Helicobacter pylori

Helicobacter pylori (H. pylori) infection is a common worldwide infection that is an important cause of peptic ulcer disease and gastric cancer.

Introduction

Helicobacter pylori has been recognized as a major pathogen of humankind for nearly four decades. However, despite the impact of treatment of infected individuals and the reduced transmission of infection in communities in which socioeconomic living standards have improved, it continues to be the most common human bacterial pathogen, infecting perhaps half of the world’s population. As a result, it is still a major cause of morbidity and mortality worldwide. (1)

H. pylori infection usually persists for life, unless it is treated with antibiotics or autoeradication occurs when long-standing infection causes widespread gastric mucosal atrophy and metaplasia with achlorhydria. There are variations in the virulence of different H. pylori strains globally. The interplay between host and environmental factors may result in differences in the expression of disease. (1)

Bacteriology and pathogenesis

Helicobacter pylori is a microaerophilic slow–growing gram negative spiral organism. It is 0.5 to 8.0μm wide and has multiple flagella at one end. It has the capability of dual existence in bacillary and coccoid forms. The bacillary form is motile while the coccoid form is non-motile. H. pylori is able to overcome the stomach high acid content by means of virulence factors which enhance colonization of the gastric epithelium and induction of tissue damage. (2)

The stomach germ (H. pylori) does not invade the mucous membrane, but lives by adhesion to the superficial mucosal epithelial cells. It releases remarkable immune responses, as it stimulates a chronic inflammatory response that includes moderate white blood cells, followed by T and B lymphocytes, plasma cells and macrophages, which together cause mucosal damage. stomach through its immune activities. And there is an antibody response to lipopolysaccharides in the stomach germ, which is mainly IgG antibodies, and there are also IgA and IgM antibodies, but they are less specific. (2)

Epidemiology of Helicobacter pylori

The prevalence of H. pylori infection increases with age. Ethnicity has been described as a risk factor, but is most likely closely correlated with socioeconomic status or practices that may increase the risk of transmission, rather than having a genetic basis. (1)

Prevalence rates ranging from 20-50% are reported in the adult populations of the developed world but the prevalence is much more in the developing countries with prevalence as high as 90% in some countries. Higher prevalence exists in regions of low socioeconomic and poor sanitary conditions, and in rural. The socioeconomic status of the family during childhood appears to be the major marker of infection. (2)

A decline in prevalence has more to do with improvements in population hygiene and sanitation than with individual, case-by-case treatment. The prevalence of infection appears to be stable in countries in which standards have not improved or have deteriorated, and it is unlikely to fall substantially until improvements do occur. (1)

Transmission of Helicobacter pylori

Transmission of the bacterium can occur thru two different modes: vertical or horizontal. In vertical transmission, H. pylori infection transmits from parents to children (oral-oral transmission is possible across individuals by infected saliva containing H. pylori), while in horizontal transmission, people are infected with the bacterium via environmental contamination or social interactions. (3)

One of the most common transmission routes of the bacterium is the fecal-oral route. Fecal-oral transmission has been verified indirectly from the results of South American studies. These studies showed that water supplies that may contain H. pylori and consumption of raw vegetables contaminated by human feces are significant risk factors for H. pylori infection. (3)

The gastro-oral route is an important transmission mode particularly in unhygienic environments. Moreover, in recent studies, H. pylori was detected at the tongue dorsum and the periodontal pockets with a nested PCR method. There was a significant relationship between tongue and fingernail positivity. According to these results, some researchers propose that H. pylori may be carried by hands and finger-mouth contact could be an important method of H. pylori transmission. (3)

Clinical manifestations of Helicobacter pylori

The infection is acquired around 10 years of age and approximately 85% have long asymptomatic periods. Clinical manifestations are non-specific, and some may be justified by the presence of complications. A meta‐analysis attempted to establish a possible association between infection and symptoms, and concluded that it was not related to vomiting, diarrhea, flatulence, chronic functional abdominal pain, halitosis, regurgitation, constipation or nausea. However, they documented a statistically significant association with epigastric pain. (4)

