HELICOBACTER PYLORI INFECTION: DETECTION, INVESTIGATION,

AND MANAGEMENT
STEVEN J. CZINN, MD, FAAP, FACG

Helicobacter pylori infection causes gastritis and peptic ulcers and is associated with the development of gastric cancer.
Approximately 50% of the world population is infected with H pylori, with the highest prevalence rates in developing countries.
In the vast majority of individuals, infection is acquired during childhood with those of low socioeconomic means and having
infected family members being at highest risk for early childhood acquisition. Definitive routes of transmission of the infection
are unclear, with evidence suggesting oral-oral, gastric-oral, and fecal-oral routes. If untreated, H pylori infection is lifelong.
Although clinical disease typically occurs decades after initial infection acquisition, children infected with H pylori may have
gastritis, ulcers, mucosal-associated lymphoid type lymphoma, and, rarely, gastric atrophy with/without intestinal metaplasia
(ie, both precursor lesions for gastric cancer). Controversy persists regarding testing for and treating H pylori, if found, in the
large number of children who present with recurrent abdominal pain. Because young children (ie, younger than 5 years of age)
who are treated and cured of their H pylori infection may be at risk for reinfection, the current recommendations do not
recommend treatment unless an ulcer or gastric atrophy is present. However, despite the lack of clinical evidence, the trend is
to more aggressively screen children for the presence of H pylori and to treat those children who are found to have the infection.
H pylori infection can be eradicated by antimicrobial therapy plus a proton pump inhibitor, but no treatment regimen is
100% effective. Multiple drugs, frequent dosing, and length of treatment often contribute to poor patient compliance, and
antibiotic eradication therapy is associated with increasing drug resistance. (J Pediatr 2005;146:S21-S26)

he Gram-negative, spiral-shaped bacterium Helicobacter pylori is a common human pathogen and public health problem

T that causes gastritis and peptic ulcers.1 Infection with H pylori has also been linked pathologically to the development of
gastric cancer. Worldwide, infection with H pylori is highly prevalent-approximately 50% of the world population is
infected, with prevalence rates in countries ranging from 20% to more than 80%.2 The highest rates of H pylori prevalence are
in Eastern Europe, Asia, and many developing countries and developing populations in developed countries (eg, Native
Americans).2 Among selected populations in the United States (ie, non-Hispanic blacks and Hispanics) prevalence rates (ie,
>50%) approach those observed in these countries.3-5
Infection with H pylori may manifest as a number of clinical disorders, primarily of the gastroduodenal mucosa.
Unfortunately, without available validated symptom assessment instruments, there are few clues in a childs history or physical
examination that lead one to suspect H pylori infection. A substantial percentage of children who present to their primary care
physician or pediatrician report abdominal or periumbilical pain (represents up to 5% of all primary care physician pediatric office
visits). However, this abdominal pain may be due to a wide variety of causes, such as
functional bowel disease, gastroesophageal reflux disease, constipation, and other causes,
with H pylori infection being lower in the differential diagnosis. Studies attempting to From Pediatrics and Pathology, Rain-
establish a causal relation between infection with H pylori and recurrent abdominal pain bow Babies and Children Hospital,
Case Western Reserve University,
have reported inconsistent results, with odds ratios ranging from 0.32 to 1.80.6,7 A recent Cleveland, Ohio.
8
study found that children referred for endoscopy due to abdominal pain (n = 373) had Submitted for publication Oct 4, 2004;
a higher rate of H pylori seropositivity (22.5%) compared with control children without revision received Nov 19, 2004.
gastrointestinal complaints from the same geographic region (14.1%, n = 619). The Reprint requests: Dr Steven J. Czinn,
Pediatrics and Pathology, Rainbow
presence of gastrointestinal symptoms was associated with an increased risk of H pylori Babies and Children Hospital, Case
seropositivity (odds ratio, 1.77; 95% CI, 1.27 to 2.47). In particular, these authors reported Western Reserve University, Cleve-
land, OH 44106.
a statistically significant association between H pylori seropositivity and subjects who had
0022-3476/$ - see front matter
Copyright 2005 Elsevier Inc. All rights
reserved.
UBT Urea breath test
10.1016/j.jpeds.2004.11.037

S21
Figure 1. Prevalence of H pylori infection by age in developing and
developed countries. Overall prevalence and age at which H pylori
infection is acquired varies substantially between developing and
developed countries. Overall estimates are that approximately 70% of
children in developing countries are infected with H pylori by age 15
as compared with approximate 10% infection rate prevalence in
developed countries. Reproduced from Logan RP, Walker MM.
