European Journal of Pediatrics

, Volume 173, Issue 2, pp 153–161 | Cite as

Meta-analysis of randomized controlled trials on the efficacy of probiotics in Helicobacter pylori eradication therapy in children

  • Shan Li
  • Xiu-li Huang
  • Jing-zhe Sui
  • Si-yuan Chen
  • Yan-tong Xie
  • Yan Deng
  • Jian Wang
  • Li Xie
  • Tai-jie Li
  • Yu He
  • Qi-liu Peng
  • Xue Qin
  • Zhi-yu Zeng
Review

Abstract

The efficacy of probiotics supplementation in children undergoing Helicobacter pylori (H. pylori) eradication therapy remains controversial. This study aimed to meta-analyze whether probiotics supplementation in triple therapy could improve H. pylori eradication rates and reduce therapy-related side effects in children. Electronic databases PubMed and Embase were searched to identify all randomized controlled trials in pediatric patients comparing probiotics supplementation with placebo or no extra intervention in H. pylori eradication therapy. Two authors independently extracted the data. Results were expressed as odds ratios (ORs) and accompanying 95 % confidence intervals (CIs). Stata version 12.0 was used to perform all statistical analyses. Seven studies consisting of 508 pediatric patients were included in our study. The pooled ORs (studies n = 7) of eradication rates by intention-to-treat and per-protocol analysis in the probiotics group versus the control group were 1.96 (95 % CI 1.28–3.02) and 2.25 (95 % CI 1.41–3.57), respectively. The pooled OR (studies n = 5) of incidence of total side effects was 0.32 (95 % CI 0.13–0.79), with significant heterogeneity observed (I2 = 71.9 %). Conclusion: Probiotics supplementation in triple therapy for H. pylori infection may have beneficial effects on eradication and therapy-related side effects, particularly diarrhea, in children.

Keywords

Helicobacter pylori Eradication Probiotics Children 

Introduction

Helicobacter pylori (H. pylori) infection is a significant public health problem with approximately 50 % prevalence rates of the world population [8]. Acquisition of H. pylori infection is usually in childhood [18], and it has been considered as the main cause of primary duodenal ulcers in children [5] and a key cofactor for developing gastric cancer [32]. Thus, H. pylori eradication therapy is necessary to manage those H. pylori-related complications. Guidelines on the management of H. pylori infection in children have been published, which recommend that children be treated with a twice-daily triple drug regimen comprising a proton pump inhibitor (PPI) plus two antibiotics (amoxicillin or metronidazole plus clarithromycin) [4, 9]. However, with triple regimens, the failure rate for eradication is very common in children (15–35 %) [7, 11, 16, 21, 24]. The most common factors associated with a significant treatment failure rate are poor compliance of patients and antibiotic resistance due to misuse or overuse of antibiotics.

Probiotics have been suggested to be a new choice for the treatment of H. pylori infection in recent years [6, 12]. Numerous studies have been conducted to evaluate the efficacy of probiotics added to anti-H. pylori regimens [2, 22, 23, 26, 34], and several reviews and meta-analyses suggest that probiotics supplementation may be beneficial in improving eradication rates and reducing adverse effects [28, 31, 33]. However, most clinical trials included in the reviews and meta-analyses focus on adult patients; data about pediatric patients is scanty and there is no sufficient evidence to demonstrate that probiotics supplementation has efficacy in children. Recently, there have been an increasing number of trials investigating the role of probiotics supplementation in anti-H. pylori therapy in children. Nevertheless, the results remain controversial due to the relatively small sample size in each individual center of these studies. To evaluate the efficacy of probiotics in H. pylori eradication therapy in children, this meta-analysis of all relevant randomized controlled trials (RCTs) was performed.

Materials and methods

Literature search and selection of studies

Trials were identified by searching the electronic databases PubMed and Embase (up to July 21, 2013). The principal search terms included the following: probiotic, probiotics, yeasts, Streptococcus salivarius, Enterococcus, yogurt, Lactobacillus, Lactococcus, E. coli Nissle, and Helicobacter pylori (H. pylori). No language restriction was applied. Furthermore, a comprehensive manual search of reference lists of the identified articles and key review articles was performed to identify any other potentially eligible trials. We included studies that met the following criteria: (1) only RCTs were included, (2) the study subjects consisted of pediatric patients 1 to 18 years old, (3) studies compared at least two treatment groups consisting of (a) triple regimen (proton pump inhibitor and two antibiotics) with placebo or no extra intervention and (b) the same triple regimen plus probiotics, and (4) H. pylori eradication was confirmed by urea breath test or stool antigen test or histology or rapid urea test at least 4 weeks after eradication therapy.

