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Received: 7 February 2019    Revised: 8 April 2019    Accepted: 14 April 2019

DOI: 10.1111/hel.12597

ORIGINAL ARTICLE

Guidelines for the management of Helicobacter pylori infection

in Japan: 2016 Revised Edition

Mototsugu Kato1  | Hiroyoshi Ota2 | Masumi Okuda3  | Shogo Kikuchi4  |

5 6 7 8
Kiichi Satoh  | Tadashi Shimoyama  | Hidekazu Suzuki  | Osamu Handa  |
Takahisa Furuta  | Katsuhiro Mabe  | Kazunari Murakami10 | Toshiro Sugiyama11 |
9 1

Naomi Uemura12 | Shin’ichi Takahashi13
1
Department of Gastroenterology, National Hospital Organization Hakodate National Hospital, Hakodate, Hokkaido, Japan
2
Department of Clinical Laboratory Sciences, Shinshu University School of Medicine, Nagano, Hyogo, Japan
3
Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
4
Department of Public Health, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
5
Department of Gastroenterology, International University of Health and Welfare Hospital, Nasushiobara, Tochigi, Japan
6
Aomori General Health Examination Center, Aomori, Japan
7
Fellowship Training Center, Medical Education Center, Keio University School of Medicine, Tokyo, Japan
8
Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
9
Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
10
Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan
11
Department of Cancer Prevention and Therapeutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
12
Department of Gastroenterology, Kohnodai Hospital, National Center for Global Health and Medicine, Ichikawa, Japan
13
Department of Gastroenterology, Kosei Hospital, Tokyo, Japan

Correspondence
Mototsugu Kato, Department of
Gastroenterology, National Hospital
Organization Hakodate National Hospital,
Hakodate, Kawaramachi 18‐16, Hakodate,
Hokkaido, 041‐8512, Japan.
Email: mkato1957@gmail.com
Funding information
The Japanese Society for Helicobacter
Research
Abstract
Background: Since “Helicobacter pylori (H. pylori) infection” was set as the indication in
the Japanese Society for Helicobacter Research (JSHR) Guidelines 2009, eradication
treatment for H. pylori gastritis is covered under insurance since 2013 in Japan, and
the number of H. pylori eradication has rapidly increased. Under such circumstances,
JSHR has made the third revision to the “Guidelines for diagnosis and treatment of H.
pylori infection” for the first time in 7 years.
Methods: The Guideline Committee held 10 meetings. Articles published between
the establishment of the 2009 Guidelines and March 2016 were reviewed and classi‐
fied according to the evidence level; the statements were revised on the basis of this
review. After inviting public comments, the revised statements were finalized using
the Delphi method.
Results: There was no change in the basic policy that H. pylori infectious disease
is an indication for eradication. Other diseases presumed to be associated with H.
pylori infection were added as indications. Serum pepsinogen level, endoscopic ex‐
amination, and X‐ray examination were added to the diagnostic methods. The effects
of 1‐week triple therapy consisting of potassium‐competitive acid blocker (P‐CAB),

Helicobacter. 2019;00:e12597. wileyonlinelibrary.com/journal/hel © 2019 John Wiley & Sons Ltd  |  1 of 17
https://doi.org/10.1111/hel.12597
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amoxicillin, and clarithromycin have improved, and high eradication rates can also be
expected with proton pump inhibitors (PPI) or P‐CAB combined with amoxicillin and
metronidazole. If the susceptibility test is not performed, the triple PPI or P‐CAB/
amoxicillin/metronidazole therapy should be chosen, because the PPI/amoxicillin/
metronidazole combination demonstrated a significantly higher eradication rate than
PPI/amoxicillin/clarithromycin. In the proposal for gastric cancer prevention, we di‐
vided gastric cancer prevention measures by age from adolescent to elderly, who are
at an increased gastric cancer risk, and presented measures for gastric cancer preven‐
tion primarily based on H. pylori eradication.
Conclusion: We expect the revised guidelines to facilitate appropriate interventions
for patients with H. pylori infection and accomplish its eradication and prevention of
gastric cancer.

KEYWORDS
diagnosis, gastric cancer prevention, guidelines, indication, treatment

1 |  I NTRO D U C TI O N 2 | M E TH O D O LO G Y

The Japanese Society for Helicobacter Research first published
“Guidelines for the Management of Helicobacter pylori (H. pylori)
Infection in Japan” in 20001 and revised edition in 2010. 2 The
present version is the third revision and is the first one in 7 years.
Since the eradication treatment for H. pylori gastritis has been
added to the list of insurance‐covered diseases in 2013, it seems
that H. pylori eradication in Japan has been expanded to establish
the foundation for gastric cancer prevention by H. pylori eradi‐
cation. This background has led us to the present revision of the
guidelines. The guidelines for adults were revised in the areas of
indications, diagnosis, and treatment according to new evidence,
similar to previous versions. In addition to the above revisions of
the clinical guidelines, recommendations on gastric cancer preven‐
tion were also added, which is of paramount importance in Japan.
The International Agency for Research on Cancer (IARC) of the
World Health Organization recommended H. pylori eradication as
a measure for gastric cancer prevention in 2014. 3 It is now the time
for Japan to tackle gastric cancer prevention on a full scale at the
national level. In this recommendation, we divided measures for
gastric cancer prevention by target age from adolescent to older
age groups, who are at an increased risk of gastric cancer, and
presented gastric cancer prevention measures, mainly consisting
of H. pylori eradication strategies. A screening and treatment for
H. pylori have already been initiated by some local governments
for junior or senior high‐school students. These measures could
potentially form the core of gastric cancer prevention, and they
make the elimination of patients with H. pylori infection possible.
We expect these preventive measures to become widespread in
the future.
Seven years after the last revision, guideline revision work was started
because the medical environment for H. pylori has changed. The edi‐
torial and evaluation committee who were consisted from the coun‐
cil member of Japanese society for Helicobacter Research listed in
Table 1. The working groups were divided into indication, diagnosis,
treatment, and gastric cancer prevention. The target group for the
guidelines comprises H. pylori‐infected patients. The guidelines are
intended for use by Japanese clinicians who see H. pylori‐infected
patients. Searches of the literature were undertaken in the PubMed
and Japan Medical Abstract Society databases using the keywords
“H. pylori,” “eradication,” “diagnosis,” “gastric cancer,” and equivalent
Japanese terms. Articles published between the establishment of the
2009 Guidelines and March 2016 were reviewed and classified ac‐
cording to the evidence level.
The Guideline Committee held 10 meetings from April 1995 to
May 1996. The statements were revised on the basis of this review.
After inviting public comments, the revised statements were final‐
ized using the Delphi method. In these guidelines, statements are
based on the level of evidence, the amount of evidence, the results
of treatment, clinical efficacy, feasibility (physician's skills, regional
availability, medical resources, and health insurance system), evi‐
dence of harm, and cost. The presence or absence of coverage by
the Japanese national health insurance system was not taken into
consideration when setting statements for these guidelines. If there
were multiple items of evidence with different levels, the evidence of
higher quality was accepted. Recommendation grade and evidence
level were based on the GRADE system.4-6 Grade of recommen‐
dation was divided into three categories: strong (recommendation
1), weak (recommendation 2), and insufficient (recommendation 3).
KATO et al. |
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TA B L E 1   Grade of recommendation and evidence level in the infected population remains substantial.10,11 Successful H. pylori
indication of Helicobacter pylori eradication eradication improves histologic gastritis and is expected to result in

