Modern approach to the diagnosis of Helicobacter pylori infection

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wileyonlinelibrary.com/journal/apt Aliment Pharmacol Ther. 2022;55(Suppl. 1):S14–S21.© 2021 John Wiley & Sons Ltd
Received: 1 June 2021
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First decision: 29 June 2021
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Accepted: 30 July 2021
DOI : 10.1111/apt.16566
Modern approach to the diagnosis of Helicobacter pylori
infection
Maria Pina Dore1 | David Y. Graham2
1Dipar timento di Scienze Mediche, Chir urgich e e Sperimenta li, Universit y of Sassari, Sas sari, Italy
2Depar tment of Medicine, Michael E. De Bakey VA Medical Center and Bay lor College of Med icine, H ouston, Texas, USA
Correspondence
David Y. Graha m, Michael E. De Bakey Veterans Aff airs Me dical C enter, RM 3A- 390A (111D), 2002 Holcombe Boulevard, Houston , TX 77030, USA .
Email: dgraham@bcm.edu
Funding information
Dr. Graham is suppor ted in part by the Office of Research and Development Medical Research Se rvice Depar tment of Veterans Af fair s, Public Health Ser vice
grant DK 56338 which fun ds the Texas Me dical C enter Digestive Diseases Cente r.
1 | INTRODUCTION
Helicobacter pylori is an important, transmissible, human pathogen ae-
tiologically related to gastric cancer, peptic ulcer disease, atrophic gas-
tritis, iron deficiency anaemia, vitamin B12 deficiency and idiopathic
thrombocytopenia. Helicobacter pylori gastritis is an insidious disease
that alters gastric physiolog y and causes progressive gastric mucosal
damage. Typically, those affected only become aware of the infec tion
when it expresses its presence by the development of clinical mani-
festations such as dyspepsia, a major upper gastrointestinal haemor-
rhage or an inc ur abl e gast ric can ce r. The infect ion is tra nsmit te d wi thin
families and is typically acquired in childhood. Helicobacter pylori is an
opportunistic pathogen and takes advantage of any chance to gain ac-
cess to the stomach, (i.e., faecal- oral, oral- oral, contaminated water or
food, etc.) where, once established, the infection is typically lifelong.
Current consensus is that the presence of the infection confers only
ris k with out any ben ef it to the hos t.1 During the 19th and most of 20 th
centuries it was a major cause of disease being responsible for both
peptic ulcer disease and gastric cancer.2 Gastric cancer was the most
common cause of cancer death until the last third of the 20 th century
and is still a major health problem worldwide.3,4 The prevalence of H.
pylori infection inversely correlates with economic development as re-
flected in sanitation, clean water, poverty, socioeconomic status and,
especially, household hygiene. In highly developed countries the prev-
alence of the infection has been declining since at least 1950 such that
the inf ect io n is mos tly conf ined to the el der ly, tho se of lower socioeco -
nomic st atu s in chi ldhood, and in imm igr ants from countrie s whe re the
prevalence of the infection is still high.2 Overall, it has been estimated
that approximately one- half of the world’s population is infected.5
The recognition that H. pylori infection provides no benefit and
that its eradication could eliminate gastric cancer has resulted in a
change in attitude toward the infection from the aim of identify-
ing and curing it among those with symptoms (e.g., uninvestigated
dyspepsia) or complications (upper gastrointestinal bleeding) to be
more proactive (Table 1).3,6,7 All recent consensus groups agree
that, whenever the infection is identified, it should be treated unless
there are compelling reasons not to do so.3,6,7 In addition, it is now
recommended that testing for the infec tion should be extended to
high risk populations, groups, and individuals including first degree
relatives of those with H. pylori- associated diseases and those living
in the same household6 (Figure 1).
1.1 | Testing for the presence of H. pylori infection
Since the discovery of H. pylori in the 1980s, there has been a pleth-
ora of diagnostic methods developed and introduced in research and
clinical practice (Table 2). Probably the most widely used has been
serolog y based on ease of use and widespread availability. Serology
remains widely available and is generally inexpensive and simple to
obtain by the patient. However, as the infection is often lifelong, a
positive test may denote an active infection or a serologic scar from
a prior infection. As with any test, the pretest probability (the prob-
ability of the presence of the condition) of a given diagnostic test is
influenced by the prevalence of the disease in that specific popula-
tion (reviewed in reference6).
