10 U/mL. Serological atrophic gastritis (AG) status was set as a combination of serum PG I level ≤70 ng/mL and PG I/II ratio ≤3.0.19,20

Study population

Of 55,282 participants, those who were missing data on H. pylori antibody titers, serum PG, and history of eradication treatment (n = 5,135) or had a history of gastric cancer before blood collection (n = 561) were excluded (Figure 1). Because proton pump inhibitors (PPI) alter the serum PG concentration, we identified those who were taking a PPI prescribed by a medical doctor at the time of enrollment using the baseline questionnaire, resulting in the exclusion of 810 subjects. A total of 48,776 eligible subjects were classified into treated (n = 6,276) or untreated (n = 42,500) groups according to their self-report. To perform a quantitative comparison of H. pylori antibody titers between pre and post-treatment at the population level, we used untreated subjects with seropositivity for H. pylori or serological AG by pepsinogen as reference in the analysis. Of 42,500 untreated subjects, we excluded those who were not seropositive or classified with AG by pepsinogen (n = 20,080). As a result, treated (n = 6,276) and untreated (n = 22,420; AG by pepsinogen only: n = 490) subjects who were previously infected with H. pylori formed the study population (n = 28,696).

Figure 1. Study flow.

Figure 1.

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Statistical analysis

Antibody titers against and seroprevalence of H. pylori in the study participants were assessed based on treatment history as (1) none (untreated group); and (2) treatment less than 1 year (<1Y group); (3) 1 to 5 years ago (1–5Y group); and (4) 6 or more years ago (6Y+ group). H. pylori antibody titers were classified into three groups of <3 U/mL, ≥3 U/mL to <10 U/mL, and ≥10 mL, as low-negative, high-negative, and positive, respectively.21 Continuous variables were expressed as the mean (standard deviation [SD]) or median (interquartile range [IQR]) when distributions were skewed. Medians were compared using unadjusted quantile regression by assigning categories as an ordinal variable. The figures for quartiles of antibody titer and seroprevalence were presented using cubic spline interpolation. The antibody distributions were further assessed by age at blood test and sex. Because a previous study has reported that the prevalence of previous infection-induced AG was around 10.0–19.8% in Japan irrespective of negative conversion,22 we further excluded subjects showing a serum titer of 3 to <10 U/mL to examine the influence of unintentional eradication among the untreated group. A P-value of <0.05 was considered statistically significant. We used STATA version 16 for all analyses (StataCorp LLC, College Station, TX, USA).

RESULTS

Among 28,696 subjects (mean age, 61.7 years; 44.8% male), a total of 21.9% were treated for H. pylori (Table 1). Mean age did not differ among groups. Men were more commonly treated than women (29.5% vs 22.4%). Compared to the untreated group, PG I and PG II were lower in all treated groups. With years since treatment, the PG I/II ratio increased while the prevalence of AG by serum pepsinogen decreased.

Table 1. Basic characteristics according to the self-reported treatment history for H. pylori among ever-infected subjects in the JPHC-NEXT Study.

  Overall Untreateda Years from treatmenta
<1Y 1–5Y 6Y+
Total, n (%) 28,696 (100.0) 22,420 (78.1) 1,100 (3.8) 2,889 (10.1) 2,287 (8.0)
Age, years, mean (SD) 61.7 (8.4) 61.7 (8.5) 61.7 (8.3) 61.6 (8.1) 61.5 (7.8)
Sex          
 Male, n (%) 12,857 (100.0) 9,583 (74.5) 484 (3.8) 1,429 (11.1) 1,361 (10.6)
 Female, n (%) 15,839 (100.0) 12,837 (81.0) 616 (3.9) 1,460 (9.2) 926 (5.8)
Serum pepsinogen          
 PG I, IQR, ng/mL 60.2 (36.5–74.6) 61.4 (36.8–77.4) 43.0 (31.2–58.8) 45.7 (34.4–60.7) 52.3 (41.0–69.7)
 PG II, IQR, ng/mL 19.4 (9.9–25.4) 21.7 (12.7–27.8) 8.2 (6.4–11.3) 8.5 (6.7–11.5) 9.8 (7.6–13.0)
 PG I/II ratio, mean (SD) 3.6 (2.0) 3.1 (1.7) 5.1 (1.9) 5.4 (1.8) 5.5 (1.7)
Serum AGb, n (%)c 10,001 (34.9) 9,565 (42.7) 133 (12.1) 181 (6.3) 122 (5.3)
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AG, atrophic gastritis; IQR, interquartile range; n, number; PG, pepsinogen; SD, standard deviation.

aSubjects were classified according to their self-reported treatment history for H. pylori as follows: none: untreated; treated less than 1 year: <1Y; treated 1 to 5 years ago: 1–5Y; and treated 6 or more years ago: 6Y+.

bDefined as a combination of the serum PG I level ≤70 ng/mL and PG I/II ratio ≤3.0.

cPercentage of atrophic gastritis by pepsinogen.

