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Office Based Testing for H.Pylori (Parts 1, 2, and 3)
| Article Date: 5/31/2007 |
Office Based Testing for Helicobacter pylori Infection
Mehnaz A. Shafi, M.D.
Department of Medicine, Baylor College of Medicine and Baylor Clinic, Houston, Texas
Send inquiries to:
Mehnaz A. Shafi, M.D.
Baylor Faculty Center Suite 8.37
1709 Dryden Street
Houston, Texas 77030
Tel: 713-798-0950
Fax: 713-798-0951
Email: mshafi@bcm.edu
INTRODUCTION
The discovery of Helicobacter pylori by Marshall and Warren in 1982 has lead to dramatic changes in our understanding of upper gastrointestinal diseases (1). H. pylori is now recognized as the single most common cause of peptic ulcer disease. It＊s etiological association with gastritis, gastric adenocarcinoma and gastric mucosa associated lymphoid tissue (MALT) lymphoma is also indisputable. H. pylori infects more than half the global population and has been classified as a Class 1 carcinogen. Many tests are available to diagnose the infection but questions remain about the optimal approach of whom to test, when to test and which diagnostic tests to use. This article presents a brief overview of the epidemiology and pathogenesis of H. pylori infection, its clinical manifestations as well as providing evidence based diagnostic strategy emphasizing the use of non invasive, office based diagnostic tests for H. pylori.
EPIDEMIOLOGY
H. pylori is acquired in childhood such all those who will get the infection typically have done so by age 20. The annual incidence reported in 3 adult studies in developed countries is between 0.3% and 0.5% per year which coincides with the low risk of reinfection after successful eradication therapy. Worldwide, but especially in developed nations, infection with H. pylori is declining. The risk of acquiring the infection correlates positively with a low childhood socioeconomic status and in most countries the risk is inversely related to the overall level of sanitation and specifically to household hygiene. (2) Transmission is typically within families and most often by the fecal-oral or gastro-oral routes. In the United States the infection is most common among immigrants, Afro-Americans, Asians and Hispanics and least among the upper middle class white population (3, 4) (Table 1).
PATHOGENESIS
H. pylori are gram-negative, flagellated, highly motile bacteria. Infection by H. pylori involves a complex interaction of both bacterial and host factors. The urease enzyme produced by the bacteria alters the microenvironment of the organism by breaking down urea to produce carbon dioxide and two ammonium ions which protect the bacterium from the highly acidic gastric environment and facilitate colonization. Adherence then occurs via interactions between the gastric mucosal cell surface and a variety of adhesins specific to H. pylori. (5) Once attached to gastric mucosa, H. pylori causes tissue injury by a complex cascade of events
CLINICAL MANIFESTATIONS
Gastritis and Gastric Cancer
The majority of individuals infected with H. pylori are asymptomatic. While some infected persons clear the infection, (probably because of antibiotic use for unrelated conditions) most infections are life long. Approximately 20% of infected people will subsequently develop clinically apparent disease, generally after a long latent period. As such the infection as been called gastric termites. The usual course of disease in infected patients begins with chronic superficial gastritis, which progresses to atrophic gastritis. This progression is key in the cellular cascade that results in the development of gastric carcinoma. There is a 90-fold increase in the rate of gastric carcinoma in patients with severe atrophic gastritis compared with normal controls. (6) H. pylori is associated with the development of adenocarcinoma of the antrum and body of the stomach and also with primary gastric MALT lymphomas. H. pylori stimulates a marked lymphocytic infiltration into the gastric mucosa and acts as a focus for cellular alteration and proliferation that in some may ultimately result in neoplastic transformation to lymphoma. H. pylori-associated gastric lymphoma often responds to H. pylori eradication and regression of low-grade gastric MALT lymphoma is expected in 70% to 90% of patients following H. pylori eradication (7)
Peptic Ulcer Disease
It is well established that H. pylori infection is the major cause of peptic ulcer disease. Eradicating the infection alters the natural course of peptic ulcer disease by dramatically reducing its recurrence rate such that effectively cure of the H. pylori infection results in cure of peptic ulcers. However, there are other causes of ulcer such as nonsteroidal anti-inflammatory drug use where H. pylori eradication would not be expected to influence the outcome. The mechanism by which H. pylori induces peptic ulcer disease most likely involves a combination of genetic predisposition of the host, virulence factors of the organism (e.g., the CagA virulence factor protein), mechanical damage to the mucosa, and alterations of gastric and duodenal secretions (8).
Non-ulcer Dyspepsia
Non-ulcer dyspepsia comprises a range of symptoms including ulcer-like, and reflux-like complaints. Many possible causes have been suggested, including altered visceral sensation, increased serotonin sensitivity, alterations in gastric acid secretion, abnormal gastric emptying, stress and H. pylori infection. (9) In a study linking H. pylori infection to non-ulcer dyspepsia, patients with the latter condition were twice as likely as controls to be positive for H. pylori infection. (10). Symptomatic H. pylori infection often presents as dyspepsia. At presentation this is called uninvestigated dyspepsia and as noted below, those patients are recommended to undergo testing for H. pylori infection. Dyspepsia in patients without gastroesophageal reflux disease, peptic ulcer, or gastric cancer is termed investigated non-ulcer dyspepsia or simply non-ulcer dyspepsia. Eradication of H. pylori in this group of patients will result in complete relief of symptoms in only about 10% suggesting that H. pylori infection is not a major cause of this problem.(11) However, eradication of H. pylori will still have benefits as it will result in healing of the patient＊s gastritis, prevention of subsequent development of peptic ulcer, and if done before atrophy occurs, prevention of gastric cancer as well as prevention of transmission of the infection. These positive attributes of H. pylori eradication have resulted in the universal recommendation that H. pylori be eradicated whenever it is found. However, patients with non-ulcer dyspepsia and H. pylori infection should be informed that cure of the infection may not result in cure of their symptoms.
