Epidemiological data

Its extensive prevalence in the general population reaching up to 80% is characterized by geographical distribution and the socio-economic status of the population [1]. Prevalence of H. pylori infection is decreasing not only in developed countries but also in the Russian Federation where a prevalence of 78% was reported in 2017 [2] and only 40% in a recent publication [3]. High H. pylori prevalence was found in countries of Latin America. In Chile, high prevalence was identified in newborns during the first month after birth. In Canada, the indigenous populations in the Arctic were found to have higher infection rates compared to non-indigenous inhabitants [4]. The same was true in the city of Amsterdam, in the Netherlands. Ethnic minority groups were significantly more infected with H. pylori compared to the indigenous Dutch population [5].

Large geographical variance in prevalence was reported in a meta-analysis with data from 62 countries. The highest pooled prevalence of 70% was found in Africa and the lowest of 24.4% in Oceania. Among countries, the lowest prevalence of 18.9% was found in Switzerland and a very high 87.7% was reported for Nigeria. Based on these findings, it was estimated that almost 4.4 billion individuals were infected by H. pylori. The global prevalence in adults has declined from an overall 50–55% to a recent 43%. However, this is not the case in Asia, Latin America, and the Caribbean [2, 6, 7].

It is generally accepted that H. pylori infection is a life-long event, when individuals are infected. However, spontaneous clearance of 15.5% was reported in children during a 20-year follow-up. Interestingly, strain concordance was detected in 56% between mother and offspring and 0% between father and offspring [8–10].

The most serious problem with H. pylori infection is the association with the development of GC. Non-cardia adenocarcinomas have been linked to H. pylori with a very high odds ratio (OR) up to 21.0 [11]. In general, H. pylori is estimated to be associated with 36.8% of GCs out of the 2.2 million cancers linked to infections. In 2018, 89% of the 850,000 cases of non-cardia GC cases and 73% of non-Hodgkin gastric lymphomas were associated with H. pylori infections [12]. A recent meta-analysis [13] reported data from 32 countries on the prevalence of GC in H. pylori-positive patients. The highest prevalence was observed in America (18.06%) and the lowest in Africa (9.52%). Among countries, Japan had the highest pooled prevalence (90.90%) whereas in Sweden the lowest prevalence (0.07%) was observed. The overall risk of GC development from birth to old age is 1.87% in males and 0.79% in females while the incidence for GC have considerably decreased over the last 75 years. However, the mortality remains high in countries such as Japan, China, and Chile [14]. Environmental and genetic factors also modify the lifetime risk of GC [6, 15–17]. Genetic factors, housing conditions, and dietary habits may be responsible for the increased risks in East Asian populations [18–20].

A global average annual percentage reduction of 2.1% has been reported. The incidence rates of GC are expected to constantly decline through 2030 in most countries except Ecuador and Lithuania [21]. It should be noted however, that even in countries such as the UK where GC is not a major problem any more, it is one of the leading causes of cancer-associated death [22, 23].

Pathogenetic mechanisms in GC development

H. pylori infection is responsible for chronic destruction of the acid-secreting glands of the stomach, evolving to atrophic gastritis (AG) and IM [24, 25]. However, only 2–3% of infected patients develop GC, and 0.1% will develop mucosa-associated lymphoid tissue (MALT) lymphoma [26, 27]. Most investigators accept that there is a point of no return during gastric carcinogenesis independent of H. pylori status. This is reported to be associated with IM and dysplasia [28]. The penetration of H. pylori penetration into the epithelial mucus layer activates the phagocytic cells macrophage and neutrophils of the mucosa. They produce reactive oxygen species (ROS) and nitric oxide (NO) to defend against the invaders [29]. However, all H. pylori strains are capable of detoxifying ROS, producing catalase and superoxide dismutase. And arginase that reduces NO production [30]. In addition, the bacterial survival is increased by inducing mitochondria-dependent apoptosis of macrophages.

It has been suggested that certain strains of H. pylori are more dangerous than others to initiate GC. These strains are producing proteins such as vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A (CagA) [11, 31, 32]. The effects of VacA on cells include induction of vacuoles, induction of apoptotic cell death, induction of autophagy, and effects on several immune cells [33]. CagA on the other hand, has a direct oncogenic effect leading to AG and GC [34, 35]. CagA is responsible for aberrant activation of several oncogenic proteins such as rat sarcoma protein (Ras), β-catenin, phosphatidylinositol 3-kinase (PI3K), and others [36] triggering thus the oncogenic stress response (OSR). One of the central regulators of the OSR is the ADP-ribosylation factor (ARF) protein. ARF protein induces apoptosis and permanent cell cycle arrest by increasing stability and activation of p53 protein [37, 38]. Ubiquitin ligases such as apoptosis regulatory protein Siva (SIVA1) that controls ARF protein degradation is inhibited by H. pylori [39, 40]. Interestingly, in contrast to VacA, CagA inhibits apoptosis activating several antiapoptotic pathways. Importantly, CagA impairs the antiapoptotic activity of the tumor suppressor factor p53 through degradation of the p53 protein [38, 41]. CagA phosphorylation also regulates the degradation of ARF tumor suppressor (p14ARF).

