Accepted Manuscript Global Prevalence of Helicobacter pylori Infection: Systematic Review and Metaanalysis James K.Y. Hooi, Wan Ying Lai, Wee Khoon Ng, Michael M.Y. Suen, Fox E. Underwood, Divine Tanyingoh, Peter Malfertheiner, David Y. Graham, Vincent W.S. Wong, Justin C.Y. Wu, Francis K.L. Chan, Joseph J.Y. Sung, Gilaad G. Kaplan, Siew C. Ng PII: DOI: Reference:

S0016-5085(17)35531-2 10.1053/j.gastro.2017.04.022 YGAST 61141

To appear in: Gastroenterology Accepted Date: 19 April 2017 Please cite this article as: Hooi JKY, Lai WY, Ng WK, Suen MMY, Underwood FE, Tanyingoh D, Malfertheiner P, Graham DY, Wong VWS, Wu JCY, Chan FKL, Sung JJY, Kaplan GG, Ng SC, Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-analysis, Gastroenterology (2017), doi: 10.1053/j.gastro.2017.04.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title: Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-analysis

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Short title: Helicobacter pylori global prevalence Authors: James K.Y. Hooi1,# , Wan Ying Lai1,#, Wee Khoon Ng1,2,#, Michael M.Y. Suen1,#, Fox E. Underwood3, Divine Tanyingoh3, Peter Malfertheiner4, David Y. Graham5, Vincent W.S. Wong1, Justin C.Y. Wu1, Francis K.L. Chan1, Joseph J.Y. Sung1, Gilaad G. Kaplan3,*,

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Siew C. Ng1,* #

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Co-First Authors – the authors contributed equally to this work

*Co-Senior Authors – the authors contributed equally to this work

1. Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, Chinese University of Hong Kong, Hong Kong, China

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2. Department of Gastroenterology and Hepatology, Tan Tock Seng Hospital, Singapore. 3. Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada

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4. Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke

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University of Magdeburg, Magdeburg, Germany 5. Gastroenterology, Baylor College of Medicine, Houston, Texas, United States Grant Support: Nil

Abbreviations: HP (Helicobacter pylori) Correspondence: Siew C Ng, MBBS, MRCP, PhD Department of Medicine and Therapeutics Chinese University of Hong Kong, Hong Kong 1

ACCEPTED MANUSCRIPT Tel: 852 2632 1420 Fax: 852 2637 3852 E-mail: [email protected] Gilaad G. Kaplan, MD, MPH, FRCPC

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Teaching Research and Wellness Center 3280 Hospital Drive NW, 6D17 Calgary, AB, T2N 4N1

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Tel: 1 403 592 5015

Email: [email protected]

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Fax: 1 403 592 5050

Disclosures: None of the authors have relevant conflict of interests to declare. Transcript Profiling: Nil Writing Assistance: Nil

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Authors' contribution: All authors have contributed to the study design, study identification, data collection, and manuscript revision. All authors have seen and approved the manuscript. SCN and GGK had full access to all of the data in the study and take responsibility for the

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integrity of the data and the accuracy of the data analysis. Acknowledgement: We are grateful to Haiyun Shi and Whitney Tang for their assistance in

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the initial systematic search.

Conflict of Interest Statements We declare no competing interests. Manuscript word count: 5798

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ACCEPTED MANUSCRIPT Abstract: Background & Aims: The epidemiology of Helicobacter pylori infection has changed with improvements in sanitation and methods of eradication. We performed a systematic review and meta-analysis to evaluate changes in the global prevalence of H pylori infection.

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Methods: We performed a systematic search of the MEDLINE and EMBASE databases for studies of the prevalence of H pylori infection published from January 1, 1970 through January 1, 2016. We analyzed data based on United Nations geoscheme regions and

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individual countries. We used a random effects model to calculate pooled prevalence estimates with 95% CIs, weighted by study size. We extrapolated 2015 prevalence estimates

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to obtain the estimated number of individuals with H pylori infection.

Results: Among 14,006 reports screened, we identified 263 full-text articles on the prevalence of H pylori infection; 184 were included in the final analysis, comprising data from 62 countries. Africa had the highest pooled prevalence of H pylori infection (70.1%; 95% CI

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62.6–77.7), whereas Oceania had the lowest prevalence (24.4%; 95% CI 18.5–30.4). Among individual countries, the prevalence of H pylori infection varied from as low as 18.9% in Switzerland (95% CI 13.1–24.7) to 87.7% in Nigeria (95% CI 83.1–92.2). Based on regional

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prevalence estimates, there were approximately 4.4 billion individuals with H pylori infection worldwide in 2015.

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Conclusions: In a systematic review and meta-analysis to assess the prevalence of H pylori infection worldwide, we observed large amounts of variation among regions—more than half the world’s population is infected. These data can be used in development of customized strategies for the global eradication. Keywords: bacteria, incidence, Europe, stomach Word Count = 266

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ACCEPTED MANUSCRIPT Impact Summaries Background and context: A significant proportion of the world’s population is infected with Helicobacter pylori (HP), but global and regional prevalence is not well known, though it varies from low levels in highly

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industrialized countries of the West to high levels in developing countries in Africa. Despite the prevalence of HP infection decreasing globally, it remains high in many countries.

Numerous population-based studies have reported the prevalence of HP. We conducted a

global prevalence of HP in the 21st century.

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New findings:

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systematic review of MEDLINE and EMBASE from 1 Jan 1970 to 1 Jan 2016 to examine the

To our knowledge, this is the first study to report the prevalence of HP worldwide. Our study provides a comprehensive systematic review of population-based prevalence studies of HP. This systematic review identified 184 population-based prevalence studies of HP since 1 Jan

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1970. The prevalence of HP varies based on time periods and geography. Overall, HP prevalence is decreasing in developed countries and in some developing countries. We also highlighted the areas with the highest HP burden.

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Limitations:

Main limitation of this systematic review contains reports from only 62 out of 196 countries

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globally, with data lacking in several developing countries. Reports were also conducted at different time periods, with several countries lacking recent data, limiting accuracy for inter-region comparison. For some reports, only selected areas of countries were sampled instead of the entire country (i.e. sub-national level), limiting its accuracy to reflect the country’s true prevalence. Impact: This review suggests that approximately 4.4 billion individuals are colonized with HP. These individuals are at risk for peptic ulcer disease and gastric cancer. Despite reduction in HP 4

ACCEPTED MANUSCRIPT prevalence in many developed countries, the trend appears to have plateaued. Our data can be used to prioritize public health efforts in countries with the highest prevalence of HP to

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reduce the sequalae associated with infection by HP.

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ACCEPTED MANUSCRIPT Introduction Helicobacter pylori (HP) is a gram-negative microaerophilic bacterium that infects the epithelial lining of the stomach. The discovery of HP as a cause of peptic ulcer disease in 1983 resulted in a change of what was once a difficult and debilitating disease into one that

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could be reliably cured with a course of antibiotics, albeit with escalating concerns due to mounting antibiotic resistance.1-3 In many countries, the incidence of HP infection has been decreasing in association with improved standards of living.4,5 Yet the prevalence of this

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bacterium is still ubiquitous, especially in the Far East.4 It is the main cause of chronic

gastritis and the principal etiological agent for gastric cancer and peptic ulcer disease.2,6 In

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most regions, the main mechanism of spread is intra-familial transmission.7 The prevalence remains high in most developing countries and is generally related to socioeconomic status and levels of hygiene. Global and regional HP prevalence has not been systematically reported until now.

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Recent interest has focused on HP eradication as a strategy of eliminating gastric cancer. However, the epidemiology and clinical manifestations of the infection has been changing, especially in developed countries. For example, gastric cancer and peptic ulcer incidence has

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continued to fall in Western Europe, the United States, and Japan. Global eradication

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strategies require up-to-date information regarding HP prevalence and disease burden.

We performed a systematic review of population-based studies reporting HP prevalence of different countries over different time periods, with the premise that these data would provide crucial updates regarding HP global disease burden and the information to plan appropriate strategies for allocating healthcare resources. We pooled HP prevalence estimates in different regions and countries, examined the trend in HP prevalence over the past four decades, and estimated the number of people infected with HP globally. Understanding the

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ACCEPTED MANUSCRIPT global epidemiologic patterns of HP will aid us in prioritizing and customizing public health efforts to better manage the burden of this disease.

Literature Search and Study Selection

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MATERIALS AND METHODS

This systematic review was performed in accordance to the PRISMA 2009 guidelines.8 A search using keywords from a combination of Medical Subject Headings (MeSH) and free

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text including terms related to HP and prevalence was performed in MEDLINE (R) and

EMBASE via OvidSP. All suitable published papers from 1 Jan 1970 to 1 Jan 2016 were

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identified and subsequently catalogued using EndNote X7. The search strategy is described in Appendix 1.

Comprehensive inclusion and exclusion criteria were predefined (Table 1) to facilitate

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objective screening of papers. Only published original observational reports on the prevalence of HP in study populations that were reflective of the general population at national or sub-national levels were included. Systematic reviews, meta-analyses,

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conference presentations, and letters or correspondences were excluded. Suitable reports identified in hand searches were also included for review. Reports that focused only on

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specific sub-groups that were not reflective of the general population were excluded (e.g. migrants and prisoners). The first phase involved a group of three reviewers (J.H., W.Y.L., and M.S.) who independently catalogued all reports using the set criteria. Outcome of this initial categorization was then cross checked by a different reviewer within this group to ensure its accuracy with a 90% level of agreement. In the second phase, full text papers were obtained for all identified potential reports for detailed analysis of inclusion suitability. All conflicts of opinion and uncertainties were discussed and resolved by consensus with third party reviewers (W.K.N., W.T., and S.C.N.). The search was not limited by language. Reports 7

ACCEPTED MANUSCRIPT written neither in English nor Chinese had been translated by Google Translate or by colleagues proficient in that language for evaluation of their suitability. Attempts were also made to clarify with the correspondence authors regarding any uncertainties or missing data (e.g. study periods not explicitly stated) in selected reports. The reports were then grouped by

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countries and subsequently into regions based on the United Nations geoscheme devised by the United Nations Statistics Division (UNSD).9 Figure 1 details the process of report

Data Extraction and Quality Appraisal

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selection.

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Full text review was performed for all the selected papers and data extracted and sorted into the following variables: name of study, leading author, journal, publication year, study period, type of study, study location (country and sub-national region), HP diagnostic methods used, participant details (number, age, gender ratio), total number of participants, number of HP

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positive participants, and HP crude prevalence rate. Data on prevalence as a percent of the number of HP positive participants relative to total number tested were recorded or calculated with 95% confidence intervals. Papers with missing data, despite attempts to contact the

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correspondence authors, were excluded. The quality of the remaining papers was rated with the Cochrane Collaboration-endorsed Newcastle-Ottawa Quality Assessment Scale (NOS),10

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which was designed to assess aspects of population-based studies of prevalence. The quality assessment of each paper is shown in Appendix 2.

Summarization of Data HP prevalence for each country was estimated by pooling the data from eligible papers. We used a random effects model to calculate pooled prevalence estimates with 95% CIs. Heterogeneity was assessed using the I2 measure and the Cochran Q-statistic. The following stratified analyses were conducted to address sources of heterogeneity: (a) geographic 8

ACCEPTED MANUSCRIPT region based on classification by UN; (b) time period of evaluating prevalence of HP split into 1970 to 1999 and 2000 to 2016; (c) restricting analysis to adult only (age ≥ 18 years); and (d) primary modality of testing HP including serology, urea breath test, stool antigen, CLO or histopathology, and serology or urea breath test.

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The prevalence data were grouped by geographic region based on the UN geoscheme: Northern America, Latin America and the Caribbean, Europe (Northern, Southern, Western, Eastern), Africa, Asia (Central, Eastern, Southern, South-Eastern, Western), and Oceania.

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Reports that focused on the indigenous population in the United States and Australia were separately analyzed from the respective general population of the country. When prevalence

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was reported for a multi-year period that extended over more than one time period, the study was included in the time period that captured the most updated data. If multiple studies reported prevalence for the same country and time period, the pooled estimate was taken.11 Quartiles of prevalence data were used to create choropleth maps. Next, we created a

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web-based interactive map to display comments associated with the prevalence of HP for each country. The static and interactive maps were created using QGIS 2.16.312 with the HTML Image Map Plugin13 for the interactive map. The geographic data were created by the

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Natural Earth Community.14

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Population-based studies that reported HP prevalence with two or more time points for the same country were included for temporal trend analyses. For the assessment of potential changes of HP prevalence over time, we stratified prevalence estimates into two time periods, 1970–1999 and 2000–2016. To obtain the number of people affected with HP, we extrapolated our prevalence estimates to the total 2015 population living in countries and regions as per the UN Population Division. We assumed that countries with missing data in a region had comparable prevalence to our pooled average prevalence. R Studio Version 0.99.903 was used for statistical analysis. The R-metafor package was 9

ACCEPTED MANUSCRIPT used to generate 95% confidence intervals from logistic regression models then converted to prevalence using the expit transformation. The results of the pooled prevalence estimates were then organized by geographical region.

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Role of funding source

There was no funding source for this study. The corresponding authors had full access to all

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data in the study and had final responsibility for the decision to submit for publication.

