Ann Allergy Asthma Immunol 113 (2014) 217e226
Contents lists available at ScienceDirect
Effects of probiotics for the treatment of atopic dermatitis: a meta-analysis of randomized controlled trials Soo-Ok Kim, MS *; Young-Mi Ah, PhD Candidate y; Yun Mi Yu, PhD Candidate *; Kyung Hee Choi, MS z; Wan-Gyoon Shin, PharmD, PhD *; and Ju-Yeun Lee, PhD y * College
of Pharmacy, Seoul National University, Seoul, South Korea College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, South Korea z College of Pharmacy, Suncheon University, Suncheon, Joellanam-do, South Korea y
A R T I C L E
I N F O
Article history: Received for publication March 19, 2014. Received in revised form May 22, 2014. Accepted for publication May 27, 2014.
A B S T R A C T
Background: The effects of probiotics on the treatment of atopic dermatitis (AD) are inconclusive. Objective: To determine the clinical effect of probiotics in the management of AD overall and in different age groups. Methods: A comprehensive search of databases through December 2013 was performed. For this metaanalysis, randomized controlled trials measuring the treatment effects of probiotics or synbiotics in patients diagnosed with AD were included. The primary outcome was a difference in Scoring of Atopic Dermatitis (SCORAD) values between the treatment and placebo groups overall and in different age populations. Results: Twenty-five randomized controlled trials (n ¼ 1,599) were available for this meta-analysis. Significant differences in SCORAD values favoring probiotics over the control were observed overall (mean 4.51, 95% confidence interval 6.78 to 2.24), in children 1 to 18 years old (5.74, 95% confidence interval 7.27 to 4.20), and in adults (8.26, 95% confidence interval 13.28 to 3.25). However, the effectiveness of probiotics in infants (5 109 cfu twice daily Bifidobacterium (BB)/synbiotics 1.3 109 cfu/100 mL
Gore et al, 201224 (UK)
3e6 mo
87/46
moderate/25.4 (22.1e29), 25.9 (22.8e29.2) vs 26.9 (23.4e30.6)i
Lactobacillus (LP) or Bifidobacterium (BL)/d; 1 1010 cfu
mild/24 (20.6e26.7) vs 24.9 (20.7e28.9)d
mixture (LP þ LA þ BL)/d; 3.9 108 þ 2.9 104 þ 5.9 104 cfu/g twice daily Bifidobacterium (BB)/d; 1 1010 cfu twice daily
Passeron et al, 200631 (France)
Infants (18 y) Roessler et al, 200834 (Germany)
Yoshida et al, 201039 (Japan)
23 yk
20e65 y
8/7
16/8
moderate/41.0 (18) vs 25.7 (6.6)e
6
12 12
8
12
12
12 12
12
positive effect of probiotics was seen only in allergic subjects (P ¼ .04) no significant difference between synbiotics and placebo positive effect of probiotics was seen only in food-sensitized children (P ¼ .047) greater SCORAD decrease in probiotic group than placebo group (P ¼ .001) decrease in SCORAD score was greater in probiotic group than in placebo group (P ¼ .008) significantly lower SCORAD value at 8 wk of treatment in synbiotic group than in placebo group (P ¼ .022) greater SCORAD decrease in probiotic group than in placebo group (P ¼ .0015) greater SCORAD decrease in probiotic group than in placebo group (P ¼ .004) greater SCORAD decrease in probiotic group than in placebo group (P ¼ .02) positive effect of probiotics was seen only in IgE-sensitized infants (P ¼ .036) no significant difference between probiotics and placebo no significant difference between probiotics and placebo positive effect of synbiotics was seen only in IgE-sensitized infants (P ¼ .04) no significant difference between probiotics and placebo
