Miao et al. BMC Pediatrics(2024) 24:543
https://doi.org/10.1186/s12887-024-05020-6

BMC Pediatrics

RESEARCH

Open Access

A randomised controlled clinical studyof standard triple therapy, bismuth-based
quadruple therapy and sequential therapy
for Helicobacter pylori infection in children
Ruixue Miao1,2, Jing Chen1,2, Shan Gao1,2, Liyuan Wang1,2, Wei Zhou1,3, Chaomin Wan1,2* and Zhiling Wang1,2*
Abstract
Background and aim Bismuth and non-bismuth quadruple therapy are the guideline-recommended first-line
therapy in children with Helicobacter pylori infection in areas with high antibiotic resistance. However, their efficacy
in children is uncertain and there are few well-designed studies. Here, we evaluated the eradication rates of standard
triple therapy, bismuth-based quadruple therapy and sequential therapy in children with H. pylori infection.
Methods A randomised controlled trial was conducted in children infected with H. pylori in West China Second
Hospital. They were randomly assigned to 14-day standard triple therapy (omeprazole + amoxicillin + clarithromycin),
14-day bismuth quadruple therapy (bismuth + omeprazole + amoxicillin + clarithromycin) and 10-day sequential
therapy (omeprazole + amoxicillin for 5 days followed by omeprazole + clarithromycin + metronidazole for 5 days).
The eradication rate was assessed by a 13C-urea breath test 4 to 6 weeks after therapy completion. Symptom
improvement and adverse events were compared among the groups.
Results In total, 132 patients were enrolled. The eradication rates of 14-day standard triple therapy, 14-day bismuth
quadruple therapy and 10-day sequential therapy were 70.0%, 78.9% and 50.0% in per-protocol analysis and 63.6%,
68.2% and 43.2% in intention-to-treat analysis, respectively. Symptom improvement and adverse drug event rates
were similar in the three groups.
Conclusion The three therapeutic regimens evaluated in this study are equally not recommendable for H. pylori
infection treatment due to unsatisfactory eradication rates. The high prevalence of clarithromycin resistance makes
the use of clarithromycin-based quadruple therapy not advisable, even in combination with amoxicillin and bismuth
salts.
Keywords Children, Helicobacter pylori, Eradication, Bismuth quadruple therapy, Sequential therapy*Correspondence:
Chaomin Wan
wcm0220@126.com
Zhiling Wang
wang_zhi_ling@126.com
1
Department of Pediatrics, West China Second Hospital, Sichuan
University, No 20, 3rd section of Renmin South Road, Chengdu
610041, PR China

2

Key Laboratory of Birth Defects and Related Diseases of Women andChildren (Sichuan University), Ministry of Education, Chengdu
610041, PR China
3
Clinical laboratory West China Second Hospital, Sichuan University,
Chengdu 610041, PR China© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you
give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified thelicensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to thematerial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation
or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://
creativecommons.org/licenses/by-nc-nd/4.0/.

