Probiotics for the treatment of Helicobacter pylori infection in children

Table 1 Clinical trials in children using probiotics as a complement during Helicobacter pylori eradication treatment

Ref.	Study design	Therapy	Probiotic strain (product; dose; time)	Patients	Diagnosis	No. of treated patients	Eradication n (%); P value	Side effects n (%); P value	Test for confirming eradication (time after completion of therapy)
Sýkora et al[56]	P, R, DB, PC	A (25 mg/kg twice daily), C (7.5 mg/ kg twice daily), and O (10 or 20 mg twice daily) 1 wk + probiotic vs same eradication therapy + placebo	L. casei DN-114 001 1010 CFU in 100 mL of fermented milk (actimel, Danone); 2 wk	86 (aged 9-15 yr) symptomatic children and adolescents	EGDS (histopathology, culture, and RUT) and HpSA	391 362vs 471 442	33 (84.6)1 33 (91.6)2vs 27 (57.5)1; 0.0045 27 (61.3)2; 0.0019	9 (23.1) vs 10 (21.2); NS (nausea, headache, abdominal pain, recurrent vomiting, diarrhoea)	HpSA and 13C-UBT (4 wk)
Gotteland et al[64]	O, R	A (50 mg/kg tid), C (15 mg/kg bid), and L (1 mg/kg bid) 8 d vs Probiotic vs Symbiotic	Lactobacillus acidophilus LB (LB); capsule containing 109 heat-killed and lyophilized LB (Lacteol Forte, Laboratoire du Dr. Boucard, Paris, France); b.i.d. for 8 wk, and Saccharomyces boulardii plus inulin (SbI); sachet containing 250 mg of lyophilized Sb (Perenteryl, Merck Quìmica Chilena, Santiago, Chile); bid for 8 wk	141 (aged 5-12 yr) asymptomatic children. 81 children were observed without any treatment	13C-UBT	452vs 462vs 502	30 (66)2vs 3 (6.5)2vs 6 (12)2; < 0.001 No spontaneous clearance was observed in children without treatment	NA	13C-UBT (1 d)
Goldman et al[58]	R, DB, PC	A (50 mg/kg per day), C (20 mg/kg per day bid), and O (1 mg/kg per day) 1-wk + probiotic vs same eradication therapy + placebo	Bifidobacterium animalis and Lactobacillus casei (107 CFU/mL) in 250 mL of a commercial yogurt; once daily for 3 mo	65 (aged 5-15 yr) symptomatic children and adolescents	EGDS and 13C-UBT (histological data NA)	3312vs 3212	15 (45.5)12vs 12 (37.5)12; 0.345 at 1 mo 14 (42.4)12vs 13 (40.6)1,2; 0.542 at 3 mo	NA	13C-UBT ( 1 and 3 mo)
Lionetti et al[57]	R, DB, PC	O (1 mg/kg/die) plus A (50 mg/kg/die) for 5 d followed by O (1 mg/kg/die) plus C (15 mg/kg/die)and T (20 mg/kg/die) for the next 5 d + probiotic vs same eradication therapy + placebo	L. reuteri [pill containing 108 CFU of L. reuteri ATCC 55730 (SD2112), Reuterin, Nòos]; one pill once daily for a period of 20 d	40 (aged 3.3-18 yr) symptomatic children and adolescents	EGDS (histopathology and RUT) [pangastritis (27); antral gastritis, mild (20); antral gastritis, moderate (14); antral gastritis, severe (10)]	2012vs 2012	17 (85)12vs 16 (80)12; NS	Reduction of GSRS score during eradication therapy [4.1 ± 2 (95%CI: 2.9-5.9) vs 6.2 ± 3 (95%CI: 5.2-8.3); P < 0.01] and at the end of follow-up [3.2 ± 2 (95%CI: 2.4-4) vs 5.8 ± 3.4 (95%CI: 4.8-6.9); P < 0.009]; Epigastric pain (15% vs 45%; P < 0.04); Abdominal distension (0% vs 25%; P < 0.02); Eructation (5% vs 35%; P < 0.04); Disorders of defecation (15% vs 45%; P < 0.04); Halitosis (5% vs 35%; P < 0.04)	13C-UBT (8 wk)
