American Journal of Gastroenterology 2007

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American Journal of Gastroenterology 2007

American Journal of Gastroenterology ? 2007 by ISSN 0002-9270 doi: Am. Coll. of Gastroenterology Published by 10.1111/j.1572-0241.2007.01393.x Blackwell Publishing

    American College of Gastroenterology Guideline on the

    Management of Helicobacter pylori Infection

    12William D. Chey, M.D., F.A.C.G., A.G.A.F., F.A.C.P., Benjamin C.Y. Wong, M.D., Ph.D., F.A.C.G., F.A.C.P., and the

    Practice Parameters Committee of the American College of Gastroenterology 12 University of Michigan Medical Center, Ann Arbor, Michigan; and Department of Medicine, University of Hong

    Kong, Hong Kong

    Helicobacter pylori (H. pylori) remains a prevalent, worldwide, chronic infection. Though the prevalence of this infection appears to be decreasing in many parts of the world, H. pylori remains an important factor linked to the development of peptic ulcer disease, gastric malignanc and dyspeptic symptoms. Whether to test for H. pylori in patients with functional dyspepsia, gastroesophageal reflux disease (GERD), patients taking nonsteroidal antiinflammatory drugs, with iron deficiency anemia, or who are at greater risk of developing gastric cancer remains controversial. H. pylori can be diagnosed by endoscopic or nonendoscopic methods. A variety of factors including the need for endoscopy, pretest probability of infection, local availability, and an understanding of the performance characteristics and cost of the individual tests influences choice of evaluation in a given patient. Testing to prove eradication should be performed in patients who receive treatment of H. pylori for peptic ulcer disease, individuals with persistent dyspeptic symptoms despite the test-and-treat strategy, those with H. pylori-associated MALT lymphoma, and individuals who have undergone resection of early gastric cancer. Recent studies suggest that eradication rates achieved by first-line treatment with a proton pump inhibitor (PPI), clarithromycin, and amoxicillin have decreased to 70-85%, in part due to increasing clarithromycin resistance. Eradication rates may also be lower with 7 versus 14-day regimens. Bismuth-containing quadruple regimens for 7-14 days are another first-line treatment option. Sequential therapy for 10 days has shown promise in Europe but requires validation in North America. The most commonly used salvage regimen in patients with persistent H. pylori is bismuth quadruple therapy. Recent data suggest that a PPI, levofloxacin, and amoxicillin for 10 days is more effective and better tolerated than bismuth quadruple therapy for persistent H. pylori infection, though this needs to be validated in the United States.

    (Am J Gastroenterol 2007;102:1808-1825)

    ican College of Gastroenterology have produced this updated

    management guideline to assist clinicians caring for patients with Helicobacter pylori (H. pylori) remains one of the most common

    H. pylori infection. To accomplish this task, literature searches worldwide human infections and is associated with a number of

    using Medline, PubMed, and the Cochrane Database were important upper gastrointestinal (GI) conditions including chronic

    performed as part of the preparation for this management gastritis, peptic ulcer disease, and gastric malignancy. The

    guideline. The document makes summary recommendations prevalence of H. pylori is closely tied to socioeconomic conditions

    (italicized statements) followed by a more detailed description of and accordingly, this infection is more common in developing

    the supporting evidence and rationale for arriving at the topline countries than in developed countries such as the United States (1).

    recommendation. As with all guidelines, this document attempts to Regardless, it has been estimated that 30-40% of the U.S.

    provide the preferred, but not the only, means by which to population is infected with H. pylori (2). The vast majority of

    diagnose and treat H. pylori infection. Specific issues, which may individuals acquire this infection during childhood. Based upon

    or may not be discussed in this document, will always influence the this observation and the fact that H. pylori infection rates in

    best course of action to be taken in an individual patient. children are decreasing, it is likely that the population-based

    prevalence of H. pylori in the United States will continue to fall in

    the coming years.

    Guidelines for the management of H. pylori infection were last

    published by the American College of Gastroenterol- ogy in 1998

    Recommendation(3). Since that time, a significant amount of new information

    • Testing for H. pylori infection is indicated in patients with active regarding the management of this infection has become available.

    peptic ulcer disease, a past history of documented peptic ulcer, Because of this, the authors, Practice Parameters Committee, and

    Governing Board of the Amer- or gastric MALT lymphoma.

    • The test-and-treat strategy for H. pylori infection is a proven pylori eradication reduces the recurrence of PUD and is cost- management strategy for patients with uninvestigated dyspepsia effective (6).

    who are under the age of 55 yr and have no "alarm features "

    (bleeding, anemia, early satiety, unexplained weight loss, GASTRODUODENAL BLEEDING. Sharma and colleagues progressive dysphagia, odynophagia, recurrent vomiting, performed a meta-analysis to compare the effectiveness of family history of GI cancer, previous esophagogastric eradicating H. pylori infection with other approaches to prevent malignancy). recurrent ulcer hemorrhage as well as a cost minimization analysis

    to determine the least costly strategy. They found that H. pylori Although the majority of those infected remain clinically silent, treatment decreased recurrent bleeding by 17% and 4% compared there are a number of well-established clinical conditions that have with ulcer healing treatment alone (bismuth 120 mg q.i.d to ulcer been associated with H. pylori infection. The indications for the healing, ranitidine 300 mg q.h.s. for 16 wk or omeprazole 20 mg diagnosis and treatment of H. pylori infection are listed in Table 1. q.d. for 2 wk) or ulcer healing treatment followed by maintenance

    therapy (raniti- dine 150-300 mg q.h.s. or omeprazole 20 mg q.d. DUODENAL AND GASTRIC ULCER. There is a clear link for 1224 months), respectively (7). A 5-yr prospective, randomized, between H. pylori infection and the pathogenesis of peptic ulcer controlled study by Liu et al. in 82 Taiwanese patients with a disease (PUD) (4). Given the overwhelming evidence supporting history of ulcer bleeding demonstrated that maintenance acid this relationship, few would question the clinical and economic suppression was not routinely necessary to prevent ulcer merits of H. pylori eradication in a patient with PUD. A recurrence after successful H. pylori eradication and ulcer healing meta-analysis including 24 randomized controlled trials and (8). Results from these studies have been confirmed by a recent randomized comparative trials including 2,102 patients with PUD Cochrane systematic review (9) revealed that the 12-month ulcer remission rate was 97% (95% CI

