A clinical reading on “World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics”

Abstract

This article was originally published online on 10 March 2016 Since the immunomodulatory properties of probiotics have been described, the effect of probiotic supplementation has been investigated in several trials and it has been also proposed as a preventive intervention for the development of allergic diseases. Recently two important evidence-based recommendations about the use of probiotics in the prevention of allergy were published [1.Fiocchi A, Pawankar R, Cuello-Garcia C, Ahn K, Al-Hammadi S, Agarwal A, et al. World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics. World Allergy Organ J. 2015;8:4.Google Scholar, 2.Muraro A. Halken S. Arshad S.H. Beyer K. Dubois A.EJ. Du Toit G. et al.EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy.Allergy. 2014; 69: 590-601Crossref PubMed Scopus (345) Google Scholar] with conflicting conclusions, in particular the most recent guideline [1.Fiocchi A, Pawankar R, Cuello-Garcia C, Ahn K, Al-Hammadi S, Agarwal A, et al. World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics. World Allergy Organ J. 2015;8:4.Google Scholar] seems to be partially in contradiction with the previous statements about prevention of eczema. For these reasons, we tried to analyze the evidences leading to these recommendations [1.Fiocchi A, Pawankar R, Cuello-Garcia C, Ahn K, Al-Hammadi S, Agarwal A, et al. World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics. World Allergy Organ J. 2015;8:4.Google Scholar] to highlight the aspects that can be more directly related or correlated with clinical practice. This clinical reading was addressed to offer some reflections about the methods used to formulate such recommendations, and the possibility to adopt in the clinical practice the proposed conclusions. We tried to retraces the path proposed by the Authors to analyse three important questions about the efficacy of probiotics in preventing allergic diseases if administrated to pregnant women (first question), to breastfeeding mothers (second question) and in healthy infants (third question). These questions have been investigated by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [3.GRADE Working GroupGrading quality of evidence and strength of recommendations.BMJ. 2004; 328: 1490-1494Crossref PubMed Google Scholar], to perform a systematic review of randomized controlled trials and formulate recommendations. In summary, the GRADE method aims to define a rigorous and explicit method for the production of clinical recommendations. According to this method, the knowledge of advantages and disadvantages, benefits and risks of an intervention is necessary to make decisions in the health field. The GRADE approach also provides a three-phases decisional framework: a) formulation of a clinical question, with the choice and the formal evaluation of its related outcomes, and systematic evaluation of the scientific literature and the quality of the evidence; b) evaluation of the benefits and risks associated to the intervention, taking also in consideration its feasibility, the necessary resources and the patients’ preferences; c) formal definition of the strength of the recommendation. From a methodological point of view, it should be noted that the recommendations are directed to patients, clinicians and other health care professionals with different objectives, as clearly explained in the guidelines introduction. Each recommendation can have different levels of strength: strong recommendation indicates that patients would like to receive the intervention and that clinicians should actuate it. Conditional or weak recommendation indicates that the majority of patients would like to receive the intervention, but many other not, as well as they hope that clinicians would recognize that different choices may be appropriate for different patients, by taking advantage of decision-making tools to help patients to make consistent choices. In the results section of the guidelines we can read that “Currently available evidence does not indicate that probiotic supplementation reduces the risk of developing allergy in children. However, considering all critical outcomes in this context, the World Allergy Organization (WAO) guideline panel determined that there is a likely net benefit from using probiotics resulting primarily from prevention of eczema” [1.Fiocchi A, Pawankar R, Cuello-Garcia C, Ahn K, Al-Hammadi S, Agarwal A, et al. World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics. World Allergy Organ J. 2015;8:4.Google Scholar]. In the first sentence, the guideline panel confirmed the absence of evidence of effectiveness in the use of probiotics in the primary prevention of the common allergic diseases (asthma, food allergy, rhinitis). The second sentence deserves a careful review, because it seems to contradict the meaning of the first sentence and the position of the other guidelines, including the recent European Academy of Allergy and Clinical Immunology (EAACI) guideline [2.Muraro A. Halken S. Arshad S.H. Beyer K. Dubois A.EJ. Du Toit G. et al.EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy.Allergy. 