Table 2 presents antibody titers according to treatment history. Median serum antibody titer level was 34.0 (IQR, 14.0–48.6) U/mL, 7.9 (IQR, 4.0–16.4) U/mL, 4.0 (IQR, 3.0–7.2) U/mL, and 2.9 (IQR, 2.9–4.5) U/mL for the untreated, <1Y, 1–5Y, and 6Y+ groups, respectively. Median H. pylori antibody titer was significantly decreased overtime since treatment in all subjects and both sexes (P < 0.01). Compared to the untreated group, median antibody titer of the <1Y, 1–5Y, and 6Y+ groups was decreased by 76.8%, 88.2%, and 91.5%, respectively. Percentages of low-negative subjects in the <1Y, 1–5Y, and 6Y+ groups were 16.6%, 34.0% and 55.7%, respectively. High-negative subjects accounted for 42.4%, 50.0% and 33.3% of the <1Y, 1–5Y, and 6Y+ groups. Meanwhile, those who were seropositive were 41.0%, 16.0%, and 11.0% in the <1Y, 1–5Y, and 6Y+ groups. Those who were both H. pylori-negative and classified with AG by serum pepsinogen were 1.8%, 1.0%, and 1.0% in the <1Y, 1–5Y, and 6Y+ groups, respectively. Figure 2A shows quartiles of antibody titer by group. The slope of the decline in titers between the 75th vs 25th percentile subjects was quite different, suggesting that pre-treatment antibody titer may have influenced the quantitative response to treatment. The smoothed-spline curve of seroprevalence for H. pylori is also shown in Figure 2B. The prevalence of seronegativity continued to increase over time from treatment, while the ratio of subject with antibody titers of 3 to <10 U/mL remained high among the <1Y and 1–5Y groups.

Table 2. Anti-H. pylori IgG titers and seroprevalence according to self-reported treatment history for H. pylori among ever-infected subjects in the JPHC-NEXT Study.

  Untreateda Years from treatmenta P-valueb
<1Y 1–5Y 6Y+  
All n = 22,420 n = 1,100 n = 2,889 n = 2,287  
H. pylori antibody titer, IQR, U/mL 34.0 (14.0–48.6) 7.9 (4.0–16.4) 4.0 (3.0–7.2) 2.9 (2.9–4.5) <0.01
 <3 U/mLc, n (%) 490 (2.2) 183 (16.6) 982 (34.0) 1,274 (55.7) <0.01
 3–<10 U/mLc, n (%) 3,700 (16.5) 466 (42.4) 1,444 (50.0) 761 (33.3)  
 ≥10 U/mLc, n (%) 18,230 (81.3) 451 (41.0) 463 (16.0) 252 (11.0)  
Men n = 9,583 n = 484 n = 1,429 n = 1,361  
H. pylori antibody titer, IQR, U/mL 32.8 (13.7–45.0) 7.6 (4.3–14.3) 3.9 (3.0–6.8) 2.9 (2.9–4.5) <0.01
 <3 U/mLc, n (%) 197 (2.1) 80 (16.5) 502 (35.1) 757 (55.6) <0.01
 3–<10 U/mLc, n (%) 1,562 (18.4) 221 (45.7) 721 (50.5) 454 (33.4)  
 ≥10 U/mLc, n (%) 7,824 (81.6) 183 (37.8) 206 (14.4) 150 (11.0)  
Women n = 12,837 n = 616 n = 1,460 n = 926  
H. pylori antibody titer, IQR, U/mL 36.0 (14.3–51.1) 8.0 (3.9–18.5) 4.2 (3.0–7.6) 2.9 (2.9–4.5) <0.01
 <3 U/mLc, n (%) 293 (2.3) 103 (16.7) 480 (32.9) 517 (55.8) <0.01
 3–<10 U/mLc, n (%) 2,138 (16.7) 245 (39.8) 723 (49.5) 307 (33.2)  
 ≥10 U/mLc, n (%) 10,406 (81.1) 268 (43.5) 257 (17.6) 102 (11.0)  
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IQR, interquartile range; n, number.

aSubjects were classified according to their self-reported treatment history for H. pylori as follows: none: untreated; treated less than 1 year ago: <1Y; treated 1 to 5 years ago: 1–5Y; and treated 6 or more years ago: 6Y+.

bChi-square test for categorical variables and unadjusted quantile regression to compare median values.

cH. pylori antibody titer of <3 U/mL, ≥3 to <10 U/mL, and ≥10 U/mL were defined as low-negative, high-negative and positive, respectively.