Grade of preventing H. pylori‐associated diseases (eg, gastric/duodenal ulcer and

recommen‐ Evidence gastric cancer).12-14 Therefore, from a preventive medicine perspective,
Indication of H. pylori eradication dation level the entire infected population represents the target of this treatment.
H. pylori gastritis 1 A In Japan, H. pylori gastritis has been approved as an insurance‐
Gastric ulcer/duodenal ulcer 1 A covered disease since 2013. Therefore, H. pylori gastritis, almost syn‐

Residual gastric mucosa after endo‐
scopic treatment of early gastric
cancer
Gastric mucosa‐associated lymphoid
tissue lymphoma
Gastric hyperplastic polyp
Functional dyspepsia (H. pylori‐associ‐
ated dyspepsia)
Gastroesophageal reflux disease
Immune (idiopathic) thrombocyto‐
penic purpura
Iron deficiency anemia
Chronic urticaria
Cap polyposis
Diffuse large B‐cell lymphoma
(DLBCL)
Rectal MALT lymphoma
Parkinson's syndrome
Alzheimer's disease
Diabetes mellitus (DM)
Quality of evidence consisted of four levels: high (level A), moderate
(level B), low (level C), and very low (level D).
3 | I N D I C ATI O N S
1 A
1 A
1 A
1 B
1 B
1 A
1 B
2 B
2 C
2 C
2 C
2 D
2 D
3 D
onymous with H. pylori infection, is recognized as a disease unit, and
diagnosis and treatment of H. pylori‐associated diseases can now be
performed simultaneously at a clinical site. This is likely to contribute
to the treatment and prevention of various diseases related to H. pylori
infection and gastric cancer prevention, which is the largest epidemio‐
logic problem in Japan. Furthermore, eradication therapy, as a defini‐
tive treatment, is also highly necessary from the viewpoint of blocking
H. pylori transmission routes and is expected to help decrease future
medical expenses significantly. In some cases, eradication cannot be
achieved because of drug resistance, and treatment may have to be
discontinued because of various adverse reactions. Therefore, a suf‐
ficient explanation regarding eradication therapy should be provided,
and the patient's willingness to undergo the eradication treatment
should be confirmed before initiating eradication therapy.
3.3 | Diseases for H. pylori eradication is
strongly indicated
3.3.1 | H. pylori gastritis (Recommendation: 1,
Evidence Level: A)
H. pylori eradication is expected to improve gastric mucosal atrophy
through the amelioration of gastric mucosal inflammation,15,16 in‐
hibit progression of intestinal metaplasia,17 and ultimately, prevent
gastric cancer.18 Thus, eradication is strongly recommended for this
disease. Eradication therapy for H. pylori gastritis is also strongly rec‐
ommended at the Kyoto Global Consensus Conference in 2014.19,20

