Effects of Probiotics on Allergic Rhinitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Abstract

Background

The prevalence of allergic rhinitis has been estimated to range from 10 to 30% in adults and up to 40% in children. Probiotics have been tested as for this condition, but no census on which probiotic types are most effective.

Objective

Our aim of this study was to provide probiotic strain-specific evaluation for the treatment of allergic rhinitis.

Methods

Databases (PubMed, Google Scholar, and ScienceDirect) were searched (from inception to October 2020) to identify randomized controlled trials (RCTs) of probiotic treatments in allergic rhinitis patients. A systematic review was done comparing types of reported outcomes, clinical and immunological parameters and safety data. A meta-analysis was done for probiotics with at least two RCTs per probiotic strain(s) and sharing a common outcome.

Results

A total of 13 randomized, double-blind, placebo-controlled trials (N = 1591 participants) were included in the systematic review. Overall, 8 of 9 probiotic types alleviated at least one clinical symptom of allergic rhinitis. The meta-analysis results showed that, neither L. paracasei Lp33 (SMD = −1.61, 95% CI −4.67, 1.45) nor L. rhamnosus GG (SMD = −1.00, 95% CI −3.01, 1.00) had significant efficacy for reducing nasal symptom scores.

Conclusions

Our analysis showed probiotics produced a slight improvement in some clinical and immunological measurements on allergic rhinitis. Due to the diversity of outcome measurements and lack of sufficient trials for each probiotic strain, future trials are needed with similar study design and uniform outcomes to better compare the effect of probiotics on allergic rhinitis.

Keywords

allergic rhinitis clinical trial meta-analysis probiotics systematic review

Introduction

The prevalence of allergic rhinitis (AR) has been estimated to range from 10% to 30% in adults and up to 40% in children.¹ Estimates of the annual direct cost of AR range from $2 to $5 billion United States Dollars (USD), with more than half of AR direct costs due to prescription medication treatments for AR.² AR is a hypersensitivity reaction caused when inhaled particles contact the nasal mucosa and induce an immunoglobulin E (IgE)-mediated inflammatory responses resulting in sneezing, nasal itching, rhinorrhea, nasal obstruction, or a combination of those symptoms.³ AR can occur after exposure to both indoor or outdoor allergens, such as dust mites, insects, animal dander, molds, and pollen. Management of AR and its associated symptoms continue to revolve around allergen avoidance, medications that provide symptomatic relief, anti-inflammatory therapies, and allergy immunotherapy.⁴ Many of these medications are costly and are not without potential adverse effects (eg, epistaxis, headache, dizziness, elevated blood pressure, nasal irritation, sedation).

Complementary and alternative approaches including probiotics may offer feasible and efficacious treatment options for AR. Unique in comparison to other common dietary supplements, probiotic preparations comprise live microorganisms when administered in adequate amounts, confer a health benefit on the host.⁵ One of the main mechanisms of action for probiotics is immunomodulation, which influences immune and inflammatory factors in the host, imparting positive health benefits, such as promoting pathogen resistance and anti-inflammation.⁶ Probiotics have shown efficacy for preventing acute upper respiratory tract infections,⁷ improving irritable bowel syndrome symptoms⁸ and a wide variety of different diseases.⁹ Prior reviews and meta-analyses of probiotics for AR indicate there may be beneficial clinical and immunologic effects of probiotics, but they have not accounted for the strain-specificity in their efficacy analysis.^10,11

The objective of our systematic review and meta-analysis is to assess the current evidence for the efficacy of probiotics for the treatment of AR, while accounting for strain-specificity.

Methods

Search Strategy

We searched databases including PubMed, Google Scholar, and ScienceDirect (from database inception to October 2020) to identify randomized controlled trials (RCTs) of probiotic for the treatment of AR. Our search strategy was as follows: (“probiotics” [MeSH Terms] OR “probiotics” [All Fields]) AND “allergic rhinitis” [MeSH Terms] AND “clinical trials” [All Fields]. Additional searches were done using search terms: “allergic diseases” AND “lactobacillus” OR “bifidobacterium” OR “lactic acid bacteria” AND “randomized controlled trial”. A recursive search was also performed, using the bibliographies of all obtained articles. There were no language restrictions, as non-English trials were translated and reviewed.

