not permitted.

It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
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COPYRIGHT 2016 EDIZIONI MINERVA MEDICA

2016 EDIZIONI MINERVA MEDICA

Online version at http://www.minervamedica.it Panminerva Medica 2016 December;58(4):304-17

REVIEW

A 2016 panorama of Helicobacter pylori

infection: key messages for clinicians
Rinaldo PELLICANO 1 *, Davide G. RIBALDONE 1, Sharmila FAGOONEE 2,
Marco ASTEGIANO 1, Giorgio M. SARACCO 1, 3, Francis MGRAUD 4

1Unit of Gastroenterology, Molinette Hospital, Turin, Italy; 2Institute for Biostructures and Bioimages (CNR) c/o Molecular Biotechnology

Center, University of Turin, Turin, Italy; 3Department of Oncology, University of Turin, Turin, Italy; 4Bacteriology Laboratory, INSERM
U 1053, Universit de Bordeaux, Bordeaux, France
*Corresponding author: Rinaldo Pellicano, Unit of Gastroenterology, Molinette-SGAS Hospital, Via Cavour 31, 10126 Turin, Italy.
E-mail: rinaldo_pellican@hotmail.com

A B S T RAC T
The discovery that the bacterium Helicobacter pylori (H. pylori) lives in the stomach has rendered out-of-date the concept of inhospitality of the
gastric environment. H. pylori is able to survive in this organ through mechanisms of acid resistance and colonization factors. The prevalence
of H. pylori infection varies depending on age, socioeconomic class, and country. Currently, in the context of a decreased trend in H. pylori
prevalence, it is estimated that about 50% of the worlds human population are carriers of the microorganism, with a higher rate in developing
countries than in developed countries. In this review, the authors provide an overview on the current status of knowledge on the clinical aspects
of H. pylori infection, with a focus on diagnostic and therapeutic challenges. In particular, the choice of the test to diagnose H. pylori infection,
defined as invasive or non-invasive based on the need or not of biopsy specimens obtained during an endoscopy, depends on the clinical context.
Regarding bacterial eradication, it is important that treatment should be decided locally on the basis of local antibiotic usage, documented anti-
biotic resistance and outcome data. For patients having previously received a clarithromycin-containing regimen, this drug should be avoided as
a second-line therapy. In this case, the tailored therapy (to test clarithromycin susceptibility before prescribing drugs) or the so-called quadruple
therapy, and triple levofloxacin-based therapy should be proposed. Rifabutin- and furazolidone-based treatments should be reserved for further
treatment.
(Cite this article as: Pellicano R, Ribaldone DG, Fagoonee S, Astegiano M, Saracco GM, Mgraud F. A 2016 panorama of Helicobacter pylori infec-
tion: key messages for clinicians. Panminerva Med 2016;58:304-17)
Key words: Helicobacter pylori - Peptic ulcer - Stomach neoplasms - Lymphoma - Therapy - Vaccines.

H elicobacter pylori (H. pylori) is a slow-growing,

micro-aerophilic, Gram-negative bacterium, usu-
ally acquired during childhood, whose natural habitat
is the luminal surface of the gastric epithelium. The dis-
covery of H. pylori, first isolated and cultured by the
Australian investigators Warren and Marshall in 1982,1
has revolutionized the world of gastroenterology, with
or other proprietary information of the Publisher.
the presence of spiral bacteria in the stomach.2 Since
the human stomach is an unfriendly place for most bac-
teria, in order to survive in the gastric environment,
H. pylori has developed a repertoire of acid resistance
mechanisms which, together with colonization factors,
help the bacterium to overcome the mucous barrier. In
particular, via the enzyme urease, the microorganism

an invaluable benefit for millions of persons worldwide. creates a cloud of acid neutralizing chemicals around it,
Furthermore, it has rendered out-of-date the concept of offering protection from the acid.3
inhospitality of microorganisms in the gastric environ- The prevalence of H. pylori infection, which has a
ment, after a long history of unrecognized reports on ubiquitous distribution, varies depending on socioeco-

