Management of Helicobacter pylori infectiondthe
Maastricht IV/ Florence Consensus Report
Peter Malfertheiner,
1
Francis Megraud,
2
Colm A O’Morain,
3
John Atherton,
4
Anthony T R Axon,
5
Franco Bazzoli,
6
Gian Franco Gensini,
8
Javier P Gisbert,
9
David Y Graham,
10
Theodore Rokkas,
11
Emad M El-Omar,
7
Ernst J Kuipers,
12
The
European Helicobacter Study Group (EHSG)
ABSTRACT
Management of Helicobacter pylori infection is evolving
and in this 4th edition of the Maastricht consensus
report aspects related to the clinical role of H pylori were
looked at again in 2010. In the 4th Maastricht/Florence
Consensus Conference 44 experts from 24 countries
took active part and examined key clinical aspects in
three subdivided workshops: (1) Indications and
contraindications for diagnosis and treatment, focusing
on dyspepsia, non-steroidal anti-inflammatory drugs or
aspirin use, gastro-oesophageal reflux disease and
extraintestinal manifestations of the infection.
(2) Diagnostic tests and treatment of infection.
(3) Prevention of gastric cancer and other complications.
The results of the individual workshops were submitted
to a final consensus voting to all participants.
Recommendations are provided on the basis of the best
current evidence and plausibility to guide doctors
involved in the management of this infection associated
with various clinical conditions.
Management of Helicobacter pylori infection is
evolving and so is our understanding of the role of
the bacterium in various clinical conditions.
The European Helicobacter Study Group
first
took the initiative in 1996 in Maastricht to gather
dedicated experts in the
field and to review and
discuss all relevant clinical data to arrive at
recommendations for the clinical management
of
H
pylori
infection.
1
The
Maastricht
conference has since been repeated at intervals of
4e5 years.
2 3
Aspects related to the clinical role of H pylori
were re-examined in Florence 2010 with the
Maastricht methodology. The meeting focused on
indications, diagnostics and treatments of H pylori
infection with additional emphasis on disease
preventiondin particular, prevention of gastric
cancer.
In the 4th Maastricht/Florence Consensus
Conference 44 experts from 24 countries took
active part. Experts invited were chosen for their
expertise and contribution to H pylori research and/
or guideline methodology.
METHODOLOGY AND STRUCTURE OF
CONFERENCE PROCESS
Current guidelines from Japan, Asia-Paci
fic, North
America and Europe, as well as the
‘Maastricht
methodology
’ were reviewed at an introductory
plenary session.
Working groups examined the following three
topics relating to H pylori infection:
<
Indications and contraindications for diagnosis
and treatment, focusing on dyspepsia, non-
steroidal anti-in
flammatory drugs (NSAIDs)
or aspirin use, gastro-oesophageal re
flux disease
and
extraintestinal
manifestations
of
the
infection.
<
Diagnostic tests and treatment of infection.
<
Prevention
of
gastric
cancer
and
other
complications.
Individual questions were submitted to all
participants, debated and modi
fied according to
a standard template. After a thorough discussion
of each statement in one of the three working
groups the strength of recommendations and the
strength of the supporting evidence were graded
according to the slightly modi
fied system, used in
our previous report
3
(table 1). In a few statements
where there are only experimental studies in
support of the biological plausibility but no
treatment studies, we did not quote the evidence,
but
graded
the
recommendation
for
the statement. For some statements the grade of
recommendation did not match the level of
evidence because either studies focusing on the
same topic reported con
flicting results or the
interpretation of the studies by the experts led
to a different grade of recommendation than
expected from the level of evidence. Aspects
related to the implementation of recommenda-
tions in daily clinical practice have also been
taken into account.
The statements and recommendations were
edited and
finally agreed at the concluding
plenary session. Consensus was de
fined as support
by 70% or more of the experts. The recommenda-
tions resulting from this rigorous process are
reported in the manuscript.
Commentaries on statements were written by
the chairmen of individual workshops based on
the data presented by the person assigned to
elaborate
the
question;
they
include
the
conclusion of discussions held at the meeting.
Coauthors were involved in the
final editing of the
commentaries. The previous strong recommenda-
tions for H pylori eradication, such as in
patients with peptic ulcer disease,
3
has been
recon
firmed.