Miao et al. BMC Pediatrics(2024) 24:543

Background
Helicobacter pylori colonises the gastric mucosa andcauses chronic gastritis, which is defined as an infectious
disease [1, 2], as well as peptic ulcer, gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT)
lymphoma [3]. H. pylori infection may also progress toiron deficiency anaemia, chronic immune thrombocytopenic purpura and inflammatory bowel disease andimpair children’s growth [4, 5]. The infection is usuallyacquired in childhood and has an overall prevalence of
30.31% in Chinese children [6]. Its successful eradication
can reduce the recurrence of peptic ulcer in infected children. Currently, the efficacy of the standard triple therapy
recommended as first-line treatment is generally decreasing due to increased antibiotic resistance. At the sametime, some antibiotics are not licensed for the paediatric population. Thus, the treatment of H. pylori infection
in children is a particular challenge in areas with severe
antibiotic resistance.
Bismuth and non-bismuth quadruple therapies, including concomitant, sequential and hybrid regimens, show
higher eradication rates than standard triple therapy in
the adult population but have been scarcely studied inchildren [7]. Moreover, concomitant and hybrid treatments are rarely used in infected children because of
the potential for additive adverse events. A Cochranereview determined that sequential therapy including
proton pump inhibitors (PPIs) with amoxicillin (AMO)
for 5 days followed by PPIs with clarithromycin (CLR)
and metronidazole (MET) for 5 days had better efficacy
than triple therapy [8]. The Chinese consensus [9] on the
diagnosis and treatment of H. pylori infection in children
states that sequential therapy can be used as first-line
treatment in areas with CLR resistance exceeding 20%
and recommends bismuth-based quadruple therapies
for rescue therapy. Nonetheless, a contradictory result
was reported in one study that found an unacceptable
eradication rate of 56.1% for sequential therapy, in which
the CLR resistance rate was 25.7% [10]. The joint ESPGHAN/NASPGHAN guidelines recommend bismuthbased quadruple therapies as first-line treatment in areasof high or unknown CLR resistance for children with H.
pylori infection based on the literature and adult studies[11]. However, well-designed clinical studies of bismuthbased therapy in children are lacking. Therefore, in thepresent randomised controlled trial, we compared theeradication rate, adverse events and adherence of 14-day
bismuth-based quadruple therapy and 10-day sequential
therapy with 14-day standard triple therapy in children
with H. pylori infection in southwest China.

Page 2 of 8

Methods
Participants

Patients were included when they met all of the following
four inclusion criteria: (1) outpatients aged from 6 to 14
years who were referred for gastroscopy in West China
Second University Hospital; (2) confirmed H. pylori
infection; (3) indication for eradication according to the2015 Chinese consensus on H. pylori infection in children; and (4) treatment-naïve.
H. pylori infection was diagnosed by one of the following conditions: (1) a positive culture of H. pylori; (2)H. pylori gastritis on histopathology and a simultaneous
positive rapid urease test (RUT); (3) if the histopathology findings and RUT result were inconsistent, a positive
13
C-urea breath test (UBT); and (4) positive histopathology or 13C-UBT when children had a bleeding peptic
ulcer.
The following patients were excluded: (1) patients who
had undergone earlier eradication treatment and hadreceived antibiotics, bismuth salt, PPIs or H2-receptor
antagonists within 4 weeks before treatment; (2) patients
who had an allergic history to the drugs being used in the
study; and (3) patients who had severe systemic diseases
such as liver or kidney failure.
Randomisation and interventions

Eligible patients were randomly assigned to one of threetreatment groups according to a computer-generated
random number table. The standard triple therapy (STT)
group received continuous 14-day therapy comprising a
PPI (omeprazole) with two antibiotics (CLR and AMO).
The bismuth quadruple therapy (BQT) group received
continuous 14-day therapy comprising a bismuth salt
(bismuth potassium citrate) with a PPI (omeprazole) plus
two antibiotics (CLR and AMO). Finally, the sequential
therapy (ST) group received 10-day therapy comprising a PPI (omeprazole) with AMO for 5 days followed
by a PPI with CLR and MET for 5 days. The dosages aredetailed in Table 1. All treatments were administered bya professor who received the random number table andcorresponding treatment regimens from the statistician.
Information on the patient demographics, symptoms
and telephone number were recorded by another paediatric resident who was blinded to the group allocation
throughout the study.
Telephone follow-ups with the children’s guardians
were conducted every 3 days during the therapy period
to monitor adherence and record adverse events andsymptom changes. After the end of the treatment, telephone follow-ups were performed once a week until
4 weeks after treatment completion to record adverse
events and symptom improvement. The eradication condition was then assessed by 13C-UBT at 4–6 weeks after
treatment completion. All follow-ups were conducted byMiao et al. BMC Pediatrics(2024) 24:543

Table 1 Description of the three treatments
Therapy

Time

drugs

STT

Day1
to14

BQT

Day1
to14

ST

Day 1
to 5
Day 6
to 10

omeprazole
AMO
CLA
Bismuthomeprazole
AMO
CLA
omeprazole
AMO
omeprazole
CLA
MET

Daily dose# (twice Maximum
daily)
does foronce
0.6-1.0 mg/kg
20 mg
50 mg/kg
1g
15-20 mg/kg
0.5 g
6-8 mg/kg
220 mg0.6-1.0 mg/kg
20 mg
50 mg/kg
1g
15-20 mg/kg
0.5 g
0.6-1.0 mg/kg
20 mg
50 mg/kg
1g
0.6-1.0 mg/kg
20 mg
15-20 mg/kg
0.5 g
20 mg/kg
0.5 g

