Diagnosing and managing H. pylori infections.

Helicobacter pylori is the most common bacterial infection found in man. The bacterium appears as a spiral or curved, motile, gram-negative rod (1.5-10 [[micro]meter] in length) that is strongly urease positive. In the lab, it can be grown on a blood-containing medium (especially horse blood) in a moist atmosphere of reduced oxygen (5-10%) and increased carbon dioxide (5-12 %). In vivo, it thrives in the acidic environment of the stomach, living beneath the mucous layer covering the gastric mucosa. The large amount of urease secreted by H. pylori splits urea into ammonia and carbon dioxide, producing a more alkaline environment for growth. Although transmission may occur from dogs or cats to humans, humans are the primary source for the infection, with transmission from one person to another occurring by either the oral-oral or fecal-oral route.

The prevalence of H. pylori is highest in Third World countries, especially in areas with poor sanitation and an inadequate water supply. However, the bacteria can also be found in industrialized countries. In the U.S., infection rates vary from less than 20% in suburban communities to almost 60% in certain urban areas. This article reviews the clinical conditions associated with H. pylori, the various diagnostic testing options, and treatment strategies.

Associated conditions

H. pylori has been strongly associated with gastritis, duodenal ulcers, gastric ulcers, and both gastric adenocarcinoma and gastric lymphoma.[1] Nearly all patients who have gastritis and whose histologic specimens show simultaneous active and chronic infiltrates are infected with H. pylori. It should be pointed out, however, that while the bacterial infection predictably induces gastritis, it doesn't necessarily imply a definitive etiology for complaints of abdominal pain.

From 80-90% of duodenal ulcers are caused by H. pylori, even in cases where the person is taking an nonsteroidal anti-inflammatory drug (NSAID) regularly. It's been convincingly demonstrated that curing the infection will reduce duodenal ulcer recurrence from approximately 75% to 5 % after 1 year.[2]

Gastric ulcers are associated with H. pylori in 60% to more than 80% of cases, depending on the frequency of NSAID use. Here it has also been shown that eradicating the infection markedly reduces ulcer recurrence and complicated ulcer disease.[3]

The association of H. pylori with gastric malignancy is strong, with reports of infection in 85-95% of cases. While preventing gastric malignancy through treatment of H. pylori is theoretically appealing, it's uncertain if this would affect the cancer incidence. Clinical studies designed to evaluate the relationship between H. pylori and gastric malignancy are underway in several countries, but the results won't be available for many years. The choice to wait for the results of these studies or to implement a diagnose-and-treat strategy for the U.S. population, or even a specific ethnic subpopulation, is the subject of much debate.

The association between H. pylori and nonulcer dyspepsia is controversial. Nonulcer dyspepsia is a poorly defined clinical entity that encompasses a heterogeneous population with no evidence of mucosal disease on visualization of the upper GI tract. There are undoubtedly subgroups of nonulcer dyspepsia patients who would benefit from treatment of H. pylori, but so far no one has been able to identify them.

Many researchers have chosen instead to evaluate H. pylori therapy within the dyspeptic population as a whole. This group would include the 10-15% of the population with undiagnosed gastroduodenal ulcer disease and some patients with nonulcer dyspepsia who would respond to treatment. Within this population, it was recently demonstrated that H. pylori treatment in seropositive patients would be economically beneficial.[4]

Diagnosing H. pylori infection

Many highly accurate diagnostic tests have been developed to establish whether a patient is infected with H. pylori.[5] They fall into 2 major categories: noninvasive/nonendoscopic and invasive/endoscopic tests (see Table 1).[6] Endoscopic tests are performed on biopsy material obtained during visualization of the stomach through an endoscope. Diagnostic tests that don't require endoscopy include fecal antigen detection, various methods of antibody detection, and carbon-labeled urea breath tests. Those that involve endoscopy are the rapid urease tests, histology, and culture.

