New Therapeutic Options in Mild Moderate COVID-19 Outpatients.

Background: In recent years, the therapeutic options for COVID have significantly improved; however, the therapies are expensive with restricted access to drugs, and expeditious and difficult to manage at home. We investigated the effect of pidotimod in preventing hospitalization in patients with mild-moderate COVID-19. Methods: A total of 1231 patients between January and June 2021 were screened. A total of 184 patients with mild-moderate COVID-19 were enrolled and divided into two groups: group-A (97) had undergone therapy with pidotimod 800 mg bid for 7−10 days and group-B (87) had other therapies. We excluded those who had undergone complete vaccination course, monoclonal anti-spike/antivirals or the co-administration of pidotimod-steroid. The primary outcome chosen was the emergency room, hospitalization, and deaths for COVID-related causes; the secondary outcome chosen was the duration of COVID-19 illness. Results: A total of 34 patients (18.5%) required hospital treatment, 11 in group-A and 23 in group-B (11.3% vs. 26.4%, p = 0.008). The median disease duration in group-A was 21 days (IQR 17−27) vs. 23 (IQR 20−31) in group-B (p = 0.005). Patients in the pidotimod group had higher SpO2 in the walking test (IQR 96−99% vs. IQR 93−98%, p = 0.01) and a lower need for steroid rescue therapy (11.5% vs. 60.9%, p < 0.001). Conclusions: In the first phase of disease, pidotimod can represent an effective, low-cost, weapon, without restrictions of use, that is able to prevent a second aggressive phase and promote faster virological recovery.

Safety and efficacy of Yupingfeng granules in children with recurrent respiratory tract infection: A randomized clinical trial.

Importance: Recurrent respiratory tract infection (RRTI) is common in children. Inappropriate RRTI treatment will lead to asthma and other diseases, thereby seriously affecting the growth and physical health of children. Immune function modulation can prevent and alleviate childhood RRTI. Yupingfeng (YPF), a patented traditional Chinese medicine (TCM), has immunomodulatory effects and is widely used in China to treat children with RRTI. Objective: To evaluate the safety and efficacy of YPF monotherapy in treating children with RRTI. Methods: This multicenter, randomized, double-blind, double-simulation, noninferiority clinical trial was conducted from January 2015 to August 2017, with an 8-week treatment period and 52-week follow-up after the drug withdrawal. Children aged 2-6 years with RRTI meeting the inclusion and exclusion criteria were enrolled in 13 hospitals in China and divided randomly into three groups (2:2:1 ratio) to receive YPF, pidotimod, or placebo. The primary outcome was the proportion of RRTI returning to normal standard level during the follow-up. The secondary outcomes were reduction in the number of RRTI recurrences, effect on clinical symptoms (in accord with TCM practice), effect per symptom, and safety. The trial was registered at the Chinese Clinical Trials Registry (www.chictr.org.cn) under the unique identifier ChiCTR-IPR-15006847. Results: Three hundred and fifty-one children were enrolled and randomly assigned to 3 groups; 124, 125, and 61 children in the YPF, pidotimod, and placebo groups, respectively, had completed the trial. During the follow-up, the proportion of RRTI returning to normal standard level was 73.13%, 67.15%, and 38.81% with YPF, pidotimod, and placebo, respectively (P < 0.0001). The proportion of cases who returned to normal standard level in the YPF group was 34.32% higher than that in the placebo group. The safety profile did not significantly differ among the groups. Interpretation: YPF granules were noninferior to the active control drug pidotimod oral solution for the treatment of RRTI in children, and were superior to placebo, with a high safety profile.

Pidotimod increases inflammation in wounded zebrafish embryos.

Pidotimod (PDT) is a synthetic dipeptide molecule which can improve immune responses in mice and humans, protecting hosts from infection. However, the exact mechanism of protection remains ill-defined. The effect of pidotimod has not yet been investigated in the inflammatory response of zebrafish. In this study, we used tail wound and infection models of zebrafish to study the effect of PDT on inflammation. We found that zebrafish larvae were sensitive to PDT immersion causing toxicity at doses above 50 µg/mL. The tail wound assay showed that PDT increased the recruitment of neutrophils and macrophages to the wound site and promoted the transcription of the pro-inflammatory cytokine il1b. However, we did not observe protection of uropathogenic Escherichia coli or Mycobacterium marinum infected zebrafish larvae following PDT treatment. This study provides a new platform for PDT research, which is worthy of further research to identify further effects of PDT therapy.

