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Recent clinical trials of as-needed fixed-dose combination of inhaled corticosteroid (ICS)/formoterol have provided new evidence that may warrant a reconsideration of current practice. A Task Force was set up by the European Respiratory Society to provide evidence-based recommendations on the use of as-needed ICS/formoterol as treatment for mild asthma. The Task Force defined two questions that were assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. The Task Force utilised the outcomes to develop recommendations for a pragmatic guideline for everyday clinical practice. The Task Force suggests that adults with mild asthma use as-needed ICS/formoterol instead of regular ICS maintenance treatment plus as-needed short-acting β 2 -antagonist (SABA) and that adolescents with mild asthma use either as-needed ICS/formoterol or ICS maintenance treatment plus as-needed SABA (conditional recommendation; low certainty of evidence). The recommendation for adults places a relatively higher value on the reduction of systemic corticosteroid use and the outcomes related to exacerbations, and a relatively lower value on the small differences in asthma control. Either treatment option is suggested for adolescent patients as the balance is very close and data more limited. The Task Force recommends that adult and adolescent patients with mild asthma use as-needed ICS/formoterol instead of as-needed SABA (strong recommendation; low certainty of evidence). This recommendation is based on the benefit of as-needed ICS/formoterol in mild asthma on several outcomes and the risks related to as-needed SABA in the absence of anti-inflammatory treatment. The implementation of this recommendation is hampered in countries (including European Union countries) where as-needed ICS/formoterol is not approved for mild asthma., Competing Interests: Conflict of interest: A. Papi reports grants from Chiesi, AstraZeneca, GSK, Sanofi and Agenzia Italiana del Farmaco (AIFA), consulting fees from Chiesi, AstraZeneca, GSK, Novartis, Sanofi, Avillion and Elpen Pharmaceutica, lecture honoraria from Chiesi, AstraZeneca, GSK, Menarini, Novartis, Zambon, Munidpharma, Sanofi, Edmond Pharma, IQVIA, Avillion and Elpen Pharmaceuticals, and advisory board participation with Chiesi, AstraZeneca, GSK, MSD, Novartis, Sanofi, IQVIA, Avillion and Elpen Pharmaceuticals, outside the submitted work. I. Agache reports lecture honoraria from Stallergennes, Pfizer and Sanofi, and advisory board participation with Pfizer, outside the submitted work. E. Baraldi reports lecture honoraria from AstraZeneca and Sanofi, outside the submitted work. R. Beasley reports grants from AstraZeneca, Genentech and Health Research Council New Zealand, consulting fees, lecture honoraria, travel support and advisory board participation with AstraZeneca, Cipla, Avillion, Health Research Council New Zealand, CSL Seqirus and Teva, outside the submitted work; R. Beasley is also chair of the Asthma and Respiratory Foundation NZ adolescent and adult asthma guidelines, member of the GOLD Board, and consultant for GINA. G. Brusselle reports lecture honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Merck, Sharp & Dohme and Sanofi, outside the submitted work. C. Coleman is an employee of the European Lung Foundation. M. Gaga reports a role as Alternate Minister of Health, Greece, outside the submitted work. E. Melén has received consulting fees from ALK, AstraZeneca, Chiesi, Novartis and Sanofi, outside the submitted work. I.D. Pavord reports speaker fees from Aerocrine AB, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Inc., Sanofi and Teva, consultant fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Inc., Sanofi, Teva, Circassia, Dey Pharma, Genentech, Knopp Biosciences, Merck, MSD, Napp Pharmaceuticals, RespiVert and Schering-Plough, payments for organisation of educational events from AstraZeneca, GSK, Regeneron Pharmaceuticals, Inc., Sanofi and Teva, international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Regeneron Pharmaceuticals, Inc., Sanofi, Teva and Napp Pharmaceuticals, and research grants from Chiesi, outside the submitted work. D. Peñate Gómez works as PMO Analyst at Asthma and Lung UK. A. Spanevello reports lecture honoraria, travel support and advisory board participation with Chiesi, AstraZeneca and GSK, outside the submitted work. T. Tonia acts as ERS methodologist. F. Schleich reports grants from GSK, AstraZeneca and Chiesi, lecture honoraria from GSK, AstraZeneca, Chiesi and Teva, and advisory board participation with GSK and AstraZeneca, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

There is growing evidence in medical literature to support an association between early-life respiratory syncytial virus lower respiratory tract-lower respiratory tract infection (RSV-LRTI) and recurrent wheezing/asthma-like symptoms. It has been estimated that children with a history of RSV-LRTI have a 2- to 12-fold higher risk of developing asthma. The connection between RSV infection and a developmental trajectory of reduced lung function remains throughout adolescence and early adulthood, suggesting a possible role for RSV even in the inception of chronic obstructive pulmonary disease. That is why the postnatal period appears to offer a specific window of opportunity for early intervention to prevent chronic obstructive lung diseases. The mechanisms by which RSV contributes to the onset of wheezing/asthma and lung function impairment are not fully understood but appear to relate to injury caused directly by the virus and/or to pre-existing predisposing factors. While awaiting a deeper understanding of the association between RSV and chronic lung diseases, the crucial role of pediatricians and physicians is to develop strategies to prevent RSV infections to try and protect children's lifelong respiratory health. KEY POINTS: · Several evidence suggest a link between RSV infection in early life and wheezing/asthma development.. · RSV infection appears to have long term respiratory effects.. · The prevention of RSV infections could reduce the incidence of chronic obstructive respiratory diseases.., Competing Interests: None declared., (Thieme. All rights reserved.)

