Treatment of Helicobacter pylori infection in children: A systematic review

Table 1 Inclusion criteria

Criteria	Description
Date range	January 2010 to April 2020
Language	Only English published articles
Location	No restriction of localization
Population	Children (< 18-years-old)
Type of study	Randomized controlled trials

Table 2 Summary of included studies

Ref.	Year	Country	Study design	Patients, n	Age range	Follow-up	Goal
Moubri et al[22]	2018	Algeria	RCT	272	5-16 yr	8-12 wk	To compare efficacy, side effects and influence of resistance of H. pylori strains between two different treatments in Algerian children.
Namkin et al[23]	2016	Iran	RCT	28	9-12 yr	4-8 wk	To evaluate the effect of S. boulardii supplementation on the eradication of H. pylori in children in the region.
Akcam et al[24]	2015	Turkey	RCT	61	7-18 yr	6 wk	To evaluate the effect of probiotics on eradication rates and side effects in association with standard triple therapy in H. pylori-positive children.
Tolone et al[25]	2012	Italy	RCT	68	4-11 yr	4 wk	To evaluate if addition of probiotics increases eradication rates and reduces side effects in children.
Farahmand et al[26]	2016	Iran	RCT	66	7-15 yr	4 wk	To compare the effect of ciprofloxacin and furazolidone on H. pylori eradication in combination with amoxicillin and omeprazole.
Ahmad et al[27]	2013	Iran	RCT	66	3-14 yr	4-8 wk	To evaluate the effect of probiotic supplementation with the combination of seven microorganisms on the treatment of H. pylori infection in childhood.
Bin et al[28]	2015	China	RCT	205	22 mo-16 yr	2 wk	To investigate the effects of Saccharomyces boulardii CNCM I-745 on eradication of H. pylori in children.
Kasiri et al[29]	2017	Iran	RCT	82	1-15 yr	4 wk	To compare the effect of amoxicillin and metronidazole in the triple therapy regimen to eradicate H. pylori infection in children aged 1 to 15 yr.
Iwańczak et al[30]	2016	Poland	RCT	69	5-17 yr	6-8 wk	To compare the efficacy of sequential therapy for 10 d with triple therapy for 7 d (PPI, amoxicillin and clarithromycin or PPI, amoxicillin and metronidazole) in children.
Tümgör et al[31]	2014	Turkey	RCT	90	10-17 yr	6 wk	To compare the treatment with lansoprazole, amoxicillin and clarithromycin (LAC) and with the combination of LAC + vitamin E (LACE) in Turkish children.
Ali Habib et al[32]	2013	India	RCT	18	12-15 yr	6 wk	To investigate which sequential or standard eradication regimen has the most effective improvement in the status of associated iron and iron deficiency in children.
Ustundag et al[33]	2017	Turkey	RCT	69	6-16 yr	4-6 wk	To evaluate the effects of the use of the symbiotic Bifidobacterium lactis B94 + inulin, together with standard triple therapy on the eradication rate, adherence, as well as in the symptoms of H. pylori infection in children.
Huang et al[34]	2013	China	RCT	360	3-16 yr	4 wk	To compare 10 d sequential therapy and standard triple therapy in Chinese children with H. pylori infection.
N Şirvan et al[35]	2017	Turkey	RCT	104	5-17 yr	4 wk	To evaluate the addition of symbiotics containing Bifidobacterium lactis to triple therapeutics in the rates of side effects, dyspeptic symptoms and H. pylori eradication in children.
Baysoy et al[36]	2013	Turkey	RCT	61	4-18 yr	6-8 wk	To compare ornidazole-based sequential therapy with standard triple therapy for the eradication of H. pylori in children.
Esmaeili-Dooki et al[37]	2015	Iran	RCT	64	2-15 yr	4-6 wk	To evaluate the effect of the classic triple therapy and azithromycin eradication regimen against H. pylori in children.
Laving et al[38]	2013	Kenya	RCT	71	2-15 yr	2-6 wk	To determine the effectiveness of a new 10 d sequential therapy compared to the standard 10 d triple therapy for the treatment of H. pylori infection in children.
Prieto-Jimenez et al[39]	2011	United States of America	RCT	110	3-11 yr	6 wk	To evaluate the efficacy of sequential quadruple eradication therapy for 10 d and observe the iron levels of positive H. pylori children.
Nguyen et al[40]	2012	Vietnam	RCT	232	3–15 yr	4 wk	To investigate the role of antibiotic resistance, drug dosage, and administration frequency in treatment of H. pylori infection in Vietnamese children.
Bontems et al[41]	2011	Belgium, France and Italy	RCT	165	2,7 a 17 yr	8 wk	To compare sequential vs tailored triple therapy regimens on H. pylori eradication rate and to assess the effect of antimicrobial susceptibility in children.

