Methods

Three‐month parallel‐group randomised controlled trial

Participants

Fifty‐one infants under 5 months age with mild/moderate eczema diagnosed using Hanifin and Rajka criteria, and a clinical history suggestive of cow's milk allergy. Randomisation was done at a 1:1 ratio: 17 participants were randomised in each arm (L rhamnosus, L GG, placebo). All participants were exclusively formula fed and received an extensively hydrolysed formula for 3 to 5 weeks before receiving the study intervention. Infants receiving antihistamines, oral corticosteroids, or any probiotic/antibiotic/antimycotic in the preceding 4 weeks were excluded, as were those with a congenital gastrointestinal malformation

Setting: primary care in the Netherlands

One participant lost to follow‐up

Interventions

Extensively hydrolysed whey‐based formula given alone, with Lactobacillus rhamnosus at 5 × 10⁹ CFUs/100 mL or with Lactobacillus GG at 5 × 10⁹ CFUs/100 mL. The study formula was offered at all feeds during the intervention period

Outcomes

SCORAD assessed at baseline, and at 1, 2, and 3 months*

Total IgE, specific IgE to food mix (cow's milk, egg white, soy, peanut, cod, and wheat) and cow's milk, and skin prick test for cow's milk

*Denotes outcomes prespecified for this review

Notes

Study was funded by unrestricted grant from Numico Research, Wageningen, the Netherlands ‐ not related to probiotic. No information on conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "all patients were randomised to either one of the study formulas..."

Comment: no other information provided; method of randomisation not known

Allocation concealment (selection bias)

Unclear risk

No information provided

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "We conducted a randomised, double‐blind, placebo‐controlled study..."

Comment: no further information provided; unclear whether blinding was adequate

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "We conducted a randomised, double‐blind, placebo‐controlled study..."

Comment: no further information provided; unclear whether blinding was adequate

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only 1 participant lost to follow‐up after randomisation; available case analysis without exclusions or imputation used

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting found: all outcomes reported

Other bias

Low risk

No other bias found

Methods

Eight‐month (3‐month intervention and 5‐month observation period) parallel‐group randomised double‐blind controlled trial

Participants

Sixty children aged up to 24 months with atopic dermatitis diagnosed according to the criteria of Hanifin and Rajka (3 out of 4 major criteria had to be met) and with symptoms of cow's milk allergy were recruited. Randomisation was done at a 1:1 ratio: 29 participants were randomised in the intervention arm and 31 in the placebo arm. Participants and mothers of breast‐fed children had to be on a non‐dairy diet. Participants who had used antibiotics and probiotics within 6 months before recruitment were excluded from the trial. Recruitment took place at a secondary paediatric centre in Poland

Interventions

Probiotic mixture: Lactobacillus casei LOCK 0900, Lactobacillus casei LOCK 08, Lactobacillus paracasei LOCK 0919 at a total daily dose of 10⁹ CFUs/d given orally for 3 months

Placebo: hydrolysed casein given orally for 3 months

Outcomes

Improvement vs exacerbation/no improvement based on SCORAD*

• If SCORAD reduction > 2: improvement

• If SCORAD reduction 0 to 2: lack of improvement

• If SCORAD increased: deterioration

*Denotes outcomes prespecified for this review

Notes

Study financed by Ministry of Education grant

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote from translation from Polish: "The study carried out was randomised, double‐blinded..."

Comment: no information provided on the random sequence generation method

Allocation concealment (selection bias)

Unclear risk

Quote from translation from Polish: "The study carried out was randomised, double‐blinded..."

Comment: no information given on allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote from translation from Polish: "The study carried out was randomised, double‐blinded..."

Comment: no information given on blinding method

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote from translation from Polish: "The study carried out was randomised, double‐blinded..."

Comment: no information given on blinding method

Incomplete outcome data (attrition bias)
All outcomes

High risk

29% of participants in probiotic group and 32% in placebo group lost to follow‐up at the end of the intervention

Comment: losses to follow‐up similar in both groups but high in both and may have influenced the outcome of short‐term change in global eczema severity; no information provided on whether available case analysis was used. No reasons for losses to follow‐up given

Selective reporting (reporting bias)

Low risk

All outcomes reported as predefined

Other bias

Low risk

No other bias found

Methods

Twenty‐week parallel‐group double‐blind placebo‐controlled randomised trial

Participants

Thiirty‐eight adult participants between 18 and 46 years with moderate to severe atopic dermatitis diagnosed according to "Consensus guidelines in diagnosis and treatment of atopic dermatitis" (Eichenfield 2004). Randomisation was done at a 1:1 ratio: 19 participants were randomised in each arm. Patients who had received probiotics or antibiotics or who had used immunomodulators (tacrolimus or pimecrolimus) within 6 months from enrolment were excluded from the trial. Also excluded were patients with active allergic disease of the skin or the respiratory tract or chronic infectious disease, and pregnant or lactating patients. All participants completed the study

Secondary care setting; recruiting from an Allergy and Immunology Unit in Italy

Interventions

Probiotic: Lactobacillus salivarius LDR0723 in maltodextrin, given in sachets dissolved in water or other cold liquid of preference twice daily at a dose of 1 × 10⁹ CFUs/g for 16 weeks. Placebo: maltodextrin alone given twice daily for 16 weeks

Outcomes

• SCORAD at baseline and at end of treatment at 16 weeks*

• DLQI at baseline, and at 4, 8, 16, and 20 weeks*

*Denotes outcomes prespecified for this review

Notes

Probiotics supplied by Probiotic Company. No information about conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A computerised randomisation schedule was prepared..."

Comment: judged as low risk

Allocation concealment (selection bias)

Low risk

Quote: "...allocation and dispensing by a blind clinical investigator..." ‐ "the probiotic and placebo sachets were matched for size, shape and volume of contents"

Comment: judged as adequate allocation concealment and hence at low risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "...allocation and dispensing by a blind clinical investigator..." ‐ "the probiotic and placebo sachets were matched for size, shape and volume of contents"

Comment: judged as adequate and hence at low risk of bias.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote for participants who completion of the DLQI questionnaires: "the probiotic and placebo sachets were matched for size, shape and volume of contents"

Quote for clinical assessor: "a single investigator who was blind to the treatment intervention performed all SCORAD assessment at the beginning.... and at the end of treatment..."

Comment: judged as adequate and hence at low risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "All patients completed the study"

Comment: no losses to follow‐up; all participants analysed in the group to they were randomised; therefore, no incomplete data

Selective reporting (reporting bias)

High risk

All outcomes reported with numerical data or narratively

Comment on SCORAD reporting: significance or non‐significance of difference in global eczema severity (SCORAD) between probiotic and placebo groups not reported. Only scores at baseline and end of treatment and at baseline and 4 weeks after treatment reported and commented on

Quote: "the mean SCORAD score in the probiotic group was 27.57±3.4 versus 24.28±3.8 in the placebo group. After 4 months we observed a significant reduction in the SCORAD score in the probiotic‐treated group only (T0: 27.57±3.4 vs T16: 13.14±0.27, P<0.001) whereas no changes were reported in the placebo group (T0: 24.28±2.15 vs T16: 20.14±0.27, NS)"

Comment on DLQI reporting: data presented at end of treatment and 4 weeks after end of treatment for the probiotic group only. Significant difference from baseline stated. Data for the placebo group not reported and given only narratively; no difference from baseline

Quote: "DLQI progressively decreased in probiotic patients during treatment. This significant modification was observed after 8 weeks of treatment (T8) and was also maintained after 4 weeks after the end of the treatment (T20) (T0: 8.28±1.79 vs T8: 4.57±1.11, P=0.02; T0: 8.28±1.79 vs T16: 4.42±0.27, P=0.04; T0: 8.28±1.79 vs T20: 3.71±0.27, P=0.02). No differences were reported in the placebo group"

Comment: only outcome data that were significant for the probiotic group reported. No comparison between probiotics and placebo. Report judged to be at high risk of reporting bias

Other bias

High risk

Commercial bias: probiotics supplied by Probiotic Company. Study double‐blind and randomised; unlikely that the commercial bias had an effect on the outcome. However, it had an impact on reporting because only positive outcomes for the probiotic group were reported

Study assessed as having high risk of other bias

Methods

Thirty‐day randomised placebo‐controlled parallel pilot trial

Participants

Twenty‐five adults 25 to 63 years of age with diagnosis of atopic dermatitis according to Hanifin and Rajka, with predominant rough fissured skin as well as pruritus for at least 2 months were recruited. Randomisation was done at a 1:2 ratio: 13 participants were randomised in the intervention arm and 12 in the control arm

Pregnant and lactating women were excluded. Also excluded were patients with chronic dermatoses such as seborrhoeic dermatitis, contact dermatitis, nummular eczema, psoriasis, ichthyosis, immunodeficiency or any immunological disorder, scabies, cutaneous fungal infection, HIV‐associated skin disorders, malignant disease, T‐cell lymphoma, Letterer‐Siwe disease, progressive systemic disease, serious internal disease (e.g. serious decompensated diseases of the heart, liver, and/or kidneys, diabetes mellitus), or hypersensitivity toward one of the ingredients in the investigational product. Excluded were patients who had been taking part in another study or had taken an investigational product during the last 4 weeks before the start of treatment, or who had been receiving treatment with physical ultraviolet therapy, anti‐inflammatory medications used to treat atopic dermatitis, or immunomodulating medications 30 days before the start of the study, or non‐steroidal antirheumatic drugs, systemic glucocorticosteroids, tranquillisers, or antiemetic agents from the phenothiazine group 14 days before the start of the study, or antidepressants 7 days before the study

All participants completed the study

Country: Italy

Setting: secondary Dermatology Unit

Interventions

Participants in the probiotic group (n = 13) received freeze‐dried mixture of 5 × 10⁹ CFUs/sachet of Lactobacillus salivarius LS01 (DSM 227775), 2 × 10⁹ CFUs/sachet of Streptococcus thermophilus ST10 (DSM 25246), and tara gum (125 mg)

Participants in the placebo group (n = 12) received treatment with sachets containing gluten‐free maltodextrins

Sachets were dissolved in water and were taken once daily for 30 days

Study participants were allowed to continue to use any medication that they had been taking before the study at the same dose, unless the medication could be discontinued

Outcomes

Objective SCORAD index before treatment and after 30 days of treatment*
Staphylococcus aureus and clostridial faecal counts before treatment and after 30 days of treatment

*Denotes outcomes prespecified for this review

Notes

The study has not been registered

Probiotics were supplied by the manufacturer. Investigators declared no conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants randomised at a 1:1 ratio to receive treatment or placebo

Quote from communication with study author: "Which was the method of randomisation? Patients were randomised to either probiotic or placebo groups with a 1:1 allocation according to computer‐generated random numbers"

Judgement: probably low risk of bias

Allocation concealment (selection bias)

Unclear risk

No information provided

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote from correspondence with study author: "Was there any blinding? Clinicians, microbiologists and participants were blinded"

Judgement: probably adequate, i.e. low risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote from correspondence with study author: "Was there any blinding? Clinicians, microbiologists and participants were blinded"

Judgement: probably adequate, i.e. low risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "All of the 25 patients who agreed to commence the protocol completed the study"

Judgement: low risk of bias

Selective reporting (reporting bias)

Low risk

Quote: "The SCORAD index significantly diminished in the active group from T0 to T1 (P<0.0001, Fig. 1), whereas no variations were observed in the placebo group (P=0.274, Fig. 1). After 1 month of treatment, the SCORAD index in group A was significantly lower than in group B (P=0.015)"

Judgement: SCORAD changes reported narratively and not numerically (P value only) between baseline and end of treatment for each group only and between the 2 groups at end of treatment

All other outcomes reported

Other bias

Unclear risk

Probiotics supplied by the manufacturer. Investigators declared no conflicts of interest but did not report numerical results. Also inadequate information on allocation concealment, and not clear whether the manufacturer had any influence on this. Study not registered

For these reasons, study judged to be at unclear risk of commercial bias

Methods

Eight‐week parallel‐group double‐blind placebo‐controlled randomised trial conducted between November 2007 and March 2009

Participants

Fifty‐two children from 3 months to 6 years of age with mild to severe atopic dermatitis. Randomisation was done at a 1:1 ratio, but no exact numbers were given for randomised participants in each arm. Patients who had prior exposure to probiotics, or who were at the time taking antibiotics, or who had major medical problems, were excluded from the trial. Twelve patients were lost to follow‐up

Setting: secondary care, paediatric Allergy and Immunology Department in Iran

Interventions

Synbiotic mixture: Lactobacillus casei, Lactobacillus rhamnosus, Streptococcus thermophilus, Bifidobacterium breve, Lactobacillus acidophilus, Bifidobacterium infantis, Lactobacillus bulgaricus, and fructo‐oligo‐saccharide in 1‐gram sachets dissolved in water or breast milk, at a dose of 1 × 10⁹ CFUs/g twice daily for 8 weeks. Placebo not specified

Outcomes

SCORAD change from baseline to 4 and 8 weeks and from 4 to 8 weeks*

*Denotes outcomes prespecified for this review

Notes

"No conflicts of interest" declared but funding not declared; probiotic provided by the manufacturer

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Participants were randomly divided into two groups..."

