Điều trị Helicobacter pylori ở trẻ

ACG Clinical Guideline: Treatment of Helicobacter pylori Infection

Chey, William D MD, FACG¹; Leontiadis, Grigorios I MD, PhD²; Howden, Colin W MD, FACG³; Moss, Steven F MD, FACG⁴

American Journal of Gastroenterology: February 2017 - Volume 112 - Issue 2 - p 212-239

doi: 10.1038/ajg.2016.563

Abstract

Helicobacter pylori(H. pylori) infection is a common worldwide infection that is an important cause of peptic ulcer disease and gastric cancer.H. pylorimay also have a role in uninvestigated and functional dyspepsia, ulcer risk in patients taking low-dose aspirin or starting therapy with a non-steroidal anti-inflammatory medication, unexplained iron deficiency anemia, and idiopathic thrombocytopenic purpura. While choosing a treatment regimen forH. pylori, patients should be asked about previous antibiotic exposure and this information should be incorporated into the decision-making process. For first-line treatment, clarithromycin triple therapy should be confined to patients with no previous history of macrolide exposure who reside in areas where clarithromycin resistance amongstH. pyloriisolates is known to be low. Most patients will be better served by first-line treatment with bismuth quadruple therapy or concomitant therapy consisting of a PPI, clarithromycin, amoxicillin, and metronidazole. When first-line therapy fails, a salvage regimen should avoid antibiotics that were previously used. If a patient received a first-line treatment containing clarithromycin, bismuth quadruple therapy or levofloxacin salvage regimens are the preferred treatment options. If a patient received first-line bismuth quadruple therapy, clarithromycin or levofloxacin-containing salvage regimens are the preferred treatment options. Details regarding the drugs, doses and durations of the recommended and suggested first-line and salvage regimens can be found in the guideline.

INTRODUCTION

Helicobacter pylori infection remains one of the most common chronic bacterial infections affecting humans. Since publication of the last American College of Gastroenterology (ACG) Clinical Guideline in 2007, significant scientific advances have been made regarding the management of H. pylori infection. The most significant advances have been made in the arena of medical treatment. Thus, this guideline is intended to provide clinicians working in North America with updated recommendations on the treatment of H. pylori infection. For the purposes of this document, we have defined North America as the United States and Canada. Whenever possible, recommendations are based upon the best available evidence from the world’s literature with special attention paid to literature from North America. When evidence from North America was not available, recommendations were based upon data from international studies and expert consensus.

This guidance document was developed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system (¹), which provides a level of evidence and strength of recommendation for statements developed using the PICO (patient population, intervention or indicator assessed, comparison group, outcome achieved) format. At the start of the guideline development process, the authors developed PICO questions relevant to Helicobacter pylori infection. The authors worked with research methodologists from McMaster University to conduct focused literature searches to provide the best available evidence to address the PICO questions. Databases searched included MEDLINE, EMBASE and Cochrane CENTRAL from 2000 to 11 September 2014. Search terms included “pylori, treat*, therap*, manag*, eradicat*”. The full literature search strategy is provided as Supplementary Appendix 1 online. After assessing the risk of bias, indirectness, inconsistency, and imprecision, the level of evidence for each recommendation was reported as “high” (further research is unlikely to change the confidence in the estimate of effect), “moderate” (further research would be likely to have an impact on the confidence in the estimate of effect), “low” (further research would be expected to have an impact on the confidence in the estimate of effect), or “very low” (any estimate of effect is very uncertain). The strength of recommendations was determined to be “strong” or “conditional” based on the quality of evidence, the certainty about the balance between desirable and undesirable effects of the intervention, the certainty about patients’ values and preferences, and the certainty about whether the recommendation represents a wise use of resources. A summary of the recommendation statements for this management guideline is provided in Table 1. The justification for the assessments of the quality of evidence for each statement can be found in Supplementary Appendix 2 online.

QUESTION 1: WHAT IS KNOWN ABOUT THE EPIDEMIOLOGY OFH. PYLORIINFECTION IN NORTH AMERICA? WHICH ARE THE HIGH-RISK GROUPS?

