Randomized, Double-Blind, Placebo-Controlled, Clinical Trial Assessing Lacticaseibacillus rhamnosus CRL 1505 Efficacy in Preventing Upper Respiratory Tract Infections in Healthy Adults

Randomized, Double-Blind, Placebo-Controlled, Clinical Trial Assessing Lacticaseibacillus rhamnosus CRL 1505 Efficacy in Preventing Upper Respiratory Tract Infections in Healthy Adults | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Randomized, Double-Blind, Placebo-Controlled, Clinical Trial Assessing Lacticaseibacillus rhamnosus CRL 1505 Efficacy in Preventing Upper Respiratory Tract Infections in Healthy Adults Valentina Taverniti, Ines Martinez, Beatrice Tavazzani, Carlos Baeza, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7371791/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The aim of this clinical trial was to probe the efficacy of the probiotic strain Lacticaseibacillus rhamnosus CRL 1505 in preventing the frequency and duration of upper-respiratory tract infections (URTI) in healthy young adults. The trial was conducted according to a randomized, double-blind, parallel, placebo-controlled design, with a treatment duration of 12 weeks and a follow-up of 4 weeks. Probiotic group consumed capsules containing 1 billion of colony forming units/day of L. rhamnosus CRL 1505. Questionnaires regarding URTI occurrence, duration and symptomatology have been collected along the study. Salivary Immunoglobulin A have been quantified at baseline and at the end of treatment. L. rhamnosus CRL 1505 reduced the proportion of subjects with at least 2 or 3 URTI episodes, leading to 2- to 3-day reduction in the duration of common cold episodes and a 3% increase in the URTI-free time rate. Moreover, participants receiving L. rhamnosus CRL 1505 used less self-administered symptomatic medication for URTI. Intervention with L. rhamnosus CRL 1505 could effectively prevent URTI in healthy adults, demonstrating to be particularly effective in more susceptible subjects. This evidence are of particular interest in the context of probiotic efficacy in the management of respiratory diseases in the healthy adult population. Registry: ClinicalTrials.gov, ID: NCT07091955, Registration date: 29 July 2025. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Biological sciences/Microbiology Figures Figure 1 Introduction Upper respiratory tract infections (URTI) are a category of infectious diseases primarily caused by viruses, and occasionally by bacteria. URTI in adults comprise pharyngitis, laryngitis, acute sinusitis, otitis media, tonsilitis, and the common cold, which can involve multiple anatomical sites within the upper respiratory tract, manifesting as a diverse and fluctuating symptomatology. Although self-limiting in most cases, URTI can lead to significant respiratory complications, including bacterial superinfections, progression to lower respiratory tract infections and exacerbations of asthma or chronic obstructive pulmonary disease (COPD), which are of particular concern in patients with underlying chronic respiratory diseases. These complications are more prevalent among at-risk populations, including the elderly, individuals with diabetes, obesity, immunocompromised individuals, and those with chronic respiratory diseases, representing a substantial source of morbidity ( 1 ). Additionally, URTI exert a worldwide impact on the economy and healthcare systems ( 2 ) by increasing healthcare demand and expenditures, causing workplace and school absenteeism, reducing overall productivity, and even involving a misuse of antibiotics. Considering that the incidence rate of URTIs is the highest among infectious diseases ( 1 ), the development of preventive measures to mitigate their impact should be a priority. Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host ( 3 ). A recent Cochrane systematic review of randomized controlled trials has shown that probiotic treatment is effective in preventing URTI by reducing both the incidence and duration of each episode ( 4 ). However, these studies exhibit considerable heterogeneity. Moreover, while the precise mechanisms of action of probiotics have not been fully elucidated, research suggests several potential pathways through which they may exert their effects, primarily by enhancing the immune response ( 5 ). In this context, Lacticaseibacillus rhamnosus CRL 1505, a probiotic strain originally isolated from goat milk ( 6 , 7 ), is supported as an immunobiotic by an extensive body of preclinical evidence accumulated over more than a decade of research. Studies using murine models have reported that oral administration of L. rhamnosus CRL 1505 beneficially modulates the antiviral immune response in the respiratory system, promoting an effective resistance while minimizing tissue damage, maintaining a balance between pro- and anti-inflammatory responses ( 8 – 11 ). A randomized, placebo-controlled clinical trial conducted in healthy children aged 2 to 5 years demonstrated that the consumption of yogurt fortified with L. rhamnosus CRL 1505 reduced incidence of URTI, tonsilitis and gastrointestinal infections ( 12 ). The recent report “Global Impact of Respiratory Diseases”, published by the Forum of International Respiratory Societies, emphasized that respiratory infections represent a significant global public health threat and underscored the urgent need for research aimed at developing strategies to improve the prevention of these diseases ( 13 ). In this perspective, we evaluated whether L. rhamnosus CRL 1505 can prevent URTI in healthy adults, addressing a preventive approach that could have meaningful implications for respiratory health. Results Included participants characteristics A total of 140 subjects were randomized in the study. Data for 60 subjects in the probiotic group and 62 in the placebo group were analysed, after removing subjects that did not complete the follow-up during the intervention and post-treatment periods. Figure 1 illustrates participant screening, randomization, and the final cases included in the analysis, along with reasons for exclusion and the number of subjects lost to follow-up for each intervention group. Primary endpoint Notably, at week 12, 100% of cases in the probiotic group (46/46) and 95.4% in the placebo group (62/65) were classified as common colds. Similarly, at week 16, 100% of cases in the probiotic group (53/53) and 94.9% in the placebo group (74/78) were identified as common colds. It is worth noting that only four URTI episodes in the placebo group were not classified as common colds but were instead clinically diagnosed as flu or bronchitis. Therefore, each URTI episode can effectively be equated to a common cold episode. Concerning the primary endpoint of the trial (Table 2 ), although a smaller proportion of individuals in the probiotic group experienced at least 1 or 2 URTI episodes compared to the placebo group, these differences did not reach statistical significance. In this regard, at 16 weeks, the proportion of participants with ≥ 2 URTI episodes was 15.5% lower in the probiotic group compared to the placebo group, approaching statistical significance. However, for patients with ≥ 3 URTI episodes, a significant reduction of 12.7% was observed at 16 weeks in the probiotic group compared to the placebo, with a trend toward significance noted for an 8% reduction already observed after 12 weeks of intervention. (P = 0.06). Table 1 Baseline demographic and clinical data. PROBIOTIC (N = 70) PLACEBO (N = 70) Sex (♂), n (%) 47 (67.1%) 55 (78.6%) Age (years), mean ± SD 28.0 ± 10.7 28.0 ± 10.4 BMI (kg/m 2 ), mean ± SD 23.2 ± 3.3 22.7 ± 3.2 Professional activity : -Student, n (%) -Health worker, n (%) -Professor, n (%) -Other, n (%) 46 (65.7%) 2 (2.8%) 6 (8.6%) 16 (22.8%) 43 (61.4%) 6 (8.6%) 6 (8.6%) 15 (21.4%) Concurrent disease A , n (%) -Neurological, n -Dermatological, n -Endocrinological, n -Psychiatric, n -Cardiovascular, n -Other, n 4 (5.7%) 1 1 0 0 1 1 5 (7.1%) 0 1 1 1 1 1 Continuous pharmacological treatment B , n (%) -Antidepressants, n -Oral contraceptives, n -Antihypertensives, n 0 (0%) 0 0 0 3 (4.8%) 1 1 1 Continuous contact with individuals at risk for URTI (elderly, children, immunocompromised), n (%) 14 (20.0%) 19 (27.1%) URTI episodes during the 3 months prior to the beginning of the study , n (%) -Common cold, n -Influenza, n -Bacterial infection, n 21 (30.0%) 21 0 0 27 (38.6%) 27 0 1 URTI episodes during the 3 months prior to the beginning of the study , mean ± SD 0.3 ± 0.5 0.4 ± 0.5 Salivary IgA (µg/mL), mean ± SD 60 ± 70 54 ± 62 A Concurrent clinical condition presented by these participants (always of mild severity), which the researcher deemed would not influence the efficacy results of the study product, was not considered an exclusion criterion in these cases. B Continuous or habitual medication that the researcher deemed would not influence the efficacy results of the study product was not considered an exclusion criterion in these cases. Table 2 Proportion of subjects who presented URTI. URTI Episodes Period PROBIOTIC Group A PLACEBO Group A Difference B P-value C ≥ 1 12 weeks 33 (55.0%) 40 (64.5%) -9.5% (-26.8–7.8%) 0.28 16 weeks 37 (61.7%) 42 (67.7%) -6.0% (-23.0–10.9%) 0.48 ≥ 2 12 weeks 12 (20.0%) 19 (30.6%) -10.6% (-25.9–4.7%) 0.18 16 weeks 13 (21.6%) 23 (37.1%) -15.5% (-31.3–0.5%) 0.06 ≥ 3 12 weeks 1 (1.7%) 6 (9.7%) -8% (-16.1–0.0%) 0.06 16 weeks 3 (5.0%) 11 (17.7%) -12.7% (-23.7% to -1.7%) 0.03 * A N (%). B 95%CI Treatment Effect (Probiotic-Placebo). C Chi-square test (*Statistically Significant Difference). Secondary endpoints URTI Episodes per Participant Subjects receiving the probiotic L. rhamnosus CRL 1505 experienced significantly fewer URTI episodes than the placebo group after 16 weeks (-0.37 URTI episodes per participant; P = 0.05) (Table 3 ), a trend already at 12 weeks (-0.28 URTI episodes per participant; P = 0.09). Table 3 URTI episodes per participant. Period PROBIOTIC Group A PLACEBO Group A Difference