3.1 | Indications for H. pylori eradication therapy

H. pylori infection is an indication for treatment. Individual H. pylori‐
associated diseases are grouped as follows: (a) diseases for which
high‐level evidence is available and eradication therapy is strongly
recommended; (b) diseases for which sufficient data have not been
accumulated, but an association with H. pylori infection is presumed.
3.2 | H. pylori infection
Helicobacter pylori eradication is not only useful for the treatment of
gastric ⁄ duodenal ulcer, but also for the treatment and prevention
of H. pylori‐associated diseases such as gastric cancer, as well as for
inhibiting the spread of this infection.
H. pylori infects the gastric mucosa and causes gastritis (H. pylori
gastritis).7-9 It is a cause of various upper gastrointestinal diseases as
listed below and has also been suggested to have a link with nongas‐
trointestinal diseases. In Japan, ~35% population has H. pylori infec‐
tion; although the prevalence has declined compared to previous rates,
3.3.2 | Gastric ulcer/duodenal ulcer
(Recommendation: 1, Evidence Level: A)
Treatment for H. pylori‐positive gastric and duodenal ulcers has been
demonstrated to prevent recurrence and decrease ulcer‐related
complications (eg, bleeding) according to high‐level evidence, includ‐
ing multiple published meta‐analyses conducted in Japan and other
countries. 21-25 Eradication therapy should be the first‐choice treat‐
ment for H. pylori‐positive peptic ulcers (including ulcer scars) unless
the patient is allergic to the drug used for eradication or has a severe
complication that hinders eradication treatment.
3.3.3 | Residual gastric mucosa after endoscopic
treatment of early gastric cancer (Recommendation:
1, Evidence Level: A)
Recurrence or metachronous multiple cancer can be observed fol‐
lowing endoscopic resection of early gastric cancer. A randomized
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4 of 17       KATO et al.
trial conducted in Japan revealed a significantly less frequent oc‐
currence of metachronous cancer in the eradicated group with no
significant differences in remnant recurrence because of an incom‐
plete resection.14 A meta‐analysis has also confirmed that H. pylori
eradication treatment significantly decreases metachronous cancer
26
incidence (odds ratio: 0.42; 95% confidence interval: 0.32‐0.56).
However, H. pylori eradication does not completely eliminate me‐
tachronous gastric cancer, which continues to remain to some ex‐
tent. Therefore, it is very important to continue regular surveillance
primarily by endoscopy, even after eradication.
3.3.4 | Gastric mucosa‐associated lymphoid tissue
lymphoma (Recommendation: 1, Evidence Level: A)
When gastric mucosa‐associated lymphoid tissue (MALT) lymphoma
is identified, it should be staged and confirmed that it is localized to
the stomach. H. pylori eradication has been shown to improve histo‐
pathologic and endoscopic findings or induce a remission in approxi‐
mately 60%–80% of H. pylori‐positive gastric MALT lymphoma. 27-29
In addition, eradication is extremely effective, as demonstrated by a
high 10‐year survival rate of 95%.30 Therefore, H. pylori eradication
should be the first‐choice treatment for patients with H. pylori‐posi‐
tive gastric MALT lymphoma.
3.3.5 | Gastric hyperplastic polyp
(Recommendation: 1, Evidence Level: A)
Gastric hyperplastic polyps have been reported to disappear or
shrink following H. pylori eradication,31-33 and polyps decrease in size
31,32
in ~70% cases. Therefore, H. pylori eradication is recommended
as the first‐choice treatment for gastric hyperplastic polyps, espe‐
cially for multiple cases. However, endoscopic resection should be
considered in cases with large lesions or bleeding.
3.3.6 | Functional dyspepsia (H. pylori‐associated
dyspepsia) (Recommendation: 1, Evidence Level: B)
A meta‐analysis on the effect of H. pylori eradication to improve symp‐
toms of functional dyspepsia (FD) has shown that eradication signifi‐
cantly improves symptoms experienced by FD patients.34 Eradication
treatment is effective for some cases of H. pylori‐positive dyspepsia, and
it has been proposed that this condition should not be grouped with FD
and instead be established as an independent disease concept of H. py‐
lori‐associated dyspepsia.35-37 A consensus has been reached to define
a case as “H. pylori‐associated dyspepsia” when symptoms disappear or
improve 6‐12 months after H. pylori eradication19,20; the Rome IV crite‐
ria,38 which were published in May 2016, also adhere to this definition.
3.3.7 | Gastroesophageal reflux disease
(Recommendation: 1, Evidence Level: B)
Gastroesophageal reflux disease (GERD) is often treated by ad‐
ministering a PPI. In H. pylori‐infected individuals, PPIs have been
reported to worsen corpus gastritis39 and progression of gastric cor‐
pus mucosal atrophy,40 which is associated with an increased risk of
carcinogenesis. Therefore, H. pylori‐infected individuals are recom‐
mended to undergo eradication treatment before long‐term PPI use.
Studies conducted in Japan have shown that H. pylori‐positive
GERD patients have increased levels of gastric acid secretion, and
experience transient emergence or worsening of acid reflux symp‐
toms or increased reflux esophagitis after H. pylori eradication.41-43
However, other reports have documented that the incidence of
erosive GERD does not increase after eradication in patients with
peptic ulcers44 and that GERD and its symptoms are improved by
eradication in GERD patients with concomitant duodenal ulcers.45
Therefore, eradication treatment is recommended for GERD
patients.
3.3.8 | Immune (idiopathic) thrombocytopenic
purpura (Recommendation: 1, Evidence Level: A)
In Japan, platelet counts have been reported to increase in 40%–
60% of H. pylori‐positive patients with immune (idiopathic) throm‐
bocytopenic purpura (ITP) following H. pylori eradication46; thus,
eradication therapy should be the first‐choice treatment.
3.3.9 | Iron deficiency anemia (Recommendation: 1,
Evidence Level: B)
Although several meta‐analyses have reported that H. pylori infection
is a risk factor for iron deficiency anemia,47-51 the underlying patho‐
genic mechanism remains to be elucidated. Eradication treatment
has been shown to improve anemia in children (age ≤18 years).52-55
Serum hemoglobin levels in adult patients have been reported to sig‐
nificantly improve with the combined use of an iron administration
and eradication compared to treatment with an iron administration
alone.49,50 These findings suggest that H. pylori infection is involved
in the etiology of iron deficiency anemia. Thus, eradication treatment
may be considered for H. pylori‐positive patients with iron deficiency
anemia.
3.4 | Diseases presumed to be associated with H.
pylori infection
Although sufficient evidence is not available for the following dis‐
eases, H. pylori eradication treatment may be considered depending
on the results of future clinical studies.
3.4.1 | Chronic urticaria (Recommendation: 2,
Evidence Level: B)
A meta‐analysis has shown that H. pylori infection and chronic urti‐
caria are slightly, but significantly correlated (odds ratio: 1.66; 95%
confidence interval: 1.12‐2.45; P = 0.01),56 and H. pylori eradication
treatment appears to be potentially effective as a treatment for
chronic urticaria.
KATO et al.
3.4.2 | Cap polyposis (Recommendation: 2, Evidence
Level: C)
Cap polyposis (CP) is a relatively rare chronic inflammatory disease of
the large intestine first reported in 1985, occurs mainly in the rectum
and sigmoid colon, and is histologically characterized by the coverage of
the polyp surface with cap‐shaped granulation tissue accompanied by
fibrinous exudate.57 In 2002, a CP case relieved by H. pylori eradication
therapy was reported,58 and several similar cases in Japan were subse‐
quently reported. Despite these findings, it remains unknown whether
H. pylori is directly involved in CP pathogenesis, and further studies are
necessary regarding the use of aggressive H. pylori eradication for CP.
3.4.3 | Diffuse large B‐cell lymphoma (DLBCL)
(Recommendation: 2, Evidence Level: C)
In a relatively large‐scale cohort study, eradication was reported to
produce complete histologic remission in more than half of 50 H.
pylori‐positive patients with DLBCL in the gastric‐localized stage;
all patients survived and remained in remission over a median fol‐
low‐up period of 7.7  years.59 The efficacy of eradication has also
been reported in a multicenter prospective phase II trial in Europe,
and H. pylori eradication therapy may be effective in patients with
60
DLBCL at the gastric‐localized stage. However, in the event that