RCTs: Randomized controlled trials. H. pylori: Helicobacter pylori; PPI: Proton pump inhibitor.

Table 3 Criteria analyzed individually in the studies

Ref.	Specific disease	Diagnosis	Groups	Randomization	Loss of follow-up	Level of evidence
Moubri et al[22]	No	Biopsy, RUT, culture, HpSA and 13C-UBT/(Biopsy, RUT, culture, HpSA and 13C-UBT)	2	The method chosen was to classify closed envelopes, which were randomly assigned to treatment	12 patients	1b
Namkin et al[23]	No	HpSA/(HpSA)	2	Limited information on the method used	4 patients	2b
Akcam et al[24]	No	Biopsy, histology, RUT and 13C-UBT/(13C-UBT)	2	Admission order	5 patients	1b
Tolone et al[25]	No	Biopsy, histology, RUT and 14C-UBT/(13C-UBT)	2	No reported	No loss	2b
Farahmand et al[26]	No	Biopsy, RUT and HpSA/(HpSA)	2	Table of aleatory numbers	No loss	1b
Ahmad et al[27]	No	RUT, histology, and HpSA/(HpSA)	2	Limited information on the method used	No loss	1b
Bin et al[28]	No	Immunoglobulin G Antibody, histology and 13C-UBT/(13C-UBT)	2	No reported	14	1b
Kasiri et al[29]	Dyspepsia, epigastric pain and GB	Biopsy, histology and RUT/(HpSA)	2	Limited information on the method used	3	1b
Iwańczak et al[30]	Dyspepsia and gastric and/or duodenal ulcer	Histology and/or culture/(Biopsy and culture)	3	No reported	No loss	1b
Tümgör et al[31]	Dyspepsia.	14C-UBT and histology/(13C-UBT)	2	No reported	2	2b
Ali Habib et al[32]	No	Immunoglobulin G Antibody and 13C-UBT/(13C-UBT)	2	No reported	2	2b
Ustundag et al[33]	Gastrointestinal symptoms, severe regurgitation, gastrointestinal bleeding, unexplained weight loss or chronic diarrhea	Histology/(14C-UBT)	2	Double-blind randomization list	5	2b
Huang et al[34]	No	RUT, HpSA, histology and culture/(HpSA)	3	Limited information on the method used	42	1b
N Şirvan et al[35]	Chronic diseases, abdominal pain and dyspepsia	Histology/(HpSA)	2	Limited information on the method used	No loss	2b
Baysoy et al[36]	No	Histology, RUT, 13C-UBT/(HpSA or Biopsy and histology)	2	Limited information on the method used	8	1b
Esmaeili-Dooki et al[37]	No	Biopsy, histology and HpSA/(13C-UBT)	2	Table of aleatory numbers	No loss	1b
Laving et al[38]	No	Histology and HpSA/(HpSA)	2	Computer-generated random numbers	33	1b
Prieto-Jimenez et al[39]	No	13C-UBT and urine antibody	6	Computer-generated random numbers	20	1b
Nguyen et al[40]	No	Biopsy, RUT, histology and culture	3	No reported	10	1b
Bontems et al[41]	Abdominal pain, nausea, vomiting, heartburn and anemia	Biopsy, histology and culture/(HpSA)	2	No reported	15	1b

The levels of evidence were based in the Oxford Centre for Evidence-based Medicine – Levels of Evidence[43]. All diagnostic methods in brackets were used after treatment to verify Helicobacter pylori (H. pylori) eradication. RUT: Rapid urease test; HpSA: H. pylori monoclonal stool antigen test;

¹³C-UBT: ¹³C-urea breath test;

¹⁴C-UBT: ¹⁴C-urea breath test; GB: Gastrointestinal bleeding.