CLA: clarithromycin; AMO amoxicillin; MET metronidazole; STT: standard triple
therapy; BQT: bismuth quadruple therapy; ST: sequential therapy#

Drugs were given to each child at the appropriate dosage according to therange shown in the table and in conveniently dispensed doses

the above-mentioned paediatric resident. The patientsand personnel involved in this study were blinded to thegroup allocation throughout the study. Treatment regimens were unblinded after all patient follow-ups werecompleted.
Outcomes

The efficacy of anti-H. pylori therapy can be assessed
based on symptom improvement, the eradication rate
and adverse events during follow-up. Symptoms were
graded according to the score improvement ratio (SIR) of
the frequency score and severity score of the main complaints at the first visit before treatment and at 6 weeks
after treatment completion [12].
SIR = (pre-treatment total score − post-treatment total
score) / pre-treatment total score × 100%
where total score is the sum of the frequency score andseverity score. The frequency score was calculated as follows: 0 = no symptoms; 1 = one symptom a week; 2 = twosymptoms a week; and 3 = three or more symptoms aweek. The severity score was graded as follows: 0 = nosymptoms; 1 = symptoms are present but tolerable;
2 = symptoms are present and affect daily activities; and3 = symptoms are intolerable and severely affect daily
life. In our study, the SIR was divided into four levels:
grade A (clinical control, SIR ≥ 85%), grade B (markedly
effective, SIR = 60-84.9%), grade C (moderately effective,
SIR = 30-59.9%) and grade D (ineffective, SIR < 30-59.9%).
The eradication rate was measured using 13C-UBT(Beijing Richen-force Science & Technology Co., Ltd.)at 4–6 weeks after therapy completion. The criterion forsuccessful eradication was a negative 13C-UBT result of< 4.0.

Page 3 of 8

Analysis

Our initial hypothesis was that the eradication rates of
14-day standard triple therapy, 14-day bismuth quadruple therapy and 10-day sequential therapy in children
with H. pylori infection would be significantly different.
We assumed that the eradication rates of the three treatment regimens would be 65%, 91.9% and 89.7% based on
the literature (with an α of 0.05 and β of 0.2 for a 20%
increase in a two-sided test) [13–15]. A minimum sample
size of 40 children in each group was thus required. Statistical analysis was performed using SPSS 20.0.
A dropout rate including withdrawal and loss to followup less than 20% was accepted. The eradication rate wasanalysed by intention-to-treat and per-protocol analyses.
For intention-to-treat, all participants enrolled in the
study were analysed, regardless of whether they dropped
out. For per-protocol, only children who completed theentire study process were included in the analysis.
Measurement and count data are expressed asmean ± standard deviation and percentage, respectively. Comparisons between groups were performed
using a t-test or analysis of variance (ANOVA) andchi-square test. The rank data of two groups and threegroups were compared by the Mann-Whitney rank-sum
test and Kruskal-Wallis rank-sum test, respectively. A
P value < 0.05 was considered statistically significant.

Results
Patients’ characteristics

A total of 2554 patients underwent upper gastrointestinal endoscopy from June 2018 to December 2019 in West
China Second University Hospital. Of these patients,
276 children were diagnosed with H. pylori infection.
The overall H. pylori infection rate in children undergoing gastroscopy was 10.81%. The study flow diagram isshown in Fig. 1. 132 patients were enrolled in this study
and 44 were allocated to each of the 14-day STT, 14-day
BQT and 10-day ST groups. The symptoms included inthis study were nonspecific and mainly manifested asabdominal pain, vomiting, nausea and lack of appetite.
In addition, three children presented mild to moderateanaemia and two children presented failure to thrive. A
symptom frequency of more than 3 times per week wasreported by 78.8% patients. In terms of symptom severity,
most patients (72.7%) had tolerable symptoms that did
not affect daily activities. The frequency score (Z = 1.804,
P = 0.801) and severity score (Z = 2.74, P = 0.252) before
treatment were similar in the three groups. There were
no differences in age (10.25 ± 2.59 years, 10.09 ± 2.87 years
and 10.07 ± 2.32 years; F = 0.064, P = 0.938) or sex (males,
31/24/20; females, 13/20/24; χ2 = 5.62, P = 0.064) among
the three groups. Four children were withdrawn because
they did not receive or complete the therapy. Twelve
children were lost to follow-up and were missing dataMiao et al. BMC Pediatrics(2024) 24:543

