Helicobacter pylori Infection

McColl KEL. Clinical practice: Helicobacter pylori infection. N Engl J Med. 2010;362:1597-1604.

Helicobacter pylori are helical, rod-shaped, Gram-negative bacteria that penetrate the mucous layer of the stomach to colonize the luminal surface of the gastric epithelium. Several features make these bacteria particularly suited to the harsh environment of the stomach. For example, their elevated urease activity allows them to efficiently convert urea (present in the gastric juice) to alkaline ammonia and carbon dioxide. Additionally, these bacteria have prominent flagella that help them to penetrate the thick mucosa of the stomach.

Chronic infection with H. pylori is widespread, occurring in approximately half of the world’s population, and infection is typically acquired early in life, especially among those in lower socioeconomic groups.¹ While H. pylori infection results in chronic inflammation of the underlying gastric mucosa, the vast majority of infected patients do not experience any clinically significant symptoms. However, H. pylori infection is linked with the development of certain upper gastrointestinal diseases.

For example, 1—10% of duodenal and gastric ulcers are thought to be related to H. pylori infection. The inflammation associated with chronic H. pylori infection, which is largely located within the non—acid-secreting antral region of the stomach, causes increased gastrin release, which in turn induces excess acid secretion from the fundic mucosa and damage and ulceration of the duodenal mucosa.^2,3 Treatment and eradication of H. pylori infection cure duodenal or gastric ulcers in over 80% of patients.

Chronic H. pylori infection is also strongly associated with the development of gastric cancers, especially those distal to the gastroesophageal junction.⁴ This risk is highest among patients who experience H. pylori— related inflammation in both the antral and fundic mucosa; this inflammation can lead to mucosal atrophy and intestinal metaplasia.⁵ Whether eradication of the infection reduces the risk of gastric cancer remains unclear. Additionally, several studies have demonstrated a link between H. pylori infection and gastric mucosa— associated lymphoid-tissue (MALT) lymphoma.⁶ Localized regression of most MALT lymphomas is typically observed with eradication of the infection.⁷

Many patients diagnosed with functional dyspepsia are found on biopsy to have H. pylori infection and associated inflammation. However, there is little evidence that the infection itself results in upper gastrointestinal symptoms, as H. pylori infection and inflammation are also common among individuals with no upper gastrointestinal symptoms. Additionally, H. pylori eradication therapy has minimal to no effect on symptoms in these cases.

Guidelines for Clinical Practice

Several available guidelines provide recommendations for the diagnosis and management of H. pylori infection. In the United States, 2 of the most widely used guidelines are those from the American College of Gastroenterology (ACG) and the Maastricht III Consensus Report.^8,9 While these guidelines are largely similar, they differ regarding a few key points.

For example, the ACG guidelines list the following criteria for H. pylori testing: a current or prior active gastric or duodenal ulcer (that was not previously treated with H. pylori eradication therapy), gastric MALT lymphoma, a history of endoscopic resection of early gastric cancer, or uninvestigated dyspepsia. The Maastricht III Consensus Report lists these same criteria but augments them with the following: gastric cancer in a first-degree relative, atrophic gastritis, unexplained iron-deficiency anemia, or chronic idiopathic thrombocytopenia purpura. Finally, the Maastricht IV Consensus Report, which was published in May 2012, also recommends testing for H. pylori in patients with a history of peptic ulcer prior to starting nonsteroidal anti-inflammatory drug treatment, in patients with a history of gastroduodenal ulcer who are taking aspirin, and in patients with unexplained vitamin B₁₂ deficiency.¹⁰

The age threshold for implementing a test-and-treat strategy also differs between the 2 guidelines; the ACG guidelines recommend testing in individuals younger than 55 years, while the Maastricht III guidelines recommend testing in those younger than 45 years. However, these age thresholds vary among countries, depending on the prevalence of upper gastrointestinal cancers in different regions. Clinicians should note that these age thresholds only apply to patients without alarm symptoms; patients with dysphagia, weight loss, evidence of gastrointestinal bleeding, or persistent vomiting require endoscopic evaluation regardless of their age. Finally, these 2 guidelines differ in terms of their recommended durations of treatment: 10—14 days in the ACG guidelines compared to 7 days in the Maastricht III guidelines.

Testing for Helicobacter pylori Infection

Because most individuals with H. pylori infection do not experience clinical symptoms, routine screening for this infection is not recommended. However, testing is recommended if patients meet any of the previously mentioned criteria, such as confirmed duodenal or gastric ulcers, gastric MALT lymphoma, or prior resection of early gastric cancer. Both nonendoscopic and endoscopic tests are available to test for H. pylori infection.