1
Department of
Gastroenterology, Hepatology
and Infectious Diseases,
Otto-von-Guericke University of
Magdeburg, Magdeburg,
Germany
2
Department of Bacteriologie,
INSERM U853, Universite
´
Bordeaux Segalen 2, Bordeaux,
France
3
Department of
Gastroenterology, Adelaide and
Meath Hospital, Trinity College,
Dublin, Ireland
4
School of Clinical Sciences,
University of Nottingham,
Nothingham, UK
5
Spire Leeds Hospital, Leeds, Uk
6
Internal Medicine and
Gastroenterology, University of
Bologna, Bologna, Italy
7
Division of Applied Medicine,
Aberdeen University, Aberdeen,
UK
8
University of Firenze, Firenze,
Italy
9
Hospital Universitario de La
Princesa, IP and CIBEREHD
Madrid, Spain
10
VA Medical Center Houston,
Texas, USA
11
Department of
Gastroenterology, Henry-Dunant
Hospital, Athens, Greece
12
Erasmus MC University
Medical Center, Rotterdam, The
Netherlands
Correspondence to
Professor Peter Malfertheiner,
Department of
Gastroenterology, Hepatology
and Infectious Diseases,
Otto-von-Guericke University of
Magdeburg, Leipziger Str 44,
Magdeburg 39120, Germany;
peter.malfertheiner@med.ovgu.
de
For author footnote see end of
the article.
Accepted 22 February 2012
646
Gut 2012;61:646e664. doi:10.1136/gutjnl-2012-302084
Guidelines
THE TEST-AND-TREAT STRATEGY (WORKSHOP 1)
Statement 1: A test-and-treat strategy is appropriate for uninvestigated dyspepsia in
populations where the H pylori prevalence is high (
$20%). This approach is subject to
local costebenefit considerations and is not applicable to patients with alarm
symptoms, or older patients (age to be determined locally according to cancer risk)
Evidence level: 1a
Grade of recommendation: A
Statement 2: The main non-invasive tests that can be used for the test-and-treat
strategy are the UBT and monoclonal stool antigen tests. Certain validated serological
tests can also be used.
Evidence level: 2a
Grade of recommendation: B
H pylori is the most successful human pathogen infecting an
estimated 50% of the global population. It is a common and
potentially curable cause of dyspepsia and peptic ulcer disease.
Test and treat is a strategy involving a non-invasive test being
carried out in patients with dyspepsia to assess whether H pylori
is present and then treatment of the infection if it is found; it
thus avoids the cost, inconvenience and discomfort of endos-
copy. The test-and-treat strategy is appropriate in situations
where the risk of the patient having gastric cancer is low; in
most countries this means dyspeptic patients below a locally
determined age cut-off point (depending on local incidence of
gastric cancer in different age groups) and without so-called
‘alarm’ symptoms or signs which are associated with an
increased risk of gastric cancer. These include weight loss,
dysphagia, overt GI bleeding, abdominal mass and iron de
ficient
anaemia. In young patients with dyspepsia, testing for and
treating H pylori is preferable to a strategy of just prescribing
a proton pump inhibitor where the H pylori prevalence is $20%.
The Urea Breath Test (UBT) and stool antigen testing are
acceptable non-invasive tests for H pylori infection in this
setting. For UBT, sensitivity is 88e95% and specificity 95%e
100%.
4
Stool antigen testing may be somewhat less acceptable
to patients in some cultures but is equally valid, with a sensi-
tivity of 94% and a speci
ficity of 92%.
5
A signi
ficant symptom
bene
fit can be obtained from a test-and-treat strategy. This has
been validated in a primary care cohort, which is the setting
where most dyspeptic patients present.
6
Test and treat must be
used cautiously in populations with a low H pylori prevalence as
it becomes less accurate in this setting.
7
In patient groups with
an increased risk of gastric cancer (over a local age cut-off point
or with alarm symptoms or signs), the test-and-treat strategy is
not recommended and a strategy of
‘endoscope and treat’ is
preferred.
8
In addition, non-invasive tests are less accurate in
older adults.
9
Acid and functional dyspepsia
Statement 3: H pylori eradication produces long-term relief of dyspepsia in one of
12 patients with H pylori and functional dyspepsia; this is better than any other
treatment.
Evidence level: 1a
Grade of recommendation: A
Statement 4: H pylori can increase or decrease acid secretion depending on the
intragastric distribution of inflammation.
Evidence level: 2b
Grade of recommendation: B
Many dyspeptic patients found to be infected by H pylori have
functional dyspepsia (FD) rather than peptic ulcer disease. The
bene
fit from eradication treatment is less clear in these patients
than in those with peptic ulcer. At a population level, there is a
signi
ficant improvement in the resolution of persistent symp-
toms in the H pylori eradication group (95% CI 6% to 14%)
compared with placebo, with a number needed to treat of 12.
