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.

Wheezing preschool children with early-onset asthma reveal a specific metabolomic profile.

BACKGROUND: Many children of preschool age present with recurrent wheezing. Most of them outgrow their symptoms, while some have early-onset asthma. Aim of this prospective preliminary study was to apply a metabolomic approach to see whether biochemical-metabolic urinary profiles can have a role in the early identification of the children with asthma. METHODS: Preschool children with recurrent wheezing were recruited and followed up for 3 years, after which they were classified as cases of transient wheezing or early-onset asthma. A urine sample was collected at recruitment and analyzed using a metabolomic approach based on UPLC mass spectrometry. RESULTS: Among 34 children aged 4.0 ± 1.1 years recruited, at the end of the 3-year follow-up, 16 were classified as having transient wheezing and 16 as cases of early-onset asthma. Through a joint multivariate and univariate statistical analyses, we identified a subset of metabolomic variables that enabled the 2 groups to be clearly distinguished. The model built using the identified variables showed an AUC = 0.99 and an AUC = 0.88 on sevenfold full cross-validation (P = .002). CONCLUSIONS: Metabolomic urinary profile can discriminate preschoolers with recurrent wheezing who will outgrow their symptoms from those who have early-onset asthma. These results may pave the way to the characterization of early non-invasive biomarkers capable of predicting asthma development.

Metabolomic profile of children with recurrent respiratory infections.

Recurrent respiratory infections (RRI) represent a widespread condition which has a severe social and economic impact. Immunostimulants are used for their prevention. It is crucial to better characterize children with RRI to refine their diagnosis and identify effective personalized prevention strategies. Metabolomics is a high-dimensional biological method that can be used for hypothesis-free biomarker profiling, examining a large number of metabolites in a given sample using spectroscopic techniques. Multivariate statistical data analysis then enables us to infer which metabolic information is relevant to the biological characterization of a given physiological or pathological condition. This can lead to the emergence of new, sometimes unexpected metabolites, and hitherto unknown metabolic pathways, enabling the formulation of new pathogenetic hypotheses, and the identification of new therapeutic targets. The aim of our pilot study was to apply mass-spectrometry-based metabolomics to the analysis of urine samples from children with RRI, comparing these children's biochemical metabolic profiles with those of healthy peers. We also compared the RRI children's and healthy controls' metabolomic urinary profiles after the former had received pidotimod treatment for 3 months to see whether this immunostimulant was associated with biochemical changes in the RRI children's metabolic profile. 13 children (age range 3-6 yeas) with RRI and 15 matched per age healthy peers with no history of respiratory diseases or allergies were enrolled. Their metabolomic urine samples were compared before and after the RRI children had been treated with pidotimod for a period of 3 months. Metabolomic analyses on the urine samples were done using mass spectrometry combined with ultra-performance liquid chromatography (UPLC-MS). The resulting spectroscopic data then underwent multivariate statistical analysis and the most relevant variables characterizing the two groups were identified. Data modeling with post-transformation of PLS2-Discriminant Analysis (ptPLS2-DA) generated a robust model capable of discriminating the urine samples from children with RRI from those of healthy controls (R2=0.92,Q2CV7-fold=0.75, p-value<0.001). The dataset included 1502 time per mass variables, and 138 of them characterized the difference between the two groups. Thirty-five of these distinctive 138 variables persisted in the profiles of the children with RRI after pidotimod treatment. Metabolomics can discriminate children with RRI from healthy controls, suggesting that the former have a dysregulated metabolic profile. Among the variables characterizing children with RRI there are metabolites that may reflect the presence of a different microbiome. After pidotimod treatment, the metabolic profile of the children with RRI was no longer very different from that of the healthy controls, except for the persistence of some microbiome-related variables. We surmise that pidotimod partially "restores" the altered metabolic profile of children with RRI, without modifying the metabolites related to the composition of the gut microbiota. In the light of these results, we hypothesize a potential synergic effect of the combined use of immunostimulants and probiotics for the purpose of prevention in children with RRI.

Health-related quality of life in adolescent survivors of bronchopulmonary dysplasia.

