PEDIATRICS Vol. 100 No. 1 July 1997,
p. e3
Copyright ©1997 by the American Academy of Pediatrics
ELECTRONIC ARTICLE:
Omeprazole-based Dual and Triple Regimens for Helicobacter
pylori Eradication in Children
Seiichi Kato*,
Junji Takeyama*,
Kyoko Ebina*, and
Hiroshi Naganuma
From the Departments of * Pediatrics and Pathology, Sendai
City Hospital, Sendai, Japan.
ABSTRACT
- INTRODUCTION
- PATIENTS AND METHODS
- RESULTS
- DISCUSSION
- REFERENCES
ABSTRACT 
Objective. To evaluate the efficacy and
safety of omeprazole-based dual and triple regimens for the treatment
of children with Helicobacter pylori infection.
Methods. Twenty-two patients (3 with gastric ulcer, 12 with duodenal ulcer, and 7 with nodular gastritis alone) were studied. Twelve ulcer patients also had nodular gastritis. The dual regimen included a 2-week course of omeprazole (0.6 mg/kg twice a day) and
amoxicillin (30 mg/kg twice a day) (n = 10), and the triple regimen included the dual regimen plus clarithromycin (15 mg/kg twice a
day) (n = 12). In patients with active ulcers, omeprazole once
daily was administered for another 4 weeks. Endoscopic biopsies were
taken before therapy and 4 weeks after completion of a 2-week course of
therapy, and patients were followed for 6 months. The gastritis score
(grade 0 to 3) and serum anti-H pylori IgG antibody titers
were also determined.
Results. The regimens were tolerated by all patients.
Eradication rates for the dual and triple regimens were 70% and 92%, respectively. Active ulcers completely healed within 6 weeks. Patients
with nodular gastritis alone showed different clinical responses to
therapy. Pretreatment histology showed chronic gastritis in all
patients. Successful H pylori eradication significantly reduced the mean gastritis score from 2.9 to 1.3, but unsuccessful eradication did not reduce it. The disappearance of antral nodularity often coincided with the success of eradication. Successful eradication significantly decreased pretreatment serum anti-H pylori
IgG antibody titers by 29% at 1 month, by 52% at 3 months, and by
67% at 6 months. Side effects were mild and were reported in 23% of
patients.
Conclusion. An omeprazole-based regimen is safe and may be
a better option for eradication of H pylori in children.
Antral nodularity is a macroscopic marker of H pylori
infection.
Key words:
Helicobacter pylori,
gastritis,
omeprazole,
amoxicillin,
clarithromycin.
INTRODUCTION
Helicobacter pylori infection is a major
etiological factor in chronic gastritis and is highly associated with
peptic ulcer disease.1,2 Eradication of H pylori
dramatically reduces the recurrence rate of duodenal
ulcer.3,4 Therefore, the aim of treatment for H
pylori-associated peptic ulcer disease has changed from the mere
suppression of gastric acidity to eradication of the organism. The
National Institutes of Health recommended treatment with antimicrobial
agents in addition to antisecretory drugs, regardless of whether
recurrence occurs.5 In adults, high eradication rates (90%
or higher) have been obtained with a traditional bismuth-based triple
regimen that includes metronidazole and either amoxicillin or
tetracycline.6,7 However, this regimen has disadvantages
(such as complex administration and side effects) which lead to poor
patient compliance in clinical practice. Metronidazole-resistant
strains are also a problem. Recently, as an alternative to the
traditional triple regimen, a simple omeprazole-based regimen has been
introduced with a low incidence of side effects.8,9 This
regimen has been most widely studied.10,11
H pylori eradication with bismuth-based regimens has been
also attempted in children with peptic ulcer disease or
gastritis.12 However, there are few studies of
omeprazole-based regimens.19 This study reports on the
efficacy and safety of omeprazole-based dual and triple regimens in
children with H pylori-associated gastroduodenal diseases.
PATIENTS AND METHODS
Patients
Between March 1995 and February 1996, 22 patients (age 8 to 16 years) were enrolled in this study (Table 1). Three patients had gastric ulcers, 12 had duodenal ulcers, and 7 had nodular gastritis
with symptoms including epigastric pain, nausea, or vomiting. Nodular
gastritis was also found in 12 of 15 patients with peptic ulcer
disease. Among 10 patients with active ulcers, 2 received eradication
therapy at the first presentation of the disease and 8 at recurrence.
The clinical symptoms of these patients included hematemesis,
epigastric pain, tarry stool, and/or anemia. At presentation, one
patient with bleeding gastric ulcer and one with bleeding duodenal
ulcer underwent endoscopic hemostasis with pure ethanol using a method
reported previously.20 Five asymptomatic patients with
a history of ulcer recurrence received eradication therapy for
prevention of recurrence; the patients and their parents requested the
therapy. None of the patients received either steroids or nonsteroidal
antiinflammatory drugs. There was one smoker who was male and 16 years
old.
|
Table 1.