1.2 | Serology
Factors to be considered for any test include cost, convenience,
accuracy, and how the information is to be used. The progressive

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decline of the prevalence of H. pylori infection correlates with an
increase in the number of false- positive tests (Figure 2) which has
undermined the use of H. pylori serology in most western popula-
tions. The problems include the fac t that many of the available test s
have poor specificity and susceptibility. For example, in 2013, 29
serologic tests were evaluated (17 enzyme- linked immunosorbent
assay and 12 near- patient test s); only t wo of the 17 enzyme- linked
immunosorbent assay tests produced excellent result s with the
five performance parameters >90%.8 A 2019 Cochrane review of
34 studies (4242 participants) also evaluated serology for H. pylori
diagnosis. The diagnostic odds ratios for serology was 47.4 (95% CI
25.5- 88.1). The sensitivit y, given a specificit y of 0.90 and a preva-
lence of 53.7% (which were the medians in the studies), was 0.84
(95% CI 0.74- 0.91).9
1.3 | Special problems with H. pylori serology in the
United States
As such, serologic testing has fallen into disfavour and, in the U.S.,
may not be reimbursed by insurance.10 Because of these issues,
Quest Diagnostics, one of the largest clinical laboratories in the
U.S., no longer lists H. pylori serology among their available tests.
Although anti- H. pylori serology may no longer be covered by insur-
ance in the USA, a common knee- jerk response is the continuing
practice of ordering a serologic test as it is very convenient to order
as part of the post- visit laboratory work.
While it is recommended that only tests for the IgG H. pylori an-
tibodies be used, the large U.S. A. commercial laboratory, LabCorp,
lists four options. The Food and Drug Administration (FDA)- approved
IgG test is listed third after test for IgA, and the combination of IgA,
IgG and IgM tests. The IgA, IgM and combined IgA , IgG, and IgM
tests are fur ther described the subheading of test details: as “This
test was developed, and its performance characteristics determined,
by LabCorp and has not been submitted or approved by the USA .
Results of these tests are listed as for investigational purposes only
and the results should not be used to justify therapy without con-
firmation of the diagnosis by another medically diagnostic product
or procedure”.11 In contrast, the IgG test is described by LabCorp
as “This assay should be used only to evaluate patient s with clini-
cal signs and symptoms suggestive of gastrointestinal disease and
is not intended for use with asymptomatic patients. A positive test
result does not allow one to distinguish between active infection and
colonization by H. pylori. A positive test only indicates the presence
of IgG antibody to H. pylori and does not necessarily indicate that
a gastrointestinal disease is present. A negative test indicates that
IgG antibody to H. pylori is not present or is at a level that cannot be
detected by the assay.” Such details require a number of additional
clicks beyond the stage where the test is ordered.
1.4 | Practical use of serology
While it is clear that the decision to treat should not be based solely
on the results of serologic testing, there are exceptions when serol-
ogy, despite its problems, is useful. Exceptions include cases with a
very high pretest probability (e.g., bleeding duodenal ulcer). A high
pretest probability in combination with positive IgG H. pylori antibod-
ies moves the odds of a current infection to the right side of Figure 2
showing that the majority of positives are true positives. Current
guidelines recommend to search for H. pylori infection in high- risk
groups such as family members of patients with an H. pylori infec-
tion or a disease associated with H. pylori (Table 1). In this instance, a
high- quality IgG serologic test can provide a rapid, convenient, and
effective method of confirming the presence of the infection. When
used for screening average or low- risk individuals for possible infec-
tion, a positive serology would still require proof of active infection
before treatment would be instituted.
TABLE 1 Recommendations for Helicobacter pylori testing for
individuals and populations
Recommendations
Agreement
(%)
Evidence
level
Houston consensus conference recommendations
When to tes t a specific individual?