Most initial H. pylori diagnoses are made by detecting antibodies to the bacteria. As a chronic infection, H. pylori elicits both local and systemic immune responses leading to the production of antibodies in blood, saliva, and urine. The detection of IgG antibodies to H. pylori in blood is the most common way to establish the presence of infection.[7] These antibodies can be measured in serum, plasma, or whole blood and can be reported as qualitative or quantitative results. In the physician's office laboratory, serum can be tested in a qualitative immunoassay kit such as Quidel's QuickVue, SmithKline Diagnostics' (Collegeville, PA) FlexSure, or Abbott Diagnostic's (Abbott Park, IL) FlexPack at a cost of $10 to $40. The results are available in 47 minutes and are read as a color change or line formation, similar to pregnancy test kits. Whole blood or serum samples are generally evaluated using separated serum in an enzyme-linked immunosorbent assay (ELISA), and quantitative results are reported. The accuracy of immunoassays and ELISAs is comparable, with recently reported sensitivity in the low- to mid-90s and specificity from the upper 70s to 80s.[8]

Table 1

Accuracy of tests used to diagnose H. pylori

Diagnostic test                  Sensitivity (%)     Specificity (%)

Noninvasive/nonendoscopic tests

Fecal antigen test                    90                  95

Antibody detection

ELISA                                 94                  78
Serum immunoassay                     89                  74
Whole blood immunoassay               83                  75
Urea breath test                      90                  96

Invasive/endoscopic tests

Rapid urease tests                   88-90               95-100
Histology                             93                  99
Culture                              80-95               100

The enzyme immunoassay for detecting H. pylori antigen in stool (fresh or frozen) uses polyclonal antibodies to H. pylori, costs approximately $50 to $100, and results are obtained within 2 hours. This test has not been evaluated for monitoring the efficacy of therapy.

Problem with fingerstick tests

Serum, plasma, or whole blood Samples can be used with the newest office kits for H. pylori antibody detection. Whole blood can be obtained by venipuncture or fingerstick. The results of serum, plasma, and venipuncture whole blood tests appear to be as accurate as other serum-based H. pylori antibody tests. However, tests performed on fingerstick whole blood specimens have not been as accurate.[8] This may simply be because of the various steps involved in obtaining an adequate fingerstick sample. The reasonable accuracy, rapid turnaround time, low cost, and CLIA waivers for most office-based test systems make them ideal screening tests for the primary care clinic.

Just as circulating antibodies are expected to remain detectable after routine childhood vaccinations, H. pylori antibodies can be measured in 65% of successfully treated, bacteria-free patients at 2,460 months after therapy. There is a detectable decline in antibody titers after the bacteria is eradicated, and some researchers have used serial quantitative antibody testing to confirm H. pylori cure.[9] The fall in titers, however, can't be measured until 46 months after therapy, so the baseline serum must be stored to run it concurrently with the convalescent serum. Isolated convalescent ELISA values should not be used to determine infection status because assay runs vary, and it's not clear if comparison to historical values yields accurate results.

Qualitative antibody tests, such as the serum and whole blood assays, can't be used to assess infection status after treatment for H. pylori. Also, detection of H. pylori antibodies in saliva and urine has been evaluated and found to be inferior to serologic testing in adults.

Urea breath tests

Helicobacter priori produces the enzyme urease, which converts gastric urea to ammonia, creating a unique, less acidic microenvironment for the bacteria. Because humans can't manufacture urease themselves, detecting the enzyme in the stomach indirectly tests for H. pylori infection.[10] Urea breath tests, using urea bound to either the heavy isotope 13C or radioactive 14C, detect H. pylori by the activity of bacterial urease.

For this test, the patient ingests the labeled carbon-urea solution. If urea is present in the stomach, the labeled carbon will be liberated as carbon dioxide, absorbed into the bloodstream, and diffused into the lungs. The patient's exhaled breath is captured 20-30 minutes later. If 13C was used, a mass spectrometer analyzes the breath and calculates the amount of 13C; if 14C was used, a scintillation counter performs this calculation.

Altogether, it takes about 30-40 minutes to perform a urea breath test. The patient's breath can't be collected too soon because urease-containing mouth flora will produce false-positive results in the first 5-10 minutes after carbon-urea ingestion.

These tests are highly accurate in establishing H. pylori infection status, both in the initial diagnosis and after treatment (see Table 1).[11] However, because they require a measurable amount of urease activity, medications that inhibit enzyme activity or reduce gastric bacterial counts can produce false-negative tests.[12] Treatment with any antibacterial, bismuth-containing compound, or proton pump inhibitor should be discontinued at least 1 week before administering a urea breath test. Confirmation of H. pylori eradication can't be established until at least 4 weeks after completion of antibacterial therapy.