ABC of the upper gastrointestinal tract: epidemiology and diagnosis
of Helicobacter pylori infection. Br Med J 2001;323:920-2, with
permission from the BMJ Publishing Group.
epigastric pain (relative risk, 2.21; 95% CI, 1.33 to 3.66), or
those having 3 or more episodes of abdominal pain in the last 3
months (relative risk, 0.59; 95% CI, 0.35 to 0.99).
CASE CONTINUED
The patient lived with his parents, one grandparent
(the paternal grandfather died of gastric cancer), and 4 siblings.
His father had been hospitalized repeatedly for peptic ulcer
disease, was treated for a bug, and had been ulcer-free for 4
years. The patients younger brother, 5 years old, often slept
with him and had recently missed several days of school
because of a recurrent stomach ache.
INFECTION WITH H PYLORI: RISK FACTORS
AND ACQUISITION
The medical and family history reveals several clues that
implicate H pylori infection as more likely on the differential
diagnosis list. In particular, this patients fathers history of
peptic ulcer disease caused by a bug and his grandfather
dying of gastric cancer are typical features of the familial
disposition for H pylori infection. Whereas the routine testing
for H pylori infection in children who present with recurrent
abdominal pain is not recommended, given this patients
history, there were data to support more aggressive in-
vestigation of this child.
H pylori is almost always acquired in childhood (usually
before age 10 years),9 and, if untreated, infection is lifelong. In
the developing world, up to 70% of children are infected with
H pylori by age 15 years (Figure 1).4 Although H pylori
seroprevalence among children residing in the United States
is much loweron the order of 10% among those 10 years
of age1 (Figure 2)selected populations are at higher risk.
A recent epidemiologic study by ORourke et al10 found that
H pylori infection was much higher in children under age 6
living on the Mexico side of the Rio Grande compared with
S22 Czinn
Figure 2. Age-specific H pylori seroprevalence rates in Bolivian,
Native Alaskan, and US children (0 to 9 years of age). Bolivian and
Native American children have similar rates of H pylori acquisition,
with the majority becoming infected by approximately 6 years of age.
Gold BD. New approaches to Helicobacter pylori infection in children.
Curr Gastroenterol Rep 2001;3:235-47.
those on the US side (odds ratio for H pylori infection, 1.70;
95% CI, 0.64 to 4.52).
Children with an infected family member, those
residing under crowded living conditions (ie, sharing a bed),
with two or more siblings, who attend day care, or have poor
hygiene are at increased risk for H pylori infection.10-13 Other
children who have higher rates of H pylori infection include
those of lower socioeconomic means, immigrant children,
American-born children of immigrant parents, and interna-
tionally adopted children.14
To date, human beings are the only known reservoir for
H pylori. Increasing evidence suggests that transmission of the
infection may potentially be facilitated through contaminated
water.2,4 Routes of H pylori transmission described include
fecal-oral, oral-oral, and gastric-oral. The latter route of
transmission was reported after identification of viable H pylori
organisms in the vomitus of infected adults and air samples
collected near the vomiting subjects.15,16
Person-to-person routes of transmission place a child
such as our patient, as well as the younger sibling, at increased
risk of acquiring the infection.17 H pylori appears to be
transmitted most readily within families, possibly from parent
to child (such as from the father and/or grandfather) and
among siblings.18 Evidence also supports child-to-child trans-
mission among those in crowded school or living conditions as
well as in chronic care facilities for multiple handicapped
children.1 In contrast, transmission among adults is rare
adults have a H pylori seroconversion rate of approximately
0.3% per person-year. Studies of families have found that one
spouse may be positive, whereas the other remains negative,
and that an uninfected parent remains negative even if children
in the household are infected. In cases such as this, in which
the brothers share a bed, it may be prudent to investigate the
younger sibling, especially if he begins manifesting gastroin-
testinal symptoms (eg, epigastric pain, dyspepsia).
CASE CONTINUED
The patients mother stated that about 4 years ago, the
patient had a severe stomachache that was associated with
The Journal of Pediatrics  March 2005
vomiting some dark stuff and was treated by his primary care
physician with a course of antacids. She recalled having to
collect his stool and mailing it back to the doctor for a test to
be performed. The patients current medications included an
iron-fortified multivitamin, as he was found to be anemic at
a previous clinic visit. Despite taking the iron therapy and
increasing his intake of iron-rich foods, the patients mother
reported that the anemia does not appear to be improving. The
mother wondered if the child had inherited the stomach bug
from his father.
