International Journal of Pediatric Otorhinolaryngology 162 (2022) 111300

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International Journal of Pediatric Otorhinolaryngology

journal homepage: www.elsevier.com/locate/ijporl

Effectiveness and safety of probiotic therapy for pediatric allergic rhinitis

management: A systematic review and meta-analysis
Xia Wang a, Xiangsheng Tan b, Jiwei Zhou c, d, e, *
a
Department of Pediatrics, The Second Affiliated Hospital of Army Medical University, Army Medical University Xinqiao Hospital, Chongqing, 400037, China
b
The First Hospital Affiliated to Army Medical University, Chongqing, 400038, China
c
Department of the General Practice, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China
d
National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International
Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China
e
Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: This meta-analysis aimed to evaluate the effectiveness and safety of probiotics for allergic rhinitis (AR)
Allergic rhinitis management in children.
Probiotics Methods: In total, 6 databases were searched, and 26 randomized controlled trials that compared the effects of
Pediatric
probiotics with those not using probiotics in pediatric AR were included. Methodological quality was assessed
Immune
using the Cochrane risk-of-bias tool. Data for relevant endpoints were extracted and analyzed.
Results: Our meta-analysis of the effectiveness of probiotics for pediatric AR showed that probiotics improved the
remission rate of nasal symptoms (risk ratio (RR) 1.21, 95% confidence interval (CI) 1.04 to 1.40; P = 0.01),
reduced the Total Nasal Symptoms Scores (TNSS) (weighted mean difference (WMD) − 2.58, 95% CI -2.77 to
− 2.39; P < 0.00001) and the total scores of Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ)
(for frequency of symptoms: WMD -9.51, 95% CI -10.34 to − 8.69; P < 0.00001; and for level of bother: WMD
-9.27, 95% CI -10.13 to − 8.41; P < 0.00001). Furthermore, they reduced the serum levels of interleukin-4 (IL-4)
(WMD -13.86 ng/L, 95% CI -15.92 to − 11.81; P < 0.00001), IL-6 (WMD -13.70 pg/mL, 95% CI -16.34 to − 11.07;
P < 0.00001), and IL-17(WMD -5.41 pg/mL, 95% CI -7.29 to − 3.52; P < 0.00001), and significantly elevated the
serum levels of interferon-γ (WMD 9.08 ng/L, 95% CI 8.10 to 10.06; P < 0.00001) and IL-10 (WMD 7.82 pg/mL,
95% CI 5.01 to 10.63; P < 0.00001). Probiotics also reduced the duration of cetirizine use in pediatric AR (WMD
-2.88 days, 95% CI -4.50 to − 1.26; P < 0.0005). No obvious adverse reactions were found to be related to
probiotic treatment.
Conclusions: This meta-analysis indicated that probiotic therapy can partially improve pediatric AR outcomes,
assisted by modulating immune balance and reducing anti-allergic medication use, without obvious adverse
reactions.

1. Introduction estimated to be approximately 2–27.6% in children [3,4]. Poorly

Allergic rhinitis (AR) is a chronic immunoglobulin E (IgE)-mediated
inflammatory disease of the nasal mucosa that always occurs following
exposure to sensitized allergens [1]. It is characterized by chronic nasal
symptoms, such as nasal obstruction, rhinorrhea, sneezing and nasal
pruritus [2]. The prevalence of AR varies across different countries, but
shows a globally increasing incidence [3]. AR affects 10–40% of the
world’s population, and the prevalence of self-reported AR has been
controlled AR can have a significant impact on children’s sleep, cogni­
tive function, growth and development, school productivity, and quality
of life and is costly to health care systems, putting considerable stress on
health care providers and society [5].
Traditional AR management strategies have included allergen
avoidance, drug therapy and immunotherapy [6]. Allergen avoidance is
always impractical and challenging. The most well-known drug thera­
pies including the use of oral or intranasal H1-antihistamines, intranasal

Abbreviations: Allergic rhinitis, AR.

* Corresponding author. Department of the General practice, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China.
E-mail addresses: wangxiahegege@outlook.com (X. Wang), txs1995@163.com (X. Tan), zhoujiwei93@163.com (J. Zhou).