Data extraction and outcome measures

Two reviewers (Xiu-li Huang and Shan Li) independently extracted the following data from all eligible studies: first author, location of trials, patient characteristics, trial design/Jadad score, the number of enrolled subjects, initial/rechecking methods for confirming H. pylori infection, probiotics regimen, eradication regimen, follow-up time, duration of antibiotic use, and major outcome data. Disagreements were resolved by discussion.

The primary outcome was the eradication rate of H. pylori, and secondary outcomes included incidence of total and specific side effects. The side effects of interest were the common gastrointestinal symptoms that appeared during treatment, including diarrhea, nausea, vomiting, constipation, etc.

Quality assessment

The Jadad scale [15] was used to evaluate the methodological quality of included RCTs. This scale is based on three items describing randomization (0–2 points), blinding (0–2 points), and withdrawals and dropouts (0–1 point). A score of 1 is given for each point described. A further point is gained if the appropriate method of randomization and/or blinding is used. The studies are considered to be of low quality when the score is ≤2 and of high quality when the score is ≥3 [17].

Statistical analysis

Stata version 12.0 (Stata Corporation) was used to perform all statistical analyses. H. pylori eradication rates and incidence of side effects were treated as dichotomous outcomes and expressed as odds ratios (ORs) and accompanying 95 % confidence intervals (CIs) for each study. Eradication rates were analyzed by intention-to-treat (ITT) and per-protocol (PP) analysis, respectively, and incidence of side effects was analyzed by an ITT. We used the I2 statistic to test heterogeneity among studies. An I2 statistic of 25–50 % indicates that low heterogeneity exists among studies, an I2 statistic of 50–75 % indicates that moderate heterogeneity exists, and an I2 statistic of >75 % indicates that high heterogeneity exists [13]. Significant heterogeneity is defined as an I2 statistic of >50 %. Pooled estimates of efficacy were analyzed using a fixed-effects model, and a random-effects model was performed when significant heterogeneity was observed.

Considering inconsistent patient characteristics, probiotics regimens, and other confounding factors across studies, we performed sensitivity analysis to evaluate the stability of our results and explore the possible sources of heterogeneity. Potential publication bias was detected by visually inspecting the funnel plots and using the Begg and Egger tests. Because of the small number of studies and patients for other outcomes, we conducted sensitivity analysis and publication bias assessment only for eradication rates by ITT analysis. A p value <0.05 was regarded to be statistically significant.

Results

Study identification and selection

The initial database search yielded a total of 263 studies. Ninety-six studies were excluded for duplicate studies, and 92 articles were excluded because of publication types. After screened for relevance based on the titles and abstracts, 29 studies were excluded. The remaining 46 potentially appropriate articles were further assessed for more details. Finally, 39 studies were excluded for they did not meet our inclusion criteria, and 7 studies [1, 10, 14, 25, 27, 29, 30] consisting of 508 pediatric patients were included in our study. No additional study was identified by hand searching. The selection process for studies identified is shown in Fig. 1. The baseline characteristics of the seven included studies are summarized in Table 1.
Fig. 1

Selection process for studies included in the meta-analysis. RCT randomized controlled trial

Table 1

Characteristics of included studies

Study and location

Patients

Trial design

Jadad score

Total(probiotics/control)

Initial/rechecking methods for confirming H. pylori infection

Probiotics regimen

Eradication regimen

Days of antibiotics

Follow-up time

% eradication (no. of patients) (probiotics/control)

% incidence of total side effects (no. of patients) (probiotics/control)

Ahmad et al. [1], Iran

H. pylori-positive, symptomatic

Single center, RCT, double-blind, placebo-controlled

4

66(33/33)

RUT, histology/HpSA

Probiotic preparation containing Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Lactobacillus casei, Streptococcus thermophilus, Bifidobacterium infantis, and Bifidobacterium breve 1 × 109 CFU/sachet, q.d. 14 days

O, 1 mg/kg/day; A, 50 mg/kg/day b.i.d; F, 6 mg/kg/day b.i.d

7

4–8 weeks

ITT 90.9 (30/33), PP 90.9 (30/33)/ITT 69.7 (23/33), PP 69.7 (23/33)

