Review Article

Helicobacter Pylori Infection in Children

Shaman Rajindrajith, Niranga M. Devanarayana1, Hithanadura Janaka de Silva2

Departments of Paediatrics,
1
Physiology and
ABSTRACT
2
Medicine, Faculty of
Medicine, University of Helicobacter pylori infection is a common problem in pediatric practice, and its acquisition is related with
Kelaniya, Ragama - 10110, poor socioeconomic conditions. Although the organism is thought to be responsible for many diseases,
Sri Lanka
only a handful of them have a direct causal relationship. At present, only a small number of children with
Address for correspondence: well-defined clinical syndromes are benefited from testing and treatment. The treatment should include
Dr. Shaman Rajindrajith, at least two antibiotics with a proton pump inhibitor.
Department of Paediatrics,
Faculty of Medicine,
Talagolla Road, Ragama, Key Words: Abdominal pain, children, Helicobacter pylori, stool antigen test, triple therapy
Sri Lanka.
E-mail: rajindrajith@mfac. Received 09.09.2008, Accepted 02.11.2008
kln.ac.lk The Saudi Journal of Gastroenterology 2009 15(2): 86-94
DOI: 10.4103/1319-3767.48964

In 1983, Robin Warren, a pathologist in Perth, reported in the gastric mucosa of the children with antral gastritis
the presence of “curved bacterium” in the mucosal layer of and duodenal ulcers. Moreover, they also demonstrated
the gastric biopsy specimen. Together with Barry Marshall, the healing of duodenal ulcers in two patients following
he subsequently isolated the organism from the gastric the eradication of the organism.[9] These findings firmly
biopsy specimens and named it Campylobacter pyloridis established H. pylori as an important pathogen in pediatric
(C. pylori),[1] which was ultimately named as Helicobacter gastroenterology.
pylori (H. pylori). Marshall and Warren also noted that C.
pylori (H. pylori) infection was associated with gastric and MICROBIOLOGICAL CHARACTERISTICS OF
duodenal ulceration.[2] In recognition with this imperative H. PYLORI
discovery, they were awarded the Nobel Prize for Medicine
in 2005. Their discovery initiated a new interest in previously H. pylori is a spiral, microaerophilic, gram-negative bacterium
neglected field of gastric microbiology. In 1994, the National with four to six unipolar sheathed flagella.[10] The surface of
Institute of Health consensus conference in USA declared H. pylori is coated with 12–15 nm ring-shaped aggregates of
an association between H. pylori and peptic ulcer disease.[3] urease and heat shock protein.[11] The urease enzyme and the
During the same year, H. pylori was identified as a carcinogen heat shock protein B are located almost exclusively within
associated with gastric adenocarcinoma[4] and gastric non- the cytoplasm in the fresh log-phase cultures of H. pylori.
Hodgkin lymphoma.[5] An association between H. pylori In subcultures, urease and heat shock protein B become
and gastric mucosa-associated lymphoid tissue lymphoma associated with the bacterial surface, suggesting bacterial
(MALToma) was identified in 1991.[6] Therefore, after a autolysis leading to release of protein and adsorption into
decade of the isolation of H. pylori, a previously obscured the bacterial surface.[12] Some of the lipopolysaccharide of
organism, it took a leap to become the most important the organism mimics the Lewis blood group antigens in
microbiological agent in the human upper gastrointestinal structure.[13] This molecular mimicry also helps in the
tract. continued existence of H. pylori in the unfavorable gastric
environment.
Shortly after the landmark paper from Warren and
Marshall, H. pylori (formerly C. pylori) was identified for Urease
the first time in children undergoing upper gastrointestinal H. pylori is one of the most powerful urea-splitting organisms.
endoscopy and having histological features of chronic Splitting urea to release nitrogen increases the pH of the
active gastritis. [7] This was followed by another study, gastric antrum. Although not essential, this is one factor
which described the association of the organism with that helps it to survive in the hostile gastric antrum. The
gastroduodenal inflammation.[8] Consequently, a Canadian other important role of urease is to provide nitrogen for the
group of researches described the presence of the organism protein synthesis by the organism.[14]

86 The Saudi Journal of

Volume 15, Number 2 Gastroenterology
Rabi' Al-Thani 1430 H
April 2009
 H. pylori in children

Vacuolating cytotoxin of the country, was observed by several independent studies