Anti-Inflammatory Effects of Immunostimulation in Patients with COVID-19 Pneumonia.

BACKGROUND: The effects of immunomodulators in patients with Coronavirus Disease 2019 (COVID-19) pneumonia are still unknown. We investigated the cellular inflammatory and molecular changes in response to standard-of-care + pidotimod (PDT) and explored the possible association with blood biomarkers of disease severity. METHODS: Clinical characteristics and outcomes, neutrophil-to-lymphocyte ratio (NLR), plasma and cell supernatant chemokines, and gene expression patterns after SARS-CoV-2 and influenza (FLU) virus in vitro stimulation were assessed in 16 patients with mild-moderate COVID-19 pneumonia, treated with standard of care and PDT 800 mg twice daily (PDT group), and measured at admission, 7 (T1), and 12 (T2) days after therapy initiation. Clinical outcomes and NLR were compared with age-matched historical controls not exposed to PDT. RESULTS: Hospital stay, in-hospital mortality, and intubation rate did not differ between groups. At T1, NLR was 2.9 (1.7-4.6) in the PDT group and 5.5 (3.4-7.1) in controls (p = 0.037). In the PDT group, eotaxin and IL-4 plasma concentrations progressively increased (p < 0.05). Upon SARS-CoV-2 and FLU-specific stimulation, IFN-γ was upregulated (p < 0.05), while at genetic transcription level, Pathogen Recognition Receptors (TRLs) were upregulated, especially in FLU-stimulated conditions. CONCLUSIONS: Immunomodulation exerted by PDT and systemic corticosteroids may foster a restoration in the innate response to the viral infection. These results should be confirmed in larger RCTs.

Effects of adjuvant pidotimod therapy on levels of inflammatory factors and expressions of serum GM-CSF and KL-6 in elderly patients with mycoplasma pneumonia.

OBJECTIVE: To observe the intervention effects of adjuvant pidotimod therapy on the serum inflammatory factor and GM-CSF and KL-6 expression levels in elderly mycoplasma pneumonia patients. METHODS: Elderly patients (n=104) diagnosed with mycoplasma pneumonia were divided into a control group (52 cases, given conventional anti-infective therapy combined with ambroxol) and a research group (52 cases, given conventional anti-infective therapy combined with ambroxol + pidotimod) according to the different treatment methods each patient was administered. The pulmonary function indexes (FVC, FEV1, FEV1/FVC), the serum inflammatory factor levels (interleukin (IL)-6, IL-8, the tumor necrosis factor α), the serum granulocyte-macrophage colony-stimulating factor (GM-CSF), and the Krebs von den Lungen-6 (KL-6) expression levels were measured before and after the treatment. The cough stopping times, the rale disappearance times, the hospital stay durations, the overall response rates, the incidences of adverse reactions during the administration, and the recurrence rates at 3, 6, and 12 months after the treatment were recorded. RESULTS: The research group had shorter cough stopping times, rale disappearance times, and hospital stays than the control group (all P<0.05). After the treatment, the FVC, FVE1, and FVE1/FVC levels in both groups were increased, and the research group had higher levels than the control group (all P<0.05). After the treatment, the serum tumor necrosis factor α, IL-6, IL-8, GM-CSF, and KL-6 levels in the two groups were significantly decreased, and the levels of these indicators in the research group were significantly lower than they were in the control group (all P<0.05). The total overall treatment response rate was higher, and the recurrence rate at 12 months after the treatment was significantly lower in the research group than they were in the control group (P<0.05). CONCLUSION: Adjuvant pidotimod therapy in the treatment of elderly patients with mycoplasma pneumonia can ameliorate patients' inflammatory responses and pulmonary functions, and reduce the serum GM-CSF and KL-6 factor levels, as well as the recurrence rate. Moreover, the combined medication is safe, and no significant increase in toxicity was found.

