Meta-analysis of single strain probiotics for the eradication of Helicobacter pylori and prevention of adverse events

Table 1 Preferred reporting items for systematic reviews and meta-analyses checklist 2009[26]

Item	Topic	Reported on page
Title
1	Title includes systematic review or meta-analysis or both	97
Abstract
2	Structured abstract/summary background, objectives, data sources, eligibility criteria, participant, interventions, appraisal and synthesis methods, results, limitation, conclusions and implication of key findings, systematic review registration number	97
Introduction
3	Rationale for review, what is already known	98
4	Objectives: Specific questions addressed: (PICOS)-participants, interventions, comparisons, outcomes, study design	99
Methods
5	If review protocol (location and accessed URL, registration number)	NA
6	Eligibility criteria (study characteristics (PICOS, follow-up, etc.) and report characteristics (years searched, language, publication status), provide rationale	99
7	Information sources (databases with dates of coverage, contact with study authors to identify additional studies, date last searched)	99
8	Search strategy: Full search strategy for at least one database, including any limits used, such that it could be repeated	99
9	Study selection: (process for screening, eligibility)	99
10	Data collection process: Method of data extraction (piloted forms, independently, in duplicate) and any processes of obtaining and confirming data from investigators)	99
11	Data items: List and define all variables sought (e.g., PICOS, funding sources, etc.) and any assumptions	99-102
12	Risk of bias in individual studies: (Describe methods used for assessing risk of bias (at study or outcome level), how this info is to be used in any data synthesis)	102
13	Summary Measures: State principal summary outcome measures (RR or Difference in means) for pooled estimates of risk	103
14	Synthesis of results: Describe method of handling data and pooling data (measures of consistency with I2 for each meta-analysis)	103
15	Risk for bias across studies: (publication bias)	103
16	Additional analysis: Any subgroup or sensitivity analysis, meta-regression and if pre-specified	103
Results
17	Study selection: N of RCT screened, # assessed for eligibility, reasons for exclusions, with flow diagram	103-104, Figure 2
18	Study characteristics (for each study: study size, PICOS, follow-up with citations)	Table 4
19	Risk of bias within studies: Data on risk for bias and if there, any outcome level assessment (see #12, study quality)	107
20	Results of individual studies: Simple summary data for txt arm, effect estimates and confidence intervals for each study, with forest plot	Figures 3-5 Tables 4, 5
21	Synthesis of results: Data on each meta-analysis, pooled data, 95%CI and measures of consistency	Figures 3-5
22	Risk of bias across studies: results of any assessment of risk across studies (see #15)	Figures 6-8
23	Additional analysis data: if done (see #16, sub-groups)	107
Discussion
24	Summary of evidence: Summarize main findings, strength of evidence for each main outcome. Relevance to key groups (providers, users, policy makers)	110
25	Limitations: Limitations at study level and outcome level (risk of bias), at review-level (incomplete retrieval of identified research, reporting bias)	113
26	Conclusions: General interpretation of results compared to other evidence, implications for future research.	113
Funding
27	Funding: describe funding sources	Not found

The PRISMA Statement. Available from: URL: http://prisma-statement.org/statement.htm. Accessed 7/25/2014.

Table 2 Excluded randomized controlled trials

Probiotic Strain	Reason for exclusion	Ref.
L. gasseri OLL2716	Study quality poor for treatment arm	Boonyaritichaikij et al[37]
L. rhamnosus GG	No H. pylori assay done	Gawrońska et al[38]
L. reuteri ATCC 55730	Outcome was H. pylori burden	Francavilla et al[39]
S. boulardii I-745 or L. acidophilus Lb	No eradication therapy given with probiotic	Gottleland et al[40]
Bifido. bifidum YIT4007	No eradication therapy given with probiotic	Miki et al[41]
L. casei Shirota	No eradication therapy given with probiotic	Cats et al[42]
L. gasseri OLL2716	No eradication therapy given with probiotic	Takagi et al[43]
L. johnsonii Lj1	No eradication therapy given with probiotic	Pantoflickova et al[44]
L. johnsonii Lj1	No eradication therapy given with probiotic	Gottleland et al[45]
L. reuteri ATCC 55730	No eradication therapy given with probiotic	Saggioro et al[46]
Bacillus clausii nr	< 2 RCT with eradication therapy	Nista et al[47]
Bifido. animalis DN173010	< 2 RCT with eradication therapy	Yaşar et al[48]
Bifido. infantis 2036	< 2 RCT with eradication therapy	Dajani et al[49]
L. johnsonii Lc-1	< 2 RCT with eradication therapy	Felley et al[50]
L. casei DN 114001	< 2 RCT with eradication therapy	Sýkora et al[51]
L. casei Shirota	< 2 RCT with eradication therapy	Sahagún-Flores et al[52]