8
no significant effects of probiotics
8
objective SCORAD decrease was significant in probiotic group (P ¼ .034); placebo group showed no change
S.-O. Kim et al. / Ann Allergy Asthma Immunol 113 (2014) 217e226
1e13 y
NA
31/15
moderate/46.3 (3.7) vs 45.0 (2.6)j
mixture (LS2 þBB)/d; 1 109 cfu twice daily
12
Drago et al, 201242 (Italy)
18e46 y
19/19
moderate/27.6 (3.4) vs 24.3 (3.5)j
Lactobacillus (LS2)/d; 1 109 cfu twice daily
16
2.5e15.7 mo
13/14
moderate/26 (17e38) vs 21 (14e31)c
Lactobacillus (LGG)/d; 5 108 cfu/g formula (500e1,000 mL)
4
Weston et al, 200530 (Australia)
6e18 mo
26/27
moderate/40.8 (6.8) vs 44.0 (10.4)e
Lactobacillus (LF)/d; 1 109 cfu twice daily
8
Fölster-Holst et al, 200621 (Germany) Chernyshov, 200935 (Ukraine)
1e55 mo
26/27
moderate/43.3 (2.4) vs 41.4 (2.7)j
8
2e48 mo
30/28
moderate/34.2 (3.8) vs 36.9 (4.0)e
Lactobacillus (LGG)/d; 5 109 cfu twice daily Lactobacillus (LR 95%, LH 5%)/d; 2 109 cfu/d
Cukrowska et al, 201037 (Poland)
2.5e20 mo
27/28
moderate/35.4 (24.1) vs 33.5 (18.1)e
Lactobacillus (LC þ LP)/d; 1 109 cfu/d
12
Gobel et all, 201036 (Denmark)
18 mok
34/16
mild/20.6 (13.1), 22.5 (11.0) vs 20.2 (8.3)e
8
19/21
NA
Lactobacillus (LA) or Bifidobacterium (BL)/d; 1 1010 cfu/d mixturel/synbiotics; 109 cfu twice daily
Age group not classified Majamaa and Isolauri, 199727 (Finland)
Farid et al, 201114 (Iran)
3e72 mo
4.3
8
greater SCORAD decrease in probiotic group than in placebo group (P < .001) SCORAD decrease significant in probiotic group (P < .001); placebo group showed no change SCORAD score improvement in LGG group (P ¼ .008) but not in placebo group (P ¼ .89) greater SCORAD decrease in probiotic group than in placebo group (P ¼ .03) no significant difference between probiotics and placebo significant decrease of SCORAD in subjects who did not use topical steroids was shown only in probiotic group (P < .01) induced clinical improvement mainly in children with IgEdependent atopic eczema no overall beneficial effects of probiotics greater SCORAD decrease in synbiotic group than in placebo group (P ¼ .001)
Abbreviations: AD, atopic dermatitis; BB, Bifidobacteria breve; BB2, Bifidobacterium bifidum; BL, Bifidobacteria lactis; BW, body weight; cfu, colony-forming units; LA, Lactobacillus acidophilus; LC, Lactobacillus casei; LF, Lactobacillus fermentum; LGG, Lactobacillus rhamnosus strain GG or Lactobacillus GG; LH, Lactobacillus helveticus; LP, Lactobacillus paracasei; LP2, Lactobacillus plantarum; LR, Lactobacillus rhamnosus; LR2, Lactobacillus reuteri; LS, Lactobacillus sakei; LS2, Lactobacillus salivarius; NA, not available; SCORAD, Scoring of Atopic Dermatitis. a Crossover study. Data from the first 6 weeks of treatment were used. b Median (range). c Median (interquartile range). d Geometric mean (95% confidence interval). e Mean (SD). f Infants treated with heat-inactivated LGG were not included in the meta-analysis. g Interquartile range. h LGG 5 109 cfu, LR 5 109 cfu, BB 2 108 cfu, and Propionibacterium freudenreichii 2 109 cfu. i De-transformed mean of square rootetransformed data (95% confidence interval). j Mean (SEM). k Mean. l LC, LR, Streptococcus thermophiles; BB, LA, Bifidobacteria infantis; and Lactobacillus bulgaricus.
