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BMJ Open logoLink to BMJ Open
. 2020 Jan 9;10(1):e031951. doi: 10.1136/bmjopen-2019-031951

Association between H. pylori infection and health Outcomes: an umbrella review of systematic reviews and meta-analyses

Liqun Li 1,#, Jinjing Tan 2,3,#, Lijian Liu 4,#, Jianfeng Li 1,#, Guangwen Chen 4, Mingbing Chen 1, Jieru Xie 5, Qingzeng Song 1, Xiaoyan Huang 4, Sheng Xie 3,
PMCID: PMC6955574  PMID: 31924635

Abstract

Objective

Systematic reviews and meta-analyses have revealed the associations between H. pylori infection and various health outcomes. We aimed to evaluate the strength and breadth of evidence on the associations.

Design

Umbrella review of systematic reviews and meta-analyses.

Setting

No settings.

Participants

No patients involved.

Data sources

Embase, PubMed, Web of Science, Cochrane Library Databases, CNKI, VIP database and Wangfang database from inception to February 1, 2019.

Outcomes measures

Diverse diseases (such as cancer and ischaemic heart disease).

Results

Sixty articles reporting 88 unique outcomes met the eligible criteria. 74 unique outcomes had nominal significance (p<0.05). Of the outcomes with significance, 61 had harmful associations and 13 had beneficial associations. Furthermore, 73% (64) of the outcomes exhibited significant heterogeneity . Of the these meta-analyses, 32 had moderate to high heterogeneity (I2=50%–75%) and 24 had high heterogeneity (I2>75%). Moreover, 20% exhibited publication bias (p<0.1). In addition, 97% of the methodological qualities were rated ‘critically low’. 36% of the evidence qualities of outcomes were rated ‘low’, 56% of the evidence qualities were rated ‘very low’ and 8% of the evidence qualities were rated ‘moderate’. H. pylori infection may be associated with an increased risk of five diseases and a decreased risk of irritable bowel syndrome.

Conclusion

Although 60 meta-analyses explored 88 unique outcomes, moderate quality evidence only existed for six outcomes with statistical significance. H. pylori infection may be associated with a decreased risk of irritable bowel syndrome and an increased risk of hypertriglyceridemia, chronic cholecystitis and cholelithiasis, gestational diabetes mellitus, gastric cancer and systemic sclerosis.

Trial registration

CRD42019124680.

Keywords: umbrella review, helicobacter pylori, human health


Strengths and limitations of this study.

  • This umbrella review is the first synthesis of systematic reviews and meta-analyses to consider the associations between H. pylori infection and various health outcomes.

  • These results provide recommendations about the relationships between H. pylori infection and various health outcomes.

  • The associations observed in the meta-analyses included in this umbrella review may reflect the uncertainty of most diseases related to H. pylori infection.

  • Only evidence derived from systematic reviews and meta-analyses was included in our umbrella review. Evidence from original observational studies and/or randomised controlled trials that were not included in the meta-analyses was beyond our scope of discussion. This condition might result in conclusion bias of association between H. pylori infection and human health.

Introduction

H. pylori is a Gram-negative bacterium that affects human health worldwide, and its prevalence ranges from 50.8% to 84%.1–4 Earlier studies demonstrated that H. pylori infection contributes to the development of several digestive diseases (e.g. gastric cancer,5 6 peptic ulcer disease (PUD)7 and dyspepsia).8 These conclusions were supported by recent studies.9–12 Over the last 20 years, the associations between H. pylori infection and a sequence of non-digestive disorders have been investigated extensively. Multiple studies and meta-analyses have revealed that H. pylori infection is harmful to human health by increasing the risk of diverse diseases, including cancers, cardiovascular and cerebrovascular diseases, respiratory disorders, endocrine diseases and neurocognitive disorders. Meta-analyses have further reported that H. pylori infection increases the risk of acquiring hepatocellular carcinoma (HCC) by more than 16-fold,13 cholangiocarcinoma by approximately 9-fold14 and myocardial infarction (MI) nearly 2-fold.15 Subsequently, with further research on H. pylori infection, it may be beneficial to health in some conditions by decreasing the risk of diseases (e.g. asthma,16 inflammatory bowel disease17 and oesophageal cancer).18 Therefore, the causal role of H. pylori infection in these diseases has been widely queried.

The observed associations between H. pylori infection and health outcomes can be causal, indicating that H. pylori infection elicits adverse effects on human health. However, the publication bias, scheme design defects or inconsistencies of studies can lead to a decrease in the strength and validity of evidence. Furthermore, confounding factors, such as age, sex, smoking or drinking status, can affect causality. The lack of adequate controls for confounders may cause reverse causality. Therefore, evidence from meta-analyses may also have uncertainty. If causal, the association of H. pylori infection and public health should be reconsidered, and the role of H. pylori infection in human health must be reanalysed. Once strong associations between H. pylori infection and diseases are confirmed, findings provide an important guidance both for conducting disease diagnosis and treatment. Therefore, the associations of H. pylori infection and health outcomes must be further evaluated.

To provide an overview of the length, validity and credibility of the evidence on the associations between H. pylori infection and human health outcomes, we systematically and comprehensively re-evaluated these pieces of evidence to make them concise for decision-makers and guideline developers. We conducted an umbrella review to estimate the findings and content of meta-analyses that investigated these associations and to estimate the evidence of potential bias and consistency of findings.

Methods

Literature search

Computerised searches on Embase, PubMed, Web of Science, Cochrane Database of Systematic Reviews, CNKI, VIP database and Wangfang database were independently and comprehensively performed by two researchers (Guangwen Chen and Mingbing Chen) to identify the systematic reviews and meta-analyses of epidemiological studies investigating the associations between H. pylori infection and diverse health outcomes. Studies published from inception to February 1, 2019 were collected using a comprehensive search strategy, and the language was limited to English and Chinese. Medical subject heading (MeSH) terms and free-text words were used: meta-analysis, meta analysis, meta-analyses, meta analyses, systematic review, Helicobacter pylori, Campylobacter pylori, Pylorus spirillum and H. pylori. The search strategies are described in online supplementary appendix 1. References from eligible systematic reviews were also manually reviewed. All identified publications were managed with EndNote X7. Two reviewers (Qingzeng Song and Jieru Xie) independently screened the titles, abstracts and full texts for eligible articles based on the inclusion and exclusion criteria. Any discrepancy was resolved by discussion, and all discrepancies that could not be resolved through a discussion were arbitrated by Sheng Xie.

Supplementary data

bmjopen-2019-031951supp001.pdf (57.8KB, pdf)

Eligibility criteria and exclusion criteria

Only systematic reviews and meta-analyses of epidemiological studies investigating the associations between H. pylori and multiple diseases were included in this umbrella review. The included systematic reviews and meta-analyses should present the data of pooled summary effects (i.e. relative risks (RRs), odds ratios (ORs), mean difference (MD), standard mean difference (SMD) and their 95% confidence intervals (CIs)), number of included studies, number of cases and participants, publication bias and heterogeneity. Table data (2×2) should be presented if pooled summary effects were unavailable. The population included was not limited to age, sex, ethnicity or country of origin. Articles were not limited to clinical setting, study region or research institution. When more than one meta-analyses were performed for the same review question, the concordance of the main conclusions was checked. If conclusions were inconsistent, the meta-analysis with the largest sample size and the latest date of publication was selected. The meta-analyses of interventional trials and diagnostic trials were unavailable for our research question. Conference abstracts on review questions were also excluded.

Patient and public involvement

Our study is a review of literature, so no patient was involved.

Data extraction

Data from each eligible systematic review and meta-analysis were independently extracted by two investigators (Liqun Li and Jinjing Tan). All of the results were carefully checked by a third investigator (Xiaoyan Huang). Any discrepancy was resolved by discussion, and all discrepancies were arbitrated by a fourth reviewer (Sheng Xie). The name of the first author, the year of publication, outcomes examined, the number of included studies, the total numbers of participants and cases, study design, study region and detection method of H. pylori were extracted by using a predesigned data extraction form. For each eligible systematic review and meta-analysis, the reported relative summary risk estimates (RRs, ORs, SMD or MD) and their 95% CIs were extracted. The p values of the overall pooled effects, Egger’s test and Cochran Q test were extracted. The results of I2 were also extracted. However, if the eligible systematic reviews or meta-analyses did not assess the quality of the included studies, assessing the quality was beyond our task in this umbrella review. If systematic reviews or meta-analyses examined more than one health outcome of interest, each outcome was recorded separately. If the included meta-analyses did not present the results of pooled meta-analysis (RRs, ORs, SMD or MD), I2, Egger’s test or publication bias, the 2×2 table data from studies included in those meta-analyses were extracted for reanalysis.