DIAGNOSING H PYLORI IN CHILDREN
There are two types of diagnostic tests used to detect
H pylori infection: noninvasive and invasive. Noninvasive
tests include the urea breath test, stool tests, and blood tests,
which include whole blood and serologic assays. Noninvasive
tests detect the presence or absence of infection. Invasive tests
include the performance of upper gastrointestinal endoscopy
with gastric biopsy. Invasive tests can determine both presence/
absence of infection and the extent and severity of mucosal
injury (ie, disease).
The urea breath test (UBT) is widely used in adults
as a diagnostic agent and to confirm treatment results (ie,
persistent infection versus cure). Performance of the study
involves having the patient drink a solution of 13C- or
14
C-labeled urea an important substrate for H pylori metab-
olism. If H pylori is present in the stomach, the bacterias
enzyme urease will hydrolyze the ammonia, a primary con-
stituent of urea into water and CO2. The labeled (either 13C
or 14C) carbon atom is then exhaled in the breath and measured.
Because of radioactivity risks, particularly in children, there
are very few data on the use of 14C-labeled urea breath tests in
the pediatric population. Although the UBT has been studied
in children,9,19-22 its diagnostic ability, especially in those
younger than 3 years of age, may be limited by several factors.
For example, performance of the test requires some level of
oral-pharyngeal coordination, with children being more likely
to retain the compound in the oropharynx that also harbors
urease-producing organisms, thereby producing false-positive
test results. Being able to breathe into a straw may also affect
the test reliability and accuracy. False-negative results may
result in those who have recently taken gastric acid anti-
secretory agents, bismuth compounds, or antibiotic agents.
Although the 13C-labeled UBT has been used in children and
appears promising, reliability and determination of threshold
values have not been adequately validated in multiple, large
multicenter, randomized, controlled trials.23
Serology with immunoglobulin G (IgG) is widely
used and is considered the first line of noninvasive diagnostic
tests in adults, particularly in Europe, with suspected H pylori
infection. Unfortunately, serology does not provide any data as
to whether there is active or past infection. In addition, as with
the UBT, serology cannot determine the current gastroduo-
denal pathology. Even in those treated and cured of their
H pylori infection, evidence of IgG antibodies (ie, a positive
serology) may exist for months and possibly years. Therefore,
Helicobacter Pylori Infection: Detection, Investigation,
And Management
serologic assay is not appropriate for monitoring the effects of
an antiH pylori treatment regimen. The serologic assays also
have varying levels of sensitivity and specificity when used in
different populations, particularly in children, because of lack
of validation of these assays in the population in which they
are then used. Studies have observed sensitivities ranging
from 54% to 94% and specificities between 59% and 97%.24 In
children, serologic assay cutoff values (ie, differentiating
between positive and negative serology) may be very different,
compared with adults. Serologic titers in children do not
appear to be related to the duration of infection and may not
attain levels typically observed in an infected adult until the
infected child reaches early adolescence.25,26 To date, there are
no validated commercial IgM or IgA serologic assays that are
commercially available, and none of the commercially available
IgG assays are approved for use in children. Salivary IgG tests
are under investigation.27
The stool antigen test (polyclonal and monoclonal)
for H pylori holds promise for the detection of infection
in children as well as assessing cure. However, studies have
found that the positive predictive values were 54%28 and
87%,29 which may limit the tests reliability. The negative
predictive values of these stool antigen tests were high,
100% and 94.9%, respectively, as were the sensitivity (89% to
100%) and specificity (70% to 94%).20,28-31 Koletzko et al32
evaluated a monoclonal enzyme stool antigen assay in 302
children whose H pylori status was defined by results of culture,
histology, the rapid urease test, and the 13C-urea breath test.
The investigations found the stool antigen test to have high
sensitivity (98%), specificity (99%), and positive (98%) and
negative (99%) predictive values.
Until more reliable, validated, noninvasive tests are
developed for use in children, the use of upper gastrointestinal
endoscopy with gastric biopsy remains the diagnostic strategy
of choice in those with suspected H pylori infection.33 Ou
patient was scheduled for upper gastrointestinal endoscopy
with gastric biopsy. On endoscopy and biopsy, he was found to
have a duodenal ulcer, and antral biopsy specimens were
positive for H pylori.