Demographic Characteristics of Patients
[View Table]
|
Informed consent was obtained from all patients and their parents
before inclusion.
Treatment and Follow-up
Patients undergoing maintenance treatment with H2-receptor
antagonists stopped the drugs at entry. In patients with active ulcers,
eradication therapy was started after H pylori infection was
confirmed by the rapid urease test (Stat-Urease, PML Microbiologicals, Canada). Drug dosage within each eradication regimen was based on the
adult experience with high-dose regimens, including 20 mg omeprazole
twice a day.10,11 The first 10 patients received the dual
regimen: 0.6 mg/kg (maximum dose, 20 mg) omeprazole twice a day and 30 mg/kg (maximum dose, 1000 mg) amoxicillin twice a day at breakfast and
at the evening meal for 14 days. The other 12 patients received the
triple regimen: the dual regimen plus 15 mg/kg (maximum dose, 500 mg)
clarithromycin twice a day for 14 days. In patients with active ulcers,
once-daily omeprazole (0.6 mg/kg with a maximum dose of 20 mg) was
administered for another 4 weeks. Patients without active ulcers or
with nodular gastritis alone received only a 2-week course of
eradication therapy.
Upper gastrointestinal endoscopy and biopsy were routinely performed
before therapy and 4 weeks after completion of a 2-week course of
treatment (at 6 weeks). Each patient was followed up for at least 6 months.
H pylori Infection and Gastritis
Two biopsy specimens were taken from the gastric antrum. The
specimens were stained with hematoxylin-eosin and Giemsa for the
histological investigation which included an H pylori test. Another two antral biopsies were examined for culture and urease activity of H pylori. The H pylori test was
considered positive if at least one test (histology, culture or urease)
gave a positive result. If all results were negative at 6 weeks,
H pylori was considered to be eradicated. The antral biopsy
specimens before and after eradication therapy were also studied for
the degree of gastritis (Table 2). The degree of
inflammation was graded according to Bazzoli et al:21 grade
0, normal gastric histology; grade 1, slight increase in the number of
mononuclear cells; grade 2, increase in the number of mononuclear cells
and neutrophils also present; grade 3, increase in the number of
mononuclear cells and neutrophils with epithelial invasion of
neutrophils. The pathologist (H.N.) was unaware of the clinical course
of the patients.
|
Table 2.
Antral Nodularity and Gastritis Score With Eradication Therapy
[View Table]
|
Serum IgG antibody against H pylori was measured using an
enzyme immunoassay (Cobas Core Anti-H pylori-EIA, Nippon
Roche, Japan) with a cutoff point of 6 U/mL. Blood samples were
obtained before treatment and at 1, 3, and 6 months after treatment
ended; they were frozen at 
20°C. To avoid day-to-day and
tube-to-tube variations, investigators collectively measured the
samples with the same lots of the assay kit.
Intragastric pH Monitoring
To evaluate acid suppression with omeprazole in six patients,
intragastric acidity was monitored for 24 hours (model KR-5010 pH
monitor, Kuraray Co., Ltd., Japan) on days 5 to 13 of eradication therapy. After calibration, the electrode was transnasally positioned in the middle body of the stomach under fluoroscopy. The data were
transferred to a personal computer and analyzed with respect to mean
intragastric pH and H+ activity.22
Safety Assessment
Drug tolerance was investigated by questioning patients and
parents about possible side effects: altered taste, diarrhea, nausea/vomiting, abdominal pain, skin eruption, and neurological symptoms (such as headache and dizziness). Laboratory examinations (including hemoglobin levels, white blood cell counts, platelet counts,
serum electrolyte levels, hepatic and renal function tests, and
urinalysis) were performed during therapy and at follow-up. Serum
gastrin levels were also measured in all patients.
Statistics
The differences in age and sex ratio of patients, frequency of
side effects, and eradication rates between dual and triple regimens
were analyzed by Fisher's exact test, and differences in the mean
gastritis score and serum anti-H pylori IgG antibody titers
before and after eradication therapy were analyzed by the paired
t test. A value of P < .05 was considered
significant. The values were presented as mean ± SEM.
RESULTS
Eradication and Gastritis
The first endoscopy demonstrated antral nodularity in 19 patients,
multiple erosions in 2, and no macroscopic lesions in 1 (Table 2).
Pretreatment histology showed chronic gastritis in all patients (mean
gastritis score, 2.9). In 14 patients (13 with the nodularity and 1 with erosions but no nodularity), pretreatment histology demonstrated
lymphoid follicles predominantly in the lamina propria. No patient had
intestinal metaplasia.