nr: Strain not reported; RCT: Randomized controlled trials.

Table 3 Characteristics of enrolled populations in patients receiving eradication therapy by 28 treatment arms

Probiotic strain	Country	Population	Symptoms	Blinding	Eradicationtherapy	Durationeradication (d)	Ref.
S. boulardii I-745	Italy	Adults	Asymptomatic	Placebo	CTR	7	Cremonini et al[53]
S. boulardii I-745	Turkey	Adults	Symptomatic	None	ACO	14	Duman et al[54]
S. boulardii I-745	Turkey	Adults	Symptomatic	Placebo	ACL	14	Cindoruk et al[55]
S. boulardii I-745	Romania	Pediatric	Symptomatic	Single	AC + O/E	7-21	Hurduc et al[56]
S. boulardii I-745	South Korea	Adults	Symptomatic	Single	ACO	7	Song et al[57]
S. boulardii I-745 + MPA	South Korea	Adults	Symptomatic	Single	ACO	7	Song et al[57]
S. boulardii I-745	Turkey	Adults	Symptomatic	None	ACL	14	Ozdil et al[58]
S. boulardii I-745	China	Adults	Symptomatic	None	ACO	14	Chu et al[59]
S. boulardii I-745	Iran	Adults	Symptomatic	None	ACO	14	Zojaji et al[60]
S. boulardii I-745	Greece	Adults	Symptomatic	Single	ACO	14	Kyriakos et al[61]
S. boulardii I-745	China	Pediatric	Symptomatic	None	ACO	14	Zhao et al[62]
Clost. butyricum 588	China	Adults	Symptomatic	None	AFO	7	Guo et al[63]
Clost. butyricum 588	Japan	Adults	Symptomatic	None	ACL	7	Shimbo et al[64]
Clost. butyricum 588 (low dose)	Japan	Adults	Symptomatic	None	ACL	7	Imase et al[65]
Clost. butyricum 588 (high dose)	Japan	Adults	Symptomatic	None	ACL	7	Imase et al[65]
L. rhamnosus GG	Italy	Adults	Asymptomatic	None	CPT	7	Armuzzi et al[66]
L. rhamnosus GG	Italy	Adults	Asymptomatic	Placebo	CRT	7	Armuzzi et al[67]
L. rhamnosus GG	Italy	Adults	Asymptomatic	Placebo	CRT	7	Cremonini et al[53]
L. rhamnosus GG	Poland	Pediatric	Asymptomatic	Placebo	ACO	7	Szajewska et al[68]
L. rhamnosus GG	Venezuela	Adults	Symptomatic	Placebo	ACO	7	Padilla Ruiz et al[69]
L. acidophilus Lb	Italy	Adults	Symptomatic	None	ACR	7	Canducci et al[70]
L. acidophilus Lb	Italy	Adults	Symptomatic	None	AO	7-30	De Francesco et al[71]
L. acidophilus nr	South Korea	Adults	Mixed	None	ACO	7	Yeom et al[72]
L. reuteri 55730	Italy	Pediatric	Symptomatic	Placebo	AO, COT	15	Lionetti et al[73]
L. reuteri 55730	Italy	Adults	Symptomatic	None	ACT	7	Scaccianoce et al[74]
L. reuteri 55730	Italy	Adults	Symptomatic	None	AELe	7	Ojetti et al[75]
L. casei DG	Italy	Adults	Symptomatic	None	ART (E/P)	10	Tursi et al[76]
L. casei DG	Italy	Adults	nr	None	ACE	7	Giovannone et al[77]

This strain is now designated: Saccharomyces boulardii CNCM I-745. Clostridium butyricum 588 (MIYAIRI). Placebo indicates double-blinded design, single indicates either just patient or outcome assessor was blinded and none indicates an open study. A: Amoxicillin; C: Clarithromycin; E: Esomeprazole; F: Furazolidone; L: Lansoprazole; Le: Levofloxacin; MPA: Mucoprotective agent; nr: Not reported in paper/abstract; O: Omeprazole; P: Pantoprazole; R: Randazole; T: Tindazole.