Inclusion/Exclusion Criteria

Inclusion criteria included: RCTs in adults or children with AR using probiotic interventions and published in peer-reviewed journals. We included only probiotics fulfilling the standard definition (must be living microbe, of adequate dose and having efficacy for a health effect.⁵ This definition excludes dead or heat-killed microbes and prebiotics. As bacterial and fungal taxonomies shift over time, the most current strain designations are presented in this review and strain identification was confirmed with the original authors or the manufacturer whenever possible. This review was registered with PROSPERO [#CRD42021241045].

Exclusion criteria included: non-human studies, early phase 1 or 2 safety or mechanism of action studies, no control group, probiotic not well-described, reviews and duplicate reports. Cross-over trials were excluded due to the potential for effect carry-over after short wash-out periods used in these trials.

For the meta-analysis, each probiotic type was required to have at least two RCTs sharing at least one common AR outcome. We followed current recommendations requiring each type of probiotic be analyzed as a separate sub-group and not to pool dissimilar types of probiotics.^12,13 If sufficient trials per probiotic type sharing a common outcome was available, a priori sub-group analyses included: age, dose of probiotic, and quality of study.

Data Extraction and Assessment of Validity

The literature was searched independently by two co-authors (KF, AM). Data from all RCTs were extracted using a standardized data extraction form and independently reviewed by all three authors following the PRISMA methods for systematic reviews and meta-analysis.^14,15 Any disagreements were discussed until consensus was reached. The data extracted included PICOS data: (1) patient population (age range, country), (2) intervention (type of probiotic or controls used, daily doses, formulation, treatment duration and follow-up times), (3) comparisons (type of control group either placebo or open, unblinded), (4) primary outcomes, including mean change in AR various symptom scores, (5) secondary outcomes, frequency of improvement and safety data. For data that were required for these analyses, but not reported in the published article, we attempted to contact the author or co-authors to obtain the missing data.

Each included RCT was reviewed for quality and risk of bias and scored independently by at least two of the co-authors using standard methods. The risk of bias was graded (high, low or not reported) for each of six types of bias [selection bias (method of randomization and blinded allocation), performance bias (degree of blinding of study personnel and study subjects), detection bias (outcome assessor blinded), attrition bias (attrition different by group), reporting bias (a priori outcomes reported) and other issues (fraud or miscellaneous)].^15,16

Statistical Analysis

Our primary outcome was the change in nasal symptom scores from enrollment to the end of the study and was measured as a continuous variable. Continuous outcomes were assessed using standard mean difference (SMD) and 95% C.I. using standard methods,¹⁵ if confidence intervals included one, this indicates a non-significant effect. In trials reporting only mean values and no standard deviations (SD), SD were estimated using methods recommended by Higgins et al¹⁵ Generation of forest plots of pooled summary estimates was performed using Stata software version 16 (Stata Corporation, College Station, Texas) with meta-analysis modules.¹⁶ Summary estimates were based on the pooled data from RCTs using the same type (strain or strains) of probiotic and sharing a common outcome measure. Heterogeneity across trials was evaluated using the I2 statistic (0% indicating none and >50% indicating a high degree of heterogeneity) across the trials. Random effects models were used for all meta-analyses.

Results

We initially reviewed abstracts for 537 studies and excluded duplicates (n = 143) and 351 non-clinical studies (reviews, meta-analyses, animal studies, thesis/dissertation work, no control group, not randomized, and other miscellaneous reasons), as shown in Figure 1. A total of 43 full articles were reviewed and 30 were excluded (cross-sectional studies, protocol studies, inactivated/non-viable probiotic studies, studies that evaluating safety, no full text available, and non-relevant clinical outcomes), resulting in 13 RCTs for our systematic review.^17–29 As nine probiotic strains or mixtures did not have a second confirmatory trial and one trial did not share a common outcome,²² only four trials assessing two different types of probiotics were eligible for the meta-analysis.^20,21,23,24