1. With suspected Helicobacter pylori
infection (e.g., active DU)
100 High
2. With current or past gastric or
duodenal ulcers
100 High
3. With uninvestigated dyspepsia 100 High
4. With gastric mucosa- associated
lymphoid tissue lymphoma
100 Moderate
5. Family members residing in same
household of patients with proven
active Helicobacter pylori infections
91 Moderate
6. Family history of peptic ulcer disease 91 Moderate
7. With family his tory of gastric cancer 100 Moderate
8. First- generation immigrant s from
high prevalence areas
82 High
9. High risk groups (e.g., in the United
States: L atino and Afric an American
racial or other ethnic groups)
91 Low
Taipei global consensus recommendations
Which specific populations to screen?
1. Populations with high incidence of
gastric cancer
84 Low
2. Young adult s in high incidence
populations before the development
of atrophic gastritis and intestinal
metaplasia
84 Low
3. Young adult s in high incidence
populations to reduce the
transmission to their children
92 Low
4. Populations with high incidence
being integrated or included into the
national healthcare priorities
92 Low
Adapted from References 3,6, with permission.

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FIGURE 1 Flow chart showing a modern approach to using diagnostic tests for the presence of Helicobacter pylori infection and
determination of antimicrobial susceptibility
Molecular or culture idenficaon
and/or suscepbility tesng
Alarm features or
increased risk due to age,
family history or ethnic
group
Convenonal/high definion
upperendoscopy Breath or Stool Collecon
Histology
Rapid urease test
Stool Angen test
Urea Breath test
Stool
Molecular idenficaon
and/or suscepbility
YesNo
Posive
Negave
TABLE 2 Tests for Helicobacter pylori infection
Tes t s Strengths Weaknesses
Non- invasive
Serology Widely available. Least expensive and does not require
medication modifications prior to testing. May not be
reimbur sed by insurance
Does not reliably delineate between active or previous
infection. Cannot be used to confirm eradication. (Low
likelihood ratio)
Does not assess the gastric mucosa status (Helicobacter
pylori infection sequelae)
GastroPanel@Widely available. Does not require treatment
modifications prior to testing. Allow to assess the
gastric mucosa status (H. pylori infection sequelae)
Expensive. Does not discriminate between active
or previous infection. C annot be used to conf irm
eradic ation. Not available in the USA
Stool antigen test
with monoclonal
antibodies
High sensitivit y and specificity. Can be used to tes t
for active infection, to evaluate eradication, and for
moleculars tes ting to assess antibiotic susceptibility
in adult s and children
Stool sample needed. Requires prior cessation of
antibiotics, bismuth products, and proton pump
inhibitors to reduce risk of false- negative results.
Unable to assess the gastric mucosa status
13C- Urea breath test High sensitivit y and specificity. Can be used to tes t for
active infection and evaluate for eradication safely in
adults and children
Requires prior cessation of antibiotics, bismuth products,
and proton pump inhibitors to reduce risk of false-
negative results.
Relatively expensive
Endoscopic
Culture Allows testing antibiotic susceptibilities Increasingly available from some major laboratories (e.g.,
Mayo., LabCorp)
Molecular- based
testing
Detects infec tion and can assess susceptibility/
resistance for all 6 commonly used antibiotics. Stool
can be used. Rapid turn- around of result s (5 business
days)
May not be covered by insur ance. Available only as a
“send out ”. (e.g. American Molecular Laboratories Inc.
http://amlab orato ries.com)
Histology C an be used to test for infection and evaluate for
eradic ation. Provides additional information such as
degree of inflammation and associate d pathology (i.e.,
intestinal metaplasia , atrophic gastritis)
Accurate results, it requires interested pathologist and
use of special stain - preferably immunohistochemical
Rapid Urease tests Rapid, inexpensive, good sensitivity and specificit y Rarely used as adds nothing to histology

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Where available, the combination of IgG serolog y coupled
with pepsinogen I and II testing (the GastroPanel®, Biohit Oyj,
Helsinki) potentially provides IgG serology coupled with screening
for the presence of atrophic gastritis.12 The IgG serolog y test in the
Gas troPa nel sc ore d hig hly in bo t h th e 2013 co m p a r a tive te sts8 and in
recent tests.12 Pepsinogen testing is especially useful in areas where
gastric cancer is still common to help identify patient s for endo-
scopic screening for gastric cancer risk determination. Importantly,
the validit y of pepsinogen testing is greatly reduced following suc-
cessful H. pylori therapy making timing of testing a critical factor.13
1.5 | Traditional non- invasive testing for active H.