there is no response, eradication therapy should be terminated and
immediately switched to immunochemotherapy (the combined use
of radiation therapy should also be considered).
3.4.4 | Rectal MALT lymphoma (Recommendation:
2, Evidence Level: C)
Several case reports have documented the efficacy of H. pylori
eradication therapy for rectal MALT lymphoma.61,62 However, im‐
provements with eradication are also observed in H. pylori‐negative
cases.62-64 Moreover, non‐ H. pylori bacterial species susceptible to
antibiotics may be involved in lesion formation. Therefore, aggres‐
sive eradication is not recommended.
3.4.5 | Parkinson's syndrome (Recommendation: 2,
Evidence Level: D)
The H. pylori infection rate in patients with Parkinson's syndrome is
37%–59%, which is not different from the rate in the general popu‐
lation.65 In patients with H. pylori‐positive Parkinson's syndrome,
successful eradication has been reported to remarkably improve
65,66
levodopa absorption and motor symptoms ; however, the num‐
ber of cases is limited.
3.4.6 | Alzheimer's disease (Recommendation: 2,
Evidence Level: D)
There is no previous meta‐analysis regarding the involvement of H.
pylori in Alzheimer's disease (AD). In a recent long‐term cohort study
|
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following 603 cases over 20 years, dementia was reported to have
occurred in 28.9% H. pylori‐positive individuals and 21.1% H. pylori‐
negative individuals (P = 0.044).67
In addition, the successful eradication of H. pylori has been re‐
ported to produce beneficial effects, including the deceleration of
cognitive decline in AD patients68 and decreased risk of death69;
however, both were small‐scale studies conducted with ≤50 cases.
3.4.7 | Diabetes mellitus (DM) (Recommendation: 3,
Evidence Level: D)
The H. pylori infection rate has been reported to be significantly higher
in patients with DM, particularly in those with type 2 DM (T2DM).70
H. pylori infection has been reported to increase the risk for onset and
progression of T2DM,71 as well as complications.72 However, a recent
meta‐analysis reported that no solid evidence is available for the wors‐
ening of T2DM control by H. pylori infection,73 and no consensus has
been reached. With regard to H. pylori eradication, it has been reported
that eradication does not improve the T2DM control status,74 and H.
pylori eradication is more likely to fail in DM (including type 1 DM)
patients than in non‐DM patients.75 Moreover, eradication has been
reported to improve insulin resistance in patients with a type B insulin
receptor abnormality, a subtype of DM.76 Therefore, it is possible that
eradication is effective for some cases and ineffective for others.
4 | D I AG N OS I S
4.1 | General theory
4.1.1 | Diagnosis of H. pylori infection and
assessment of H. pylori eradication
1. One of the following examination methods is used for the
diagnosis of H. pylori infection before and after eradication
treatment, and the accuracy of diagnosis is improved when
multiple diagnostic methods are combined. A choice is made
after understanding the characteristics of each method.
(Recommendation: 1, Evidence level: B)
2. Diagnosis of H. pylori infection after eradication treatment
Assessment of the efficacy of H. pylori eradication therapy should be
performed at least 4 weeks after the completion of treatment. A urea
breath test (UBT)77 and fecal H. pylori antigen assay using monoclonal
antibodies are useful for eradication judgment.78 Because false‐neg‐
ative test results are possible after eradication treatment because of
decreased bacterial counts, retesting after follow‐up is recommended
when the result is unclear. (Recommendation: 1, Evidence level: B).
3. Examination methods
a.. Examination methods requiring endoscopic biopsy tissue
(1)rapid urease test, (2) histology, and (3) culture test
b.. Examination methods not requiring endoscopic biopsy tissue
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6 of 17       KATO et al.
(1)UBT, (2) anti‐ H. pylori antibody assay, and (3) fecal H. pylori
antigen assay
(Recommendation: 1, Evidence level: B).
4.1.2 | Supplementary notes
1. Because H. pylori may be distributed unevenly in the stom‐
ach, biopsies from two sites in the greater curvature of the
pyloric antrum and upper‐middle part of the gastric corpus
79
are desirable. (Recommendation: 1, Evidence level: B)
2. When drugs that show bacteriostatic action on H. pylori and/or
inhibit urease activity (eg, antibacterial agents, PPIs, potassium‐
competitive acid blockers [P‐CAB], and some protective fac‐
tor potentiators) are administered, it is desirable to discontinue
these drugs for ≥2 weeks before the pre‐eradication and poster‐
adication diagnosis of H. pylori infection. 80,81 (Recommendation:
1, Evidence level: B)
3. The antibody assay method is not affected by PPIs, etc The fecal
antigen assay is not highly affected by PPIs, depending on the kit
used.78,82 (Recommendation: 1, Evidence level: B)
4.2 | Individual methods for diagnosis
4.2.1 | Invasive tests
Rapid urease test
The rapid urease test is a rapid, simple, and accurate method for
identifying H. pylori. The test itself cannot be preserved as evidence.
83-85
Moreover, the sensitivity following eradication varies greatly.
the rapid urease test, it is desirable to collect biopsy tissue for histol‐
ogy at the same time. Because the specificity is high, samples tested
positive with the rapid urease method can be concluded to be posi‐
tive for H. pylori infection.83-86 When sodium bicarbonate (alkaline) is
used in pronase treatment for removal of the gastric mucus, samples
should be wiped before use to avoid false‐positive results because
of the effect of sodium bicarbonate.
83,85
Diagnostic accuracy: Pre‐eradication sensitivity is 91.0%–
98.5% and specificity is 90.9%–100%.
83-85
Posteradication sensitivity is 58.8%–86% and specificity is
97.8%–99.2%.
Histology
The histology method for the detection of H. pylori has a high capac‐
ity for test result preservation and can be combined with histologic
diagnosis. It is desirable to combine specific staining such as Giemsa
staining with hematoxylin‐eosin (H&E) staining.87-90 Immunostaining
is useful for the differentiation between H. pylori and other bacteria
when the bacterial count is small and when the bacteria are in the coc‐
coid form, among other cases, in which judgment is difficult with non‐
87-90
specific staining. When the patient is taking a PPI, H. pylori may
change to the coccoid form and migrate to the deeper part of the gas‐
tric foveola. Furthermore, aberrant parietal cells may be observed in
the intracellular canaliculi.89 Immunostaining is useful in such cases.89
Diagnostic accuracy: pre‐eradication H&E staining90,91; sensitiv‐
ity is 92%–98.8% and specificity is 89%–100%.
Culture test and antimicrobial susceptibility test
The presence of H. pylori can only be directly confirmed by culturing.
This method is excellent regarding specificity and allows for pres‐
ervation, typing, and antimicrobial susceptibility testing of bacte‐
rial strains. The susceptibility to antibacterial agents is desirable to
test whenever possible. Although the agar plate dilution method is
recommended for drug susceptibility tests to determine the mini‐
mal inhibitory concentration, other methods (eg, E test and broth
microdilution) are also used. For preserving bacterial strains, a single
colony of H. pylori is cultured with shaking in brain heart infusion
(BHI) broth (1‐2  mL) or similar for enrichment, and pure culturing
is subsequently carried out in a blood agar medium. The collected
bacterial cells are suspended in BHI broth containing 15% glycerin,
after confirming that the cells are not in the coccoid form, and then
stored frozen.
Diagnostic accuracy: sensitivity of 68%–98% and specificity of
100%.87
4.2.2 | Noninvasive tests
UBT
Urea labeled with 13C is administered orally. If H. pylori is present in
the stomach, its urease activity decomposes labeled urea into 13CO2
and ammonia. 13CO2 enters the blood from the gastrointestinal tract
13
and is excreted in expiration. The rate of C increase in carbon di‐
In oxide in the expired air is measured. The use of film‐coated tablets
13
of C‐urea decreases the effect from urease‐producing bacteria in
the oral cavity, thereby improving diagnostic accuracy.91 False‐nega‐
tive results can occur at a significant frequency while taking medi‐
cation and immediately after medication discontinuation, showing
bacteriostatic action on H. pylori or an inhibitory effect on the urease
activity (eg, antibacterial agents, PPIs, P‐CABs, and some protective
