PERSPECTIVES

TIMELINE the early phasewas in standing against

opposition from opinion leaders in gastro-
Helicobacter pylori: perspectives enterology who did not appreciate (and even
disqualified) research in the H.pylori field.
andtime trends The number of publications on H.pylori
that can be retrieved as of today is >34,000;
Peter Malfertheiner, Alexander Link and Michael Selgrad this article outlines in brief a selection of
essential findings from the beginning and
Abstract | The discovery of Helicobacter pylori three decades ago is a modern medical over time about H.pylori infection. The major
success story. It markedly changed our understanding of the pathophysiology of focus is on the clinical impact of research on
gastroduodenal diseases and led to an improvement in the treatment of diseases this infection.
related to H.pylori infection. Many of these diseases (such as ulcer disease and
mucosal associated lymphoid tissue lymphoma) have become curable, and others Microbiological characterization
(gastric cancer) might be preventable with the application of H.pylori eradication On its discovery, H.pylori was originally clas-
therapy. Since its discovery, H.pylori has also been identified as a trigger for some sified as a Campylobacter (first as C. pyloridis
extragastric diseases. Promising results in this exciting field might have a clinical effect and then as C. pylori), but was renamed and
in the near future. This Timeline gives an overview of the success of clinical research assigned to the genus Helicobacter in 1989
on H.pylori to date and highlights some future trends in this area. owing to specific taxonomic criteria.8
Production of urease was the first unique
Malfertheiner, P. et al. Nat. Rev. Gastroenterol. Hepatol. advance online publication 8 July 2014; characteristic feature of H.pylori to be
doi:10.1038/nrgastro.2014.99 identified and appreciated for its role as an
Introduction causative agent of chronic active gastritis essential factor in resisting the acidic gastric
The hardest thing to see is what is in front by ingestion of these bacteria, thus fulfill- milieu and permitting colonization of the
of your eyes, professed the German poet ing Kochs postulates.6 Much research has gastric epithelium. 912 The extraordinary
and universal genius Johann Wolfgang since been conducted on this infection, and mobility of the bacterium has been attrib-
Goethe. This saying encapsulates the missed the H.pylori-infected stomach has probably uted to flagella and flagellin (FlaA).13 Within
opportunities of generations of pathologists become the best-studied human model of a a few years the list of H.pylori virulence
who failed to interpret what they might (single) specific bacterium interacting with factors for colonizing and persisting on the
have seen in the form of Helicobacter pylori. (a single) specific type of epithelium. gastric surface epithelium, as well as factors
Several pioneers observed and described The relationship that H.pylori has with damaging the mucosa, expanded greatly.
bacteria on the gastric surface epithelium the stomach is unique. Specific virulence VacA induces vacuolation in cultured
and some even attempted to propose a factors permit H.pylori to resist the acidic cell lines14 and has been associated with a
causal relationship between these bacteria environment and persist on the gastric variety of severe clinical conditions, such
and gastric pathologies, but their tenta- surface epithelium. Eventually, inflamma- as peptic ulcer disease and gastric cancer.
tive findings remained unconfirmed. 1,2 tion of the gastric mucosa can lead to severe Following purification of VacA,15 several
Their ideas were hindered by the dogma gastroduodenal pathologies in subsets of groups succeeded in sequencing the vacA
of the acidic stomach as a sterile organ and patients. The easy endoscopic access for gene.1619 Although all H.pylori strains have
the absence of bacteria in a large series gastric mucosal sampling for histology, vacA genes, differences exist in vacA alleles
of gastric biopsy samples. 3 The discov- bacterial culture and molecular research between various strains, including two
ery of H.pylori 30years ago was a break- has certainly been a major contributor to signal sequence types and two mid-region
through. The pathologist Robin Warren the advancement of this field. Another types.20 Polymorphisms in the intermediate
first reported curved bacteria colonizing important driver has been the exemp region have subsequently been identified
the gastric mucosa and suggested that these lary interdisciplinary cooperation among as well.21 Despite significant associations of
bacteria were the cause of inflammation of gastroenterologists, pathologists, micro vacA genotypes with peptic ulcer disease20
the gastric mucosa.4 Barry Marshall and biologists, epidemiologists and researchers and gastric cancer 21 the expectation that
Warren together carried out their assiduous in basic science since the discovery of this VacA subtype classification would enable
research and succeeded in culturing the bacterium. The multidisciplinary inter prediction of the severity of gastric diseases
bacteria.5 Marshall courageously provided action in exploring H.pylori infection led has failed.
the ultimate evidence for H.pylori as a to the early foundation of the European One of the milestones of research on
Helicobacter Study Group,7 which started H.pylori virulence factors was the iden-
off with a small meeting of enthusiasts in tification of cytotoxin associated gene
Competing interests
P.M. receives honoraria for speaking from Aptalis,
1987 and has held annual meetings since. product (CagA). The immune reaction of
AstraZeneca and Nycomed. The other authors The merit of this groupas well as promot- sera from patients infected with H.pylori
declare no competing interests. ing research and educational activities in against the bacterium led to the discovery