Assessment of methodological quality

The methodological quality of the included studies was independently assessed by two investigators (Liqun Li and Jianfeng Li) using AMSTAR 2 (A Measurement Tool to Assess systematic Reviews),19 and the results were checked by a third investigator (Xiaoyan Huang) . Inconsistencies were resolved through a discussion or consultation with a fourth reviewer (Sheng Xie). AMSTAR 2 is a reliable, valid and critical assessment tool developed from AMSTAR in 2017.19–21 It contains 16 checklists (7 critical checklists and 9 non-critical checklists) for assessing systematic reviews and meta-analyses, including randomised controlled trial (RCT) studies, observational studies on exposures or both. The rating criteria of AMSTAR 2 were as follows: zero or one non-critical weakness was defined as high quality; more than one non-critical weakness was defined as moderate quality; one critical flaw with or without non-critical weaknesses was defined as low quality; and more than one critical flaw with or without non-critical weaknesses was defined as critically low quality.

Assessment of the quality of evidence

In this umbrella review, we used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system to evaluate the quality of evidence for each outcome.22 23 The GRADE system includes five factors for downgrading and three factors for upgrading the quality of evidence. The baseline quality of evidence of health outcomes depends on the design of the primary studies. The summary estimate result of the random-effect model was used if potential heterogeneity was observed. Otherwise, the result of the fixed-effect model was used. When a serious or very serious defect could occur because of downgrading factors, the evidence quality was downgraded by one or two levels, respectively. If the effect was large (RR/OR either >2.0 or <0.5) or very large (RR/OR either>5.0 or <0.2), the evidence quality was upgraded by one level or two levels, respectively. If there was evidence that the influence of all plausible confouding would reduce a demonstrated effect or suggest a apurious effect when results show no effect, the evidence quality was upgraded by one level.The rating criteria of GRADE22 23 were as follows: the primary evidence quality of an observational study was considered ‘low’; the evidence quality was downgraded to ‘very low quality’ by downgrading one level, upgraded to ‘moderate quality’ by increasing one level and upgraded to ‘high quality’ by increasing two levels. The GRADE system approach classifies the evidence quality of outcomes from eligible articles as high, moderate, low and very low.22 23 GRADE classification was independently performed by two investigators (Liqun Li and Jinjing Tan), and the results were checked by a third researcher (Xiaoyan Huang). Any discrepancy was resolved via a discussion, and all discrepancies that could not be resolved through a discussion were arbitrated by Sheng Xie.

Data analysis

If the included meta-analyses did not present results of pooled meta-analysis, they were reanalysed. For example, a study was reanalysed if it did not present the results of pooled meta-analysis (RRs, ORs, SMD or MD), Egger’s test, publication bias or I2. The heterogeneity between different studies was assessed using the I2 metric of inconsistency and the p value of χ2 based on the Cochran Q test. If heterogeneity was observed, a random-effect model was used to calculate the relative summary risk estimates. Otherwise, a fixed-effect model was used.24 25 Publication bias was estimated by using Egger’s test.26 The overall effects of pooled meta-analysis, heterogeneity was considered significant at p value <0.1. Publication bias was cnsidered significant at p<0.1. Statistical analyses were conducted using Stata V.15.

Results

Description of the meta-analyses

Overall, 3036 articles that met our search criteria were first identified from the seven databases. Sixty articles9–18 27–76 of observational studies were finally selected, covering 88 unique outcomes (figure 1). Fifty-four meta-analyses10–17 28–34 38–40 42–44 47–50 54–60 64–70 72–75 were reanalysed because they did not present all of the results of estimates (i.e. OR, RR), Egger’s test, I2 or publication bias. These 60 eligible non-overlapping meta-analyses are summarised in table 1. A total of 1239 individual study estimates were included in the included meta-analyses. Various measurement methods, including serology, histology, rapid urease test and 18 other detection methods, were used to determine H. pylori positivity. A range of 2–79 study estimates were pooled per meta-analysis, and the median of the study estimate was 10. Among the 1239 individual studies, 274 (22%) were cross-sectional studies, 748 (60%) were case–control studies, 124 (10%) were cohort studies and 93 (8%) were mentioned as observational studies. Furthermore, 1 meta-analysis62 did not present the number of participants, and 12 meta-analyses27 35 36 41 45 49 51 53 54 61–63 72 did not present the number of cases. Among the meta-analyses that indicated the number of cases or participants, the median number of cases was 1032 (28–96 753) and the median number of participants was 3826 (222–377 976). A total of 76 meta-analyses included more than 1000 participants, 34 meta-analyses included more than 1000 cases and 11 meta-analyses included less than 300 cases. The 60 included articles were published from 2003 to 2019, 77% were published between 2014 and 2019, and the number of publication increased yearly before 2016 (figure 2). Various health outcomes associated with H. pylori infection included cancer outcomes (n=12), cardiovascular and cerebrovascular diseases (n=8), respiratory disorders (n=3), endocrine disease (n=10), urological disease (n=2), digestive disorders (n=18), neurocognitive disorders (n=5), pregnancy-related disorders (n=9), ophthalmic diseases (n=2), thyroid disease (n=3), haematological disorders (n=3) and other outcomes (n=13) (figure 3). A total of 23 articles conducted subgroup meta-analysis based on different study region (table 2). H. pylori infection was most harmful to Asians, followed by Europeans.

Figure 1.

Figure 1

Flowchart of study selection process for umbrella review.

Table 1.

Description of 60 meta-analyses of H. pylori infection and prevalence or incidence of diseases included in umbrella review

