Helicobacter Pylori: A Worldwide Perspective 2014

H. pylori is an S-shaped microaerophilic, gram-negative bacterium which colonizes the epithelial stomach surface of half the world’s population. The colonisation of H. pylori in human stomachs results in chronic gastritis and sometimes ulcers or gastric cancer. Infection mostly occurs during childhood and unless treated lasts for life. Treatment of H. pylori is relatively complicated and requires antibiotics to which the bacterium is sensitive. Thus a microbiological culture determining antibiotic resistance is a prerequisite for rational antibiotic treatment. Unfortunately, routine clinical practice is often done without such a culture, and hence, the treatment is frequently empirical, not based on antibiotic resistance data. In this chapter we will elaborate on how to isolate and culture this fastidious bacterium.

Helicobacter pylori is a Gram-negative bacterium living in the stomach of its human host. The infection causes chronic gastric mucosal inflammation and is etiologically related to gastritis-associated diseases, gastric cancer and peptic ulcer disease. As with other chronic infectious diseases associated with a long latent period (e.g., syphilis and tuberculosis), clinical manifestations develop in only a minority of infected individuals. The outcome for any of these diseases is dependent on the interplay between host, environmental, and bacterial factors. The variable virulence of H. pylori in relation to the presence or absence of a specific virulence factor reflects the differences in risk of a clinical outcome. The best-studied virulence factors are the vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A product (CagA). This chapter will discuss the clinical relevance of typing H. pylori virulence factors CagA and VacA. Approximately 1,600 genes make up the H. pylori genome suggesting that there may be other unidentified virulence factors, many likely to be discovered using whole-genome sequencing.

Across western countries, the observed prevalence of H. pylori infection ranges from 4% to 95% in adults and 4% to 82% in children, with estimates varying by country and subpopulation within countries. Reported incidence ranges from 0 to 7.3% per year in adults, with higher rates observed among travelers to high prevalence areas. Reported incidence ranges from 0 to 1.7% per month in children under 2 years old and 0.11% to 16% per year in 2- to 18-year olds. Reported elimination rates in children range from 0.37% to 35% per year. Evidence points to direct person-to-person contact as the predominant mode of transmission. Factors linked to increased prevalence in adults include residential crowding, institutionalization, and having hepatitis A virus. In children, H. pylori infection is associated with age, indicators of poor socioeconomic status such as residential crowding and parents’ education level, and migration from high prevalence areas. Factors associated with elimination of H. pylori in childhood are age, sex, ethnicity, and antibiotic use. Recurrence of H. pylori infection after successful treatment is not frequently observed in western countries. Studies investigating the relationship between intrafamilial clustering of H. pylori infection and H. pylori recurrence have had inconsistent results. Development of cost-effective prevention strategies requires more evidence pertaining to transmission pathways and risk factors, as well as more effective treatments, particularly for high prevalence subpopulations.

Helicobacter pylori (H. pylori) infection is the main cause of gastritis, gastroduodenal ulcer and gastric cancer. Evidence for the prevention of metachronous gastric cancer has been established in Japan. The committee of the Japanese Society for Helicobacter Research has revised the guidelines for diagnosis and treatment of H. pylori infection in 2009. H. pylori eradication therapy achieved a grade A recommendation, being useful for the treatment of gastric or duodenal ulcer, for the treatment and prevention of H. pylori-associated diseases such as gastric cancer, and for inhibiting the spread of H. pylori infection. According to Japanese guidelines, first-line therapy for treating H. pylori infection consists of proton pump inhibitor (PPI) with amoxicillin and clarithromycin given for 7 days. Even with the recommended regimens, eradication failure is still seen in more than 20% of the patients. The recommended second-line therapy is PPI with amoxicillin and metronidazole for 7 days. In case of second-line treatment failure, a PPI + amoxicillin + fluoroquinolone or high-dose PPI/amoxicillin therapy is recommended in Japan.