pylori infection
Currently, the focus has been on tests that can non- invasively iden-
tify active H. pylori infec tion (i.e., 13C- urea breath test [UBT] or the
stool antigen test using monoclonal antibodies). Both are highly ac-
curate but require a relatively high bacterial load and false- negative
results may occur if the load of H. pylori is reduced by treatment
with proton pump inhibitors (PPIs), bismuth compounds or antibiotic
therapy.
The UBT is based upon the presence of a high concentration of
urease produced by the organism. This enzyme produces ammonia
and CO2 from ingested urea. If the urea contains labelled carbon,
for instance the radioactive isotope of carbon 14 C or the stable non-
radioactive 13C, the labelled CO2 released can easily be measured in
the exhaled breath collected in bags or tubes. Because the 14C - u r e a
breath test uses radioactive carbon, the test may require personnel
trained in the use and detection of radioactive chemicals. In clinical
practice, UBT utilizing 13C is preferred. Testing is widely available
from large testing laboratories and in many hospitals using small
portable point- of- care devices to analyse the breath samples. The
method is simple to perform and no special handling is required. In
addition, it is devoid of side effects and thus pregnant women and
children can be tested, and repetitive testing can be done without
concerns for safety. However, the UBT, like histology, the rapid ure-
ase test (RUT) and stool antigen test require a high density of bac-
teria. Therefore, drugs such as PPIs, bismuth- containing compounds
or antibiotics may decrease the number of H. pylori and produce
false- negative test s. A s such, it is recommended to wait 2 weeks to
be certain that the effects of the suppression of bacterial load have
disappeared. However, if the test is done sooner, and is positive,
one can trust the result. False- positive UBT results are potentially
a problem in patients with achlorhydria where non- H. pylori urease-
containing organisms may populate the stomach. This problem is
reduced if the test meal contains citric acid which reduces the intra-
gastric pH and inhibits non- H. pylori urease.1 4 - 1 6 Histamine2 antago-
nists do not reduce the H. pylori ba c te ria l loa d an d can be sub sti tut ed
for those requiring continuing acid suppression thus obviating the
need to delay testing. The UBT is now considered the diagnostic test
of choice if endoscopy is not required or if biopsies are contraindi-
cated and to confirm eradication in adults and children.6,17
1.6 | Biopsy- based testing
As noted above, until recently, testing focused on identifying and
treating those with symptomatic H. pylori dis e ase s. In ma ny in s t anc e s
this would include gastroscopy and resulted in the development of
a variety of excellent biopsy- based tests and improved methods of
identif ying the organism histologically. Endoscopy is an expensive
test and is not without risk. For this reason, the procedure should
include evaluation and biopsy of not only observable abnormalities
but also should include biopsies of the normal- appearing mucosa
from both the antrum and corpus to exclude or diagnose the infec-
tion and also be able to assess the degree and potential reversibility
of the damage.18 As such, five biopsies are recommended using the
Sydney system and placed in separate jars (Figure 3).18 If atrophy/
intestinal metaplasia is found, this approach to biopsy also provides
the appropriate specimens for cancer risk staging.19, 20 If inflamma-
tion is present, the presence of H. pylori should be assessed using
immunohistochemical stains.21 For patients in whom the infection
is highly likely, biopsies for culture or molecular- based susceptibil-
ity testing can also be taken and stored at −70°C for analysis if the
patient is proven to be infected. An indirect test for the presence of
H. pylori urease (i.e., RUT) is also available but is rarely used today as
it provides no information in addition to that obtained by histology.