Results

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A total of 14,006 records were identified from both databases, of which 6,188 records were duplicates, 7,611 records were excluded based on selection criteria, 22 records were removed due to inaccessible full text, and 3 records could not be translated for review (Figure 1). Two records were found in hand searches, and a total of 184 papers were included after

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full text review (11 from Africa, 75 from Asia, 66 from Europe, 13 from Latin America and Caribbean, 13 from Northern America, and 6 from Oceania), reporting HP prevalence in 62 countries with 257,768 (48.5%) participants tested HP positive, out of a total of 531,880

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participants. The countries with the highest number of reports were China (n=21), Korea (n=12), Japan (n=11), United States (US) (n=10), Germany (n=8) and Iran (n=8). A summary

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of the distribution of papers by regions is shown in Appendix 3 and details of individual papers (including age range, gender, and methods to diagnose HP) in Appendix 4 and Appendix 5.

Prevalence of HP in the indigenous population of the US and Australia was higher than the general population. In Australia, the pooled HP prevalence estimate for the general population was 24.6% (95% CI 17.2–32.1), but was as high as 76.0% (95% CI 72.3–79.6) in the rural Western Australian indigenous community. In the US, the pooled HP prevalence 10

ACCEPTED MANUSCRIPT estimate for the general population was 35.6% (95% CI 30.0–41.1), but it was 74.8% (72.9–76.7) in the Alaskan indigenous population. The countries with the highest HP burden were Nigeria (87.7%, 95% CI 83.1–92.2), Portugal (86.4%, 95% CI 84.9–87.9), Estonia (82.5%, 95% CI 75.1–90.0), Kazakhstan (79.5%, 95% CI 74.9–84.2) and Pakistan (81.0%,

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95% CI 75.6–86.4). Countries with the lowest HP prevalence were Switzerland (18.9%, 95% CI 13.1–24.7), Denmark (22.1%, 95% CI 17.8–26.5), New Zealand (24.0%, 95% CI

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21.4–26.5), Australia (24.6%, 95% CI 17.2–32.1), and Sweden (26.2%, 95% CI 18.3–34.1).

Regions with the highest reported HP prevalence were Africa (70.1%, 95% CI 62.6–77.6),

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South America (69.4%, 95% CI 63.9–74.9), and Western Asia (66.6%, 95% CI 56.1–77.0). Regions with the lowest reported HP prevalence were Oceania (24.4%, 95% CI 18.5–30.4), Western Europe (34.3%, 95% CI 31.3–37.2), and Northern America (37.1%, 95% CI 32.3–41.9). HP prevalence and the number of people with HP living in the general population

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in the six UN regions were reported in Tables 2 and 3. Forest plots of pooled HP prevalence stratified by country and UN region are shown in Appendix 6. Significant heterogeneity was observed for pooled analyses in each region (Appendix 6). In order to assess potential

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sources of heterogeneity, pooled prevalence was stratified by modality of testing for HP

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(Appendix 7) and adult-only studies (Appendix 8).

Two time periods (1970–1999 and 2000–2016) were used to analyze the HP prevalence trend with time. HP prevalence after 2000 was lower than before in Europe from 48.8% (95% CI 39.4–58.2) to 39.8% (95% CI 34.2–45.3), Northern America 42.7% (95% CI 32.7–52.6) to 26.6% (95% CI 19.0–34.1), and Oceania 26.6% (95% CI 20.4–32.8) to 18.7% (95% CI 11.6–25.7). In contrast, the prevalence of HP positivity was similar in Asia (53.6% before 2000 vs. 54.3% after 2000), and Latin America and the Caribbean (62.8% before 2000 vs. 60.2% after 2000). Summary of the time trend prevalence for each country and region is 11

ACCEPTED MANUSCRIPT shown in Appendix 9. After extrapolation to the 2015 world population, 4.4 billion individuals were estimated to be HP positive globally (Table 3).

Discussion

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HP infection continues to be a major public health issue worldwide. This global systematic review shows that approximately 4.4 billion individuals in 2015 worldwide were estimated to be positive for HP. This is the most comprehensive and up-to-date systematic review of the

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worldwide prevalence of HP. We confirmed a wide variation in the prevalence of HP between regions and countries. Prevalence is highest in Africa (79.1%), Latin America and the

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Caribbean (63.4%), and Asia (54.7%). In contrast, HP prevalence is lowest in Northern America (37.1%) and Oceania (24.4%). At the turn of the 21st century the prevalence of HP has been declining in highly industrialized countries of the Western world, whereas prevalence has plateaued at a high level in developing and newly industrialized countries. The widening

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differential gap in prevalence has important implications on the future worldwide prevalence of sequalae associated with HP, including peptic ulcer disease and gastric cancer. These differences in HP prevalence likely reflect the level of urbanization, sanitation, access to

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clean water, and varied socioeconomic status. There are significant differences in the HP prevalence even within the same country. Different racial groups in the United States have

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different HP prevalence. It was reported that the prevalence in non-Hispanic whites ranges from 18.4% to 26.2% and that in non-whites ranges from 34.5% to 61.6%.15,16 Prevalence can be as high as 75.0% in the Alaskan Native population.17

Our review demonstrated that there is still a significant burden of HP in most of the world. Even in Switzerland, which had the lowest reported HP prevalence (18.9%), there were still approximately 1.6 million infected individuals. Eradication of gastric cancer will thus require further efforts and research focused on prevention of HP acquisition and HP eradication. 12

ACCEPTED MANUSCRIPT Innovative strategies will likely be needed to reduce HP prevalence in areas such as Africa, India, and South America, whereby access to healthcare and resources may be limited.

HP has been identified as a Group I carcinogen by the International Agency for Research on

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Cancer (IARC) and currently is considered a necessary but insufficient cause of gastric

adenocarcinoma.18-22 Approximately 89% of all gastric cancers can be attributable to HP infection.23 Gastric cancer remains the third most common cancer worldwide with more than

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half coming from China, Japan, and Korea. Prognosis is poor with only one in five patients surviving longer than five years after diagnosis. HP eradication has been associated with a

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reduction of gastric cancer incidence and this benefit is present irrespective of risk group.24-26 There is also evidence that screening and eradication of HP in young adults in China would be cost-effective and could help in preventing one gastric cancer in every four to six cases.26 The appropriate strategy may differ between countries and is further complicated by

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increasing antibiotic resistance, which could prove to be a major hindrance to eradication. Increasing prophylactic HP vaccination appears to be an option.27 The development of HP vaccine has been challenging, but there is yet to be an effective vaccine available in the

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market. One promising phase III trial of an oral vaccine in China has demonstrated vaccine-mediated protection against HP, leading to a reduced risk of HP acquisition amongst

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the younger population.28 The high global prevalence of HP in many parts of the world and the non-diminishing HP prevalence in developed countries should serve as the impetus for researchers to hasten the process to create an effective vaccine. Of interest, HP vaccination has also been demonstrated to be cost effective in US, which has one of the lowest HP prevalence globally.29

In Africa, despite the high HP prevalence, the reported incidence of gastric cancer was considerably lower compared to China or Japan and was postulated to be related to the 13

ACCEPTED MANUSCRIPT predominant non-atrophic gastritis pattern in Africa; the archetypal hpAfrica2 type strain largely restricted in South Africa, which lacks cag A pathogenicity island; and lastly intestinal parasitic infestation modulating the immune response against HP towards a Th2 type (anti-inflammatory), which may reduce risk of gastric cancer.30,31 The now defunct

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phenomenon known as ‘African Enigma’ was attributed to the inadequate sampling of the African population obtained through endoscopic data, limited access to health care, and a relatively short life expectancy in the population. More recent and robust data on the African

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gastric ulcer and cancer prevalence confirmed that it is not as low as previously reported.32 Ongoing efforts to monitor HP prevalence and its disease burden in a systematic manner is

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crucial, as it will minimize any skewed data, which may adversely affect the allocation of healthcare resources.

As has been reported in the literature, our review observed that HP prevalence is lower in

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certain ethnic groups, like Malay, despite having the similar environmental exposures as other ethnic groups.4 Malaysia’s population consisted of approximately 67.4% Malays33 and has a low pooled HP prevalence of 28.6%. Among the varied ethnicities in Malaysia, the

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prevalence of HP in Malays is 19.6%, which is significantly lower than the Chinese (40.0%) and Indians (50.7%).34 Besides Malaysia, the Malays in Singapore also had a low HP

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prevalence of 25.0%.35 Of interest, the age-standardized rate of gastric cancer is 1.7 per 100,000 in Malay males, 1.1 per 100,000 in Malay females, compared to 5.6 per 100,000 in Chinese males and 4.1 per 100,000 in Chinese females.36 The reasons for a lower prevalence in Malays and some other ethnic groups need to be further investigated, while genetic factors and environmental factors also must be evaluated. Additionally, indigenous populations in developed countries have much higher HP prevalence. For example, Alaskan Natives in the US had a HP prevalence of 75.0%,17 while the Martu community in Western Australia had a prevalence of 91.0%.37 These differences likely reflect the disparity in care, 14

ACCEPTED MANUSCRIPT reduced sanitation, and lower socioeconomic status that is observed in indigenous populations.

This study has several strengths. It is one of the most comprehensive and up-to-date reviews

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on the evolution of the global epidemiology of HP in the 21st century. We included only

population-based data, which limited selection bias. Secondly, we pooled data to highlight differences within and between different regions around the world. Recent declines in HP

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prevalence – particularly in more industrialized nations such as the United States of America, China, and Japan – are likely due to rising standards of living, and improved sanitation.

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However, the cohort effect associated with these changes has become gradually less important for consequent stabilization of the prevalence. What remains unclear is whether the prevalence of HP will continue to drop or remain static. Regardless, surveillance cohorts that track disease burden and preventive strategies are paramount to discovering or confirming

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suspected environmental factors.

This paper has some limitations. This systematic review contains reports from only 62 out of

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196 countries globally. Reports were also conducted at different time periods, with several countries lacking recent data, limiting accuracy for inter-region comparison. HP prevalence is

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generally higher in developing countries, yet reports for many developing countries are not available. For some reports, only selected areas of countries were sampled instead of the entire country (i.e. sub-national level), limiting its accuracy to reflect the country’s true prevalence. We assumed that countries with missing data in a region have comparable prevalence to our pooled average prevalence. Future studies are necessary in areas lacking prevalence to HP to confirm our estimates. Also, our pooled analyses demonstrated significant heterogeneity. We explored some sources of heterogeneity including age, geographic region, time period, and modality of testing. However, a comprehensive 15

ACCEPTED MANUSCRIPT evaluation of heterogeneity was limited by the information available in the primary studies. As well, HP is not a notifiable disease in many countries and its prevalence is mainly derived from willing participants of population-based studies. It is likely these reports may underestimate the true prevalence, especially in areas with poorer access to healthcare

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facilities. HP is also usually not routinely included in health screening, reducing the chance of identifying this disease in the general population. Furthermore, the reports used different methods and assays for the diagnosis of HP, with different sensitivities and specificities,

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which may limit the accuracy of inter-region comparison. Additionally, an underestimation of the lifetime prevalence may occur in older subjects, as infection tends to disappear with the

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progression of gastric lesions caused by the HP, resulting in a decline in the circulating IgG titers. Despite these limitations, IgG serology was commonly used as it is a relatively simple, less invasive and convenient method to screen large populations. In the developing world, defining HP prevalence is considerably more challenging because many countries lack

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healthcare systems that compile outcomes into population-based registries.

Thus, prevalence rates reported are likely to be underestimated in studies published early in

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the observation period and in developing countries. This may explain why HP prevalence seemed to have remained stable in parts of Asia and Latin America, and the Caribbean when

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compared to the developed areas in Europe, North America, and Oceania, due to better diagnostics but also a declining HP prevalence. HP prevalence is related to the acquisition rate in children, which is related to sanitation and clean water. Despite rapidly falling pediatric HP prevalence in China, Korea, and Japan, HP prevalence remained relatively stable artefactually due to the mixed populations, which will take decades to demonstrate a significant change in rate. Lastly, most primary studies lacked key covariates to conduct regression models to evaluate for any additional factors significantly associated with HP prevalence. 16

ACCEPTED MANUSCRIPT Despite these limitations, this systematic review provides a comprehensive overview of the prevalence of HP. Variation in prevalence of HP observed in different geographic areas and across time suggests that prevalence is influenced by living conditions such as hygiene status and industrialization of society. Consequently, these data can be used to support

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regional initiatives to prevent and eradicate HP, with the goal of reducing the complications of

Figures: Figure 1: Flowchart of study selection

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HP.

Figure 2: Global prevalence of Helicobacter pylori choropleth map. The online interactive global map showing the HP prevalence can be found at the following URL:

Tables:

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https://people.ucalgary.ca/~ggkaplan/HP2016.html

Table 1: Study selection criteria

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Table 2: HP prevalence and number of people living with HP in the general population within

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each country grouped by UN regions Table 3: HP prevalence and number of people living with HP in general population in the UN regions

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Figure 1: Flowchart of study selection

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Figure 2: Global prevalence of Helicobacter pylori (Interactive Map: https://people.ucalgary.ca/~ggkaplan/HP2016.html)

Certain regions are magnified to display the smaller countries better.

