From the Cochrane Library: Probiotics for treating eczema

To the Editor: Eczema characterized by noninfectious chronic pruritic inflammation is a common inflammatory skin condition in children and adults. In 1 study, stool of allergy-prone infants contained fewer Lactobacillus sp and Bifidobacteria sp compared to healthy infants,1Björkstén B. Sepp E. Julge K. Voor T. Mikelsaar M. Allergy development and the intestinal microflora during the first year of life.J Allergy Clin Immunol. 2001; 108: 516-520https://doi.org/10.1067/mai.2001.118130Google Scholar suggesting associations between intestinal microbiota and eczema development. Therefore, targeting the gut microbiome has been proposed for eczema interventions, although its role is uncertain.2Sidbury R. Tom W.L. Bergman J.N. et al.Guidelines of care for the management of atopic dermatitis: section 4. Prevention of disease flares and use of adjunctive therapies and approaches.J Am Acad Dermatol. 2014; 71: 1218-1233https://doi.org/10.1016/j.jaad.2014.08.038Google Scholar Probiotics (live microorganisms, especially lactic acid bacteria Lactobacillus sp and Bifidobacteria sp) are ingested orally and can modify intestinal microbiota with potential immunomodulatory effects, along with aiding lactose digestion and preventing diarrhea. Because they are consumed worldwide in fermented milk products, probiotics may be a promising and accessible approach to eczema prevention and treatment. A 2018 Cochrane systematic review, “Probiotics for Treating Eczema,” offered a comprehensive assessment of evidence from randomized controlled trials (RCTs).3Makrgeorgou A. Leonardi-Bee J. Bath-Hextall F.J. et al.Probiotics for treating eczema.Cochrane Database Syst Rev. 2018; 11: CD006135https://doi.org/10.1002/14651858.CD006135.pub3Google Scholar The review included 39 RCTs for a total of 2599 participants with eczema, of either sex, and aged from the first year of life to 55 years. Probiotic dosage (mainly Lactobacillus and Bifidobacteria strains) and duration of treatment varied, with follow-up for most studies ranging from 3 weeks to 3 months (Tables I and II). At the conclusion of active probiotics treatment spanning 6 weeks to 3 months, the impact on participant- or parent-rated eczema symptoms was slight to none as compared to no treatment with probiotics (13 RCTs, 754 patients; −0.44 score [0-20 severity]; 95% CI [confidence intervals] [−1.22, 0.33]). Conversely, severity SCORAD (SCORing Atopic Dermatitis) symptoms, including itch and sleep loss ratings from investigators and participants, showed mild improvement after probiotics treatment (24 RCTs, 1596 patients; −3.91 [0-103 total SCORAD points]; 95% CI [−5.86, −1.96]). However, clinical significance is uncertain below SCORAD's suggested minimum clinically important difference of 8.7 points. Probiotics also were not significantly associated with differences in validated quality of life measures (6 RCTs, 552 patients; standardized mean difference, 0.03; 95% CI [−0.36, 0.42]), or risks of reported adverse events (all gastrointestinal symptoms, 7 RCTs, 402 patients; risk ratio, 1.54; 95% CI [0.90, 2.63]). Overall, extensive heterogeneity of results and moderate-to-low evidence quality limited the generalizability of findings. High follow-up losses (23%-30% in 6 RCTs) and potential attrition bias were also noted.Table ICharacteristics of 23 single-strain probiotic eczema treatment studies summarized in Cochrane reviewStudy ID∗Studies were ordered by study ID used in the primary Cochrane systematic review.3NParticipant ageProbiotics single-strain interventionCo-interventionPrebiotic†Prebiotics are nondigestible sugars (found in some foods) encouraging growth of certain intestinal bacteria.PlaceboEczema-related outcomes measuredFollow-up period151<5 monthsL rhamnosus or L GG (5 × 10⁹ CFU/100 mL per feed)Extensively hydrolyzed whey-based formula and elimination dietNoNot specifiedSCORAD; total immunoglobulin E; food-specific immunoglobulin E3 months33818-46 yearsL