BACKGROUND AND OBJECTIVE: Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy in the developed countries. Outcomes for BPD patients have traditionally been assessed using physiological parameters such as lung function, and no data are available on the health-related quality of life (HRQOL) for adolescents with BPD. The aim of this study was to assess HRQOL in adolescents with BPD, in comparison with age-matched and sex-matched control groups of healthy volunteers and asthmatic subjects. METHODS: We enrolled 27 BPD patients (age range 11-19 years), 27 asthmatic patients and 27 healthy controls. HRQOL was assessed by the Short Form 36 (SF-36) questionnaire. Lung function was assessed by spirometry. RESULTS: The BPD group did not differ significantly from the healthy controls in any scale or dimension of the SF-36 (the BPD group's summary scores were as follows: physical component summary mean 55.6 + 4.98 and mental component summary 51.8 + 7.75 vs 55.8 + 6.25 and 49.2 + 9.45 for the healthy control group, P > 0.5 and P = 0.26, respectively). Asthmatic adolescents scored lower than those of both healthy controls and patients with BPD in several SF-36 dimensions despite adolescents with BPD having lower lung function. No correlation emerged between lung function and HRQOL in BPD subjects. CONCLUSION: Despite their impaired lung function, BPD patients have an HRQOL comparable with healthy peers and better than asthmatic patients. We did not find any association between HRQOL and lung function parameters.

Severe asthma in childhood: diagnostic and management challenges.

PURPOSE OF REVIEW: Problematic severe asthma is a heterogeneous disease with multiple phenotypes. It is rare (<5% of children with asthma), but accounts for 30-50% of all pediatric asthma healthcare costs. This review looks into the currently used management strategies and the innovative treatments, considering both conventional medications and innovative biological therapies for targeting airway inflammation. RECENT FINDINGS: Patients with problematic severe asthma should be seen by pediatric asthma specialists using a stepwise approach. The first step is to exclude alternative diagnoses; the second is to consider and exclude comorbidities, and assess adherence to medication; the third step involves identifying the pattern of inflammation; and response to treatment in the fourth. Innovative biological therapies are emerging and healthcare professionals should know how to handle them. Patient phenotyping is the main step towards a targeted therapeutic strategy. SUMMARY: A careful management is important for children with severe asthma, who form a small but challenging group of patients. More research efforts are needed to enable a personalized medicine and a biomarker-driven approach.

Childhood asthma biomarkers: present knowledge and future steps.

Asthma represents the most common chronic respiratory disease of childhood. Its current standard diagnosis relies on patient history of symptoms and confirmed expiratory airflow limitation. Nevertheless, the spectrum of asthma in clinical presentation is broad, and both symptoms and lung function may not always reflect the underlying airway inflammation, which can be determined by different pathogenetic mechanisms. For these reasons, the identification of objective biomarkers of asthma, which may guide diagnosis, phenotyping, management and treatment is of great clinical utility and might have a role in the development of personalized therapy. The availability of non-invasive methods to study and monitor disease inflammation is of relevance especially in childhood asthma. In this sense, a promising role might be played by the measurement of exhaled biomarkers, such as exhaled nitric oxide (FE(NO)) and molecules in exhaled breath condensate (EBC). Furthermore, recent studies have shown encouraging results with the application of the novel metabolomic approach to the study of exhaled biomarkers. In this paper the existing knowledge in the field of asthma biomarkers, with a special focus on exhaled biomarkers, will be highlighted.

Bioelectrical impedance vector analysis to evaluate relative hydration status.

The objective was to present our clinical experience with bioelectrical impedance vector analysis (BIVA). Forty-six patients with chronic kidney disease (CKD) without oedema, 21 oedematous nephrotic children and 15 in remission from nephrotic syndrome were studied. The age range was 2-14 years. Data were obtained with the vector bioelectric impedance analysis method (Piccoli's RXc graph with 95% confidence ellipses) and compared with normal paediatric values. The mean vector position differs significantly among the groups of evaluated patients (Hotelling T(2) test, p < 0.05). Mean vector position along the 45 degrees direction (major axis of ellipses) indicates a progressive increase in body fluid volume from patients with CKD stage IV to stages II-III to patients in remission from nephrotic syndrome to oedematous subjects. We observed a progressive vector lengthening in children with severe renal disease (separate 95% confidence ellipse). This pattern indicates relative dehydration. BIVA represents a useful clinical tool that is able to detect changes in hydration.