B P-value C 12 weeks 0.77 (0.11) 1.05 (0.13) -0.28 (-0.61 to 0.04) 0.09 16 weeks 0.88 (0.11) 1.26 (0.15) -0.37 (-0.74 to -0.01) 0.05 * A Mean (Standard Error). B Mean (95%CI). C T-test (*Statistically Significant Difference). URTI Complications per Participant No URTI complications (pneumonia, otitis media, or acute sinusitis) were diagnosed in either the probiotic or placebo group during the 16-week follow-up. Time to First URTI Episode per Participant There were no significant differences in the days to the first URTI episode between study groups over the 12-week intervention period (Probiotic: 36.8 days [SE 3.7] versus Placebo: 38.6 days [SE 3.6]; P = 0.72). Duration of URTI Episodes per Participant For subjects treated with L. rhamnosus CRL 1505, the mean number of days with URTI per participant was significantly lower at 16 weeks compared to the placebo group (P = 0.03), showing a mean reduction of approximately 3 days (Table 4 ). After 12 weeks of intervention, the difference trended towards statistical significance (P = 0.07), with a mean reduction of 2.34 days. Table 4 Days with URTI episode per participant. Period PROBIOTIC Group A PLACEBO Group A Difference B P-value C 12 weeks 4.35 (0.81) 6.69 (0.99) -2.34 (-4.90 to 0.21) 0.07 16 weeks 4.77 (0.81) 7.77 (1.10) -3.01 (-5.73 to -0.29) 0.03 * A Mean (Standard Error). B Mean (95%CI). C T-test (*Statistically Significant Difference). URTI-Free Time Rate Participants treated with L. rhamnosus CRL 1505 exhibited a 2.9% higher URTI-free time rate compared to those who received placebo, with this difference being statistically significant (Table 5 ). Table 5 URTI-Free Time Rate (%). Period PROBIOTIC Group PLACEBO Group Difference A P-value B 12 weeks 94.8% 91.9% 2.9% (1.9–3.9%) < 0.0001* 16 weeks 96.0% 93.1% 2.9% (2.2–3.7%) < 0.0001* A 95%CI Treatment Effect (Probiotic-Placebo). B Chi-square test (*Statistically Significant Difference). WURSS-21 Score by Day of Common Cold The overall severity of each day of common cold episodes, as assessed by the WURSS-21 questionnaire score, was similar between subjects treated with L. rhamnosus CRL 1505 and those receiving placebo, with no significant differences at 12 or 16 weeks. The complete data for this comparison are provided in the Online Supplementary Material . Proportion of Participants Requiring Antibiotic Treatment Throughout the 16-week follow-up period, antibiotic treatment prescribed by a physician was required for only 1 URTI episode in both the probiotic and placebo groups. Due to the limited number of cases, no further analysis was conducted. Proportion of URTI Episodes and Proportion of Days with URTI where Symptomatic Medication Was Used Most of the symptomatic medication was self-administered, with only 3 URTI episodes in the placebo group requiring a medical prescription. Importantly, the analysis excluded antibiotic medication, which was already accounted for. Participants treated with L. rhamnosus CRL 1505 used symptomatic medication in a smaller proportion of URTI episodes and had a lower percentage of URTI days with symptomatic medication compared to the placebo group, with both differences being statistically significant (P = 0.001) (Table 6 ). Table 6 Proportion of URTI Episodes and Proportion of Days Where Symptomatic Medication Was Used. Period PROBIOTIC Group PLACEBO Group Difference C P-value D URTI Episodes where Participants Received Symptomatic Medication 12 weeks 50.0% (23/46) A 64.6% (42/65) A -14.6% (-33.1–3.9%) 0.12 16 weeks 49.0% (26/53) A 68.0% (53/78) A -19.0% (-35.4% to -1.9%) 0.03 * Days with URTI where Participants Received Symptomatic Medication 12 weeks 30.3% (79/261) B 42.2% (175/415) B -11.9% (-19.2% to -4.6%) 0.001 * 16 weeks 30.8% (88/286) B 43.6% (210/482) B -12.8% (-19.7% to -5.9%) 0.001 * A % (Number of episodes relative to the total URTI episodes) B % (Number of days relative to the total days with URTI) C 95%CI Treatment Effect (Probiotic-Placebo). D Chi-square test (*Statistically Significant Difference). Proportion of Participants Suffering Gastrointestinal Infections During the 16-week follow-up, 2 cases of gastrointestinal infection (diarrhoea) were reported in the placebo group, precluding further analysis. Salivary Immunoglobulin A (IgA) After 12 weeks, salivary IgA levels decreased from baseline in both probiotic and placebo groups, with no statistically significant difference between these changes (Probiotic-Placebo Difference: CI95%=-10µg/mL [-36 to 16µg/mL]; P = 0.47). Safety analysis All reported adverse events (AE) were classified as mild. A total of 18 AE were attributed to the study product (possible relationship): 8 in the probiotic group and 10 in the placebo group, all involving the digestive system. No participants were withdrawn from the study due to AE, and none dropped out due to intolerance to the study product. Additionally, adherence among the 122 analyzed participants exceeded 95% in both groups, indicating a high rate of compliance. The full data on the number and types of AEs during the 12-week intervention in both study groups are provided in the Online Supplementary Material . Discussion The findings of this clinical trial support the beneficial effects of L. rhamnosus CRL 1505 in reducing the burden of URTI in adults. Despite numerous published trials evaluating the efficacy of probiotics on the incidence, duration, and severity of respiratory infections in children ( 16 – 18 ), evidence specifically addressing their impact on URTI in healthy adults remains limited. Overall, previous clinical trials exhibit heterogeneity in their design, methodology, and interventions, posing a challenge for the comparative analysis of outcomes. Nevertheless, a recent Cochrane meta-analysis concluded that probiotic treatment could reduce the proportion of adult subjects experiencing at least 1 URTI episode by 23% ( 4 ). Other meta-analyses have reported reductions in the likelihood of suffering at least of 1 respiratory infection episode in adults ( 19 , 20 ). Notably, L. rhamnosus CRL 1505 demonstrated benefits by reducing individuals contracting at least 2 or 3 URTI, underscoring its potential to more vulnerable populations with more recurrent infections. Another advantage of L. rhamnosus CRL 1505 was its ability to significantly decrease the days with URTI per participant and increase the URTI-free time, which can lead to a positive impact on labour productivity and absenteeism, and overall health ( 21 ). The aforementioned meta-analyses also provide evidence of reduction of approximately 1 day in the duration of URTI episodes ( 4 ) or respiratory infections in general ( 19 ). L. rhamnosus CRL 1505 did not alleviate the severity of each common cold episode, as measured by the WURSS-21 ( 15 ). In this context, there are limited systematic reviews ( 19 ), particularly in the case of URTI, even though certain clinical trials have demonstrated positive outcomes in this regard ( 22 ). However, assessing the use of symptomatic medication for URTI could also provide an indirect measure of disease severity. Importantly, L. rhamnosus CRL 1505 intake was associated with a lower need for over-the-counter drugs. This result is of interest in view of the increasing misuse of over-the-counter drugs and related safety risks ( 23 , 24 ). To explore potential therapeutic mechanisms, the study also quantified salivary IgA. No significant modulation was observed with L. rhamnosus CRL 1505 treatment, unlike the clinical trial conducted in children ( 12 ). However, the children trial had a 6-month intervention, used a different ELISA method for salivary IgA quantification and employed a distinct sample collection method. In addition, although biologically plausible, the current evidence indicates that salivary IgA is not yet a reliable URTI biomarker due to problems of reproducibility, high interindividual variability and confounding factors ( 25 ). A limitation of the present study is the reliance on a self-diagnosed definition for a common cold episode. The Jackson scale was employed in this study ( 14 ) which has several limitations that hinder its universal applicability to the diagnosis of the common cold ( 26 ). Nevertheless, the term common cold is widely used in medical literature, but defining it precisely remains challenging. A strategy to diagnose URTI to specific anatomical sites was clinically impractical due to the significant overlap and variability of symptoms over time. This variability arises from the fact that more than 200 recognized viruses can cause URTI, and the clinical presentation is influenced largely by factors such as age, immune system status, and the presence of concurrent diseases ( 27 ). In this regard, we believe that the strategy employed in the present study, which involves daily monitoring of symptoms and medication, represents a rigorous approach given the inherent problems with the disease concept. In conclusion, L. rhamnosus CRL 1505 demonstrated beneficial effects in a healthy adult population, alleviating URTI burden. Considering that URTI often act as triggers for exacerbations in chronic respiratory diseases, these findings could be valuable for guiding future research in vulnerable populations. The limited number of studies focusing on probiotic use to alleviate URTI in the adult population make this study especially relevant in trying to address the existing gap in knowledge. Methods Study desing and ethical considerations The present clinical trial features a randomized, double-blind, parallel-group, placebo-controlled design, with a 12-week intervention period followed by an additional 4-week follow-up period without intervention. The study was designed to coincide with the peak months of URTI incidence, with inclusion beginning in October and November 2023 and follow-up concluding between January and February 2024. The study was conducted in accordance with the Declaration of Helsinki and its later amendments. Ethical approval was