Included meta-analyses Outcomes HP detection
method
Number of studies Number of participants Number of cases Type of metric Relative risk (95% CI) P value* P value I2 (%) P value Whether exist publication bias
Cancer outcomes
 Xuan et al 13 Hepatocellular carcinoma HP DNA 9 CCS; 1 CSS 522 129 OR 16.52 (6.63 to 41.12) 0.00 0.07 44 0 Yes
 Mounika
44
Lung cancer ELISA 5 CCS;1 PNCCS;
1 PCS
17 951 16 244 OR 2.29 (1.34 to 3.91) 0.032 <0.01 83.9 NA No§
 Xie et al 18 ESCC in Eastern populations S; H; R; His +; HpSe + 16 OS 7665 1961 OR 0.66 (0.43 to 0.89) NA <0.01 74.5 0.42 No
 Xie et al 18 EAC in the overall population S; H; U; His +; HpSe + 15 OS 6035 1330 OR 0.59 (0.51 to 0.68) NA 0.13 29.9 0.37 No
 Wang et al 58 Colorectal adenomatous polyp S; H; several 12 CS 2678 1783 OR 1.89 (1.59 to 2.25) 0 0.10 35.9 0.61 No
 Xiao et al 14 Cholangiocarcinoma PCR; ELISA; WB 10 CCS 489 220 OR 8.88 (3.67 to 21.49) 0 0.02 56 0.01 Yes
 Dong and Hao75 Colorectal cancer IgG; UBT; CagA 21 CCS; 2 CSS 182 561 24 295 OR 1.42 (1.38 to 1.46) 0 <0.01 71 0.74 No
 Zhou et al 74 Laryngeal carcinoma ELISA; H; PCR 11 CCS 1030 418 OR 2.87 (1.7 to 4.84) 0 0.00 67.1 0.62 No
 Liu28 Colon neoplasia IgG; IgA; UBT; H; CaA 24 CCS; 7 CSS;
2 NCCS
25 897 12 145 OR 1.63 (1.39 to 1.90) 0 <0.01 80 0.14 No
 Li et al 12 Gastric cancer WB; Chip; ELISA;
neutralisation assay; EIA
10 CCS 1094 664 OR 2.78 (1.98 to 3.89) 0 0.23 22.8 0.1 No
 Ma et al 42 Oesophagogastric junction adenocarcinoma NA 9 CCS; 4 PCS 5547 2893 OR 0.95 (0.06 to 1.36) 0.769 0.00 78 0.61 No
 Liu et al 41 Pancreatic cancer ELISA 6 NCCS; 2 PCS 44 193 NA OR 1.09 (0.81 to 1.47) 0.58 <0.01 76 0.59 No
Cardiovascular and cerebrovascular diseases
 Pasceri et al 47 Ischaemic heart disease CagA 3 PCS 2140 966 OR 1.26 (1.05 to 1.51) <0.00001 0.01 53 NA No§
 Pasceri et al 47 Cerebral ischaemia CagA 4 RCCS 1103 446 OR 2.43 (1.89 to 3.13) <0.00001 0.43 0 NA No§
 Wang et al 55 Diabetic IHD S; H 5 CS 1805 469 RR 1.12 (0.95 to 1.32) 0.172 0.14 42.30 0.21 No
 Liu et al 15 Myocardial infarction NA 19 CSS; 7 PCS 21 960 11 156 OR 1.73 (1.37 to 2.17) 0 0.00 87.9 0.71 No
 Chen et al 48 Coronary heart disease NA 12 CSS; 5 PCS;
1 NA
17 514 9165 OR 1.64 (1.22 to 2.23) 0.001 <0.01 90 0.58 No
 Saburi et al 43 Atherosclerosis PCR 4 CCS 222 102 OR 5.98 (0.69 to 51.99) 0.105 0.03 67.6 0.04 Yes
 Yan et al 65 Arrhythmia IgG; 13C-UBT; UBT 7 CCS 2014 1032 OR 1.80 (1.08 to 2.99) 0.024 <0.001 80 0.28 No
 Dong et al 76 Carotid intima thickness NA 9 CCS 1370 694 SMD 0.80 (0.69 to 0.92) <0.01 0.00 89.7 NA No§
Respiratory disorders
 Wang et al 57 COPD S; 14C-UBT 9 CCS 9465 3192 OR 2.25 (1.73 to 2.92) 0 0.00 75.5 0.27 No
 Wang et al 57 Chronic bronchitis S; 14C-UBT 5 CCS 5674 1824 OR 1.57 (1.33 to 1.86) 0 0.04 58.2 0.51 No
 Chen et al 16 Asthma SA; ELISA; IgG;
13C-UBT
8 CCS; 16 CSS 53 947 5648 OR 0.83 (0.74 to 0.94) 0.002 0.00 53.4 0.67 No
Endocrine disease
 Upala et al 54 Metabolic syndrome S; R; H; SA;
UBT; biopsy
5 CSS; 1 CS 19 771 NA OR 1.34 (1.17 to 1.53) NA <0.01 39 0.92 No
 Upala et al 54 Fasting blood glucose S; R; H; SA 11 CSS; 3 CS 7905 NA MD 2.37 (0.98 to 3.77) NA 0.04 55 0.92 No
 Upala et al 54 HDL-C UBT; biopsy 9 CSS; 3 CS 7701 NA MD -2.43 (-3.75 to -1.12) NA <0.01 92 0.92 No
 Upala et al 54 Triglyceride level S; R; H; SA 8 CSS; 3 CS 7596 NA MD 8.12 (3.05 to 13.2) NA 0.04 71 0.92 No
 Upala et al 54 Systolic blood pressure UBT; biopsy; culture 5 CSS; 1 CS 7172 NA MD 2.88 (0.20 to 5.57) NA 0.01 89 0.92 No
 Upala et al 54 Body mass index S; R; H; SA 8 CSS; 2 CS 10 707 NA MD 0.30 (0.01 to 0.58) NA <0.01 57 0.92 No
 Upala et al 54 HOMA-IR UBT; biopsy 7 CSS; 3 CS 7935 NA MD 0.38 (0.03 to 0.73) NA 0.03 85 0.92 No
 Li et al 39 DM 13C-UBT; R; 14C-UBT; SA; biopsy;
culture; H
8 CSS; 68 CCS;
3 PCS
57 397 28 542 OR 1.69 (1.47 to 1.95) 0 <0.00001 86 0 Yes
 Li et al 39 T2 DM 13C-UBT; R; 14C-UBT; SA; biopsy;
culture; H
8 CSS; 57 CCS;
2 PCS
41 684 21 286 OR 2.05 (1.67 to 2.52) 0 <0.00001 89 0 Yes
 Li et al 39 T1 DM 13C-UBT; R; 14C-UBT; biopsy; H 1 PCS; 11 CCS 3175 969 OR 1.23 (0.77 to 1.96) 0.499 <0.00001 82 0.46 No
Urological disease
 Wang et al 56 Diabetic nephropathy 13C-UBT; ELISA; H 6 CCS 636 211 OR 1.6 (1.1 to 2.33) 0.018 0.44 0 0.98 No
 Wijarnpreecha et al 62 ESRD in adult A; H; R; UBT; SA;
culture
33 CSS NA NA RR 0.71 (0.55 to 0.94) NA <0.00001 79 NA No§
Digestive disorders
 Erőss et al 32 Barrett’s oesophagus S; H; UBT; PCR; R; SA 70 CCS 91 656 12 134 OR 0.68 (0.58 to 0.79) 0 0.00 84 <0.001 Yes
 Li et al 12 Gastric ulcer WB; Chip; ELISA;
neutralisation assay; EIA
8 CCS 517 260 OR 1.64 (1.02 to 2.62) 0.042 0.26 20.8 0.96 No
 Li et al 12 Duodenal ulcer WB; Chip; ELISA;
neutralisation assay; EIA
17 CCS 2359 1333 OR 2.06 (1.50 to 2.84) 0 0.01 51.3 0.63 No
 Cremonini et al 30 GERD in population with HP-negative status R; S; biopsy; H; UBT; Gram stain;
culture; H&E; Giemsa stain
14 CCS 2010 1683 OR 1.34 (1.15 to 1.55) 0 <0.001 NA NA No§
 Weck and Brenner11 Chronic atrophic gastritis NA 34 OS 7726 5048 OR 6.37 (4.01 to 10.11) 0 0.00 91.2 0.01 Yes
 Zhou et al 73 Biliary lithiasis ELISA; PCR; culture 13 CCS 1333 432 OR 2.59 (1.21 to 5.55) 0.014 <0.0001 69.5 0.18 No
 Shiota et al 10 Peptic ulcer disease PCR 42 CCS 4601 2524 OR 1.25 (1.09 to 1.44) 0.002 0.39 4.6 0.78 No
 Jiang et al 37 Ammonia levels in cirrhotic patients 14C-UBT; R; H; culture; IgG 6 OS 396 632 SMD 0.34 (0.21 to 0.47) NA 0.12 42.1 0.11 No
 Ford et al 9 Dyspepsia NA 13 CSS 25 305 9010 OR 1.18 (1.04 to 1.33) NA <0.001 63 0.3 No
 Feng et al 33 Alcoholic cirrhosis in all population R; UBT; H; ELISA 8 CCS 14 226 10053 OR 0.82 (0.35 to 1.91) 0.648 0.00 84.5 0.67 No
 Feng et al 33 Alcoholic cirrhosis in European R; H; ELISA 3 CCS 1171 516 OR 2.14 (1.19 to 3.86) 0.011 0.31 15.5 0.74 No
 Wu et al 17 Inflammatory bowel disease IgG; UBT; H; culture 10 OS 3116 1202 RR 0.48 (0.43 to 0.54) 0 0.25 21 0.2 No
 Wang et al 60 Chronic hepatitis C PCR; S 12 CCS 3826 2185 OR 2.93 (2.30 to 3.75) 0 0.05 45 0.31 No
 Wang et al 59 Chronic hepatitis B S 15 CCS 5129 2845 OR 3.17 (2.38 to 4.22) 0 0.00 77.9 0.02 Yes
 Wijarnpreecha et al 63 NAFLD EIA; IgG; 14C-UBT; H; S; SA 5 CSS; 1 CCS 38 594 NA OR 1.21 (1.07 to 1.37) 0.002 0.08 49 NA No§
 Cen et al 27 Chronic cholecystitis and cholelithiasis H; PCR; culture 18 CCS 1544 NA OR 3.02 (1.90 to 4.82) NA 0.21 20.1 0.43 No
 Shah et al 49 Eosinophilic oesophagitis Biopsy; R; H; IgG; ELISA; EIA; H&E; SA; 13C-UBT 5 CCS;
3 CS or CCS
371 274 26 442 OR 0.63 (0.51 to 0.78) 0.00 0.02 57.9 0.77 No
 Shah et al 49 Oesophageal eosinophilia Biopsy; R; H; IgG; ELISA; EIA; H&E; SA; 13C-UBT 5 CCS;
6 CS or CCS
377 976 28 007 OR 0.64 (0.52 to 0.78) 0.00 0.00 69.4 0.7 No
Neurocognitive disorders
 Wang et al 55 Diabetic neuropathy S; H 5 CS 1607 520 RR 1.20 (1.03 to 1.40) 0.018 0.29 19.1 0.99 No
 Wang et al 61 Ischaemic stroke IgG; CagA; C-UBT 13 CCS 4041 NA OR 1.60 (1.21 to 2.11) NA 0.00 65.2 0.01 Yes
 Yu et al 70 Stroke S 6 CS; 4 CCS 166 041 1769 OR 0.96 (0.78 to 1.14) NA 0.03 48 0.68 No
 Shindler-Itskovitch et al 51 Dementia Biopsy; IgG; IgA; R; H; CagA 1 CS; 6 CCS 86 606 NA OR 1.71 (1.17 to 2.49) 0.01 <0.001 76.1 0.33 No
 Shen et al 50 Parkinson’s disease ELISA; PCR; 13C-UBT; H; prescriptions for HP eradication drug 6 CCS; 2 CSS 28 201 1101 OR 1.59 (1.37 to 1.85) 0 0.55 0 0.02 Yes
Pregnancy-related disorders
 Ng et al 45 Hyperemesis gravidarum Biopsy; H; ELISA; IgG; CagA;
EIA; 13C-UBT; SA
33 CCS; 4 CSS;
1 CS
10 289 NA OR 1.35 (1.16 to 1.54) <0.01 0.06 28 0.76 No
 Zhan et al 72 Pre-eclampsia ELISA; CLIA; Heli‐Blot assay; SA; UBT; WB 3 CS; 12 CCS;
1 CSS
10 402 1077 OR 2.51 (1.18 to 3.34) 0 0.00 63 0.02 Yes
 Zhan et al 72 Fetal growth restriction Heli‐Blot assay; ELISA; SA 3 CCS; 2 CS 6009 202 OR 2.28 (1.21 to 4.32) 0.011 0.02 66 0.17 No
 Zhan et al 72 Gestational DM ELISA; SA; WB; UBT 2 CCS; 3 CS 3697 270 OR 2.03 (1.56 to 2.64) 0 0.81 0 0.77 No
 Zhan et al 72 Spontaneous abortion ELISA; SA 2 CS; 3 CCS; 1 CSS 5909 226 OR 1.5 (1.05 to 2.14) 0.024 0.23 27 0.76 No
 Zhan et al 72 Birth defect ELISA; CLIA 1 CS; 2 CCS 737 132 OR 1.63 (1.05 to 2.54) 0.031 0.48 0 0.14 No
 Zhan et al 72 Stillbirth SA; ELISA 1 CS; 1 CCS 3008 28 OR 2.53 (0.79 to 8.13) 0.118 0.61 0 0.79 No
 Zhan et al 72 Low birth weight NA 7 CS or CCS 10 121 NA OR 1.35 (0.88 to 2.08) NA 0.16 72 NA Unclear
 Zhan et al 72 Premature delivery NA 8 CS or CCS 12 356 NA OR 1.35 (0.86 to 2.12) NA 0.18 70 NA Unclear
Ophthalmic diseases
 Wang et al 55 Diabetic retinopathy S; H 7 CS 1815 406 RR 1.32 (0.97 to 1.80) 0.058 0.04 55 0.27 No
 Zeng et al 71 Open-angle glaucoma H; IgG; 13C-UBT 18 CCS 1580 695 OR 2.08 (1.42 to 3.04) NA <0.001 63.6 0.36 No
Thyroid disease
 Hou et al 67 Autoimmune thyroid diseases ELISA; WB; UBT; SA 15 CCS 3046 2408 OR 2.25 (1.72 to 2.93) 0 0.00 61.6 0.68 No
 Hou et al 67 Grave’s disease ELISA; SA; UBT 5 CCS 917 498 OR 2.78 (1.68 to 4.61) 0 0.07 53.4 1.51 No
 Hou et al 67 Hashimoto’s thyroiditis ELISA; SA; UBT; NR 8 CCS 1594 872 OR 2.16 (1.44 to 3.23) 0 0.00 68.2 0.51 No
Haematological disorders
 Hudak et al 35 Iron deficiency anaemia R; H; 13C-UBT; 14C-UBT;
IgG; SA; IgA; gastroscopy
11 CSS; 3 CCS 15 905 NA OR 1.72 (1.23 to 2.42) NA 0.00 61.5 0.38 No
 Hudak et al 35 Iron deficiency 30 CSS 23 521 NA OR 1.33 (1.15 to 1.54) NA 0.01 41.1 0.49 No
 Hudak et al 35 Anaemia 23 CSS 11 622 NA OR 1.15 (1.00 to 1.32) NA 0.01 NA 0.81 No
Other outcomes
 Nweneka and Prentice46 Circulating ghrelin levels UBT; ELISA; S; H; culture; R; PCR 7 CS; 11 CSS;
6 CCS
956 1288 SMD −0.42 (−0.57 to −0.27) <0.00001 0.00 59 0.12 No
 Xiong et al 64 Henoch-Schonlein purpura R; UBT; IgG; H. pylori antigen 10 CCS 1309 500 OR 3.46 (2.68 to 4.47) 0 0.06 46 0.03 Yes
 Su et al 52 Migraine 13C-UBT; ELISA; biopsy 5 CCS or CSS 903 355 OR 1.92 (1.05 to 3.51) 0.033 0.00 77.4 0.08 yes
 Li et al 40 Recurrent aphthous stomatitis PCR; UBT 7 CCS 510 154 OR 1.85 (1.24 to 2.74) 0.002 0.21 28.5 0.49 No
 Taye et al 53 Atopy H; IgG; ELISA; UBT; SA; IgA 2 CS; 3 CCS;
11 CSS
10 968 NA OR 0.82 (0.73 to 0.91) <0.01 0.66 0 0.85 No
 Hwang et al 36 Chronic tonsillitis R; PCR; culture; CLO 6 OS 436 NA OR 1.99 (0.91 to 4.37) 0.09 0.06 53.6 0.42 No
 Gu et al 34 Chronic urticaria ELISA; UBT; S; H; IgG 16 CCS 2200 984 OR 1.66 (1.12 to 2.45) 0.022 <0.0001 66 0.01 Yes
 Yao et al 66 Multiple sclerosis ELISA; WB; CIA
IF
9 CCS 2806 782 OR 0.73 (0.56 to 0.96) 0 0.05 48 0.07 yes
 Dou et al 31 Halitosis R; H; BUT; culture; PCR;
Gram stain; ELISA; SA; endoscopy; CLO
6 CCS;1 CSS 2312 467 OR 4.03 (1.41 to 11.5) 0.009 <0.0001 89 0.05 Yes
 Jørgensen et al 38 Rosacea NA 14 OS 2455 1268 OR 1.74 (1.03 to 2.93) 0.039 0.00 85.6 0.09 yes
 Chen et al 29 Sjogren’s syndrome Biopsy; ELISA;
IgG
9 CCS 2018 1054 OR 1.19 (1.01 to 1.41) 0.033 0.86 0 0.77 No
 Yong et al 68 Psoriasis IgG; ELISA; UBT; SA 4 CSS; 3 PCS;
2 CCS
1546 728 OR 1.58 (1.02 to 2.46) 0.041 0.00 64 0.03 Yes
 Yong et al 69 Systemic sclerosis IgG; ELISA; IgM; 13C-UBT; R 7 CSS; 1 PCS 1446 749 OR 2.11 (1.62 to 2.76) 0.00 0.33 13 0.84 No