2014; 69: 590-601Crossref PubMed Scopus (345) Google Scholar]. In order to comment this phrase, we started from the description of the evidences (GRADE) in Appendix 2 - Question 1: “Should probiotics vs. no probiotics be used in pregnant women?” In this appendix we can found declared how many studies addressing this question have been selected for each of the clinical objectives: 15 randomized trials were considered for the prevention of eczema. The comment of this question can be also reliable if it is applied to the other two questions above, as approximately the same studies have been selected for critical review. In this regard, we carefully examined the individual trials to better analyze and understand the results of the question. The most important clinical features that supported our considerations are reported in Table 1 and Table 2.Table 1Characteristics of the 15 trials included in the meta-analysis and addressing the guideline’s Question 1: “Should probiotics vs. no probiotics be used in pregnant women?”.ReferencesPopulation at risk of atopyN° patientsProbioticDuration of ante-partum therapyDuration of therapy in breastfed infantsDuration of therapy in infants fed with formulasKalliomaki et al. 2001 [4.Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: A randomised placebo-controlled trial. Lancet. 2001;357:1076–9.Google Scholar]yes159Lactobacillus rhamnosus GG (ATCC 55103)2-4 weeks6 months6 monthsRautava et al. 2002 [5.Rautava S. Kalliomaki M. Isolauri E. Probiotics during pregnancy and breastfeeding might confer immunomodulatory protection against atopic disease in the infant.J Allergy Clin Immunol. 2002; 109: 119-121Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar]aAnalysis of a subgroup of patients previous analyzed by Kalliomaki et al. [4]yes62Lactobacillus rhamnosus GG (ATCC 53103)4 weeks3 months3 monthsAbrahamsson et al. 2007 [6.Abrahamsson TR, Jakobsson T, Bottcher MF, Fredrikson M, Jenmalm MC, Bjorksten B, et al. Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2007;119:1174–80.Google Scholar]yes232Lactobacillus reuteri (ATCC55730)4 weeks12 months12 monthsKukkonen et al. 2007 [7.Kukkonen K. Savilahti E. Haahtela T. Juntunen-Backman K. Korpela R. Poussa T. et al.Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: A randomized, double-blind, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 192-198Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar]yes1223Lactobacillus rhamnosus GG (ATCC 55103), Lactobacillus rhamnosus LC705 (DSM7061), Bifidobacterium breve Bb99 (DSM13692), Propionibacterium freudenreichiii ssp shermanii JS (DSM7076)2-4 weeks6 months6 monthsHuurre et al. 2008 [8.Huurre A, Laitinen K, Rautava S, Korkeamäki M, Isolauri E. Impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization: A double-blind placebo-controlled study. Clin Exp Allergy. 2008;38:1342–8.Google Scholar]yes171Lactobacillus rhamnosus GG (ATCC 55103) Bifidobacterium lactis Bb126 monthsend of breastfeeding-Marschan et al. 2008 [9.Marschan E. Kuitunen M. Kukkonen K. Poussa T. Sarnesto A. Haahtela T. et al.Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation.Clin Exp Allergy. 2008; 38: 611-618Crossref PubMed Scopus (144) Google Scholar]bAnalysis of a subgroup of patients previous analyzed by Kukkonen et al. [7]yes98Lactobacillus rhamnosus GG (ATCC 55103), Lactobacillus rhamnosus LC705 (DSM7061), Bifidobacterium breve Bb99 (DSM13692), Propionibacterium freudenreichiii ssp shermanii JS (DSM7076)2-4 weeks6 months6 monthsWickens et al. 2008 [10.Wickens K. Black P.N. Stanley T.V. Mitchell E. Fitzharris P. Tannock G.W. et al.A differential effect of 2 probiotics in the prevention of eczema and atopy: A double-blind, randomized, placebo-controlled trial.J Allergy Clin Immunol. 2008; 122: 788-794Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar]yes512Lactobacillus rhamnosus HN001, Bifidobacterium animalis subspec lactis HN0195 weeks6 months24 monthsKopp et al. 2008 [11.Kopp M.V. Hennemuth I. Heinzmann A. Urbanek R. Double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical effects of Lactobacillus GG supplementation.Pediatrics. 2008; 121: e850-856Crossref PubMed Scopus (346) Google Scholar]yes105Lactobacillus rhamnosus GG ( ATCC 53103)4-6 weeks6 months6 monthsNiers et al. 2009 [12.Niers L. Martin R. Rijkers G. Sengers F. Timmerman H. van Uden N. et al.The effects of selected probiotic strains on the development of eczema (the PandA study).Allergy. 2009; 64: 1349-1358Crossref PubMed Scopus (203) Google Scholar]yes156Bifidobacterium bifidum W23, Bifidobacterium lactis W52 Lactococcus lactis W586 weeks12 monthsDotterud et al. 2010 [13.Dotterud CK, Storro O, Johnsen R, Oien T. Probiotics in pregnant women to prevent allergic disease: a randomized, double-blind trial. Br J Dermatol. 