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ACCEPTED MANUSCRIPT Tables: Table 1: Study Selection Criteria Selection, grading, and clarification of studies HP diagnosis must be confirmed by either one of the following tests: HP serology, HP stool

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antigen, urea breath test, biopsies for Campylobacter-like organism (CLO) test, rapid urease

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test, histology, or culture ●

The study participants must be reflective of the general population in the region

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Data from multicentre and multinational studies were extracted separately and sorted by countries and regions

Studies were classified as national (if stated in the report or multicentre study involving multiple

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regions in the country), sub-national (if only a particular region was evaluated), and city level Clarifications with the corresponding authors of studies with missing data were made if possible

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(e.g. without specified HP diagnostic method or study period)

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Attempts were made to rectify any data errors found in the studies, in consultation with the

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corresponding authors whenever possible Exclusion criteria Publication Type Guidelines

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Perspectives, correspondence, letters

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Conference abstract or presentation without formal publication

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Systematic reviews or meta-analyses

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Surveillance registration or national notifiable disease reports of Helicobacter Pylori

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Studies without defined study periods

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Study Type Economic analyses

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Modelling, time series, or transmission studies; mortality or survival analyses; diagnostic assay

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or test performance studies; animal studies Study Population ●

Study populations that are typically associated with higher prevalence of HP (e.g. patients with

gastric cancer, peptic ulcers)

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High-risk population groups (migrants, refugees, prisoners, individuals [groups] classified as low

socio-economic status, homeless people, adoptees)

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Study participants that were restricted to selected age groups (e.g. children, elderly)

Testing ●

HP diagnosis made from methods other than the four conventional tests stated above

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Studies not reporting the method of HP diagnosis

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Self-reported HP infection

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Studies not reporting the number of individuals on which the prevalence estimate was based 20

ACCEPTED MANUSCRIPT Table 2: HP prevalence and number of people living with HP in the general population within each country grouped by UN regions Number of

Number of

Prevalence estimates

reporting studies

participants

(%, 95% CI)

Population size

HP-positive

per country*

population

8 056 640

UN African region 1

446

74.1 (70.0–78.1)

10 880 000

Burkina Faso

1

188

46.8 (39.7–53.9)

18 106 000

8 475 419

Democratic Republic of Congo

1

133

77.4 (70.3–84.6)

77 267 000

59 835 565

Egypt

1

200

40.9 (15.4–66.4)

91 508 000

37 435 923

Libya

1

360

76.4 (72.0–80.8)

6 278 000

4 795 764

Nigeria

2

648

87.7 (83.1–92.2)

182 202 000

159 700 053

South Africa

2

1 539

77.6 (59.8–95.5)

54 490 000

42 306 036

Tunisia

2

348

72.8 (53.7–91.9)

11 254 000

8 191 787

21 313 405

UN Latin American and Caribbean region

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Benin

1

493

49.1 (44.7–53.5)

43 417 000

Bahamas

1

204

57.8 (51.1–64.6)

388 000

224 419

Brazil

6

2 937

71.2 (66.0–76.4)

207 848 000

147 946 206

Chile

1

2 615

74.6 (72.9–76.2)

17 948 000

13 383 824

Ecuador

1

90

72.2 (63.0–81.5)

16 144 000

11 659 197

Guadeloupe^

1

854

49.0 (35.3–62.8)

468 000

229 367

Mexico

2

11 820

52.5 (24.7–80.3)

127 017 000

66 709 328

Panama

1

74

54.1 (42.7–65.4)

3 929 000

2 123 625

13 646 418

Canada

1

Greenland

2

United States of America+

8

UN Asian region

M AN U

UN Northern American region

SC

Argentina

316

38.0 (32.6–43.3)

35 940 000

756

41.4 (37.9– 44.9)

56 000

23 178

16 235

35.6 (30.0–41.1)

321 774 000

114 455 012

79.5 (74.9–84.2)

17 625 000

14 013 638

Central Asia (n=1)

Kazakhstan

1

288

Eastern Asia (n=47)

22

103 128

55.8 (51.8–59.9)

1 376 049 000

768 110 552

Japan

11

48 979

51.7 (44.7–58.7)

126 573 000

65 387 612

11

121 493

54.0 (50.1–57.8)

25 155 000

13 571 123

3

10 616

53.9 (36.6–71.2)

23 381 000

12 600 021

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China

Korea Taiwan

Southern Asia (n=13)

Iran India

5 256

59.0 (51.5–66.5)

79 109 000

46 658 488

2

407

63.5 (53.4–73.5)

1 311 051 000

831 861 860

1

308

52.0 (46.4–47.5)

5 851 000

3 039 595

383

70.1 (65.9–75.1)

28514 000

19 974 057

205

81.0 (75.6–86.4)

1 88 925 000

152 991 465

EP

Lebanon

8

Nepal

1

Pakistan

1

3

9 168

28.6 (19.0–38.2)

30 331 000

8 677 699

Singapore

2

953

40.8 (37.7–43.9)

5 604 000

2 287 553

Thailand

1

179

43.6 (36.3–50.8)

67 959 000

29 616 532

2

1 241

70.3 (63.3–77.4)

93 448 000

65 712 634

Vietnam

Israel Oman

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South–Eastern Asia (n=8)

Western Asia (n=8) 2

688

68.9 (62.7–75.1)

8 064 000

5 555 290

2

499

49.1 (11.5–86.7)

4 491 000

2 205 081

Saudi Arabia

1

364

65.9 (61.1–70.8)

31 540 000

20 794 322

Turkey

3

6 036

77.2 (71.4–83.1)

78 666 000

60 761 618

UN European region Eastern Europe (n= 10) Czech Republic

3

4 644

41.2 (24.8–57.6)

10 543 000

4 342 662

Poland

3

7 806

66.6 (56.4–76.7)

38 612 000

25 707 870

Romania

1

960

68.5 (65.6–71.5)

19 511 000

13 372 839

Russian Federation

3

4 771

78.5 (67.1–89.9)

143 457 000

112 585 054

Denmark

2

22.1 (17.8–26.5)

5 669 000

1 254 550

Northern Europe (n = 22) 37 741

21

ACCEPTED MANUSCRIPT Estonia

2

2 198

82.5 (75.1–90.0)

1 313 000

1 083 356

Finland

1

896

56.8 (46.5–67.0)

5 503 000

3 124 603

Iceland

2

834

36.0 (32.7–39.2)

329 000

118 341

Ireland

1

1 000

43.0 (39.9–46.1)

4 688 000

2 015 840 1 561 229

Latvia

1

3 564

79.2 (77.9–80.5)

1 971 000

Norway

3

4 068

30.7 (20.5–40.8)

5 211 000

1 597 172

Sweden

5

7 149

26.2 (18.3–34.1)

9 779 000

2 563 076

United Kingdom

5

15 098

35.5 (14.5–56.5)

64 716 000

22 974 180

Southern Europe (n= 22) 1

101

53.5 (43.7–63.2)

Croatia

3

6 538

52.7 (42.5–62.8)

Greece

3

1 571

52.1 (40.2–64.0)

10 955 000

5 708 651

Italy

5

9 055

56.2 (46.9–65.4)

59 798 000

33 606 476

Portugal

1

2 067

86.4 (84.9–87.9)

10 350 000

8 942 400

San Marino

2

3 765

47.5 (40.5–54.5)

32 000

15 200

Spain

7

2 721

54.9 (48.6–61.1)

46 122 000

25 307 141

Belgium

3

27 845

32.7 (22.4–43.0)

11 299 000

3 694 773

France#

1

64

46.9 (34.7–59.1)

64 395 000

30 188 376

Germany

8

19 015

35.3 (31.2–39.4)

80 689 000

28 483 217

Netherlands

3

8 592

35.5 (30.1–41.0)

16 925 000

6 011 760

Switzerland

1

18.9 (13.1–24.7)

8 299 000

1 565 191

4 485

24.6 (17.2–32.1)

23 969 000

5 905 962

1 060

24.0 (21.4–26.5)

4 529 000

1 085 148

Australia+

4

New Zealand

1

M AN U

UN Oceania region

SC

Western Europe (n= 16)

175

2 897 000

1 549 026

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Albania

4 240 000

2 234 056

* Based on United Nations 2015 Revision of World Population Prospects total population estimates ^

Insular region of France located in the Caribbean

Data related to the indigenous population was excluded from this table

#

Guadeloupe data not included in the pooled analysis for France due to different demographics

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Table 3: HP prevalence and number of people living with HP in the general population in the UN regions Prevalence estimates Population size per * (%, 95% CI) region / country HP-positive population (range) UN Africa region 79.1 (62.6–95.6) 1 186 178 282 938 267 021 (742 547 604 – 1 133 986 437) UN Latin American and Caribbean 63.4 (59.2–67.6) 634 386 567 402 201 083 (375 556 847 – 428 845 319) region Caribbean 52.6 (45.2–60.0) 43 199 297 22 731 470 (19 526 082 – 25 919 578) Central America 53.0 (32.6–73.5) 172 740 074 91 621 335 (56 313 264 – 126 963 954) South America 69.4 (63.9–74.9) 418 447 196 290 318 665 (267 387 758 – 313 416 949) UN Northern American region 37.1 (32.3–41.9) 357 838 036 132 614 776 (115 581 685 – 149 934 137) UN Asian region 54.7 (51.3–58.1) 4 393 296 014 2 403 132 920 (2 253 760 855 – 2 552 504 984) Central Asia 79.5 (74.9–84.2) 67 314 033 53 521 388 (50 418 210 – 56 678 415) Eastern Asia 54.1 (50.8–57.5) 1 612 286 941 872 892 150 (819 041 766 – 92 706 4991) Southern Asia 61.6 (55.9–67.4) 1 822 974 074 1 123 134 327 (1 019 042 507 – 1228 684 525) South–Eastern Asia 43.1 (31.5–54.8) 633 489 946 273 287 563 (199 549 332 – 347 152 490) Western Asia 66.6 (56.1–77.0) 257 231 020 171 212 967 (144 306 602 – 198 067 885) UN European region 47.0 (41.8–52.1) 738 442 070 347 067 773 (308 668 785 – 384 728 318) Eastern Europe 62.8 (48.3–77.2) 292 942 778 183 850 887 (141 491 361 – 226 151 824) Northern Europe 41.6 (32.4–50.7) 102 357 768 42 550 124 (33 163 916 – 51 895 388) Southern Europe 55.0 (49.1–61.0) 152 347 892 83 852 280 (74 802 814 – 92 932 214) Western Europe 34.3 (31.3–37.2) 190 793 632 66 396 184 (59 718 406 – 70 975 231) UN Oceania region 24.4 (18.5–30.4) 39 331 130 9 608 595 (7 276 259 – 11 956 663) Global 4 356 096 968 (3 750 167 566 – 4 961 780 681) * Based on United Nations 2015 Revision of World Population Prospects total population estimates

23

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1. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984; 1(8390): 1311-5. 2. Malfertheiner P, Megraud F, O'Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007; 56(6): 772-81. 3. Liou JM, Fang YJ, Chen CC, et al. Concomitant, bismuth quadruple, and 14-day triple therapy in the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial. Lancet 2016; 388(10058): 2355-65. 4. Graham DY. History of Helicobacter pylori, duodenal ulcer, gastric ulcer and gastric cancer. World J Gastroenterol 2014; 20(18): 5191-204. 5. Nagy P, Johansson S, Molloy-Bland M. Systematic review of time trends in the prevalence of Helicobacter pylori infection in China and the USA. Gut Pathog 2016; 8: 8. 6. Wang C, Yuan Y, Hunt RH. The association between Helicobacter pylori infection and early gastric cancer: a meta-analysis. Am J Gastroenterol 2007; 102(8): 1789-98. 7. Yokota S, Konno M, Fujiwara S, et al. Intrafamilial, Preferentially Mother-to-Child and Intraspousal, Helicobacter pylori Infection in Japan Determined by Mutilocus Sequence Typing and Random Amplified Polymorphic DNA Fingerprinting. Helicobacter 2015; 20(5): 334-42. 8. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535. 9. Composition of macro geographical (continental) regions, geographical sub-regions, and selected economic and other groupings 26 September 2016 2016. http://unstats.un.org/unsd/methods/m49/m49regin.htm. 10. Wells GA SB, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2014. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. 11. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142(1): 46-54 e42; quiz e30. 12. QGIS Development Team. QGIS Geographic Information System. Open Source Geospatial Foundation Project. http://www.qgis.org/. 2016. 13. Duivenvoorde R. HTML Image Map Plugin for QGIS. Open Source Geospatial Foundation Project. http://hub.qgis.org/projects/imagemapplugin. 2014. 14. Natural Earth Development Team. Cultural Vectors. North American Cartographic Information Society. http://www.naturalearthdata.com. 2016. 15. Everhart JE, Kruszon-Moran D, Perez-Perez GI, Tralka TS, McQuillan G. Seroprevalence and ethnic differences in Helicobacter pylori infection among adults in the United States. Journal of Infectious Diseases 2000; 181(4): 1359-63. 16. Cardenas VM, Mulla ZD, Ortiz M, Graham DY. Iron deficiency and Helicobacter pylori infection in the United States. American Journal of Epidemiology 2006; 163(2): 127-34. 17. Parkinson AJ, Gold BD, Bulkow L, et al. High prevalence of Helicobacter pylori in the Alaska Native population and association with low serum ferritin levels in young adults. Clinical and Diagnostic Laboratory Immunology 2000; 7(6): 885-8. 18. Eslick GD, Lim LL, Byles JE, Xia HH, Talley NJ. Association of Helicobacter pylori infection with gastric carcinoma: a meta-analysis. Am J Gastroenterol 1999; 94(9): 2373-9. 19. Helicobacter, Cancer Collaborative G. Gastric cancer and Helicobacter pylori: a 24

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ACCEPTED MANUSCRIPT 37. Windsor HM, Abioye-Kuteyi EA, Leber JM, Morrow SD, Bulsara MK, Marshall BJ. Prevalence of Helicobacter pylori in Indigenous Western Australians: Comparison between urban and remote rural populations. Medical Journal of Australia 2005; 182(5): 210-3.

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Author names in bold designate shared co-first authorship

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ACCEPTED MANUSCRIPT Appendix

Appendix to ‘Global helicobacter pylori prevalence: A systematic review and meta–analysis of population–based studies published between 1970 and 2016’.