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PERSPECTIVES
Timeline | Key developments in Helicobacter pylori clinical research
Discovery New taxonomy:
of H. pylori Helicobacter pylori
by Marshall (renamed from
and Warren Campylobacter pylori)
Bismuth dual therapy
PPIamoxicillin dual therapy
1983 1984 1987
Foundation of European H. pylori study
group (EHSG)
First demonstration of relationship between
Kochs H. pylori infection and duodenal ulcers
postulate Duodenal ulcer relapse shown to be
fulfillment reduced by bismuth monotherapy
of CagA.22 An association between serologic
responses to CagA and peptic ulcer disease
was convincingly demonstrated.23 In 1993,
the cloning of CagA, a 128-kDa protein,
achieved by two independent groups, 23,24
led to the identification of its role in
H.pylori-related diseases. Intensive research
onCagA has enabled the description of
the CagA pathogenicity island, which is a
complex functional entity.25,26 Thereafter,
the mechanism of CagA translocation into
gastric epithelial cells by typeIV secre-
tion system was revealed,27 opening up an
avenue for more precise understanding of
the pathomechanisms related to this critical
H.pylori virulence factor. In 2008, thefirst
direct pathogenic effect of CagA on the
gastric mucosa was demonstrated invivo
in transgenic mice expressing CagA in the
stomach.28 The functional overexpression
of phosphorylated CagA was associated
not only with the development of gastric
epithelial hyperplasia and adenocarcinoma,
but also with myeloid leukaemias and Bcell
lymphomas. The same was not the case in
phosphorylation-resistant CagA mice.
CagA and the Cag pathogenicity island have
a crucial role in H.pylori-associated patho-
genesis through multiple direct and indirect
molecular mechanisms.
Neutrophil activating protein (NapA)29
and outer inflammatory protein A (oipA)30
have been shown to induce gastric inflam-
mation and are associated with peptic ulcer
disease. The observation that some H.pylori
bind to epithelial cells led to identification
of blood group antigen-binding adhesin
(BabA),31 which binds to Lewis antigens
(most strongly to Lewis b) and is associ-
ated with increased proliferation of epi-
thelial cells, inflammation, and increased
2 | ADVANCE ONLINE PUBLICATION
H. pylori suggested to be a Sydney System for
risk factor for gastric cancer the classification
of gastritis
Other Helicobacter
species discovered Start of vaccine
e.g. H. felis and H. bilis trials
1989 1990 1991 1992
First trial to confirm H. pylori eradication
as a definitive cure for duodenal ulcer
H. pylori noninvasive testing with
13
C-urea breath test
Compliance and resistance are
recognized as challenges in therapy
risk of peptic ulcer disease and preneo-
plastic gastric conditions. 3234 Two addi-
tional virulence factors are associated with
the development of peptic ulcer disease:
induced-by-contact-with epithelium gene
(IceA1)35 and duodenal ulcer promoting
gene A (DupA).36 However, to date these
virulence factors do not have a direct effect
on clinical management, but continue to be
a topic for further investigation. Another
important step in H.pylori research was the
sequencing of the entire H.pylori genome
(1,667,867 base pairs).37
Clinical effects of infection
The clinical effects of H.pylori infection are
heterogeneous and the spectrum of associ-
ated manifestations is wide. H.pylori infec-
tion always causes chronic active gastritis,
but up to 80% of infected patients are esti-
mated to remain asymptomatic. The first
documented complication of H. pylori
infection was peptic ulcer disease in 1984.5
A decade later, H.pylori became recognized
as the principal aetiological agent in gastric
mucosa associated lymphoid tissue (MALT)
lymphoma and gastric cancer.38 Lymphoma is
the first neoplastic disease that can be cured
by a short course of antibiotics. The chal-
lenge now is the fight against gastric cancer;
strategies directed towards prevention have
been developed and in part implemented in
clinical practice.
In search of the explanation for the
diverse clinical outcomes of H.pylori infec-
tion (in particular the development of sig-
nificant gastroduodenal complications),
the severity, extension and topographic
pattern of chronic gastritis (that is, pheno-
typic expression) has been recognized to
be critically important. Two main forms of
2014 Macmillan Publishers Limited. All rights reserved
Updated Sydney System (revised
at the Houston Gastritis Workshop)
Maastricht I Consensus report
Screen-and-treat strategy proposed
Eradication trials: MACH 1, MACH 2, DU MACH, GU MACH
1994 1996 1997 1998
WHO classifies H. pylori as a
class I carcinogen
Inverse
NIH recommends H. pylori eradication relationship
in peptic ulcer disease between
H. pylori
Ulcer healing trials with PPItriple and GERD
therapies proposed
gastritis are now proposed to be associated
with specific diseases: antrum-predominant
gastritis is associated with duodenal ulcer,
and multifocal atrophic pangastritis (or
corpus-predominant gastritis) is associated
with gastric cancer.39
The inflamed stomach is also considered
to be a potential trigger for diseases outside
the stomach, including autoimmune and
systemic disease. This intriguing relationship
has been studied increasingly since the turn
of the new millennium. The challenge in this
area is to separate the wheat from the chaff
as most reports are limited by indicating
associations but no clues for causality.
How H.pylori infection persists despite a
rigorous active immune response and why
and how it progresses to severe clinical com-
plications in a subset of individuals are still
burning issues. Moreover, the question of
whether H.pylori can even exert beneficial
effects under certain circumstances (and if
so, why), continues to stimulate intensive
research. The key developments in clinical
research over the past 30years are illustrated
in Figure 1 (Timeline).
Peptic ulcer disease
Recognition of H.pylori as the principle
cause of peptic ulcer disease, and the dem-
onstration that permanent cure of peptic
ulcer could be achieved by eradication
of this bacteria, changed the history of
this disease and led to the Nobel Prize in
Physiology or Medicine being awarded to
Warren and Marshall in 2005.40
The first step in understanding the rela-
tionship between H.pylori and peptic ulcer
disease was the observation of the constant
association of pyloric Campylobacter (as
H.pylori was defined in 1989) with peptic
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 PERSPECTIVES

