Abstract
Background
Respiratory tract infections (RTIs) are common in children and contribute substantially to healthcare burden. Although randomized controlled trials (RCTs) have shown probiotic benefits, evidence from large-scale, real-world community settings remains limited.
Objective
This prospective, multicenter, community-based study evaluated the effects of combined Lactobacillus rhamnosus CRL1505 and Bifidobacterium breve M-16V supplementation on respiratory and general health outcomes in children.
Methods
In this prospective, multicenter, single-arm, community-based study without a placebo control group, 236 children aged 0–14 years with a recent history of RTIs received a 4-week probiotic course and were included in the per-protocol analysis. Symptom frequency, medical visits, and caregiver-reported quality of life (QoL) were assessed through structured questionnaires.
Results
At baseline, rhinorrhea (51.7%), cough (43.2%), and allergic manifestations (47.0%) were common. After four weeks of probiotic intake, 95.34% of guardians reported that probiotic use was associated with reduced cold frequency (p < 0.001 vs null), and 94.49% observed fewer medical visits (p < 0.001). Complete symptom disappearance occurred in 22.88% of children, while 57.63% showed marked improvement. Symptom relief occurred within 1–3 days in 58.47% of cases. Quality of life improved in 97.88% of children, including better appetite/digestion (32.63%), greater energy (31.78%), and improved sleep quality (30.93%). Gastrointestinal comfort improvement was significantly higher in children <3 years (p = 0.039). No discontinuations due to adverse events were reported. Product palatability was rated “Excellent” or “Good” by 83.05% of respondents, and 99.15% of caregivers were willing to recommend it.
Conclusion
In this large, real-world pediatric population, probiotic supplementation was associated with caregiver-reported reductions in RTI burden and improvements in daily well-being. These findings complement prior RCTs and support probiotic use in community settings as a preventive strategy.
Trial Registration
ChiCTR2500102509.
Keywords: probiotics, respiratory tract infections, children, real-world study, gut–lung axis
Introduction
Respiratory tract infections (RTIs) constitute one of the most prevalent causes of pediatric morbidity and medical consultation globally. In 2021, all-cause upper respiratory tract infections (excluding COVID-19) accounted for an estimated 12.8 billion incident episodes worldwide, with the highest incidence observed among children younger than two years of age and substantial disease burden persisting in early childhood and school-age groups.1 According to recent epidemiological analyses, over 19 million children experience at least one RTI episode annually, accounting for nearly 30% of all pediatric outpatient visits. Community-based cohort studies indicate that RTIs represent the most frequent reason for medical consultation in childhood, particularly among preschool-aged children, with repeated episodes occurring throughout the year rather than as isolated events.2–4 While most infections are self-limiting, recurrent RTIs impose a heavy burden on healthcare systems, increase parental anxiety, and contribute to overprescription of antibiotics, fueling antimicrobial resistance.5,6 The immature immune system, combined with high interpersonal exposure in kindergartens and schools, creates a critical window during which respiratory infections frequently recur.7 Furthermore, early-life microbial disturbances due to cesarean delivery, antibiotic use, and urbanized lifestyles have been linked to impaired immune maturation and heightened infection susceptibility.8,9
Recent years have witnessed growing parental and medical interest in non-pharmacological preventive strategies for RTIs, including nutritional and microbiome-based interventions.10 Among these, probiotics represent a scientifically supported approach for enhancing mucosal and systemic immunity.11 Through modulation of the gut–lung axis, probiotics can regulate local and systemic immune responses, strengthen epithelial barrier integrity, and reduce the incidence and severity of respiratory infections.12
The efficacy of probiotics is highly strain-specific.13 Lactobacillus rhamnosus CRL1505 (CRL1505) and Bifidobacterium breve M-16V (M-16V) are two well-characterized strains with distinct but complementary immune-modulating profiles. CRL1505, extensively studied by Villena et al, has demonstrated potent immunobiotic properties including enhanced production of type I interferons, increased activity of alveolar macrophages, and protection against viral and bacterial respiratory pathogens.14–16 M-16V, conversely, is a bifidobacterial strain commonly used in neonates and infants, where it promotes colonization of the developing gut, supports epithelial integrity, and modulates Th1/Th2 balance, reducing allergic sensitization and inflammation.17–20
Mechanistically, CRL1505 enhances antiviral and mucosal immune responses, while M-16V supports gut barrier integrity and immune regulation.16,18,19 Their combination may therefore provide complementary effects on respiratory and intestinal immune homeostasis through modulation of the gut–lung axis.
Because probiotic products are already widely used in community pediatric practice, there is increasing interest in understanding their performance under routine, non-controlled conditions. In this context, real-world observational designs can provide complementary information regarding feasibility, acceptability, caregiver adherence, and perceived effectiveness across heterogeneous community settings.
While randomized controlled trials (RCTs) provide foundational evidence for efficacy under controlled conditions, these findings do not always directly translate to effectiveness in heterogeneous real-world community settings. A crucial evidence gap remains regarding whether this probiotic combination confers measurable benefits amid the variables of adherence, comorbid conditions, and heterogeneous care environments encountered in daily practice. This prospective, community-based study was therefore designed to provide complementary real-world evidence (RWE), assessing the pragmatic effectiveness and implementation potential of the CRL1505/M-16V combination in a diverse pediatric population.