Comment: no other information provided; method of randomisation unknown; therefore unclear risk of bias

Allocation concealment (selection bias)

Unclear risk

Quote: "Participants were randomly divided into two groups..."

Comment: unclear whether allocation was concealed; no more information provided

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Participant: "placebo powder was matched for size, shape and volume of contents"

Clinicians: "this randomised, double blind, placebo controlled trial..." ‐ "SCORAD index assessment was performed by a single clinician who was blinded to intervention"

Comment: risk of bias unclear regarding blinding of personnel allocating participants to treatment; no relevant information

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "SCORAD index assessment was performed by a single clinician who was blinded to intervention" ‐ "placebo powder was matched for size, shape and volume of contents" ‐ "placebo powder was matched for size, shape and volume of contents"

Comment: blinding of participants and investigators who assess the global eczema severity score (the only clinical outcome of this study) judged to be adequate; therefore study judged to be of low risk of detection bias

Incomplete outcome data (attrition bias)
All outcomes

High risk

High rate of losses to follow‐up: 12 participants (23%) lost to follow‐up and excluded from analysis. We judged this to lead to high risk of attrition bias. Not clear whether rates of loss to follow‐up were similar in both groups. Reasons for loss to follow‐up given, but treatment group from which losses occurred not specified

Selective reporting (reporting bias)

Unclear risk

Twelve participants (23%) lost to follow‐up and excluded from analysis. Baseline characteristics and outcomes reported only for participants completing the trial. Unclear whether reporting only characteristics of participants can lead to reporting bias. Trial registered in the Iranian Registry for Clinical Trials retrospectively, and number of participants registered pertains to those who completed the study only. Unclear risk of bias, as not clear whether this could have influenced the outcome for global eczema severity

Other bias

Unclear risk

"No conflicts of interest" declared, but not the funding. Probiotic provided by the manufacturer

Methods

Three‐month parallel‐group randomised double‐blind placebo‐controlled trial

Participants

Thirteen children from 0 to 3 years of age with atopic dermatitis, skin prick test ≥ 2+ for at least 2 food allergens, strong clinical history suggestive of food allergy, or positive placebo‐controlled challenge and IgE RAST. Randomisation was done at a 1:2 ratio: 7 participants were randomised in the intervention arm, and 6 in the control arm

≥ 0.7 KU/L for at least 2 food allergens were recruited in the trial. Patients on systemic immunomodulating drugs and those with other systemic diseases or immunodeficiency were excluded from the trial

Recruitment took place at a secondary care setting in the Netherlands

Interventions

Probiotic mixture:

Lactobacillus acidophilus W55, Lactobacillus casei W56, Lactobacillus salivarius W57, Lactobacillus lactis W58, Bifidobacterium infantis W52, Bifidobacterium lactis W18, Bifidobacterium longum W51

In rice starch and maltodextrin powder dissolved in warm water or infant formula before administration given once daily at a dose of 1 × 10⁹ CFUs for 3 months

Placebo: rice starch and maltodextrin powder dissolved in warm water or infant formula before administration given once daily for 3 months

Outcomes

• Total SCORAD: secondary outcome for the trial ‐ not reported in relevant publication*

• Allergen‐specific T‐ and B‐cell response in vivo and ex vivo

• RAST (IgE levels)

• Skin prick test

*Denotes outcomes prespecified for this review

Notes

Study sponsored by probiotic manufacturer; no information on conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote from communication with author: "Randomization was performed by the sponsor (Winclove Bio Industries BV), by using a randomisation table. They provided us with boxes with blinded sachets, with only study numbers on it. We anticipated to include 12 children (6 in each group), so Winclove made sure that the randomisation was performed as such that the first 12 numbers included 6 verum and 6 placebo" ‐ "We had 20 sets of blinded sachets at start of the study, to be able to include more children if there would be dropouts during the study"

Comment: judged as adequate for low risk of bias

Allocation concealment (selection bias)

Low risk

See above quote. Study author confirmed that the allocation sequence was concealed

Comment: judged as adequate for low risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

See above quote and: "The participants, clinician and outcome assessor were blinded until after the analysis of the results had been performed"

Comment: judged as adequate for low risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

See above quote and: "The participants, clinician and outcome assessor were blinded until after the analysis of the results had been performed"

Comment: judged as adequate for low risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Low risk

1/13 participants lost to follow‐up but no exclusions from analysis. Reason for exclusion given by study author: "one child had to stop during the study because of the use of antibiotics and high fever"

Judged as low attrition bias

Selective reporting (reporting bias)

Low risk

All primary outcomes reported

SCORAD ‐ secondary outcome ‐ not reported in the publication but provided by the study author

Other bias

Unclear risk

Study sponsored by probiotic manufacturer. Role of the sponsor in data analysis and publication unclear; hence study was judged to be at unclear risk of other bias

Methods

Eight‐week parallel‐group randomised controlled trial from 2001 until 2002

Participants

Fifty‐four children 1 to 55 months of age with eczema diagnosed using Hanifin and Rajka criteria

Setting: German Dermatology Centre

Randomisation was done at a 1:1 ratio: 27 participants were randomised in each arm. Two‐centre trial. Six participants were lost to follow‐up, and 1 participant dropped out post randomisation but before treatment started

Interventions

Lactobacillus GG at 10¹º CFU/d as a twice‐daily dose, or microcrystalline cellulose placebo. Interventions given as capsules, which were mixed with milk if bottle fed, or mixed with water if not bottle fed

Outcomes

• Parent global assessment of disease severity*
• Quality of life score (Ruden 1999)*
• SCORAD*
• Use of topical corticosteroid and systemic antihistamine treatment. Assessments made at 2, 4, 6, and 8 weeks after the start of the study*

*Denotes outcomes prespecified for this review

Notes

Study was supported by InfectoPharm GmbH (Heppenheim, Germany) and Pharmacia GmbH (Freiburg, Germany) ‐ not related to probiotic

"No conflicts of interest" declared

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "...randomly allocated"

Comment: no concrete information on randomisation method ‐ inadequate for a judgement

Allocation concealment (selection bias)

Unclear risk

No information provided. Unable to assess the risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quotes: "double blind..." ‐ "...placebo preparation (microcrystalline cellulose) with identical appearance"

Comment: inadequate information for a judgement on risk of bias.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quotes: "double blind..." ‐ "...placebo preparation (microcrystalline cellulose) with identical appearance"

Comment: inadequate information for a judgement on risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Seven participants lost to follow‐up post randomisation (13%); of those, 1 after randomisation (not clear from which group) but before treatment started. Low rates of loss to follow‐up in both groups (15.4% in probiotic group and 7.4% in placebo). Available case analysis used without exclusions

Comment: low incomplete data and judged as low risk for attrition bias for all outcomes

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting found. All outcomes reported

Other bias

Low risk

No other bias found

Methods

Eight‐week parallel‐group randomised double‐blind placebo‐controlled trial held between June 2007 and June 2008

Participants

Ninety‐six children between 1 and 3 years of age with moderate to severe atopic dermatitis diagnosed according to the criteria of Hanifin and Rajka were recruited Randomisation was done at a 1:1 ratio: 48 participants were randomised in each arm. Only patients whose parents or legal guardians had the ability to comprehend the study requirements and to provide informed consent and those with direct telephone access were recruited

Patients with clinically evident bacterial skin lesions, chronic concomitant disease that would likely require use of immunosuppression or antihistamines during research period, presence of severe systemic disease or cancer at any site and stage, suspected or established primary/secondary immune deficiency, and food allergy other than egg or cow’s milk were excluded from the study. Also excluded were patients with mild disease and those currently taking systemic corticosteroids

Six participants were lost to follow‐up

Recruitment took place at a paediatric secondary care unit in Ukraine

Interventions

Synbiotic: mixture of Lactobacillus acidophilus DDS‐1 and Bifidobacterium lactis UABLA‐12 with fructo‐oligosaccharide in a rice maltodextrin powder given twice daily reconstituted in tepid water or juice or baby food and immediately fed for 8 weeks. Dose given: 5 × 10⁹ CFU/gr for the 2 probiotics and 50 mgr/gr of fructo‐oligosaccharide

Placebo: rice maltodextrin powder only given twice daily reconstituted in tepid water or juice or baby food and immediately fed for 8 weeks

Parents were given 140 doses of the intervention and were asked to give 112 doses in total

Treatment of atopic dermatitis during intervention: skin hydration, emollients, avoidance of allergens and irritants according to PRACTALL (Practical Allergology) recommendations. Hydrocortisone 1% or Mometasone 0.1% ointment was allowed as rescue medication. Elimination diet for 2 months before and during trial period. Diet was cow's milk or egg free, depending on which food allergy the participant had. No elimination diet for participants without food allergies

Outcomes

• IDQoL changes at 4 and 8 weeks*

• DFI at 4 and 8 weeks*

• SCORAD parts A, B, and C at 2, 4, and 8 weeks*

• Frequency of topical corticosteroid use (days per week) at 8 weeks*

• Cumulative use of topical corticosteroids during intervention period*

*Denotes outcomes prespecified for this review

Notes

Study was funded by the Lviv National Medical University of Ukraine. "No conflicts of interest" declared

Twenty‐six participants in the probiotic group (60.5%) and 24 in the placebo group (51.1%) developed adverse effects: upper respiratory tract infection, lower respiratory tract infection, herpetic stomatitis, diarrhoea, constipation, abdominal colic. Two children in the probiotic group (4.7%) and 3 in the placebo group (6.4%) experienced severe adverse events (head injury and food poisoning) that were reported to be unrelated to the intervention under investigation

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "patients were randomised using computer‐generated random codes to receive either probiotic or placebo treatment"

Comment: judged as adequate for low risk of bias

Allocation concealment (selection bias)

Unclear risk

Inadequate information; study judged to be at unclear risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "probiotic and placebo were identical in appearance, taste, smell, packing and manner of administration. All formulations were dispensed by a technician with investigator and patient blinded regarding the identity of the treatment"

Comment: judged as adequate for low risk of performance bias

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "probiotic and placebo were identical in appearance, taste, smell, packing and manner of administration. All formulations were dispensed by a technician with investigator and patient blinded regarding the identity of the treatment"

Comment: judged as having unclear risk of bias; no information on blinding of outcome assessor

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Six participants lost to follow‐up (6.25%): 5/48 (10%) in the probiotic group and 1/48 (2%) in the placebo group. Reasons for losses to follow‐up given: intercurrent illness (2 in probiotic and 1 in placebo group, 1 protocol violation in probiotic group and 1 diet deviation in probiotic group). Participants analysed in the group to which they were randomised