Both the 13C and 14C urea breath tests have been approved by the Food and Drug Administration and are commercially marketed. The issue of third-party reimbursement has restricted widespread use of the test. Although it's difficult to recommend routine use of breath tests over serum antibody tests in the untreated patient, urea breath tests should be the test of choice to confirm H. pylori eradication in patients with complicated ulcers and in those with recurrent symptoms after treatment.

Table 2

Test selection for diagnosing H. pylori

Clinical condition                  Recommended test

History of gastroduodenal ulcer     Antibody/fecal antigen detection

New-onset dyspepsia

age [greater than] 50               Antibody/fecal antigen detection
age [greater than or equal to] 50   Endoscopic evaluation
alarm symptoms (at any age)         Endoscopic evaluation

Evaluation at endoscopy             Rapid urease test [+ or -]
                                    antibody/fecal antigen detection

Mucosal abnormalities               Histologic evaluation
requiring biopsies

Post-treatment

Uncomplicated duodenal ulcer        Test with recurrent symptoms (as
                                    above)

Dyspepsia                           Test with recurrent symptoms (as
                                    above)

Recurrent symptoms                  Urea breath test or endoscopy
                                    with biopsies

Complicated ulcer                   Confirm bacterial eradication by
                                    urea breath test or serial
                                    quantitative serology or
                                    endoscopy with biopsies

Gastric ulcer                       Histologic evaluation at
                                    follow-up endoscopy

Rapid urease tests

Based on the same principle as the urea breath test, rapid urease tests detect the presence of bacterial urease in gastric mucosal biopsies.[13] Each of the 3 commercially available kits (CLOtest, Ballard Medical Products, Draper, UT; Hpfast, GI Supply, Camp Hill, PA; and PyloriTek, Serim Research Corp., Elkhart, IN) contains urea and a pH-sensitive marker. Upper endoscopy is used to collect 1 or more gastric tissue specimens, which are placed into the rapid urease kit. If H. pylori is present in the mucosal biopsy, then urease will be present and will convert the urea in the kit to ammonia, causing a color change in the pH-sensitive marker.

Rapid urease tests are highly accurate. However, as with urea breath tests, their accuracy depends on the presence of adequate numbers of H. priori with functionally active urease. Test sensitivity, therefore, can also be affected by recent ingestion of an antibacterial, bismuth-containing compound, or proton pump inhibitor. In these cases, negative rapid urease test results should be confirmed with an antibody test.

Histologic evaluation and culture

Helicobacter priori is widely but unevenly distributed throughout the gastric mucosa.[14] Two gastric antral biopsies with routine staining (H&E) should be sufficient for most experienced pathologists to establish a patient's infection status. Diagnosis of H. prior/infection is based on the morphologic features of the organism and its appropriate location within the gastric mucous layer, as well as associated chronic active gastritis.

No stain, either routine or special, is specific for H. pylori bacteria. Expensive, special stains should not be requested in most cases. However, patients who have recently taken an antibacterial, bismuth-containing compound, or a proton pump inhibitor and those with gastric atrophy may have fewer bacteria and a more patchy distribution. In these cases, using a special stain to help identify the bacteria is probably warranted. The Diff-Quik (Scientific Products, McGraw Park, IL), modified Giemsa, Genta (H&E, Steiner silver, and Alcian blue combined), and Warthin-Starry stains have been used on these occasions. (manufacturers?) These stains can improve the sensitivity of the histological examination for H. pylori, but ultimately the sensitivity is dependent on the density of the organism and the experience of the pathologist.

Culture, of course, is the traditional method of diagnosing an infectious agent. While this test would precisely identify H. pylori bacteria and allow detection of antibiotic resistance, its expense and clinical difficulty has limited its application. There are a few centers in the U.S. that perform cultures of gastric tissue specimens. Culture, however, is generally reserved for research protocols or for cases where treatment has failed and antibiotic resistance is suspected.

Benefits of testing and treating

Depending on the patient's history and presentation, the benefits of testing and treatment for H. pylori run the gamut from definitive to nonexistent.[15]

Definitive benefit. Treating H. pylori-positive duodenal and gastric ulcers produces a definitive benefit and is considered the standard of care. Furthermore, successful bacterial cure almost completely eliminates the risk of recurrent bleeding from gastric or duodenal ulcers. Even in patients who take NSAIDs, H. pylori infection should be considered an important independent risk factor for ulcer recurrence and should therefore be treated.