Page 4 of 8

Fig. 1 Flow diagram of the patient selection and allocation process
STT: standard triple therapy; BQT: bismuth quadruple therapy; ST: sequential therapy

on symptoms and 13C-UBT due to poor adherence at 6
weeks. These 16 children were excluded from the perprotocol analysis. The dropout rates did not differ among
the three treatment groups.
Treatment outcomes

The eradication rates of 14-day standard triple therapy,
14-day bismuth quadruple therapy and 10-day sequential
therapy were 70.0% (28 of 40, 95%Cl 55.2-84.8%), 78.9%(30 of 38, 95%Cl 65.4-92.5%) and 50.0% (19 of 38, 95%Cl
33.3%%-66.7%) in per-protocol analysis and 63.6% (28of 44, 95%Cl 48.8-78.4%), 68.2% (30 of 44, 95%Cl 53.982.5%) and 43.2% (19 of 44, 95%Cl 27.9-58.4%) in intention-to-treat analysis. The results indicated that there
was a significant difference among the three groups, withthe efficiency of 10-day sequential therapy significantly
lower than that of 14-day standard triple therapy and of
14-day bismuth quadruple therapy. The eradication rate
did not differ between the STT and BQT groups. Eradication results are summarised in Fig. 2. The outcomes
were similar for per-protocol analysis and intention-totreat analysis.
Symptoms were determined to have improved based on
the scores obtained before and after treatment. No significant difference was found among the groups (Table 2).

Interestingly, we found that the symptom improvementof children with a positive 13C-UBT was not significantly
different from that of children with a negative 13C-UBT
at 4–6 weeks (Z = 1.18, P = 0.80). In this study, 8 children(3 in the STT group, 3 in the BQT group and 2 in the ST
group) had mild adverse reactions after taking the drugs,
including headache, diarrhoea, stomach discomfort andnausea, but none of them needed to discontinue thetreatment due to the adverse events. There were no significant differences in adverse events among the groups.
In addition, we conducted H. pylori culture, but unfortunately, no resistance results were obtained due to bacterial purification failure.

Discussion
Standard triple therapy is still the preferred regimen inareas where the predominant strain is susceptible to CLR.
However, studies have reported worrisome levels of resistance to agents such as CLR and MET [16]. CLR-resistant
H. pylori has been designated a high priority by the World
Health Organization. The use of standard triple therapy
is generally decreasing, and guidelines for children with
H. pylori infection recommend that bismuth and nonbismuth quadruple therapy be used as first-line therapy
in areas with high antibiotic resistance, based on adultMiao et al. BMC Pediatrics(2024) 24:543

Page 5 of 8

Fig. 2 The eradication rate of three group
STT: standard triple therapy; BQT: bismuth quadruple therapy; ST: sequential therapy; PP: per-protocol; ITT: intention-to-treat

Table 2 Symptom improvements in children with H. Pylori infection in the different groups
Groups by therapy
STT
BQT
ST
Group by UBT in 4 weeks
Negative
Positive

Grade A

Grade B

Grade C

Grade DP-valueP-value

21
16
21

5
5
5

14
16
9

0
0
2

5.49

0.451

42
19

9
6

26
14

1
1

1.18

0.80

STT: standard triple therapy; BQT: bismuth quadruple therapy; ST: sequential therapy; grade A: clinical control, SIR ≥ 85%; grade B: markedly effective, SIR = 60-84.9%;
grade C: effective, SIR = 30-59.9%; grade D: ineffective, SIR < 30-59.9%; UBT: urea breath test
Three children had no symptoms in this study

