Bacterial virulence factors play a significant role in the outcome and progression of H. pylori infection[4]. The linkages of virulence factors may show how they interact with each other[5].

The cag pathogenicity island (cag PAI) contains 27-31 genes flanked by a 31-p direct repeats. H. pylori exhibits a high degree of genetic heterogeneity due to genomic rearrangements, gene insertions, and/or deletion[6].

At least 18 cag genes encode components of the bacterial type IV secretion system, which functions to export bacterial protein across the bacterial membrane and into host gastric epithelial cells. The presence of cag PAI (cag+) amplifies the risk for severe gastritis, atrophic gastritis, and distal gastric cancer in comparison with cag-deficient (cag-) bacteria[6].

CagA: Cytotoxin-associated gene A product (CagA) is translocated into the host cell by the type IV secretion system. Phosphorylation of CagA at the glutamate-proline-isoleucine-tyrosine-alanine (EPIYA) motifs by the host Abl and Src kinases results in morphological changes to the cell (the so-called “hummingbird phenotype”). Four EPIYA motifs (-A, -B, -C, and -D) are distinguished with different degrees of phosphorylation and geographical distribution[6]. EPIYA-A and EPIYA -B sites are less phosphorylated in comparison with EPIYA-C. EPIYA-C is typically found only in strains from Western countries (Europe, North America, and Australia), and is an indicator of gastric cancer risk. EPIYA-D is found in East Asian strains. EPIYA-D containing strains induce more relief of interleukin-8 (IL-8) from gastric epithelial cells[6] (Figure 1).

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Figure 1 Cytotoxin-associated gene pathogenicity island. CagA: Cytotoxin-associated gene A product; EPIYA: Glutamate-proline-isoleucine-tyrosine-alanine.

Phospho-CagA interacts with numerous intracellular effectors, including eukaryotic tyrosine phosphatase with sustained activation of extracellular signal-regulated kinases 1 and 2 (ERK ½), Crk adaptor, and C-terminal Src kinase[6]. The activation of ERK and focal adhesion kinase with the tyrosine dephosphorylation of the actin binding proteins cortactin, ezrin, and vinculin leads to cell elongation[1,6] (Figure 2).

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Figure 2 Targets of phosphorylated cytotoxin-associated gene A. Based on the article from Current Opinion in Microbiology, Hatakeyama M, SagA of CagA in Helicobacter pylori pathogenesis, 11, 30-37, Copyright (2008), with permission from Elsevier[7]. CagA: Cytotoxin-associated gene A product; NFκB: Nuclear factor κB; FAK: Focal adhesion kinase; Csk: C-terminal Src kinase.

The targets of non-phosphorylated CagA comprise E-cadherin, β-catenin, hepatocyte growth factor receptor c-Met, phospholipase C gamma, adaptor protein Grb2, kinase partitioning-defective 1b/microtubule affinity-regulating kinase 2, epithelial tight junction scaffolding protein zonula occludens 1, and the transmembrane protein junctional adhesion molecule A. The main effects are pro-inflammatory and mitogenic cell-cell junction disruption and loss of cell polarity that may be important in gastric carcinoma development[1,6] (Figures 3 and 4).

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Figure 3 Targets of non-phosphorylated cytotoxin-associated gene a product. Based on the article from Current Opinion in Microbiology, Hatakeyama M, SagA of CagA in Helicobacter pylori pathogenesis, 11, 30-37, Copyright (2008), with permission from Elsevier[7]. CagA: Cytotoxin-associated gene A product; PLC: Phospholipase C gamma; PAR1: Kinase partitioning-defective 1b; ZO-1: Zonula occludens 1; JAM: Junctional adhesion molecule A; NFκB: Nuclear factor κB; TNF-α: Tumor necrosis factor-α; IL: Interleukin.

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Figure 4 Development of “hummingbird phenotype”. CagA: Cytotoxin-associated gene A product; PLC: Phospholipase C gamma; PAR1: Kinase partitioning-defective 1b; ZO-1: Zonula occludens 1.

Activity of CagA on tumor-suppressor pathways has also been investigated. CagA is able to modulate the H. pylori induced apoptotic signal, but the exact mechanism remains to be elucidated. The initial host response upregulates p53 expression followed by the proteasomal degradation of p53[8].