Examinations of the second biopsy specimens demonstrated that H
pylori was eradicated in 7 of 10 patients (70%) with the dual regimen and 11 of 12 patients (92%) with the triple regimen (Tables 1
and 2). There was no difference in eradication rate between regimens
(P = .19). In all 10 patients with active
ulcers, the symptoms ceased within several days after the initiation of
therapy and the ulcers completely healed with a full 6-week course of treatment. Antral nodularity disappeared in 6 of 15 patients with successful eradication (Table 2). Successful eradication therapy significantly reduced the mean gastritis score from 2.9 to 1.6 (P < .005), but unsuccessful eradication did
not reduce it (P = .50). Lymphoid follicles were
detected in 11 patients after eradication therapy.
Intragastric Acidity
With the eradication therapy, the mean intragastric pH was
4.7 ± 0.3 (range, 3.5 to 6.0) and the mean intragastric
H+ activity was 0.99 ± 0.29 mmol/L (range, 0.04 to 2.06). The percentages of time at a pH of 2 or more, at a pH of 3 or
more, and at a pH of 4 or more were 96.9 ± 1.2%, 85.3 ± 3.8%, and 64.7 ± 8.3%, respectively.
Serum Anti-H pylori Antibody
Two patients were excluded from this serological study, because
they were seronegative at entry. Of the remaining 20 patients, the mean
pretreatment titer of anti-H pylori IgG antibody was 66.9 U/mL (range, 7.8 to 567.9). In successfully treated patients, the IgG
antibody titer decreased by an average of 29% at 1 month (P < .001), by 52% at 3 months
(P < .001), and by 67% at 6 months (P < .001), compared with the pretreatment
titers (Fig 1). Two patients became seronegative at 6 months. In contrast, the IgG antibody titers remained at baseline
levels in patients with persistent H pylori infection. Two
patients who were excluded from this serological study continued to be
seronegative in the follow-up period.
Fig. 1.
Serum anti-H pylori IgG antibody titers.
Posttreatment titers are expressed as percentages of pretreatment
levels in successfully treated (solid bars) and unsuccessfully treated
(shaded bars) patients. *P < .001.
[View Larger Version of this Image (59K GIF file)]
Safety and Follow-up
Drug compliance was good in all patients. The overall incidence of
side effects was 23%; diarrhea was recorded in one patient given the
dual regimen, and metallic taste, dry mouth, and/or diarrhea in four
patients given the triple regimen (Table 1). Because the side effects
were mild, however, discontinuation of treatment was not necessary.
Laboratory examinations showed no abnormalities during or after
therapy. Although serum gastrin levels were greater than normal at 2 to
4 weeks after treatment started, they normalized within 3 months.
In patients with nodular gastritis alone in whom H pylori
was eradicated, the symptoms disappeared in two patients, improved in
three, and persisted in two at 6 months. One patient with unsuccessful therapy continued to have epigastric pain. Some patients took 3 to 6 months to confirm a symptomatic response to eradication therapy. Ulcer
recurred 3 months after treatment ended in one patient with duodenal
ulcer in whom H pylori was not eradicated. In the remaining
ulcer patients, however, ulcer did not recur in the follow-up period
(ranging between 6 and 17 months). In four patients with successful
eradication who agreed to endoscopic biopsy at 6 months, H
pylori colonization continued to be negative.
DISCUSSION
An omeprazole-based regimen consists of the combination of
omeprazole with one or two antibiotics effective against H
pylori. Amoxicillin has a low minimum inhibitory concentration for
H pylori in vitro, but its monotherapy demonstrates low
eradication rates of 20%.6 Because amoxicillin operates
optimally at neutral pH levels, decreasing intragastric acidity with
omeprazole seems to be important in eradicating H pylori.
Omeprazole is an essential component of new eradication
regimens.10 However, eradication rates with a dual regimen
of omeprazole/amoxicillin vary from study to study, with a pooled rate
of 60%.23 It has been speculated that differences in
H pylori strains or host factors may explain the
discrepancies among studies.24 The role of omeprazole in an
amoxicillin dual regimen also holds true for that in a clarithromycin dual regimen. On the dual regimen, clarithromycin is almost equal to
amoxicillin with respect to the eradication rate and
safety.10 Katelaris et al stated that amoxicillin is the
first choice for omeprazole dual regimens, however, because
clarithromycin-resistant strains are demonstrated in 5 to 10% of
patients.25
Many adult studies using 20 to 40 mg/day omeprazole have been
attempted. In one pediatric study with 20 mg omeprazole daily and 250 mg or 500 mg amoxicillin twice a day, H pylori was
eradicated in only two of eight patients.19 We previously
reported that an average of 0.6 mg/kg daily of omeprazole is
appropriate in most children with H2-receptor antagonist-resistant
acid-related diseases.22 The dose of omeprazole in this
study is twice as high as the suggested dose, which is relatively high
for children compared with 40 mg daily in adults. The pH study has
shown that 1.2 mg/kg daily of omeprazole powerfully reduces
intragastric acidity, although the reduction may be insufficient in
some patients. Eradication rates do not differ between 20 mg and 40 mg
twice daily of omeprazole.26 A dose more than 1.2 mg/kg
daily of omeprazole might be unnecessary in children.