Recommendation

H. pylori infection is chronic and is usually acquired in childhood. The exact means of acquisition is not always clear. The incidence and prevalence of H. pylori infection are generally higher among people born outside North America than among people born here. Within North America, the prevalence of the infection is higher in certain racial and ethnic groups, the socially disadvantaged, and people who have immigrated to North America (factual statement, low quality of evidence).

H. pylori infection is usually acquired during childhood (²^,³^,⁴^,⁵^,⁶) although the exact means of acquisition is not always clear. Risk factors for acquiring the infection include low socioeconomic status (⁶^,⁷^,⁸) increasing number of siblings (⁹) and having an infected parent—especially an infected mother (¹⁰). In the Ulm (Germany) Birth Cohort Study, the odds ratio (OR) for acquiring H. pylori infection if a child’s mother was infected was 13.0 (95% confidence interval (CI) 3.0–55.2) (¹⁰) Apart from intra-familial spread, the infection may also be transmitted through contaminated water supplies (¹¹) particularly in developing countries.

Although infection rates for male and female children are similar (³^,¹²) there may be a slight male preponderance of the infection in adulthood. In a meta-analysis of observational, population-based studies, men were slightly more likely to be H. pylori-positive than women; OR=1.16 (95% CI 1.11–1.22) (¹²) This was confirmed in a study of adults in Ontario, Canada, in which the overall seroprevalence was 23.1% but higher in men (29.4%) than women (14.9%) (¹³). One explanation that has been proposed for the lower seroprevalence in women is that they may be more likely to clear H. pylori infection because of higher rates of incidental antibiotic use for other indications (¹²).

There is evidence for a birth cohort effect on H. pylori prevalence; for example, people who were born in the 1930s are more likely to have been infected during childhood than people born in the 1960s. In a study conducted among 7310 US veterans with gastrointestinal symptoms, seroprevalence was 73% among those born before 1920 and 22% in those born after 1980 (¹⁴). The overall prevalence of the infection in these US veterans fell from 70.8% in 1997 to a plateau of around 50% after 2002.

Within North America, the prevalence of H. pylori infection varies with socioeconomic status and race/ethnicity (¹⁴^,¹⁵^,¹⁶^,¹⁷). In general, the prevalence is lower among non-Hispanic whites than among other racial/ethnic groups including African Americans, Hispanic Americans, Native Americans, and Alaska natives (⁵^,¹⁴^,¹⁵^,¹⁸). African Americans with a higher proportion of African ancestry have been reported to have higher rates of H. pylori infection than African Americans with a lower proportion of African ancestry suggesting that racial/genetic factors may have some role in predisposition to the infection unrelated to socioeconomic factors (¹⁶). Higher prevalence rates have been found among those living close to the US/Mexico border (¹⁹^,²⁰); in one study (¹⁹), prevalence of H. pylori assessed by stool antigen testing was 38.2%. Prevalence has also been reported to be high among Alaska natives (¹⁸) and Canadian First Nations populations (²¹).

The prevalence of H. pylori infection is generally lower in the United States than in many other parts of the world, particularly in comparison to Asia and Central and South America (⁸^,²²). There is, however, preliminary evidence that it may be falling in some previously high prevalence areas (²²). People immigrating to North America from Asia and other parts of the world have a much higher prevalence of the infection than people born in North America (²³). In one study, the seroprevalence among immigrants from East Asia was 70.1% (²⁴). Hispanic immigrants to North America have higher rates of the infection than first- or second-generation Hispanics who were born here (²⁵).

QUESTION 2: WHAT ARE THE INDICATIONS TO TEST FOR, AND TO TREAT,H. PYLORIINFECTION?