*p value of significance level.

†p value of Q test.

‡p value for Egger’s test.

§The publication bias was assessed using funnel plot.

¶ prevalence or incidence unless otherwise specified.

A, antibody; CagA, cytotoxin-associated gene A; CCS, case–control study; CI, confidence intervals; CLIA, chemiluminescent immunoassay; CLO, Campylobacter-like organism test; COPD, chronic obstructive pulmonary disease; CS, cohort study; CSS, cross-sectional study; DM, diabetes mellitus; EAC, oesophageal adenocarcinoma; EIA, enzyme immunoassay; ESCC, oesophageal squamous cell carcinoma; ESRD, end-stage renal disease; GERD, gastro-oesophageal reflux disease; H, histology; HDL-C, high-density lipoprotein cholesterol; H&E, Hematoxylin and eosin stain; His +, positive histological examination of tissue samples; HOMA-IR, homeostatic model assessment of insulin resistance; HP, H. pylori; HpSe +, seropositivity for antibodies to whole cell; IF, immunofluorescence; IHD, ischaemic heart disease; MD, mean difference; NA, not applicable; NAFLD, non-alcoholic fatty liver disease; NCCS, nested case-control study; NR, not reported; OS, observational study; PCR, polymerase chain reaction; PCS, prospective cohort study; PNCS, prospective nested cohort study; R, rapid urease test; RCCS, retrospective case–control study; RCSS, retrospective cross-sectional study; RR, relative rate; S, serology; SA, stool antigen; several, several methods; SMD, standard mean difference; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; U, rapid urease test; UBT, urea breath test; WB, western blot.

Figure 2.

Figure 2

Number of publications per annum.

Figure 3.

Figure 3

Map of 88 . H. pylori–related outcomes: percentage of outcomes per outcome category for all studies.

Table 2.

Association between H. pylori infection and diverse diseases based on study region

Study region Associations between H. pylori infection and outcomes No association with
Increase risk of Decrease risk of
Europe Cholangiocarcinoma,14 colorectal, cancer,75
diabetes mellitus,39 diabetic nephropathy,56 alcoholic cirrhosis,33 Parkinson’s disease50
Barrett's oesophagus32 Arrhythmia,65 asthma,16 biliary lithiasis,73 migraine,52 recurrent aphthous stomatitis,40 chronic urticaria34
America Colorectal cancer,75 biliary lithiasis,73 chronic urticaria34 Barrett’s oesophagus,32 asthma,16 asthma16 Arrhythmia,65 diabetes mellitus,39 alcoholic cirrhosis,33 recurrent aphthous stomatitis40
East
(Asia, China)
Cholangiocarcinoma,14 colorectal cancer,75 colon neoplasia,28 arrhythmia,65 diabetes mellitus,39 diabetic nephropathy,56 biliary lithiasis,73 ammonia levels in cirrhotic patients,37 chronic cholecystitis and cholelithiasis,27 Parkinson’s disease,50 open-angle glaucoma,71 Henoch-Schonlein purpura,64 migraine,52 chronic urticaria34 Oesophageal squamous cell carcinoma,13 Barrett’s oesophagus,32 asthma16 Myocardial infarction,15 COPD,57 biliary lithiasis,73 peptic ulcer disease,10 alcoholic cirrhosis,33 recurrent aphthous stomatitis,40 multiple sclerosis66
West Colon neoplasia,28 myocardial infarction,15 COPD,57 peptic ulcer disease,10 open-angle glaucoma71 Oesophageal adenocarcinoma,13 asthma,16 multiple sclerosis66 Oesophageal squamous cell carcinoma,13 ammonia levels in cirrhotic patients37
Africa Arrhythmia65 Barrett’s oesophagus,32 diabetes mellitus,39 peptic ulcer disease10
Australia Barrett’s oesophagus32
Oceania Biliary lithiasis73

COPD, chronic obstructive pulmonary disease.