salivarius in maltodextrin (10⁹ CFU/g 2x daily)NoneNoMaltodextrin aloneSCORAD, Dermatology Life Quality Index20 weeks42525-63 yearsL salivarius (5 × 10⁹ CFU), Streptococcus thermophilus (2 × 10⁹ CFUs), and tara gum (125 mg) mixNoneNoMaltodextrinSCORAD; Staphylococcus aureus and clostridia fecal counts30 days7541-55 monthsL GG (total 1010 CFU/day)NoneNoMicrocrystalline celluloseSCORAD; Parent global assessment; QoL; topical steroid or systemic antihistamine use8 weeks9507-24 monthsArm 1: L acidophilus, Arm 2: B lactis, dose 1010 CFU/day in placebo mix (Arm 3: cellulose, silicone dioxide, rice maltodextrin)NoneNoCellulose, silicon dioxide, rice maltodextrinSCORAD8 weeks101373-6 monthsArm 1: B lactis, Arm 2: L paracasei, 1010 CFU/day in maltodextrinExtensively hydrolyzed formula and elimination dietNoMaltodextrinSCORAD; QoL; topical steroid, emollient, or other eczema treatment use12 weeks11503 months-4 yearsL reuteri (108 CFU/day)NoneNoNot specifiedSCORAD; subjective itch/sleep loss; steroid use12 months121063-12 monthsL GG (total 1010 CFU/day)NoneNoNot specifiedSCORAD; 1% hydrocortisone ointment use12 weeks141181-13 yearsL plantarum (0.5 × 1010 CFU 2x day)NoneNoMaltodextrin and anhydrous glucoseSCORAD, topical corticosteroid use16 weeks1727InfantsL GG (3 × 108 CFU/g) or B lactis (109 CFU/g) in formulaExtensively hydrolyzed whey-based formulaNoCo-intervention aloneSCORADUnclear1927Infants (5.5 months mean)L GG 3 × 1010 CFU/kg/day in formulaExtensively hydrolyzed whey-based formulaNoCo-intervention aloneSCORADUnclear2044<3 yearsB bifidum capsules (no concentration specified)NoneNoNo treatmentSCORAD; B bifidum stool levels4 weeks21312-16 monthsL GG 5 × 108 CFU/g in formulaExtensively hydrolyzed formula, elimination diet, topical treatmentNoCo-intervention aloneSCORAD1 month2244AdultsB lactis 6 × 109 CFU capsules in skim milk, glucose, inulin, dextrin, and silicone dioxide excipientNoneNoExcipient onlyItch score behavioral rating/visual analog scale; skin severity score; QoL; fecal B lactis levels8 weeks2339InfantsL rhamnosus GG (3.4 × 109 CFU/day) in formulaExtensively hydrolyzed casein formulaNoCo-intervention aloneSCORAD3 months24482-12 yearsL rhamnosus (3.6 × 109 CFU/day) in skim milk powder, potato starch, and lactose-containing prebiotic mixtureLactose-containing prebioticYesMixture onlySCORAD; Parent-, participant-, or investigator-rated global assessment of eczema severity3 months29173-18 monthsB breve (5-15 × 109 CFU/day) in formulaExtensively hydrolyzed cow's milk formula and raffinose prebioticYesCo-intervention aloneInvestigator-rated eczema scoring3 months30900-7 monthsB breve (1.3 × 109 CFU/100 ml) in formulaExtensively hydrolyzed whey-based formula and prebiotic (90% galacto-oligosaccharide and 10% fructo-oligosaccharide)YesCo-intervention aloneSCORAD; topical steroid use12 weeks33566-18 monthsL fermentum (2 × 109 CFU/day)NoneNoMaltodextrinSCORAD; Parent global assessment; Dermatology Family Impact; topical corticosteroid use8 weeks34882-10 yearsL sakei (5 × 109 CFU not specified)Standardized topical treatmentNoMicrocrystalline celluloseSCORAD; topical corticosteroid use12 weeks35602-14 yearsL salivarius (2 × 10⁹ CFU/25 mg)Fructo-oligosaccharideYesCo-intervention aloneSCORAD; QoL; global eczema severity, topical corticosteroid or calcineurin inhibitor use10 weeks36674-48 monthsL rhamnosus and maltodextrin (350 mg/day)NoneNoMaltodextrin aloneSCORAD; topical corticosteroid use; symptom-free duration; QoL; Dermatology Family Impact8 weeks3924AdultsB breve (2 × 1010 CFU/day)NoneNoNot SpecifiedSCORAD; Japanese Skindex-298 weeksArm, Treatment arm; B, Bifidobacterium; CFU, colony-forming unit; GG, Gorbach-Goldin; L, Lactobacillus; QoL, Quality of Life; SCORAD, Severity SCORing of Atopic Dermatitis.