Gastroesophageal Reflux Disease
There has been concern about a possible relation between H. pylori and gastroesophageal reflux disease. Gastroesophageal reflux disease is associated with high levels of acid secretion. Duodenal ulcer caused by H. pylori is also associated with high levels of acid secretion and therefore it is not surprising that there is a strong association between H. pylori-related duodenal ulcer and gastroesophageal reflux. In these patients eradication of the H. pylori results in cure of the ulcer and often an improvement but not an elimination of gastroesophageal reflux symptoms. In contrast, H. pylori-associated atrophic gastritis is associated with low acid secretion and therefore even those patients who have impaired gastroesophageal antireflux barriers and reflux do so with minimal or no symptoms. In these instances one can consider that H. pylori is acting as a biologic antisecretory agent. Unfortunately, those patients are also at highest risk for development of H. pylori-associated gastric cancer. Cure of the infection will reduce their cancer risk but may result in their underlying gastroesophageal reflux becoming more symptomatic.(12) Overall, in Western countries, eradication of H. pylori has no effect on the incidence or treatment of gastroesophageal reflux disease. There are now sufficient data to discount concerns about H. pylori infections as either a cause of or having a detrimental effect on gastroesophageal reflux disease. H. pylori is now recognized as a serious global human pathogen that is responsible for high morbidity and mortality worldwide. It does not confer protection from disease and whenever detected it should be eradicated.(13)
PRACTICE GUIDELINES
In 1994, a National Institutes of Health consensus conference concluded that the evidence linking H. pylori and peptic ulcer was sufficient that H. pylori infection should be eradicated in patients with peptic ulcer disease. Several gastroenterological organizations have since released more detailed guidelines for the diagnosis and treatment of dyspepsia as the understanding of the contribution of H pylori infection to gastrointestinal disease has developed.(14)
One of the key recommendations of the various guidelines has been that clinicians should use non-endoscopic tests (eg, urea breath tests or stool antigen tests) to detect H. pylori infection. (14,15,16,17). All guidelines agree that patients who test positive should receive H. pylori eradication therapy. Endoscopy should be limited to those in whom it is otherwise clinically indicated (Figure1). Prompt endoscopy is reserved for older patients and for patients with alarm features, such as persistent vomiting, bleeding, weight loss, dysphagia, and anemia. The 2005 practice guidelines of the American College of Gastroenterology recommend that dyspeptic patients over 55 years of age or those with alarm features should undergo prompt upper endoscopy.(15) In all other patients, there are two approximately equivalent options: (i) test and treat for H. pylori using a validated noninvasive test and if eradication is successful but symptoms do not resolve patients should receive a trial of acid suppression or (ii) an empiric trial of acid suppression with a proton pump inhibitor (PPI) for 4 to 8 weeks.(15,16) The test-and-treat option is preferable in populations with a moderate to high prevalence of H. pylori infection (≡10%) whereas empirical PPI therapy is an initial option in low prevalence situations. If initial acid suppression fails after 4 weeks, it is reasonable to consider changing drug class or dosing. If the patient fails to respond or relapses rapidly upon stopping antisecretory therapy, then the test-and-treat strategy is best applied before referral for upper gastrointestinal endoscopy. The decision to endoscope and when as always must be based on the physician＊s clinical judgment. In patients who respond to initial PPI therapy, treatment is stopped after 4 to 8 weeks; if symptoms recur, another course of the same treatment may be justified.(15)
WHOM TO TEST FOR H. PYLORI
Definite indications for testing for H. pylori include peptic ulcer disease, gastric or duodenal, acute or prior diagnosis, with or without NSAID use, the presence of gastric MALT lymphoma and family history of gastric cancer (Table 2). Other indications relate to prevention of disease. For example, eradication of H. pylori reduces the risk of a complicated ulcer among NSAID users by half and prevents the rapid increase in corpus gastritis seen in H. pylori infected PPI users. H. pylori should also be suspected in all patients with uninvestigated dyspepsia.
The decision as to which tests (eg, endoscopy, PPI challenge, or diagnostic test for H. pylori) is based on the physicians judgment, cost benefit ratio and also the likelihood of H. pylori, gastric cancer, or other possible diagnoses presenting as dyspepsia.(18,19,20)
Diagnostic Tests for H. pylori
Diagnostic tests for H. pylori can be grouped as non-invasive tests including serology, urea breath test (UBT) and stool antigen; and invasive tests including endoscopy, biopsy, rapid urease test, histology and culture. (Table 3).
Non-invasive tests
Non-invasive tests can be sub classified as these that detect active infection and those that detect evidence of present or past infection. The urea breath test is based on the detection of gastric urease activity. Urease is not found in mammals and its presence in the stomach is evidence of an active H. pylori infection. H. pylori in the stomach are shed into the intestinal contents and thus pass out through the stool. Stool antigen tests are based on identifying H. pylori antigen in stool samples.
H. pylori infection is associated with a marked cellular and humoral immune response. This has led to the development of serologic tests for the presence of the infection. Only tests for anti-H. pylori IgG have proven clinically useful, thus IgM or IgA tests should not be requested. Unfortunately, serologic tests can not differentiate between active or past infection. The most common test serologic format is the enzyme-linked immunosorbent assay (ELISA) test which is generally not done in the office setting and is a ※send out§ test. However, in the office tests are available using different formats. They are technically simple to perform and the most convenient of them uses a drop of whole blood obtained by finger-prick. The results can vary significantly and have a lower sensitivity and specificity 71% and 87%, respectively (21,22,23) (Table 4). The current office based serological tests are not recommended for diagnosis as they are likely to be false-positive results if the prevalence of the disease is low.