S.-O. Kim et al. / Ann Allergy Asthma Immunol 113 (2014) 217e226
Iemoli et al, 201243 (Italy)
221
222
S.-O. Kim et al. / Ann Allergy Asthma Immunol 113 (2014) 217e226
Table 2 Methodologic quality of the trials by Jadad scale and quality assessment of controlled clinical trials Study
Jadad scale
Quality assessment of controlled clinical trials
Representation Appropriateness Representation Appropriateness Representation Total Generation of Concealment Patient ITT of of method for of double of method for of score allocation adequate blinding performed randomization randomization blinding double blinding withdrawals sequences adequate Majamaa and Isolauri, 1997 Kirjavainen et al, 2003 Rosenfeldt et al, 2003 Viljanen et al, 2005 Weston et al, 2005 Brouwer et al, 2006 Fölster-Holst et al, 2006 Passeron et al, 2006 Sistek et al, 2006 Gruber et al, 2007 Rossler et al, 2008 Chernyshov et al, 2009 Cukrowska et al, 2010 Gerasimov et al, 2010 Gobel et al, 2010 van der Aa et al, 2010 Woo et al, 2010 Yoshida et al, 2010 Drago et al, 2011 Farid et al, 2011 Wu et al, 2011 Gore et al, 2012 Han et al, 2012 Iemoli et al, 2012 Yesilova et al, 2012
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
0 0 1 1 1 0 0 1 1 1 0 1 0 1 0 1 0 0 1 0 1 0 1 0 1
1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 1 1 1 1
1 1 1 1 1 0 0 1 1 1 1 0 0 1 0 1 1 1 1 1 1 0 1 0 1
0 0 1 1 1 1 1 1 1 1 1 1 0 1 0 1 1 1 1 1 1 1 1 1 1
3 3 5 5 5 3 3 3 5 5 4 1 2 5 2 5 4 4 5 4 5 3 5 3 5
unclear unclear yes yes yes unclear unclear unclear yes yes unclear no unclear yes unclear yes unclear unclear yes unclear yes yes yes unclear yes
unclear unclear yes yes yes unclear unclear unclear yes yes yes unclear yes yes unclear yes unclear yes yes unclear yes yes yes unclear yes
yes yes yes yes yes yes yes yes yes yes yes unclear yes yes yes yes yes yes yes yes yes yes yes yes yes
no yes no no yes yes yes no yes yes yes yes no yes unclear yes no yes yes no yes yes yes yes yes
Abbreviation: ITT, intention to treat.
the IgE-sensitized subjects over the placebo group. The other studies showed a significant decrease in SCORAD value only in IgE-sensitized subjects and not in the placebo group. Sensitivity Analysis of Studies Including Only High-Quality Trials To take into account the effect of study quality on the outcome of this analysis, each trial was evaluated according to the Jadad score and categorized as high or low. The 22 trials that scored at least 3 were categorized as high, and the other 3 trials with scores of 1 or 2 were categorized as low.35e37 The exclusion of low-quality trials showed similar results to those of the overall result (WMD 5.02, 95% CI 7.48 to 2.56, P < .001, I2 ¼ 88%), implying the robustness of this meta-analysis. Also, in the children population, similar significant effects were maintained after excluding 1 study with a Jadad score of 331 (WMD 5.79, 95% CI 7.33 to 4.24, P < .001, I2 ¼ 37%).
Adverse Events of Probiotics Of the 25 trials included in this meta-analysis, 9 trials reported adverse events (AEs).14,16,23,26,29,31,32,34,40 However, in a study by Kirjavainen et al,28 AEs were noticed only in a group using a heatinactivated Lactobacillus rhamnosus strain GG. In other studies, most AEs were associated with gastrointestinal symptoms (eg, diarrhea, vomiting) and did not show any significant differences in the incidence of AEs between the probiotic and placebo groups. The reported AEs other than gastrointestinal symptoms were fever, infections, skin disorders, wheezing, and coughing. Some studies reported serious AEs, such as acute enteritis, eczema herpeticatum, food poisoning, and respiratory syncytial virus bronchiolitis.13,15,33 However, it was mentioned that these events were not associated with the study medication. The incidence of AEs varied among studies, from 30.7% to 91.1% in the probiotic group. Discussion
Figure 2. Funnel plot of SE by weighted mean difference. Each dot represents 1 trial.