304 Panminerva Medica December 2016

not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
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COPYRIGHT 2016 EDIZIONI MINERVA MEDICA
H. PYLORI INFECTION PELLICANO
nomic factors and age. In the context of a decreased trend
in H. pylori prevalence, at least 50% of the worlds hu-
man population are carriers of the microorganism, with
a prevalence much higher in developing countries than
in developed countries.4 H. pylori infection is acquired
in the preschool period and the risk declines sharply af-
ter 5 years of age. The higher prevalence in older age
groups is thought to reflect a cohort-effect related to
poorer living conditions in the past during childhood.5
In this review, we provide an overview of the current
status of knowledge concerning the clinical aspects of
H. pylori infection, with a focus on diagnostic and ther-
apeutic challenges, as well as the usefulness of translat-
ing some bench research to the clinical setting.
Clinical impact of H. pylori infection
Gastroduodenal diseases
Gastritis and Peptic Ulcer
H. pylori infection is now accepted as the most im-
portant cause of gastritis and peptic ulcer (PU) in hu-
mans. The pathophysiology of PU is thought to involve:
1) mucosal damage mediated by the virulence factors of
the bacterium (the main factors being cytotoxins, ure-
ase, phospholipases, and adhesins); 2) mucosal inflam-
matory response both to tissue damage and H. pylori
antigens; 3) disturbances in gastrin, somatostatin and
acid secretion; and 4) development of duodenal gastric
metaplasia. Acid secretion in the stomach is mediated
by the oxyntic cell, one of several cell types comprising
the gastric glands. The physiological stimuli includes
gastrin, histamine and acetylcholine which operate by
activation of the so-called proton pump enzyme.6 From
the topographical distribution of the gastritis, which is
closely linked with acid output, the risk of subsequent
gastroduodenal disease can be predicted. In patients
with duodenal ulcers (DU), the inflammation of the
gastric mucosa induced by the infection is most pro-
nounced in the gastric antrum and stimulates the in-
creased release of gastrin.7 The hypergastrinemia in turn
stimulates an excess acid secretion from the more proxi-
mal acid-secreting fundic mucosa, which is relatively
or other proprietary information of the Publisher.
free of inflammation. The increased duodenal acid load
induces gastric metaplasia. The metaplastic mucosa can
then become colonized by H. pylori (usually resident
in the stomach), which leads to duodenitis and then to
Vol. 58 - No. 4 Panminerva Medica 305
the ulcerative process. Thus, DU is the result of the im-
balance between duodenal acid load and the buffering
capacity of the duodenum.8
The patterns of gastritis associated with gastric ulcer
(GU) are different from those associated with DU. While
the latter is accompanied with an antrum-predominant
gastritis, the former is associated with a diffuse or a cor-
pus-predominant gastritis. The last phenotype is linked
with low acid output, gastric atrophy and a high risk of
adenocarcinoma. Disruption of the mucosal defence, as
a result of intense inflammation, is the key mechanism
leading to GU in the absence of an increased acid load.9
Before the discovery of H. pylori, ulcers were known
to recur, and for years the standard practice was to keep
patients on acid suppression maintenance drugs.9 Now,
it is well-known that eradication of the infection pro-
vides a long-term remission of both DU and GU. DU
recurrence occurs in 6% of H. pylori-cured patients
compared to 67% of H. pylori non-cured patients, and
GU recurrence occurs in 4% of the former group versus
59% of the latter.10 Thus, bacterial eradication modifies
the natural history of PU disease.
Both H. pylori infection and non-steroidal anti-
inflammatory drug (NSAID) use are independent risk
factors for the development of DU and GU and asso-
ciated bleeding. This risk increases when both factors
are present.11 While in naive NSAID users it is clearly
beneficial to eradicate H. pylori, in those who are al-
ready long-term users the benefit is less impressive.
Furthermore, it is well-known that bacterial cure alone
is not sufficient to prevent ulcer bleeding in NSAID us-
ers with high gastrointestinal (GI) risks, such as a his-
tory of ulcer bleeding.9 Hence, in clinical practice these
patients should be kept on long-term acid suppression.
Dyspepsia
Dyspepsia refers to pain or discomfort, centered in
the upper abdomen, for which patients seek medical
care.12 In the clinical setting, a crucial issue is the accu-
rate identification of patients who require further inves-
tigation to rule out serious structural diseases and those
who can safely be treated empirically. Nevertheless, it
should be considered that symptoms do not predict the
diagnosis.13
In the case of uninvestigated dyspepsia, it is possible
to apply a test-and-treat strategy. This is an approach
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
COPYRIGHT 2016 EDIZIONI MINERVA MEDICA
PELLICANO H. PYLORI INFECTION
involving a non-invasive test to assess the presence of
H. pylori infection followed by antimicrobial treatment
when appropriate. The rationale is to avoid endosco-
py.14 In this context, a test-and-treat strategy is suitable
for populations where H. pylori prevalence is 20%,
and it should be highlighted that this approach is not ap-
plicable to patients with alarm symptoms (weight loss,
dysphagia, overt GI bleeding, abdominal mass and iron-
deficiency anemia).14 Economic models suggest that in
an area with <20% H. pylori prevalence, the test-and-
treat approach may not be cost-effective.12
The umbrella term functional dyspepsia (FD) in-
cludes patients with one or more of the following symp-
toms: epigastric pain, epigastric burning, early satiation
and postprandial fullness. These should be associated
with the absence of structural disease, which is likely
to explain the symptoms, as shown by upper GI endos-
copy. The symptoms should have been present in the
last 3 months with an onset at least 6 months before
diagnosis.13 The Kyoto global consensus report on H.
pylori gastritis has specified, with a strong grade of rec-
ommendation, that H. pylori gastritis should be distin-
guished by FD, and only patients with persistent dys-
pepsia after bacterial eradication should be considered
as having FD.15 Dyspeptic symptoms persist over the
long-term in the majority of patients while periods of
remission may occur, hence FD patients often require
recurrent medical consultations and therapy.16 In Italy,
the prevalence of FD in the general population is 11%;
indeed unemployment, divorce and smoking have been
associated with an increased risk. There is no association
between FD and H. pylori infection.17 The pathophysi-
ology of FD is multifactorial and poorly understood.13
Several trials and meta-analyses have shown that cure
of H. pylori infection is associated with a small (10%)
but significant therapeutic gain compared to a placebo.
However, it should be noted that these trials are some-
what different in study design, symptom definition, as-
sessment of symptom relief, follow-up, and some may
be flawed by potential pitfalls.16 In patients with FD, the
overall response is much better and more cost-effective
in regions with a high H. pylori prevalence.14 In this
context, to confirm the uncertainties, some reports have
or other proprietary information of the Publisher.