Additional proteins that increase the risk of GC development, are the outer membrane proteins (OMPs) such as the blood-group antigen-binding adhesin (BabA) and the outer inflammatory protein A (OipA). BabA binds to epitopes that increase production of cytokines involved in cell proliferation. OipA activates β-catenin and the PI3K-protein kinase B (AKT) signaling pathway [20, 42].

An additional mechanism of H. pylori pathogenicity is the release of outer membrane vesicles (OMVs) by certain strains, consisting of a variety of cellular constituents. OMVs, may be either harmful or defensive [43]. OMVs from H. pylori induce the secretion of interleukin-8 (IL-8) by gastric epithelial cells and activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase (ERK) pathways, modulating thus cell proliferation and cancer initiation [44]. This hypothesis was supported by the finding that the presence of OMVs is significantly increased in the gastric juice of GC patients compared to normal controls [45]. The biologically active compounds of OMVs also, promote apoptosis of gastric epithelial and immunocompetent cells such as macrophages [46]. Furthermore, H. pylori-induced oxidative stress activates the intrinsic pathway of apoptosis leading to cell death. As mentioned before, VacA also promotes apoptosis. Thus, excessive apoptosis will result in cell mass loss, as observed in gastric ulcers [47] being therefore the background of the association of H. pylori with peptic ulceration.

Additionally, H. pylori activates the innate immune response. At the initial stages of the infection H. pylori releases several pathogens associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and flagellin that are recognized by several innate pattern recognition receptors (PRRs). H. pylori PAMPs are weak activators of the host receptors allowing a chronic infection. Some other PAMPs such as ADP-heptose, nucleic acids, and OMVs are not yet fully studied in detail [48].

Apoptosis inhibition is an important element in carcinogenesis. Equally important is the process of autophagy. Autophagy is a survival mechanism at the initial stages of cellular insult. Autophagy polymorphisms were associated with GC in Chinese patients, and 28 autophagy related genes (ATGs) were down-regulated in H. pylori-infected gastric cells. The presence of the ATG16L1 rs2241880 increased the risk of GC while the presence of the immunity-related GTPase M (IRGM) rs4958847 decreased the GC risk [49]. The ATG16L1 rs2241880 G-allele is associated with the progression of gastric premalignant lesions and cancer possibly due to the modulation of H. pylori-induced endoplasmic reticulum (ER) stress [50–52]. Experimental evidence suggests that at the initial stages of H. pylori infection autophagy regulation is different during evolution of the infection [53, 54]. It has been shown that during the acute infection, autophagy is initiated through secretion of VacA and in turn degrades VacA and CagA. However, at the chronic stage VacA and CagA restrict autophagy inhibiting their degradation, and increasing the damage of the epithelial cells [55].

Treatment of H. pylori infection in AG

Asymptomatic individuals with H. pylori-positive AG are the most important source for Helicobacter transmission [66]. According to certain guidelines [67–69], all H. pylori-positive individuals should receive eradication treatment including therefore AG positive patients. The rationale is that eradication will reverse the atrophic and metaplastic changes and stop the Correa cascade of evolution to the point of no return [61, 70, 71]. However, GC appears even after successful eradication, leading to a debate for the point of no return. The presence of IM is the current point beyond which the eradication strategy may not prevent GC compared to earlier stages of the infection [28]. The potential benefits of eradication are probably dependent on the degree of atrophic damage already present at the time of eradication [67, 68]. This is supported by a recent single-center retrospective study, where diffuse-type GC development was associated with the degree of gastric atrophy at the time of the initial diagnosis after a long follow-up (mean 7.1 years). The standardized incidence ratio for diffuse GC was negligible in mild gastric mucosal atrophy and 10.9 in moderate atrophy. GC developed more frequently in the second decade of follow-up, suggesting that endoscopic surveillance should be continued for at least 10 years after H. pylori eradication in high-risk areas [72].