South-Eastern Asia is a subregion of Asia, consisted of the countries that are geographically South of China, East of India, West of New Guinea and North of Australia. South-Eastern Asian countries such as Korea, Japan, Singapore, Malaysia, Thailand, Vietnam, Indonesia, and the Philippines are known as endemic area of Helicobacter pylori infection. Food, lifestyle, and prevalence of H. pylori infection, physiological functions, and genetic factors are widely different in these countries. Although the prevalence of H. pylori infection has been declining in the Asian countries, H. pylori infection is still a health treat in South-Eastern Asia, and thus consensus on eradication has been actively implemented. H. pylori eradication is indicated for H. pylori-positive patients with the gastritis-associated diseases such as peptic ulcer disease, gastric cancer, or primary gastric B-cell lymphoma (MALToma). In areas with a high prevalence of gastric cancer, eliminating H. pylori infection through improvements had an impact in reducing the burden of gastric cancer. The currently recommended first-line therapy for H. pylori infection is proton pump inhibitor (PPI), amoxicillin and clarithromycin for 7 days. Classic quadruple therapy is consistent with bismuth, PPI, metronidazole, and tetracycline. Increasing rate of resistance to clarithromycin and metronidazole has led to reduced efficacy of PPI-based triple therapy. Further salvage therapy includes levofloxacin-based triple therapy; and rifabutin-based triple therapy. In this chapter, peculiarities on the aspect of epidemiology, diagnosis, treatment on H. pylori infection in South-Eastern Asian countries, excluding those countries which are mentioned in other chapters, will be discussed.

In most South American countries, H. pylori infection prevalence is high, affecting over 70% in populations with precarious living conditions. Due to poor sanitation and low standards of living conditions, the infection is acquired in early childhood. Also, it is estimated that gastric cancer, the main clinical sequela of H. pylori infection, has an average incidence rate of 12.4 cases per 100,000 inhabitants (8.4 cases per 100,000 inhabitants for women and 17.3 cases per 100,000 for men) in the continent. It is worth pointing out that there is initial evidence of a decline in prevalence of H. pylori infection in some more privileged fragments of the population. The chapter also review the main methods used to diagnosis H. pylori infection and their results in South America setting. The management of the infection including anti-H. pylori drugs, therapeutic regimes, eradication control, bacterial resistance, relapse and reinfection, and therapy failure is outlined.

In Israel, there is a 60% prevalence of H. pylori infection in the adult population. The annual incidence of gastric cancer is approximately 15 per 100,000 population. The male/female ratio for a positive 13C urea breath test (UBT) in diagnosing H. pylori infection is 1:1.77. Women have significantly higher UBT results than men. H. pylori infection is associated with a more severe inflammatory reaction, decreased gastric acid secretion and increased mucin secretion in relatives of patients with gastric cancer. Primary resistance to clarithromycin and metronidazole has been reported as 8.2% and 38.2%, respectively. Secondary resistance of clinical isolates from previously treated adults to clarithromycin, metronidazole, and levofloxacin is 65.7%, 57.1%, and 18.6%, respectively. Resistance to both clarithromycin and metronidazole is 32.8%, and to clarithromycin, metronidazole, and levofloxacin, 12.8%. All isolates are sensitive both to amoxicillin and tetracycline. In untreated children, the rate of resistance to metronidazole is 19%, and to clarithromycin, 25%. Corresponding rates among the isolates from children previously treated for H. pylori are 52% and 42%. No resistance is found to amoxicillin, tetracycline or levofloxacin in either group. Sequential regimen, used as primary therapy, attained significantly higher eradication rates than the standard triple therapy. The addition of cranberry to triple therapy improves the rate of H. pylori eradication in females. Susceptibility-guided retreatment is associated with better eradication rates than empiric treatment. The annual recurrence rate of H. pylori after successful eradication in Israel is 0.37% to 0.55%.

In the last two decades, Romanians dealt with post-revolution economic problems and extensive reforms. In this context we analyzed the prevalence trends of Helicobacter pylori (H. pylori) infection in symptomatic and asymptomatic patients, focused more on northwestern region of our country. An interesting part of our report describes the prevalence of Helicobacter species in pets; coinfection with different strains of Helicobacter such as H. pylori, H. felis and H. heilmannii being identified in dogs and cats. Specific risk factors were analyzed, like intrafamilial transmission, occupational exposure and zoonotic transmission, as H. pylori was proved to be a pathogenic factor in cats and dogs. Diagnostic methods used for clinical and research purposes are comparative debated in humans and animals. Original Romanian research about H. pylori involvement in gastro-duodenal pathology is also presented. Our studies focused both on human and animal pathology, in functional and organic disorders (from chronic gastritis till carcinogenesis). Some remarks are done about clinical and experimental treatment. The efficacy of actual treatment in use is debated as the eradication rates are very low using first line therapy.