Almost all cagA+ strains are classified as vacA s1 genotypes (either m1 or m2), whereas almost all cagA- strains are classified as the vacA s2/m2 strain (see below)[5]. Specific vacA genotypes of H. pylori strains are associated with a level of in vitro cytotoxin activity with clinical consequences[9].

Peptidoglycans: Peptidoglycans translocated by the cag secretion system interact with the nucleotide-binding oligomerization domain 1 (Nod1) molecule which leads to the activation of nuclear factor κB (NF-κB), pro-inflammatory secretion of interleukin-8 (IL-8), and β-defensin-2[6,10]. H. pylori enhances the phosphoinositide 3-kinase Akt signaling pathway, leading to decreased apoptosis and increased cell migration. NOD1 ligand binding can activate the interferon (IFN)-stimulated gene factor 3 signaling cascade, resulting in type I IFN production usually associated with protection against viral infection and possibly other mucosal infections[11].

VacA toxin: The cytotoxin gene vacA is present in all strains. The VacA cytotoxin induces the vacuolation, gastric epithelial barrier function disruption, disturbance of late endosomal compartments, and modulation of the inflammatory response. VacA reduces the mitochondrial transmembrane potential, releases cytochrome c from mitochondria, activates caspase 8 and 9, and induces apoptosis[6,12].

Binding of VacA to receptor-type protein tyrosine phosphatase (RPTPβ) regulates cell proliferation, differentiation, and adhesion, which all play a role in ulcerogenesis[13].

Variations in vacA gene structure (in the signal s: s1, s2, or in the middle regions m: m1, m2) make differences in vacuolating activity and specificity. The intermediate (i) region also plays role in the vacuolating activity of H. pylori. All s1, m1 strains were classified as i1 (vacuolating) type, and all s2, m2 strains were classified as i2 (non-vacuolating) type, while s1, m2 alleles could be i1 or i2. A novel intermediate variant (i3) has been identified. The fourth pathogenic region is d, a 69-81 bp-region between the m and i regions[1,5].

The variants in s and m regions seem to be a good indicator of clinical outcomes. However the roles of i and d regions should be further investigated[5]. The s1, m1 strains can induce greater vacuolation, and are associated with peptic ulcer disease and gastric cancer in Western countries, but have no pathogenic role in East Asian countries[1,6]. vacA i1 strains were associated with gastric cancer in Iranian patients[14], but not in the East Asian or Southeast Asian populations[14]. i1 genotype appeared to be a better predictor of carcinoma-associated H. pylori strains than the s or m genotype[15]. In Western countries, d1 strains without the deletion of the d region are predictors of histological inflammation, atrophy, and an increased risk of peptic ulceration and gastric cancer, compared with the presence of the vacA s-, m-, and i-region strains[16].

Adhesins and outer membrane proteins: 4% of the H. pylori genome encodes for outer membrane proteins (BabA, BabB, SabA, and OipA) which function as adhesins and porins, and are implicated in complement resistance and immune regulation[17].

The blood group antigen binding adhesin BabA is thought to mediate host-bacterial interactions and maintain colonization of the H. pylori targeting human Lewis-b surface epitopes[18,19]. The babA2 gene is associated with duodenal ulcer and gastric cancer. When in conjunction with cagA and vacA s1 alleles (“triple-positive strains”), it is associated with a greater risk of the more severe duodenal ulcer and gastric adenocarcinoma in Western populations[1,6,19].

Sialic acid-binding adhesin (SabA) binds to the carbohydrate structure sialyl-Lewis antigen expressed on the gastric epithelium. SabA can mediate the binding of H. pylori to neutrophils and erythrocytes, but the pathophysiological importance of these findings is uncertain[1]. SabA positive status was associated with increased gastric cancer risk and a negative status associated with duodenal ulceration[12].

The outer inflammatory protein (OipA) has a role in the increased expression of mucosal IL-1, -8, -17, tumor necrosis factor-α (TNF-α), and in gastric mucosal inflammation. Upregulation of matrix metalloproteinase 1, inhibition of glycogen synthase kinase 3β, and nuclear accumulation of β-catenin can influence carcinogenesis[6]. OipA positive status was significantly associated with duodenal ulcer and gastric cancer[12].