Materials and Methods
Study Design and Ethical Approval
This multicenter, questionnaire-based, single-arm intervention study was conducted between January and December 2025 across 35 participating sites, including pediatric clinics, pharmacies, and community health centers in 15 provinces throughout China (Anhui, Chongqing, Fujian, Guangdong, Guangxi, Hebei, Henan, Inner Mongolia, Jiangsu, Jiangxi, Shaanxi, Shandong, Shanxi, Sichuan, Zhejiang). The study aimed to evaluate the real-world efficacy, tolerability, and acceptability of a probiotic formulation containing Lactobacillus rhamnosus CRL1505 and Bifidobacterium breve M-16V on respiratory tract infections (RTIs) and overall well-being in children. The research was approved by the Shanghai Jiao Tong University School of Medicine Public Health and Nursing Research Ethics Committee (Approval No. SJUPN-2024-026-KS1-KS2-KS3), and the protocol complied with the principles of the Declaration of Helsinki. Written informed consent was obtained from all legal guardians, and child assent was obtained when appropriate. The study was retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR2500102509).
Study Population
Children aged 0–14 years with a recent history of respiratory tract infections (RTI) were recruited from participating centers. In this study, a “recent history of RTI” was defined as the occurrence of at least one RTI episode within the previous 3 months prior to enrollment, based on caregiver report and/or available medical records. Assessments for RTI were based on having at least two of the following signs and symptoms: fever (even if only reported not measured), nasal obstruction, chills, sore throat, headache, cough, runny nose, olfactory disturbances, or taste disturbances.21 Inclusion criteria required that participants were clinically stable, able to consume oral supplements, and had caregivers willing to complete follow-up questionnaires. Exclusion criteria included congenital diseases, immune deficiencies, hereditary metabolic disorders, or any known allergy to probiotic components. To account for developmental differences in immune and gut microbiota maturity, participants were stratified into three age groups for subgroup analysis: <3 years, 3–<6 years, and 6–<14 years.
The target sample size for this pragmatic, real-world study was determined based on the ability to detect a clinically meaningful improvement in RTI outcomes following probiotic use. Using Cohen’s h method for a one-sample proportion test, we assumed a conservative expected improvement rate of 70%, compared with a null reference value of 50%. This corresponds to a moderate effect size (h = 0.42), requiring a minimum of 68 participants to achieve 80% power at a two-sided α of 0.05. With a total of three age cohorts, a minimum total of 204 participants is needed.
The study design reflected daily community practice rather than a controlled experimental setting, aiming to evaluate probiotic effects under natural conditions of use. Caregivers recorded symptom onset, duration, and absenteeism in standardized electronic diaries reviewed weekly by trained site coordinators. Data verification included random cross-checking of 10% of entries against clinic visit records to minimize reporting bias. No placebo control was included, preserving the real-world design. All participants followed uniform baseline health and dietary guidance. The large sample size and geographic diversity strengthened external validity.
Intervention
All participants received ANTRRIX™ (DiproX, Shanghai, China), an oil-based probiotic formulation composed of 90% medium-chain triglyceride (MCT) oil and 10% probiotic powder (Manufactured by Biofarma, Mereto, Italy on May 31, 2024, batch number 1284). Each daily 6-drop dose delivered approximately 2 × 109 colony-forming units (CFU) of a dual-strain preparation containing Lacticaseibacillus rhamnosus CRL1505 and Bifidobacterium breve M-16V. The supplement was administered orally once per day for four consecutive weeks, following the manufacturer’s on-label instructions. Caregivers were instructed on dosage, adherence, and storage conditions, with refrigeration recommended when ambient temperatures exceeded 40 °C. Adherence was monitored through weekly caregiver reports. No placebo or comparator product was used to preserve the real-world design, reflecting routine community use conditions.
Data Collection and Outcome Measures
Data were collected at baseline and then weekly throughout the 4-week intervention using structured, validated questionnaires administered either in person by trained investigators or electronically via online surveys. The questionnaire was developed based on the Clinical Pathway for Recurrent Respiratory Tract Infections in Children (2022 Edition)22 and the Guideline for Preventive Interventions in Children with Recurrent Respiratory Tract Infections,23 and was content-validated by pediatric respiratory specialists (Cronbach’s α = 0.89). Caregivers completed the questionnaire to document respiratory and gastrointestinal symptoms, illness frequency, healthcare utilization, and overall well-being.
The instrument comprised four major domains: (1) respiratory tract infection (RTI) symptoms, including cough, sore throat, fever, nasal congestion, rhinorrhea, sneezing, and sleep disturbance; (2) symptom severity, assessed using 4- to 5-point Likert scales adapted from validated pediatric illness scoring tools; (3) illness frequency and healthcare use, including number of colds in the past month or year, doctor visits, medication use, and illness duration; and (4) gastrointestinal comfort and daily functioning, including stool patterns, appetite, digestion, energy level, absenteeism from school or kindergarten, and impact on caregiver routines. Additional items assessed product acceptability (palatability, flavor, and willingness to recommend) and safety outcomes, including any adverse or serious adverse events. All items were written in parent-friendly language appropriate for community settings.