Summary effect size

Table 1 shows the summary effects of the included meta-analysis. Of the 88 outcomes, 74 (84%) had nominal significance (p<0.05). Of these outcomes, 61 (82%) were harmful associations enumerated as follows: 8 (67%) meta-analyses in cancer outcomes, 6 (75%) in cardiovascular and cerebrovascular diseases, 2 (67%) in respiratory disorders, 6 (60%) in endocrine diseases, 1 (50%) in urological diseases, 12 (67%) in digestive disorders, 4 (80%) in neurocognitive disorders, 6 (67%) in pregnancy-related disorders, 1 (50%) in ophthalmic diseases, 3 (100%) in thyroid diseases, 3 (100%) in haematological disorders and 9 (69%) in other outcomes. These associations had significant pooled estimates (p<0.05). Thus, H. pylori infection was associated with an increased risk of disease and harmful to human health (table 3). By contrast, 13 (15%) evidence from meta-analyses were beneficial associations enumerated as follows: 1 (33%) meta-analyses in respiratory disorders, 2 (15%) in cancer outcomes, 1 (10%) endocrine disease, 1 (50%) urological disease, 5 (28%) digestive disorders and 3 (23%) in other outcomes. These associations had significant pooled estimates (p<0.05), indicating that H. pylori infection was related to a decreased risk of some diseases. These findings could be beneficial to human health in some situations (table 3).

Table 3.

Results of evidence quality for all outcomes classified by GRADE

Level of evidence Outcomes
Increased risk of Increase Decreased risk of Reduce No association with
High
Moderate Chronic cholecystitis and cholelithiasis,27 gestational diabetes mellitus,72 gastric cancer12 and systemic sclerosis69 Triglyceride level54 Inflammatory bowel disease17 Stillbirth72
Low Hepatocellular carcinoma,13 biliary lithiasis,73 peptic ulcer disease,10 chronic hepatitis C,60 non-alcoholic fatty liver disease,63 diabetic neuropathy,55 Parkinson’s disease,50 hyperemesis gravidarum,45 fetal growth restriction,72 spontaneous abortion,72 birth defect,72 open-angle glaucoma,71 autoimmune thyroid diseases,67 Grave’s disease,67 Hashimoto’s thyroiditis,67 Henoch-Schonlein purpura,64 colorectal adenomatous polyp,58 Sjogren’s syndrome,29 duodenal ulcer,12 laryngeal carcinoma,74 chronic obstructive pulmonary disease,57 diabetic nephropathy,56 gastric ulcer,12 alcoholic cirrhosis in Europian,33 cerebral ischaemia47 Ammonia levels in patients with cirrhosis37 Oesophageal adenocarcinoma in the overall population,18 eosinophilic oesophagitis,49 oesophageal eosinophilia,49 atopy53 Diabetic ischemic heart disease, 55 fasting blood glucose54 and diabetic ischaemic heart disease56
Very low Lung cancer,44 cholangiocarcinoma,14 chronic tonsillitis,36 colorectal cancer, colon neoplasia,28 ischaemic heart disease,47 myocardial infarction,15 coronary heart disease,48 arrhythmia,65 chronic bronchitis,57 metabolic syndrome,54 diabetes mellitus,39 type 2 diabetes mellitus,39 chronic atrophic gastritis,11 dyspepsia,9 chronic hepatitis B,59 ischaemic stroke,61 dementia,51 pre-eclampsia,72 iron deficiency anaemia,35 iron deficiency,31 anaemia,26 migraine,52 recurrent aphthous stomatitis,40 chronic urticaria,34 halitosis,31 rosacea38 and psoriasis68 Carotid intima thickness,76 body mass index54 and homeostatic model assessment of insulin resistance54 Oesophageal squamous cell carcinoma in Eastern populations,18 Barrett’s oesophagus,32 asthma,16 end-stage renal disease in adult,62 multiple sclerosis66 and gastro-oesophageal reflux disease30 High-density lipoprotein cholesterol,54 circulating ghrelin levels46 Oesophagogastric junction adenocarcinoma,42 pancreatic cancer,41 systolic blood prssure,54 atherosclerosis,43 type 1 diabetes mellitus,39 alcoholic cirrhosis in all populations,28 stroke,70 low birth weight,72 premature delivery72 and diabetic retinopathy70

Heterogeneity and publication bias of the included studies

All of the included meta-analyses presented the results of heterogeneity between studies (table 1). In particular, 24 (27%) outcomes of meta-analyses showed no heterogeneity between studies (p≥0.1 of Q test), whereas 64 (73%) exhibited significant heterogeneity (p<0.1 of Q test). Moreover, 32 (57%) of 64 meta-analyses showed moderate to high heterogeneity (I2=50%–75%), and 24 (43%) showed high heterogeneity (I2>75%). Among 88 meta-analyses, 68 (77%) demonstrated no statistical evidence on publication bias according to Egger’s, whereas 18 (20%) of the meta-analyses presented publication bias (p<0.1 of Egger’s test). Only 2 (2%) meta-analyses did not report publication bias.

Summary of the methodological quality of the included meta-analyses

The methodological qualities of the 60 included articles were assessed using AMSTAR 2, and the results are shown in table 4. A total of 52 (87%) meta-analyses did not report a predefined explicit statement or protocol; only 8 (13%) meta-analyses were conducted using a comprehensive literature search strategy, and 24 (40%) meta-analyses did not perform a duplicate selection. Twelve (20%) meta-analyses did not conduct a duplicate data extraction, 53 (88%) meta-analyses provided a list of excluded studies but did not justify the exclusions, 6 (10%) meta-analyses did not provide a list of excluded studies, 50 (83%) meta-analyses partially described the included studies and 22 (37%) meta-analyses did not assess the risk of bias in the included studies. Furthermore, none of the meta-analyses reported the details of funding sources for the included studies, and 28 (47%) meta-analyses did not report potential sources of conflicts of interest. Overall, 85 (97%) methodological qualities of the included meta-analyses were categorised as ‘critically low’, and only 3 (3%) methodological qualities of the included meta-analyses were assessed as low quality (figure 4).

Table 4.