The present meta-analysis of 25 RCTs suggests that the administration of probiotics might have a positive effect on the treatment of AD. Although the result of a 4.51-point difference in SCORAD value for the overall subject population was greater than that of a previous meta-analysis,18 its clinical significance is still questionable. In addition, the authors could not conclude the positive effect of probiotics in the overall subject population owing to the high heterogeneity among studies. However, from the current study, we could conclude the positive effect of probiotics on the treatment of AD in children (1e18 years old) and adults based on the analysis of clinical trial results that were stratified by age of participants and had low heterogeneity. Conversely, the current evidence does not favor the use of probiotics in infants (
Contents lists available at ScienceDirect
Effects of probiotics for the treatment of atopic dermatitis: a meta-analysis of randomized controlled trials Soo-Ok Kim, MS *; Young-Mi Ah, PhD Candidate y; Yun Mi Yu, PhD Candidate *; Kyung Hee Choi, MS z; Wan-Gyoon Shin, PharmD, PhD *; and Ju-Yeun Lee, PhD y * College
of Pharmacy, Seoul National University, Seoul, South Korea College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, South Korea z College of Pharmacy, Suncheon University, Suncheon, Joellanam-do, South Korea y
A R T I C L E
I N F O
Article history: Received for publication March 19, 2014. Received in revised form May 22, 2014. Accepted for publication May 27, 2014.
A B S T R A C T
Background: The effects of probiotics on the treatment of atopic dermatitis (AD) are inconclusive. Objective: To determine the clinical effect of probiotics in the management of AD overall and in different age groups. Methods: A comprehensive search of databases through December 2013 was performed. For this metaanalysis, randomized controlled trials measuring the treatment effects of probiotics or synbiotics in patients diagnosed with AD were included. The primary outcome was a difference in Scoring of Atopic Dermatitis (SCORAD) values between the treatment and placebo groups overall and in different age populations. Results: Twenty-five randomized controlled trials (n ¼ 1,599) were available for this meta-analysis. Significant differences in SCORAD values favoring probiotics over the control were observed overall (mean 4.51, 95% confidence interval 6.78 to 2.24), in children 1 to 18 years old (5.74, 95% confidence interval 7.27 to 4.20), and in adults (8.26, 95% confidence interval 13.28 to 3.25). However, the effectiveness of probiotics in infants (5 109 cfu twice daily Bifidobacterium (BB)/synbiotics 1.3 109 cfu/100 mL
Gore et al, 201224 (UK)
3e6 mo
87/46
moderate/25.4 (22.1e29), 25.9 (22.8e29.2) vs 26.9 (23.4e30.6)i
Lactobacillus (LP) or Bifidobacterium (BL)/d; 1 1010 cfu
mild/24 (20.6e26.7) vs 24.9 (20.7e28.9)d
mixture (LP þ LA þ BL)/d; 3.9 108 þ 2.9 104 þ 5.9 104 cfu/g twice daily Bifidobacterium (BB)/d; 1 1010 cfu twice daily
Passeron et al, 200631 (France)
Infants (18 y) Roessler et al, 200834 (Germany)
Yoshida et al, 201039 (Japan)
23 yk
20e65 y
8/7
16/8
moderate/41.0 (18) vs 25.7 (6.6)e
6
12 12
8
12
12
12 12
12
positive effect of probiotics was seen only in allergic subjects (P ¼ .04) no significant difference between synbiotics and placebo positive effect of probiotics was seen only in food-sensitized children (P ¼ .047) greater SCORAD decrease in probiotic group than placebo group (P ¼ .001) decrease in SCORAD score was greater in probiotic group than in placebo group (P ¼ .008) significantly lower SCORAD value at 8 wk of treatment in synbiotic group than in placebo group (P ¼ .022) greater SCORAD decrease in probiotic group than in placebo group (P ¼ .0015) greater SCORAD decrease in probiotic group than in placebo group (P ¼ .004) greater SCORAD decrease in probiotic group than in placebo group (P ¼ .02) positive effect of probiotics was seen only in IgE-sensitized infants (P ¼ .036) no significant difference between probiotics and placebo no significant difference between probiotics and placebo positive effect of synbiotics was seen only in IgE-sensitized infants (P ¼ .04) no significant difference between probiotics and placebo