2010;163:616–23.Google Scholar]no415Lactobacillus rhamnosus GG, Bifidobacterium animalis subsp.Bb-12, Lactobacillus acidophilus La-54 weeks3 monthsKim et al. 2010 [14.Kim JY, Kwon JH, Ahn SH, Lee SI, Han YS, Choi YO, et al. Effect of probiotic mix (Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus) in the primary prevention of eczema: A double-blind, randomized, placebo-controlled trial. Pediatr Allergy Immunol. 2010;21:e386–93.Google Scholar]yes112Bifidobacterium bifidum BGN4, Bifidobacterium lactis AD011, Lactobacillus acidophilus AD0318 weeks3 months4-6 monthsBoyle et al. 2011 [15.Boyle RJ, Ismail IH, Kivivuori S, Licciardi PV, Robins-Browne RM, Mah LJ, et al. Lactobacillus GG treatment during pregnancy for the prevention of eczema: a randomized controlled trial. Allergy. 2011;66:509–16.Google Scholar]yes250Lactobacillus rhamnosus GG ( ATCC 53103)4 weeksOu et al. 2012 [16.Ou C.Y. Kuo H.C. Wang L. Hsu T.Y. Chuang H. Liu C.A. et al.Prenatal and postnatal probiotics reduces maternal but not childhood allergic diseases: A randomized, double-blind, placebo-controlled trial.Clin Exp Allergy. 2012; 42: 1386-1396Crossref PubMed Scopus (77) Google Scholar]Yes (maternal hystory)191Lactobacillus rhamnosus GG ( ATCC 53103)4 months6 months6 monthsAllen et al. 2012 [17.Allen S.J. Jordan S. Storey M. Thornton C.A. Gravenor M.B. Garaiov I. et al.Probiotics and atopic ECZEMA: A double-blind randomised controlled trial.Arch Dis Child. 2012; 97: A2Crossref Google Scholar]the most of partecipants454Lactobacillus salivarius CUL61, Lactobacillus paracasei CUL08, Bifidobacteriums animalis ssp. lactis CUL34, Bifidobacterium bifidum CUL204 weeks6 months6 monthsRautava et al. 2012 [18.Rautava S. Kainonen E. Salminen S. Isolauri E. Maternal probiotic supplementation during pregnancy and breast-feeding reduces the risk of eczema in the infant.J Allergy Clin Immunol. 2012; 130: 1355-1360Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar]yes241Lactobacillus rhamnosus LP + Bifidobacterium longum (ATCC BAA-999)orLactobacillum paracasei ST11 + Bifidobacterium longum (ATCC BAA-999 )2 months2 monthsa Analysis of a subgroup of patients previous analyzed by Kalliomaki et al. [4.Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: A randomised placebo-controlled trial. Lancet. 2001;357:1076–9.Google Scholar]b Analysis of a subgroup of patients previous analyzed by Kukkonen et al. [7.Kukkonen K. Savilahti E. Haahtela T. Juntunen-Backman K. Korpela R. Poussa T. et al.Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: A randomized, double-blind, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 192-198Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar] Open table in a new tab Table 2Main clinical characteristics related to the diagnosis of eczema in 15 trials included in the meta-analysis for the guideline’s Question 1: “Should probiotics vs. no probiotics be used in pregnant women?”.ReferencesDuration of follow up (months)Diagnostic criteria for eczemaPatients evaluable at the end of follow-up periodPersistence of eczemaAllergic sensitizationPROBIOTICPLACEBOP value%P valueKalliomaki et al. 2001 [4.Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: A randomised placebo-controlled trial. Lancet. 2001;357:1076–9.Google Scholar]24Harrigan 199964/77 68/82 (Pl)15/64 23 %31/68 46 %0.008(sIgE) 27 % vs 25 % (Pl) (SPT) 18 % vs 14 % (Pl)NS NSRautava et al. 2002 [5.Rautava S. Kalliomaki M. Isolauri E. Probiotics during pregnancy and breastfeeding might confer immunomodulatory protection against atopic disease in the infant.J Allergy Clin Immunol. 2002; 109: 119-121Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar]aAnalysis of a subgroup of patients previous analyzed by Kalliomaki et al. [4]24Harrigan 199932 30 (Pl)4/27 15 %14/30 47 %0.0098(sIgE) 28 % vs 37 % (Pl) (SPT) 23 % vs 21 % (Pl)NS NSAbrahamsson et al. 2007 [6.Abrahamsson TR, Jakobsson T, Bottcher MF, Fredrikson M, Jenmalm MC, Bjorksten B, et al. Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2007;119:1174–80.Google Scholar]24H-R95/117 93/115(Pl)36 % IgE-Eczema 8 %34 % IgE-Eczema 20 %NS 0.02(sIgE) 37 % vs 48 % (SPT) 18 % vs 29 %NS NSKukkonen et al. 2007 [7.Kukkonen K. Savilahti E. Haahtela T. Juntunen-Backman K. Korpela R. Poussa T. et al.Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: A randomized, double-blind, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 192-198Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar]24UK-WP461/610 464/613 (Pl)26 % IgE-Eczema 12.4 %32.3 % IgE-Eczema 17.7 %0.035 0.025(sIgE e/o SPT) 28 % vs 31.2 (Pl)NSHuurre et al. 2008 [8.Huurre A, Laitinen K, Rautava S, Korkeamäki M, Isolauri E. Impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization: A double-blind placebo-controlled study. Clin Exp Allergy. 2008;38:1342–8.Google Scholar]12H-R72 68 (Pl)9.7 %17.6 %NS29 % vs 31 % (Pl) Subgroup with maternal sensitization. 26 % vs 50 % (Pl)NS 0.023Marschan et al. 2008 [9.Marschan E. Kuitunen M. Kukkonen K. Poussa T. Sarnesto A. Haahtela T. et al.Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation.Clin Exp Allergy. 