This protein is capable of inducing vacuolation in eucaryotic across the world.[29–33,36]
cells. The gene for vacuolating cytotoxin (VacA) protein has
also been cloned. All Helicobacter strains have VacA gene Factors predisposing to H. pylori infection in children
but only about 50% of them produce VacA protein. It is have been studied in detail. The main predisposing
believed that VacA inserted into the membranes of endosomal factors identified in these studies were low socioeconomic
vesicles form pores with chloride channel activity. This alters status.[29,37] H. pylori infection is greater among those living
the composition of the anions within the endosomes and in crowded dwellings.[30] In their study, McCallion et al.
subsequently leads to osmotic swelling, which may have showed that the association between social class and H.
effects on the gastric epithelium.[15] Furthermore, it also pylori becomes insignificant after adjustment for household
induces apoptosis, leading to cell death.[16,17] Animal studies density and bed-sharing between a child and an adult.
have shown that the supernatant from H. pylori expressing This finding suggests that with regard to the acquisition of
the toxin causes severe acute superficial mucosal injury.[14] H. pylori infection, social class was acting as a proxy measure
for conditions and practices within the household that
Cytotoxin-associated antigen increase the transmission of the organism from infected
Cytotoxin-associated antigen (CagA) is probably the to uninfected subjects.[38] Improvements in the standards
most important virulent factor in H. pylori. The CagA of living have resulted in a marked reduction in H. pylori
gene is found in the Cag pathogenic island (PAI), a transmission.[39]
genome segment of 40 kb that encodes approximately 30
genes.[18] CagA PAI genes are thought to encode a complex TRANSMISSION OF H. PYLORI INFECTION
syringe-like structure called type IV secretary complex
that helps in translocating the CagA protein into the However hostile, the human stomach is the only identified
gastric epithelial cells. [19–21] After translocation, CagA reservoir for H. pylori. Although extensively studied,
is phosphorylated, possibly by known oncogenes[22] and efforts to confirm the exact route of transmission have
causes rearrangement of the host cytoskeleton and alters been disappointing. It has been speculated that the
cell signaling[18] and perturbs cell cycle control,[23] which person-to-person spread currently appeared to be the most
are important pathogenic mechanisms of gastroduodenal likely mode of transmission, especially between family
disease. Both CagA and the secretory system, by members.[40,41] Hence, the possible routes are feco–oral,
independent mechanisms, activate proinflammatory oral–oral and gastro–oral.[42] Thomas et al. were able to
signals and interleukin-8 secretion. [24,25] Furthermore, isolate H. pylori DNA and culture H. pylori from human
the CagA PAI-positive strains are known to induce the feces, suggesting a feco–oral transmission.[43] Oral–oral
expression of a DNA-editing enzyme, which leads to transmission has also been recognized because H. pylori
accumulation of mutations in the tumor suppressor was isolated from dental plaques and saliva.[44] Furthermore,
p53.[26]On the other hand, it had been shown that there gastric–oral transmission was also suggested after the
are many CagA PAI-negative strains in gastroduodenal organism was cultured from vomitus.[45,46] This was further
ulcers and gastric carcinomas.[14] Therefore, it is possible strengthened by Perry et al., who found that this transmission
that other factors such as host immune mechanisms and correlates with exposure to an infected family member with
environmental factors also play a role in the pathogenesis gastroenteritis, especially with vomiting.[47] Other possible
of the H. pylori-associated gastroduodenal disease. ways of transmission include water-borne transmission[48] and
vector-borne transmission.[49,50] Therefore, it is evident that
EPIDEMIOLOGY OF H. PYLORI the current knowledge on the exact modes of transmission
is not optimal, and further studies are needed to clarify this
More than a half of the world’s population is infected with clinically and epidemiologically important aspect of H. pylori.
H. pylori, which is acquired almost always within the first 5
years of life.[27] In the developed world, the prevalence rates DIAGNOSIS OF H. PYLORI INFECTION
vary from 1.2% to 12.2%.[28–31] In developing countries, the
prevalence rates are much higher. The serological prevalence Diagnosis of H. pylori may be divided into invasive and
rates of H. pylori were 15% and 46% in Gambian children noninvasive techniques. Invasive tests need an upper
aged less than 20 months and 40–60 months, respectively[32] gastrointestinal endoscopy (UGIE) and biopsy material for
and 45% among Indian children.[33] In Bolivia and Alaska, tests, and the noninvasive techniques use other methods.
at the age of 9 years, the seroprevalence was 70% and 69%, Generally, biopsy cannot be justified, especially in children,
respectively.[34] The seroprevalence in preschoolers in Brazil unless one wishes to isolate the organism for antibiotic
was found to be 69.7%.[35] An age-related increase of the sensitivity testing or there is a clear clinical indication for
prevalence of H. pylori, irrespective of the economic state UGIE. If one opted to test for H. pylori by biopsies with

The Saudi Journal of

87
Gastroenterology Volume 15, Number 2
Rabi' Al-Thani 1430 H
April 2009
Rajindrajith, et al.

UGIE, it needs a specimen from multiple regions of the children unless used in the populations in which they were
stomach, including antrum, body and transitional zones initially developed.[54] The choice of the antigen used in
(i.e., cardia and incisura). this test to detect the antibody is critical. The strains in
Asia are different from those that are circulating in the rest
Invasive testing using biopsies from UGIE of the world.[55] The sensitivity, specificity and positive and
Histology negative predictive values of the same test kit may differ in
The standard hematoxylin and eosin stain demonstrates different ethnic or geographic populations.[56] It is observed
inflammation (gastritis type) and H. pylori itself. Special that commercially available serum-based immunoassays have
stains are used to detect H. pylori if they are lesser in number. a range of sensitivity from 63% to 78%.[57] Besides, the mean
Silver stain detects organisms in small numbers but the antibody levels in young children are significantly lower than
disadvantage is that it is not possible to study the histology in older children and adults and these age-related standard
with silver stain and it is expensive. Less-expensive modified values have not been established for children. Furthermore,
Giemsa stain is sensitive and specific for the organism and most commercial kits have not been validated for children
is much easier to perform than the silver stain.[51] and the cut-off point for adults may be too high for
children, resulting in a low sensitivity for the test.[58] Lastly,
Culture the antibodies persist even for months after eradication of
Culturing this fastidious organism is relatively difficult, the infection, reflecting a “scar” of a past infection, rather
expensive and needs special media. The organism is than indication of an acute infection. Owing to all these
identified as H. pylori if it is positive for urease, catalase problems, the European and North American societies of
and oxidase and produces a negative reaction for hippurate Pediatric Gastroenterology, Hepatology and Nutrition do not
hydrolysis and nitrate reduction.[51] Currently, cultures recommend using serological tests in clinical settings until a
are only obtained in research settings and suspected drug further validation of serologic commercial kits.[52,55]
resistance.[52]
Salivary IgG antibodies
Rapid urease test Commercial kits are available to detect IgG antibodies in the
The ability of the organism to split urea using the enzyme saliva of infected children. Apart from all the disadvantages
urease is used to identify H. pylori in tissue biopsy specimens. of the antibody assay discussed above, this test is less
A specimen is placed on a commercially available urea- sensitive than the urea breath test (UBT).[59] The only
containing medium. The hydrolysis of the urea by urease advantage of this test is that it is less invasive and can be
brings about a color change in the pH-sensitive chemicals in used in epidemiological studies.
the medium allowing the investigator to identify the presence
of the organism. The accuracy of the test is dependent on UBT
the number of tissue specimens tested, the location from The 13C UBT has been used to diagnose H. pylori infection
which the biopsy is obtained, the bacterial load and previous in children. Isotope urea (13C) ingested by the patient is
use of antibiotics and proton pump inhibitors as well as the split into 13CO2 and ammonia. Labeled CO2 is absorbed into
prevalence of the infection in the community.[51] the bloodstream and is detected and measured in expired
air using a mass spectrometer. The sensitivity, specificity,
Noninvasive tests for H. pylori positive predictive value and negative predictive value of
Serology UBT were approximately 96%, 93–97%, 91–97% and 97%,
As in any other infection, H. pylori infection of the stomach respectively in children and adolescents.[60,61] However, in
exerts an immunological response in the body. The antibody the consensus statement of the European Helicobacter pylori
response in children is to low-molecular weight antigens in Study Group, Drumm et al. state the high sensitivity and
the 15–30 kD range and take up to 60 days to develop.[51] specificity of UBT in children over 6 years. Experience in
Tests of serum immunoglobulin (Ig) A or IgM antibodies children 5 years and below, particularly in infants, is relatively
are unreliable to detect gastric colonization and, therefore, limited and needs further validation.[55]
only IgG antibodies are used in clinical laboratory practice,
which is measured using an enzyme-linked immunosorbent Stool antigen test
assay (ELISA). The presence of IgG antibodies against H. Another novel approach in the diagnosis of H. pylori infection
pylori denotes active infection because once an individual is the detection of bacterial antigen in stools: H. pylori stool
is colonized, the infection continues throughout life antigen test. The initially developed stool antigen test was
unless a course of appropriate eradication therapy is a polyclonal antibody test (Premier Platinum HpSA test;
instituted.[53] Meridian Diagnostic Inc., Cincinnati, OH, USA) and was
found to have variable sensitivities and specificities for the
Nonetheless, the sensitivity of serological assays is poor in diagnosis of H. pylori infection. The development of a new
88 The Saudi Journal of
Volume 15, Number 2 Gastroenterology
Rabi' Al-Thani 1430 H
April 2009
 H. pylori in children