Figure 2. Quartiles of H. pylori antibody titer and seroprevalence according to history of eradication treatment for H. pylori among ever-infected subjects in the JPHC–NEXT Study. Subjects were classified according to self-reported treatment history for H. pylori as follows: none: untreated; treated less than 1 year: <1Y; treated 1 to 5 years ago: 1–5Y; and treated 6 or more years ago: 6Y+. A) Spline-smoothed lines connecting the 25th, 50th, and 75th percentiles of antibody titers in each group, respectively. B) Spline-smoothed lines for seroprevalence of H. pylori according to treatment history. H. pylori antibody titers of <3 U/mL, ≥3 to <10 U/mL, and ≥10 U/mL were defined as low-negative, high-negative and positive, respectively.

Figure 2.

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Median antibody titer was slightly decreased with age among the untreated group (P = 0.02), while little difference was seen among age groups after treatment, irrespective of years since treatment (eTable 1). Seroprevalence did not much differ among age groups (eTable 2). Median antibody titers and seroprevalence tended not to differ by sex.

Sensitivity analysis, in which untreated subjects with serum titers 3 to <10 U/mL were excluded, showed that the median antibody titer of the untreated group was 34.3 (IQR, 21.9–54.6) U/mL and that the percentage decrease in antibody titer between the untreated and <1Y groups was 77.0%.

DISCUSSION

In this study, we assessed the serological response of anti-H. pylori IgG titer after eradication treatment using large-scale cross-sectional data from a cohort study. The median antibody titer was lower in the group with the longest period since eradication treatment. A previous study with successful eradication cases using the same kit reported a similar result,23 indicating that any bias arising from the unclear status of H. pylori elimination in this study did not significantly affect our results.

Compared with the untreated group, median antibody titer was decreased by 76.8% in the <1Y, 88.2% in the 1–5Y, and 91.5% in the 6Y+ groups. This indicated that a significant reduction in antibody titer occurred within 1 year of treatment and then continued to decline over time. Previous studies reported that IgG level decreased from 2 months to 1 year after successful treatment by approximately 16–87%.24–26 Although this initial drop following treatment was reported to occur irrespective of eradication results, the degree of the initial drop and the following serological course depended on whether the eradication had been successful or not.27 Those with successful eradication continued to have low IgG titers due to the disappearance of H. pylori from the gastric mucosa; conversely, titers were slightly elevated among those in whom eradication failed.25–27

In this study, 59.0% of subjects in the <1Y group were found to be seronegative. Previous study reported negative conversion rates of 35–62% at 1 year from H. pylori elimination.25,26,28,29 It took 17.9 months for those with an intermediate level of antibody titer before eradication to convert to negative, and 42.8 months for those with a higher level.30 Complete negative conversion was usually not observed within 1 year after eradication.31,32

Approximately 84% and 89% of the 1–5Y and 6Y+ groups, respectively, with IgG titers became seronegative. Previous studies focused on Japanese patients showed varied results on the seronegative rate. Shirai reported that 62% of patients had an antibody titer level below the cut-off within 2 years.33 Only 7.5% of patients in the highest antibody titer group before elimination was seronegative 3 years after eradication, versus 60% in the lowest titer group.34 Ohara reported that no seropositive cases were seen from 4 years after successful eradication,23 but that no seropositive cases during a long follow-up is unlikely because of the possibility of reinfection and recurrence. Matsuhisa demonstrated a cumulative seronegative rate of only 23.5% during the 6 years since H. pylori elimination.30 The different results shown in studies might have been due to differences in the usage of kits, different conditions before elimination in patients, and loss to follow-up due to the disappearance of symptoms.30