2008; 38: 611-618Crossref PubMed Scopus (144) Google Scholar]bAnalysis of a subgroup of patients previous analyzed by Kukkonen et al. [7] *Persistence of eczema P < 0,00324UK-WP52 46 (Pl)31 %39 %(sIgE) 35 % vs 26 % (Pl)Wickens et al. 2008 [10.Wickens K. Black P.N. Stanley T.V. Mitchell E. Fitzharris P. Tannock G.W. et al.A differential effect of 2 probiotics in the prevention of eczema and atopy: A double-blind, randomized, placebo-controlled trial.J Allergy Clin Immunol. 2008; 122: 788-794Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar]24UK-WP144/157 152/158 150/159 (Pl)Lrha 14.8 % Bl 24.2 % IgE-Eczema Lrha 9.9 % Bl 12.8 %26.8 % 18.5 %0.03 NS 0.04 NS(SPT) Lrha 21.3 % e Bl 23.5 % vs 28.8 % (Pl)NSKopp et al. 2008 [11.Kopp M.V. Hennemuth I. Heinzmann A. Urbanek R. Double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical effects of Lactobacillus GG supplementation.Pediatrics. 2008; 121: e850-856Crossref PubMed Scopus (346) Google Scholar]24UK-WP50/54 44/51 (Pl)28 %27.3 %NS(sIgE to inhalants) 8 % vs 11.3 % (Pl)NSNiers et al. 2009 [12.Niers L. Martin R. Rijkers G. Sengers F. Timmerman H. van Uden N. et al.The effects of selected probiotic strains on the development of eczema (the PandA study).Allergy. 2009; 64: 1349-1358Crossref PubMed Scopus (203) Google Scholar]24H-R50/78 48/78 (Pl)(Questionnaire) 3 months 12 % 24 months 54 % (Clinical) 3 months 6 % IgE-eczema 20 %(Questionnaire) 3 months 29 % 24 months 68.7 % (Clinical) 3 months 21 % IgE-eczema 16.6 %0.035 0.05 0.021 NS(sIgE o SPT) 20 % vs 14.6 % (Pl)NSDotterud et al. 2010 [13.Dotterud CK, Storro O, Johnsen R, Oien T. Probiotics in pregnant women to prevent allergic disease: a randomized, double-blind trial. Br J Dermatol. 2010;163:616–23.Google Scholar]24UK-WP138/211 140/204 (Pl)21 % IgE-Eczema 6.9 % Non IgE-Eczema 13 %34.3 % IgE-Eczema 7.5 % Non IgE-Eczema 25.6 %0.022 NS 0.009(IgEs o SPT) 15.3 % vs 11.3 % (Pl)NSKim et al. 2010 [14.Kim JY, Kwon JH, Ahn SH, Lee SI, Han YS, Choi YO, et al. Effect of probiotic mix (Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus) in the primary prevention of eczema: A double-blind, randomized, placebo-controlled trial. Pediatr Allergy Immunol. 2010;21:e386–93.Google Scholar]12H -R33/57 35/55 (Pl)36.4 % IgE-eczema 9.7 %62.9 % IgE-eczema 20.7 %0.029 NS(sIgE) 38.7 % vs 51.7 % (Pl)NSBoyle et al. 2011 [15.Boyle RJ, Ismail IH, Kivivuori S, Licciardi PV, Robins-Browne RM, Mah LJ, et al. Lactobacillus GG treatment during pregnancy for the prevention of eczema: a randomized controlled trial. Allergy. 2011;66:509–16.Google Scholar]12UK-WP109/125 103/125 (Pl)32 %42 %NS(SPT) 33 % vs 33 % (Pl)NSOu et al. 2012 [16.Ou C.Y. Kuo H.C. Wang L. Hsu T.Y. Chuang H. Liu C.A. et al.Prenatal and postnatal probiotics reduces maternal but not childhood allergic diseases: A randomized, double-blind, placebo-controlled trial.Clin Exp Allergy. 2012; 42: 1386-1396Crossref PubMed Scopus (77) Google Scholar]3665/95 63/96 (Pl)6 months 3.3 % 18 months 25 % 36 months 24.6 %6 months 23.6 % 18 months 17.7 % 36 months 25 %NS NS NSAllergic symptoms 47.7 % vs 46.9 % (Pl)NSAllen et al. 2012 [17.Allen S.J. Jordan S. Storey M. Thornton C.A. Gravenor M.B. Garaiov I. et al.Probiotics and atopic ECZEMA: A double-blind randomised controlled trial.Arch Dis Child. 2012; 97: A2Crossref Google Scholar]24Clinical187/220 172/234 (Pl)34.1 % IgE-eczema 5.3 %32.4 % IgE-eczema 12.1 %NS 0.02410.5 % vs 18.5 %0.036Rautava et al. 2012 [18.Rautava S. Kainonen E. Salminen S. Isolauri E. Maternal probiotic supplementation during pregnancy and breast-feeding reduces the risk of eczema in the infant.J Allergy Clin Immunol. 2012; 130: 1355-1360Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar]24H-R73/81 (Lrha) 70/82 (Lpar) 62/78 (Pl)29 % (10 %)* 29 % (6 %)*71 % (26 %)*0.001 0.001(SPT) 22 % 26 % 26 % (Pl)NSH-R: Hanifin and Rajka; UK-WP: UK Working Party; Harrigan 1999: Harrigan’s criteria [28.Harrigan E. Rabinowitz L. Atopic dermatitis.Immunol Allergy Clin North Am. 1999; 19: 383-396Abstract Full Text Full Text PDF Scopus (8) Google Scholar]; Lrha: Lactobacillus rhamnosus; Bl: Bifidobacterium lactis; Lpar: Lactobacillus paracasei; Pl: Placebo; SPT: skin prick test; sIgE: specific IgEa Analysis of a subgroup of patients previous analyzed by Kalliomaki et al. [4.Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: A randomised placebo-controlled trial. Lancet. 2001;357:1076–9.Google Scholar]b Analysis of a subgroup of patients previous analyzed by Kukkonen et al. [7.Kukkonen K. Savilahti E. Haahtela T. Juntunen-Backman K. Korpela R. Poussa T. et al.Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: A randomized, double-blind, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 192-198Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar] *Persistence of eczema P < 0,003 Open table in a new tab H-R: Hanifin and Rajka; UK-WP: UK Working Party; Harrigan 1999: Harrigan’s criteria [28.Harrigan E. Rabinowitz L. Atopic dermatitis.Immunol Allergy Clin North Am. 1999; 19: 383-396Abstract Full Text Full Text PDF Scopus (8) Google Scholar]; Lrha: Lactobacillus rhamnosus; Bl: Bifidobacterium lactis; Lpar: Lactobacillus paracasei; Pl: Placebo; SPT: skin prick test; sIgE: specific IgE A preliminary observation about the 15 trials above [4.Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: A randomised placebo-controlled trial. Lancet. 