How can I be sure that the patient has Helicobacter pylori infection?

What signs and symptoms are usually found?

The initial infection typically occurs in childhood and is not recognized clinically. Challenge experiments have shown that approximately a week after challenge, most infected volunteers experience epigastric symptoms that resolve within a short time. This is followed by a latent period such that most with active H. pylori infection only become clinically apparent following development of a complication, such as peptic ulcer disease.

What is the usual constellation of clinical features?

H. pylori infection damages gastric structure and function. Clinical features are myriad, depending on which H. pylori-associated disease is present. H. pylori infection causes gastroduodenal inflammation (e.g., gastritis and duodenitis) that may proceed to atrophic gastritis with the attendant complications such as iron deficient anemia, vitamin B12 deficiency with pernicious anemia, gastric ulcer, gastric adenocarcinoma, and gastric mucosal-associated (MALT) lymphoma. H. pylori duodenitis may eventuate in duodenal ulcer disease.

The clinical features are those of the clinical manifestations of the infection (e.g., peptic ulcer or gastric malignancy) or a complication of the H. pylori disease (e.g., gastrointestinal bleeding associated with peptic ulcer disease). Heartburn, but not gastroesophageal reflux disease (GERD), is also associated with H. pylori infection. Because 20% to 25% of those with H. pylori infections ultimately develop a clinical manifestation and these diseases (e.g., peptic ulcer) which are associated with potentially life-threatening complications, whenever a patient presents with symptoms related to the upper gastrointestinal tract other than classic GERD, the physician should consider the presence of an H. pylori infection and order appropriate tests. (Figure 1).

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Figure 1.

Constellation of clinical features indicating H. pylori infection.

Confirming the diagnosis

There are a variety of validated tests, ranging from culture to simple breath tests that can be used to confirm the presence of H. pylori.

A tabular or chart listing of features and signs and symptoms


How can I confirm the diagnosis?

What tests should be ordered first?

Diagnostic tests for H. pylori can be broadly classified into two categories: invasive tests that require endoscopy and noninvasive tests.

Noninvasive tests are preferred and there are three choices: serology, urea breath tests, and stool antigen tests. Breath tests and stool antigen tests are preferred because they diagnose the presence of active infection, whereas serology cannot distinguish between active and cured infections. A variety of commercial stool antigen tests are available. The most reliable results are obtained with ones using monoclonal antibodies to detect H. pylori antigens, such that tests using monoclonal antibodies are preferred over first generation tests using polyclonal antibodies.

Breath tests are based on the fact that the organism contains the enzyme urease and thus will hydrolyze labeled urea to labeled carbon dioxide that can be detected in the breath. These urea breath tests are available with either a 13C or 14C label and in different formats. All are simple and accurate. Urea breath tests and stool antigen tests are approximately equal in terms of sensitivity and specificity. Both breath tests and stool antigen tests may become false negative when the patient has recently used antibiotics, bismuth, or proton pump inhibitors (PPI) – all of which will reduce the bacterial load below the detection limit for these tests. H2-receptor antagonists do not have an iimportant effect on bacterial load such that one can either stop PPI therapy or switch to an H2-receptor antagonist for approximately 2 weeks before testing to prevent false negative results.

Serologic tests are not recommended for initial testing as they have limited specificity and sensitivity and remain positive long after an infection has been eradicated. Although IgG, IgA, and IgM tests are available, only the IgG tests are reliable. IgM anti-H. pylori are widely available through commercial laboratories, none is FDA approved and panels offering IgG, IgA,and IgM anti-H. pylori tests should alert the clinician to the fact that their laboratory is offering unapproved and generally inaccurate tests. Serologic tests may, however, be used when there is a high pretest probability of an H. pylori infection (e.g., active duodenal ulcer disease), although tests that confirm the active infection (breath tests or stool antigen tests) are preferred. Stool antigen and urea breath tests are available through the major national and regional clinical laboratories.

Invasive tests are those that require endoscopy. At the time of endoscopy, the endoscopist can identify features strongly suggestive of an active H. pylori infection, such as the presence of a peptic ulcer. However, one gold standard for diagnosis of H. pylori infections is histologic examination of gastric mucosal biopsies. The typical histologic picture is one showing both acute and chronic inflammation. The H. pylori organisms can also be visualized with special stains (silver, Diff-Quick, or immunohistochemistry). For the highest yield, the endoscopist should take specimens from the antrum, corpus, and angulus.