Send out serological tests are commonly used tests in clinical practice because of their low cost and availability. The sensitivity of these tests has been reported as ranging between 90% and 97% and the specificity as between 50% and 96%. The current guidelines do not recommend using serologic tests for the primary diagnosis of H. pylori infection (15,16). Because serology can not distinguish between active infection and a past exposure to H. pylori, and antibody levels can persist for long periods of time,in the blood of individuals cured of H. pylori infection, serologic tests can not be used to evaluate if eradication therapy has been successful.
Tests for Active Infection
Urea breath tests
As noted previously, H. pylori produce urease, an enzyme that splits urea into ammonia and carbon dioxide. The urea breath test is based on the principle that urease activity is present in the stomach of individuals infected with H. pylori (24) (Figure 2). The 13C urea breath test is similar to the 14C urea breath test except that 13C is non-radioactive. and can be used safely in children and pregnant woman and there are no restriction on handling or shipping. The standard urea breath test uses 75 mg of 13C-urea and the 13C urea breath test is FDA approved for both the diagnosis of H. pylori infection and for confirmation of post treatment eradication. Patients ingest urea labelled with either 13C or 14C. Urease, if present, splits the urea into ammonia and isotope-labeled carbon dioxide. The CO2 is absorbed into the epithelial blood vessels and, within a few minutes, the isotopic CO2 appears in the breath where it can be detected (22,23).
Labeled urea is usually given to the patient with a citric acid test meal to delay gastric emptying, increase contact time with the mucosa, and increase gastric urease activity. Performance of the 13C urea breath test is simple. The patient provides a pretest breath sample in a special bag, ingests the urea solution and 15 minute later provides a second breath sample. The two breath test sample bags are then connected to the infrared spectrometer and the results are printed out in approximately 5 minutes (Figure 2). The breath samples need not be analyzed immediately as they remain stable for up to seven days. Urea breath tests have a very high sensitivity and specificity, ranging from 93% to 95% (24) (Table 4),
Stool Antigen Testing
Stool antigen testing is a relatively new methodology that uses an enzyme immunoassay to detect the presence of H. pylori antigen in stool specimens. It is a reliable means of diagnosing active infection and confirming cure with a sensitivity and specificity comparable to other noninvasive tests (22). Generally, the stool sample is sent to a reference laboratory for testing but near patient versions of stool antigen tests have been introduced in some countries. These in-the-office tests have not yet proven to have equivalent accuracy to tests done in the hospital or reference laboratory but one expects that further improvements are in the offering.
The original stool antigen tests used polyclonal detection antibodies. More recent versions have used monoclonal antibodies and have proven to be more accurate. Both polyclonal and monoclonal antibody tests are currently available but only the monoclonal antibody containing tests are recommended. Urea breath tests and stool antigen test are equally accurate in confirming H. pylori eradication.
Caveats for Non-invasive Testing
Testing for active infection using histology, culture, rapid urease testing (see below) or the urea breath test or stool antigen test require a relatively high bacterial load in the stomach. Therefore their accuracy and reliability drops among those who have had gastric surgery and those are taking proton pump inhibitors, antibiotics or bismuth compounds. The recommendation is to have an antibiotic free period of 4 weeks after antibiotic treatment when using the urea breath test to confirm eradication or to wait 6 to 8 weeks when using the stool antigen test. This recommendation is based on allowing any remaining organisms to recover and to repopulate the stomach as well as to ensure that all H. pylori antigens have been eliminated from the stool. PPI therapy should be stopped for at least 2 weeks before testing (25). H2-receptor antagonists do not affect the bacterial load such that those who require antisecretory drug therapy can be switched to an H2-receptor antagonist for several weeks prior to testing. If testing is done earlier, a positive test would be indicative of treatment failure but a negative test would not be definite evidence of treatment success.
Invasive tests: Endoscopy
Upper gastrointestinal endoscopy is an expensive procedure that carries some risks. (14) As noted above endoscopy is indicated when the likelihood of an important problem is high as evidenced by the patients history, age, or symptoms (eg, evaluation of the cause of persistent vomiting). The 2005 American Gastroenterology Association guidelines for dyspepsia recommend that patients 55 years of age or younger without alarm features should receive H. pylori test and treat followed by acid suppression if symptoms remain. Endoscopy is therefore recommended for patients older than 55 years of age and for younger patients with alarm features (e.g., weight loss, progressive dysphagia, recurrent vomiting, gastrointestinal bleeding, or family history of cancer) presenting with new-onset dyspepsia (Figure 1). Biopsies should be obtained for H. pylori at endoscopy and eradication therapy offered to those who are infected.
CHOICE OF TEST
Testing for H. pylori is clearly indicated for a wide variety of patients. The decision regarding which test and whether to do the test in the office is more complex (15), Referral for endoscopy is recommended for those with increased probability of a significant problem such as gastric cancer. For those for whom referral is not the first step, the choice of test depends on test availability and reimbursement. The choice will also depend on the population served by the physician (i.e., those serving a wealthy white population would predict a low prevalence whereas those serving a more ethnically and economically mixed population would expect the H. pylori prevalence to be relatively high). In the office testing provides the physician and patient with immediate feedback such that therapy can be instituted without delay. The 13C urea breath test can be done entirely in the office or the breath sample bags can be sent to a reference laboratory stool antigen testing is not yet recommended for in the office testing and has experienced relatively low patient acceptability. Serology , as noted above, does not a test for active infection and is not recommended for the confirmation of post treatment eradication.
