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Treatment of Helicobacter pyloriinfectionNimish Vakil, MD,* and Mae F. Go, MD

Combination antimicrobial therapies for the effective eradica-tion of Helicobacter pyloriinfection have been identified and

are commercially available. Ongoing studies to improve eradi-

cation rates are based on modification of currently approved

treatments. Management of H. pyloriinfection now focuses on

which patients should be treated and, by extension, which

should be tested, because all patients should have a positive

test result for H. pyloribefore starting antimicrobial therapy.

Peptic ulcer disease was believed to be caused by acid abnor-

malities until about two decades ago, when H. pyloriwas

successfully cultured; the clinical records of an early propo-

nent of an infectious cause of peptic ulcer disease were

recently discovered. The role of H. pyloriinfection in gastroe-

sophageal disease and in ulcer disease associated with nons-teroidal anti-inflammatory drugs have become intensely investi-

gated topics. Consensus conferences among pediatric

physicians are establishing practice guidelines for H. pylori

management in children and adolescents. Curr Opin Gastroenterol

2000, 16:3239 2000 Lippincott Williams & Wilkins, Inc.

*University of Wisconsin Medical School, Department of Gastroenterology,Milwaukee, Wisconsin, USA; Veterans Affairs Medical Center, Houston, Texas,USA

Correspondence to M.F. Go, Veterans Affairs Medical Center (111D), 2002

Holcombe Boulevard, Houston, TX 77030, USA

Current Opinion in Gastroenterology 2000, 16:3239

Abbreviations

BMT bismuth, metronidazole, and tetracyclineGERD gastroesophageal reflux diseaseNSAID nonsteroidal anti-inflammatory drugPPI proton-pump inhibitorRBC ranitidine bismuth citrate

ISSN 02671379 2000 Lippincott Williams & Wilkins, Inc.

Helicobacter pyloridiagnosis: the stoolantigen testThe stool antigen test is based on a multiwell enzyme-

linked immunosorbent assay (ELISA) for the detection

ofHelicobacter pyloriantigens. In a large multicenter trial

[2], 501 patients underwent testing with the stool

antigen enzyme immunoassay (HpSA Premier platinum,

Meridian Diagnostic, Cincinnati, OH). H. pylori was

detected with a sensitivity of 94% (95% CI, 91% to 97%)

and a specificity of 92% (95% CI, 87% to 95%). Post-

treatment sensitivity in a smaller cohort (n = 107) was

90% (95% CI, 68% to 99%) and specificity was 95%

(95% CI, 88% to 99%). If the high accuracy of the test is

confirmed in US multicenter trials, the test should beuseful both before and after antimicrobial treatment. It

is noninvasive and inexpensive and may be ideal for

identifyingH. pyloriinfection in pediatric patients.

DyspepsiaDyspepsia is defined as pain or discomfort centered in

the middle part of the upper abdomen (ROME II defin-

ition). When large numbers of unselected consecutive

patients with dyspepsia in primary care are studied, 15%

to 18% have peptic ulcer disease, 10% to 15% have

esophagitis, 10% to 12% have abnormalities that are less

specific (eg, gastritis or duodenitis), and approximately

50% have no visible abnormalities on endoscopy.

Nonulcer dyspepsia is defined as the presence of

dyspeptic symptoms in the absence of endoscopic

abnormalities.

Predictive value of symptoms in dyspeptic patients

The type or severity of symptoms does not predict endo-

scopic findings. Grouping of dyspeptic symptoms into

subclasses, such as ulcer type or dysmotility-type,

also lacks predictive value in differentiating between

organic and functional dyspepsia. Endoscopy provides a

definitive diagnosis but is too expensive to use in all

dyspeptic patients. Various strategies have been devel-oped with which to address dyspeptic symptoms in

primary care.

Empirical treatment of dyspeptic patients with

H2-receptor antagonists

In 1985, the American College of Physicians developed

a guideline recommending that dyspeptic patients

receive a trial of H2-receptor antagonists for 6 to 8

weeks. Patients who achieve symptomatic relief would

have no further diagnostic or therapeutic interventions.

Patients who do not respond in 7 to 10 days or patients


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who have relapse after therapy would undergo

endoscopy. It was implicitly assumed that many

patients would have no symptoms after the course of

H2-receptor antagonists and would not need endoscopy

and that this would reduce the cost of managing

dyspepsia. Bytzer et al. [3] conducted a randomized

study of early endoscopy and empirical H2-receptorantagonist therapy. At 1 year, most patients in the

empirical therapy group had undergone endoscopy for

recurrent or persistent symptoms. Costs were higher

but patient satisfaction was poorer in the empirical

therapy group. This study showed that many dyspeptic

patients have recurrent symptoms despite short courses

of treatment with H2-receptor antagonists. Another

problem with empirical strategies that rely on acid-

suppressive agents is that increasing numbers of

patients are receiving long-term treatment with these

agents with no clear diagnosis of their underlying

condition.

Current guidelines for the management of dyspepsia

and nonulcer dyspepsia

European consensus guidelines developed in 1997

recommended that patients younger than 45 years of age

who have no alarm symptoms (eg, anemia, weight loss,

dysphagia, palpable mass, and malabsorption), have posi-

tive results forH. pylori(on urea breath tests or serologic

tests), and have not previously been treated forH. pylori

should receive eradication therapy from their primary

care physicians. Patients older than 45 years of age who

have severe dyspeptic symptoms and all patients with

alarm symptoms should be referred for endoscopy.