Because this study was designed to reflect real-world community use, the questionnaire also included items evaluating caregiver motivations for probiotic use, sources of product awareness, and prior familiarity with probiotics. These measures were collected to better characterize parental health behaviors and factors influencing probiotic adoption in routine practice. Although caregiver expectations regarding probiotic efficacy may have influenced subjective reporting, this potential expectation bias is an inherent consideration in community-based observational studies relying on caregiver-reported outcomes. To reduce reporting variability, standardized questionnaires with predefined response categories were used, and weekly follow-up assessments were conducted by trained site coordinators.
Due to ethical review requirements and participant privacy protection policies, the original version of the questionnaire cannot be provided. Baseline assessments referred to symptoms and healthcare utilization occurring during the month prior to enrollment, whereas post-intervention assessments collected at Week 4 evaluated caregiver-perceived changes relative to each child’s usual RTI condition before probiotic supplementation. Therefore, the post-intervention outcome categories reflect perceived overall improvement among participants with a prior history of recurrent RTI, rather than only children with active symptoms at baseline. Participants without symptoms during the month immediately preceding enrollment could still report improvement if caregivers perceived reductions in RTI frequency, symptom severity, or healthcare utilization compared with the child’s typical recurrent RTI pattern over preceding months.
Statistical Analysis
Given the exploratory, single-arm real-world study design, analyses were primarily descriptive and focused on evaluating observed changes in caregiver-reported outcomes following probiotic supplementation. All analyses were performed using R software (version 4.3.2). Continuous variables were reported as mean ± standard deviation, while categorical variables were expressed as counts and percentages. Between-group comparisons were evaluated using the chi-square or Fisher’s exact tests for categorical variables and ANOVA for continuous variables. Trends across age groups were analyzed using the Linear-by-Linear Association chi-square test. The one-proportion Z-test was used to determine whether the observed proportion of “improved” outcomes significantly exceeded the null hypothesis of 50%. Integration, pre-processing and harmonization of data where needed, were conducted using Gi-MAPS prior to downstream statistical analyses. All statistical tests were two-sided, and significance was accepted at p < 0.05.
Results
Participant Characteristics
A total of 254 children completed the baseline questionnaire, and 236 children aged 0–14 years completed the 4-week intervention and were included in the per-protocol analysis (Figure 1). Participants were stratified into three age groups: <3 years (n = 91, 38.56%), 3–<6 years (n = 76, 32.20%), and 6–<14 years (n = 69, 29.24%). Baseline demographic characteristics were comparable across the age groups, with an overall equal sex distribution (50.0% male and 50.0% female). As expected, mean height and weight increased with age, and most children (77.54%) were at or above the 25th percentile for height-for-age (Table 1). The study population represented a well-distributed pediatric cohort with typical growth parameters across all age groups.
Figure 1.
Participant recruitment and completion flow diagram. CONSORT-style flowchart illustrating enrollment, stratification, and study completion. No participants were excluded due to adverse events or protocol deviations. A total of 236 children completed the 4-week probiotic intervention and were included in the per-protocol set.
Table 1.
Baseline Demographic Characteristics of Participants (n = 236)
| Variable | <3 Years | 3–<6 Years | 6–<14 Years | Total |
|---|---|---|---|---|
| n(%) | 91 (38.56) | 76 (32.20) | 69 (29.24) | 236 |
| Sex | ||||
| Male | 43 (47.25) | 44 (57.89) | 31 (44.93) | 118 (50.00) |
| Female | 48 (52.75) | 32 (42.11) | 38 (55.07) | 118 (50.00) |
| Height, cm | 83.5 ± 10.8 | 109.0 ± 8.8 | 136.0 ± 12.8 | 107.1 ± 24.1 |
| Weight, kg | 11.2 ± 2.6 | 18.2 ± 3.6 | 31.4 ± 9.8 | 19.4 ± 10.2 |
| Height-for-age | ||||
| < 25th percentile | 20 (21.98) | 21 (27.63) | 12 (17.39) | 53 (22.46) |
| ≥ 25th percentile | 71 (78.02) | 55 (72.37) | 57 (82.61) | 183 (77.54) |
Notes: Data are presented as mean ± SD for continuous variables and n (%) for categorical variables. Height-for-age percentiles were assessed according to WHO growth standards. Anthropometric and demographic data were comparable across age groups, ensuring baseline balance for subsequent analyses.
Baseline Health and Symptom Profiles
Prior to intervention, respiratory symptoms were prevalent (Table 2). Rhinorrhea (51.69%) and cough (43.22%) were the most common. The prevalence of sneezing (p = 0.036), itchy throat (p = 0.006), and sore throat (p < 0.001) increased significantly with age. Allergic diseases affected 47.03% of participants, with respiratory allergies being most frequent (34.82%, p = 0.006). Gastrointestinal complaints were also common (49.58%), particularly abdominal pain (p < 0.001) and gastroenteritis (p = 0.003) among older children. Baseline symptom profiles revealed high RTI and allergy prevalence across all age groups, supporting the clinical relevance of intervention.
Table 2.