Chronic obstructive respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD) have their roots in the womb. Together with a genetic predisposition, prenatal and early-life factors, including maternal smoking, prematurity, and bronchopulmonary dysplasia (BPD), have a pivotal role in later respiratory health. Then, inappropriate responses to respiratory viruses (especially respiratory syncytial virus and rhinovirus) and early allergic sensitization are the strongest contributors to the inception of wheezing and early-onset asthma. There is an urgent need for early disease biomarkers to identify profiles at higher risk of chronic respiratory conditions. Applying the "-omic" technologies to urine, blood and breath condensate, and non-invasive inflammometry seem promising in this regard. The description of specific risk profiles may be the key to the use of targeted personalized therapies., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Introduction: The association between respiratory syncytial virus (RSV) infections and long-term respiratory sequelae has long been recognized. It is estimated that individuals with a history of RSV bronchiolitis have 2- to 12-fold higher risk of developing asthma. Although this risk tends to decrease with age, persistent airway obstruction and hyperresponsiveness are observed even 30 years after RSV infection., Evidence Acquisition: Our data search strategy was designed to address the following questions: What is the epidemiological evidence available on the association between RSV infection and long-term respiratory morbidity? What are the potential pathogenic pathways linking RSV infection to long-term respiratory morbidity? Are there any host genetic backgrounds that can predispose to both severe RSV lower respiratory tract infection and asthma? Are antiviral therapies and RSV prevention measures effective in reducing respiratory morbidities?, Evidence Synthesis: This article reviews the recent scientific literature on the epidemiological association and pathogenic links between early RSV infection and long-term respiratory morbidities., Conclusions: Nowadays, asthma is increasingly considered a heterogeneous disease, caused by interactions between several host and environmental factors. Understanding the specific causative role of respiratory viruses, and the pathogenic mechanisms through which bronchiolitis predisposes to asthma, is a challenging, but essential starting point for the development of prevention and treatment strategies potentially capable of preserving lung function.

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., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

The diagnosis of asthma is currently based on clinical history, physical examination and lung function, and to date, there are no accurate objective tests either to confirm the diagnosis or to discriminate between different types of asthma. This consensus exercise reviews the state of the art in asthma diagnosis to identify opportunities for future investment based on the likelihood of their successful development, potential for widespread adoption and their perceived impact on asthma patients. Using a two-stage e-Delphi process and a summarizing workshop, a group of European asthma experts including health professionals, researchers, people with asthma and industry representatives ranked the potential impact of research investment in each technique or tool for asthma diagnosis and monitoring. After a systematic review of the literature, 21 statements were extracted and were subject of the two-stage Delphi process. Eleven statements were scored 3 or more and were further discussed and ranked in a face-to-face workshop. The three most important diagnostic/predictive tools ranked were as follows: "New biological markers of asthma (eg genomics, proteomics and metabolomics) as a tool for diagnosis and/or monitoring," "Prediction of future asthma in preschool children with reasonable accuracy" and "Tools to measure volatile organic compounds (VOCs) in exhaled breath.", (© 2018 John Wiley & Sons Ltd.)

Background: Isocyanate-induced asthmatic reactions are associated with delayed increase in fractional exhaled nitric oxide measured at expiratory flow of 50 mL/s (FeNO50), a biomarker of airway inflammation. The time course of FeNO increase is compatible with the activation of NO synthase, but the origin of NO production in the lung is undetermined., Objective: The aim of this study was to define the dynamics of airway and alveolar NO during specific inhalation challenge (SIC) with isocyanates and the role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase., Methods: Spirometry, exhaled NO parameters (FeNO50, bronchial wall NO concentration, NO airway diffusing capacity, NO flux to luminal space, alveolar NO) and ADMA levels in exhaled breath condensate were measured before and at intervals up to 24 h after exposure to isocyanates. The results were compared between 17 SIC-positive and eight SIC-negative subjects., Results: A significant FeNO50 increase in SIC-positive subjects was detected 24 h after exposure and was associated with the augmented NO flux from airway wall to the lumen, whereas airway NO diffusion and alveolar NO were not affected. The changes in NO dynamics were specific for the subjects who developed an asthmatic reaction, but were independent from the pattern and magnitude of bronchoconstriction. There was no evidence that exhaled NO is modulated by the changes in ADMA concentration., Conclusions and Clinical Relevance: Because isocyanate-induced increase in FeNO50 was almost exclusively determined by the increase in NO flux, the use of FeNO50 appears adequate to monitor the exhaled NO dynamics during SIC. FeNO50 measurement may provide additional information to spirometry, because bronchoconstriction and airway inflammatory responses are dissociated., (© 2016 John Wiley & Sons Ltd.)

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., (© 2016 Asian Pacific Society of Respirology.)

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.

Background: The main aim of this study was to evaluate Streptococcus pneumoniae carriage in a group of school-aged children and adolescents with asthma because these results might indicate the theoretical risk of invasive pneumococcal disease (IPD) of such patients and the potential protective efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13)., Methods: Oropharyngeal samples were obtained from 423 children with documented asthma (300 males, 70.9%), and tested for the autolysin-A-encoding (lytA) and the wzg (cpsA) gene of S. pneumoniae by means of real-time polymerase chain reaction., Results: S. pneumoniae was identified in the swabs of 192 subjects (45.4%): 48.4% of whom were aged <10 years, 46.9% aged 10-14 years, and 4.7% aged ≥15 years (p < 0.001). Carriage was significantly less frequent among the children who had received recent antibiotic therapy (odds ratio [OR 0.41]; 95% confidence interval [95% CI] 0.22-0.76). Multivariate analyses showed no association between carriage and vaccination status, with ORs of 1.05 (95% CI 0.70-1.58) for carriers of any pneumococcal serotype, 1.08 (95% CI 0.72-1.62) for carriers of any of the serotypes included in 7-valent pneumococcal conjugate vaccine (PCV7), and 0.76 (95% CI 0.45-1.28) for carriers of any of the six additional serotypes of PCV13. Serotypes 19 F, 4 and 9 V were the most frequently identified serotypes in vaccinated subjects., Conclusions: These results showed that carriage of S. pneumoniae is relatively common in all school-aged children and adolescents with asthma, regardless of the severity of disease and the administration of PCV7 in the first years of life. This highlights the problem of the duration of the protection against colonisation provided by pneumococcal conjugate vaccine, and the importance of re-colonization by the same pneumococcal serotypes included in the previously used vaccine.