Guidelines from the American Gastroenterological

Association [4] recommend a noninvasive test (a sero-

logic test or breath test), followed by eradication therapy

if H. pylori is detected, in patients with dyspepsia who

are younger than 45 years of age and have no alarm

features. Older patients should undergo investigation.

Clinical evaluations of Helicobacter pylorieradication

in dyspepsia

The test-and-endoscope strategy assumes that seroposi-

tive patients are more likely than nonseropositive patients

to have lesions at endoscopy. Limiting endoscopy toseropositive patients will increase endoscopic yield,

reduce the total number of endoscopic procedures

performed, and decrease costs. Primary care physicians

refer approximately 10% of their dyspeptic patients for

endoscopy. In dyspeptic populations in the United States,

the prevalence of H. pylori infection is 30%. Test-and-

endoscope strategies could paradoxically increase costs by

increasing the number of patients who undergo

endoscopy. However, many patients seek endoscopy for

reassurance, and endoscopy has had a positive effect on

quality of life in dyspepsia in short-term studies.

The premise of the test-and-treat strategy is that ifH.

pylori eradication therapy cures dyspeptic symptoms,

precise knowledge of the underlying lesion is unneces-

sary. To minimize the risk for missing upper gastroin-

testinal cancer, the strategy is used only in patients

younger than 45 to 50 years of age. In a randomized

controlled study [5], prompt endoscopy orH. pylorierad-ication in 500 H. pyloriinfected dyspeptic patients

produced similar outcomes with respect to symptom-

free days (58% in the test-and-treat group; 60% in the

prompt endoscopy group). The number of endoscopic

procedures done at 1 year was lower in the test-and-treat

group (n = 117) than in the prompt endoscopy group (n

= 314), but more patients in the test-and-treat group

(12%) than in the prompt endoscopy group (4%) were

dissatisfied with their care.

One study randomly assigned 104 H. pyloriinfected

patients to receive endoscopy or eradication therapy

with the test-and-treat strategy [6]. Patients assigned to

eradication therapy had significantly better dyspepsia

scores at 1 year and had fewer return visits to the physi-

cian. Over-the-counter and prescription drug use were

substantially lower in patients assigned to empirical

therapy, and 75% of the patients treated empirically did

not require endoscopy. In contrast, a recent US study in

primary care suggested that test-and-treat strategies did

not lead to fewer referrals to gastroenterologists or fewer

endoscopic procedures in dyspeptic patients presenting

to primary care physicians. This study indicated that the

economic benefits suggested by computer models might

not be achieved in clinical practice [7].

The problem of nonulcer dyspepsia

An earlier review determined that all trials done to evalu-

ate the effect ofH. pyloritreatment on nonulcer dyspep-

sia have had significant deficiencies. Another systematic

review of therapy in functional dyspepsia found subopti-

mal design or unclear presentation of data in most

studies. None of the trials provided unequivocal

evidence that an efficacious therapy for functional

dyspepsia exists.

Three recent large European trials have reached

conflicting conclusions. Blum et al. [8] randomlyassigned 438 patients to proton-pump inhibitor (PPI)

triple therapy or omeprazole alone for 1 week and

followed patients for 1 year. Treatment success was

reported in 27% of patients in the triple-therapy group

and 21% of patients in the control group; the difference

between the groups was not significant.

Talley et al. [9] randomly treated 275 patients with

triple therapy or omeprazole for 1 week. Relief of

dyspepsia at 1 year was similar in the two groups: 24% in

the active treatment group and 21% in the control

Treatment of Helicobacter pyloriinfection Vakil and Go 33


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group. Data from a recent large US multicenter trial also

showed no benefit from eradication therapy in nonulcer

dyspepsia [10]. Three hundred thirty-seven patients

were randomly assigned to receive H. pylorieradication

therapy or placebo and were followed for 1 year; 45% of

those in the active treatment group and 50% of those in

the control group had a successful response to therapy(P= 0.55). No significant association was found between

symptom type (ulcer-like, reflux-like, or dysmotility-

like) and outcome, and there was no correlation with

improvement in chronic gastritis at 12 months.

In contrast, a single-center study from Scotland

showed a significant benefit with eradication therapy.

McColl et al. [11] reported that dyspepsia resolved in

significantly more patients with H. pyloritriple therapy

(21%) than with placebo (7%). One possible explana-

tion for the disparate results in this study is that the

baseline prevalence ofH. pylorirelated ulcer disease is

high in Scotland and eradication therapy may cure a

larger pool of occult ulcer disease in Scotland than in

other countries.

Acid suppression

The efficacy of H2-blockers is questionable, but two

recent studies have been done on the effectiveness of

PPIs in functional dyspepsia. A total of 1262 patients

with functional dyspepsia were enrolled in two studies

(BOND or OPERA) and assigned to receive omepra-

zole, 20 mg/d; omeprazole, 10 mg/d; or an identical

placebo for 4 weeks [12]. Complete symptom relief was

seen on the last 3 days of therapy in 38% of patients

receiving omeprazole, 20 mg/d; 36% of patients receiv-

ing omeprazole, 10 mg/d; and 28% of patients receiving

placebo (P = 0.002). Symptom relief was similar in

patients who were positive and negative for H. pylori. A

major limitation of these studies is that they were of

relatively short duration.

Helicobacter pyloriand gastroesophagealreflux diseaseSignificant proportions of patients with gastroesophageal

reflux disease (GERD) have H. pylori infection. It has

been argued that H. pylori infection should be eradi-

cated in all of these patients, particularly those likely toreceive life-long acid-suppressive therapy with PPIs.

Conversely, data have suggested that eradication of H.

pylori in patients with duodenal ulcer may unmask or

predispose to GERD.

