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.

Mid-childhood lung function in a cohort of children with "new bronchopulmonary dysplasia".

OBJECTIVE: Recent advances in perinatal care and neonatal respiratory therapy have led to a new phenotype of bronchopulmonary dysplasia ("new BPD"). The long-term respiratory outcome of this new form of BPD has yet to be adequately described. Aim of this study was to provide longitudinal data on lung function of an unselected cohort of children born extremely premature (EP) with an extremely low birth weight in the post-surfactant era. STUDY DESIGN: Respiratory function was assessed twice (at 8 and 12 years) in 48 children born at a gestational age <28 weeks with a birth weight <1,000 g. Twenty-eight of them had BPD (oxygen-dependency at 36 weeks postmenstrual age) (EP-BPD), and 20 not (EP non-BPD). Twenty-seven children born at term served as control group. RESULTS: The EP-BPD group had significantly lower spirometric values (given as z-scores) than controls, especially in parameters indicating airflow obstruction (8 ys: zFEV1:-1.3 ± 1 vs. 0.5 ± 0.8; 12 ys:-1.6 ± 1 vs. 0.5 ± 0.8, P < 0.001). Despite their better spirometric profile, EP-non-BPD children also had significantly lower parameters than controls (8ys: zFEV1:-0.5 ± 0.8; 12 ys:-0.5 ± 0.9, P < 0.001). During the 4-year follow-up, EP-non-BPD and controls had stable mean z-scores, but EP-BPD had a significant decline in mean zFEV1 (from -1.3 ± 1 to -1.6 ± 1, P = 0.03), zFEV1/FVC (from -0.4 ± 1 to -1.1 ± 1, P = 0.008), and zFEF 25-75% (from -1.2 ± 1 to -1.8 ± 1, P = 0.03). CONCLUSION: EP children born in the post-surfactant era showed a significant airflow limitation, particularly pronounced in BPD subjects who in addition, presented an abnormal airway growth trajectory with a decline in lung function between the ages of 8 and 12 years. Pediatr Pulmonol. 2016;51:1057-1064. © 2016 Wiley Periodicals, Inc.

Severe asthma features in children: a case-control online survey.

BACKGROUND: Very few studies have explored the distinguishing features of severe asthma in childhood in Europe, and only one study was conducted in Southern Europe. The aim of this study was to provide a detailed characterization of children with severe asthma treated in specialized pediatric asthma centers across Italy. METHODS: We conducted a web-based data collection of family, environmental, clinical and laboratory characteristics of 41 patients aged 6-17 years with severe asthma, defined according to the recent guidelines of the European Respiratory Society and the American Thoracic Society, and 78 age-matched peers with non-severe persistent asthma. The patients have been enrolled from 16 hospital-based pediatric pulmonology and allergy centers in Northern, Central, and Southern Italy. Logistic regression analysis assessed the relationship between patients' characteristics and severe asthma or non-severe persistent asthma. RESULTS: Features independently and significantly associated with severe asthma included lifetime sensitization to food allergens [Odds ratio (OR), 4.73; 95 % Confidence Interval (CI), 1.21-18.53; p = 0.03], lifetime hospitalization for asthma (OR, 3.71; 95 % CI, 1.11-12.33; p = 0.03), emergency-department visits for asthma during the past year (OR = 11.98; 95 % CI, 2.70-53.11; p = 0.001), and symptoms triggered by physical activity (OR = 12.78; 95 % CI, 2.66-61.40; p = 0.001). Quality-of-life score was worse in patients with severe asthma than in subjects with non-severe persistent asthma (5.9 versus 6.6, p = 0.005). Self-perception of wellbeing was compromised in more than 40 % of patients in both groups. Children with severe asthma had lower spirometric z scores than non-severe asthmatic peers (all p < 0.001), although 56 % of them had a normal forced expiratory volume in 1 s. No differences were found between the two groups for parental education, home environment, patients' comorbidities, adherence to therapy, exhaled nitric oxide values, and serum eosinophils and IgE . CONCLUSIONS: As expected, children with severe asthma had more severe clinical course and worse lung function than peers with non-severe persistent asthma. Unlike previous reports, we found greater sensitization to food allergens and similar environmental and personal characteristics in patients with severe asthma compared to those with non-severe persistent asthma. Psychological aspects are compromised in a large number of cases and deserve further investigation.

Immunotherapy for food allergies in children.

Food allergy is an increasingly prevalent problem all over the world and especially in westernized countries, and there is an unmet medical need for an effective form of therapy. During childhood natural tolerance development is frequent, but some children with cow's milk or hen's egg allergy and the majority of children with peanut allergy will remain allergic until adulthood, limiting not only the diet of patients but also their quality of life. Within the last several years, the usefulness of immunotherapy for food allergies has been investigated in food allergic patients. Several food immunotherapies are being developed; these involve oral, sublingual, epicutaneous, or subcutaneous administration of small amounts of native or modified allergens to induce immune tolerance. The approach generally follows the same principles as immunotherapy of other allergic disorders and involves administering small increasing doses of food during an induction phase followed by a maintenance phase with regular intake of a maximum tolerated amount of food. Oral immunotherapy seems to be a promising approach for food allergic patients based on results from small uncontrolled and controlled studies. Diet containing heated milk and egg may represent an alternative approach to oral immunomodulation for cow's milk and egg allergic subjects. However, oral food immunotherapy remains an investigational treatment to be further studied before advancing into clinical practice. Additional bigger, multicentric and hopefully randomized-controlled studies must answer multiple questions including optimal dose, ideal duration of immunotherapy, degree of protection, efficacy for different ages, severity and type of food allergy responsive to treatment.

Asymmetric dimethylarginine in exhaled breath condensate and serum of children with asthma.

BACKGROUND: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor and uncoupler of nitric oxide synthase. By promoting the formation of peroxynitrite, ADMA is believed to contribute to several aspects of asthma pathogenesis (ie, airway inflammation, oxidative stress, bronchial hyperresponsiveness, and collagen deposition). The aim of the present study was to compare this mediator in healthy children and children with asthma using the completely noninvasive exhaled breath condensate (EBC) technique. METHODS: We recruited 77 children with asthma (5-16 years of age) and 65 healthy children (5-15 years of age) who underwent EBC collection and spirometry. Serum ADMA levels and fractional exhaled nitric oxide levels were measured on the same day in a subgroup of children with asthma. EBC was collected using the Turbo-Deccs (Medivac). ADMA levels were measured using the ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique. RESULTS: ADMA could be detected in the EBC of 71 subjects with asthma and 64 healthy subjects. ADMA levels in the EBC of children with asthma were significantly higher than in the healthy control subjects (median, 0.12 [interquartile range, 0.05-0.3] vs 0.07 [0.05-0.12]; P = .017), whereas no difference emerged between the children with asthma who were or were not receiving inhaled steroid treatment. No correlation was found between serum and EBC ADMA levels (P > .5). CONCLUSIONS: We measured ADMA in EBC by UPLC-MS/MS, a reference analytical technique. Higher ADMA levels were found in children with asthma, supporting a role for this mediator in asthma pathogenesis. This oxidative stress-related mediator also seems to be scarcely affected by steroid therapy. We speculate that ADMA might be a target for new therapeutic strategies designed to control oxidative stress in asthma.