    95-99%) for gastric ulcer, and 98% (95% CI 97-99%) for duodenal Gastric MALT Lymphomaulcer in patients successfully eradicated of H. pylori infection, A growing body of literature from nonrandomized observational compared with 61% (95% CI 52-70%) for gastric ulcer and 65% trials supports the importance of H. pylori infection in the (95% CI 5065%) for duodenal ulcer in those with persistent pathogenesis and natural history of mucosa associated lymphoid infection (5). Recently, a meta-analysis by Ford et al., including 52 tissue (MALT) lymphoma (10, 11). For localized gastric MALT trials, demonstrated that H. pylori eradication therapy yielded lymphoma, H. pylori treatment achieves tumor regression in superior healing rates for duodenal ulcer but not gastric ulcer 60-90% of patients (11). Several recent prospective studies have compared with short courses of ulcer healing medications such as addressed the long-term outcome of gastric MALT lymphoma histamine-2 receptor antagoinists (H2RAs) or proton pump after eradication of H. pylori infection. These reports suggest that inhibitors (PPIs). This study found that H. pylori eradication was H. pylori eradication provides durable remission in patients with superior to no treatment in preventing duodenal and gastric ulcer low-grade MALT lym- phoma with recurrence rates of 3-13% over recurrence. H. pylori eradication was also superior to maintenance 5 yr of follow- up (12-14). Finally, Chen and colleagues evaluated therapy with acid suppressive medications in preventing gastric a trial of 24 patients with high-grade transformed tumors (diffuse ulcer but not duodenal ulcer recurrence (6). In a Markov model large B-cell with features of MALT, DLBCL [MALT] lymphoma). analysis, H. pylori eradication was cost-effective for duodenal H. pylori eradication led to complete remission in 64% (95% CI ulcer over 1 yr and gastric ulcer over 2 yr. The authors concluded 42-86%) (14). Amongst patients with complete remission that H. following H. pylori cure, relapse rates were 0% for high-grade

    MALT lymphoma after a median follow-up of more than 5 yr. This

    is one of the first studies to suggest that H. pylori eradication may

    offer a treatment option not only for low grade MALToma but also

    for early-stage H. pylori-positive gastric DLBCL (MALT).

     Indications for Diagnosis and Treatment of H. pylori Uninvestigated DyspepsiaEstablished The test-and-treat strategy provides an evidence-based man- Active peptic ulcer disease (gastric or duodenal ulcer) agement strategy for patients with uninvestigated dyspepsia who Confirmed history of peptic ulcer disease (not previously are under the age of 55 yr and have no alarm features. For a treated for H. pylori) detailed discussion of the role of H. pylori eradication in the Gastric MALT lymphoma (low grade) After endoscopic resection of early gastric cancer management of uninvestigated dyspepsia, the reader is referred to Uninvestigated dyspepsia (depending upon H. pylori the American College of Gastroenterology's recently published prevalence) Practice Guideline on the Management of Dyspepsia (15). Controversial Nonulcer dyspepsia Gastroesophageal reflux disease Persons using nonsteroidal antiinflammatory drugs Unexplained iron deficiency anemia Populations at higher risk for gastric cancer

Gastroesophageal Reflux Disease (GERD)

    Despite a large number of studies that have addressed this issue, the relationship between H. pylori infection and GERD remains incompletely defined. It is known that H. pylori infection results in There is evidence to suggest that a small but significant different levels of severity and patterns of gastric inflammation in subgroup of patients with functional dyspepsia will experience different individuals. This in turn can lead to varied effects on clinical benefit following H. pylori eradication. gastric acid secretion. For example, it has been proposed that There is no clear evidence to support that eradicating H. pylori patients with antral predominant gastritis, the phenotype most consistently worsens or improves GERD symptoms. Treatment commonly encountered in the United States, exhibit increased acid of H. pylori should not be withheld related to concerns secretion and are at increased risk of developing duodenal ulcer. ofcreating or worsening GERD. On the other hand, those with corpus-predominant or pangastritis H. pylori and NSAIDs are independent risk factors for the tend toward decreased acid secretion and a greater risk of development of PUD. Therefore, regardless of whether or not a developing gastric cancer (30). As such, eradication of this patient is taking an NSAID, all patients with a peptic ulcer infection can be associated with a wide spectrum of effects on should be tested and when infected, treated for H. pylori. gastric acid secretion. Whether a patient has abnormal lower The available data support an association between H. pylori esophageal sphincter function or esophageal clearance mech-infection and iron deficiency but do not prove cause and effect. anisms, which would predispose to a greater risk of GERD, Though there is some evidence to suggest that curing H. pylori undoubtedly also affects outcomes. In this way, one can envision may prevent progression of intestinal metaplasia to gastric scenarios where eradication of H. pylori infection could be adenocarcinoma, there is no definitive population- based data associated with worsening, no change, or improvement in GERD. to suggest that H. pylori eradication reduces the incidence of A recent study found that antral predominant gastritis was the most gastric adenocarcinoma. Pursuing H. pylori in patients at common H. pylori associated phenotype in functional dyspepsia increased risk for gastric cancer should be individualized patients from western countries and that eradication therapy in this taking into consideration co- morbid illness, which might have subgroup of patients led to overall improvements in heartburn and bearing on the benefits offered by treatment, and patient regurgitation at 1 yr of follow-up (31). preferences. Some investigators have suggested that H. pylori status is inversely related to the likelihood of suffering with GERD (32). Functional Dyspepsia (FD)Unfortunately, the heterogeneity of the available data makes it Whether eradicating H. pylori infection is of clinical and economic difficult to arrive at a confident conclusion on this matter. A recent benefit in patients with dyspeptic symptoms who have undergone a systematic review pointed out that geographical location of the negative structural evaluation remains controversial. Whereas studies contributes to the confusion, as GERD patients from the some studies observed a beneficial effect (16-19), others have Far East tended to have a lower prevalence of H. pylori than failed to confirm such benefits (20-24). The most recent patients from Europe or North America (33). meta-analyses and systematic reviews have reported that Regarding the issue of whether eradication of H. pylori infection eradication of H. pylori infection offers a small but statistically may provoke or worsen GERD, a recent systematic review by significant clinical benefit (therapeutic gain of H. pylori Raghunath et al. including 27 studies concluded that the available eradication over placebo = 8%, NNT = 15, RRof remaining evidence does not support an association between H. pylori symptomatic 0.91 [95% CI 0.86-0.95]) and may be cost-effective eradication and the development of reflux esophagitis or in FD (25, 26). worsening of heartburn in patients with a duodenal ulcer (34). Eradicating H. pylori in patients with FD may offer benefits Perhaps more relevant to North America, Laine and colleagues beyond symptom improvement. Studies have reported that peptic performed a post hoc analysis of 8 double-blind, prospective U.S. ulcers develop in 1 -14% of patients with FD when followed over trials of H. pylori therapy for patients with active DU or a history of extended periods (16,27-29). Aplacebo- controlled study from DU to quantify the development of GERD symptoms in patients Taiwan found that H. pylori eradication reduced the 1 yr incidence without a prior history of symptomatic GERD or esophagitis (35). of peptic ulcer in patients with ulcer-like functional dyspepsia but They assessed whether GERD symptoms worsened in patients not in those with dysmotility-like or unclassifiable FD (28). No with prior symptomatic GERD. Their analysis found no difference such data from the United States are currently available. in the likelihood of developing new GERD symptoms or With these thoughts in mind, the decision of whether to test for esophagitis in individuals cured of H. pylori infection compared to and treat H. pylori in FD should be individualized taking into those with persistent infection. Further, they found that H. pylori consideration patient concerns as well as the presence of risk eradication was not associated with a worsening of symptoms in factors for PUD (age, NSAID use) (29) and gastric malignancy those with preexisting GERD. Recent evidence from (ethnic background, family history of gastric malignancy).

