National rates of Helicobacter pylori recurrence are significantly and inversely correlated with human development index

Authors

  • T.-L. Yan,

    1. Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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    • Both authors contributed equally to this work.
  • Q.-D. Hu,

    1. Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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    • Both authors contributed equally to this work.
  • Q. Zhang,

    1. Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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  • Y.-M. Li,

    Corresponding author
    • Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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  • T.-B. Liang

    Corresponding author
    1. Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
    • Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Correspondence to:

Dr Y.-M. Li, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.

E-mail: zlym@zju.edu.cn

T.-B. Liang, Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China.

E-mail: liangtingbo@zju.edu.cn

Summary

Background

Helicobacter pylori infection is a worldwide threat to human health with recurrence rates that vary widely. The precise correlation between H. pylori recurrence and socioeconomic development has not been determined.

Aim

To determine H. pylori recurrence rates after successful eradication and their association with socioeconomic development metrics.

Methods

Bibliographical searches were performed in the MEDLINE database. We reviewed all results, filtered by inclusion criteria, extracted primary results to calculate H. pylori recurrence rates and calculated national Human Development Index (HDI) values for the periods during which the studies were conducted.

Results

One thousand two hundred and twenty six cases of H. pylori recurrence in 77 eligible studies were observed in 43 525.1 follow-up patient-years after successful eradication therapy, giving a recurrence rate of 2.82 ± 1.16% per patient-year (weighted mean ± 95% confidence interval). H. pylori recurrence rate was inversely correlated with national HDI on linear (r = −0.633) and weighted least square (r = −0.546) regression analysis. Countries with very high HDI had a mean recurrence rate significantly lower than that of high, medium and low HDI countries (P < 0.01, 0.001, and 0.001, respectively).

Conclusions

Less-developed areas, as measured by HDI, are more likely to have high H. pylori recurrence rates. A different approach to follow-up after H. pylori eradication is needed in developing countries where reinfection is highly prevalent, paying special attention to sources of reinfection and high-risk groups.

Introduction

Helicobacter pylori infection is an important risk factor for numerous gastrointestinal diseases, including gastritis, peptic ulcers, gastric carcinoma and gastric lymphoma.[1] Affecting 20–50% of people in industrialised nations and up to 80% of those in less-developed countries,[2] H. pylori infection is a worldwide threat to human health. In developing areas, H. pylori infection is acquired more frequently at an early age, mainly by oral ingestion of the bacterium.[2-4]

Several effective therapies have been applied to eradicate H. pylori infection.[5] Successful eradication leads to a dramatic reduction in the incidence of microorganism-associated diseases.[6, 7] The incidence of H. pylori infection depends on four factors: the intrinsic transmissibility of the agent, barriers imposed on transmission, the innate immunity of the host and the prevalence of the infection within the population.[8] A high prevalence of infection increases the possibility of interhuman transmission. Recurrence of H. pylori infection is therefore an important consideration after clearance of the bacterium.[9, 10]

Given observed differences in the prevalence of H. pylori infection and other risk factors between populations, the recurrence rate is likely to be high in developing areas. Recent approaches based on large samples showed that H. pylori infection is rare in Japan[11] and Spain,[12, 13] suggesting that relapse after eradication is not a problem in developed countries.[14] By contrast, high recurrence rates have been reported in less-developed regions where the prevalence of H. pylori is very high.[9] A pooled analysis demonstrated an annual recurrence rate of 1.45% in developed countries, compared with 12% in developing countries.[15] Definitive cure of peptic disease and mucosa-associated lymphoid tissue (MALT) lymphoma, as well as reduction in the progression of atrophic gastritis, is dependent on successful eradication of H. pylori infection.[8] Furthermore, H. pylori is an underlying carcinogen in gastric cancer, the second commonest cause of cancer death worldwide. Thus, prompt detection of reinfection must be taken seriously, especially in developing countries in which gastric cancer is one of the most common cancers.[16]

The precise correlation between H. pylori recurrence rate and socioeconomic development has not been determined, due to the lack of a suitable standard to evaluate development level. This study aimed to review previous studies to determine national H. pylori recurrence rates and to identify the relationship between recurrence rate and socioeconomic development assessed according to the Human Development Index (HDI).