Table 4 Summary of therapeutic schemes used in included studies

Ref.	Treatment schemes
Moubri et al[22]	Group A - Amoxicillin-based triple therapy: (1) Children > 30 kg: Omeprazole 40 mg/d, amoxicillin 50 mg/kg/d with a maximum of 2 g/d and clarithromycin 15 mg/kg/d for 7 d. All given in two daily doses; and (2) Children < 30 kg: omeprazole 2 × 10 mg/d b.i.d., amoxicillin 50 mg/kg/d b.i.d. with a maximum of 2 g/d, and clarithromycin 15 mg/kg/d b.i.d. for 7 d.
	Group B - Metronidazole-based triple therapy: (1) Children > 30 kg: Omeprazole 2 × 20 mg/d, amoxicillin 50 mg/kg/d b.i.d. with a maximum of 2 g/d and metronidazole 40 mg/kg/d b.i.d. for 10 d; and (2) Children < 30 kg: omeprazole 2 × 10 mg/d, amoxicillin 50 mg/kg/d b.i.d. with a maximum of 2 g/d and metronidazole 40 mg/kg/d b.i.d., for 10 d, with a maximum of 1.5 g/d in children above 30 kg and 1 g/d in children below 30 kg body weight.
Namkin et al[23]	Probiotic group: Yomogi® 250 mg lyophilizate - 1 capsule daily for 30 d.
	Placebo group: placebo capsule 250 mg - lactose and powdered wheat starch - 1 capsule daily for 30 d.
Akcam et al[24]	Standard triple therapy group: Omeprazole 1 mg/kg, before breakfast, amoxicillin 50 mg/kg b.i.d. after meals, clarithromycin 15 mg/kg b.i.d. after meals for 7 d.
	Standard triple therapy group + probiotics: Omeprazole 1 mg/kg, before breakfast + amoxicillin 50 mg/kg b.i.d. after meals, clarithromycin 15 mg/kg b.i.d. after meals, PROBINUL® 5 g once a day for 7 d.
Tolone et al[25]	Standard triple therapy group - lansoprazole 30 mg, before breakfast, amoxicillin 50 mg/kg/d b.i.d., clarithromycin 15 mg/kg/d b.i.d. for 14 d.
	Standard triple therapy group + probiotics: Lansoprazol 30 mg, before breakfast + amoxicillin 50 mg/kg/d b.i.d., clarithromycin 15 mg/kg/d b.i.d., Maflor® plus 1 capsule, b.i.d. for 14 d.
Farahmand et al[26]	Group A - Ciprofloxacin-based triple therapy: Ciprofloxacin 30 mg/kg/d b.i.d. and amoxicillin 50 mg/kg/d b.i.d. for 1 wk. Omeprazole 1 mg/kg/d b.i.d for 4 wk.
	Group B - Furazolidone-based triple therapy: furazolidone 6 mg/kg/d single-dose over and amoxicillin 50 mg/kg/d b.i.d. for 1 wk. omeprazole 1 mg/kg/d b.i.d. for 4 wk.
Ahmad et al[27]	Group A - Triple therapy + placebo: Amoxicillin 50 mg/kg/d b.i.d., as syrup or capsule, and furazolidone 6 mg/kg/d b.i.d. as syrup or tablet for 1 wk. Omeprazole 1 mg/kg/d plus placebo for 4 wk.
	Group B - Triple therapy + probiotics: Amoxicillin 50 mg/kg/d b.i.d., as syrup or capsule, and furazolidone 6 mg/kg/d b.i.d. as syrup or tablet, for 1 wk. Omeprazole 1 mg/kg/d plus placebo for 1 sachet/d for 4 wk.
Bin et al[28]	Group A - Triple therapy + Saccharomyces boulardii: Amoxicillin, omeprazole, clarithromycin and 2 sachet S. boulardii 250 mg per day, for 2 wk. Allergic to penicillin: metronidazole + omeprazole, clarithromycin and S. boulardii (dosages not reported).
	Group B - Only triple therapy: Amoxicillin, omeprazole, clarithromycin. Allergic to penicillin: metronidazole + omeprazole, clarithromycin (dosages not reported).
Kasiri et al[29]	Group A - Amoxicillin-based triple therapy: Omeprazole 1–2 mg/kg b.i.d. for 1 mo. Amoxicillin 50 mg/kg and clarithromycin 15 mg/kg b.i.d. for 2 wk.