Prevalence of Respiratory, Allergic, and Gastrointestinal Symptoms Prior to Probiotic Intervention
| Variable | <3 Years | 3–<6 Years | 6–<14 Years | p-value | Total |
|---|---|---|---|---|---|
| Symptoms of respiratory tract infections in the past month | |||||
| None | 20 (21.98) | 19 (25.00) | 10 (14.49) | 0.287 | 49 (20.76) |
| Cough | 40 (43.96) | 35 (46.05) | 27 (39.13) | 0.575 | 102 (43.22) |
| Nasal congestion | 26 (28.57) | 24 (31.58) | 21 (30.43) | 0.779 | 71 (30.08) |
| Rhinorrhea | 49 (53.85) | 40 (52.63) | 33 (47.83) | 0.461 | 122 (51.69) |
| Sneezing | 16 (17.58) | 18 (23.68) | 22 (31.88) | 0.036 | 56 (23.73) |
| Itchy throat | 3 (3.30) | 8 (10.53) | 11 (15.94) | 0.006 | 22 (9.32) |
| Sore throat | 4 (4.40) | 8 (10.53) | 15 (21.74) | <0.001 | 27 (11.44) |
| Others | 1 (1.10) | 3 (3.95) | 3 (4.35) | 0.213 | 7 (2.97) |
| Symptoms of allergic diseases in the past month | |||||
| None | 54 (59.34) | 38 (50.00) | 33 (47.83) | 0.136 | 125 (52.97) |
| Skin | 21 (23.08) | 15 (19.74) | 5 (7.25) | 0.011 | 41 (17.37) |
| Gastrointestinal | 12 (13.19) | 10 (13.16) | 7 (10.14) | 0.578 | 29 (12.29) |
| Respiratory | 21 (23.08) | 30 (39.47) | 30 (43.48) | 0.006 | 81 (34.82) |
| Symptoms of gastrointestinal diseases in the past month | |||||
| None | 55 (60.44) | 33 (43.42) | 31 (44.93) | 0.040 | 119 (50.42) |
| Diarrhea | 20 (21.98) | 13 (17.11) | 14 (20.29) | 0.747 | 47 (19.92) |
| Vomiting | 8 (8.79) | 6 (7.89) | 11 (15.94) | 0.168 | 25 (10.59) |
| Abdominal pain | 5 (5.49) | 14 (18.42) | 22 (31.88) | <0.001 | 41 (17.37) |
| Constipation | 12 (13.19) | 20 (26.32) | 11 (15.94) | 0.535 | 43 (18.22) |
| Gastroenteritis | 1 (1.10) | 7 (9.21) | 9 (13.04) | 0.003 | 17 (7.20) |
| Others | 6 (6.59) | 1 (1.32) | 1 (1.45) | 0.061 | 8 (3.39) |
Notes: Data expressed as n (%); p-values represent age-stratified trends by chi-square test. “Symptoms in the past month” reflect caregiver reports at baseline. Older children exhibited more upper respiratory and gastrointestinal symptoms, indicating age-related variability in susceptibility.
Historical RTI Burden and Medical Utilization
Nearly all participants (97.46%) reported at least one cold in the preceding year, with 44.49% experiencing 3–5 episodes (Table 3). Over 73% required at least one medical visit for RTIs. Antibiotic use was reported by 9.75% within the past month, with no significant age-related differences (p = 0.759). The cohort had a substantial burden of recurrent RTIs and high healthcare utilization, consistent with target population expectations.
Table 3.
History of Respiratory Tract Infections, Medical Visits, and Antibiotic Use Prior to Study Enrollment
| Variable | <3 Years | 3–<6 Years | 6–<14 Years | p-value | Total |
|---|---|---|---|---|---|
| Number of common colds in the past year | 0.599 | ||||
| 0 times | 5 (5.49) | 1 (1.32) | 0 (0.00) | 6 (2.54) | |
| 1-2 times | 41 (45.05) | 30 (39.47) | 37 (53.62) | 108 (45.76) | |
| 3-5 times | 41 (45.05) | 36 (47.37) | 28 (40.58) | 105 (44.49) | |
| ≥6 times | 4 (4.40) | 9 (11.84) | 4 (5.80) | 17 (7.20) | |
| Medical visits for RTI in the past year | 0.641 | ||||
| 0 visits | 26 (28.57) | 16 (21.05) | 21 (30.43) | 63 (26.69) | |
| 1-2 visits | 41 (45.05) | 39 (51.32) | 33 (47.83) | 113 (47.88) | |
| 3-5 visits | 22 (24.18) | 17 (22.37) | 12 (17.39) | 52 (22.03) | |
| ≥6 visits | 2 (2.20) | 4 (5.26) | 2 (2.90) | 8 (3.39) | |
| Antibiotic use in the past month | 0.759 | ||||
| No | 84 (92.31) | 66 (86.84) | 63 (91.30) | 213 (90.25) | |
| Yes | 7 (7.69) | 10 (13.16) | 6 (8.70) | 23 (9.75) | |
Notes: n (%) of participants by age group; statistical comparisons via chi-square. Past-year data obtained from caregiver recall. High RTI recurrence and medical dependency justified evaluation of probiotic intervention efficacy.
Motivations for Probiotic Use
Caregivers primarily used probiotics to enhance immunity (62.29%) and alleviate RTI symptoms (59.75%) (Table 4). The majority (80.08%) were influenced by recommendations from family or friends. Motivation to shorten RTI duration peaked in the 3–<6-year group (57.89%). Parental motivation was largely preventive and peer-driven, reflecting increasing community awareness of probiotic health benefits.
