1 Introduction
Asthma is a chronic condition characterized by recurrent attacks of breathlessness and wheezing, which occurs in people of all ages. Asthma is the most common chronic disease in children, with approximately 235 million people suffering from asthma as of August 2017.[1] [2] [1]
In recent years, with the spread of clinical guidelines and increased access to drugs and other new treatments, asthma mortality and disease burden have been reduced.[3–5] [6,7] [8] [9–14] [15]
Probiotics are a class of active microorganisms that are beneficial to the host by colonization in the human body and altering the composition of the flora at a certain part of the host. Prebiotics are nondigestible food ingredients that have a beneficial effect on the host by selectively stimulating the growth and activity of probiotics to improve host health. Synbiotics are a combination of probiotics and prebiotics.[16,17] [18] [19–21] [22,23]
Since asthma is often associated with allergies,[1] systematic review has been registered on open science framework (OSF) (DOI 10.17605/OSF.IO/V7DM9).
2 Methods
This systematic review has been registered in OSF (https://osf.io/v7dm9/ Systematic review is a secondary literature research that does not require direct contact with patients, so the ethical approval and patient consent form are not necessary. We will develop and report this study in compliance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA).[24] [25]
2.1 Database search
Three English medical databases (Cochrane Library, PubMed, and EMBASE) and 4 Chinese medical databases (China National Knowledge Infrastructure Database, Chinese Biomedical Literature Database, VIP Chinese Science and Technology Periodical Database, and Wan Fang Data) will be systematically searched from their inceptions up to July 31, 2019. The search strategy will be based on the guidance of the Cochrane handbook.[26] ∗ OR Lactobacill∗ OR Saccharomyce∗ OR Lactic Acid Bacteria) AND (asthma OR bronchial asthma OR allergic airway inflammation) AND (random∗ ). All relevant publications including academic dissertation and conference will be researched. There will be no language and publication date restrictions.
2.2 Inclusion criteria
2.2.1 Types of studies
Only randomized controlled trials (RCTs) will be included.
2.2.2 Types of participants
All of the participants who were diagnosed with asthma.
2.2.3 Types of intervention
Probiotics, prebiotics, or synbiotics as the intervention treatment compared with blank control, placebo, or conventional treatment will be selected. Probiotics, prebiotics, or synbiotics in combination with conventional therapies compared with conventional therapies alone will also be included. All interventions will be treated for no less than 12 weeks. Basic medical treatment like oxygen therapy, infection control, and nutritional support can be used in intervention or control groups.
2.2.4 Types of outcome measures
Primary outcomes: symptoms (asthma control questionnaire score and asthma control and quality of life assessment score) and lung function (forced vital capacity, forced expiratory volume in one second, and peak expiratory flow variability).
Secondary outcomes: asthma exacerbations, quality of life, and adverse event. The time endpoint of the above outcomes will be no earlier than 12 weeks after starting the medication.
2.3 Exclusion criteria
(1) The unrelated and duplicated documents will be deleted.
(2) Animal experiments, reviews, theoretical discussions, experience summaries, and case reports.
(3) Review articles without original data.
2.4 Data collection and extraction
Referring to the Cochrane collaborative network system evaluator handbook[26]
(1) Importing the search results into the document management software of NoteExpress (version: 3.2, Beijing Aegean Software Company, Beijing, China);
(2) Excluding the duplicate literature using NoteExpress3.2 and excluding the unrelated articles by reading the title and abstract;
(3) Reading the full text and reserving clinical studies that meet the inclusion criteria.
Two researchers (GJ and HL) will extract the data independently using a self-developed data extraction form. The differences encountered in the process will be resolved by discussing with another team member (LWY), to determine, by agreement, the final selection of studies.
Data extraction contents will include:
(1) General information: research ID, author, title, publication status, report sources, and fund support.
(2) Methodology information: design, number of arms, random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, sample size calculation, and baseline comparability.
(3) Participant information: diagnostic criteria, inclusion criteria, exclusion criteria, setting, population, sample size, age, gender, and course of disease.
(4) Intervention information: name of intervention and comparation, dosage form, comparison, duration of treatment, and patient follow-up.
(5) Outcomes.
(6) Adverse events.
The selection process was shown in a PRISMA flow chart (http://www.prisma-statement.org/ Fig. 1 ).