The prevalence of GERD seems to be increasing,

whereas the prevalence of duodenal ulcer is decreasing.

In a systematic review, Connor [13] found that 26

studies have evaluated the prevalence of H. pyloriinfec-

tion in patients with GERD. Of 2112 patients with

GERD, 40% were infected with H. pylori; the preva-

lence ranged from 16% to 88%. Prevalence increased

with age, which is indicative of the age-cohort effect,

but no relationship was seen betweenH. pyloriinfection

and degree of esophagitis and no difference was seen

between the sexes. In 13 casecontrol studies, 562 of

1426 patients with GERD (39%) and 1009 of 2010

controls (50.2%) were positive forH. pylori. This findingraises the question of whetherH. pyloriinfection is asso-

ciated with a lower prevalence of GERD.

Helicobacter pyloriand gastroesophageal reflux

disease after cure of the infection

In a study of 450 patients with duodenal ulcer who had

no endoscopic evidence of reflux esophagitis at base-

line and were treated for H. pylori infection, Labenz et

al. [14] found that that the infection was cured in 244

patients and persisted in 216. Using life-table analysis,

the authors estimated that the incidence of esophagitis

detected at endoscopy was 25.8% 3 years after eradica-

tion of H. pylori and 12.9% in patients with ongoing

infection. Factors predicting the development of reflux

esophagitis were severity of corpus gastritis, weight

gain, and male sex. In contrast, Vakil et al. [15] studied

242 patients with endoscopically documented ulcer

disease and no endoscopic evidence of reflux esophagi-

tis at baseline who received H. py lori eradication

therapy. One month after eradication therapy, new

symptoms of heartburn were reported by 19% of

patients with H. pylori infection and 26% of patients

with successful eradication ofH. pylori (P= 0.410). At 6

months, new symptoms of heartburn were reported by

15% of patients with persistent symptoms and 22% ofpatients with successful eradication (P = 0.474). Only

one patient developed endoscopic evidence of

esophagitis. This study suggests that heartburn is

frequently reported by patients who have received

eradication therapy but is independent of whether

eradication has occurred. One possible explanation for

this is that many patients have reflux disease in addi-

tion to duodenal ulcer disease and discontinuation of

acid-suppressive therapy, which is customary after erad-

ication therapy, may unmask symptoms of reflux

disease.

A study of UK patients with established reflux diseaseshowed that symptomatic relapse of GERD (as opposed

to endoscopic findings) was similar in patients with

eradication (83%), patients with ongoing infection

(84%), and patients negative for H. pylori (81%). This

study suggested thatH. pyloriinfection or its eradication

did not affect the development of symptomatic relapse.

In a study of 24-hour ambulatory pH monitoring,

Gisbert et al. [16] found no significant difference in the

prevalence of H. pylori infection in patients with an

abnormal pH study (57% of patients) and patients with

an with a normal study (52%).

34 Gastrointestinal infections


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Acid secretion, gastroesophageal reflux disease, and

Helicobacter pyloriinfection

Previous studies have shown that PPI treatment results

in higher intragastric pH values in patients infected with

H. pyl or i than in patients who are not infected.

Furthermore, intragastric pH values are significantly

higher during PPI therapy in patients with duodenalulcer who are infected withH. pylori; the effect is most

pronounced with nighttime acid secretion.

Holtmann et al. [17] recently confirmed earlier studies

showing that patients with H. pylori infection who are

treated with PPIs have better early symptom relief and

better healing of esophagitis than patients who do not

have H. pylori infection; at 8 weeks, symptoms were

similar in the two groups. These data suggest that H.

pylori infection may be associated with a better early

response to acid-suppressive therapy with PPIs but is

similar on long-term follow-up. In contrast, Schenk et al.

[18] reported that no significant difference in the dose of

omeprazole was required for relief of symptoms or healing

of esophagitis in 177 patients with reflux esophagitis.

Helicobacter pyloriinfection of Barretts epithelium invari-

ably occurs in the presence of H. pyloriinfection of the

stomach. Colonization is generally mild, and there is no

correlation between the severity of esophageal inflamma-

tion and the presence of H. pylori infection. Recently,

Vicari et al. [19] examined patients with reflux esophagitis

(n = 84), Barrett esophagus (n = 48), or esophageal adeno-

carcinoma or dysplasia (n = 21) and compared them with

controls who did not have reflux disease (n = 57). The

prevalence of H. pylori infection was not significantly

different in the control group, but the prevalence of cagA-

positive strains was lower in the few patients with more

severe complications of reflux disease.

The role ofH. pyloriinfection in GERD remains contro-

versial and is a subject of debate among experts in the

field. In patients with peptic ulcer disease, the benefits

of eradicating H. pylori infection clearly outweigh the

risks, in both clinical and economic terms. In patients

with nonulcer dyspepsia or reflux esophagitis, there is

little evidence of therapeutic benefit from the eradica-

tion of H. pylori. In these patients, the potential forworsening reflux disease may be an argument against

eradication therapy.

Nonsteroidal anti-inflammatory drugs andHelicobacter pyloriChan et al. [20] reported a randomized controlled trial of

H. pylorieradication therapy in the prevention of peptic

ulcers in patients using nonsteroidal anti-inflammatory

drugs (NSAIDs). They assigned 100 infected patients to

receive naproxen or naproxen plus bismuth triple

therapy. Cure rates were 89% in the triple-therapy group

and 0% in the naproxen group. The incidence of ulcer

disease was 7% in the triple-therapy group and 26% in

the naproxen group; this suggests that elimination ofH.

pylori before NSAID therapy reduces the incidence of

NSAID-induced peptic ulcer disease.