studies. The present randomised controlled study showed
unsatisfactory eradication rates (< 80%) of 14-day standard triple therapy (PPI + AMO + CLR), 14-day bismuth
quadruple therapy (PPI + AMO + CLR + Bismuth) andsequential therapy (PPI + AMO and PPI + CLA + MET).
Eradication success is primarily influenced by good
adherence and low antibiotic resistance. The need to takethe medication as prescribed was constantly emphasised
throughout the treatment process in this study, and theoverall drug adherence among children who completed
the therapy exceeded 90%. Although we failed to obtain
antimicrobial susceptibility testing results, another of ourcontemporaneous studies determined primary resistance
rates in our area of 45.3% for CLR and 73.6% for MET
and a dual resistance rate of 28.3% for CLR and MET[17]. The high rate of resistance to CLR and MET helps to
explain the low eradication rates. In our area, CLR-based

therapy should not be recommended as the first-line
treatment. Antimicrobial susceptibility testing shouldbe performed prior to H. pylori eradication treatment inchildren to improve eradication rate rather than using
empiric regimens. However, we need to admit the tricky
fact that many hospitals even tertiary medical centers areunable to complete susceptibility testing due to fastidious
culture of H. pylori in China.
Bismuth was initially mainly used as a mucosal protective agent for peptic ulcer and gastritis. In vitro, thecombination of bismuth and antibiotic has shown asynergistic bacteriostatic and bactericidal effect in H.
pylori treatment [18]. Accordingly, bismuth-containing
therapy has become an effective alternative treatment toovercome antimicrobial resistance. In a review of studies conducted in children from 2011 to 2021, Lai et al.
demonstrated that bismuth-based therapy had higher

Miao et al. BMC Pediatrics(2024) 24:543

eradication rates [19]. A paediatric population study inShanghai showed eradication rates of 89.8% for bismuthbased quadruple therapy and of 74.1% for standard triple
therapy, in a population with CLR resistance in 18.5%
and dual CLR and MET resistance in 18.5% [20]. However, the present study indicated that bismuth-based quadruple therapy had comparable efficacy to standard triple
therapy (78.9% vs. 70%), which is inconsistent with theresults of other studies. We believe that the unsatisfactory eradication rate for bismuth-based quadruple therapy may be related to the resistance. It is unclear whether
higher antibiotic resistance has a greater impact on theeradication rate of bismuth-based quadruple therapy.
Several adult studies have also reported that CLR andMET resistance are risk factors for failure of bismuthbased quadruple therapy and suggested that bismuth
regimens not be recommended when the strains develop
dual CLR/MET resistance or when there is a high levelof metronidazole resistance with a minimum inhibitory
concentration MIC > 32 μg/mL [21–23]. Currently, theimpact of antibiotic resistance on the efficiency of bismuth in children is unclear, and further multicentre clinical studies should be performed.
In most studies, 10-day sequential therapy eradication
appeared to be superior to 14-day standard triple therapy[19]. The 2015 Chinese consensus on H. pylori infection recommends sequential therapy as first-line therapy
in areas where CLR resistance exceeds 20%. However,it remains controversial whether 10-day sequential
therapy is better than 14-day standard triple therapy
because a growing number of studies reached inconsistent conclusions, finding a similar or even inferior
efficacy for sequential therapy [20, 24, 25]. In the present study, we found a shocking eradication rate of 50%
in 10-day sequential therapy. An unacceptably low efficacy of 56.1% was also reported in a Turkish study with25.7% CLR resistance [10]. The reasons for the results
are unknown, CLR resistance and the duration of treatments may be important impact factors. Bontems et al.
identified a lower eradication rate in children with CLR
resistance than in those without resistance [26]. The latest 2022 Chinese expert consensus on children with H.
pylori infection [27] no longer recommends sequential
therapy as the first-line treatment, which is consistent
with our current results. In addition, sequential therapy
exposes children to three different antibiotics, and the
ESPGHAN/NASPGHAN guidelines recommend against
the use of sequential therapy in treatment-naïve children
when the strain is CLR resistant or susceptibility testing is not available. However, Several adult studies haveproposed that the efficacy of sequential therapy can be
improved by extending the duration and have reported
that 14-day sequential treatment is better than 14-day
triple therapy [28]. A retrospective study in children