factor potentiators).81,92,93 False‐positive tests occur when there is
hypochlorhydria or achlorhydria and other bacteria that produce
urease are present.94 Diagnostic accuracy: sensitivity of 98% and
specificity of 98%.91
Antibody‐based test
In antibody‐based tests, local validation is important because the
diagnostic accuracy depends on the bacterial strain from which the
antigen was extracted and the prevalence of diseases associated
with H. pylori infection.95 Kits that use an antigen extracted from a
strain found in Japan are suitable for use in Japan.
The antibody‐based test is useful when the number of bacteria
in the gastric mucosa is decreased, and the results from other tests
are suspected to be false negatives. The test is not affected by PPIs
or mucosal protective drugs and thus does not require drug with‐
drawal. However, positive results are not obtained immediately after
infection, and the results can be below the cutoff when H. pylori has
been spontaneously eradicated in patients with advanced atrophic
KATO et al.
gastritis. In the diagnosis of infection, attention should also be paid
to the antibody titer; if the result was negative but close to the cutoff
value, other tests should be used to confirm the presence or absence
of H. pylori infection.
Several serum antibody measurement kits are available in Japan,
and kits based on the latex method have also recently been made
available. However, the latex method has not undergone sufficient
evaluation for diagnostic accuracy, and attention must be paid to the
accuracy and other characteristics of the particular kit that is used.
Serum antibodies take a long period to become negative follow‐
ing a successful eradication. When the antibody‐based test is used
to check whether eradication was successful, a quantitative compar‐
ison should be made between the pre‐eradication level and the level
measured ≥6 months after the eradication treatment; eradication is
deemed successful if the post‐treatment antibody titer is decreased
to half or less of the pretreatment titer.96
Urinary anti‐ H. pylori antibodies are assayed using enzyme
immunoassay (EIA) or immunochromatography. With the latter
method, judgment is somewhat subjective, and caution is neces‐
sary. In urinary antibody measurement with EIA, although numer‐
ical results are obtained, they are semiquantitative and are not
recommended to use for determining if eradication was success‐
ful. False‐positive results can occur when high‐protein samples
(eg, early morning urine) are used. Diagnostic accuracy before
eradication97,98:
Serum antibody: sensitivity of 88%–100% and specificity of
50%–100%; urinary antibody: sensitivity of 85%–96% and specific‐
ity of 79%–90%.
Stool antigen test
This is a method used for the direct detection of H. pylori‐derived
antigens excreted in feces. The currently available kits use monoclo‐
nal antibodies, and both the sensitivity and specificity are high.78,99
The assay is recommended in the European guidelines as a test to be
used for assessment of eradication.100
Although H. pylori in the coccoid form gives negative results
with UBT, the antigenicity is retained in this assay. This method also
shows excellent diagnostic accuracy with remnant stomach.
Similar to the antibody‐based test, local validation is import‐
ant because accuracy depends on the antigen used and the preva‐
lence of diseases associated with H. pylori infection. All current kits
78,101,102
commonly used in Japan have a high diagnostic accuracy.
Although the European and US guidelines recommend EIA for the as‐
sessment of eradication, even the rapid type can determine whether
eradication was successful according to the results in Japan.102 In
addition, the EIA method can process a large number of specimens
similar to the serum antibody test, and it is thus possible to use this
method to conduct tests in health checkups.
In practice, caution is necessary for watery feces that may pro‐
vide false‐negative results because of antigen dilution. Correct as‐
sessment with excreted feces become impossible 24‐48 hours after
collection; however, feces collected with a dedicated sampling kit can
be stored for approximately 1 week at or below room temperature.99
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Diagnostic accuracy: pre‐eradication99: sensitivity of 96%–100%
and specificity of 97%–100%.
Posteradication101,102: sensitivity of 75%–90% and specificity of
96%–100%.
4.2.3 | Molecular biology technique
This is a method of detecting H. pylori‐specific base sequences
from various specimens. As even transient and dead bacteria can
be detected, this method should be used with caution regarding
false‐positive results for diagnosis or assessment of eradication. In
eradication therapy, this method can be used to detect mutations in
genes related to antibiotic resistance.
This method can be used for both the diagnosis of H. pylori in‐
fection and investigating pathogenicity‐related genes (eg, cagPAI
and vacA). Comparison of bacterial strains in polymorphisms/base
sequences is also useful to search for routes of transmission (eg, in‐
trafamily infection) and to diagnose reinfection.103 DNA extracted
from cryopreserved bacterial strains or paraffin‐embedded biopsy
tissues can be tested even after long‐term storage.
4.3 | Diagnostic aids
4.3.1 | Serum pepsinogen (PG) measurement
The ratio of PGI to PGII (hereafter PG I/II) is known to decrease upon
inflammation of the gastric mucosa.104 After successful H. pylori
eradication, it is confirmed that PGI and PGII decrease and the PGI/
II ratio increases as inflammation improves.105,106 In addition to the
above characteristics, PG reference levels for individuals with and
without H. pylori infection have recently been proposed, as PG levels
have been found to differ depending on the presence or absence of
H. pylori infection.107
However, PG levels are altered and not suitable when the patient
has undergone a gastric resection, has advanced renal failure, or is
taking a potent acid secretion inhibitor (eg, P‐CAB and PPI).
At diagnosis of gastritis before eradication treatment
With the chemiluminescent enzyme immunoassay (CLIA) method,
PGI/II of ≤5.0 or PGII of ≥10 ng/mL is considered positive.
(With the latex enhanced turbidimetric immunoassay (LIA)
method, PGI/II of ≤4.0 or PGII of ≥12 ng/mL is considered positive).
At diagnosis of gastritis after eradication treatment
When the pretreatment PGI/II ratio is <5.0, a ≥25% increase in PGI/
II upon treatment is judged to be an improvement; when the pre‐
treatment PG I/II ratio is ≥5.0, a ≥10% increase is judged to be an
improvement.
Serum PG levels serve as a marker for the state of inflammation
due to H. pylori infection, but cannot be used as a marker to directly
diagnose the presence of H. pylori. It is only used to observe the
state of inflammation and gastric mucosal atrophy. With regard to its
clinical significance, the method should be treated separately from
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8 of 17       KATO et al.
conventional methods for assessment of eradication, because it can‐
not directly diagnose bacterial presence. However, it can be used to
aid for diagnosing whether the eradication treatment was successful
through serum PG changes upon eradication.105,106
4.3.2 | Endoscopic findings
In upper gastrointestinal endoscopy examinations, H. pylori infection
can be suspected on the basis of findings of gastritis. Kyoto classifi‐
cation findings are frequently observed in individuals with and with‐
out H. pylori infection and after eradication.108 Changes between
pre‐ and posteradication images are useful to assist with assessment
of eradication. Endoscopic findings are also useful for differentiat‐
ing between uninfected and infected individuals when the infection
diagnosis is negative.
4.3.3 | Stomach X‐ray examination
In stomach X‐ray examinations, H. pylori infection can be sus‐
pected on the basis of features of the gastric mucosal surface,
as well as the properties and distribution (atrophy) of gastric
rugae.109 Swelling of the rugae that reflects H. pylori infection is
≥3.9  mm when 5  g of a blowing agent is used or ≥4  mm when
3.5‐4.0  g is used. If infection of H. pylori is suspected, an endo‐
scopic examination should be performed and infection should be
tested by adequate diagnostic tests.
5 |  TR E ATM E NT
5.1 | The standard eradication treatment for H.
pylori in Japan is 7‐day triple therapy with a PPI or a
P‐CAB combined with amoxicillin and clarithromycin
or metronidazole. (Recommendation: 1, Evidence
level: A)
Although no differences were observed in a study comparing ome‐
prazole (OPZ), lansoprazole (LPZ), and rabeprazole (RPZ),110 the