obtained from the Ethics Committee of the Universidad Católica San Antonio de Murcia, Spain (approval code CE092303), and written informed consent was obtained from all participants prior to enrolment. The study was retrospectively registered in ClinicalTrial.gov repository with the ID: NCT07091955 ( https://clinicaltrials.gov/study/NCT07091955 ) and in the public repository of the Universidad Católica San Antonio de Murcia ( https://repositorio.ucam.edu/handle/10952/7702 ). Recruitment and participant selection criteria Participants were recruited through an advertisement displayed at the Universidad Católica San Antonio de Murcia. Eligible candidates were then invited for an in-person interview and those that met all the inclusion and exclusion criteria were included in the study. Once enrolled and after signing the informed consent form, participants were provided with detailed explanations of the trial procedures, baseline clinical and demographic data were collected, and a saliva sample was obtained for immunoglobulin A (IgA) determination. The included population consisted of healthy men and women aged 18 to 65 years with a body mass index (BMI) lower than 35 kg/m 2 . The exclusion criteria primarily consisted of individuals with significant acute or chronic diseases and those with an immunocompromised status. These clinical conditions included metabolic disorders such as diabetes or obesity (BMI greater than 35.1 kg/m 2 ); congenital and acquired immune defects (including allergies); nasal ulcers or polyps causing nasal obstruction; abuse of alcohol, tobacco, or other substances; pregnancy or breastfeeding; influenza vaccination within the previous six months; ongoing treatment with medications or dietary supplements that could influence outcomes. This included immunosuppressants, immune stimulants (such as echinacea supplements), and other substances like analgesics, anti-inflammatory drugs, antitussives/expectorants, anti-flu preparations, decongestants, antibiotics, antihistamines, and probiotics within the four weeks prior to the start of the study. Study groups and interventions Included participants were randomized into two treatment groups at a 1:1 allocation ratio. The study groups were differentiated by the type of treatment received: probiotic or placebo. The probiotic product was a lyophilized preparation containing L. rhamnosus CRL 1505, with a concentration of 1×10 9 colony-forming units (CFUs) per daily dose. The CRL 1505 strain belongs to the culture collection of the Reference Center for Lactobacilli (CERELA-CONICET). A placebo with the same appearance as the active product was used as the comparator and contained only corn starch and maltodextrin as excipients. The daily dose for both products was one capsule per day for 12 weeks. In addition, participants were instructed not to alter their diet or physical activity during the study period. Randomization and blinding The block randomization method was employed to ensure balance in the number of subjects assigned to each intervention group. After inclusion, participants were assigned consecutively according to a computer-generated, pre-established randomization sequence based on the aforementioned method. The treatment (probiotic or placebo) was unknown to both the researchers and the participants, as the study followed a double-blind design. The treatments were labelled with the protocol and randomization code and did not display any distinctive features indicating the treatment group. Outcomes, procedures and data analysis Participants were required to complete an online questionnaire daily throughout the clinical trial. Data for outcomes analysis were extracted from these responses. The complete procedure is detailed in the Online Supplementary Material. The primary endpoint was the difference between study groups in the proportion of participants diagnosed with at least 1, 2, or 3 URTI episodes. For this purpose, it was crucial to establish precise criteria for defining a common cold episode. The onset of a common cold episode was defined by meeting two criteria for at least two consecutive days: responding “yes” to the question, “Do you think you have a cold or are you getting a cold?' and achieving a score of at least two points on the Jackson scale ( 14 ). The end of a common cold episode was defined as the last day of symptoms, followed by at least two consecutive symptom-free days. During data analysis, researchers defined the number and duration of common cold episodes using this data source. Other URTI, including influenza and bacterial infections should be diagnosed by a physician. As secondary endpoints, the trial evaluated the following: the difference between study groups in the number of URTI episodes per participant; the proportion of participants who developed URTI complications (bacterial infections such as pneumonia, otitis media, or acute sinusitis); the time to the first URTI episode (in days); the duration of URTI episodes per participant (days with URTI/participants); the URTI-free time rate (proportion of accumulated days without URTI symptoms relative to the total study period for all participants); the “Wisconsin Upper Respiratory Symptoms Survey 21” (WURSS-21) score per day of common cold ( 15 ); the proportion of participants requiring antibiotics; the proportion of URTI episodes and proportion of days with URTI where symptomatic medication was used (including self-administration of analgesics, antipyretics, anti-inflammatories, antitussives, expectorants, decongestants, antihistamines, or anti-influenza preparations); and the proportion of participants who experienced gastrointestinal infections. In addition, at baseline and at the end of the intervention period (week 12), participants were instructed to collect saliva samples using a Salivette® device. The quantification of IgA levels was performed using a commercial ELISA kit (DiaMetra, UK) in accordance with the manufacturer’s instructions. The safety profile of the study product was assessed by monitoring adverse events (AE), including their incidence and severity, throughout the intervention period. Sample size estimation Using G*Power (version 3.1.9.7), the sample size was calculated assuming 50% of healthy adults would experience at least one URTI episode, with a 23% reduction expected between probiotic and placebo groups ( 4 ). With a significance level of 0.05, a power of 0.8, and a 15% drop-out rate, 140 participants (70 per group) were required. Statistical analysis Baseline demographic data were used to describe the study population and assess intergroup homogeneity. Descriptive quantitative variables were summarized as mean and standard deviation (SD), and categorical variables as proportions. The efficacy analysis was performed on participants who completed the 16-week study protocol, following a per-protocol (PP) approach. Group comparisons for continuous variables were conducted using the t-test, while proportions were compared with the Chi-square test. To control for potential confounders, a multiple linear regression model was applied with treatment type as the main explanatory variable and demographic and contextual variables included as covariates. No confounding variables or relevant interactions were found. Data were analyzed with R statistical software (version 4.1.3). Microorganism Lacticaseibacillus rhamnosus CRL 1505 was obtained from the CERELA culture collection. Declarations Competing Interests Valentina Taverniti, Ines Martinez and Beatrice Tavazzani work for Sacco Srl which owns the license and manufactures the strain Lacticaseibacillus rhamnosus CRL 1505.Julio Villena, Susana Salva, María Pía Taranto, Susana Álvarez, Graciela Font work for CERELA-CONICET which owns the strain Lacticaseibacillus rhamnosus CRL 1505. Authors contribution statement V.T., I.M., C.B., F.LG., C.CD., P.SP. and V.NL. wrote the main manuscript text; V.NL., V.T. and I.M. designed the intervention study; V.NL., C.B. and F.LG. coordinated the trial; B.T., C.CD. and P.SP executed the data elaboration; J.V., S.S., MP.T., S.A. and G.F. revised the manuscript. All authors reviewed the manuscript. Competing interest statement Valentina Taverniti, Ines Martinez and Beatrice Tavazzani work for Sacco Srl which owns the license and manufactures the strain Lacticaseibacillus rhamnosus CRL 1505. Funding declaration Sacco Srl financially supported the study. Author Contribution V.T., I.M., C.B., F.LG., C.CD., P.SP. and V.NL. wrote the main manuscript text; V.NL., V.T. and I.M. designed the intervention study; V.NL., C.B. and F.LG. coordinated the trial; B.T., C.CD. and P.SP executed the data elaboration; J.V., S.S., MP.T., S.A. and G.F. revised the manuscript. All authors reviewed the manuscript. Acknowledgement Thanks to the professional collaboration of Martha Núñez, Verónica Molina, María José Fornaguera, Lourdes Cruz Pintos and Mariano Obregozo, part of the technical team of CERELA-CONICET Data Availability The raw data collected during the current study are available from the corresponding author upon request. References Global regional, and national burden of upper respiratory infections and otitis media, 1990–2021: a systematic analysis from the Global Burden of Disease Study 2021. Lancet Infect. Dis. S1473-3099 (24), 00430–00434 (2024). Fendrick, A. M., Monto, A. S., Nightengale, B. & Sarnes, M. 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Pediatr. 177 (7), 979–994 (2018). Emre, I. E., Eroğlu, Y., Kara, A., Dinleyici, E. C. & Özen, M. The effect of probiotics on prevention of upper respiratory tract infections in the paediatric community - a systematic review. Benef Microbes . 