The endoscopist can also take a sample for rapid urease testing (RUT), in which the biopsy is placed into a medium containing urea and a pH indictor. The presence of the infection is then identified by a color change caused by the urea being hydrolyzed into ammonium. As with urea breath tests and stool antigen tests, histology and RUT tests can be false negative when the patient has reduced his/her bacterial load by recently taking antibiotics, bismuth, or PPIs, thus, the recommendation regarding stopping the PPI or switching to an H2-receptor antagonist for approximately 2 weeks prior to the procedure. If the histology is suggestive (e.g., acute and chronic inflammation) but not diagnostic (i.e., H. pylori organisms are not seen), consider obtaining an IgG antibody test because serology is not influenced by any of the factors that reduce bacterial load and make interpretation of direct testing difficult (Figure 2).

Figure 2.

Diagnostic testing for H. pylori.

What tests should be used to confirm the initial tests?

In asymptomatic individuals (e.g., a first degree relative of a duodenal ulcer patient) or patients with non-ulcer dyspepsia or GERD, in whom the prevalence of H. pylori is low (i.e., low pretest probability), the clinician should always be concerned about the possibility of false positive results. This is especially true with serologic tests, where the typical sensitivities and specificities are below 90%.

As a general rule, prior to institution of therapy, it is worthwhile to confirm the serologic results with a test for active infection such as a urea breath test or stool antigen test. Alternatively, if the clinical condition warrants endoscopy, one would recommend endoscopy with antral and corpus biopsies for both for its diagnostic value and to evaluate the health of the gastric mucosa. If the initial test was endoscopy and it is suggestive but not diagnostic, one should order a noninvasive test to help solve the dilemma.

What tests are useful if the diagnosis is still in doubt?

See section “Which tests should be used to confirm initial tests?”

What other diseases, conditions, or complications should I look for in patients with H. pylori infection?

As noted in the subsection “What is the constellation of clinical features?” H. pylori infection causes gastroduodenal inflammation (e.g., gastritis and duodenitis) that may proceed to duodenal ulcer or atrophic gastritis with the attendant complications that include iron deficient anemia, vitamin B12 deficiency, gastric ulcer, gastric adenocarcinoma, and gastric mucosal-associated (MALT) lymphoma. Cure of the infection stops the progressive damage to the stomach and allows healing to take place. If the stomach is not atrophic, it returns to normal or near normal function and the risk of subsequent diseases in low enough to be ignored. However, atrophic gastritis itself carries an ongoing risk of gastric cancer or vitamin B12 deficiency and all its consequences.

Patients with duodenal ulcer typically have near normal corpus mucosa and, except for confirmation of eradication, no further studies are needed as in the vast majority of cases the disease is cured. In contrast, in regions or populations where gastric cancer is a problem, it is important to evaluate the health of the mucosa using either biopsy of the antrum and corpus or noninvasively by assessing serum pepsinogen I and pepsinogen II levels and the pepsinogen I:II ratio. In some instances, a gastrin level may be useful – high serum gastrin levels in the face of atrophic changes suggest achlorhydria. Atrophic gastritis is also associated with vitamin B12 deficiency such that a vitamin B12 level should be checked to ascertain if replacement therapy is needed.

In patients with atrophic gastritis or gastric atrophy, the risk of gastric cancer is reduced following H. pylori eradication. However, if that risk remains sufficiently high, post-treatment endoscopic surveillance should be considered.

Other conditions that suggest the presence of H. pylori infection are the presence of gastric polyps, with the exception of fundic gland polyps, follicular gastritis, idiopathic thrombocytopenia, and, possibly, chronic urticaria.

What is the right therapy for the patient with H. pylori infection?

What treatment options are effective?

Therapy is first directed to the clinical manifestation of the infection (e.g., an active peptic ulcer with a visible vessel). The details of therapy of the different clinical presentations of H. pylori infections are to be found in chapters related to those entities. Treatment of the infection itself will be discussed here. H. pylori infections are typically acquired in childhood and clinical manifestations follow a long latent period. As such, the clinical should never feel pushed to start therapy and therapy can safely be delayed until convenient and the events surrounding the presentation are under control, or even fully resolved (Figure 3).

Figure 3.

Treatment options for the patient with H. pylori infection.

H. pylori is a Gram-negative bacterium that is susceptible to many common antibiotics. H. pylori occupies a unique niche, being able to survive within the stomach, which is actually an acid milieu. The organisms infrequently invade the gastric cells and live either attached to the surface epithelium or within the mucus layer. The stomach is a hostile environment for antibiotics to penetrate and within which to remain effective, as most antibiotics require neutral or near neutral pH. The most effective regimens contain an antisecretory agent, typically a PPI to increase the intragastric pH and reduce gastric volume and two or three antimicrobial agents. Resistance develops rapidly to clarithromycin and fluoroquinolones (e.g., levofloxacin) such that currently, many infections will have already developed resistance to these previously useful antibiotics. Resistance to amoxicillin and tetracycline are infrequent. Resistance to metronidazole can be partially overcome by using higher doses and longer durations of therapy when used as a component of bismuth quadruple therapy.