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This appendix provides supplemental information on this systematic review. It is divided into six appendices (Appendix 1 – 6).

Table of contents

MEDLINE and EMBASE search strategy for article selection (from 1 Jan 1970 till 1 Jan 2016)

Appendix 2:

Quality assessment of selected papers

Appendix 3:

Distribution of included papers by regions and countries

Appendix 4:

Country and region specific prevalence of HP since 1 Jan 1970 to 1 Jan 2016 in Northern America, Southern America, Oceania, Eastern Asia, Southern Asia, Western Asia, Northern Europe, Southern Europe, Western Europe and Northern Africa

Appendix 5:

Studies included in this systematic review

Appendix 6:

Pooled HP prevalence stratified by country and UN region

Appendix 7:

Pooled HP prevalence stratified by modality of testing

Appendix 8:

Pooled HP prevalence stratified by adult-only studies

Appendix 9:

HP prevalence time trend in the six United Nations regions

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Appendix 1:

ACCEPTED MANUSCRIPT Appendix 1: MEDLINE and EMBASE search strategy for article selection (1 Jan 1970 to 1 Jan 2016)

-

EMBASE: MEDLINE(R):

1 Jan 1970 to 1 Jan 2016 1 Jan 1970 to 1 Jan 2016

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Keywords used - HP or - Helicobacter Pylori or - H$ Pylori or - Campylobacter pylori & - Prevalence

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ACCEPTED MANUSCRIPT Appendix 2: Quality assessment of selected papers

Aguemon, B. D. (2005)

Representativeness + of the cases B A

Alavi, S. M. (2010)

B

Al–Balushi, M. S. (2013)

B

Al–Moagel, M. A. (1990)

B

Alwahaibi, N. (2013)

B

Ang, T. L. (2005)

A

Apostolopoulos, P. (2002)

B

Aro, P. (2004)

A

Asfeldt, A. M. (2008)

A

Awdalla, H. I. (2010)

B

Babus, V. (1997)

A

Babus, V. (1998)

B

Baena Diez, J. M. (2002)

B

M AN U

Akin, L. (2004)

Bakka, A. S. (2002)

B

Bastos, J. (2013)

A

Bazzoli, F. (2001)

A

Ben Ammar, A. (2003)

B

Bergenzaun, P. (1996)

B

Blecker, U. (1995)

A B

Breckan, R. K. (2012) Brenner, H. (1997) Brenner, H. (1999) Brown, L. M. (2002)

TE D

Borch, K. (2000) Breckan, R. K. (2009)

A A B A B B

Bures, J. (2006)

A

EP

Buckley, M. J. M. (1998) Bures, J. (2012)

RI PT

*

SC

First Author (Publication Year)

A A

Cardenas, V. M. (2010)

B

Carter, F. P. (2011)

B

Cataldo, F. (2004)

B

Celinski, K. (2006)

B

Chen, J. (2007)

B

Chen, S. (2002)

B

Chen, S. L. (2003)

B

Chen, S. Y. (2005)

B

Chen, T. S. (2007)

B

Cheng, H. (2009)

B

Collett, J. A. (1999)

B

Correa, P. (1990)

B

AC C

Cardenas, V. M. (2006)

De Oliveira, A. M. R. (1999)

B

Dite, P (1998)

B

Do, M. Y. (2009)

B

Dominici, P. (1999)

A

Dooley, C. P. (1989)

B

Dube, C. (2009)

B

Everhart, J. E. (2000)

B

Fan, H. M. (2006)

B

Farshad, S. (2010)

B

Ferreccio, C. (2007)

A

Fich, A. (1993)

B

Fitzgibbons, P. L. (1988)

B

Forman, D. (1990)

B

Fujimoto, Y. (2007)

B

Fujisawa, T. (1999)

B

Fukao, A. (1993)

B

Gasbarrini, G. (1995)

A

Gilboa, S. (1995)

B

Gill, H. H. (1994)

B

Glupcyznski, Y. (1992)

B

Goh, K. L. (2001)

A

Graham, D. Y. (1991)

B B

Hirai, I. (2010) Hirayama, Y. (2014) Hoang, T. T. (2005)

EP

Holcombe, C. (1992)

TE D

Guo, X. (2011) Hirai, I. (2009)

SC

A

M AN U

Dahlerup, S. (2011)

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B B B B B B

Holtmann, G. (2001)

B

Hong, S. N. (2012)

B

AC C

Holtmann, G. (1994)

Jafarzadeh, A. (2006)

B

Jafarzadeh, A. (2007)

B

Kang, J. Y. (1997)

B

Katsanos, K. H. (2010)

B

Kawamura, A. (2001)

B

Kebria, F. G. (2011)

B

Kikuchi, S. (2004)

B

Kim, H. J. (2008)

B

Kim, J. H. (2001)

B

Kim, N. (2008)

B

Koch, A. (2005)

B

Kuepper–Nybelen, J. (2005)

A

Laszewicz, W. (2014)

A

Le Bodic, M. F. (1987)

B

Lee, S. P. (2015)

B

Lehmann, F. S. (2000)

B

Leja, M. (2012)

A

Lim, S. H. (2013)

B

Lin, J. T. (1993)

B

Lin, Y. L. (2010)

B

Linneberg, A. (2003)

A

Loffeld, R. J. (2003)

B

Loffeld, R. J. L. F. (2003)

B

Luzza, F. (1997)

B

Lyra, A. C. (2003)

B

Macenlle Garcia, R. (2006)

B

Malaty, H. M. (1996)

B

Malaty, H. M. (1996)

B

Malaty, H. M. (2003)

B

Mansour, K. B. (2010)

B

Martin–de–Argila, C. (1996)

B

Marusic, M. (2013)

A

Matysiak–Budnik, T. (1996)

B

McDonagh, T. A. (1997)

A B

Miendje Deyi, V. Y. (2011) Milman, N. (2003) Moujaber, T. (2008) Naja, F. (2012) Nam, J. H. (2014)

EP

Murray, L. J. (1997)

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Melius, E. J. (2013) Mendall, M. A. (1992)

SC

B

M AN U

Kumagai, T. (1998)

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AC C

Nascimento, R. S. (2002)

B A B B A A B B

Nguyen, T. L. (2010)

B

Nouraie, M. (2009)

B

Nurgalieva, Z. Z. (2002)

B

Olmos, J. A. (2000)

B

Ophori, E. A. (2011)

B

Ozaydin, N. (2013)

A

Palli, D. (1993)

B

Pandeya, N. (2011)

A

Parkinson, A. J. (2000)

B

Pateraki, E. (1990)

B

Patterson, T. (2012)

B

Peach, H. G. (1997)

B

Ràfols Crestani, A. (2000)

B

Rasheed, F. (2011)

B

Replogle, M. L. (1996)

B

Reshetnikov, O. V. (2001)

B

Robertson, M. S. (2003)

B

Rodrigo Sáez, L. (1997)

A

Rothenbacher, D. (1997)

B

Russo, A. (1999)

B

Salomaa–Rasenen, A. (2006)

B

Sanchez Ceballos, F. (2007)

B

Santos, I. S. (2005)

B

Santos, I. S. (2009)

B

Sasaki, T. (2009)

B

Sasaki, T. (2009)

B

Sasidharan, S. (2009)

B

Sathar, M. A. (1994) Seher, C. (2000) Senra–Varela, A. (1998)

B A B

SC

A

So ̈rberg, M. (2003)

M AN U

Pretolani, S. (1997)

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Sporea, I. (2003) Stone, M. A. (1998) Sung, K. C. (2005)

B A B

Sheikhian, A. (2011)

B

Sherpa, T. W. (2012)

B

Shi, R. (2008)

B

Singh, V. (2002)

B

Talaiezadeh, A. (2013) Tang, H. R. (2014)

EP

Thjodleifsson, B. (2007)

TE D

B

B B B

Tomasi, J. P. (1990)

A

Torres, J. (1998)

A B

Ueda, J. (2014)

B

Us, D. (1998)

B

Uyub, A. M. (1994)

B

van Blankenstein, M. (2013)

B

Veldhuyzen Van Zanten, S. J. O. (1994)

B

Vorobjova, T. (1994)

A

Vyse, A. J. (2002)

A

Wang, M. Y. (2011)

B

Weill, F. X. (2002)

B

Wex, T. (2011)

B

Windsor, H. M. (2005)

B

Wong, B. C. Y. (1999)

B

AC C

Tsukanov, V. V. (2007)

Wong, B. C. Y. (1999)

B

Xu, C. (2014)

B

Yim, J. Y. (2007)

B

Zaterka, S. (2007)

B

Zhang, D. H. (2009)

B

Zhang, X. (1999)

B

Zheng, Y. (2014)

B

Zhou, X. (2013)

B

RI PT

ACCEPTED MANUSCRIPT

Zhou, Z. F. (1997) B * All included papers were graded ‘A’ under the category of ‘Is the case definition adequate’

+ Representativeness of the cases

SC

A: Truly representative of the average prevalence of Helicobacter Pylori in the community

B: Somewhat representative of the average prevalence of Helicobacter Pylori in the community C: Selected group of users; e.g. nurses, volunteers

M AN U

D: No description of the derivation of the cohort

AC C

EP

TE D

A representative study population is a prerequisite for a study to be included in this systematic review. Studies which included study populations that were not randomly sampled across the entire country or had a small population size were graded ‘B’.

ACCEPTED MANUSCRIPT Appendix 3: Distribution of included reports by regions and countries Number of countries represented

Number of studies

Number of Total number positive of participants participants detected Africa 8 11 2 806 3 862 Asia 18 75 165 318 309 811 Europe 24 66 68 501 173 502 # Latin America and Caribbean 8 13 12 696 19 087 Northern America 3 13 6 905 19 553 Oceania 2 6 1 542 6 065 Total number of countries 62 184 257 768 531 880 # Includes Guadeloupe which is an insular region of France located in the Caribbean

AC C

EP

TE D

M AN U

SC

RI PT

UN geoscheme

ACCEPTED MANUSCRIPT

Appendix 4: Country and region specific prevalence of HP since 1 Jan 1970 to 1 Jan 2016 in Northern America, Southern America, Oceania, Eastern Asia, Southern Asia, Western Asia, Northern Europe, Southern Europe, Western Europe and Northern Africa Country

Region

Study period

At risk population

HP prevalence (%)

Africa (n=11)

2-73

44.2

~

188

46.8

39.7-53.9

Serology

16-65

53.7

133

77.4

70.3-84.6

UBT

5-67

~

~

Bakka, A. S. (2002)

Libya

Holcombe, C. (1992)6

Nigeria

Northern Nigeria

7

Nigeria

Agbor

8

South Africa

~ ~

Alice, Nkonkobe Municipality

Tunisia Tunis

China

14

China

Yunnan

China

Serology

16-60

57.0

44.2-63.8

Serology

16-60

63.0

360

76.4

72.0-80.8

Serology

1-70

49.0

268

85.1

80.8-89.3

Serology

≥5

~

380

89.7

86.7-92.8

Serology

≥1

47.4

1183

68.6

65.9-71.2

Serology

17-87

~

86.8

83.3-90.3

Stool antigen

3m-60 yo

47.2

2000

98

82.7

75.2-90.2

Histology, serology, RUT

18-80

50.0

2006–2007

250

63.2

57.2-69.2

Serology

25-55

84.8

74.9-84.2

Serology

10-69

~

1999

13

19.2-36.8

54.0

356

AC C

Kazakhstan

28.0

100

2008

EP

Tunisia

100

TE D

South Africa

~ 1989

SC

72.3

~

Zhou, Z. F. (1997) Wong, B. C. Y. (1999a)15 Wong, B. C. Y. (1999b)16 Wong, B. C. Y. (1999b)16

Serology

206

Unshass

Forman, D. (1990)

66.2-78.4

2003–2005

Nasr City

Nurgalieva, Z. Z. (2002)12

48.3

Pahou

Egypt

Ben Ammar, A. (2003)10 Mansour, K. B. (2010)11

2-73

Benin

Awdalla, H. I. (2010)4

Dube, C. (2009)9

Serology

75.4

Awdalla, H. I. (2010)4

Sathar, M. A. (1994)

70.0-80.9

240

~

Ophori, E. A. (2011)

Sex (Male%)

2003–2004

Katana

5

Age Range

Cotonou

Burkina Faso Democratic Republic of Congo Egypt

Glupcyznski, Y. (1992)3

Methods to diagnose HP

Benin

M AN U

Aguemon, B. D. (2005)1 Aguemon, B. D. (2005)1 Cataldo, F. (2004)2

95% Confidence interval (%)

RI PT

First Author (Publication Year)

Central Asia (n=1) 288

79.5

Eastern Asia (n=45)

1983

1882

60.4

58.2-62.6

Serology

35-64

50.0

1994

1084

51.1

48.1-54.1

Serology

5-80

85.1

Changle (Fujian)

1994

755

81.7

79.0-84.5

Serology

~

~

China

Changle (Fujian)

1994

1456

80.4

78.3-82.4

Serology

36-65

61.2

China

Hong Kong

1993–1994

397

58.4

53.6-63.3

Serology

36-65

57.4

ACCEPTED MANUSCRIPT

Zhang, X. (1999)17

China

Zanhuang County, Hebei Province

Chen, S. (2002)18

China

Shanghai urban

1996–1997

1504

66.4

64.0-68.7

Serology

≥30

37.1

1990

896

42.8

39.5-46.0

Serology

7-85

61.2

18

Chen, S. (2002)

