Delivered by Ingenta to: Vanderbilt University IP: 37.230.212.82 On: Sun, 18 Sep 2016 08:37:48 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm Do probiotics have a role in the treatment of allergic rhinitis? A comprehensive systematic review and meta- analysis Is ¸ıl Adadan Gu ¨ venc ¸, M.D., 1 Nuray Bayar Muluk, M.D., 2 Fezan S ¸ahin Mutlu, Ph.D., 3 Erkan Es  ki, M.D., 4 Niyazi Altıntoprak, M.D., 5 Tugba Oktemer, M.D., 6 and Cemal Cingi, M.D. 7 ABSTRACT Objective: To investigate clinical evidence for the efficacy of probiotics in the treatment of allergic rhinitis (AR). Methods: A systematic search was conducted to review the results of all randomized, double-blind, placebo-controlled trials by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. Primary outcome measurements were total nasal and ocular symptom scores (SS) and quality of life (QoL) questionnaires. Secondary outcome measurements were individual nasal SS and immunologic parameters. Results: Twenty-two randomized, double-blind, placebo-controlled studies were included. Seventeen trials showed significant benefit of probiotics clinically, whereas eight trials showed significant improvement in immunologic parameters compared with placebo. All five studies with Lactobacillus paracasei (LP) strains demonstrated clinically significant improvements compared with placebo. Probiotics showed significant reduction in nasal and ocular SS (standardized mean difference [SMD], -1.23, p  0.001; and SMD, -1.84, p  0.001; respectively), total, nasal, and ocular QoL scores compared with placebo (SMD, -1.84, p  0.001; SMD, -2.30, p = 0.006; and SMD, -3.11, p = 0.005; respectively). Although heterogeneity was high, in subgroup analysis, SMD for total nasal and ocular symptoms with patients with seasonal AR and for nasal QoL scores for studies with LP-33 strain were significant and homogenous. Scores of nasal blockage, rhinorrhea, and nasal itching were significantly lower in the probiotic group compared with placebo. The meta-analysis studies SS the Japanese guidelines revealed a significant, homogenous SMD score of -0.34 for individual nasal SS, above the minimal important clinical difference value of 0.3. The T-helper 1 to T-helper 2 ratio was significantly lower in the probiotic group compared with placebo (SMD, -0.78; p = 0.045). Conclusion: Despite high variability among the studies, synthesis of available data provided significant evidence of beneficial clinical and immunologic effects of probiotics in the treatment of AR, especially with seasonal AR and LP-33 strains. With the rising pool of studies, the most promising strains in specific allergies can be revealed and adjuvant therapy with probiotics can be recommended for the treatment of AR. (Am J Rhinol Allergy 30, e157–e175, 2016; doi: 10.2500/ajra.2016.30.4354) T he prevalence of allergic rhinitis (AR) has been substantially increasing over the past 4 decades in all the world. 1 According to the “hygiene hypothesis,” atopic march may be altered by feeding probiotics to infants at risk for allergic diseases. 2 Probiotics are living microorganisms that provide a health benefit to the host when ad- ministered in adequate amounts. 3 Well-known probiotics are most commonly Lactobacillus and Bifidobacterium species, but Lactococcus, Streptococcus, Enterococcus species, some nonpathogenic strains of Escherichia coli, and certain yeast strains, viz., Saccharomyces are also listed. 4 Probiotics are believed to induce immunomodulatory mechanisms by the stimulation of gut-associated lymphoid tissue. 5 Dendritic cells are potent antigen-presenting cells and have a critical role in directing T-helper (Th) cell responses toward Th1, Th2, or regulatory path- ways. 4 Probiotics induce dendritic cell maturation so that the Th1:Th2 balance is restored by induction of Th1 responses through the pro- duction of interleukin (IL) 12 and interferon (IFN) , or by suppres- sion of Th2 responses through the reduction of IL-4, specific immu- noglobulin E (sIgE), IgG1, and IgA production. Induction of T-regulatory cells by dendritic cells results in the secretion of IL-10 and transforming growth factor , and thereby oral tolerance is induced. 5 Although a 50% decrease in the frequency of clinical eczema to that of the placebo with supplementation of Lactobacillus rhamnosus strain GG (ATCC 53103) (LGG) 6 was reported, the development of asthma and AR was found to be increased to 3.5- and 2.3-fold, respectively, by the age of 7. 7 A recent meta-analysis reported no significant difference in terms of prevention of asthma or rhinoconjunctivitis. 8 Analysis of these data built serious concerns about the assumed preventive effects of probiotics for allergic diseases. The reviews that studied the efficacy of probiotics on the treatment of AR elicited contradictory results. We decided that a comprehensive meta-analy- sis of these studies could highlight this controversy and conducted a systematic search to gather the results of all randomized, double- blind, placebo-controlled (RDBPC) trials on the effects of probiotics in the treatment of AR. METHODS This meta-analysis was prepared by following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. 9 The review question was framed according to Patients, Intervention, Comparator, Outcomes, Study design criteria. Criteria for Considering Studies for This Review Study Population. Participants in the trials were of either sex and of any age diagnosed with AR and/or rhinoconjunctivitis. Diagnosis had been based on clinical history and on positive objective tests, such as a skin-prick test or a radioallergosorbent test. Interventions and Comparators. Interventions consisted of daily treat- ment with probiotics or placebo administered at the beginning of the study and continued for a minimum of 4 weeks, with or without From the 1 Department of Otorhinolaryngology, C ¸ igli Regional Education Hospital, I ˙ zmir, Turkey, 2 Department of Otorhinolaryngology, Kirikkale University, Medical Faculty, Kirikkale, Turkey, 3 Department of Biostatistics, Medical Faculty, Eskisehir Osmangazi University, Eskisehir, Turkey, 4 Department of Otorhinolaryngology, Zubeyde Hanım Re- search and Training Center, Medical Faculty, Baskent University, I ˙ zmir, Turkey, 5 Ear, Nose and Throat (ENT) Department, Tuzla State Hospital, Istanbul, Turkey, 6 ENT Department, Private Polatlı Can Hospital, Ankara, Turkey, and 7 Department of Otorhi- nolaryngology, Medical Faculty, Eskisehir Osmangazi University, Eskisehir, Turkey With the exception of data collection, the preparation of this manuscript, including its design and planning, was supported by the Continuous Education and Scientific Research Association The authors have no conflicts of interest to declare pertaining to this article Address correspondence to Isı l Adadan Gu ¨ venc ¸, M.D., Department of Otolaryngol- ogy—Head and Neck Surgery, C ¸ ig ˘li Regional Education Hospital, Yeni Mahalle, 8206 Sk: No. 88 C ¸ ig ˘li, I ˙ zmir, Turkey E-mail address: isiladadan@yahoo.com Copyright © 2016, OceanSide Publications, Inc., U.S.A. 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