The reversibility of AG after H. pylori eradication is still debatable [73]. The most objective way to answer the question requires histological confirmation preferably by using the histological staging systems of operative link for gastritis assessment (OLGA) and operative link for gastric IM assessment (OLGIM) [74, 75]. Endoscopic scoring systems such as the proposed by Kimura and Takemoto can be used, but they require considerable experience and cannot substitute for histological confirmation [76]. A recent meta-analysis of 12 studies showed that eradication improved AG in the corpus but not in the antrum. Moreover, there was no evidence for a significant resolution of IM either in the corpus or in the antrum [77]. Two other meta-analyses reported significant improvement of gastric atrophy after eradication, but no improvement of IM [28, 78]. Controversial results were obtained in a long-term follow-up study where IM in the antrum and corpus improved after successful eradication [79]. A very recent study with 69 participants from arctic territories of Canada reported that compared to baseline precancerous gastric pathology was substantially lower at follow-up. Eradication of H. pylori led to reduction of severity of active and AG. No data on IM is reported in this study [80].

Recurrence after eradication of H. pylori is an important problem in GC prevention. The recurrence rate is higher in countries with higher prevalence of H. pylori infection and lower socio-economic conditions [81, 82]. High recurrence rates were reported in areas such as Alaska, Vietnam, and Bangladesh [83–85]. The overall annual recurrence rates after H. pylori treatment, but without mass eradication policies, was 4.3%, according to a meta-analysis [81]. There are many reasons for recurrence [81, 82]. Recurrence can be due to the reappearance of the original strain or to the reinfection by a different strain [86, 87]. The recurrence is also dependent on the pattern of eradication program. In a study without mass eradication, the annual recurrence was 7% per person-year [88], but only 1% in the small community in the Matsu Islands, where almost 82% of the population participated in the eradication program [89].

An additional problem with H. pylori eradication is the administration of antibiotic-based regimens in children as children very rarely suffer serious consequences particularly in the west. The matter is still open to debate [90]. An interesting possibility for children is the hypothesis that administration of probiotics reduces H. pylori adhesion to gastric epithelial cells and prevents colonization. Further clinical trials are needed [91]. Probiotic co-supplementation to antibiotic therapies is reported in several studies in adults. A substantial reduction in resistance genes for several antibiotics was reported for Saccharomyces boulardii supplementation during H. pylori eradication [92]. Furthermore, a meta-analysis showed that probiotic administration increased the H. pylori eradication rate [93]. However, the significance of gut microbiota alterations after probiotic administration is not clear. Long-term follow-up studies to clarify possible detrimental consequences of the probiotic intervention in H. pylori eradication are required before recommendations can be made [94].

The recommendations for testing for the presence of H. pylori are intimately connected to eradication recommendations. A Chinese consensus panel suggested screening and eradication in all high-risk populations [95]. On similar grounds, it was suggested that test and eradication should be applied to all individuals with IM although the suggestion is based on moderate quality of evidence. The authors also urge for more widespread availability of antimicrobial susceptibility tests in the United States [96, 97]. Patients with peptic ulcers are regularly tested as part of the standard of care recommendations. However, nearly 20% of all hospital admissions with bleeding peptic ulcers were not tested for H. pylori particularly those who were admitted in an ICU. Failing to test and eradicate resulted in twice as high re-bleeding or death rates when compared to tested patients [98].

Symptomatic improvement as a surrogate indication for successful eradication should not be advocated and there is a strong recommendation that a non-invasive test should be used particularly in those where eradication has been administered for GC prevention [27].

H. pylori eradication costs

The quality-adjusted life year (QALY) is the quantification of the disease burden including both the quantity and quality of life (QoL). However, a number of questions on the interpretation of derived QALY remain unresolved [99]. This is particularly true for studies in children where the relative cost-effectiveness (cost per QALY gained) in many diseases and populations, should be faced with extreme caution [100]. The derivative of the cost divided by QALY gained is called incremental cost effectiveness (ICER). It is also used for assessment of the cost of diseases but its use is not without problems [101].

There have been several attempts to estimate the cost of eradication strategies in H. pylori infection. Only recent papers were reviewed, as financial situations are changing rapidly over time. A previous consensus report has estimated that it would need 125 individuals to be treated to prevent one case of GC in countries with high GC incidence. A higher number would be needed in countries with low incidence making eradication possibly not necessary in these populations. Yet, the consensus recommendation was in favor of the test-and-treat policy [68].