ELISA test using monoclonal antibodies (Femtolab H. pylori; (GORD). Some studies suggest that H. pylori protects
Connex, Martinsried, Germany) gave a new dimension and human subjects from developing GORD,[70] whereas others
greater precision for stool antigen testing. In comparative postulate a causative association between them. Some
studies, stool antigen test using monoclonal antibodies studies have identified an association between the CagA-
showed a higher sensitivity than the polyclonal test.[62] positive strains and the increased acid secretion that in
This test has demonstrated sensitivities, specificities and turn leads to gastro-esophageal reflux.[71] The causative
positive and negative predictive values of 98%, 99%, 98% and association between H. pylori and GORD needs further
99%, respectively[63] proving that monoclonal stool antigen research for confirmation.
enzyme immune assay is an excellent tool in diagnosing
H. pylori infection and confirming eradication in children. Iron deficiency anemia
Therefore, the stool antigen test has now been adopted Several studies have shown a relationship between H. pylori
as part of the standard of care for children with suspected and iron deficiency anemia.[72,73] Whether this is caused by
H. pylori infection.[64] the increased iron loss or the decreased iron absorption is not
clear yet. According to the First World Congress of Pediatric
H. PYLORI–RELATED PATHOLOGICAL Gastroenterology, Hepatology and Nutrition working group
CONDITIONS report, children infected with H. pylori have lower body iron
stores in comparison to age-matched controls.[74]
Gastritis
Many studies convincingly demonstrate that H. pylori Growth faltering in children
colonization of the gastric mucosa is associated with gastritis, Several studies have shown that H. pylori infection in
with chronic inflammatory cell infiltrate in children. The childhood is associated with growth faltering.[75–78] However,
macroscopic nodular gastritis was significantly associated these studies are confounded by the coexistence of variables
with active chronic gastritis and follicular gastritis.[65,66] such as poor socioeconomic status, which may contribute to
Microscopically, the gastric antrum shows lymphonodular both the development of malnutrition and the early H. pylori
hyperplasia and a small number of neutrophils as compared colonization. Therefore, H. pylori and growth faltering may
with adults.[67] Colonization of the gastric antrum by H. be mere associations rather than cause and effect.
pylori is graded as mild, moderate or marked. In children, the
number of bacteria present on the gastric mucosa is usually Recurrent abdominal pain
less than that in adults.[51] After 20 years of isolating H. pylori, its association and cause
of recurrent abdominal pain has been one of the most debated
Peptic ulcer disease controversies in pediatric gastroenterology. Researchers
There is a wide body of evidence indicating that H. pylori across the globe who investigated this association have found
causes both gastric and duodenal ulceration in children. contradicting results. In these researches, several methods
It had also been compellingly shown that children with were used to define positive H. pylori status, including
duodenal ulcer disease experience less relapse if H. pylori is serology, histology, bacterial cultures, rapid urease test and
eradicated from the gastroduodenal mucosa.[68,69] UBT. Some investigators used treatment trials to eradicate
H. pylori. The heterogenicity of their definition of recurrent
Gastric malignancies abdominal pain and the methodologies may have led to the
Epidemiological evidence indicates that there is a link controversies in the results and conclusions.
between H. pylori infection and gastric adenocarcinoma and
non-Hodgkin lymphoma. However, there are no studies to Many investigators from different parts of the world have
prove that H. pylori eradication during childhood prevents observed an association between H. pylori and recurrent
subsequent development of gastric malignancies.[52] abdominal pain, [79–81] whereas many others have failed
to find an association between the same.[82–87] Finally, a
MALToma meta-analysis of 45 studies in children with H. pylori and
The association of H. pylori and MALToma is an established outcome found a weak and inconsistent evidence of an
fact. Therefore, it is recommended to test and treat for H. association between H. pylori infection and classic recurrent
pylori in circumstances of histopathological evidence of abdominal pain.[88] The medical positional statement of
MALTomas in children.[52] the North American Society of Pediatric Gastroenterology,
Hepatology and Nutrition regarding H. pylori infection in
Gastro-esophageal reflux disease children also found no convincing data to support the routine
Yet another highly controversial topic is the role of H. pylori testing of children with recurrent abdominal pain for
in the pathogenesis of gastro-esophageal reflux disease H. pylori.[52]