2001;357:1076–9.Google Scholar, 5.Rautava S. Kalliomaki M. Isolauri E. Probiotics during pregnancy and breastfeeding might confer immunomodulatory protection against atopic disease in the infant.J Allergy Clin Immunol. 2002; 109: 119-121Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar, 6.Abrahamsson TR, Jakobsson T, Bottcher MF, Fredrikson M, Jenmalm MC, Bjorksten B, et al. Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2007;119:1174–80.Google Scholar, 7.Kukkonen K. Savilahti E. Haahtela T. Juntunen-Backman K. Korpela R. Poussa T. et al.Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: A randomized, double-blind, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 192-198Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar, 8.Huurre A, Laitinen K, Rautava S, Korkeamäki M, Isolauri E. Impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization: A double-blind placebo-controlled study. Clin Exp Allergy. 2008;38:1342–8.Google Scholar, 9.Marschan E. Kuitunen M. Kukkonen K. Poussa T. Sarnesto A. Haahtela T. et al.Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation.Clin Exp Allergy. 2008; 38: 611-618Crossref PubMed Scopus (144) Google Scholar, 10.Wickens K. Black P.N. Stanley T.V. Mitchell E. Fitzharris P. Tannock G.W. et al.A differential effect of 2 probiotics in the prevention of eczema and atopy: A double-blind, randomized, placebo-controlled trial.J Allergy Clin Immunol. 2008; 122: 788-794Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar, 11.Kopp M.V. Hennemuth I. Heinzmann A. Urbanek R. Double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical effects of Lactobacillus GG supplementation.Pediatrics. 2008; 121: e850-856Crossref PubMed Scopus (346) Google Scholar, 12.Niers L. Martin R. Rijkers G. Sengers F. Timmerman H. van Uden N. et al.The effects of selected probiotic strains on the development of eczema (the PandA study).Allergy. 2009; 64: 1349-1358Crossref PubMed Scopus (203) Google Scholar, 13.Dotterud CK, Storro O, Johnsen R, Oien T. Probiotics in pregnant women to prevent allergic disease: a randomized, double-blind trial. Br J Dermatol. 2010;163:616–23.Google Scholar, 14.Kim JY, Kwon JH, Ahn SH, Lee SI, Han YS, Choi YO, et al. Effect of probiotic mix (Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus) in the primary prevention of eczema: A double-blind, randomized, placebo-controlled trial. Pediatr Allergy Immunol. 2010;21:e386–93.Google Scholar, 15.Boyle RJ, Ismail IH, Kivivuori S, Licciardi PV, Robins-Browne RM, Mah LJ, et al. Lactobacillus GG treatment during pregnancy for the prevention of eczema: a randomized controlled trial. Allergy. 2011;66:509–16.Google Scholar, 16.Ou C.Y. Kuo H.C. Wang L. Hsu T.Y. Chuang H. Liu C.A. et al.Prenatal and postnatal probiotics reduces maternal but not childhood allergic diseases: A randomized, double-blind, placebo-controlled trial.Clin Exp Allergy. 2012; 42: 1386-1396Crossref PubMed Scopus (77) Google Scholar, 17.Allen S.J. Jordan S. Storey M. Thornton C.A. Gravenor M.B. Garaiov I. et al.Probiotics and atopic ECZEMA: A double-blind randomised controlled trial.Arch Dis Child. 2012; 97: A2Crossref Google Scholar–18.Rautava S. Kainonen E. Salminen S. Isolauri E. Maternal probiotic supplementation during pregnancy and breast-feeding reduces the risk of eczema in the infant.J Allergy Clin Immunol. 2012; 130: 1355-1360Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar] is that they are all randomized against placebo, they were published between 2001 and 2012, that is a rather brief period to be well compared. It should be mentioned that the study of Rautava et al. (2002) [5.Rautava S. Kalliomaki M. Isolauri E. Probiotics during pregnancy and breastfeeding might confer immunomodulatory protection against atopic disease in the infant.J Allergy Clin Immunol. 2002; 109: 119-121Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar] analyzes a subset of patients previous described by Kalliomaki et al. (2001) [4.Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: A randomised placebo-controlled trial. Lancet. 2001;357:1076–9.Google Scholar], as well as Marschan et al. (2008) [9.Marschan E. Kuitunen M. Kukkonen K. Poussa T. Sarnesto A. Haahtela T. et al.Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation.Clin Exp Allergy. 2008; 38: 611-618Crossref PubMed Scopus (144) Google Scholar] analyzed a subgroup of patients described by Kukkonen et al. (2007) [7.Kukkonen K. Savilahti E. Haahtela T. Juntunen-Backman K. Korpela R. Poussa T. et al.Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: A randomized, double-blind, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 192-198Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar]. Almost all studies identified patients with family history of atopy as targets for treating, indicating that children at high risk of atopy should be the potential beneficiaries of a preventive intervention with probiotic supplementation. The total number of subjects included in the trials is relevant, but the type of probiotic or association of probiotics used is widely different among the studies. As the Authors underlined, we have to face a "heterogeneity of the interventions and limitations in reporting of original studies”, so it was not possible to analyze neither the effects in each group separately nor the effects of individual probiotic species. This statement is clearly expressed in the guideline, but it deserves some particular considerations. The term probiotic currently includes bacteria associated with beneficial effects; according to the World Health Organization definition [19.FAO/WHO. Report of a Joint FAO/WHO Working Group on Drafting Guidelines for the Evaluation of Probiotics in Food. 2002. ftp://ftp.fao.org/es/esn/food/wgreport2.pdf.Google Scholar], the term probiotics refers to “live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host". Probiotics may act by different mechanisms, as well as the Authors have pointed out, that means it is important to consider also if the action is the same or if there are differences of action between the different probiotics used in the different trials. Since a wide literature is available on probiotics, we can take for example the data related to Lactobacillus rhamnosus, the most used probiotic species. A recent trial examined 100 strains of Lactobacillus rhamnosus isolated from different food sources and habitats from the human body (mouth, bowel, vagina) [20.Douillard FP, Ribbera A, Kant R, Pietilä TE, Järvinen HM, Messing M, et al. Comparative genomic and functional analysis of 100 Lactobacillus rhamnosus strains and their comparison with strain GG. PLoS Genet. 2013;9(8):e1003683.Google Scholar] by carrying out a genomics and functional comparative analysis. A wide spectrum of phenotypes with different functional properties, which have been grouped by the Authors according to the two most common geno-phenotypes (A and B). The geno-phenotype A seems to be related permanently to a greater ability to adapt to nutrient-rich foods such as dairy products, but also to the loss of some biological functions involved in the antimicrobial activity, in the resistance and ability to adapt to different habitats. The geno-phenotype B shows a greater ability to adapt to different habitats and resources with different nutrients and different effects on the host. A recent study analyzed the relationship between dental caries and Lactobacillus rhamnosus, showing a likely causal role of two strains: Lactobacillus rhamnosus LRHMDP2 and LRHMDP were isolated in the dental pulp, furthermore the analysis of their genes showed differences with the probiotic Lactobacillus rhamnosus GG (ATCC 53103) which does not seem implicated in the pathogenesis of dental caries [21.Nadkarni M.A. Chen Z. Wilkins M.R. Hunter N. Comparative genome analysis of Lactobacillus rhamnosus clinical isolates from initial stages of dental pulp infection: identification of a new exopolysaccharide cluster.PLoS One. 2014; 9Crossref PubMed Scopus (19) Google Scholar]. Also a comparison between Lactobacillus strains isolated from dairy products market of Lactobacillus rhamnosus GG (ATCC53103), Lactobacillus rhamnosus LRV, Lactobacillus rhamnosus LRI, Lactobacillus casei BL23 (ATCC393), Lactobacillus casei LCY, and Lactobacillus casei LCA showed different genomic profiles, as well as different functional capabilities in glucose metabolism and in the ability to adhere to intestinal mucus [22.Douillard F.P. Kant R. Ritari J. Paulin L. Palva A. de Vos W.M. Comparative genome analysis of Lactobacillus casei strains isolated from Actimel and Yakult products reveals marked similarities and points to a common origin.Microb Biotechnol. 2013; 6: 576-587Crossref PubMed Scopus (27) Google Scholar]. As the Authors also point out, we believe that this evidence is a critical point for the definition of the quality of the evidence, described as very low. In the selected studies, different strains have been used in various combinations: it is necessary to consider different mechanisms of action and possible interactions in the bowel, in addition to the different effects of different combinations of micro-organisms. The species Lactobacillus rhamnosus GG (ATCC 55103) is the most widely studied probiotic, both alone and in combination, but the data only from studies that use this type of probiotic would be insufficient. The duration of treatment in the late pregnancy is fairly homogeneous across all studies, and it varies from 2 to 6 weeks before the expected date of birth. Among the 15 selected studies, we considered the main clinical features associated with the diagnosis of eczema useful to analyze the question 1 of the guideline and we reported them in Table 2. The predominant duration of follow-up was 24 weeks, a sufficient period to evaluate the appearance of atopic dermatitis, since in most cases it begins within 24 months of life. The criteria used for the diagnosis of atopic eczema are the most widely recognized in the literature: Hanifin and Rajka criteria [23.Hanifin J.M. Rajka G. Diagnostic features of atopic dermatitis.Acta Derm Venereol Suppl (Stockh). 