The urea breath test and the stool antigen test have similar specificity and sensitivities values in the range of 93-95%. (Table 4). Follow-up testing after therapy is now the standard of practice, especially since the cure rates with current triple therapy are generally below 80%. The urea breath test and stool antigen tests both have sensitivities and specificities greater than 90% and are recommended to document that therapy has been successful and the patient has been cured.
Cost Effectiveness
A recent cost-benefit analysis evaluated single test and the sequential testing strategy using costs in the US healthcare system (26).The serology test had the lowest cost per correct diagnosis at low (30%), intermediate (60%) and high (90%) prevalence ($90每95/correct diagnosis) but its diagnostic accuracy was low (80每84%). At low and intermediate prevalence, the stool test was more accurate (93%), with an average cost of $126每127 per correct diagnosis and an incremental cost of $336每381 per additional correct diagnosis. ELISA testing was preferable when prevalence rates were very high (90%) and using a confirmatory urea breath test when the ELISA test was negative increased the diagnostic accuracy to 96% with modest incremental costs.
Summary
H. pylori is a major human pathogen and when identified should be eradicated. Generally diagnostic testing should use noninvasive tests. Office based tests such as the 13C- urea breath test offer rapid results along with high sensitivity and specificity. Accurate non-invasive tests available through reference laboratories include the 13C- urea breath test and the stool antigen test. Serology is not recommended for testing or for confirmation of H. pylori eradication. Eradication success should be confirmed with a non-invasive active test such as the stool antigen or urea breath test.
Table 1 Prevalence of H. pylori infections in the United States*
By race and ethnicity H. pylori seropositivity
Non-Hispanic white 18.4%
Non-Hispanic black 46.2%
Mexican-American 49.2%
Other Hispanic 47.1%
Birth in United States 21.9%
Birth outside United States 56.3%
*adapted from reference 4
Table 2. Recommendations for testing for Helicobacter pylori infection*
Duodenal or gastric ulcer present or history of Gastric low-grade MALT lymphoma Atrophic gastritis Relatives of gastric cancer patients After endoscopic resection of early cancer Uninvestigated dyspepsia Non-ulcer dyspepsia Chronic NSAID/aspirin therapy** Chronic antisecretory drug therapy (eg, Gastro-esophageal reflux disease)*** Relatives of patients with duodenal ulcer Relatives of patients with H. pylori infection Evaluate success of eradication therapy Patient desires to be tested _________________________________________________________________________
*All proven to have an active H. pylori infection should be treated
**When planning long term therapy,
***When planning long term anti-secretory therapy
Table 3 Diagnostic Tests for H.pylori
Non-invasive tests
Active infection tests
13 C- urea breath test
Stool antigen test
Passive tests
Serology
Antibody testing using saliva or urine
Invasive tests
Endoscopy with
Histology
Culture
Rapid Urease Testing
Table 4. Office based testing for H.pylori infection in the United States*
Office based test Sensitivity (%) Specificity (%)
Urea Breath test 95% 95%
Stool antigen test 93% 93%
Serology 87% 79%
*adapted from reference 24
Figure 1. Management of uninvestigated dyspepsia (2005 ACG practice guidelines)
Adapted from reference 15
Figure 2. Office-based 13C-urea breath testing
References
1. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;1:1311每5
2. Malaty HM, Graham DY Importance of childhood socioeconomic status on the current prevalence of Helicobacter pylori infection. Gut 1994;35:742每5
3. Malaty HM, Evans DG, Evans DJ Jr.Helicobacter pylori in Hispanics: comparison with blacks and whites of similar age and socioeconomic class. Gastroenterology 1992;103:813每6.
4. Cardenas VM, Mulla ZD, Ortiz M Iron deficiency and Helicobacter pylori infection in the United States. Am J Epidemiol 2006 163(2):127-34.
5. Go MF Crowe SE. Virulence and pathogenicity of Helicobacter pylori. Gastroenterol Clin N Amer 2000;29:649每70.
6. Sipponen P, Kekki M, Haapakoski J. Gastric cancer risk in chronic atrophic gastritis: statistical calculations of cross-sectional data. Int J Cancer 1985;35:173每7.
7. Morgner A, Bayerdorffer E, Neubauer A,.Gastric mucosa-associated lymphoid tissue lymphoma and Helicobacter pylori. Gastroenterol Clin North Am 2000;29:593每607.
8. Peek RM Jr, Thompson SA, Donahue JP Adherence to gastric epithelial cells induces expression of a Helicobacter pylori gene, iceA that is associated with clinical outcome. Proc Assoc Amer Physicians 1998;110:531每44.
9. Olden KW, Drossman DA. Psychologic and psychiatric aspects of gastrointestinal disease. Med Clin North Am 2000;84:1313每27.
10. Armstrong D. Helicobacter pylori infection and dyspepsia. Scand J Gastroenterol Suppl 1996;215:38每47.
11. Talley NJ, Vakil NB, Ballard ED 2nd, Fennerty MB. Absence of benefit of eradicating Helicobacter pylori in patients with nonulcer dyspepsia. N Engl J Med 1999; 341:1106每11.
12. Graham DY. The changing epidemiology of GERD:geography and Helicobacter pylori. Am J Gastroenterol2003;98:1462-70.
13. Graham DY. Helicobacter pylori is not and never was ※protective§ against anything, including GERD. DigDis Sci 2003;48:629-30.