Prevention of New Respiratory Episodes in Children with Recurrent Respiratory Infections: An Expert Consensus Statement.

In healthy infants and young children, the development of respiratory tract infections (RTIs) is extremely common. In this paper, we present an international consensus of the available approaches for the prevention of recurrent RTIs in children, including the atopic/allergic ones as well as those with asthma. Few convincing measures for reducing the frequency and clinical relevance of recurrent respiratory episodes in RTI-prone children have been developed until now. Among the most recently suggested measures, immunotherapy is attractive, but only for OM-85 is there a sufficient number of well-conducted clinical trials confirming efficacy in RTIs prevention with an adequate safety profile. In the case of probiotics, it is not clear which bacteria can offer the best results and which dosage and schedule of administration are the most effective. The problems of dosage and the schedule of administration are not solved also for vitamin D, despite some promising efficacy results. While we wait for new knowledge, the elimination or reduction as much as possible of the environmental factors that favor RTIs, vaccination when available and/or indicated, and the systematic application of the traditional methods for infection prevention, such as hand washing, remain the best measures to prevent recurrent infections in RTI-prone children.

Proposal for a new therapeutic high dosage of Pidotimod in children with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome: a randomized controlled study.

BACKGROUND: Despite to PFAPA syndrome is considered a benign and self-limited condition in childhood its impact on patients and families can be remarkable in many cases. Currently, the therapeutic options for managing are non-specific and no consensus exists about the best treatment to use. Pidotimod has been suggested as a new potential treatment in PFAPA syndrome for its immunodulatory effects. We conducted a preliminary, prospective, controlled, open, cross-over trial to assess the efficacy and the safety of Pidotimod in the treatment of children with PFAPA syndrome. METHODS: 22 children with PFAPA syndrome were randomly allocated to treatment with pidotimod (with 2 vials of 400 mg daily) in combination with betamethasone 0.5-1 mg on need, based on parents/caregivers' decision (group A) or betamethasone 0.5-1 mg on need, based on parents/caregivers' decision (group B). Each treatment period was for 3 months (Phase 1), after that patients were switched to the other arm for other 3 months (Phase 2). Efficacy was expressed in terms of number of episodes of fever, pharyngitis, or aphthous stomatitis, as well as the additional use of betamethasone on need. Safety and tolerability of the Pidotimod were evaluated on the basis of the number and type of adverse events (AEs) recorded during the treatment. RESULTS: Patients receiving Pidotimod and use betametasone showed a significant decrease in frequency of fevers (p = 0.002); number of episodes of pharyngitis (p = 0.049); aphthous stomatitis (p = 0.036) as well as the betamethasone use on need (p = 0.007). Overall, 19/22 (86.4%) showed benefits from Pidotimod administration. The safety profile of Pidotimod was excellent as no serious adverse events have been reported in the treated groups. CONCLUSIONS: We firstly showed that high dosage of Pidotimod could be an effective and safe to reduce the PFAPA attacks in children.

Efficacy of Pidotimod use in treating allergic rhinitis in a pediatric population.