    North America and Europe suggests that esophageal acid exposure, P = 0.005). On the other hand, there is evidence to suggest that the severity of erosive esophagitis, and efficacy of proton pump recurrent ulcer bleeding in persons using low-dose aspirin is inhibitor therapy is similar in GERD patients with and without H. similar 6 months after H. pylori eradication or with PPI therapy (6 pylori infection (36-38). month rate of recurrent bleeding 1.9% for H. pylori therapy vs There is no clear evidence to support that a test-and-treat 0.9% for PPI therapy, P = NS) (46). For patients with a history of strategy for H. pylori consistently worsens or improves GERD an ulcer complication who require subsequent therapy with an symptoms. Therefore, it is reasonable to conclude that therapy for NSAID or aspirin, H. pylori eradication alone may not be a H. pylori should not be withheld related to concerns of creating or sufficient risk reduction strategy. Co-therapy with a PPI in such worsening GERD. patients at high risk for recurrence of an ulcer complication has

    been recommended (44).

    Persons Using Nonsteroidal Antiinflammatory Drugs Iron Deficiency Anemia(NSAIDs) or AspirinA number of studies have suggested a potential association The interaction between H. pylori infection and NSAIDs in the between unexplained iron deficiency anemia and H. pylori pathogenesis of PUD remains controversial. Studies attempting to infection. The explanation most commonly offered for this clarify this interaction have yielded conflicting results (39-44). relationship is based upon the development of H. pylori- associated The discordant results can, in part, be explained by differences in chronic pangastritis with resultant achlorhydria and reduced study methodology, outcome measures, definitions of ulcer, and ascorbic acid secretion leading to reduced intestinal iron patient populations. It is also important to realize that there may be absorption. Other potential explanations for an association differences in clinical outcomes based upon whether a patient has between iron deficiency and H. pylori include occult blood loss or has not previously taken NSAIDs and whether one is from erosive gastritis and sequestration and utilization of iron by contemplating primary or secondary prophylaxis (40). the organism (47). From a practical standpoint, the clinician is interested in Recent large studies from North America have reported H. knowing whether testing for and treating H. pylori in patients pylori infection was an independent risk factor for iron deficiency taking an NSAID will reduce the risk of developing ulcers or more anemia in 688 school-aged children from Alaska (48) and 7,462 importantly, ulcer complications. A meta- analysis, which children, adolescents, and adults from the United States (49). In the included data from 25 observational studies, demonstrated that study by Cardenas and colleagues, H. pylori infection was both H. pylori infection and nonse- lective NSAID use are associated with an increased risk of iron deficiency anemia (OR independent risk factors for the development of peptic ulcer and 2.6, 95% CI 1.5-4.6). There is emerging evidence to suggest that ulcer bleeding. Moreover, this meta-analysis also suggested that eradication of H. pylori can improve iron deficiency anemia (50-52) these risk factors are at least additive and possibly synergistic for though this remains controversial. A recent unblinded study in 219 the development of peptic ulcer and ulcer bleeding (41). In another H. pylori- infected children (7-11 yr) with pretreatment iron recent meta-analysis of five studies including 939 patients, H. py-deficiency from Alaska found no difference in the likelihood of lori eradication was associated with a reduced incidence of peptic iron deficiency or anemia at 2 months or 14 months following a ulcer in patients taking NSAIDs (OR 0.43, 95% CI 0.20-0.93). 6-wk course of oral iron and antibiotics or no antibiotics (53). Subanalyses demonstrated that risk reduction was evident in The available data support an association between H. pylori NSAID-na'ive individuals (OR 0.26,95% CI 0.14-0.49) but not for infection and iron deficiency but do not prove cause and effect. those previously taking NSAIDs (OR 0.95, 95% CI 0.53-1.72) (42). Further properly designed, adequately powered randomized trials While H. pylori eradication may reduce the risk of PUD, it does are needed to assess whether H. pylori eradication offers benefit to not eliminate the risk of ulcer development or complications in patients with unexplained iron deficiency anemia. those using an NSAID.