Characteristics of Included Trials

The 13 RCTs enrolled a total of 1591 participants (n = 815 probiotic, n = 776 control subjects), involving all age groups (6 months to 65 years) and both genders (male and female). The study size of the trials ranged from 8 to 215 participants, with a mean number per trial of 61 in the probiotic groups and 60 in control groups. Trials were performed in a variety of countries, including: two trials (15.4%) each in Iran, Taiwan, Italy, and one trial (7.7%) each in Pakistan, China, France, Switzerland, Finland, Indonesia, and Japan. Four RCTs studied children diagnosed with AR, two included teenagers and young adults, four enrolled adults and three enrolled a mixed age population (Table 1). Nine different probiotic types were assessed (Table 1). Overall, the duration of probiotic therapy ranged from four weeks (23.1%), or five weeks (7.7%), or six weeks (7.7%), or eight weeks (30.8%), or 12 weeks (15.4%), or 22 weeks (7.7%), to 48 weeks (7.7%). Daily doses of probiotics ranged from 1 × 10⁸ to 4 × 1010 colony-forming units/day (cfu/d). More information on the individual trials reported in this systematic analysis is provided in Table 1. Including nine trials with a shared outcome (changes in nasal symptom scores, no significant publication bias found [p = 0.2], as shown in Figure 2.

Table 1.

Probiotic and Control Intervention Characteristics of 13 Randomized, Controlled Trials for the Treatment of Allergic Rhinitis.

Probiotic strain(s)	Daily dose (cfu/d)	Formulation	Duration study treatment (weeks)	Study location	Study population	Follow-up post-study medication (weeks)	Type of allergic rhinitis	Overall risk of bias	Ref.
Lactobacillus casei DN-114 001	10⁸	Fermented milk	48	Italy	children (2-5 yrs)	nr	Perennial and Seasonal	Low	¹⁷
Lactobacillus salivarius PM-A006	4 × 10⁹	Sachet	12	Taiwan	children (6-12 yrs)	28	Perennial	Moderate	¹⁸
Lactobacillus casei strain Shirota (LcS)	4 × 10¹⁰	Fermented milk	8	Japan	adults	2	Seasonal	Low	¹⁹
Lactobacillus rhamnosus GG (ATCC 53103)	4 × 10⁹	Capsule	12	Taiwan	children (<18 yrs)	28	Perennial	Moderate	²⁰
Lactobacillus rhamnosus GG (ATCC 53103)	2 × 10¹⁰	Capsule	22	Finland	teenagers	nr	Seasonal	Moderate	²¹
Lactobacillus paracasei LP-33	2 × 10⁹	Chewable tablet	6	Pakistan	children (0.5-5 yrs)	2 to 6	Perennial	Moderate	²²
Lactobacillus paracasei LP-33	2 × 10⁹	Fermented milk	4	China	teenagers (12-18 yrs)	3	Perennial	Moderate	²³
Lactobacillus paracasei LP-33 + microcrystalline cellulose, dicalcium phosphate and magnesium stearate	2 × 10⁹	Capsule	5	France	adults (18-60 yrs)	0	Seasonal	Low	²⁴
Bifidobacterium lactis NCC2818 + maltodextrin	4 × 10⁹	Can	8	Switzerland	adults (20-65 yrs)	nr	Seasonal	Low	²⁵
Lactobacillus casei and Lactobacillus acidophilus	nr	Liquid milk	4	Indonesia	adults (18-21 yrs)	nr	nr	Moderate	²⁶
Bifidobacterium longum BB536, B infantis M-63, and B breve M-16 V	5 × 10⁹	Sachet	4	Italy	mixed (4-17 yrs)	nr	Seasonal	Moderate	²⁷
Lactobacillus casei + Lactobacillus acidophilis + Lactobacillus rhamnosus + Lactobacillus bulgaricus + Bifidobacterium breve + Bifidobacterium longum + Streptococcus thermophilus + Fructooligosaccharides	nr	Capsule	8	Iran	mixed (9-53 yrs)	nr	Perennial	Moderate	²⁸
Lactobacillus casei + L. acidophilus + L. rhamnosus + L. bulgaricus + Bifidobacterium breve + B. longum + Streptococcus thermophilus + Fructooligosaccharides	2 × 10⁹	Capsule	8	Iran	mixed (>15 yrs)	8	nr	High	²⁹

Abbreviations: nr: not reported, Ref: reference.