With few exceptions in most of the world, clarithromycin resistance has increased to the point that results with a PPI, amoxicillin, clarithromycin triple therapy are no longer acceptable and we do not recommend it any longer unless there is culture or other evidence that the infecting strain is susceptible to clarithromycin. Current best choices are a four-drug regimen with or without bismuth. As with any other infectious disease, results are best when the therapy is based on pretreatment susceptibility testing. Lacking this, one would wish for data regarding the frequency of resistance to different antimicrobials in the local population. That too is often not available, requiring the clinician to make an empiric choice. This emphsizes the importance of post treatment testing for cure to identify which regimens are currently effective and to give a “heads up” when currently favored empiric regimens are becoming less effective.

Recommended regimens for anti-H. pylori therapy

1. Recommended treatment regimens for use as an empiric therapy

Concomitant therapy: 4 drugs without bismuth: Amoxicillin 1 g, clarithromycin 500 mg, tinidazole or metronidazole 500 mg, a PPI (double dose) all given b.i.d. for 14 days (e.g., PrevPac® or generics with an additional metronidazole or tinidazole 500 mg b.i.d. for 14 days). (However, generics are much cheaper.)

Sequential therapy: Amoxicillin 1 g plus a PPI b.i.d. for 7 days, then clarithromycin 500 mg, and tinidazole or metronidazole 500 mg b.i.d. plus a PPI b.i.d. for 7 days to complete 14 days of total therapy. However, sequential therapy is sensitive to metronidazole resistance and dual clarithromycin resistance, whereas concomitant therapy is only sensitive to dual restance and is thus preferred.

Sequential-concomitant hybrid therapy: Amoxicillin 1 g plus a PPI b.i.d. for 7 days, then amoxicillin 1 gm bid, plus clarithromycin 500 mg and tinidazole or metronidazole 500 mg b.i.d for 7 days to complete 14days.

Bismuth quadruple therapy: Bismuth subsalicylate or subcitrate 2 tabs q.i.d., tetracycline HCl 500 mg q.i.d. (with meals and bedtime), metronidazole or tinidazole 500 mg t.i.d. (with meals), and a PPI b.i.d. for a minimum of 10 days. When metronidazole resistance is suspected (prevalence about 25% in the United States), 14 days is preferable. The combination package Helicac® can be given with the addition of 3 extra 250 mg metronidazole, to bring the dose up to and acceptable level, plus a PPI given b.i.d. Therapy with the combination package Pylera® should be extended to 14 days whenever metronidazole resistance is suspected and one must not forget to prescribe a PPI b.i.d., as it is not included in the package. Currently, tetracycline and Helidac are not available in the United States. Tetracycline can be obtained from Canada. Doxycycline is not an effective substitute for tetracycline.

2. Acceptable regimens only if resistance is known not to be present based on culture or molecular testing (tailored therapy)

Legacy triple therapy: 3 drugs including 2 of the following: amoxicillin 1 g, clarithromycin 500 mg, tinidazole or metronidazole 500 mg plus a PPI all given b.i.d. for 14 days

Fluoroquinolone triple therapy: Once a day fluoroquinolone (e.g., 500 mg of levofloxacin) plus a PPI and amoxicillin 1 gm, B.I.D. for 14 days.

What is the most effective initial therapy?

Review of the patient’s prior antibiotic use is important to identify when resistance to a preferred antibiotic may be present. Prior use of any macrolide or fluoroquinolone makes resistance highly likely. In most treatment-naive populations in the United States, concomitant therapy or bismuth quadruple therapy is the best choice for initial therapy. Generally, concomitant therapy is better tolerated but contains penicillin, which eliminates its use for patients with penicillin allergy. With all regimens, compliance is critical and time spent with the patient to discuss the importance of compliance is time well spent.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

How do I know if the infection was cured?

Because treatment success is not assured with current anti-H. pylori therapy, it is recommended that post-therapy proof of cure testing always be performed. This is most conveniently done with a noninvasive test. Testing should be delayed 4 or more weeks after the end of therapy to allow any remaining organisms to repopulate the stomach and become easily detected. The caveats regarding s that reduce bacterial load as discussed earlier (subsection “What tests should be ordered first?”) are also relevant here (e.g., the need to stop PPI therapy for 2 weeks prior to testing).