https://doi.org/10.1016/j.ijporl.2022.111300
Received 14 March 2022; Received in revised form 15 August 2022; Accepted 27 August 2022
Available online 5 September 2022
0165-5876/© 2022 Elsevier B.V. All rights reserved.
X. Wang et al.
corticosteroids and leukotriene receptor antagonists, can only partially
alleviate allergic symptoms and are often costly. They are also associ­
ated with side effects that affect children’s daily activities and school
performance, such as fatigue, dizziness and sleepiness [1,7]. Immuno­
therapy might offer long-term alleviation of allergic symptoms by
providing increased amounts of allergens to induce desensitization [8].
However, the treatment course is always very long (3–5 years), and great
compliance is needed.
Recently, probiotics have been widely reported as an alternative
treatment method for AR that may regulate the host immune system [9].
Probiotics are defined as “live microorganisms that when administered
in sufficient quantities confer a health benefit on the host” [10]. In
adults, numerous original studies and systematic reviews have shown
that probiotics can effectively improve the clinical symptoms and
quality of life in AR patients [6,11–15]. However, due to the disparity of
age and immune system development features, it might be inaccurate to
apply the conclusions of adult studies to pediatric patients. Ultimately,
relevant systematic reviews or meta-analysis are rare in children. Ran­
domized controlled trials (RCTs) have widely discussed the effectiveness
of using probiotics in pediatric AR patients, but opinions remain con­
flicting. Some studies have suggested that routinely oral probiotics yield
better outcomes than drug therapy alone by reducing nasal symptoms
scores and medication scores [16–19], while improving pediatric quality
of life [20,21], immunologic parameters and lung function [22–25].
However, some scholars have remained skeptical of these conclusions or
oppose this view [26,27]. This lack of consensus can be partially
attributed to the small sample sizes of the relevant studies, making
outcomes difficult to gauge accurately. Therefore, more comprehensive
evidence for probiotic application in pediatric AR is urgently needed.
The aim of this systematic review and meta-analysis was to sum­
marize the evidence and evaluate the effectiveness and safety of pro­
biotics for AR management in children. The findings from this study are
expected to provide insight into the clinical management of children
with AR.
2. Method
This meta-analysis was prepared in compliance with the Cochrane
Handbook for Systematic Reviews of Interventions and reported ac­
cording to the Preferred Reporting Items for Systematic reviews and
Meta-analysis (PRISMA) statement [28].
2.1. Search strategy
Two researchers (X Wang and J Zhou) comprehensively searched the
following electronic databases from their start date to January 31, 2022:
China National Knowledge Infrastructure (CNKI), China Biology Medi­
cine (CBM) Database, Wanfang Data, PubMed, Cochrane Library, and
Web of Science. Google Scholar and Baidu Scholar were also searched
for any relevant articles. In addition, reference lists of relevant system­
atic reviews were searched for further potential studies. The detailed
search strategy can be found in Appendix 1.
2.2. Eligibility of studies
We included research on pediatric patients (age <18 years old)
diagnosed with AR, with no restrictions on gender, race, and
geographical location or setting. AR was diagnosed according to pub­
lished guidelines [4,29]. Both seasonal and perennial allergies were
included. Studies that had the mother ingest probiotics to determine the
risk of AR on their child or analyzed prenatal data were excluded.
We included all RCTs that compared the effectiveness and safety of
probiotics with placebo or compared the combination of probiotics and
routine treatment (including drug therapy and immunotherapy) with
routine treatment alone. All formulations of probiotics (irrespective of
the species, concentration and strain) were included. Conference
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International Journal of Pediatric Otorhinolaryngology 162 (2022) 111300
articles, reviews, case reports, duplicates, and non-English- or Chinese-
language texts were excluded, along with literature with only partial
text available or missing data.
The primary outcome measurements included Total Nasal Symptoms
Scores (TNSS: total scores of nasal blockage, nasal itching, sneezing and
rhinorrhea) [30], Pediatric Rhinoconjunctivitis Quality of Life Ques­
tionnaire (PRQLQ) [27], and the remission rate of nasal symptoms (AR
remission was defined as AR symptoms significantly improved or dis­
appeared after treatment, or symptom scores reduced more than 20%)
[16,23]. The secondary outcomes were antihistamine drug consump­
tion, immunologic parameters (including the serum levels of IgE and
cytokines) and adverse reactions.