Others: Duodenal ulcer promoting gene (dupA) product induces the production of IL-8 and -12[5]. DupA may enhance duodenal ulceration and /or decrease gastric cancer development in some populations[1,5,6].

Variants of gene encoding flagellar proteins (flaA) of H. pylori may affect motility and colonization, and, therefore, the carcinogenic effect[6].

Annexin family members (AnxA1 and AnxA4) are involved in epithelial cell membrane repair response induced by H. pylori-generated VacA and CagA-independent plasma membrane disruption. Plasma membrane disruption and AnxA4 can promote cell proliferation[19].

TNF-α-inducing protein (Tipα) binds to cell-surface nucleolin and then enters the gastric cancer cells where TNF-α and chemokine gene expressions are induced by NF-κB activation in a cag PAI independent manner[20].

Bacterial factors like urease, AmiE, AmiF, hydrogenase, and arginase are essential for H. pylori survival in the acidic gastric environment[4].

Immune response to H. pylori: The host’s innate and adaptive immune system plays a crucial role in the initiation and progression of H. pylori infection[21].

Innate immunity effectors and a complex mixture of T helper (Th) 1, Th17, and regulatory T cells (Treg) adaptive immunity effectors are involved in H. pylori infection[22].

H. pylori initially targets gastric epithelial cells which form part of the innate immune response via signaling through pattern recognition receptors, such as Toll-like receptors (mainly TLR2)[21].

The neutrophil-activating protein of H. pylori polarizes Th1 cells, stimulating IL-12 and IL-23 secretion from neutrophils and macrophages. Th1 cytokines, such as gamma interferon (IFN-γ) and TNF-α, can increase the release of pro-inflammatory cytokines and augment apoptosis induced by H. pylori[22,23].

IL-17 expressing Th17 cells are important in the pro-inflammatory immune response to H. pylori. Th17 cells produce Il-17, IL-21, and IL-22 cytokines[6]. H. pylori infected macrophages produce IL-6, IL-23, and transforming growth factor (TGF)-β, which are required for Th17 cell development and maintenance[6,21]. The literature on Th1 and Th17 H. pylori-associated gastric pathology is confusing and requires intensive investigation[6].

Tregs (formerly suppressor T cells) are also implicated in the pathogenesis of H. pylori infection. TGF-β and IL-18 are responsible for Treg development[21]. H. pylori-specific Tregs suppress memory T cell responses that prolong the infection[6]. Tregs suppress the inflammatory reaction driven by IL-17, thereby also favoring bacterial persistence[24].

Antimicrobial defense of macrophages is nitric oxide (NO) dependent. H. pylori’s arginase enzyme can compete with macrophages for the inducible nitric oxide synthase (iNOS) substrate L-arginine so that host NO production is impaired; this leads to enhanced bacterial survival. H. pylori can evade macrophage phagocytosis. VacA protein prevents the fusion of phagosomes with lysosomes needed for phagocytosis. Fused phagosomes contain large numbers of live bacteria[6].

The role of B cells in the host response to H. pylori has been suggested[21]. Immunoglobulin (Ig) G and IgA antibody release from B cells in response to H. pylori may be involved in protective immunity, however it was suggested this antibody-mediated response may be counterproductive. B cells can also produce autoreactive antibodies that may be pathogenic[6]. B cell activation and survival may have implications for MALT lymphoma development[6].

Peptic ulcer: Some H. pylori colonized individuals may develop corpus gastritis associated with gastric hypochlorhydria, gastric atrophy, gastric ulcer, and an increased risk of gastric cancer. Conversely, others may develop antral-predominant gastritis, which is associated with gastric hyperchlorhydria and an increased risk of duodenal ulcer[8,25].

Since the discovery of H. pylori in the 1980s, the availability of effective eradication therapy has led to a decline in recurrent peptic ulcer disease and its complications. The pathogenetic role of H. pylori in 90% of duodenal ulcers and 80% of gastric ulcers is proven[26,27]. Effective eradication decreased the yearly recurrence rate of duodenal and gastric ulcers from 80% and 60%, respectively, to less than 5%[28].