    At present, it seems reasonable to recommend that any patient Prevention of Gastric Cancerwith an ulcer should be tested for H. pylori regardless of whether Whether curing H. pylori infection can reduce the risk of or not he/she is taking an NSAID or aspirin (44). There are some developing gastric adenocarcinoma remains unknown (54). data to support the identification and treatment of H. pylori in However, there have been a number of recent studies that have NSAID-na'ive patients who are to be treated with an NSAID (45). evaluated the effect of H. pylori eradication on surrogate outcomes To date, similar data demonstrating the utility of H. pylori such as the severity and distribution of gastritis and gastric eradication in aspirin-naive patients starting aspirin are not preneoplastic lesions (multifocal atrophic gastritis, intestinal available. In patients already taking an NSAID, H. pylori metaplasia, or dysplasia) (55-58). In a randomized, eradication appears to be less effective than PPI therapy in placebo-controlled trial, Leung et al. followed 435 H. reducing the risk of peptic ulcer recurrence or ulcer bleeding (6 pylori-infected patients for 5 yr after a course of anti-H. pylori month rate of recurrent bleeding 18.8% for H. pylori therapy vs therapy or placebo. In a multiple logistic regression analysis, 4.4% for PPI therapy,

    they observed that persistent H. pylori infection (OR 2.13, 95% CI populations (58). No such evidence is available from regions of the 1.41-3.24), age >45 yr (OR 1.92, 95% CI 1.183.11), alcohol world where gastric cancer is rare, such as the United States. consumption (OR 1.67, 95% CI 1.07-2.62), and drinking local well A recent international working group reviewed the literature water (OR 1.74, 95% CI 1.13-2.67) were independent risk factors addressing this topic. The majority of the scientific task force associated with intestinal metaplasia progression. They concluded favored testing and treating H. pylori in first-degree relatives of that H. pylori eradication was protective against progression of gastric cancer patients. The task force also endorsed the evaluation premalignant gastric lesions in their Chinese population study (55). of the chemopreventive benefits for gastric malignancy with a In a study from Columbia, 795 adults with preneoplastic gastric more general screen and treat strategy in populations with a high lesions were randomized to anti-H. pylori therapy or antioxidants incidence of H. pylori-associated diseases (54). and were followed with serial endoscopies over 12 yr. Multivariate

    analysis revealed a significant regression in histopathology score

    as a function of the square of time without H. pylori infection.

    Further, patients treated for H. pylori were 13.7% less likely to Testing for H. pylori should only be performed if the clinician experience progression of preneoplastic gastric lesions (57). Wong plans to offer treatment for positive results. et al. recruited 1,630 asymptomatic H. pylori-infected subjects in a Deciding which test to use in which situation relies heavily upon high-risk region of China, and randomly allocated them to H. whether a patient requires evaluation with upper endoscopy pylori therapy or placebo, after which they were followed for 7.5 yr. and an understanding of the strengths, weaknesses, and costs of They reported that gastric cancer developed in 18 cases. There was the individual tests. an absolute reduction in gastric cancer incidence in subjects who The methods of diagnostic testing for H. pylori can be divided received H. pylori eradication therapy when compared with into those that do and those that do not require en- doscopy. Table placebo, which was not statistically significant (37% reduction, P = 2 provides a list of the available diagnostic tests for H. pylori. 0.33). However, in a subgroup of H. pylori carriers without There is no single test that can be considered the gold standard for precancerous lesions at index endoscopy, the incidence of gastric the diagnosis of H. pylori. Rather, the most appropriate test for any cancer was significantly lower in subjects receiving eradication specific situation will be influenced by the clinical circumstances, therapy than in those receiving placebo (P = 0.02). This study the pretest probability of infection, as well as the availability and supports the possibility that H. pylori eradication may reduce the costs of the individual diagnostic tests. risk of developing gastric cancer in individuals without

    precancerous lesions from high-risk

     Diagnostic Testing for Helicobacter pylori

    Endoscopic Testing Advantages Disadvantages

    * 1. Histology Excellent sensitivity and specificity Expensive and requires infrastructure and trained personnel *2. Rapid urease testing Inexpensive and provides rapid results. Excellent Sensitivity significantly reduced in the specificity and very good sensitivity in properly posttreatment setting selected patients *3. Culture Excellent specificity. Allows determination of Expensive, difficult to perform, and not widely antibiotic sensitivities available. Only marginal sensitivity *4. Polymerase chain reaction Excellent sensitivity and specificity. Allows Methodology not standardized across determination of antibiotic sensitivities laboratories and not widely available Nonendoscopic Testing Advantages Disadvantages 1. Antibody testing (quantitative and qualitative)

    Inexpensive, widely available, very good NPV PPV dependent upon background H. pylori *2. Urea breath tests (prevalence. Not recommended after H. pylori 1314therapy C and Reimbursement and availability remain Identifies active H. pylori infection. Excellent PPV and C) NPV regardless of H. pylori prevalence. Useful before inconsistent and after H. pylori therapy Identifies active H. pylori infection. Excellent positive and negative predictive *values regardless of H. pylori prevalence. Useful before 3. Fecal antigen test Polyclonal test less well validated than the UBT in and after H. pylori therapy the posttreatment setting. Monoclonal test appears reliable before and after antibiotic therapy. Unpleasantness associated with collecting stool *The sensitivity of all endoscopic and nonendoscopic tests that identify active H. pylori infection is reduced by the recent use of PPIs, bismuth, or antibiotics PPI = proton pump inhibitor; PPV = positive predictive value; NPV = negative predictive value; UBT = urea breath test.

    been performed to define the duration of a PPI's deleterious effects Endoscopic Diagnostic Tests

    on the sensitivity of the RUT. Data with the urea breath test (UBT) In patients who have not been on a PPI within 1-2 wk or an

    antibiotic or bismuth within 4 wk of endoscopy, the rapid urease suggest that PPI therapy can cause false-negative test results for

    1-2 wk (68, 69). As the UBT and RUT rely upon the identification test (RUT) provides an accurate, inexpensive means

    of H. pylori's urease activity, it is reasonable to suggest that PPIs ofidentifying H. pylori.

     For patients who have been taking a PPI, antibiotics, or bismuth, should be withheld for 1-2 wk before performance of the RUT. In

    situations where a patient has not taken a PPI for a period of 1-2 wk endoscopic testing for H. pylori should include biopsies from

    the gastric body and antrum for histology with or without rapid before their procedure, the sensitivity of the RUT is likely

    sufficient to justify its use as a single test for H. pylori. urease testing.