Probable benefit. As noted earlier, H. pylori has been associated with both gastric adenocarcinoma and gastric lymphoma.[16] It's probably beneficial to treat H. pylori in patients with early gastric mucosa-associated lymphoid tissue (MALT) lymphoma and in those rare patients who have undergone early gastric cancer resection.[17] Most other lymphomas would not respond to H. pylori treatment, nor would gastric adenocarcinoma.

We haven't reached the point where all patients should be routinely screened and treated for H. pylori infection to prevent the development of gastric malignancy. However, it may be beneficial to screen population subgroups in the United States who have emigrated from regions of the world known to have high rates of gastric malignancy as well as those individuals with family histories of gastric malignancy.

Uncertain or no benefit. Of uncertain benefit is H. pylori treatment for symptomatic nonulcer dyspepsia patients in whom upper GI endoscopy has revealed minimal or no mucosal defects. Finally, identifying and treating H. pylori in asymptomatic individuals, except possibly for the subgroups mentioned above, would be of no benefit at all.

Which test is right for the patient

In testing for H. pylori infection, it is necessary to find out whether the patient has been previously treated for the infection as well as the accuracy of the test. Any special clinical circumstances that may affect test results, such as treatment with an antibacterial, a bismuth-containing compound, or a proton pump inhibitor, must also be taken into account.

An antibody test would be appropriate for a previously untreated patient with a documented history of gastroduodenal ulcer disease and unknown H. pylori-infection status (see Table 2). It would also be indicated in a young dyspeptic patient (younger than 50 years old) for whom an empiric trial of H. pylori therapy is being considered. Patients older than 50 with new-onset dyspepsia require early upper-GI endoscopy to exclude malignancy and complicated ulcer. The same test should be conducted for a patient of any age with alarm symptoms such as nausea, emesis, iron-deficiency anemia, early satiety, unexplained weight loss, hematemesis, or melena.

A rapid urease test may be performed during upper endoscopy to evaluate a patient's H. pylori infection status. Positive tests should be accepted as accurate without further confirmation. Negative tests may require follow-up serum antibody or fecal antigen testing, especially in cases where the probability of bacterial infection is high (for example, in the presence of known gastric or duodenal ulcers).

Patients undergoing upper endoscopy in whom mucosal abnormalities, including gastric ulcers, are found will have biopsies taken for histologic evaluation. In these cases, tissue samples could also be obtained away from the area of obvious deformity to evaluate for H. pylori without significant additional expense.

It's not necessary to confirm H. pylori eradication in most patients who have undergone antimicrobial therapy. To do so would incur an unreasonable expense. The infection status of patients with an uncomplicated duodenal ulcer or dyspepsia can be reevaluated after treatment if their symptoms recur, using a urea breath test or repeat endoscopy.

Patients with complicated ulcers (those that have bled, perforated, or become obstructed) should have posttreatment bacterial eradication confirmed by a urea breath test, serial serology, or upper endoscopy with rapid urease testing and/or histology. Detection of a gastric ulcer generally requires repeat endoscopy to confirm that the ulcer has healed. If H. pylori therapy is initiated soon after the ulcer is detected, then the patient's infection status can be reassessed at the follow-up endoscopy.

How to treat H. pylori

Antimicrobial therapy for H. pylori requires at least 2 drugs; at least 1 has to be an antibiotic.[18] In general, therapy is built around a nitroimidazole (such as metronidazole) or a macrolide (such as clarithromycin). Some treatment regimens, however, combine both types of agents.

Several 2- and 3-drug combinations have been approved by the FDA for H. pylori eradication with concomitant healing of an active duodenal ulcer. The approved indications are for 14 days of combination antibiotic therapy followed by another 14 days of antisecretory treatment.

The combination of lansoprazole, amoxicillin, and clarithromycin was recently approved by the FDA for 14-day therapy for H. pylori eradication alone, without regard to duodenal ulcer healing, and there are a number of therapies for H. pylori presently undergoing clinical evaluation or FDA review. Further approvals should be forthcoming. Bacterial reinfection after successful therapy is uncommon in industrialized countries; in the United States, the incidence is less than 1% per year.[19]

The issue of antibiotic resistance is important in deciding on a treatment regimen for a patient. But the notion that failed therapy may induce widespread H. pylori resistance in the community is mistaken, because the rate of bacterial transmission from one person to another is so low. In fact, most cases of H. pylori antibiotic resistance are due to exposure to drugs that were given to treat infections other than H. pylori.

