H. PYLORI INFECTION

EPIDEMIOLOGY

1. pyloriis a ubiquitous organism. At least 50% of all people are infected, but an exact determination is not available, mostly because exact data are not available from developing countries. H.pylorimay be detected in approximately 90% of individuals with peptic ulcer disease; however, less than 15% of infected persons may have this disease. The pathogenetic role of H.pylori may differ depending on the geography and race. White persons are infected with H.pylori less frequently than persons of other racial groups. The prevalence rate is approximately 20% in white persons, 54% in African American persons, and 60% in Hispanic persons.

H.pylori infection may be acquired at any age. According to some epidemiologic studies, this infection is acquired most frequently during childhood. Children and females have a higher incidence of re-infection (5-8%) than adult males.

The prevalence of H.pylori infection in Pakistan was found to be 73.5% in males and 75.4% in females (p = 0.622) and increased with increasing age (p < 0.001).⁽¹⁾

PATHOPHYSIOLOGY:

In a susceptible host, H.pylori results in chronic active gastritis that may lead, in turn, to duodenal and gastric ulcer disease, gastric cancer, and MALTomas. H.pylori infection causes chronic active gastritis, which is characterized by a striking infiltrate of the gastric epithelium and the underlying lamina propria by neutrophils, T and B lymphocytes, macrophages, and mast cells. Mast cells, usually responsible for the immune response balance, may be important effector cells in the pathogenesis of gastritis. However, H.pylori does not seem to invade the gastric mucosa, although evidence suggests that the mucus layer provides a niche wherein the germ is protected from gastric secretions.

The release of host cytokines after direct contact of H.pylori with the epithelial cells of the gastric lining could recall the inflammatory cells in the infected area. One study demonstrated that the gastric epithelium, when infiltrated by neutrophils and macrophages in the lamina propria, highly expresses 2 neutrophil chemotactic factors: gro-alpha and interleukin-8. In addition, the interferon-gamma inducible protein–10 (IP-10) and the monokine induced by interferon-gamma (MIG), 2 selective chemotactic factors for T lymphocytes, are expressed by the endothelium and mononuclear cells of the gastric mucosa in patients with H.pylori -related gastritis. According to the same study, gro-alpha and interleukin-8 may have a central role in neutrophils trafficking from the vessels to the mucosal epithelium, while IP-10 and MIG determine T lymphocyte recruitment into the mucosa.

NATURAL HISTORY:

In fact, although peptic ulcer disease is the most studied disease related to H.pylori infection, this bacterium is seemingly involved in the pathogenesis of several extragastric diseases, such as mucosa-associated lymphoid tissue lymphomas (MALTomas), coronaritis (inflammation of coronary arteries), gastroesophageal reflux disease (GERD), iron deficiency anemia, skin disease, and rheumatologic conditions. However, at present, many of these associations remain largely uncertain, and the debate to confirm or refute causality related to these associations is still open.

The association of chronic H.pylori infection with alterations in gastric mucosal cell proliferation is recognized worldwide. In addition, H.pylori can produce and release several bioactive factors that may directly affect the stomach's parietal cells, which produce hydrochloric acid, and enterochromaffin like (ECL) cells (i.e. G cells and D cells), which produce gastrin and somatostatin, respectively. Evidence suggests that H.pylori inhibits D cells and stimulates G cells. H.pylori has some control mechanisms that are able to switch the transcription of different genes on or off when needed.

A strong association has been reported between H.pylori infection and gastric lymphoma and adenocarcinoma of the body and antrum of the stomach. Some cofactors may play a key role in determining such diseases. Whether H.pylori eradication can decrease the risk of cancer remains unknown.

SIGN AND SYMPTOMS:

In general, patients infected with H.pylori are asymptomatic, and no specific clinical signs have been described. When signs and / or symptoms are present, they may include the following:

• Nausea
• Vomiting
• Abdominal pain
• Heartburn
• Diarrhea
• Hunger in the morning
• Halitosis

DIAGNOSTIC TESTS:

In patients with suspected H.pylori infection, the following laboratory studies may aid in the diagnosis:

H.PYLORI FECAL ANTIGEN TEST: Very specific (98%) and sensitive (94%); positive results obtained in the initial stages of infection; can be used to detect post treatment eradication.

CARBON-13 UREA BREATH TEST: Concentration of the labeled carbon is high only when urease is present in the stomach, a reaction possible only with H.pyloriinfection.

H.pylori serology High (>90%) specificity and sensitivity; useful for detecting a newly infected patient but not a good test for follow-up of treated patients.