Helicobacter pylori related diseases

It has been demonstrated that H. pylori is involved in the pathogenesis of several diseases include:

Gastritis

This could occur in form of either acute or chronic gastritis. Acute infection is typically manifested as a transient mild illness characterized by epigastric pain, nausea, histological finding of neutrophilic gastritis and a transient hypochlorhydria. Chronic gastritis often presents in form of chronic active, non-atrophic superficial antral gastritis, with a picture of focal epithelial cell damage. This is usually asymptomatic, although it may be associated with peptic ulcer disease. Chronic atrophic gastritis resulting from progression of the non-atrophic chronic gastritis may also occur in a smaller percentage of patients with gastritis. (2)

Peptic ulcer disease

An individual infected with H. pylori has an estimated lifetime risk of about 10-20% for the development of PUD. This is at least 3-4 folds higher than in non-infected subjects. H. pylori infection can be diagnosed in 90-100% of duodenal ulcer (DU) patients and in 60-100% of gastric ulcer (GU) patients. The gastritis induced by H. pylori can progress to ulceration of the mucosa. Apoptosis of epithelial cells and subsequent compromise in the mucosal protective barrier exposes gastric mucosa to the direct assault of luminal acid and pepsin. (2) Duodenal ulcer And 60-100% patients have stomach ulcers. Gastritis caused by gastrobacteria can also develop into ulceration of the mucous membrane as a result of programmed epithelial cell death and subsequent damage to the mucosal protective barrier, exposing the gastric mucosa to direct attack from luminal acid and pepsin. (2)

Acid hypersecretion in duodenal ulcer (DU) is virtually always due to H. pylori infection because secretion returns to normal after the infection is eradicated. The predominantly antral gastritis in DU diminishes the number of somatostatin-producing cells in the antrum. This leads to a reduction in production of somatostatin, reduced somatostatin-mediated inhibition of gastrin release from the G cells, and eventual development of hypergastrinemia. The increased acid secretion may, on its own, increase the risk of duodenal ulceration or may induce gastric metaplasia in the duodenum, which becomes colonized by H. pylori, then inflamed (duodenitis), and finally ulcerated. Successful eradication of H. pylori leads to PUD healing and less frequent recurrence of the ulcer. (2)

Gastric adenocarcinoma

On the basis of compelling evidence, the World Health Organization (WHO) has classified H. pylori as a group 1 carcinogen leading to gastric adenocarcinoma. In addition to Japan, areas with an increased incidence of gastric carcinoma attributable to this infection include the Middle East, Southeast Asia, the Mediterranean, Eastern Europe, Central America, and South America. (5)

The pathogenesis of gastric cancer includes a sequence of events that begins with H. pylori-induced chronic superficial gastritis, progressing towards atrophic gastritis, intestinal metaplasia, dysplasia and eventually gastric cancer. This sequence takes decades to complete. (2)

Although H. pylori is now thought to account for 80% or more of gastric cancers, it is noteworthy that only 3% of infected patients progress to gastric cancer.This suggests that H. pylori infection only on its own is generally not sufficient to cause gastric carcinoma. A combination of bacterial factors, environmental insults, the host immune response and other genetic factors is responsible. (2)

Gastric mucosal associated lymphoid tissue MALT lymphoma

The molecular pathogenesis of MALT lymphoma is incompletely understood but seems to also involve strain-specific H. pylori factors, as well as host genetic factors, such as polymorphisms in the promoters of inflammatory cytokines. It is believed that H. pylori infection leads to the formation of H. pylori-reactive T cells, which then cause polyclonal B-cell proliferations. In time, a monoclonal B-cell tumour emerges in the proliferating B cells, probably as a result of accumulation of mutations in growth-regulatory genes. (2)