11 (3), 201–211 (2020). Rashidi, K., Darand, M., Garousi, N., Dehghani, A. & Alizadeh, S. Effect of infant formula supplemented with prebiotics and probiotics on incidence of respiratory tract infections: A systematic review and meta-analysis of randomized clinical trials. Complement. Ther. Med. 63 , 102795 (2021). Coleman, J. L. et al. Orally Ingested Probiotics, Prebiotics, and Synbiotics as Countermeasures for Respiratory Tract Infections in Nonelderly Adults: A Systematic Review and Meta-Analysis. Adv. Nutr. 13 (6), 2277–2295 (2022). Chan, C. K. Y., Tao, J., Chan, O. S., Li, H. B. & Pang, H. Preventing Respiratory Tract Infections by Synbiotic Interventions: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Adv. Nutr. 11 (4), 979–988 (2020). Mosegui, G. B. G., Antoñanzas, F. & de Mello Vianna, C. M. Cost of lost productivity from acute respiratory infections in South America. Rev. Panam. Salud Publica . 47 , e65 (2023). Smith, T. J., Rigassio-Radler, D., Denmark, R., Haley, T. & Touger-Decker, R. Effect of Lactobacillus rhamnosus LGG® and Bifidobacterium animalis ssp. lactis BB-12® on health-related quality of life in college students affected by upper respiratory infections. Br. J. Nutr. 109 (11), 1999–2007 (2013). Schifano, F. et al. Focus on Over-the-Counter Drugs’ Misuse: A Systematic Review on Antihistamines, Cough Medicines, and Decongestants. Front. Psychiatry . 12 , 657397 (2021). Jackson Allen, P. & Simenson, S. Management of common cold symptoms with over-the-counter medications: clearing the confusion. Postgrad. Med. 125 (1), 73–81 (2013). Turner, S. E. G., Loosemore, M., Shah, A., Kelleher, P. & Hull, J. H. Salivary IgA as a Potential Biomarker in the Evaluation of Respiratory Tract Infection Risk in Athletes. J. Allergy Clin. Immunol. Pract. 9 (1), 151–159 (2021). Eccles, R. Is the common cold a clinical entity or a cultural concept? Rhinology 51 (1), 3–8 (2013). Kardos, P. & Malek, F. A. Common Cold - an Umbrella Term for Acute Infections of Nose, Throat, Larynx and Bronchi. Pneumologie 71 (4), 221–226 (2017). Additional Declarations Competing interest reported. Valentina Taverniti, Ines Martinez and Beatrice Tavazzani work for Sacco Srl which owns the license and manufactures the strain Lacticaseibacillus rhamnosus CRL 1505. Julio Villena, Susana Salva, María Pía Taranto, Susana Álvarez, Graciela Font work for CERELA-CONICET which owns the strain Lacticaseibacillus rhamnosus CRL 1505. Supplementary Files Supplementarymaterial.docx RawdataCRL1505URTIs.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7371791","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":506497788,"identity":"e6b11552-2d48-4267-bc2a-8c5245c7d86a","order_by":0,"name":"Valentina Taverniti","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYDADNgbGxgdQNuMBBgN8apmhWtgYm+HqgFrw6WGGW8MmgdCCxxqDA/wHP/NU3Mvjk29uq/xRYyfPz3/2wQGGgj94tDAzS/OcKS4GOqztNs+xZMOZM9IN8DpMsoGZQXJmW0JiG0gLA9uBBIMbbPj9AtTC/HPmP4iWwh//gFrOH8OvhZ+BmU3iYwNECwNvG1DLgTQCWpiZzSw+HANpSWyW5u0D+QWoJcHAGKcWNvbGxzcSahIS5zcff/jxxzdQiB1jfPDhjxxOLfBoQQUJuDWMglEwCkbBKCACAAD56EuprnwsJwAAAABJRU5ErkJggg==","orcid":"","institution":"Sacco Srl","correspondingAuthor":true,"prefix":"","firstName":"Valentina","middleName":"","lastName":"Taverniti","suffix":""},{"id":506497789,"identity":"99ab59b7-e370-45b5-b01b-29344e0a211c","order_by":1,"name":"Ines Martinez","email":"","orcid":"","institution":"Sacco Srl","correspondingAuthor":false,"prefix":"","firstName":"Ines","middleName":"","lastName":"Martinez","suffix":""},{"id":506497790,"identity":"2e93b4f0-657b-419d-87d3-d7da72f4bbf4","order_by":2,"name":"Beatrice Tavazzani","email":"","orcid":"","institution":"Sacco Srl","correspondingAuthor":false,"prefix":"","firstName":"Beatrice","middleName":"","lastName":"Tavazzani","suffix":""},{"id":506497791,"identity":"43383039-829a-4987-a850-c8562093792b","order_by":3,"name":"Carlos Baeza","email":"","orcid":"","institution":"Servicio de Neumología. 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18:04:57","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":74296,"visible":true,"origin":"","legend":"","description":"","filename":"RawdataCRL1505URTIs.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7371791/v1/12e260f4810c9409088748c2.xlsx"}],"financialInterests":"Competing interest reported. Valentina Taverniti, Ines Martinez and Beatrice Tavazzani work for Sacco Srl which owns the license and manufactures the strain Lacticaseibacillus rhamnosus CRL 1505.\nJulio Villena, Susana Salva, María Pía Taranto, Susana Álvarez, Graciela Font work for CERELA-CONICET which owns the strain Lacticaseibacillus rhamnosus CRL 1505.","formattedTitle":"Randomized, Double-Blind, Placebo-Controlled, Clinical Trial Assessing Lacticaseibacillus rhamnosus CRL 1505 Efficacy in Preventing Upper Respiratory Tract Infections in Healthy Adults","fulltext":[{"header":"Introduction","content":"\u003cp\u003eUpper respiratory tract infections (URTI) are a category of infectious diseases primarily caused by viruses, and occasionally by bacteria. URTI in adults comprise pharyngitis, laryngitis, acute sinusitis, otitis media, tonsilitis, and the common cold, which can involve multiple anatomical sites within the upper respiratory tract, manifesting as a diverse and fluctuating symptomatology. Although self-limiting in most cases, URTI can lead to significant respiratory complications, including bacterial superinfections, progression to lower respiratory tract infections and exacerbations of asthma or chronic obstructive pulmonary disease (COPD), which are of particular concern in patients with underlying chronic respiratory diseases. These complications are more prevalent among at-risk populations, including the elderly, individuals with diabetes, obesity, immunocompromised individuals, and those with chronic respiratory diseases, representing a substantial source of morbidity (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Additionally, URTI exert a worldwide impact on the economy and healthcare systems (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) by increasing healthcare demand and expenditures, causing workplace and school absenteeism, reducing overall productivity, and even involving a misuse of antibiotics. Considering that the incidence rate of URTIs is the highest among infectious diseases (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), the development of preventive measures to mitigate their impact should be a priority. Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). A recent Cochrane systematic review of randomized controlled trials has shown that probiotic treatment is effective in preventing URTI by reducing both the incidence and duration of each episode (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). However, these studies exhibit considerable heterogeneity. Moreover, while the precise mechanisms of action of probiotics have not been fully elucidated, research suggests several potential pathways through which they may exert their effects, primarily by enhancing the immune response (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In this context, \u003cem\u003eLacticaseibacillus rhamnosus\u003c/em\u003e CRL 1505, a probiotic strain originally isolated from goat milk (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), is supported as an immunobiotic by an extensive body of preclinical evidence accumulated over more than a decade of research. Studies using murine models have reported that oral administration of \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 beneficially modulates the antiviral immune response in the respiratory system, promoting an effective resistance while minimizing tissue damage, maintaining a balance between pro- and anti-inflammatory responses (\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). A randomized, placebo-controlled clinical trial conducted in healthy children aged 2 to 5 years demonstrated that the consumption of yogurt fortified with \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 reduced incidence of URTI, tonsilitis and gastrointestinal infections (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The recent report \u0026ldquo;Global Impact of Respiratory Diseases\u0026rdquo;, published by the Forum of International Respiratory Societies, emphasized that respiratory infections represent a significant global public health threat and underscored the urgent need for research aimed at developing strategies to improve the prevention of these diseases (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In this perspective, we evaluated whether \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 can prevent URTI in healthy adults, addressing a preventive approach that could have meaningful implications for respiratory health.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eIncluded participants characteristics\u003c/h2\u003e\u003cp\u003eA total of 140 subjects were randomized in the study. Data for 60 subjects in the probiotic group and 62 in the placebo group were analysed, after removing subjects that did not complete the follow-up during the intervention and post-treatment periods. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates participant screening, randomization, and the final cases included in the analysis, along with reasons for exclusion and the number of subjects lost to follow-up for each intervention group.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePrimary endpoint\u003c/h3\u003e\n\u003cp\u003eNotably, at week 12, 100% of cases in the probiotic group (46/46) and 95.4% in the placebo group (62/65) were classified as common colds. Similarly, at week 16, 100% of cases in the probiotic group (53/53) and 94.9% in the placebo group (74/78) were identified as common colds. It is worth noting that only four URTI episodes in the placebo group were not classified as common colds but were instead clinically diagnosed as flu or bronchitis. Therefore, each URTI episode can effectively be equated to a common cold episode.