CLINICAL COMPLICATIONS OF H PYLORI
INFECTION
H pylori infection, which has a very narrow host range,
colonizing and persisting in only the gastric mucosa, generally
manifests as gastroduodenal disorders. These conditions
include gastritis and peptic ulcer disease (primarily duodenal
ulcers, and to a lesser extent gastric ulcers)in which the
ulcers are present as an infection sequelae in approximately
15% of those infected.34-37 In addition, H pylori infection can
result in atrophic corpus-predominant gastritis with and
without intestinal metaplasia, which has been described in
childhood.38 These lesions are precursors for neoplasia/
dysplasia and have long been described in the natural history
of gastric cancer development. Thus, the presence of these
lesions increases the risk for gastric adenocarcinoma and
S23
Table. North American Society for Pediatric Gas-
troenterology, Hepatology, and Nutrition
Position Statement: Recommended Regimens
for Helicobacter pylori Treatment
First-line regimens, each agent administered twice-daily for 10 to 14 days
d Proton pump inhibitor (1-2 mg/kg/day) plus amoxicillin
(50 mg/kg/day) plus clarithromycin (15 mg/kg/day)
d Proton pump inhibitor (1-2 mg/kg/day) plus amoxicillin
(50 mg/kg/day) plus metronidazole (20 mg/kg/day)
d Proton pump inhibitor (1-2 mg/kg/day) plus metronidazole
(20 mg/kg/day) plus clarithromycin (15 mg/kg/day)
Adapted from: Gold BD, Colletti RB, Abbott M, Czinn SJ, Elitwar Y,
Hassall E, Macarthur C, Snyder J, Sherman PM. Helicobacter pylori
infection in children: Recommendations for diagnosis and treatment.
J Pediatr Gastroenterol Nutr 2000;31:490-7.
gastric mucosaassociated lymphoid tissue lymphoma
affecting less than 1% and 0.1% of infected individuals,
respectively.2,34,39,40 Generally, these H pylorirelated clinical
diseases occur decades after the acquisition of infection.
Among children, the occurrence of H pylorirelated
gastroduodenal disorders such as gastritis and peptic ulcer
disease have been observed as well as, albeit significantly less
frequently, gastric atrophy and intestinal metaplasia.38
However, children infected with H pylori are at substantial
risk for primary duodenal ulcer disease, with between 33% and
100% of children with duodenal ulcer disease found to harbor
the bacterium.41 The causative role of H pylori in duodenal
ulcer disease among children is supported by the finding of
a low rate (<5% to 10%) of disease recurrence in children
treated and cured of the bacterial infection.33,41,42
In addition to predisposing children to gastrointestinal
diseases, H pylori has been observed in association with other
clinically significant disorders, including growth retardation
and anemia.43 An increasing body of literature44-51 supports
an association between H pylori infection and iron-deficiency
(or sideropenic) anemia in children and adults. For example,
among teenagers in South Korea, the relative risk of iron-
deficiency anemia in those infected with H pylori was 2.9 (95%
CI, 1.5 to 5.6), compared with children not infected with the
bacterium.46 Treatment with iron supplementation produced
no improvement in hemoglobin levels in those with persistent
infection, whereas significant increases in hemoglobin, iron,
and ferritin levels were observed in children who underwent
H pylori treatment and cure.
The definitive mechanism(s) of iron deficiency anemia
in those infected with H pylori is unclear. However, a number
of biologically plausible causes have been postulated, in-
cluding gastrointestinal blood loss, poor iron intake, iron
malabsorption, or diversion of iron in the reticuloendothelial
system.52 Some studies have suggested a bacteria-specific
mechanism(s) of anemia. Theories include receptors on the
outer membrane of H pylori organisms in the antrum acting
as an iron sequestering focus that captures and utilizes iron
for growth,52 infection-associated changes in either lacto-
S24 Czinn
ferrin,50 or changes in intragastric pH that impair iron
absorption.53
TREATMENT OF H PYLORI INFECTION
IN CHILDREN
It is well established in the literature as well as in
clinical practice that treatment of H pylori infection requires
a combination of gastric acid antisecretory plus antimicrobial
agents administered for 7 to 14 days. In adults infected with
H pylori, the greatest rates of bacterial eradication, on the
order of >80%, have been observed with triple and quadruple
regimens. In children, several first-line regimen options, each
administered for 14 days, have been recommended by the
North American Society for Pediatric Gastroenterology,
Hepatology, and Nutrition (Table).33 Once treated and cured
of H pylori, studies indicate that children are at low risk for
reinfection.54
Few clinical studies of cure rates with triple therapy
regimens in children have been published in particular
multicenter, randomized, placebo-controlled trials. In one of
these, Gottrand et al55 randomly assigned 73 children with
confirmed H pylori to 7 days of treatment with triple therapy
(omeprazole, amoxicillin, and clarithromycin, n = 31) or dual
therapy (amoxicillin and clarithromycin, n = 32). In analyses of
the intent-to-treat and the per-protocol cohorts, significantly
higher rates of H pylori cure (confirmed by UBT) were observed
with triple therapy (74.2% and 80%) as compared with dual
therapy (9.4% and 10.7%). The cure rates observed with triple
therapy in this study are lower than clinically desirable and may
have been influenced by the low duration of therapy (7 days
instead of 14), the reliability of the UBT to assess eradication,
compliance issues, or a combination of these factors.