	Group B - Metronidazole-based triple therapy: Omeprazole 1 mg/kg b.i.d. divided into two doses for 1 mo. Metronidazole 15 mg/kg and clarithromycin 15 mg/kg b.i.d. for 2 wk.
Iwańczak et al[30]	Group I - Amoxicillin-based triple therapy: Omeprazole, amoxicillin and clarithromycin for 7 d (dosages not reported).
	Group II - Metronidazole-based triple therapy: Omeprazole, amoxicillin and metronidazole for 7 d (dosages not reported).
	Group III - Sequential therapy: omeprazole 1 mg/kg of body weight/d, max 20 mg b.i.d. and amoxicillin 50 mg/kg of body weight/d, max 1000 mg/24 h for 5 d, b.i.d. followed by 5 d treatment with omeprazole 1 mg/kg of body weight/d, max 20 mg/24 h twice daily, clarithromycin 15 mg/kg of body weight/d, max 500 mg/24 h twice daily and metronidazole 20 mg/kg of body weight/d, max 500 mg/24 h twice daily.
Tümgör et al[31]	Group A - Clarithromycin-based triple therapy: Lansoprazole 1 mg/kg/d, amoxicillin 50 mg/kg/d, and clarithromycin 14 mg/kg/d, all medications b.i.d. for 14 d.
	Group B - Clarithromycin-based triple therapy + vitamin E: Lansoprazole 1 mg/kg/d b.i.d., amoxicillin 50 mg/kg/d b.i.d., and clarithromycin 14 mg/kg/d b.i.d., vitamin E 200 IU/d for 14 d.
Ali Habib et al[32]	Group A - Standard therapy: Rabeprazole 20 mg, clarithromycin 250 mg, and amoxicillin 500 mg each administered orally twice daily for 10 d.
	Group B - Sequential therapy: Rabeprazole 20 mg and amoxicillin 500 mg for 5 d, followed by rabeprazole 20 mg clarithromycin 250 mg and tinidazole 500 mg for another 5 d, twice daily.
Ustundag et al[33]	Group A - Standard triple therapy: Amoxicillin 50 mg/kg/d, clarithromycin 15 mg/kg/d twice daily for 14 d and omeprazole 1 mg/kg/d once daily for 1 mo.
	Group B - Standard triple therapy + symbiotic: Amoxicillin 50 mg/kg/d and clarithromycin 15 mg/kg/d twice daily for 14 d. Omeprazole 1 mg/kg/d once daily for 1 mo and Maflor® a single dose for 14 d concurrently.
Huang et al[34]	Group A – 1 d sequential therapy: Omeprazole 0.8–1.0 mg/kg/d, amoxicillin 30 mg/kg/d for the first 5 d, followed by omeprazole 0.8–1.0 mg/kg/d, clarithromycin 20 mg/kg/d, and metronidazole 20 mg/kg/d for the remaining 5 d.
	Group B – 7 d triple standard therapy: Omeprazole 0.8–1.0 mg/kg/d, amoxicillin 30 mg/kg/d, and clarithromycin 20 mg/kg/d.
	Group C – 10 d triple standard therapy: Omeprazole 0.8–1.0 mg/kg/d, amoxicillin 30 mg/kg/d, and clarithromycin 20 mg/kg/d.
N Şirvan et al[35]	Group 1 - Standard triple therapy + symbiotic: Amoxicillin 50 mg/kg/d b.i.d. for 7 d, clarithromycin 15 mg/kg/d b.i.d. for 14 d, and lansoprazole 1 mg/kg/d - single dose, in the morning for 14 d. Maflor® sachet - single dose for 14 d.
	Group 2 - Standard triple therapy: Amoxicillin 50 mg/kg/d b.i.d. for 14 d, clarithromycin 15 mg/kg/d b.i.d. for 14 d, and lansoprazole 1 mg/kg/d - single dose, in the morning for 14 d.
Baysoy et al[36]	Group A - Standard triple therapy: Amoxicillin 50 mg/kg/d, clarithromycin 15 mg/kg/d, and lansoprazole 1 mg/kg/d for 14 d.