     Though culture or polymerase chain reaction (PCR) are the

    primary means by which antibiotic sensitivities can be Histologydetermined, neither is widely available for clinical use in the Histology has been considered by some to be the gold standard for United States and therefore, cannot be routinely recommended. detection of H. pylori (70). Unfortunately, histology is an imperfect

    gold standard as the detection of H. pylori relies upon a number of There are presently four biopsy-based diagnostic methods for H. issues including the site, number, and size of gastric biopsies, pylori infection. These include the RUT, histology, culture, and method of staining, and the level of experience of the examining PCR. pathologist (70). A significant advantage of histology over other

    diagnostic methods is the ability to evaluate for pathologic changes Rapid Urease Testingassociated with H. pylori infection such as inflammation, atrophy, The RUT identifies active H. pylori infection through the or-intestinal metaplasia, and malignancy (71). In fact, some have ganism's urease activity. Gastric biopsies are obtained and placed argued that type B chronic gastritis (nonatrophic diffuse antral into an agar gel or on a reaction strip containing urea, a buffer, and gastritis or atrophic pangastritis) can be used as a surrogate marker a pH-sensitive indicator. In the presence of H. pylori's urease, urea for the infection when organisms are not identified (72). Certainly is metabolized to ammonia and bicarbonate leading to a pH the absence of chronic gastritis is a potent negative predictor for the increase in the microenvironment of the organism. A change in presence of H. pylori infection. color of the pH sensitive indicator signifies the presence of active As the prevalence and density of H. pylori varies throughout the infection. Commercially available kits yield results in 1 -24 h. stomach, particularly in the face of medications that may reduce There are a number of commercially available RUT kits in the the density of H. pylori, multiple biopsies are needed for accurate United States including the CLOtest, HpFast, HUT-test, Pronto diagnosis. It is therefore recommended that a minimum of three Dry, and Pyloritek with overall pretreatment sensitivities of >90% biopsies be obtained, one from the anglularis, one from the greater and specificities of >95% (59, 60). Though the overall performance curvature of the corpus, and one from the greater curvature of the of the different tests is comparable, there are some practical antrum, to maximize the diagnostic yield of histology (70). A differences between the individual tests (61). recent study found that the addition of corpus biopsies to antral Medications that reduce the density and/or urease activity of H. biopsies increased the detection of H. pylori infection by ~10% pylori, such as bismuth-containing compounds, antibiotics, or PPIs, when compared with antral biopsies alone (73). Similar to the RUT, can decrease the sensitivity of the RUT by up to 25% (59). Though the sensitivity of histology is significantly affected by the use of controversial, acute ulcer bleeding at the time of testing may medications such as bismuth, antibiotics, and PPIs (67). Although decrease the sensitivity and negative predictive value of the RUT widely available and capable of achieving sensitivity and (62-66). As a result of the patchy distribution of H. pylori infection specificity of >95%, the cost and need for properly trained after antibiotics or PPIs, it is recommended that biopsies for the personnel are limitations of histology in clinical practice. RUT be obtained from two sites, the body at the gastric anglularis

    and greater curvature of the antrum (67). The simplicity, low cost,

    Cultureand relatively rapid results make the RUT a practical and cost-

    Culture is another highly specific method for identifying active H. effective means of testing for H. pylori in patients not taking

    pylori infection. Conceptually, culture is attractive because it not antibiotics, bismuth, or PPIs who require upper endoscopy.

    only provides a means by which to identify infection, but also Unfortunately, the usefulness of the RUT in routine clinical

    allows characterization of antimicrobial sensitivities (74). practice has been compromised by the widespread use of PPIs as

    Unfortunately, culture is not as sensitive as RUT or histology (75, an empiric treatment for upper GI symptoms. As such, the RUT

    76). Furthermore, culturing techniques for H. pylori are demanding can rarely be used as a sole means of identifying H. pylori infection.

    and costly and as a consequence, only available in a limited More commonly, the RUT is combined with other endoscopic or

    number of clinical laboratories. Nonculture-based means of nonendoscopic modalities to establish the presence or absence of

    determining antibiotic this infection. No studies have

     Effect of H. pylori prevalence on the positive predictive value resistance are being developed but have not been adequately (PPV) of antibody testing (where sensitivity = 85% and specificity = 79%) standardized and are not widely available. (144). Polymerase Chain Reaction

    PCR is a DNA amplification technique that utilizes the rapid (83) . Three of the qualitative whole blood antibody kits were production of multiple copies of a target DNA sequence to identify directly compared in another study demonstrating sensitivities H. pylori. This testing method is highly specific and may be more ranging from 76% to 84% and specificities of 79-90% sensitive than other biopsy-based diagnostic techniques. A recent (84) . In general, performance characteristics for the quali-study found that PCR was able to detect H. pylori in approximately tative office-based tests have been more variable than those yielded 20% of gastric biopsies with chronic gastritis but no identifiable by the quantitative tests. It is very important to understand that the organisms by histology (77). PCR also provides a means of PPV of antibody testing is greatly influenced by the prevalence of identifying mutations associated with antimicrobial resistance H. pylori infection (85) (Fig. 1). This issue will be further (78-80). Although presently restricted to the research arena, this discussed in the section addressing the use of diagnostic testing in method may some day provide a practical, reproducible method for clinical practice. Further, antibody tests developed using antigens antibiotic sensitivity testing, organism typing, and organism from one region of the world may not perform well when applied to virulence testing (81). patients in another part of the world suggesting that local validation