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., (Copyright © 2015. Published by Elsevier Ltd.)

This review focuses on the methods available for measuring reversible airways obstruction, bronchial hyperresponsiveness (BHR) and inflammation as hallmarks of asthma, and their role in monitoring children with asthma. Persistent bronchial obstruction may occur in asymptomatic children and is considered a risk factor for severe asthma episodes and is associated with poor asthma outcome. Annual measurement of forced expiratory volume in 1 s using office based spirometry is considered useful. Other lung function measurements including the assessment of BHR may be reserved for children with possible exercise limitations, poor symptom perception and those not responding to their current treatment or with atypical asthma symptoms, and performed on a higher specialty level. To date, for most methods of measuring lung function there are no proper randomised controlled or large longitudinal studies available to establish their role in asthma management in children. Noninvasive biomarkers for monitoring inflammation in children are available, for example the measurement of exhaled nitric oxide fraction, and the assessment of induced sputum cytology or inflammatory mediators in the exhaled breath condensate. However, their role and usefulness in routine clinical practice to monitor and guide therapy remains unclear, and therefore, their use should be reserved for selected cases., (Copyright ©ERS 2015.)

The goal of asthma treatment is to obtain clinical control and reduce future risks to the patient. To reach this goal in children with asthma, ongoing monitoring is essential. While all components of asthma, such as symptoms, lung function, bronchial hyperresponsiveness and inflammation, may exist in various combinations in different individuals, to date there is limited evidence on how to integrate these for optimal monitoring of children with asthma. The aims of this ERS Task Force were to describe the current practise and give an overview of the best available evidence on how to monitor children with asthma. 22 clinical and research experts reviewed the literature. A modified Delphi method and four Task Force meetings were used to reach a consensus. This statement summarises the literature on monitoring children with asthma. Available tools for monitoring children with asthma, such as clinical tools, lung function, bronchial responsiveness and inflammatory markers, are described as are the ways in which they may be used in children with asthma. Management-related issues, comorbidities and environmental factors are summarised. Despite considerable interest in monitoring asthma in children, for many aspects of monitoring asthma in children there is a substantial lack of evidence., (Copyright ©ERS 2015.)

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.

Chronic obstructive respiratory disorders such as asthma and chronic obstructive pulmonary disease often originate early in life. In addition to a genetic predisposition, prenatal and early-life environmental exposures have a persistent impact on respiratory health. Acting during a critical phase of lung development, these factors may change lung structure and metabolism, and may induce maladaptive responses to harmful agents, which will affect the whole lifespan. Some environmental factors, such as exposure to cigarette smoke, type of childbirth and diet, may be modifiable, but it is more difficult to influence other factors, such as preterm birth and early exposure to viruses or allergens. Here, we bring together recent literature to analyse the critical aspects involved in the early stages of lung development, going back to prenatal and perinatal events, and we discuss the mechanisms by which noxious factors encountered early on may have a lifelong impact on respiratory health. We briefly comment on the need for early disease biomarkers and on the possible role of "-omic" technologies in identifying risk profiles predictive of chronic respiratory conditions. Such profiles could guide the ideation of effective preventive strategies and/or targeted early lifestyle or therapeutic interventions., (©ERS 2014.)

There is limited information on which data primary care pediatricians (PCPs) use to decide whether to prescribe or not asthma maintenance treatment, and what drives prescribing a specific therapy. The study aim was to investigate how prescribing anti-asthma maintenance treatment to preschool wheezing children is influenced by patient, family, environmental, and PCP characteristics. We conducted a cross-sectional study at 32 PCPs sites in Campania, Italy. Medical, family, and environmental information of 376 preschool wheezy children, and characteristics of the enrolled PCPs were collected. Main outcome measures of multilevel multivariate logistic regression analyses were the prescribing of maintenance treatment, and the prescription of a combined therapy as opposed to monotherapy. Variables significantly associated with long-term inhaled corticosteroids (ICS) and/or leukotriene modifiers prescription included frequent wheezing (OR = 7.19), emergency department (ED) visits (OR = 2.21), personal allergic diseases (OR = 8.49), day-care/kindergarten attendance (OR = 2.67), a high PCP prescribing volume (OR = 2.74), and a low proportion of 0- to 5-year-old patients with wheezing diagnosis (OR = 1.16). Leukotriene modifiers plus ICS were much more likely prescribed than ICS or leukotriene modifiers alone to older children (OR = 1.06) and to patients experiencing frequent wheezing (OR = 3.00), ED visits (OR = 3.12), or tobacco smoke exposure during the first 2 years of life (OR = 2.04). Finally, PCP's characteristics significantly associated with ICS plus leukotriene modifiers prescription were group practice (OR = 4.16) and a high prescribing volume (OR = 1.45). Our findings suggest that child characteristics alone are not sufficient to explain how PCPs decide to prescribe maintenance treatment and which therapy to assign, but variables associated to PCPs are crucial as well., (© 2013 Wiley Periodicals, Inc.)

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 &gt; .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.

Background: Asthma is a heterogeneous disease and its different phenotypes need to be better characterized from a biochemical-inflammatory standpoint. This study aimed to apply the metabolomic approach to exhaled breath condensate (breathomics) to discriminate different asthma phenotypes, with a particular focus on severe asthma in children., Methods: In this cross-sectional study, we recruited 42 asthmatic children (age, 8-17 years): 31 with nonsevere asthma (treated with inhaled steroids or not) and 11 with severe asthma. Fifteen healthy children were enrolled as controls. Children performed exhaled nitric oxide measurement, spirometry, exhaled breath condensate (EBC) collection. Condensate samples were analyzed using a metabolomic approach based on mass spectrometry., Results: A robust Bidirectional-Orthogonal Projections to Latent Structures-Discriminant Analysis (O2PLS-DA) model was found for discriminating both between severe asthma cases and healthy controls (R(2)  = 0.93; Q(2)  = 0.75) and between severe asthma and nonsevere asthma (R(2)  = 0.84; Q(2)  = 0.47). The metabolomic data analysis leads to a robust model also when the 3 groups of children were considered altogether (K = 0.80), indicating that each group is characterized by a specific metabolomic profile. Compounds related to retinoic acid, adenosine and vitamin D (Human Metabolome Database) were relevant for the discrimination between groups., Conclusion: The metabolomic profiling of EBC could clearly distinguish different biochemical-metabolic profiles in asthmatic children and enabled the severe asthma phenotype to be fully discriminated. The breathomics approach may therefore be suitable for discriminating between different asthma metabolic phenotypes., (© 2012 John Wiley & Sons A/S.)