Functional dyspepsia

The prevalence of H. pylori is generally high in patients with dyspepsia irrespective of the subgroup. The implication of H. pylori in the pathogenesis of ulcer dyspepsia is well established but there are dissenting views on the role it plays in the pathogenesis of functional dyspepsia. While some studies showed association between H. pylori infection and the clinical diagnosis of functional dyspepsia [49], others did not show any association. (2)

Non-gastric conditions

Conditions outside the gastrointestinal tract have also been associated with H. pylori infection. An observed association with coronary artery disease probably reflects shared risk factors, such as poverty and suboptimal nutrition. Unexplained iron-deficiency anemia and immune thrombocytopenia have been associated with H. pylori infection; although the pathogenesis is not well understood, reports of successful treatment of H. pylori infection leading to an increased hemoglobin level or higher platelet count suggest causal relationships. (5)

Diagnosis of Helicobacter pylori infection

Invasive tests

Histology: Biopsies are obtained from the gastric antrum and corpus. Multiple levels of each biopsy are routinely stained with haematoxylin and eosin (H&E) and with other special stain. The standard H&E stain is used to determine histological chronic or chronic active inflammation (gastritis) but could also demonstrate H. pylori if a large number of the organism is present. Small numbers of bacteria are better detected by the special stains. An important advantage of histology is that sections from biopsies can be examined in the future. The drawbacks of the test include high observer-dependency, relatively long waiting time for result. (2)

Rapid urease test (RUT): The urease enzyme which is produced by H. pylori is utilized in performing this test. Gastric biopsy is placed in a medium that contains urea and a pH indicator. The urease breaks down the urea to produce ammonia that increases the pH of the medium which leads to a color change. The specificity and sensitivity of the test are greater than 90%, but false-positive results do occur. It can be performed and read within 1 to 24 hour. Its comparative advantage to histology lies in its rapidity, simplicity and inexpensiveness; but it cannot be used to evaluate gastritis. (2)

Culture: This is done under stringent conditions. Endoscopy biopsy must be transported to the laboratory at 4°C within 24 hrs. or at -70°C for a longer period. After introduction of the specimen into the culture medium, the plates are inspected for about 10 days. Due to the focal nature of inflammatory lesions produced by H. pylori, multiple biopsies are usually taken from the gastric antrum and corpus to increase the yield of the test. The specificity of the test is 100% while the sensitivity is slightly less. A major advantage of the test is that, pure growth of the organism can be obtained for proper identification and detailed studies e.g. antibiotics sensitivity when there is failure of the second line drugs, strain typing, genetic studies etc. The disadvantages of the test include longer duration for result availability, high cost and the stringent condition needed for transportation to the laboratory. (2)

Polymerase chain reaction (PCR): As a result of the development of string-capsule test device, gastric sample for PCR can now be obtained without having to biopsy the stomach. PCR has a sensitivity and specificity that are well above 90%. It can be used to analyze bacterial genotypes, study pattern of antibiotic resistance and H. pylori transmission within families and the community. The main disadvantages are that it is expensive, and the procedure requires technical expertise to perform. (2)

DNA-Enzyme immunoassay: It is ELISA-based and involves the use of coated microwells. This method is more rapid than the standard PCR and result can be obtained within a few hours. (2)

Fluorescent in situ hybridization (FISH): This is another molecular test for diagnosing H. pylori that is particularly useful in detection of H. pylori clarithromycin resistance/sensitivity. (2)

Non-invasive tests

Serology: chronic H. pylori infection elicits a circulating antibody response that can be quantitatively measured by serological assay technique like enzyme-linked immunosorbent assay (ELISA). Though tests for IgG, IgA and IgM antibodies can be done, only IgG antibody test is reliable. It involves the use of serum or plasma, and lately tests on whole blood. (2)