    may be necessary (75, 86). Finally, antibody tests are of little Nonendoscopic Diagnostic Testsbenefit in documenting eradication as results can remain positive Antibody testing is inexpensive and widely available but for years following successful cure of the infection (82). poorPPVin populations with a low prevalence of H. pylori infection limits its usefulness in clinical practice. Urea Breath Tests The UBTs and fecal antigen tests provide reliable means of The UBT, like the RUT, identifies active H. pylori infection by identifying active H. pylori infection before antibiotic therapy. way of the organism's urease activity. In the presence of H. pylori, The UBT is the most reliable nonendoscopic test to document the ingestion of urea, labeled with either the non- radioactive eradication of H. pylori infection. 1314isotope C or the radioactive isotope C, results in production of The monclonal fecal antigen test provides another nonen-labeled CO2, which can be quantitated in expired breath (87-90). doscopic means of establishing H. pylori cure after antibiotic 14Although the amount of radiation in the C UBT is less than daily treatment. 13background radiation exposure (88), the C test is preferred in Testing to prove H. pylori eradication appears to be most children and pregnant females (87). Overall, the performance accurate if performed at least 4 wk after the completion of characteristics ofboth tests are similar with sensitivity and antibiotic therapy. specificity typically exceeding 95% in most studies (87, 88). Test

    reproducibility has been found to be excellent (89). The UBT also There are currently three nonendoscopic diagnostic testing

    provides an accurate means of posttreatment testing (90-93). Most methods for H. pylori infection. Antibody testing identifies an

    tests utilize a citrate test meal (50-75 mg), which is administered immunological reaction to the infection while the nonendo- scopic

    before the labeled urea (87). A urease blood test, which relies upon urease tests and fecal antigen test identify the presence of active H.

    the detection of labeled bicarbonate in a blood sample, also reliably pylori infection.

    identifies active H. pylori infection before and after treatment (94,

    95). As the nonendoscopic urease tests rely upon the identification Antibody Tests

    of H. pylori's robust urease activity, test sensitivity is decreased by Antibody testing relies upon the detection of IgG antibodies

    medications that reduce organism density or urease activity, specific to H. pylori in serum, whole blood, or urine. IgG an-

    including bismuth containing compounds, antibiotics, and PPIs. It tibodies to H. pylori typically become present approximately 21

    is currently recommended that bismuth and antibiotics be withheld days after infection and can remain present long after eradication

    for at least 28 days and a PPI for 7-14 days prior to the UBT (68, (82). Antibodies to H. pylori can be quantitatively assessed using

    enzyme-linked immunosorbent assay (ELISA) and latex

    agglutination techniques or qualitatively assessed using

    office-based kits. The advantages of the antibody tests are their

    low cost, widespread availability, and rapid results. Unfortunately,

    several factors limit the usefulness of antibody testing in clinical

    practice. A meta-analysis evaluated the performance

    characteristics of several commercially available quantitative

    serological assays and found their overall sensitivity and specificity to be 85% and 79%, respectively, with no differences

    between the different assays

     Performance Characteristics of the Fecal Antigen Test (95) When testing for H. pylori in populations with a low pretest # Studies / Sensitivity Specificity PPV NPprobability of infection, the FAT provides greater accuracy than # Patients V serologic testing with only a modest increase in incremental costs Pretreatment (107). Similar to the UBT, the sensitivity of the FAT is affected by

    the recent use of bismuth compounds, antibiotics, and PPIs (108, Polyclonol 89/10,858 91 93 92 87 109). Recent studies also suggest that the specificity of the FAT is Monoclonol 8/1,399 96 97 96 97 Posttreatment reduced in the setting of bleeding PUD and, for this reason, should Polyclonol 39/3,147 86 92 76 93 not be the sole diagnostic test employed in this setting (110-113). Monoclonol 6/418 95 97 91 98 Although the FAT is simple to administer and perform, issues

    PPV = positive predictive value; NPV = negative predictive value. slowing its widespread use include the unpleasantness of handling

    and storing stool, limited availability, and variable state-to- state

    reimbursement. The development of in-office stool tests is under 69, 96). It is controversial whether HRAs affect the sensitivity of 2way and may improve upon some of the practical limitations of the the UBT (97-99) though many laboratories recommend currently available tests (102). At present, in-office tests have not withholding these drugs for 24-48 h before the UBT. Antacids do

    been adequately validated in clinical trials. not appear to affect the accuracy of the UBT (100). Aside from the

    Based upon the available data, it is reasonable to conclude that issues just discussed, other factors affecting the acceptance of the the FAT can be used interchangeably with the UBT to identify H. UBT in clinical practice include the need for infrastructure to

    pylori before antibiotic therapy. The polyclonal FAT has been less perform the test, the need for a patient to attend an additional well validated than the UBT in the post- treatment setting. outpatient visit to undergo the test, and cost. At current levels of

    Compared with the polyclonal test, the monoclonal FAT appears to reimbursement in the United States, the UBT is more costly than

    provide a more reliable means of proving H. pylori eradication. the antibody tests or fecal antigen test. The expense of the UBT is

    largely driven by equipment costs and the cost of labeled urea. 13UBTs using lower dose C, which have recently been found to

    yield excellent performance characteristics, may in part address Testing When There Is a Need for Endoscopythis issue (101). If endoscopy is necessary based upon the patient's clinical

    presentation, biopsy-based endoscopic tests are most appropriate. Fecal Antigen TestProvided the patient has not been on recent bismuth, antibiotics, or The fecal antigen test (FAT) identifies H. pylori antigen in the a PPI, the RUT offers the desirable combination of accuracy and stool by enzyme immunoassay with the use of polyclonal anti-H. low cost. If there are mucosal abnormalities identified at the time pylori antibody. Recently, a stool test utilizing a monoclonal of endoscopy, which require further his- tologic evaluation, anti-H pylori antibody has been evaluated (102,103). As both tests biopsies should be obtained for histology. Unfortunately, most detect bacterial antigen(s) suggestive of ongoing infection, they patients referred for upper endoscopy are taking acid-suppressive can be used to screen for infection and as a means of establishing agents such as a PPI or HRA or have recently received drugs that 2cure following therapy. A recent systematic review (102) reported can suppress H. pylori (antibiotics or bismuth). In such patients, it performance characteristics of the FAT before and after is appropriate to obtain biopsies for histology with or without RUT eradication therapy (Table 3). While this analysis demonstrated or plan testing with a UBT or FAT at a later date after withholding excellent sensitivity, specificity, positive and negative predictive the offending agents for an appropriate period of time. values for the polyclonal test before treatment, sensitivity and PPV In the setting of an active ulcer bleed, there are case series and were less satisfactory after treatment. On the other hand, the cohort studies that suggest that the sensitivity of the RUT and, to a monoclonal test yielded sensitivity, specificity, and predictive lesser extent, histology may be reduced (62, 63, 114, 115). These values greater than 90% before and after treatment. The precise studies suggest that although positive results reliably identify the explanations for the differences in accuracy between the poly- presence of H. pylori infection, the likelihood of false-negative clonal and monoclonal tests remain unclear but may have to do results may be increased in the setting of acute upper with the need for intraperitoneal injection of H. pylori antigens gastrointestinal bleeding. A recent prospective cohort study from into rabbits to produce antibodies for the polyclonal assay (102). the United States did not confirm findings from previous studies The FAT has been approved by the U.S. Food and Drug (65). In this study, 61 patients with variceal hemorrhage underwent Administration and endorsed by the European "Maastricht 2-2000 biopsy-based H. pylori testing during an initial endoscopy for acute Consensus Report" as an alternative means of establishing H. bleeding and again 1 month later. The sensitivities of RUT and pylori cure to urea breath testing (104). Recent studies indicate that histology performed during acute bleeding and 1 month later were the FAT may be effective in confirming eradication as early as 14 not significantly different. However, it is notable that days after treatment (105, 106). However, there is evidence to

