Helicobacter Pylori : A Review of Epidemiology , Treatment , and Management

C l i n M e d International Library Citation: Thaker Y, Moon A, Afzali A (2016) Helicobacter Pylori: A Review of Epidemiology, Treatment, and Management. J Clin Gastroenterol Treat 2:019 Received: January 30, 2016: Accepted: April 06, 2016: Published: April 09, 2016 Copyright: © 2016 Thaker Y, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Thaker et al. J Clin Gastroenterol Treat 2016, 2:019


Background
Helicobacter pylori, a gram-negative, helical bacilli that live in the gastric epithelium was first isolated in 1983 [1].It was discovered by Marshall and Warren who cultured Campylobacter pyloridis, which was later reclassified as Helicobacter pylori.It is transmitted via the fecal-oral, gastro-oral, or oral-oral routes [2][3][4].H. pylori is able to thrive in the gastric environment due to urease [5], motility [6], and adherence to gastric epithelium [7,8], which allow it to neutralize gastric acid, penetrate through the mucus layer to the gastric epithelium, and colonize.It induces inflammation, leading to peptic ulcer disease (PUD) [9], gastric cancer [10][11][12], and gastric mucosa associated lymphoid-tissue (MALT) lymphoma [13][14].Although infection with H. pylori persists without treatment, the majority of infections do not lead to symptoms or gastrointestinal disease [15,16].

Epidemiology
Simulations indicate that H. pylori spread from East Africa around 58,000 years ago, later evolving into many strains with varying degrees of pathogenicity [17,18].Most individuals acquire infection during childhood [19] and infection is more common in developing countries [20].In the United States, H. pylori infection is more common in Hispanic and black populations although this may be related to socioeconomic factors, including low income, less education, household crowding, and immigration into the United States [21,22].

Incidence/Prevalence
Infection with H. pylori has a reported annual incidence of 0.3-0.7% in developed countries and 6-14% in developing countries [23].One study in Italy which followed a cohort of H. pylori-negative individuals from 2002 to 2012 identified four new infections out of 207 individuals (2.5%), equating to a 0.25% (0.10-0.63) yearly incidence rate [24].H. pylori is the most prevalent bacterial infection

Diagnosis
The test of choice for diagnosing H. pylori is determined by necessity for endoscopic intervention as 4 of the 6 tests require biopsies (Table 1).Test selection is also determined by cost, availability of equipment and reagents, expertise, and pre-test probability for H. pylori.Diagnostic accuracy for most modalities are affected by medications used for H. pylori treatment since these medications suppress H. pylori infection and thus reduce test sensitivity [37,45,46].To increase detection of infection, the patient should be off antibiotics for 4 weeks, off proton pump inhibitors (PPIs) for 2 weeks, and off H2-receptor antagonists and bismuth-containing compounds for several days [37,45,46].

Treatment
The first line, Food and Drug Administration (FDA) approved drug regimens for the treatment of H. pylori are listed in table 2. These therapies include proton pump inhibitor (PPI) and two antibiotics or bismuth subsalicylate, acid suppressor, and two antibiotics.However, eradication rates using these regimens are a disappointing 75% in the United States due to increased H. pylori resistance to standard antibiotics [48].Clarithromycin and metronidazole show the highest rates of resistance and the factors associated with resistance include geographic region, sex, ethnicity, age, and active versus inactive ulcer disease [49].As a result of the declining eradication rates, other Affected by use of H2-receptor antagonists, PPIs, and antibiotics.Expensive

Polymerase chain reaction (PCR)
Several genes can be used for DNA amplification.
Determine mutations causing resistance.

Expensive
Requires specialized equipment and reagents.
Antibody testing Detection of IgG antibodies against H. pylori using enzyme-linked immunosorbent assay (ELISA) and latex agglutination.

Rapid Readily available
Remains positive for years even after eradication of the infection.
Influenced by the prevalence of the infection.

Requires local validation of reagents.
Not appropriate for detection of active infection or confirmation of eradication.

Urea breath test (UBT)
Patient ingests non-radioactive isotope 13 C or radioactive isotope 14  Those allergic to penicillin or failed triple therapy or prevalence of macrolide-resistance is > 20%.

ISSN: 2469-584X
more promising therapies have been proposed.In a recent metaanalysis comprised mostly of trials from Italy, five days of a PPI with amoxicillin followed by five days of a PPI with clarithromycin and tinidazole had an eradication rate of 93.4% [47].This regimen has not yet been validated in the United States and it is not clear if it is superior to quadruple therapy.Sequential therapy (e.g.five days of PPI + amoxicillin followed by 5 days of PPI + clarithromycin and metronidazole) may increase medication adherence compared to quadruple therapy since it requires fewer medications.Another promising therapy that requires validation in the United States is PPI with levofloxacin and amoxicillin, with a reported 87% eradication rate in a recent meta-analysis [50].

Confirmation of Eradication
Testing for eradication of H. pylori is generally recommended in patients with H. pylori-associated peptic ulcer disease, H. pyloriassociated MALT lymphoma, resection of early gastric cancer, or persistent symptoms despite treatment of confirmed H. pylori infection [37].Urea breath test provides the most reliable means for confirming H. pylori eradication [51][52][53][54] but PPI therapy within 1-2 weeks of testing can cause false-negative results [55,56].
Other options for establishing cure of H. pylori after treatment include monoclonal fecal antigen test, which is more sensitive than tests for polyclonal H. pylori antibody, [54] and endoscopic tests including histology or histology plus rapid urease testing.All tests of cure are considered to be most accurate when performed at least 4 weeks after completion of antibiotic therapy.These tests are less accurate in patients taking bismuth-containing compounds or PPIs [37].To limit costs, endoscopic tests of cure should be limited to patients with other indications for EGD [37].Lastly, serologic antibody testing should not be used to document cure since serologies remain positive for years after successful eradication of H. pylori [54].