1980; 59: 44-47Google Scholar] and the UK-Working Party’s criteria [24.Williams H.C. Burney P.GJ. Pembroke A.C. Hay R.J. The U.K. Working Party's diagnostic criteria for atopic dermatitis. III. Independent hospital validation.Br J Dermatol. 1994; 131: 406-416Crossref PubMed Scopus (738) Google Scholar]. The number of patients with a complete follow-up usually exceed the 80 % of the enrolled patients, so the quality of the available data seems to be very good for the statistical analysis. It is more difficult to evaluate the results on the occurrence of eczema with its two clinical phenotypes: the IgE-associated and non IgE-associated, which differ both in the clinical features and in the evolution toward other allergic diseases. IgE-associated forms are more prone to the evolution in allergic rhinitis and asthma, especially if there is also a clear sensitization to inhalant allergens. The data shown in Table 2 at the end of follow-up period include 13 trials, excluding the two trials above mentioned [5.Rautava S. Kalliomaki M. Isolauri E. Probiotics during pregnancy and breastfeeding might confer immunomodulatory protection against atopic disease in the infant.J Allergy Clin Immunol. 2002; 109: 119-121Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar, 9.Marschan E. Kuitunen M. Kukkonen K. Poussa T. Sarnesto A. Haahtela T. et al.Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation.Clin Exp Allergy. 2008; 38: 611-618Crossref PubMed Scopus (144) Google Scholar] that analyzed subsets of patients of broader studies [4.Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: A randomised placebo-controlled trial. Lancet. 2001;357:1076–9.Google Scholar, 7.Kukkonen K. Savilahti E. Haahtela T. Juntunen-Backman K. Korpela R. Poussa T. et al.Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: A randomized, double-blind, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 192-198Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar]. Among these, 6 studies [4.Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: A randomised placebo-controlled trial. Lancet. 2001;357:1076–9.Google Scholar, 7.Kukkonen K. Savilahti E. Haahtela T. Juntunen-Backman K. Korpela R. Poussa T. et al.Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: A randomized, double-blind, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 192-198Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar, 10.Wickens K. Black P.N. Stanley T.V. Mitchell E. Fitzharris P. Tannock G.W. et al.A differential effect of 2 probiotics in the prevention of eczema and atopy: A double-blind, randomized, placebo-controlled trial.J Allergy Clin Immunol. 2008; 122: 788-794Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar, 13.Dotterud CK, Storro O, Johnsen R, Oien T. Probiotics in pregnant women to prevent allergic disease: a randomized, double-blind trial. Br J Dermatol. 2010;163:616–23.Google Scholar, 14.Kim JY, Kwon JH, Ahn SH, Lee SI, Han YS, Choi YO, et al. Effect of probiotic mix (Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus) in the primary prevention of eczema: A double-blind, randomized, placebo-controlled trial. Pediatr Allergy Immunol. 2010;21:e386–93.Google Scholar, 18.Rautava S. Kainonen E. Salminen S. Isolauri E. Maternal probiotic supplementation during pregnancy and breast-feeding reduces the risk of eczema in the infant.J Allergy Clin Immunol. 2012; 130: 1355-1360Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar] showed a significant reduction in the rate of occurrence of eczema in the group treated with probiotics if compared with placebo group, while the other 8 studies [6.Abrahamsson TR, Jakobsson T, Bottcher MF, Fredrikson M, Jenmalm MC, Bjorksten B, et al. Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2007;119:1174–80.Google Scholar, 8.Huurre A, Laitinen K, Rautava S, Korkeamäki M, Isolauri E. Impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization: A double-blind placebo-controlled study. Clin Exp Allergy. 2008;38:1342–8.Google Scholar, 10.Wickens K. Black P.N. Stanley T.V. Mitchell E. Fitzharris P. Tannock G.W. et al.A differential effect of 2 probiotics in the prevention of eczema and atopy: A double-blind, randomized, placebo-controlled trial.J Allergy Clin Immunol. 2008; 122: 788-794Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar, 11.Kopp M.V. Hennemuth I. Heinzmann A. Urbanek R. Double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical effects of Lactobacillus GG supplementation.Pediatrics. 2008; 121: e850-856Crossref PubMed Scopus (346) Google Scholar–12.Niers L. Martin R. Rijkers G. Sengers F. Timmerman H. van Uden N. et al.The effects of selected probiotic strains on the development of eczema (the PandA study).Allergy. 2009; 64: 1349-1358Crossref PubMed Scopus (203) Google Scholar, 15.Boyle RJ, Ismail IH, Kivivuori S, Licciardi PV, Robins-Browne RM, Mah LJ, et al. Lactobacillus GG treatment during pregnancy for the prevention of eczema: a randomized controlled trial. Allergy. 2011;66:509–16.Google Scholar, 16.Ou C.Y. Kuo H.C. Wang L. Hsu T.Y. Chuang H. Liu C.A. et al.Prenatal and postnatal probiotics reduces maternal but not childhood allergic diseases: A randomized, double-blind, placebo-controlled trial.Clin Exp Allergy. 