Major challenge

In the realm of infectious disease, H. pylori presents the primary care physician with a major clinical challenge. Detecting and eradicating the infection is particularly important in patients who have active or historical gastroduodenal ulcer disease. Understanding the various diagnostic tests and treatment regimens available for H. pylori will help you provide clinicians with information on this common infection with skill and confidence.

CONTINUING EDUCATION

To earn CEUs, see test on page 30.

LEARNING OBJECTIVES:

1. Describe the epidemiology and pathogenesis of Helicobacter pylori.

2. Identify 3 clinical conditions associated with H. pylori infection.

3. Compare and contrast 4 diagnostic testing options for H. pylori infection.

4. Describe 1 treatment regimen for H. pylori infection.

References

1. Howden CH: Clinical expressions of Helicobacter pylori infection. Am J Med. 1996; 100(5A): 27S.

2. Hunt RH: Eradication of Helicobacter pylori infection. Am J Med. 1996; 100(5A):42S.

3. Vaira D, Menegatti M, Miglioli M: What is the role of Helicobacter pylori in complicated ulcer disease? Gastroenterology. 1997;113(6 Suppl):S78.

4. Ofman JJ, Etchason J, Fullerton S, et al: Management strategies for Helicobacter pylori-seropositive patients with dyspepsia: Clinical and economic consequences. Ann Intern Med. 1997; 126(4):280.

5. Cutler AF: Testing for Helicobacter pylori in clinical practice. Am J Med 1996; 100(5A):35S.

6. Cutler AF, Havstad S, Ma CK, et al: Accuracy of invasive and noninvasive tests to diagnosis Helicobacter pylori infection. Gastroenterology. 1995;109(1):136.

7. Brown KE, Peura DA: Diagnosis of Helicobacter pylori infection. Gastroenterol Clin North Am 1993;22(1):105.

8. Sadowski D, Cohen H, Laine L, et al: Evaluation of the FlexSure HP fingerstick blood test for the detection of H. pylori infection. Gastroenterology. 1996; 110(4):A246.

9. Prasad VM, Santogade P, Cutler AF: Helicobacter pylori serology following successful eradication: Four year follow-up. Gut. 1995; 37:A45

10. Mobley HL: Defining Helicobacter pylori as a pathogen: strain heterogeneity and virulence. Am J Med. 1996; 100(5A):2S.

11. Klein PD, Malaty HM, Martin RF, et al: Noninvasive detection of Helicobacter pylori infection in clinical practice: The 13C urea breath test. Am J Gastroenterol. 1996;91(4):690.

12. Chey WD, Spybrook M, Carpenter S, et al: Prolonged effect of omeprazole on the 14C-urea breath test. Am J Gastroenterol. 1996;91(1):89.

13. Laine L, Lewin D, Naritoku W, et al: Prospective comparison of commercially available rapid urease tests for the diagnosis of Helicobacter pylori. Gastrointest Endosc. 1996;44(5):523.

14. Genta RM, Graham DY: Comparison of biopsy sites for the histopathologic diagnosis of Helicobacter pylori: A topographic study of H. pylori density and distribution. Gastrointest Endosc. 1994;40(3):342.

15. NIH Consensus conference: Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. JAMA. 1994;272(1):65.

16. Asaka M, Takeda H, Sugiyama T, et al: What role does Helicobacter pylori play in gastric cancer? Gastroenterology. 1997; 113(6 Suppl):S56.

17. Thiede C, Morgner A, Alpen B, et al: What role does Helicobacter pylori eradication play in gastric MALT and gastric MALT lymphoma? Gastroenterology. 1997; 113 (6 Suppl):S61.

18. Walsh JH, Peterson WL: The treatment of Helicobacter pylori infection in the management of peptic ulcer disease. N Engl J Med. 1995;333(15):984.

19. Abu-Mahfouz MZ, Prasad VM, Santogade P, et al: Helicobacter pylori recurrence after successful eradication: 5-year follow-up in the United States. Am J Gastroenterol. 1997;92(11):2025.

Alan F. Cutler is director of research, department of medicine, and associate director, laboratory of clinical immunology, Sinai Hospital, and assistant professor of medicine, Wayne State University, Detroit, MI.