Table 4.
Guardian Motivations and Information Sources for Probiotic Use
| Variable | <3 Years | 3–<6 Years | 6–<14 Years | p-value | Total |
|---|---|---|---|---|---|
| Purpose of purchase | |||||
| Prevent RTI | 37 (40.66) | 43 (56.58) | 27 (39.13) | 0.997 | 107 (45.34) |
| Alleviate RTI symptoms | 58 (63.74) | 46 (60.53) | 37 (53.62) | 0.202 | 141 (59.75) |
| Shorten RTI duration | 31 (34.07) | 44 (57.89) | 21 (30.43) | 0.865 | 96 (40.68) |
| Enhance immunity | 55 (60.44) | 51 (67.11) | 41 (59.42) | 0.961 | 147 (62.29) |
| Others | 6 (6.59) | 3 (3.95) | 3 (4.35) | 0.496 | 12 (5.08) |
| Information source | 0.263 | ||||
| Recommendation from family/friends | 71 (78.02) | 59 (77.63) | 59 (85.51) | 189 (80.08) | |
| Others | 20 (21.98) | 17 (22.37) | 10 (14.49) | 47 (19.92) |
Notes: Data presented as n (%); no significant age-dependent differences were found (p > 0.05). “Information sources” included healthcare professionals, family, and digital platforms. Peer influence was the strongest factor in probiotic adoption across age groups.
Product Palatability and Acceptability
The probiotic product demonstrated excellent acceptability (Table 5). Palatability and flavor were rated “Excellent” or “Good” by 83.05% and 79.24% of guardians, respectively (both p < 0.05). The vast majority (99.15%) expressed willingness to recommend the product, with higher enthusiasm in older children (p = 0.003). No adverse or serious adverse events were reported. The formulation was well-accepted, safe, and suitable for pediatric compliance.
Table 5.
Guardian-Rated Palatability, Flavor Acceptability, and Recommendation Intent
| Variable | <3 Years | 3–<6 Years | 6–<14 Years | p-value | Total |
|---|---|---|---|---|---|
| Palatability (mouthfeel) | 0.004 | ||||
| Excellent | 35 (38.46) | 33 (43.42) | 33 (47.83) | 101 (42.80) | |
| Good | 29 (31.87) | 35 (46.05) | 31 (44.93) | 95 (40.25) | |
| Average | 26 (28.57) | 8 (10.53) | 5 (7.25) | 39 (16.53) | |
| Poor or very poor | 1 (1.10) | 0 (0.00) | 0 (0.00) | 1 (0.42) | |
| Flavor (taste) | 0.041 | ||||
| Excellent | 34 (37.36) | 39 (51.32) | 25 (36.23) | 98 (41.53) | |
| Good | 26 (28.57) | 28 (36.84) | 35 (50.72) | 89 (37.71) | |
| Average | 28 (30.77) | 9 (11.84) | 9 (13.04) | 46 (19.49) | |
| Poor or very poor | 3 (3.30) | 0 (0.00) | 0 (0.00) | 3 (1.27) | |
| Willingness to recommend | 0.003 | ||||
| Definitely | 54 (59.34) | 51 (67.11) | 56 (81.16) | 161 (68.22) | |
| Probably | 36 (39.56) | 24 (31.58) | 13 (18.84) | 73 (30.93) | |
| Not sure | 1 (1.10) | 1 (1.32) | 0 (0.00) | 2 (0.85) | |
Notes: Responses categorized from “Excellent” to “Poor”; chi-square test for trend applied. No adverse events were reported throughout the intervention. Excellent taste and safety profiles ensured strong adherence and consumer satisfaction.
Clinical Outcomes After 4 Weeks of Probiotic Use
After four weeks of supplementation, nearly all caregivers (95.34%) noticed that their children caught fewer colds (p < 0.001) (Table 6). About one in five reported complete symptom disappearance (22.88%), and more than half (57.63%) observed clear relief in daily symptoms. The need for medical visits dropped in 94.49% of participants, particularly in the older age group (p < 0.001). Notably, more than half of the caregivers (58.47%) reported visible improvement within three days of starting the product. Age-stratified analysis also revealed distinct therapeutic profiles (Figure 2). The most notable improvement in cough and rhinorrhea was reported in children < 3 years old. Meanwhile, the most significant reduction in overall RTI burden, characterized by fewer and shorter episodes, was seen in the 3–<6 years age group. The probiotic combination was associated with rapid and significant symptom relief and reduced healthcare use across age groups.
Table 6.