2012; 42: 1386-1396Crossref PubMed Scopus (77) Google Scholar–17.Allen S.J. Jordan S. Storey M. Thornton C.A. Gravenor M.B. Garaiov I. et al.Probiotics and atopic ECZEMA: A double-blind randomised controlled trial.Arch Dis Child. 2012; 97: A2Crossref Google Scholar] didn’t show significant differences between the two groups. The study of Wickens et al. [10.Wickens K. Black P.N. Stanley T.V. Mitchell E. Fitzharris P. Tannock G.W. et al.A differential effect of 2 probiotics in the prevention of eczema and atopy: A double-blind, randomized, placebo-controlled trial.J Allergy Clin Immunol. 2008; 122: 788-794Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar] is considered twice as the group receiving Lactobacillus rhamnosus HN001 was statistically significant while that one treated with Bifidobacterium animalis lactis subspec HN019 was not significant. In 7 of these trials, the analysis can be restricted to the appearance of IgE-associated eczema: 4 studies showed a statistical significance [6.Abrahamsson TR, Jakobsson T, Bottcher MF, Fredrikson M, Jenmalm MC, Bjorksten B, et al. Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2007;119:1174–80.Google Scholar, 7.Kukkonen K. Savilahti E. Haahtela T. Juntunen-Backman K. Korpela R. Poussa T. et al.Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: A randomized, double-blind, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 192-198Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar, 10.Wickens K. Black P.N. Stanley T.V. Mitchell E. Fitzharris P. Tannock G.W. et al.A differential effect of 2 probiotics in the prevention of eczema and atopy: A double-blind, randomized, placebo-controlled trial.J Allergy Clin Immunol. 2008; 122: 788-794Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar, 17.Allen S.J. Jordan S. Storey M. Thornton C.A. Gravenor M.B. Garaiov I. et al.Probiotics and atopic ECZEMA: A double-blind randomised controlled trial.Arch Dis Child. 2012; 97: A2Crossref Google Scholar], while 4 studies [10.Wickens K. Black P.N. Stanley T.V. Mitchell E. Fitzharris P. Tannock G.W. et al.A differential effect of 2 probiotics in the prevention of eczema and atopy: A double-blind, randomized, placebo-controlled trial.J Allergy Clin Immunol. 2008; 122: 788-794Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar, 12.Niers L. Martin R. Rijkers G. Sengers F. Timmerman H. van Uden N. et al.The effects of selected probiotic strains on the development of eczema (the PandA study).Allergy. 2009; 64: 1349-1358Crossref PubMed Scopus (203) Google Scholar, 13.Dotterud CK, Storro O, Johnsen R, Oien T. Probiotics in pregnant women to prevent allergic disease: a randomized, double-blind trial. Br J Dermatol. 2010;163:616–23.Google Scholar–14.Kim JY, Kwon JH, Ahn SH, Lee SI, Han YS, Choi YO, et al. Effect of probiotic mix (Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus) in the primary prevention of eczema: A double-blind, randomized, placebo-controlled trial. Pediatr Allergy Immunol. 2010;21:e386–93.Google Scholar] didn’t show significant differences (the study of Wickens et al. [10.Wickens K. Black P.N. Stanley T.V. Mitchell E. Fitzharris P. Tannock G.W. et al.A differential effect of 2 probiotics in the prevention of eczema and atopy: A double-blind, randomized, placebo-controlled trial.J Allergy Clin Immunol. 2008; 122: 788-794Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar] was considered twice). Finally, the analysis of the presence of allergic sensitization assessed by specific IgE and/or skin prick test provided significant results only in two cases, while in 13 others it was not statistically significant. Another important issue discussed in this guideline is the detection of adverse effects. The analysis took into consideration also an extensive review of a study carried out by the Health Assessment Technology [25.Hempel S. Newberry S.J. Maher A.R. Wang Z. Miles J.N. Shanman R. et al.Probiotics for the prevention and treatment of antibiotic-associated diarrhea: A systematic review and meta-analysis.JAMA. 2012; 307: 1959-1969Crossref PubMed Scopus (574) Google Scholar], which did not report significant adverse effects and in any case, it did not describe an increased risk, despite some limitations indicated in the study. Lastly, the adverse events reported in these 15 trials are mild and short-term events, without substantial clinical differences between the groups receiving probiotics and those receiving placebo. This guideline indicates the lack of clear evidence of efficacy of probiotic supplementation in the primary prevention of allergies. In the recommendation 1, the WAO guideline panel suggests "using probiotics in pregnant women at high risk for allergy in their children, because considering all critical outcomes, there is a net benefit resulting primarily from prevention of eczema (conditional recommendation, very low quality evidence)”; in the case of eczema this recommendation is also provided regarding the other two clinical questions.