The Saudi Journal of

89
Gastroenterology Volume 15, Number 2
Rabi' Al-Thani 1430 H
April 2009
Rajindrajith, et al.

MANAGEMENT OF CHILDREN WITH H. PYLORI case series and uncontrolled anecdotal observations
INFECTION that do not meet the minimum criteria for determining
efficacy.[52] There are several reasons why good treatment trials
When to test children for H. pylori infection? are lacking in the pediatric population. Firstly, prevalence of
It is important to keep in mind that testing children for infection in developed countries is low, and large series could
Helicobacter infection should be performed only after a only be collected by multicenter studies. Secondly, such
reasonable clinical diagnosis. The tests that the clinician studies are expensive and pharmaceutical companies are not
selects need to have the ability to diagnose active infection, willing to invest money in the pediatric market. Thirdly, in
such as demonstration of the organism by histology or culture less-developed countries, where prevalence of infection in
from endoscopic biopsy, UBT or fecal antigen test. The children is high, facilities to perform clinical trials are not
following are the current indications for testing: widely available.[90] Therefore, current treatment strategies
1. Endoscopically proven gastric or duodenal ulcer to eradicate H. pylori have been developed primarily by using
2. Radiographically defined duodenal ulcer data from adults.
3. Histological evidence of gastric MALToma
4. Pathologically proven gastric metaplasia or atrophic Monotherapy with a single antibiotic has shown very low
gastritis eradication rates and hence is not recommended as an
effective therapy. Several combinations of dual therapies
It is tempting to test children with recurrent abdominal pain were used by researchers worldwide. In a recent meta-analysis
for H. pylori. But, as discussed earlier, there are no convincing using the metaregression model, Khurana et al. showed
data to suggest that the syndrome of recurrent abdominal that the combined treatment of amoxicillin and a proton
pain is caused by infection with H. pylori. Therefore, pump inhibitor has a very low eradication rate [e.g., Spain
currently, it is not recommended to test these children for (21%), Mexico (48%), Germany (52%) and Japan (70%)].
H. pylori. Similarly, there are no compelling data to support However, the efficacy of dual therapy with amoxicillin and
routinely testing children without symptoms, including nitroimidazole was far more encouraging, with a clearance
those residing in long-term care facilities, children with rate of 84% in European studies when given for 2–6
short stature and those with an increased risk of acquisition weeks.[91]
of the infection.[52]
Triple therapy is considered to be the standard treatment
Indications for treatment for children. Proton pump inhibitor combined with two
1. Documented gastric or duodenal ulcer antibiotics has been shown to be very effective in clearing
2. Histologically proven gastric metaplasia H. pylori from the stomach. Current recommendation is
3. Gastric MALToma treatment with amoxicillin, clarithromycin and a proton
4. Prior documented gastric or duodenal ulcer with current pump inhibitor for 2 weeks [Table 1]. An additional two
active infection triple therapy regimens that are effective in children include
a proton pump inhibitor combined with clarithromycin and
Yet again, treatment is not indicated in children with recurrent metronidazole or amoxicillin and metronidazole combined
abdominal pain and nonulcer dyspepsia. Furthermore, it is with bismuth given for a 2-week duration[91] [Table 1].
not justifiable to treat children with unexplained short
stature or at risk of infection, including asymptomatic In adults, triple therapy based on amoxicillin, clarithromycin
children who have a family member with either peptic ulcer and a proton pump inhibitor was shown to be more effective
or gastric cancer with anti-Helicobacter therapy.[52] when given for 14 days rather than for 7 days[92], but showed
an equal efficacy in 1- and 2-week regimens for children.[91]
As in any other infection, the treatment is intended to However, head-to-head comparisons are needed to confirm
eradiate H. pylori from the gastroduodenal mucosa. It is whether differences exist between these regimens before
vital to accomplish complete eradication as re-infection and definite recommendations. Efficacy of the 10-day treatment
development of drug resistance are two important problems with proton pump inhibitor-based therapy or bismuth-based
in children. Therefore, it is imperative that when treatment therapy is not very widely studied in children. Two studies
is offered, complete courses are given, appropriate protocols on 10-day triple therapy and 10-day sequential therapy
that account for common local resistance patterns are showed eradication rates of 92%[93] and 97.3%,[94] respectively.
followed and treatment is reserved for those patients who However, data regarding efficacy of the 10-day therapy is still
will benefit from eradication.[89] inadequate, and therefore, it is not recommended in a recent
meta-analysis[91] and a systematic review.[90] Confirmation of
Anti-Helicobacter treatment in children is not effectively H. pylori eradication should be performed at least 4 weeks
evidence-based as that in adults. Most are open-label, after treatment using a noninvasive test such as UBT or
90 The Saudi Journal of
Volume 15, Number 2 Gastroenterology
Rabi' Al-Thani 1430 H
April 2009
 H. pylori in children

Table 1: Recommended first-line treatment for Helicobacter pylori infection in children

Option Drug Dosage Duration
1 Amoxicillin 50 mg/kg/day up to 1 g twice daily
Clarithromycin 15 mg/kg/day up to 500 mg twice daily 14 days
Proton pump inhibitor (e.g., Omeprazole) 1 mg/kg/day up to 20 mg twice daily
2 Amoxicillin 50 mg/kg/day up to 1 g twice daily
Metronidazole 20 mg/kg/day up to 500 mg twice daily 14 days
Proton pump inhibitor 1 mg/kg/day up to 20 mg twice daily
3 Clarithromycin 15 mg/kg/day up to 500 mg twice daily
Metronidazole 20 mg/kg/day up to 500 mg twice daily 14 days
Proton pump inhibitor 1 mg/kg/day up to 20 mg twice daily