Maastricht II First randomized controlled Bismuth quadruple therapy revisited Nonbismuth

Consensus Report trial of H. pylori eradication quadruple
for gastric cancer prevention therapies
Maastricht IV/Florence Consensus Report
Relationship between
H. pylori and other extragastric Maastricht III Probiotics proposed as an adjunct therapy
diseases revealed Consensus Report in H. pylori eradication

2000 2001 2004 2005 2008 2010 2012 2013 2014

New quadruple therapies: Start of vaccine trials with bacterial vectors

Sequential and recombinant antigens in humans
Concomitant
Observational
trial: H. pylori Screen-and-treat strategies
eradication might be most effective approach Screen-and-treat
Many other Helicobacter prevents gastric Nobel prize for in gastric cancer prevention strategies become
species discovered cancer Marshall and Warren Is mass eradication the way to go? popular

ulcer disease.5,41 The finding that suppres-
sion of H.pylori with monotherapy or dual
therapies led to a reduced relapse rate of
duodenal ulcers was the next piece in the
puzzle. 41,42 Compared with H 2-receptor
antagonists, bismuth monotherapy proved
to be superior at preventing duodenal ulcer
relapses (with a therapeutic gain of 10%
fewer ulcer relapses in favour of bismuth
monotherapies). The effect was explained
by the fact that bismuth consistently clears
or suppresses the infection in some patients
and succeeds at eradicating the infection in
around 10% of patients. This benefit of 10%
fewer duodenal relapses when compared
with treatment with H 2-receptor antago-
nists41 enabled the prediction for the first
time that cure of the infection equals cure
of the ulcer.
The development of more effective
therapiesincluding acid suppression with
the PPI omeprazole in different combina-
tions with bismuth salts, metronidazole and
tetracyclineprovided the definitive proof
that eradication of H.pylori leads to perma-
nent cure of ulcer disease with no relapses.42
The idea that ulcer healing was the result of
curing the H.pylori infection and not just a
consequence of simultaneous acid suppres-
sion was strengthened by the finding that
ulcer healing can be achieved by antibiotic
regimens in the absence of concomitant
acid suppression.43
In parallel to clinical trials, mechan
istic studies have completed the picture of
H.pylori as the key player in peptic ulcer
disease. The sequence of steps leading from
H.pylori infection to a peptic duodenal
ulcer has been elucidated in great detail. In
duodenal ulcer disease, H.pylori induces
antrum-predominant gastritis that leads to
hyperchlorhydria. Mechanisms involved in
the upregulation of gastric acid secretion
are hormonal as well as neural in nature.
Hormonal changes are led by H.pylori-
induced local suppression of somatostatin,
which in turn results in hypergastrinaemia
and consequent acid hypersecretion. 44
H.pylori also leads to impairment of neural
inhibitory reflexes on acid secretion, which
further contributes to acid hypersecretion.45
These effects can be reversed by cure of the
infection. Gastric acid hypersecretion pro-
motes the generation of gastric metaplasia
in the duodenum, which in turn can be
colonized and infected by H.pylori, leading
to inflammation of the duodenal mucosa.
Facultative factors (for example, smoking)
might also contribute to duodenal ulceration,
but require synergy with H.pylori infection.46
The switch from understanding peptic
ulcer disease to be an acid-driven disease
to being caused by an infectious immuno
pathogenetic entity has markedly changed
the clinical management of this condition.
In addition, an immense field for research
into gastric mucosal immunity and repair
phenomena has opened up.
Several novel bacterial virulence factors
that exhibit a significant association with
peptic ulcer disease (see section on virulence
factors) have been identified over the years.47
The often postulated ulcerogenic strain20
of H.pylori, however, has not yet been
identified and probably never will be. The
complexity of H.pylori-driven peptic ulcer
disease means that all aspects of bacteria,
host and environmental factors need to work
in synergy to cause peptic ulcer disease.
Clinical management of peptic ulcer
disease has led to changes in the prevalence
of specific causal factors. Current trendsin
peptic ulcer disease indicate an increase
in NSAID-induced peptic ulcers and an
increased prevalence of H.pylori negative,
non-NSAID peptic ulcers.48 This phenom-
enon is more pronounced in certain parts
of the Western hemisphere and reflects the
decreasing prevalence of H.pylori in these
populations.49 From a clinical perspective,
careful aetiological assessment is needed
for each patient followed by appropriate
individualized therapeutic management.
Lymphoma
Another major breakthrough in H.pylori
research was the discovery of the patho
genetic role of H.pylori in the pathogenesis
of MALT lymphoma. As lymphoid tissue is
normally absent in healthy gastric mucosa,
prelymphoid tissue is acquired as a result
of colonization by H.pylori.50,51 The first
evidence for an association of H.pylori
with gastric MALT lymphoma was obtained
from carefully conducted histopathological
studies on a large cohort of endoscopically
obtained gastric mucosal specimens.38,50
The prevalence of lymphoid follicles in
those specimens was closely associated
with colonization by H.pylori.38,50 In a large
cohort of 110 patients with MALT lym-
phoma, 92% were infected with H.pylori,38
further strengt hening the hypothesis of
a causal link. The next important step in
proving causality was the empiric trial
of H.pylori eradication in patients with
MALT lymphoma.52 This study provided
proof of principle by showing that eradi-
cation of H.pylori infection in six patients
led to regression of low-grade Bcell gastric
MALT lymphoma. 52 Several large clini-
cal trials confirmed complete and lasting
regression in >70% of patients with MALT