Background: Exhaled breath condensate (EBC) is a biofluid collected non invasively that, enabling the measurement of several biomarkers, has proven useful in the study of airway inflammatory diseases, including asthma, COPD and cystic fibrosis. To the best of our knowledge, there is no previous report of any analytical method to detect ADMA in EBC., Objectives: Aim of this work was to develop an online sample trapping and enrichment system, coupled with an UPLC-MS/MS method, for simultaneous quantification of seven metabolites related to "Arginine-ADMA cycle", using the isotopic dilution., Methods: Butylated EBC samples were trapped in an online cartridge, washed before and after each injection with cleanup solution to remove matrix components and switched inline into the high pressure analytical column. Multiple reaction monitoring in positive mode was used for analyte quantification by tandem mass spectrometry., Results: Validation studies were performed in EBC to examine accuracy, precision and robustness of the method. For each compound, the calibration curves showed a coefficient of correlation (r(2)) greater than 0.992. Accuracy (%Bias) was <3% except for NMMA and H-Arg (<20%), intra- and inter-assay precision (expressed as CV%) were within ±20% and recovery ranged from 97.1 to 102.8% for all analytes. Inter-day variability analysis on 20 EBC of adult subjects did not demonstrate any significant variation of quantitative data for each metabolite. ADMA and SDMA mean concentrations (μmolL(-1)), measured in EBC samples of asthmatic adolescents are significantly increased (p<0.0001) than in normal controls (0.0040±0.0021 vs. 0.0012±0.0005 and 0.0020±0.0015 vs. 0.0002±0.0001, respectively), as well the ADMA/Tyr (0.34±0.09 vs. 0.12±0.02, p<0.0001) and the SDMA/Tyr ratio (0.10±0.04 vs. 0.015±0.004, p<0.0001)., Conclusions: The proposed method features simple specimen preparation, maintenance of an excellent peak shape of all metabolites and reduced matrix effects as well mass spectrometer noise. Moreover, the possibility to perform different cycles of enrichment, using large injection volumes, compensated for the low concentration of analytes contained in EBC, leading to a good analytical sensitivity. Preliminary data obtained from asthmatic and healthy adolescents, demonstrated that the analytical method applied to EBC seems suitable not only for research purposes, but also for clinical routinely analysis., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re-evaluate and fine-tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype-specific treatment choices; however, this goal has not yet been achieved., (© 2012 John Wiley & Sons A/S.)

Background: Fractional exhaled Nitric Oxide (FeNO) is a biomarker for eosinophilic airway inflammation and can be measured at home on a daily basis. A short-term increase in FeNO may indicate a higher risk of future asthma exacerbations., Objective: To assess changes in FeNO before and after asthma exacerbations compared to a stable control period., Methods: A post hoc analysis was performed on daily FeNO measurements over 30 weeks in children with asthma (n = 77). Moderate exacerbations were defined by an increase in symptom scores and severe exacerbations by prescription of prednisone. Individual mean and maximum FeNO, the variability of FeNO assessed by the coefficient of variation (CV), and slopes of FeNO in time were all quantified in 3-week blocks. Cross-correlation of FeNO with symptoms and autocorrelation of FeNO were assessed in relation to exacerbations and examined as predictors for exacerbations compared to reference periods using logistic regression., Results: Fractional exhaled nitric oxide could be assessed in relation to 25 moderate and 12 severe exacerbations. The CV, slope, cross-correlation, and autocorrelation of daily FeNO increased before moderate exacerbations. Increases in slope were also randomly seen in 19% of 2-week blocks of children without exacerbations. At least 3-5 FeNO measurements in the 3 weeks before an exacerbation were needed to calculate a slope that could predict moderate exacerbations. No specific pattern of FeNO was seen before severe exacerbations., Conclusion: Fractional exhaled nitric oxide monitoring revealed changes in FeNO prior to moderate exacerbations. Whether this can be used to prevent loss of asthma control should be further explored., (© 2011 John Wiley & Sons A/S.)

The recent discovery that every tissue in the human body has vitamin D receptors and that vitamin D has pleiotropic effects has prompted an increased interest in this hormone. Vitamin D deficiency is widespread and on the increase. There is no consensus on the serum vitamin D levels to consider appropriate for global health, the cutoffs for its deficiency, or the doses to use for its supplementation. Vitamin D seems to correlate closely with host reactions against various respiratory infections. Epidemiological studies have shown that low serum 25-hydroxyvitamin D levels are associated with a higher risk of upper and lower respiratory infections in children and a shortage of vitamin D may contribute to asthmatic patients' symptoms and morbidity rates. There are studies highlighting associations between childhood asthma, fetal lung and/or immune development, and maternal vitamin D intake. An insufficiency of this vitamin also seems to be implicated in the onset of childhood atopy and food allergies. The hypothesis is that vitamin D could have a central role in these pathological situations and that it may represent a novel preventive and/or therapeutic strategy. This article reviews and discusses published data on the relationship between vitamin D and asthma and allergy, emphasizing the need for controlled, prospective studies on vitamin D supplementation to clarify whether it has a role in the prevention of and treatment for asthma and allergic conditions., (© 2011 John Wiley & Sons A/S.)