stool antigen test.[92] 3. NIH consensus conference. Helicobacter pylori in peptic ulcer disease.
NIH consensus development panel on Helicobacter pylori in peptic ulcer
disease. JAMA 1994;272:65-9.
Other therapies
4. World Health Organization/International Agency of Research on Cancer.
Bismuth-based quadruple therapy is considered as the
Infection with Helicobacter pylori. In: Schistosomes, Liver flukes and
preferred second-line therapy in adults. There is one trial Helicobacter pylori. Lyon:Lyon international agency for research on
in children using bismuth-based quadruple therapy that cancer, 1994. p. 177-244.
showed an eradication rate of 84%.[93] In children, quadruple 5. Personnet J, Hansen H, Rodriguez L, Gelb AB, Warnke RA, Jellum E,
therapy with metronidazole, clarithromycin, amoxicillin and et al. Helicobacter pylori infection and gastric lymphoma. N Engl J Med
omeprazole was effective, with an eradication rate of 94%.[95] 1994;330:1267-71.
Furazolidone, metronidazole, amoxicillin and a proton pump 6. Wotherspoon AC. Oritz-Hidalga C, Falzon MR, Issacson PG. Helicobacter
associated gastritis and primary gastric B cell lymphoma. Lancet
inhibitor cured 80% of the cases.[96] Amoxicillin, omeprazole,
1991;338:1175-6.
clarythromycin and Lactobacillus eradicated more than 90% 7. Hill R, Pearman J, Worthy P, Caruso V, Goodwin S, Blincow
of the infection.[97] Because quadruple therapy is used as a E. Campylobacter pyloridis and gastritis in children. Lancet
second-line treatment, more pediatric research in this area 1986;1:387.
is urgently needed. 8. Cadranel S, Goossens H De Boeck M, Malengreau A, Rodesch P, Butzler
JP. Campylobacter pyloridis in children. Lancet 1986;1:735-6.
Only one trial has tested the efficacy of sequential therapy 9. Drumm B, Sherman P, Cutz E, Karmail M. Association of Campylobacter
in children, which reported eradication of H. pylori pylori on the gastric mucosa with antral gastritis in children. N Engl J
Med 1987;316:1557-61.
infection in more than 90% of the children.[94] Therapy
10. Goodwin CS, McCulloch RK, Armstrong JA, Wee SH. Unusual cellular
with a combination of rifabutin, rifamycin or levofloxacin fatty acid and distinctive ultrastructure in a new spiral bacterium
is yet to be tested in children, but it is recommended that (Campylobacter pyloridis) from the human gastric mucosa. J Med
these therapeutic options should be based on antimicrobial Microbiol 1987;19:257-67.
susceptibility testing.[92] 11. Austin J, Doig WP, Stewart M, Trust TJ. Structural comparison of urease
and a GroEL analog from Helicobacter pylori. J Bacteriol 1992;174:7470-3.
Recent studies have assessed the value of probiotics in the 12. Phadnis SH, Paelow MH, Levy M, Ilver D, Caulkins CM, Conners JB, et al.
Surface localization of Helicobacter pylori urease and heat shock protein
management of H. pylori infection. Some studies have shown
homolog requires bacterial autolysis. Infec Immun 1996;64:905-12.
a higher eradication of infection when probiotics were used 13. Applemelk BJ, Simoons-Smit I, Negrini R, Moran AP, Aspinall GO, Forte
in combination with triple therapy in adults.[98] Several JG, et al. Potential role of molecular mimicry between Helicobacter
studies have shown a significant reduction in the antibiotic- pylori lipopolysaccharide and host Lewis blood group antigens in
associated side effects and an increase in the overall autoimmunity. Infec Immun 1996;64:2031-40.
treatment tolerability[99,100] while some others have failed 14. Peterson WL, Graham DY. Helicobacter pylori. In: Feldman M, Friedman,
to show such effects.[98] However, further pediatric studies Sleisenger MH, Scharschmidt BF, editor. Sleisenger and Fordtran’s
are needed for a definite identification of the therapeutic gastrointestinal and liver disease pathophysiology diagnosis
management. Philadelphia: WB Saunders Company; 2002. p. 732-46.
value of probiotics in the management of H. pylori before
15. Amieva MR, El-Omar EM. Host-bacterial interactions in Helicobacter
recommending it as a standard therapy. pylori infection. Gastroenterology 2008;134:306-23.
16. Willhite DC, Blanker SR. Helicobacter pylori vaculating cytotoxin enters
REFERENCES cells, localizes to mitochondria, and induces mitochondrial membrane
permeability changes correlated to toxin channel activity. Cell Microbiol
1. Warren JR, Marshall BJ. Unidentified curved bacilli on gastric epithelium 2004;6:143-54.
in active chronic gastritis. Lancet 1983;1:1273-5. 17. Yamasaki E, Wada A, Kumaroti A, Nakagawa I, Funao J, Nakayama M,
2. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of et al. Helicobacter pylori vacuolating cytotoxin induces activation of the
patient with gastritis and peptic ulceration. Lancet1984;1:1311-5. proapoptotic proteins Bax and Bak, leading to cytochrome c release and