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PERSPECTIVES

Timeline | Discovery of the causal association between Helicobacter pylori infection and MALT lymphoma

H. pylori discovery Discovery of t(11;18)(q21;q21) H. pylori eradication Patients with minimal histological residuals
as the most frequent translocation performed despite of MALT lymphoma can be followed up with a
in MALT lymphoma negative H. pylori tests watch-and-wait strategy

High H. pylori prevalence in H. pylori eradication performed CagA-positive H. pylori Decreasing incidence
patients with MALT lymphoma in high-grade MALT lymphoma strains associated with of MALT lymphoma
t(11;18)(q21;q21)

1985 1990 1995 2000 2005 2010

First report of MALT lymphoma API2MALT is involved in Unique H. pylori isolates found
regression after H. pylori eradication oncogenesis of MALT lymphoma in patients with MALT lymphoma

Lymphoid follicles associated Confirmation of H. pylori eradication Poor response to H. pylori eradication in
with H. pylori colonization as cure in low-grade MALT lymphoma patients with t(11;18)(q21;q21) translocation

Abbreviation: MALT, mucosal associated lymphoid tissue

lymphoma. Onthe basis of such evidence,
H.pylori eradication became the current
standard of treatment for low-grade MALT
lymphomas.53 However, to further deepen
the knowledge and understanding of this
topic, multiple additional studies have been
conducted. A remarkable finding is that
most patients with minimal histological
residuals of gastric MALT lymphoma
who have undergone successful H.pylori
eradication have no further progression
of the disease. 54 Translated into clinical
practice, this finding means that patients
with minimal lymphoid residuals can be
followed up with a watch-and-wait strat-
egy instead of starting chemotherapy, and
remission is likely to continue even after
many years of follow up. 53 Following the
observation of a clinical response in patients
with low-grade MALT lymphoma, complete
remission has been achieved in >50% of
patients with high-grade MALT lymphoma
after successful H.pylori eradication.55,56
Furthermore, H.pylori eradication should
also be considered in H.pylori negative
MALT lymphoma; a response is seen in up
to 30% of such patients57 owing to difficul-
ties with current diagnostic tests consist-
ently detecting H.pylori in the setting of
MALT lymphoma.58
However, successful H.pylori eradication
with long-standing remission of low-grade
MALT lymphoma does not always prevent
H.pylori-related tumorigenesis or gastric
adenocarcinoma.59 Close follow up is there-
fore necessary as denovo tumours can arise
or MALT lymphoma relapse can occur.60
Updated consensus-based recommendations
provide an excellent summary of progress
inthe area of gastric MALT lymphoma.59
The pathogenesis of MALT lymphoma is
linked to H.pylori-triggered, Tcell mediated
proliferation of Bcells via activation of the
CD40 pathway.61 Inflammatory mechanisms
promote Bcell proliferation along with inhi-
bition of apoptosis.62 Several genetic abnor-
malities have been associated with MALT
lymphoma; the most clinically relevant is
the translocation t(11,18)(q21;q21), which
is found in >25% of patients.6365 Extensive
analyses have identified specific rearrange-
ment of the apoptosis inhibitor gene BIRC3
(also known as API2) and MALT1 genes,
creating a new fusion gene API2MALT1
that is involved in oncogenesis of MALT
lymphoma.66 From a clinical perspective,
t(11,18)(q21;q21) translocation is most rel-
evant as it is associated with failure of MALT
lymphoma regression after H.pylori eradica-
tion.67,68 In a large series of patients, t(11,18)
(q21;q21)-positive MALT lymphoma did
not respond to H.pylori treatment, regard-
less of tumour stage.68 According to current
recommendations, translocation t(11;18)
(q21;q21) should be tested for to identify
patients with a probable failure of response
to H.pylori eradication.57
A number of studies have been performed
to identify the role of H.pylori-related vir-
ulence factors in MALT lymphoma. No
association has been found between CagA
positive strains and MALT lymphoma,69 but
CagA positivity is more frequently found in
high-grade MALT Bcell lymphoma than
in low-grade lymphoma.70 H.pylori infec-
tion with CagA positive strains was strongly
associated with t(11;18)(q21;q21) trans
location in gastric MALT lymphoma, sug-
gesting a potential role of CagA in a subset of
MALT lymphomas.71 A study in CagA trans-
genic mice showed development of gastric
epithelial hyperplasia, adenocarcinomas,
myeloid leukaemias and Bcell lympho-
mas in the presence of functionally active
phosphorylated CagA. This finding was the
first demonstration of the direct oncogenic
potential of H.pylori by its production of
CagA.28 Many issues remain uncertain; for
example, some H.pylori strains found in
patients with MALT lymphoma are missing
the Cag pathogenicity island, VacA and
other virulence factors (unlike in peptic
ulcer disease or gastric cancer). 72,73 The
model of gastric MALT lymphoma remains
of great interest in immunological and onco-
logical research. Figure 2 (Timeline) gives
an overview of the important steps in gastric
MALT lymphoma research.
Gastric cancer
From a clinical perspective, gastric cancer is
now the primary challenge on the scene in
H.pylori research. Even in their first com-
munication in The Lancet in 1984,5 Warren
and Marshall made a reference to the poten-
tial association of bacterial gastritis with
gastric cancer.
The first indication that H.pylori infec-
tion might be a risk factor for gastric cancer
came from epidemiological studies.39,74 On
the basis, mainly, of epidemiological evi-
dence, the IARC (International Agency for
Research on Cancer, part of the WHO) clas-
sified H.pylori infection as a class 1 carcin
ogen in 1994.75 Causality and mechanisms
of H.pylori infection in gastric cancer have
since been investigated in various invitro
and invivo models. Studies on a Japanese
Mongolian gerbil model have defined
H.pylori as a complete carcinogen able to
induce gastric adenocarcinoma without any
co-carcinogens. 76 Although this idea has
been challenged by studies that have not
confirmed H.pylori as a complete carcin
ogen, no doubt has ever been cast on the
carcinogenic potential of H.pylori.77