Table 4 Description of the interventions and Helicobacter pylori eradication rates n (%)

Probiotic strain	Daily dose (cfu/d)	Form	Duration treatment (wk)	Follow-up post-treatment (wk)	H. pylori eradication probiotic	H. pylori eradication in controls	Ref.
S. boulardii I-745	1 × 1010	Sachet	2	5-7	17 (81)	16 (80)	Cremonini et al[53]
S. boulardii I-745	1 × 1010	Capsule	2	4	nr	nr	Duman et al[54]
S. boulardii I-745	2 × 1010	Sachet	2	6	44 (71)	37 (60)	Cindoruk et al[55]
S. boulardii I-745	1 × 1010	Capsule	4	4-6	45 (93.3)	34 (80.9)	Hurduc et al[56]
S. boulardii I-745	2 × 1010	Capsule	4	4	264 (80)a	237 (71.6)	Song et al[57]
S. boulardii I-745 + MPA	2 × 1010	Capsule	4	4	271 (82.1)b	237 (71.6)	Song et al[57]
S. boulardii I-745	5 × 109	Capsule	2	5	71 (72)	82 (86)a	Ozdil et al[58]
S. boulardii I-745	5 × 109	Sachet	2	52	42 (84)a	32 (64)	Chu et al[59]
S. boulardii I-745	1 × 1010	Capsule	2	8	70 (87.5)	65 (81)	Zojaji et al[60]
S. boulardii I-745	6 × 106	Capsule	2	6	30 (83.4)a	20 (58.8)	Kyriakos et al[61]
S. boulardii I-745	1 × 1010	Capsule	2	4	102 (85)c	91 (75.8)	Zhao et al[62]
Clost. butyricum 588	1 × 107	Tablet	1	4	44 (94)	44 (88)	Guo et al[63]
Clost. butyricum 588	3 × 107	Tablet	2	6	17 (94)	13 (76)	Shimbo et al[64]
Clost. butyricum 588 (low dose)	6 × 107	Tablet	1	0	7 (100)	6 (87)	Imase et al[65]
Clost. butyricum 588 (high dose)	1.2 × 108	Tablet	1	0	4 (80)	6 (87)	Imase et al[65]
L. rhamnosus GG	1.2 × 1010	Sachet	2	6	48 (80)	46 (76.6)	Armuzzi et al[66]
L. rhamnosus GG	1.2 × 1010	Sachet	2	6	25 (83)	24 (80)	Armuzzi et al[67]
L. rhamnosus GG	1.2 × 1010	Sachet	2	5-7	16 (76)	16 (80)	Cremonini et al[53]
L. rhamnosus GG	2 × 109	Capsule	1	6	23 (69)	22 (68)	Szajewska et al[68]
L. rhamnosus GG	1.2 × 1010	Liquid	2	0	nr	nr	Padilla Ruiz et al[69]
L. acidophilus Lb	1.5 × 1010	Capsule	1.4	6	52 (87)a	42 (70)	Canducci et al[70]
L. acidophilus Lb	2 × 1010	Capsule	2	4-6	30 (64)	26 (70)	De Francesco et al[71]
L. acidophilus nr	2 × 108	nr	2	4-8	19 (83)	21 (95.5)	Yeom et al[72]
L. reuteri 55730	1 × 108	Tablet	2.9	8	17 (85)	16 (80)	Lionetti et al[73]
L. reuteri 55730	2 × 108	Tablet	1	4-6	9 (53)	10 (62)	Scaccianoce et al[74]
L. reuteri 55730	3 × 108	Liquid	2	6	36 (80)a	27 (60)	Ojetti et al[75]
L. casei DG	1.6 × 1010	Capsule	1.4	4	33 (94.3)	30 (85.7)	Tursi et al[76]
L. casei DG	2 × 1010	nr	4	6	22 (73)	21 (70)	Giovannone et al[77]

^aP < 0.05,

^bP < 0.01,

^cTrend, 0.05 ≤P < 1.0. This strain is now designated: Saccharomyces boulardii CNCM I-745, nr: Not reported; S. boulardii: Saccharomcyes boulardii; L. rhamnosus: Lactobacillus rhamnosus.