\u003c/p\u003e\u003cp\u003eConcerning the primary endpoint of the trial (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), although a smaller proportion of individuals in the probiotic group experienced at least 1 or 2 URTI episodes compared to the placebo group, these differences did not reach statistical significance. In this regard, at 16 weeks, the proportion of participants with \u0026ge;\u0026thinsp;2 URTI episodes was 15.5% lower in the probiotic group compared to the placebo group, approaching statistical significance. However, for patients with \u0026ge;\u0026thinsp;3 URTI episodes, a significant reduction of 12.7% was observed at 16 weeks in the probiotic group compared to the placebo, with a trend toward significance noted for an 8% reduction already observed after 12 weeks of intervention. (P\u0026thinsp;=\u0026thinsp;0.06).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline demographic and clinical data.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePROBIOTIC\u003c/p\u003e\u003cp\u003e\u003cem\u003e(N\u0026thinsp;=\u0026thinsp;70)\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePLACEBO\u003c/p\u003e\u003cp\u003e\u003cem\u003e(N\u0026thinsp;=\u0026thinsp;70)\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSex\u003c/b\u003e (♂), n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e47 (67.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e55 (78.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge\u003c/b\u003e (years), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28.0\u0026thinsp;\u0026plusmn;\u0026thinsp;10.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28.0\u0026thinsp;\u0026plusmn;\u0026thinsp;10.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI\u003c/b\u003e (kg/m\u003csup\u003e2\u003c/sup\u003e), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eProfessional activity\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e-Student, n (%)\u003c/p\u003e\u003cp\u003e-Health worker, n (%)\u003c/p\u003e\u003cp\u003e-Professor, n (%)\u003c/p\u003e\u003cp\u003e-Other, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46 (65.7%)\u003c/p\u003e\u003cp\u003e2 (2.8%)\u003c/p\u003e\u003cp\u003e6 (8.6%)\u003c/p\u003e\u003cp\u003e16 (22.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43 (61.4%)\u003c/p\u003e\u003cp\u003e6 (8.6%)\u003c/p\u003e\u003cp\u003e6 (8.6%)\u003c/p\u003e\u003cp\u003e15 (21.4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eConcurrent disease\u003c/b\u003e\u003csup\u003e\u003cb\u003eA\u003c/b\u003e\u003c/sup\u003e, n (%)\u003c/p\u003e\u003cp\u003e-Neurological, n\u003c/p\u003e\u003cp\u003e-Dermatological, n\u003c/p\u003e\u003cp\u003e-Endocrinological, n\u003c/p\u003e\u003cp\u003e-Psychiatric, n\u003c/p\u003e\u003cp\u003e-Cardiovascular, n\u003c/p\u003e\u003cp\u003e-Other, n\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (5.7%)\u003c/p\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e0\u003c/p\u003e\u003cp\u003e0\u003c/p\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (7.1%)\u003c/p\u003e\u003cp\u003e0\u003c/p\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eContinuous pharmacological treatment\u003c/b\u003e\u003csup\u003e\u003cb\u003eB\u003c/b\u003e\u003c/sup\u003e, n (%)\u003c/p\u003e\u003cp\u003e-Antidepressants, n\u003c/p\u003e\u003cp\u003e-Oral contraceptives, n\u003c/p\u003e\u003cp\u003e-Antihypertensives, n\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003cp\u003e0\u003c/p\u003e\u003cp\u003e0\u003c/p\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (4.8%)\u003c/p\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e1\u003c/p\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eContinuous contact with individuals at risk for URTI\u003c/b\u003e (elderly, children, immunocompromised), n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (20.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e19 (27.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eURTI episodes during the 3 months prior to the beginning of the study\u003c/b\u003e, n (%)\u003c/p\u003e\u003cp\u003e-Common cold, n\u003c/p\u003e\u003cp\u003e-Influenza, n\u003c/p\u003e\u003cp\u003e-Bacterial infection, n\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21 (30.0%)\u003c/p\u003e\u003cp\u003e21\u003c/p\u003e\u003cp\u003e0\u003c/p\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27 (38.6%)\u003c/p\u003e\u003cp\u003e27\u003c/p\u003e\u003cp\u003e0\u003c/p\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eURTI episodes during the 3 months prior to the beginning of the study\u003c/b\u003e, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSalivary IgA\u003c/b\u003e (\u0026micro;g/mL), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60\u0026thinsp;\u0026plusmn;\u0026thinsp;70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e54\u0026thinsp;\u0026plusmn;\u0026thinsp;62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003eA\u003c/sup\u003e Concurrent clinical condition presented by these participants (always of mild severity), which the researcher deemed would not influence the efficacy results of the study product, was not considered an exclusion criterion in these cases.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003eB\u003c/sup\u003e Continuous or habitual medication that the researcher deemed would not influence the efficacy results of the study product was not considered an exclusion criterion in these cases.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eProportion of subjects who presented URTI.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eURTI Episodes\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePeriod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePROBIOTIC Group\u003csup\u003eA\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePLACEBO Group\u003csup\u003eA\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDifference\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eP-value\u003csup\u003eC\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e33 (55.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e40 (64.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-9.5% (-26.8\u0026ndash;7.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.28\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e37 (61.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e42 (67.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-6.0% (-23.0\u0026ndash;10.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.48\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e12 (20.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e19 (30.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-10.6% (-25.9\u0026ndash;4.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.18\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e13 (21.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e23 (37.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-15.5% (-31.3\u0026ndash;0.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.06\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1 (1.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6 (9.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-8% (-16.1\u0026ndash;0.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.06\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3 (5.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e11 (17.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-12.7% (-23.7% to -1.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.03\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003eA\u003c/sup\u003e N (%).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003eB\u003c/sup\u003e 95%CI Treatment Effect (Probiotic-Placebo).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003eC\u003c/sup\u003e Chi-square test (*Statistically Significant Difference).\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eSecondary endpoints\u003c/h3\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eURTI Episodes per Participant\u003c/h2\u003e\u003cp\u003eSubjects receiving the probiotic \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 experienced significantly fewer URTI episodes than the placebo group after 16 weeks (-0.37 URTI episodes per participant; P\u0026thinsp;=\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), a trend already at 12 weeks (-0.28 URTI episodes per participant; P\u0026thinsp;=\u0026thinsp;0.09).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eURTI episodes per participant.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeriod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePROBIOTIC Group\u003csup\u003eA\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePLACEBO Group\u003csup\u003eA\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDifference\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP-value\u003csup\u003eC\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.77 (0.11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.05 (0.13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.28 (-0.61 to 0.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.09\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.88 (0.11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.26 (0.15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.37 (-0.74 to -0.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.05\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eA\u003c/sup\u003e Mean (Standard Error).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eB\u003c/sup\u003e Mean (95%CI).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eC\u003c/sup\u003e T-test (*Statistically Significant Difference).\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eURTI Complications per Participant\u003c/h3\u003e\n\u003cp\u003eNo URTI complications (pneumonia, otitis media, or acute sinusitis) were diagnosed in either the probiotic or placebo group during the 16-week follow-up.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eTime to First URTI Episode per Participant\u003c/h2\u003e\u003cp\u003eThere were no significant differences in the days to the first URTI episode between study groups over the 12-week intervention period (Probiotic: 36.8 days [SE 3.7] \u003cem\u003eversus\u003c/em\u003e Placebo: 38.6 days [SE 3.6]; P\u0026thinsp;=\u0026thinsp;0.72).