14. Howden CW, Hunt RH. Guidelines for the Helicobacter pylori infection. Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. Am J Gastroenterol 1998;93:2330每8.
15. Talley NJ Practice guidelines for the management of dyspepsia. Am J Gastroenterol 2005;100:2324每2337
16 Tally NJ American Gastroenterological Association Medical Position Statement: Evaluation of Dyspepsia Gastroenterology 2005;129:1753每1755
17. Lassen, AM Pedersen FM and Bytzer J., Helicobacter pylori test and eradicate or prompt endoscopy for management of dyspeptic patients. A randomized controlled trial with one year follow up, Lancet 2000 Aug 5;356(9228):455-60.
18. Heaney A,. Collins JS, Watson RG A prospective randomized trial of a test and treat policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia referred to a hospital clinic, Gut 45 1999;45(2):186-90.
19. Talley NJ. Dyspepsia management in the millennium: The death of test and treat? Gastroenterology 2002;122(5):1521每5.
20. McNulty C, Teare L Owen R Test and treat for dyspepsia每but which test?, BMJ 2005 15;330(7483):105-6
21. CutlerAF Havstad S Ma CK Accuracy of invasive and non invasive tests to diagnose Helicobacter pylori infection, Gastroenterology 1995 Jul;109(1):136-41.
22. Monteiro L, de Mascarel A. Sarrasqueta AM Diagnosis of Helicobacter pylori infection: noninvasive methods compared to invasive methods and evaluation of two new tests, Am J Gastroenterol 2001 Feb;96(2):353-8.
23. Ricci, C Diagnosis of Helicobacter pylori: Invasive and non-invasive tests. Best Pract Res Clin Gastroenterol. 2007;21(2):299-313.
24. Graham DY, Klein PD Accurate diagnosis of Helicobacter pylori. 13C-urea breath test. Gastroenterol Clin North Am. 2000 Dec;29(4): 885-93
25. Gatta L, N. Vakil and C. Ricci Effect of proton pump inhibitors and antacid therapy on 13C-urea breath tests and stool test for Helicobacter pylori infection, Am J Gastroenterol 2004 ;99(5):823-9.
26 Vakil N, Rhew D, Soll A. The cost-effectiveness of diagnostic testing strategies for Helicobacter pylori, Am J Gastroenterol 2000;95(7):1691-8.
Mehnaz A. Shafi, M.D.
Department of Medicine, Baylor College of Medicine and Baylor Clinic, Houston, Texas
Send inquiries to:
Mehnaz A. Shafi, M.D.
Baylor Faculty Center Suite 8.37
1709 Dryden Street
Houston, Texas 77030
Tel: 713-798-0950
Fax: 713-798-0951
Email: mshafi@bcm.edu
INTRODUCTION
The discovery of Helicobacter pylori by Marshall and Warren in 1982 has lead to dramatic changes in our understanding of upper gastrointestinal diseases (1). H. pylori is now recognized as the single most common cause of peptic ulcer disease. It＊s etiological association with gastritis, gastric adenocarcinoma and gastric mucosa associated lymphoid tissue (MALT) lymphoma is also indisputable. H. pylori infects more than half the global population and has been classified as a Class 1 carcinogen. Many tests are available to diagnose the infection but questions remain about the optimal approach of whom to test, when to test and which diagnostic tests to use. This article presents a brief overview of the epidemiology and pathogenesis of H. pylori infection, its clinical manifestations as well as providing evidence based diagnostic strategy emphasizing the use of non invasive, office based diagnostic tests for H. pylori.
EPIDEMIOLOGY
H. pylori is acquired in childhood such all those who will get the infection typically have done so by age 20. The annual incidence reported in 3 adult studies in developed countries is between 0.3% and 0.5% per year which coincides with the low risk of reinfection after successful eradication therapy. Worldwide, but especially in developed nations, infection with H. pylori is declining. The risk of acquiring the infection correlates positively with a low childhood socioeconomic status and in most countries the risk is inversely related to the overall level of sanitation and specifically to household hygiene. (2) Transmission is typically within families and most often by the fecal-oral or gastro-oral routes. In the United States the infection is most common among immigrants, Afro-Americans, Asians and Hispanics and least among the upper middle class white population (3, 4) (Table 1).
PATHOGENESIS
H. pylori are gram-negative, flagellated, highly motile bacteria. Infection by H. pylori involves a complex interaction of both bacterial and host factors. The urease enzyme produced by the bacteria alters the microenvironment of the organism by breaking down urea to produce carbon dioxide and two ammonium ions which protect the bacterium from the highly acidic gastric environment and facilitate colonization. Adherence then occurs via interactions between the gastric mucosal cell surface and a variety of adhesins specific to H. pylori. (5) Once attached to gastric mucosa, H. pylori causes tissue injury by a complex cascade of events
CLINICAL MANIFESTATIONS
Gastritis and Gastric Cancer
The majority of individuals infected with H. pylori are asymptomatic. While some infected persons clear the infection, (probably because of antibiotic use for unrelated conditions) most infections are life long. Approximately 20% of infected people will subsequently develop clinically apparent disease, generally after a long latent period. As such the infection as been called gastric termites. The usual course of disease in infected patients begins with chronic superficial gastritis, which progresses to atrophic gastritis. This progression is key in the cellular cascade that results in the development of gastric carcinoma. There is a 90-fold increase in the rate of gastric carcinoma in patients with severe atrophic gastritis compared with normal controls. (6) H. pylori is associated with the development of adenocarcinoma of the antrum and body of the stomach and also with primary gastric MALT lymphomas. H. pylori stimulates a marked lymphocytic infiltration into the gastric mucosa and acts as a focus for cellular alteration and proliferation that in some may ultimately result in neoplastic transformation to lymphoma. H. pylori-associated gastric lymphoma often responds to H. pylori eradication and regression of low-grade gastric MALT lymphoma is expected in 70% to 90% of patients following H. pylori eradication (7)
Peptic Ulcer Disease
It is well established that H. pylori infection is the major cause of peptic ulcer disease. Eradicating the infection alters the natural course of peptic ulcer disease by dramatically reducing its recurrence rate such that effectively cure of the H. pylori infection results in cure of peptic ulcers. However, there are other causes of ulcer such as nonsteroidal anti-inflammatory drug use where H. pylori eradication would not be expected to influence the outcome. The mechanism by which H. pylori induces peptic ulcer disease most likely involves a combination of genetic predisposition of the host, virulence factors of the organism (e.g., the CagA virulence factor protein), mechanical damage to the mucosa, and alterations of gastric and duodenal secretions (8).