shown that 4 years post eradication, 55% of patients
with FD versus 32% (P<0.05) of those with previous
PU, are still using acid-suppressive medications.18 The
test-and-treat strategy has gained endorsement from
306 Panminerva Medica December 2016
both several opinion leaders and International Scientific
Societies. Nevertheless, the European guidelines state
that bacterial cure produces long-term benefits in one of
12 patients with H. pylori infection and FD; this is bet-
ter than any other treatment.14
Gastric cancer
Famous as the cause of Napoleon Bonapartes death,
gastric cancer (GC) is a major global health threat be-
ing the third leading cause of cancer deaths worldwide
causing more than 720,000 deaths per year global-
ly.19 An estimated 89% of non-cardia GCs, which ac-
count for 78% of GC cases, are attributable to H. pylori
infection.20 Although in 1994 the International Agency
for Research on Cancer classified H. pylori as a group I
carcinogen, i.e. a definite cause of GC, to date the bacte-
rium is recognized as a necessary but insufficient cause
of GC. This is due to the fact that such a malignancy is a
complex, multifactorial disease caused by initiators and
other continuator agents.2
H. pylori promotes gastric carcinogenesis via mul-
tiple mechanisms. The bacterium causes chronic gas-
tric inflammation that may progress to the precancerous
changes of atrophic gastritis and intestinal metaplasia
(IM). As mentioned above, people with corpus-predom-
inant chronic gastritis and atrophic gastritis have low
acid production (hypochlorhydria). This phenotype,
its severity and its extent are closely linked to a loss
of specialized glands with an evolution toward atrophic
gastritis, premalignant gastric lesions and an increased
risk of GC.21 Chronic H. pylori infection may also con-
tribute to gastric mucosal genetic instability by hypo-
chlorhydria,22 which can promote the growth of a gas-
tric microbiome that processes dietary components into
carcinogens.23
Since the accepted model for the development of GC
consists of a series of precancerous steps, notoriously
non-atrophic gastritis, multifocal atrophic gastritis, IM
and dysplasia, prospective studies, especially those with
long term follow-up, have provided an important aid in
understanding the association between H. pylori infec-
tion and gastric carcinogenesis. The first step, i.e. the
progression of atrophic gastritis, occurred in 43% of in-
fected versus 0% of uninfected patients, during a 10-year
follow-up.24 A prospective Japanese study, involving
1526 patients followed for a mean period of 7.8 years,
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
COPYRIGHT 2016 EDIZIONI MINERVA MEDICA
H. PYLORI INFECTION PELLICANO
reported that 2.9% of infected compared to 0% of unin-
fected subjects, developed GC; the presence of severe
gastric atrophy, body gastritis or IM increased the risk.25
Yamagata et al., in a population study of 2602 subjects
40 years of age, showed a significant correlation be-
tween infection and cancer risk in men (Relative Risk
[RR] 2.59, 95% Confidence Interval [CI]: 1.03-6.50), but
not in women (RR 0.99, 95% CI: 0.36-2.68).26 Ohata et
al. reported, in a cohort of 4,655 asymptomatic individu-
als followed for 7.7 years, that the presence of H. pylori
infection was associated with chronic atrophic gastritis,
and both conditions were associated with the develop-
ment of GC. Among the 45 documented cases of GC, 43
(95.6%) developed in people who were infected with H.
pylori and 26 (57.8%) in those who suffered from chron-
ic atrophic gastritis.27 Including homogeneous groups in
a meta-analysis, the risk of progression to GC in infect-
ed patients was 1.92 (95% CI: 1.32-2.78). In particular,
considering the surveys with a follow-up of >8 years, the
odds ratio [OR] increased to a value >8.28 These obser-
vations were confirmed in the meta-analysis conducted
by the Helicobacter and Cancer Collaborative Group,
which included 1,228 GC cases, documenting a RR of
5.9 (95% CI: 3.4-10.3) of GC development in infected
patients.29 Some bacterial strains (cytotoxin-associated
gene A [cagA]-positive) determine the virulence asso-
ciated with an increased risk of GC. This is even more
evident in young patients (<40 years of age).30 However,
this finding is not universal and, in some studies, the
variation in prevalence of cagA positive strains did not
explain the geographical heterogeneity in GC rates any
better than the simple evidence of H. pylori infection.31
A meta-analysis of randomized controlled trials (RCTs)
and cohort studies, conducted on both asymptomatic H.
pylori carriers (i.e., primary prevention) and individu-
als undergoing endoscopic resection for early GC (i.e.,
tertiary prevention), supported the concept that H. py-
lori eradication effectively reduces the incidence of this
malignancy, and the magnitude of the protective effect
is greater among individuals with a higher baseline GC
risk.21 This is an argument against an absolute point-of-
no-return and has important implications supporting the
theory that H. pylori eradication is beneficial in individu-
or other proprietary information of the Publisher.
als with atrophic gastritis and/or IM. The Maastricht V/
Florence Consensus Report stated that H. pylori eradica-
tion reverse gastric atrophy if IM is not present, while
IM cannot be reversed (manuscript in publication).
Vol. 58 - No. 4 Panminerva Medica 307
Considering that the integrity of the gastric epitheli-
um is maintained by gastric stem cells which proliferate
and self-renew, giving rise to transient amplifying cells
that replace the constantly renewing epithelium, a new
field of research has emerged. Since stomach stem cells
live long enough to accumulate the multiple genetic
changes required for transformation, two models have
been postulated. In the first model, resident stem cells
may over time, in a chronically inflamed environment as
in the case of H. pylori-induced gastritis, accumulate a
series of genetic and epigenetic changes that lead to the
emergence of GC stem cells. In the second, the setting
of chronic inflammatory stress may lead to recruitment
and engraftment of bone marrow derived stem cells into
the gastric epithelium, thus contributing to GC. These
scenarios, which currently do not have clinical implica-
tions, are detailed in several manuscripts.32, 33
Gastric mucosa-associated lymphoid tissue lym-
phoma
A strong association between H. pylori infection and
gastric mucosa-associated lymphoid tissue (MALT)
lymphomas has been proven by epidemiologic, biologi-
cal, and molecular genetic studies.34 The gastric mucosa
normally contains few lymphocytes but the number in-
creases in case of H. pylori infection leading to chronic
gastritis and they can become organized in lymphoid
follicles. In a susceptible host, the MALT may evolve
to a MALT lymphoma whose growth depends on the
presence of the bacterium; these cases accumulate ge-
nomic abnormalities that are shared by some gastric
diffuse large B-cell lymphomas (DLBCL) suggesting
an increased risk of histological transformation. This
MALT lymphoma once established becomes indepen-
dent of H. pylori presence, harbors the cytogenetically
stable translocation t(11;18), lacks a methylator phe-
notype and shows fewer genomic imbalances.35 These
cases rarely transform into DLBCL, yet are associated
with more advanced stages and clinically aggressive be-
havior.33, 36 Since the treatment of the infection causes a