The current belief is that an eradication rate more than 90% is
essential for an ideal regimen. Additionally, simplicity of drug
administration, low doses of antibiotics and a low incidence of side
effects are desirable.10 On these grounds, wide study of
omeprazole-based triple regimens shows that eradication rates of around
90% have been achieved;10,11 the two antibiotics prescribed are usually amoxicillin and clarithromycin or a
nitroimidazole. However, there are only a few reports describing a
regimen consisting of omeprazole, amoxicillin, and
clarithromycin.27,28 The advantage of this regimen is that
the risk of nitroimidazole resistance is excluded. This study showed a
high eradication rate, which is consistent with the results of adult
studies.10,11,27,28 Although there was no statistical
difference between dual and triple regimens (this study was not
randomized), it may be attributable to the small number of patients
studied. We believe that an omeprazole-based regimen is safe and a
better therapeutic option for children with H
pylori-associated gastroduodenal ulcers. More recently, a one-week course of an omeprazole-based triple regimen has been reported to have
an eradication rate greater than 90%.21 Drug compliance is
an important factor in determining the success of
eradication.7 In this sense, the duration as well as doses
of regimens must be further investigated.
Chronic gastritis with H pylori infection has various
endoscopic appearances, including macroscopically normal mucosa with histologically confirmed inflammation. Antral nodularity is frequently observed especially in children with H pylori
gastritis.12 Furthermore, many children with
H pylori-associated duodenal ulcer also have antral
nodularity.18 As previously
reported,12,13,15 the present study proved that curing
H pylori infection reduces the degree of gastric
inflammation especially with a reduced number of neutrophils. In
addition, the disappearance of antral nodularity was often demonstrated
with H pylori eradication. On the contrary, Ashorn et al
have stressed that the nodularity does not resolve along with active
gastritis and persistent nodularity does not indicate persistent
H pylori infection.13 The lymphoid follicles with germinal centers demonstrated by histology are probably involved in the pathogenesis of nodularity; however, lymphoid follicles were
detectable in some patients in whom the nodularity subsided as
evidenced by endoscopy. Although the degree of gastritis is reduced
with successful eradication, the inflammatory reaction does not
completely disappear in the short-term period after H pylori
is eradicated. Antral nodularity is a macroscopic marker of H
pylori infection and its eradication.
There is controversy regarding whether H pylori infection is
related to symptoms of gastritis/nonulcer
dyspepsia.12,16 Our patients with nodular gastritis
alone demonstrated different symptom responses to eradication therapy.
It was difficult to estimate the response shortly after eradication
therapy. The symptomatic efficacy of the bismuth-based regimen may be
associated with other mechanisms of bismuth salts (such as
cytoprotection) rather than H pylori eradication. The role
of H pylori and its eradication in the symptomatic relief of
gastritis/nonulcer dyspepsia remains unclear.
H pylori eradication significantly reduced serum
anti-H pylori IgG antibody titers; however, many patients
continued to be seropositive. It may take more than 6 months after
treatment to become seronegative.14,16,29 A 20% reduction
of the IgG antibody titers by 6 months suggests successful eradication
therapy, whereas no reduction suggests persistent H pylori
infection.30 On the other hand, one study showed a decrease
of antibody titers in half of the children with persistent H
pylori infection.13 Our data suggests that serial
assay of serum anti-H pylori IgG antibody titers is useful
in long-term monitoring of H pylori eradication. At present,
however, evidence of eradication should be founded on biopsy-based
tests performed at 4 weeks or more after the completion of eradication
therapy. In the future, noninvasive urea breath tests may be routinely
available in the monitoring of H pylori infection. All
children with H pylori-associated peptic ulcer disease
should be treated not only for the ulcer but also for the H
pylori infection. It is possible that successful eradication means
cure of peptic ulcer disease.
FOOTNOTES
Received for publication Sep 6, 1996; accepted Dec 12, 1996.
Reprint requests to (S.K.) Department of Pediatrics, Sendai
City Hospital, 3-1 Shimizukoji, Wakabayashi-ku, Sendai 984, Japan.
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