Efficacy of Lactobacillus rhamnosus GG in treatment of acute pediatric diarrhea: A systematic review with meta-analysis

Table 1 Characteristics of the included trials

Article	Type of article	Age group	Country	Patient source	n (exp/control)	Inclusion criteria	Exclusion criteria	LGG (dosage)	Control group	Duration of intervention	Etiology
Basu et al[25], 2007	RCT; 1 center; Duration: 1 yr	Children	India	Inpatients	323/323	≥ 3 watery stools/day without visible blood or mucus; <10 white blood cells/high-power field and no red cells, mucus flakes, or bacteria on stool microscopy; negative hanging drop preparation; negative bacterial stool culture	Systemic illness other than diarrhea on admission; systemic complications of diarrhea during hospitalization; failure to provide informed consent	120 × 106 ; CFU/day	ORF	7 d	Bacterial diarrhea excluded; Rotavirus-induced diarrhea 75.8%
Basu et al[24], 2009a	RCT; 1 center Duration: 1 yr	Children	India	Inpatients	188/185	≥ 3 watery stools/day without macroscopic blood or mucus, <10 white blood cells/high-power field, and no red blood cells, mucus flakes, or bacteria on stool microscopy; negative hanging drop preparation; negative bacterial stool culture	Symptoms of illness other than diarrhea; development of any systemic complication of diarrhea during hospitalization; failure to provide informed consent	2 × 1010 CFU/day	ORF	7 d or until diarrhea stopped	Bacterial diarrhea excluded; Rotavirus diarrhea 57.1%
Basu et al[24] 2009b	RCT; 1 center Duration: 1 yr	Children	India	Inpatients	186/185	≥ 3 watery stools/day without macroscopic blood or mucus, <10 white blood cells/high-power field, and no red blood cells, mucus flakes, or bacteria on stool microscopy; negative hanging drop preparation; negative bacterial stool culture	Symptoms of illness other than diarrhea; development of any systemic complication of diarrhea during hospitalization; failure to provide informed consent	2 × 1012 CFU/day	ORF	7 d or until diarrhea stopped	Bacterial diarrhea excluded; Rotavirus-induced diarrhea 56.06%
Canani et al[26], 2007	RCT; 6 centers Duration: 12 mo	3-36 mo	Italy	Outpatients	100/92	> 2 loose or liquid stools/day for <48 h	Malnutrition; severe dehydration; coexisting acute systemic illness; immunodeficiency; underlying severe chronic disease; cystic fibrosis; food allergy or other chronic GI diseases; use of probiotics in the previous 3 wk; antibiotics or any other antidiarrheal medication in the previous 3 wk; poor compliance	12 × 109 CFU/day	No details given	5 d	Stool culture in only a few participants and no data presented
Costa et al[27] 2003	RCT; 1 center	Boys, 1-24 mo	Brazil	Inpatients	61/63	Acute diarrhea (3 or more watery or loose stools per 24 h during at least one 24-h period in the 72 h before admission) with moderate or severe dehydration after correction with rapid IV fluids	Systemic infections requiring antibiotics; severe malnutrition (weight for age < 65% of NCHS standards; bloody diarrhea	1010 CFU/day	Inulin 320 mg/day	Unclear	Rotavirus-induced diarrhea 50%; Bloody diarrhea excluded
Czerwionka-Szaflarska et al[28], 2009	RCT; 1 center	Unclear	Poland	Inpatients	50/50	Infants and children with acute infectious diarrhea and failed oral rehydration	Bloody stools; coexisting disease that may influence the course of diarrhea	50 ml/kg/day	Unclear	Unclear	Bloody diarrhea excluded; Rotavirus-induced diarrhea 58%
Schnadower et al[8] 2018	RCT	3-48 mo	United States	University-affiliated PED	483/488	≥ 3 watery stools per day, with or without vomiting, for fewer than 7 d	Pancreatitis, bilious emesis, or hematochezia; a known allergy to L. rhamnosus GG or to microcrystalline cellulose or a known allergy to erythromycin, clindamycin, and beta-lactam antibiotic agents; caregiver did not speak English or Spanish; children receiving antibiotics	1 × 1010 CFU twice daily	Matching placebo	5 d	Norovirus GI or GII 19.6%; Rotavirus 17.7%; Adenovirus 9.1%; Clostridium difficile 7.4%; Shigella 5.0%
Guandalini et al[29], 2000	RCT; multicenter Duration: 1 yr	1-36 mo	Listed as follows	Inpatients and outpatients	147/140	Infants and children with > 4 liquid or semiliquid stools/day for 1 to 5 d	Previous probiotic usage; untreated underlying chronic small bowel disease; inflammatory bowel disease; any underlying chronic disease or immunosuppressive disease or treatment	≥10 × 109 CFU/250 mL/day with ORF	ORF	As tolerated for 4-6 h, then ad libitum	Rotavirus 35%; Bacteria 24%; Parasites 4.5%; No pathogens 34.5%; Bloody diarrhea 8.7%