regression of most localized gastric MALT lymphomas,
the Maastricht V/Florence Consensus Report of the Eu-
ropean Helicobacter and Microbiota Study Group rec-
ommends H. pylori eradication as first-line treatment
for low-grade gastric MALT lymphomas (manuscript in
publication).
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
COPYRIGHT 2016 EDIZIONI MINERVA MEDICA
PELLICANO H. PYLORI INFECTION
Extragastroduodenal diseases
Over the last decades, several studies have reported
on the link between H. pylori infection and a variety of
extragastroduodenal manifestations, based on potential
mechanisms involving a low-grade inflammatory state,
molecular mimicry patterns, and interference with the
absorption of nutrients.37, 38 Although the Maastricht
V/Florence Consensus Report of the European Heli-
cobacter and Microbiota Study Group has considered
causal associations of H. pylori only with unexplained
iron-deficiency anemia, idiopathic thrombocytopenic
purpura and vitamin B12 deficiency (manuscript in
publication), other potential links cannot be ruled out.39
These encompass ischemic heart disease, liver diseases,
skin diseases, blood disorders, neurologic disorders and
others. For several of these supposed associations, the
hypothesis of an etiological role remains uncertain. The
difficulty arises from the multifactorial pathogenesis
of some diseases as well as from the epidemiological
design of the studies. Several epidemiological investi-
gations on this issue have frequently shown biases in
control selection, populations of small size, and pres-
ence of confounders, like age and socioeconomic condi-
tions. Furthermore, randomized, long-period, and large
studies on the follow-up after H. pylori eradication are
scarce.40
The possibility that H. pylori might confer benefits
to humans has engendered considerable controversy in
the literature. In this context, a possible relationship be-
tween a reduction rate of H. pylori infections and the
increased prevalence of esophageal adenocarcinoma,
childhood asthma, inflammatory bowel diseases and
microscopic colitis, has been postulated.41, 42 It could
be possible that factors associated with decreases in H.
pylori infection prevalence also lead to the emersion
of unrecognized positive associations. In this case, the
presence of H. pylori might be beneficial in childhood
(e.g. decreasing the risk of autoimmune diseases) but
more deleterious later in life (increasing the risk of GC).
Diagnostic methods
or other proprietary information of the Publisher.
Initial diagnosis
The main indications for identifying and treating H.
pylori infection are reported in Table I.
The methods to diagnose H. pylori infection can be
308 Panminerva Medica December 2016
Table I.Indications for identifying and treating H. pylori infec-
tion.
Peptic ulcer
Dyspepsia
Gastric MALT lymphoma
After resection of early gastric cancer
First-degree relatives of patients with gastric cancer
Atrophic gastritis
Unexplained iron deficiency anemia
Chronic idiopathic thrombocytopenic purpura
Vitamin B12 deficiency
classified as invasive or non-invasive, the former being
based on biopsy specimens obtained at endoscopy. The
choice of the test depends on the clinical context.
When a patient needs an upper GI endoscopy, due to
alarming symptoms or older age (generally >45 years,
but age should be determined locally according to GC
risk),14 H. pylori infection can be detected on biopsies
taken in the stomach from two topographical locations,
the antrum and the corpus. Since the inherent risk of any
biopsy procedure is sampling error, to biopsy both gas-
tric compartments (two biopsies from the antrum and
two from the corpus) increases the tests sensitivity, es-
pecially if the patient was recently treated with a proton
pump inhibitor (PPI) drug. H. pylori is recognized by
histological examination on sections stained with hema-
toxylin and eosin or Giemsa stain. Immunohistological
stainings have a special interest under such conditions
as well as when there is an endoscopic control post treat-
ment. The rapid urease test (RUT) requires the place-
ment of a biopsy specimen in a solution of urea and pH-
indicator. If H. pylori is present, its urease converts urea
to ammonia, increasing the pH and changing the color of
the dye. Recommendations for avoiding PPIs, H2 recep-
tor antagonists, and antimicrobial therapy before testing
apply to this method as well, to minimize the chance of
false negative results.43 Such tests have a sensitivity of
<90% and a specificity of >95%.44 Its interest is to al-
low an immediate prescription of eradication therapy.
Microbiological culture of H. pylori offers the possibil-
ity of performing antimicrobial susceptibility testing
(AST). The rationale behind this method relates to the
fact that, in case of clarithromycin-resistance, the rate of
success of the clarithromycin-containing triple therapy
is very low. While the cost-effectiveness may vary ac-
cording to the cost of care in a given country, the rec-
ommendation is to perform culture and AST in regions
of high clarithromycin resistance before prescription of
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
H. PYLORI INFECTION PELLICANO
the first-line therapy, in all regions before second-line
treatment if endoscopy is carried out for other reasons,
or when a second-line treatment has failed. If AST can-
not be performed with the standard method, molecular
tests can be used to detect H. pylori and clarithromycin
and/or fluoroquinolone-resistance directly on gastric
biopsies.14 Currently, polymerase chain reaction (PCR)
and real-time PCR are the most frequently used molecu-
lar methods.4
Non-invasive methods include 13C-urea breath test
(UBT), stool antigen test (SAT) and serological test. 13C-
UBT is the most accurate tool to detect H. pylori infection
and is more cost-effective than endoscopy. It is based on
the principle that, in the presence of H. pylori urease,
labelled carbon dioxide is exhaled in the expired breath
(Figure 1). 13C-UBT is a semiquantitative test of active
H. pylori infection and, in contrast to biopsy-based tests,
is not liable to sampling errors (it tests the entire stom-
ach). Hence, reports show a sensitivity and specificity
>95%. In the standard procedure, two breath collections
are obtained at baseline (8 hours of fasting, no PPIs nor
antibiotics 30 days beforehand) and 30 minutes, respec-
tively, after drinking a 100 mg dose of 13C-labeled urea
with 1.2 g of citric acid in 100 mL of water.45 Various
modified versions have been proposed.46 Samples are
analyzed for the 13C/12C ratio with a mass spectrometer.
Results are expressed as excess 13CO2 excretion per
mil, which represents 13C enrichment over and above
the baseline sample: a value 4 delta per mil is con-
sidered positive. Stopping PPIs two weeks before test-
ing allows the bacteria to repopulate the stomach and
the tests previously negative can once again become
positive.14 False positive results could be due to oro-
13/14 CO2 expired
or other proprietary information of the Publisher.
13/14 CO2 into the blood
Figure 1.Principle of the urea breath test.
Vol. 58 - No. 4 Panminerva Medica 309
COPYRIGHT 2016 EDIZIONI MINERVA MEDICA
evaluation of antibodies to H. pylori in serum, a mark-
has some drawbacks. The most important is its marked
analyzed for 13C/12C ratio with a mass spectrometer
Urease
tion of therapy, to avoid false negative results due to