Figure 1: Flow chart of the selection process.
2.5 Assessment of methodological quality
Risk of bias will be assessed by the Cochrane risk assessment tool[25]
The 2 researchers (LH and JG) will independently assess the risk of bias for each included study. We will use “L,“ “H,“ and “U” as a code for the evaluations of the above bias risks. “L” indicating a low risk of bias, “H” indicating a high risk of bias, “U” indicating that the risk of bias is unclear. Disagreements will be resolved by discussion between all the researchers. When necessary, we will contact the study authors to inquire some missing information. Trials of high risk of bias will be considered when conducting sensitive analysis.
2.6 Data synthesis and analysis
Review Manager Software (RevMan, Version 5.3 for windows, The Cochrane Collaboration, Oxford, England) will be used to analyze and synthesize the outcomes. Quantitative synthesis will be done when clinical heterogeneity is not considered by at least 2 authors in discussion. Continuous variable will be described by mean difference, P -value and 95% confidence interval (CI). For dichotomous outcomes, we will use the relative risk, with 95% CI and P -values, to evaluate the efficacy and safety of probiotics/prebiotics/synbiotics. I 2 test will be used to judge the heterogeneity of meta-analysis. I 2 value >50% or more will be considered as an indication of substantial heterogeneity. If heterogeneity exists in the pooled studies, the data will be analyzed using a random-effects model. Otherwise, a fixed-effect model will be adopted. Sensitivity analysis or subgroup analysis will be performed if included trials are sufficient. The grouping factor for subgroup analysis will be age, asthma severity, and treatment duration. Qualitative description will be adopted if clinical heterogeneity exist.
2.7 Publication bias
The publication bias will be analyzed by the Egger test. The analysis software is R 3.5.1 for Windows.
2.8 Quality of evidence
This study evaluates the evidence according to GRADE standard, which refers grading of recommendations assessment, development, and evaluation. GRADE Pro GDT online software will be used to form the summary of findings table (SoF table).
3 Discussion
Probiotics, prebiotics, and synbiotics used for treating and preventing several diseases have been assessed systematically in recent years. Allergic diseases and inflammation are 2 important fields of these diseases. Intestinal flora composition plays an important role in the development of allergic diseases and airway inflammation because of its potential effects on TH1-type immunity, generation of TGF, and IgA production.[27] [28] [29–33]
Are probiotics, prebiotics, and synbiotics effective and safe for asthma? In order to answer this question, we searched databases but found no systematic review of RCTs published. We need more comprehensive and credible evidence to guide clinical practice. We should also assess the shortcomings of existing clinical evidence to guide future clinical trials. This study will solve the above problems.
Author contributions
Tiegang Liu, Xiaohong Gu, and Fei Wang conceived and designed the project. Jing Guo, Ling Huang Wenyuan Li, Mei Jiang, Fei Wang, Jia Kang, Tiegang Liu, and Xiaohong Gu implemented the methods. Mei Jiang contributed analysis tools and edited review. Tiegang Liu contributed reagents/materials. Xiaohong Gu and Fei Wang revised the manuscript. All authors read and approved the final manuscript.
Ling Huang orcid: 0000-0002-0887-5544.
References
[1]. WHO. 10 Facts on Asthma.
www.who.int 2011; Available at:
https://www.who.int/features/factfiles/asthma/en/ . [Accessed on June 26, 2019]
[2]. Huang K, Yang T, Xu J, et al. Prevalence, risk factors, and management of asthma in China: a national cross-sectional study. Lancet 2019;394:407–18.
[3]. Tual S, Godard P, Bousquet J, et al. Diminution de la mortalité par asthme en France. Rev Mal Respir 2008;25:814–20.
[4]. Demoly P, Paggiaro P, Plaza V, et al. Prevalence of asthma control among adults in France, Germany, Italy, Spain and the UK. Eur Respir Review 2009;18:105–12.
[5]. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43:343–73.
[6]. Martinez FD. New insights into the natural history of asthma: primary prevention on the horizon. J Allergy Clin Immunol 2011;128:939–45.
[7]. Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Eng J Med 2006;354:1985–97.
[8]. Wenzel SE, Busse WW. Severe asthma: lessons from the severe asthma research program. J Allergy Clin Immunol 2007;119:14–21.
