Effect and safety of probiotics for treating urticaria: A systematic review and meta‐analysis

To assess the effect and safety of probiotics for treating urticaria.


| INTRODUC TI ON
Urticaria is a dermatologic disorder characterized mainly by skin wheals, angioedema, or a combination of both. 1 The classification of the urticaria subgroups is based on clinical criteria and is divided into acute and chronic urticaria. 2Acute urticaria is characterized by the recurrent occurrence of urticaria with or without angioedema over a period of up to 6 weeks, while recurrence of lesions beyond 6 weeks is considered chronic. 3In contrast to acute urticaria, chronic urticaria is associated with an imbalance of immunity, inflammation, and coagulation. 4Chronic urticaria is common in infancy and childhood. 5For now, the pathogenesis of chronic urticaria remains unclear, but the disease has a significant impact on the physical and mental health of patients.
Second-generation non-sedating H1 antihistamines are currently recommended as first-line treatment options at doses up to four times higher to increase medical outcomes. 2However, these drugs and their long-term use for the treatment of childhood urticaria have been associated with adverse effects.There is growing evidence that the microbiota that lives in our bodies and on our surfaces is critical to human health and disease. 6Intestinal probiotics are live bacteria that settle in the gut, and they can modify the commensal bacteria in the host gut to produce effective effects. 7Studies have shown that the composition of the gut microbiota in patients with chronic urticaria is significantly different from that of healthy individuals. 8For example, E. coli was significantly higher in chronic urticaria than in healthy controls. 9At present, the commonly used probiotics in clinical practice are bifidobacteria and Lactobacillus. 10 Lactobacillus strains can enhance the immune response by stimulating lactic acid secretion to lower intestinal pH and thus produce some products friendly to the growth of beneficial microorganisms. 11Probiotics can restore unbalanced intestinal flora to normal levels, promote intestinal mucosal immune barrier function, reduce blood levels of intestinal antigens, and decrease the production of pro-inflammatory factors and allergic IgE antibodies.It also promotes the production of lymphocyte cytokines, participates in immune regulation, and treats urticaria, eczema, and allergic rhinitis. 12clinical study by Bi et al. 13 found that Yimingjia® probiotic formula was safe and effective in the adjunctive treatment of chronic urticaria in children for 4 weeks.However, there are no articles summarizing the clinical efficacy of probiotics in the treatment of urticaria.Therefore, in this study, a systematic analysis of probiotic treatment of urticaria was conducted from a randomized controlled trial (RCT) of oral probiotic administration group and placebo group (or antihistamine group) to evaluate the efficacy and safety of probiotic treatment of urticaria and provide evidence-based medical evidence for clinical application.

| Search strategy
The literature of RCTs of probiotics for urticaria published before May 2019 were searched in PubMed, EMbase, MEDLINE (Ovid), SCI-Hub, Springer, ClinicalKey, VIP, and CNKI.The search language was limited to Chinese and English.English search terms include "probiotics" OR "prebiotics" OR "lactobacilli" OR "bifidobacteria" OR "bifidobacterium" OR "gram-positivecocci" OR "streptococcus" OR "lactococcus" And "angioedema" OR "quincke" OR "urticaria" OR "giant angioneurotic" OR "hives".Chinese search terms correspond to them.

| Inclusion criteria
1. Study type: The RCTs of two groups of therapy for urticaria (probiotics and controls: placebo or antihistamines) was searched.

| Exclusion criteria
Non-randomized controlled trials of animal experiments, simple case reports, or empirical presentations were excluded; literature with poor quality, incomplete data, and repeated reports were excluded.

| Evaluation method
The collected literature was evaluated by two researchers independently from reading the title, abstract, and full text to determine whether the documents met the inclusion criteria or not.Discussion with the third party would be involved if different opinions occurred.The quality evaluation criteria are designed based on the methods recommended by Cochrane, 14 including random assignment methods, allocation, blind methods, and the people loss to follow-up.

| Statistical analysis
The data were processed by the RevMan 5.3 software provided by the Cochrane Collaboration.The statistical heterogeneity between RCTs was tested by Q test and I-square (I 2 ) value.p > 0.10 and I 2 < 50% representing that there was not enough evidence to prove substantial heterogeneity among the included RCTs.And the fixedeffect models were applied to combined statistics.Subgroup analyses were also being processed if the data was available.Statistically significant was reflected by relative risk (RR) and 95% confidence interval (CI), with p < 0.05 as the reference value.Publication bias was assessed with the funnel plot.Sensitivity analysis was performed by means of fixed effect analysis or random-effect analysis comparison.A series of different inclusion criteria were adopted to estimate its impact on the meta-analysis with the RR values as references, respectively.