We showed that 42.4%, 50.0%, and 33.3% of subjects in the <1Y, 1–5Y, and 6Y+ groups, respectively, had a high-negative antibody titer level. Similar results were reported in a study that focused on subjects with successful eradication; high-negative cases accounted for 50–65% between 1–9 years after successful eradication.23 Approximately 41.0%, 16.0%, and 11.0% for the <1Y, 1–5Y, and 6Y+ groups, respectively, were seropositive in this study. A quantitative association between pre-eradication H. pylori antibody titer and time to seronegative conversion was reported,31 indicating that the high-negative and seropositive subjects may have had a higher antibody titer before treatment. We observed a difference in the slope of reduction between subjects in the 25th and 75th percentiles of antibody titers. A slow decrease in antibodies might also reflect delayed eradication due to invasion of the bacteria in the mucosa and translocation to the gastric lymph nodes.35 Another reason for incomplete negative conversion might include eradication failure, recurrence, and reinfection.36 As the success rate in first-line eradication treatment is 75–90%,37–41 most seropositivity among the 6Y+ group may be explained by treatment failure. Although new infection in adulthood and recurrence is not common,42–44 a return to seropositivity in subjects with successful eradication is possible.36 A study with long follow-up revealed that recurrence could occur within 4 years after H. pylori eradication and that the annual reinfection rate was 0.2–2.0% in Japanese,42,43 albeit that reinfection and recurrence were not completely distinguished.

Although previous studies indicate that the success rate of eradication varies by gender and age because of antimicrobial susceptibility and differences in compliance,45,46 we observed that median antibody titer and seroprevalence among those treated for H. pylori did not much differ by gender or age.

Given that negative conversion of antibody takes more than 1 year after successful eradication,47 a guideline indicates that measurement of IgG titer is not a suitable way of determining prompt eradication results.48 Used alone, antibody measurement may lead to a misdiagnosis of failed primary eradication, resulting in unnecessary second treatment.49 Quantitative comparison of antibody titers pre- and post-eradication may nevertheless serve as a monitor in evaluating the short- and long-term impact with regard to eradication, recurrence, reinfection, and disease prediction.27,36 Elevated antibodies after successful eradication may be associated with persistent mild chronic inflammation.50 Moreover, a higher level of IgG after successful eradication was observed in a gastric cancer group compared to a no-gastric cancer group.51 Once the association between post-eradication antibody titers for H. pylori and risk of gastric cancer is clarified, measurement of antibody titers after eradication will have a major impact on population health.

Strengths and limitations

This study is the largest report on the long-term response of H. pylori antibody titers after eradication treatment in middle-aged and elderly Japanese. However, several methodological limitations warrant mention. First, the history of eradication treatment was based on self-report, which might have introduced misclassification due to misunderstanding therapy with other medications. We addressed this issue by confirming the history of eradication treatment using the follow-up questionnaire and medical claims data in the Saku area (n = 2,443). The sensitivity, specificity, and positive predictive values of a self-reported eradication history were 96.7%, 89.1%, and 78.8%, respectively, showing the validity of the usage of a self-reported history of eradication treatment for H. pylori. Besides, the higher PG I/II ratio seen in the treated groups compared to the untreated group may support H. pylori eradication.48,52 Second, we were unable to verify whether eradication treatment had been successful or not. The possible inclusion of subjects with failed eradication might have overestimated the seropositive rate and antibody titer level because the antibody titer of patients with unsuccessful eradication should have been higher than that of those with successful eradication.36 Third, unexpected eradication resulting from unintended eradication and spontaneous disappearance of H. pylori as a result of advanced AG cannot be excluded completely, especially among the untreated group.53,54 Additionally, it is important to note that there is no definitive method to identify unintended elimination of H. pylori among those who do not have a history of eradication even using endoscopy, serology, or a medical examination.22 Fourth, we were unable to identify which H. pylori eradication regimens the subjects received. Antibody response may have varied among procedures. Fifth, quantitative comparison before and after treatment was not derived from serial blood samples from individuals. Last, the study subjects were recruited mainly from annual health checkup surveys provided by the local government for general community residents, which might have introduced selection bias.

In summary, this study demonstrated the serological responses of eradication treatment for H. pylori at the population level. While the subjects treated with H. pylori in the previous year had a 76.8% lower antibody titer than untreated cases, approximately 40% were still seropositive. An initial drop in antibody titer occurs within 1 year after treatment, but a long period is required to achieve negative conversion. As there were several methodological limitations, our study provides insights for further investigation of the use of chronological change in H. pylori antibody titer as a potential marker of gastric cancer risk.

ACKNOWLEDGEMENTS

We would like to thank all participants and members of the JPHC-NEXT study for their valuable contributions. We thank Dr Tomomi Kihara (University of Tsukuba) for technical assistance in assessing the validity of self-reported history of treatment for H. pylori.