China

Shanghai rural

1990

1040

61.0

Chen, S. (2002)18

China

Shanghai urban

2001

1557

58.3

Brown, L. M. (2002)19

China

Linqu County, Shandong Province

1997–1998

3013

66.2

Chen, S. L. (2003)20

China

Shanghai urban

1990

896

40.5

20

China

Shanghai urban

2001

1557

58.3

21

China

Shanghai urban

2003–2004

1822

66.4

64.2-68.6

263

57.4

22

China

Zunhua City, Hebei

2004

23

Chen, J. (2007)

China

Guangzhou

1993

Chen, J. (2007)23

China

Guangzhou

2003

China

Jiangsu

Cheng, H. (2009)25

China

Beijing: rural Pinggu and urban Haidian

2003

Zhang, D. H. (2009)26

China

Beijing: Yanqing County

2006

Zhang, D. H. (2009)26

China

Shandong: Muping County

2006

Guo, X. (2011)27

China

Northern China

Wang, M. Y. (2011)

China

ShanDong

Zhou, X. (2013)29

China

Jiangsu

Tang, H. R. (2014)30

China

Chengdu, Sichuan

China

Beijing

Xu, C. (2014)

China

Zhejiang

Lin, J. T. (1993)33

Taiwan

Chu–Tung, Po–Tzu, Pei–Nan, and Ta–An

28

31

Zheng, Y. (2014) 32

Serology and UBT

35-69

44.4

37.3-43.7

Serology

1-87

62.3

55.9-60.8

1-87

63.1

15-72

50.7

51.4-63.4

Serology Serology, UBT, stool antigen Serology

6-86

45.3

RI PT 64.5-67.9

56.0

52.7-59.4

Serology

3-92

51.1

47.0

44.5-49.6

Serology

3-92

51.7

1371

62.1

59.5-64.6

Serology, UBT

5-100

42.7

1232

46.8

44.0-49.5

UBT

2-79

53.1

503

41.4

37.1-45.7

Stool antigen

40-79

47.4

526

51.0

46.7-55.2

Histology

40-79

47.4

~

798

54.5

51.1-58.0

Serology

> 17

55.3

2008–2010

1637

35.5

33.2-37.8

Serology, UBT

~

60.8

2009–2011

5417

63.4

62.1-64.7

UBT

30-69

43.2

2009–2012

8365

53.1

52.1-54.2

UBT

11-95

59.1

2005–2011

54036

47.0

46.6-47.4

UBT

15-81

68.0

2013

8820

43.8

42.7-44.8

UBT

39-53

59.7

1992

823

54.4

51.0-57.8

Serology

70

49.8

2004–2005

TE D

Shi, R. (2008)

61.2 63.0

830

EP

24

7-85 1-87

1471

AC C

Fan, H. M. (2006)

Serology Serology

SC

Chen, S. Y. (2005)

M AN U

Chen, S. L. (2003)

58.0-63.9

55.9-60.8

Chen, T. S. (2007)34

Taiwan

Taipei

1999–2000

482

68.3

64.1-72.4

Serology

56.9±14.0

58.1

Lin, Y. L. (2010)35

Taiwan

Chiayi County

2004–2006

9311

39.2

38.3-40.2

CLO

> 40

42.0

ACCEPTED MANUSCRIPT

Japan

Akita, Iwate, Miyagi, Okinawa

Japan

Tokyo

Japan

South Kiso town

51.7

49.4-54.0

Serology

16-64

50.0

1979–1993

1207

38.9

36.2-41.7

Serology

0-94

~

1986–1994

664

73.2

69.8-76.6

Serology

6-80

~

Japan

Seven prefectures (Nagano, Niigata, Gunma, Toyama, Shizuoka, Mie, and Miyagi)

1974

264

72.7

67.4-78.1

Serology

0-89

43.6

Japan

Seven prefectures (Nagano, Niigata, Gunma, Toyama, Shizuoka, Mie, and Miyagi)

1984

238

54.6

48.3-61.0

Serology

0-89

43.6

Japan

Seven prefectures (Nagano, Niigata, Gunma, Toyama, Shizuoka, Mie, and Miyagi)

1994

33.5-45.3

Serology

0-89

43.6

Malaty, H. M. (2003)40

Japan

South Kiso town

Kikuchi, S. (2004)41

Japan

Fujimoto, Y. (2007)42

Japan

Ishigaki City

Fujimoto, Y. (2007)42

Japan

Fujimoto, Y. (2007)42

Japan

Hirai, I. (2009)

Japan

Osaka

Kawamura, A. (2001)44

Japan

Shimane

Hirayama, Y. (2014)

Japan

Tokyo

Ueda, J. (2014)46

Japan

Seven areas in Japan

1997–2013

Malaty, H. M. (1996)47

Korea

Seoul

Kim, J. H. (2001)48

Korea

Seoul

Sung.K.C (2005)49

Korea

Seoul and Kyunggi

Yim, J. Y. (2007)50

Korea

Seoul, Jeju, Kangwon

Kim, H. J. (2008)51

Korea

39

Fujisawa, T. (1999)

43

45

1986

264

SC

39.4

394

80.0

76.0-83.9

Serology

0-80

~

3014

42.7

40.9-44.4

Serology

81.1

2002

238

52.5

46.2-58.9

Serology

Kasuya Town

2002

3310

55.0

53.3-56.7

Serology

39->65 35

87.0

13707

41.2

40.4-42.0

Serology, stool antigen

≥ 20

42.4

1992–1993

413

42.6

37.9-47.4

Serology

1-75

~

1998

1155

41.9

39.1-44.8

Serology

0-79

50.0

2001–2002

58981

70.9

70.5-71.3

Serology

60

62.7

2005

8020

59.6

58.5-60.7

Serology

≥ 20

54.1

2003–2007

713

57.6

54.0-61.3

CLO, histology

23-85

41.8

EP

Fujisawa, T. (1999)39

AC C

Replogle, M. L. (1996)37 Kumagai, T. (1998)38

RI PT

1815

M AN U

Fukao, A. (1993)36

ACCEPTED MANUSCRIPT

Do, M. Y. (2009)53

Korea

Do, M. Y. (2009)53

Korea

Do, M. Y. (2009)53

Korea

Do, M. Y. (2009)53

Korea

Do, M. Y. (2009)53

Korea

Do, M. Y. (2009)53

Korea

59.7-61.1

Serology, CLO, histology

16->70

59.0

1998

696

64.7

61.1-68.2

CLO, histology

17-92

69.1

1999

1253

58.1

CLO, histology

17-92

68.2

2000

684

54.2

50.5-58.0

CLO, histology

17-92

68.1

1352

50.4

47.8-53.1

CLO, histology

17-92

71.8

2001

RI PT

Korea

60.4

55.4-60.3

SC

Do, M. Y. (2009)53

20154

M AN U

Korea

2006

TE D

Do, M. Y. (2009)53

The Health Promotion Centers of Severance hospital or Chung– Ang University hospital The Health Promotion Centers of Severance hospital or Chung– Ang University hospital The Health Promotion Centers of Severance hospital or Chung– Ang University hospital The Health Promotion Centers of Severance hospital or Chung– Ang University hospital The Health Promotion Centers of Severance hospital or Chung– Ang University hospital The Health Promotion Centers of Severance hospital or Chung– Ang University hospital The Health Promotion Centers of Severance hospital or Chung– Ang University hospital The Health Promotion Centers of Severance hospital or Chung– Ang University

2002

1620

48.9

46.5-51.3

CLO, histology

17-92

68.6

EP

Korea

1435

49.6

47.0-52.1

CLO, histology

17-92

68.5

2004

1851

39.6

37.4-41.8

CLO, histology

17-92

69.2

2005

1662

40.0

37.7-42.4

CLO, histology

17-92

71.1

2003

AC C

Kim, N. (2008)52

ACCEPTED MANUSCRIPT

hospital Korea

Kyonggi

1998

1308

47.3

44.6-50.0

Serology

0-79

50.0

48

Korea

Kangwon

1998

251

53.4

47.2-59.6

Serology

0-79

50.0

48

Kim, J. H. (2001)

Korea

Chungcheong

1998

799

43.7

40.2-47.1

Serology

0-79

50.0

Kim, J. H. (2001)48

Korea

Kyungsang

1998

1266

47.1

44.3-49.8

Serology

0-79

50.0

48

Kim, J. H. (2001)

Korea

Cholla

1998

728

50.6

46.9-54.2

Serology

0-79

50.0

Kim, J. H. (2001)48

Korea

Cheju

1998

225

52.9

46.4-59.4

Serology

0-79

50.0

Hong, S. N. (2012)

Korea

Seoul

2010

2195

57.1

55.0-59.2

Serology

~

62.0

Lim, S. H. (2013)55

Korea

Seoul

2011

5829

50.0

48.8-51.3

Serology

Above 16

54.8

55

Lim, S. H. (2013)

Korea

Gyeonggi

2011

1683

53.4

51.0-55.7

Serology

Above 16

54.8

Lim, S. H. (2013)55

Korea

Chungcheong

2011

536

55.4

51.2-59.6

Serology

Above 16

54.8

55

Korea

Kyungsang

2011

914

65.1

62.0-68.2

Serology

Above 16

54.8

Lim, S. H. (2013)

55

Lim, S. H. (2013)

Korea

Cholla

2011

Lim, S. H. (2013)55

Korea

Kangwon

2011

Lim, S. H. (2013)55

Korea

Jeju

Nam, J. H. (2014)56

Korea

Lee, S. P. (2015)57

Korea

2011 2006–2007 2010–2013

1194

66.2

63.5-68.9

Serology

Above 16

54.8

331

60.4

55.2-65.7

Serology

Above 16

54.8

299

58.9

53.3-64.4

Serology

Above 16

54.8

632

59.0

55.2-62.9

Serology

21-68

49.2

3314

59.5

57.8-61.2

Serology

70

60.8

TE D

Seoul

SC

54

M AN U

Kim, J. H. (2001)

RI PT

Kim, J. H. (2001)48

Jafarzadeh, A. (2006)58

Iran

Rafsanjan

2004

59

Jafarzadeh, A. (2007)

Iran

Rafsanjan

Nouraie, M. (2009)60

Iran

Tehran province

Alavi, S. M. (2010)61

Iran

Razi hospital in Ahvaz

Farshad, S. (2010)62

Iran

EP

Southern Asia (n=13) 73.2

65.8-80.6

Serology

17-60

47.1

2005

200

67.5

61.0-74.0

Serology

20-60

51.4

2005

2326

69.0

67.1-70.9

Serology

18-65

58.4

2004–2005

96

57.3

47.4-67.2

Serology

60

48.0

2005–2007

226

41.6

35.2-48.0

CLO

18-83

49.0

AC C

63

138

Kebria, F. G. (2011)

Iran

Golestan province

2008–2009

1028

66.4

63.6-69.3

Serology

1-83

47.6

Sheikhian, A. (2011)64 Talaiezadeh, A. (2013)65 Singh, V. (2002)66

Iran

Khorramabad

2008

381

43.0

38.1-48.0

Serology

15-88

40.5

Iran

Khuzestan Province

2009

861

53.5

50.2-56.9

Stool antigen

0-80

~

India

Chandigarh

~

67

56.7

44.9-68.6

Serology, RUT, histology

> 15

48.0

Gill, H. H. (1994)67

India

Hospital

~

340

67.4

62.4-72.3

Serology

0-68

66.8

Sherpa, T. W. (2012)68

Nepal

Upper Khumbu Region

~

383

70.5

65.9-75.1

Stool antigen

>=0

45.4

ACCEPTED MANUSCRIPT

Pakistan

Naja, F. (2012)70

Barakho, Islamabad

205

81.0

75.6-86.4

UBT

Lebanon

2009–2010

308

52.0

46.4-57.5

Serology

Uyub, A. M. (1994)71

Malaysia

1991–1992

1417

4.7

Goh, K. L. (2001)72

Malaysia

Kuala Pilah, West Malaysia

~

626

31.8

Goh, K. L. (2001)72

Malaysia

Kuala Lumpur, West Malaysia

~

548

26.5

Goh, K. L. (2001)72

Malaysia

Kota Baru, West Malaysia

~

322

26.4

Goh, K. L. (2001)72

Malaysia

Kota Kinabalu, East Malaysia

~

Goh, K. L. (2001)72

Malaysia

Sibu, East, East Malaysia

~

Malaysia

Penang

75

Singapore

Ang, T. L. (2005)

Singapore

Hirai, I. (2010)76

Thailand

Hoang, T. T. (2005)77

Vietnam

1992–1993 1998

Urban Hanoi

46.8

Serology

11-91

~

28.1-35.4

Serology

12-92

43.3

22.8-30.2

Serology

12-92

85.2

21.6-31.2

Serology

12-92

~

55.0

49.9-60.0

Serology

12-92

87.7

512

43.2

38.9-47.5

Serology

12-92

62.7

5370

14.2

13.2-15.1

Serology

10-70

68.5

358

40.2

35.1-45.3

Serology

20-60

~

595

41.2

37.2-45.1

Serology

25-39,55-69

~

2007–2008

179

43.6

36.3-50.8

Stool antigen

40-80

28.5

~

546

78.8

75.3-82.2

Serology

1-88

42.3

Hoang, T. T. (2005)