[9]. Dhruti P, Amar P, Viswanatha B. Systematic effects of inhaled corticosteroids: an overview. Open Respir Med J 2014;8:59–65.
[10]. Kelly HW, Stemberg AL, Lescher R, et al. Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med 2012;367:904–12.
[11]. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a
systematic review and meta-analysis. Arch Intern Med 1999;159:941–55.
[12]. Nelson HS, Weiss ST, Bleecker ER, et al. The salmeterol multicenter asthma research trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15–26.
[13]. Philip G, Hustad C, Noonan G, et al. Reports of suicidality in clinical trials of montelukast. J Allergy Clin Immunol 2009;124:691–6.e6.
[14]. Philip G, Hustad CM, Malice MP, et al. Analysis of behavior-related adverse experiences in clinical trials of montelukast. J Allergy Clin Immunol 2009;124:699–706.e8.
[15]. Burch J, Griffin S, Mckenna C, et al. Omalizumab for the treatment of severe persistent allergic asthma in children aged 6-11 years: a NICE single technology appraisal. Pharmacoeconomics 2012;30:991–1004.
[16]. Reid G, Sanders ME, Gaskins HR, et al. New scientific paradigms for probiotics and prebiotics. J Clin Gastroenterol 2003;37:105–18.
[17]. Roberfroid M. Prebiotics: the concept revisited. J Nutr 2007;137:830S–7S.
[18]. Perdigon G, Alvarez S, Rachid M, et al. Immune system stimulation by probiotics. J Dairy Sci 1995;78:1597–606.
[19]. Matsuzaki T, Yamazaki R, Hashimoto S, et al. The effect of oral feeding of Lactobacillus casei strain Shirota on immunoglobulin E production in mice. J Dairy Sci 1998;81:48–53.
[20]. Murosaki S, Yamamoto Y, Ito K, et al. Heat-killed Lactobacillus plantarum L-137 suppresses naturally fed antigen-specific IgE production by stimulation of IL-12 production in mice. J Allergy Clin Immunol 1998;102:57–64.
[21]. Shimada T, Cheng L, Ide M, et al. Effect of lysed Enterococcus faecalis FK-23(LFK) on allergen- induced peritoneal accumulation of eosinophils in mice. Clin Exp Allergy 2003;33:684–7.
[22]. Cuello-Garcia CA, Brożek JL, Fiocchi A, et al. Probiotics for the prevention of allergy: a
systematic review and meta-analysis of randomized controlled trials. J Allergy Clin Immunol 2015;136:952–61.
[23]. Kalliomaki M, Salminen S, Poussa T, et al. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet 2003;361:1869–71.
[24]. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700.
[25]. Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for
systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4:1.
[26]. Higgins JPT, Thomas J, Chandler J.
Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. Available from
www.training.cochrane.org/handbook .
[27]. Prokesova L, Lodinova-Zadnikova R, Zizka J, et al. Cytokine levels in healthy and allergic mothers and their children during the first year of life. Pediatr Allergy Immunol 2006;17:175–83.
[28]. McMilan SJ, Lloyd CM. Prolonged allergen challenge in mice leads to persistent airway remodelling. Clin Exp Allergy 2004;34:497–507.
[29]. Ezendam J, de Klerk A, Gremmer ER, et al. Effects of Bifidobacterium animals administered during lactation on allergic and autoimmune responses in rodents. Clin Exp Immunol 2008;154:424–31.
[30]. Hougee S, Vriesema AJ, Wijering SC, et al. Oral treatment with probiotics reduces allergic symptoms in ovalbumin-sensitized mice: a bacterial strain comparative study. Int Arch Allergy Immunol 2010;151:107–17.
[31]. Forsythe P, Inman MD, Blenenstock J. Oral treatment with live Lactobacillus reuteri inhibits the allergic airway response in mice. Am J Respir Crit Care Med 2007;175:561–9.
[32]. Eder W, Klimecki W, Yu L, et al. Association between exposure to farming, allergies and genetic variation in CARD4/NOD1. Allergy 2006;61:1117–24.
[33]. Nonaka Y, Izumo T, Izumi F, et al. Antiallergic effects of Lactobacillus pentosus strain S-PT84 mediated by modulation of Th1/Th2 immunobalance and induction of IL-10 production. Int Arch Allergy Immunol 2008;145:249–57.