∗ Studies were ordered by study ID used in the primary Cochrane systematic review.3Makrgeorgou A. Leonardi-Bee J. Bath-Hextall F.J. et al.Probiotics for treating eczema.Cochrane Database Syst Rev. 2018; 11: CD006135https://doi.org/10.1002/14651858.CD006135.pub3Google Scholar† Prebiotics are nondigestible sugars (found in some foods) encouraging growth of certain intestinal bacteria. Open table in a new tab Table IICharacteristics of 16 mixed-strain probiotic eczema treatment studies summarized in Cochrane reviewStudy ID∗Studies were ordered by study ID used in the primary Cochrane systematic review.3NParticipant ageProbiotics Mixture interventionCo-interventionPrebiotic†Prebiotics are nondigestible sugars (found in some foods) encouraging growth of certain intestinal bacteria.PlaceboEczema-related outcomes measuredFollow-up period260<2 yearsL casei and L paracasei mix (total 10⁹ CFU/day)Elimination dietNoHydrolyzed caseinSCORAD8 months5523 months-6 yearsL casei, L rhamnosus, Streptococcus thermophilus, B breve, L acidophilus, B infantis, and L bulgaricus mix (10⁹ CFU/g 2x daily)Fructo-oligosaccharideYesNot specifiedSCORAD8 weeks6130-3 yearsL acidophilus, L casei, L salivarius, L lactis, B infantis, B lactis, and B longum mix (total 10⁹ CFU/day) in rice starch and maltodextrinNoneNoRice starch and maltodextrinSCORAD; allergen-specific T- and B- cell response; Immunoglobulin E levels; skin prick3 months8961-3 yearsL acidophilus and B lactis (5 × 10⁹ CFU/g) with fructo-oligosaccharide in rice maltodextrinNoneNoRice maltodextrinSCORAD; Quality of Life; Dermatology Family Impact; topical steroid use8 weeks131802 months-3 yearsBifidobacterium, Lactobacillus, Enterococcus, and Bacillus cereus tablets (no concentration specified), routine symptomatic treatmentNoneNoControl arm routine symptomatic treatmentInterleukin (IL) 4, IL-10, Immunoglobulin E, IFN-γ; Th1:Th2 ratio; eczema relapse or improvement3 months15119<6 monthsL casei, B lactis, 107 CFU/g formula eachExtensively hydrolyzed formulaNoCo-intervention aloneSCORAD; cow's milk tolerance; T- and B-cells18 months164818-55 yearsL salivarius and B breve (109 CFU/g each daily) in maltodextrinNoneNoMaltodextrin aloneSCORAD; Dermatology Life Quality Index20 weeks18603-12 monthsB lactis (109 CFU/day) and Streptococcus thermophilus (108 CFU/day)Elimination dietNoNot specifiedSCORAD8 weeks251618-40 yearsStreptococcus thermophilus with L paracasei (7.8 × 1010 CFU/day), L acidophilus (5.8 × 106 CFU/day), and B lactis (1.2 × 107 CFU/day)NoneNoNot specifiedSCORAD20 weeks26581-13 yearsL rhamnosus and L reuteri 2 × 1010 CFU/day eachNoneNoSkim milk powder with dextrose anhydrateSCORAD; parent- or participant-rated global self-assessment; need for topical corticosteroids6 weeks27411-36 months7-strain probiotic/synbiotic (total 109 CFU/day) and fructo-oligosaccharideFructo-oligosaccharideYesSucroseSCORAD11 months28601-10 yearsL rhamnosus and B lactis (total 2 × 1010 CFU/day)NoneNoMicrocrystalline celluloseSCORAD12 weeks31252<12 monthsL GG (1010 CFU/day), or L GG (1010 CFU/day), B breve (4 × 10⁸ CFU/day), L rhamnosus (1010 CFU/day), and Propionibacterium (4 × 10⁹ CFU/day) mixExtensively hydrolyzed formula and elimination dietNoMicrocrystalline cellulose and study formulaSCORAD4 weeks322201-18 yearsArm 1: L paracasei (2 × 109 CFU/day); Arm 2: L fermentum (2 × 109 CFU/day); Arm 3: L paracasei and L fermentum (total 4 × 109 CFU/day); Arm 4: placeboNoneNoUnspecified study formulaSCORAD; Dermatology Life Quality Index, Total immunoglobulin E; skin prick; serum and urine biomarkers; fecal probiotic species composition21 months371002-9 yearsL casei, L rhamnosus, L plantarum, B lactis (109 CFU/day each) in glucose anhydrous crystalline powderNoneNoGlucose anhydrous crystalline powderEczema Area Severity Index; Visual Analogue Scale of Pruritus6 weeks38401-13 yearsB bifidum, L acidophilus, L casei, L salivarius (total 4 × 10⁹ CFU/day)NoneNoSkim milk powder with dextroseSCORAD8 weeksB, Bifidobacterium; CFU, colony-forming unit; IFN-γ, interferon gamma; L, Lactobacillus; SCORAD, Severity SCORing of Atopic Dermatitis; Th1, T helper type 1 cells; Th2, T helper type 2 cells; GG, Gorbach-Goldin; Arm, treatment arm.