10
Treatment response is dif
ficult to predict for the individual
patient. H pylori eradication led to a 25% reduction in dyspepsia
consultations between 2 and 7 years of follow-up in a rando-
mised controlled trial.
11
Another study suggested that H pylori
eradication provides a similar long-term symptom reduction in
patients with dyspepsia and duodenal ulcer.
12
The cost-effec-
tiveness of H pylori eradication in FD varies between regions. In
Europe H pylori eradication is cost-effective compared with
offering no treatment but in the USA it is less certain that this is
a cost-effective approach owing to the higher cost of eradication
treatment.
13
Overall response, however, is much better in
regions where H pylori is highly prevalent and this is where it
may be most cost-effective. Patients with FD in Asia would
bene
fit from treatment for H pylori infection with an increased
chance of symptom resolution as high as 3.6e13 after its
eradication.
14 15
Successful treatment of H pylori infection may increase,
decrease or have no overall effect on acid secretion. The effect on
acid secretion depends upon the initial pattern of gastritis.
People with an antral-predominant, body-sparing, non-atrophic
gastritis have high stimulated acid production due to low
somatostatin production in the antrum, higher gastrin levels
compared with non-infected controls and so higher acid
production by the unin
flamed gastric corpus. Clinically,
duodenal ulcer and non-ulcer dyspepsia are common in this
group. In contrast, people with body-predominant and atrophic
gastritis affecting the gastric body have low acid production
despite the same hormonal changes. This phenotype is associ-
ated with premalignant gastric lesions and with an increased
Table 1
Grades of recommendation and evidence levels in support of the recommendations formulated
in the Maastricht IV / Florence Consensus Report
Grade of
recommendation*
Evidence level
Type of studies
A
1
1a
Systematic review of randomised controlled trial (RCT) of good
methodological quality and with homogeneity
1b
Individual RCT with narrow CI
1c
Individual RCT with risk of bias
B
2
2a
Systematic review of cohort studies (with homogeneity)
2b
Individual cohort study (including low quality RCT, eg
<80% follow-up)
2c
Non-controlled cohort studies/ecological studies
3
3a
Systematic review of caseecontrol studies (with homogeneity)
3b
Individual caseecontrol study
C
4
Case series/poor quality cohort or caseecontrol studies
D
5
Expert opinion without explicit critical appraisal or based on physiology,
bench research or ‘first principles’
*The highest grade of recommendation does not always correspond to the highest evidence level.
Gut 2012;61:646e664. doi:10.1136/gutjnl-2012-302084
647
Guidelines
risk for gastric cancer.
16 17
Therefore it can be concluded that the
pattern of gastritis and associated disturbance in acid secretion
determine disease outcomes. In both situations, treatment of
H pylori resolves the gastritis and leads to an, at least partial,
correction of the high or low acid state. While interesting, these
changes in acid production after H pylori treatment have no
proven clinical relevance and they should not be used as an
argument to treat or not to treat H pylori.
H pylori and gastro-oesophageal reflux disease (GORD)
Statement 5: On average, H pylori status has no effect on symptom severity, symptom
recurrence and treatment efficacy in GORD. H pylori eradication does not exacerbate
pre-existing GORD or affect treatment efficacy.
Evidence level: 1a
Grade of recommendation: A
Statement 6: Epidemiological studies show a negative association between the
prevalence of H pylori and the severity of GORD and incidence of esophageal
adenocarcinoma.
Evidence level: 2a
Grade of recommendation: B
At a population level, H pylori and GORD are negatively
associated,
18
and this is most marked for cytotoxin-associated
gene product (CagA)-positive strains of H pylori. A review of 26
studies showed a rate of H pylori infection in patients with
GORD of 39% compared with 50% in controls.
19
Similarly, the
sequelae of GORD, such as Barrett
’s oesophagus and oesopha-
geal adenocarcinoma, are also less common in infected individ-
uals.
20
However, eradication of H pylori in populations of
infected patients, on average, neither causes nor exacerbates
GORD.
21e23
Therefore the presence of GORD should not
dissuade practitioners from H pylori eradication treatment where
indicated. In addition, the long-term ef
ficacy of proton pump
inhibitor (PPI) maintenance treatment for GORD is not in
flu-
enced by H pylori status.
24
An interesting phenomenon has been
observed whereby some H pylori-positive patients may develop
a sudden-onset, transient epigastric pain shortly after the start
of PPI treatment for re
flux, but this again should not affect
decisions on management, and more studies are needed to
con
firm and explore this phenomenon.