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDuration of URTI Episodes per Participant\u003c/h3\u003e\n\u003cp\u003eFor subjects treated with \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505, the mean number of days with URTI per participant was significantly lower at 16 weeks compared to the placebo group (P\u0026thinsp;=\u0026thinsp;0.03), showing a mean reduction of approximately 3 days (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). After 12 weeks of intervention, the difference trended towards statistical significance (P\u0026thinsp;=\u0026thinsp;0.07), with a mean reduction of 2.34 days.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDays with URTI episode per participant.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeriod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePROBIOTIC Group\u003csup\u003eA\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePLACEBO Group\u003csup\u003eA\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDifference\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP-value\u003csup\u003eC\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4.35 (0.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6.69 (0.99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-2.34 (-4.90 to 0.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.07\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4.77 (0.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e7.77 (1.10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-3.01 (-5.73 to -0.29)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.03\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eA\u003c/sup\u003e Mean (Standard Error).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eB\u003c/sup\u003e Mean (95%CI).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eC\u003c/sup\u003e T-test (*Statistically Significant Difference).\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eURTI-Free Time Rate\u003c/h3\u003e\n\u003cp\u003eParticipants treated with \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 exhibited a 2.9% higher URTI-free time rate compared to those who received placebo, with this difference being statistically significant (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eURTI-Free Time Rate (%).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeriod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePROBIOTIC Group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePLACEBO Group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDifference\u003csup\u003eA\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP-value\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e94.8%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e91.9%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.9% (1.9\u0026ndash;3.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.0001*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e96.0%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e93.1%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.9% (2.2\u0026ndash;3.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.0001*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eA\u003c/sup\u003e 95%CI Treatment Effect (Probiotic-Placebo).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003eB\u003c/sup\u003e Chi-square test (*Statistically Significant Difference).\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eWURSS-21 Score by Day of Common Cold\u003c/h2\u003e\u003cp\u003eThe overall severity of each day of common cold episodes, as assessed by the WURSS-21 questionnaire score, was similar between subjects treated with \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 and those receiving placebo, with no significant differences at 12 or 16 weeks. The complete data for this comparison are provided in the \u003cb\u003eOnline Supplementary Material\u003c/b\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eProportion of Participants Requiring Antibiotic Treatment\u003c/h2\u003e\u003cp\u003eThroughout the 16-week follow-up period, antibiotic treatment prescribed by a physician was required for only 1 URTI episode in both the probiotic and placebo groups. Due to the limited number of cases, no further analysis was conducted.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eProportion of URTI Episodes and Proportion of Days with URTI where Symptomatic Medication Was Used\u003c/h2\u003e\u003cp\u003eMost of the symptomatic medication was self-administered, with only 3 URTI episodes in the placebo group requiring a medical prescription. Importantly, the analysis excluded antibiotic medication, which was already accounted for.\u003c/p\u003e\u003cp\u003eParticipants treated with \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 used symptomatic medication in a smaller proportion of URTI episodes and had a lower percentage of URTI days with symptomatic medication compared to the placebo group, with both differences being statistically significant (P\u0026thinsp;=\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eProportion of URTI Episodes and Proportion of Days Where Symptomatic Medication Was Used.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePeriod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePROBIOTIC Group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePLACEBO Group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDifference\u003csup\u003eC\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eP-value\u003csup\u003eD\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eURTI Episodes\u003c/b\u003e where Participants Received Symptomatic Medication\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50.0% (23/46)\u003csup\u003eA\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e64.6% (42/65)\u003csup\u003eA\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-14.6% (-33.1\u0026ndash;3.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49.0% (26/53)\u003csup\u003eA\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e68.0% (53/78)\u003csup\u003eA\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-19.0% (-35.4% to -1.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.03\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eDays with URTI\u003c/b\u003e where Participants Received Symptomatic Medication\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30.3% (79/261)\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e42.2% (175/415)\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-11.9% (-19.2% to -4.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.001\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30.8% (88/286)\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e43.6% (210/482)\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-12.8% (-19.7% to -5.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.001\u003cb\u003e*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003eA\u003c/sup\u003e % (Number of episodes relative to the total URTI episodes)\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003eB\u003c/sup\u003e % (Number of days relative to the total days with URTI)\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003eC\u003c/sup\u003e 95%CI Treatment Effect (Probiotic-Placebo).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003eD\u003c/sup\u003e Chi-square test (*Statistically Significant Difference).\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eProportion of Participants Suffering Gastrointestinal Infections\u003c/h2\u003e\u003cp\u003eDuring the 16-week follow-up, 2 cases of gastrointestinal infection (diarrhoea) were reported in the placebo group, precluding further analysis.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eSalivary Immunoglobulin A (IgA)\u003c/h2\u003e\u003cp\u003eAfter 12 weeks, salivary IgA levels decreased from baseline in both probiotic and placebo groups, with no statistically significant difference between these changes (Probiotic-Placebo Difference: CI95%=-10\u0026micro;g/mL [-36 to 16\u0026micro;g/mL]; P\u0026thinsp;=\u0026thinsp;0.47).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eSafety analysis\u003c/h2\u003e\u003cp\u003eAll reported adverse events (AE) were classified as mild. A total of 18 AE were attributed to the study product (possible relationship): 8 in the probiotic group and 10 in the placebo group, all involving the digestive system. No participants were withdrawn from the study due to AE, and none dropped out due to intolerance to the study product. Additionally, adherence among the 122 analyzed participants exceeded 95% in both groups, indicating a high rate of compliance.\u003c/p\u003e\u003cp\u003eThe full data on the number and types of AEs during the 12-week intervention in both study groups are provided in the \u003cb\u003eOnline Supplementary Material\u003c/b\u003e.