The cost-effectiveness of population-wide eradication strategy has produced controversial results in different populations. In Denmark, a country with low incidence of H. pylori prevalence neither improvement of QoL nor cost-effectiveness were demonstrated [102]. Markov models from a high prevalence country such as China, showed that the population-wide screening was cost-effective in prevention of GCs in asymptomatic individuals [103, 104]. As the majority of H. pylori infections is acquired during childhood, eradication policies in young adults are now implemented in Japan [105]. A meta-analysis based on eight studies reported that the lowest ICER calculated was 1,230 US dollars per life-year gained and 1,500 US dollars per QALY. However, the cost-effectiveness analysis was dependent on many factors that make direct comparisons difficult [106]. A recent study from China compared the ICERs of three treatment strategies, namely the annual, triennial, and five-yearly H. pylori screening, and concluded that screening for H. pylori in asymptomatic populations is cost-effective. The significance of the frequency of screening was inferior compared to increased participation [107]. In Japan, an eradication strategy was more cost-effective compared to endoscopic screening provided acceptance to pay a threshold of 50,000 US dollars per QALY gained according to Monte Carlo simulations. They concluded that over a lifetime, an eradication strategy, may prevent 4.47 million GC cases, and may save 319,870 lives from GC [108]. In the special population of eradicated H. pylori, it was suggested that biennial endoscopy is the cost-effective screening for mild to moderate atrophy and annual endoscopy for those with severe atrophy compared to no screening [109].

There are two points that should be commented on when costs are concerned. The first is that all estimations are based on mathematical Markov models and Monte Carlo simulations. However, acceptable these methods may be, they are based nonetheless on many assumptions that may prove to be erroneous in real-time evaluations. The second point is that no model has taken into account the consequences of the recent SARS-CoV-2 pandemic that crippled many health systems and may have changed spending priorities and the willingness to pay thresholds in many countries.

H. pylori and reduced risk of inflammatory bowel disease

The potential protective effect of H. pylori in inflammatory bowel disease (IBD) may be related to its influence on the gut microbiota and the modulation of the immune response [176]. The microbiota modulation is supported by an inverse association between H. pylori and several pro-inflammatory microbes such as Fusobacterium varium, Rhodococcus, and Sphingomonas, while the activation of colonic mucus production by H. pylori via the NLR family pyrin domain containing 3 (NLRP3)/caspase-1/IL-18 axis argues in favor of the immunomodulation effect [177, 178]. An additional possibility was proposed suggesting a non-causal relationship between H. pylori and IBD. Individuals with a defective fucosyl transferase 2 (FUT2) gene cannot secrete fucosylated glycans in the GI mucosa. They are susceptible to pathogens such as Escherichia coli, Neisseria meningitidis, and Candida albicans. The FUT2 non-secretors are more susceptible to Crohn’s disease (CD), ulcerative colitis (UC), and other so-called autoimmune diseases but at the same time, they are protected against H. pylori adhesion in the gastric mucosa [162, 179–181]. Patients with UC and CD had decreased FUT2 expression in the colon [182]. The increased susceptibility to IBD was possibly associated to increased production of microbial lysophosphatidylcholine that promotes the secretion of pro-inflammatory cytokines, damaging the tight junctions and the intestinal epithelial barrier [182]. These deleterious effects were reversed by upregulation of FUT2 [183]. However, even this theory cannot rule out that H. pylori is in fact the mediator of the protection offered by fucosylation against IBD modulating either the gut microbiota or the immune system [178].

From the clinical point of view, epidemiological studies revealed that IBD is more prevalent in areas with low prevalence of H. pylori infection while several meta-analyses reported a negative correlation between H. pylori infection and IBD attributing a protective role to H. pylori [184–186]. H. pylori infection seems to provide more protection against UC than CD, and in East Asian populations compared to Mediterranean ones [185]. A meta-analysis involving 13,549 patients with IBD and 50,654 controls [187] reported that the prevalence of H. pylori infection was 22.8 % in patients with IBD and 36.3% in controls, finding a significant negative association (pooled OR = 0.45). Another meta-analysis also demonstrated a strong negative correlation between H. pylori prevalence and IBD. The odds of colonization were 0.36 for CD and 0.54 for UC. Most importantly, H. pylori eradication could lead to IBD flares, while patients had a higher probability of relapse after the eradication (OR = 1.41) [188].

H. pylori and esophageal diseases

The absence of H. pylori, mostly after eradication, has been linked to some esophageal diseases including gastro-esophageal reflux disease (GERD), Barrett’s esophagus, and adenocarcinoma of the gastroesophageal junction [14, 189–191] as the incidences of these diseases have risen in developed countries and are negatively associated with H. pylori prevalence [192–195].

Explanations for the protective effect of H. pylori include the reduction of acid secretion and the colonization with other organisms. There is a reduced production of acid by the infected stomach and the microbiota of the distal esophagus is probably affected when reflux occurs [145] a situation similar to protracted administration of PPIs [196, 197]. A protective H. pylori effect has been also proposed for the new entity of eosinophilic esophagitis, but this conclusion is controversial [198].