This article reviews aspects concerning Helicobacter pylori (H. pylori) epidemiology, diagnosis and treatment in Greece. As in most countries H. pylori is the cause of most peptic ulcer disease and a primary risk factor for gastric cancer. Eradication of the organism results in ulcer healing and reduces the risk of ulcer recurrence and complications. Testing and treatment have no clear value in patients with documented nonulcer dyspepsia; however, a strategy of testing and treating is preferred in non-differentiated dyspepsia patients without endoscopy. In the office setting, initial serology testing is practical and affordable, with endoscopy reserved for use in patients with alarm symptoms for ulcer complications, cancer or those who do not respond to treatment. Treatment involves 10- to 14-day multidrug regimens including antibiotics and acid suppressants, combined with education about avoidance of other ulcer-causing factors and close follow-up. Follow-up testing (i.e., urea breath or stool antigen test) is recommended for patients who do not respond to therapy or those with a history of ulcer complications or cancer.

Helicobacter pylori infection contributes to the development of various gastroduodenal disorders. Clinical manifestation after H. pylori infection is an important issue for gastroenterologist. Design and optimizing usage of new drugs against H. pylori has always been a major topic in Helicobacter pylori (H. pylori) research. There are many articles published over the last decade on H. pylori treatment and diagnosis. Since the incidence, virulence, and resistance of H. pylori are different for each region diagnosis and treatment require a local approach. Iran is a country with a high rate of H. pylori infection and consequently a huge number of patients suffer from H. pylori induced digestive diseases. In this chapter we will present a comprehensive summary on H. pylori epidemiology, diagnosis and treatment in Iran over the last years.

A number of methods have been proposed to diagnose Helicobacter pylori infection. In this chapter, each method is presented and the critical aspects are highlighted. It is common practice to distinguish the methods which necessitate an endoscopy and obtention of biopsy specimens, the so-called invasive methods, from the methods which are performed on blood, stools, air, etc., the so-called non-invasive methods. Among the invasive methods, histology is probably the most commonly used worldwide, and has been recently completed by the use of the OLGA or OLGIM system to evaluate the gastric cancer risk. Culture is demanding for transport but there has been a renewed interest because of the increase in H. pylori antimicrobial resistance. The rapid urease test, while not as sensitive, has the great advantage of providing a quick result allowing to prescribe immediately a treatment. Molecular methods are developing, especially real-time PCR for which kits are now available, detecting H. pylori and its resistance to clarithromycin, and allowing standardization. An advantage of this method is the possibility to apply it to stools, rendering it non-invasive. However, at this stage, DNA extraction is still a problem. The best method to be used in such specimens is a stool antigen test using an ELISA with monoclonal antibodies. However, many still prefer the urea breath test which has become a standard in the field. Finally ELISA serological tests have also experienced a revival since they are the only tests to be used on patients taking proton pump inhibitors, nowadays a common situation.

Optimal treatment of H. pylori should produce cure rates of at least 90%, preferably 94% or greater per protocol. Initially, 14-day triple therapy was highly successful but clarithromycin resistance led to a fall in cure rates to 80% or less. Intelligent choice of empiric therapy requires knowledge of the local or regional patterns of drug resistance and monitoring the outcome of therapy to provide early warning of development of resistance.

We recommend the following general rules 1) Do not use legacy triple therapy consisting of a PPI, clarithromycin and amoxicillin unless it has been proven to be highly effective locally; 2) Do not reduce the doses of commonly used antibiotics unless it has been shown that lower doses reliably produce eradication rates of 90% or greater; 3) The duration of therapy should be 14 days unless a shorter duration has been shown locally to produce equally high treatment success; 4) Following treatment failure avoid reuse clarithromycin or fluoroquinolones as resistance had likely developed and cannot be overcome by increasing the dose or duration of therapy; and 5) Avoid clarithromycin and fluoroquinolones in first line therapy if either has been used in the past even for a different indication. We recommend using four drug combinations as first line (i.e., concomitant, hybrid, or bismuth-containing regimens). Second-line therapy should consist of antimicrobials that have not been used previously. Salvage therapy (i.e., after 2 or more failures) should be chosen on the basis of the results of antimicrobial susceptibility testing.