In contrast, in a study comparing omeprazole and raniti-dine for NSAID-associated ulcers, Yeomans et al. [21]

found that outcomes with therapy were better in patients

infected with H. pylor i than in those who were not

infected. Patients with established NSAID-related ulcers

had better healing rates with omeprazole or ranitidine if

they hadH. pyloriinfection than if they were uninfected.

Similarly, after healing, H. pyloriinfected persons were

more likely than their uninfected counterparts to remain

in remission during maintenance therapy with omepra-

zole or ranitidine. In another study, Hawkey et al. studied

285 patients who needed continuous NSAID treatment

and were positive for H. pylori. They were randomly

assigned to receive H. pylori treatment or omeprazole.

The possibility of being ulcer-free at 6 months was

similar in both groups, but ulcers present at baseline

were more likely to heal in infected persons (100%) than

in those assigned to eradication therapy (72%).

Taha et al. [22] studied 120 patients who received famo-

tidine or placebo for the prophylaxis of NSAID gastropa-

thy. Patients who had neutrophils on gastric biopsy were

more likely to develop NSAID-associated ulcers, and

patients withH. pyloriinfection were more likely to have

neutrophils on gastric biopsy. In NSAID users who

received placebo, the incidence of ulcer was 49% in

patients with H. pylori infection and 7% in uninfected

patients (P < 0.001). In patients who received famoti-

dine, the difference in the incidence of ulcer in infected

and uninfected patients was not significant. In a

casecontrol study of H. pylori infection and risk for

gastrointestinal bleeding, Aalykke et al. [23] found that

NSAID users infected with H. pylori had an increased

risk for bleeding peptic ulcers relative to patients

withoutH. pylori(odds ratio, 1.81 [95% CI, 1.02 to 3.21]).

Konturek et al. [24] reported that gastric adaptation to

aspirin ingestion is impaired in patients with H. pylori

infection, but eradication of H. pylori restores this

process.

These data cannot currently be reconciled. It seems

reasonable to treatH. pyloriinfection in all patients with

proven peptic ulcer disease whether they are taking

NSAIDs or not. Eradication therapy is not warranted in

all patients placed on NSAID therapy.

Antimicrobial treatment guidelines,retreatment, and antimicrobial resistancePractice guidelines from the American College of

Gastroenterology for the management of H. pylorirein-



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force recommendations from the 1997 H. pyl or i

International Update Conference [25]. H. pyloritesting

is indicated only if treatment is planned in a patient

with peptic ulcer disease or gastric MALT lymphoma.

Routine testing and treatment of patients without symp-

toms or patients with GERD are not indicated. First-

line treatments are multidrug therapies consisting of 1) aPPI; clarithromycin; and metronidazole or amoxicillin; 2)

ranitidine bismuth citrate (RBC); clarithromycin; and

amoxicillin, metronidazole, or tetracycline; or 3) a PPI;

bismuth; metronidazole; and tetracycline. Treatments

are ideally administered for 2 weeks.

The most effective antimicrobial regimens cure approxi-

mately 90% of H. pylori infections; 10% of patients or

more remain infected, depending on the regimen used,

patient compliance, and the presence of antimicrobial

resistance. Retreatment in patients for whom treatment

fails is often problematic. If initial therapy fails, the dura-

tion of therapy can be extended and doses can be

increased. For example, if failure occurs with a PPI, 20

mg; amoxicillin, 1 g; and clarithromycin, 250 mg, given

twice daily for less than 10 days, the patient can receive

another regimen, such as the bismuth, metronidazole, and

tetracycline (BMT) 14-day regimen with an antisecretory

agent. Alternatively, the patient can receive 10 or 14 days

of the PPI, amoxicillin, and clarithromycin regimen with a

full dose of clarithromycin (500 mg). If antimicrobial

resistance is suspected, retreatment with an antibiotic not

used initially should be prescribed. For example, if the

BMT regimen was used as the first therapy, metronida-

zole resistance should be suspected and retreatment isbest done with a regimen that contains clarithromycin. In

patients in whom a regimen containing both clar-

ithromycin and metronidazole has failed, Houben et al.

[26] suggest using a salvage therapy consisting of a PPI

with BMT. In their study, the eradication rate was 100%

in 11 patients in whom a 7-day regimen containing both

clarithromycin and metronidazole failed.

Recent studies suggest that RBC-based triple therapy

may overcome resistance to clarithromycin and metron-

idazole. Wouden et al. [27] gave patients RBC, 400 mg;

metronidazole, 500 mg; and clarithromycin, 500 mg,

twice daily for 7 days. H. pylori infection was eradicatedin 95% of patients (20 of 21) with metronidazole-resis-

tantH. pyloristrains and 100% of patients (four of four)

with clarithromycin resistance.

Clarithromycin resistance is uncommon, but current

surveys indicate that secondary resistance is increasing

because of the widespread use of clarithromycin both as

a component ofH. pyloritreatment and as a single agent

for respiratory disease. Vakil et al. [28] reported US

primary clarithromycin resistance in 4% of patients in

19931994. From 19941996, overall clarithromycin

resistance increased to 12.6%, although primary resis-

tance remained low at 5%.

Few cases of Clostridium difficilecolitis have been

reported in relation to H. pylori treatment, but one

should be aware of the potential for antibiotic-associated

colitis. Nawaz et al. [29] report one of the few cases of C.difficilecolitis detected to date afterH. pyloritherapy.