Funding: This study was supported by the National Cancer Center Research and Development Fund (since 2011) and the Funds for Integrated Promotion of Social System Reform and Research and Development by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (2011–2013), and by Practical Research for Innovative Cancer Control, Japan Cancer Research Project, Japan Agency for Medical Research and Development (AMED) (20ck0106561h0001).

Author’s contribution: STa, AG, KY, NS and MIn conceptualized and designed the study. Data collection and management were performed by AG, KY, MIn, TY, TS, HI, IM, NY, IS, TK, KAo, KAr, KS, KT, MIw, NS, STs. STa analyzed the data and wrote first draft of the manuscript. All authors reviewed, interpreted the result and approved the final version.

Data availability: We cannot publicly provide the data analyzed during the current study because permission has not been obtained from the ethical board, but the information on how to access to JPHC-NEXT data is available following instructions at https://epi.ncc.go.jp/jphcnext/en/access/index.html.

Conflicts of interest: Dr Shimazu reports grants from The Dai-ichi Life Insurance Company, Limited, outside the submitted work. No other conflicts of interest declared.

SUPPLEMENTARY MATERIAL

The following is the supplementary data related to this article:

eTable 1. Median (interquartile) of H. pylori antibody titers according to the self-reported treatment history for H. pylori by age at blood test among ever-infected subjects in the JPHC-NEXT Study

eTable 2. Seroprevalence of H. pylori according to the self-reported treatment history for H. pylori by age at blood test among ever-infected subjects in the JPHC-NEXT Study

eFigure 1. Quartiles of H. pylori antibody titers according to the self-reported treatment history for H. pylori by age at blood test among ever-infected subjects in the JPHC–NEXT.

eFigure 2. The seroprevalence of H. pylori according to the self-reported treatment history for H. pylori by age at blood test among ever-infected subjects in the JPHC–NEXT Study

je-33-001-s001.pdf (425.2KB, pdf)

