pylori antigen in stool is a reliable noninvasive test to determine
whether H pylori has been eradicated.
Agree: 86% (AR 21%, A 29%, AS 36%, D 7%, DR 7%).
Grade of evidence: moderate.
Comment on Recommendation 9:
Detection of H pylori antigen in stool is an attractive
noninvasive method that seems suitable for both clinical use and
epidemiological studies. Several methods are available for the
detection of H pylori antigen in stool, such as enzyme immunoassay
(EIA) based on polyclonal or monoclonal antibodies, and immuno-
chromatographic tests (so-called rapid or quick tests). Stool tests are
generally more convenient in pediatric patients than the UBT. Stool
samples can be obtained from children without their active
collaboration and are transportable by mail for analysis. Neither
keeping the samples at room temperature for up to 5 days nor
freezing for months or even years seems to influence the accuracy of
the stool tests (86–89). In most countries, an EIA would be less
costly than the UBT. In addition, the EIA stool test is the only
diagnostic noninvasive test that has not shown an age dependence
on the accuracy of the test results (64,87). Therefore, validation
studies in adults may be extrapolated to children.
The first commercial EIA test to detect H pylori antigen in
stool was the Premier Platinum HpSA (Meridian Diagnostics,
Cincinatti, OH). This test is based on polyclonal antibodies. There
is a wide range for sensitivity and specificity of the test in children,
both pretreatment (86,90–98) and posttreatment (89,91,92,95).
Testing the same stool samples with different production lots of
the polyclonal test indicated interassay variation (99). This may
explain the wider range reported for the sensitivity and specificity of
the polyclonal stool tests. A different polyclonal EIA (Equipar
Diagnostici, Saronno, Italy) was recently evaluated against invasive
methods, but the present study included only 33 children with
a biopsy-proven H pylori status (100).
So far, only the EIA based on monoclonal antibodies
has achieved the accuracy of the UBT, which is considered the
reference standard of the noninvasive tests (87,99,101–103).
A systematic review and meta-analysis of the 8 studies directly
comparing the polyclonal with the monoclonal EIA, including
pediatric and adult patients, confirmed the significantly better
performance with respect to sensitivity of the monoclonal test,
both before and after therapy (104). No difference in accuracy has
been observed between studies in adults and children, and within the
pediatric studies, young age did not influence the performance of
the tests (87,99,101–103).
So-called rapid or office-based fecal tests based on an
immunochromography using monoclonal antibodies have been
evaluated in children (102,105). The accuracy was lower compared
with EIA, even though the tests were based on the same antigens.
Although these tests have improved over time, the problem
of interobserver variability in weakly positive tests remains
unresolved (102,106).
Additional ELISA tests for the detection of H pylori antigen
in stool will be developed and evaluated in the near future. There-
fore, this statement applies only to the tests that have been evaluated
in pediatric populations and have shown an equal or better
performance as the UBT or validated stool tests (87,104).
Recommendation 10
Tests based on the detection of anti-
bodies (IgG, IgA) against H pylori in serum, whole blood, urine,
and saliva are not reliable for use in the clinical setting.
Agree: 87% (AR53%, A 20%, AS 13%, DS 7%, D 7%).
Grade of evidence: high.
Comment on Recommendation 10:
H pylori
infection induces an early increase of specific IgM
and a later and persistent increase of specific IgA and IgG anti-
bodies. These antibodies can be detected in whole blood, serum,
urine, and saliva (63). In general, serologic assays cannot be used on
their own to perform the diagnosis of H pylori infection or to
monitor the success of therapy because the sensitivity and
specificity for detection of antibodies (IgG or IgA) against H pylori
in children vary widely. Specific IgG may remain positive for
several months or even years after the infection resolves. Thus, the
tests cannot be used reliably for treatment outcomes.
Many tests based on the detection of antibodies are commer-
cially available, easy to perform, and inexpensive. In spite of these
advantages, they have not been recommended for clinical practice
in pediatric patients by previous American, Canadian, or European
consensus statements (6,14,15).