Detail of results for AMSTAR 2 assessing

Included meta-analyses AMSTAR 2 checklist Overall assessment quality
No. 1 No. 2 No 3 No. 4 No. 5 No. 6 No. 7 No. 8 No. 9 No. 10 No. 11 No. 12 No. 13 No. 14 No. 15 No. 16
Xuan et al 13 Yes No Yes Yes Yes Yes No Partial yes No No Yes Yes Yes Yes Yes No Critically low
Mounika44 Yes No Yes Partial yes No No Partial yes Partial yes Yes No Yes Yes Yes Yes Yes No Critically low
Xie et al 18 Yes No Yes No Yes Yes Partial yes Partial yes No No Yes Yes Yes Yes Yes No Critically low
Wang et al 58 Yes No Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes No Critically low
Xiao et al 14 Yes No Yes Partial yes Yes Yes Partial yes Yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Dong and Hao75 Yes No Yes Partial yes No No Partial yes Partial yes No No No No Yes Yes Yes No Critically low
Zhou et al 74 Yes No Yes Partial yes No Yes Partial yes Partial yes No No Yes Yes Yes Yes Yes No Critically low
Liu28 Yes No Yes Partial yes No Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Li et al 12 Yes No Yes Partial yes No Yes Partial yes Partial yes No No Yes No Yes Yes Yes Yes Critically low
Ma et al 42 Yes No Yes Partial yes No Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes No Critically low
Liu et al 41 Yes No Yes No Yes Yes Partial yes Partial yes No No Yes Yes Yes Yes Yes No Critically low
Erőss et al 32 Yes Yes Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes Yes Low
Pasceri et al 47 Yes No Yes Partial yes Yes Yes Partial yes Partial yes No No Yes Yes Yes Yes Yes No Critically low
Liu et al 15 Yes No Yes Partial yes Yes Yes No Yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Chen et al 48 Yes No Yes Partial yes No Yes No Partial yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Saburi et al 43 Yes No Yes Partial yes No No Partial yes Partial yes Yes No Yes No Yes No Yes Yes Critically low
Yan et al 65 Yes No Yes Yes Yes Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Dong et al 76 Yes No No Yes No Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes No Critically low
Wang et al 57 Yes No Yes Partial yes No Yes No Yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Chen et al 16 Yes No Yes No Yes Yes Partial yes Yes Yes No Yes Yes Yes Yes Yes No Critically low
Upala et al 54 Yes Yes Yes Partial yes No Yes No Partial yes No No Yes Yes Yes Yes Yes No Critically low
Li et al 39 Yes No Yes Yes No No Partial yes Partial yes No No Yes Yes Yes Yes Yes Yes Critically low
Wang et al 56 Yes No Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Wijarnpreecha et al 62 Yes No Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes Yes No No Yes No Critically low
Cremonini et al 30 Yes No Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes No Critically low
Weck and Brenner11 Yes No No No No No Partial yes Yes No No Yes No Yes Yes Yes No Critically low
Zhou et al 73 Yes No Yes Yes Yes Yes Partial yes Partial yes No No Yes Yes Yes Yes Yes No Critically low
Shiota et al 10 Yes No Yes Partial yes Yes No Partial yes Partial yes No No Yes Yes Yes Yes Yes Yes Critically low
Jiang et al 37 Yes No Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Ford et al 9 Yes No Yes Partial yes No Yes Partial yes Partial yes No No Yes Yes Yes Yes Yes No Critically low
Feng et al 33 Yes No Yes Partial yes No No Partial yes Partial yes No No Yes No Yes Yes Yes No Critically low
Wu et al 17 Yes No Yes Partial yes No Yes Partial yes Partial yes No No Yes No Yes Yes Yes No Critically low
Wang et al 60 Yes No Yes Yes Yes Yes Partial yes Yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Wang et al 59 Yes No Yes Yes Yes No Partial yes Partial yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Wijarnpreecha et al 63 Yes No Yes Yes Yes Yes Partial yes Yes Yes No Yes Yes Yes Yes Yes No Critically low
Cen et al 27 Yes No Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Shah et al 49 Yes No Yes Partial yes No Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes No Critically low
Wang et al 55 Yes No No Partial yes Yes Yes No Partial yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Wang et al 61 Yes No Yes Partial yes No Yes Partial yes Yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Yu et al 70 Yes No Yes Partial yes No Yes Partial yes Yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Shindler-Itskovitch et al 51 Yes No Yes Partial yes No Yes Partial yes Yes No No Yes Yes Yes Yes Yes Yes Critically low
Shen et al 50 Yes No Yes Partial yes Yes Yes Partial yes Partial yes No No Yes Yes Yes Yes Yes Yes Critically low
Ng et al 45 Yes No Yes Partial yes Yes Yes Partial yes Partial yes No No Yes No Yes Yes Yes Yes Critically low
Zhan et al 72 Yes No Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Zeng et al 71 Yes No Yes Partial yes No Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes No Critically low
Nweneka and Prentice46 Yes No Yes Partial yes No No Yes Partial yes No No Yes Yes Yes Yes Yes Yes Critically low
Xiong et al 64 Yes Yes Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes Yes Low
Su et al 52 Yes No Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes No Critically low
Li et al 40 Yes No Yes No Yes No Partial yes Partial yes Yes No Yes No Yes Yes Yes Yes Critically low
Taye et al 53 Yes Yes Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes Yes Low
Hwang et al 36 Yes No No Partial yes Yes No Partial yes Partial yes No No Yes No Yes Yes Yes Yes Critically low
Gu et al 34 Yes No Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes Yes Critically low
Yao et al 66 Yes No Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes No Critically low
Dou et al 31 Yes No Yes Partial yes Yes Yes Partial yes Partial yes No No Yes No Yes Yes No No Critically low
Jørgensen et al 38 Yes No Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes No Yes Yes Yes Yes Critically low
Hou et al 67 Yes No Yes Partial yes No No Partial yes Partial yes Yes No Yes Yes Yes No Yes Yes Critically low
Hudak et al 35 Yes Yes Yes Partial yes No Yes Partial yes Partial yes Yes No Yes Yes Yes Yes Yes No Critically low
Chen et al 29 Yes Yes Yes Partial yes Yes Yes Partial yes Partial yes No No Yes Yes Yes Yes Yes No Critically low
Yong et al 68 Yes Yes Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes No Yes No Yes Yes Critically low
Yong et al 69 Yes Yes Yes Partial yes Yes Yes Partial yes Partial yes Yes No Yes No Yes No Yes No Critically low

AMSTAR 2 checklists: No.1: Did the research questions and inclusion criteria for the review include the components of PICO? No.2: Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol? No. 3: Did the review authors explain their selection of the study designs for inclusion in the review? No. 4: Did the review authors use a comprehensive literature search strategy? No. 5: Did the review authors perform study selection in duplicate? No. 6: Did the review authors perform data extraction in duplicate? No. 7: Did the review authors provide a list of excluded studies and justify the exclusions? No. 8: Did the review authors describe the included studies in adequate detail? No. 9: Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? No. 10: Did the review authors report on the sources of funding for the studies included in the review? No. 11: If meta-analysis was performed, did the review authors use appropriate methods for statistical combination of results? No. 12: If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis? No. 13: Did the review authors account for RoB in primary studies when interpreting/discussing the results of the review? No. 14: Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review? No. 15: If they performed quantitative synthesis, did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review? No. 16: Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?

Figure 4.

Figure 4

Map of results of AMSTAR 2: percentage of outcomes per outcome category for 88 meta-analyses.

Evidence classification of the outcomes

The evidence quality of every outcome was assessed using the GRADE system (table 5). None of the evidence quality for any outcome was rated ‘high’. Most of the qualities of evidence were downgraded by the potential risk of bias and serious heterogeneity. A total of 32 (36%) evidence qualities of outcomes were rated ‘low’, 49 (56%) evidence were rated ‘very low’ and only 7 (8%) evidence were rated ‘moderate’ (figure 5). Table 5 shows the results of evidence quality from 88 outcomes.

Table 5.