eradication rate of 7‐day triple therapy including clarithromycin and
amoxicillin with vonoprazan (VPZ) has been reported to be signifi‐
cantly higher than those with PPIs.111,112 The merit of vonoprazan is
greater in patients infected with clarithromycin‐resistant strains of
H. pylori. The eradication rates in major studies conducted in Japan
using secondary eradication therapy with OPZ, LPZ, RPZ, EPZ, and
VPZ were generally around 90%.111,113,114
5.2 | Antimicrobials for eradication therapy
should be chosen on the basis of antimicrobial
susceptibility tests and used in a combination
expected to achieve the highest eradiation rate.
(Recommendation: 1, Evidence level: A)
The eradication regimen expected to provide the highest eradication
rate should be selected. Globally, it is required that the eradication
regimens should achieve ≥90% eradication,100 and therefore, bis‐
muth/nonbismuth quadruple regimens are used rather than the tri‐
ple therapy outside of Japan. However, the data corresponding to the
results of these eradication regimens in Japan remain insufficient.
The eradication rate with the triple PPI/amoxicillin/clarithro‐
mycin therapy, which is the standard triple regimen for primary
eradication therapy in Japan, has been decreasing with the increas‐
ing frequency of clarithromycin‐resistant strains.115 Therefore,
clarithromycin should not be used if patients are already known
to be infected with clarithromycin‐resistant strain, even for pri‐
mary eradication. It is desirable to test clarithromycin resistance in
advance. clarithromycin should be used for clarithromycin‐sensi‐
tive strains and metronidazole for clarithromycin‐resistant strains
instead of clarithromycin, for which 94.3% eradication can be
achieved.116 It is recommended that antibacterial agents should be
chosen according to the results of an antimicrobial susceptibility
test.
If the susceptibility test is not performed, the triple PPI or P‐
CAB/amoxicillin/metronidazole therapy should be chosen, because
the PPI/amoxicillin/metronidazole combination demonstrated a
significantly higher eradication rate than PPI/amoxicillin/clarithro‐
mycin in a study comparing these regimens in a primary eradication
setting.117
5.3 | H. pylori acquires resistance to various
antibacterial agents, and the eradication rate
decreases when an antibacterial drug to which H.
pylori is resistant is used for eradication therapy.
(Recommendation: 1, Evidence level: A)
The eradication rate with the PPI/amoxicillin/clarithromycin regimen
has decreased as the proportion of clarithromycin‐resistant H. pylori
has increased. Failed eradication further facilitates the emergence of
resistant bacteria.115 Although the clarithromycin resistance rate in
Japan was 7.1% around 2000, it has gradually increased to 18.9% in
2002, 21.1% in 2003, 31% in 2010‐2011, and 38.5% in 2013‐2014.118
When bacteria are resistant to a certain antibacterial agent in‐
volved in the eradication regimen, successful eradication is difficult
to achieve with that regimen. Because the frequency of bacteria re‐
sistant to various antimicrobial agents is currently high, antimicrobial
agent susceptibility tests are recommended in order to choose the
most appropriate antibacterial drugs.
5.4 | Regarding the duration of eradication
treatment, it has been reported that a 7‐day
administration is required with the combination of
PPI/amoxicillin/clarithromycin. (Recommendation: 1,
Evidence level: A)
A study comparing the five‐ and 7‐day administration of amoxicillin
750 mg twice daily + clarithromycin 400 mg twice daily has shown
that the eradication rate was 66% (46/70) with the former treat‐
ment, which was significantly lower than 84% (58/69) with the latter
KATO et al.
treatment.119 Moreover, in a comparison between 7‐day and 14‐day
treatment, one study reported an improved eradication rate for the
latter treatment120 and another reported comparable eradication
rates117; however, side effects were observed at an increased fre‐
quency with 2‐week therapy. Therefore, the 7‐day duration is rec‐
ommended. The eradication rate attained by the triple regimen with
vonoprazan 20 mg bid, clarithromycin 200 or 400 mg bid, and amoxi‐
cillin 750 mg bid for 7 days was reported to be 92.6%.111 Therefore,
7‐day treatment is considered sufficient.
5.5 | The recommended clarithromycin dose for H.
pylori eradication therapy is 200 mg twice daily
In primary eradication with the triple PPI or P‐CAB/amoxicillin/
clarithromycin regimen, clarithromycin doses of 200 mg twice daily
versus 400 mg twice daily produce no differences in the eradication
rate.111,122 Regarding side effects, a large‐scale study found that the
frequency of side effects significantly increases with higher doses of
clarithromycin.123 Therefore, the 200 mg twice daily dose is recom‐
mended in Japan on the basis of the balance between the eradica‐
tion rate and side effects.
5.6 | Sufficient suppression of gastric acid
secretion is necessary for H. pylori eradication.
(Recommendation: 1, Evidence level: A)
During H. pylori eradication therapy, sufficient suppression of gastric
acid secretion is necessary to increase the susceptibility of H. pylori
to antibacterial agents and the stability of antibacterial agents in the
stomach.124 LPZ, OPZ, RPZ, EPZ, and VPZ are used as PPI and P‐CAB,
respectively. The eradication rate increases with higher PPI doses.125
Plasma levels and the inhibitory efficacy of PPIs on gastric acid
secretion are affected by polymorphisms of CYP2C19, which is a
primary enzyme responsible for metabolizing PPIs. The eradication
rate is decreased in individuals with the extensive metabolizer gen‐
otype of CYP2C19; however, the eradication rate can be improved
by using an increased dose of a PPI or adding an H2 receptor antag‐
onist.126,127 Moreover, the inhibitory effect of VPZ on gastric acid
secretion and the eradication rate with VPZ‐containing regimen are
reportedly not affected by CYP2C19 polymorphisms.111
5.7 | Drugs used for eradication therapy
impact the pharmacokinetics of concomitantly
used drugs through the suppression of gastric
acid secretion and effects on drug‐metabolizing
enzymes, drug transporters, and intestinal bacteria.
(Recommendation: 1, Evidence level: A)
Among eradication drugs, PPIs and P‐CABs suppress gastric acid se‐
cretion, thereby affecting the absorption of other drugs. They can
also have effects on the drug interactions via P450.128
Clarithromycin is an inhibitor of CYP3A4 and MDR1 and also
impacts the pharmacokinetics of drugs that are metabolized or
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transported by the same enzyme or transporter. Metronidazole af‐
fects CYP3A4 and impacts the pharmacokinetics of drugs that are
substrates of this enzyme.
Antimicrobial agents decrease vitamin K production by intestinal
bacteria and thus increase the effect of warfarin. Because warfarin
is also affected by PPIs, clarithromycin, and metronidazole due to
drug interactions via P450, caution is required for eradication in pa‐
tients on warfarin.
Regarding drug interactions, it is vital to perform eradication
therapy with adequate attention to safety after double‐checking the
description in the package insert of each drug.
5.8 | During eradication, side effects (eg, diarrhea,
loose stool, glossitis, dysgeusia, hypersensitivity such
as shock, anaphylaxis, and rash, liver disorder, and
kidney disorder) occur at certain frequencies.
(Recommendation: 1, Evidence level: A)
The occurrence rate of side effects associated with eradication
treatment is 4%–5%, and specific side effects primarily include diar‐
rhea, loose stool, and dysgeusia.111,122,123 When diarrhea is a con‐
cern, it has been reported that the concomitant use of probiotics can
prevent diarrhea.129 Risk factors for side effects include the female
sex, high‐dose clarithromycin, and a history of allergy. The risk of
side effects is not elevated in the elderly123; thus, the elderly does
not need to refrain from undergoing eradication therapy because of
a concern for side effects.
5.9 | An adequate explanation of
eradication therapy should be provided to patients
in advance and should cover drug compliance during
eradication, potential side effects, and follow‐up
observations following eradication. The physician
who administers eradication therapy should also be
responsible for the patient following eradication.
(Recommendation: 1, Evidence level: B)
Patients undergoing eradication therapy should receive an adequate
explanation of H. pylori eradication and understand at least the fol‐
lowing contents:
1. Drug compliance: For standard therapy, patients should be in‐