Methods

Definitions

Diagnostic methods for H. pylori infection

We included only those studies that used an eligible method for detection of H. pylori infection, namely: (i) 13C/14C urea breath test (UBT); (ii) endoscopy with rapid urease test; (iii) histology with bacterial culture; (iv) stool antigen test; or (v) serologic test. H. pylori infection was defined as at least one positive result obtained by an eligible method.

H. pylori recurrence after eradication

Successful eradication was defined as the achievement of negative H. pylori status in a previously H. pylori positive patient 4 weeks after eradication treatment. The regimen should have contained at least one antibiotic. H. pylori recurrence referred to the situation in which H. pylori status became positive again after successful eradication.

HDI

The HDI is a composite index measuring average achievement in three basic dimensions of human development: (i) long and healthy life (life expectancy at birth); (ii) education (mean and expected years of schooling); and (iii) decent standard of living (gross national income per capita).

Search strategy and literature evaluation

We performed a MEDLINE search in PubMed up to September, 2012 using the string ‘(Helicobacter pylori OR H. pylori) AND (recurrence OR recrudescence OR reinfection)’, resulting in 1598 publications. All articles identified by the PubMed search were reviewed. After screening based on titles or abstracts, 1457 articles were excluded due to irrelevant topics. Inclusion criteria for further analysis were: (i) research conducted in an adult population; (ii) follow-up duration of at least 6 months after successful eradication; and (iii) diagnosis of H. pylori infection and recurrence used at least one eligible method. Ninety-nine studies were included for further analysis. An additional six studies were identified from the references listed in each study and were carefully reviewed using the same criteria. Thirteen of the 105 studies did not have reliable or adequate data to calculate annual recurrence rates and were excluded. Primary results (research duration, follow-up methods, recurrent cases, follow-up patient-years, and annual recurrence rate) in each study were extracted into an Excel sheet for further analysis. For articles without precise information on the period during which the research was undertaken, this was estimated according to: end date = publication date−3 years, start date = end date−2.5 × mean follow-up duration.

All articles were assessed by two authors. In the event of disagreement on study eligibility or data extraction, the views of a third reviewer were sought.

Sample size requirements

The sample size required was determined using the formula math formula, where the significance level α = 0.05 (tα ≈ 2) and the mean recurrence rate p was estimated to be 5%. An expected recurrence rate of 5 ± 5% (mean ± standard deviation) required a sample size of 76 follow-up patient-years.

Estimation of national HDI

Data for Union Nations member states in 1980–2011 were obtained from the United Nations Development Programme database (http://hdr.undp.org/en/statistics). HDI was calculated according to the 2011 Human Development Report (HDR 2011),[17] which lists data for 2011 and previous years in the table ‘Human Development Index Trends, 1980–2011’. We downloaded this information and calculated the average HDI over the research period of each study; for example, if a study was performed from 2005 to 2010, the final HDI was the average of the annual HDIs for 2005–2010. Missing data were estimated from the available information, based on the hypothesis that HDI progresses linearly over short periods of time. HDIs for Taiwan were obtained from the National Statistics (Taiwan) website (http://www.stat.gov.tw) and were double-checked afterwards. Two studies without available data for estimation of HDI were included in the calculation of annual H. pylori recurrence rates but excluded from the later regression analysis.

The HDI for each study was defined as the mean HDI during the research period. Based on quartiles of HDI distribution in the HDR 2011,[17] countries were placed into four predefined socioeconomic groups as follows: very high (HDI ≥ 0.788), high (0.788 > HDI ≥ 0.698), medium (0.698 > HDI ≥ 0.516) and low (HDI < 0.516).

Statistical analysis

Correlations between national HDI and H. pylori recurrence rate were fitted by linear and weighted least square (WLS) regression analysis. Residuals were analysed using the Durbin–Watson test, in which (4−d) > dU was defined as no significant residual autocorrelation. The statistical significance of differences in recurrence rate among the four groups was determined by one-way analysis of variance (anova) followed by the Tukey–Kramer post hoc test. P values less than 0.05 were considered significant. Associated data were calculated and plotted using Prism 5 (GraphPad, San Diego, CA, USA). Statistical analysis was performed using spss 16.0 (IBM, Chicago, IL, USA).