Study Quality

Overall, four (31%) trials had a low risk of bias (see Table 1), eight (61%) had a moderate risk of bias and one (8%) had a high risk.²⁹ All 13 trials were randomized, however only five trials (38.5%) stated the method of randomization (e.g., computer random number generator, blocked randomization design, or software package). In one study, randomization did not produce equal groups (n = 60 to probiotic vs. n = 20 to control).²³ Of the 13 trials, all used placebos as controls and 12 trials were double-blinded,^{17–25,27–29} and one was single-blinded.²⁶ The placebo in 13 trials used the same appearance and was provided in the same delivery form as the probiotic to patients; either in the form of milk,^17,19,23,26 chewable tablet,²² can,²⁵ sachet^18,27 or capsules.^{20,21,24,28,29}

Single-Strain Probiotic Treatments

Of the 13 trials, nine (69%) tested one of six different single-strain probiotics including: Lactobacillus casei DN-114 00,¹⁷ Lactobacillus salivarius PM-A006,¹⁸ Lactobacillus casei Shirota (LcS),¹⁹ Lactobacillus rhamnosus GG (ATCC 53103),^20,21 Lactobacillus paracasei LP-33,^22–24 and Bifidobacterium lactis NCC2818.²⁵ The duration of probiotic treatments ranged from one to 48 months. The follow-up post-probiotic treatment ranged from two weeks to 28 weeks, and 33% did not have any follow-up post-treatment.

Multi-Strain Probiotic Mixtures Treatments

Of the 13 trials, four used one of three different multi-strain mixtures,^26–29 as shown in Table 1. One trial used a mixture of two different types of Lactobacilli (L. casei and L. acidophilus),²⁶ but failed to report strain designations. Another trial used a mixture of three strains of Bifidobacteria (B. longum BB536, B. infantis M-63, B. breve M-16 V)²⁷ and two trials used a 7-strain mixture (strain designations not reported).^28,29 Bacteria (Lactobacillus bulgaricus or Streptococcus thermophilus) used as fermenter starters were not considered as a probiotic strain. Most of probiotic mixture formulations were in capsule form (2, 50%).^28,29 The duration of probiotic treatments ranged from 4 to 8 weeks and only one trial reported post-study medication follow-up.²⁹ The number of study participants ranged from 7 to 40 per trial.^26–29

Clinical Outcomes

In the systematic review, a variety of different clinical outcomes were found (Table 2), and not all trials reported the same types of clinical outcomes. The most commonly reported outcomes were the change in nasal symptom score^{18,21,23–25,28} and the change in global AR symptom scores.^{20,23,24,27,28} Other reported outcomes included frequency of patients reporting an improvement in AR symptoms,^22,23,29 or other symptom changes,^17–19 or changes in immune markers.^{17–20,25,26,28} Other outcomes (quality of life, medication use, physical activity changes) were not consistently reported. Overall, nine trials reported an improvement in at least one AR symptom outcome in the probiotic group compared to the placebo group,^{17–19,23–25,27–29} while three trials did not report an improvement in any AR symptom^20–22 and one trial did not report any clinical outcomes.²⁶ Two trials reported significant changes in AR medication use in probiotic groups compared to placebo,^18,29 while no significant medication changes were noted in two trials.^19,20 Trials using a strain of Lactobacillus paracasei LP-33 alone significantly improved the quality of life in patients suffering from AR.^23,24 In contrast, Lactobacillus rhamnosus GG (ATCC 53103) was not effective for any AR outcome measured.^20,21 The diversity of outcomes used in the 13 RCTs makes a summary of the efficacy of the different probiotics difficult.

Table 2.

Clinical Outcomes of the 13 RCTs That Evaluated the Effects of Probiotics on Allergic Rhinitis.