ITT 21.2 (7/33)/ITT 63.6 (21/33)

Tolone et al. [30], Italy

H. pylori-positive, symptomatic

Single center, RCT

2

68(34/34)

Histology/UBT

Probiotic formula containing 5 × 109Lactobacillus plantarum, 2 × 109Lactobacillus reuteri, 2 × 109Lactobacillus casei subsp. rhamnosus, 2 × 109Bifidobacterium infantis and Bifidobacterium longum, 1 × 109Lactobacillus salivarius, 1 × 109Lactobacillus acidophilus, 5 × 109Streptococcus thermophilus, and 1 × 109Lactobacillus sporogenes (Lactobacillaceae) 5 g/dose, q.d. 7 days

O, 1 mg/kg/day; A, 50 mg/kg b.i.d.; C, 15 mg/kg b.i.d

7

4 weeks

ITT 88.2 (30/34), PP 88.2 (30/34)/ITT 76.4 (26/34), PP 76.4 (26/34)

ITT 14.7 (5/34)/ITT 61.8 (21/34)

Saneeyan et al. [25], Iran

H. pylori-positive, symptomatic

Single center, RCT, double-blind, placebo-controlled

3

50(25/25)

RUT, histology, UBT/UBT

Protexin containing Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus bulgaricus, Streptococcus, Bifidobacterium bifidum, and Bifidobacterium infantis 1 × 109 CFU/sachet, q.d. 14 days

O, 0.5 mg/kg b.i.d.; A, 25 mg/kg b.i.d; C, 10 mg/kg b.i.d

14

4 weeks

ITT 100 (25/25), PP 100 (25/25)/ITT 92 (23/25), PP 92 (23/25)

NA

Szajewska et al. [29], Poland

H. pylori-positive, symptomatic

Single center, RCT, double-blind, placebo-controlled

5

83(44/39)

UBT, histology, RUT/UBT

Lactobacillus GG at a dose of 109 CFU, b.i.d. 7 days

O, 0.5 mg/kg b.i.d.; A, 25 mg/kg b.i.d.; C, 10 mg/kg b.i.d

7

4–6 weeks

ITT 52.3 (23/44), PP 67.6 (23/34)/ITT 56.4 (22/39), PP 68.7 (22/32)

ITT 45.5 (20/44)/ITT 48.7 (19/39)

Hurduc et al. [14], Romania

H. pylori-positive symptomatic

Single center, RCT

3

90(48/42)

RUT, histology/RUT, histology

Saccharomyces boulardii 250 mg/day, b.i.d. 4 weeks

O or E, 1 mg/kg/day b.i.d; A, 50 mg/kg/day b.i.d; C, 15 mg/kg/day b.i.d

7–10

4–6 weeks

ITT 93.8 (45/48), PP 93.8 (45/48)/ITT 80.9 (34/42), PP 80.9 (34/42)

ITT 8.3 (4/48)/ITT 30.9 (13/42)

Goldman et al. [10], Argentina

H. pylori-positive symptomatic

Single center, RCT, double -blind, placebo-controlled

5

65(33/32)

Histology, UBT/UBT

Commercial yogurt containing Bifidobacterium animalis and Lactobacillus casei at a concentration of 107 CFU/ml, q.d. 3 months

O, 1 mg/kg/day; A, 50 mg/kg/day; C, 15 mg/kg/day

7

3 months

ITT 42.4 (14/33), PP 42.4 (14/33)/ITT 40.6 (13/32), PP 40.6 (13/32)

_

Sykora et al. [27], Czech Republic

H. pylori-positive symptomatic

Multicenter, RCT, double-blind, placebo-controlled

5

86(39/47)

Histology, RUT, culture, HpSA/UBT, HpSA

100 ml fermented milk containing 1010 CFU Lactobacillus casei DN-114001, q.d. 14 days

O, 20 mg/30 kg b.i.d.; A, 25 mg/kg b.i.d.; C, 7.5 mg/kg b.i.d

7

4 weeks

ITT 84.6 (33/39), PP 91.6 (33/36)/ITT 57.5 (27/47), PP 61.3 (27/44)

ITT 17.9 (7/39)/ITT 19.1 (9/47)