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings of this clinical trial support the beneficial effects of \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 in reducing the burden of URTI in adults. Despite numerous published trials evaluating the efficacy of probiotics on the incidence, duration, and severity of respiratory infections in children (\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), evidence specifically addressing their impact on URTI in healthy adults remains limited. Overall, previous clinical trials exhibit heterogeneity in their design, methodology, and interventions, posing a challenge for the comparative analysis of outcomes. Nevertheless, a recent Cochrane meta-analysis concluded that probiotic treatment could reduce the proportion of adult subjects experiencing at least 1 URTI episode by 23% (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Other meta-analyses have reported reductions in the likelihood of suffering at least of 1 respiratory infection episode in adults (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Notably, \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 demonstrated benefits by reducing individuals contracting at least 2 or 3 URTI, underscoring its potential to more vulnerable populations with more recurrent infections. Another advantage of \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 was its ability to significantly decrease the days with URTI per participant and increase the URTI-free time, which can lead to a positive impact on labour productivity and absenteeism, and overall health (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). The aforementioned meta-analyses also provide evidence of reduction of approximately 1 day in the duration of URTI episodes (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) or respiratory infections in general (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 did not alleviate the severity of each common cold episode, as measured by the WURSS-21 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). In this context, there are limited systematic reviews (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), particularly in the case of URTI, even though certain clinical trials have demonstrated positive outcomes in this regard (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). However, assessing the use of symptomatic medication for URTI could also provide an indirect measure of disease severity. Importantly, \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 intake was associated with a lower need for over-the-counter drugs. This result is of interest in view of the increasing misuse of over-the-counter drugs and related safety risks (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). To explore potential therapeutic mechanisms, the study also quantified salivary IgA. No significant modulation was observed with \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 treatment, unlike the clinical trial conducted in children (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). However, the children trial had a 6-month intervention, used a different ELISA method for salivary IgA quantification and employed a distinct sample collection method. In addition, although biologically plausible, the current evidence indicates that salivary IgA is not yet a reliable URTI biomarker due to problems of reproducibility, high interindividual variability and confounding factors (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eA limitation of the present study is the reliance on a self-diagnosed definition for a common cold episode. The Jackson scale was employed in this study (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) which has several limitations that hinder its universal applicability to the diagnosis of the common cold (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Nevertheless, the term common cold is widely used in medical literature, but defining it precisely remains challenging. A strategy to diagnose URTI to specific anatomical sites was clinically impractical due to the significant overlap and variability of symptoms over time. This variability arises from the fact that more than 200 recognized viruses can cause URTI, and the clinical presentation is influenced largely by factors such as age, immune system status, and the presence of concurrent diseases (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). In this regard, we believe that the strategy employed in the present study, which involves daily monitoring of symptoms and medication, represents a rigorous approach given the inherent problems with the disease concept.\u003c/p\u003e\u003cp\u003eIn conclusion, \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 demonstrated beneficial effects in a healthy adult population, alleviating URTI burden. Considering that URTI often act as triggers for exacerbations in chronic respiratory diseases, these findings could be valuable for guiding future research in vulnerable populations. The limited number of studies focusing on probiotic use to alleviate URTI in the adult population make this study especially relevant in trying to address the existing gap in knowledge.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003cdiv id=\"Sec19\" class=\"Section3\"\u003e\u003ch2\u003eStudy desing and ethical considerations\u003c/h2\u003e\u003cp\u003eThe present clinical trial features a randomized, double-blind, parallel-group, placebo-controlled design, with a 12-week intervention period followed by an additional 4-week follow-up period without intervention. The study was designed to coincide with the peak months of URTI incidence, with inclusion beginning in October and November 2023 and follow-up concluding between January and February 2024.\u003c/p\u003e\u003cp\u003e The study was conducted in accordance with the Declaration of Helsinki and its later amendments. Ethical approval was obtained from the Ethics Committee of the Universidad Cat\u0026oacute;lica San Antonio de Murcia, Spain (approval code CE092303), and written informed consent was obtained from all participants prior to enrolment. The study was retrospectively registered in ClinicalTrial.gov repository with the ID: NCT07091955 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://clinicaltrials.gov/study/NCT07091955\u003c/span\u003e\u003cspan address=\"https://clinicaltrials.gov/study/NCT07091955\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and in the public repository of the Universidad Cat\u0026oacute;lica San Antonio de Murcia (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://repositorio.ucam.edu/handle/10952/7702\u003c/span\u003e\u003cspan address=\"https://repositorio.ucam.edu/handle/10952/7702\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003eRecruitment and participant selection criteria\u003c/h2\u003e\u003cp\u003eParticipants were recruited through an advertisement displayed at the Universidad Cat\u0026oacute;lica San Antonio de Murcia. Eligible candidates were then invited for an in-person interview and those that met all the inclusion and exclusion criteria were included in the study. Once enrolled and after signing the informed consent form, participants were provided with detailed explanations of the trial procedures, baseline clinical and demographic data were collected, and a saliva sample was obtained for immunoglobulin A (IgA) determination.\u003c/p\u003e\u003cp\u003eThe included population consisted of healthy men and women aged 18 to 65 years with a body mass index (BMI) lower than 35 kg/m\u003csup\u003e2\u003c/sup\u003e. The exclusion criteria primarily consisted of individuals with significant acute or chronic diseases and those with an immunocompromised status. These clinical conditions included metabolic disorders such as diabetes or obesity (BMI greater than 35.1 kg/m\u003csup\u003e2\u003c/sup\u003e); congenital and acquired immune defects (including allergies); nasal ulcers or polyps causing nasal obstruction; abuse of alcohol, tobacco, or other substances; pregnancy or breastfeeding; influenza vaccination within the previous six months; ongoing treatment with medications or dietary supplements that could influence outcomes. This included immunosuppressants, immune stimulants (such as echinacea supplements), and other substances like analgesics, anti-inflammatory drugs, antitussives/expectorants, anti-flu preparations, decongestants, antibiotics, antihistamines, and probiotics within the four weeks prior to the start of the study.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003eStudy groups and interventions\u003c/h2\u003e\u003cp\u003eIncluded participants were randomized into two treatment groups at a 1:1 allocation ratio. The study groups were differentiated by the type of treatment received: probiotic or placebo. The probiotic product was a lyophilized preparation containing \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505, with a concentration of 1\u0026times;10\u003csup\u003e9\u003c/sup\u003e colony-forming units (CFUs) per daily dose. The CRL 1505 strain belongs to the culture collection of the Reference Center for Lactobacilli (CERELA-CONICET). A placebo with the same appearance as the active product was used as the comparator and contained only corn starch and maltodextrin as excipients. The daily dose for both products was one capsule per day for 12 weeks. In addition, participants were instructed not to alter their diet or physical activity during the study period.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\u003ch2\u003eRandomization and blinding\u003c/h2\u003e\u003cp\u003eThe block randomization method was employed to ensure balance in the number of subjects assigned to each intervention group. After inclusion, participants were assigned consecutively according to a computer-generated, pre-established randomization sequence based on the aforementioned method. The treatment (probiotic or placebo) was unknown to both the researchers and the participants, as the study followed a double-blind design. The treatments were labelled with the protocol and randomization code and did not display any distinctive features indicating the treatment group.\u003c/p\u003e\u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\u003ch2\u003eOutcomes, procedures and data analysis\u003c/h2\u003e\u003cp\u003eParticipants were required to complete an online questionnaire daily throughout the clinical trial. Data for outcomes analysis were extracted from these responses. The complete procedure is detailed in the \u003cb\u003eOnline Supplementary Material.