2.3. Selection of studies
After eliminating duplicates, two authors (X Wang and J Zhou)
independently screened the article titles, abstracts, and potentially
relevant full-texts by using the predefined criteria, and any disagree­
ment was resolved by consensus. All reasons for the exclusion of ineli­
gible studies were carefully recorded, and the process of study selection
was documented using a PRISMA flow diagram.
2.4. Data extraction
The two authors (X Wang and J Zhou) independently extracted data
by using a standard Excel sheet, and any discrepancies were discussed.
The following data were extracted: 1) basic information, including title,
authors, publication year, countries, study design, sample size, age,
gender, types of AR and whether there was accompanying asthma; 2)
details of the intervention and control strategies; 3) outcomes, including
those of dichotomous data, were used for the number of events, while
continuous data, means, standard deviations (SD) or interquartile range
(IQR) were used.
2.5. Quality assessment of the included studies
The Cochrane risk-of-bias tool [31] was used which consists of 7
domains: random sequence generation, allocation concealment, blind­
ing of participants and personnel, blinding of outcome assessment,
incomplete outcome data, selective outcome reporting, and other biases.
The risk of bias of each domain was graded as “low”, “unclear”, or
“high”, and the overall risk of bias within each study was based on the
combined results of the individual domains.
2.6. Statistical analysis
All statistical analyses were performed using Review Manager 5.3
[32] and Stata 15.0 software [33]. A meta-analysis of outcomes was
conducted for which the data were sufficiently compatible. Otherwise, a
qualitative synthesis was performed. For continuous data, weighted
mean difference (WMD) or standardized mean difference (SMD) with
95% confidence intervals (CI) was analyzed; for dichotomous data, risk
ratios (RR) with 95% CI were analyzed. A fixed-effects model or
random-effects model was used, and data were processed according to
the Cochrane Handbook for Systematic Reviews of Interventions [28]. A
P value < 0.05 was considered to be statistically significant. Heteroge­
neity was assessed by forest plot and I2 statistic, with values higher than
50% indicating substantial heterogeneity. Subgroup analysis was con­
ducted for particular outcomes. Sensitivity analysis was carried out, in
which one study at a time was removed and the others were analyzed to
check the stability and reliability of the merged effects.
X. Wang et al.
3. Results
3.1. Search results
In total, 1044 records were identified from the databases, 402 du­
plicates were excluded, and 642 records were considered to be poten­
tially relevant. After screening the titles, abstracts, and full texts, 26
eligible studies were ultimately included (Appendix 2).
3.2. Characteristics of the included studies
This meta-analysis included 26 RCTs comprising 2644 pediatric pa­
tients with AR (1362 in the intervention group vs. 1282 in the control
group). All studies were carried out between 2004 and 2021. Fifteen
studies were presented in English [1,18–22,26,27,30,34–39], and the
remaining studies were presented in Chinese [16,17,23–25,40–45]. The
age of the patients ranged from 2 to 18 years, the sample sizes ranged
from 20 to 300, and the ratio of males to females was 1.3:1. Thirteen
studies reported perennial AR [1,16,18,20–22,26,27,35–37,44,45],
eight studies reported seasonal AR [1,19,20,30,34,35,38,39], and the
remaining did not mention the type of AR [17,23–25,40–43]. Fourteen
studies reported that AR children had accompanying asthma [1,17,18,
20,22,24,25,30,35,36,38,40–42]. Strategies of AR management were
based on drug therapy such as antihistamines, intranasal corticosteroids
and leukotriene receptor antagonists, immunotherapy or placebo for the
control group compared with probiotics plus any of the above for the
intervention group. Microcrystalline cellulose, maltodextrin or common
milk that looked and tasted the same as the probiotics was used as
placebo. The species of probiotics in the included studies were Bifido­
bacterium, Saccharomyces boulardii, Lactobacillus, Streptococcus thermo­
philus, Bacillus and Enterococcus faecium. Twelve trials used single
probiotics [17–22,26,27,37–39,44], and fourteen trials used probiotic
mixtures [1,16,23–25,30,34–36,40–43,45]. The dosage of probiotics
varied across studies. The duration of intervention ranged from 14 days
to 12 months. More details are shown in Appendix 3 and Appendix 4.