Asthma is a heterogeneous disorder and one of the most common chronic childhood diseases. An improved characterization of asthma phenotypes would be invaluable for the understanding of the pathogenic mechanisms and the correct treatment of this disease. The aim of this pilot study was to explore the potential of metabolomics applied to urine samples in characterizing asthma, and to identify the most representative metabolites. Urine samples of 41 atopic asthmatic children (further subdivided in sub-groups according to the symptoms) and 12 age-matched controls were analyzed. Untargeted metabolic profiles were collected by LC-MS, and studied by multivariate analysis. The group of the asthmatics was differentiated by a model that proved to be uncorrelated with the chronic assumption of controller drugs on the part of the patients. The distinct sub-groups were also appropriately modeled. Further investigations revealed a reduced excretion of urocanic acid, methyl-imidazoleacetic acid and a metabolite resembling the structure of an Ile-Pro fragment in the asthmatics. The meaning of these findings was discussed and mainly correlated with the modulation of immunity in asthma. Metabolic profiles from urines have revealed the potential to characterize asthma and enabled the identification of metabolites that may have a role in the underlying inflammation., (Copyright © 2011 John Wiley & Sons, Ltd.)

There is a lack of high-quality evidence on what treatment should be used in children with properly characterised severe, therapy-resistant asthma. Data have to be largely extrapolated from trials in children with mild asthma, and adults with severe asthma. Therapeutic options can be divided into medications used in lower doses for children with less severe asthma, and those used in other paediatric diseases but not for asthma (for example, methotrexate). In the first category are high-dose inhaled corticosteroids (ICS) (≤ 2,000 μg · day(-1) fluticasone equivalent), oral prednisolone, the anti-immunoglobulin (Ig)E antibody omalizumab, high-dose long-acting β(2)-agonists, low-dose oral theophylline and intramuscular triamcinolone. If peripheral airway inflammation is thought to be a problem, the use of fine-particle ICS or low-dose oral corticosteroids may be considered. More experimental therapies include oral macrolides, cyclosporin, cytotoxic drugs such as methotrexate and azathioprine, gold salts, intravenous infusions of Ig, subcutaneous β(2)-agonist treatment and, in those sensitised to fungi, oral antifungal therapy with itraconazole or voriconazole. Those with recurrent severe exacerbations, particularly in the context of good baseline asthma control, are particularly difficult to treat; baseline control and lung function must be optimised with the lowest possible dose of ICS, and allergen triggers and exposures minimised. The use of high-dose ICS, leukotriene receptor antagonists or both at the time of exacerbations can be considered. There is no evidence regarding which therapeutic option to recommend. Better evidence is required for all these treatment options, underscoring the need for the international and co-ordinated approach which we have previously advocated.

Background: Few data are available on the usefulness of short term treatment with low-medium dose of inhaled corticosteroids (ICS) in pre-school children with wheezing exacerbations., Methods: To compare the efficacy of one week treatment with 400 μg b.i.d. nebulized beclomethasone dipropionate (BDP), plus nebulized 2500 μg prn salbutamol (BDP group), versus nebulized b.i.d. placebo, plus nebulized prn 2500 μg salbutamol (placebo group), a post-hoc analysis was performed on data obtained in 166 pre-school children with multiple-trigger wheezing, recruited during an acute wheezing episode., Results: The percentage of symptom-free days (SFDs) was significantly higher in the BDP group (54.7%) than in the placebo group (40.5%; p = 0.012), with a 35% relative difference. Day-by-day analysis showed that the percentage of SFDs was already higher in the BDP group after 2 days (7.4%), the difference reaching statistical significance at day 6 (12.3%; p = 0.035). Cough score was also reduced in the BDP group (0.11) as compared with the placebo group (0.39; p = 0.048), the difference reaching statistical significance after 5 days of treatment (0.18 and 0.47 respectively; p = 0.047). The mean number of nebulizations per day of prn salbutamol was lower in the BDP group as compared to the placebo group (0.26 and 0.34, respectively), but the difference was not significant (p = 0.366). There were no differences in positive effects of BDP treatment between children with and without risk factors for asthma., Conclusions: A 1-week treatment with nebulized BDP and prn salbutamol is effective in increasing SFDs and improving cough in children with wheezing, providing a clinical rationale for the short term use of ICS in episodic wheeze exacerbations in pre-school children.

Background: Fraction of exhaled nitric oxide (Feno), a marker of airway inflammation, has been proposed to be useful for asthma management, but conclusions are inconsistent. This might be due to the failure of mean statistics to characterize individual variability in Feno values, which is possibly a better indicator of asthma control than single measurements., Objective: We characterized fractal fluctuations in daily Feno values over time and the relationship between Feno values and symptom scores. We investigated whether these are associated with asthma severity, control, and exacerbation risk., Methods: Daily Feno values and symptom scores over 192 days in 41 atopic asthmatic children from the Childhood Asthma Respiratory Inflammatory Status Monitoring study were analyzed. Two methods of time-series analysis were used: detrended fluctuation analysis to quantify fractal patterns in fluctuations in daily Feno values (α value) and cross-correlation to quantify the strength of the relationship between daily Feno values and symptom scores. The associations of α values and cross-correlation with markers of asthma severity and control were assessed by means of regression analysis., Results: Daily fluctuations in Feno values exhibited fractal-type long-range correlations. Those subjects receiving higher doses of inhaled corticosteroids at study entry had a significantly lower α value, corresponding to more random fluctuations in Feno values in those with greater inhaled corticosteroid need. The cross-correlation between Feno values and symptom scores was significantly higher in those subjects who had exacerbations., Conclusions: Fluctuation in Feno values and their cross-correlation to symptom scores contains information on asthma severity and control. Methods that quantify the complexity of asthma over time might assist in identifying asthmatic subjects with concordance between eosinophilic inflammation and symptoms and thus increased exacerbation risk., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Assessment of problematic severe asthma in children should be performed in a step-wise manner to ensure an optimal approach. A four-step assessment scheme is proposed. First, a full diagnostic work-up is performed to exclude other diseases which mimic asthma. Secondly, a multi-disciplinary assessment is performed to identify issues that may need attention, including comorbidities. Thirdly, the pattern of inflammation is assessed, and finally steroid responsiveness is documented. Based upon these four steps an optimal individualised treatment plan is developed. In this article the many gaps in our current knowledge in all these steps are highlighted, and recommendations for current clinical practice and future research are made. The lack of good data and the heterogeneity of problematic severe asthma still limit our ability to optimise the management on an individual basis in this small, but challenging group of patients.