Vietnam

Rural Hatay

~

425

69.2

64.8-73.6

Serology

1-88

46.4

Nguyen, T. L. (2010)78

Vietnam

Ho Chi Minh

~

136

64.7

56.7-72.7

Serology, culture, histology

14-86

43.3

Nguyen, T. L. (2010)78

Vietnam

Urban Hanoi

EP

77

2000–2002

49.0

373

TE D

Sasidharan, S. (2009)73 Kang, J. Y. (1997)74

> 19 mean age:40.97 ± 15.5

3.6-5.8

SC

South-Eastern Asia (n=8)

RI PT

2009–2010

M AN U

Rasheed, F. (2011)69

134

66.4

58.4-74.4

Serology, culture, histology

14-86

43.3

60.3-70.9

Serology

20-70

54.7

Israel 80

~

AC C

Fich, A. (1993)79

~

Gilboa, S. (1995)

Israel

Kibbutzim

Us, D. (1998)81

Turkey

Ankara

Akin, L. (2004)82

Turkey

Gulveren Health District, Ankara

Ozaydin, N. (2013)83 Alwahaibi, N. (2013)84

Western Asia (n=8) 311

65.6

~

377

71.9

67.4-76.4

Serology

30-90

~

1996–1997

284

70.1

64.7-75.4

Serology

20-59

50.0

2004

1089

77.4

74.9-79.9

Serology

25-64

54.3

Turkey

2000

1089

82.6

81.5-83.7

UBT

45.2

Oman

2007–2010

366

30.1

25.4-34.8

CLO

Above 18 males with mean age of 47.87±19

46.7

Al–Balushi, M. S. (2013)85

Oman

SQU Hospital’s Blood Bank

Al–Moagel, M. A. (1990)86

Saudi Arabia

Riyadh City

2011–2012

133

68.4

~

364

65.9

Czech Republic

Bures, J. (2006)88

Czech Republic Czech Republic

Bures, J. (2012)89 Matysiak–Budnik, T. (1996)90

Serology

15-50

73.7

61.1-70.8

Serology

5-91

47.9

The South Moravia Region

1998

309

58.9

53.4-64.4

Serology

20-59

~

Across the country

2001

2509

41.7

39.8-43.6

UBT

5-100

47.4

1826

23.6

21.6-25.5

UBT

5-98

46.9

656

73.0

69.6-76.4

Serology

0-86

~

585

68.7

65.0-72.5

Serology

19-89

~

6565

58.3

57.1-59.5

Serology

2-89

~

M AN U

Dite, P. (1998)87

years females with mean age of 45.21±17.56 years

60.5-76.3

SC

Eastern Europe (n=10)

RI PT

ACCEPTED MANUSCRIPT

2010

Poland

Wroclaw

Poland

Lublin

Poland

10 regions Timis County

~

960

68.5

65.6-71.5

Serology

18-60

78.5

St. Petersburg

~

520

61.9

57.8-66.1

Serology

1-75

~

Reshetnikov, O. (2001)95

Romania Russian Federation Russian Federation

Novosibirsk, Siberia

1994–1995

649

86.0

83.3-88.7

Serology

18-64

48.8

Tsukanov, V. V. (2007)96

Russian Federation

Eastern Siberia: Evenkia, Khakassia, Tuva

~

3602

87.0

85.9-88.1

Serology

92

Laszewicz, W. (2014) 93

Sporea, I. (2003)

94

Malaty, H. M. (1996)

~ 2002–2003

TE D

Celinski, K. (2006)

1992

EP

91

47.3

AC C

Northern Europe (n=19)

97

Linneberg, A. (2003)

Denmark

Copenhagen

1990–1991

1112

24.6

22.0-27.1

Serology

15-69

~

Dahlerup, S. (2011)98

Denmark

East coast of the Danish peninsula of Jutland

~

36629

20.1

19.7-20.5

UBT

2-95

40.3

Vorobjova, T., (1994)99

Estonia

Vorobjova, T., (1994)99

Estonia

Karksi–Nuia

1990

1461

87.0

85.3-88.7

Serology

15-95

43.6

Abja–Paluoja

1990

497

89.3

86.6-92.1

Serology

50-91

38.0

Thjodleifsson, B. (2007)100

Estonia

Tartu

1991–2001

240

69.2

63.3-75.0

Serology

25-50

40.0

ACCEPTED MANUSCRIPT

Finland population based study; Vammala

1977–1980

336

64.9

Salomaa–Rasenen, A. (2006)101Ω

Finland

Finland population based study; Vammala

1997–1998

336

58.9

Salomaa–Rasenen, A. (2006)101Ω

Finland

Finland population based study; Vammala

1994

224

46.0

Bergenzaun, P. (1996)102

Iceland

Three primary care centres in Sweden, Iceland

1991–1992

387

35.7

Thjodleifsson, B. (2007)100

Iceland

Reykjavik

1991–2001

Buckley, M. J. M. (1998)103

Ireland

Dublin

Leja, M. (2012)104

Latvia

Riga, Kurzema, Zemgale, Vidzeme, Latgale

Asfeldt, A. M. (2008)105

Norway

Municipality of Sørreisa

Breckan, R. K. (2009)106

Norway

The city of Bodø (the Bodø Helicobacter Study) and the municipality of Sørreisa (the Sørreisa Gastro– intestinal Disorder Study).

Breckan, R. K. (2012)107

Norway

Bodo and Sorreisa

Bergenzaun, P. (1996)102

Sweden

Three primary care centres in Sweden, Iceland

Borch, K. (2000)108

Sweden

Municipality of Linköping

Sorberg, M. (2003)109

Sweden

109

Sweden

Sorberg, M. (2003)

Serology

over 30

38.4

53.7-64.2

Serology

over 30

38.4

39.5-52.5

Serology

15-59

41.5

30.9-40.4

Serology

0-over 80

~

M AN U 447

36.2

31.8-40.7

Serology

25 -50

48.3

1000

43.0

39.9-46.1

Serology

18-60

60.8

3564

79.2

77.9-80.5

Serology

17-99

34.0

TE D

2008–2009

59.8-70.0

RI PT

Finland

SC

Salomaa–Rasenen, A. (2006)101Ω

916

38.0

34.9-41.1

Histology

18-85

44.8

2004–2005

1736

21.2

19.3-23.1

Stool antigen

"Adults"

44.7

~

1416

32.9

30.5-35.4

Stool antigen

"Adults"

54.6

1991–1992

443

35.7

21.9-30.0

Serology

10-over 69

35.2

~

482

44.8

40.4-49.3

Histology

35-85

54.4

25 Cities in Sweden

1995

3502

17.7

16.4-19.0

Serology

17-over 80

62.6

Stockholm

1995

1087

24.0

21.5-26.6

Serology

17-over 80

38.5

AC C

EP

2004

ACCEPTED MANUSCRIPT

Thjodleifsson, B. (2007)100 Mendall, M. A. (1992)111 Murray, L. J. (1997)112

Sweden

Kalix and Haparanda

1998

989

34.3

31.3-37.2

Histology

18-80

~

Sweden

Uppsala

1991–2001

359

11.1

7.9-14.4

Serology

25-50

52.1

UK

London

~

215

32.6

26.3-38.8

Serology, histology

18-82

~

49.1-51.9

Serology

12-64

~

63.4-68.4

Serology

25-74

49.2

13.2-16.8

Serology

21-55

44.7

12.6-14.2

Serology

1-84

69.2

Northern Ireland

1986–1987

4742

50.5

UK

North Glasgow

1992

1428

65.9

Stone, M. A. (1998)114

UK

Leicestershire

~

1566

15.0

Vyse, A. J. (2002)115

UK

Public Health Laboratories in England and Wales

1986 and 1996

7147

13.4

M AN U

SC

UK

McDonagh, T. A. (1997)113

RI PT

Aro, P. (2004)110

Southern Europe (=21) Albania 117

Babus, V. (1997)

2005–2008

Croatia

Babus, V. (1998)118

Croatia

Marusic, M. (2013)119

Croatia

~ The communities of Marija Bistrica, Zlatar Bistrica, Valpovo and Donji Miholjac, The Zadar and Sibenik communities Zagreb

Greece

Apostolopoulos, P. (2002)121

Greece

Athens

Apostolopoulos, P. (2002)121

Greece

Athens

Katsanos, K. H. (2010)116Ω∞

Greece

Palli, D. (1993)122

Italy

Luzza, F. (1997)123

Italy

Dominici, P. (1999)124

Italy

Campogalliano, a town in northern Italy

43.7-63.2

Histology

50

59.4

3082

60.4

58.7-62.1

Serology

20-70

~

456

50.9

46.3-55.5

Serology

25-34, 5564

22.4

3000

46.7

44.9-48.5

UBT

14-93

~

~

1069

64.0

61.1-66.9

Serology

1-50

~

1997

201

49.3

42.3-56.2

Serology

16-85

~

1987

200

59.5

52.7-66.3

Serology

15-82

~

2005–2008

101

33.7

24.5-42.9

Histology

50

59.4

1985–1988

930

45.1

41.9-48.3

Serology

35-74

58.1

1995

705

63.3

59.7-66.8

Serology

1-87

38.7

~

3289

59.7

58.0-61.4

Serology

12-65

~

AC C

Central and Northern Italy, Genoa in Northern Italy, Cagliaro in Sardinia Cirò

53.5

2008–2011

EP

Pateraki, E. (1990)

All over Greece, Athens

120

~

101

TE D

Katsanos, K. H. (2010)116Ω∞

ACCEPTED MANUSCRIPT

with about 5000 residents. Italy

1995–1997

2598

44.7

1996

1533

67.9

Italy

Bastos, J. (2013)127

Portugal

Porto

1999–2003

2067

86.4

Gasbarrini, G. (1995)128

San Marino

Nine districts in the Republic of San Marino

1990–1991

2237

51.0

Pretolani, S. (1997)129

San Marino

1990

1528

43.9

Martin–de–Argila, C. (1996)130

Spain

~

381

53.0

Rodrigo Sáez, L. (1997)131

Spain

Asturias

Senra–Varela, A. (1998)132

Spain

Ubrique and Grazalema, Barbate

Ràfols Crestani, A. (2000)133

Spain

Girona

Baena Diez, J. M. (2002)134

Spain

Barcelona

Macenlle Garcia, R. (2006)135

Spain

Province of Ourense

Sanchez Ceballos, F. (2007)136

Spain

Madrid

42.8-46.6

M AN U

1995–1996 1997 ~

25-60

~

65.6-70.2

UBT

28-80

51.7

84.9-87.9

Serology

18-92

~

48.9-53.1

Serology

20->70

46.8

41.4-46.3

Serology

20-85

~

48.0-58.0

Serology

5-77

36.2

480

49.2

44.7-53.6

Serology

up to 80

~

332

43.4

38.0-48.7

Serology

18-over 60

49.1

397

56.2

51.3-61.1

UBT

14-80

43.6

267

52.4

46.4-58.4

Serology

1-69

~

TE D

1999–2001

Serology

SC

Bazzoli, F. (2001)

Loiano and Mong– Hidoro

126

RI PT

Russo, A. (1999)125

1998

383

69.2

64.6-73.8

UBT

18-over 84

51.2

2004–2006

481

60.3

55.9-64.7

UBT

4-82

36.4

Belgium

All over Belgium

138

Belgium

Brussels

Belgium

Brussels

France

Nantes

Germany

Essen

Brenner, H. (1997)

Germany

Blaustein

Rothenbacher, D. (1997)143

Germany

Ulm

Germany

West Germany

Blecker, U. (1995) Miendje Deyi, V. Y. (2011)139 Le Bodic, M. F. (1987)140 Holtmann, G. (1994)141 142

144

Brenner, H. (1999)

~

4053

42.3

40.8-43.8

Serology

80

45.7

~

1180

18.0

15.8-20.2

Serology

1-40

~

1988–2007

22612

37.7

37.1-38.3

Culture

0-100

~

~

64

46.9

34.7-59.1

Histology, culture

~

~

~

180

31.7

24.9-38.5

HP Serology, CLO

20-over 50

58.9

1996

447

21.0

17.3-24.8

UBT

15-79

33.3

1996

501

23.4

19.7-27.1

UBT

15-79

37.5

1987–1988

1785

39.2

37.0-41.5

Serology

18-88

44.1

AC C

Tomasi, J. P. (1990)

EP

Western Europe (n=16)

137

ACCEPTED MANUSCRIPT

Seher, C. (2000)145

Germany 146

1997–1998

6748

40.0

38.8-41.2

Serology

18-79

39.4

~

491

39.5

35.2-43.8

Serology

18-65

59.1

39.5-41.9

Serology

18-79

~

42.4-46.4

Serology

0-90

50.9

38.0-40.1

Histology

4-99

48.5

30.9-40.3

Serology

19-65

~

Germany

Essen

Kuepper–Nybelen, J. (2005)147

Germany

East and West Germany

1997–1999

6545

40.7

Wex, T. (2011)148

Germany

Saxony–Anhalt

2009–2010

2318

44.4

Loffeld, R. J. L. F. (2003)149

Netherlands

Zaanstreek region

1993–2000

8190

39.1

Loffeld, R. J. (2003)150

Netherlands

402

35.6

2005

1551

31.7

29.4-34.0

Serology

17-80

~

~

175

18.9

13.1-24.7

Histology, CLO, UBT

18-81

58.9

204

57.8

51.1-64.6

Serology

16-61

57.4

764

55.2

51.7-58.8

Serology

18-70

45.9

90

41.1

31.0-51.3

Serology

18-70

66.7

Lehmann, F. S. (2000)152

Switzerland

Bern

SC

Netherlands

M AN U

van Blankenstein, M. (2013)151

Rotterdam, Nijmegen, West, South, Zeeland, Limburg

RI PT

Holtmann, G. (2001)

Caribbean (n=2)

154

Weill, F. X. (2002)