Metronidazole resistance inH. pyloriis common in both

developing and developed countries. It has been shown

to markedly reduce the efficacy of any regimen contain-

ing metronidazole, so many authorities do not recom-

mend a metronidazole-containing regimen as first-line

therapy. Many investigators suggest that H. py lori

metronidazole resistance is an important predictor of

treatment failure.

Jenks et al. [30] used the H. pyloriSS1 mouse model to

characterize resistance after metronidazole treatment andthe effect of previous exposure ofH. pylorito metronida-

zole on the efficacy of a metronidazole-containing

regimen. Two groups of mice infected with H. pylori

were exposed to metronidazole monotherapy; the second

group also received the mouse equivalent of triple

therapy: omeprazole, 20 mg, clarithromycin, 250 mg, and

metronidazole, 400 mg, twice daily for 7 days. Of the

mice treated with metronidazole alone, 70% developed

H. pylori populations containing both susceptible and

resistant strains. The eradication rate was 70% with triple

therapy and 25% with metronidazole alone (P< 0.01).H.

pylori readily developed metronidazole resistance after

metronidazole monotherapy. Repeated exposure to

metronidazole increased selection for a resistant popula-

tion. This study confirmed that previous metronidazole

exposure is directly linked to metronidazole resistance

and has a significant negative effect on eradication rate.

Kusters et al. [31] showed that amoxicillin resistance is a

stable genetic factor, which is a homologue of the

Escherichia colipenicillin-binding protein 1A. The substitu-

tion of a single arginine for serine in penicillin-binding

protein 1A leads to amoxicillin resistance. The significance

of this resistance in combination therapies is unclear

because this resistance is uncommon. In the few clinicalstudies that have described it, it has had little to no impact

on H. pylorieradication rates. Another penicillin-binding

protein from H. pylori, penicillin-binding protein 4, has

been characterized [32]. Expression of this protein is signif-

icantly increased in mid- to late-log phase, but whether it is

associated with antimicrobial resistance is unclear.

Helicobacter pyloriinfection in the pediatricpopulationBecause H. pylor i infection is primarily acquired in

childhood, rigorous studies in the pediatric population



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are needed. Consensus conferences among pediatric

clinicians are now developing guidelines for the pedi-

atric population. Because of regional differences in the

frequency ofH. pyloriinfection and variability in gastro-

duodenal disease manifestations, guidelines must be

developed on a regional basis, at least initially. Methods

for diagnosingH. pyloriinfection must be independentlyvalidated in children at different ages. Antimicrobial

regimens have been evaluated in children and are effec-

tive at eradicating infection.

Guidelines for management of Helicobacter pyloriin

pediatrics

Practice guidelines from the Canadian Consensus Meeting

on the approach to H. pylori infection in children and

adolescents are now available [33]. Indiscriminate testing

for H. pyloriis not recommended. Evidence is currently

inadequate to support the use of a test-and-treat approach.

Treatment should be offered to children who test positive

forH. pylori. Antibody tests are not recommended because

of the low prevalence of the infection and the low sensitiv-

ity and specificity of the tests in children. First-line therapy

consists of twice-daily PPI plus two antibiotics (clar-

ithromycin and amoxicillin or clarithromycin and metron-

idazole). Practical suggestions for testing and treatment

indications in children were reviewed by Rowland et al.

[34]. The only unequivocal indication for H. pylorieradi-

cation is peptic ulcer disease in a child.

Diagnosing Helicobacter pyloriin the pediatric

population

Rocha de Oliveira et al. [35] present data showing that

serologic testing may not be useful for widespread

screening for H. pylori infection in symptomatic chil-

dren. One hundred thirty consecutive Brazilian children

undergoing endoscopic evaluation for gastrointestinal

symptoms were examined for H. pylori with cultures,

urease tests, and histologic tests. The results were

compared with the results of a second-generation IgG-

based ELISA that was accurate in their adult popula-

tion. Variability in accuracy of the ELISA correlated

with different age groups; sensitivity was 44.4% in chil-

dren 2 to 6 years of age; 76.7% in children 7 to 11 years

of age; and 93% in children 12 to 16 years of age. The

performance of serologic tests in children can be highlyvariable. The variable accuracy of serologic assays in

children seems to be related to the fact that H. pylori

antibody titers are lower in young children than in older

children and adults. Many commercially available sero-

logic assays are not sensitive and specific enough for

screening in children younger than 12 years of age.

Most investigators have been unable to show a link

between H. pylori and abdominal pain, but Camorlinga-

Ponce et al. [36] found a statistically significant associa-

tion in a Mexican pediatric population. These investiga-

tors validated ELISAs for H. pylori and its CagA and

urease antigens by using H. pylori strains from the

geographic population. They compared 82 children with

RAP and 246 age- and sex-matched asymptomatic chil-

dren and found a strong association between H. pylori

infection and RAP; children with RAP were more likely

than asymptomatic children to be infected (65%compared with 48%;P= 0.009). However, CagA seropos-

itivity was lower in children with RAP than in asympto-

matic children. The immune response to urease was low

in both groups. These findings differ from those of other

pediatric studies in which H. pylori was not associated

with RAP. Whether these differences are due to variabil-

ity in diagnostic tests is unknown. Diagnostic tests

should be validated in specific geographic populations,

especially in the pediatric population, because the pedi-

atric immune response may differ from that of the adult.