Unlabelled: Asthma drugs are amongst the most frequently used drugs in childhood, but international comparisons on type and indication of use are lacking. The aim of this study was to describe asthma drug use in children with and without asthma in the Netherlands (NL), Italy (IT), and the United Kingdom (UK). We conducted a retrospective analysis of outpatient medical records of children 0-18 years from 1 January 2000 until 31 December 2005. For all children, prescription rates of asthma drugs were studied by country, age, asthma diagnosis, and off-label status. One-year prevalence rates were calculated per 100 children per patient-year (PY). The cohort consisted of 671,831 children of whom 49,442 had been diagnosed with asthma at any time during follow-up. ß2-mimetics and inhaled steroids were the most frequently prescribed asthma drug classes in NL (4.9 and 4.1/100 PY), the UK (8.7 and 5.3/100 PY) and IT (7.2 and 16.2/100 PY), respectively. Xanthines, anticholinergics, leukotriene receptor antagonists, and anti-allergics were prescribed in less than one child per 100 per year. In patients without asthma, ß2-mimetics were used most frequently. Country differences were highest for steroids, (Italy highest), and for ß2-mimetics (the UK highest). Off-label use was low, and most pronounced for ß2-mimetics in children <18 months (IT) and combined ß2-mimetics + anticholinergics in children <6 years (NL)., Conclusion: This study shows that among all asthma drugs, ß2-mimetics and inhaled steroids are most often used, also in children without asthma, and with large variability between countries. Linking multi-country databases allows us to study country specific pediatric drug use in a systematic manner without being hampered by methodological differences. This study underlines the potency of healthcare databases in rapidly providing data on pediatric drug use and possibly safety.

Asthmatic airways are characterised by enhanced oxidative stress, which can be studied by measuring biomarkers, such as 8-isoprostane. The aims of the present study were: 1) to measure the concentrations of 8-isoprostane in exhaled breath condensate (EBC) and urine of children with problematic and well-controlled asthma; 2) to compare the concentrations of 8-isoprostane measured by gas chromatographic/negative ion chemical ionisation mass spectrometry (GC/NICI-MS) and by an enzymatic immunoassay (EIA). We recruited 20 asthmatic allergic children, 13 with well-controlled asthma and seven with problematic asthma. They underwent exhaled nitric oxide measurements and spirometry, and both EBC and urine samples were collected. 8-isoprostane was measured in EBC by GC/NICI-MS and EIA. 8-isoprostane concentrations in EBC were significantly higher in children with problematic asthma than in children with well-controlled asthma (p = 0.01). An acceptable reproducibility emerged between GC/NICI-MS and EIA (coefficient of reproducibility 11.5 pg x mL(-1)). 8-isoprostane levels measured in urine did not correlate with those measured in EBC. We showed that 8-isoprostane in EBC was significantly increased in children with problematic asthma, suggesting a role for oxidative stress in this asthma phenotype. In addition we found an acceptable reproducibility of EIA compared to GC/NICI-MS, even if the latter method had higher accuracy.

Background: The Childhood Asthma Control Test (C-ACT) has been proposed as a tool in assessing the level of disease control in asthmatic children. To evaluate the position of C-ACT in the clinical management of asthmatic children, in relationship to the level of airway inflammation as assessed by fractional exhaled nitric oxide (FeNO) and with lung function., Methods: A total of 200 asthmatic children were included in the study: 47 children with newly diagnosed asthma ('New') and without any regular controller therapy; and 153 children with previously diagnosed asthma, treated according to GINA guidelines, and evaluated during a scheduled follow-up visit ('Follow-up'). Childhood Asthma Control Test, FeNO and lung function [forced expiratory volume 1 (FEV1) and forced vital capacity (FVC)] were evaluated., Results: In New vs Follow-up participants, C-ACT score (P < 0.001), FVC (P < 0.005) and FEV1 (P < 0.05) were significantly lower, and FeNO (P = 0.011) were significantly higher. In New, but not in Follow-up participants, significant correlations were observed between C-ACT score and FeNO (r = -0.51; P < 0.001), FEV1 (r = 0.34; P = 0.022) and FEV1/FVC (r = 0.32; P = 0.03). This lack of correlation in Follow-up visits seemed attributable to dissociation between inadequately controlled asthma by C-ACT ratings with normalization of other measures such as FeNO levels., Conclusions: This study confirms and expands the concept that C-ACT is complementary to, but not a substitute for, other markers of disease control in asthmatic children, especially in the context of follow-up visits.

Background: International guidelines recommend regular treatment with inhaled glucocorticoids for children with frequent wheezing; however, prn inhaled bronchodilator alone or in combination with glucocorticoid is also often used in practice. We aimed to evaluate whether regular nebulized glucocorticoid plus a prn bronchodilator or a prn nebulized bronchodilator/glucocorticoid combination is more effective than prn bronchodilator alone in preschool children with frequent wheeze., Methods: Double-blind, double-dummy, randomized, parallel-group trial. After a 2-week run-in period, 276 symptomatic children with frequent wheeze, aged 1-4 years, were randomly assigned to three groups for a 3-month nebulized treatment: (1) 400 microg beclomethasone bid plus 2500 microg salbutamol prn; (2) placebo bid plus 800 microg beclomethasone/1600 microg salbutamol combination prn; (3) placebo bid plus 2500 microg salbutamol prn. The percentage of symptom-free days was the primary outcome measure. Secondary outcomes included symptom scores, use of relief medication and exacerbation frequency., Results: As compared with prn salbutamol (61.0 +/- 24.83 [SD]), the percentage of symptom-free days was higher with regular beclomethasone (69.6%, SD 20.89; P = 0.034) but not with prn combination (64.9%, SD 24.74). Results were no different in children with or without risk factors for developing persistent asthma. The effect of prn combination was no different from that of regular beclomethasone on the primary and on several important secondary outcomes., Conclusions: Regular inhaled glucocorticoid is the most effective treatment for frequent wheezing in preschool children. However, prn bronchodilator/glucocorticoid combination might be an alternative option, but it requires further study.