Type of probiotics	Outcome measures	Probiotics versus placebo	P value	Ref.
Lactobacillus casei DN-114 001	Mean time free of episodes of rhinitis	6.2 versus 5.1 months	0.94	¹⁷
	Cumulative No. of episodes of rhinitis	3.2 versus 4.8	0.04
	Mean duration of a single episode of diarrhea	1.04 versus 1.85 days	0.05
	Mean duration of an episode of rhinitis	1.02 days	NS
	Skin prick tests	91.01% versus 95.69%	NS
	Difference in amount of:
	IgA (mg/dl)	105.1 versus 104.0	0.76
	IgG (mg/dl)	954.5 versus 917.8	0.35
	IgM (mg/dl)	98.5 versus 90.9	0.23
	IgE (U/ml)	244.3 VS 318.4	0.2
L. salivarius PM-A006	Changes in:			¹⁸
	Specific eye symptom scores	-3.7 versus -2	0.001
	Specific Nasal Symptom Scores	-5.6 versus -3.7	0.001
	Specific Lung Symptom Scores	No differences	NS
	Specific Medication Scores	2.4 versus 2.8	0.006
	WBC	2.11 versus 2.60	NS
	Eosinophil	4.542 versus 4.27	NS
	IgE	392.55 versus 632.76	NS
L. casei Shirota	Changes in nasal SMS	Decreased in probiotic group	NS	¹⁹
	Swelling, redness of nasal mucosa, amount, nature of mucus	No differences	NS
	ECP level, anti-JCP IgE level, eosinophil number, eosinophil cationic protein levels, Th1/Th2	No significant differences were showed	NS
L. rhamnosus GG	Changes in SSS	Not significantly reduced	NS	²⁰
	Decreasing drug score	No significant change was shown	NS
	Blood cell counts, total IgE, and blood eosinophil counts	No differences were showed	NS
L. rhamnosus GG	Frequency changes score for:			²¹
	Nose symptoms	-11.7 versus -7.7	NS
	Eye symptoms	-3.9 versus -7.5	NS
	Lung symptoms	-2.3 versus 0.9	NS
L. paracasei Lp33	Full improvement symptoms after 6 weeks:			²²
	Rhinitis	Increased (81.1% vs 86.8%)	0.53
	Sneezing	Increased (84.0% vs 89.2%)	0.44
	Nasal Blocking	Increased (84.6% vs 85.5%)	0.98
	Coughing	Increased (82.8% vs 83.8%)	0.52
	Feeding difficulties	Decreased (90.1% vs 88.0%)	0.47
	Sleeping difficulties	Decreased (93.8% vs 91%)	0.76
L. paracasei Lp33	Frequency score for:			²³
	Nose symptoms	Decreased (-4.12 vs -1.63)	0.08
	Eye symptoms	Decreased (-2.25 vs -1.25)	0.38
	Practical problems	Decreased (-1.78 vs -1.40)	0.54
	Other symptoms	Decreased (-4.31 vs -1.94)	0.04
	Activity limitations	Decreased (-3.95 vs -1.00)	0.05
	Overall quality of life	Decreased (-16.02 vs -7.27)	0.04
	Level of bother:
	Nose symptoms	Decreased (-5.39 vs -2.31)	0.04
	Eye symptoms	Decreased (-2.84 vs -0.07)	0.08
	Practical problems	Decreased (-2.27 vs -0.80)	0.08
	Other problems	Decreased (-3.31 vs -1.50)	0.15
	Activity limitations	Decreased (-2.53 vs -1.44)	0.23
	Overall quality of life	Decreased (-16.35 vs -6.20)	0.02
L. paracasei Lp33	Changes in symptom scores:			²⁴
	RQLQ global score	Decreased (-1.9 vs -1.61)	0.05
	RQLQ “Nose symptoms” domain	Decreased (-2.70 vs -2.46)	0.13
	RQLQ “Eye symptoms” domain	Decreased (-1.89 vs -1.80)	0.46
		Decreased (-1.75 vs -1.36)	0.03
	Time to first exacerbation of symptoms (d):
	Well-being VAS	Decreased (-3.17 vs -2.81)	0.50
	RTSS-5 “nasal symptoms”	Decreased (-2.15 vs -1.95)	0.18
	RTSS-5 “ocular symptoms”	Decreased (-0.56 vs -0.50)	0.07
Bifido. lactis NCC2818	Changes in total nasal symptom score (TNSS)	-3.40 versus -1.1	0.03	²⁵
	Immune markers:
	IL-5	Decreased significantly	0.02
	IL-13	Decreased significantly	0.005
	TNF-a	Decreased significantly	0.04
	IL-1 β	Decreased	0.06
	IFN-γ	No significant difference	NS
	Total IgE	No significant difference	NS
L. casei and L. acidophilus	Changes in:			²⁶
	IFN gamma	1.5 increase in probiotics	<0.05
	Interleukin-4	Decreased in probiotic group	0.000
	IFN γ/IL-4	Increased in probiotic group (2 times)	0.000
Bifidobacterium longum BB536, B infantis M-63, and B breve M-16 V	Changes in:			²⁷
	total symptom score (TSS)	-5.8 versus 2.6	< 0.005
	practical problems	25.7 versus 15.1	< 0.001
Lactobacillus casei + Lactobacillus acidophilis + Lactobacillus rhamnosus + Lactobacillus bulgaricus + Bifidobacterium breve + Bifidobacterium longum + Streptococcus thermophilus + FOS	Changes scores after 6 months:			²⁸
	SNOT-22	-33.2 versus -29.3	0.9
	Mini-RQLQ	-35.4 versus -23.9	0.9
	Immune markers:
	IFN-γ	No significant difference between the two groups	0.7
	IL-4		0.2
	IL-10		0.2
	TGF-β		0.43
	FoxP3		0.16
	IL-17		0.48
Lactobacillus casei + L. acidophilus + L. rhamnosus + L. bulgaricus + Bifidobacterium breve + B. longum + Streptococcus thermophilus + FOS	Frequency of:			²⁹
	Sneezing	Decreased (4.6% vs 14.3%)	<0.01
	Nasal and oral corticosteroids	Decreased in probiotic group	<0.01
	Cough, nasal discharge, conchae hypertrophy, and night sleep disorders	Lower but not significantly	NS
	Chest x-ray changes	92.9% versus 100%	0.32