Comment: judged as low risk, as rates for follow up are low and were unlikely to have influenced outcomes

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Low risk

No other bias found

Methods

Eight‐week 3‐arm parallel‐group randomised double‐blind placebo‐controlled trial

Participants

Fifty children from 7 to 24 months of age with atopic dermatitis diagnosed by general practitioner or dermatologist were recruited. Randomisation was done at a 1:1 ratio: 17 participants were randomised in the 2 intervention arms and 16 in the control arm. All participants completed the trial

Setting: Danish primary care centre

Interventions

First arm/probiotic: Lactobacillus acidophilus NCFM in cellulose, silicon dioxide, and rice maltodextrin in a capsule given daily at a dose of 10¹º CFUs for 8 weeks

Second arm/probiotic: Bifidobacterium animalis subsp lactis (B lactis Bi‐07) in cellulose, silicon dioxide, and rice maltodextrin in a capsule given daily at a dose of 10¹º CFUs for 8 weeks

Third arm/placebo: cellulose, silicon dioxide, and rice maltodextrin in a capsule given daily

Outcomes

Total and subjective SCORAD at baseline and end of treatment at 8 weeks*

*Denotes outcomes prespecified for this review

Notes

Funding was by Danish Directorate of Food Fisheries and Agri Business Danish Dairy Research Foundation. "No conflicts of interest" declared

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote from communication with author: "Randomization sequence was generated by the online available program http://www.randomizer.org/"

Comment: judged as adequate for low risk

Allocation concealment (selection bias)

Low risk

Quote from communication with author: "The producer of the intervention product blinded the capsules as A, B and C before shipment"

Comment: allocation sequence judged as adequate for low risk of bias after the study author's assurance

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote from communication with author: "The producer of the intervention product blinded the capsules as A, B and C before shipment, and blinding was maintained for participants, clinician and outcome assessor until finalized data analysis"

Comment: judged as adequate for low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote from communication with author: "The producer of the intervention product blinded the capsules as A, B and C before shipment, and blinding was maintained for participants, clinician and outcome assessor until finalized data analysis"

Comment: judged as adequate for low risk.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up. All participants analysed in the group were randomised

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Low risk

No other bias found

Methods

Twelve‐week 3‐arm parallel‐group randomised double‐blind placebo‐controlled trial with follow‐up up to 36 months

Participants

One hundred thirty‐seven infants between 3 and 6 months of age with physician‐diagnosed atopic dermatitis, in good general health, with normal growth, and consuming > 200 mL standard formula/d were recruited. Randomisation was done at a 1:2 ratio: 45 participants were randomised in the 2 intervention arms, and 45 in the control arm. SCORAD score at recruitment had to be ≥ 10 after standardised skin treatment for 2‐week run‐in period: 1% hydrocortisone ointment twice daily and emollients 2 to 4 times daily. Infants who were taking antibiotics or were on soya or extensively hydrolysed formula, those with congenital abnormalities or chronic disease, and those at less than 34 weeks' gestation were excluded from the trial

Participants who were exclusively breastfed and those whose parents declined use of extensively hydrolysed formula were followed up as an open observational group

Four participants were lost to follow‐up at 12 weeks

Participants were recruited from primary care community clinics in the United Kingdom

Interventions

First probiotic arm: Bifidobacterium lactis in powder sachets at a dose of 10¹º CFUs/d given with meals for 12 weeks

Second probiotic arm: Lactobacillus paracasei in powder sachets at a dose of 10¹º CFUs/d given with meals for 12 weeks

Placebo arm: maltodextrin in powder sachets given with meals for 12 weeks

All arms followed a dairy elimination diet and used an extensively hydrolysed whey formula

Outcomes

• Total SCORAD before 2‐week run‐in period, at baseline, at 4 and 12 weeks, and at 12, 18, and 36 months*

• IDQoL before 2‐week run‐in period, at baseline, at 12 weeks, and at 12, 18, and 36 months*

• Use of other eczema treatment at 12 weeks (end of intervention period)*

• Number of infants receiving standard skin care: combination of topical steroids (TSs), emollients (≥ twice/d), and bath emollient*

• Potency of TS*

*Denotes outcomes prespecified for this review

Notes

Funding and "no conflict of interest" declared

Forty‐two out of 137 (30.7%) parents reported some difficulties, e.g. green loose stools, increased vomiting, feed refusal, or colic thought to be related to change in formula), and 24 of 137 (17.5%) stopped the formula

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Minimization method was applied to allocate subjects to study groups applying breast feeding, family history and initial SCORAD as stratification factors (TrialBalance randomisation programme; Nestec, Lausanne, Switzerland)"

Comment: judged as adequate for low risk

Allocation concealment (selection bias)

Unclear risk

No information to confirm whether treatment allocation could be predicted

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All interventions identical

Blinding of clinicians confirmed by study author

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Confirmed by study author

Incomplete outcome data (attrition bias)
All outcomes

Low risk

2/45 (4.4%) participants inL paracasei group, 1/45 (2.2%) in B lactis group, and 1/47 (2.1%) in placebo group lost to follow‐up. 10/45 (22.2%) participants in L paracasei group, 9/45 in B lactis group, and 9/47 (19.1%) in placebo group stopped the study diet as per protocol but continued the intervention. Available case analysis used without exclusions, with imputation for missing data

Comment: judged as unlikely to have influenced outcomes on eczema severity and quality of life, as similar and low rates of loss to follow‐up in all groups

Also similar rates of stopping study formula in all groups

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Low risk

No other bias found

Methods

Twelve‐month parallel‐group double‐blind placebo‐controlled randomised trial

Participants

Fifty children from 3 months to 4 years of age with moderate atopic dermatitis. No additional information provided on randomised numbers of participants in each arm

Interventions

Probiotic:Lactobacillus reuteri at a dose of 1 × 10⁸ CFUs/d taken orally suspended in 5 drops of food oil for 12 months

Placebo: not specified but also given for 12 months

Outcomes

• SCORAD*

• Subjective symptoms of atopic dermatitis: itching and loss of sleep*

• Use of steroid treatment*

*Denotes outcomes prespecified for this review

Notes

All available information taken from a conference abstract. No publication found, and study authors could not be contacted

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "In this prospective, double blind, randomised study..."

Inadequate information: information on this study taken only from a conference abstract

Allocation concealment (selection bias)

Unclear risk

Inadequate information: information on this study taken only from a conference abstract

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "In this prospective, double blind, randomised study..."

Inadequate information: information on this study taken only from a conference abstract

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "In this prospective, double blind, randomised study..."

Inadequate information: information on this study taken only from a conference abstract

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Inadequate information: information on this study taken only from a conference abstract

Selective reporting (reporting bias)

Unclear risk

Inadequate information: information on this study taken only from a conference abstract

Other bias

Unclear risk

Inadequate information: information on this study taken only from a conference abstract

Methods

Twelve‐week parallel‐group randomised controlled trial

Last observation carried forward approach used for missing continuous data

Participants

106 children 3 to 12 months of age with mild/moderate eczema and SCORAD 15 to 40, not receiving anti‐inflammatory treatment. Randomisation was done at a 1:1 ratio: 56 participants randomised in the intervention arm and 50 in the control arm. Four participants excluded from analysis after randomisation due to protocol breaches

Interventions

Lactobacillus GG at 10¹º CFUs/d as a twice‐daily dose, or placebo

Outcomes

• SCORAD*
• Use of 1% hydrocortisone ointment*

*Denotes outcomes prespecified for this review

Notes

Funding declared and provided by InfectoPharm Arzneimittel und Consilium GmbH, Heppenheim, Germany (not linked with probiotics). No information on conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Inadequate information for a judgement

Allocation concealment (selection bias)

Unclear risk

No information provided

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Described as double‐blind but no details given

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Described as double‐blind but no details given

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up. Four participants (3.9%) excluded from analysis after randomisation because of protocol breaches. Unlikely to have an impact on effect estimate

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting found

Other bias

Low risk

No other bias found

Methods

Randomised trial

Participants

180 children with eczema, from 2 months to 3 years of age. No additional information provided on exact ratio of randomisation into 2 arms. Patients with other medical conditions excluded

Interventions

Active: routine symptomatic treatment and combination of 4 living bacterium tablets (Bifidobacterium, Lactobacillus, Enterococcus, and Bacilus cereus) taken orally at a dose of 1 tablet twice a day for 1 month

Control: routine symptomatic treatment

Routine symptomatic treatment: mild disease – calamine lotion and zinc oxide ointment, 3 times daily for 2 weeks

Severe disease – loratadine syrup, topical mometasone and topical mupirocin to stop after disease control

All participants advised to avoid washing with hot water/spa products and scratching, and to look for potential allergens and avoidance advice

Outcomes

IL‐4, IL‐10, IgE, IFN‐γ, and Th1:Th2 ratio

Relapse rate of the 2 groups in the 3‐month follow‐up visit. Relapse is defined as recurrence of rash within the 3 months

Eczema improvement:

• Complete resolution: ‐ complete clearance of rash and itch; and normal eating and sleeping patterns

• Good response: > 70% eczema clearance, no obvious lichenification, almost complete resolution of itch/intermittent itch, eating and daily activities not affected

• Partial response: 30% to 70% clearance, symptom improvement

• No response: < 30% rash clearance, no obvious reduction in itch

Complete resolution, good response, and partial response make up total percentage of responding participants

Notes

Contact: [email protected]

Trial was conducted in a secondary care setting at a paediatric clinic

No information provided on sponsorship/conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Inadequate information for a judgement

Allocation concealment (selection bias)

Unclear risk

Inadequate information for a judgement

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Inadequate information for a judgement

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Inadequate information for a judgement

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Inadequate information for a judgement

Selective reporting (reporting bias)

Unclear risk

All outcomes reported; however dose of probiotics not given, and results reported only narratively

Other bias

Unclear risk

No information on trial registration and sponsorship

Methods

Sixteen‐week parallel‐group double‐blind placebo‐controlled randomised trial

Participants

One hundred eighteen children between 1 and 13 years of age with atopic dermatitis diagnosed according to Hanifin and Rajka criteria with SCORAD between 20 and 50 Randomisation was done at a 1:1 ratio: 58 participants were randomised in the intervention arm, and 60 in the control arm. After selection, participants went through a 2‐week washout period, when both groups were administered placebo only. Patients who had taken systemic corticosteroids, probiotics, or phototherapy within a month before enrolment, with systemic immunosuppression within 3 months before enrolment, with SCORAD < 20 after a 2‐week washout period, or with other concomitant skin disease or systemic illness were excluded from the study. One recruiting centre was located in Korea. Thirty‐five participants were lost to follow‐up

Interventions

Probiotic: Lactobacillus plantarum CJLP 133 given orally twice daily at a dose of 0.5 × 10¹º CFUs for 12 weeks

Placebo: maltodextrin and anhydrous glucose twice daily for 2 weeks as a washout period by both groups, and then for 12 weeks by the control group

Outcomes

• Total SCORAD at baseline, after 2‐week washout period, and at 8, 14, and 16 weeks, and changes from week 2 (start of intervention) to week 14 (end of intervention) and week 16 (2‐week follow‐up after end of intervention)*

• Amount in weight of topical corticosteroids used during the whole study and during intervention only*

• Number of participants using topical corticosteroids during the study*

*Denotes outcomes prespecified for this review

Notes

Trial sponsored by probiotic supplier; 2 investigators are employed by this company. No other information on conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "...using a computer‐generated list of random numbers"

Comment: judged as adequate for low risk

Allocation concealment (selection bias)

Low risk

Quote: "The random number list was prepared and posted on the fronts of the bags containing the materials by an investigator who was not involved clinically in the trial", "...placebo preparation with identical appearance and taste"

Comment: probably done and judged as adequate for low risk.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Intervention and placebo identical in appearance and taste

Also quote from correspondence with study author: "clinicians and outcome assessors had been blinded during the study period"