    suggest that the FAT should be done more than 4 wk and perhaps

    as long as 8-12 wk after treatment of H. pylori (102).

    the sensitivity of the RUT in this study was relatively low at both Any patient with an H. pylori-associated ulcer. time points (initial RUT = 79%, follow-up RUT = 71%). Individuals with persistent dyspeptic symptoms despite the

    Regardless of which results one chooses to believe, it is important test-and-treat strategy. to emphasize that a positive RUT indicates the presence of active H. Those with H. pylori-associated MALT lymphoma. pylori infection. On the other hand, a negative RUT and/or Individuals who have undergone resection of early gastric

    histology in the setting of acute upper GI bleeding should be cancer.

    confirmed with another test. An antibody test provides a When confirmation of eradication is necessary, testing should reasonably sensitive nonendoscopic testing option. In this setting, generally be performed no sooner than 4 wk after the completion because the pretest probability of H. pylori infection is high in a of treatment. Because of its high cost, endoscopic tests should only patient with an ulcer, the PPV of an antibody test is reasonably be used if endoscopy is clinically indicated for other reasons. If high (Fig. 1). Alternatively, a patient can undergo a UBT or FAT at testing to prove eradication were performed in the setting of a later date after withholding medications that can negatively affect endoscopy, most would advocate using histology or the the sensitivity of these tests for an appropriate period of time. combination of histology and RUT as RUT alone has reduced Recent work suggests that engaging in such a practice significantly sensitivity in the posttreat- ment setting (119). When endoscopic increases the detection of H. pylori infection in patients with recent follow-up is unnecessary, testing to prove eradication of H. pylori ulcer bleeding. Arecent retrospective study from Spain found that infection is best accomplished with the UBT. The FAT provides an 57 of 72 (79%) patients with ulcer bleeding and no evidence of H. alternative means of establishing eradication though, as has pylori on emergency endoscopy had a positive "delayed" UBT already been discussed, the timing and reliability of this test have (116). not been as clearly demonstrated as for the UBT. Because antibody

    tests can remain positive for prolonged periods following Testing in Patients With Uninvestigated Dyspepsiasuccessful cure of H. pylori infection, they should be avoided in Primary care providers are frequently asked to evaluate and treat the posttreatment setting. If antibody testing is performed in the patients with uninvestigated dyspepsia. The test- and-treat strategy posttreatment setting, only a negative result is reliable. A positive for H. pylori has been endorsed for the management of result should be confirmed with a UBT or FAT before offering uninvestigated dyspepsia by a number of organizations, including antibiotic therapy for presumed persistent infection. the American Gastroenterological Association (117) and the

    American College of Gastroenterology (15). For a detailed

    discussion regarding H. pylori testing in patients with

    uninvestigated dyspepsia, the reader is referred to these recent

    Primary Treatment of H. pylori Infectionpublications (15, 117). Both documents emphasize that in regions

     In the United States, the recommended primary therapies for H. where the prevalence of H. pylori infection is high, such as urban

    pylori infection include: a PPI, clarithromycin, and amoxicillin, areas or communities with large immigrant populations, the PPV

    or metronidazole (clarithromycin-based triple therapy) for 14 of antibody testing is reasonably good and therefore provides an

    days or a PPI or HRA, bismuth, metronidazole, and acceptable means of screening for H. pylori infection. However, in 2

    tetracycline (bismuth quadruple therapy) for 10-14 days. regions where H. pylori prevalence is low, the PPV of antibody

     Sequential therapy consisting of a PPI and amoxicillin for 5 testing is poor (85). From a pragmatic standpoint, this means that if

    days followed by a PPI, clarithromycin, and tinidazole for an a physician practices in a community with an H. pylori prevalence

    additional 5 days may provide an alternative to of less than ~20%, as is the case in much of the United States,

    clarithromycin-based triple or bismuth quadruple therapy but though a negative antibody test suggests the absence of infection, a

    requires validation within the United States before it can be positive test is no better than a coin toss in predicting the presence

    recommended as a first-line therapy. of active infection (Fig. 1). As such, in low prevalence populations,

    The first course of therapy offers the greatest likelihood of antibody tests should be avoided altogether or positive results

    eradicating H. pylori infection. Subsequent treatment trials, should be confirmed with a test that identifies active infection such

    particularly if the same antibiotics are utilized or if the patient has as the UBT or FAT prior to initiating eradication therapy (117,

    been previously exposed to any antibiotics contained in the 118).

    treatment regimen, are less likely to achieve a successful outcome. Testing to Prove Eradication After Antibiotic TherapyAs such, it is important to only use treatment regimens for which In an ideal world, all patients treated for H. pylori infection would there is evidence of proven effectiveness (120). undergo testing to prove eradication of the infection. Unfortunately, In the United States, the recommended primary therapies for H. universal posttreatment testing is neither practical nor pylori infection include: a PPI, clarithromycin, and amoxicillin or cost-effective. Since publication of the last ACG guideline on H. metronidazole (clarithromycin-based triple therapy) or a PPI or H 2pylori infection (3), the accepted indications for testing to prove RA, bismuth, metronidazole, and tetra- eradication after antibiotic therapy, largely based upon expert

    consensus, have broadened to include:

     First-Line Regimens for Helicobacter pylori Eradication

    Regimen Duration Eradication Rates Comments

    Standard dose PPI b.i.d. (esomeprazole is q.d.), Consider in nonpenicillin allergic patients who 10-14 7070-- 85% clarithromycin 500 mg b.i.d., amoxicillin 1,000 mg b.i.d. Standard have not previously received a macrolide Consider dose PPI b.i.d., clarithromycin 500 mg b.i.d. metronidazole 500 mg in penicillin allergic patients who have not 10-14 -85% b.i.d. previously received a macrolide or are unable to tolerate bismuth quadruple therapy

    10-14 75-90% Consider in penicillin allergic patients Bismuth subsalicylate 525 mg p.o. q.i.d. metronidazole 250 mg p.o. q.i.d., tetracycline 500 mg p.o. q.i.d., ranitidine 150 mg p.o. b.i.d. or standard dose PPI q.d. to b.i.d.

    PPI + amoxicillin 1 g b.i.d. followed by: >90% Requires validation in North America 5 5 PPI, clarithromycin 500 mg, tinidazole 500 mg b.i.d.

    PPI = proton pump inhibitor; pcn = penicillin; p.o. = orally; q.d. = daily; b.i.d. = twice daily; t.i.d. = three times daily; q.i.d. = four times daily. * Standard dosages for PPIs are as follows: lansoprazole 30 mg p.o., omeprazole 20 mg p.o., pantoprazole 40 mg p.o., rabeprazole 20 mg p.o., esomeprazole 40 mg p.o. Note: the above recommended treatments are not all FDA approved. The FDA approved regimens are as follows: 1. Bismuth 525 mg q.i.d. + metronidazole 250 mg q.i.d. + tetracycline 500 mg q.i.d. x 2 wk + H2RA as directed x 4 wk. 2. Lansoprazole 30 mg b.i.d. + clarithromycin 500 mg b.i.d. + amoxicillin 1 g b.i.d. x 10 days. 3. Omeprazole 20 mg b.i.d. + clarithromycin 500 mg b.i.d. + amoxicillin 1 g b.i.d. x 10 days. 4. esomeprazole 40 mg q.d. + clarithromycin 500 mg b.i.d. + amoxicillin 1 g b.i.d. x 10 days. 5. Rabeprazole 20 mg b.i.d. + clarithromycin 500 mg b.i.d. + amoxicillin 1 g b.i.d. x 7 days.

    cycline (bismuth quadruple therapy). Details regarding these associated with reduced eradication rates and are not recom-regimens can be found in Table 4. When given at the recommended mended. The currently available PPIs perform comparably when doses, most recent studies report intention-to-treat (ITT) used in these regimens (128, 129). Data from a recent eradication rates in the range of 70-80% (121-124). Large meta-analysis of 13 studies suggests that b.i.d. dosing of a PPI in randomized trials suggest that the inclusion of amoxicillin or clarithromycin-based triple regimens is more effective than q.d. metronidazole yields similar results when combined with a PPI and dosing (130). Pretreatment with a PPI prior to a course of H. pylori clarithromycin (125). Though international guidelines have eradication therapy does not appear to adversely influence recommended treatment durations of at least 7 days, treatment treatment outcomes (131). Further, it appears that an HRA can be 2durations of 10-14 days have typically been employed in the substituted if a patient cannot tolerate a PPI United States (3). A recent large trial from the United States, which (132) .

    evaluated the combination of rabepra- zole, clarithromycin, and Bismuth quadruple therapy has been advocated as a primary amoxicillin, found that 7 and 10 days of therapy yielded equivalent therapy for H. pylori (133). Bismuth quadruple therapy offers eradication rates. The ITT eradication rate for 7 days was 77% eradication rates that are similar to clarithromycin triple therapy. A (95% CI 71-83%) versus 78% (95% CI 72-84%) for the 10-day recent meta-analysis including 5 randomized trials reported ITT regimens. This study also reported an eradication rate of 27% for a and per protocol (PP) eradication rates of 79% (95% CI 74-81%) 3-day treatment regimen (123). A recent meta-analysis of seven and 85% (95% CI 8188%) for clarithromycin triple therapy and

    studies involving more than 900 patients found that a 14-day 80% (95% CI 77-84%) and 87% (95% CI 84-91%) for bismuth course of clarithromycin triple therapy provided better eradication quadruple therapy, respectively (134). Though this regimen has rates than a 7-day course of therapy (Peto OR 0.62 favors 14 vs 7 been evaluated with an HRA or PPI, a recent meta-analysis found 2

    days of therapy for eradication of H. pylori infection [95% CI that quadruple therapy with a PPI provides greater efficacy in

    patients with metronidazole-resistant H. pylori strains (135). A 0.45-0.84]). There was also a trend towards improved efficacy with

    10 days of therapy compared with 7 days of therapy, which did not criticism of this regimen involves its complexity (q.i.d. dosing reach statistical significance (126). The superiority of 14-day regimen and high pill count) and perceived frequency of side versus 7-day treatment duration has been confirmed by a recent effects. A simplified 14-day b.i.d.- dosing regimen recently large randomized single center trial from Italy (127). As a result of evaluated by Graham and colleagues in the United States achieved the falling eradication rates with clarithromycin-based triple an eradication rate of92% (95% CI 79-98%) (136). Another recent therapy, it is essential to take every opportunity to optimize study reported comparable eradication rates with a novel triple

    treatment success. Given the results of this meta-analysis, it seems antibiotic capsule given t.i.d. and a PPI b.i.d. for 10 days (137).

    prudent to recommend a 14-day course of clarithromycin triple Although minor side effects with bismuth-based quadruple therapy therapy, particularly in the United States where eradication rates occur commonly, the frequency of moderate or severe side effects have typically been 80% or less with shorter durations of therapy. is no greater than with clarithromycin-based triple therapy Treatment durations of less than 7 days are clearly (133) .

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