Clinical efficacy of synbiotics in children with allergic rhinitis: An observational cohort study from a private medical center in Peru

Abstract Background Probiotics in allergic rhinitis (AR) have shown improvement in clinical and quality of life scores, whereas the role of synbiotics in the treatment of AR has been poorly investigated. The purpose of this study was to evaluate the clinical efficacy of synbiotics in children with AR. Methods An observational, prospective cohort study of pediatric outpatients with AR from a private medical center in Peru (2021) was conducted. At baseline, patients who were prescribed synbiotics during routine and those who were not (controls) recruited and followed up on Days 30, 60, and 90 of follow‐up. Clinical efficacy was assessed with differences in Visual Analogous Scale (VAS), Total Nasal Symptom Score (TNSS), Rhinitis Control Assessment Test (RCAT), and the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) scores between groups at follow‐up. Mean differences ± standard deviation (SD) and 95% confidence intervals (95% CI) are reported. Results Two hundred and fifteen participants were analyzed. Compared to controls (n = 115), those who used synbiotics (n = 100) had significantly lower VAS (mean difference 1.3; 95% CI: 0.8–1.8), TNSS (mean difference 1.1; 95% CI: 0.5–1.7) and higher RCAT scores and PRQLQ scores (mean difference 2.2; 95% CI: −3.3 to −1.2) and (mean difference 7.0; 95% CI: 3.1–10.9), respectively, at Day 90 of follow‐up Conclusions This paper reports significant improvement in clinical (VAS, RCAT, TNSS) and quality of life (PRQLQ) scores of small and large sizes, respectively. These preliminary findings support the need of future trials to assess the role of synbiotics in children with AR.


| INTRODUCTION
Allergic rhinitis (AR) affects up to 20%-25% of children worldwide, 1,2 in addition to showing a trend of increasing prevalence over the last years. 2 A group of patients with AR (e.g., of moderate or severe disease severity) do not achieve control with standard therapy alone and may benefit from add-on treatment with probiotics, prebiotics, or synbiotics. In synbiotics both pre-and probiotics act synergistically to regulate the intestinal immune response related to allergic diseases; thus, providing a basis to be used in the prevention and treatment of AR. 3 Several systematic reviews have shown that probiotics have a safety profile, 4,5 and although they may not prevent incident AR in childhood (if used earlier in life), [6][7][8] when used as a treatment in patients with AR, probiotics might improve their symptoms burden, disease control, disease severity, and quality of life. 9,10 Nonetheless, synbiotics have been less investigated 11 : a few number of studies have found that synbiotics administration in AR improved symptoms, 5 quality of life, 12 and interleukin-17 levels. 13 Thus, more contributing research is needed to assess the benefits of synbiotics in AR.
Therefore, the purpose of this prospective observational study was to evaluate the clinical efficacy of synbiotics in children with AR in a private medical center in Lima, Peru.

| Study design
We conducted a prospective cohort study of pediatric outpatients with AR from a private medical center located in Lima, Peru, between February 2021 and November 2021. At baseline, a group of patients receiving synbiotics (as part of their routinary care) and a group who did not (controls) were recruited; then, they were followed up monthly up to 3 months later.

| Sampling and sample size
Patients were recruited consecutively as they were identified after their routinary medical outpatient consultations. The sample size was calculated with Epidat® v.4.2, considering a potency of 80% with a minimum mean difference to detect of 1.1 for the Total Nasal Symptom Score (TNSS) between groups, a standard deviation of 2.7, and a confidence level (CI) of 95%.

| Statistical analysis
The data analysis considered the assessment of the difference in means of the result variables through the application of the T-test for independent samples. The analysis was performed in the statistical software IBM SPSS version 26 with a significance level of .05.

| Ethics
The protocol of this study was approved by the Ethics Committee of the Hospital Nacional Madre Niño San Bartolomé (reference number 01094-21, Supporting Information: Appendix 1).

| Procedures
A summary of study procedures is shown in Table 1. All enrolled patients were verified to receive the appropriate doses according to local guidelines. Patients receiving synbiotics were instructed not to consume drinks or foods with probiotics or prebiotics, a list of such products was provided.