Dyspepsia comprises a group of symtpoms including epigastric pain, burning, postprandial fullness and early satiation. Its prevalence in general population ranges from 10 to 40%. Functional dyspepsia prevalence estimates are 5-12%. The relationship between Helicobacter pylori and functional dyspepsia is complicated. There are no differences between infected and uninfected patients in prevalence and severity of dyspepsia. The meta-analysis of the efficacy of eradication therapy in functional dyspepsia showed a small but significant benefit in curing dyspeptic symptoms after one year therapeutic gain in comparison with placebo was 8% and the number of patients needed to treat was 15. According to the Maastricht IV guidelines, eradication therapy is considered appropriate for patients that have a confirmed Helicobacter pylori infection and a diagnosis of functional dyspepsia (recommendation grade: A).

After 30 years of experience in Helicobacter pylori treatment, however, the ideal regimen to treat this infection has still to be found. Systematic reviews and metaanalyses are essential to summarize evidence relating to efficacy and safety of health care interventions accurately and reliably. The aim of this chapter is to review published meta-analyses focused on H. pylori eradication treatments. Initially, dual therapies containing one antibiotic combined with bismuth compounds or proton pump inhibitors (PPIs) obtained sub-optimal cure rates. The most recommended therapies have been triple therapies containing a PPI and two antibiotics. PPI-based regimens are more effective than H2-antagonists-based ones. Bismuth-containing quadruple therapy is roughly equivalent to triple therapy in terms of effectiveness, compliance and safety profile. The influence of the type of PPI, the dosage and the length of treatment have been discussed. Clarithromycin and metronidazole antibiotic resistance are the most relevant factors causing eradication failure. As a progressive decrease in the eradication rate after standard triple therapy has been reported, more recently, sequential and nonbismuth quadruple (concomitant) therapies have been recommended in settings where the efficacy of triple therapy is unacceptably low. The role of prebiotics and probiotics as adjunctive treatment for H. pylori infection has also been reviewed. Several rescue options have been proposed. Bismuth-based quadruple therapy is effective, but its complexity and the associated adverse effects affect compliance. PPI plus amoxicillin combined with levofloxacin or moxifloxacin is at least as effective, and better tolerated.

Helicobacter pylori (H. pylori) infects more than half of the world’s human population, but only 1 to 3% of infected persons develop gastric adenocarcinoma. H. pylori is a definite or class I carcinogen in humans. The mechanisms of H. pyloriassociated gastric carcinogenesis are still poorly defined. The clinical outcome of the infection is determined by host genetic predisposition (IL-1β, TNFα, IL-10), bacterial virulence factors (VacA, CagA), as well as environmental factors (salt intake, smoking). Eliminating H. pylori from a large part of the population may be unfeasible economically, and the long-term consequences are still unpredictable; this is why identifying high-risk individuals is very important.

It has long been known that chronic bacterial infections have an impact upon the overall organism. H. pylori infection is no exception to the rule. Indeed, the infection is acquired early in life and induces an intense/moderate local and systemic inflammatory status that lasts for the entire patients’ life. During this time, different organs and systems of infected individuals are exposed to injures exerted by the inflammation and immune responses to the infection, as well as to autoimmune reactions triggered by mechanisms of antigenic mimicry between human tissue cells and H. pylori. The CagA-positive bacterial genotype is mostly involved in extradigestive manifestations of such an infection, due to the increased inflammatory potential of this organism. The organs and systems that most of all may suffer from the detrimental consequences of H. pylori infection are the cardiovascular (ischaemic heart diseases), haematological (purpura, urticaria etc.), central nervous (Parkinson’s and Alzheimer’s diseases) and endocrine systems (autoimmune thyroid disorders). There is an increasing evidence, however, that no district of the human body is sheltered from the harmful effects of H. pylori infection. In conclusion, H. pylori infection may have deleterious consequences on organs and systems different from the gastroduodenal tract. To better understand the pathogenic mechanisms of extradigestive disorders associated with H. pylori infection, is essential to determine the CagA status of the infecting organisms.

Helicobacter pylori (H. pylori) infection is the main cause of ulcerous conditions affecting half of the world population. Previously the symptoms described only in adults but recently the studies focusing on chronic childhood gastrointestinal diseases. Besides the chronic inflammation resulting in gastritis and peptic ulcers, the H. pylori thought to be the root of some malignancies, like adenocarcinomas and lymphomas of gastrointestinal system. As long as the presence of H. pylori in stomach can be observed lifelong without treatment, the serious complications of the infection need to be prevented even in childhood. However, the presenting signs and symptoms are not clearly described in pediatric population and also the screening is not resolved; recent recommendations are well defined the therapeutic strategy in children.