pharyngeal bacteria, if breath samples are taken within
10-15 minutes of swallowing the isotope. False nega-
tive results may occur if the UBT is performed within
seven days of taking antibiotics, bismuth salts or PPIs.
Because 13C-urea is a non-radioactive isotope, samples
can be sent for analysis by post to a central laboratory,
which allows 13C-UBT to be performed in outlying hos-
pitals and in primary health care clinics.45 The infection
can also be detected by identifying H. pylorispecific
antigens with the SAT using polyclonal or monoclonal
antibodies.47 The monoclonal-antibody test (which has
a specificity and a sensitivity of 95%) is more accurate
than the polyclonal-antibody test. Hence, in case of a
validated laboratory-based monoclonal test, the diag-
nostic accuracy could be equivalent to UBT.14 Rapid in-
office polyclonal tests are reputed to have a low level of
accuracy.4 For the SAT, the patient should also stop tak-
ing PPIs and should avoid taking antimicrobial agents
2 weeks and 4 weeks before testing, respectively, since
these medications may suppress the bacterial load and
reduce the sensitivity of testing. Given that H. pylori
infection is a chronic one, for serologic testing only IgG
detection is considered and the favored method is the
enzyme-linked immunosorbent assay (ELISA). A meta-
analysis showed an overall sensitivity and specificity of
85% and 79%, respectively, for serologic testing.48 The
er of exposure and not necessarily of true infection,
variability in accuracy according to the kits available.
Moreover, since after treatment a return to seronega-
tivity may take months or even years, this test cannot
be used to confirm a successful treatment. In practice,
serology should be considered when other diagnostic
tests could be falsely negative, such as in patients with
bleeding ulcers, gastric atrophy, or recent use of PPIs
and antibiotics.14
Confirmation of eradication
Due to the fact that there is no correlation between
symptoms and H. pylori infection, the clinical improve-
ment after bacterial treatment is not synonymous with
eradication. Hence, it is important to confirm H. pylori
eradication by means of 13C-UBT or SAT. These tests
should be performed 4 weeks or longer after comple-
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
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COPYRIGHT 2016 EDIZIONI MINERVA MEDICA
PELLICANO H. PYLORI INFECTION
suppression of H. pylori.14 Eradication can also be con-
firmed by testing during repeat endoscopy in patients
for whom this approach is required. This is true in pa-
tients with GU, on the basis that some GUs that initially
appear to be endoscopically and histologically benign
may eventually prove to be malignant. The American
Society for Gastrointestinal Endoscopy recommends
surveillance endoscopy in patients whose GU appears
endoscopically suspicious for malignancy, even if bi-
opsy samples from the index endoscopy are benign.
Surveillance endoscopy is also suggested for patients
who remain symptomatic despite an appropriate course
of antisecretory therapy for 8-12 weeks, to rule out re-
fractory PU and occult malignancy.49
It has been shown that H. pylori infection/eradica-
tion has no effect on an early rebleeding rate, in patients
with PU bleeding, after endoscopic hemostasis.50 On
the other hand, delaying treatment until after discharge
leads to reduced compliance or loss to follow-up with-
out receiving treatment.51 Current consensus in upper
GI bleeding recommends performing a delayed test,
4-8 weeks after the bleeding episode;52 if a physician is
worried about the possibility of losing the patient during
the follow-up, a suboptimal strategy is to search for IgG
antibodies to H. pylori, not conditioned by the bleeding,
but with the uncertainty to treat a portion of subjects
who are not in fact infected.
Treatment of H. pylori infection
Since a profound acid suppression is required to erad-
icate H. pylori infection, over the past 30 years mul-
tidrug regimens consisting of a PPI and two or three
antibiotics, among clarithromycin, amoxicillin, and
metronidazole, have been used as first choice in treating
H. pylori infection. Nevertheless, in different countries,
conflicting results on efficacy have been reported using
these regimens. Although on the basis of their identi-
cal pharmacodynamic and very similar pharmacokinet-
ic properties, all marketed PPIs have been considered
equivalent, a recent meta-analysis has concluded that
esomeprazole and rabeprazole have the best efficacy.53
Nevertheless, the variability in effectiveness is essen-
or other proprietary information of the Publisher.
tially due to antimicrobials. The choice of the most ap-
propriate treatment should be based on local antibiotic
usage, documented antibiotic resistance and outcome
data. Thus, recommended therapies should vary region-
310 Panminerva Medica December 2016
ally.14 The most widely used treatment remains the stan-
dard triple therapy, consisting of a PPI, amoxicillin and
clarithromycin. Several alternatives are available and
various combinations of traditional drugs have been in-
vestigated in order to overcome the increasing H. pylori
antibiotic resistance, in particular, to clarithromycin.
Considering that an acceptable eradication rate is de-
fined differently in the literature (>75%,54 90-95% 55),
clinicians should use only what works locally.56, 57
First-line treatment
Since clarithromycin is unusually acid stable,58 it is
the most common antibiotic used in regimens for the
elimination of H. pylori. The dominant mechanisms
underlying the development of clarithromycin resis-
tance are several point mutations in domain V of the
23S ribosomal RNA (rRNA) gene, which result in de-
creased affinity between the ribosome and the drug and
leads to the absence of clarithromycin binding to the
50S ribosome subunit and, thus, failure of influencing
protein synthesis. It is noteworthy that there is well-
documented evidence for cross-resistance to macrolides
and that clarithromycin resistance may originate from
the previous consumption of macrolides to treat other
diseases such as respiratory infections.59, 60 The almost
doubling of the prevalence of clarithromycin resistance
in Europe over 10 years, from 9.8% to 17.5%,61 could
have be anticipated given the genetic basis of this resis-
tance (i.e., vertically transmitted point mutations) and
the long-lasting character of H pylori infection when
left untreated. Clarithromycin resistance has a major
negative impact on the efficacy of the recommended
first-line triple therapy and a progressive increase in the
prevalence of resistance to this antibiotic may limit its
use.62 For this reason the recent Maastricht V/Florence
Consensus Report of the European Helicobacter and
Microbiota Study Group has recommended a thresh-
old of 15% to define countries with low and high clar-
ithromycin-resistance rates (manuscript in publication).
By contrast, metronidazole resistance, although highly
prevalent, can be partly overcome and is of secondary
importance. Moreover, it remains at the same high level
as 10 years ago, with no major changes in the regional
distribution.14, 63 Based on a multicenter study published
in 2013, the resistance rate of H. pylori in Europe is
34.9% for metronidazole, 17.5% for clarithromycin,
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
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COPYRIGHT 2016 EDIZIONI MINERVA MEDICA
H. PYLORI INFECTION PELLICANO