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A number of animal studies, as well as
experimental work on H.pylori-infected
cell culture models, lend indirect support
to strengthen the causal association
between H.pylori and the development
of gastric cancer.78,79 In primates infected
with H.pylori, it was found that synergism
ofH.pylori infection with other factors, such
as intake of nutrient carcinogens, was essen-
tial for development of gastric neoplasia.80 In
human gastric carcinogenesis, the concept
that is currently best supported by the evi-
dence is that a defined genetic predisposition
is required for the inflammatoryimmune
response to H.pylori infection sh ifting
towards to the neoplastic pathway.81 Fur
thermore, direct pathogenic action of the
bacteria in gastric carcinogenesis has also
been indicated.81 Genetic variants of the
most relevant bacterial virulence factors
for gastric cancer development involve dif-
ferent allotypes of VacA82 and CagA;79,83,84
CagA translocated into the host cell by the
complex typeIV secretion system behaves as
a classic oncogene.85
Host-related aspects of H.pylori-driven
gastric carcinogenesis have been revealed
by the discovery of single nucleotide poly
morphisms (SNPs) of cytokines involved
in the human inflammatory response to
H.pylori infection.86,87 Following the report
on IL1 polymorphisms (and the strong
biological plausibility of an association with
gastric cancer given the associated increased
release of IL1 in gastric mucosa), the
number of known host susceptibility gene
polymorphisms has been extended and
includes the adaptive as well as the innate
immune system.88,89 Genome-wide associa-
tion studies of structural gene aberrations
have opened new avenues and contributed
to the identification of new factors involved
in gastric carcinogenesis.90
Individual pathogenetic factors all need
to be taken into account given that gastric
cancer is the result of a complex interplay
involving bacterial virulence, host suscepti
bility genes91 and environmental factors
(with particular reference to carcinogenic
nutrients, such as salt 92).
Molecular mechanisms involved in the
progression from chronic active inflam
mation to gastric atrophic changes and
intestinal metaplasia share many of the
molecular pathways known from other
tumours in the digestive tract. Howe ver,
gastric carcinogenesis has some unique
traits as well; 81,93 in animal experiments
as well as human studies, the focus is now
directed towards immune mechanisms,
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY ADVANCE ONLINE PUBLICATION | 5
including imbalance of Tcell subsets and
the interplay between immunosuppressive
and immunostimulating cytokines.94,95
Epidemiological, basic and translational
studies have all made essential contribu-
tions to establishing the link between
H.pylori and gastric cancer; however, the
ultimate and most relevant support has
come from clinical observations and trials.
The pivotal observational study by Uemura
et al. in 2001 reported that only patients
infected with H.pylori developed gastric
cancer over time.39 Several studies were per-
formed after this initial observation and the
results have been summarized in a meta-
analysis.96 These studies clearly point to the
fact that H.pylori eradication is effective at
preventing gastric cancer.96
The benefit of H.pylori eradication is
best achieved in the subset of patients who
are not yet at the stage of severe gastritis
with preneoplastic changes.97 The presence
of preneoplastic gastric changes is gener-
ally considered the point of no return, and
progression to gastric cancer might occur
in spite of successful H.pylori eradication.
However, this concept has been challenged
by observations that even in conditions of
established early gastric cancer H.pylori
eradication might prevent the recurrence
of disease after endoscopic resection.98
In the latest consensus conferences
therecommendation expressed has been
to embrace screen-and-treat strategies in
asymptomatic individuals at risk as well
as in populations at high and intermediate
risk. It is recommended that first-degree
relatives of patients with gastric cancer
undergo a screen-and-treat strategy in
an attempt to prevent gastric cancer by
eradicating H.pylori.99,100 Various analy-
sis models indicate that H.pylori screen-
and-treat strategies might be the most
effective approach in gastric cancer pre-
vention.101,102 It is possible that H.pylori
eradication might be recommended in all
patients who test positive for H.pylori infec-
tion. Likewise, the presence of H.pylori-
associated gastritis might become an
indication for treatment independent of
whether or not it is accompanied by symp-
toms. Screen-and-treat strategies need to
be adapted to local circumstances, taking
into consideration the prevalence of the
infection, incidence of gastric cancer, and
local sanitary resources. Screening strate-
gies can be based on noninvasive H.pylori
testing via the 13C urea breath test, faecal
antigens, serology (including pepsinogens)
or endoscopy 103
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PERSPECTIVES
Extradigestive diseases
The first reports on the relationship of
H.pylori infection with extragastric systemic
diseases date back as early as 1994. 104,105
Theunderlying rationale for H.pylori as a
trigger for extradigestive diseases is that the
inflammatory state of the gastric mucosa
leads to the systemic release of inflamma-
tory mediators with a consequent negative
effect on several organs. Even a modest
increase in Creactive protein and fibrino-
gen levels in the blood is associated with an
increased, albeit modest, risk of vascular
and cardiovascular diseases.106108 Another
suggested mechanism involved in H.pylori-
related extradigestive manifestations is the
molecular mimicry of H.pylori-expressed
antigens with antigens expressed on the
gastric surface epithelium. This phenom-
enon has been interpreted as a possible
mechanism contributing to arteriosclerotic
plaque formation.109
The list of potential effects of H.pylori
outside the stomach include cardiovascular,
metabolic and neurodegenerative con
ditions, as well as hepatobiliary, pancreatic
and colorectal diseases.110112 Studies indi-
cate that H.pylori infection might act as a
trigger for skin diseases such as urticaria as
well as rheumatic disorders.113,114 However,
data are conflicting for all these conditions,
and the interpretation of their relevance
remains inconclusive. H.pylori, especially if
harbouring the CagA pathogenicity island,
is likely to act as a trigger that, in the pres-
ence of host predisposing factors, leads to
the clinical expression of systemic diseases.
In some cases H.pylori might be a minor
factor contributing to disease development
owing to the persistent inflammatory state
of the gastric mucosa.
If strong scientific criteria for evidence
are applied, there are only three conditions
currently confirmed for which H.pylori is
a relevant factor for morbidity. These con
ditions include idiopathic thrombocyto-
penic purpura, unexplained iron-deficiency
anaemia and vitamin B12 deficiency.100 How
ever, even in the presence of these condi-
tions it is essential that other possible and
more likely causes are excluded first. So, for
iron-deficiency anaemia, chronic blood loss
from a lesion in the gastrointestinal tract or
coeliac disease need to be excluded before
H.pylori is considered as the most likely