The CagA antibody has been associated with the devel-

opment of more severe gastroduodenal disease in the

adult. Mitchell et al. [37] compared the seroprevalence

of antibody to the CagA antigen in 21 H. pyloripositive

symptomatic Australian children with peptic ulcer

disease (n = 5) or RAP (n = 16) with that in 33 H.

pyloripositive asymptomatic Chinese children and 20H.

pylorinegative Australian children. The prevalence of

antibody response to CagA was higher in the sympto-

matic Australian children with peptic ulcer disease than

in those with RAP, but no statistically significant differ-

ence was seen. The CagA antibody was common in the

asymptomatic Chinese children (81.8%) but the differ-

ence between these children and the symptomaticAustralian children was not statistically significantly

different. These findings support observations in adults

that CagA is common in Asian populations and is not a

marker of specific disease development.

The urea breath test for Helicobacter pyloriin

pediatrics

Kalach et al. [38] compared the accuracy of 13C-UBT

(urea breath test) for diagnosis of H. pylori with histo-

logic testing, culture, and serologic testing in 100 French

children 0.7 to 18.3 years of age. They found all four

tests to be highly sensitive and specific. They were able

to select a cutoff for 13C enrichment with good concor-dance between 13C-UBT and culture results. Delvin et

al. [39] also showed the usefulness of 13C-UBT for

detection ofH. pyloriin a Canadian pediatric population.

Of 79 consecutive children undergoing endoscopic eval-

uation for gastrointestinal tract symptoms, 12 had H.

pylorigastritis. Concordance between 13C-UBT results

and the results of histologic testing with Warthin-Starry

stain was 100%.

As in adults, the UBT seems to be reliable both before

and after H. pyloritreatment in children. Cadranel et al.



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[40] evaluated 13C-UBT both before and after H. pylori

treatment in Belgian children. H. pylori gastritis was

detected in 52.8% (94 of 178) of the children prospec-

tively studied. Accuracy was 95% before therapy and

100% after therapy.

Eradication of Helicobacter pyloriin the pediatricpopulation

Combination therapies have been effective for H. pylori

eradication in children. Pediatric regimens are typically

variations of those used in adult studies; dosages must

be adjusted for age and size. Moshkowitz et al. [41] used

a 1-week treatment regimen with twice-daily omepra-

zole, 20 mg; clarithromycin, 250 mg; and tinidizole or

metronidazole, 500 mg, with an eradication rate of 89%

(24 of 27) in a pediatric patient sample. A similar 7-day

PPI-based triple-therapy regimen was evaluated for

eradication ofH. pyloriin a Swedish study. Casswall et al.

[42] treated 32 children with RAP with a 7-day course of

omeprazole, clarithromycin, and metronidazole; the

eradication rate was 87.5%. Two children were not cured

of infection after two courses of antibiotics; both had

resistance to metronidazole and clarithromycin.

Pretreatment antimicrobial resistance can negatively

affect the H. pylori eradication rate in children as in

adults. Raymond et al. [43] evaluatedH. pyloriantimicro-

bial susceptibility by E-test or disk diffusion in children

receiving a 2-week regimen of 1) lansoprazole, metron-

idazole, and amoxicillin or 2) lansoprazole, metronida-

zole, and spiramycin. Eradication rates were 83.3% for

the former regimen and 63.6% for the latter and were not

significantly different because of the small sample size;

the overall eradication rate was 74%. When results were

analyzed by metronidazole susceptibility, the eradication

rate was 83% overall (14 of 17) compared with only 17%

(one of six) in patients with metronidazole resistance.

Reduction in ulcer recurrence rates is now being

confirmed in children cured ofH. pyloriinfection. Kato et

al. [44] obtained anH. pylorieradication rate of 85% (23

of 27) in children receiving combination therapy for H.

pyloriinfection. The reinfection rate at 12 to 19 months

was 2.4% per patient-year. Ulcer recurrence occurred in

two of three patients with ulcer and continued H. pyloriinfection, but no ulcer recurrence was seen in the 16

patients with ulcer in whom infection was eradicated.

In an Asian pediatric study, 26 Taiwanese children with

duodenal ulcer and H. pylori infection received triple

therapy consisting of omeprazole, bismuth, and metron-

idazole [45]. The eradication rate was 96% (25 of 26),

and complete ulcer healing occurred in 92% of patients

(24 of 26) at 8-week endoscopic follow-up. The annual

ulcer relapse rate was approximately 9% over a 2-year

follow-up period.

References and recommended readingPapers of particular interest, published within the annual period of review,have been highlighted as: Of special in terest Of outstanding interest

1 Rigas B, Feretis C, Papavassiliou ED: J Lykoudis: an unappreciated discov-erer of the infectious etiology and treatment of peptic ulcer disease. Lancet

1999, In press.This paper discusses an early proponent of an infectious cause for peptic ulcerdisease and his unsuccessful efforts to obtain support for his belief.

2 Vaira D, Malfertheiner P, Megraud F, Axon ATR, Delentre M, Hirschl A, etal.: Diagnosis of Helicobacter pylori infection with a new non-invasiveantigen based assay. Lancet 1999, 354:3033.

This large, controlled European trial demonstrates the efficacy of the stoolantigen test.

3 Bytzer P, Hansen J, de Muckadell O: Empirical H2

blocker therapy orprompt endoscopy in management of dyspepsia. Lancet 1994,343:811815.

4 American Gastroenterological Association medical position statement:evaluation of dyspepsia. Gastroenterology 1998, 114:579581.

5 Lassen AT, Pederson FM, Bytzer P, de Muckadel Schaffalitzky OB: H.pylori test and treat or prompt endoscopy for dyspeptic patients in primarycare. A randomized controlled trial of 2 management strategies: one yearfollow-up. Gastroenterology 1998, 114:A196.