Abbreviations: ECP: eosinophil cationic protein, FOS: Fructooligosaccharides, JCP: Japanese cedar pollen, nr: not reported, NS: Not significant, RQLQ: Rhinoconjunctivitis Quality of Life Questionnaire, Ref: reference, RTSS-5: Rhinitis Total Symptoms Score, SMS: symptom-medication score, SNOT-22 = Sinonasal Outcome Test-22, SSS: specific symptoms scores, TSS: total symptom score.

Immunologic Outcomes

Seven trials recorded at least one allergy immunologic measurements, including total IgA, IgG, IgM, or IgE immunoglobulin levels and allergen specific IgE, peripheral blood cell counting, blood eosinophils, TH1/TH2 ratio, the assessment of interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 10 (IL-10), interleukin 13 (IL-13), interleukin 17 (IL-17), interleukin 1β (IL-1β) and interferon-gamma (IFNγ), tumor necrosis factor alpha (TNF-a), transforming growth factor beta (TGF-β), forkhead box P3 (FoxP3) gene expression.^{17–20,25,26,28}

In two trials,^25,26 probiotics improved immunological parameters compared to the control group, while in the other five trials, no difference was observed in immune response between the placebo and probiotic groups. Probiotics did not have a significant impact on changes in total IgE, and/or specific IgE levels in AR patients.^17–20,25 A significant increase in blood eosinophils was not observed in any of the RCTs.^18–20 Some trials evaluated the changes in the levels of cytokines. The results showed that in one trial, IL-4 levels significantly decreased in the probiotic group,²⁶ while another trial reported no significant difference²⁸ In addition, IFNγ level was increased significantly in one trial,²⁶ but no significant changes were observed in other trials.^25,28 Trials that evaluated changes in the number of blood cells^18,20 did not report any significant differences between intervention and placebo groups.

Meta-Analysis

Two probiotics had at least one confirmatory trial with similar outcomes evaluating nasal symptoms (Table 3), however only one trial evaluated improvement in nasal symptoms,²² rather than the change in nasal symptom scores and was excluded from the meta-analysis. Four trials evaluated the primary outcome and were included in the meta-analysis: two trials with L. rhamnosus GG^20,21 and two trials with L. paracasei Lp33.^23,24 A total of 739 patients with AR were included in the data from these four trials.

Table 3.

Main Outcomes for Probiotic and Control Groups from Five Randomized, Controlled Trials Having at Least Trials/Probiotic Type for the Treatment of Allergic Rhinitis.