cause. If this is the conclusion, H.pylori
eradication is recommended.100 Renewed
interest has been directed toward H.pylori
as a weak risk factor for the development
of colorectal neoplasias.115 Aspects of this
PERSPECTIVES
relationship deserve detailed investigations,
including the role of the gut microbiota
in the context of the presence or absence
ofH.pylori.
Benefits of H.pylori infection?
Owing to the long evolutionary cohabita-
tion of H.pylori with humankind, it has
been suggested that this bacterium might
confer some benefits to individuals. Clinical
observations led to reports that H.pylori
eradication in patients with duodenal ulcers
increased the risk of denovo development of
erosive GERD;116 this claim became an issue
of intensive debate.117,118 The hypothesis that
H.pylori is a protective factor against the
development of GERD has been rebutted
as data are conflicting and even contra
dictory.119 Reasons for discordant results
are the different selection of patients and
controls, differences in ethnic character-
istics and of cultural habits of populations
in various geographical regions, and dif-
ferences in the methodologies applied
for the assessment of the H.pylori status.
Nevertheless, two meta-analyses refute that
H.pylori is a relevant factor with influence
on symptom severity, symptom evolution
and treatment response in GERD. 120,121
However, the dispute as to whether H.pylori
confers protection to the oesophagus is
ongoing among gastroenterologists. In the
latest Maastricht IV/Florence Consensus
Report, the conclusion on this area of con-
troversy was that the relationship between
H.pylori and GERD is of no clinical rele-
vance.100 Arecommendation was made for
H.pylori eradication in patients who require
long-term administration ofPPIs.100
The negative association of H.pylori
with atopic and allergic diseases gives some
indication for causality. 122 A considerate
hypothesis in the relationship with asthma
and skin allergy is related to hygiene con-
ditions in childhood. H.pylori infection
in early childhood drives primarily a TH1
immune response and thus deviates the
immunoreactivity from a T H 2 allergo-
genic immune response. This TH1 immune
response might protect infected individu-
als from development of atopic diseases.
To substantiate these ideas, animal experi-
ments were carried out in which neonate
mice infected with H.pylori were found to
have a reduced hyperergic reaction of the
bronchiolar system.123,124 These phenom-
ena observed in animal experiments open
new perspectives for research and more
detailed insights in immune mechanisms
of atopic diseases that might ultimately
6 | ADVANCE ONLINE PUBLICATION
lead to translation into clinical manage-
ment. One speculation is that infection
early in childhood and during adolescence
might be beneficial, whereas if the infec-
tion persists beyond that timescale and
with progressive aging, H.pylori becomes
the dominant pathogenetic risk factor for
peptic ulcer disease and gastric malignan-
cies.125 The pathogenetic role of H.pylori in
gastroduodenal pathologies has been eluci-
dated and confirmed in the past 30years;
thus the clinical action of eradication of
H.pylori is warranted. Nevertheless, it is
critically important that research continues,
remains unbiased and does not succumb
todogmata.
Development of H.pylori therapy
Monotherapies
The development of effective therapies
against H.pylori infection has progressed
in steps. The first therapeutic studies were
already being performed in 1984, reporting
suppression or elimination of the micro
organism with improvement and transient
healing of gastritis.126,127 However, eradica-
tion with monotherapies such as amoxy-
cillin, tripotassium dicitrate bismuthate
and metronidazole was minimal. With all
monotherapies, clearance of the bacteria
was transient.128,129 The positive effects of
amoxycillin monotherapy were misleading
as clearance of the bacteria and histological
improvement lasted only a short time and
recrudescence of the infection appeared
in almost all cases 4weeks after stopping
amoxicillin treatment.130
Bismuth subsalicylate produced similar
results with only transient histological
improvement, although eradication was
achieved in ~10% of patients.131 Notably,
improvement of dyspeptic symptoms was
frequent with bismuth treatment in patients
infected with H.pylori.129,132 Combination of
bismuth salts with a single other antibiotic
agent led to some improvement in treat-
ment, but more importantly set the ground
for complex and effective regimens.
Bismuth-based triple therapies
The failure of bismuth-based dual thera-
pies led to the development of bismuth-
based triple therapies. The combination of a
bismuth salt, metronidazole and tetracycline
became a successful eradication treatment
for H.pylori infection,133 and was able to
overcome metronidazole resistance.134 Acid
suppressants were added to bismuth-based
antibiotic therapies and an increased effi-
cacy was observed in several studies, with
2014 Macmillan Publishers Limited. All rights reserved
95% eradication success.135,136 One study
also proved that administration of bismuth,
tetrac ycline and metronidazole alone
without antacid treatmentwas effective
for peptic ulcer healing.43 However, the com-
plexity of these regimens was often met by
poor patient compliance in clinical practice.
PPIs and amoxicillin
The introduction of PPIs in 1989 created
new opportunities for a variety of therapeu-
tic regimens for cure of H.pylori infection.
Initial observations suggested that PPIs
could clear H.pylori colonization in the
gastric antrum owing to their strong acid
suppression; for a time PPIs were believed to
be able to achieve this effect alone. However,
it was demonstrated that PPIs only led to
clearance of H.pylori in the antrum but not
in the body mucosa. Therefore, the require-
ment for at least one antibiotic became
obvious.137 PPI and amoxicillin combination
therapy was the first therapeutic strategy
that proved to be effective for eradication
of H.pylori, achieving eradication rates of
up to 80%.138140 The concept was based on
the idea that elevation of gastric pH would
increase the bi oavailability and efficacy
ofamoxicillin.
Triple therapy
The most important modification of anti-
biotic regimens started in 1994 with the
creation of a simple, safe and effective short-
term (1week) therapy with a PPI in combi-
nation with clarithromycin and tinidazole or
metronidazole. Consistently high eradica-
tion rates were achieved with this regimen in
different countries, and this therapy became
the standard of care for almost a decade.
The first randomized controlled trial was
performed by Bazzoli and colleagues in
1998, with an eradication rate of 93.8%.141
Comparable results have been reported
with clarithromycin in combination with
amoxicillin and a PPI.142144
Following the successful introduction
of PPI-based triple therapy, well-designed
large trials have focused on dose finding
and optimal duration of treatment. In the
MACHI study clarithromycin in combi
nation with omeprazole and metronidazole
or amoxicillin given for 1week produced
high eradication rates and was a well-
tolerated therapy, with high patient compli-
ance.145 This study included patients with
duodenal as well as gastric ulcers, and con-
firmed the high efficacy of clarithromycin-
based triple therapies. Both regimens (that is,
with metronidazole or amoxicillin) were safe
www.nature.com/nrgastro