structed to properly take medications twice daily for 7 days,
for a total of 14 doses.
2. Drinking: Instruct patients to avoid drinking while taking
metronidazole.
3. Explanation of side effects: Side effects during eradication
and actions to be taken if they occur should be adequately
explained.
4. Posteradication GERD: Explain that reflux esophagitis or GERD
symptoms may occur temporarily or become exacerbated fol‐
lowing eradication treatment. However, these symptoms do not
interfere with eradication treatment.
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5. Nutritional status following eradication: Because the risk for life‐
style‐related diseases (eg, obesity and cholesterol elevation)130
increases after successful eradication, patients should receive
lifestyle guidance even after successful eradication.
6. Recurrence of positivity: Explain that recurrence of H. pylori posi‐
tivity after eradication has been reported in some cases131 and
can occur at an approximate frequency of 0%–2% per year.
7. Follow‐up after eradication: The onset of gastric cancer has been
reported even after successful eradication,132 and there is also
the problem of H. pylori recurrence. Thus, patients are recom‐
mended to undergo periodic gastric examinations even after suc‐
cessful eradication.
5.10 | Salvage therapies following second‐line
eradication therapy include eradication using
sitafloxacin and high‐dose PPI/amoxicillin therapy.
(Recommendation: 1, Evidence level: B)
When second‐line eradication is unsuccessful, regimens for third‐
line eradication therapy such as PPI/amoxicillin/sitafloxacin and PPI/
sitafloxacin/metronidazole have also been reported.133
High‐dose PPI//amoxicillin therapy is an eradication method
used to maximize the efficacy of amoxicillin by increasing the num‐
ber of amoxicillin oral administrations (because it is a time‐depen‐
dent antibacterial agent) and the number of PPI administrations to
134
strongly suppress gastric acid secretion.
5.11 | For individuals with a penicillin allergy,
a regimen not containing penicillin antibiotics
(eg, amoxicillin) is used for eradication therapy.
(Recommendation: 1, Evidence level: B)
In the case of clarithromycin susceptibility, a combination of PPI/
clarithromycin/metronidazole is recommended; in the case of resist‐
ant bacteria or unknown, a PPI/sitafloxacin/metronidazole or PPI/
135,136
minomycin/metronidazole combination is recommended.
5.12 | For individuals with decreased renal
function, the dose of antibacterial agents should be
decreased and the indication should be carefully
considered. (Recommendation: 1, Evidence level: A)
Amoxicillin administration should be considered carefully when the
patient's renal function is impaired.137 It is desirable to consult with a
nephrologist as required. Clarithromycin metabolites metabolized by
CYP3A4 are also excreted through the kidneys, and a 200  mg once
daily is generally recommended for individuals with an advanced impair‐
ment of renal function. An metronidazole dose of 250  mg once daily
is also recommended. Pack formulations, for which dosages cannot be
adjusted, should not be used. Because eradication therapy may trigger
an irreversible adverse effect on renal function, adequate considera‐
tions are needed (eg, risk–benefit balance) regarding the indication of
eradication.
5.13 | For dialysis patients, the dose of antibacterial
drugs should be decreased, and the dose on the
days of dialysis should be administered after dialysis.
(Recommendation: 1, Evidence level: A)
In dialysis patients, the maximum amoxicillin blood level is extremely
high and half‐life is also long. Moreover, because it is dialyzable, amox‐
icillin should be administered at a dose of 250 mg once daily on the
day of dialysis after dialysis. Clarithromycin metabolites in the liver are
also excreted through the kidneys, and it is recommended that 200 mg
clarithromycin and 250 mg metronidazole should be administered once
daily to dialysis patients on the day of dialysis after dialysis. Pack formu‐
lations, with which the dosages cannot be adjusted, should not be used.
5.14 | Eradication in individuals with decreased
liver function is performed with regular doses, but
caution regarding adverse events is necessary.
(Recommendation: 2, Evidence level: B)
According to a report on eradication in individuals with chronic hep‐
atitis and hepatic cirrhosis, eradication could be performed with no
particular problems in individuals with impaired hepatic function138;
however, the liver is involved in the metabolization of many drugs
used for eradication therapy; thus, such drugs should be used with
adequate caution to adverse events.
5.15 | The effects of probiotics in H. pylori
eradication therapy. (Recommendation: 1, Evidence
level: B)
In a meta‐analysis, certain probiotics have an additive effect on
eradication.139 Moreover, another meta‐analysis showed that the
combined use of probiotics significantly decreases side effects (eg,
diarrhea and nausea), whereas it tends to have an additive effect,
albeit statistically insignificant, on the eradication rate.140
6 | PRO P OSA L : G A S TR I C C A N C E R
PR E V E NTI O N
6.1 | General theory
We describe how to prevent gastric cancer from a perspective of H.
pylori infection control separately for adolescent, low gastric cancer
risk, and high gastric cancer risk stages.
6.1.1 | Currently in Japan, infection with
H. pylori primarily occurs during the infant
stage, and the main infection route is via family
infection. (Recommendation: 1, Evidence level: B)
Studies that followed uninfected children overseas141 and in
Japan142,143 have shown that H. pylori infection primarily occurs
during the infant stage and is less common in later stages. Infected
KATO et al.
children often have bacterial strains/bacteria whose genes are iden‐
tical to those of their family members with the highest matching rate
with mothers and the next highest with fathers.103,144,145 Moreover,
the parents of infected children have a high positive rate.143
6.1.2 | The H. pylori infection rate (prevalence)
has been decreasing in Japan. (Recommendation: 1,
Evidence level: A)
The rate of H. pylori infection in Japan continues to decline because
146 147-150
of improvements in water supply and sewage systems, etc
The rates among individuals born during the 1970s and 1980s were
20% and 12%, respectively, which were significantly lower than the
rate for those born before 1950, which is >40%. 150
This decrease
should be considered regarding gastric cancer countermeasures.
6.1.3 | In Japan, the cause of most cases of gastric
cancer is H. pylori infection, and gastric cancer risk in
H. pylori‐uninfected individuals is extremely low. H.
pylori infection increases the risk for undifferentiated
gastric cancer, as well as the risk for differentiated
gastric cancer. (Recommendation: 1, Evidence level: B)
Gastric cancer risk in individuals with an ongoing infection is at
least 15 times,151,152 higher than that in uninfected individuals. The
frequency of H. pylori‐negative gastric cancer in Japan has been re‐
ported as 0.42% endoscopically treated cases of differentiated early
gastric cancer,153 and 0.66% endoscopically or surgically treated
cases, including undifferentiated gastric cancer.154
Because H. pylori infection increases the risk of both differenti‐
ated and undifferentiated gastric cancer, 148,151,152 the prevention of
infection has a major impact on gastric cancer prevention.
6.1.4 | Gastric cancer risk varies greatly
depending on the presence or absence of H. pylori
infection and the extent of gastric mucosal atrophy.
Therefore, it is recommended that an H. pylori
infection test be performed early. (Recommendation:
1, Evidence level: B)
The status of H. pylori infection includes uninfected individuals, in‐
dividuals with an ongoing infection, and individuals who were previ‐
ously infected but are currently not infected. Although successful
eradication decreases gastric cancer risk, gastric cancer incidence
remains higher than that in never‐infected people.132 Gastric mu‐
cosal atrophy is advanced in individuals with a persistent infection,
and gastric cancer risk increases with the progression of gastric
mucosal atrophy.151,155 Gastric cancer risk varies greatly depend‐
ing on the extent of H. pylori infection and gastric mucosal atrophy.
Therefore, a test for H. pylori infection at an earlier stage of infection
is desirable to evaluate gastric cancer risk. Individuals with H. pylori
infection history should also be examined regarding gastric mucosal
atrophy, when they are in high gastric cancer risk stage.
|
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6.1.5 | Gastric cancer risk is decreased by