3.3. Methodological quality
Overall, eleven studies were rated low risk of bias on every domain
[1,17,18,22,25,34,35,37,38,41,43], six studies were rated as high risk of
bias [16,23,24,26,40,42], and the remaining were rated as unclear risk
of bias [19–21,27,30,36,39,44,45] (Fig. 1).
3.4. Effectiveness and safety evaluation
3.4.1. Remission rate of nasal symptoms
Nine trials (n = 939 patients) reported the effects of probiotic ther­
apy on the remission rate of nasal symptoms in pediatric AR [16,22,23,
Fig. 1. Risk of bias summary of included studies.
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International Journal of Pediatric Otorhinolaryngology 162 (2022) 111300
34,36,37,43–45]. The meta-analysis showed that probiotic therapy
versus control could significantly improve the remission rate of nasal
symptoms in pediatric AR (RR = 1.21, 95% CI 1.04 to 1.40, P = 0.01, I2
= 88%) (Fig. 2).
3.4.2. Total Nasal Symptoms Scores
Ten studies reported the effects of probiotic therapy on TNSS. One
study showed a significant reduction in TNSS after probiotic treatment
(P < 0.05), but it presented TNSS without SD [1]. One study showed no
benefit of probiotics on TNSS, and the data could not be extracted [27].
Thus, their data could not be merged. Finally, eight trials (n = 687 pa­
tients) were included in the meta-analysis [16–19,23,30,39,43], and the
result showed that probiotic therapy could significantly reduce TNSS in
pediatric AR patients compared with control (WMD = − 2.58, 95% CI
-2.77 to − 2.39, P < 0.00001, I2 = 97%) (Fig. 3).
3.4.3. Pediatric Rhinoconjunctivitis Quality of Life Questionnaire
Two trials (n = 140 patients) were included in the meta-analysis on
the change of total scores of PRQLQ (frequency of symptoms) [20,21],
and the result showed significantly lower scores of PRQLQ (frequency of
symptoms) in the intervention group (WMD = − 9.51, 95% CI -10.34 to
− 8.69, P < 0.00001, I2 = 9%). Two trials (n = 140 patients) reported the
effects of probiotics on the change in PRQLQ (level of bother) scores [20,
21]. The result of the meta-analysis showed significantly lower PRQLQ
(level of bother) scores in the intervention group (WMD = − 9.27, 95%
CI -10.13 to − 8.41, P < 0.00001, I2 = 49%).
Moreover, one study reported no significant difference in PRQLQ
scores between the intervention group and the control group (P > 0.05)
[26]. The presentation of the PRQLQ in this study was different from the
above two studies and thus not merged. One trial showed more
improvement in individual parameters in the PRQLQ after probiotic
treatment (P < 0.05), but the data could not be extracted [27]. The
remaining one study reported that only one item (practical problems) of
the PRQLQ was significantly decreased in the intervention group versus
control (P < 0.05) [30] (Appendix 4).
3.4.4. Immunologic parameters
Five trials reported the effects of probiotic therapy on interleukin-4
(IL-4). Two studies showed no significant difference in the serum level
of IL-4 between the intervention group and the control group (P > 0.05),
but the raw data could not be merged [26,27]. Three trials (n = 460
patients) were included in the meta-analysis [23,25,40], and the result
showed a significantly lower serum level of IL-4 in the intervention
group versus control (WMD = − 13.86 ng/L, 95% CI -15.92 to − 11.81, P
< 0.00001, I2 = 77%) (Fig. 4).
Two trials (n = 188 patients) reported the effects of probiotic therapy
on IL-6 [24,42]. The meta-analysis showed that probiotic therapy versus
control could significantly reduce the serum level of IL-6 in pediatric AR
X. Wang et al. International Journal of Pediatric Otorhinolaryngology 162 (2022) 111300

Fig. 2. Forest plot comparing the effect of probiotics versus control on the remission rate of nasal symptoms.