	Probiotic		Control		Probiotic Improved no. (%)	Control Improved no. (%)	Probiotic AE (%)	Control AE (%)
Probiotic	No.	Change in nasal symptom scores (mean ± sd)	No.	Change in nasal symptom scores (mean ± sd)	Probiotic Improved no. (%)	Control Improved no. (%)	Probiotic AE (%)	Control AE (%)	Reference
L. paracasei Lp33	106	nr	106	nr	102 (96.2)	103 (97.2)	nr	nr	²²
L. paracasei Lp33	60	−4.12 ± 0.65	20	−1.63 ± 1.09	nr	nr	0 (0)	0 (0)	²³
L. paracasei Lp33	215	−2.15 ± 2.89	210	−1.95 ± 2.86	nr	nr	64 (30)	56 (27)	²⁴
L. rhamnosus GG (ATCC 53103)	98	−0.9 ± 0.1*	100	−0.7 ± 0.1*	nr	nr	nr	nr	²⁰
L. rhamnosus GG (ATCC 53103)	15	+ 3.7 ± 7.2*	16	+ 3.3 ± 10.3*	nr	nr	nr	nr	²¹

*Estimated or from author communication.

Abbreviations: AE, adverse events; L., Lactobacillus; no., number; nr, not reported in paper; ns, not significantly different; sd, standard deviation.

The meta-analysis (Figure 3) shows that neither L. paracasei Lp33 (SMD = −1.61, 95% CI −4.67, 1.45) nor L. rhamnosus GG (SMD = −1.00, 95% CI −3.01, 1.00) had significant efficacy for reducing nasal symptom scores. There is significant heterogeneity between the trials (I² = 98%). Sub-group analyses were not possible due to the limited number of trials eligible for meta-analyses.

Safety

Data on adverse events were only provided in seven of the 13 (54%) trials. Only in one trial was a serious adverse event reported (which was acute appendicitis and periarthritis of the shoulder).²⁴ Minor side effects were reported in two trials,^19,22 including nausea, cold, diarrhea, and vomiting, and no side effects were reported in the remaining of four trials.^23,25,27,28

Discussion

The aim of this systematic review and meta-analysis was to examine the effect of probiotic administration on clinical symptomology and circulating immune markers in individuals with AR. We found a weak level of evidence for specific strains of probiotics impacting the target outcomes as compared to placebo, but no specific probiotic strain had convincing evidence for AR efficacy. The present review is unique, in that we placed more strict inclusion criteria on study selection, such as excluding trials that investigated heat-killed probiotics, cross-over designs, and non-clinical safety or formulation studies. In the present analysis we captured five trials published after 2016, adding an up-to-date review of the literature.¹¹

We demonstrated several important findings. Of the trials that assessed clinical symptoms as their primary aim, nine trials noted at least one improved AR symptom, while three did not detect any significant improvements. Our meta-analysis did not find significant efficacy for reducing nasal symptom scores for two tested strains (ie, L. paracasei Lp33 and L. rhamnosus GG). For immunological parameters, only two out of seven trials that recorded allergy immunologic measurements noted an improvement compared to the control group.^25,26 However, we were limited by the wide variation in the type of immune parameters used between trials.

In this systematic review we noted a range of strains and dosages used. Species and strains were the same in only a few instances (eg, Lactobacillus rhamnosus GG [ATCC 53103]^20,21 and Lactobacillus paracasei Lp33.^22–24 While different probiotic strains may have shared core mechanisms in terms of functionality, other mechanisms are likely narrowly distributed among probiotic species. Indeed, strain specificity of probiotic benefits is assumed unless mechanistic and clinical evidence suggests otherwise.^12,13 This may have attributed to the varied findings in the present review given the range of strains used in the included trials. Another important consideration is the range in treatment dosages. A review of probiotics used in randomized trials found doses ranged from 1 × 10⁸ to 1.8 × 1012 cfu/d depending on the strain and health indication.⁹ However, there is no set consensus on ideal dosage or length of treatment, as it is highly dependent upon both the strain[s] used and the disease.¹² Of the 13 included articles, we noted a several instances where the dosage was the same or similar and length of treatment generally fell within a similar range [≤12 weeks]. There were two exceptions with Giovannini et al¹⁷ implementing a 48-week long intervention and Helin et al²¹ that had a 22-week long intervention. Notably, both of these trials reported reductions in clinical symptomology in their study groups of younger individuals. While examination of length of treatment course on the target effects is of interest, we had too few trials reporting duration to make a proper comparison. In addition, there was heterogeneity in the measurement of clinical symptoms and immune markers across the included trials.