| Exposure variables
The product of exposure was the synbiotics, we use BagoVital Inmune® that is compounded by Lactobacillus acidophilus Rosell-52, Bifidobacterium infantis Rosell-33, Bifidobacterium bifidum Rosell-71 (5 × 10 9 colony forming units) fructooligosaccharides 750 mg and Vitamin C 12 mg and is free of sale. Synbiotics were indicated before recruitment by the attending physician during regular medical appointments.

| Outcome variables
The severity of AR symptoms, measured by changes in Visual Analogous Scale (VAS) total scores between exposure groups at follow-up; the intensity of AR symptoms, measured by changes in total symptoms score total scores between exposure groups at followup; the control of AR symptoms, measured by changes in Rhinitis Control Assessment Test (RCAT) total scores between exposure groups at follow-up; and quality of life, measured by changes in the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) total scores between exposure groups at follow-up.

| Baseline description of the total sample
Data from a total of 215 participants, with a mean (SD) age of 10.4 (3.7), and 55.4% of males were analyzed (baseline characteristics are shown in Table 2). The most frequent comorbidity was allergic conjunctivitis (74.4%). Regarding family history, most patients had a first-degree relative with allergic rhinoconjunctivitis (78.2%).
Clinical characteristics related to AR are shown in Table 3.

| Evaluation of clinical efficacy
Results of the association between synbiotics use and the outcomes of clinical efficacy are presented in Table 4. At baseline, there were no differences in the VAS, TNSS, RCAT, and PRQLQ scores between those who used synbiotics and those who not. At Month 3 of follow-up, synbiotics use was associated with improved disease severity, intensity of symptoms, and quality of life: the VAS, TNSS, and PRQLQ scores were significantly lower by 1.3 points (95% CI: 0.8-1.8), 1.1 points (95% CI: 0.5-1.7), and 7.0 points (95% CI: 3.1-10.9), accordingly, among those who received synbiotics compared to controls. The RCAT score after 3 months of follow-up was significantly higher by 2.2 points (95% CI: −3.3 to −1.2) in those who received synbiotics (vs. controls).

| DISCUSSION
Our findings in this observational cohort study showed evidence supporting the preliminary clinical benefits of add-on treatment with synbiotics in children with AR. Among those who used synbiotics compared to controls, there was a significant improvement in quality of life (PRQLQ) scores. Differences in clinical scores of disease severity (VAS), disease control  (RCAT), and intensity of symptoms (TNSS) were also significant but in less proportion. These findings may guide further assessments of the efficacy of synbiotics in children with AR.
These study results contribute to the scarce previous evidence evaluating synbiotics treatment in patients with AR. 3 Jalali et al. 12 [12][13][14] show the need to standardize target populations (of higher sample sizes), the type of synbiotic used, the outcomes of interest, and the length of follow-up in the assessment of synbiotics for the prevention or treatment of AR. Besides, our findings of improved clinical (TNSS, VAS, and RCAT) and quality of life scores (PRQLQ) with synbiotics treatment may be compared with minimal important differences for each instrument and with studies using probiotics only.
A significant improvement in quality of life was associated with synbiotics in our study: PRQLQ score was significantly higher (mean difference 7.0; 95% CI: 3.1-10.9) among children who used synbiotics (vs. controls); this difference was large and above the minimal important difference of 0.5. In the case of probiotics, the same meta-analysis (2016) 10 associated their use with significant improvement in the total quality of life scores (mean standard difference: −1.84). 10 However, our study has limitations related to the observational design and the prescription bias may be present since there were relevant differences between synbiotic and control groups. Additionally, even though this study has a control group a placebo effect may be present. Our findings may inform future studies to define the role of synbiotics in the context of AR.
AUTHOR CONTRIBUTIONS Cesar A. Galvan Calle, Cecilia Díaz Vásquez, Ricardo Muñoz Leon, Edgar E. Matos Benavides, and Alejandra V. Verde Leon were involved in the same proportion in the design of the study, collection of clinical data, redaction, and revision of the paper.

ACKNOWLEDGMENTS
We acknowledge to the medical staff of the Unidad Funcional de Alergia, Asma e Inmunologia del Instituto Nacional de Salud del Niño, Lima, Peru, for the revision of our study. This study was funded by the authors and a research grant from Laboratorio Bago.

CONFLICT OF INTEREST
Cesar Alberto Galvan Calle has received a research grant from Laboratorio Bago. Honorarios as a speaker from Laboratorio Bago and Laboratorio Mead Johnson Nutritional. The remaining authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.