REFERENCES

  • 1.Plummer M, Franceschi S, Vignat J, Forman D, de Martel C. Global burden of gastric cancer attributable to Helicobacter pylori. Int J Cancer. 2015;136(2):487–490. 10.1002/ijc.28999 [DOI] [PubMed] [Google Scholar]
  • 2.IARC Helicobacter pylori Working Group. Helicobacter pylori Eradication as a Strategy for Preventing Gastric Cancer. Lyon, France: International Agency for Research on Cancer (IARC); December 2013 2014. [Google Scholar]
  • 3.Ueda J, Gosho M, Inui Y, et al. Prevalence of Helicobacter pylori infection by birth year and geographic area in Japan. Helicobacter. 2014;19(2):105–110. 10.1111/hel.12110 [DOI] [PubMed] [Google Scholar]
  • 4.Kamada T, Haruma K, Ito M, et al. Time trends in Helicobacter pylori infection and atrophic gastritis over 40 years in Japan. Helicobacter. 2015;20(3):192–198. 10.1111/hel.12193 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Matsuda T, Saika K. Cancer burden in Japan based on the latest cancer statistics: need for evidence-based cancer control programs. Ann Cancer Epidemiol. 2018;2. 10.21037/ace.2018.08.01 [DOI] [Google Scholar]
  • 6.Inoue M, Tsugane S. Epidemiology of gastric cancer in Japan. Postgrad Med J. 2005;81(957):419–424. 10.1136/pgmj.2004.029330 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Fukase K, Kato M, Kikuchi S, et al. ; Japan Gast Study Group . Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet. 2008;372(9636):392–397. 10.1016/S0140-6736(08)61159-9 [DOI] [PubMed] [Google Scholar]
  • 8.Li WQ, Ma JL, Zhang L, et al. Effects of Helicobacter pylori treatment on gastric cancer incidence and mortality in subgroups. J Natl Cancer Inst. 2014;106(7):dju116. 10.1093/jnci/dju116 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Chen HN, Wang Z, Li X, Zhou ZG. Helicobacter pylori eradication cannot reduce the risk of gastric cancer in patients with intestinal metaplasia and dysplasia: evidence from a meta-analysis. Gastric Cancer. 2016;19(1):166–175. 10.1007/s10120-015-0462-7 [DOI] [PubMed] [Google Scholar]
  • 10.Ford AC, Forman D, Hunt RH, Yuan Y, Moayyedi P. Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals: systematic review and meta-analysis of randomised controlled trials. BMJ. 2014;348:g3174. 10.1136/bmj.g3174 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Jung DH, Kim JH, Chung HS, et al. Helicobacter pylori eradication on the prevention of metachronous lesions after endoscopic resection of gastric neoplasm: a meta-analysis. PLoS One. 2015;10(4):e0124725. 10.1371/journal.pone.0124725 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Kim N, Park RY, Cho SI, et al. Helicobacter pylori infection and development of gastric cancer in Korea: long-term follow-up. J Clin Gastroenterol. 2008;42(5):448–454. 10.1097/MCG.0b013e318046eac3 [DOI] [PubMed] [Google Scholar]
  • 13.Lee YC, Chiang TH, Chou CK, et al. Association between Helicobacter pylori eradication and gastric cancer incidence: a systematic review and meta-analysis. Gastroenterology. 2016;150(5):1113–1124.e5. 10.1053/j.gastro.2016.01.028 [DOI] [PubMed] [Google Scholar]
  • 14.Yoon SB, Park JM, Lim CH, Cho YK, Choi MG. Effect of Helicobacter pylori eradication on metachronous gastric cancer after endoscopic resection of gastric tumors: a meta-analysis. Helicobacter. 2014;19(4):243–248. 10.1111/hel.12146 [DOI] [PubMed] [Google Scholar]
  • 15.Hiroi S, Sugano K, Tanaka S, Kawakami K. Impact of health insurance coverage for Helicobacter pylori gastritis on the trends in eradication therapy in Japan: retrospective observational study and simulation study based on real-world data. BMJ Open. 2017;7(7):e015855. 10.1136/bmjopen-2017-015855 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Tsuda M, Asaka M, Kato M, et al. Effect on Helicobacter pylori eradication therapy against gastric cancer in Japan. Helicobacter. 2017;22(5):e12415. 10.1111/hel.12415 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Sawada N, Iwasaki M, Yamaji T, et al. The Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT): Study Design and Participants. J Epidemiol. 2020;30(1):46–54. 10.2188/jea.JE20180182 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Ueda J, Okuda M, Nishiyama T, Lin Y, Fukuda Y, Kikuchi S. Diagnostic accuracy of the E-plate serum antibody test kit in detecting Helicobacter pylori infection among Japanese children. J Epidemiol. 2014;24(1):47–51. 10.2188/jea.JE20130078 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Kishikawa H, Kimura K, Takarabe S, Kaida S, Nishida J. Helicobacter pylori antibody titer and gastric cancer screening. Dis Markers. 2015;2015:156719. 10.1155/2015/156719 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Miki K, Morita M, Sasajima M, Hoshina R, Kanda E, Urita Y. Usefulness of gastric cancer screening using the serum pepsinogen test method. Am J Gastroenterol. 2003;98(4):735–739. 10.1111/j.1572-0241.2003.07410.x [DOI] [PubMed] [Google Scholar]