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe primary endpoint was the difference between study groups in the proportion of participants diagnosed with at least 1, 2, or 3 URTI episodes. For this purpose, it was crucial to establish precise criteria for defining a common cold episode. The onset of a common cold episode was defined by meeting two criteria for at least two consecutive days: responding \u0026ldquo;yes\u0026rdquo; to the question, \u0026ldquo;Do you think you have a cold or are you getting a cold?' and achieving a score of at least two points on the Jackson scale (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The end of a common cold episode was defined as the last day of symptoms, followed by at least two consecutive symptom-free days. During data analysis, researchers defined the number and duration of common cold episodes using this data source. Other URTI, including influenza and bacterial infections should be diagnosed by a physician.\u003c/p\u003e\u003cp\u003eAs secondary endpoints, the trial evaluated the following: the difference between study groups in the number of URTI episodes per participant; the proportion of participants who developed URTI complications (bacterial infections such as pneumonia, otitis media, or acute sinusitis); the time to the first URTI episode (in days); the duration of URTI episodes per participant (days with URTI/participants); the URTI-free time rate (proportion of accumulated days without URTI symptoms relative to the total study period for all participants); the \u0026ldquo;Wisconsin Upper Respiratory Symptoms Survey 21\u0026rdquo; (WURSS-21) score per day of common cold (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e); the proportion of participants requiring antibiotics; the proportion of URTI episodes and proportion of days with URTI where symptomatic medication was used (including self-administration of analgesics, antipyretics, anti-inflammatories, antitussives, expectorants, decongestants, antihistamines, or anti-influenza preparations); and the proportion of participants who experienced gastrointestinal infections.\u003c/p\u003e\u003cp\u003e In addition, at baseline and at the end of the intervention period (week 12), participants were instructed to collect saliva samples using a Salivette\u0026reg; device. The quantification of IgA levels was performed using a commercial ELISA kit (DiaMetra, UK) in accordance with the manufacturer\u0026rsquo;s instructions.\u003c/p\u003e\u003cp\u003eThe safety profile of the study product was assessed by monitoring adverse events (AE), including their incidence and severity, throughout the intervention period.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\u003ch2\u003eSample size estimation\u003c/h2\u003e\u003cp\u003eUsing G*Power (version 3.1.9.7), the sample size was calculated assuming 50% of healthy adults would experience at least one URTI episode, with a 23% reduction expected between probiotic and placebo groups (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). With a significance level of 0.05, a power of 0.8, and a 15% drop-out rate, 140 participants (70 per group) were required.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec25\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eBaseline demographic data were used to describe the study population and assess intergroup homogeneity. Descriptive quantitative variables were summarized as mean and standard deviation (SD), and categorical variables as proportions. The efficacy analysis was performed on participants who completed the 16-week study protocol, following a per-protocol (PP) approach. Group comparisons for continuous variables were conducted using the t-test, while proportions were compared with the Chi-square test. To control for potential confounders, a multiple linear regression model was applied with treatment type as the main explanatory variable and demographic and contextual variables included as covariates. No confounding variables or relevant interactions were found. Data were analyzed with R statistical software (version 4.1.3).\u003c/p\u003e\u003cdiv id=\"Sec26\" class=\"Section3\"\u003e\u003ch2\u003eMicroorganism\u003c/h2\u003e\u003cp\u003e\u003cem\u003eLacticaseibacillus rhamnosus\u003c/em\u003e CRL 1505 was obtained from the CERELA culture collection.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eValentina Taverniti, Ines Martinez and Beatrice Tavazzani work for Sacco Srl which owns the license and manufactures the strain Lacticaseibacillus rhamnosus CRL 1505.Julio Villena, Susana Salva, Mar\u0026iacute;a P\u0026iacute;a Taranto, Susana \u0026Aacute;lvarez, Graciela Font work for CERELA-CONICET which owns the strain Lacticaseibacillus rhamnosus CRL 1505.\u003c/p\u003e\n\u003ch2\u003eAuthors contribution statement\u003c/h2\u003e\n\u003cp\u003eV.T., I.M., C.B., F.LG., C.CD., P.SP. and V.NL. wrote the main manuscript text; V.NL., V.T. and I.M. designed the intervention study; V.NL., C.B. and F.LG. coordinated the trial; B.T., C.CD. and P.SP executed the data elaboration; J.V., S.S., MP.T., S.A. and G.F. revised the manuscript. All authors reviewed the manuscript.\u003c/p\u003e\n\u003ch2\u003eCompeting interest statement\u003c/h2\u003e\n\u003cp\u003eValentina Taverniti, Ines Martinez and Beatrice Tavazzani work for Sacco Srl which owns the license and manufactures the strain \u003cem\u003eLacticaseibacillus rhamnosus\u003c/em\u003e CRL 1505.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003edeclaration\u003c/p\u003e\n\u003cp\u003eSacco Srl financially supported the study.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eV.T., I.M., C.B., F.LG., C.CD., P.SP. and V.NL. wrote the main manuscript text; V.NL., V.T. and I.M. designed the intervention study; V.NL., C.B. and F.LG. coordinated the trial; B.T., C.CD. and P.SP executed the data elaboration; J.V., S.S., MP.T., S.A. and G.F. revised the manuscript. All authors reviewed the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eThanks to the professional collaboration of Martha N\u0026uacute;\u0026ntilde;ez, Ver\u0026oacute;nica Molina, Mar\u0026iacute;a Jos\u0026eacute; Fornaguera, Lourdes Cruz Pintos and Mariano Obregozo, part of the technical team of CERELA-CONICET\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe raw data collected during the current study are available from the corresponding author upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGlobal regional, and national burden of upper respiratory infections and otitis media, 1990\u0026ndash;2021: a systematic analysis from the Global Burden of Disease Study 2021. \u003cem\u003eLancet Infect. 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Med.\u003c/em\u003e \u003cb\u003e125\u003c/b\u003e (1), 73\u0026ndash;81 (2013).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTurner, S. E. G., Loosemore, M., Shah, A., Kelleher, P. \u0026amp; Hull, J. H. Salivary IgA as a Potential Biomarker in the Evaluation of Respiratory Tract Infection Risk in Athletes. \u003cem\u003eJ. Allergy Clin. Immunol. Pract.\u003c/em\u003e \u003cb\u003e9\u003c/b\u003e (1), 151\u0026ndash;159 (2021).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEccles, R. Is the common cold a clinical entity or a cultural concept? \u003cem\u003eRhinology\u003c/em\u003e \u003cb\u003e51\u003c/b\u003e (1), 3\u0026ndash;8 (2013).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKardos, P. \u0026amp; Malek, F. A. Common Cold - an Umbrella Term for Acute Infections of Nose, Throat, Larynx and Bronchi. \u003cem\u003ePneumologie\u003c/em\u003e \u003cb\u003e71\u003c/b\u003e (4), 221\u0026ndash;226 (2017).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7371791/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7371791/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe aim of this clinical trial was to probe the efficacy of the probiotic strain \u003cem\u003eLacticaseibacillus rhamnosus\u003c/em\u003e CRL 1505 in preventing the frequency and duration of upper-respiratory tract infections (URTI) in healthy young adults. The trial was conducted according to a randomized, double-blind, parallel, placebo-controlled design, with a treatment duration of 12 weeks and a follow-up of 4 weeks. Probiotic group consumed capsules containing 1\u0026nbsp;billion of colony forming units/day of \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505. Questionnaires regarding URTI occurrence, duration and symptomatology have been collected along the study. Salivary Immunoglobulin A have been quantified at baseline and at the end of treatment. \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 reduced the proportion of subjects with at least 2 or 3 URTI episodes, leading to 2- to 3-day reduction in the duration of common cold episodes and a 3% increase in the URTI-free time rate. Moreover, participants receiving \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 used less self-administered symptomatic medication for URTI. Intervention with \u003cem\u003eL. rhamnosus\u003c/em\u003e CRL 1505 could effectively prevent URTI in healthy adults, demonstrating to be particularly effective in more susceptible subjects. This evidence are of particular interest in the context of probiotic efficacy in the management of respiratory diseases in the healthy adult population. Registry: ClinicalTrials.gov, ID: NCT07091955, Registration date: 29 July 2025.\u003c/p\u003e","manuscriptTitle":"Randomized, Double-Blind, Placebo-Controlled, Clinical Trial Assessing Lacticaseibacillus rhamnosus CRL 1505 Efficacy in Preventing Upper Respiratory Tract Infections in Healthy Adults","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-21 18:04:52","doi":"10.21203/rs.3.rs-7371791/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fc4d54cd-eb2a-46a4-8042-e3c4cb7c7733","owner":[],"postedDate":"November 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":53800914,"name":"Health sciences/Diseases"},{"id":53800915,"name":"Health sciences/Health care"},{"id":53800916,"name":"Health sciences/Medical research"},{"id":53800917,"name":"Biological sciences/Microbiology"}],"tags":[],"updatedAt":"2026-01-28T10:04:30+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-21 18:04:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7371791","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7371791","identity":"rs-7371791","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}