Weill, F. X. (2002)154

Bahamas France (Guadeloupe) France (Guadeloupe)

2009 Main Islands

2000

Dependencies

2000

Central America (n=3) Mexico

All 32 states

Cardenas, V. M. (2010)156

Mexico Panama

157

Sasaki, T. (2009)

1987–1988

11605

66.5

65.7-67.4

Serology

1- 90

~

Ciudad Juarez

2004

215

38.1

31.7-44.6

Stool antigen

≥0

~

El Pantano

2007

74

54.1

42.7-65.4

Stool antigen

21-82

62.2

EP

Torres, J. (1998)155

1996

493

49.1

44.7-53.5

Serology

18-80

36.1

~

131

87.0

81.3-92.8

Serology

20-78

12.2

1997–1999

100

68.0

58.9-77.1

Serology

≥ 21

~

1997–2000

79

76.0

66.5-85.4

Serology

≥ 21

~

1997–1999

274

68.3

62.7-73.8

Serology

~

80.3

South America (n=9) Argentina

De Oliveira, A. M. R. (1999)159

Brazil

Nascimento, R. S. (2002)160 Nascimento, R. S. (2002)160 Lyra, A. C. (2003)161 162

Brazil Brazil Brazil

Minas Gerais

AC C

Olmos, J. A. (2000)158

TE D

Carter, F. P. (2011)153

Urban of Uberlândia, Minas Gerais Rural of Uberlândia, Minas Gerais Salvador

Santos, I. S. (2005)

Brazil

Pelotas

~

359

64.4

59.4-69.3

UBT

≥ 20

~

Zaterka, S. (2007)163

Brazil

Sao Paolo

~

993

65.7

62.7-68.6

Serology

~

75.1

Santos, I. S. (2009)164

Brazil

Pelotas

2006–2007

1001

70.7

67.9-73.6

UBT

18-45

~

ACCEPTED MANUSCRIPT

Ferreccio, C. (2007)165 166

Sasaki, T. (2009)

Chile

2003

Ecuador

2007

2615

74.6

72.9-76.2

Serology

≥ 17

47.9

90

72.2

63.0-81.5

Stool antigen

~

~

32.6-43.3

Serology

18-72

40.8

34.9-58.1

Serology

22-76

40.8

37.2-44.6

Serology

5-87

47.0

Greenland

Koch, A. (2005)169

Greenland

Fitzgibbons, P. L. (1988)170

United States of America United States of America United States of America United States of America United States of America United States of America

Graham, D. Y. (1991)173 Everhart, J. E. (2000)174 Cardenas, V. M. (2006)175Ω∞ Cardenas, V. M. (2010)156 Patterson, T. (2012)176 Parkinson, A. J. (2000)177 178

Melius, E. J. (2013)

179

Collett, J. A. (1999)

180

United States of America United States of America United States of America United States of America

38.0

Nuuk, Ilulissat

1993–1994

71

46.5

Sisimiut community, West Greenland

1996–1998

685

40.9

~

116

31.0

22.6-39.5

Histology

19-91

50.0

~

113

31.9

20.8-37.6

Histology, Serology

18-91

46.0

275

56.4

50.5-62.2

Serology

18-84

~

485

52.2

47.7-56.6

Serology, UBT

15-80

47.6

7465

32.5

31.4-33.6

Serology

≥ 20

50.2

7462

27.1

26.1-28.1

Serology

3-70

~

Los Angeles

New Orleans Houston

1988–1990 1988–1991 1999–2000

El Paso Texas

2004

73

38.4

27.2-49.5

Stool antigen

≥0

~

Texas

2011

246

18.7

13.8-23.6

Serology

≥ 21

~

Alaska

1980–1986

2080

74.8

72.9-76.7

Serology

≥0

50.0

166

52.4

44.8-60.0

UBT

5-88

48.8

Northern Plains

New Zealand

Christchurch

Peach, H. G. (1997) Robertson, M. S. (2003)181 Moujaber, T. (2008)182

Australia

Ballarat

Australia

Victoria

Pandeya, N. (2011)183

Australia

Windsor, H. M. (2005)184

Australia

Australia

~

EP

Correa, P. (1990)172

316

~

Jigalong, Parnngurr, Perth, Punmu

~ Information not available in primary source article

Oceania (n=6)

1996

1060

24.0

21.4-26.5

Serology

> 18

41.9

1994–1995

217

30.4

24.3-36.5

Serology

Adults

~

~

500

32.0

27.9-36.1

Serology

16-71

55.0

AC C

Dooley, C. P. (1989)171

~

SC

Nova Scotia

M AN U

Canada

TE D

Veldhuyzen Van Zanten, S. J. O. (1994)167 Milman N. (2003)168

RI PT

Northern America (n=13)

2002

2413

15.1

13.7-16.6

Serology

1-59

49.9

2002–2005

1355

22.3

20.1-24.5

Serology

18-79

~

2003–2004

520

76.0

72.3-79.6

UBT

2-90

43.3

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Ω Age adjusted prevalence ∞ Gender adjusted prevalence UBT: Urea Breath Test RUT: Rapid Urease Test CLO: Campylobacter like organism test

ACCEPTED MANUSCRIPT

Appendix 5: Studies included in this systematic review Africa

RI PT

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SC

3. Glupczynski Y, Bourdeaux L, Verhas M, DePrez C, DeVos D, Devreker T. Use of a urea breath test versus invasive methods to determine the prevalence of Helicobacter pylori in Zaire. European Journal of Clinical Microbiology and Infectious Diseases. 1992;11(4):322–7.

M AN U

4. Awdalla HI, Ragab MH, Hanna LN. Environmental risk factors affecting transmission of Helicobacter pylori infection in Egypt. Journal of Public Health. 2010;18(3):237–44. 5. Bakka AS, Salih BA. Prevalence of Helicobacter pylori infection in asymptomatic subjects in Libya. Diagnostic Microbiology and Infectious Disease. 2002;43(4):265–8. 6. Holcombe C, Omotara BA, Eldridge J, Jones DM. H. pylori, the most common bacterial infection in Africa: A random serological study. American Journal of Gastroenterology 1992;87(1):28–30.

TE D

7. Ophori EA, Isibor C, Onemu SO, Johnny EJ. Immunological response to Helicobacter pylori among healthy volunteers in Agbor, Nigeria. Asian Pacific Journal of Tropical Disease. 2011;1(1):38–40. 8. Sathar MA, Simjee AE, Wittenberg DF, Fernandes–Costa FJTD, Soni PM, Sharp BL, et al. Seroprevalence of helicobacter pylori infection in Natal/KwaZulu, South Africa. European Journal of Gastroenterology and Hepatology. 1994;6(1):37–41.

EP

9. Dube C, Nkosi TC, Clarke AM, Mkwetshana N, Green E, Ndip RN. Helicobacter pylori antigenemia in an asymptomatic population of Eastern Cape Province, South Africa: Public health implications. Reviews on Environmental Health. 2009;24(3):249–55.

AC C

10. Ben Ammar A, Cheikh I, Kchaou M, Chouaib S, Ouerghi H, Chaabouni H. Prevalence of Helicobacter pylori infection in normal or asymptomatic patients. [French] Prevalence de l'infection a Helicobacter pylori chez les sujets normaux ou asymptomatiques. La Tunisie medicale. 2003;81(3):200–4. 11. Mansour KB, Keita A, Zribi M, Masmoudi A, Zarrouk S, Labbene M, et al. Seroprevalence of Helicobacter pylori among Tunisian blood donors (outpatients), symptomatic patients and control subjects. Gastroenterologie Clinique et Biologique. 2010;34(1):75–82.

Asia 12. Nurgalieva ZZ, Malaty HM, Graham DY, Almuchambetova R, Machmudova A, Kapsultanova D, et al. Helicobacter pylori infection in Kazakhstan: Effect of water source and household hygiene. American Journal of Tropical Medicine and Hygiene. 2002;67(2 SUPPL.):201–6.

ACCEPTED MANUSCRIPT

13. Forman D, Sitas F, Newell DG, Stacey AR, Boreham J, Peto R, et al. Geographic association of Helicobacter pylori antibody prevalence and gastric cancer mortality in rural China. International Journal of Cancer. 1990;46(4):608–11.

RI PT

14. Zhou ZF, Zhang YS, Wang YM. Seroprevalence of Helicobacter pylori infection among Yi and Han nationalities in Yunxian County, Yunnan Province. [Chinese]. Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi. 1997;18(1):18–21. 15. Wong BCY, Lam SK, Ching CK, Hu WHC, Ong LY, Chen BW, et al. Seroprevalence of cytotoxin–associated gene A positive Helicobacter pylori strains in Changle, an area with very high prevalence of gastric cancer in South China. Alimentary Pharmacology and Therapeutics. 1999;13(10):1295–302.

SC

16. Wong BCY, Lam SK, Ching CK, Hu WHC, Kwok E, Ho J, et al. Differential helicobacter pylori infection rates in two contrasting gastric cancer risk regions of South China. Journal of Gastroenterology and Hepatology (Australia). 1999;14(2):120–5.

M AN U

17. Zhang X, Sun X, Zhao W. Seroepidemiological study on Helicobactor pylori infection in rural adult residents. [Chinese]. Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi. 1999;20(4):212–4. 18. Chen S, Xiao S, Liu W, Xu W, Pan Y. Comparison of seroepidemiology of Helicobacter pylori in Shanghai urban area during 1990 and 2001. Chinese Journal of Gastroenterology. 2002;7(3):146–8. 19. Brown LM, Thomas TL, Ma JL, Chang YS, You WC, Liu WD, et al. Helicobacter pylori infection in rural China: Demographic, lifestyle and environmental factors. International Journal of Epidemiology. 2002;31(3):638–46.

TE D

20. Chen SL, Xiao SD. Seroepidemiological comparison of Helicobacter pylori infection rates in Shanghai urban districts in 1990 and 2001. Chinese Journal of Digestive Diseases. 2003;4(1):40–4. 21. Chen SY, Liu TS, Fan XM, Dong L, Fang GT, Tu CT, et al. [Epidemiological study of Helicobacter pylori infection and its risk factors in Shanghai]. Chung–Hua i Hsueh Tsa Chih [Chinese Medical Journal]. 2005;85(12):802–6.

EP

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144. Brenner H, Berg G, Lippus N, Kliebsch U, Bode G, Boeing H. Alcohol consumption and Helicobacter pylori infection: Results from the German National Health and Nutrition survey. Epidemiology. 1999;10(3):214–8. 145. Seher C, Thierfelder W, Dortschy R. Helicobacter pylori – Prevelance in the German population. [German] Helicobacter pylori – Pravalenz in der Deutschen bevolkerung. Gesundheitswesen. 2000;62(11):598–603. 146. Holtmann G, Gschossmann J, Holtmann M, Talley NJ. H. pylori and functional dyspepsia. Increased serum antibodies as an independent risk factor? Digestive Diseases and Sciences. 2001;46(7):1550–7.

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147. Kuepper–Nybelen J, Thefeld W, Rothenbacher D, Brenner H. Patterns of alcohol consumption and Helicobacter pylori infection: results of a population–based study from Germany among 6545 adults. Aliment Pharmacol Ther. 2005;21(1):57–64 148. Wex T, Kreutzer J, Venerito M, Gotze T, Kandulski A, Malfertheiner P. Serological prevalence of helicobacter pylori–infection in Saxony–Anhalt, Germany. Helicobacter. 2011;16:106.

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149. Loffeld RJLF, Van Der Putten ABMM. Changes in prevalence of Helicobacter pylori infection in two groups of patients undergoing endoscopy and living in the same region in The Netherlands. Scandinavian Journal of Gastroenterology. 2003;38(9):938–41.

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150. Loffeld RJ, van der Putten AB. Changes in prevalence of Helicobacter pylori infection in two groups of patients undergoing endoscopy and living in the same region in the Netherlands. Scandinavian Journal of Gastroenterology. 2003;38(9):938–41. 151. van Blankenstein M, van Vuuren AJ, Looman CW, Ouwendijk M, Kuipers EJ. The prevalence of Helicobacter pylori infection in the Netherlands. Scandinavian Journal of Gastroenterology. 2013;48(7):794–800. 152. Lehmann FS, Renner EL, Meyer–Wyss B, Wilder–Smith CH, Mazzucchelli L, Ruchti C, et al. Helicobacter pylori and gastric erosions: Results of a prevalence study in asymptomatic volunteers. Digestion. 2000;62(2–3):82–6.

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153. Carter FP, Frankson T, Pintard J, Edgecombe B. Seroprevalence of Helicobacter pylori infection in adults in the bahamas. West Indian Medical Journal. 2011;60(6):662–5. 154. Weill FX, Margeridon S, Broutet N, Le Hello S, Neyret C, Megraud F. Seroepidemiology of Helicobacter pylori infection in Guadeloupe. Transactions of the Royal Society of Tropical Medicine & Hygiene. 2002;96(5):517–9. 155. Torres J, Leal–Herrera Y, Perez–Perez G, Gomez A, Camorlinga–Ponce M, Cedillo–Rivera R, et al. A community–based seroepidemiologic study of Helicobacter pylori infection in Mexico. Journal of Infectious Diseases. 1998;178(4):1089–94.

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156. Cardenas VM, Mena KD, Ortiz M, Karri S, Variyam E, Behravesh CB, et al. Hyperendemic H. pylori and tapeworm infections in a U.S.–Mexico border population. Public Health Reports. 2010;125(3):441–7.