Changes in RTI Symptoms, Frequency of Colds, Medical Visits, and Time to Symptom Relief Following Probiotic Intervention
| Variable | <3 Years | 3–<6 Years | 6–<14 Years | p-value | Total |
|---|---|---|---|---|---|
| Reduction in number of colds | 0.262 | ||||
| Yes | 85 (93.41) | 73 (96.05) | 67 (97.10) | 225 (95.34) | |
| No | 6 (6.59) | 3 (3.95) | 2 (2.90) | 11 (4.66) | |
| RTI symptom improvement | 0.270 | ||||
| Complete disappearance | 20 (21.98) | 23 (30.26) | 11 (15.94) | 54 (22.88) | |
| Marked improvement | 55 (60.44) | 40 (52.63) | 41 (59.42) | 136 (57.63) | |
| Moderate improvement | 14 (15.38) | 11 (14.47) | 15 (21.74) | 40 (16.95) | |
| Non-observed improvement | 2 (2.20) | 2 (2.63) | 2 (2.90) | 6 (2.54) | |
| Change in medical visit frequency | <0.001 | ||||
| Marked decrease | 47 (51.65) | 51 (67.11) | 54 (78.26) | 152 (64.41) | |
| Slight decrease | 36 (39.56) | 23 (30.26) | 12 (17.39) | 71 (30.08) | |
| No change | 8 (8.79) | 2 (2.63) | 3 (4.35) | 13 (5.51) | |
| Time to symptom relief | 0.777 | ||||
| Within 1 day | 3 (3.30) | 4 (5.26) | 2 (2.90) | 9 (3.81) | |
| 1-3 days | 51 (56.04) | 45 (59.21) | 42 (60.87) | 138 (58.47) | |
| 4-7 days | 33 (36.26) | 22 (28.95) | 21 (30.43) | 76 (32.20) | |
| ≥7 days | 4 (4.40) | 5 (6.58) | 4 (5.80) | 13 (5.51) | |
Notes: n (%) of participants by age group; p-values indicate age-group comparisons via chi-square test. Week 4 outcomes reflect caregiver-perceived changes compared with each participant’s usual RTI pattern prior to probiotic supplementation, rather than only symptoms present during the baseline month. Participants without active RTI symptoms during the month before enrollment remained eligible if they had a recent history of recurrent RTI. Significance vs null hypothesis (50% improvement) confirmed by one-proportion Z-test, p < 0.001.
Figure 2.
Improvement in specific RTI symptoms after 4 weeks of probiotic intervention by age group. Percentages of participants reporting improvement in cough, rhinorrhea, and other RTI-related symptoms. Participants could select multiple symptoms. Younger children (<3 years) exhibited the greatest improvement in cough and rhinorrhea frequency.
These findings represent real-world trends observed under natural household and community conditions, rather than controlled experimental settings. Although causal inference cannot be confirmed without a placebo group, the direction and consistency of the effects across multiple parameters support biological plausibility. The greater reduction in RTI frequency among younger children and those with higher baseline RTI rates suggests stronger probiotic responsiveness in immune-developing populations. Given the unblinded observational design and reliance on caregiver-reported assessments, the magnitude of the observed improvements should be interpreted cautiously, as expectation and placebo effects may have contributed to perceived clinical benefit.
Quality of Life Improvements
Overall quality of life improved in 97.88% of children (Table 7). Substantial improvement was noted in 36.86% and moderate in 61.02%. Key benefits included mitigation of RTI symptoms (77.12%), fewer illnesses (63.14%), improved appetite/digestion (32.63%), better sleep (30.93%), and higher energy (31.78%). Younger children were more likely to experience relief from constipation or diarrhea (p = 0.039). The probiotic intervention enhanced multidimensional well-being, extending beyond respiratory symptom relief.
Table 7.
Caregiver-Reported Improvement in Overall Quality of Life Following 4 Weeks of Probiotic Use
| Variable | <3 Years | 3–<6 Years | 6–<14 Years | p-value | Total |
|---|---|---|---|---|---|
| Magnitude of improvement | 0.957 | ||||
| Substantial improvement | 34 (37.36) | 29 (38.16) | 24 (34.78) | 87 (36.86) | |
| Moderate improvement | 54 (59.34) | 46 (60.53) | 44 (63.77) | 144 (61.02) | |
| Non-observed improvement | 3 (3.30) | 1 (1.32) | 1 (1.45) | 5 (2.12) | |
| QoL aspects | |||||
| Mitigation of RTI symptoms | 64 (70.33) | 65 (85.53) | 53 (76.81) | 0.258 | 182 (77.12) |
| Fewer illnesses | 56 (61.54) | 48 (63.16) | 45 (65.22) | 0.634 | 149 (63.14) |
| Improved appetite and digestion | 34 (37.36) | 22 (28.95) | 21 (30.43) | 0.323 | 77 (32.63) |
| Greater energy/vitality | 29 (31.87) | 23 (30.26) | 23 (33.33) | 0.865 | 75 (31.78) |
| Better sleep quality | 34 (37.36) | 22 (28.95) | 17 (24.64) | 0.079 | 73 (30.93) |
| Improved constipation or diarrhea | 23 (25.27) | 11 (14.47) | 9 (13.04) | 0.039 | 43 (18.22) |
| Improved other gastrointestinal discomfort | 15 (16.48) | 20 (26.32) | 17 (24.64) | 0.189 | 52 (22.03) |
| Better skin condition with fewer allergy/inflammation/infection manifestations | 9 (9.89) | 14 (18.42) | 2 (2.90) | 0.227 | 25 (10.59) |
| No changes | 2 (2.20) | 1 (1.32) | 0 | 0.222 | 3 (1.27) |
Notes: QoL domains include physical comfort, vitality, sleep, and gastrointestinal function. p-values represent chi-square tests for age-dependent trends. Significant holistic benefits were observed across gastrointestinal, respiratory, and behavioral domains.