Non-ulcer Dyspepsia
Non-ulcer dyspepsia comprises a range of symptoms including ulcer-like, and reflux-like complaints. Many possible causes have been suggested, including altered visceral sensation, increased serotonin sensitivity, alterations in gastric acid secretion, abnormal gastric emptying, stress and H. pylori infection. (9) In a study linking H. pylori infection to non-ulcer dyspepsia, patients with the latter condition were twice as likely as controls to be positive for H. pylori infection. (10). Symptomatic H. pylori infection often presents as dyspepsia. At presentation this is called uninvestigated dyspepsia and as noted below, those patients are recommended to undergo testing for H. pylori infection. Dyspepsia in patients without gastroesophageal reflux disease, peptic ulcer, or gastric cancer is termed investigated non-ulcer dyspepsia or simply non-ulcer dyspepsia. Eradication of H. pylori in this group of patients will result in complete relief of symptoms in only about 10% suggesting that H. pylori infection is not a major cause of this problem.(11) However, eradication of H. pylori will still have benefits as it will result in healing of the patient＊s gastritis, prevention of subsequent development of peptic ulcer, and if done before atrophy occurs, prevention of gastric cancer as well as prevention of transmission of the infection. These positive attributes of H. pylori eradication have resulted in the universal recommendation that H. pylori be eradicated whenever it is found. However, patients with non-ulcer dyspepsia and H. pylori infection should be informed that cure of the infection may not result in cure of their symptoms.
Gastroesophageal Reflux Disease
There has been concern about a possible relation between H. pylori and gastroesophageal reflux disease. Gastroesophageal reflux disease is associated with high levels of acid secretion. Duodenal ulcer caused by H. pylori is also associated with high levels of acid secretion and therefore it is not surprising that there is a strong association between H. pylori-related duodenal ulcer and gastroesophageal reflux. In these patients eradication of the H. pylori results in cure of the ulcer and often an improvement but not an elimination of gastroesophageal reflux symptoms. In contrast, H. pylori-associated atrophic gastritis is associated with low acid secretion and therefore even those patients who have impaired gastroesophageal antireflux barriers and reflux do so with minimal or no symptoms. In these instances one can consider that H. pylori is acting as a biologic antisecretory agent. Unfortunately, those patients are also at highest risk for development of H. pylori-associated gastric cancer. Cure of the infection will reduce their cancer risk but may result in their underlying gastroesophageal reflux becoming more symptomatic.(12) Overall, in Western countries, eradication of H. pylori has no effect on the incidence or treatment of gastroesophageal reflux disease. There are now sufficient data to discount concerns about H. pylori infections as either a cause of or having a detrimental effect on gastroesophageal reflux disease. H. pylori is now recognized as a serious global human pathogen that is responsible for high morbidity and mortality worldwide. It does not confer protection from disease and whenever detected it should be eradicated.(13)
PRACTICE GUIDELINES
In 1994, a National Institutes of Health consensus conference concluded that the evidence linking H. pylori and peptic ulcer was sufficient that H. pylori infection should be eradicated in patients with peptic ulcer disease. Several gastroenterological organizations have since released more detailed guidelines for the diagnosis and treatment of dyspepsia as the understanding of the contribution of H pylori infection to gastrointestinal disease has developed.(14)
One of the key recommendations of the various guidelines has been that clinicians should use non-endoscopic tests (eg, urea breath tests or stool antigen tests) to detect H. pylori infection. (14,15,16,17). All guidelines agree that patients who test positive should receive H. pylori eradication therapy. Endoscopy should be limited to those in whom it is otherwise clinically indicated (Figure1). Prompt endoscopy is reserved for older patients and for patients with alarm features, such as persistent vomiting, bleeding, weight loss, dysphagia, and anemia. The 2005 practice guidelines of the American College of Gastroenterology recommend that dyspeptic patients over 55 years of age or those with alarm features should undergo prompt upper endoscopy.(15) In all other patients, there are two approximately equivalent options: (i) test and treat for H. pylori using a validated noninvasive test and if eradication is successful but symptoms do not resolve patients should receive a trial of acid suppression or (ii) an empiric trial of acid suppression with a proton pump inhibitor (PPI) for 4 to 8 weeks.(15,16) The test-and-treat option is preferable in populations with a moderate to high prevalence of H. pylori infection (≡10%) whereas empirical PPI therapy is an initial option in low prevalence situations. If initial acid suppression fails after 4 weeks, it is reasonable to consider changing drug class or dosing. If the patient fails to respond or relapses rapidly upon stopping antisecretory therapy, then the test-and-treat strategy is best applied before referral for upper gastrointestinal endoscopy. The decision to endoscope and when as always must be based on the physician＊s clinical judgment. In patients who respond to initial PPI therapy, treatment is stopped after 4 to 8 weeks; if symptoms recur, another course of the same treatment may be justified.(15)
WHOM TO TEST FOR H. PYLORI
Definite indications for testing for H. pylori include peptic ulcer disease, gastric or duodenal, acute or prior diagnosis, with or without NSAID use, the presence of gastric MALT lymphoma and family history of gastric cancer (Table 2). Other indications relate to prevention of disease. For example, eradication of H. pylori reduces the risk of a complicated ulcer among NSAID users by half and prevents the rapid increase in corpus gastritis seen in H. pylori infected PPI users. H. pylori should also be suspected in all patients with uninvestigated dyspepsia.