Nonendoscopic strategies include serologic tests, urea breath testing, and fecal antigen tests. Serologic testing for the presence of immunoglobulin (Ig) G antibodies directed against H. pylori is less expensive and more widely used than other nonendoscopic tests, but the overall sensitivity and specificity of these assays are limited, and their appropriate threshold values vary among different populations.¹¹ Further, serologic testing is not adequate to determine if an infection has been eradicated, as anti—H. pylori antibodies may persist for several months following treatment.

The urea breath test measures the amount of labeled carbon (¹³C or ¹⁴C) that is converted to carbon dioxide by the H. pylori urease; for this test, patients drink a solution containing labeled urea, after which the amount of labeled carbon dioxide in the breath is measured. This method is associated with a sensitivity and specificity of 95%.¹² Also, unlike IgG testing, urea breath testing can effectively determine the presence of infection following H. pylori eradication therapy.

Similarly, fecal antigen tests are associated with high sensitivities and specificities (especially when monoclonal antibodies are used), and these tests can be used to measure the effectiveness of eradication therapy.¹³ However, both urea breath testing and fecal antigen tests may yield false-negative results if patients have been recently exposed to proton pump inhibitors, antibiotics, or bismuth preparations.

Nonendoscopic testing is suggested for patients with uninvestigated and uncomplicated dyspepsia. However, this strategy is not appropriate for patients with alarm symptoms—such as weight loss, persistent vomiting, or gastrointestinal bleeding—as endoscopic examination is warranted in these individuals. Nonendoscopic testing is also not appropriate for patients with new-onset dyspepsia who are older than 45—55 years. In a randomized trial of 294 patients with uninvestigated dyspepsia who were found to be positive for H. pylori infection, it was shown that 7 patients would need to receive eradication therapy in order for 1 patient to experience a benefit.¹⁴

Finally, endoscopic tests for H. pylori infection— including urease-based tests, histologic assessment, and culture—all rely on biopsy of the gastric mucosa. Urease-based tests, which measure the conversion of urea to ammonia within a biopsy specimen, are rapid and inexpensive. In most patients, urease-based endoscopic tests are highly accurate, but recent exposure to proton pump inhibitors or antibiotics may trigger a false-negative result. Alternatively, both histologic staining and culture allow for direct assessment of H. pylori infection, but these tests require highly trained technicians and adequate facilities.

Treatment of Helicobacter pylori Infection

A number of treatment strategies are used to manage chronic H. pylori infection. Standard therapy consists of 1 of 3 regimens: 7—14 days of triple therapy (with a proton pump inhibitor, amoxicillin, and clarithromycin); 10—14 days of quadruple therapy (with a proton pump inhibitor, tripotassium dicitratobismuthate, tetracycline, and metronidazole); or sequential therapy (with a proton pump inhibitor and amoxicillin on Days 1—5, followed by proton pump inhibitor therapy, clarithromycin, and tini-dazole on Days 6—10). In all of these regimens, the proton pump inhibitor is administered at a healing dose twice per day, and metronidazole can be used as an alternative to amoxicillin in patients who are allergic to penicillin.

Triple therapy is the most widely used first-line therapy for H. pylori infection. In terms of the duration of therapy, statistically significant (but not clinically meaningful) differences have been demonstrated when 10-day or 14-day regimens were compared to 7-day regimens. Quadruple therapy is generally reserved for treatment of H. pylori in regions with higher rates of resistance to clarithromycin or metronidazole or for treatment of patients who are at a heightened risk of resistance to these antibiotics.

It is important to confirm effective eradication of H. pylori infection following therapy. As discussed above, serologic testing is not useful in this setting. Follow-up testing via urea breath testing or a fecal antigen test should be performed in patients who continue to experience dyspepsia symptoms despite H. pylori eradication therapy; however, not all patients require second-line therapy. Second-line therapy is appropriate for patients with a confirmed complication (ie, a duodenal or gastric ulcer, gastric cancer, or gastric MALT lymphoma), but it is not necessarily indicated for patients with functional dyspepsia.

The choice of the second-line regimen depends on which regimen was used initially, as treatment failure may be due to resistance to the antibiotic(s) included in the first-line therapy (especially resistance to clarithromycin and/or metronida-zole). Culturing may be helpful to determine the antibiotic resistance profiles of difficult-to-treat strains of H. pylori. Commonly, second-line therapy consists of either a 7—14-day regimen of triple therapy (including a proton pump inhibitor, amoxicillin, and metronidazole) or a 10—14-day regimen of quadruple therapy (including a proton pump inhibitor, tripo-tassium dicitratobismuthate, tetracycline, and metronidazole). Salvage therapies may include levofloxacin or rifabutin.

Future Research

Researchers still have several important areas to explore regarding the diagnosis and management of H. pylori infection. Currently, there is a lack of data from randomized trials of patients with uninvestigated dyspepsia who continue to experience symptoms following H. pylori eradication therapy; studies are needed to determine the best management strategy in these cases. Another important point of investigation is whether eradication of pylori infection reduces the risk of gastric cancer.