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

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. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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.

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

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 detectionmethod	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; CIAIF	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

Number of publications per annum.

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

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

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.