6 Heaney A, Collins JSA, Watson RGP, McFarland RJ, Bamford KB, ThamTCK: A prospective randomized trial of a test and treat policy versusendoscopy based management in young Helicobacter pylori positivepatients with ulcer-like dyspepsia referred to a hospital clinic. Gut 1999,45:186190.

7 Ladabaum U, Fendrick AM, Schieman JM: Utilization and outcomes ofoffice-based testing for Helicobacter pylori (HP) in symptomatic primarycare patients. Gastroenterology 1998, 114:A24.

8 Blum AL, Talley NJ, OMorain, Veldhyyzen van Zanten S, Labenz J, StolteM, et al.: Lack of effect of treating Helicobacter pylori infection in patientswith nonulcer dyspepsia. N Engl J Med 1998, 339:18751881.

9 Talley NJ, Janssens J, Lauritsen K, Racz I, Bolling-Sternevald E, on behalf ofthe Optimal Regimen Cures Helicobacter pylori Induced Dyspepsia(ORCHID) Study Group: Eradication of Helicobacter pylori in functionaldyspepsia: randomised double blind placebo controlled trial with 12months follow up. BMJ 1999, 318:833837.

10 Talley NJ, Vakil N, Ballard ED, Fennerty B: Absence of benefit of eradicat-ing Helicobacter pylori in patients with nonulcer dyspepsia. N Engl J Med1999, 341:11061111.

11 McColl K, Murray L, El-Omar E, Dickson A, El-Nujumi A, Wirz A, et al.:Symptomatic benefit from eradicating H. pylori in patients with nonulcerdyspepsia. N Engl J Med 1998, 339:18691874.

The above four papers are the major studies exploring the relationship betweenH. pylorieradication and symptoms in nonulcer dyspepsia.

12 Talley NJ, Meineche-Schmidt V, Pare P, Duckworth M, Raisanen P, Pap A,et al.: Is acid suppression efficacious in non-ulcer dyspepsia? A double-blind randomized controlled trial with omeprazole. Gastroenterology 1998,114:A305.

13 Connor H: Helicobacter pylori and gastro-esophageal reflux disease-clini-cal implications and management. Aliment Pharmacol Ther 1999,13:117127.

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Helicobacter pylori infection in patients with duodenal ulcer may provokereflux esophagitis. Gastroenterology 1997, 112:14421447.

15 Vakil N, Hahn B, McSorley D: Recurrent symptoms and gastro-esophagealreflux disease in patients with duodenal ulcer after treatment forHelicobacter pylori infection. Aliment Pharmacol Ther 2000, In press.

The data presented in this paper, on the emergence of heartburn and refluxesophagitis in patients with ulcer after H. pylorieradication therapy, conflict withthose of Labenz et al. [14].

16 Gisbert J, De-Pedro C, Barreiro A, Cabrera M, Valle J, Cruzado A, PajaresJ: H. pylori and gastro-esophageal reflux disease: lack of influence of infec-tion on pH-metric and endoscopic findings. Gastroenterology 1999,116:A172.

17 Holtmann G, Cain C, Malfertheiner P: Gastric Helicobacter pylori infectionaccelerates healing of reflux esophagitis during treatment with the protonpump inhibitor pantoprazole. Gastroenterology 1999, 117:1116.



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18 Schenk B, Kuipers E, Klinkenberg-Knol E, Eskes S, Meuwissen S:Helicobacter pylori and the efficacy of omeprazole therapy for gastroe-sophageal reflux disease. Am J Gastroenterol 1999, 94:884887.

19 Vicari J, Peek R, Falk G, Goldblum J, Easley K, Schnell J, et al.: The sero-prevalence of cagA positive Helicobacter pylori strains in the spectrum ofgastroesophageal reflux disease. Gastroenterology 1998, 115:5057.

20 Chan F, Sung J, Chung S, To K, Yung M, Leung C, et al.: Randomized trial

of eradication of Helicobacter pylori before non-steroidal anti-inflammatorydrug therapy to prevent peptic ulcers. Lancet 1997, 350:975979

21 Yeomans M, Tulassy Z, Juhasz L, Racz I, Howard J, van Rensberg J, et al.:A comparison of omeprazole with ranitidine for ulcers associated withnonsteroidal anti-inflammatory drugs. N Engl J Med 1998, 338:719726

22 Taha A, Dahil l S, Morran C, Hudson N, Hawkey C, Lee F, et al .:Neutrophils, H. pylori and NSAID ulcers. Gastroenterology 1999,116:254258.

23 Aalykke C, Lauritsen JM, Hallas J, Reinholdt S, Krogfelt K, Lauritsen K:Helicobacter pylori and risk of ulcer bleeding among users of nonsteroidalanti-inflammatory drugs: a case-control study. Gastroenterology 1999,116:13051309.

24 Konturek J, Dembinski A, Konturek S, Stachura J, Domschke W: Infectionof Helicobacter pylori in gastric adaptation to continued administration ofaspirin in humans. Gastroenterology 1998, 114:245255.

25 Howden CW, Hunt RH: Guidelines for the management of Helicobacter

pylori infection. Am J Gastroenterol 1998, 93:23302338.

26 Houben MHMG, van de Beek D, van t Hoff BWM, van der Hulst RWM,Rauws EAJ, van der Ende A, et al.: PPI-triple therapy failure in Helicobacterpylori (Hp) infection: re-treatment with PPI-triple therapy or quadrupletherapy? Digestion 1998, 59(suppl 3):413.