Comment: judged as adequate for low risk

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote from correspondence with study author: "clinicians and outcome assessors had been blinded during the study period"

Comment: judged as adequate for low risk

Incomplete outcome data (attrition bias)
All outcomes

High risk

Intention‐to‐treat analysis used but high rates of losses to follow‐up (30%). 14/58 (24%) participants from probiotic group and 21/60 (35%) from placebo group lost to follow‐up. Reasons for losses to follow‐up given and similar in both groups

Incomplete data likely to have an impact on the effect estimate; judged as high risk

Selective reporting (reporting bias)

High risk

Symptom scores (i.e. for pruritus, sleep loss, and SCORAD part C) after intervention not reported

Other bias

High risk

Commercial bias: trial sponsored by probiotic supplier, and 2 of the investigators employed by the company. It is likely that the sponsor had an influence on the outcome and on selective reporting

Selection bias: power calculation and final numbers of participants suggest that study did not meet the target

According to publication: "Study discontinued after the second interim analysis showed statistically significant differences between the groups"

Study assessed to be at high risk of bias

Methods

Eighteen‐month multi‐centre double‐blind randomised controlled parallel‐group trial conducted from March 2004 until May 2007

Participants

One hundred nineteen infants younger than 6 months of age with documented cow's milk allergy, judged by an elimination challenge test (open) and re‐elimination, in conformity with guidelines of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Randomisation was done at a 1:1 ratio. Excluded from the study were infants breastfeeding during the study, infants older than 6 months of age, patients with chronic disease that may be relevant to this study, such as pre‐existing chest abnormalities (e.g. bronchopulmonary dysplasia (BPD), relevant congenital abnormalities), gastrointestinal disease (coeliac disease, enzyme disorders), and metabolic disease, premature infants at less than 32 weeks, infants with congenital abnormalities that may be relevant to this study, and infants using systemic drugs for allergy (corticosteroids and antihistamines)

Multi‐centre trial recruiting in a paediatric secondary care setting in the Netherlands

One hundred six infants completed the study (89%)

Interventions

Probiotic group: Lactobacillus casei CRL431 (Lactobacillus paracasei, subspparacasei) and Bifidobacterium lactis Bb‐12 (B animalis subsp lactis). For each probiotic, 10⁷ CFUs/gr of formula was provided. This was given for 6 months in extensively hydrolysed formula and was continued in standard formula if infants became cow's milk tolerant, or in the same extensively hydrolysed formula if not

Control group: extensively hydrolysed formula for 6 months and continued in standard formula if infants became cow's milk tolerant, or in the same extensively hydrolysed formula if not

Outcomes

• Development of tolerance for cow's milk, observed by a challenge test (double‐blind) at 6 months

• Eczema severity by SCORAD index at 6 and 12 months*

• T‐ and B‐lymphocyte subsets at 12 months

*Denotes outcomes prespecified for this review

Notes

Study co‐sponsored by probiotic/formula supplier. No information on conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A computerized randomisation schedule was prepared by a statistician" ‐ "the groups were stratified and block randomised according to age at inclusion (<20 weeks and >20 weeks), birth weight (<2500gr or >2500gr) and (reported) atopic diseases in first‐degree relatives (yes or no)"

Comment: judged as adequate for low risk

Allocation concealment (selection bias)

Unclear risk

No information available to allow a judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Probiotics and formula were image and taste matched, and participants and researchers remained blinded to group assignment for the duration of the study"

Comment: probably done for all parties

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Probiotics and formula were image and taste matched, and participants and researchers remained blinded to group assignment for the duration of the study"

Comment: probably done for all parties

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Overall losses to follow‐up 11%. No data available for the 2 groups separately, and no data available for the subgroup of participants who had eczema

Inadequate for a judgement for that subgroup only

Low risk of attrition bias for the primary outcome of the study (development of tolerance to cow's milk)

Selective reporting (reporting bias)

Low risk

All outcomes reported. No detailed data reported on all eczema participants (only moderate to severe), but significance of the difference noted

Quote: "The probiotic group (n=51) showed improvement at 6 and 12 months, and the placebo group (n=54) showed improvement only at 6 months. However, after adjusting for the baseline values there were no significant differences in the change from baseline between probiotics and placebo treatment at 6 months (P=.9) and at 12 months (P=.14)"

Other bias

Unclear risk

Commercial bias: formula and probiotics supplied by producer company. The role of the manufacturer in data analysis and publication is unknown; therefore we assessed this study to be at unclear risk of other bias

Methods

Twenty‐week parallel‐group double‐blind placebo‐controlled randomised trial from April until September 2010

Participants

48 adults between 18 and 55 years of age with moderate to severe atopic dermatitis diagnosed according to "Consensus guidelines in diagnosis and treatment of atopic dermatitis" (Eichenfield 2004). Participants were randomised at a 2:1 intervention:control ratio (32 participants in intervention arm/16 participants in control arm). Patients who had taken probiotics in the 6 months before enrolment, or topical immunomodulators, corticosteroids, or antihistamines; who had chronic disease, congenital or acquired immunosuppression, acute or chronic infection, or allergic contact dermatitis; and pregnant or lactating patients were excluded from the trial. Also excluded were patients who were on elimination diets without a known food allergy and those with hypersensitivity to the components of the probiotics

Participants were recruited at a secondary Immunology centre in Italy

Two participants were lost to follow‐up

Interventions

Mixture of probiotics in maltodextrin: Lactobacillus salivarius LS01 DSM 2275, Bifidobacterium breve BR03 DSM 16604, given twice daily at a dose of 1 × 10⁹ CFUs/gr for each probiotic for 12 weeks

Placebo: maltodextrin given only twice daily for 12 weeks

Outcomes

• DLQI at baseline and at 12 and 20 weeks*

• SCORAD at baseline and at 12 and 20 weeks*

*Denotes outcomes prespecified for this review

Notes

"No conflicts of interest" declared. No information on funding. Probiotics provided by the manufacturer

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "patients were randomised with a 2:1 ratio..."

Quote from communication with study author: "A computerized randomisation schedule was prepared..."

Comment: judged as adequate for low risk of bias

Allocation concealment (selection bias)

Low risk

Quote from communication with study author: "allocation and dispensing by blind clinical investigator"

Comment: judged as adequate for low risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Probiotic and placebo sachets were matched for size, shape and volume of contents"

Quote from communication with study author: "allocation and dispensing by blind clinical investigator"

Comment: judged as adequate for low risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "A single investigator blinded to the treatment arm, performed all SCORAD assessments..."

Comment: judged as adequate for low risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Low rates of loss to follow‐up (4%) overall. 1 participant lost to follow‐up in each arm: 3% in probiotic group and 6% in placebo group. Different reasons for losses to follow‐up given but overall low rates unlikely to have a significant influence on effect estimates for all outcomes

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Unclear risk

"No conflicts of interest" declared. Unavailable information on funding. Probiotics provided by the manufacturer

Methods

Parallel‐group three‐arm randomised controlled trial. Duration of treatment unclear

Participants

Twenty‐seven infants ‐ ages not stated ‐ with eczema diagnosed using the Hanifin and Rajka criteria. Randomisation was done at a 1:1 ratio: 9 participants were randomised in each arm. All infants were exclusively breastfed and were tolerant of the study formula without added probiotic

Setting: paediatric service in Finland

Unclear how many participants lost to follow‐up

Interventions

Extensively hydrolysed whey‐dominant cow's milk formula with no probiotic added, with Lactobacillus GG added at 3 × 10⁸ CFUs/g, or with Bifidobacterium lactis Bb‐12 added at 1 × 10⁹ CFUs/g

Outcomes

SCORAD ‐ interval of assessment unclear*

*Denotes outcomes prespecified for this review

Notes

Study funded by the Academy of Finland, European Union (FAIR CT96‐1028), and the Medical Research Funds of Tampere and Turku University Hospital

"No conflict of interest" declared

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "In this randomised, double blind study, the patients were divided into three groups..."

Comment: inadequate information to assess risk of bias

Allocation concealment (selection bias)

Unclear risk

No information given. No assessment of risk of bias can be done

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "In this randomised, double blind study, the patients were divided into three groups..."

Comment: inadequate information for a judgement on risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "In this randomised, double blind study, the patients were divided into three groups..."

Comment: inadequate information for a judgement on risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Information on losses to follow‐up not given. Inadequate information for a judgement on risk of bias

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting found

Other bias

Low risk

No other bias found

Methods

Eight‐week parallel‐group open‐label randomised placebo‐controlled trial

Participants

Sixty full‐term infants 3 to 12 months of age with clinically diagnosed eczema and challenge proven cow's milk allergy, breast and formula fed. Randomisation was done at a 1:1 ratio: 30 participants were randomised in each arm. Excluded were patients who had received any probiotics within a month before recruitment and those with other allergies, severe comorbidities, and malformations

Country: Ukraine

5 participants lost to follow‐up

Interventions

Probiotic: Bifidobacterium lactis BB‐12 and Streptococcus thermophilus TH‐4 for 4 weeks

No information on placebo

Daily dose of probiotics: 1 × 10⁹ CFUs for BB‐12 and 1 × 10⁸ CFUs for TH‐4. Both groups on cow's milk elimination diet

Outcomes

SCORAD at 4 and 8 weeks*

*Denotes outcomes prespecified for this review

Notes

No mention of sponsor. No declaration of conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote from translated Russian article: "In this open label randomised prospective clinical study..."

Comment: inadequate information for a judgement on risk of bias

Allocation concealment (selection bias)

Unclear risk

Inadequate information for assessment, so study judged as having unclear risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label study

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Open‐label study

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Five participants lost to follow‐up (8%), with 2 participants from probiotic group (6.6%) and 3 participants (10%) from placebo group. Reasons for losses to follow‐up not given for each group. Not clear whether losses to follow‐up were excluded from analysis. However overall rates of loss to follow‐up were low and were unlikely to have a significant influence on effect estimates for study outcomes

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Unclear risk

No mention of sponsor. No declaration of conflicts of interest

Methods

Parallel‐group randomised controlled trial. Intended duration of treatment not clear

Participants

Twenty‐seven infants (mean age 5.5 months) with eczema and suspected cow's milk allergy. Method for diagnosing eczema not described

Setting: hospital paediatric department in Finland

Unclear how many participants lost to follow‐up

Participants randomised 2:1, probiotic:control

Interventions

Lactobacillus GG at 3 × 10¹º CFUs/kg/d, mixed with extensively hydrolysed whey formula, or the same formula without probiotic. A third treatment arm (excluded from this review) used heat‐inactivatedLGG at 3 × 10¹º CFUs/kg/d, mixed with extensively hydrolysed whey formula

Outcomes

SCORAD*

*Denotes outcomes prespecified for this review

Notes

Study terminated early due to adverse effects in a third treatment arm. Third treatment arm not included in this systematic review because it involved the use of killed bacteria

Study funded by the Academy of Finland

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "These infants were randomly assigned into placebo, viable LGG..."

Comment: inadequate information for a judgement on risk of bias

Allocation concealment (selection bias)

Unclear risk

No information reported. Inadequate information for a judgement on risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "These infants were randomly assigned into placebo, viable LGG or heat‐inactivated LGG groups and accordingly given in a double blind manner..."

Comment: inadequate information for a judgement on risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "These infants were randomly assigned into placebo, viable LGG or heat‐inactivated LGG groups and accordingly given in a double blind manner..."