Gastric cancer: H. pylori is a class I carcinogen in humans[1]. It is considered to be the most common aetiological factor of infection-related cancers (followed by human papilloma, hepatitis B and C, Epstein-Barr, human immunodeficiency, and human herpesvirus-8)[1,29]. H. pylori infection-related cancer represents 5.5% of the global cancer burden[6].

Gastric cancer develops in 2.9% of H. pylori infected patients[30]. H. pylori infection is responsible for about 75% of all non-cardia gastric cancers and 63.4% of all stomach cancers worldwide[1]. H. pylori infection also plays a fundamental role in non-cardia gastric carcinogenesis, but its association with cardia cancer is still uncertain[31].

The prevalence of infection is statistically significantly much higher in patients with intestinal-type gastric cancer (89.2%) compared to the diffuse-type (31.8%)[32]. H. pylori infection is regarded as the trigger of intestinal-type gastric adenocarcinoma[33]. According to Correa and Piazuelo, intestinal-type gastric carcinogenesis progresses as follows: normal gastric mucosa - no atrophic gastritis - multifocal atrophic gastritis without intestinal metaplasia - intestinal metaplasia of complete (small intestine) type - low-grade dysplasia - high-grade dysplasia - invasive adenocarcinoma[34]. Altered cell proliferation, apoptosis, epigenetic modifications to the tumor suppressor genes, oncogene activation, and dysregulation of DNA repair may occur and eventually lead to inflammation-associated carcinogenesis[35].

Eradication of H. pylori infection decreases the risk of premalignant lesions and gastric cancer in infected individuals[36-38]. Follow-up endoscopy and histology is crucial, even in patients with apparently non-malignant gastric ulcers, in improving the malignancy detection rate in populations with a high prevalence of gastric cancer[39].

H. pylori plays a role in the development and progression of gastric (MALT) lymphoma[40]. The average prevalence of H. pylori infection in MALT lymphoma was 79%; it was higher in low-grade (79%) than in high-grade (60%) cases[41]. Treatment for localized stage I gastric MALT lymphoma with H. pylori infection is eradication[40]. Eradication of H. pylori resulted in a complete remission in 60%-80% of patients with MALT lymphoma[42,43], and a 10-year sustained remission in up to 64% of cases[44].

The carcinogenic effect of H. pylori can be modified by dietary and environmental factors. H. pylori infection is more frequent in less developed Asian countries (e.g., India, Bangladesh, Pakistan, and Thailand) in comparison with the more developed Asian countries (e.g., Japan and China). However, the frequency of gastric cancer is paradoxically very low in these less developed regions than in Japan and China (the so-called “Asian enigma”)[33,45]. Several other large populations with high infection prevalence show a very low rate of gastric cancer. The so-called “African enigma” remains unexplained as well, but it does verify that not all H. pylori infected patients have an increased risk of gastric cancer[32,33,46].

Host and environmental factors also affect the development of gastroduodenal diseases in H. pylori infected individuals[6,47]. Individuals with a high-expression of IL-1β polymorphisms (C-T or T-C transitions, at positions -511, -31, and +3954 base pairs from the transcriptional start site) have an increased risk for hypochlorhydria, gastric atrophy, and distal gastric adenocarcinoma in comparison with low-expression polymorphisms; they have no effect on cancers associated with high acid exposure such as esophageal adenocarcinomas and some cardia cancers[47,48]. The combined effects of pro-inflammatory IL-1 genotypes and H. pylori bacterial virulence factors have been reported[48].

Gene polymorphisms (-308 G > A) of the pro-inflammatory cytokine TNF-α that increase the expression of the cytokine and polymorphisms (promoter polymorphisms at positions -592, -819, and -1082) that reduce the production of the anti-inflammatory cytokine (IL-10) have been associated with an increased risk of distal gastric cancer[48-50].

The effects of pro-inflammatory genotypes (IL-1β, TNF-α and IL-10) are additive[6,50].

High dietary salt intake increases the risk of gastric cancer by directly damaging gastric mucus and mucosa, improving temporary epithelial proliferation, increasing the incidence of endogenous mutations, upregulating cytokine production, and H. pylori gene expression modulation, especially that of virulence factors[51-53].