Relationship between quality of life and behavioural disorders in children with persistent asthma: a Multiple Indicators Multiple Causes (MIMIC) model.

Knowledge on multiple interdependences between quality of life (QoL) and behavioural problems in relation to asthma severity and control is undetermined. The aims of the study were: (i) to assess the relationship of QoL and behavioural problems with asthma severity and control (ii) to predict children's "abnormal/borderline" status with variation in QoL. For these purposes a multicenter case-control study on 47 Severe Asthma (SA) and 94 Moderate Asthma (MA) children was performed. The MIMIC approach was applied to investigate the effect of SA and non-controlled asthma (NC) on QoL and behavioural disorders. Logistic regression was used to estimate probabilities of having an "abnormal/borderline" status with variation in QoL. The MIMIC model showed that the magnitude of the effect of SA and NC was larger on QoL (ß = -0.37 and ß = -0.30, respectively) than on behavioural problems (ß = 0.27). With regards to the probability of having a borderline status, in MA a QoL of 1 returned a probability of 0.81, whereas in SA a QoL of 1 returned a probability of 0.89. In conclusion, SA children are highly affected by impaired QoL and behavioural problems. The MIMIC model allowed us to obtain a comprehensive assessment of QoL and behavioural problems with asthma severity and control.

Exhaled biomarkers in childhood asthma: old and new approaches.

BACKGROUND: Asthma is a chronic condition usually characterized by underlying inflammation. The study of asthmatic inflammation is of the utmost importance for both diagnostic and monitoring purposes. The gold standard for investigating airway inflammation is bronchoscopy, with bronchoalveolar lavage and bronchial biopsy, but the invasiveness of such procedures limits their use in children. For this reason, in the last decades there has been a growing interest for the development of noninvasive methods. MAIN BODY: In the present review, we describe the most important non-invasive methods for the study of airway inflammation in children, focusing on the measure of the fractional exhaled nitric oxide (feNO), on the measure of the exhaled breath temperature (EBT) and on the analysis of both exhaled breath condensate (EBC) and exhaled air (Volatile Organic Compounds, VOCs), using targeted and untargeted approaches. We summarize what is currently known on the topic of exhaled biomarkers in childhood asthma, with a special emphasis on emerging approaches, underlining the role of exhaled biomarkers in the diagnosis, management and treatment of asthma, and their potential for the development of personalized treatments. CONCLUSION: Among non-invasive methods to study asthma, exhaled breath analysis remains one of the most interesting approaches, feNO and "-omic" sciences seem promising for the purpose of characterizing biomarkers of this disease.

Accessory-lobed accessory cardiac bronchus: Presentation and treatment in a pediatric patient.

Accessory cardiac bronchus (ACB) is a supernumerary bronchus usually arising from right main or intermediate bronchus. We report the case of a 9-year-old male who presented a 6-month history characterized by two right pneumonia episodes followed by persistent productive cough, recurrent bloody sputum, and chest x-ray persistence of a segmental thickening of right inferior lobe. Bronchoscopy revealed no abnormalities. Computed tomography documented an accessory-lobed ACB originating from right lower brochus. Surgical removal of ACB and related parenchyma was approached thoracoscopically and converted to thoracotomy for evidence of a bronchial injury. Two-year follow-up showed no recurrent infections or respiratory symptoms.

Chronic lung disease of prematurity: long-term respiratory outcome.

Chronic respiratory morbidity is a common adverse outcome of preterm birth, especially in infants who develop bronchopulmonary dysplasia (BPD), which is still a major cause of long-term lung dysfunction with a heavy burden on health care services and medical resources throughout childhood. The most severely affected patients remain symptomatic even in adulthood, and this may be influenced also by environmental variables (e.g. smoking), which can contribute to persistent obstruction of airflow. Of all obstructive lung diseases in humans, BPD has the earliest onset and probably lasts the longest. Since the prevention of BPD is an elusive goal, minimizing neonatal lung injury and closely monitoring survivors remain the best courses of action. This review describes the clinical and functional changes characteristic of the long-term pulmonary sequelae of preterm birth, focusing particularly on BPD.