The decision as to which tests (eg, endoscopy, PPI challenge, or diagnostic test for H. pylori) is based on the physicians judgment, cost benefit ratio and also the likelihood of H. pylori, gastric cancer, or other possible diagnoses presenting as dyspepsia.(18,19,20)
Diagnostic Tests for H. pylori
Diagnostic tests for H. pylori can be grouped as non-invasive tests including serology, urea breath test (UBT) and stool antigen; and invasive tests including endoscopy, biopsy, rapid urease test, histology and culture. (Table 3).
Non-invasive tests
Non-invasive tests can be sub classified as these that detect active infection and those that detect evidence of present or past infection. The urea breath test is based on the detection of gastric urease activity. Urease is not found in mammals and its presence in the stomach is evidence of an active H. pylori infection. H. pylori in the stomach are shed into the intestinal contents and thus pass out through the stool. Stool antigen tests are based on identifying H. pylori antigen in stool samples.
H. pylori infection is associated with a marked cellular and humoral immune response. This has led to the development of serologic tests for the presence of the infection. Only tests for anti-H. pylori IgG have proven clinically useful, thus IgM or IgA tests should not be requested. Unfortunately, serologic tests can not differentiate between active or past infection. The most common test serologic format is the enzyme-linked immunosorbent assay (ELISA) test which is generally not done in the office setting and is a ※send out§ test. However, in the office tests are available using different formats. They are technically simple to perform and the most convenient of them uses a drop of whole blood obtained by finger-prick. The results can vary significantly and have a lower sensitivity and specificity 71% and 87%, respectively (21,22,23) (Table 4). The current office based serological tests are not recommended for diagnosis as they are likely to be false-positive results if the prevalence of the disease is low.
Send out serological tests are commonly used tests in clinical practice because of their low cost and availability. The sensitivity of these tests has been reported as ranging between 90% and 97% and the specificity as between 50% and 96%. The current guidelines do not recommend using serologic tests for the primary diagnosis of H. pylori infection (15,16). Because serology can not distinguish between active infection and a past exposure to H. pylori, and antibody levels can persist for long periods of time,in the blood of individuals cured of H. pylori infection, serologic tests can not be used to evaluate if eradication therapy has been successful.
Tests for Active Infection
Urea breath tests
As noted previously, H. pylori produce urease, an enzyme that splits urea into ammonia and carbon dioxide. The urea breath test is based on the principle that urease activity is present in the stomach of individuals infected with H. pylori (24) (Figure 2). The 13C urea breath test is similar to the 14C urea breath test except that 13C is non-radioactive. and can be used safely in children and pregnant woman and there are no restriction on handling or shipping. The standard urea breath test uses 75 mg of 13C-urea and the 13C urea breath test is FDA approved for both the diagnosis of H. pylori infection and for confirmation of post treatment eradication. Patients ingest urea labelled with either 13C or 14C. Urease, if present, splits the urea into ammonia and isotope-labeled carbon dioxide. The CO2 is absorbed into the epithelial blood vessels and, within a few minutes, the isotopic CO2 appears in the breath where it can be detected (22,23).
Labeled urea is usually given to the patient with a citric acid test meal to delay gastric emptying, increase contact time with the mucosa, and increase gastric urease activity. Performance of the 13C urea breath test is simple. The patient provides a pretest breath sample in a special bag, ingests the urea solution and 15 minute later provides a second breath sample. The two breath test sample bags are then connected to the infrared spectrometer and the results are printed out in approximately 5 minutes (Figure 2). The breath samples need not be analyzed immediately as they remain stable for up to seven days. Urea breath tests have a very high sensitivity and specificity, ranging from 93% to 95% (24) (Table 4),
Stool Antigen Testing
Stool antigen testing is a relatively new methodology that uses an enzyme immunoassay to detect the presence of H. pylori antigen in stool specimens. It is a reliable means of diagnosing active infection and confirming cure with a sensitivity and specificity comparable to other noninvasive tests (22). Generally, the stool sample is sent to a reference laboratory for testing but near patient versions of stool antigen tests have been introduced in some countries. These in-the-office tests have not yet proven to have equivalent accuracy to tests done in the hospital or reference laboratory but one expects that further improvements are in the offering.
The original stool antigen tests used polyclonal detection antibodies. More recent versions have used monoclonal antibodies and have proven to be more accurate. Both polyclonal and monoclonal antibody tests are currently available but only the monoclonal antibody containing tests are recommended. Urea breath tests and stool antigen test are equally accurate in confirming H. pylori eradication.