  • 21.Inoue M, Sawada N, Goto A, et al. ; JPHC Study Group . High-negative anti-Helicobacter pylori IgG antibody titers and long-term risk of gastric cancer: results from a large-scale population-based cohort study in Japan. Cancer Epidemiol Biomarkers Prev. 2020;29(2):420–426. 10.1158/1055-9965.EPI-19-0993 [DOI] [PubMed] [Google Scholar]
  • 22.Kishikawa H, Ojiro K, Nakamura K, et al. Previous Helicobacter pylori infection–induced atrophic gastritis: A distinct disease entity in an understudied population without a history of eradication. Helicobacter. 2020;25(1):e12669. 10.1111/hel.12669 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Ohara N. An examination of the decline in serum immunoglobulin G antibody titers after Helicobacter pylori eradication. Jpn J Helicobactor Res. 2017;19(1):43–49 (in Japanese). [Google Scholar]
  • 24.Vukadinović MV, Mihaljević I. IgG serology pattern in long-term follow-up of patients successfully treated for Helicobacter pylori eradication. Acta Med Croatica. 1999;53(4–5):185–189. [PubMed] [Google Scholar]
  • 25.Fanti L, Ieri R, Mezzi G, Testoni PA, Passaretti S, Guslandi M. Long-term follow-up and serologic assessment after triple therapy with omeprazole or lansoprazole of Helicobacter-associated duodenal ulcer. J Clin Gastroenterol. 2001;32(1):45–48. 10.1097/00004836-200101000-00011 [DOI] [PubMed] [Google Scholar]
  • 26.Lee JH, Kim N, Chung JI, et al. Long-term follow up of Helicobacter pylori IgG serology after eradication and reinfection rate of H. pylori in South Korea. Helicobacter. 2008;13(4):288–294. 10.1111/j.1523-5378.2008.00616.x [DOI] [PubMed] [Google Scholar]
  • 27.Kosunen TU, Seppälä K, Sarna S, Sipponen P. Diagnostic value of decreasing IgG, IgA, and IgM antibody titres after eradication of Helicobacter pylori. Lancet. 1992;339(8798):893–895. 10.1016/0140-6736(92)90929-W [DOI] [PubMed] [Google Scholar]
  • 28.Ando H, Kagaya T, Takemori Y, Noda Y. [Changes in serum anti-Helicobacter pylori IgG antibody, pepsinogen I, and pepsinogen II after eradication therapy of Helicobacter pylori]. Nihon Shokakibyo Gakkai Zasshi. 1997;94(11):723–729. [PubMed] [Google Scholar]
  • 29.Kim JH, Lee JS, Kwon YH, Jeon SW, Nam SY, Jin S. Changes in Helicobacter pylori immunoglobulin G levels and gastric mucosal atrophy after successful eradication of Helicobacter pylori. Korean J Helicobacter Up Gastrointest Res. 2019;19(4):291–292. 10.7704/kjhugr.2019.19.3.174.e1 [DOI] [Google Scholar]
  • 30.Matsuhisa T, Tsukui T. Follow-up study of serological anti-H. pylori IgG antibody values after the eradication treatment for Helicobacter pylori infection. Prog Dig Endosc. 2006;69(2):31–36. 10.11641/pde.69.2_31 [DOI] [Google Scholar]
  • 31.Koizumi W, Tanabe S, Imaizumi H, et al. Effect of anti-Helicobacter pylori IgG antibody titer following eradication of Helicobacter pylori infection. Hepatogastroenterology. 2003;50(49):293–296. [PubMed] [Google Scholar]
  • 32.Marchildon P, Balaban DH, Sue M, et al. Usefulness of serological IgG antibody determinations for confirming eradication of Helicobacter pylori infection. Am J Gastroenterol. 1999;94(8):2105–2108. 10.1111/j.1572-0241.1999.01285.x [DOI] [PubMed] [Google Scholar]
  • 33.Shirai T, Kurumada T, Kouda K, et al. [Long-term endoscopic follow-up for peptic ulcer patients after eradication of H. pylori; comparison with the maintainance therapy by H2-blocker]. Nihon Rinsho. 1999;57(1):157–161. [PubMed] [Google Scholar]
  • 34.Uno A, Nakajima N, Iwasaki A, Arakawa Y. Changes in the serum level of pepsinogen and titers of Helicobacter pylori IgG antibody after eradication therapy in patients with peptic ulcer. J Nihon Univ Med Ass. 2007;66(3):261–266. [Google Scholar]
  • 35.Ito T, Kobayashi D, Uchida K, et al. Helicobacter pylori invades the gastric mucosa and translocates to the gastric lymph nodes. Lab Invest. 2008;88(6):664–681. 10.1038/labinvest.2008.33 [DOI] [PubMed] [Google Scholar]