Recommendations

Since all patients with a positive test of active infection with H. pylori should be offered treatment, the critical issue is which patients should be tested for the infection (strong recommendation, quality of evidence: not applicable),
All patients with active peptic ulcer disease (PUD), a past history of PUD (unless previous cure of H. pylori infection has been documented), low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma, or a history of endoscopic resection of early gastric cancer (EGC) should be tested for H. pylori infection. Those who test positive should be offered treatment for the infection (strong recommendation, quality of evidence: high for active or history of PUD, low for MALT lymphoma, low for history of endoscopic resection of EGC).
In patients with uninvestigated dyspepsia who are under the age of 60 years and without alarm features, non-endoscopic testing for H. pylori infection is a consideration. Those who test positive should be offered eradication therapy (conditional recommendation, quality of evidence: high for efficacy, low for the age threshold).
When upper endoscopy is undertaken in patients with dyspepsia, gastric biopsies should be taken to evaluate for H. pylori infection. Infected patients should be offered eradication therapy (Strong recommendation, high quality of evidence).
Patients with typical symptoms of gastroesophageal reflux disease (GERD) who do not have a history of PUD need not be tested for H. pylori infection. However, for those who are tested and found to be infected, treatment should be offered, acknowledging that effects on GERD symptoms are unpredictable (strong recommendation, high quality of evidence).
In patients taking long-term low-dose aspirin, testing for H. pylori infection could be considered to reduce the risk of ulcer bleeding. Those who test positive should be offered eradication therapy (conditional recommendation, moderate quality of evidence).
Patients initiating chronic treatment with a non-steroidal anti-inflammatory drug (NSAID) should be tested for H. pylori infection (strong recommendation, moderate quality of evidence). Those who test positive should be offered eradication therapy. The benefits of testing and treating H. pylori in patients already taking NSAIDs remains unclear (conditional recommendation, low quality of evidence).
Patients with unexplained iron deficiency (ID) anemia despite an appropriate evaluation should be tested for H. pylori infection. Those who test positive should be offered eradication therapy (conditional recommendation, high quality of evidence).
Adults with idiopathic thrombocytopenic purpura (ITP) should be tested for H. pylori infection. Those who test positive should be offered eradication therapy (conditional recommendation, very low quality of evidence).
There is insufficient evidence to support routine testing and treating of H. pylori in asymptomatic individuals with a family history of gastric cancer or patients with lymphocytic gastritis, hyperplastic gastric polyps and hyperemesis gravidarum (no recommendation, very low quality of evidence).

The ACG’s 2007 treatment guideline on the management of H. pylori infection (²⁶) listed the following as established indications for diagnosis and treatment:

Active PUD (gastric or duodenal).
Confirmed history of PUD (not previously treated for H. pylori).
Gastric MALT lymphoma (low grade).
After endoscopic resection of EGC.

The current guideline extends the list of potential indications to test patients for H. pylori infection. There are varying levels of evidence in support of the different potential indications for testing that are listed below. For some of these, the decision to test an individual patient for H. pylori will be influenced by clinical judgment and considerations of a patient’s general medical condition. Not all of these potential indications are given a definite recommendation, so that clinicians may exercise their judgment for individual patients. There is no justification in North America for universal or population-based screening.

PUD

The evidence in support of the 2007 recommendation was substantive at that time and these broad recommendations are still pertinent. All patients with a new diagnosis or a past history of PUD should be tested for H. pylori infection. Ideally, tests which identify active infection such as a urea breath test, fecal antigen test, or when endoscopy is performed, mucosal biopsy-based testing should be utilized. Because of the higher pretest probability of infection, patients with documented PUD represent a rare group, where it is acceptable to utilize an IgG H. pylori antibody test. In most other circumstances where the pretest probability of infection is lower, tests which identify active disease are preferred over antibody testing. Patients with a history of PUD who have previously been treated for H. pylori infection should undergo eradication testing with a urea breath test or fecal antigen test. Patients with evidence of ongoing infection should be treated appropriately.

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma

The term “MALT lymphoma” has largely been supplanted by “marginal zone B-cell lymphoma of MALT type”. Identification of this neoplasm remains a key indication to test for, and to eradicate, H. pylori infection.

A review published in 2009 identified and summarized six prospective cohort studies of treatment for H. pylori infection in patients with gastric MALT lymphoma (also referred to as “localized B-cell lymphoma of the stomach”) but found no systematic reviews or randomized controlled trials (²⁷). Tumor regression was reported in 60–93% of patients after eradication of H. pylori infection, but response was inconsistent, with some patients showing a delayed response and some showing tumor relapse within a year of treatment.