Comment: inadequate information for a judgement on risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No data given on losses to follow‐up. Inadequate information for a judgement on risk of bias

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting

Other bias

Low risk

No other bias found

Methods

Four‐week randomised parallel controlled trial

Participants

Forty‐four infants of both genders with newly diagnosed eczema based on the diagnostic criteria for eczema up to 3 years of age were recruited. Randomisation was done at 1:2 ratio: 22 participants were randomised in each group. Infants who had been treated with antibiotics, probiotics, or other drugs and food at least 2 weeks before the start of the study were excluded. Also excluded were children suffering from pneumonia, capillary bronchitis, and other diseases, or who had been treated with antibiotics or hormones during the experimental process

Infants were treated with antiallergic therapy and dietary guidance

Recruitment took place in a secondary paediatric setting in China between December 2010 and March 2011

Interventions

Intervention group received triple viable capsules containing Bifidobacterium bifidum 3 times daily for 4 weeks

Control group received no treatment

Outcomes

• Total SCORAD index at baseline and after 4 weeks of intervention

• Bifidobacterium bifidum stool levels at baseline and after 4 weeks of treatment

Notes

Sponsorship of the trial not declared. Not clear what role the supplier of the probiotic played in the study

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The 40 infants were randomly divided into treatment and control groups"

Judgement: inadequate information on randomisation method; risk of bias judged as unclear

Allocation concealment (selection bias)

Unclear risk

Inadequate information for a judgement

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "The control group … did not receive any special treatment and were not administered a placebo drug"

Judgement: unlikely to be done adequately with no treatment and no placebo in the control group

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "The control group … did not receive any special treatment and were not administered a placebo drug"

Otherwise no information on blinding of outcome assessors; hence risk of detection bias judged to be unclear

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No information provided on losses to follow‐up and missing outcome data

Judgement: unclear risk of bias

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Unclear risk

Not clear what role the supplier of the probiotic played in the study. Sponsorship of the trial not declared

Judgement: unclear risk of commercial bias

Methods

One‐month parallel‐group randomised controlled trial

Participants

Thirty‐one children 2 to 16 months of age with eczema diagnosed using the Hanifin and Rajka criteria, and a history suggestive of cow's milk allergy. Randomisation was done at a 1:1 ratio. Children currently receiving systemic corticosteroid treatment were excluded

Setting: paediatric clinic in Finland

Unclear how many participants were lost to follow‐up

Interventions

Cow's milk elimination diet, topical eczema treatment, and extensively hydrolysed cow's milk formula with or without addition of probiotic Lactobacillus GG. Probiotic given at 5 × 10⁸ CFUs/g formula

Outcomes

SCORAD assessed at 1 and 2 months*

*Denotes outcomes prespecified for this review

Notes

No information available on funding or conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The patients....participated in a randomised double blind study"

Comment: inadequate information for a judgement on risk of bias

Allocation concealment (selection bias)

Unclear risk

No information provided

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "The patients....participated in a randomised double blind study"

Comment: inadequate information for a judgement on risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "The patients....participated in a randomised double blind study"

Comment: inadequate information for a judgement on risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No data on losses to follow‐up. Inadequate information for a judgement on risk of bias

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting

Other bias

Unclear risk

No information on funding available

Methods

Eight‐week multi‐centre randomised double‐blind placebo‐controlled parallel trial

Participants

Forty‐four adults with moderate to severe atopic dermatitis diagnosed according to the criteria of Hanifin and Rajka were recruited. Randomisation was done at a 1:1 ratio: 22 participants were randomised in each arm. Participants continued to use their medications as usual and did not change quantities or levels of corticosteroid medicine during the experimental period. Participants were asked to avoid probiotic supplements, fermented milk, lactic acid bacterial drinks, and fermented soybean (natto) during the experimental period

Recruitment took place at 8 dermatology clinics in Japan

Interventions

Participants in the intervention group received capsules containing approximately 6 × 10⁹ CFUs of Bifidobacterium animalis subsp lactis and an excipient that consisted of skim milk, glucose, inulin, dextrin, and silicone dioxide for 8 weeks

Control group received capsules containing the excipient only for 8 weeks

Outcomes

• Itch score by behavioural rating scales and by 100‐mm visual analogue scale (VAS) at baseline and at 4 and 8 weeks

• Skin severity score using the reference proposed by the Research Group granted by the Japanese Ministry of Health, Labor and Welfare at baseline and at 4 and 8 weeks

• Quality of life using Skindex‐29 (Japanese version) at baseline and at 4 and 8 weeks

• Faecal levels of B lactis at baseline and at 4 and 8 weeks

Notes

Trial registration: UMIN000005695

Four of the investigators/study authors are employed by the supplier

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The 44 participants eligible for the study were randomly assigned to receive LKM512 capsule or a placebo by the masked quota director"

Judgement: inadequate information on randomisation method; hence judgement of unclear risk of selection bias

Allocation concealment (selection bias)

Unclear risk

Inadequate information for a judgement

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"Double‐blind" mentioned, but trial registration shows open‐label

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Double‐blind" mentioned, but trial registration shows open‐label

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No information provided

Selective reporting (reporting bias)

Unclear risk

All outcomes reported but not numerically, and any favourable information/outcome for probiotics particularly analysed, even if not statistically significant

Other bias

High risk

Commercial bias: 4 investigators/study authors employed by supplier; likely that this has influenced the design and outcome of the trial

Methods

Three‐month parallel‐group randomised placebo‐controlled trial

Participants

Thirty‐nine full‐term and otherwise healthy infants with atopic dermatitis diagnosed according to the Hanifin and Rajka criteria were recruited. Randomisation was done at a 1:1 ratio: 19 participants were randomised in the intervention arm, and 20 in the control arm. Patients with skin or other severe infections were excluded

Recruitment was done at a paediatric secondary care setting in Finland

Two participants were lost to follow‐up

Interventions

Probiotic: Lactobacillus rhamnosus GG in extensively hydrolysed casein formula given at a dose of 5.0 × 10⁷ CFUs/gr, achieving a daily dose of 3.4 × 10⁹ CFUs/d for 3 months

Placebo: extensively hydrolysed casein formula for 3 months

Outcomes

• Total SCORAD*

*Denotes outcomes prespecified for this review

Notes

Study was partially funded by the formula manufacturer and a grant from the Academy of Finland. No conflicts of interest declared

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote from correspondence with study author: "the randomisation was carried out by the formula supplier (Mead Johnson, Evansville, IN, USA). The method used was block randomisation..."

Comment: probably done; judged as adequate for low risk of bias

Allocation concealment (selection bias)

Unclear risk

No information given; inadequate information for a judgement

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote from correspondence with study author: "The study was a double‐blind, placebo controlled intervention study" ‐ "The information disclosing the codes of the study products was kept by a person not involved in the study and opened after the study was completed"

Comment: probably done; judged as adequate for low risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote from correspondence with study author: "The study was a double‐blind, placebo controlled intervention study" ‐ "The information disclosing the codes of the study products was kept by a person not involved in the study and opened after the study was completed"

Comment: probably done; judged as adequate for low risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Two participants lost to follow‐up, all from placebo group. Available case analysis unclear but very low rates of loss to follow‐up (5% in total and 10% in placebo group) unlikely to change the effect estimate. Reasons for losses to follow‐up given

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Low risk

No other bias found

Methods

Three‐month parallel‐group randomised controlled trial

Participants

Forty‐eight children 2 to 12 years of age with moderate/severe eczema diagnosed by UK Working Party Criteria and total SCORAD over 14. Randomisation was done at a 1:1 ratio: 24 participants were randomised in each arm. Exclusion criteria included current flare of eczema, exposure to systemic corticosteroids or immunosuppressants in the previous 3 months, and other known immune deficiency

Setting: hospital dermatology clinic in France

Nine participants lost to follow‐up

Interventions

Skim milk powder, potato starch, and lactose‐containing prebiotic, with or without Lactobacillus rhamnosus Lcr35 at 3.6 × 10⁹ CFUs/d, given as a 3‐times‐daily dose mixed with cold water or other liquid

Outcomes

• Parent or participant global assessment of eczema severity*
• SCORAD*
• Investigator global assessment of eczema severity*
Assessments were done at baseline and at 1, 2, and 3 months

*Denotes outcomes prespecified for this review

Notes

Three episodes of mild abdominal pain reported ‐ 2 in probiotic group, 1 in placebo (prebiotic alone) group

Funding and conflict of interest not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation sequence as confirmed by study authors. Judged as having low risk of bias

Allocation concealment (selection bias)

Low risk

Adequate as confirmed by study authors and judged as having low risk

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The patients, their parents and the dermatologists were blinded to the treatment the patient was receiving" ‐ "Each patient was examined by the same dermatologist at each visit"

Study authors confirmed blinding of all parties in the trial

Comment: probably done and judged as adequate for low risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The patients, their parents and the dermatologists were blinded to the treatment the patient was receiving" "Each patient was examined by the same dermatologist at each visit"

Study authors confirmed blinding of all parties in the trial

Comment: probably done and judged as adequate for low risk of bias

Incomplete outcome data (attrition bias)
All outcomes

High risk

Available case analysis used without exclusions after randomisation with low total rates of loss to follow‐up (18.7%). Losses to follow‐up per group: 29% in synbiotic group and 8% in placebo group. Reasons for losses in the synbiotic group were non‐attendance at follow‐up visits (5/24 participants) and withdrawal of consent (2/24). In the prebiotic group, 2/24 participants did not attend for follow‐up

Significant differences in rates of loss to follow‐up in the 2 groups, which probably had an impact on all outcomes

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting

Other bias

Unclear risk

Funding and conflict of interest not reported

Methods

Twenty‐week cross‐over randomised double‐blind placebo‐controlled trial

Participants

Sixteen adults between 18 and 40 years of age with eczema diagnosed based on Erlangen score > 10 (atopic score of Diepgen) and SCORAD severity score 5 to 30 were recruited. Only patients who were willing to apply cosmetic products and the Class II topical corticosteroid Advantan were recruited. Exclusion criteria were

disease necessitating medication with systemic corticosteroids, immunosuppression, or cytostatics within 4 weeks before the start of the study; phototherapy or systemic treatments within 4 weeks before the start of the study; long‐acting antihistamines, antibiotics, long‐term systemic corticosteroids, depot steroids, tranquillisers, and psychopharmaceuticals with antihistamine effect or within 7 days from skin prick test; or astemizole intake within 4 weeks before prick testing. Also excluded were patients with active skin infection; asthma needing treatment with corticosteroids; indigestibility/allergy to milk components (including skin prick test); lactose intolerance; acute or chronic symptomatic heart disease or severe internistic disease; autoimmune disease; immune deficiency (including immune suppressive treatment); immune complex‐induced immunopathy or malignant tumour; or abuse of alcohol, drugs, or medicaments, as well as pregnant and breastfeeding women

Recruitment was done at a secondary care centre in Germany

One participant withdrew after randomisation and before treatment started

Interventions

Probiotic yoghurt drink containing Streptococcus thermophilus enriched with Lactobacillus paracasei Lpc‐37 (3.9 × 10⁸ CFUs/g), Lactobacillus acidophilus 74‐2 (2.9 × 10⁴ CFUs/g), Bifidobacterium lactis DGCC 420 (5.9 × 10⁴ CFUs/g) taken as 100 mL twice daily for 8 weeks

Total daily dose was Lpc‐37: 7.8 × 10¹º CFUs/d, 74‐2: 5.8 × 10⁶ CFUs/d, and DGCC 420: 1.2 × 10⁷ CFUs/d

Placebo drink not otherwise specified given as 100 mL twice daily

Crossing over from one to the other intervention involved a washout period of 2 weeks

Instructions were given for elimination of other probiotic and prebiotic products for 3 weeks before the start of treatment and during the 20 weeks of intervention

Outcomes

Total SCORAD and SCORAD part C at baseline and after 8 weeks of each intervention*

*Denotes outcomes prespecified for this review

Notes

Study was sponsored by a grant from Zott Dairy GmbH (not the probiotic supplier). It was declared that Zott had no involvement in study design, data analysis, and publication, and study authors declared no conflict of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "all subjects were randomly assigned to 2 treatment groups (1:1) according to a computer generated blocked randomisation list (blocked randomisation)"

Comment: judged as adequate for low risk of bias

Allocation concealment (selection bias)