BACKGROUND: Allergic rhinitis (AR) and adenoidal hypertrophy (AH) are the most frequent causative disorders of nasal obstruction in children, leading to recurrent respiratory infections. Both nasal cavities are colonized by a stable microbial community susceptible to environmental changes and Staphylococcus aureus seems to play the major role. Furthermore, nasal microbiota holds a large number and variety of viruses with upper respiratory tract infections. This local microbiota deserves attention because its modification could induce a virtuous cross-talking with the immune system, with a better clearance of pathogens. Although AR and AH present a different etiopathogenesis, they have in common a minimal chronic inflammation surrounding nasal obstruction; hence it would be challenging to evaluate the effect of an immunomodulator on this minimal chronic inflammation with possible clinical and microbiological effects. The aim of this study is therefore to evaluate the efficacy of an immunomoldulator (Pidotimod) on nasal obstruction in children with AR and/or AH and whether its action involves a variation of nasal microbiota. METHODS: We enrolled 76 children: those with allergic rhinitis (AR) sensitized to dust mites entered the AR group, those with adenoidal hypertrophy (AH) the AH group, those with both conditions the AR/AH group and those without AR ± AH as controls (CTRL). At the first visit they performed: skin prick tests, nasal fiberoptic endoscopy, anterior rhinomanometry, nasal swabs. Children with. AR ± AH started treatment with Pidotimod. After 1 month they were re-evaluated performing the same procedures. The primary outcome was the evaluation of nasal obstruction after treatment and the secondary outcome was the improvement of symptoms and the changes in nasal microflora. RESULTS: All patients improved their mean nasal flow (mNF) in respect to the baseline. In AR children mNF reached that one of CTRL. In AH children±AR the mNF was lower in respect to CTRL and AR group. We did not find any differences among all the groups at the two different time points in nasal microflora. CONCLUSIONS: Pidotimod is able to give an improvement in nasal obstruction, especially in AR children but this effect seems to be not mediated by changes in nasal microbiota.

Pidotimod enhanced the anti-growth effect of cisplatin on lung cancer in mice via promoting anti-tumor immune response.

Cisplatin-based chemotherapeutics represent a mainstay of lung cancer therapy, but resistance limits their curative potential. In the current study, we reported that Pidotimod, which is an immunostimulant and used for the prevention of acute respiratory infections, elevated cisplatin sensitivity, leading to the synergistic attenuation of tumor growth in mouse lewis lung cancer (LLC) model. With further exploration, we found that Pidotimod enhanced the anti-growth effect of cisplatin on LLC via promoting anti-tumor response, such as increased infiltration of dendrite cells (DCs) and CD8+ T cells as well as enhancement of IFN-γ and Granzyme B expression. In summary, Pidotimod affects the anti-tumor function of cisplatin via promoting anti-tumor immune response and these findings provide a novel approach for the development of therapeutic strategies for lung cancer.

Effects of Pidotimod on recurrent respiratory infections in children with Down syndrome: a retrospective Italian study.

BACKGROUND: Children with Down syndrome (DS) show a high susceptibility to recurrent infections (RI), caused by immune defects and abnormalities of the airways. Our goal was to investigate the effects of Pidotimod on RI prevention in children with DS, comparing immune and clinical parameters before (T0) and after (T1) the treatment with Pidotimod. METHODS: The study was conducted at the Down syndrome outpatient Center of Bambino Gesù Children's Hospital, in Rome. We reviewed the medical records of all children with a positive history for RI and who received oral prophylaxis of Pidotimod from September 2016 to February 2017. RESULTS: Thirty-three children met the inclusion criteria (males: 51.5%; average age: 6 years ±SD: 3). We found a significant decrease in the number of children with upper respiratory infections (82% at T0 vs 24% at T1; p = 0,0001) and with lower respiratory infections (36% at T0 vs 9% at T1; p = 0.003) after treatment with Pidotimod. We also demonstrated a significant decrease in the number of children hospitalized for respiratory infections (18% at T0 vs 3% at T1; p = 0.03). We measured T and B cells in the peripheral blood and B cell function in vitro at T0 and T1. We found that the response to CpG improved at T1. A significant increase of B cell frequency (p = 0.0009), B cell proliferation (p = 0.0278) and IgM secretion (p = 0.0478) were observed in children with DS after treatment. CONCLUSIONS: Our results provided evidence that Pidotimod may be able to prevent RI in children with Down syndrome.

Immunostimulants in respiratory diseases: focus on Pidotimod.