Complications of Untreated Disease
Untreated H. pylori is associated with an increased risk of peptic ulcer disease, gastric adenocarcinoma, and gastric MALT lymphoma.A systematic review of observational studies concluded that H. pylori infection increased the odds of uncomplicated peptic ulcer disease by 18-fold in patients not using NSAIDs [57].Both NSAID use and smoking in combination with H. pylori synergistically increase the risk of PUD [57,58].
H. pylori infection is associated with increased risk of histologic progression of gastric intestinal metaplasia [59] and gastric adenocarcinoma [60][61][62][63].Furthermore, retrospective studies have identified a strong association between H. pylori infection and MALT lymphoma [64].In addition, successful treatment of H. pylori causes regression of MALT lymphoma [65].While dyspepsia is one of the hallmark symptoms of H. pylori infection, most randomized controlled trials have shown that treatment of non-ulcer dyspepsia does not result in statistically significant symptomatic benefit [66,67].Lastly, some studies have linked H. pylori with unexplained irondeficiency anemia, idiopathic thrombocytopenic purpura (ITP), and vitamin B12 deficiency [44].

New Frontiers in H. pylori Research
In the decades following the discovery of H. pylori a lot has been learned about this bacterium and its association with PUD and gastric cancer.It is evident that treatment of H. pylori infection decreases complications associated with active disease but rising rates of bacterial resistance to current antibiotic options have increased the frequency of treatment failure.New frontiers in research are focusing on ways to improve eradication rates, including the use of probiotics as an adjuvant to triple and quadruple therapies.There have been multiple promising studies and meta-analyses published on the topic of probiotic supplementation and eradication of H. pylori infection.Specifically, Saccharomyces boulardii and Lactobacillus have been the most frequently studied probiotics and shown to increase eradication rates by 10% when compared to placebo [68][69][70].Furthermore, probiotics have been shown to decrease side effects of antibiotic therapy, specifically diarrhea, without significantly increasing adverse effects [68][69][70].There are currently no guidelines recommending probiotics in conjunction with antibiotic therapy.However, probiotics are thought to be generally safe in immunocompetent individuals and thus can probably be supplemented in conjunction with antibiotics.
Other research has emerged showing an association between H. pylori and idiopathic thrombocytopenic purpura (ITP).There have been several studies documenting H. pylori infection in adult patients with chronic ITP with subsequent improvement in platelet count following eradication of infection [71,72].Consequently, the 2011 American Society of Hematology Clinical Practice Guidelines recommend evaluation and treatment of H. pylori in adult patients with ITP [73].
More controversial recent research has suggested an inverse association between H. pylori infection and celiac disease [74,75].Two cross-sectional studies have shown that patients colonized with H. pylori have a lower prevalence of celiac disease, although it is unclear if these findings are incidental or the result of confounding factors.Study authors suggested that H. pylori might mediate immune responses to gluten.
Other areas of controversy include the evaluation and treatment of H. pylori infection in non-ulcer dyspepsia, unexplained iron deficiency anemia, and those at risk for gastric cancer.Lastly, it is not certain if H. pylori has protective effects against reflux disease.

Conclusions
In summary, patients should be evaluated for H. pylori when they have PUD or gastric cancer and the treatment of choice is either triple or quadruple therapy with subsequent documentation of eradication of infection.However, in the era of antibiotic resistance these treatment options could soon become obsolete; thus new research is focusing on other antibiotic regiments along with vaccine development to combat this pathogen [47,50,76].Other areas of study are attempting to elucidate the oncogenesis of H. pylori, finding that strains that carry cytotoxin-associated antigen A (cagA) gene are associated with gastric carcinoma [77].The new frontiers in H. pylori research will provide for better understanding of its impact on human health and allow for the development of targeted therapies.

Test Description of Test Sensitivity Specificity Advantages Limitations Rapid urease testing
Requires endoscopy to obtain samples.Accuracy is dependent on size and site of biopsies, histological staining techniques, use of PPIs, use of antibiotics, and interpretation by pathologist.Expensive Requirement for trained personnel for sample processing and interpretation.Possible false positive results if other H. pylori species are present.CultureRequires special transport medium (e.g.Stuart's), growth medium (e.g.Pylori agar) and incubation environment (microaerobic environment) for 5-7 days.Requires endoscopy to obtain samples.Can take a week to detect infection.Test affected by quality of specimens, transportation method, exposure to aerobic conditions, and growth conditions.
PPI twice a day, clarithromycin 500 mg twice a day, metronidazole 500 mg twice a day 10-14 70-85% Allergic to penicillin and have not received a macrolide.Bismuth subsalicylate 525 mg four times a day, metronidazole 250 mg four times a day, tetracycline 500 mg four times a day, PPI twice a day for 2 weeks, or H2RA for 4 weeks.10-1475-90%

Table 2 :
FDA approved first line oral therapy for H. pylori treatment.