	Group B - Sequential therapy group: Amoxicillin 50 mg/kg/d and lansoprazole 1 mg/kg/d for the first 5 d and clarithromycin 15 mg/kg/d, ornidazole 30 mg/kg/d and lansoprazole 1 mg/kg/d for another 5 d.
Esmaeili-Dooki et al[37]	Group 1 - Clarithromycin-based triple therapy: Clarithromycin 7.5 mg/kg/d b.i.d. and amoxicillin 50 mg/kg/d every b.i.d. for 10 d, and omeprazole 1 mg/kg/d b.i.d. for 2 wk.
	Group 2 - Amoxicillin-based triple therapy: Azithromycin 10 mg/kg/d once a day, before meal, for 6 d along with amoxicillin and omeprazole.
Laving et al[38]	Conventional therapy group: Omeprazole plus 1 mg/kg/d, amoxicillin plus 50 mg/kg/d and clarithromycin 15 mg/kg/d for 10 d.
	10 d sequential therapy group: Omeprazole plus 1 mg/kg/d, amoxicillin plus 50 mg/kg/d for 5 d followed by omeprazole plus 1 mg/kg/d, clarithromycin 15 mg/kg/d, and tinidazole 20 mg/kg/d for the next 5 d.
Prieto-Jimenez et al[39]	Group I - Quadruple sequential eradication and placebo: Lansoprazole, once per day before breakfast, plus an oral solution containing amoxicillin 50 mg/kg/d for 5 d followed by lansoprazole, once per day, plus an oral solution containing clarithromycin 15 mg/kg/d and an oral solution containing tinidazole 20 mg/kg/d for another 5 d. 6 wk of a placebo matched to iron supplementation.
	Group II - Quadruple sequential eradication and iron: Lansoprazole, once per day before breakfast, plus an oral solution containing amoxicillin 50 mg/kg/d for 5 d followed by lansoprazole, once per day, plus an oral solution containing clarithromycin 15 mg/kg/d and an oral solution containing tinidazole 20 mg/kg/d for another 5 d. 6 wk of iron supplementation.
	Group III: Iron and placebo: A 10 d course of a placebo matched to H pylori sequential eradication therapy plus 6 wk of iron supplementation.
	Group IV: Placebo alone: A 10 d course of placebo matched to H. pylori sequential eradication therapy plus 6 wk of a placebo matched to iron supplementation.
Nguyen et al[40]	Group A: Lansoprazole, amoxicillin and clarithromycin: (1) Children weighing 13–22 kg: lansoprazole 15 mg once daily, amoxicillin 500 mg twice daily and clarithromycin 250 mg once daily; and (2) Children weighing 23–45 kg: lansoprazole 15 mg, amoxicillin 750 mg and clarithromycin 250 mg, all given twice daily.
	Group B: Lansoprazole, amoxicillin and metronidazole: (1) Children weighing 13-22 kg: lansoprazole 15 mg once daily, amoxicillin 500 mg and metronidazole 250 mg twice daily; and (2) Children weighing 23–45 kg: Lansoprazole 15 mg, amoxicillin 750 mg and metronidazole 500 mg, all given twice daily.
Bontems et al[41]	Group A: 10 d sequential treatment: 5 d therapy with a combination of omeprazole (10 mg b.i.d. below 30 kg body weight or 20 mg b.i.d. above 30 kg) and amoxicillin 25 mg/kg b.i.d.—maximum 2 g/d), followed by 5 d of omeprazole, clarithromycin (7.5 mg/kg b.i.d.—maximum 1 g/d), and metronidazole (10 mg/kg b.i.d.—maximum 1.5 g/d).
	Group B: 7 d triple therapy: 7 d treatment tailored comprising omeprazole and amoxicillin with clarithromycin in cases of H. pylori strains susceptible to clarithromycin or with clarithromycin in cases of H. pylori strains susceptible to metronidazole and resistant to clarithromycin.