Co-infection with helminths (Ascaris lumbricoides) and Toxoplasma gondii reduces the severity of H. pylori-induced gastritis via a reduced Th1 response with higher levels of Th2 cytokines[54].

Fruit and vegetables are rich sources of carotenoids, vitamin C, folate, and phytochemicals, which may modulate xenobiotic-metabolizing enzymes and have antioxidant activity, thereby playing a preventive role in carcinogenesis[6,55-57].

Smoking is an established risk factor for gastric cancer. Swallowed carcinogenic substances (nitrosamine and other nitroso compounds), greater concentrations of smoking-related DNA adducts in the gastric mucosa, lower levels of free radical scavengers (ascorbic acid and β-carotene), and increased mRNA expression of chemokines in the gastric mucosa are in the background[58].

Epidemiological studies have suggested that H. pylori might be involved in the pathogenesis of pancreatic cancer (OR = 1.87, 2.1), however results are inconsistent[59,60]. A meta-analysis showed significant association between H. pylori seropositivity and development of pancreatic cancer (pooled adjusted OR = 1.38), but further research is needed to confirm this result[61,62].

Despite good scientific reasoning for the involvement of H. pylori in pancreatic diseases, direct pancreatic infection seems unlikely[63] (Table 2).

On the basis of the epidemiological results showing high mortality rates from gastric and colorectal cancer in similar areas, it can be speculated that gastric cancer and colorectal cancer have common risk factors like H. pylori infection[68]. Although the role of H. pylori in colorectal carcinogenesis has been widely examined, the association has remained inconclusive[69]. Several studies demonstrated conflicting positive and negative associations[68,69]. A meta-analysis showed that H. pylori infection was associated with an increased risk of colorectal adenoma (OR = 1.66) and colorectal cancer (OR = 1.39), however there was significant heterogeneity among the studies[70]. The inconsistent results might be due to sample bias, small sample size, varying frequencies of cagA+ strains in the study population, incomplete colonoscopies, and evaluation of H. pylori infection with the IgG serum test[69].

H. pylori was detected in colorectal carcinoma tissue in a pilot study[71]. Higher prevalence was proven in adenoma and colorectal cancer compared with control[72,73]. H. pylori was more prevalent in moderate/severe dysplastic adenomas compared with mild dysplasia, and in tubular and tubulovillous adenoma compared with villous type[72].

The pathogenetic mechanisms of H. pylori induced colorectal carcinogenesis are not fully understood[69] (Table 2). However, not every study confirms the correlation between atrophic gastritis, hypergastrinemia, and colorectal cancer[68]. Conversely, atrophic gastritis and hypergastrinemia demonstrated a significant elevation in the odds ratio (3.15) for rectal cancer[68]. Overall, chronic atrophic gastritis did not seem to contribute to an increase in colorectal adenoma risk. Chronic atrophic gastritis and its progression appear to further increase the risk for proximal colorectal adenoma formation[77]. The inconsistent results correlating hypergastrinemia and colorectal carcinogenesis may be explained by the fact that gastrin precursors (progastrin and glycine-extended gastrin) act as important promoters of colorectal carcinogenesis, but cannot be measured by most commercially available assays[77,78].

Concomitant H. pylori infection with metabolic syndrome further increases the possibility of colorectal adenoma formation; however the pathomechanism for this possible association is still unclear[69]. Insulin might exert proliferative effects on colonic tumor cells directly or indirectly via the insulin-like growth factor pathway[79]. Chronic inflammation, increased pro-inflammatory cytokine production, and decreased anti-inflammatory adiponectin production might be associated with carcinogenesis[69,80]. Triglycerides are energy sources for cancer cell growth and are linked with increased synthesis of bile acids, which have a carcinogenesis promoting effect[81].

It has been shown that H. pylori may play a potential pathogenic role in extra-intestinal diseases via multiple mechanisms[82]. Atrophic gastritis caused by infection, an increase in gastric vascular permeability and therefore increased exposure to alimentary antigens, release of inflammatory mediators, and systemic immune responses (auto-immunity, pro-inflammatory substances, and immune complex formation induced by molecular mimicry and cross-reactive antibodies) have been suspected in the background[82,83].