and effective for eradication of H.pylori and
healing and prevention of ulcer disease.146,147
In 1999 the MACH2 study was performed,
including H.pylori culture from gastric
biopsies, and with this study the concept of
antimicrobial-susceptibility driven therapy
was introduced.148 At the time, clarithro
mycin and metronidazole resistance were
3% and 27%, respectively. The importance
of local resistance monitoring and the
effect of primary and secondary resistance
on treatment failure started from there. To
date, clarithromycin-based triple therapy
remains the first therapeutic option in areas
with clarithromycin resistance of <15%.100
Resistance and compliance
For more than a decade (19972007)
standard triple therapy was considered the
most effective therapeutic regimen, but
owing to its wide use, and the increasing
use of antibiotics in general, this regimen
lost more and more efficacy because
of increasing antibiotic resistance. The
problem of H.pylori resistance to anti
biotics and consecutive treatment failure
was first observed in 1990.149,150 The first
reports focused on metronidazole-resistant
H.pylori strains, with resistance rates to
metronidazole already comparably high at
around 2030%.151 Metronidazole resist-
ance was observed at an increased rate in
patients with treatment failure, which was
one of the reasons to establish new treat-
ment regimens, including clarithromycin-
based triple therapy. In 1996, susceptibility
to clarithromycin and metronidazole was
determined in a large number of H.pylori
samples. 152 At the time clarithromycin
resistance was low (4.5%) and metroni
dazole resistance was high (37.8%). The low
clarithromycin resistance (which was also
seen in other studies) further strengthened
the use of clarithromycin-based therapies
as a first-line option in the treatment of
H.pyloriinfection.153
Other concerns with PPI-based triple
therapy that were raised comparably early
were possible adverse effects and poor
patient compliance.134,154,155 In particular,
adverse effects have been recognized as a
reason for discontinuation of therapy and
as a possible reason for treatment failure.
Astudy from Graham and colleagues in
1992 investigated factors that predicted
eradication success. 149 Interestingly, the
most important factor was patient com-
pliance. The eradication rate was reduced
from 96% to 69% when only 60% of the
medication was taken. 154 Thus, several
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY ADVANCE ONLINE PUBLICATION | 7
investigators demanded a simple, effective
and short treatment regimen coupled with
few adverse effects.
Variations of quadruple therapy
In the past decade increasing failure rates
for H. pylori eradication (<80%) with
clarithromycin-based standard triple ther
ap ies have been reported, 156,157 and the
demand for effective therapies is becom-
ing more important. New treatment regi-
mens have substituted clarithromycin with
a quinolone. Further modifications have
been made by the successful introduction of
quadruple therapies. So-called sequential
therapy is a dual 10-day therapy consisting
of a PPI and amoxicillin given for the first
5days followed by triple therapy including
a PPI, clarithromycin and tinidazole for the
remaining 5days. This therapy was tested in
Italy in 2000, which indicated a high success
rate of eradication of 9094%.158 Sequential
therapy was found to cure infection even
in patients with clarithromycinresistance.
Another treatment modification using the
same antibiotic agents is a quadruple therapy
called concomitant therapy. This four-drug
regimen contains a PPI, clarithromycin,
amoxicillin and metronidazole, which are
all given together twice daily for 510days.
When this regimen was compared with
sequential therapy, similar results were
achieved in terms of efficacy and safety.
Ahead-to-head noninferiority trial showed
that these regimens are equivalent.159,160
These results were confirmed in further
randomized controlled trials.156 Another
new approach is hybrid therapy which con
sists of dual therapy with a PPI and amoxi
cillin for 7days followed by concomitant
quadruple therapy with a PPI, amoxicillin,
clarithromycin, and metronidazole for
another 7days. This regimen provides excel-
lent eradication rates in patients with dual
resistance to clarithromycin and metroni
dazole,160 but is inferior compared to sequen-