FIGURE 2 The effect of disease prevalence (pretest probability)
on the positive and negative predictive values. Results are shown
for a test with an 85% sensitivity and specificity and population
prevalence of 20% and 80%. In a study with a sensitivity and
specificity of 85% (i.e., 15% false negative and 15% false positive)
and a Helicobacter pylori prevalence of 20%, approximately 40% of
positive tests will be false positive. If the specificit y and sensitivit y
are equal, the curves will retain their shape and the lines will cross
at the 50% mark. At a H. pylori prevalence of 20%, there will be 80
negative and 20 positive patients per 100 patients. The proportions
can be calculated as 80 negative times 15% = 12 false positive
test + 20 true positive patient ’s times 85% = 17 true positive
patient producing the total of 12 + 17 or 29 positive results of
which 12 (41%) are false positive

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However, there is the possibility the RUT may be resurrected be-
cause the biopsy specimen embedded in the jell medium for the RUT
can also be used for reflex molecular susceptibility testing.22
Advanced endoscopy techniques such as the narrow band imag-
ing, blue laser imaging (BLI) and the linked colour imaging (LCI) can
also be used for real- time diagnosis of H. pylori infection, detection
of premalignant and malignant gastric lesions and targeted mucosal
biopsy sampling.7 In addition, a new technique of endocytoscopy or
ultra- high magnification endoscopy is reported to enable histologic
assessment in vivo23 as well as to be used, theoretically, to diagnose
active infection by in situ hybridization fluorescence.24 Further de-
velopment of high- definition endoscopy for the diagnosis of H. py-
lori infection and detection of pre- malignant and malignant gastric
lesions to permit real- time decision- making led to a revision of the
Kyoto endoscopic classification.25 Recently, increasingly sophisti-
cated tools including artificial intelligence have been used to diag-
nose H. pylori infection.26 For example, Nakashima et al developed an
artificial intelligence able to imitate the brain neural net work using
BLI- bright and LCI.27 They reported improved accuracy and produc-
tivity compared to white light with a sensitivity for BLI- bright and for
LCI of 96.7% and 96.7%, respectively. Nonetheless, the availability
of these advanced techniques remains, limited while the tried and
true histologic techniques discussed above are universally available.
1.7 | Molecular- based tests that add the ability to
include some susceptibility data
The concept that clinical specimens obtained for diagnosis could be
reused or repurposed is not a new one. For example, gastric biopsies
have long been obtained for culture, histology and RUT. By 1994 the
polymerase chain reaction (PCR) had been also used as a diagnostic
test using gastric biopsies.28 In 20 0 0 , fl u o r e s cent in si t u hy bridiz atio n
(FISH) was also introduced as a new PCR- based method of H. pylori
diagnosis.29 As noted above, both FISH and PCR are currently used
for susceptibilit y testing. Biopsy specimens that have been success-
fully used to obtain antimicrobial susceptibility data from H. pylori-
infected patients included those collected specifically for molecular
testing as well as those reclaimed from an RUT.2 8 - 3 4
Helicobacter pylori eventually are excreted in the stool making this
an excellent source for material for tests designed to identify H. pylori
antigens and H. pylori DNA, which is used for molecular diagnosis and
to determine antimicrobial susceptibility.31 Recently, a number of kits
using molecular detection methods have been developed and are com-
mercially available. These tests allow rapid and accurate non- invasive
assessment of clarithromycin susceptibility/resistance and can utilize
gastric biopsies and/or faeces. E xamples include: Amplidiag® H. py-
lori+ClariR assay (AB ANALITICA s.r.l.), the RIDA®GENE Helicobacter
pylori assay (R- Biopharm AG), H . pylori ClariRes (Ingenetix), Allplex H.