The main problems are age dependence, particularly with
respect to sensitivity in younger children, and test-to-test varia-
bility. IgA-based tests detect only 20% to 50% of H pylori–infected
children, and are not suitable for diagnosis. IgG-based tests offer a
Koletzko et al
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better sensitivity than IgA-based tests, but the sensitivity of most
tests is much lower when used in children compared with
adults from the same geographic region. The use of cutoff values
obtained in validation studies in adults results in a failure to detect a
large proportion of infected children, especially in children younger
than 6 to 8 years. Oliveira et al (107) used a second-generation
EIA in comparison with biopsy-based methods and found a low
sensitivity of 44% in children ages 2 to 6 years. Sensitivity
increased to 77% in children ages 7 to 11 years and to 93% in
adolescents, which is comparable with results in adults. When
2 IgG-based EIAs were applied to sera of 175 children with
biopsy-proven H pylori status, a remarkable difference of sensi-
tivity was observed, mainly in the younger age groups (108).
Immunoblotting was found to be superior to serology for diagnosis
of H pylori infection in children (109). In a European multicenter
study, however, a more recent third-generation EIA seems to
perform better, with sensitivity just less than the UBT (76).
Tests based on the detection of H pylori antibodies in saliva or
office-based tests on whole blood or serum display even worse
performance characteristics than laboratory-based serologic EIAs.
Therefore, these tests cannot be recommended in children of any
age group (63).
Recommendation 11
It is recommended that clinicians wait at
least 2 weeks after stopping PPI therapy and 4 weeks after
stopping antibiotics to perform biopsy-based and noninvasive
tests (UBT, stool test) for H pylori
.
Agree: 100% (AR 47%, A 40%, AS 13%). Grade of
evidence: high.
Comment on Recommendation 11:
Studies in adults suggest that antibiotic or PPI therapy can
cause false-negative test results because of a reduction in bacterial
load without eradication of the bacterium (69,110,111). Therefore,
it is recommended that testing be performed at least 4 weeks after
completion of antibiotic treatment and 2 weeks following cessation
of PPI therapy.
3.4. Who Should Be Treated?
Recommendation 12
In the presence of H pylori–positive
PUD, eradication of the organism is recommended.
Agree: 100% (AR 79%, A, 13%, AS 7%). Grade of
evidence: high.
Comment on Recommendation 12:
Several meta-analyses in adults consistently demonstrate
that eradication of H pylori in patients with PUD significantly
reduces the relapse rate for ulcer disease and for recurrent
bleeding ulcers (112,113). Previous pediatric studies in children
with PUD indicated that the relapse rate is high without treatment
of H pylori infection (114). Only 1 randomized controlled pediatric
trial in H pylori – infected children with PUD (n
¼ 106) has been
published. This trial compared the eradication rate of H pylori and
the cure rate of PUD with 3 different treatment regimens, but did
not report the recurrence of ulcer or bleeding ulcer in those who
failed bacterial eradication (115). Although there are differences in
the etiologies and clinical presentation and frequency of PUD in
children compared with adults (1,116), it can be assumed that
recurrence of H pylori – related PUD can be prevented in children
by eradication of the infection. Therefore, eradication of the
infection is recommended in a child with H pylori infection and
PUD. The indication applies also for healed ulcers or a history of
PUD.
Recommendation 13
When H pylori infection is detected by
biopsy-based methods in the absence of PUD, H pylori treatment
may be considered.
Agree: 79% (AR 29%, A 50%, DS 21%). Grade of
evidence: low.