Several trials reported using multi-strain preparations.^26–29 Currently, it is not clear whether these treatments offer an advantage over single-strain probiotic treatments.³⁰ Multi-strain formulations make it difficult to identify which strain is causing an effect, or whether an additive, synergistic, or antagonistic effect is occurring. Such issues likely have important clinical implications and require continued inquiry. Moreover, other constitutional factors may also modulate the potential response to probiotics as medication exposure (eg, antibiotics), age, disease state, diet, and environment/location can significantly impact host condition and the microbiota.

This review and meta-analysis were not free from limitations. First, the quality of the trials varied. Five of these trials were published at or prior to 2011, before important reporting standards were fully established. Indeed, we noted several important features absent from some of these trials. Later research was not immune to these issues as some of the later published trials also lacked important information. For example, only five trials stated the method of randomization. Another limitation of our analysis was the inability to do a sub-group analysis by the age of the included subjects (which ranged from 6 months to 60 years old) due to the low number of trials within the same probiotic type that used different age inclusion criteria. Finally, adverse events were examined in only seven of the trials, indicating a need of recording and reporting in future studies. Of the seven trials, one study reported a serious adverse event²⁴ and two reported minor side effects.^19,22 While limited, these results show a generally good safety level. While there were similarities in some of the methodologies, the majority of trials used different measurements and approaches. Immune markers were also varied which, combined with their inherent complexities, made interpretation less straightforward in terms of probiotic effects for allergenic rhinitis.

Though limited in the quantity of extracted articles, the results of this review do confirm findings from a previous systematic review¹⁰ and a meta-analyses on this topic.¹¹ Güvenç et al found significant amelioration in nasal and ocular symptoms and quality of life scores in patients with AR with probiotic treatment compared with placebo.¹¹ They included 22 trials, including eight trials that were eligible for our review,^{17–21,23–25} but neither the review by Vliagoftis et al nor the meta-analysis by Güvenç et al accounted for strain-specificity in their analyses.^10,11

In future probiotic research assessing the impact of probiotic supplementation for allergenic rhinitis a consensus on shared AR outcome measures would be helpful to pool data from various trials. In addition, future trials should strive to improve reporting study design characteristics (degree of blinding, population characteristics, probiotic strain designations and number and reasons for withdrawals). Furthermore, only few trials reported sample size calculations, which calls into question whether the studies were appropriately powered to accurately detect an effect.

Due to the diversity of clinical and immunological-trials outcomes, further studies are needed to determine the effect of specific probiotics on AR. However, our analysis showed that some probiotic strains showed improvement in at least one AR symptom, indicating probiotics may have the potential as a treatment for AR, but further research is needed. Although Lactobacillus paracasei LP-33 improved the quality of life of AR patients, neither Lactobacillus paracasei LP-33 nor Lactobacillus rhamnosus GG had any significant effect on reducing the nasal symptom score in these patients.

Supplemental Material

sj-docx-1-ajr-10.1177_19458924211073550 - Supplemental material for Effects of Probiotics on Allergic Rhinitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Supplemental material, sj-docx-1-ajr-10.1177_19458924211073550 for Effects of Probiotics on Allergic Rhinitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials by Kajal Farahmandi, Alex E. Mohr and Lynne V. McFarland in American Journal of Rhinology & Allergy

Footnotes

Abbreviations:

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics Approval

Not required-data are aggregate, open access and non-identifiable.

Author Contributions

KF and LM conceived the study. KF and AM designed the literature search, and searched the articles. KF and LM selected the studies. KF and AM contributed to the data extraction process and performed the quality assessment. All the authors analyzed the data. KF and AM wrote the first draft of the manuscript. LM performed the statistical analysis, meta-analysis, and graph, and critically revised successive drafts of the paper. All the authors revised the article and approved the final version.

Declaration of Conflicting Interests

LM is on Scientific Advisory Board (Bio-K Plus, Canada) and on Microbiome Advisory Board (Biocodex, France) and paid lecturer for both companies. She owns no stock of equity in either company. KF and AM have no conflicts.

Informed Consent

Not applicable, because this article does not contain any studies with human or animal subjects.

ORCID iDs

Kajal Farahmandi

Alex E. Mohr

Trial Registration

Not applicable, because this article does not contain any clinical trials.

Supplemental Material

Supplemental material for this article is available online.

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