pylori, ClariR (Seegene), the Lightmix® H. pylori (TIBMolbiol) and the
H. pylori Taqman® real- time PCR assay (Meridian Bioscience).3 5 - 4 1 The
Genotype HelicoDR assay (Germany) and whole genome sequenc-
ing have been used for both clarithromycin and levofloxacin resis-
tance.42, 43 Although there are a number of validated tests and test
kits commercially available, the majority have been tested with gastric
biopsies and they are infrequently per formed. Overall, the availability
of these tests and test kit s has not changed the frequent admonition
about the lack of susceptibility testing or the continuing decrease in
cure rates.4 4,45 Some of the reasons for slow acceptance may be that
none of these molecular tests has been promoted by major reference
laboratories and key opinion leaders, and major groups such as the
European, Korean, Chinese, and other Helicobacter Study Groups
have not stressed the usefulness and availability or provided guid-
ance to assist clinicians about how to obtain these kits or how best
to encourage their hospital laboratories to of fer them. It behooves
clinicians to become knowledgeable regarding which of these tests
are available locally, which also test stool, as well as to encourage
the laboratories that analyse their stool antigen tests to add reflex
molecular testing for clarithromycin and, preferably also, levofloxacin
resistance. The recent developments in the USA likely predict the di-
rection of diagnostic testing worldwide. Although, the USA was slow
to introduce molecular testing, this may have been in par t related to
the stringent requirements for specificity and sensitivity imposed
by the FDA and by long delays in reimbursement being approved.
However, the USA represents a very large homogenous mass market
with only a few major country- wide laboratories such that once the
hur dl es are over come, test s ca n be introduced rapidly and wid el y. The
Mayo Cli nic La bo ra tory, a majo r USA ref er en ce labo ratory, was one of
the first in the USA to of fer reflex molecular testing for clarithromy-
cin resistance of positive H. pylori stool tests (Mayo Clinic Laborator y,
https://www.mayoc linic labs.com/test- catal og/Overv iew/607594).37
In addition, American Molecular laboratories offer targeted next-
gene rat io n seq uen ci ng (N GS ) using sto ol, gast ric bio psies , or form ali n-
fixed gastric biopsies that test for antimicrobial resistance to six
antibiotics (amoxicillin, clarithromycin, levofloxacin, metronidazole,
tetracycline and rifabutin) (http://amlab orato ries.com/testi ng- servi
FIGURE 3 Gastric biopsy sites using the updated Sydney system

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c e s / h e l i c o b a c t e r - p y l o r i - d e t e c t i o n - a n t i b i o t i c - r e s i s t a n t - a n a l y s i s / p y l o r
iar- amhpr - h- pylor i- antib iotic - resis tance - next- gener ation - seque ncing
- panel/).46 Testing of stool allows obtaining susceptibility data with-
out endoscopy. They also offer reflex testing of stool samples using
next- generation sequencing and will accept samples from anywhere
in the world which, for the first time, makes molecular- based antimi-
crobial susceptibility testing potentially universally available. Other,
USA commercial laboratories are expec ted to rapidly follow the Mayo
Clinic Laboratories' lead as these tests are reimbursed by insurance.
The turnaround time for molecular tests is typically less than 1 week.
1.8 | Culture and susceptibility testing
Although still underutilized, culture and susceptibility testing for H.
pylori is now generally available in the U.S. Susceptibility is now of-
fered by many major diagnostic laboratories including: Mayo Clinic
Laboratories® (HELIS), ARUP laboratories ® (MC HPYL), Labcorp®
(180885) and Quest Diagnostics (36994). Culture and susceptibility
testing from Microbiology Specialists Msi@microbiologyspecialists.
com is available both in the U.S. and internationally.
1.9 | How to practically use non- invasive tests to
identify H. pylori infection
Indications for testing can be separated into testing for patients in
whom the diagnosis of an H. pylori- related disease is a serious con-
sideration, or for those where it is only a possibility (e.g., a member
of a high- risk group who is currently without symptoms or history of
an H. pylori- related disease). For those with a reasonable probability
of an H. pylori- related disease (e.g., dyspepsia, idiopathic thrombo-
cytopenia, MALT lymphoma, etc.) a positive diagnosis is likely to be
followed by treatment. For such a patient, only tests for active in-
fection (e.g., UBT, stool antigen, endoscopy with biopsy, etc.) should
be used; the choice would depend on whether the signs/symptoms/
laboratory findings were sufficient to warrant upper gastrointestinal
endoscopy.