  • 36.Wang T, Zhang Y, Su H, et al. Helicobacter pylori antibody responses in association with eradication outcome and recurrence: a population-based intervention trial with 7.3-year follow-up in China. Chin J Cancer Res. 2017;29(2):127–136. 10.21147/j.issn.1000-9604.2017.02.05 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Murakami K, Sakurai Y, Shiino M, Funao N, Nishimura A, Asaka M. Vonoprazan, a novel potassium-competitive acid blocker, as a component of first-line and second-line triple therapy for Helicobacter pylori eradication: a phase III, randomised, double-blind study. Gut. 2016;65(9):1439–1446. 10.1136/gutjnl-2015-311304 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Asaoka D, Nagahara A, Matsuhisa T, et al. Trends of second-line eradication therapy for Helicobacter pylori in Japan: a multicenter study in the Tokyo metropolitan area. Helicobacter. 2013;18(6):468–472. 10.1111/hel.12063 [DOI] [PubMed] [Google Scholar]
  • 39.Matsuhisa T, Kawai T, Masaoka T, et al. Efficacy of metronidazole as second-line drug for the treatment of Helicobacter pylori Infection in the Japanese population: a multicenter study in the Tokyo Metropolitan Area. Helicobacter. 2006;11(3):152–158. 10.1111/j.1523-5378.2006.00394.x [DOI] [PubMed] [Google Scholar]
  • 40.Sugano K, Osawa H, Satoh K. Clinical Management of Helicobacter pylori - The Japanese Perspective. Dig Dis. 2014;32(3):281–289. 10.1159/000357859 [DOI] [PubMed] [Google Scholar]
  • 41.Asaka M, Mabe K, Matsushima R, Tsuda M. Helicobacter pylori eradication to eliminate gastric cancer: the Japanese strategy. Gastroenterol Clin North Am. 2015;44(3):639–648. 10.1016/j.gtc.2015.05.010 [DOI] [PubMed] [Google Scholar]
  • 42.Take S, Mizuno M, Ishiki K, et al. Reinfection rate of Helicobacter pylori after eradication treatment: a long-term prospective study in Japan. J Gastroenterol. 2012;47(6):641–646. 10.1007/s00535-012-0536-9 [DOI] [PubMed] [Google Scholar]
  • 43.Okimoto T, Murakami K, Sato R, et al. Is the recurrence of Helicobacter pylori infection after eradication therapy resultant from recrudescence or reinfection, in Japan. Helicobacter. 2003;8(3):186–191. 10.1046/j.1523-5378.2003.00143.x [DOI] [PubMed] [Google Scholar]
  • 44.Cave DR. How is Helicobacter pylori transmitted? Gastroenterology. 1997;113(6 Suppl):S9–S14. 10.1016/S0016-5085(97)80004-2 [DOI] [PubMed] [Google Scholar]
  • 45.Kobayashi I, Murakami K, Kato M, et al. Changing antimicrobial susceptibility epidemiology of Helicobacter pylori strains in Japan between 2002 and 2005. J Clin Microbiol. 2007;45(12):4006–4010. 10.1128/JCM.00740-07 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Wermeille J, Cunningham M, Dederding JP, et al. Failure of Helicobacter pylori eradication: is poor compliance the main cause? Gastroenterol Clin Biol. 2002;26(3):216–219. [PubMed] [Google Scholar]
  • 47.Cutler AF, Prasad VM, Santogade P. Four-year trends in Helicobacter pylori IgG serology following successful eradication. Am J Med. 1998;105(1):18–20. 10.1016/S0002-9343(98)00134-X [DOI] [PubMed] [Google Scholar]
  • 48.Kato M, Ota H, Okuda M, et al. Guidelines for the management of Helicobacter pylori infection in Japan: 2016 Revised Edition. Helicobacter. 2019;24(4):e12597. 10.1111/hel.12597 [DOI] [PubMed] [Google Scholar]
  • 49.Deguchi H, Uda A, Murakami K. Current status of Helicobacter pylori diagnosis and eradication therapy in Japan using a nationwide database. Digestion. 2020;101(4):441–449. 10.1159/000500819 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Veijola L, Oksanen A, Linnala A, Sipponen P, Rautelin H. Persisting chronic gastritis and elevated Helicobacter pylori antibodies after successful eradication therapy. Helicobacter. 2007;12(6):605–608. 10.1111/j.1523-5378.2007.00549.x [DOI] [PubMed] [Google Scholar]
  • 51.Kodama M, Okimoto T, Mizukami K, et al. Differences in Helicobacter pylori and CagA antibody changes after eradication between subjects developing and not developing gastric cancer. J Clin Biochem Nutr. 2019;65(1):71–75. 10.3164/jcbn.19-30 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Pimanov SI, Makarenko EV, Voropaeva AV, Matveenko ME, Voropaev EV. Helicobacter pylori eradication improves gastric histology and decreases serum gastrin, pepsinogen I and pepsinogen II levels in patients with duodenal ulcer. J Gastroenterol Hepatol. 2008;23(11):1666–1671. 10.1111/j.1440-1746.2007.04983.x [DOI] [PubMed] [Google Scholar]
  • 53.Dinis-Ribeiro M, Areia M, de Vries AC, et al. ; European Society of Gastrointestinal Endoscopy; European Helicobacter Study Group; European Society of Pathology; Sociedade Portuguesa de Endoscopia Digestiva . Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). Endoscopy. 2012;44(1):74–94. 10.1055/s-0031-1291491 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Kokkola A, Kosunen TU, Puolakkainen P, et al. Spontaneous disappearance of Helicobacter pylori antibodies in patients with advanced atrophic corpus gastritis. APMIS. 2003;111(6):619–624. 10.1034/j.1600-0463.2003.1110604.x [DOI] [PubMed] [Google Scholar]

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