27 Vd Wouden EJ, Thijs JC, can Zwet AA, et al.: Metronidazole resistancedoes not influence the efficacy of triple therapy with ranitidine bismuthcitrate (RBC), clarithromycin (CLA), and metronidazole (MET) for H. pylori(Hp) infection. Gastroenterology 1998, 114:A323.

28 Vakil N, Hahn B, McSorley D: Clarithromycin resistant Helicobacter pyloriin the United States. Am J Gastroenterol 1998, 93:14321435.

29 Nawaz A, Mohammed I, Ahsan K, Karakurum A, Hadjiyane C, Pellecchia C:Clostridium difficile colitis associated with treatment of Helicobacter pyloriinfection. Am J Gastroenterol 1998, 93:11751176.

30 Jenks PJ, Labigne A, Ferrero RL: Exposure to metronidazole in vivo readilyinduces resistance in Helicobacter pylori and reduces the efficacy of eradi-cation therapy in mice. Antimicrob Agents Chemother 1999, 43:777781.

31 Kusters JG, Schuijffel DF, Gerrits MM, Zwet van AA, Vandenbroucke-Grauls MJE: A PBP-1A homologue is involved in stable amoxicillin resis-tance of Helicobacter pylori. Gastroenterology 1999, 116:A226.

32 Krishnamurthy P, Parlow MH, Schneider J, Burroughs S, Wickland C, VakilNB, et al.: Identification of a novel penicillin-binding protein fromHelicobacter pylori. J Bacteriol 1999, 181:51075110.

33 Sherman P, Hassall E, Hunt RH, Fallone CA, Veldhuyzen van Zanten S,Thomson ABR, and the Canadian Helicobacter Study Group: CanadianHelicobacter Study Group consensus conference on the approach toHelicobacter pylori infection in children and adolescents. Can JGastroenterol 1999, 13:17.

This was one of the first pediatric conferences to establish practice guidelineson the management of H. pyloriinfection on the basis of published evidence.

34 Rowland M, Imrie C, Bourke B, Drumm B: How should Helicobacter pyloriinfected children be managed? Gut 1999, 45(suppl 1):136139.

This paper discusses the practical management of H. pyloriinfection in pediatricpatients and examines literature on the association of H. pylori infection withsystemic disorders.

35 Rocha de Oliveira AM, Rocha GA, Queiroz DmdeM, Mendes EN, deCarvalho AST, Ferrari TCA, Nogueira AMMF: Evaluation of enzyme-linkedimmunosorbent assay for the diagnosis of Helicobacter pylori infectionfrom different age groups with and without duodenal ulcer. J PediatrGastroenterol Nutr 1999, 28:157161.

These authors describe the accuracy of serologic assays for detection of H.pyloriinfection in pediatric patients related to patient age. Serologic assays mayhave significantly less sensitivity in very young pediatric patients.

36 Camorlinga-Ponce M, Torres J, Perez-Perez G, Leal-Herrera Y, Gonzalez-Ortiz B, Madrazo de la Garza A, et al.: Validation of a serologic test for thediagnosis of Helicobacter pylori infection and the immune response tourease and CagA in children. Am J Gastroenterol 1998, 93:12641270.

37 Mitchell HM, Hazell SL, Bohane TD, Hu P, Chen M, Li YY: The prevalenceof antibody to CagA in children is not a marker for specific disease. JPediatr Gastroenterol Nutr 1999, 28:7175.

This paper examines CagA antibody prevalence in various pediatric populations.The antibody is common in pediatric and adult Asian populations, independentof clinical presentation.

38 Kalach N, Briet F, Raymond J, Benhamou P-H, Barbet P, Bergeret M, et al.:The 13carbon urea breath test for the noninvasive detection of Helicobacterpylori in children: comparison with culture and determination of minimumanalysis requirements. J Pediatr Gastroenterol Nutr 1999, 26:291296.

39 Delvin EE, Brazier JL, Deslandres C, Alvarez F, Russo P, Seidman E:Accuracy of the [13C]-urea breath test in diagnosing Helicobacter pylorigastritis in pediatric patients. J Pediatr Gastroenterol Nutr 1999,28:5962.

40 Cadranel S, Corvaglia L, Bontems P, Deprez C, Glupczynski Y, Riet AV,Keppens E: Detection of Helicobacter pylori infection in children with astandardized and simplified 13C-urea breath test. J Pediatr GastroenterolNutr 1999, 27:275280.

41 Moshkowitz M, Reif S, Brill S, et al.: One-week triple therapy with omepra-zole, clarithromycin, and nitroimidazole for Helicobacter pylori infection inchildren and adolescents. Pediatrics 1998, 102:e14.

42 Casswall TH, Alfven G, Drapinski M, Bergstrom M, Dahlstrom KA: One-

week treatment with omeprazole, clarithromycin, and metronidazole in chil-dren with Helicobacter pylori infection. J Pediatr Gastroenterol Nutr 1998,27:415418.

43 Raymond J, Kalach N, Bergeret M, Benhamou PH, Barbet JP, Gendrel D,Dupont C: Effect of metronidazole resistance on bacterial eradication ofHelicobacter pylori in children. Antimicrob Agents Chemother 1998,42:13341335.

44 Kato S, Abukawa D, Furuyama N, Iinuma K: Helicobacter pylori reinfectionrates in children after eradication therapy. J Pediatr Gastroenterol Nutr1998, 27:543546.

45 Huang F-C, Chang M-H, Hsu H-Y, Lee P-I, Shun C-T: Long-term follow-upof duodenal ulcer in children before and after eradication of Helicobacterpylori. J Pediatr Gastroenterol Nutr 1999, 28:7680.

Treatment h Pylori

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