Hurduc et al[60]	O, R	A (50 mg/kg per day, bid) and C (15 mg/kg per day, bid) 7-10 d; O or E (1 mg/kg per day, bid) 3-wk + probiotic vs same eradication therapy + placebo	Saccharomyces boulardii, Enterol, Biocodex, Gentilly Cedex; 250 mg bid; 4-wk	90 (aged 3-18 yr) children and adolescents with dyspepsia	EGDS (histopathology and RUT) [chronic gastritis: mild (8); moderate-to-severe (82); active (32); inactive (58)]	4812vs 4212	45 (93.3)12vs 34 (80.9)12; NS	4 (8.3) vs 13 (30.9); P = 0.047 (bloating, taste disturbance, nausea, abdominal pain, diarrhoea, constipation, loss of appetite, fatigue)	EGDS (4-6 wk) (histopathology and RUT)
Szajewska et al[59]	R, DB, PC	A (50 mg/kg per day bid), C (20 mg/kg per day bid), and O (1 mg/kg per day) 1-wk + probiotic vs same eradication therapy + placebo	Lactobacillus GG 1 × 109 CFU; 7 d	83 (aged 5-17 yr) symptomatic children and adolescents. Excluded from the analysis were 17 children for lack of diary and/or 13C-UBT	EGDS (2 of 3 tests - 13C-UBT, histopathology or RUT) [histological data NA]	342vs 322	23 (69)2vs 22 (68); RR = 0.98 (95%CI: 0.7-1.4)2	Therapy-related diarrhea: 2 (6) vs 6 (20); P = NS Total side effects: 18 (51.4) vs 13 (40.6); P = NS Abdominal pain: 0 vs 0 Nausea: 4 (11.4) vs 3 (9.4); P = NS Vomiting: 2 (5.7) vs 1 (3.1); P = NS Constipation: 2 (5.7) vs 2 (6.2); P = NS Flatulence: 3 (8.6) vs 1 (3.1); P = NS Taste disturbance: 4 (11.4) vs 5 (15.6); P = NS Loss of appetite: 3 (8.6) vs (3.1); P = NS Need for discontinuation of therapy: 0 vs 0	13C-UBT (4 wk)
Tolone et al[61]	R	A (50 mg/kg per day bid), C (15 mg/kg per day bid), and O (1mg/kg per day) 1-wk + probiotic vs same eradication therapy + placebo	Lactobacillus Plantarum 5 × 109, L. reuterii 2 × 109, L. casei subsp. Rhamnosus 2 × 109, Bifidobacterium infantis and B. longum 2 × 109, L. salivarius 1 × 109, L. acidoPhilus 1 × 109, Streptococcus termophilus 5 × 109, and L. sporogenes 1 × 109 + inuline as a prebiotic (5 g/dayose q.d., Probinul , Cadigroup); 7 d	68 (mean age, 8.3 yr) children with heartburn, dyspepsia, nausea and epigastric pain	EGDS (histopathology) [histological data: NA]	3412vs 3412	30 (88.2)12vs 26 (76.4)12; 0.1	Epigastric pain: 2 (5.8) vs 6 (17.6); P < 0.05 Nausea: 1 (2.9) vs 3 (8.8); P < 0.05 Vomiting : 0 vs 2 (5.8); P < 0.05 Diarrhea: 0 vs 8 (23.5); P < 0.05	13C-UBT (4 wk)
Ahmad et al[62]	R, DB, PC	A (50 mg/kg per day bid) and F (6 mg/kg per day bid) 1-wk; O (1 mg/kg per day) 4-wk + probiotic vs same eradication therapy + placebo	Lactobacillus acidophilus, L. rhamnosus, L. bulgaricus, L. casei, Streptococcus thermophilus, Bifidobacterium infantis, B. breve; 1 × 109 CFU/1 sachet, Protexin Co; 4 wk	66 (aged 3-14 yr) children with chronic abdominal pain, gastrointestinal bleeding, unexplained frequent vomiting and unexplained iron deficiency anemia	EGDS (positive RUT or histopathology) [Antral nodularity (57); Gastric erythema (16); Duodenal ulcer (14); Gastric ulcer (1)]	3312vs 3312	30 (90.1)12vs 23 (69.7)12; 0.04	ConstiPation: 2 (5.8) vs 2 (5.8); P = NS Nausea/vomiting: 2 (6.1) vs 9 (27.3); P = 0.02 Diarrea: 2 (6.1) vs 8 (24.2); P = 0.04 Abdominal bloating: 3 (9.1) vs 4 (12.1); P = 1	HpSA (4-8 wk)