Unclear risk

Comment: not clear whether treatment allocation was concealed

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The placebo drink had an identical composition except for the probiotic cultures and had the same appearance, taste and smell as the probiotic drink" ‐ "Enrollment and assignment to interventions were performed by the trial physician and AR. All involved persons (trial physician and scientific staff) were blinded. In addition study products were blinded and labelled with a numerical code by the production dairy"

Comment: judged as adequate for low risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The placebo drink had an identical composition except for the probiotic cultures and had the same appearance, taste and smell as the probiotic drink" ‐ "Enrollment and assignment to interventions were performed by the trial physician and AR. All involved persons (trial physician and scientific staff) were blinded. In addition study products were blinded and labelled with a numerical code by the production dairy"

Comment: judged as adequate for low risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Low risk

One participant (6.6%) withdrew after randomisation and before the start of treatment and was excluded from analysis. All other participants were analysed in the group to which they had been randomised. Low rates of loss to follow‐up were unlikely to have a significant influence on effect estimates

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Low risk

No other bias found

Methods

Six‐week randomised controlled cross‐over trial

Participants

Fifty‐eight children 1 to 13 years of age with eczema diagnosed using the UK Working Party Criteria. Children who had received systemic corticosteroids at any time were excluded

Setting: hospital paediatric and dermatology departments in Denmark

15 participants lost to follow‐up

Interventions

Skimmed milk powder with dextrose anhydrate 2 g/d or a mix of Lactobacillus rhamnosus 19070‐2 and Lactobacillus reuteri DSM12246 at 2 × 10¹º CFUs/d of each strain. Both placebo and probiotic preparations administered twice daily with 2.5 to 5 mL water

Outcomes

• Global self‐assessment by participant or parent*
• SCORAD*
• Need for other treatment ‐ topical corticosteroid*

*Denotes outcomes prespecified for this review

Notes

Study was supported by Danish Research and Development Programme for Food Technology

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The patients were randomised in a double‐blind crossover design...." ‐ "Blocked randomisation with 4 patients in each block was applied"

Comment: inadequate information for a judgement on risk of bias

Allocation concealment (selection bias)

Unclear risk

No information provided. Inadequate information for a judgement

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "The patients were randomised in a double‐blind crossover design...."

Comment: inadequate information for a judgement on risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "The patients were randomised in a double‐blind crossover design...."

Comment: inadequate information for a judgement on risk of bias

Incomplete outcome data (attrition bias)
All outcomes

High risk

Fifteen participants (25.9%) excluded from analysis. Five of these excluded during active treatment and 9 during placebo. Reasons for exclusion reported

Comment: high rates of exclusion probably affecting all outcomes

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting

Other bias

Low risk

No other bias found

Methods

Parallel‐group double‐blind placebo‐controlled randomised trial conducted between December 2008 and November 2009

Participants

Forty‐one children from 1 to 36 months of age with moderate to severe (SCORAD > 25) atopic dermatitis diagnosed according to Hanifin and Rajka criteria were recruited. Randomisation was done at a 1:1 ratio: 20 participants were randomised in the intervention arm, and 21 in the control arm. Exclusion criteria were administration of systemic steroids, recurrent infection, evidence of immunodeficiency, congenital abnormality, chronic disease, and problems in eating. Five participants were lost to follow‐up

Setting: Iranian Paediatric Allergy and Immunology Department

Interventions

Synbiotic: 7‐strain probiotic and synbiotic in a sachet given daily at a dose of 1 × 10⁹ CFUs of probiotic and 990 mgr of fructo‐oligosaccharide for 2 months (59 days)

Placebo: sucrose in a 1000‐mgr sachet given daily for 2 months (58 days)

Both interventions were prepared by mixing with water, breast milk, formula, or solid food

Outcomes

Total and objective SCORAD changes from baseline to end of intervention after 2 months*

*Denotes outcomes prespecified for this review

Notes

Sponsorship is unclear. Conflicts of interest are not declared

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomisation was performed according to a computer‐generated balanced block randomisation to synbiotic and placebo groups"

Comment: judged as adequate for low risk of bias

Allocation concealment (selection bias)

Unclear risk

Quote: "At enrolment we assigned the study number and provided the participants with the appropriate sachet"

Comment: not clear whether allocation to a treatment could have been predicted

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

It is stated: "Partcipants and investigators blinded for the duration of the trial" ‐ "Placebo and intervention image‐matched and identical in appearance, taste and smell"

Comment: judged as adequate for low risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

It is stated: "Partcipants and investigators blinded for the duration of the trial", but no specific information provided on outcome assessor

Comment: judged as unclear risk due to lack of specific information

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Five participants out of 41 (12%) were lost to follow‐up: 2 participants were from the probiotic group (10%) and 3 from the placebo group (14%). Reasons for loss to follow‐up were given and were similar in both groups. Case analysis was available. Low rates of loss to follow‐up unlikely to have a significant impact on the effect estimate

Selective reporting (reporting bias)

Unclear risk

Baseline characteristics and outcomes reported only for participants who completed the trial. Unclear whether groups were matched at baseline

Other bias

Unclear risk

Sponsorship unclear

Methods

Twelve‐week parallel‐group randomised controlled trial

Participants

Sixty children 1 to 10 years of age with eczema diagnosed by UK Working Party criteria, SCORAD of at least 10 at recruitment, and a positive skin prick or RAST test to at least 1 common environmental or food allergen. Randomisation was done at a 1:1 ratio: 30 participants were randomised in each arm. Exclusion criteria were oral corticosteroid, immunosuppressant, or antibiotic in the previous month; previous immune deficiency or malignancy; and greater than 10‐point improvement in SCORAD during 2 weeks before the start of study treatment

Setting: hospital clinic in New Zealand

One participant lost to follow‐up

Interventions

Microcrystalline cellulose placebo or Lactobacillus rhamnosus and Bifidobacterium lactis given together once daily at a combined total dose of 2 × 10¹º CFUs/d. Treatment capsules administered as a powder mixed with food or drink, or taken in capsule form

Outcomes

SCORAD assessed at 2 weeks before treatment, at the start of treatment, and 2, 12, and 16 weeks later*

*Denotes outcomes prespecified for this review

Notes

One participant noted to be taking another non‐investigational probiotic

Study was was funded by New Zealand Research Council. No conflicts of interest were declared

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Children were randomly assigned to treatment or placebo groups, using computer‐generated random numbers"

Comment: judged as adequate for low risk of bias

Allocation concealment (selection bias)

Low risk

Adequate: treatment allocated by third party as confirmed by study authors

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quotes: "The control group received a placebo....that looked and tasted the same as the probiotic" ‐ "Both subjects and investigators were blind to the treatment groups"

Comment: judged as adequate for low risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quotes: "The control group received a placebo....that looked and tasted the same as the probiotic" ‐ "Both subjects and investigators were blind to the treatment groups"

Comment: judged as adequate for low risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Available case analysis used without exclusions after randomisation and very low rates of loss to follow‐up (1/60 participants, 1.7%)

Comment: low risk of attrition bias

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting

Other bias

Unclear risk

Significant differences in baseline SCORAD in the 2 groups, with more severe mean SCORAD in the placebo group. Study authors state that this could have been avoided if randomisation had been blocked

Comment: uncertain how this difference could have influenced the effect estimate

Methods

Three‐month parallel‐group randomised controlled trial

Participants

Seventeen children 3 to 18 months of age with eczema diagnosed by Hanifin and Rajka criteria, and with cow's milk hypersensitivity diagnosed by suggestive history plus evidence of cow's milk‐specific IgE. No information on the randomisation ratio was given. All participants had reduced levels of Bifidobacteria in their faeces (< 30% of total bacteria) and were receiving extensively hydrolysed cow's milk formula for at least 2 weeks before randomisation

Setting unclear

Unclear how many participants were lost to follow‐up

Interventions

Raffinose prebiotic containing extensively hydrolysed cow's milk formula with or without Bifidobacterium breve M‐16V at 5 to 15 × 10⁹ CFUs/d

Outcomes

Investigator‐rated eczema scoring system*

*Denotes outcomes prespecified for this review

Notes

No numerical outcome data available

Study was supported by Grants‐in‐Aid from the Morianga Houshikai and the Mami Mitzutani Foundation. No conflicts of interest reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The 17 infants were divided into 2 groups at random"

Comment: inadequate information; inadequate information for a judgement on risk of bias

Allocation concealment (selection bias)

Unclear risk

No information; inadequate information for a judgement on risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information available

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information available

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No information on losses to follow‐up or data analyses

Selective reporting (reporting bias)

Low risk

No risk found

Other bias

Low risk

No other bias found

Methods

Twelve‐week multi‐centre parallel‐group double‐blind placebo‐controlled randomised trial

Participants

Ninety infants 0 to 7 months of age, exclusively formula fed, with a diagnosis of atopic dermatitis based on Hanifin and Rajka diagnostic criteria and SCORAD > 15 were recruited in the study. Randomisation was done at a 1:1 ratio: 46 participants were randomised in the intervention arm, and 44 in the control arm

Infants who had received systemic corticosteroids, antibiotics, antimycotics, calcineurin inhibitors, or probiotics during 4 weeks or antihistamines during 2 weeks before enrolment were excluded from the study. Also excluded were infants needing systemic treatments other than antibiotics during the study and infants with major medical problems or GI or skin conditions other than atopic dermatitis

Setting: participants recruited at 7 paediatric and dermatology secondary care centres in the Netherlands

Eight participants were lost to follow‐up. Five participants (4 in the symbiotic group and 1 in the placebo group) were excluded from analysis because no SCORAD assessment was undertaken after baseline assessment

Interventions

Synbiotic: extensively hydrolysed whey‐based formula with Bifidobacterium breve M‐16V with 90% scGOS and 10% lcFOS given on demand at a dose of 1.3 × 10⁹ CFUs/100 mL of probiotic and 0.8 gr/100 mL of prebiotic for 12 weeks

Placebo: formula given only on demand for 12 weeks

Outcomes

• Changes in total SCORAD from baseline to 4, 8, and 12 (end of treatment) weeks*

• Total SCORAD in 1 year after the intervention

• Frequency and mean class of topical steroids used at baseline and at end of treatment*

*Denotes outcomes prespecified for this review

Notes

Two participants experienced severe adverse events: RSV bronchiolitis and severe cow's milk allergy. These were not related to the intervention

Sponsored by a probiotic/formula company

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Participants were randomised, using computer‐generated 4‐blocked design lists, drawn up by a statistician with stratification according to recruiting hospital and current use of topical steroids..."

Comment: judged as adequate for low risk of bias

Allocation concealment (selection bias)

Low risk

Quote: "Formulas were prepared and coded by Danone Research and dispensed by the pharmacy of the Academic Medical Centre", "both formulas were identical with respect to smell, taste, texture, colour and packaging"

Comment: third party involved; judged as adequate for low risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quotes: "both formulas were identical with respect to smell, taste, texture, colour and packaging. The investigator, participants' own physicians and parents were all blind to the treatment groups"

Comment: judged as adequate for low risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The investigator, participants' own physicians and parents were all blind to the treatment groups. Participants were clinically assessed by one investigator (L.B.A.), at weeks 0, 4, 8 and 12"

Comment: judged as adequate for low risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Low risk

6/46 (13%) participants from the probiotic group and 2/44 (4.5%) from the placebo group discontinued treatment but were not excluded from analysis. Five participants (5.5%) were excluded post randomisation because of unavailable assessment data after baseline. Four were from the probiotic group, and one from the placebo group. Losses to follow‐up included in analysis but not certain how missing data were handled

Comment: overall low rates of missing data; judged to have low risk of attrition bias

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Unclear risk

Sponsored by a probiotic/formula company. The role of the sponsor in data analysis is unclear; therefore the study was judged to be at unclear risk of bias

Methods

Four‐week parallel‐group randomised controlled trial

Participants

252 infants younger than 12 months of age with a clinical diagnosis of eczema and a clinical history suggestive of cow's milk allergy. Randomisation was done at a 1:1 ratio: 84 participants were randomised in each arm. Infants who had received a probiotic preparation for over a week in the preceding 6 weeks were excluded

Participants were selected from primary care referrals to a hospital clinic in Finland

Twenty‐two participants were lost to follow‐up

Interventions

Cow's milk elimination diet, extensively hydrolysed formula, and capsules of microcrystalline cellulose placebo, Lactobacillus GG (10¹º CFUs/d), or probiotic mix (Lactobacillus GG 10¹º CFUs/d, Bifidobacterium breve Bbi 99 4 × 10⁸ CFUs/d,Lactobacillus rhamnosus LC705 10¹º CFUs/d, and Propionibacterium JS 4 × 10⁹ CFUs/d). Capsules were mixed with food twice daily

Outcomes

SCORAD assessed at end of treatment and 4 weeks later*

*Denotes outcomes prespecified for this review

Notes

Study was supported by Finnish Research foundations and the probiotic supplier. No information on conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Infants were randomised at the first visit according to computer‐generated block randomisation..."