Comment on Recommendation 13:
The finding of H pylori–associated gastritis in the absence of
PUD during diagnostic endoscopy poses a dilemma for the endo-
scopist (see comment for recommendations 1, 2, and 3). As outlined
in the comments for recommendations 1 and 2, there is inadequate
evidence supporting a causal relation between H pylori gastritis and
abdominal symptoms in the absence of ulcer disease. Therefore,
eradication of the organism in the absence of ulcers may not result
in improvement of symptoms. As reviewed in the comment for
recommendation 3, H pylori is a risk factor for the development of
gastric malignancies; however, only a fraction of infected
individuals develop cancer. The carcinogenic risk is modified by
strain-specific bacterial factors, host responses, and/or specific
host–microbe interactions. (117). Current evidence suggests that
in high-risk populations such as in China, the eradication of H pylori
may have the potential to decrease the risk of gastric cancer in a
subset of individuals without precancerous lesions (39). Prospective
intervention trials are of variable quality and results may not be
generalizable from 1 population to another. As noted in the
comment to recommendation 12, eradication of H pylori can
prevent recurrence of PUD. In adults with nonulcer dyspepsia,
eradication of H pylori may reduce the development of peptic ulcers
(118). A potential benefit of chronic infection with certain H pylori
strains cannot be excluded (119). Therefore, the decision to treat
H pylori
-associated gastritis without duodenal or gastric ulcer is
subject to the judgment of the clinician and deliberations with the
patient and family, taking into consideration the potential risks and
benefits of the treatment in the individual patient.
Recommendation 14
A ‘‘test and treat’’ strategy is not
recommended in children.
Agree: 80% (AR 47%, A 20%, AS 13%, DS 13%, D
7%). Grade of evidence: moderate.
Comment on Recommendation 14:
The primary goal of testing is to diagnose the cause of
clinical symptoms. By definition, a ‘‘test and treat’’ strategy (the
detection of the presence of H pylori infection by a noninvasive test
followed by treatment in the case of a positive test) will not provide
this information in children (see comments on recommendations
1 and 2). Therefore, in contrast to current guidelines for adults
(8,120), current evidence does not support this practice in children.
3.5. Which Treatment Should Be Applied in
Which Situation?
Recommendation 15
In children who are infected with
H pylori and whose first-degree relative has gastric cancer,
treatment can be offered.
Agree: 93% (AR 20%, A 47%, AS 27%, DR 6%). Grade
of evidence: low.
Comment on Recommendation 15:
Please refer to the comment on recommendation 3.
Recommendation 16
Surveillance of antibiotic resistance
rates of H pylori strains in children and adolescents is
recommended in different countries and geographic areas.
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Agree: 100% (AR 60%, A 20%, AS 20%). Grade of
evidence: not applicable.
Comment on Recommendation 16:
Several European studies have documented high resistance
rates to clarithromycin and metronidazole in pediatric and
adult populations (1,121 – 123). Increasing rates of primary
clarithromycin resistance have been reported from several
countries (124 – 126). A prospective US multicenter study in adults
and children also documented similar high resistance rates (127).
In 2 small studies from the United States (Michigan and
West Virginia), a high proportion of isolates were resistant to
clarithromycin (128,129). Antibiotic resistance is an important
factor in treatment success (130). Indeed, eradication rates in
children treated with standard therapy are also decreasing over
time, in part related to increased antibiotic resistance. H pylori
antibiotic susceptibility data are not available for most geo-
graphic regions. Therefore, it is recommended that continuous
surveillance of resistance rates be undertaken to effectively
guide initial empiric therapy with the aim of improving treatment
outcomes.
Recommendation 17
First-line eradication regimens are the
following: triple therapy with a PPI R amoxicillin R imidazole;
or PPI R amoxicillin R clarithromycin; or bismuth salts R
amoxicillin R imidazole; or sequential therapy.
Agree: 100% (AR 36%, A 40%, AS 14%). Grade of
evidence: moderate.
Recommendation 18
Antibiotic susceptibility testing for
clarithromycin is recommended before initial clarithromycin-
based triple therapy in areas/populations with a known high
resistance rate (>20%) of H pylori to clarithromycin.
Agree: 93% (AR 33%, A 40%, AS 20%, DS 7%). Grade
of evidence: moderate.
Recommendation 19
It is recommended that the duration of
triple therapy be 7 to 14 days. Costs, compliance, and adverse
effects should be taken into account.