25
H pylori, aspirin and NSAIDs
Statement 7: H pylori infection is associated with an increased risk of uncomplicated
and complicated gastroduodenal ulcers in NSAID and low-dose aspirin (acetosalicylic
acid (ASA)) users.
Evidence level: 2a
Grade of recommendation: B
Eradication reduces the risk of complicated and uncomplicated gastroduodenal ulcers
associated with either NSAID or low-dose ASA use.
Evidence level: 1b
Grade of recommendation: A
Statement 8: H pylori eradication is beneficial before starting NSAID treatment. It is
mandatory in patients with a peptic ulcer history.
Evidence level: 1b
Grade of recommendation: A
However, H pylori eradication alone does not reduce the incidence of gastroduodenal
ulcers in patients already receiving long-term NSAID treatment. They require continued
PPI treatment as well as eradication treatment.
Evidence level: 1b
Grade of recommendation: A
Statement 9: Testing for H pylori should be performed in ASA users with a history of
gastroduodenal ulcer. The long-term incidence of peptic ulcer bleeding is low in these
patients after receiving eradication even in the absence of gastroprotective treatment.
Evidence level: 2b
Grade of recommendation: B
Both H pylori infection and NSAID use are independent risk
factors for the development of peptic ulcer disease and associated
bleeding and these conditions are uncommon in those who do not
have either risk factor. It has been shown that there is an increased
risk when these factors are both present.
26
There is a difference
between naive users and those receiving long-term NSAID
treatment in the bene
fits of searching for, and eradicating, H pylori.
In naive users it is clearly bene
ficial to eradicate H pylori.
27 28
In
those who are already long-term users there is no clear
bene
fit.
29e31
A meta-analysis showed, however, that eradication
seems less effective than treatment with a maintenance PPI for
preventing NSAID-associated ulcers.
32
Further research is needed
on whether selective cyclo-oxygenase-2-inhibiting NSAIDs may
be safer options. For aspirin, even given at low dose, H pylori
eradication can prevent gastropathy and should be undertaken in
patients with a history of peptic ulcers.
33 34
In such patients, the
residual risk of peptic ulcer bleeding due to continued aspirin use
after H pylori has been successfully treated is very low.
35
H pylori and PPIs
Statement 10a: Long-term treatment with PPIs in H pylori-positive patients is
associated with the development of a corpus-predominant gastritis. This accelerates
the process of loss of specialised glands, leading to atrophic gastritis.
Evidence level: 1c
Grade of recommendation: A
Statement 10b: Eradication of H pylori in patients receiving long-term PPIs heals
gastritis and prevents the progression to atrophic gastritis. However, there is no
evidence that this reduces the risk of gastric cancer.
Evidence level: 1b
Grade of recommendation: A
Acid suppression affects the pattern and distribution of gastritis
and favours corpus-predominant gastritis. It may accelerate the
process of loss of specialised glands, leading to atrophic gastritis.
In H pylori-positive patients, active inflammation increases in
the corpus and decreases in the antrum during PPI treatment.
36 37
This shift in gastritis appears to be accompanied by an increase
in corpus atrophy.
38 39
Studies in H pylori-infected Mongolian
gerbils showed that PPI treatment accelerated the progression to
gastric cancer.
40 41
But there are no such data in humans.
H pylori and intestinal metaplasia
Statement 11a: There is accumulating evidence that after H pylori eradication, corpus
function may improve. However, whether this is associated with regression of atrophic
gastritis remains equivocal.
Evidence level: 2a
Grade of recommendation: B
Statement 11b: There is no evidence that H pylori eradication can lead to regression of
intestinal metaplasia.
Evidence level: 2a
Grade of recommendation: B
H pylori eradication has the potential to prevent gastric
cancers.
42
A study on the effect of H pylori eradication on
patients with premalignant lesions showed that eradication may
prevent their progression.
43
It is thought though that a so-called
‘point of no return’ may exist in the histological cascade from
chronic gastritis to adenocarcinoma after which eradication is
unlikely to prevent gastric cancer. It appears that by the time
intestinal metaplasia (IM) has become established eradication,
although retarding the progression of IM, cannot completely
prevent gastric cancer.
44 45
This is not necessarily true for gastric
atrophy, where there appears to be a discrepancy between the
effect of eradication in the corpus and in the antrum. A meta-
analysis of 12 studies on 2658 patients concluded that eradication
of H pylori results in significant improvement in atrophy in the
corpus but not in the antrum, but has no effect on gastric IM.
46
H pylori and gastric mucosa-associated lymphoid tissue (MALT)
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