From the clinical point of view, an earlier prospective study with endoscopic assessment demonstrated that eradication therapy in duodenal ulcer patients will increase the prevalence of reflux esophagitis compared to those without H. pylori eradication. Risk factors were the corpus atrophy and weight gain [199].

It was also reported that H. pylori presence can considerably reduce the risk of esophageal adenocarcinoma in Western populations. On the other hand, esophageal squamous cell carcinoma (ESCC) risk was not affected for the combined populations from East and West. However, when populations were separated, there was an association with decreased risk of ESCC in populations in East Asia [200]. This observation is difficult to be attributed only to H. pylori eradication as ESCC is related to several dietary and lifestyle factors such as alcohol consumption, cigarette smoking, and hot-temperature food [200, 201]. Different genetic background cannot be excluded as well [202]. A study from Greece, reported an inverse association of H. pylori infection with both esophageal adenocarcinoma and Barrett’s esophagus, suggesting a protective role of H. pylori. On the contrary, no association with ESCC could be established [203]. A cross-sectional study in a large Japanese population found that seropositivity for H. pylori was related to a lower rate of long-segment Barrett’s esophagus and a higher rate of short-segment Barrett’s esophagus [204], findings that are difficult to reconcile. Another study confirmed that the presence of H. pylori in the stomach was associated with a significantly decreased risk of Barrett’s esophagus, and esophageal adenocarcinoma [205]. The OR for the association between H. pylori and Barrett’s esophagus after controlling for age and white race was 0.55 with an even higher inverse association (OR = 0.28) among participants with corpus atrophy or anti-secretory drug use more than once per week. Although the authors imply that these factors are the reason for the negative association, it should be noted that H. pylori infection is the main reason for corpus atrophy. By contrast, no inverse association was found in patients without these factors [206]. A recent meta-analysis also observed an inverse relationship between H. pylori and Barrett’s esophagus (OR = 0.70) [207]. However, these inverse associations are still debatable [208], and evidence for positive [195, 203, 209, 210] and negative associations exist [208, 211]. It should be noted however, that in the recent negative study, almost 50% of patients had only 1–2 years follow up and only 15% of them had a maximum follow-up of 5–7 years [211]. A recent meta-analysis found an inverse association between H. pylori infection and erosive gastritis but no association with Barrett esophagus [212]. At present, the most recent recommendations have chosen to ignore the alarming positive studies, which made no impact on the management of the H. pylori infection [213].

This attitude was influenced by a recent large retrospective study in the USA that reported no association of H. pylori infection or eradication with the development of either esophageal cancer or proximal gastric adenocarcinoma. Despite the large number of patients enrolled, there are substantial drawbacks in the study. Only gender, age, race, and smoking habits were considered as covariates. Critical risk factors such as dietary habits and alcohol use were not included possibly due to the retrospective nature of the study. Moreover, smoking was tested on the yes or no situation without any attempt to categorize patients on the basis of pack/years. More importantly, only 30% of treated patients had a confirmed outcome while almost 70% were categorized as unknown outcomes. Probably these are the explanations for the somewhat curious finding that Asians and native Hawaiians were protected from the future cancers [214].

H. pylori and protection from asthma and allergy

Earlier reports from Europe and the USA have demonstrated a significant inverse association between asthma and H. pylori infection [146, 147, 215–218]. Protection from childhood-onset asthma, hay fever, and cutaneous allergies by the presence of H. pylori infection has been confirmed by several reports [219–223] including a recent report from Greece [224] and a meta-analysis of 24 reports where it was shown that H. pylori infection, especially CagA-positive infection, is inversely associated with the risk of asthma [225]. Therefore, there is considerable evidence to support the hypothesis that the rise in asthma prevalence may be related to the reduced prevalence of H. pylori and the protective immunological functions elicited by its presence [145, 223, 226]. Murine studies reported that H. pylori protects from allergic asthma by modulating effector T-cells and T regulatory cells (Tregs) and by limiting dendritic cell (DC) function [226–229].

Additional rodent experiments showed that mothers infected by H. pylori during pregnancy initiate a tolerogenic immunity response to their offsprings that mitigated the development of allergic diseases later in life [230]. In a murine study of mice sensitized with house dust mite, it was shown that extracts of H. pylori were an effective treatment to reduce mucus production and features of inflammation when re-challenged with dust several months after rest [231]. In a similar model, a very recent report demonstrated that treatment with H. pylori-derived VacA reduced several asthma indicators such as inflammation and goblet cell metaplasia. An induction of tolerogenic DCs and regulatory T cells were observed after VacA administration. Depletion of regulatory T cells, reversed the CagA suppression of allergic airway disease [232, 233]. VacA targets DCs and macrophages of the gastric lamina propria [234] promoting the secretion of anti-inflammatory molecules such as IL-10 and transforming growth factor-β, and modulating the development of Tregs [234]. Moreover, naive human DCs incubated with VacA increased the expression of programmed death-ligand 1 (PD-L1), a molecule that is strongly associated with amelioration of T cell reactions [235, 236]. In addition, VacA also initiated the expression of immunoglobulin-like transcript 3 (ILT3), an inhibitory receptor that is found in tolerogenic DCs [237].