14.1% for levofloxacin, 1.1% for rifabutin, 0.9% for
tetracycline and 0.7% for amoxicillin. The same study
assessed the fits of models and the degree of ecological
association between antibiotic use and resistance data.
A significant association was found between fluoroqui-
nolone use and the proportion of levofloxacin resistance
in H. pylori, and between the use of long-acting mac-
rolides and clarithromycin resistance.63 A prevalence
of clarithromycin resistance higher than 15% has now
been reached in most countries in Western/Central and
Southern Europe.63 Data of the multicentre European
study have shown that in Italy, the primary rate of H.
pylori clarithromycin resistance was 26.7%,63 with a
variety in regional distribution.64 In the period between
1996 and 2006, in Central (Lazio region) and South-
ern (Puglia region) Italy, with a standard clarithromy-
cin-based triple therapy, there has been a dramatically
significant decrease of H. pylori eradication rate (from
90% to 51%, P=0.001).65 In 2002, in Turin, Northern
or other proprietary information of the Publisher.
Italy, a triple therapy with clarithromycin, amoxicillin
and a PPI for 7 or for 10 days, achieved an eradica-
tion rate of 68% and 76%, respectively. Lengthening
the treatment conferred no major advantage in case of
clarithromycin resistance. Although these values were
significantly lower, compared to those reported earlier,
in the year 2012 the same regimen was equally effec-
tive (70.7% and 73.4% for 7 and 10 days of treatment,
respectively) than 10 years ago.66 In France, a survey
on H. pylori antimicrobial resistance was performed
during the year 2014. The bacterial strains showed high
rates of clarithromycin (22.2%) and metronidazole re-
sistance (45.9%), and a moderate rate of resistance to
levofloxacin (15.4%).67
As regards the triple therapy, a meta-analysis includ-
ing 21 RCTs showed that the rate of eradication increased
by 4% with the use of a 10 day scheme compared to 7
days and by 5% with the use of a 14 day scheme com-
pared to 7 days; absolute differences showed a marginal