Agree: 93% (AR 27%, A 40%, AS 27%, DS 6%). Grade
of evidence: moderate.
Comment on Recommendations 17–19:
The goal of treatment is at least a 90% eradication rate on a
per-protocol basis at the first attempt. A high initial eradication rate
will prevent the development of antibiotic resistance and spread of
resistant H pylori strains in the population. For individual patients, a
high initial success rate will reduce the need for further treatments
and procedures, including endoscopies.
The combination of 2 antibiotics and a PPI has been the
recommended first-line therapy since the first published pediatric
guidelines (6,14,15). Studies comparing the various treatment
options in the pediatric population remain limited. In 2000, Oderda
et al (131) performed a systematic review of the published
eradication treatment studies in children. Because of the marked
heterogeneity and the limited number of well-designed studies,
it was difficult to make definitive recommendations. In 2001,
the first randomized double-blind trial comparing dual therapy of
amoxicillin and clarithromycin with triple therapy including
omeprazole in children confirmed that in intention-to-treat analysis,
triple therapy was far superior to dual therapy with eradication rates
of 74.2% versus 9.4% (132).
A recent meta-analysis of eradication treatment efficacy in
children concluded that, in general, the methodological quality of
the studies was poor and that additional well-designed randomized
trials are needed (7). Thus, current recommendations remain mainly
extrapolated from adult studies.
Recent data indicate a falling rate of H pylori eradication
in response to treatment. For example, the European pediatric
treatment registry reported results from the use of 27 different
regimens in 518 children with H pylori (133). The overall eradica-
tion rate was 65.6%, lower than previously reported, but was higher
in children with peptic ulcers (79.7%). One potential reason for this
decline is antibiotic resistance (134). Based on the negative effect of
antibiotic resistance on treatment outcomes, the rates of resistance
in the area where the child lives or comes from should be taken
into account when deciding on the initial therapeutic regimen for
eradication (1).
Clarithromycin resistance adversely affects eradication rates
in children (135,136). Studies in children addressing the role of
susceptibility testing to target initial therapy are limited; however,
3 studies in children suggest that tailoring therapy based on
antibiotic susceptibility testing can enhance eradication rates
(137–139). In a study of 58 German children, clarithromycin
and metronidazole susceptibility testing was used to guide standard
triple therapy and resulted in a high eradication rate of 93% (137).
An earlier study of 2 consecutive groups of 75 H pylori –infected
children treated with either triple therapy, including amoxicillin and
clarithromycin (group 1), or antibiotic therapy, guided by suscepti-
bility testing (group 2), demonstrated enhanced eradication in the
group with susceptibility-guided therapy (93% vs 81%) (138).
Therefore, clarithromycin-based triple therapy can only be recom-
mended as first-line therapy if susceptibility testing in the individual
patient revealed a clarithromycin-susceptible strain or if the
clarithromycin resistance rate in this area is known to be low. In
the absence of these conditions, clarithromycin-based triple therapy
cannot be recommended as first-line therapy.
Declining eradication rates with these standard triple
regimens have led to the development of alternate treatment options
(134). Sequential therapy involves dual therapy with a PPI and
amoxicillin for 5 days followed sequentially by 5 days of triple
therapy (a PPI with clarithromycin and metronidazol/tinidazol).
In fact, this regimen can be considered as quadruple therapy
provided in a sequential manner. It is speculated that the initial
use of amoxicillin reduces the bacterial load and provides protection
against clarithromycin resistance. In 2005, 74 children were
randomized to receive either sequential treatment (omeprazole
þ
amoxicillin for 5 days, followed by omeprazole
þ clarithromycin þ
tinidazole for another 5 days) or triple therapy for 1 week (140).
Successful eradication was achieved in 97.3% of children receiving
sequential therapy compared with 75.7% on standard triple therapy.