Interestingly, the effect of H. pylori may be dependent on ethnicity as demonstrated in a multiethnic study of children. Children of European ancestry colonized with CagA-negative H. pylori had an increased prevalence of asthma in contrast to children of non-European origin. In addition, only positive children with H. pylori-negative mothers had an increased risk of asthma suggesting again that, in agreement with the previously mentioned animal data, infection of the mother may protect the H. pylori-positive children [238]. In a case-control study, abdominal obesity and H. pylori infection were associated with reduced risk of asthma and allergy. H. pylori infection was associated with a considerable reduction odd of asthma and allergic diseases in individuals with abdominal obesity [219]. This is in concert with the change in BMI after eradication [173]. A significant increase in BMI and body weight after eradication of H. pylori has been reported which possibly due to the restoration of ghrelin secretion and the relief of dyspepsia, as mentioned before [171, 239, 240].

Negative studies have also been published [241]. However, they included only adults [242] and/or a specific Hispanic/Latino population of 18–74 years old [243]. In the last recent cross-sectional the diagnosis of asthma was only based on self-reported information, while the significant co-variate of smoking was reported as current, past, and never smokers without further quantification according to pack/years of smoking.

Despite these negative reports, the overwhelming evidence supports the protective role of H. pylori infection in asthma and other allergic diseases.

Coeliac disease

Coeliac disease affects approximately 0.5–1% of the global population. Increasing evidence of H. pylori involvement has been proposed [244] based on a previous large meta-analysis of 25 studies and more than 140,000 participants. The infection rate of H. pylori infection of celiac disease patients was almost 50% lower compared to controls with an OR of 0.57 [245].

Other putative protective effects

H. pylori infection was also proposed to protect from pathogens that cause diarrhea, but this observation is not consistent and may be associated with recent changes in other factors [246, 247]. Moreover, this protection may be related to the improvement of sanitation in the industrialized West, rather than to H. pylori [145]. Individuals infected by H. pylori also show a negative association with tuberculosis. More plausible is the reported reduction of latent tuberculosis re-activation of individuals with H. pylori infection in West Africa [145]. It was proposed that H. pylori infection may interfere with T-cell signaling pathways that enhance the innate response of the host and reduce the risk of active tuberculosis [145, 248].

Other reasons for abandoning the “test-and-treat” suggestion

A well-known paradox in the relationship between H. pylori and GC, is the low incidence of GC in Africa, Asia, and Latin America associated with a high prevalence of H. pylori infection even with high virulence strains. This is called the African [249] or Asian/Indian enigma [250]. The very existence of this paradox has been disputed [251], but the genetics of the host population, their dietary habits, smoking, alcohol consumption, and co-infection with parasites should be examined as they may initiate the protective Th2 immune response [249, 250]. The expected GC incidence is 5.7 in African countries, 7.0 in Asia and Oceania, 16.0 in America, and 26.0 in Europe, considering the alcohol and tobacco availability and the consumption of fruit and vegetables. The interaction between H. pylori and cigarette or alcohol consumption and dietary habits may explain the so-called African and Asian enigmas [252]. Dietary differences were also proposed to explain a similar enigma in Chile. They studied two areas with similar prevalence of H. pylori colonization and similar prevalence of VacA and CagA factors but with different GC prevalence. Chilly consumption was much higher in the high GC incidence area and daily non-green vegetable consumption was more common in the low incidence area [253].

An additional explanation for the enigmas was recently proposed linking them with the co-evolution of H. pylori and humans. It was demonstrated that the African human ancestry adapted well to the co-evolution with H. pylori, while the European ancestors failed to do so. The Asian ancestry was closer to the African adaptation [254]. Certainly, this cannot be the explanation for the Cretan enigma where in Crete (Greece) a dissociation between GC rates and H. pylori infection was reported. In Crete, there is a prevalence of H. pylori colonization of over 70% for individuals over 50 years of age associated with the lowest mortality from GC among participants from 17 populations in 13 countries [255]. And this is not due to a low prevalence of CagA, as its prevalence is high in the Greek population [256].

Is QoL improved?