Objectives: Recent studies have explored the potential for swimming pool disinfection by-products (DBPs), which are respiratory irritants, to cause asthma in young children. Here we describe the state of the science on methods for understanding children's exposure to DBPs and biologics at swimming pools and associations with new-onset childhood asthma and recommend a research agenda to improve our understanding of this issue., Data Sources: A workshop was held in Leuven, Belgium, 21-23 August 2007, to evaluate the literature and to develop a research agenda to better understand children's exposures in the swimming pool environment and their potential associations with new-onset asthma. Participants, including clinicians, epidemiologists, exposure scientists, pool operations experts, and chemists, reviewed the literature, prepared background summaries, and held extensive discussions on the relevant published studies, knowledge of asthma characterization and exposures at swimming pools, and epidemiologic study designs., Synthesis: Childhood swimming and new-onset childhood asthma have clear implications for public health. If attendance at indoor pools increases risk of childhood asthma, then concerns are warranted and action is necessary. If there is no such relationship, these concerns could unnecessarily deter children from indoor swimming and/or compromise water disinfection., Conclusions: Current evidence of an association between childhood swimming and new-onset asthma is suggestive but not conclusive. Important data gaps need to be filled, particularly in exposure assessment and characterization of asthma in the very young. Participants recommended that additional evaluations using a multidisciplinary approach are needed to determine whether a clear association exists.

Rationale: Asthma treatment might improve when inhaled steroids are titrated on airway inflammation. Fractional exhaled nitric oxide (FeNO0.05), a marker of eosinophilic airway inflammation, can be measured at home., Objectives: We assessed daily FeNO0.05 telemonitoring in the management of childhood asthma., Methods: Children with atopic asthma (n = 151) were randomly assigned to two groups: FeNO0.05 plus symptom monitoring, or monitoring of symptoms only. All patients scored asthma symptoms in an electronic diary over 30 weeks; 77 received a portable nitric oxide (NO) analyzer. Data were transmitted daily to the coordinating centers. Patients were phoned every 3 weeks and their steroid dose was adapted according to FeNO0.05 and symptoms, or according to symptoms. Children were seen at 3, 12, 21, and 30 weeks for examination and lung function testing. The primary end point was the proportion of symptom-free days in the last 12 study weeks., Measurements and Main Results: Telemonitoring was feasible with reliable FeNO0.05 data for 86% of days, and valid diary entries for 79% of days. Both groups showed an increase in symptom-free days, improvement of FEV1 and quality of life, and a reduction in steroid dose. None of the changes from baseline differed between groups. The difference in symptom-free days over the last 12 weeks was 0.3% (P = 0.95; 95% confidence interval, -10 to 11%). There was a trend for fewer exacerbations in the FeNO0.05 group., Conclusions: Thirty weeks of daily FeNO0.05 and symptom telemonitoring was associated with improved asthma control and a lower steroid dose. We found no added value of daily FeNO0.05 monitoring compared with daily symptom monitoring only.

Swimming is often recommended as a sport because of its several benefits to health. It is also recommended in asthmatic children as a sport with a lower potential for prompting exercise-induced asthma. However, there is growing interest in the potentially harmful effects of repeated respiratory tract exposure to chlorinated products and the problem of possible swimming-related health hazards is gaining importance at international level. It is already known that acute exposure to chlorine gas as in swimming pool accidents causes lung damage and also that elite swimmers may have increased airway inflammation and bronchial hyperreactivity, probably as a result of repeated exposure to chlorine derivatives. Recently some studies have been conducted to investigate whether repeated exposure to chlorine by-products in recreational swimmers might also lead to lung damage. In addition, some studies have been lately published on the even more debated issue of the possible harmful effects of baby swimming on respiratory health. This article reviews and discusses data from the literature on the effects of chlorine derivatives in different categories of people routinely attending swimming pools. The need for longitudinal studies is emphasized to definitely clarify any role of chlorinated swimming pool attendance in the development of asthma in recreational swimmers., (Copyright 2008 Wiley-Liss, Inc.)

Background: Though asthma is an airway inflammatory disease, the assessment of treatment efficacy is mainly based on symptom monitoring and the evaluation of lung function parameters. This study was aimed to evaluate the feasibility of exhaled nitric oxide monitoring in allergic asthmatic children who were exposed to relevant allergens in their homes., Methods: Twenty-two children allergic to mites underwent twice-daily fractional exhaled nitric oxide (FeNO) therapy using a portable device (NIOX MINO; Aerocrine AB; Stockholm, Sweden) and peak expiratory flow (PEF) measurements before, during, and after periods of natural exposure to mite allergens. The children were admitted to the study if they had lived in a mite-free environment for 3 months. They were observed in this environment for 10 days and then were moved to a site with natural mite exposure at sea level for 19 days. Finally, they were relocated to the mite-free environment for a period of 6 days for follow-up measurements., Results: Significant differences were seen between the mite-free baseline FeNO level (26.4 parts per billion [ppb]; range, 19.3 to 36.2 ppb) and FeNO levels measured during natural mite exposure (37.3 ppb; 27.3 to 51 ppb) and after natural mite exposure (34.9 natural mite exposure; 25.2 to 48.2 ppb). Six children reported asthma symptoms during the mite exposure, and an increase in FeNO was observed in each case (p<0.031); PEF values showed no significant differences, whether between the different environments or between different periods., Conclusions: These data give further evidence for a possible role of frequent determinations of FeNO in order to promptly assess changes in the level of airway inflammation in asthmatic children.