Usefulness of Pidotimod and its role as immunostimulant, has been discussed, we know, for several decades. Nevertheless, there is still much to know. Understanding its mechanisms and its potential usefulness in airway infections and its prevention, asthma both Th2 and non Th2 type, bronchiectasis, as adjuvant in vaccination and in allergen immunotherapy still remains to clearly unveil. The aim of this paper was to provide a useful updated review of the role of the main available immunostimulants, giving particular focus on Pidotimod use and its potentials utility in respiratory diseases. Pidotimod showed its usefulness in reducing need for antibiotics in airway infections, increasing the level of immunoglobulins (IgA, IgM, IgG) and T-lymphocyte subsets (CD3+, CD4+) endowed with immunomodulatory activity that affect both innate and adaptive immune responses. Higher expression of TLR2 and of HLA-DR molecules, induction of dendritic cell maturation and release of pro-inflammatory molecules, stimulation of T lymphocyte proliferation and differentiation toward a Th1 phenotype, as well as an increase of the phagocytosis have been demonstrated to be associated with Pidotimod in in vitro studies. All these activities are potentially useful for several respiratory conditions such as asthma, COPD, and recurrent respiratory tract infections.

The Synthetic Dipeptide Pidotimod Shows a Chemokine-Like Activity through CXC Chemokine Receptor 3 (CXCR3).

In recent years immunomodulators have gained a strong interest and represent nowadays an active expanding area of research for the control of microbial diseases and for their therapeutic potential in preventing, treating and reducing the morbidity and mortality of different diseases. Pidotimod (3-L-pyroglutamyl-L-thiaziolidine-4carboxylic acid, PDT) is a synthetic dipeptide, which possesses immunomodulatory properties and exerts a well-defined pharmacological activity against infections, but its real mechanism of action is still undefined. Here, we show that PDT is capable of activating tyrosine phosphorylation-based cell signaling in human primary monocytes and triggering rapid adhesion and chemotaxis. PDT-induced monocyte migration requires the activation of the PI3K/Akt signaling pathway and chemokine receptor CXCR3. Indeed, a mAb to CXCR3 and a specific receptor inhibitor suppressed significantly PDT-dependent chemotaxis, and CXCR3-silenced primary monocytes lost responsiveness to PDT chemoattraction. Moreover, our results highlighted that the PDT-induced migratory activity is sustained by the CXCR3A isoform, since CXCR3-transfected L1.2 cells acquired responsiveness to PDT stimulation. Finally, we show that PDT, as CXCR3 ligands, is also able to direct the migration of IL-2 activated T cells, which express the highest levels of CXCR3 among CXCR3-expressing cells. In conclusion, our study defines a chemokine-like activity for PDT through CXCR3A and points on the possible role that this synthetic dipeptide may play in leukocyte trafficking and function. Since recent studies have highlighted diverse therapeutic roles for molecules which activates CXCR3, our findings call for an exploration of using this dipeptide in different pathological processes.

Pidotimod: a review of its pharmacological features and clinical effectiveness in respiratory tract infections.

Introduction: The majority of acute respiratory tract infections (RTIs) are caused by viruses and the overzealous use of antibacterial drugs, when not really required, is a cause for concern. This has led to evaluation of alternative approaches such as boosting the immune response in individuals who are most vulnerable to develop RTIs such as the very young and the elderly. Areas covered: This article overviews the immunostimulant activity and pharmacokinetic properties of pidotimod, and focuses on assessing its role in the treatment and prevention of acute RTIs through evaluation of clinical trials and real-world evidence. Articles were obtained from a full search of Medline, and this was augmented by published clinical studies known to the authors and manufacturer. Expert opinion: Pidotimod's activity was shown to be mediated via multiple pathways of the immune system. Comparison with placebo demonstrated significant advantages for pidotimod in terms of reduced reinfection rates [OR 0.20, 95% CI 0.12 to 0.33; p < 0.00001], a lesser need for antibiotics [mean difference -2.65, 95% CI -3.68 to -1.62; p < 0.00001] and rescue medications, and decreased absenteeism [mean difference-2.99, 95% CI -4.03 to -1.95; p < 0.00001]. No safety concerns were raised in these studies.

Effect of pidotimod combined with azithromycin on children with mycoplasma pneumonia and the expression levels of IL-10 and G-CSF in serum.