Because of its easy availability, affordability, and simplicity, it is commonly used in prevalence studies of H. pylori. Its major drawback is its poor discriminatory power between current infection and previous exposure, since it may still be positive several months after H. pylori eradication. It is therefore generally not useful in confirming cure after antimicrobial therapy but it is useful for the initial diagnosis of H. pylori infection and epidemiological surveys [59]. Page number not for citation purposes.(2)

Urea breath test (UBT): This is an indirect method of detecting the presence of H. pylori in the stomach premised on the ability of H. pylori to produce the urease enzyme. Urea labeled with either 13C or 14C is ingested by the patient. If urease is present in the stomach as a result of H. pylori infection, labeled CO2will be split off and absorbed into the circulation, where its presence can be determined by analysis of expired breath by means of a spectrometer. UBT is now being considered as the gold standard by some researchers. It is the non-invasive not expensive test with the highest sensitivity and specificity (>95%) and is the preferred means of evaluating the success of antimicrobial therapy in clinical practice. There is the possibility of false positive results when there is bacterial overgrowth of urease-producing organisms. (2)

Stool antigen test (SAT): The test is based on the detection of H. pylori antigen in the stool. Helicobacter pylori adhering to gastric epithelium in infected persons appear in their stool as a consequence of the normal shedding of the epithelium. This means that the test is a direct test of active infection which gives it an advantage over serology. It is an enzyme immunoassay test which is available in both polyclonal and monoclonal forms. The monoclonal immunoassay is newer and more sensitive and specific than the polyclonal assay and may be considered as an alternative to UBT in the initial diagnosis of patients with dyspepsia who do not require immediate endoscopy. It is now generally recommended to wait for about 12 weeks to reliably confirm eradication. Its diagnostic accuracy is impaired by PPIs and gastrointestinal bleeding. A major drawback is related to the inconvenience of stool handling. (2)

Treatment of Helicobacter pylori infection

First-line eradication therapy

PPI, amoxicillin, clarithromycin triple therapy

The first-line option for H. pylori infection is represented by a standard triple therapy (STT) consisting of two antibiotics, clarithromycin and amoxicillin or metronidazole in combination with a proton pump inhibitor (PPI). (6)

This combination was the first very widely recommended therapy and superseded less effective triple therapies. It has been very well evaluated over the years. The major determinant of eradication success with this combination is pretreatment clarithromycin resistance (CR). The optimal duration of therapy is a matter of contention. Recent calls for universal 14-day PPI-AC therapy usually originate from regions with higher CR. Initial studies were mostly for 7 days. (1)

Overall antibiotic use will be much lower with the second strategy, as long as first-line eradication rates are at least moderately high. The longer therapy is usually recommended in some well-resourced countries, but more modeling of shorter courses in resource poor-regions is needed. It must also be noted that acceptable eradication rates with 1-week PPI-AC therapy have been reported from several countries, and the incremental benefit of a longer course has not been studied. (1)

Bismuth-based quadruple therapy

Bismuth-based quadruple therapy has been proven to have better results regarding the treatment of H. pylori. Luminal bismuth is responsible for the action of bismuth salts within the upper gastrointestinal system. Inhibiting a variety of enzymes, ATP generation, and the bacteria’s adhesion to the stomach mucosa are only a few of the ways that bismuth has a direct bactericidal effect on H. pylori. Additionally, bismuth promotes the release of prostaglandin, epidermal growth factor, and bicarbonate, which are mucosa-protective substances that aid in the healing of ulcers. No reports of bismuth resistance exist as of yet. (6)

Good results have been achieved with 7-day therapy, although there are proponents of longer (10–14-day) treatments. The major drawbacks of this therapy are the clumsy dosage regimen (as it is usually dosed four times daily) and common but usually mild adverse effects, which may impair adherence. (1)

Nonbismuth quadruple therapies

There are advocates of nonbismuth quadruple therapies usually meaning the addition of metronidazole to PPI-AC triple therapy (PPI-ACM). This may increase eradication rates if MR rates are low or moderate. Patients in whom the treatment fails will often be found to have dual resistance (MR and CR). (1)