H. pylori: Helicobacter pylori.

Table 5 Synthesis of results from included studies

Ref.	Adverse events	Deaths	Eradication rates	Conclusion
Moubri et al[22]	Mild and moderate symptoms, mainly gastrointestinal.	No	(1) ITT: Group A - Amoxicillin - based triple therapy: 68%; Group B - Metronidazole - based triple therapy: 80%; and (2) PP: Group A - Amoxicillin - based triple therapy: 71%; Group B - Metronidazole - based triple therapy: 88%.	The group B eradication rates were higher than Group A rates. The differences were only significant for PP (P < 0.03).
Namkin et al[23]	Loss of appetite.	No	Probiotic group: 0.40 ± 0.32 to 0.21 ± 0.27 average HpSA title; P = 0.005. Placebo group: 0.24 ± 0.2 to 0.24 ± 0.27 average HpSA title; P = 0.89.	There was no significant difference between the two groups in relation to the eradication rate of H. pylori infection (P = 0.16), however the decrease in the concentration of HpSA was significantly greater in the group treated with probiotics (P = 0.005 vs P = 0.89).
Akcam et al[24]	Abdominal pain, nausea, vomiting, constipation, belching, changes in taste, poor appetite and diarrhea.	No	Standard triple therapy group: 68.9%; Standard triple therapy group + probiotics: 66.6%; P = 0.78.	There was no statistically significant difference between the two groups.
Tolone et al[25]	Epigastric pain, nausea, vomiting, diarrhea and constipation.	No	Group A standard therapy group: 76.4%; Group B standard therapy + probiotics: 88.2%; P = 0.1.	There was no significant difference in the rate of H. pylori eradication between group A and group B, however, the side effects were significantly greater (P < 0.05) in group A than in group B.
Farahmand et al[26]	Vomiting, abdominal pain, iron deficiency, anemia and gastrointestinal bleeding.	No	Group A - Ciprofloxacin-based triple therapy: 87.9%; Group B - Furazolidone-based triple therapy: 60.6%; P = 0.011.	This study concludes that triple therapy consisting of ciprofloxacin, amoxicillin and omeprazole is highly valuable as H. pylori is not resistant to the antimicrobials.
Ahmad et al[27]	Diarrhea, nausea, vomiting and abdominal swelling.	No	Group A - Triple therapy + placebo: 69.69%; Group B - Triple therapy + probiotics: 90.09%; P = 0.04.	The group treated with the combination of probiotic and standard therapeutic regimen showed a more significant eradication rate. Supplementation with probiotics has a positive effect on H. pylori and decreases adverse events and effectiveness.
Bin et al[28]	Diarrhea.	11	Group A - Triple therapy + S. boulardii: 71.4%; Group B - Only triple therapy: 61.9%; P = 0.51	The probiotic prevented diarrhea associated with triple H. pylori eradication therapy. In addition, when diarrhea developed, it was less severe and of shorter duration in the S. boulardii group. The probiotic increased the adherence to H. pylori eradication therapy, which may be related to a small increase in H. pylori eradication by 10 percent.
Kasiri et al[29]	Intolerance to clarithromycin.	No	Group A - Amoxicillin-based triple therapy: 87.2%; Group B - Metronidazole-based triple therapy: 92.5%; P = 0.43.	There was no significant difference in the complete recovery and eradication of H. pylori between the two regimens. Both therapeutic regimens were considered to be effective, since both have similar rates of eradication, recovery and side effects.
Iwańczak et al[30]	-	-	Group I - Amoxicillin-based triple therapy: 78.2%; Group II Metronidazole-based triple therapy: 78.2%; Group III - Sequential therapy: 91.3%; P > 0.5.	For strains susceptible to clarithromycin: treatment with amoxicillin-based triple therapy was the most effective. For regions with clarithromycin resistance greater than 20%, quadruple therapy or therapy based on the susceptibility of the strains is recommended.
Tümgör et al[31]	Nausea, headache, vomiting, abdominal pain and diarrhea.	-	Group A - Clarithromycin-based triple therapy: 46.6%; Group B - Clarithromycin-based triple therapy + vitamin E: 64.4%; P = 0.13.	Although, Group B showed a higher rate of eradication, no statistically significant difference was observed between the two groups.
Ali Habib et al[32]	-	No	Group A - Standard therapy: 55.6%; Group B - Sequential therapy: 57.1%; P = 0.949.	The rates of H. pylori eradication were not significantly different in sequential vs standard therapy. In addition, serum ferritin was not significantly different between the two therapies and in the same therapy group before and after treatment.