| General situation
A total of 1082 papers were retrieved from the above-mentioned databases, which included 1076 articles from PubMed, EMbase, MEDLINE (Ovid), Sci-Hub, SCI + Springer, ClinicalKey, VIP, and CNKI databases; and 6 articles were obtained through other channels (database of China Clinical Trial Registration Center), 533 articles were left after reading the abstract or the full text and excluding duplicate articles, 367 articles were left after deleting articles without results and detailed contents, 15 articles were left after excluding articles that did not meet the inclusion requirements (conference papers, animal experiments, reviews, series of articles), and 9 articles were left after excluding articles that did not meet the inclusion criteria and non-RCT, of which two articles were only results and did not report information such as experimental process and follow-up results, so they were not included.Finally, seven studies [15][16][17][18][19][20][21] were included for meta-analysis.The flowchart of the study selection process was shown in Figure 1.

| Document quality
Details of the participants, interventions, and outcomes included in the study were shown in Table 1.All literature mentions random assignments and are double-blind studies.Seven papers applied the blind method in the result evaluation.However, placebo has not been used in all the studies: two of them Shi Hua, 15 Li Qingxiang, 16 used antihistamine in the control group.All the studies were analyzed according to the intervention methods at the randomization stage.
F I G U R E 1 Flow diagram of the study inclusion of the meta-analysis.

TA B L E 1
The general characteristics of the included studies.

| Risk of bias
Baseline comparability was reported in all literature and possible confounding factors were analyzed.However, Kukkonen 21 did not analyze the family history of allergies in the two groups of subjects, and information about newborns without urticaria was unclear.Shi 15 and Canani 17 have a relatively short administration time, and their medical effects may be biased.The risk of bias summary was shown in Figure 2.

| Therapeutic effect
Randomized controlled trials of probiotics and control groups for the treatment of urticaria, including oral administration of single probiotics, oral administration of multiple probiotics, and oral administration of probiotic combined with antihistamines.Seven papers compared the therapeutic effects of probiotics in the treatment of urticaria.There was significant heterogeneity (p = 0.04, I 2 = 54%) among the included studies, so a randomized model was used for analysis.The results of the meta-analysis showed that patients in the probiotic group had significantly higher therapeutic effects than the control group (RR = 1.09; 95% CI: 1.03-1.16;p = 0.006) (Figure 3).

| Subgroup analysis
Subgroup analysis was applied in the assessment of efficacy of the probiotics group for the treatment of urticaria according to the treatment plan (regardless of the administration method and dosage), which were categorized into three groups: (i) oral administration of a single type of probiotics, (ii) oral administration of multiple probiotics, and (iii) oral probiotics combined with antihistamines.
Analysis on the therapeutic effect of oral administration of single-type probiotic group showed that there was no significant heterogeneity in the literature (p = 0.19, I 2 = 40%).A random effect model was used, and the results showed that the treatment effect was significantly higher in the single probiotic group compared to the placebo group (RR = 1.11; 95% CI: 1.01-1.21;p = 0.03) (Figure 4).
The results of the analysis of the treatment by oral administration of multiple probiotics showed no significant heterogeneity among the literature (p = 0.42, I 2 = 0%).And there was no statistically significant difference in the treatment effect between the complex probiotic group and the placebo group (RR = 1.00; 95% CI: 0.94-1.07,p = 0.91) (Figure 4).analysis showed that the treatment effect of single probiotic combined with antihistamines was significantly higher than that of the antihistamines group (RR = 1.13; 95% CI: 1.07-1.19;p < 0.001) (Figure 4).
The above analyses have shown that the therapeutic effect of probiotics combined with antihistamines is superior to the other two groups, but the results of oral administration of multiple probiotics and placebo groups are unclear.

| DISCUSS ION
In this study, a total of seven RCTs were included in this study for meta-analysis, with a total of 3903 patients with urticaria.We found that the probiotics therapy for urticaria could be categorized into three groups: (i) oral administration of single type of probiotics, (ii) oral administration of multiple probiotics, and (iii) oral probiotics combined with antihistamines.Although the trials may be biased to some extent due to some reasons such as hidden allocation, doubleblind method, missing data, and computational limitations of sample size, it can be concluded from this study that probiotics have a significant effect on the treatment of urticaria.
F I G U R E 4 Subgroup analysis was applied in the assessment of efficacy of the probiotics group for the treatment of urticaria according to the treatment plan.