A amoxicillin, C clarithromycin, O omeprazole, E esomeprazole, F furazolidone, H. pylori Helicobacter pylori, ITT intention-to-treat, PP per-protocol analysis, RUT rapid urea test, UBT urea breath test, HpSA H. pylori stool antigen test, RCT randomized controlled trial, CFU colony-forming unit, NA not available

The primary outcome: eradication rate

There were seven studies evaluating H. pylori eradication rates. Overall, 508 pediatric patients were included in this analysis (256 in the probiotics group and 252 in the control group). The pooled ORs of eradication rates by ITT analysis and by PP analysis in the probiotics group versus the control group were 1.96 (95 % CI 1.28–3.02) (Fig. 2) and 2.25 (95 % CI 1.41–3.57) by the fixed-effects model (Mantel and Haenszel method), respectively. Low heterogeneity was tested between studies both by ITT analysis (I2 = 35.6 %) (Fig. 2) and by PP analysis (I2 = 34.1 %).
Fig. 2

Meta-analysis of studies evaluating effects of probiotics supplementation on eradication rates by intention-to-treat

In the sensitivity analysis, the overall pooled OR did not materially change even if any single study was excluded, with the results ranging from 1.66 (95 % CI 1.03–2.68) to 2.61 (95 % CI 1.57–4.34). Excluding one low-quality study (Jadad score ≤2), we yielded similar results (OR 1.92, 95 % CI 1.22–3.03) with low heterogeneity (I2 = 45.8 %) [30]. Exclusion of two studies with the duration of probiotics administration to be 4 weeks or longer did not alter the pooled results (OR 2.12, 95 % CI 1.26–3.54), yet low heterogeneity was still present (I2 = 44.4 %) [10, 14]. After exclusion of three studies in which combining probiotic preparation was not used, the results were still maintained (OR 2.03, 95 % CI 1.06–3.88), but there was almost no heterogeneity observed across the remaining studies (I2 = 4.7 %) [14, 27, 29].

The secondary outcomes: side effects

Five studies provided data for incidence of total side effects. The pooled OR of incidence of total side effects in the probiotics group was significantly decreased (OR 0.32, 95 % CI 0.13–0.79) by the random-effects model (Mantel and Haenszel method), with significant heterogeneity observed (I2 = 71.9 %) (Fig. 3). The individual side effects, such as diarrhea and constipation (Fig. 4) and nausea or vomiting (Fig. 5), were also analyzed. Probiotics supplementation reduced the incidence of diarrhea (OR 0.16, 95 % CI 0.06–0.45). Incidence of constipation and nausea/vomiting showed no significant difference between the probiotics group and the control group (OR 0.94, 95 % CI 0.23–3.90; OR 0.39, 95 % CI 0.09–1.77).
Fig. 3

Meta-analysis of studies evaluating effects of probiotics supplementation on the incidence of total side effects

Fig. 4

Meta-analysis of studies evaluating effects of probiotics supplementation on the incidence of diarrhea and constipation

Fig. 5

Meta-analysis of studies evaluating effects of probiotics supplementation on the incidence of nausea/vomiting

Publication bias

Visual inspection of the funnel plot found a slightly asymmetrical distribution (Fig. 6). However, both the Begg and Egger tests suggested that no evidence of substantial publication bias existed among the included trials (Begg test, p = 0.230; Egger test, p = 0.147).
Fig. 6

Funnel plot of included studies for eradication rates

Discussion

Unsatisfactory H. pylori eradication rate and antibiotic-related side effects are two limitations of the first-line triple regimen for H. pylori eradication therapy. Probiotics supplementation has been considered a new choice in anti-H. pylori therapy for it may partially stabilize or restore physiological endogenous microflora and inhibit H. pylori growth. Many clinical trials have suggested that probiotics supplementation might be a good strategy to enhance the effectiveness of anti-H. pylori therapy and to decrease antibiotic-associated side effects. In the recent years, more and more studies have been carried out to investigate this topic in children, but the efficacy of probiotics supplementation in children undergoing H. pylori eradication therapy has not been entirely established. We therefore conducted this meta-analysis of the evidence obtained from seven RCTs to provide a quantitative assessment of the efficacy of probiotics supplementation in H. pylori eradication therapy in children.