Ustundag et al[33]	Abdominal pain and nausea.	No	ITT: Group A - Standard triple therapy: 58.8%; Group B - Standard triple therapy + symbiotic: 77.1%; P = 0.16. PP: Group A: 64.5%; Group B: 81.8%; P = 0.19.	The results of the study demonstrated that the addition of Bifidobacterium lactis B94 (5 × 109 CFU/dose) plus inulin once daily to standard triple therapy did not show superiority in eradication rates compared to standard triple therapy administered alone.
Huang et al[34]	Nausea, vomiting and diarrhea.	-	(1) ITT: Group A – 10-d sequential therapy: 81.4%; Group B – 7 d triple standard therapy: 61.9%; Group C – 10 d triple standard therapy: 67.7%; P < 0.05; and (2) PP: Group A – 10 d sequential therapy: 89.7%; Group B – 7 d triple standard therapy: 70.8%; Group C – 10 d triple standard therapy: 77.8%; P < 0.05.	The 10 d sequential regimen was significantly more effective than the 7 or 10 d triple regimens in eradicating Chinese children. In addition, the adverse events between the three groups were also similar, with no statistical differences P > 0.05.
N Şirvan et al[35]	Abdominal pain, nausea and diarrhea.	-	Group 1 - Standard triple therapy + symbiotic: 88%; Group 2 - Standard triple therapy: 72%; P = 0.046.	The rate of eradication was statistically higher in group I. The addition of probiotics to triple therapy is effective in eradicating H. pylori infection in children and is generally useful in reducing or eliminating dyspeptic symptoms, such as abdominal pain, diarrhea and vomiting.
Baysoy et al[36]	Metallic taste sensation, abdominal pain, diarrhea, vomiting, rash, itching.	-	(1) ITT: Group A- Standard triple therapy: 46.0%; Group B - Sequential therapy group: 40.9%; and (2) PP: Group A - Standard triple therapy: 54.2%; Group B - Sequential therapy group: 48.6%.	Sequential ornidazole therapy did not show superiority compared to standard triple treatment in children with H. pylori infection.
Esmaeili-Dooki et al[37]	-	-	(1) ITT: Group 1 - Clarithromycin-based triple therapy: 62.5%; Group 2 - Amoxicillin-based triple therapy: 56.2%; P = 0.4; and (2) PP: Group 1 - Clarithromycin-based triple therapy: 69%; Group 1 - Amoxicillin-based triple therapy: 61.9%; P = 0.431.	The therapeutic response was observed in more than half of the patients treated with triple therapy of the H. Pylori eradication regimen, including azithromycin or clarithromycin, and there was no significant difference between the two treatment groups.
Laving et al[38]	-	-	Conventional therapy Group: 48.8%; 10 d sequential therapy Group: 84.6%; P = 0.02.	The sequential treatment had a significantly higher rate of H. pylori eradication than conventional treatment.
Prieto-Jimenez et al[39]	Abdominal pain, nausea, diarrhea, rash.	No	(1) ITT: Group I - Quadruple sequential eradication and placebo: 44.8%; Group II - Quadruple sequential eradication and iron: 43.7%; Group III: Iron and placebo: 17.4%; Group IV: Placebo alone: 7.7%; P < 0.001; and (2) PP: Group I - Quadruple sequential eradication and placebo: 56.5%; Group II - Quadruple sequential eradication and iron: 50%; Group III: Iron and placebo: 20%; Group IV: Placebo alone: 10.5%; P < 0.001.	A sequential quadruple regimen eradicated H. pylori in only half of asymptomatic children who received this treatment. Eradication rates did not differ between patients who received iron supplementation and those who received placebo.
Nguyen et al[40]	No reported.	No	(1) Group A: Antibiotic sensitive - 79% using high medication dosages, P = 0.278; 75% using lansoprazole twice daily, P = 0.096. Antibiotic resistant - 67.5% using high medication dosages, P = 0.006; 69.2% using lansoprazole twice daily, P = 0.004; and (2) Group B: Antibiotic sensitive - 85.2% using high medication dosages, P = 0.278; 87.5% using lansoprazole Twice daily, P = 0.096. Antibiotic resistant - 45.3% using high medication dosages, P = 0.096; 50.0% using lansoprazole Twice daily, P = 0.004.	The prevalence of resistance to clarithromycin, metronidazole, and amoxicillin was 50.9%, 65.3% and 0.5%, respectively. The two treatment regimens used did not successfully eradicate H. pylori in Vietnamese children, mainly because of the unexpectedly high prevalence of antibiotic resistance.
Bontems et al[41]	Abdominal pain, diarrhea, nausea and vomiting.		(1) ITT: Group A – 10 d sequential treatment: 81.9%; Group B: 7 d triple therapy: 71.9%; and (2) PP: Group B – 10 d sequential treatment: 88.3%, Group B: 7 d triple therapy: 80.8%.	The sequential treatment is greatly effective for eradicating H. pylori in children except in clarithromycin-resistant strains. Sequential treatment can be used as a first-line therapy, but only in areas with a low clarithromycin resistance rate.

ITT: Intention-to-treat; PP: Per protocol; H. pylori: Helicobacter pylori.