8
no significant effects of probiotics
8
objective SCORAD decrease was significant in probiotic group (P ¼ .034); placebo group showed no change
S.-O. Kim et al. / Ann Allergy Asthma Immunol 113 (2014) 217e226
1e13 y
NA
31/15
moderate/46.3 (3.7) vs 45.0 (2.6)j
mixture (LS2 þBB)/d; 1 109 cfu twice daily
12
Drago et al, 201242 (Italy)
18e46 y
19/19
moderate/27.6 (3.4) vs 24.3 (3.5)j
Lactobacillus (LS2)/d; 1 109 cfu twice daily
16
2.5e15.7 mo
13/14
moderate/26 (17e38) vs 21 (14e31)c
Lactobacillus (LGG)/d; 5 108 cfu/g formula (500e1,000 mL)
4
Weston et al, 200530 (Australia)
6e18 mo
26/27
moderate/40.8 (6.8) vs 44.0 (10.4)e
Lactobacillus (LF)/d; 1 109 cfu twice daily
8
Fölster-Holst et al, 200621 (Germany) Chernyshov, 200935 (Ukraine)
1e55 mo
26/27
moderate/43.3 (2.4) vs 41.4 (2.7)j
8
2e48 mo
30/28
moderate/34.2 (3.8) vs 36.9 (4.0)e
Lactobacillus (LGG)/d; 5 109 cfu twice daily Lactobacillus (LR 95%, LH 5%)/d; 2 109 cfu/d
Cukrowska et al, 201037 (Poland)
2.5e20 mo
27/28
moderate/35.4 (24.1) vs 33.5 (18.1)e
Lactobacillus (LC þ LP)/d; 1 109 cfu/d
12
Gobel et all, 201036 (Denmark)
18 mok
34/16
mild/20.6 (13.1), 22.5 (11.0) vs 20.2 (8.3)e
8
19/21
NA
Lactobacillus (LA) or Bifidobacterium (BL)/d; 1 1010 cfu/d mixturel/synbiotics; 109 cfu twice daily
Age group not classified Majamaa and Isolauri, 199727 (Finland)
Farid et al, 201114 (Iran)
3e72 mo
4.3
8
greater SCORAD decrease in probiotic group than in placebo group (P < .001) SCORAD decrease significant in probiotic group (P < .001); placebo group showed no change SCORAD score improvement in LGG group (P ¼ .008) but not in placebo group (P ¼ .89) greater SCORAD decrease in probiotic group than in placebo group (P ¼ .03) no significant difference between probiotics and placebo significant decrease of SCORAD in subjects who did not use topical steroids was shown only in probiotic group (P < .01) induced clinical improvement mainly in children with IgEdependent atopic eczema no overall beneficial effects of probiotics greater SCORAD decrease in synbiotic group than in placebo group (P ¼ .001)
Abbreviations: AD, atopic dermatitis; BB, Bifidobacteria breve; BB2, Bifidobacterium bifidum; BL, Bifidobacteria lactis; BW, body weight; cfu, colony-forming units; LA, Lactobacillus acidophilus; LC, Lactobacillus casei; LF, Lactobacillus fermentum; LGG, Lactobacillus rhamnosus strain GG or Lactobacillus GG; LH, Lactobacillus helveticus; LP, Lactobacillus paracasei; LP2, Lactobacillus plantarum; LR, Lactobacillus rhamnosus; LR2, Lactobacillus reuteri; LS, Lactobacillus sakei; LS2, Lactobacillus salivarius; NA, not available; SCORAD, Scoring of Atopic Dermatitis. a Crossover study. Data from the first 6 weeks of treatment were used. b Median (range). c Median (interquartile range). d Geometric mean (95% confidence interval). e Mean (SD). f Infants treated with heat-inactivated LGG were not included in the meta-analysis. g Interquartile range. h LGG 5 109 cfu, LR 5 109 cfu, BB 2 108 cfu, and Propionibacterium freudenreichii 2 109 cfu. i De-transformed mean of square rootetransformed data (95% confidence interval). j Mean (SEM). k Mean. l LC, LR, Streptococcus thermophiles; BB, LA, Bifidobacteria infantis; and Lactobacillus bulgaricus.