The Saudi Journal of

91
Gastroenterology Volume 15, Number 2
Rabi' Al-Thani 1430 H
April 2009
Rajindrajith, et al.

cell death, independent of vaculation. J Biol Chem 2006;281:11250-9. 37. Ndip RN, Malange AE, Akoachere JF, MacKay WG, Titanji VP, Weaver
18. Figueiredo C, Machado JC, Yamaoka Y. Pathogenesis of Helicobacter LT. Helicobacter pylori antigens in faeces of asymptomatic children in
pylori. Helicobacter 2005;10:14-20. the Buea and Limbe health districts of Cameroon: A pilot study. Trop
19. Stein M, Rappuoli R, Covacci A. Tyrosin phosphorylation of the Med Int Health 2004;9:1036-40.
Helicobacter pylori CagA antigen after cag-driven host cell translocation. 38. McCallion WA, Murray LJ, Bailie AG, Dalzell AM, O’Reilly OJ, Bamford
Proc Natl Acad Sci USA 2000;97:1263-8. KB. Helicobacter pylori in children: Relation with current household
20. Asahi M, Azuma T, Ito S, Ito Y, Suto H, Nagai Y, et al. Helicobacter pylori living conditions. Gut 1996;39:18-21.
CagA protein can be tyrosin phosphorilated in gastric epithelial cells. 39. Tkachenko M, Zhannat NZ, Erman LV, Blashenkova EL, Isachenko SV,
J Exp Med 2000;191:593-602. Isachenko OB, et al. Dramatic changes in the prevalence of Helicobacter
21. Odenbreit S, Puls J, Sedlmaier B, Gerland E, Fischer W, Haas R. pylori infection during childhood: A 10 year follow-up study in Russia.
Translocation of Helicobacter pylori CagA into gastric epithelial cells J Peditr Gastroenterol Nutr 2007;45:428-32.
by type IV secretion. Science 2000;287:1497-5000. 40. Weyermann M, Adler G, Brenner H, Rothenbacher D. The mother as
22. Tammer I, Brandt S, Hartig R, König W, Backert S. Activation of Abl by source of Helicobacter pylori infection. Epidemiology 2006;17:332-4.
Helicobacter pylori:a novel kinase for CagA and crucial mediator of host 41. Kivi M, Johansson AL, Reilly M, Tindberg Y. Helicobacter pylori status
cell scattering. Gastroenterology 2007;132:1309-19. in family members as risk factors for infection in children. Epidemiol
23. Chang YJ, Wu MS, Lin JT, Pestell RG, Blaser MJ, Chen CC. Mechanisms Infect 2005;133:645-52.
for Helicobacter pylori CagA-induced cyclin D1 expression that affect 42. Gold BJ. New approach to Helicobacter pylori infection in children. Curr
cell cycle. Cell Microbiol 2006;8:1740-52. Gastroenterol Rep 2001;3:235-47.
24. Shibata W, Hirata Y, Maeda S, Ogura K, Ohmae T, Yanai A, et al. CagA 43. Thomas JE, Gibson GR, Darboe MK, Dale A, Weaver LT. Isolation of
protein secreted by the intact type IV secretion system leads to Helicobacter pylori from human faeces. Lancet 1992;340:1194-5.
gastric epithelial inflammation in the Mongolian gerbil model. J Pathol 44. Goosen C, Theron J, Ntsala M, Maree FF, Olckers A, Botha SJ,
2006;210:306-14. et al. Evaluation of a novel heminested PCR assay based on the
25. Kim SY, Lee YC, Kim HK, Blaser MJ. Helicobacter pylori CagA transfection phosphoglucosamine mutase gene for detection of Helicobacter pylori
of gastric epithelial cells induces interleukin-8. Cell Microbiol in saliva and dental plaque. J Clin Microbiol 2002;40:205-9.
2006;8:97-106. 45. Leung WK, Siu KL, Kwok CK, Chan S, Sung R, Sung JJ. Isolation of
26. Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, Morisawa Helicobacter pylori from vomitus of children and its implication in
T, et al. Helicobacter pylori infection triggers aberrant expression of gastro-oral transmission. Am J Gastroenterol 1999;94:2881-4.
activation-induced cytidine deaminase in gastric epithelium Nat Med 46. Personnet J, Shmuely H, Haggeerty T. Fecal and oral shedding of
2007;13:470-6. Helicobacter pylori from healthy infected adults. JAMA 1999;282:2240-5.
27. Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl Med 47. Perry S, de la Luz Sanchez M, Yang S, Haggerty TD, Hurst P,
2002;347:1175-86. Perez-Perez G, et al. Gastroenteritis and transmission of Helicobacter
28. Rothenbacher D, Bode G, Berg G, Gommel R, Gonser T, Alder G, pylori infection in Households. Emerg Infect Dis 2006;12:1701-8.
et al. Prevalence and determinants of Helicobacter pylori infection in 48. Klein PD, Graham DY, Gaillour A, Gaillour A, Opekun AR, Smith
preschool children: A population based study from Germany. Int J EO. Water source as risk factor for Helicobacter pylori infection in
Epidemiol 1998;27:135-41. Peruvian children: Gastrointestinal physiology working group. Lancet
29. Opekun AR, Gilger MA, Denyes SM, Nirken MH, Philip SP, Osato MS, et al. 1991;337:1503-6.
Helicobacter pylori infection in children of Texas. J Pediatr Gastroenterol 49. Grubel P, Hoffman JS, Chong FK, Burstein NA, Mepani C, Cave DR.
Nutr 2000;31:405-10. Vector potential of house fly (Musca domastica) for Helicobacter pylori.
30. Wizla-Derambure N, Michaud L, Ategbo S, Vincent P, Ganga-Zandzou J Clin Microbiol 1997;35:1300-3.
S, Turck D, et al. Familial and community environmental risk factors 50. Grubel P, Haung L, Masubuchi N, Stuzenberger, Cave DR. Detection
for Helicobacter pylori infection in children and adolescents. J Pediatr of Helicobacter pylori DNA in house fly (Musca domastica). Lancet
Gastroenterol Nutr 2001;33:58-63. 1998;352:788-9.
31. Mourad-Baars PE, Verspaget HW, Mertens BJ, Luisa Merain M. Low 51. Rowland M, Bourke B, Drumm B. Helicobacter pylori and peptic ulcer
prevalence of Helicobacter pylori infection in young children in the disease. In: Walker WA, Goulet O, Kleinman RE, Sherman PM, Shneider
Netherlands. Eur J Gastroenterol Hepatol 2007;19:213-6. BL, Sanderson IR, editor. Pediatric Gastrointestinal disease. Ontario:
32. Sullivan PB, Thomas JE, Wight DG, Neale G, Easthan EJ, Corrah T, et BC Decker Inc: 2004. p. 491-512.
al. Helicobacter pylori in Gambian children with chronic diarrhoea and 52. Gold BD, Colletti RB, Abbott M, Czinn S, Elitsur Y, Hassall E, et al.
malnutrition. Arch Dis Child 1990;65:189-91. Helicobacter pylori infection in children: Recommendation for diagnosis
33. Kate V, Ananthakrishanan N, Ratnakar C, Badrinath S. Anti-H.pylori IgG and treatment. J Pediatr Gastroenterol Nutr 2000;31:490-7.
seroprevalence rates in asymptomatic children and adults form south 53. Day AS, Sherman PM. Accuracy of office-based immunoassay for the
India. Indian J Med Microbiol 2001;19:20-5. diagnosis of Helicobacter pylori infection in children. Helicobacter
34. Gold BJ. Helicobacter pylori infection in children. Curr Prob Pediatr 2002;7:205-9.
2001;31:247-66. 54. Makristathis A, Hirschl AM, Lehours P, Megraud F. Diagnosis of
35. Rocha GA, Rocha AM, Silva LD, Samtos A, Bocewicz AC, Queiroz Helicobacter pylori infection. Helicobacter 2002;9:7-14.
RM, et al. Transmission of Helicobacter pylori infection in families of 55. Drumm B, Koletzko S, Oderda G. Europian Paediatric task force on
preschool-aged children from Minas Gerais, Brazil. Trop Med Int Health Helicobacter pylori. Helicobacter pylori infection in children: A consensus
2003;8:987-91. statement. J Pediatr Gastroenterol Nutr 2000;30:207-13.
36. Malaty HM, Haveman T, Graham DY, Fraley K. Helicobacter pylori 56. De Olivaria AM, Rocha GA, Queiroz DM, Mendes EN, de Carvalho AS,
infection in asymptomatic children: Impact of epidemiological factors Ferrari TC, et al. Evaluation of enzyme-linked immunosorbant assay for
on accuracy of diagnostic tests. J Ped Gastroenterol Nutr 2002;35: the diagnosis of Helicobacter pylori infection in children from different
59-63. age grups with and without duodenal ulcer. J Pediatr Gastroenterol