Waiting 4 weeks post therapy is sufficient when using a urea breath test for confirmation of cure. Waiting 6 to 8 weeks is recommended when using the stool antigen testing to reduce the possibility of false positive results. For patients who need follow-up endoscopy for evaluation of a gastric lesion (e.g., gastric ulcer or dysplastic epithelium), endoscopy with antral and corpus biopsies would be used to confirm cure.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

What do I do if treatment failed?

Retreat using a different regimen while avoiding antibiotics the patient has taken before and in which acquired resistance is common (e.g., clarithromycin or a fluoroquinolone). Therefore, if a four-drug nonbismuth containing regimen was used and failed, the clinician would use a four-drug bismuth-containing regimen the second time. Alternately and preferably, the clinician would obtain culture and susceptibility testing prior to choosing therapy, but in most places, this is not available. Failure with concomitant therapy and bismuth quadruple therapy should prompt consultation with someone experienced with the treatment of multidrug resistant H. pylori infections.

Listing of these, including any guidelines for monitoring side effects.

What do I do following multiple treatment failures?

Failure of both a 4-drug nonbismuth and a bismuth-containing regimen generally identifies infection with a multidrug resistant strain, and consultation with an H. pylori expert is recommended. The alternative regimens include 14-day therapy with furazolidone, in which furazolidone 100 mg t.i.d. is substituted for metronidazole in bismuth quadruple therapy or rifabutin with high dose amoxicillin and high dose PPI for 10 to 14 days. Furazolidone currently is not available in the United States or Canada.

How should I monitor the patient with H. pylori infection?

H. pylori infection is a chronic infection and the monitoring issues include (1) Was treatment successful? (2) Is follow-up needed after eradication? (3) Is disease specific follow-up needed?

How should I monitor progress of stages of the disease?

After treatment, all patients should undergo a test for cure (see subsection How do I know if the infection was cured?). In developed countries, reinfection is rare (i.e., generally 1% or less) and can be ignored. In developing countries where there are significant sanitation issues, reinfection may occur.

There are no guidelines about if, when, or how often to evaluate the patient. Common sense suggests that the major determinant would depend on the risk of the disease manifestation recurring. For those with nonatrophic gastritis, the risk would be low. For those with atrophic gastritis, they would still have a risk of developing gastric cancer and follow-up would depend on the extent and severity of the atrophy and the presentation (i.e., those with premalignant lesions or successfully endoscopically removed early gastric cancer would require at least annual surveillance). For details, refer to the sections dealing with these specific diseases.

What's the evidence?

Malfertheiner, P, Megraud, F, O’Morain, C. “Management of Helicobacter pylori infection–the Maastrict IV Consensus Report”. Gut. vol. 61. 2012. pp. 646-64. (Excellent overview of the issues surrounding H. pylori infections, diagnosis, indications, and diseases. However, it is out of date in terms of therapy [see next reference].)

Rimbara, E, Fischbach, LA, Graham, DY. “Optimal therapy of Helicobacter pylori infections”. Nat Rev Gastroenterol Hepatol. vol. 8. 2011. pp. 79-88. (Up-to-date overview of H. pylori therapy and molecular approaches to susceptibility testing.)

Graham, DY, Lee, YC, Wu, MS. “Rational Helicobacter pylori therapy: evidence-based medicine rather than medicine-based evidence”. Clin Gastroenterol Hepatol. vol. 12. 2014. pp. 177-86.e3. (Up-to-date overview of H. pylori therapy, including the data regarding failure of previously popular regimens to currently provide adequate treatment success.)

Wu, JY1, Liou, JM, Graham, DY. “Evidence-based recommendations for successful Helicobacter pylori treatment”. Expert Rev Gastroenterol Hepatol. vol. 8. 2014. pp. 21-8. (Up-to-date overview of H. pylori therapy.)

Gisbert, JP, Pajares, JM. “Review article: C-urea breath test in the diagnosis of Helicobacter pylori infection–a critical review”. Aliment Pharmacol Ther. vol. 20. 2004. pp. 1001-17. (Excellent review of the urea breath test in the diagnosis of H. pylori infections.)

Gisbert, JP, de la Morena, F, Abraira, V. “Accuracy of monoclonal stool antigen test for the diagnosis of H.pylori infection: a systematic review and meta-analysis”. Am J Gastroenterol. vol. 101. 2006. pp. 1921-30. (Excellent review of stool antigen tests for H. plyori infection.)

Attumi, TA, Graham, DY. “Follow-up testing after treatment of Helicobacter pylori infections: cautions, caveats, and recommendations”. Clin Gastroenterol Hepatol. vol. 9. 2011. pp. 373-5. (Explanation and approaches to overcoming the effects of PPI's on reducing the accuracy of diagnostic testing for H. pylori infections.)