H. pylori antibiotic resistance is the main factor affecting the efficacy of the current H. pylori eradicating therapies. Epidemiological aspects and different resistance mechanisms (point mutations, redox intracellular potential, pump efflux systems, membrane permeability) to clarithromycin, metronidazole, quinolones, amoxicillin and tetracycline, are accurately detailed on the basis of the most recent data available from the literature. In addition, the impact of resistance toward each antibiotic on efficacy of current therapies is thoroughly described.

The pathological and therapeutical aspects of the Helicobacter pylori infection in patients with peptic ulcer disease, chronic atrophic gastritis and gastric cancer have been widely studied. However, various observations have indicated controversial results and highlighted a few questionable aspects of the broadly accepted role of Helicobacter pylori in generating certain gastroduodenal disorders. These are the following: 1. The sonicated Helicobacter pylori culture did not cause any direct cellular-damaging effect (at the level of the cell membrane, mitochondrion, DNA) in an application of 10⁶-to 10⁸ germ/mL given alone or in combination with indomethacin (10^-8 to 10^-4 M) on freshly isolated gastric mucosal cells. 2 Ethanol (EtOH) dose-dependently induced cellular damage (at the level of the cell membrane, mitochondrion and DNA), however, the sonicated Helicobacter pylori culture did not aggravate the damaging effect produced by EtOH. 3. The gastric acid secretory responses in patients with classical duodenal ulcer did not decrease depending on the patients’ age and on the period since the onset of complaints, however, the gastric basal acid output (BAO) increased significantly in correlation with these parameters. Meanwhile the maximal acid output (MAO) did not change. 4. Authors never observed gastric cancer in duodenal ulcer patients without gastric surgery (in time period from 1962 to 2012), however, the gastric (stump) cancer developed after a partial gastrectomy in patients with duodenal ulcer. 5. The capsaicin-sensitive afferentation of the vagal nerve is involved in the development of gastric mucosal damage and prevention, which seems to be an independent pathway from the Helicobacter pylori infection or eradication treatment. Conclusions: the results of our experimental and clinical observations might offer some details underlying a reconsideration of the widely accepted etiological role of Helicobacter pylori in the development of gastric mucosal damage, gastroduodenal ulcers, chronic atrophic gastritis, gastric cancer and the treatment of Helicobacter pylori positive gastritis.

The discovery of H. pylori led to a paradigm shift in the Hungarian medical community about the pathogenesis and treatment of peptic ulcer disease. H. pylori is the most prevalent infection also in our country. Epidemiologic studies revealed an overall prevalence of 52-63% of the infection in healthy blood donors with an age-dependent increase and no geographic differences. Endoscopic studies found a 83-92% prevalence in duodenal and 63- 92% in gastric ulcer patients. All known diagnostic methods are available in Hungary: serology and endoscopic biopsy + histology are mainly used in practice, urea breath tests are reserved for eradication control. The test-and treat, search-and-treat and scope-and treat strategies are not, however, used systematically and their cost-benefit ratio has not been determined. Antimicrobial resistance testing encounters the same difficulties as in Western countries, while fluorescence in situ hybridisation and polymerase chain reaction-based methods are used in research centres. The first consensus meeting of the Helicobacter pylori Working Group of the Hungarian Society of Gastroentrerology was held in 2000 and the results updated in 2002, following the Maastricht I provisions. A meta-analysis of the Hungarian studies showed that between 1992-2002, the proton pump inhibitor- based triple therapies achieved an overall eradication rate of 82.9% (71.3-93.7%) on an intention-to-treat basis, and are the most extensively used regimens. The efficiency of second- and third-line therapies is, unfortunately, unacceptably low. Several groups of researchers participated in randomised controlled trials which were later incorporated in international guidelines. Resistance to chlarithromycin was low in the 1990’s, then increased to 18% between 2005- 2009 in Budapest, came it at 10% in towns around the country and remained low in rural areas. Basic research on H. pylori has been developed in university centres from Budapest, Pécs and Szeged and published in major journals of gastroenterology.