Effects of Pidotimod and Bifidobacteria Mixture on Clinical Symptoms and Metabolomic Profile of Children with Recurrent Respiratory Infections: a Randomized Placebo Controlled Trial

Abstract

BACKGROUND: Many preschool children develop recurrent respiratory tract infections (RRI). Strategies to prevent RRI include the use of immunomodulators, as pidotimod or probiotics, but there is limited evidence on the clinical effects of the treatment, alone or combined, as well as on the changes of urine metabolic profile following it. OBJECTIVES. To investigate whether the treatment with pidotimod and/or bifidobacteria were associated with 1) a reduced morbidity related to RRI and 2) differences in the urine metabolic profile. MATERIALS AND METHODS: The study is a four-arm, exploratory, prospective, randomized, double-blinded, placebo-controlled clinical trial conducted during 2 autumn seasons, over the same three-months periods in 2 consecutive years. Children aged 3-6 years with RRI who attended the nursery school were enrolled and randomly assigned to one of the 4 arms to receive active medications or placebos for the first 10 days of each month for 4 consecutive months. Metabolomic analyses on urine samples collected before and after treatment were performed using mass spectrometry combined with ultra-performance liquid chromatography (UPLC-MS). RESULTS: Compared to the placebo group, children receiving pidotimod, alone or combined with bifidobacteria, had a significantly higher proportion of symptom-free days (p=0.02 and p=0.003, respectively) and a significantly lower percentage of days with common cold (p=0.004 and p=0.005, respectively). In those children, we also found relevant changes in the urine metabolomic profile compared to children receiving placebo. Furthermore, children treated with pidotimod alone showed a different metabolic profile compared to children treated with pidotimod plus bifidobacteria. On the other side, children receiving bifidobacteria alone did not show differences with respect to the placebo group in clinical outcomes or metabolomic profiles. CONCLUSIONS: this study shows that children with RRI treated with pidotimod have a better clinical outcome and a different metabolomics profile after treatment, compared to subject receiving placebo while patients treated only with bifidobacteria did not show any difference in clinical outcomes and metabolomic profile in comparison to the placebo group. The combined treatment (pidotimod plus bifidobacterium) did not modify the clinical outcome, but metabolomic analysis was able to reveal, going beyond the clinic, a different behavior for these two groups, suggesting a possible role for the microbiota composition in the underlying physiopathologic mechanism