This study explored the effect of pidotimod combined with azithromycin on children with mycoplasma pneumonia and the expression of interleukin-10 (IL-10) and granulocyte colony-stimulating factor (G-CSF) in serum. The clinical data of 149 children with mycoplasma pneumonia from May 2014 to May 2018 in Zhangqiu District Maternal and Child Health Care Hospital were collected. Among them, 70 children treated with azithromycin sequential therapy were the control group, and 79 children treated with the combination of pidotimod and azithromycin were the observation group. Double antibody sandwich enzyme-linked immunosorbent assay (ELISA) was used to determine the expression levels of IL-10 and G-CSF in serum before and after treatment. Pearson's correlation coefficient was used to analyze the correlation between IL-10 and G-CSF in serum. The total effective rate in the observation group (94.94%) was significantly higher than that in the control group (81.43%) (P<0.05). There was no significant difference in the expression levels of IL-10 and G-CSF between the two groups before treatment (P>0.05). The expression levels of IL-10 and G-CSF in the two groups after treatment were significantly lower than those before treatment (P<0.05). After treatment, the expression levels of IL-10 and G-CSF in serum in the observation group were significantly lower than those in the control group. There was a significant positive correlation between the expression levels of IL-10 and G-CSF before and after treatment in the observation group (P<0.05), and a significant positive correlation between the expression levels of IL-10 and G-CSF before and after treatment in the control group (P<0.05). Compared with sequential treatment with azithromycin alone, pidotimod combined with azithromycin significantly reduced the expression levels of IL-10 and G-CSF in serum of children with mycoplasma pneumonia, improved the curative effect and reduced the occurrence of adverse reactions, which has high application value in clinic.

Pidotimod: In-depth review of current evidence.

Pidotimod, an immunostimulant, is researched for over two decades. Current evidence indicates its utility in a variety of indications in children as well as in adults. Its immunostimulant activity has been firmly established in the management of recurrent respiratory infections in children with or without asthma. Compared to standard of care alone, addition of pidotimod to standard of care significantly prevents the recurrences and reduces the severity and duration of acute episodes, ultimately resulting in reduced visits to pediatric clinics and lower absenteeism at school. In adults, pidotimod is effective in the prevention and treatment of acute infectious exacerbations of chronic bronchitis and chronic obstructive pulmonary disease (COPD). Further, it has been evaluated in indications such as pneumonia, hand-food-mouth disease, bronchiectasis, and chronic idiopathic urticaria. From a total of 32 studies conducted in child (24 studies) and adult (8 studies) population, this in-depth review discusses the current evidence of pidotimod. With further exploration, the immunostimulant activity of pidotimod might be extended to different immunological disorders.

Pidotimod in the treatment of pediatric recurrent respiratory tract infection.

OBJECTIVE: To observe the clinical efficacy of pidotimod in the treatment of recurrent respiratory tract infection in children. METHODS: One hundred thirty-two patients with recurrent respiratory tract infection who received treatment in Tianan City Central Hospital were selected and divided into an observation group and a control group using random number table, 66 in each group. Patients in the control group were given conventional treatment, while patients in the observation group were given conventional treatment and pidotimod treatment; the clinical efficacy of the two therapies was compared. The levels of IgG and IgM were measured after treatment. RESULTS: The vital signs and the content of inflammatory mediator and Th1/Th2 in serum before and after treatment were compared, and the clinical efficacy of the two groups was evaluated. The fever, pulmonary rale, cough and antiadoncus of patients in the observation group disappeared earlier than those in the control group (P<0.05). The onset duration of respiratory tract infection and days of antibiotic application of the observation group were shorter than those of the control group after treatment (P<0.05). The times of infection of the observation group were less than that of the control group (P<0.05). Before treatment, the two groups had no significant difference in the content of inflammatory mediators and Th1/Th2 in the serum (P>0.05). The serum content of tumor necrosis factor (TNF)-α and interleukin (IL)-4 of the two groups one week after treatment was lower than that before treatment, and the content of interferon (IFN)-γ and IFN-γ/IL-4 were higher than that before treatment; moreover the observation group had lower serum content of TFN-α and IL-4 and lower content of IFN-γ and IFN-γ/IL-4 compared to the control group (P<0.05). The overall response rate of the observation group was 92.4%, much higher than 81.8% in the control group (P<0.05). CONCLUSION: Pidotimod has a remarkable efficacy in the treatment of pediatric recurrent respiratory tract infection because it can effectively inhibit the infection and optimize Th1/Th2 immune function.