ANTIBIOGRAM: Useful in geographic areas with a high resistance rate against metronidazole and clarithromycin;^(2,3) these antibiotics should not be recommended as first-line drugs in such areas.

STAGING: There is no staging system for H.pylori infection, but the following steps in the disease process are well described:

• Chronic gastritis
• Atrophic gastritis
• Intestinal metaplasia: May evolve into dysplasia
• Gastric adenocarcinoma: Consider ultrasonography and esophagogastroduodenoscopy (EGD) in patients with gastric MALTomas (mucosa-associated lymphatic tissue lymphomas) for more precise staging of the disease.

IMAGING STUDIES: Imaging studies are not helpful in the diagnosis of H.pylori infection. However, they may be useful in patients with complicated disease (e.g. ulcer disease, gastric cancer, MALToma).

PROCEDURES:

• EGD: Often necessary in patients with symptoms of peptic ulcer disease to view the condition of the mucosal lining of the stomach and duodenum
• Biopsy plus EGD: To obtain biopsy specimens from the gastric antrum and to perform a histologic examination on the obtained specimens
• Echography plus EGD: Mandatory in patients with positive biopsy results for gastric MALTomas to allow a more precise staging of the disease

PATIENT SELECTION FOR TREATMENT:

Only treat patients who have a positive test result for H.pylori infection. Carefully educate patients regarding the importance of completing the prescription and about the potential adverse effects of the medications. Importantly, consider possible antibiotic resistance when selecting the treatment regimen. Note that surgery is not required for patients with H.pylori infection, but it may be considered in patients with severe complications, such as cancer.

THERAPY CONSIDERATIONS:

The US Food and Drug Administration has approved some regimens, which are now accepted internationally, for the treatment of H.pylori infection in patients with peptic ulcer disease, both gastric and duodenal. These regimens are also known as triple therapies and have reported cure rates from 85-90%. Unfortunately, with the increasing rise in antimicrobial resistance there has been an associated increase in the failure rate of standard triple therapy for H.pylori infection.⁽⁴⁾

TREATMENT OPTIONS:

PHARMACOLOGICAL OPTIONS:

Triple therapy ⁽⁵⁾

Triple therapy for Helicobacter pylori infection consists of the following:

1. Proton pump inhibitor (PPI) (omeprazole 20 mg BID, lansoprazole 30 mg BID, esomeprazole 40 mg QD, pantoprazole 40 mg QD, rabeprazole 20 mg BID)⁽⁶⁾plus
2. Clarithromycin 500 mg BID⁽⁶⁾(first-line) or metronidazole 500 mg BID (when clarithromycin resistance increasing) ⁽⁸⁾  plus
3. Amoxicillin 1000 mg BID⁽⁶⁾or metronidazole (if not used above)

Duration options are as follows (each duration below yields good outcomes of around 80% and is associated with similar risks because of good tolerance):

• 14 days (deemed the most prudent recommendation based on a meta-analysis of 7 studies and confirmed by a large Italian randomized single-center trial)⁽⁶⁾
• 7 days (no significant difference from 14 days based on a prospective randomized comparative trial in Nairobi)⁽⁷⁾
• 10 days (also showed high cure rates with metronidazole 500 mg TID and high-dose esomeprazole (40 mg BID) based on a pilot study)⁽⁸⁾

NON-BISMUTH QUADRUPLE THERAPY⁽⁵⁾:

SEQUENTIAL THERAPY: Sequential therapy is superior to standard triple therapy based on 2 systematic reviews ^{(9, 10)} and consists of the following:

1. PPI plus amoxicillin for 5-7 days, followed by
2. PPI plus 2 other antibiotics (usually, clarithromycin and metronidazole) for 5-7 days

Duration options of sequential therapy are as follows:

• 14 days (90.7-92.5% eradication rates)^(11,12)
• 10 days⁽⁶⁾ (87% eradication rate)⁽¹¹⁾

CONCOMITANT THERAPY: Concomitant therapy consists of the following (using doses similar to those in triple therapy; or all drugs BID in one study):

• PPI plus
• Amoxicillin plus
• Clarithromycin (1 g modified-release tablet QD in one study) plus
• Metronidazole (500 mg TID in one study)

Duration of concomitant therapy is 10-14 days. ^{(13, 14)}

Concomitant therapy is better for clarithromycin-resistant strains ⁽¹³⁾ and superior to triple therapy.^{(15, 16, 17)}

HYBRID THERAPY: Hybrid therapy is a combination of sequential and concomitant therapy,^{(5, 18)} as follows:

1. PPI plus amoxicillin for 7 days, followed by
2. PPI plus amoxicillin plus 2 other antibiotics (usually, clarithromycin and metronidazole) for 7 days

NOVEL CONCOMITANT THERAPY:

Novel concomitant therapy consists of the following: ⁽¹⁹⁾

1. PPI (rabeprazole 20 mg TID) for 10 days plus
2. Amoxicillin 1 g TID for 10 days (or bismuth subcitrate, if penicillin allergic, 240 mg QID for 10 days) plus
3. Rifabutin 150 mg BID for 10 days plus
4. Ciprofloxacin 500 mg BID for 10 days

BISMUTH-BASED THERAPIES:

Bismuth-based therapy is an alternative first-line therapy or second-line therapy (see below).⁽⁵⁾ It consists of the following:

1. PPI or H₂ receptor antagonist (e.g. ranitidine 150 mg BID⁽⁶⁾) plus
2. Bismuth subsalicylate 525 mg QID⁽⁶⁾plus
3. Metronidazole 250 mg QID⁽⁶⁾(or levofloxacin) plus
4. Tetracycline 500 mg QID⁽⁶⁾

Duration is 10-14 days ^{(6, 20)}

LEVOFLOXACIN-CONTAINING THERAPY ⁽⁵⁾:

This is an alternative first-line regimen ^{(21, 22)} and consists of a PPI plus amoxicillin 1g BID plus levofloxacin 500 mg QD.⁽⁶⁾ 

Duration options are as follows:

• 7 days
• 10 days⁽⁶⁾

SURGICAL OPTION:

Surgical intervention is not required for patients with H.pylori infection, but it may be a consideration for patients with severe complications, such as cancer.

GOALS OF THERAPY:

The goals of the therapy are simple: avoid further morbidity, mortality, and prevent disease while minimizing further utilization of healthcare resources, thus saving money.

GUIDELINES:

To view the guidelines of American College of Gastroenterology on the Management of H.Pylori infections, Click on the following link

http://gi.org/guideline/management-of-helicobacter-pylori-infection/

LONG TERM MONITORING:

• Consider performing a urea breath test (UBT) 4-12 weeks after the end of treatment. An esophagogastroduodenoscopy (EGD) with biopsy and a urease test also may be useful, but, importantly, remember that this test does have a significant rate of false-negative results. Serology can remain positive for up to one year after eradication.
• If the patient was taking NSAIDs it will be necessary to discuss further management.
• Low-dose misoprostol is less effective than acid suppression

CONSULTATION AND COUNSELING:

Note that the risk is increased in patients who have an H.pylori infection and whose first-degree relatives have a history of gastric cancer, even if they are asymptomatic.

Persons emigrating from geographic areas with a high incidence of gastric cancer have an increased risk.

Consider any patient with pre-cancerous lesions of the stomach (i.e. intestinal metaplasia) for treatment of H.pylori infection.

PRECAUTIONS:

Patient should be instructed on following precautions:

• Ensure a hygienic environment that is free of germs as this helps to keep H.pylori at bay.
• Avoid drinking water or eating food that may be contaminated.
• Wash hands well with soap, both after using the rest room and before meals.

REFERENCES:

1. http://pjms.com.pk/index.php/pjms/article/view/1022
2. Horiki N, Omata F, Uemura M, et al. Annual change of primary resistance to clarithromycin among Helicobacter pylori isolates from 1996 through 2008 in Japan.Helicobacter. 2009 Oct. 14(5):86-90.[Medline].
3. Fallone CA. Epidemiology of the antibiotic resistance of Helicobacter pylori in Canada.Can J Gastroenterol. 2000 Nov. 14(10):879-82.
4. Hsu PI, Wu DC, Chen WC, et al. Randomized controlled trial comparing 7-day triple, 10-day sequential, and 7-day concomitant therapies for Helicobacter pylori infection.Antimicrob Agents Chemother. 2014 Oct. 58 (10):5936-42.
5. O'Connor A, Molina-Infante J, Gisbert JP, O'Morain C. Treatment of Helicobacter pylori infection 2013.Helicobacter. 2013 Sep. 18 Suppl 1:58-65.[Medline]
6. Chey WD, Wong BC. American College of Gastroenterology guideline on the management of Helicobacter pylori infection.Am J Gastroenterol. 2007 Aug. 102(8):1808-25.
7. Sokwala A, Shah MV, Devani S, Yonga G. Helicobacter pylori eradication: A randomised comparative trial of 7-day versus 14-day triple therapy.S Afr Med J. 2012 Jun. 102(6 Pt 2):368-71.
8. Sánchez-Delgado J, García-Iglesias P, Castro-Fernández M, Bory F, Barenys M, Bujanda L. High-dose, ten-day esomeprazole, amoxicillin and metronidazole triple therapy achieves high Helicobacter pylori eradication rates.Aliment Pharmacol Ther. 2012 Jul. 36(2):190-6.
9. Zullo A, De Francesco V, Hassan C, Ridola L, Repici A, Bruzzese V, et al. Modified sequential therapy regimens for Helicobacter pylori eradication: a systematic review.Dig Liver Dis. 2013 Jan. 45(1):18-22
10. Zullo A, Hassan C, Ridola L, De Francesco V, Vaira D. Standard triple and sequential therapies for Helicobacter pylori eradication: an update.Eur J Intern Med. 2013 Jan. 24(1):16-9.
11. Liou JM, Chen CC, Chen MJ, Chen CC, Chang CY, Fang YJ. Sequential versus triple therapy for the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial.Lancet. 2013 Jan 19. 381(9862):205-13.
12. Manfredi M, Bizzarri B, de'Angelis GL. Helicobacter pylori infection: sequential therapy followed by levofloxacin-containing triple therapy provides a good cumulative eradication rate.Helicobacter. 2012 Aug. 17(4):246-53.
13. Molina-Infante J, Pazos-Pacheco C, Vinagre-Rodriguez G, Perez-Gallardo B, Dueñas-Sadornil C, Hernandez-Alonso M. Nonbismuth quadruple (concomitant) therapy: empirical and tailored efficacy versus standard triple therapy for clarithromycin-susceptible Helicobacter pylori and versus sequential therapy for clarithromycin-resistant strains.Helicobacter. 2012 Aug. 17(4):269-76.
14. Kongchayanun C, Vilaichone RK, Pornthisarn B, Amornsawadwattana S, Mahachai V. Pilot studies to identify the optimum duration of concomitant Helicobacter pylori eradication therapy in Thailand.Helicobacter. 2012 Aug. 17(4):282-5.
15. Georgopoulos S, Papastergiou V, Xirouchakis E, Laoudi F, Lisgos P, Spiliadi C. Nonbismuth quadruple "concomitant" therapy versus standard triple therapy, both of the duration of 10 days, for first-line H. pylori eradication: a randomized trial.J Clin Gastroenterol. 2013 Mar. 47(3):228-32.
16. Kim SY, Lee SW, Hyun JJ, Jung SW, Koo JS, Yim HJ. Comparative study of Helicobacter pylori eradication rates with 5-day quadruple "concomitant" therapy and 7-day standard triple therapy.J Clin Gastroenterol. 2013 Jan. 47(1):21-4.
17. Yanai A, Sakamoto K, Akanuma M, Ogura K, Maeda S. Non-bismuth quadruple therapy for first-line Helicobacter pylori eradication: A randomized study in Japan.World J Gastrointest Pharmacol Ther. 2012 Feb 6. 3(1):1-6.
18. Sardarian H, Fakheri H, Hosseini V, Taghvaei T, Maleki I, Mokhtare M. Comparison of hybrid and sequential therapies for Helicobacter pylori eradication in Iran: a prospective randomized trial.Helicobacter. 2013 Apr. 18(2):129-34.
19. Tay CY, Windsor HM, Thirriot F, Lu W, Conway C, Perkins TT. Helicobacter pylori eradication in Western Australia using novel quadruple therapy combinations.Aliment Pharmacol Ther. 2012 Dec. 36(11-12):1076-83.
20. Salazar CO, Cardenas VM, Reddy RK, Dominguez DC, Snyder LK, Graham DY. Greater than 95% success with 14-day bismuth quadruple anti- Helicobacter pylori therapy: a pilot study in US Hispanics.Helicobacter. 2012 Oct. 17(5):382-90.
21. Qian J, Ye F, Zhang J, Yang YM, Tu HM, Jiang Q, et al. Levofloxacin-containing triple and sequential therapy or standard sequential therapy as the first line treatment for Helicobacter pylori eradication in China.Helicobacter. 2012 Dec. 17(6):478-85. [Medline].
22. Shah A, Javid G, Zargar SA, Teli F, Khan BA, Yattoo GN. Safety and efficacy of 1-week levofloxacin-based triple therapy in first-line treatment for Helicobacter pylori-related peptic ulcer disease in Kashmir, India.Indian J Gastroenterol. 2013 Jan. 32(1):32-6.