Results

Study selection

Ninety-two studies were included in our analysis (Figure 1). Seventy-seven studies were conducted with at least 76 follow-up patient-years. Primary results including first author, research period, follow-up methods, recurrent cases/follow-up patient-years and annual recurrence rate are summarised in Table S1 in the Supporting Information for further analysis. The 77 studies included 16 827 patients who were followed up for 0.50–10.0 years with a mean duration of 2.59 ± 0.52 years [95% confidence interval (CI)]. One thousand two hundred and twenty six cases of H. pylori recurrence were observed in 43 525.1 follow-up patient-years after successful eradication therapy, giving an annual recurrence rate of 2.82 ± 1.16% per patient-year (weighted mean ± 95% CI).

Figure 1.

Study flowchart with inclusion criteria.

H. pylori recurrence rate and national HDI

Annual H. pylori recurrence rates varied among studies conducted in different countries or during different research periods. High national HDI was associated with relatively low recurrence rates. Among the 75 analysed studies, H. pylori recurrence rate was inversely correlated with national HDI according to linear regression analysis [β = −35.86 ± 10.24 (95% CI), = −0.633; = 2.355, dU = 1.652, Durbin–Watson test] (Figure 2). β was significantly non zero (= 48.80 with P < 0.0001, anova). Furthermore, the inverse correlation also existed on WLS regression (β = −25.09 ± 8.98 (95% CI), = −0.546; = 2.189, Durbin–Watson test), with a significantly non zero value of β (= 31.01 with P < 0.0001, anova) (Figure 2). Two studies (56, 66)[18, 19] were not included in current analysis, due to lack of data to calculate HDI.

Figure 2.

Annual Helicobacter pylori recurrence rate and Human Development Index (HDI). Best-fit lines by linear (solid) and weighted least square (WLS; dashed) regression analysis are indicated. The data show that H. pylori recurrence rate was inversely correlated with national HDI on linear regression analysis (= −0.633). Furthermore, an inverse correlation existed on WLS regression analysis (= −0.546).

Recurrence rate and socioeconomic development

The 75 studies were classified into four groups according to national HDI. Forty-one studies were conducted in very high HDI countries, 17 in high HDI countries, 12 in medium HDI countries and five in low HDI countries. We concluded that countries with lower HDI were more likely to have high mean recurrence rates; countries with very high HDI had a mean recurrence rate of only 1.68 ± 0.87% (weighted mean ± 95% CI), which was significantly lower than that of high HDI countries at 6.05 ± 2.55% (95% CI; P < 0.01, one-way anova followed by Tukey–Kramer post hoc test), medium HDI countries at 7.04 ± 4.21% (95% CI; P < 0.001, Tukey–Kramer test) and low HDI countries at 9.63 ± 13.13% (95% CI; P < 0.001, Tukey–Kramer test) (Figure 3).

Figure 3.

Annual recurrence rates differed significantly between countries with different development levels. *P < 0.01, **P < 0.001 vs. very high HDI countries; one-way analysis of variance followed by the Tukey–Kramer post hoc test. Countries with very high HDI had a mean recurrence rate of 1.68 ± 0.87%, which was significantly lower than that of high HDI countries at 6.05 ± 2.55%, medium HDI countries at 7.04 ± 4.21%, and low HDI countries at 9.63 ± 13.13%.

Discussion

Despite the low incidence in highly developed countries,[14] recurrence of H. pylori after successful eradication remains a serious problem worldwide, especially in less-developed areas. We reviewed published studies of H. pylori recurrence and calculated the annual recurrence rate for each paper. A global recurrence rate of 2.82% per patient-year was determined from studies with at least 76 follow-up patient-years. A previous review reported a mean recurrence rate of 4.5% (range 0–54%) per patient-year in studies with a small sample size.[9] The lower recurrence rate in the present study might result from socioeconomic improvements in these countries and/or different inclusion criteria. In addition, small sample sizes with regard to follow-up patient-years might lead to either overestimation[20, 21] or underestimation[22] of true recurrences rates.

The incidence of H. pylori recurrence varies with regional development, with differing rates in developed and developing countries[15, 23]; Gisbert et al.[9] reported rates of 3.4% and 8.7% per patient-year in developed and developing areas respectively. However, the precise correlation between H. pylori recurrence rate and socioeconomic development has been unclear.