F I G U R E 5
The forest plot of adverse effects in the probiotics group.
| 2669 Intestinal probiotics can restore unbalanced intestinal flora, and can treat various diseases such as urticaria, eczema, and allergic rhinitis. 22,23Recent studies have shown that regulation of intestinal microflora regulation and elevated levels of immunoregulatory cytokines can reduce allergenic factors, treating urticaria. 24Among them, Lactobacillus rhamnosus GG (LGG) is a kind of Lactobacillus isolated from the intestine of healthy people and is one of the most widely studied probiotics in humans. 25LGG lives in the gastrointestinal tract for a short time.It can balance the intestinal flora, strengthen the natural defense ability against infection, and improve the treatment of various diseases. 26In this study, there are three articles 17,18,20 related to LGG, and they make this kind of probiotics the most talked about.In addition, the World Gastroenterology Organization (WGO) has published a clinical application guideline for probiotics and prebiotics therapy, 17 indicating that bifidobacteria can treat chronic diarrhea, antibiotic-associated diarrhea, and constipation.Moreover, it also has a very good effect on the treatment of food-allergic urticaria.In this study, the food-allergic urticaria is one of the most research objects among the included articles (milk and dairy are the common allergens).The experiments of Shi, 15 Li, 16 and Simpson 19 can prove the authenticity and reliability of this conclusion.In addition, in a prospective, randomized, double-blind, placebo-controlled design study, it was shown that feeding healthy term infants with anaphylactic parental history with hypoallergenic formula supplemented with oligosaccharide prebiotics or placebo (maltodextrin) could significantly reduce the cumulative incidence of allergic symptoms and allergic dermatitis, repeated wheezing and allergic urticaria in infants, and also protect allergic manifestations and infections, And this dual protective effect may play a major role in the immune regulation effect through the modification of intestinal flora. 27Mastrandrea et al. also showed that probiotics (a mixture of Lactobacillus acidophilus, Lactobacillus delbrueckii, and Streptococcus thermophilus) can significantly reduce the number of circulating CD34 + hematopoietic progenitor cells in the peripheral blood of subjects to enhance the immunity of patients. 28It has also been reported that the combination of Lactobacillus salivarius LS01 and Bifidobacterium brevis BR03 can reduce the symptom scores and improve the quality of life scores in some patients with chronic spontaneous urticaria, and no side effects were found during the treatment. 29Thus, a single probiotic or a combination of probiotics may improve the symptoms and quality of life of patients with urticaria by improving immunity and regulating intestinal flora.
In this study, we found that the probiotic group had a higher therapeutic effect on urticaria than the control group.However, further analysis found that oral administration of a single type of probiotic combined with antihistamines has significant therapeutic effects, but the therapeutic effect of multiple types of probiotics on urticaria is not clear.However, a recent study showed that compared with the antihistamine group, the antihistamine + probiotics group had a higher rate of pruritus reduction, a significantly reduced amount of urticaria, and a greater improvement in the quality of life (DLQI) of the patients. 30Atefi et al. also proposed probiotics as an effective, safe, and satisfactory adjuvant treatment for chronic spontaneous urticaria. 30This shows that probiotics have important value in improving patients' immunity and regulating intestinal flora, which is a great boon for children with urticaria.Therefore, the clinical application of probiotics has broad application prospects.However, the exact treatment mechanism needs further experiments to be clarified.
There are some limitations to this study.5) We are unable to perform sensitivity analysis to evaluate statistical heterogeneity variability.These factors limit the robustness of this systematic review.
These need to be clarified by larger sample size, multi-center RCT studies.

| CON CLUS ION
Probiotics appear to be beneficial and safe for urticaria, but the evidence is inconclusive.Well-designed trials are required to test the effectiveness and safety of probiotics for urticaria as well as to test the methods that were once widely used in the clinics.

E TH I C A L A PPROVA L
Authors declare human ethics approval was not needed for this study.

2 .
Study subjects: Patients diagnosed with urticaria according to symptoms, urticaria activity score (UAS), serum-specific IgE, food challenge test, and skin prick test (SPT).

3 .
Interventions: Probiotics group adopted oral administration therapy of probiotics (strains and doses are varied), including oral administration of a single type of probiotics, multiple types of probiotics, and probiotics combined with antihistamines.The control group was given antihistamine or placebo.4. Results: Symptoms, urticaria activity score (USA), serum-specific IgE as a measure of outcome.

3
Analysis of the group of oral administration of probiotics combined with antihistamines showed no significant heterogeneity among the literature (p = 0.85, I 2 = 0%).Random effects model F I G U R E 2 The risk of bias summary.Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Forest plot comparing the therapeutic effects of the probiotics group and the control group in urticaria.

( 1 )
Due to the differences in the strains, time, dosage, and method of probiotics used in each literature, further research is needed to specify the strains and dosage that have a positive effect on the treatment of urticaria.(2) There are certain differences in the diagnostic criteria, follow-up time, and the administration course, which may affect the results.(3) There is less literature on the use of probiotics to treat urticaria alone.The diseases shown in the literature included in this study also include patients with urticaria in protein-induced allergic diseases (infants and young children), which are included in accordance with the research purpose.(4) The small number of included literature did not allow us to further analyze the effect of probiotics on urticaria subtypes.(