Comment: judged as adequate for low risk of bias

Allocation concealment (selection bias)

Low risk

Adequate: treatment allocated by third party as confirmed by study author

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants and clinician blinded as confirmed by study author

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessor blinded as confirmed by study author

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Analysis was by "treatment received", and 4 participants (1.6%) were excluded from analysis because they did not tolerate the study formula. Twenty‐two (8.7% to 5.9% in LGG group, 10.6% in probiotic mix group, and 9.75% in placebo group) losses to follow‐up occurred. Unlikely to have an impact on effect estimate and judged as having low risk of attrition bias

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting

Other bias

Unclear risk

Study was supported by Finnish Research foundations and the probiotic supplier. Not clear whether the probiotic supplier had any influence on data analysis

Methods

Four‐arm parallel‐group double‐blind randomised placebo‐controlled trial conducted from December 2011 until September 2013

Participants

220 children and adolescents from 1 to 18 years of age with moderate to severe atopic dermatitis (SCORAD > 15) diagnosed according to the criteria of Hanifin and Rajka with symptoms present for at least 6 months before the study and with atopy as shown by at least 1 positive skin test (weal size ≧ 3 mm) or 1 positive RAST (IgE ≥ 0.7 kU/L) test to any common food or environmental allergens. Randomisation was done at a 1:1 ratio: 55 participants were randomised in each arm

Excluded were patients on systemic corticosteroids, immunosuppressive therapy, or antibiotic or antimycotic treatment 4 weeks before the study, or using antihistamine 3 days before enrolment; and those who used probiotic preparations within 4 weeks before the study. Also excluded were patients with immune deficiency or other major medical problems

Setting: secondary paediatric centre

Country: Taiwan

Interventions

Four intervention arms: first arm received Lactobacillus paracasei GMNL‐133 (LP) at a dose of 2 × 10⁹ CFUs/d. Second arm received Lactobacillus fermentum GM‐090 (LF) at a dose of 2 × 10⁹ CFUs/d. Third arm received Lactobacillus paracasei GMNL‐133 (LP) and Lactobacillus fermentum GM‐090 (LF) at a dose of 4 × 10⁹ CFUs/d. Fourth arm received placebo. Interventions were given orally in capsule form for 3 months

During the study, corticosteroids, antibiotics, calcineurin inhibitors, antihistamines, and other probiotics were not permitted, with the exception of topical corticosteroids (fluticasone propionate) in case of severe flares and itching. All patients applied emollients and were educated on skin care

Outcomes

For AD: SCORAD, Children's Dermatology Life Quality Index (CDLQI) and Family Dermatology Life Quality Index (FDLQI) at baseline and at 1, 2, 3, and 4 months Changes in total serum IgE and skin prick test reactivity, serum and urine biomarkers, and faecal probiotic species composition at baseline and at 3 months

For asthma: GINA guideline asthma severity

Notes

Trial registration: NCT01635738. Approval by the Ethics Committee of the Taipei Hospital Ministry of Health and Welfare

GenMont Biotec Inc.: probiotic manufacturer that provided study costs for probiotics. No information on conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Participants were randomised, using computer‐generated 4‐block design lists, drawn up by a statistician, with stratification according to age, gender, AD severity, and current use of topical steroids"

Allocation concealment (selection bias)

Low risk

Comment: probably done and judged as having low risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Patients were enrolled by the investigator and sequentially assigned a patient number connected to a code. Capsules were prepared and coded by GenMont Biotec Inc, with cGMP facilities and dispensed by the study nurse" ‐ "All investigators, study nurses and participants were blind to treatment assignment for the duration of the study"

Judgement: probably done

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Patients were enrolled by the investigator and sequentially assigned a patient number connected to a code. Capsules were prepared and coded by GenMont Biotec Inc, with cGMP facilities and dispensed by the study nurse" ‐ "All investigators, study nurses and participants were blind to treatment assignment for the duration of the study"

Judgement: probably done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quotes: "Finally analysed 100% of LP, 96% of LF, 98% of LP + LF group, and 96% of placebo" ‐ "Intention‐to‐treat analysis regardless of compliance"

Judgement: low risk of attrition bias

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Unclear risk

GenMont Biotec Inc.: probiotic manufacturer that provided study costs for probiotics. It is not clear what the role of the sponsor was in data analysis and publication; hence the study was judged to be at unclear risk of bias

Methods

Eight‐week parallel‐group block randomised controlled trial

Participants

Fifty‐six children 6 to 18 months of age with moderate/severe eczema diagnosed by Hanifin and Rajka criteria and modified SCORAD score of at least 25 at enrolment Randomisation was done at a 1:1 ratio: 28 participants were randomised in each arm. Those previously exposed to probiotics, currently receiving antibiotics, or with other major medical problems were excluded

Setting: community and hospital outpatient clinic in Australia
Three participants lost to follow‐up

Interventions

Lactobacillus fermentum VR1‐003PCC 2 × 10⁹ CFUs/d as a sachet reconstituted by parents with 5 to 10 mL water twice daily, or maltodextrin placebo

Outcomes

• Global self‐assessment by parent*
• Dermatitis Family Impact Questionnaire (Lawson 1998)*
• SCORAD*
• Need for other eczema treatment ‐ topical corticosteroid. Assessments made at baseline and at 2, 4, 8, and 16 weeks*

*Denotes outcomes prespecified for this review

Notes

One probiotic‐treated participant withdrew due to gastrointestinal illness (vomiting)

Funding for principal investigator was provided by Research Fellowship by television channel and funding for IgE assay by VRI Biomedical. Probiotics and placebo supplied by manufacturer. No conflicts of interest declared

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A computerised randomisation schedule was prepared by the hospital biostatistician with allocation and dispensing of sachets by the pharmacy department" ‐ "The groups were stratified and block randomised according to following criteria: (a) modified SCORAD (25‐50; 50 and over), (b) current topical corticosteroid potency.... and (c) age..."

Comment: judged as adequate for low risk of bias

Allocation concealment (selection bias)

Low risk

Quote: "A computerised randomisation schedule was prepared by the hospital biostatistician with allocation and dispensing of sachets by the pharmacy department. The probiotic and placebo sachets were matched for size, shape and volume of contents"

Comment: third party involved in the allocation process and interventions were identical. Judged as adequate for low risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quotes: "The probiotic and placebo sachets were matched for size, shape and volume of contents" ‐ "A SCORAD assessment was also performed by a clinician blind to the intervention" ‐ "...a single investigator performed all SCORAD assessments at week 0, 8, and 16"

Comment: outcome assessor clearly stated as blinded and interventions probably identical. However no other information provided to clarify whether other personnel and the parents of infants were blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quotes: "The probiotic and placebo sachets were matched for size, shape and volume of contents" ‐ "A SCORAD assessment was also performed by a clinician blind to the intervention" ‐ "...a single investigator performed all SCORAD assessments at week 0, 8, and 16"

Comment: outcome assessor clearly stated as blinded and interventions probably identical. However no other information provided to clarify whether other personnel and the parents of infants were blinded, which may have affected patient/parent‐reported outcomes (DFI and global self‐assessment)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Available case analysis was used without exclusions after randomisation. Low rates of loss to follow‐up (5.4% overall; 7.1% in probiotic group and 3.6% in placebo group). Reasons for losses to follow‐up presented

Low risk of attrition bias for all outcomes

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting

Other bias

Low risk

No other bias found

Methods

Twelve‐week parallel‐group randomised double‐blind placebo‐controlled trial conducted between January 2007 and August 2008

Participants

Eighty‐eight children between 2 and 10 years of age with atopic eczema‐dermatitis syndrome (AEDS) defined as pruritic chronic or chronically relapsing non‐infectious dermatitis with features and distribution as suggested by Hanifin. Randomisation was done at a 1:1 ratio: 45 participants were randomised in the intervention arm, and 43 in the control arm. Participants had to have the disease for at least 6 months, with SCORAD ≥ 25 and change in SCORAD not more than 10% within the first 2 weeks

Excluded from the trial were patients who had used cyclosporine, systemic corticosteroids, topical calcineurin inhibitors, or Chinese herbal medicine during the 3 months before recruitment

Recruitment was carried out at a secondary care paediatric unit in Korea

Thirteen participants were lost to follow‐up

Interventions

Probiotic: freeze‐driedLactobacillus sakei KCTC 10755BP in microcrystalline cellulose dissolved in 2.5 to 5 mL of water or any liquid preferred by the participant at a dose of 5 × 10⁹ CFUs not otherwise specified for 12 weeks

Placebo: microcrystalline cellulose dissolved in 2.5 to 5 mL of water or any liquid preferred by the participant for 12 weeks

Standardised topical treatment for all participants: take a bath once daily with warm water for 5 to 10 minutes and apply an emollient immediately after bathing. Permitted to use topical corticosteroids as required but only 0.1% prednicarbate

Outcomes

• Total SCORAD and SCORAD part C*

• Amount of topical corticosteroid (TCS) used during the study, change in TCS use from baseline, and number of participants using TCS during the intervention*

*Denotes outcomes prespecified for this review

Notes

Research supported by the Basic Science Research Program, National Research Foundation of Korea

Funded by the Ministry of Education, Science and Technology, Korea. No conflicts of interest reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "patients were randomised in a double‐blind design..."

Comment: inadequate information for a judgement on risk of bias

Allocation concealment (selection bias)

Unclear risk

No information given

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "patients were randomised in a double‐blind design..."

Comment: inadequate information on which part was blinded and the method of blinding interventions; inadequate information for a judgement on risk of bias for blinding

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "patients were randomised in a double‐blind design..."

Comment: inadequate information on which part was blinded and the method of blinding interventions; inadequate information for a judgement on risk of bias for blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants were analysed in the group to which they were initially randomised. 4/45 participants (8.9%) from the probiotic group and 9/43 (21%) from the placebo group were lost to follow‐up and were excluded from analysis. The difference in losses to follow‐up in the 2 groups was found to be statistically insignificant (P = 0.11). Overall losses to follow up were low (14%)

Comment: judged as low risk for attrition bias

Selective reporting (reporting bias)

Low risk

All outcomes reported

Other bias

Low risk

Baseline characteristics presented only for participants who completed the study, but low rates of loss to follow‐up; hence the study was judged to be at low risk of bias

Methods

Ten‐week parallel‐group double‐blind randomised placebo‐controlled trial

Participants

Sixty children from 2 to 14 years of age with eczema diagnosed by Hanifin and Rajka criteria and moderate to severe disease (SCORAD > 25) who had eczema symptoms for at least 4 days before diagnosis. Randomisation was done at a 1:1 ratio: 30 children were randomised in each arm

Setting: secondary care with 1 recruiting centre in Taiwan

Six participants were excluded post randomisation but before treatment started

Interventions

Synbiotic: Lactobacillus salivarius PM‐A0006 2 × 10⁹ CFUs/25 mgr and fructo‐oligosaccharide 475 mgr in a capsule preparation twice daily

Control: corn starch 25 mgr and fructo‐oligosaccharide 475 mgr in a capsule twice daily

Outcomes

• SCORAD*

• 13‐item quality of life daily diary

• Global eczema severity

• SCORAD parameters for pruritus and sleep loss*

• Frequency of use of topical corticosteroid or calcineurin inhibitor (times/month)*

*Denotes outcomes prespecified for this review

Notes

Two probiotic‐treated participants initially had mild diarrhoea but overall tolerated treatment well

Sponsorship declared and no conflicts of interest reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The children were randomised into two groups...in a double‐blind manner using a computer‐generated blocked randomisation list provided by ProMD Biotech Co., Taiwan. A block size of four was used and stratified according to sex, age and diagnosis of moderate to severe AD"

Comment: judged as adequate for low risk of bias

Allocation concealment (selection bias)

Low risk

Quote: "The code was opened only after all data were analysed."