eradication. (Recommendation: 1, Evidence level:
A) Eradication at an earlier stage of infection is
more effective for gastric cancer prevention.
(Recommendation: 1, Evidence level: B)
A randomized study of eradication therapy for H. pylori gastritis has
shown a 0.61 times lower prevalence of gastric cancer, a 0.36 times
lower prevalence in participants at age ≥55  years, and a 0.26 times
lower mortality rate.156 A meta‐analysis has shown that gastric cancer
risk is significantly decreased to a level 0.66 times lower in the eradi‐
cation group.157 A randomized study evaluating metachronous cancer
incidence following an endoscopic resection of early‐stage gastric can‐
cer in Japan14 demonstrated that eradication decreased gastric cancer
risk by 0.34‐fold. A meta‐analysis of similar studies158 has shown a de‐
crease in gastric cancer risk by 0.42‐fold or by 0.39‐fold if the analysis is
limited to prospective studies. The involvement of H. pylori infection is
also substantial in juvenile gastric cancer, of which 80% cases are undif‐
ferentiated cancer.159 The number of deaths due to gastric cancer in in‐
dividuals aged ≤40 years has decreased by 1/6 from 1970 to 2010 with
the decline of the H. pylori infection rate,160 and H. pylori infection also
has a strong impact on gastric cancer incidence in young individuals.
The preventive effect of gastric cancer is shown to be higher if
eradication treatment is performed at an earlier stage before the
atrophy becomes advanced.13,161-163 For adolescent, no results are
available to prove the direct preventive effect against gastric can‐
cer in humans, because a long observation period is required before
gastric cancer develops; however, the results from animal experi‐
ments164 suggest that eradication at an earlier stage of infection has
a greater preventive effect against gastric cancer.
6.1.6 | Follow‐up observation with an
endoscope and other methods is essential after
eradication. (Recommendation: 1, Evidence level: A)
Gastric cancer risk remains high even after eradication (general
theory 4). In the high gastric cancer risk stage (Figure 1), follow‐up
observation with an endoscope and other methods is necessary.165
In the adolescence and low gastric cancer risk stage, actions in ac‐
cordance with the condition of the gastric mucosa are necessary.
6.2 | Adolescence
Screening and treatment for H. pylori infection at this age are con‐
sidered as measures for decreasing the lifetime gastric cancer risk.
These measures should be implemented by municipalities as policies.
6.2.1 | Screening tests for H. pylori infection is
possible for middle‐school students and older.
(Recommendation: 1, Evidence level: B)
In younger children, the risk for reinfection is high,166-168 and the
sensitivity of an infection diagnosis using antibody measurement
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12 of 17       KATO et al.
F I G U R E 1   Schema of gastric cancer prevention utilizing the
relationship between H. pylori and gastric cancer
kits is low.169-171 In middle‐school students or older, the accuracy
of antibody tests is equivalent to that in adults,172 and screening
for infections is possible for students in middle school or older.
Because middle‐school education is compulsory, middle‐school
students represent an ideal target population for screening if it is
implemented by local governments. For students confirmed to be
infected with H. pylori, it is recommended that eradication treatment
be performed as soon as possible after considering the benefits and
risks of eradication treatment and the preferences of students and
guardians. Note that eradication treatment for children is currently
not covered by the health insurance system in Japan.
6.2.2 | Eradication therapy for adolescence is an
effective method of infection control for the next
generation. (Recommendation: 1, Evidence level: B)
Undergoing eradication therapy before becoming a parent can be a
measure against transmission to the next generation by preventing
intrafamilial infection. This is effective in Japan, where reinfection is
173
not common.
6.2.3 | Urinary antibodies or fecal antigens are
recommended as a screening test for H. pylori
infection in adolescence. (Recommendation: 2,
Evidence level: C)
In Japan, urinalysis is performed for all children and students.
Therefore, H. pylori infection screening using urine is a noninvasive
and low‐cost means by which a high screening rate can be achieved.
Likewise, a noninvasive fecal antigen test is also recommended;
however, this test is associated with problems such as reluctance in
children in this age to collect fecal samples, and false‐positive results
that increase with sample exposure to elevated temperatures during
transport.
6.2.4 | A highly accurate UBT is recommended
as a test for H. pylori infection in adolescence.
(Recommendation: 1, Evidence level: B)
When a screening test for H. pylori infection is performed with urine
antibodies, there is a 30%‐40% false‐positive rate because of the in‐
fluence of urine proteins and other factors. Therefore, a UBT, which
has the highest diagnostic accuracy, is recommended for the diagno‐
sis of infection.174,175
6.2.5 | Because there is a high rate of H. pylori
resistance to clarithromycin among adolescence
in Japan, it is recommended that the treatment
method be determined after conducting a bacterial
drug susceptibility test. (Recommendation: 1,
Evidence level: A) If a drug susceptibility test cannot
be performed, the treatment method is selected
in consideration of clarithromycin resistance.
(Recommendation: 1, Evidence level: B)
The clarithromycin resistance rate in Japanese children is as high as
29%‐43.4%.176-179 The treatment method is selected on the basis of
the latest information, including susceptibility, eradication rate, and
safety.
6.3 | Low gastric cancer risk stage (adults aged
<50 years)
6.3.1 | At this stage, a test for H. pylori infection and
a test for gastric mucosal atrophy should be used in
combination. (Recommendation: 2, Evidence level: C)
It is important to evaluate the extent of atrophy of the stomach mu‐
cosa by an endoscopic examination. For gastric mucosa with a high
gastric cancer risk, endoscopy is recommended according to the risk
level, even for those aged <50 years.
6.3.2 | Eradication treatment at this
stage is effective as a means of protecting
against transmission to the next generation.
(Recommendation: 1, Evidence level: B)
To prevent their children from infected parents, it is recommended
that H. pylori‐infected individuals undergo eradication treatment be‐
fore having children.
KATO et al.
6.4 | High gastric cancer risk stage (age ≥50 years)
6.4.1 | Eradication treatment is still expected to
have a preventive effect against gastric cancer at this
stage. (Recommendation: 1, Evidence level: A)
It is necessary to carefully confirm the absence of gastric cancer by
endoscopy before eradication treatment. Eradication even at age
≥70 years is effective for gastric cancer prevention.14
6.4.2 | At this stage, a serum H. pylori antibody
test and pepsinogen test may yield false‐negative
results. (Recommendation: 1, Evidence level: B)
11. Ueda J, Gosho M, Inui Y, et al. Prevalence of H. pylori infec‐
Because of advanced gastric mucosal atrophy in cases in which H.
pylori has spontaneously disappeared or in posteradication cases, H.
pylori antibody test and pepsinogen tests may often yield false‐nega‐
tive results in individuals with an ongoing or past infection. Note that
there are false‐negative results, particularly when conducting these
tests for individuals aged ≥65 years.
C O N FL I C T O F I N T E R E S T
The authors disclose conflict of interest with the following compa‐
nies. This study received lecture fees and/or payment of manuscripts
from AstraZeneca KK, Eisai Co. Ltd., Otsuka Pharmaceutical Co., Ltd.,
Daiichi Sankyo Company, Takeda Company and scholarship grants
from Astellas Pharma Inc, Abbott Japan Co. Ltd., Eisai Co. Ltd., Otsuka
Pharmaceutical Co., Ltd., Daiichi Sankyo Company. Kikuchi S accepted
fee for speaking from Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan).
ORCID
Mototsugu Kato  https://orcid.org/0000-0001-7913-8384
Masumi Okuda  https://orcid.org/0000-0001-5263-2868
Shogo Kikuchi  https://orcid.org/0000-0001-9499-9668
Tadashi Shimoyama  https://orcid.org/0000-0001-9615-0000
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How to cite this article: Kato M, Ota H, Okuda M, et al.
Guidelines for the management of Helicobacter pylori
infection in Japan: 2016 Revised Edition. Helicobacter.
2019;e12597. https​://doi.org/10.1111/hel.12597​