With the exception of unexplained iron deficiency anemia (evidence level 1a) and idiopathic thrombocytopenic purpura (evidence level 1b), H. pylori infection has no proven role in other extra-intestinal diseases[82,84,85].

Helicobacter DNA has been detected in hepatic tissues from patients with various hepatobiliary diseases, hepatitis C virus-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC)[86,87]. The association between H. pylori and Child-Pugh classification is inconsistent[87]. It can be proposed that H. pylori infection may play a role in hepatic carcinogenesis as well[88]. The odds ratio for the association between H. pylori infection and the risk of HCC was 13.63[89] (Table 2).

Laryngeal cancer: Colonization of bacteria in the upper aerodigestive tract was confirmed, however the relationship between H. pylori infection and laryngeal cancer risk have produced conflicting results. Meta-analysis showed a 2.03-fold increased risk[92].

H. pylori was detected in larynx cancerous tissue. The presence of the cagA gene in larynx cancer tissues significantly decreased survival rate and increased the possibility of disease recurrence[93] (Table 2).

Lung cancer: The results of previous studies of H. pylori seropositivity and lung cancer are inconclusive[94], with an odds ratio between 1.24 and 17.78 on the basis of the epidemiological studies[95]. The NHANES study observed an inverse association between H. pylori and lung cancer in older participants, with a significant inverse association for cagA+ strains; this was without histological examination[96]. A case-control study found no evidence of an association between H. pylori and lung cancer in Finish male smokers. Neither overall H. pylori seropositivity nor CagA-specific H. pylori seropositivity were associated with lung cancer[94]. Causal relationships must be confirmed with exact determination of smoking status[95] (Table 2).

Epidemiological studies showed significant associations with metabolic syndrome (OR = 1.39)[99,100]. Furthermore, multiple linear regression analysis showed that H. pylori seropositivity was significantly associated with higher systolic blood pressure, lower high-density lipoprotein (HDL)-cholesterol level, and higher low-density lipoprotein (LDL)-cholesterol level[99]. It has been suggested that H. pylori eradication could lead to an improvement of atherogenic blood lipid profile, insulin resistance, and low-grade inflammation, which were deduced from a decreased C-reactive protein level[101]. Other studies did not find an association between H. pylori infection and insulin resistance[102,103].

The relationship between H. pylori infection and metabolic syndrome is both poorly understood[104] (Table 2) and controversial[106-108].

Studies investigating the pathogenetic role of H. pylori in cardiovascular diseases have produced conflicting results[108-111]. A meta-analysis of 18 epidemiological studies involving 10,000 patients did not find any positive association between H. pylori and cardiovascular risk factors and coronary heart diseases[112]. A higher prevalence of more virulent cagA+ H. pylori was reported in patients with ischemic heart disease, unstable angina, acute myocardial infarction, and restenosis after percutaneous transluminal coronary angioplasty and essential hypertension[108,111,113].

Evidence on the relationship between H. pylori infection and ischemic heart disease is weak, with some inconclusive, albeit plausible, mechanisms (Table 2). There are also no adequate interventional studies done to demonstrate that H. pylori eradication is associated with a lower incidence of ischemic heart disease[108].

Chronic urticaria: A correlation between H. pylori infection and chronic urticaria has been suggested (Table 2). H. pylori eradication in patients with chronic urticaria leads to symptomatic improvement in some patients, while others showed no improvement[83].

Immune thrombocytopenic purpura: The prevalence of H. pylori infection in patients with immune thrombocytopenic purpura (ITP) is significantly higher than that in age- and gender-matched controls[108,115,116]. The most plausible mechanism is cross-mimicry involving H. pylori, platelet antigens, and infected host factors (antibody production cross-reacts with platelet glycoprotein antigens)[108,117].

Eradication of H. pylori results in an increasing platelet count in nearly half of infected ITP patients, although geographical differences in the efficacy of eradication were also presumed[83,115,116]. The European Helicobacter Study Group consensus in 2012 and the Second Asia-Pacific Consensus Guidelines have recommended H. pylori infection eradication in patients with chronic idiopathic thrombocytopenic purpura[84,85]. However, larger randomized controlled trials with long-term follow-up are still required before a firm conclusion can be drawn[108].