In a subsequent study evaluating adjunctive probiotic supplement-
ation, eradication of 82.5% was obtained from a group of
40 children receiving sequential therapy (141). Based on these
studies suggesting that sequential therapy is at least as effective as
standard therapy, sequential therapy was recommended as a first-
line treatment option. It is important to note that the data in children
are mostly limited to Italian studies, and therefore additional studies
in North America and different European countries are needed to
confirm that the findings apply to other locations. Furthermore,
clarithromycin resistance has a negative effect on eradication
success even with this regimen, although less so compared with
standard triple therapy (136,142,143).
Bismuth-based triple therapy is also recommended as an
alternate first-line therapy. Although there are no well-designed
randomized studies directly comparing this regimen with the
alternate recommended first-line therapies, in a study reported
by the European pediatric treatment registry, bismuth-containing
triple therapies were more efficacious than PPI-containing
ones (77% versus 64%) when used as first-line treatment (133).
Koletzko et al
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In addition, bismuth-based triple therapy may be less costly than the
other options; however, concerns regarding the palatability of
bismuth potentially affecting adherence should also be considered.
Conflicting data exist regarding the benefit of longer
duration of therapy for first-line regimens in adults (142,144).
A systematic review of therapy in children found no benefit from
longer duration of therapy (131). In contrast, a recent meta-analysis
of studies in children suggested that longer duration of therapy was
associated with improved eradication rates (7). Similarly, a meta-
analysis comparing sequential therapy with standard triple
therapy showed higher eradication rates with longer duration of
triple therapy up to 14 days (142). Therefore, based on these data,
recommended duration of therapy is 7 to 14 days, taking into
consideration cost, compliance, and side effects. Suggested doses
are given in Table 1.
Recommendation 20
A reliable noninvasive test for eradica-
tion is recommended at least 4 to 8 weeks following completion
of therapy.
Agree: 93% (AR 53%, A 27%, AS 13%, DS 7%). Grade
of evidence: low.
Comment on Recommendation 20:
Even when children become asymptomatic after treatment,
it is recommended that the success of treatment regardless of the
initial endoscopic findings be evaluated. The absence of symptoms
does not necessarily mean the infection has been eradicated (30).
Particularly in children who had PUD, persistence of infection
would warrant additional treatment. Reliable tests to monitor
successful eradication include the
13
C-UBT and a monoclonal
ELISA for detection of H pylori antigen in stool. A follow-up
endoscopy is not routinely indicated unless other causes of
ulceration (eg, eosinophilic gastroenteropathy, Crohn disease) are
suspected or if biopsies are needed for culture and antibiotic
susceptibility testing.
Recommendation 21
If treatment has failed, there are 3
options recommended:
1.
EGD, with culture and susceptibility testing, including
alternate antibiotics if not performed before guide therapy.
2.
FISH on previous paraffin-embedded biopsies if clarithro-
mycin susceptibility testing has not been performed before
guide therapy.
3.
Modify therapy by adding an antibiotic, using different
antibiotics, adding bismuth, and/or increasing dose and/or
duration of therapy.
Agree: 100% (AR 29%, A 43%, AS 28%) Grade of
evidence: not applicable
.
Comment on Recommendation 21:
Primary antibiotic resistance adversely affects treatment
outcomes (see comment for recommendation 20). In addition, a
12-year observational study from Belgium demonstrated secondary
resistance following treatment in 39 of 87 strains obtained from
children who had failed initial therapy (122). The present study
suggests that development of secondary antibiotic resistance
may be common in children. Thus, if possible, primary culture
with antibiotic sensitivity testing should be performed to
guide second-line therapy in an H pylori–infected child who has
failed initial therapy.
If primary culture and sensitivity testing is not available, then
the choice of second-line therapy must take into account the initial
therapy administered and avoid readministering an antibiotic that
was previously provided (145). Another option available at some
centers is FISH to detect primary clarithromycin resistance on
previously obtained biopsies (65,129,146). Clarithromycin should
only be used as part of second-line therapy if the strain is found to
be sensitive.