tial and concomitant therapy.161 Optimized
non-bismuth-based quadruple therapies
apply modified hybrid and concomitant
therapies for 14days. These therapeutic regi-
mens have demonstrated eradication rates of
>90% in areas with high clarithromycin and
metronidazoleresistance.162
Probiotics have been proposed as adju-
vants but at present only a few solid scien-
tific data are available; 163 this idea needs
to be explored further. In current clinical
practice probiotics might be useful if gastro
intestinal adverse effects develop during
H.pylori eradication.
2014 Macmillan Publishers Limited. All rights reserved
PERSPECTIVES
Vaccine trials
To fight antibiotic resistance, the best
solution would be the development of
avaccine.164 As early as 1992 studies of oral
vaccination with bacterial antigens and a
mucosal adjuvant demonstrated a protec-
tive immune response in a mouse model
infected with H.felis.165167 In animal studies
a therapeutic effect of H.pylori vaccination
has been reported.168 Oral vaccination with
bacterial antigens then started to be tested
in humans with the aim of prevention of
H.pylori infection.168
Unfortunately all attempts to develop a
successful vaccine for humans have failed.
Bacterial factors including urease, VacA,
CagA and NapA have been used for vaccina-
tion purposes.168 Urease administered either
as a soluble protein or expressed in bacte-
rial vectors in healthy volunteers has been
able to elicit an immune response but was
not protective against H.pylori exposure.169
Amixture of recombinant H.pylori antigens
(VacA, NapA and CagA) induced a signifi-
cant immune response in H.pylori-negative
healthy volunteers after intramuscular
administration of the vaccine together with
aluminium hydroxide as an adjuvant.170 All
human studies had in common that the
administration of antigens together with
an adjuvant elicited a variable moderate-
to-strong immune response but could not
provide protection from H.pylori infec-
tion. More basic insights into the immune
response in patients infected with H.pylori
in early and chronic infection is crucial
for moving on with the development of a
prophylactic and even therapeutic vaccine.
Conclusions
The discovery of H.pylori redirected our
understanding of certain gastroduodenal
diseases. Successful H.pylori eradication
leads to healing of chronic active gastritis,
reverses inflammation of the mucosa and
cures symptoms in a large subset of patients
with dyspeptic symptoms. In addition,
H.pylori eradication cures peptic ulcer
disease and most gastric MALT lympho-
mas. The challenge now is gastric cancer.
Well-defined concepts in prevention strat-
egies are expected to be implemented and
tailored to meet local needs in all parts of
the world. The optimal solution is that all
patients with H.pylori infection get offered
treatment when they present to their physi
cians, independent of whether they have
symptoms or not. Gastric cancer research
must identify underlying pathogenic mech-
anisms and investigate new potential targets
PERSPECTIVES
for treatment development. Huge expecta-
tions rest on more detailed understand-
ing of how H.pylori drives the immune
response and which mechanisms are related
to clinical outcome. The potential benefits
of H.pylori in protection against atopic dis-
eases in childhood need further explanation
as well.
H.pylori treatment with current drugs is
at a turning point. The efficacy of established
treatment regimens has markedly decreased
and the major challenge is increasing anti-
biotic resistance. New drug combinations
with different administration strategies cur-
rently provide acceptable results for H.pylori
eradication, with appropriate safety and
controllable adverse effects.171 Looking to
the future, global eradication of the bacteria
should remain a focus for development of
a vaccine.
Department of Gastroenterology,
Hepatologyand Infectious Diseases, Otto-
vonGuericke University Hospital, Leipziger
Strasse 44, D39120 Magdeburg, Germany
(P.M., A.L., M.S.).
Correspondence to: P.M.
peter.malfertheiner@med.ovgu.de
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Author contributions
P.M. and M.S. contributed to researching data,
discussion of content, writing and reviewing/editing
the manuscript before submission. A.L. contributed
to researching data and writing the article.