Discussion
This multicenter, community-based study provides strong real-world evidence that a 4-week intervention with the probiotic combination Lactobacillus rhamnosus CRL1505 and Bifidobacterium breve M-16V was associated with significant improvements in respiratory health and quality of life in children. The findings highlight consistent clinical efficacy, systemic wellness benefits, and outstanding safety and acceptability. The single-arm, real-world design was strategically chosen to assess implementation potential, answering the crucial public health question of whether efficacy demonstrated in randomized controlled trials (RCTs) translates to effectiveness in daily practice. The high adherence, exceptional acceptability, and rapid benefits observed across our diverse cohort demonstrate that this probiotic combination delivers tangible results in community settings.
Efficacy in Context: Bridging RCT Evidence and Real-World Effectiveness
The reduction in cold frequency reported by 95.34% of caregivers extends previous RCT findings demonstrating that CRL1505 enhances mucosal antiviral defense through interferon-mediated pathways.15,24 Our real-world effectiveness aligns with controlled trials showing 40–60% reductions in respiratory infections,24 while the greater magnitude observed may reflect synergistic action with M-16V, known to stabilize gut microbiota and promote regulatory immune balance.17,18 Probiotics have been reported to exert part of their systemic immunomodulatory and health-promoting effects through the production of bioactive metabolites and modulation of host metabolic pathways, which could contribute to improved mucosal and immune homeostasis.25,26 The convergence of high real-world effectiveness with established RCT efficacy underscores the translational potential of this specific probiotic combination. Furthermore, the significant reduction in healthcare utilization (94.49%), particularly notable in school-aged children, suggests the probiotic may reduce episode severity sufficiently to decrease medical consultations, a finding with important implications for healthcare systems and family resources.
The present findings extend evidence from controlled RCTs by demonstrating probiotic effectiveness in a large, unselected, community-based pediatric population. Consistent with RCTs from Malaysia, Finland, and Japan, probiotic supplementation reduced RTI incidence and duration. Importantly, these results are in line with meta-analytic data showing that probiotics can reduce RTI risk by 20–30% in children.27 This alignment with international data reinforces the translational relevance of our large-scale, community-based study for everyday clinical and public health practice. However, unlike tightly controlled trials, the present community-based design reflects routine pediatric practice and everyday lifestyle variability, offering complementary translational insight alongside controlled efficacy data.
Although the direction of the observed findings is biologically plausible and consistent with previously reported immunomodulatory effects of CRL1505 and M-16V, the magnitude of several caregiver-reported benefits was notably high for an unblinded observational study. In particular, the high proportion of caregivers reporting reductions in RTI frequency and visible symptom improvement within the first few days of supplementation may have been influenced by expectation bias, placebo effects, or heightened caregiver attention during participation. Accordingly, these effect sizes should be interpreted cautiously and viewed as exploratory real-world observations rather than definitive estimates of treatment efficacy.
Mechanistic Synthesis: Explaining Rapid and Multidimensional Benefits
The rapid symptom relief observed within 1–3 days in many participants may reflect early modulation of innate immune responses associated with L. rhamnosus CRL1505, a strain previously reported to enhance antiviral defense pathways and mucosal immune activity.15,28 Concurrently, the greater improvement in gastrointestinal symptoms among younger children may be related to the known ability of B. breve M-16V to support gut microbiota stability, intestinal barrier function, and immune regulation during early life.19,20
Together, these complementary effects on respiratory and intestinal immune homeostasis provide a biologically plausible explanation for the multidimensional improvements observed in respiratory symptoms, gastrointestinal comfort, appetite, energy, and sleep quality. However, because no objective immunological or microbiome biomarkers were measured, these mechanistic interpretations remain hypothetical and require confirmation in future controlled studies.
Age-Stratified Responses and Study Strengths
Our age-stratified analysis revealed distinct therapeutic patterns that inform clinical application. The most pronounced improvement in core respiratory symptoms like cough and rhinorrhea in children under 3 years may reflect direct modulation of a developing immune system. Conversely, the marked reduction in medical visits in school-aged children suggests the probiotic helps prevent episodes from reaching severity thresholds requiring professional care. The nationwide representation across 15 provinces, large sample size, and demonstration of rapid effects (within 3 days) coupled with exceptional acceptability (99% recommendation rate) provide compelling evidence of practical utility often missing from efficacy trials.
Limitations and Future Research Directions
The primary limitation is the absence of a concurrent placebo-controlled comparator group, which limits definitive causal inference regarding the observed improvements following probiotic supplementation. Although the study was intentionally designed to reflect routine community practice, the lack of a control arm prevents exclusion of potential confounding factors such as placebo effects, temporal changes in RTI incidence, or concurrent lifestyle modifications. Because RTI incidence varies seasonally, particularly during fall and winter months, part of the observed reduction in respiratory symptoms and healthcare utilization may reflect natural temporal variation rather than probiotic supplementation alone. The study period overlapped with seasonal fluctuations in circulating respiratory pathogens, and therefore inclusion of a placebo arm would have been valuable for distinguishing intervention-related effects from background epidemiological trends.