Human Development Index is a composite measure of human development based on the length and quality of life, access to knowledge and standard of living.[17] As an indicator of socioeconomic status, HDI may represent the gold standard for international comparisons of development. Several types of cancer, including stomach and liver cancer, have been confirmed to be more common in lower HDI areas than in higher HDI areas.[16] Using data from the HDR 2011,[17] HDIs for 1980–2011 were calculated based on national development levels in 2011; thus, the actual HDI for the period of each study could be estimated, rather than using the current HDI.

In this study, we demonstrated that the annual H. pylori infection recurrence rate is inversely correlated with socioeconomic development as represented by the HDI. Both linear and WLS regression analysis suggested a significant inverse correlation. Furthermore, countries with very high HDI had significantly lower recurrence rates than high, medium and low HDI countries, consistent with previous approaches based on the dichotomous developed/developing classification.[8, 9, 15, 23] The low recurrence rate (1.68% per patient-year in very high HDI countries) confirmed that H. pylori relapse is not a critical problem in developed countries.[14] By contrast, high recurrence rates were associated with low development levels. Interestingly, some paradoxes, identified by residual statistics in our regression analysis, were observed in some studies conducted in countries such as Bangladesh[24] and China,[25] where recurrence rates were low despite a high prevalence of infection. This could be explained by countries with lower HDI being less well equipped to establish studies to measure H. pylori recurrence rates, to use the most accurate observation methods, and to follow cases over time. Therefore, there may be fewer observations at this end of the spectrum and less certainty in these results.

Recurrence of H. pylori occurs via two distinct mechanisms: recrudescence and reinfection, which depends on identification of the infecting strain.[4, 9] Reinfection contributes to 62.5% of cases of H. pylori recurrence in the first 6 months after eradication, as well as most cases in the first year.[4] Given that person-to-person transmission is a predominant route of H. pylori infection, living conditions, lifestyle and socioeconomic status are all associated with H. pylori occurrence.[4] Accordingly, living in a lower HDI area might carry an increased risk of becoming reinfected even after effective treatment.

Recurrence of H. pylori infection thus remains a burden in less-developed areas. Recurrence of peptic ulcer, MALT lymphoma and other complications are associated with H. pylori reinfection after eradication, although the recurrence can sometimes be an asymptomatic event without clinical consequences.[9] Furthermore, H. pylori infected patients have a higher risk of developing gastric cancer[26]; 622 000 cases of gastric cancer occurred in lower HDI countries in 2008, compared with 366 000 in higher HDI countries.[16] Thus, prompt detection of reinfection must be taken seriously, especially in developing countries where people are at high risk for gastric cancer.

In patients with diseases that are associated with H. pylori such as bleeding peptic ulcers, MALT lymphoma and mild to moderate dysplasia gastritis,[27] systematically repeating diagnostic tests to confirm their H. pylori negative status after eradication is important. When symptoms recur, reinfection screening must be performed again, because reinfection is a clinically relevant event.[9] Given its high sensitivity (95%) and specificity (95%), as well as its usefulness both before and after treatment,[8] UBT is the most commonly used method for reinfection screening clinically.

In conclusion, this study reviewed previous studies reporting H. pylori recurrence and determined a global recurrence rate of 2.82% per patient-year. The inverse correlation between H. pylori recurrence rate and HDI suggests that areas of low socioeconomic development are more likely to have higher recurrence rates. This association is likely to be due to differences in living conditions and socioeconomic status during childhood in such countries. This is the first time that H. pylori reinfection has been associated with poor socioeconomic conditions using an objective measurement. Future research may assess whether more effective primary prevention strategies alongside detection and eradication treatment could reduce the recurrence of H. pylori. A different follow-up approach to H. pylori eradication is needed in patients in developing countries where reinfection is highly prevalent, paying special attention to sources of reinfection and high-risk groups.

Authorship

Guarantor of the article: Tian-Lian Yan.

Author contributions: Tian-Lian Yan and Qi-Da Hu collected the data, did the statistical analysis and wrote the paper. Tian-Lian Yan revised the manuscript. You-Ming Li, Ting-Bo Liang and Qi Zhang contributed to conception and design of the study. All authors approved the final version of the manuscript.

Acknowledgement

Declaration of personal and funding interests: None.

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