The last point that should be examined is the unequivocal evidence that generalized eradication of H. pylori improves the QoL. Several different questionnaires have been used to assess QoL in H. pylori associated diseases before and after eradication. The results have been controversial. Eradication of H. pylori was reported to either improve [257] or have no effect on QoL. A large randomized controlled study of QoL using a validated dyspepsia reported no effect on QoL following eradication [258], a finding confirmed by a later smaller study [259]. By contrast, reports from Hungary, Croatia, and Rwanda showed improved QoL [260–262]. However, a study also from Rwanda reported reduced quality [263]. No conclusive comments can therefore be made.

Are all metaplasias similar?

IM is classified into three distinctive types: the small intestinal phenotype, the complete type, or type I, where cells secrete sialomucins and the incomplete types, or types II and III, where goblet cells secrete neutral and acid sialomucins in type II and sulfomucins in type III. It has been reported that type III IM has an increased risk of malignant transformation compared to types I and II [292, 293]. Specifically, in type I, the expression of the mucin MUC2 is dominant, while mucins MUC1, MUC5AC, and MUC6 are decreased. Instead, in type II/III, there is co-expression of MUC2 with the other mucins [294, 295]. Moreover, in IM, the presence of a metaplastic mucous cell lineage called spasmolytic polypeptide-expressing metaplasia (SPEM) is very important. It strongly expresses trefoil factor 2 (TFF2), formerly known as spasmolytic polypeptide. The name pseudopyloric metaplasia was used in the past to indicate the presence of SPEM. SPEM is more closely associated with the development of GC compared with IM [296]. Interestingly, IM is usually spotty or multifocal, but SPEM is diffuse throughout the body and corpus of the stomach in patients that will develop GC [293]. The connection between IM and SPEM and the relationship between SPEM and GC requires further investigation [297]. SPEM appearance is probably due to acute injury or inflammation of the gastric mucosa and the overproduction of IL-33 by macrophages. Gastric glands with lineage mixture such as incomplete IM intermixed with SPEM metaplasia are at particular risk for progression to dysplasia and cancer. The connection of H. pylori with SPEM malignant evolution is under investigation [298–300].

An additional problem with the interpretation of studies corelating H. pylori with the GC is the role of pathological reports. Pathologists’ agreement is very poor in the evaluation and categorization of atrophy with kappa coefficients varying from 0.08 and 0.29 [301, 302]. In a more recent study, the interobserver agreement was very good for IM (κ = 0.81), not so good for dysplasia (κ = 0.42), and poor for AG (κ < 0) [303].

The extent of the problem of GC

It is a common practice in all studies on H. pylori and GC to declare their connection based on epidemiological and experimental research. The exact quantification of this relationship is not always clear. A large study from a cohort in the Netherlands reported that 24% of patients were diagnosed with AG, 67% with IM, 8% with mild-to-moderate dysplasia, and only 0.6% with severe dysplasia. A re-evaluation after 5 years showed that the annual incidence of GC was 0.1% for patients with AG, 0.25% for IM, 0.6% for mild-to-moderate dysplasia, and 6% for severe dysplasia. Risk factors for GC development were severe dysplasia, old age, and male gender [304]. A recent study endoscopically assessed the evolution of the Correa’s cascade after H. pylori eradication. Correa’s steps III–V, but not I–II, were at risk of GC after H. pylori eradication. Age, OLGA stages I, and OLGIM stages were also independent factors of GC development. Eradication of H. pylori decreased Correa’s step progression (relative risk = 0.66), but it did not regress OLGA and OLGIM [305]. Moreover, as was already mentioned, the results between the prevalence of H. pylori infection and the actual appearance of GC are not linear. Even European countries have high H. pylori colonization and low GC [252].

Problems with eradication studies

The vast majority of the trials are retrospective. Most of them do not take into account the three fundamental risk factors in the development of GC namely, smoking, alcohol consumption, and salted food consumption. Even those that use it as a co-variate either smoking or alcohol do it in a crude way. Smoking is not categorized according to pack/years, and alcohol is not reported according to various levels of daily or weekly consumption.

Meta-analysis is considered the holy grail of evidence-based medicine considered superior to any other form of study. However, meta-analyses have an inherent problem. They end up analyzing a few studies after rejecting hundreds of others for various reasons. For example, in a systematic meta-analysis, the authors initially identified 8,061 papers and finally included only 24 [61]. Another study started with 17,438 reports screened and finally included only 149 [13].

An additional problem with this type of report is the fact that conclusions may have a different approach. As an example, two systematic studies conclude that there is a strong relationship between H. pylori infection and GC prevalence. However, in the majority of included studies, the statistical significance is doubtful as the 95% confidence intervals in the forest plot cross the significance line [61, 306].