Figure 2.Helicobacter pylori therapy in regions with low clarithromycin resistance.

Vol. 58 - No. 4 Panminerva Medica 311

not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
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COPYRIGHT 2016 EDIZIONI MINERVA MEDICA
PELLICANO H. PYLORI INFECTION

clinical significance (eradication rate of approximately
90%).68 Furthermore, increasing the PPI dose may in-
crease the H. pylori eradication rate by 8-12%.69 In Fig-
ure 2 therapeutic regimens are proposed in case of low
clarithromycin resistance rates.
In countries with high clarithromycin-resistance rates
(Figure 3) the Maastricht V/Florence Consensus Report
of the European Helicobacter and Microbiota Study
Group suggests to prescribe a 14 day quadruple therapy
(unless that a 10 day period has proven effective locally)
including three antibiotics (amoxicillin, clarithromycin
and metronidazole) and a PPI, namely the concomi-
tant therapy or a bismuth-containing quadruple therapy
(with metronidazole, tetracycline and a PPI). In case of
both high clarithromycin and metronidazole resistance
(>15%) a bismuth-containing quadruple therapy should
be considered as first line (manuscript in publication).
For bismuth salts no resistance has been described;
however, considering that this drug may not be avail-
or other proprietary information of the Publisher.
able in some countries, regimens based on levofloxa-
cin, rifabutin and high dose dual (PPI and amoxicillin)
therapies are valid options. Alternative regimens, as the
so-called sequential and hybrid therapies, are no longer
recommended (manuscript in publication). The sequen-
tial therapy consists of 5 days of PPI plus amoxicillin
followed by 5 days of PPI, metronidazole and clarithro-
mycin. The hybrid therapy consists of 7 days of PPI
plus amoxicillin followed by PPI, amoxicillin, metro-
nidazole and clarithromycin for the other 7 days.70, 71
In recent years several trials, systematic reviews and
meta-analyses on the issue of these new strategies have
been published. In a systematic review and a network
meta-analysis, Li et al. showed that concomitant treat-
ments, 10 or 14 days of probiotic supplemented stan-
dard triple therapy, 10 or 14 days of levofloxacin-based
triple therapy, 14 days of hybrid treatment, might be
better alternatives for H. pylori eradication.70 The net-
work meta-analysis rather than comparing trials that

Figure 3.Helicobacter pylori therapy in regions with high clarithromycin resistance.