Details of evidence quality for outcomes classified by GRADE

Included meta-analyses Association between H. pylori and* Downgrade factors Upgrade factors GRADE class
Risk of bias Inconsistency Indirectness Imprecision Publication bias Large effect Plausible confounding would change the effect
Cancer outcomes
 Xuan et al 13 Hepatocellular carcinoma −1 0 0 -1 −1 2 1 Low
 Mounika44 Lung cancer −1 −2 0 0 0 1 1 Very low
 Xie et al 18 ESCC in Eastern populations −1 −1 0 0 0 0 1 Very low
 Xie et al 18 EAC in the overall population −1 0 0 0 0 0 1 Low
 Wang et al 58 Colorectal adenomatous polyp −1 0 0 0 0 0 1 Low
 Xiao et al 14 Cholangiocarcinoma −1 −1 0 −1 −1 2 1 Very low
 Dong and Hao75 Colorectal cancer −1 −1 0 0 0 0 1 Very low
 Zhou et al 74 Laryngeal carcinoma −1 −1 0 0 0 1 1 Low
 Liu28 Colon neoplasia −1 −2 0 0 0 0 1 Very low
 Li et al 12 Gastric cancer −1 0 0 0 0 1 1 Moderate
 Ma et al 42 Oesophagogastric junction adenocarcinoma −1 −2 0 0 0 0 1 Very low
 Liu et al 41 Pancreatic cancer −1 −2 0 0 0 0 1 Very low
Cardiovascular and cerebrovascular diseases
 Pasceri et al 47 Ischaemic heart disease −2 −1 0 0 0 0 1 Very low
 Pasceri et al 47 Cerebral ischaemia −2 0 0 0 0 1 1 Low
 Wang et al 55 Diabetic IHD −1 0 0 0 0 0 1 Low
 Liu et al 15 Myocardial infarction −1 −2 0 0 0 0 1 Very low
 Chen et al 48 Coronary heart disease −2 −2 0 0 0 0 1 Very low
 Ramezani-Binabaj et al 43 Atherosclerosis −2 −1 0 −1 −1 0 1 Very low
 Yan et al 65 Arrhythmia −1 −2 0 0 0 0 1 Very low
 Dong et al 76 Carotid intima thickness −1 −2 0 0 0 0 1 Very low
Respiratory disorders
 Wang et al 57 COPD −1 −1 0 0 0 1 1 Low
 Wang et al 57 Chronic bronchitis −1 −1 0 0 0 0 1 Very low
 Chen et al 16 Asthma −1 −1 0 0 0 0 1 Very low
Endocrine disease
 Upala et al 54 Metabolic syndrome −1 −1 0 0 0 0 1 Very low
 Upala et al 54 Fasting blood glucose −1 −1 0 0 0 1 1 Low
 Upala et al 54 HDL-C −1 −2 0 0 0 1 1 Very low
 Upala et al 54 Triglyceride level −1 −1 0 0 0 2 1 Moderate
 Upala et al 54 Systolic blood pressure −1 −2 0 0 0 1 1 Very low
 Upala et al 54 Body mass index −1 −1 0 0 0 0 1 Very low
 Upala et al 54 HOMA-IR −1 −2 0 0 0 0 1 Very low
 Li et al 39 DM −1 −2 0 0 −1 0 1 Very low
 Li et al 39 T2DM −1 −2 0 0 −1 1 1 Very low
 Li et al 39 T1DM −1 −2 0 0 0 0 1 Very low
Urological disease
 Wang56 Diabetic nephropathy −1 0 0 0 0 0 1 Low
 Wijarnpreecha et al 62 ESRD in adult −1 −2 0 0 0 0 1 Very low
Digestive disorders
 Erőss et al 32 Barrett’s oesophagus −1 −2 0 0 −1 0 1 Very low
 Li et al 12 Gastric ulcer −1 0 0 0 0 0 1 Low
 Li et al 12 Duodenal ulcer −1 −1 0 0 0 1 1 Low
 Cremonini et al 30 GERD in population with HP-negative status −1 −1 0 0 0 0 1 Very low
 Weck and Brenner11 Chronic atrophic gastritis −1 −2 0 0 −1 2 1 Very low
 Zhou et al 73 Biliary lithiasis −1 −1 0 0 0 1 1 Low
 Shiota et al 10 Peptic ulcer disease −1 0 0 0 0 0 1 Low
 Jiang et al 37 Ammonia levels in cirrhotic patients −1 0 0 0 0 0 1 Low
 Ford et al 9 Dyspepsia −1 −1 0 0 0 0 1 Very low
 Feng et al 33 Alcoholic cirrhosis in all population −1 −2 0 0 0 0 1 Very low
 Feng et al 33 Alcoholic cirrhosis in European −1 0 0 −1 0 1 1 Low
 Wu et al 17 Inflammatory bowel disease −1 0 0 0 0 1 1 Moderate
 Wang et al 60 Chronic hepatitis C −1 −1 0 0 0 1 1 Low
 Wang et al 59 Chronic hepatitis B −1 −2 0 0 −1 1 1 Very low
 Wijarnpreecha et al 63 NAFLD −1 0 0 0 0 0 1 Low
 Cen et al 27 Chronic cholecystitis and cholelithiasis −1 0 0 0 0 1 1 Moderate
 Shah et al 49 Eosinophilic oesophagitis 0 −1 0 0 0 0 1 Low
 Shah et al 49 Oesophageal eosinophilia 0 −1 0 0 0 0 1 Low
Neurocognitive disorders
 Wang et al 55 Diabetic neuropathy −1 0 0 0 0 0 1 Low
 Wang et al 61 Ischaemic stroke −1 −1 0 0 −1 0 1 Very low
 Yu et al 70 Stroke −1 −1 0 0 0 0 1 Very low
 Shindler-Itskovitch
et al 51
Dementia −1 −2 0 0 0 0 1 Very low
 Shen et al 50 Parkinson’s disease 0 0 0 0 −1 0 1 Low
Pregnancy-related disorders
 Ng et al 45 Hyperemesis gravidarum −1 0 0 0 0 0 1 Low
 Zhan et al 72 Pre-eclampsia −1 −1 0 0 −1 1 1 Very low
 Zhan et al 72 Fetal growth restriction −1 −1 0 0 0 1 1 Low
 Zhan et al 72 Gestational DM −1 0 0 0 0 1 1 Moderate
 Zhan et al 72 Spontaneous abortion −1 0 0 0 0 0 1 Low
 Zhan et al 72 Birth defect −1 0 0 0 0 0 1 Low
 Zhan et al 72 Stillbirth −1 0 0 0 0 1 1 Moderate
 Zhan et al 72 Low birth weight −1 −1 0 0 0 0 1 Very low
 Zhan et al 72 Premature delivery −1 −1 0 0 0 0 1 Very low
Ophthalmic diseases
 Wang et al 55 Diabetic retinopathy −1 −1 0 0 0 0 1 Very low
 Zeng et al 71 Open-angle glaucoma −1 −1 0 0 0 1 1 Low
Thyroid disease
 Hou et al 67 Autoimmune thyroid diseases −1 −1 0 0 0 1 1 Low
 Hou et al 67 Grave’s disease −1 −1 0 0 0 1 1 Low
 Hou et al 67 Hashimoto’s thyroiditis −1 −1 0 0 0 1 1 Low
Homeopathy disorders
 Hudak et al 35 Iron deficiency anaemia −1 −1 0 0 0 0 1 Very low
 Hudak et al 35 Iron deficiency −1 −1 0 0 0 0 1 Very low
 Hudak et al 35 Anaemia −1 −1 0 0 0 0 1 Very low
Other outcomes
 Nweneka and Prentice46 Circulating ghrelin levels −1 −1 0 0 0 0 1 Very low
 Xiong et al 64 Henoch-Schonlein purpura −1 0 0 0 −1 1 1 Low
 Su et al 52 Migraine −1 −1 0 0 -1 0 1 Very low
 Li et al 40 Recurrent aphthous stomatitis −1 0 0 −1 0 0 1 Very low
 Taye et al 53 Atopy −1 0 0 0 0 0 1 Low
 Hwang et al 36 Chronic tonsillitis −1 −1 0 0 0 0 1 Very low
 Gu et al 34 Chronic urticaria −1 −1 0 0 −1 0 1 Very low
 Yao et al 66 Multiple sclerosis −1 0 0 0 -1 0 1 Very low
 Dou et al 31 Halitosis −1 −2 0 0 −1 0 1 Very low
 Jørgensen et al 38 Rosacea −1 −2 0 0 0 0 1 Very low
 Chen et al 29 Sjogren’s syndrome −1 0 0 0 0 0 1 Low
 Yong et al 68 Psoriasis −1 −1 0 0 −1 0 1 Very low
 Yong et al 69 Systemic sclerosis −1 0 0 0 0 1 1 Moderate

Reference: −1 means downgrade one level; −2 means downgrade two levels; 1 means upgrade one level.

* prevalence or incidence unless otherwise specified.

COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; DM, diabetes mellitus; EAC, oesophgeal adenocarcinoma; ESCC, oesophageal squamous cell carcinoma; ESRD, end-stage renal disease; GERD, gastro-oesophageal reflux disease; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, hemeostatic model assessment of insulin resistance; HP, H. pylori; IHD, ischemic heart disease; NAFLD, non-alcoholic fatty liver disease; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

Figure 5.

Figure 5

Map of results of GRADE: percentage of outcomes per outcome category for 88 evidence.

Harmful outcomes associated with H. pylori infection

Our confidence level in the following was moderate: H. pylori infection is associated with an increased risk of chronic cholecystitis and cholelithiasis,27 gestational diabetes mellitus,72 systemic sclerosis69 and gastric cancer,12 and increased serum triglyceride level.54 Our confidence level in the following was low: H. pylori infection is associated with an increased risk of HCC,13 biliary lithiasis,73 PUD,10 duodenal ulcer,12chronic hepatitis C,60 non-alcoholic fatty liver disease,63 diabetic neuropathy,55 Parkinson’s disease,50 hyperemesis gravidarum,45 fetal growth restriction,72 spontaneous abortion,72 birth defect,72 open-angle glaucoma,71 autoimmune thyroid diseases,67 Grave’s disease,67 Hashimoto’s thyroiditis,67 Henoch-Schonlein purpura,64 diabetic nephropathy,56 gastric ulcer,12 alcoholic cirrhosis Europeans,33 and Sjogren’s syndrome29; ammonia levels decrease in patients with cirrhosis.37 Our confidence level in the following was very low: H. pylori infection is associated with an increased risk of lung cancer,44 cholangiocarcinoma,14 colorectal cancer75, colon neoplasia,28 chronic tonsillitis,36 ischaemic heart disease,47 MI,15 coronary heart disease,48 arrhythmia,65 chronic bronchitis,57 metabolic syndrome,54 diabetes mellitus,39 type 2 diabetes mellitus,39 chronic atrophic gastritis,11 dyspepsia,9 chronic hepatitis B,59 ischaemic stroke,61 dementia,51 pre-eclampsia,72 iron deficiency anaemia,35 iron deficiency,31 anaemia,26 migraine,52 recurrent aphthous stomatitis,40 chronic urticaria,34 halitosis,31 rosacea,38 laryngeal carcinoma,74 cerebral ischaemia,47 chronic obstructive pulmonary disease57 and psoriasis68; an increase in the following parameters is observed: carotid intima thickness,76 body mass index54 and homeostatic model assessment of insulin resistance.54

Beneficial outcomes associated with H. pylori infection

Our confidence level in the following was moderate: H. pylori infection is associated with a decreased risk of irritable bowel syndrome.17 Our confidence level in the following was low: H. pylori infection is associated with a decreased risk of oesophageal adenocarcinoma in the overall population,18 colorectal adenomatous polyp,58 eosinophilic oesophagitis,49 oesophageal eosinophilia49 and atopy53. Our confidence level in the following was very low: H. pylori infection is associated with a decreased risk of oesophageal squamous cell carcinoma in Eastern populations,18 Barrett’s oesophagus,32 asthma,16 end-stage renal disease in adults,62 multiple sclerosis66 and gastro-oesophageal reflux disease30; decreasing high-density lipoprotein cholesterol54 and circulating ghrelin levels are also observed.46

Discussion

Principal findings and possible explanations

This umbrella review summarised the current existing evidence from meta-analyses on the associations between H. pylori infection and diverse health outcomes. In this umbrella review, 60 publications of interest were systematically reviewed. The role of H. pylori infection was explored in relation to a wide range of diseases (74 in total), including cancers, cardiovascular and cerebrovascular diseases, respiratory disorders, endocrine diseases, urological diseases, digestive disorders, neurocognitive disorders, pregnancy-related disorders, ophthalmic diseases, thyroid disease, haematological disorders and other outcomes (figure 3). H . pylori infection is likely more harmful in Asians by increasing the risk of 15 types of diseases (table 2). Through this umbrella review, an uptrend of research on the associations between H. pylori infection and health outcomes was found (figure 2). However, gaps in studies exploring the association between H. pylori infection and the musculoskeletal system diseases were identified as formal meta-analyses were not found. A clear reference exposure time of H. pylori infection could not be obtained because all of the meta-analyses did not present this aspect.