Another important limitation is the reliance on caregiver-reported outcomes without incorporation of objective clinical or laboratory biomarkers. Although caregiver-reported assessments are highly relevant in community-based pediatric practice, they remain susceptible to recall bias, expectation bias, and subjective interpretation of symptom severity or improvement. The absence of blinded assessment may have further amplified perceived treatment effects. Future studies incorporating objective endpoints such as viral load, inflammatory markers, salivary IgA, immune profiling, or microbiome analyses would strengthen mechanistic interpretation and clinical validity.
Because post-intervention outcomes were based on caregiver-perceived changes relative to each child’s usual RTI status rather than exclusively active baseline symptoms, some degree of subjective interpretation may have influenced outcome categorization. Although this reflects real-world parental assessment in community practice, future studies should incorporate objective longitudinal symptom tracking and validated clinical severity scoring systems.
Our large sample size (n = 236), which offers >99% statistical power to detect the observed effect sizes, allowed us to capture the broad heterogeneity of everyday pediatric environments, variability in adherence, lifestyle, and exposure patterns that cannot be reproduced in tightly controlled hospital-based trials. However, efficacy analyses were performed in participants who completed the intervention and follow-up assessments, which may not fully capture adherence variability encountered in broader routine practice populations. Although such ecological validity enhances the translational relevance of the findings for routine community use and parental decision-making, nonetheless, definitive causal inference will require more controlled designs.
An additional limitation is that many caregivers demonstrated pre-existing positive perceptions toward probiotics, as reflected by the high proportion reporting probiotic use for immune support or RTI prevention. Such pre-existing beliefs may have contributed to expectation bias in caregiver-reported outcomes, particularly in the absence of blinded assessment or a placebo control group. While these attitudes are representative of current community practices and therefore relevant to real-world implementation research, they may have influenced subjective assessments of symptom improvement and quality of life. Furthermore, because outcome assessments were not blinded, the possibility of expectation-driven reporting bias cannot be excluded. Future randomized and blinded studies incorporating objective clinical and immunological endpoints are warranted to further validate these findings.
The relatively short 4-week intervention period was sufficient to evaluate short-term symptom changes and tolerability, but it does not permit assessment of long-term prophylactic efficacy, sustained immunological effects, or recurrence prevention across different respiratory infection seasons. In addition, because RTI incidence fluctuates seasonally, the limited study duration restricts interpretation of whether observed improvements would persist under varying epidemiological conditions.
Incorporating objective biomarkers such as viral load, salivary IgA, serum biochemistry, immune cell activation profiles, and microbiome sequencing will help validate mechanistic pathways and clarify the age-specific responses observed in this study.
Implications for Pediatric Health
The present findings highlight the potential of probiotic supplementation as a practical, low-risk measure to support respiratory health in children, particularly in populations experiencing recurrent RTIs. The significant reduction in medical visits and symptomatic burden implies not only health benefits but also potential social and economic value for families and healthcare systems. Scientifically, the data reinforce the concept of the gut–lung axis as a modifiable target in pediatric immunity. Continued research combining clinical and mechanistic approaches will strengthen the translational bridge between microbial modulation and long-term respiratory resilience. Future studies incorporating objective immune markers and seasonal adjustments are warranted to confirm the observed associations.
Conclusion
This study suggests that the CRL1505/M-16V probiotic combination may represent a practical, low-risk approach for supporting respiratory health in children, particularly those with recurrent infections. Probiotic supplementation was associated with caregiver-reported improvements in respiratory symptoms, healthcare utilization, and overall well-being, indicating potential clinical, social, and economic relevance in community settings. These findings further support the gut–lung axis as a potentially modifiable target in pediatric immunity and provide complementary real-world evidence regarding probiotic use in routine practice. However, given the observational, unblinded, single-arm design, the findings should be interpreted cautiously, and definitive causal conclusions cannot be established. Future randomized, placebo-controlled studies incorporating objective clinical and immunological endpoints are warranted to confirm these associations and further define the role of probiotics in reducing respiratory infection burden in children.
Acknowledgment
The authors thank Xue Bai, Wenmei Cao, Jie Chen, Xin Deng, Tongjian Ding, Ying Fan, Hainan Li, Fang Ren, Fei Sun, Jianping Xiao, Chao Yang, Jiang Yu, Yingying Zhang, Yugang Zhao, Zhiyong Zhou, Qijuan Zhuang from the DiPRO Microecological Health Management Center for their invaluable voluntary contribution and dedicated commitment to this study.
Funding Statement
This study was supported by the Major Investment Project of Shanghai Science and Technology Service Industry (24KF3501200). The funder had no role in study design, data collection, analysis, interpretation, or manuscript preparation.
Data Sharing Statement
The de-identified dataset generated and analyzed during this study are available from the corresponding authors, Dongbo Chen, upon reasonable request, subject to review and approval of the proposed use.
Ethics Approval
Shanghai Jiao Tong University School of Medicine Public Health and Nursing Research Ethics Committee (Approval No: SJUPN-2024-026-KS1-KS2-KS3).
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
XL, JY, MTL and DC are employees of DiPROBIO (Shanghai) Co., Ltd., which provided the probiotic product and had no role in study design, data collection, data analysis, data interpretation, or manuscript preparation. All authors declare that they have no other competing interests in this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The de-identified dataset generated and analyzed during this study are available from the corresponding authors, Dongbo Chen, upon reasonable request, subject to review and approval of the proposed use.