312 Panminerva Medica December 2016

not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
COPYRIGHT 2016 EDIZIONI MINERVA MEDICA
H. PYLORI INFECTION PELLICANO
evaluated the same treatment, extends the number and
type of trials included for clinical decision making. This
tool also allows to make indirect comparison across tri-
als and among treatments that have not been tested head
to head, as long as the trials are linked by a common
treatment arm.72 However, several weaknesses were re-
ported by the authors, mainly due to the great variety
regarding study design, antibiotic type, dose and admin-
istration frequency, and the lack of information about
antibiotic susceptibility of H. pylori.70 Accordingly,
network meta-analysis is most valid when combining
similar studies conducted in similar populations and is
unlikely to be the case for different studies from differ-
ent regions of the world, as antibiotic resistance rates
and H. pylori strains vary widely.72 A systematic review
with meta-analysis compared the results of RCTs in the
assessment of the optimal duration of sequential thera-
py versus 14-day triple therapy as first-line treatment.
Including 13 RCTs and more than 2,000 patients in the
former and in the latter groups, sequential therapy given
for 14 days was more effective than triple therapy (RR
1.09, 95%CI: 1.04-1.16). Important limitations were the
open-label design of all included trials and that the bet-
ter results were obtained in a study conducted in Tai-
wan, a country with low clarithromycin and metroni-
dazole resistance.73 Recently, a Cochrane Database of
Systematic Reviews was published. The authors evalu-
ated the difference in intention-to-treat eradication be-
tween sequential and standard triple therapy regimens
amongst the studies. Based on the results, although the
sequential therapy offers an advantage when compared
with standard triple therapy, it cannot be presented as a
valid alternative, given that neither the former nor the
latter regimen achieved optimal efficacy (90% eradi-
cation rate).74 It should be highlighted that, although it
has been reported that clarithromycin resistance could
be overcome in a number of cases during sequential
therapy,54 these important results have not been con-
firmed in all countries.75
Second-line treatment
The best and most rational option after a first failure
or other proprietary information of the Publisher.
is to use a tailored therapy, that is, to test clarithromycin
susceptibility before prescribing drugs. Several clinical
trials comparing tailored treatment and empiric treat-
ment, have reported a satisfactory eradication rate with
Vol. 58 - No. 4 Panminerva Medica 313
the former and not with the latter strategy.76 Thus, after
a first failure, if an endoscopy should be carried out, cul-
ture (and standard susceptibility testing) or a real-time
PCR should be considered in all regions before giving a
second-line treatment.14 Any of these susceptibility tests
will allow the H. pylori strain to be classified as clar-
ithromycin susceptible or resistant. If the strain is still
susceptible, another reason other than resistance must be
explored, especially compliance. If the strain is resistant,
a treatment without clarithromycin must be prescribed.76
In the context in which endoscopy is not requested,
the rationale of the second-line treatment is to abandon
clarithromycin in an empirical therapy, because there is
a likelihood that selection of a clarithromycin-resistant
strain occurred.14 According to the latest recommenda-
tions, the patients having received the concomitant
therapy should be prescribed a bismuth-based quadru-
ple therapy while the patients having received a bis-
muth-based quadruple therapy should be prescribed a
fluoroquinolone-containing triple therapy unless a high
quinolone resistance has been shown. In this case al-
ternative combinations, for example with rifabutin, are
considered appropriate (manuscript in preparation). In
this clinical setting, it is important to report the results
of a new drug formulation with bismuth subcitrate po-
tassium, metronidazole, and tetracycline contained in a
single capsule (three-in-one). In a randomized, open-
label, non-inferiority, phase 3 trial, including naive pa-
tients, the efficacy of omeprazole with a single three-
in-one capsule (quadruple therapy) for 10 days versus
standard therapy given for 7 days was assessed. The
intention-to-treat analysis was used for superiority test-
ing, and quadruple therapy was significantly better than
the standard regimen (93% versus 68%, respectively,
P<0.0001).77 The limitation is that 3 tablets need to be
taken 4 times a day as well as a PPI separately twice a
day for 10 days. This new drug is now available in Italy.
The levofloxacin-containing triple therapy is also a
possible option. As a rescue therapy after the failure of
the standard triple therapy, it shows satisfactory results
when local fluoroquinolone resistance is <10%.58 How-
ever, the rapid acquisition of resistance may jeopardize
its future efficacy. It is strongly advised that levofloxa-
cin should not be used for patients with chronic infec-
tious bronchopneumopathy who may have received flu-
oroquinolones. Whenever possible, it is recommended
to test levofloxacin susceptibility before prescribing it.14
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
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(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
COPYRIGHT 2016 EDIZIONI MINERVA MEDICA
PELLICANO H. PYLORI INFECTION
Third-line (and further) treatment
After two treatment failures it is recommended to
perform AST, whenever possible.14 Besides levofloxa-
cin (if not previously used with the same aim), rifabutin
is another candidate. Rifabutin is a rifamycin-S derivate
commonly used as antimycobacterial drug. Based on
data including 2,982 patients treated for H. pylori infec-
tion worldwide, cure rates for second-line, third-line and
fourth/fifth-line rifabutin therapies were 79%, 66% and
70%, respectively. In this context, while the usual dos-
age of rifabutin is 150 mg twice a day, the ideal length
of treatment remains unclear, but 10- to 12-day regi-
mens are generally recommended. Although rare, my-
elotoxicity is the most significant complication.79 Since
multidrug-resistant mycobacterial strains are rapidly in-
creasing, the use of rifabutin should be restricted to pa-
tients who have experienced several H. pylori treatment
failures.75 As a salvage regimen, furazolidone-based
triple therapy has been shown to be effective in small
size studies. Although this drug has been less well stud-
ied than rifabutin- and levofloxacin-based treatments,
its low cost makes this regimen attractive in developing
countries.75
Adding an adjuvant treatment
In a systematic review with a meta-analysis of RCTs,
Szajewska et al. showed that adding Saccharomyces
boulardii, a yeast probiotic, as a supplement to a stan-
dard eradication regimen, increased H. pylori eradica-
tion rate from 71% to 80% (RR 1.11, 95%CI: 1.06-1.17;
moderate quality of evidence). Moreover, S. boulardii
reduced the risk of overall H. pylori therapy-related ad-
verse effects, particularly diarrhea (RR 0.51, 95%CI:
0.42-0.62; high quality evidence) and nausea (moderate
quality of evidence). Quality of evidence was assessed
using the Grading of Recommendations, Assessment,
Development and Evaluation (GRADE) guidelines.80
Meta-analyses on the use of Lactobacilli showed that
studies on this issue are heterogeneous as they consider
different species and strains. Additional work needs to
be performed to determine the strain, dose and adminis-
tration to be used.81
or other proprietary information of the Publisher.
Lactoferrin is an iron-binding protein found in the
specific granules of the neutrophils where it exerts an
antimicrobial activity. The potential role of lactoferrin
to improve H. pylori treatment outcome has been in-
314 Panminerva Medica December 2016
vestigated. Two meta-analyses obtained similar results
and showed that lactoferrin increased the efficacy of the
standard triple therapy.82, 83 However, the poor quality of
many trials and the limited number of centers involved
should be emphasized and preclude giving a positive
recommendation.14
At present, all these treatments, taken together, are
most likely to lead to a decrease in adverse events, espe-
cially diarrhea, and may indirectly help to improve the
eradication rate.14
Relapse and reinfection
The relapse of H. pylori is the result of either recur-
rence or reinfection.84, 85 The annual relapse rate per
patient-year of follow-up can reach 1.45% in developed
countries and may be as high as 12% in some develop-
ing countries.86
Recurrence refers to the recrudescence of the original
strain of H. pylori that remains suppressed and unde-
tectable before 4 weeks after the end of the treatment,
and is related to a temporary decrease in bacterial load.
The inadequacy of biopsy sampling, the inaccuracy of
techniques monitoring eradication, and insufficiency of
the 4-week rule to define the success of eradication ther-
apy, are responsible for recrudescence of the infection.87
Reinfection refers to the emergence of a new strain
of H. pylori after the original strain has been complete-
ly eradicated.87 The annual H. pylori reinfection rate
is reported to be <1% in developed countries whereas
relatively higher rates are reported in developing coun-
tries favored by a high prevalence of the infection.88
Although interfamilial transmission has been reported,
studies investigating the potential role of a partner in re-
infection have shown that this event was not significant-
ly increased when the spouse was infected. Moreover,
when patients agreed to have an endoscopy performed,
the molecular study demonstrated different strains in re-
infected patients and partners. Thus, the patients part-
ner does not act as reservoir in H. pylori reinfection.89
Vaccine
The fact that H. pylori infection induces strong hu-
moral and cellular immune responses, and that these
responses are not able to eliminate the bacterium, raises
doubts about the possibility of developing an effec-
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo,
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
COPYRIGHT 2016 EDIZIONI MINERVA MEDICA
H. PYLORI INFECTION PELLICANO
tive vaccine. Despite this, efforts began in the early
1990s, with disappointing results.90, 91
At present, the most advanced study was published by
Zeng et al., who, in a randomized, double-blind, place-
bo-controlled, phase 3 trial, recruited children without
H. pylori infection. The oral vaccination with a fusion
protein composed of the B subunit of H. pylori urease
and heat-labile toxin of Escherichia coli, was given
on days 0, 14, and 28. Participants fasted for at least 2
hours and were given 80 mL of buffer solution, contain-
ing 2.8 g of sodium bicarbonate and 1.1 g of sodium
citrate, 2 minutes before the oral vaccination. The event
rate of H. pylori infection was significantly lower in the
vaccine group (2199 children) than in the placebo group
(2204), resulting in a vaccine efficacy of 71.8% (95%
CI: 48.2-85.6) in the first year. This efficacy decreased
to 55% in the second and the third years after vaccina-
tion. Concerning the adverse events, within 3 days after
vaccinations, all of the adverse reactions were mild and
resolved within 24 hours. Five (<1%) participants in
the vaccine group and seven (<1%) participants in the
placebo group reported serious adverse events during
the first year of follow-up.92 Some criticisms have been
raised for this study. The age of enrolled children was
6-15 years, a period in which a non-negligible percent-
age of children (roughly 20%) is already infected by H.
pylori, showing a need to vaccinate younger children.
However, in the latter case, this vaccine might not be
suitable because of the volume of each dose (80 mL of
buffer solution and 30 mL of dissolved vaccine), which
might be too large a quantity for young children to take
in several minutes. Furthermore, if protection levels fall
within a year, booster immunizations might be needed
to maintain adequate protection levels in subsequent
years. This adds further complexity to an already full
childhood vaccination programme.93
Conclusions
For clinicians, simple key messages useful to manage
H. pylori infection should be:
since the decision to test should be made with
therapeutic intent, when the bacterium is found it should
or other proprietary information of the Publisher.
be treated;
treatment should be decided upon locally and
should be based on local antibiotic usage, documented
antibiotic resistance and outcome data;
Vol. 58 - No. 4 Panminerva Medica 315
in countries with a high rate of clarithromycin
resistance (>15%), in the first line therapy, either con-
comitant or bismuth-based quadruple therapies are
recommended as empiric treatment if antimicrobial sus-
ceptibility testing is not possible. If antimicrobial test-
ing is performed and the strain is found to be clarithro-
mycin susceptible, an optimized clarithromycin-based
triple therapy can be prescribed (with high dose esome-
prazole or rabeprazole for 14 days)
in the second-line therapy, again as with empiric
treatment, if antimicrobial susceptibility testing is not
possible, the quadruple therapy which was not used as
a first-line treatment is recommended. Triple therapy
combining PPI with amoxicillin and levofloxacin is also
possible;
drugs such as rifabutin and furazolidone should
be reserved for further steps.
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