92 The Saudi Journal of

Volume 15, Number 2 Gastroenterology
Rabi' Al-Thani 1430 H
April 2009
 H. pylori in children

Nutr 1999;28:157-61. 75. Fall CH, Goggin PM, Hawtin P, Fine D, Duggleby S. Growth in infancy,
57. Czinn SJ. Serodiagnosis of Helicobacter pylori in Pediatric patients. J infant feeding, childhood living conditions, and Helicobacter pylori
Pediatr Gastroenterolo Nutr 1999;28:132-4. infection at age 70. Arch Dis Child 1997;77:310-4.
58. Westblom TU, Madan E, Gudipati S, Midkiff BR, Czinn SJ. Diagnosis 76. Perri F, Pastore M, Leandro G, Clemente R, Ghoos Y, Peeters M, et al.
of Helicobacter pylori infection in adult and pediatric patients by using Helicobacter pylori infection and growth delay in older children. Arch
Pyloriset: A rapid latex agglutination test. J Clin Microbiol 1992;30:96-8. Dis Child 1997;77:46-9.
59. Bode G, Marchildon P, Peacock J, Brenner H, Rothenbacher D. Diagnosis 77. Thomas JE, Dale A, Bunn JE, Harding M, Coward WA, Cole TJ, et al. Early
of Helicobacter pylori infection in children: Comparison of a salivary Helicobacter pylori colonization: The association with growth faltering
immunoglobulin G antibody test with the 13C urea breath est. Clin in the Gambia. Arch Dis Child 2004;89:1149-54.
Diagn Lab Immunol 2002;9:493-5. 78. Mera RM, Correa P, Fonthan EE, Reina JC, Pradilla A, Alzate A, et al.
60. Kawakami E, Machado RS, Reber M, Patricio FR. 13C-Urea breath test Effects of a new Helicobacter pylori infection on height and weight in
with infrared spectroscopy for diagnosing Helicobacter pylori infection Colombian children. Ann Epidemiol 2006;16:347-51.
in children and adolescents. J Pediatr Gastroenterol Nutr 2002;35: 79. Frank F, Stricker T, Stallmach T, Braegger CP. Helicobacter pylori infection
39-43. in recurrent abdominal pain. J Pediatr Gastroenterol Nutr 2000;31:
61. Megraud F; On behalf of the European Paediatric Task Force on 424-7.
Helicobacter pylori. Comparison of non-invasive tests to detect 80. Kimia A, Zahavi H, Shaprio R, Rosenbach Y, Hirsh A, Drudz T, et al. The
Helicobacter pylori infection in children and adolescents: Results of a role of Helicobacter pylori gastritis in children with recurrent abdominal
multicenter European study. J Pediatr 2005;146:198-203. pain. Indian Med Assoc J 2000;2:126-8.
62. Makristathis A, Barousch W, Pasching E, Binder C, Kuderna C, Apfalter P, 81. Ozen H, Dinler G, Akyon Y, Kocak N, Yuce A, Gurakan F. Helicobacter
et al. Two enzyme immunoassays and PCR for detection of Helicobacter pylori infection and recurrent abdominal pain in Turkish children.
pylori in stool specimens from pediatric patients before and after Helicobacter 2001;6:234-8.
eradication therapy. J Clin Microbiol 2000;38:3710-4. 82. Macarthur C, Saunders N, Feldman W, Ipp M, Winder-Lee P,
63. Koletzko S, Konstantopopulos N, Bosman D, Feydt-Schmidt A, vander Roberts S, et al. Helicobacter pylori and childhood recurrent abdominal
Ende A, Kalach N, et al. Evaluation of a novel monoclonal enzyme pain: Community based case-control study. Br Med J 1999;319:
immunoassay for detection of Helicobacter pylori antigen in stool from 822-23.
children. Gut 2003;52:804-6. 83. Hardikar W, Colin F, Arnold S, Frank O, Keith G. Helicobacter pylori
64. Crone J, Gold BD. Helicobacter pylori in pediatrics. Helicobacter and recurrent abdominal pain. J Pediatr Gastroenterol Nutr 1996;22:
2004;9:49-56. 148-52.
65. Bahu MG, da Silvaria TR, Maguilnick I, Ulbrich-Kulczynski J. Endoscopic 84. Bode G, Brenner H, Adler G, Rothenbacher D. Recurrent abdominal pain
nodular gastritis: An endoscopic indicator of high-grade bacterial in children: Evidence from a population-based study that social and
colonization and severe gastritis in children with Helicobacter pylori. J familial factors play a major role but not Helicobacter pylori infection.
Pediatr Gastroenterol Nutr 2003;36:217-22. J Psychosom Res 2003;54:417-21.
66. Uc A, Chong SK. Treatment of Helicobacter pylori gastritis improves 85. Bansal D, Patwari AK, Malhotra VL, Malhotra V, Anand VK. Helicobacter
dyspeptic symptoms in children. J Pediatr Gastroenterol Nutr pylori infection in recurrent abdominal pain. Indian Pediatr 1998;35:
2002;34:281-5. 329-37.
67. Genta RM, Hammer HW, Graham DY. Gastric lymphoid follicles in 86. Wewer V, Anderson LP, Paerregaard A, Gernow A, Hansen JP,
Helicobacter pylori infection: Frequency, distribution and response to Matzen P, et al. Treatment of Helicobacter pylori in children with recurrent
triple therapy. Hum Pathol 1993;24:577-83. abdominal pain. Helicobacter 2001;6:244-8.
68. Goggin N, Rowland M, Imrie C, Walsh D, Clyne M, Drumm B. Effect of 87. Devanarayana NM, de Silva DG, de Silva HJ. Aetiology of recurrent
Helicobacter pylori eradication on the natural history of duodenal ulcer abdominal pain in a cohort of Sri Lankan children. J Paediatr Child
disease. Arch Dis Child 1998;79:502-5. Health 2008;44:195-200.
69. Huang FC, Chang MH, Hsu HY, Lee PI, Shun CT. Long-term follow-up of 88. Macarthur C, Saunders N, Feldman W. Helicobacter pylori, gastroduodenal
duodenal ulcer in children before and after eradication of Helicobacter disease, and recurrent abdominal pain in children. JAMA 1995;273:
pylori. J Pediatr Gastroenterol Nutr 1999;28:76-80. 729-34.
70. Blaster MJ. Helicobacter pylori and gastric disease. BMJ 1998;316: 89. Campbell DI, Thomas JE. Helicobacter pylori infection in paediatric
659-69. practice. Arch Dis Child Educ Pract 2005;90:ep25-30.
71. Gold BD. Outcome of pediatric gastroesophageal reflux disease: In the 90. Oderda G, Rapa A, Bona G. A systematic review of Helicobacter pylori
first year of life, in childhood and in adults… oh and should we really eradication treatment schedules in children. Aliment Pharmacol Ther
leave Helicobacter pylori alone. J Pediatr Gastroenterol Nutr 2003;37: 2000;14:59-66.
S33-9. 91. Khurana R, Fischbach L, Chiba N, van Zanten SV, Sherman PM, George
72. Choi JW. Does Helicobacter pylori infection related to iron deficiency BA, et al. Meta-analysis: Helicobacter pylori eradication treatment efficacy
anaemia in prepubescent children under 12 years of age. Acta Paediatr in children. Aliment Pharmacol Ther 2007;25:523-36.
2003;92:970-2. 92. Malfertheiner P, Megaraud F, O’Morain C, Bazzoli F, El-Omar E, Graham
73. Choe YH, Kim SK, Hong YC. The relationship between Helicobacter pylori D, et al. Current concepts in the management of Helicobacter pylori
infection and iron deficiency: Seroprevalence study in 937 pubescent infection: The Maastricht III consensus report. Gut 2007;56:772-81.
children. Arch Dis Child 2003;88:178. 93. Bahremand S, Nematollahi LR, Fourutan H, Tirgari F, Nouripour S,
74. Sherman P, Czinn S, Drumm B, Gottrand F, Kawagami E, Madrazo A, Mir E, et al. Evaluation of triple and quadruple Helicobacter pylori
et al. Helicobacter pylori infection in children and adolescents: Working eradication therapies in Iranian children: A randomized clinical trial.
group report of the first world congress of Pediatric Gastroenterology Eur J Gastroenterol Hepatol 2006;18:511-4.
Hepatology and nutrition. J Pediatr Gastroenterol Nutr 2002;35: 94. Francavilla R, Lionetti E, Castellaneta SP, Magista AM, Boscarelli G,
S128-33. Piscitelli D, et al. Improved efficacy of 10-day sequential treatment for