Children with persistent H pylori despite treatment
with a triple therapy regimen should be assessed for several
predictors of treatment failure, in particular, treatment
compliance. H pylori antimicrobial resistance is one the other
top reasons for treatment failures and thus should also be
considered in a child with persistent infection. Several studies
observed treatment failure associated with H pylori resistance
to either metronidazole or clarithromycin.55-57 Worldwide, the
rates of clarithromycin resistance range from 0% to 20%, with
much higher rates of resistance to metronidazole (on the
order of 7% to 95%) being reported.58 Some studies report that
H pylori resistance to metronidazole can be overcome
despite conferring treatment failures of up to 37%, but that
clarithromycin resistance is not only associated with treatment
failures of >50%, but that resistance is then conferred to all
of the macrolide antibiotics, thereby making these strains of
H pylori very difficult to eradicate. Song et al57 reported that
19% of H pylori strains obtained in children were resistant to
clarithromycin, 22% were resistant to metronidazole, and
11.6% (8/69) were resistant to both antimicrobial agents. This
study demonstrated that H pylori strains isolated from children
tend to have higher rates of resistance to clarithromycin overall
and may in fact be more difficult to cure.
The Journal of Pediatrics  March 2005
 In a case such as our patient, particularly in a patient
with H pylori infection complicated by duodenal ulcer,
confirmation of cure may be desirable to allay parents fear
that the disorder will recur. Unfortunately, at present, the only
reliable method to test for cure is repeat endoscopy. However,
urea breath testing or stool antigen testing may have some
value for posteradication cure confirmation. Because endos-
copy is an invasive procedure, confirmation of H pylori
eradication is generally not performed unless the child has
a history of complications such as an ulcer. If endoscopy, UBT,
or stool antigen testing is to be performed, it is best to wait at
least 6 weeks and preferably 3 months after the completion of
the triple-therapy regimen to improve the diagnostic value.
Children who retest positive for H pylori should be
assessed for bacterial resistance, if a laboratory that has the
expertise is available for the clinician. Retreatment should
be initiated, using a regimen that does not include the
antimicrobial agent with documented resistance. The need
for good compliance and the use of the entire 14 days of the
triple-therapy regimen should be reinforced. Alternatively, the
use of proton pump inhibitorbased quadruple therapy or
ranitidine-bismuth citratebased triple-therapy regimen may
be considered.56-59
SUMMARY
H pylori is an important human pathogen that is
a significant source of gastroduodenal disease in adults as
well as children. Overall, approximately one half of the worlds
population is infected with the bacterium, with acquisition of
the infection commonly occurring before age 10 and in some
developing populations before age 6 years. Person-to-person
transmission occurs through several routes, oral-oral, gastric-
oral, and fecal-oral, and may occur through contaminated
water and/or air. Children living in low socioeconomic,
crowded conditions with infected household members are at
greatest risk of acquiring the infection and may transmit the
infection to their siblings. Specific symptoms suggestive of
H pylori infection are vague, inconsistent, and similar to several
other more common childhood disorders, manifesting as
recurrent abdominal pain, dyspepsia, or epigastric pain.
Generally, one does not investigate for H pylori unless the
child has symptoms suggestive of an ulcer. Although several
noninvasive tests have been evaluated, endoscopy with gastric
biopsy is, at present, considered the gold standard to
confirming the diagnosis of H pylori. Despite the lack of
clinical evidence, the clinical trend has been to
more aggressively test children for the presence of H pylori
and to treat those children who are found to have the infec-
tion. H pylori infection can be eradicated by antimicrobial
therapy, but no treatment regimen is 100% effective, and the
multiple drugs, frequent dosing, and length of treatment often
contribute to poor patient compliance, and antibiotic eradi-
cation therapy is associated with increasing drug resistance.
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The Journal of Pediatrics  March 2005