Exhaled nitric oxide (FE(NO)) is a surrogate marker of eosinophilic airway inflammation. The measurement of this gas can be easily performed in children and the result is immediately available. Because of these characteristics, measurement of FE(NO) is slowly becoming part of the routine clinical evaluation of an asthmatic patient. FE(NO) measurement may have a role both in the diagnosis of asthma and as a guide in therapy algorithms. For example when FE(NO) levels are persistently normal and the asthmatic child is asymptomatic, the steroid therapy may be decreased or even stopped. In patients with acute or chronic rhinosinusitis the levels of nasal nitric oxide (nNO) are significantly decreased, while they rise up after a course of antibiotics. The measurement of nasal NO has been proposed as a functional test to evaluate sinus ventilation. Nasal NO is significantly reduced also in primary ciliary dyskinesia and can be used as a screening tool to identify patients affected by this condition.

Rationale: Metabolomic analysis provides biochemical profiles of low-molecular-weight endogenous metabolites in biological fluids., Objectives: The aim of this study was to assess the feasibility of nuclear magnetic resonance (NMR)-based metabolomic analysis applied to exhaled breath condensate ("breathomics"). Information coming from NMR spectra was analyzed with a view to establish the NMR variables that best discriminate between children with asthma and healthy children., Methods: Twenty-five children with asthma (17 with persistent asthma treated with inhaled corticosteroids, 8 with intermittent asthma inhaled corticosteroid naive; age, 7-15 yr) and 11 healthy age-matched control subjects were enrolled. Every child performed exhaled nitric oxide measurement, spirometry, and condensate collection. Condensate samples were analyzed by means of NMR spectroscopy. Linear and partial least squares discriminant analyses were applied to data obtained from the NMR spectra., Measurements and Main Results: The combination of exhaled nitric oxide and FEV(1) discriminates children with asthma and healthy children with a success rate of approximately 81%, whereas selected signals from NMR spectra offer a slightly better discrimination (approximately 86%). The selected NMR variables derive from the region of 3.2 to 3.4 ppm, indicative of oxidized compounds, and from the region of 1.7 to 2.2 ppm, indicative of acetylated compounds., Conclusions: Metabolomics can be applied to exhaled breath condensate, leading to the characterization of airway biochemical fingerprints. The presence of acetylated compounds suggests new metabolic pathways that may have a role in asthma pathophysiology.

A growing interest has recently directed toward non invasive methods, such as exhaled nitric oxide (FE(NO)) measurement and exhaled breath condensate (EBC) collection, for the assessment of asthmatic inflammation. FE(NO) is a reliable marker of eosinophilic airway inflammation and it can be measured by means of a standardized technique in children starting from the age of 4. FE(NO) may have useful applications both in asthma diagnosis and monitoring. EBC is obtained cooling exhaled air and its composition is believed to mirror the characteristics of airway lining fluid. The compounds detected in EBC are markers of inflammation and oxidative stress occurring in asthmatic lung. While EBC is still only a research tool, FENO measurement is closer to clinical practice and lately it has been included in some treatment algorithms for asthma.

Background: Asthmatic patients have high exhaled nitric oxide (NO) levels. NO-mediated inflammatory actions are mainly due to NO conversion into reactive nitrogen species, which can lead to nitrotyrosine formation. The aim of this study was to assess 3-nitrotyrosine (3-NT) levels in exhaled breath condensate (EBC) of asthmatic and healthy children and to investigate whether there is any relationship with exhaled NO (FE(NO)) and lung function., Methods: The study included 20 asthmatic children (10 steroid-naive with intermittent asthma, 10 steroid-treated with unstable persistent asthma) and 18 healthy controls. They underwent FE(NO) measurement, EBC collection and spirometry. 3-NT was measured by a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method in isotopic dilution., Results: The median EBC concentration of 3-NT (expressed as nitrotyrosine/tyrosine ratio x 100) in asthmatic children was fivefold higher than in healthy subjects [0.23% (0.12-0.32) vs 0.04% (0.02-0.06), P < 0.001] with no difference between steroid-naive and unstable steroid-treated asthmatic patients. FE(NO) levels were higher in asthmatic [44.6 ppb (36.0-66.0)] than in healthy children [7.5 ppb (6.0-8.8), P < 0.001]. No correlation was found among 3-NT, FE(NO) and lung function parameters., Conclusion: Nitrotyrosine is high in EBC of asthmatic children and could be considered as a noninvasive marker of nitrosative events in the airways.

Background: Fractional exhaled nitric oxide (FE NO ) is used in monitoring of asthma., Objectives: The aim of this multicenter study was to establish normal values of FE NO and assess feasibility in children with a standardized method and equipment approved for clinical use., Methods: FE NO was measured in healthy subjects of 4 to 17 years according to American Thoracic Society guidelines (single breath online, exhalation flow 50 mL/s) with a chemiluminescence analyzer (NIOX Exhaled Nitric Oxide Monitoring System, Aerocrine, Sweden) in 3 European and 2 US centers. Each child performed 3 acceptable nitric oxide measurements within 6 attempts and completed an extended International Study of Asthma and Allergy in Children questionnaire., Results: Measurement of FE NO was attempted in 522 children. Four hundred five children completed the study according to the protocol. Geometric mean FE NO in 405 children was 9.7 ppb, and the upper 95% confidence limit was 25.2 ppb. FE NO increased significantly with age, and higher FE NO was seen in children with self-reported rhinitis/conjunctivitis or hay fever. The success rate was age-dependent and improved from 40% in the children 4 years old to almost 100% from the age of 10 years. The repeatability of 3 approved measurements was 1.6 ppb (95% CI, 1.49-1.64 ppb)., Conclusion: FE NO in healthy children is below 15 to 25 ppb depending on age and self-reported atopy. Measurement of FE NO by NIOX is simple and safe and has a good repeatability. Feasibility depends on age and may be difficult in the preschool child.