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157. Sasaki T, Hirai I, Yamamoto Y. Analysis of Helicobacter pylori infection in a healthy Panamanian population. [Japanese]. Kansenshogaku zasshi. 2009; The Journal of the Japanese Association for Infectious Diseases. 83(2):127–32. 158. Olmos JA, Rios H, Higa R, Adami J, Barclay C, Barrena M, et al. Prevalence of Helicobacter pylori infection in Argentina: Results of a nationwide epidemiologic study. Journal of Clinical Gastroenterology. 2000;31(1):33–7. 159. De Oliveira AMR, Rocha GA, De Magalhaes Queiroz DM, Barbosa MT, Silva SC. Prevalence of H. pylori infection in a population from the rural area of Aracuai, MG, Brazil. Revista de Microbiologia. 1999;30(1):59–61.

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160. Nascimento RS, Valente SR, Oliveira LC. Seroprevalence of Helicobacter pylori infection in chronic chagasic patients, and in the rural and urban population from Uberlandia, Minas Gerais, Brazil. Revista do Instituto de Medicina Tropical de Sao Paulo. 2002;44(5):251–4.

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161. Lyra AC, Santana G, Santana N, Silvany–Neto A, Magalhaes E, Pereira EM, et al. Seroprevalence and risk factors associated with Helicobacter pylori infection in blood donors in Salvador, Northeast–Brazil. The Brazilian journal of infectious diseases: an official publication of the Brazilian Society of Infectious Diseases. 2003;7(5):339–45.

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162. Santos IS, Boccio J, Santos AS, Valle NC, Halal CS, Bachilli MC, et al. Prevalence of Helicobacter pylori infection and associated factors among adults in Southern Brazil: a population–based cross–sectional study. BMC public health. 2005;5:118. 163. Zaterka S, Eisig JN, Chinzon D, Rothstein W. Factors related to Helicobacter pylori prevalence in an adult population in Brazil. Helicobacter. 2007;12(1):82–8. 164. Santos IS, Minten GC, Valle NC, Tuerlinckx GC, Boccio J, Barrado DA, et al. Helicobacter pylori and anemia: a community–based cross–sectional study among adults in Southern Brazil. Cadernos de saude publica / Ministerio da Saude, Fundacao Oswaldo Cruz, Escola Nacional de Saude Publica. 2009;25(12):2653–60. 165. Ferreccio C, Rollan A, Harris PR, Serrano C, Gederlini A, Margozzini P, et al. Gastric cancer is related to early Helicobacter pylori infection in a high– prevalence country. Cancer Epidemiology Biomarkers and Prevention. 2007;16(4):662–7.

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166. Sasaki T, Hirai I, Izurieta R, Kwa BH, Estevez E, Saldana A, et al. Analysis of Helicobacter pylori genotype in stool specimens of asymptomatic people. Laboratory Medicine. 2009;40(7):412–4.

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167. Veldhuyzen Van Zanten SJO, Pollak PT, Best LM, Bezanson GS, Marrie T. Increasing prevalence of Helicobacter pylori infection with age: Continuous risk of infection in adults rather than cohort effect. Journal of Infectious Diseases. 1994;169(2):434–7.

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168. Milman N, Byg KE, Andersen LP, Mulvad G, Pedersen HS, Bjerregaard P. Indigenous Greenlanders have a higher sero–prevalence of IgG antibodies to Helicobacter pylori than Danes. International journal of circumpolar health. 2003;62(1):54–60.

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169. Koch A, Krause TG, Krogfelt K, Olsen OR, Fischer TK, Melbye M. Seroprevalence and risk factors for Helicobacter pylori infection in Greenlanders. Helicobacter. 2005;10(5):433–42. 170. Fitzgibbons PL, Dooley CP, Cohen H, Appleman MD. Prevalence of gastric metaplasia, inflammation, and Campylobacter pylori in the duodenum of members of a normal population. American Journal of Clinical Pathology. 1988;90(6):711–4. 171. Dooley CP, Cohen H, Fitzgibbons PL, Bauer M, Appleman MD, Perez–Perez GI, et al. Prevalence of Helicobacter pylori infection and histologic gastritis in asymptomatic persons. New England Journal of Medicine. 1989;321(23):1562–6.

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172. Correa P, Fox J, Fontham E, Ruiz B, Lin Y, Zavala D, et al. Helicobacter pylori and gastric carcinoma. Serum antibody prevalence in populations with contrasting cancer risks. Cancer. 1990;66(12):2569–74. 173. Graham DY, Malaty HM, Evans DG, Evans Jr DJ, Klein PD, Adam E. Epidemiology of Helicobacter pylori in an asymptomatic population in the United States: Effect of age, race, and socioeconomic status. Gastroenterology. 1991;100(6):1495–501.

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174. Everhart JE, Kruszon–Moran D, Perez–Perez GI, Tralka TS, McQuillan G. Seroprevalence and ethnic differences in Helicobacter pylori infection among adults in the United States. Journal of Infectious Diseases. 2000;181(4):1359–63.

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175. Cardenas VM, Mulla ZD, Ortiz M, Graham DY. Iron deficiency and Helicobacter pylori infection in the United States. American Journal of Epidemiology. 2006;163(2):127–34. 176. Patterson T, Straten E, Jimenez S. The prevalence of Helicobacter pylori antibody in different age groups in Central Texas. Clinical laboratory science: journal of the American Society for Medical Technology. 2012;25(2):102–6. 177. Parkinson AJ, Gold BD, Bulkow L, Wainwright RB, Swaminathan B, Khanna B, et al. High prevalence of Helicobacter pylori in the Alaska Native population and association with low serum ferritin levels in young adults. Clinical and Diagnostic Laboratory Immunology. 2000;7(6):885–8. 178. Melius EJ, Davis SI, Redd JT, Lewin M, Herlihy R, Henderson A, et al. Estimating the prevalence of active Helicobacter pylori infection in a rural community with global positioning system technology–assisted sampling. Epidemiology and Infection. 2013;141(3):472–80.

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180.

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179. Collett JA, Burt MJ, Frampton CM, Yeo KH, Chapman TM, Buttimore RC, et al. Seroprevalence of Helicobacter pylori in the adult population of Christchurch: risk factors and relationship to dyspeptic symptoms and iron studies. The New Zealand medical journal. 1999;112(1093):292–5. Peach HG. Helicobacter pylori infection in an Australian regional city: Prevalence and risk factors. Medical Journal of Australia. 1997;167(6):310–3.

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181. Robertson MS, Cade JF, Savoia HF, Clancy RL. Helicobacter pylori infection in the Australian community: Current prevalence and lack of association with ABO blood groups. Internal Medicine Journal. 2003;33(4):163–7.

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182. Moujaber T, MacIntyre CR, Backhouse J, Gidding H, Quinn H, Gilbert GL. The seroepidemiology of Helicobacter pylori infection in Australia. International Journal of Infectious Diseases. 2008;12(5):500–4. 183. Pandeya N, Whiteman DC, Australian Cancer S. Prevalence and determinants of Helicobacter pylori sero–positivity in the Australian adult community. Journal of Gastroenterology & Hepatology. 2011;26(8):1283–9.

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184. Windsor HM, Abioye–Kuteyi EA, Leber JM, Morrow SD, Bulsara MK, Marshall BJ. Prevalence of Helicobacter pylori in Indigenous Western Australians: Comparison between urban and remote rural populations. Medical Journal of Australia. 2005;182(5):210–3.

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99.8 99.7 99.2 97.1 99.6

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95% Confidence Interval 50.3-58.5 55.5-70.3 35.7-63.1 46.0-56.8 35.6-73.6

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HP Prevalence (%) 54.4 62.9 49.4 51.4 54.6

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HP diagnostic methods used Serology Urea Breath Test Stool Antigen CLO, histology Serology, UBT

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Appendix 8: Pooled HP prevalence stratified by adult-only studies

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Appendix 9: HP prevalence time trend in the six United Nations regions

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95% CI 1970–1999 2000–2016 50.6–60.5 48.7–57.7 53.0–68.0 48.1–56.4 51.0–57.8 25.3-82.1 44.9–66.2 36.5–56.4 45.5–54.9 51.3–60.3 – – – 51.5–66.5 – – 3.6–5.8 13.2–15.1 37.7–43.9 – – – 64.7–75.4 75.0-85.2 45.5–61.7 49.7–59.0

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Time trends in HP prevalence in UN Asian region Country Prevalence Estimates 1970–1999 2000–2016 Eastern Asia 55.6 53.2 China 60.5 52.2 Taiwan 54.4 53.7 Japan 55.5 46.5 Korea 50.2 55.8 + Southern Asia – – Iran – 59.0 + South–Eastern Asia – – Malaysia 4.7 14.2 Singapore 40.8 – + Western Asia – – Turkey 70.1 80.1 UN Asia 53.6 54.3 + Insufficient data for pooled analysis * Number of individuals included in analysis

# of reporting studies 1970–1999 2000–2016 – 2 1 – – 1 – 2 – 5

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95% CI 1970–1999 2000–2016 – 70.0–78.1 80.8–89.3 – – 83.3–90.3 – 53.7–91.9 – 67.3–85.0

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Time trends in HP prevalence in UN African region Country Prevalence Estimates 1970–1999 2000–2016 Benin – 74.1 Nigeria 85.1 – South Africa – 86.8 Tunisia – 72.8 UN Africa – 76.2

# of reporting studies 1970–1999 2000–2016 30 42 11 14 1 2 8 6 10 20 – – – 8 – – 1 1 2 – – – 1 2 34 53

# of subjects* 1970–1999 2000–2016 – 446 268 – – 356 – 348 – 1 150

# of subjects* 1970–1999 2000–2016 30978 242 245 13 753 88 577 823 1 413 8 308 38 856 8 094 113 399 – – – 5 256 – – 1 417 5 370 953 – – – 284 5 752 33 632 156 563

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95% CI 1970–1999 2000–2016 52.3–80.0 20.4–61.9 53.4–64.4 14.8–50.4 69.6–76.4 57.1–59.5 31.0–63.3 20.5–49.5 85.7–90.2 75.1–90.0 46.5–67.0 – 30.9–40.4 31.8–40.7 – 13.1–46.0 17.8-33.0 7.9–14.4 11.1-75.4 – 47.2–59.3 36.2–62.6 44.4–64.4 24.5–42.9 42.5–68.0 – 40.5–54.5 – 38.7-69.2 49.0–64.3 15.4–40.5 36.4–41.3 27.8–38.6 42.4–46.4 – 30.1–41.0 40.3–56.2 32.5–46.9

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Time trends in HP prevalence in UN European region Country Prevalence Estimates 1970–1999 2000–2016 Eastern Europe 66.1 41.2 Czech Republic 58.9 36.6 Poland 73.0 58.3 Northern Europe 47.2 35.0 Estonia 87.9 69.2 Finland 56.8 – Iceland 35.7 36.2 Norway – 29.5 Sweden 25.4 11.1 UK 43.3 – Southern Europe 53.3 49.4 Greece 54.4 33.7 Italy 55.2 – San Marino 47.5 – Spain 53.9 56.6 Western Europe 27.9 38.8 Germany 33.1 44.4 Netherlands – 35.5 UN Europe 48.2 39.7 * Number of individuals included in analysis

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Time trends in HP prevalence in UN Latin American and the Caribbean region Country Prevalence Estimates 95% CI 1970–1999 2000–2016 1970–1999 2000–2016 Bahamas – 57.8 – 51.1–64.6 ^ Guadeloupe – 49.0 – 35.3–62.8 Mexico 66.5 38.1 65.7–67.4 31.7–44.6 Panama – 54.1 – 59.2–67.6 Argentina 49.1 – 44.7–53.5 – Brazil 68.2 71.3 63.5–72.9 68.1-74.6 Chile – 74.6 – 72.9–76.2 Ecuador – 72.2 – 63.0–81.5 UN Latin America and 62.8 60.2 53.6–71.9 52.0–68.4 Caribbean ^ Insular region of France located in the Caribbean

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Time trends in HP prevalence in UN Northern America region Country Prevalence Estimates 95% CI 1970–1999 2000–2016 1970–1999 2000–2016 Greenland 41.4 – 37.9–44.9 – United States of America 42.2 26.6 22.9–61.5 19.0–34.1 UN Northern America 42.7 26.6 32.7–52.6 19.0–34.1 * Number of individuals included in analysis

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# of reporting studies 1970–1999 2000–2016 2 – 2 3 4 3

# of subjects* 1970–1999 2000–2016 – 204 – 854 11 605 215 – 74 493 – 374 1 080 – 2 615 – 90 12 472

5 132

# of subjects* 1970–1999 2000–2016 756 – 7 950 7 781 8 706 7 781

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Time trends in HP prevalence in UN Oceania region Country Prevalence Estimates 1970–1999 2000–2016 New Zealand 24.0 – Australia 30.4 18.7 UN Oceania 26.6 18.7 * Number of individuals included in analysis

# of subjects* 1970–1999 2000–2016 1 060 – 217 3 768 1 277 3 768

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Supplementary Material: (see separate file) Appendix 1: MEDLINE and EMBASE search strategy for article selection (from 1 Jan 1970 to 1 Jan 2016) Appendix 2: Quality assessment of selected papers

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Appendix 3: Distribution of included papers by regions and countries Appendix 4: Country and region specific prevalence of HP since 1 Jan 1970 to 1 Jan 2016 in Northern America, Southern America, Oceania, Eastern Asia, Southern Asia, Western Asia, Northern Europe, Southern Europe, Western Europe and Northern Africa

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Appendix 6: Pooled HP prevalence stratified by country and UN region

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Appendix 9: HP prevalence time trend in the six United Nations regions