∗ Studies were ordered by study ID used in the primary Cochrane systematic review.3Makrgeorgou A. Leonardi-Bee J. Bath-Hextall F.J. et al.Probiotics for treating eczema.Cochrane Database Syst Rev. 2018; 11: CD006135https://doi.org/10.1002/14651858.CD006135.pub3Google Scholar† Prebiotics are nondigestible sugars (found in some foods) encouraging growth of certain intestinal bacteria. Open table in a new tab Arm, Treatment arm; B, Bifidobacterium; CFU, colony-forming unit; GG, Gorbach-Goldin; L, Lactobacillus; QoL, Quality of Life; SCORAD, Severity SCORing of Atopic Dermatitis. B, Bifidobacterium; CFU, colony-forming unit; IFN-γ, interferon gamma; L, Lactobacillus; SCORAD, Severity SCORing of Atopic Dermatitis; Th1, T helper type 1 cells; Th2, T helper type 2 cells; GG, Gorbach-Goldin; Arm, treatment arm. Thus, the present use of probiotics for eczema treatment may not be evidence-based, corroborating recent recommendations.2Sidbury R. Tom W.L. Bergman J.N. et al.Guidelines of care for the management of atopic dermatitis: section 4. Prevention of disease flares and use of adjunctive therapies and approaches.J Am Acad Dermatol. 2014; 71: 1218-1233https://doi.org/10.1016/j.jaad.2014.08.038Google Scholar After the Cochrane review, subsequent surveys of probiotics RCTs for systemic atopic eczema therapy found that decreased participant diversity (eg, male-biased participant distribution) and lack of blinding were contributors to an increase in the number of placebo responses.4Lee H.H. Patel K.R. Rastogi S. et al.Placebo responses in randomized controlled trials for systemic therapy in atopic dermatitis: a systematic review and meta-analysis.J Am Acad Dermatol. 2020; 82: 62-71https://doi.org/10.1016/j.jaad.2019.05.102Google Scholar This encourages additional blinded studies of participant subgroups with different allergies or skin types, because decreased diversity in the cutaneous microbiome also may be correlated with the severity atopic dermatitis and an increase in pathogenic bacteria (eg, Staphylococcus aureus) colonization.5Paller A.S. Kong H.H. Seed P. et al.The microbiome in patients with atopic dermatitis.J Allergy Clin Immunol. 2019; 143: 26-35https://doi.org/10.1016/j.jaci.2018.11.015Google Scholar Additionally, although not currently observed in probiotics RCTs, infection and sepsis have been reported in immunocompromised individuals or those with comorbidities.3Makrgeorgou A. Leonardi-Bee J. Bath-Hextall F.J. et al.Probiotics for treating eczema.Cochrane Database Syst Rev. 2018; 11: CD006135https://doi.org/10.1002/14651858.CD006135.pub3Google Scholar Healthy individuals on probiotics have also presented with sporadic cases of other acute gastrointestinal disturbances.3Makrgeorgou A. Leonardi-Bee J. Bath-Hextall F.J. et al.Probiotics for treating eczema.Cochrane Database Syst Rev. 2018; 11: CD006135https://doi.org/10.1002/14651858.CD006135.pub3Google Scholar Further investigation of this and dose-stratified studies of particular bacterial strains with standardized outcomes (eg, Harmonizing Outcomes Measures for Eczema) validated quality of life scores, and longer follow-ups (>6 months) are necessary to elucidate the long-term effects of probiotic usage. Dr Boyle participates in the advisory boards at DBV Technologies and Prota Therapeutics; is a Senior Editor and Joint Coordinating Editor at Cochrane; and gives expert testimony in cases concerning food anaphylaxis and a class action concerning infant formula health claims. Dr Dellavalle is a Joint Coordinating Editor for Cochrane Skin, a dermatology section editor for UpToDate, a Social Media Editor for the Journal of the American Academy of Dermatology, a podcast editor for the Journal of Investigative Dermatology (JID), Editor-in-Chief of the Journal of Medical Internet Research (JMIR) Dermatology, and a coordinating editor representative on Cochrane Council. Dr Sivesind is a Section Editor for JMIR Dermatology. Authors Szeto, Hassan, Hamp, and Anderson and Drs Anderson, Laughter, Makrygeorgou, and Boyle have no conflicts of interest to disclose.