Comment: probably done, so judged as adequate for low risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The synbiotic and prebiotic products, which were identical in appearance, odour and taste, were delivered in numbered packages directly to the parents according to randomisation list. The code was opened only after all data were analysed" ‐ "the same investigator (KGW), who was blinded to group assignment, enrolled patients and performed all SCORAD assessments at weeks 0, 4, 8 and 10"

Comment: judged as adequate for low risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The synbiotic and prebiotic products, which were identical in appearance, odour and taste, were delivered in numbered packages directly to the parents according to randomisation list. The code was opened only after all data were analysed" ‐ "the same investigator (KGW), who was blinded to group assignment, enrolled patients and performed all SCORAD assessments at weeks 0, 4, 8 and 10"

Comment: judged as adequate for low risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Six participants (10% in total and in each group) withdrew after randomisation but before treatment initiation and were excluded from analysis. Reasons for withdrawal given and similar in both groups

Comment: low rates of excluded patients unlikely to have a significant impact on effect estimate; hence low risk of attrition bias

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting

Other bias

Low risk

No other bias found

Methods

Eight‐week parallel‐group 2‐centre randomised double‐blind placebo‐controlled trial

Participants

Sixty‐seven children 4 to 48 months of age with atopic dermatitis diagnosed using Hanifin‐Rajka criteria with SCORAD > 15 at enrolment. Randomisation was done at a 1:1 ratio: 34 participants were randomised in the intervention arm, and 33 in the control arm

Exclusion criteria: clinically evident infection in skin lesions, severe asthma or acute asthma attack within 3 months, autoimmune disease, immunodeficiency, exposure to phototherapy, use of systemic corticosteroids within 1 month

Interventions

Active: 1 capsule of ComProbi containing 350 mg ofLactobacillus rhamnosus (MP108) and maltodextrin per day

Control: 1 capsule of maltodextrin per day

If capsule could not be swallowed, parents were instructed to mix the powder in water, breast milk, milk, or food heated to < 40°C

Rescue medication: Cutivate cream (GlaxoSmithKline, Duhram, UK) in cases of uncontrolled symptoms

Outcomes

Primary

• Change in SCORAD after 8‐week treatment

Secondary

• Change in SCORAD at post‐baseline visits

• Frequency and total quantity of corticosteroids used during 8‐week treatment

• Comparison of frequency of atopic dermatitis and symptom‐free duration

• Comparisong of mean changes from baseline in IDQoL at weeks 4 and 8

• Comparisong of mean changes from baseline on Dermatitis Family Impact Questionnaire at weeks 4 and 8

Notes

Contact: [email protected]

Country: Taiwan

Study registration not given

CY Biotech provided probiotic, but it is not clear whether the company had a role in study design, data analysis, or interpretation or other aspects of the study. However, study authors declared no conflicts of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Inadequate information provided; stated that the study was "randomised"

Allocation concealment (selection bias)

Unclear risk

No information provided

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Study stated as "double‐blind", but no information provided to explain who was blinded and how blinding was done

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Study stated as "double‐blind", but no information provided to explain who was blinded and how blinding was done

Incomplete outcome data (attrition bias)
All outcomes

Low risk

3 (9%) from the probiotic arm and 1 (3%) from the control arm

Study authors present data derived from intention‐to‐treat analysis

Selective reporting (reporting bias)

Unclear risk

All predefined outcomes were at least described, but not all data were given. No clinical trial registration was given

Other bias

Unclear risk

CY Biotech provided probiotic, but it is not clear whether the company had a role in study design, data analysis or interpretation, or other aspects of the study. However study authors declared no conflict of interest

Hence we judged the study to be at unclear risk of commercial bias

Methods

Six‐week parallel‐group double‐blind placebo‐controlled randomised trial conducted between November 2010 and October 2011

Participants

One hundred children from 2 to 9 years of age with mild to moderate (SCORAD < 40) atopic dermatitis diagnosed according to the criteria of Hanifin and Rajka were recruited. Randomisation was done at a 1:1 ratio: 50 participants were randomised in each arm

Exposure to commercial probiotic products during the 4 weeks before the study

Premature children and those receiving antibiotic, systemic corticosteroid, immunosuppressive, or Chinese herbal therapies within 4 weeks before enrolment were excluded form the study. Also excluded were patients with acute gastrointestinal infection, chronic underlying disease, or baseline factors predisposing to infection (e.g. neurological disease; metabolic disease; chronic respiratory disease; congenital anomaly of the heart, gastrointestinal system, or lung; known or suspected immunodeficiency)

Recruitment took place at a tertiary paediatric centre in Korea

Twenty‐nine participants were lost to follow‐up

Interventions

Probiotic mixture: Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus plantarum, Bifidobacterium lactis in glucose anhydrous crystalline powder derived from cornstarch prepared in warm water or juice given orally immediately after meals twice daily at a dose of 1 × 10⁹ CFUs of each probiotic strain for 6 weeks

Control (placebo): glucose anhydrous crystalline powder prepared in warm water or juice given orally immediately after meals twice daily for 6 weeks

Instructions given to stop topical corticosteroids and calcineurin inhibitors, oral antihistamines, and any commercial probiotic‐containing products 2 weeks before study initiation

Parents were trained in appropriate bathing and skin care practices and were given instructions on application of emollients

Outcomes

• EASI score at baseline and end of treatment and change from baseline*

• VASP score at baseline and end of treatment and change from baseline*

*Denotes outcomes prespecified for this review

Notes

Study sponsored by the probiotic supplier; the supplier's role in data analysis and publication is unclear

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomisation software was used to randomly allocate children..."

Comment: computer‐generated and so judged as adequate for low risk of bias

Allocation concealment (selection bias)

Low risk

Comment: third party ‐ not involved in the trial ‐ allocated treatment. Study judged as adequate for low risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "The probiotics mixture and placebo controls were identical in colour, taste, smell, packing and manner of administration. All formulations were dispensed by a pharmacist not associated with the study.", "both investigators and study subjects were blinded to the identity of the intervention"

Comment: not clear if clinicians were blinded; patients were blinded; judged as having unclear risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "The probiotics mixture and placebo controls were identical in colour, taste, smell, packing and manner of administration. All formulations were dispensed by a pharmacist not associated with the study" ‐ "both investigators and study subjects were blinded to the identity of the intervention"

Comment: not clear if outcome assessor was blinded; judged as having unclear risk of bias

Incomplete outcome data (attrition bias)
All outcomes

High risk

Available case analysis but high rates of loss to follow‐up (29%: 26% in probiotic group and 32% in placebo group), which were excluded from analysis

Comment: effect estimate for all outcomes may have been affected; judged as having high risk of attrition bias

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting

Other bias

Unclear risk

Study sponsored by the probiotic supplier, and the supplier's role in data analysis and publication is unclear. Therefore the study was judged to be at unclear risk of bias

Methods

Eight‐week parallel‐group double‐blind randomised placebo‐controlled trial

Participants

Forty children 1 to 13 years of age with atopic dermatitis diagnosed according to Hanifin and Rajka criteria and with moderate to severe disease. Randomisation was done at a 1:1 ratio: 20 participants were randomised in each arm. Excluded were patients on medication including antihistamines and corticosteroids for 14 days before recruitment, as well as those with malabsorption. One participant was lost to follow‐up

Interventions

Probiotic mixture:Bifidobacterium bifidum,Lactobacillus acidophilus,Lactobacillus casei,Lactobacillus salivarius given orally at a dose of 2 × 10⁹ CFUs and a total daily dose of 4 × 10⁹ CFUs for 8 weeks

Placebo: skim milk powder and dextrose

Outcomes

SCORAD at baseline and at 8 weeks*

*Denotes outcomes prespecified for this review

Notes

Conflicts of interest/sponsorship not declared

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The patients were referred to a nurse who was involved in the study to receive either probiotic or placebo. The nurse randomised each patient to two different treatment groups using the closed‐envelope method"

Comment: not clear how the "closed envelopes" had been created and whether the sequence generation had been random. Judged as having unclear risk of bias

Allocation concealment (selection bias)

Low risk

Quote: "Closed envelope method"

Comment: probably done; judged as adequate for low risk of bias

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "The patients were referred to a nurse who was involved in the study to receive either probiotic or placebo. The nurse randomised each patient to two different treatment groups using the closed‐envelope method. The authors had no role in the treatment decision and were blinded to the treatment groups"

Comment: inadequate information provided on which parts were blinded and whether the interventions were identical. Judged as having unclear risk of bias

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: "The patients were referred to a nurse who was involved in the study to receive either probiotic or placebo. The nurse randomised each patient to two different treatment groups using the closed‐envelope method. The authors had no role in the treatment decision and were blinded to the treatment groups"

Comment: inadequate information on which parts were blinded and whether interventions were identical. Judged as having unclear risk of bias

Incomplete outcome data (attrition bias)
All outcomes

Low risk

One participant from the placebo group was lost to follow‐up (2.5%). Available case analysis was used. Very few losses to follow‐up were unlikely to affect the effect estimate for any outcome

Selective reporting (reporting bias)

Low risk

All outcomes reported. Differences between probiotic and placebo not given but reported narratively: "Our results demonstrated an improved SCORAD index in both groups, but with higher levels in the probiotic group (65%) than in the placebo group (46%). In the probiotic group, a greater decrease of SCORAD index scores was shown after treatment in patients with high SCORAD index scores. However this difference did not reach a statistically significant level"

Other bias

Unclear risk

Conflicts of interest/sponsorship not declared

Baseline characteristics of 2 groups not given. Uncertain if they were matched

Judged to be at uncertain risk of other bias

Methods

Eight‐week parallel‐group placebo‐controlled trial

Participants

Twenty‐four adults with atopic dermatitis diagnosed according to the Guideline for Management of AD by the Japanese Dermatological Association were recruited and randomised at a 2:1 ratio of intervention:control (16 participants in intervention arm/8 participants in control arm)

Recruitment took place in a centre in Japan

No participants were lost to follow‐up

Interventions

Probiotic: Bifidobacterium breve (lyophilised powder of live B breve YY) in a capsule preparation at a dose of 1.0 × 10¹º CFUs/capsule taken twice daily after breakfast and after dinner for 8 weeks

Placebo not described

Outcomes

• SCORAD: total, objective, subjective*

• Japanese version of Skindex‐29*

*Denotes outcomes prespecified for this review

Notes

Sponsorship was not declared, but 2 of the authors of the report are linked to the supplier of the probiotic

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Test meals for 24 subjects were randomly allocated..."

Comment: no other information provided; judged as having unclear risk

Allocation concealment (selection bias)

Unclear risk

No information given

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information given

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information given

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up. All participants analysed

Selective reporting (reporting bias)

Low risk

No evidence of selective reporting

Other bias

High risk

Selection bias: baseline SCORAD scores not matched between the 2 groups

Commercial bias: sponsorship not declared but 2 of the authors of the report linked to the supplier of the probiotic; this may have affected the outcome

Study was judged to have high risk of other bias