Caveats for Non-invasive Testing
Testing for active infection using histology, culture, rapid urease testing (see below) or the urea breath test or stool antigen test require a relatively high bacterial load in the stomach. Therefore their accuracy and reliability drops among those who have had gastric surgery and those are taking proton pump inhibitors, antibiotics or bismuth compounds. The recommendation is to have an antibiotic free period of 4 weeks after antibiotic treatment when using the urea breath test to confirm eradication or to wait 6 to 8 weeks when using the stool antigen test. This recommendation is based on allowing any remaining organisms to recover and to repopulate the stomach as well as to ensure that all H. pylori antigens have been eliminated from the stool. PPI therapy should be stopped for at least 2 weeks before testing (25). H2-receptor antagonists do not affect the bacterial load such that those who require antisecretory drug therapy can be switched to an H2-receptor antagonist for several weeks prior to testing. If testing is done earlier, a positive test would be indicative of treatment failure but a negative test would not be definite evidence of treatment success.
Invasive tests: Endoscopy
Upper gastrointestinal endoscopy is an expensive procedure that carries some risks. (14) As noted above endoscopy is indicated when the likelihood of an important problem is high as evidenced by the patients history, age, or symptoms (eg, evaluation of the cause of persistent vomiting). The 2005 American Gastroenterology Association guidelines for dyspepsia recommend that patients 55 years of age or younger without alarm features should receive H. pylori test and treat followed by acid suppression if symptoms remain. Endoscopy is therefore recommended for patients older than 55 years of age and for younger patients with alarm features (e.g., weight loss, progressive dysphagia, recurrent vomiting, gastrointestinal bleeding, or family history of cancer) presenting with new-onset dyspepsia (Figure 1). Biopsies should be obtained for H. pylori at endoscopy and eradication therapy offered to those who are infected.
CHOICE OF TEST
Testing for H. pylori is clearly indicated for a wide variety of patients. The decision regarding which test and whether to do the test in the office is more complex (15), Referral for endoscopy is recommended for those with increased probability of a significant problem such as gastric cancer. For those for whom referral is not the first step, the choice of test depends on test availability and reimbursement. The choice will also depend on the population served by the physician (i.e., those serving a wealthy white population would predict a low prevalence whereas those serving a more ethnically and economically mixed population would expect the H. pylori prevalence to be relatively high). In the office testing provides the physician and patient with immediate feedback such that therapy can be instituted without delay. The 13C urea breath test can be done entirely in the office or the breath sample bags can be sent to a reference laboratory stool antigen testing is not yet recommended for in the office testing and has experienced relatively low patient acceptability. Serology , as noted above, does not a test for active infection and is not recommended for the confirmation of post treatment eradication.
The urea breath test and the stool antigen test have similar specificity and sensitivities values in the range of 93-95%. (Table 4). Follow-up testing after therapy is now the standard of practice, especially since the cure rates with current triple therapy are generally below 80%. The urea breath test and stool antigen tests both have sensitivities and specificities greater than 90% and are recommended to document that therapy has been successful and the patient has been cured.
Cost Effectiveness
A recent cost-benefit analysis evaluated single test and the sequential testing strategy using costs in the US healthcare system (26).The serology test had the lowest cost per correct diagnosis at low (30%), intermediate (60%) and high (90%) prevalence ($90每95/correct diagnosis) but its diagnostic accuracy was low (80每84%). At low and intermediate prevalence, the stool test was more accurate (93%), with an average cost of $126每127 per correct diagnosis and an incremental cost of $336每381 per additional correct diagnosis. ELISA testing was preferable when prevalence rates were very high (90%) and using a confirmatory urea breath test when the ELISA test was negative increased the diagnostic accuracy to 96% with modest incremental costs.
Summary
H. pylori is a major human pathogen and when identified should be eradicated. Generally diagnostic testing should use noninvasive tests. Office based tests such as the 13C- urea breath test offer rapid results along with high sensitivity and specificity. Accurate non-invasive tests available through reference laboratories include the 13C- urea breath test and the stool antigen test. Serology is not recommended for testing or for confirmation of H. pylori eradication. Eradication success should be confirmed with a non-invasive active test such as the stool antigen or urea breath test.
Table 1 Prevalence of H. pylori infections in the United States*
By race and ethnicity H. pylori seropositivity
Non-Hispanic white 18.4%
Non-Hispanic black 46.2%
Mexican-American 49.2%
Other Hispanic 47.1%
Birth in United States 21.9%
Birth outside United States 56.3%
*adapted from reference 4
Table 2. Recommendations for testing for Helicobacter pylori infection*
Duodenal or gastric ulcer present or history of Gastric low-grade MALT lymphoma Atrophic gastritis Relatives of gastric cancer patients After endoscopic resection of early cancer Uninvestigated dyspepsia Non-ulcer dyspepsia Chronic NSAID/aspirin therapy** Chronic antisecretory drug therapy (eg, Gastro-esophageal reflux disease)*** Relatives of patients with duodenal ulcer Relatives of patients with H. pylori infection Evaluate success of eradication therapy Patient desires to be tested _________________________________________________________________________
*All proven to have an active H. pylori infection should be treated
**When planning long term therapy,
***When planning long term anti-secretory therapy
Table 3 Diagnostic Tests for H.pylori
Non-invasive tests
Active infection tests
13 C- urea breath test
Stool antigen test
Passive tests
Serology
Antibody testing using saliva or urine
Invasive tests
Endoscopy with
Histology
Culture
Rapid Urease Testing
Table 4. Office based testing for H.pylori infection in the United States*
Office based test Sensitivity (%) Specificity (%)
Urea Breath test 95% 95%
Stool antigen test 93% 93%
Serology 87% 79%
*adapted from reference 24
Figure 1. Management of uninvestigated dyspepsia (2005 ACG practice guidelines)
Adapted from reference 15
Figure 2. Office-based 13C-urea breath testing
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