Effects of pidotimod and bifidobacteria mixture on clinical symptoms and urinary metabolomic profile of children with recurrent respiratory infections: a randomized placebo-controlled trial.

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 of their efficacy on clinical features or on urine metabolic profile. OBJECTIVE: To evaluate whether pidotimod and/or bifidobacteria can reduce RRI morbidity and influence the urine metabolic profile in preschool children. MATERIALS AND METHODS: Children aged 3-6 years with RRI were enrolled in a four-arm, exploratory, prospective, randomized, double-blinded, placebo-controlled trial. Patients were randomly assigned to receive pidotimod plus bifidobacteria, pidotimod plus placebo, bifidobacteria plus placebo or double placebo for the first 10 days of each month over 4 consecutive months. Respiratory symptoms and infections were recorded with a daily diary by parents during the study. Metabolomic analyses on urine samples collected before and after treatment were performed. RESULTS: Compared to placebo, children receiving pidotimod, alone or with bifidobacteria, had more symptom-free days (69 versus 44, p = 0.003; and 65 versus 44, p = 0.02, respectively) and a lower percentage of days with common cold (17% versus 37%, p = 0.005; and 15% versus 37%, p = 0.004, respectively). The metabolomic analysis showed that children treated with Pidotimod (alone or in combination with bifidobacteria) present, respect to children treated with placebo, a biochemical profile characterized by compounds related to the pathway of steroids hormones, hippuric acid and tryptophan. No significant difference in the metabolic profile was found between children receiving bifidobacteria alone and controls. CONCLUSIONS: Preschool children with RRI treated with pidotimod have better clinical outcomes and a different urine metabolomic profile than subjects receiving placebo. Further investigations are needed to clarify the connection between pidotimod and gut microbiome.

Pidotimod, an immunostimulant in pediatric recurrent respiratory tract infections: A meta-analysis of randomized controlled trials.

OBJECTIVES: Recurrent respiratory tract infections (RRTIs) remain a great challenge to pediatricians, because they can increase the risk of various complications and there is no confirmed effective treatment. In the present study, we aimed to assess the effectiveness and safety of pidotimod (PDT), an immunostimulant, in treatment of RRTIs in children aged 14 years and under. METHODS: PubMed, EMBASE, Web of Science, Cochrane Library, ClinicalTrials.gov, CBM and CNKI were searched from their inception up to February 2018. All randomized controlled trials (RCTs) using PDT with various treatment durations and enrolling participants <14 years of age were included in the present review. The interventions were PDT plus conventional treatment (e.g. anti-bacterial and antiviral therapy) or PDT alone versus the conventional treatment plus placebo or conventional treatment alone. RESULTS: A total of 29 RCTs consisting of 4344 pediatric patients were included in this meta-analysis. Ten RCTs were published from Italy, Russia or Greece, and 19 RCTs were published by Chinese groups. However, appropriate randomization methods were only used in 15 trials. Only one study had explicit allocation concealment. Since only eight RCTs were double-blind and placebo controlled, the evidence was not assessed as high quality. The meta-analysis indicates that treatment with PDT resulted in a significant increase in the proportion of participants who had lower RTIs (RR 1.59; 95% CI 1.45-1.74, p < 0.00001) compared with the conventional treatment. PDT could significantly decrease the duration of cough and fever. The number of patients in using antibiotics was also remarkably decreased in the PDT treatment group. Moreover, PDT administration improved the levels of serum immunoglobulin (IgG, IgA, or IgM) and T-lymphocyte subtypes (CD3+, CD4+). Besides, PDT administration did not increase the risk of adverse events of any cause (RR = 1.05, 95% CI 0.72-1.54, p = 0.80). CONCLUSIONS: PDT showed a good efficacy and safety in treatment of pediatric RRTIs. Further high-quality and large-scale RCTs are still required to provide confirmatory evidence. TRIAL REGISTRATION: The protocol of this study can be found at PROSPERO with the registration number of CRD42018093541.