The Saudi Journal of

93
Gastroenterology Volume 15, Number 2
Rabi' Al-Thani 1430 H
April 2009
Rajindrajith, et al.

Helicobacter pylori in children: A randomized trial. Gastroenterology of probiotics on PPI triple therapy for Helicobacter pylori eradication.
2005;129:1414-9. Helicobacter 2008;13:261-8.
95. Chan KL, Zhou H, Ng DK, Tam PK. A prospective study of one-week non- 99. Lionetti E, Miniello VL, Casterllaneta SP, Magista AM, de Canio A,
bismuth quadruple therapy for childhood Helicobacter pylori infection. Maurogiovanni G, et al. Lactobacillus reuteri therapy to reduce
J Pediatr Surg 2001;36:1008-11. side-effects during anti-Helicobacter pylori treatment in children:
96. Carvalho AS, Queiroz DM, Maides EN, Rocha GA. Triple antimicrobial A randomized, placebo controlled trail. Aliment Pharmacol Ther
therapy plus H2-receptor antagonists or omeprazole in the eradication 2006;24:1661-8.
of Helicobacter pylori in children with duodenal ulcer. Gut 1998;43:A74. 100. Armuzzi A, Cremonini F, Bartolozzi F, Conducci F, Candelli M, Ojetti
97. Sykora J, Valeckova K, Amlerova J, Siala K, Dedek P, Watkins S, V, et al. The effects of oral administration of Lactobacillus GG on
et al. Effects of specially designed fermented milk product containing antibiotic-associated gastrointestinal side-effects during Helicobacter
probiotic Lactobacillus casei DN-114 001 and the eradication of H. pylori eradication therapy. Aliment Pharmacol Ther 2001;15:163-9.
pylori in children: A prospective randomized double-blind study. J Clin
Gastroenterol 2005;39:692-8. Source of Support: Nil, Conflict of Interest: None declared.
98. Kim MM, Kim N, Lee SH, Park YS, Hwang JH, Kim JW, et al. The effects

Author Institution Mapping (AIM)

Please note that not all the institutions may get mapped due to non-availability of the requisite information in the Google Map. For AIM of other
issues, please check the Archives/Back Issues page on the journal’s website.

94 The Saudi Journal of

Volume 15, Number 2 Gastroenterology
Rabi' Al-Thani 1430 H
April 2009