Levofloxacin triple therapy

Levofloxacin triple therapy (PPI, amoxicillin and levofloxacin, PPI-AL for 10–14 days) has been used in first-line therapy when levofloxacin resistance (LR) is known or presumed to be low, but the combination has not been studied extensively in this role. Reports of high levofloxacin resistance rates in some countries will limit the usefulness of this therapy in these locations. The treatment is generally well tolerated. There have been recent concerns about the risks of levofloxacin, this is related to the rare risk of tendinitis or myositis, which is more common in the elderly and those with inflammatory arthritis or renal impairment. (1)

Second-line or salvage therapies

Bismuth-based quadruple therapy and levofloxacin triple therapy

The most commonly studied and used second-line therapies include standard bismuth-based quadruple therapy for 7–14 days and levofloxacin triple therapy for 10–14 days. Both have been shown to achieve eradication rates above 80%. The choice between the two depends on whether or not there is knowledge of local primary levofloxacin resistance rates, availability, experience, adherence, and cost. (1)

Other salvage therapies

Other salvage therapies that have been used include a rifabutin-based triple therapy (PPI-AR). It is generally less effective, and the risk of significant neutropenia may be as high as 1%, which tends to limit its use. It is usually avoided in regions with a high prevalence of tuberculosis. High-dose dual PPI with amoxicillin therapy (PPI-A) has been used with some success. Nonbismuth quadruple therapies are generally ineffective as salvage therapies, due to secondary CR and MR. Where metronidazole sensitivity is known after testing, PPI-AM may be used as a second-line treatment with reasonable outcomes. (1)

Testing to assess the outcome after eradication therapy

As the success of eradication is very variable, outcome assessment should ideally be done in all patients, although this may not be feasible universally. Priority should be given to those who remain at highest risk for harm if the infection is ongoing, such as those who are being treated for complicated ulcer disease (bleeding or perforation). (1)

Biopsy-based testing may be used to determine the outcome after eradication therapy when endoscopy is required (to assess gastric ulcer healing and exclude neoplasia for example). Otherwise, noninvasive tests are preferred. UBTs and stool tests should be done not less than 1 month after the completion of eradication therapy. To minimize false-negative results, no antibiotics or bismuth compounds should be taken by the patient for at least a month before testing, and proton-pump inhibitor (PPI) use should be avoided for at least one and preferably two weeks. Serology is not useful for assessing the outcome, as antibody levels often persist for years after therapy. (1)

The suboptimal results in the classical therapies merged with the need for the development of new treatment agents for H. pylori-induced gastritis. Based on the high rates of antibiotic resistance and recent epidemiological evidence, in 2017, the WHO listed H. pylori among the sixteen antibiotic-resistant bacteria ranked as high-priority bacteria that pose the greatest threat to human health worldwide. (6)

---

References

1. World Gastroenterology Organization Global Guidelines. Helicobacter pylori 2021.
2. Abiodun Christopher Jemilohun et al. Helicobacter pylori infection: past, present and future. The Pan African Medical Journal 2016;23:216.
3. M. Bagirova, AM Allahverdiyev, ES Abamor, H. Aliyeva, G. Unal, TD Tanalp. An overview of challenges to eradication of H. pylori infection and future prospects. European Review of Medical and Pharmacological Sciences 2017; 21: 2199-2219.
4. Aguilera Matos I, Diaz Oliva SE, Escobedo AA, et al. Helicobacter pylori infection in children. BMJ Paediatrics Open 2020;4:1-7.
5. Sheila E. Crowe. Helicobacter pylori Infection. The new England journal of medicine 2019;380:1158-1165.
6. Pop, R.; Tabaran, A.-F.; Ungur, AP; Negoescu, A.; Catoi, C. Helicobacter Pylori-Induced Gastric Infections: From Pathogenesis to Novel Therapeutic Approaches Using Silver Nanoparticles. Pharmaceutics 2022;14:1463.