Guarino et al[30], 1997	RCT; 1 center Duration: 3 mo	3-36 mo	Italy	Outpatients	52/48	Infants and children with ≥ 3 watery stools/day for < 48 h	Antibiotic treatment in the last 3 wk, breastfeeding; a weight: height ratio < the 5th percentile	6 × 109 CFU/day with ORF	ORF	≤5 d	Rotavirus-induced diarrhea 61%
Isolauri et al[31], 1994	RCT; 1 center Duration: not stated	≤ 36 mo	Finland	Inpatients	21/21	Infants and children with > 3 watery stools/day for < 7 d and stools positive for rotavirus; average dehydration of approximately 5% in both groups	Not stated	2 × 1010 CFU/day	No probiotic	5 d	Rotavirus-induced diarrhea 100%
Jasinski et al[32], 2002	RCT; 12 centers Duration: not stated	1-36 mo	Africa Egypt Europe America	Inpatients and outpatients	45⁄52	> 3 watery stools in 12 h or 1 liquid or semiliquid stool with mucus, pus, or blood; < 5 d	Antibiotic or probiotic use in the last 5 d; chronic diseases of the small or large intestine; immunosuppression; phenylketonuria	ORS + LGG 1010 CFU⁄ day	ORS with no LGG	Unclear	Bacterial pathogens 68%; Rotavirus 40.0%; parasites 6%; No pathogens identified: probiotic group 25%
Misra et al[33], 2009	RCT; 1 center Duration: not stated	≤ 36 mo	India	Inpatients	105/ 105	> 3 stools per day (watery or assuming the shape of the container)	Parents refused consent; children living outside the municipal area; bloody diarrhea; severe dehydration; shock, inability to take and retain oral foods; suspected systemic infection	1 × 106-9 CFU/day	Crystalline micro cellulose	Unclear	Rotavirus 25.6%; Bloody diarrhea excluded; White blood cells in stools 14.3%; Bacterial diarrhea 4.7%
Nixon et al[34], 2012	RCT	6-72 mo	United States	PED	77/78	More than 2 loose stools in the last 24 h	Risk factors for non-viral diarrhea (prolonged diarrhea lasting more than 7 d, gross blood, antibiotic exposure, or inflammatory bowel disease); immune compromise; risk factors for probiotic-associated systemic illness or an allergy to milk products	LGG powder twice daily	Inulin	5 d	Unclear
Pant et al[35], 1996	RCT; 1 center Duration: 6 wk	1-24 mo	Thailand	Inpatients	20/19	Infants and children with > 3 watery stools in last 24 h and diarrhea for < 14 d	Exclusive breastfeeding; septicemia	109-10 CFU twice daily	Placebo	2 d	Bloody stools 33.3%; Rotavirus 17.9%; Astrovirus 2.5%
Raza et al[36], 1995	RCT; 1 center Duration: 2 mo	1-24 mo	Pakistan	Inpatients	21/19	Undernourished infants and children with > 3 watery stools in the last 24 h for < 14 d and at least moderate dehydration	Severe malnutrition; septicemia	2 × 1011-12 CFU/day	Placebo	2 d	Bloody diarrhea
Ritchie et al[37], 2010	RCT; 1 center Duration: 21 mo	4-24 mo	Australia	Unclear	33/31	Aboriginal children with acute diarrhea defined as ≥ 3 loose stools during 24 h before presentation for < 7 d and able to tolerate ORF	Oxygen required during the study period; chronic cardiac, renal, or respiratory disease; previous gastrointestinal surgery; proven sucrose intolerance; suspected on known immunodeficiency; probiotic use before enrollment; younger than 4 mo of age	> 15 × 109 CFU/day	Identical placebo	3 d	Bacterial pathogens 12.5%; Rotavirus 8.5%; Parasites 6%
Shornikova et al[38], 1997	RCT; 1 center Duration: 1 yr	1-36 mo	Russia	Inpatients	59/64	≥ 1 watery stool in the last 24 h and diarrhea for < 5 d	Not stated	1010 CFU/day	Placebo	5 d	Rotavirus 27.4%; Bacterial diarrhea 21%
Sindhu et al[39], 2014	RCT	6-60 mo	India	Unclear	65/59	Diarrhea was defined as ≥ 3 loose watery stools within a 24-h period	Coinfections (the presence of both rotavirus and Cryptosporidium); severe malnutrition; probiotic consumption in the preceding month; allergy to probiotics; acute abdomen or colitis	1010 CFU and 170 mg of microcrystalline /day cellulose	170 mg of cellulose	4 wk	Rotavirus 52.4%; Cryptosporidium species 47.6%
Sunny et al[40] 2014	Open-label RCT	6-60 mo	India	OPD or PED	100/100	Passage of three or more loose stools in the last 24 h	Severe malnutrition; dysentery; clinical evidence of coexisting acute systemic illnesses; clinical evidence of chronic disease; probiotic use in the preceding three weeks; antibiotic use	1 × 1010 CFU per day	ORS and zinc 20 mg/d	5 d	Rotavirus 24.1%

The study of Guandalini et al[29] was conducted in Poland, Pakistan, Egypt, Croatia, Italy, Slovenia, Netherlands, Greece, Israel, the United Kindom, and Portugal. RCT: Randomized controlled trial; PED: Pediatric emergency department; OPD: Outpatient department; LGG: Lactobacillus rhamnosus GG.