If it is not possible to perform a primary culture, then the
following therapeutic regimens are suggested as second-line or
salvage therapy.
Quadruple
therapy:
PPI
þ metronidazole þ amoxicillin þ
bismuth. Quadruple therapy is the recommended second-
line therapy in most guidelines (8,15); however, this regimen
is complicated to administer. Furthermore, bismuth salts are
not universally available.
Triple therapy: PPI
þ levofloxacin (moxifloxacin) þ amoxi-
cillin. Evaluation of regimens using fluoroquinolones,
including levofloxacin, as second-line therapy in children
is limited. In adult studies, this regimen appears to be
effective. In a recent meta-analysis of studies in adults (147),
triple therapy with levofloxacin appeared to be as efficacious
as quadruple therapy for second-line treatment; however,
there are concerns regarding increasing rates of quinolone
resistance (145). Therefore, this regimen should not be used if
the child has received fluoroquinolones previously. Although
the studies on the ideal duration of therapy for second-line
treatment are not conclusive, a longer duration of therapy of
up to 14 days is recommended.
4. CONCLUSIONS
These clinical guidelines represent updated, best-available
evidence, and expert opinion regarding the management of H pylori
infection in children in Europe and North America developed
through a rigorous standardized process. The goal of these
recommendations is to improve the care of children and adolescents
with H pylori infection. As the clinical implications of H pylori
infection in the pediatric setting continue to evolve, these guidelines
will need to be updated.
Acknowledgments:
We
thank
Kathleen Ismond,
library
scientist, who conducted searches and helped prepare tables;
Stephanie Joyce and Monica Sierra, student research assistants,
who helped prepare tables; and Andrea Schwarzer, MD, who
assisted during the consensus meeting and helped with the
voting system. We also thank Stephen Czinn, Mark Gilger,
TABLE 1. First-line treatment recommendations for H pylori
eradication in children
PPI (1–2 mg
Á kg
À1
Á day
À1
)
þ amoxicillin (50 mg Á kg
À1
Á day
À1
)
þ metronidazole (20 mg kg day)
Ã
PPI (1–2 mg
Á kg
À1
Á day
À1
)
þ amoxicillin (50 mg Á kg
À1
Á day
À1
)
þ clarithromycin (20 mg Á kg
À1
Á day
À1)
Ã
Bismuth salts (bismuth subsalicylate or subcitrate 8 mg
Á kg
À1
Á
day
À1
)
þ amoxicillin (50 mg Á kg
À1
Á day
À1
)
þ metronidazole
(20 mg
Á kg
À1
Á day
À1
)
Ã
PPI (1–2 mg
Á kg
À1
Á day
À1
)
þ amoxicillin (50 mg Á kg
À1
Á day
À1
)
for 5 days then PPI (1–2 mg
Á kg
À1
Á day
À1
)
þ clarithromycin
(20 mg
Á kg
À1
Á day
À1
)
þ metronidazole (20 mg Á kg
À1
Á day
À1
)
for 5 days
Maximum daily dose for amoxicillin 2000 mg, for metronidazole
1000 mg, for clarithromycin 1000 mg/day. PPI
¼ proton pump inhibitor.
Ã
Administered twice daily for 10 to 14 days.
JPGN
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239
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Richard Peek, Fre´de´rick Gottrand, and the members of the
ESPGHAN Working Group on H pylori Infection for their fruitful
input and the members of the GI Committee of ESPGHAN for the
critical review of the manuscript.
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Document Outline - Evidence-based Guidelines From ESPGHAN and NASPGHAN for Helicobacter pylori Infection in™Children
- SYNOPSIS
- SCOPE AND PURPOSE
- DEVELOPMENT OF GUIDELINES
- RESULTS
- Statements and Comments
- Who Should Be Tested?
- Which Diagnostic Test Should Be Applied in Which Situation?
- Who Should Be Treated?
- Which Treatment Should Be Applied in Which Situation?
- CONCLUSIONS
- Acknowledgments
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