As a consequence of the unresolved problems of heterogeneity, almost all studies manipulate statistics as they try to incorporate as many confounding factors as possible. This is a perfectly accepted practice, but may end up with precarious results. Two decades ago, a very illuminating observation was reported in the field of hepatology, but it is relevant in other fields as well. The authors investigated the 20-year survival of the scientific truth according to the type of publication. They found that there was no difference between randomized controlled trials and nonrandomized studies. Unexpectedly, the lowest truth survival was observed in the meta-analyses and the conclusions founded on good methodology remained true for similar periods as those based on poor methodology. This rather unorthodox view should be seriously taken into consideration when assessing papers heavily based on statistical adjustments [307, 308].

Finally, the multi-national studies of mixed populations should be scrutinized as the evolution of H. pylori infection is heavily dependent on geographical and genetic criteria as suggested in a real-world report from Japan [309].

Reinfection is another problem in this group of patients

Most studies on eradication results, including studies on the relevant costs, do not evaluate the effects of re-infections. Recent studies reported on the reinfection rates of H. pylori. In a cohort from South Korea of over 10,000 eradicated individuals, reinfection of H. pylori was calculated to be 3.06% per person-year [310]. In a prospective, observational study in China the annual reinfection rate was 1.5% [311]. The oral cavity is considered as an extra-gastric source of H. pylori, because of the presence of H. pylori DNA in certain areas of the oral cavity. Bacteria from the oral cavity may therefore be responsible for eradication failure, and reinfection [312]. The annual reinfection rate after successful eradication is low (< 2%) in the developed countries, where eradication may not be the first health priority, but is considerably higher (5–10%) in developing countries and children [6, 171]. A meta-analysis showed that a strategy of family-based H. pylori screening and treatment may be more effective than a single-patient approach [313].

Recommendations again

Despite the previously described problems and reservations, it is somewhat odd that most recent recommendations still support that eradication therapy should be offered to all individuals infected with H. pylori on the test-and-treat strategy [6]. Some reservations are related to substantial health costs and risks of the massive use of antibiotics. Although the generalized elimination is still on, the identification of population subsets with a higher-than-average risk of GC is also considered [213].

The American College of Gastroenterology (ACG) recommends extensive testing, including all peptic ulcer patients, patients with uninvestigated dyspepsia under the age of 60, patients on long-term non-steroidal, anti-inflammatory drugs, and patients with unexplained iron deficiency anemia [69]. The Taipei consensus [6] and the Houston conference [96] support similar recommendations with the inclusion of first-generation immigrants from high prevalence areas or populations with a high incidence of GC [314]. Gastroenterologists from China in their consensus report also recommend a population test-and-treat policy adding that eradication of H. pylori is a cost-effective measure to prevent cancer in high-risk areas despite the fact that the evidence they refer to is rather obsolete and a recent robust study with proof of cost-effectiveness is lacking. They also suggest that no adverse consequences should be expected [95]. The last notion is at least very doubtful. The prevalence of antibiotic resistance to H. pylori is rising in Asia [315]. The primary resistance in Asia is approximately 17% for clarithromycin, 44% for metronidazole, and 18% for levofloxacin and rising [152] as mentioned before.

Adding a one to two-week course of H. pylori eradication therapy is suggested in the above recommendations to treat and prevent recurrence of peptic ulceration. However, this is not supported by current evidence. There is no evidence supporting the idea that H. pylori eradication is an effective treatment for people with gastric ulcer or that it is more effective in the prevention of recurrence of duodenal ulcer compared to traditional drugs such as PPIs. When observing the forest plots of a Cochrane systemic review this is evident and only a slight advantage is present in duodenal ulcer [316]. This is further supported by a recent review indicating that H. pylori is not the main cause of peptic ulceration so empirical eradication should not be used in these patients [27]. Moreover, the old practice of biopsy all gastric ulcers to check for malignancy and to repeat endoscopy after PPI treatment to check for ulcer healing is still imperative [317]. It is now evident that there are several causes of peptic ulceration in addition to H. pylori infection [318]. Peptic ulcers are detected without an obvious etiological agent, so they are called true idiopathic peptic ulcers and account for approximately 10% of the total [319]. Therefore, the traditional practice of empirical eradication in patients with duodenal ulcers is no longer justified.

Another important problem with the current recommendations is the age when test-and-treat should start. It is rationale that treatment should be given before dysplasia has been reached, but no reliable marker exists to detect premalignancy on time. Serum pepsinogen assay has been proposed as a screening test but a mass scale implementation may not be feasible [320]. Extensive validation studies are also required. On the other hand, the prevalence of H. pylori infection has significantly reduced in recent years, and screening for the very young is probably not cost-effective. The suitable age for screening therefore is still open to debate [321].