More recent studies have confirmed these observations. In a Japanese series, 77% out of 420 patients treated for H. pylori infection showed either complete histological response or probable minimal residual disease (the investigators’ definition of response), although 10 (3%) responders relapsed in a mean of 6.5 years (²⁸). Among infected patients who did not respond to eradication treatment, there was progression of the disease in 27%. Among 120 patients in Germany followed for a median of 122 months, there was initial complete remission in 80% following treatment of H. pylori infection (²⁹). Out of these, 3% had macroscopic recurrence of disease within 24 months, and another 17% had histological residual disease found after a median of 48 months.

A recent review has suggested that treatment of H. pylori infection may also be beneficial for patients diagnosed with diffuse large B-cell lymphoma of the stomach (³⁰).

Early gastric cancer

Three recent meta-analyses have each found that the incidence of metachronous gastric cancer following the endoscopic resection of a gastric neoplasm was reduced by the eradication of H. pylori infection (³¹^,³²^,³³). The most inclusive analysis by Yoon et al. (³³) included 13 studies (three prospective and 10 retrospective) comprising 6687 patients. The pooled OR of gastric cancer in patients successfully cured of H. pylori was 0.42 (95% CI 0.32–0.56); in a subgroup analysis of the three prospective studies, the OR was 0.39 (95% CI 0.20–0.75) (³³^,³⁴). The other two meta-analyses yielded similar results (³¹^,³²). Most recently, a meta-analysis comprising 24 studies (22 out of which were conducted in Asia) confirmed a lower rate of metachronous EGC following treatment of H. pylori infection; the incidence rate ratio was 0.54 (95% CI 0.46–0.65) (³⁴).

Dyspepsia (uninvestigated)

Dyspepsia (defined as pain or discomfort centered in the upper abdomen) is highly prevalent in North America and elsewhere. In North America, most patients with dyspepsia will not have serious underlying, organic disease to explain their symptoms. That is, most will be found to have functional dyspepsia (FD), which is discussed elsewhere in this guideline. The ACG’s 2007 guideline on H. pylori management (²⁶) included uninvestigated dyspepsia (depending upon H. pylori prevalence) in its list of established indications for diagnosis and treatment of H. pylori infection. The test and treat strategy for H. pylori infection was endorsed for patients under age 55 with dyspeptic symptoms and without alarm features.

In the UK, the Bristol Helicobacter Project randomized 1517 H. pylori-positive adults to treatment for H. pylori infection or placebo and followed them prospectively (³⁵). Among those treated for the infection, of whom over 90% achieved successful eradication, there was a small but statistically significant (P<0.05) reduction in subsequent consultations at the primary care level for dyspeptic complaints.

The Cochrane Collaboration’s review on initial management strategies for dyspepsia was published in 2005 (³⁶). As of early 2016, it had not been updated. A “test and treat” strategy for H. pylori had been found to be more effective than empirical acid suppression with either a proton pump inhibitor (PPI) or H2-receptor antagonist in managing dyspepsia (relative risk (RR) 0.59; 95% CI 0.42–0.83). This conclusion differs from an individual patient data meta-analysis which included three RCTs of 1537 patients randomized to the “test and treat” strategy or empirical acid suppression for the management of dyspepsia in the primary care setting (³⁷). Although there was no significant difference between the groups in terms of symptom cure at 12 months, there was a trend for reduced overall costs in those assigned to “test and treat”.

An individual patient data meta-analysis included five RCTs of 1924 patients randomized to “test and treat” or to prompt upper endoscopy for the evaluation of dyspeptic symptoms (³⁸). After 1 year, the RR of remaining symptomatic was 0.95 (95% CI 0.92–0.99) in favor of prompt endoscopy. However, costs were lower with the “test and treat” approach. Prompt endoscopy for all patients with dyspepsia is neither feasible nor cost-effective.

Functional dyspepsia

A Cochrane systematic review published in 2006 concluded that there was a small but statistically significant benefit of treating H. pylori infection in patients with FD (³⁹). In 17 RCTs comprising over 3500 patients, the RR reduction seen with treatment of H. pylori infection was 10% (95% CI 6–14%) and the number needed to treat (NNT) to cure one patient with FD was 14 (95% CI 10–25) (³⁹). A subsequent update of that Cochrane review included 21 trials comprising 4331 patients (⁴⁰). Most trials assessed patients’ symptoms 12 months after treatment. This study validated the NNT of 14 but with a narrower 95% CI (10–20).

The Rome IV criteria have suggested subgrouping patients with