Page 6 of 8

also concluded that 14-day sequential therapy tended
to be better than 14-day triple treatment. Moreover, anovel 14-day bismuth-based sequential therapy has beenreported in Turkish children with H. pylori infection; itachieved a high eradication rate of 92% [29]. However,
the efficacy and practicality of the above-mentioned new
regimens and adverse antibiotic events need to be further
explored based on antibiotic sensitivity testing.
In this study, we also evaluated symptoms in the children with H. pylori infection. It is worth mentioning that
there was no significant difference in symptom improvement between the two groups of children with or without
H. pylori eradication. A similar result was also reported
in a randomised controlled study [30]. This suggests thatH. pylori infection may not be the main cause of these
symptoms. Therefore, nonspecific clinical manifestations should not be an indication for H. pylori testing anderadication therapy in children. This opinion is also supported by a meta-analysis indicating that the prevalenceof abdominal symptoms was not different between H.
pylori-positive and -negative children [31]. The updated
JSPGHAN 2020 guidelines recommend testing for H.
pylori in children with alarm signs rather than in children
diagnosed with functional abdominal pain. The guidelines also propose that a paediatrician discuss the advantages and disadvantages of eradication therapy before
treatment, in contrast to the ‘test and treat’ principle
used in adults.
A limitation of this study is that antibiotic susceptibility testing was not conducted and that the relationship between antibiotic resistance and the eradication
regimen was absent. Nevertheless, another of our studies performed in the same hospital has provided useful information on the antibiotic resistance of H. pylori
strains. Despite the aforementioned limitation, this study
comprises a randomised controlled trial with few biases
that compared standard triple therapy, bismuth-based
quadruple therapy and sequential therapy in children
with H. pylori infection.

Conclusion
10-day sequential therapy is not recommendable in children with high antibiotic resistance to CLR and MET.
At the same time, the eradication rate of bismuth-based
quadruple therapy was not always superior to that ofstandard triple therapy. The risk factors for bismuth failure in children undergoing H. pylori eradication treatment need further exploration.
Abbreviations
AMO	Amoxicillin
BQT	Bismuth quadruple therapy
CLR	Clarithromycin
MALT	Mucosa-associated lymphoid tissue
MET	Metronidazole
PPIs	Proton pump inhibitors

Miao et al. BMC Pediatrics(2024) 24:543

RUT	Rapid urease test
SIR	Score improvement ratio
ST	Sequential therapy
STT	Standard triple therapy
UBT	C-urea breath test

Page 7 of 8

4.
5.
6.

Supplementary Information

The online version contains supplementary material available at https://doi.
org/10.1186/s12887-024-05020-6.
Supplementary Material 1

7.

8.

Supplementary Material 2
9.
Acknowledgements
We thank all of the children and their parents for their participation in thisstudy.
Author contributions
Drs Ruixue Miao designed the study, followed-up, carried out the data
analyses, drafted the initial manuscript. Shan Gao, Liyuan Wang and Jing Chen
performed gastroscopy, collected specimens, conducted histopathology
examination and made 13 C-urea breath test. Wei Zhou cultured H pylori andtested. Zhiling Wang and Professor Wan designed the study, guided process
and reviewed and revised the manuscript. All authors approved the final
manuscript as submitted and agree to be accountable for all aspects of thework.
Funding
This study was supported by the Research Development Project of Sichuan
Provincial Science and Technology Department (No. 2018SZ0130) and theClinical Research Project of West China Second Hospital, Sichuan University(No. KL039).
Data availability
The authors confirm that the data supporting the findings of this study areavailable within the article.

Declarations
Ethics approval and consents to participate
This randomised controlled study was approved by the Ethical Committeeof West China Second Hospital, Sichuan University, and has been registeredin the China Clinical Trial Center (ChiCTR1900027450, the date of first trail
registration 13/11/2019). Informed consent was obtained from the guardianof each child.

10.
11.
12.
13.
14.

15.

16.
17.
18.
19.
20.

Consent for publication
Not applicable.

21.

Competing interests
The authors declare no competing interests.

22.

Received: 30 April 2024 / Accepted: 19 August 2024

23.
24.

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