A large proportion (84%) of the health outcomes was associated with H. pylori infection. However, most of them (64%) had serious heterogeneity between studies. The potential heterogeneity might be due to possible confounding factors (e.g. different H. pylori measurement methods, alcohol consumption, smoking, sex, study region, different nationalities and time of follow-up). Substantial heterogeneity affected the results of meta-analyses, indicating that some associations between H. pylori infection and diverse health outcomes might be inflated or false positives. In addition, some of them 20%) had a notable publication bias, revealing that some negative results were not reported. In practice, associations between H. pylori infection and diseases might be found in thousands of individuals. However, only a small proportion of associations were recorded, and an even smaller fraction was finally published. Positive results were probably more easily published than negative results that might not be even published. If researchers strongly believed in the association between H. pylori infection and the risk of developing diseases, their work might be under pressure to comply with the hypothesis during publication. These requirements could cause publication biases in the results. Our result showed that 97% of the meta-analyses had ‘critically low’ methodological quality (figure 4). Evidence was downgraded by serious heterogeneity, potential bias and low method quality. Hence, none of the outcomes had high-quality evidence after evaluation based on the evidence classification criteria. Based on this metric, moderate-quality evidence only existed in six health outcomes, suggesting that H. pylori infection was probably associated with an increased risk of hypertriglyceridemia, chronic cholecystitis and cholelithiasis, gestational diabetes mellitus, gastric cancer and systemic sclerosis and a decreased risk of irritable bowel syndrome. Among these risks, the outcome of triglyceride level exhibited moderate heterogeneity (I2=71%), demonstrating that this association should be cautiously interpreted. This umbrella reivew shows there is no association between H.ylori infection and risk of stillbirth.

Strengths and limitations of the umbrella review

Our umbrella review has several great strengths. An umbrella review systematically searches, collects and assesses the strength and credibility of the evidence derived from various systematic reviews and meta-analyses on any clinical health outcomes related to a particular exposure.77 Studies have also revealed the strengths and significance of umbrella reviews in detail.78–80 Considering that the associations between H. pylori infection and diverse health outcomes have not been systematically and comprehensively assessed, this umbrella review comprehensively evaluated the methodological quality of meta-analyses and assessed the evidence quality of outcomes from the published meta-analyses of observational studies. The quality of the included studies in meta-analyses affects the quality of the meta-analyses. When possible, we reanalysed the summary estimates and explored the heterogeneity and publication bias of the included meta-analyses by using a standardised method. In this umbrella review, seven databases were comprehensively and systematically searched using a standard search strategy to identify eligibility. An uptrend of studies on associations between H. pylori infection and various health outcomes was found, indicating that the associations of H. pylori infection and diseases were widely explored. However, meta-analyses investigated on associations between H. pylori infection and musculoskeletal disorders, and mucosa associated limphoid tissue (MALT) lymphoma were not found in our scope.

We used AMSTAR 2, which is a standard methodological quality assessment approach, to assess the quality of the method used for meta-analyses. Since AMSTAR 2 was developed from AMSTAR in 2017, it has been considered a valid and reliable methodological quality assessment tool.19 81 The lengths of AMSTAR 2 have been described in other studies.21 82 83 This tool helped us identify the highest methodological quality of the meta-analyses of RCTs and also the meta-analyses of observational studies. Therefore, AMSTAR 2 is more practical and applicable than AMSTAR. In this umbrella review, 95% of the methodological qualities of existing meta-analyses studying the associations between H. pylori infection and diverse health outcomes were critically low, suggesting that the results of the meta-analyses might be inconclusive, and further meta-analyses with high methodological quality should be conducted to verify such conclusions.

We also adopted the GRADE system criteria, which are credibility-assessment criteria, to assess the evidence quality of outcomes from meta-analyses. The certainty of evidence is important for the recommendation of guidelines, affecting a patient’s outcomes.84 GRADE re-evaluates the quality of evidence and rates the certainty evidence for clinical decision-makers and guideline developers.22 84 This system is also used worldwide. We downgraded the evidence level because all of the meta-analyses exhibited a potential risk of bias, but we upgraded the evidence level because the result of the included meta-analyses might be affected by various potential confounders, such as age, sex or smoking. Although conducting AMSTAR 2 and GRADE classification was relatively subjective, they were performed by two investigators independently, and the results were checked by another investigator. The inconsistencies were resolved via a discussion, and all discrepancies were arbitrated by another researcher, thereby greatly reducing the subjectivity.

In terms of the study weakness, this umbrella review focused on the existing and published systematic review and meta-analyses and only included publications in Chinese and English. Thus, we might have missed some studies on the associations between H. pylori infection and diverse health outcomes. The potential missing data in other languages might affect the evaluation results. In this umbrella review, only systematic reviews and meta-analyses were included. Evidence from individual observational studies involving undeveloped a meta-analysis was not in the scope of our discussion, such as MALT lymphoma.85 This situation might result in conclusion bias of association between H. pylori infection and human health. In addition, we could not obtain a clear exposure time because most of the meta-analyses did not present the length of time of H. pylori infection. Most of the meta-analyses had heterogeneity, but we did not re-explore the factors causing heterogeneity, such as population characteristics (eg, age, sex and nationality), study design and study region. Common flaws are evident among meta-analyses.86 The evidence quality of meta-analyses depends on the quality of original individual studies included in meta-analyses. However, this umbrella review did not assess the quality of the original individual studies included in the meta-analyses. We extracted the data for calculation from the included meta-analyses but not from the original individual studies, possibly affecting the conclusion of this umbrella review.

Clinical implications and future research

Clinicians have considered whether individuals should be tested for H. pylori or offered eradication therapy for H. pylori infection since multiple unfavourable influences on human health related to H. pylori infection have been found. Different suggestions on addressing H. pylori infection have been provided in different guidelines because of objective factors (eg, local drug resistance, economic level, and medical and health conditions). Several guidelines, including Asian guidelines, recommend screening in every individual, whereas other guidelines recommend no screening.87 The different recommendations regarding H. pylori detection and eradication in different guidelines may cause confusion among clinicians. The significance of our study mostly included the summary of the diseases associated with H. pylori and the clarification of evidence quality to guide clinical practice.

Our umbrella review found that 69% of outcomes were unfavourable influences on human health which should be paid attention to by clinicians, even though most of them were low-quality evidence. In terms of eradicating therapy for H. pylori infection, the beneficial influence (H. pylori infection as a protect factor) on human health might be considered by clinicians. This umbrella review found that a decreased risk of 13 types of conditions (eg, inflammatory bowel disease, laryngeal and oesophageal carcinoma) was also found, even though H. pylori was associated with an increased risk of a large proportion of diseases. H. pylori–eradicating drugs have adverse effects, such as increased resistance of H. pylori.88 Therefore, for an individual who tests positive, whether H. pylori infection is a risk factor or a protective factor should be distinguished before he/she receives eradicating therapy. Before deciding on administering eradicating therapy, clinicians should weigh the advantages and disadvantages of eradicating H. pylori based on an individual’s situation.

Future prospective studies on H. pylori infection and health outcomes should use time-varying exposure (H. pylori infection duration) and confounder information to better model the association between H. pylori infection and health outcomes. Data remain scarce, and a large heterogeneity exists in some associations of H. pylori infection and diseases. Prospective studies should be carried out to better characterise these associations. In the absence of data from RCTs for H. pylori infection and risk of developing diseases, Mendelian randomisation analyses may be useful in determining whether an observed association is likely to be causal. Meta-analyses investigating associations between H. pylori infection and some diseases, such as autoimmune liver disease,89 90 have not been found in our scope. A meta-analysis may be conducted to confirm these conclusions in the future because of the possible inconsistent results in different individual studies.

Conclusion

This umbrella review systematically and comprehensively collected a large amount of existing evidence on the associations between H. pylori infection and diverse health outcomes from published meta-analyses to help clinical decision-makers, guideline developers and investigators evaluate these associations. Although 60 meta-analyses explored 88 unique outcomes, moderate evidence only existed in six outcomes with statistical significance. H. pylori infection may be associated with a decreased risk of irritable bowel syndrome and an increased risk of hypertriglyceridemia, chronic cholecystitis and cholelithiasis, gestational diabetes mellitus, gastric cancer and systemic sclerosis. Further prospective studies and large RCTs with a good assessment of associations between H. pylori infection and health outcomes should be conducted to draw a firm conclusion.

Supplementary Material

Reviewer comments
Author's manuscript

Acknowledgments

The authors would like to thank Dr Honghui Li, Shengan Mo and Jiang for their help in this umbrella review.

Footnotes

LL, JT, LL and JL contributed equally.

Funding: This study is supported by National Natural Science Foundation of China (No. 81573914 and No. 81460723).

Competing interests: None declared.

Patient consent for publication: Not required.

Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information.

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