In our meta-analysis, the pooled results of seven RCTs using a fixed-effects model indicated that probiotics supplementation with triple therapy regimen improved H. pylori eradication rates in children. In a previous meta-analysis, Tong et al [31] found a pooled OR of 2.36 (95 % CI 1.17–4.76) for eradication rates in children by including two studies [10, 27] for the child subgroup. Our finding is consistent with this analysis. In another previous review, Lionetti et al [19] suggested that there was no sufficient evidence to demonstrate that the addition of probiotics to H. pylori eradication therapy had a positive effect on eradication rates, which seems to contradict our result. They included five studies for analysis, including four studies described here [10, 14, 27, 29]. Our meta-analysis did not include one study that was included in the previous review [20] because probiotics were combined with sequential eradication regimens in the study which did not meet our criteria of triple therapy. Besides, three RCTs published in recent years were included in our analysis [1, 25, 30] resulting in a total of 508 subjects. Furthermore, our meta-analysis provided a quantitative assessment of estimates of efficacy and increased the statistical power.

In the current meta-analysis, exclusion of any single study and sensitivity analysis based on different exclusion criteria did not materially change our pooled results, which added robustness to our main finding. In addition, the difference in quality of studies and duration of probiotics administration seemed to have little influence on the heterogeneity. However, our sensitivity analysis indicated that three studies conducted in children undergoing triple therapy supplemented with single probiotic preparation (not combining probiotic preparation) for H. pylori eradication mainly contributed to the heterogeneity [14, 27, 29].

Side effects are commonly experienced by patients undergoing triple therapy for H. pylori infection, although they may be mild in most cases, usually leading to discontinued therapy [3]. Furthermore, they are generally not well tolerated by children. In our analysis, evidence from five studies for incidence of total side effects through a random-effects model showed that probiotics supplementation had a positive effect on reducing the incidence of total side effects in children. Also, significant heterogeneity was observed across the studies (I2 = 71.9 %). Meanwhile, incidences of the common side effect, diarrhea, were lower in the probiotics group (OR 0.16, 95 % CI 0.06–0.45). Incidences of constipation and nausea/vomiting showed no significant difference between the probiotics group and the control group, but the pooled results were from a limited number of studies. Some factors may lead to heterogeneity, such as the characteristics of patients and the probiotics regimen (species, duration of administration, etc.). Because of the small number of studies and patients, no sensitivity analysis and subgroup analysis were conducted for the incidence of side effects. Therefore, more clinical trials for children are needed to confirm the results.

Several disadvantages in our meta-analysis should be taken into consideration. First, we acknowledge that our meta-analysis is based on only seven RCTs and most of them have a relatively small sample size and is limited by lack of complete availability of relevant data, particularly for the incidence of side effects. Second, there is no standardized protocol of species, dosage, and duration of administration for probiotics supplementation in the studies, which may result in heterogeneity across studies, and it seems that not all probiotics contribute equally to the beneficial effects. Next, patients included in our study were symptomatic, and the effect of probiotics supplementation on asymptomatic patients was not investigated. Additionally, studies included in this meta-analysis did not involve patients from Africa or North America. The above may have a potential impact on the results.

In summary, the current limited evidence suggests that probiotics supplementation in triple therapy for H. pylori infection may have beneficial effects on eradication and therapy-related side effects, particularly diarrhea, in children. However, our results should be interpreted with caution for the heterogeneity across the included studies. Further well-designed and large-scale trials on this topic are needed to confirm these findings. Such future studies should focus on clarifying which probiotic preparation is preferred for pediatric patients, in what dosage and for how long.

Notes

Conflict of interest

The authors declare that they have no conflicts of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Shan Li
    • 1
  • Xiu-li Huang
    • 1
  • Jing-zhe Sui
    • 1
  • Si-yuan Chen
    • 2
  • Yan-tong Xie
    • 3
  • Yan Deng
    • 1
  • Jian Wang
    • 1
  • Li Xie
    • 1
  • Tai-jie Li
    • 1
  • Yu He
    • 1
  • Qi-liu Peng
    • 1
  • Xue Qin
    • 1
  • Zhi-yu Zeng
    • 4
  1. 1.Department of Clinical LaboratoryFirst Affiliated Hospital of Guangxi Medical UniversityNanningChina
  2. 2.Guangxi University of Chinese MedicineNanningChina
  3. 3.Guangxi Medical UniversityNanningChina
  4. 4.Department of GeriatricsFirst Affiliated Hospital of Guangxi Medical UniversityNanningChina

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