In contrast, a healthy asymptomatic individual with one parent
who died of gastric cancer, would only be suspected of possibly
having asymptomatic infection and might receive initial testing with
validated H. pylori IgG serology which, if positive, should be fol-
lowed by a confirmatory test of active infection before institution
of therapy.
2 | DISCUSSION
Helicobacter pylori infection remains a serious but decreasingly
encountered problem. However, the recent worldwide influx of
immigrants and refugees from regions where H. pylori infection
and its most serious sequela, gastric cancer, are still common
has produced sizable at- risk populations.47 Early diagnosis and
treatment can markedly reduce the risk of gastric cancer, mak-
ing the question of whom to test as important as whom to treat.
The admonition to cure all H. pylori infect io ns encounter ed ca rr ie s
with it the onus to ensure that active infection is present before
institution of therapy and, after therapy, that the infection was
cured.3 The approach to the individual patient will largely depend
on the pretest probability of active infection (e.g., a patient with
a duodenal ulcer contr asted to a similar aged asymptomatic immi-
grant from a high cancer risk count ry). It beh ooves clinicians to be
ex pe r ie nce d wit h t he us e and inte rpr et atio n of th e vari et y of test s
available, and to be especially war y of serologic tests that often
provide misleading information.
The ability to identify H. pylori infection continues to evolve and
to incorporate new technologies. We anticipate that, in the near fu-
ture, identification of new active infections will preferentially utilize
stool testing with reflex susceptibility testing for multiple antibiotics.
This approach seems an ideal and most efficient diagnostic strategy
and probably the most cost- effective, as uninfected patients are ini-
tially only charged for the H. pylori diagnostic test, whereas in those
with active infection, the positive diagnosis is accompanied by the
antimicrobial susceptibility profile allowing tailored therapy to be
prescribed.
SUMMARY
The increasing availability of molecular- and culture- based sus-
ce p t ibil i t y pr o fili n g ha s re s ult ed in a m ajor ch ang e in th e ap p r o ach
to the diagnosis of H. pylori infection. It is now possible to rap-
idly or reflexively link positive diagnostic tests with susceptibil-
ity testing, which largely eliminates the guesswork in identifying
an appropriate tailored therapy. Molecular susceptibility testing
also allows for rapid testing of formalin- fixed gastric biopsies
remaining from the original endoscopy when the infection was
first recognized. Alternately, and for infections diagnosed non-
invasively, molecular susceptibility profiling of stool is available
and can ent irely obviate th e nee d for endosc op y. The se ad va nc es
allow for better integration of diagnosis with therapy and should
largely eliminate the current practice of empirically administer-
ing poorly performing clarithromycin- or levofloxacin- containing
therapies. It is hoped that the recent availability of molecular and
culture- based susceptibility profiling of H. pylori infection ongo-
ing in the U.S. will serve as a model and encourage similar avail-
ability worldwide.
ACKNOWLEDGEMENT
Declaration of personal interests: Dr. Graham is a consultant for RedHill
Biopharma and Phathom Pharmaceuticals regarding novel H. pylori
therapies and has received research support for culture of Helicobacter
pylori. He is also a consultant for DiaSorin regarding H. pylori diagnos-
tics and with Otsuka Japan regarding nove l breath test s. He has ongo-
ing collaborative research projects with American Molecular regarding
molecular diagnostics for H. pylori. Recently, he was the PI of an in-
ternational study of the use of antimycobacterial therapy for Crohn's
disease. Dr. Maria Pina Dore has nothing to declare.

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AUTHORSHIP
Guarantor of article: David Y. Graham, M.D.
Author contributions: Each author contributed to the research,
data collection and analysis, design and writing of the paper. All au-
thors approved the final version of the article including the author-
ship list.
ORCID
Maria Pina Dore https://orcid.org/0000-0001-7305-3531
David Y. Graham https://orcid.org/0000-0002-6908-8317
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How to cite this article: Dore MP, Graham DY. Modern
approach to the diagnosis of Helicobacter pylori infection.
Aliment Pharmacol Ther. 2022;55(Suppl. 1):S14– S21. ht t p s : //d oi .
org /10.1111/apt.16566