Fig. 3. Forest plot comparing the effect of probiotics versus control on TNSS. Subgroup by the types of probiotics and treatment duration. TNSS: Total Nasal
Symptoms Scores.

4
X. Wang et al.
Fig. 4. Forest plot comparing the effect of probiotics versus control on immunologic parameters.
(WMD = − 13.70 pg/mL, 95% CI -16.34 to − 11.07, P < 0.00001, I2 =
0%) (Fig. 4).
Four trials reported the effects of probiotics therapy on IL-10. Two
trials showed no significant difference in the serum level of IL-10 be­
tween the intervention group and the control group (P > 0.05), but the
raw data could not be merged [26,27]. Two trials (n = 188 patients)
were included in the meta-analysis [24,42], and the result showed a
significantly higher serum level of IL-10 in the intervention group versus
control (WMD = 7.82 pg/mL, 95% CI 5.01 to 10.63, P < 0.00001, I2 =
83%) (Fig. 4).
Three trials (n = 288 patients) reported the effects of probiotic
therapy on IL-17 [17,24,42]. The meta-analysis showed that probiotic
therapy versus control could significantly reduce the serum level of
IL-17 in pediatric AR (WMD = − 5.41 pg/mL, 95% CI -7.29 to − 3.52, P
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International Journal of Pediatric Otorhinolaryngology 162 (2022) 111300
< 0.00001, I2 = 56%) (Fig. 4).
Four trials reported the effects of probiotic therapy on interferon-γ
(IFN-γ). Two trials (n = 400 patients) were included in the meta-analysis
[25,40], and the result showed a significantly higher serum level of
IFN-γ in the intervention group versus control (WMD = 9.08 ng/L, 95%
CI 8.10 to 10.06, P < 0.00001, I2 = 0%) (Fig. 4). Another two trials were
excluded from the meta-analysis for raw data could not be merged [26,
27]. Their results showed no significant difference in the serum level of
IFN-γ between the intervention group and the control group (P > 0.05).
Seven trials reported the effects of probiotic therapy on the serum
level of total IgE. The raw data could not be merged due to presenting
different units. Three studies reported a significantly lower serum level
of total IgE after probiotic treatment (P < 0.05) [16,23,43]. The
remaining four studies showed no significant difference in the serum
X. Wang et al.
level of total IgE between the intervention group and the control group
(P > 0.05) [18,22,26,35] (Appendix 4).
3.4.5. Anti-allergic drug use
Two trials (n = 60 patients) reported the effects of probiotic therapy
on the duration of cetirizine use [30,39]. The meta-analysis showed that
probiotic therapy versus control could significantly reduce the duration
of cetirizine use in pediatric AR (WMD = − 2.88 days, 95% CI - 4.50 to
− 1.26, P < 0.0005, I2 = 0%). Another four studies reported significantly
less use of anti-allergic medications after probiotic therapy versus con­
trol (P < 0.05) [1,16,18,19] (Appendix 4).
3.4.6. Adverse reactions
Two studies reported potential adverse reactions during treatment,
including diarrhea, vomiting, abdominal pain and fever [35,42]. How­
ever, no significant difference in the occurrence of adverse reactions was
found between the intervention group and the control group (P > 0.05)
(Appendix 4).
3.5. Subgroup analysis
Subgroup analysis was conducted on TNSS in terms of the types of
probiotics and treatment duration.
3.5.1. Types of probiotics
For TNSS, the overall WMDs of studies using single probiotics
[17–19,39,43] and those using probiotic mixtures [16,23,30] were
− 2.47 (95% CI -2.67 to − 2.26, P < 0.00001) and − 3.15 (95% CI -3.62 to
− 2.68; P < 0.00001), respectively (Fig. 3).
3.5.2. Treatment duration
For TNSS, the overall WMDs of studies with treatment duration ≤8
weeks [23,30,39,43] and those with treatment duration >8 weeks
[16–19] were − 3.43 (95% CI -3.82 to − 3.05, P < 0.00001) and − 2.31
(95% CI -2.52 to − 2.09; P < 0.00001), respectively (Fig. 3).
3.6. Sensitivity analysis
A sensitivity analysis was conducted for all merged outcomes. The
results from the sensitivity analysis did not alter the direction (Appendix
5).