Henoch-Schönlein purpura: A study in China found increasing evidence suggesting that Henoch-Schönlein purpura (HSP), especially abdominal HSP, might be associated with H. pylori infection (OR = 4.62); this underlines the necessity of screening H. pylori infection in children with HSP with gastrointestinal manifestations[82].

It was found that eradication of H. pylori infection resulted in prompt resolution of the HSP, or at least prevented its recurrence[118].

More investigations are needed to confirm the pathogenetic role of H. pylori in HSP (Table 2). HSP children with serious gastrointestinal symptoms must be screened and treated for H. pylori infection[82].

Iron deficiency anemia: Several epidemiological studies have shown lower ferritin levels among patients with H. pylori infection, although there were studies that produced a negative association[108]. Meta-analyses showed an association between H. pylori infection and iron deficiency anemia (IDA)[119,120]. H. pylori eradication improves iron absorption[121].

Possible pathomechanisms are: increased iron loss due to active hemorrhage secondary to gastritis, peptic ulcer, gastric cancer, reduced iron absorption caused by achlorhydria induced by chronic pangastritis, reduced secretion of ascorbic acid to the gastric mucosa, and iron utilization for protein synthesis by the bacterium for colonization in the host environment[122]. Elevated serum prohepcidin might also indicate the role of inflammation in its aetiology[123].

Testing and eradication of H. pylori for unexplained IDA are supported by the current evidence and approved by the Maastricht IV Consensus and the Second Asia-Pacific Consensus Guidelines[84,85]. However, larger sample randomized controlled trials are necessary to clarify the reason why only a small proportion of H. pylori-positive patients develop IDA[108].

Gastroesophageal reflux disease/esophageal adenocarcinoma: A meta-analysis showed that H. pylori infection displays a negative association with the development of endoscopic gastroesophageal reflux disease (GORD). Eradication of the infection may be a risk factor for development of de novo GORD[124].

H. pylori infection protects against gastroesophageal reflux[2]. H. pylori-induced corpus gastritis and profound suppression of gastric acid secretion have also been shown to prevent patients from developing GORD[125]. cagA+ H. pylori strains have a more protective effect against GORD[126], and it was found that H. pylori infection was inversely associated with Barrett’s esophagus[127].

The Maastricht consensus IV confirmed a negative association between the prevalence of H. pylori and the severity of GORD. The consensus stated that H. pylori status exerts no effect on symptom severity, recurrence, or treatment efficacy in GORD. H. pylori eradication does not exacerbate pre-existing GORD or affect treatment efficacy[85].

Esophageal adenocarcinoma risk due to H. pylori infection was 0.58-fold, and squamous cell carcinoma risk was 0.80-fold compared with that of controls. Compared with cagA- H. pylori, cagA+ H. pylori markedly decreased esophageal cancer risk[129].

The underlying mechanism in the background of the protective effect of H. pylori against GORD is not fully understood (Table 2).

H. pylori infection acts as neither a preventive factor nor a risk factor for squamous cell carcinoma. This discrepancy might be due to the relatively small number and heterogeneity of the included studies[129].

There is further need to assess the benefits of H. pylori in connection with GORD and its complications.

Bronchial asthma: An infection in the early phase of life is essential for the normal maturation of the immune system, achieving a balance between T-helper type 1 (protective immunity) and T-helper type 2 (allergic diseases) cytokine responses, which can reduce the risk of atopy later[129].

H. pylori infection might play a role in the development of chronic bronchitis, bronchiectasis, tuberculosis, and lung cancer[130]. Moreover, H. pylori might have an influence on the developing immune system, which might reduce the risk of asthma in later life[131].

The associations between H. pylori and asthma were contradictory. Inverse associations were reported, but other studies demonstrated different results[131]. A meta-analysis found weak evidence (OR = 0.81, 0.84) for an inverse association between H. pylori infection and asthma in children and adults, respectively[131,132]. Another meta-analysis failed to prove a significant association between H. pylori infection and asthma risk[130].

The mechanism of the preventive effect of H. pylori on asthma has been unambiguous (Table 2).

It seemed that H. pylori infection (especially cagA+ strains) may prevent children from developing asthma, but must be studied in the future[131] due to the inconsistent result[134].