Table 5 Prevention of adverse events associated with Helicobacter pylori eradication therapy in 28 treatment arms with adjunct probiotics n (%)

Probiotic strain	Any adverse events in probiotic	Any adverse events in controls	Antibiotic associated diarrhea in probiotic	Antibiotic associated diarrhea in controls	Ref.
S. boulardii I-745	3 (14)b	12 (60)	1 (5)a	6 (30)	Cremonini et al[53]
S. boulardii I-745	3 (1.5)	3 (1.7)	14 (6.9)b	28 (15.6)	Duman et al[54]
S. boulardii I-745	14 (23)b	37 (60)	9 (14.5)a	19 (30.6)	Cindoruk et al[55]
S. boulardii I-745	4 (8)a	13 (31)	nr	nr	Hurduc et al[56]
S. boulardii I-745	48 (14)	63 (19)	9 (3.3)a	20 (6)	Song et al[57]
S. boulardii I-745 + MPA	30 (9)b	63 (19)	11 (3)	20 (6)	Song et al[57]
S. boulardii I-745	nr	nr	nr	nr	Ozdil et al[58]
S. boulardii I-745	8 (16)b	34 (68)	3 (6)	8 (16)	Chu et al[59]
S. boulardii I-745	nr	nr	10 (12.5)a	21 (26)	Zojaji et al[60]
S. boulardii I-745	nr	nr	1 (2.8)a	7 (20.6)	Kyriakos et al[61]
S. boulardii I-745	nr	nr	27 (22.5)b	47 (39.1)	Zhao et al[62]
Clost. butyricum 588	6 (12.8)a	15 (30)	nr	nr	Guo et al[63]
Clost. butyricum 588	nr	nr	1 ( 6)	2 (11.8)	Shimbo et al[64]
Clost. butyricum 588 (low dose)	nr	nr	1 (14)	3 (43)	Imase et al[65]
Clost. butyricum 588 (high dose)	nr	nr	0 (0)	3 (43)	Imase et al[65]
L. rhamnosus GG	26 (43)a	37 (62)	8 (13.2)b	29 (48.2)	Armuzzi et al[66]
L. rhamnosus GG	12 (40)a	20 (66.6)	1 (3.3)b	8 (26.6)	Armuzzi et al[67]
L. rhamnosus GG	3 (15)b	12 (60)	1 (5)	6 (30)	Cremonini et al[53]
L. rhamnosus GG	18 (51)	13 (41)	2 ( 6)	6 (20)	Szajewska et al[68]
L. rhamnosus GG	10 (34)	10 (33)	4 (13.8)	6 (20)	Padilla Ruiz et al[69]
L. acidophilus Lb	6 (10)	6 (10)	nr	nr	Canducci et al[70]
L. acidophilus Lb	nr	nr	nr	nr	De Francesco et al[71]
L. acidophilus nr	4 (15)	5 (19)	nr	nr	Yeom et al[72]
L. reuteri 55730	0 (0)	0 (0)	nr	nr	Lionetti et al[73]
L. reuteri 55730	1 (5.9)c	4 (26.7)	0 (0)a	2 (13)	Scaccianoce et al[74]
L. reuteri 55730	nr	nr	10 (22)b	26 (58)	Ojetti et al[75]
L. casei DG	5 (14.3)a	13 (37)	0 (0)	3 (8.6)	Tursi et al[76]
L. casei DG	nr	nr	nr	nr	Giovannone et al[77]

^aP < 0.05,

^bP < 0.01,

^cTrend, 0.05 ≤P < 1.0. This strain is now designated: Saccharomyces boulardii CNCM I-745. nr: Not reported in paper/abstract. Numbers in table given as frequency and percent (%). S. boulardii: Saccharomcyes boulardii; L. rhamnosus: Lactobacillus rhamnosus.