4. Discussion
We conducted a systematic and comprehensive meta-analysis that
included 26 studies to examine the effectiveness and safety of probiotic
therapy in children with AR. The remission rate of nasal symptoms,
TNSS and PRQLQ were significantly improved in the probiotics group
versus the control group. Meanwhile, immunologic parameters, such as
the serum levels of IL-4, IL-6 and IL-17 were significantly decreased,
while the serum levels of IL-10 and IFN-γ were significantly increased. A
significant reduction in anti-allergic medication use was observed. No
obvious adverse reactions were related to probiotic treatment. This
meta-analysis showed that probiotic therapy can partially improve the
outcomes of pediatric AR and regulate the balance of the immune sys­
tem. The main novelty of this meta-analysis is the systematic review of
the Chinese literature, which comprises 1288 patients of the pooled
data.
Probiotics are microbes that benefit the host. The underlying
mechanism for these beneficial effects of probiotics for AR is not clear.
Noverr’s research reported that microbiota-mediated mechanisms of
immunological tolerance in the mucosa were disrupted by perturbations
in the gastrointestinal microbiota because of dietary changes, antibiotic
use and microbial inoculation [46]. The respiratory tract and the
gastrointestinal tract are exposed to the same antigens. Disruption of the
normal microbiota further breaks airway tolerance to aeroallergens,
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International Journal of Pediatric Otorhinolaryngology 162 (2022) 111300
thus leading to an increase in the incidence of allergic airway disease
[46]. The occurrence of AR might be related to an imbalance of Th1/Th2
and Treg/Th17 immune responses [22]. Cytokines secreted by Th2 cells,
such as IL-4 and IL-6, and IL-17 secreted by Th17 cells can help recruit
and activate eosinophils in the local nasal mucosa and promote IgE
production, thus causing an increased incidence of AR [24,25,42]. Cy­
tokines secreted by Th1 cells, such as IFN-γ, and IL-10 secreted by Treg
cells can inhibit the function of Th2 and Th17 cells, thus reducing the
incidence of AR [22]. Our meta-analysis showed that the serum levels of
IL-4, IL-6 and IL-17 and eosinophil infiltration in the nasal mucosa were
significantly decreased, while the serum levels of IL-10 and IFN-γ were
significantly increased in the probiotic-treated group versus the control
group. Probiotics have been shown to downmodulate Th2- and
Th17-mediated immune responses while upregulating Th1- and
Treg-mediated immune responses. Therefore, adding probiotics to AR
treatment might help to restore normal gastrointestinal microbiota and
rebuild immunological tolerance.
Researchers have reported that the effects of probiotics might be
related to species, strains, dose and treatment durations [11,14]. The
predominant beneficial microflora in the gastrointestinal tract of infants
are Bifidobacterium and Lactobacillus [23]. Children who develop al­
lergies harbor lower levels of Bifidobacterial, Enterococci and other
Gram-positive organisms (Lactobacillus) but increased levels of Clostridia
and Staphylococcus aureus [23,46]. Thus, well-designed probiotics can
enhance the beneficial microflora. In our study, the probiotics used in
the included studies were Bifidobacterium, Saccharomyces boulardii,
Lactobacillus, Streptococcus thermophilus, Bacillus and Enterococcus fae­
cium. Twelve trials used single probiotics [17–22,26,27,37–39,44],
while fourteen trials used probiotic mixtures [1,16,23–25,30,34–36,
40–43,45]. A subgroup analysis of probiotic species on TNSS showed
significantly lower scores in the probiotic mixture-treated group. This
indicates that probiotic mixtures might yield better outcomes in AR
children.
Studies with different probiotic strains also showed different effects.
Lue et al. reported no benefit of Lactobacillus johnsonii on improving
PRQLQ in pediatric AR [26]. Lin et al. reported a significant benefit of
Lactobacillus paracasei on PRQLQ [21,27]. However, as the sample
populations are different, the results mentioned above might also be
influenced by population baseline characteristics in addition to pro­
biotic strains. Therefore, RCTs to explore the effects of different pro­
biotic strains on pediatric AR are needed by using the same sample
populations and study design.