¹Intention-to-treat analysis;

²Per-protocol analysis. O: Open; R: Randomized; DB: Double-blind; SB: Single blind; PC: Placebo controlled; P: Prospective; A: Amoxicillin; C: Clarithromycin; F: Furazolidone ; M: Metronidazole; T: Tinidazole; O: Omeprazole; E: Esomeprazole; L: Lansoprazole; CFU: Colony forming units; RUT: Rapid urease test; UBT: Urea breath test; H. Pylori: Helicobacter pylori; HpSA: H. Pylori stool antigens; GSRS: Gastrointestinal symptom rating scale; NA: Not available; L. johnsonii: Lactobacilli johnsonii; L. paracasei: Lactobacilli paracasei.

Table 2 Clinical trials using probiotics in the treatment of Helicobacter pylori infection in children

Ref.	Study design	Probiotic strain (product; dose; time)	Patients	Diagnosis	Eradication	Test for confirming eradication	Comments
					n (%); P value	(time after completion of therapy)
Cruchet et al[63]	DB, R	Lactobacillus johnsonii (La1), living or heat-killed, 80 mL/die, (> 107 CFU/mL) (Chamyto, Nestlé) and L. helveticus (LH) for 4 wk; Lactobacilli paracasei ST11, living or heat-killed, (> 107 CFU/mL) and LH for 4 wk	252 (aged 6-17 yr) asymptomatic children and adolescents: Living La1/LH, n = 511; Heat-killed La1/LH, n = 501; Living ST11/LH, n = 501; Heat-killed ST11/LH, n = 511; LH, n = 501	13C-UBT	A moderate but significant difference in 13C-UBT values was detected in children receiving live La1, whereas no differences were observed in the other groups	13C-UBT (at the end of treatment)
Gotteland et al[65]	R, DB, PC	Lactobacillus johnsonii La1, living or heat-killed, 80 mL/die, (> 107 CFU/mL) for 3 wk (Chamyto, Nestlé) with or without cranberry juice (CB) (200 mL)	271 (aged 6-16 yr) asymptomatic children and adolescents: CB/La1, n = 701; Placebo juice/La1, n = 671; CB/heat-killed La1, n = 651; Placebo juice/heat-killed La1 (control), n = 691	13C-UBT	16 (22.9)1 11 (16.9)1 10 (14.9)1vs 1 (1.5)1; P < 0.01	13C-UBT (a second 13C-UBT at the end of treatment and a third 13C-UBT after 1 mo)	The third UBT was carried out in only 19 of the 38 children found to be H. Pylori-negative in the second UBT: 12, 2, and 5 subjects from the CB/La1, placebo juice/La1, and CB/heat-killed La1 groups, respectively. Only four children (21) remained negative, after 1 mo without treatment: two from the placebo juice/La1 group and two from the CB/La1 group
Boonyaritichaikij et al[66]	SB, PC	Lactobacillus gasseri OLL2716 (LG21), pieces of cheese weighing 1.6-2.0 g, approximately 5 × 108 CFU/g for 1 yr	88 (aged 3-7 yr) asymptomatic children and adolescents completed the eradication arm: LG21, n = 821; ordinary cheese, n = 61 while 222 completed the prevention arm: LG21, n = 1231; Ordinary cheese, n = 991	HpSA	24 (29.3)1vs 0. In the randomized prevention arm: 5 (4.1) vs 8 (8.1); P = 0.21 were HpSA positive at 12 mo	HpSA (1 yr)	A total of 440 asymptomatic children were screened by the HpSA test. Thereafter 132 H. Pylori positive and 308 H. Pylori negative children were recruited to eradication and randomized prevention arms, respectively. Eradication was defined as reversion by HpSA at 12 mo; prevention as persistently HpSA negative at 12 mo

¹Per-protocol analysis. R: Randomized; DB: Double-Blind; SB: Single Blind; PC: Placebo Controlled; CFU: Colony Forming Units;

¹³C-UBT:Urea Breath Test; H. Pylori: Helicobacter pylori; HpSA: H. Pylori stool antigens.