S.-O. Kim et al. / Ann Allergy Asthma Immunol 113 (2014) 217e226
Iemoli et al, 201243 (Italy)
221
222
S.-O. Kim et al. / Ann Allergy Asthma Immunol 113 (2014) 217e226
Table 2 Methodologic quality of the trials by Jadad scale and quality assessment of controlled clinical trials Study
Jadad scale
Quality assessment of controlled clinical trials
Representation Appropriateness Representation Appropriateness Representation Total Generation of Concealment Patient ITT of of method for of double of method for of score allocation adequate blinding performed randomization randomization blinding double blinding withdrawals sequences adequate Majamaa and Isolauri, 1997 Kirjavainen et al, 2003 Rosenfeldt et al, 2003 Viljanen et al, 2005 Weston et al, 2005 Brouwer et al, 2006 Fölster-Holst et al, 2006 Passeron et al, 2006 Sistek et al, 2006 Gruber et al, 2007 Rossler et al, 2008 Chernyshov et al, 2009 Cukrowska et al, 2010 Gerasimov et al, 2010 Gobel et al, 2010 van der Aa et al, 2010 Woo et al, 2010 Yoshida et al, 2010 Drago et al, 2011 Farid et al, 2011 Wu et al, 2011 Gore et al, 2012 Han et al, 2012 Iemoli et al, 2012 Yesilova et al, 2012
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
0 0 1 1 1 0 0 1 1 1 0 1 0 1 0 1 0 0 1 0 1 0 1 0 1
1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 1 1 1 1
1 1 1 1 1 0 0 1 1 1 1 0 0 1 0 1 1 1 1 1 1 0 1 0 1
0 0 1 1 1 1 1 1 1 1 1 1 0 1 0 1 1 1 1 1 1 1 1 1 1
3 3 5 5 5 3 3 3 5 5 4 1 2 5 2 5 4 4 5 4 5 3 5 3 5
unclear unclear yes yes yes unclear unclear unclear yes yes unclear no unclear yes unclear yes unclear unclear yes unclear yes yes yes unclear yes
unclear unclear yes yes yes unclear unclear unclear yes yes yes unclear yes yes unclear yes unclear yes yes unclear yes yes yes unclear yes
yes yes yes yes yes yes yes yes yes yes yes unclear yes yes yes yes yes yes yes yes yes yes yes yes yes
no yes no no yes yes yes no yes yes yes yes no yes unclear yes no yes yes no yes yes yes yes yes
Abbreviation: ITT, intention to treat.
the IgE-sensitized subjects over the placebo group. The other studies showed a significant decrease in SCORAD value only in IgE-sensitized subjects and not in the placebo group. Sensitivity Analysis of Studies Including Only High-Quality Trials To take into account the effect of study quality on the outcome of this analysis, each trial was evaluated according to the Jadad score and categorized as high or low. The 22 trials that scored at least 3 were categorized as high, and the other 3 trials with scores of 1 or 2 were categorized as low.35e37 The exclusion of low-quality trials showed similar results to those of the overall result (WMD 5.02, 95% CI 7.48 to 2.56, P < .001, I2 ¼ 88%), implying the robustness of this meta-analysis. Also, in the children population, similar significant effects were maintained after excluding 1 study with a Jadad score of 331 (WMD 5.79, 95% CI 7.33 to 4.24, P < .001, I2 ¼ 37%).
Adverse Events of Probiotics Of the 25 trials included in this meta-analysis, 9 trials reported adverse events (AEs).14,16,23,26,29,31,32,34,40 However, in a study by Kirjavainen et al,28 AEs were noticed only in a group using a heatinactivated Lactobacillus rhamnosus strain GG. In other studies, most AEs were associated with gastrointestinal symptoms (eg, diarrhea, vomiting) and did not show any significant differences in the incidence of AEs between the probiotic and placebo groups. The reported AEs other than gastrointestinal symptoms were fever, infections, skin disorders, wheezing, and coughing. Some studies reported serious AEs, such as acute enteritis, eczema herpeticatum, food poisoning, and respiratory syncytial virus bronchiolitis.13,15,33 However, it was mentioned that these events were not associated with the study medication. The incidence of AEs varied among studies, from 30.7% to 91.1% in the probiotic group. Discussion
Figure 2. Funnel plot of SE by weighted mean difference. Each dot represents 1 trial.
The present meta-analysis of 25 RCTs suggests that the administration of probiotics might have a positive effect on the treatment of AD. Although the result of a 4.51-point difference in SCORAD value for the overall subject population was greater than that of a previous meta-analysis,18 its clinical significance is still questionable. In addition, the authors could not conclude the positive effect of probiotics in the overall subject population owing to the high heterogeneity among studies. However, from the current study, we could conclude the positive effect of probiotics on the treatment of AD in children (1e18 years old) and adults based on the analysis of clinical trial results that were stratified by age of participants and had low heterogeneity. Conversely, the current evidence does not favor the use of probiotics in infants (