The dosage and treatment durations of probiotics varied greatly
across the included studies. In fact, no recognized standard of probiotic
dosage or duration is available in guidelines and published reviews.
Some studies have suggested eight weeks as a separate line of treatment
duration to evaluate the effects of probiotics in AR [14]. However, in our
study, subgroup analysis of probiotic treatment duration on TNSS
showed lower scores in the ≤ 8-week group. This finding disagrees with
previous reports, which included both adult patients and pediatric pa­
tients, with lower scores at > 8 weeks [14]. This difference could be
explained by the great disparities in populations and study designs. The
results of the subgroup analysis were also influenced by population
baseline, probiotic species, strains and dosage besides of treatment
duration. Therefore, the existing evidence is not sufficient to verify
whether the effects of probiotics are strengthened by a longer treatment
duration. Thus, we do not suggest excessively prolonging treatment
duration due to potential risks when probiotic treatment is given to
pediatric AR patients without significant remission of symptoms.
Anti-allergic drugs, including antihistamines and intranasal corti­
costeroids, are first-line drugs for treating pediatric AR. The effects of
these anti-allergic drugs on relieving nasal symptoms are absolutely
certain but are also accompanied by side effects and increased health
costs [1]. This meta-analysis showed that probiotic therapy can effec­
tively reduce anti-allergic medication use in pediatric AR patients
without obvious adverse reactions. The mechanism may be related to
X. Wang et al.
the reduction of eosinophil infiltration in the nasal mucosa and serum
levels of IgE and cytokines. Probiotics are ideal as they are easily
available, inexpensive, come in various oral forms for different ages,
well tolerated orally and safe. Thus, they might be a good adjuvant
therapy in pediatric AR management.
Substantial heterogeneity was observed across the included studies.
Population, age, baseline severity of AR, being accompanied by asthma,
methodological quality, probiotic species, probiotic strains, probiotic
dosage, treatment duration, outcome scales might have contributed to
the heterogeneity in the meta-analysis. The results from the sensitivity
analysis did not alter the direction. Thus, the conclusions in this sys­
tematic review are still reliable. However, these factors should be
considered, and a consistent methodology should be adopted in future
research to decrease heterogeneity across studies.
There are several strengths of our study. First, this systematic review
and meta-analysis has reported the effectiveness and safety of probiotic
therapy in pediatric AR management, with a large sample size involving
2644 pediatric patients. It can therefore be considered the best evidence
for the management of pediatric AR thus far. Second, a substantive
discussion on the application of probiotics in AR management was un­
dertaken and offers useful advice on how to apply probiotics in clinical
practice. Third, this meta-analysis included only RCTs, which limited
the selection and observational bias. Fourth, a sensitivity analysis was
conducted to check the stability and reliability of the results. However,
there are also some limitations to this analysis. First, significant het­
erogeneity was detected in our meta-analysis for methodological di­
versity. Second, some merged results contained relatively small sample
sizes due to the use of variable scales. Third, a considerable number of
included studies were rated as having an unclear risk of bias or a high
risk of bias; thus, caution is warranted in the interpretation of our results
and application to clinical practice. Consequently, we look forward to
future efforts and explorations in this field to overcome these
deficiencies.
5. Conclusion
In conclusion, our meta-analysis of the effectiveness and safety of
probiotics for AR management in children indicates that probiotic
therapy helps improve nasal symptoms and quality of life, assisted by
modulating immune balance and reducing anti-allergic medication use,
without obvious adverse reactions. Based on the current evidence, we
suggest that probiotics can be a good adjuvant therapy in pediatric AR
management. However, probiotic species, strains, dosage and treatment
duration need to be considered in the clinic.
Contributions
Xia Wang and Jiwei Zhou equally contributed to the conception and
design of the research, acquisition, analysis and interpretation of the
data, and drafted the manuscript. Xiangsheng Tan contributed to the
design of the research and interpretation of the data. All authors criti­
cally revised the manuscript, agree to be fully accountable for ensuring
the integrity and accuracy of the work, and read and approved the final
manuscript.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Data availability statement
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
7
International Journal of Pediatric Otorhinolaryngology 162 (2022) 111300
Declaration of competing interest
None.
Acknowledgments
None.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.ijporl.2022.111300.
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