Role of Nasal Nitric Oxide in Primary Ciliary Dyskinesia and Other Respiratory Conditions in Children.

Nitric oxide (NO) is produced within the airways and released with exhalation. Nasal NO (nNO) can be measured in a non-invasive way, with different devices and techniques according to the age and cooperation of the patients. Here, we conducted a narrative review of the literature to examine the relationship between nNO and some respiratory diseases with a particular focus on primary ciliary dyskinesia (PCD). A total of 115 papers were assessed, and 50 were eventually included in the review. nNO in PCD is low (below 77 nL/min), and its measurement has a clear diagnostic value when evaluated in a clinically suggestive phenotype. Many studies have evaluated the role of NO as a molecular mediator as well as the association between nNO values and genotype or ciliary function. As far as other respiratory diseases are concerned, nNO is low in chronic rhinosinusitis and cystic fibrosis, while increased values have been found in allergic rhinitis. Nonetheless, the role in the diagnosis and prognosis of these conditions has not been fully clarified.

Metabolomic Profiling of Infants With Recurrent Wheezing After Bronchiolitis.

BACKGROUND: Bronchiolitis is associated with a greater risk of developing recurrent wheezing, but with currently available tools, it is impossible to know which infants with bronchiolitis will develop this condition. This preliminary prospective study aimed to assess whether urine metabolomic analysis can be used to identify children with bronchiolitis who are at risk of developing recurrent wheezing. METHODS: Fifty-two infants <1 year old treated in the emergency department at University Hospital of Padova for acute bronchiolitis were enrolled (77% tested positive for respiratory syncytial virus [RSV]). Follow-up visits were conducted for 2 years after the episode of bronchiolitis. Untargeted metabolomic analyses based on mass spectrometry were performed on urine samples collected from infants with acute bronchiolitis. Data modeling was based on univariate and multivariate data analyses. RESULTS: We distinguished children with and those without postbronchiolitis recurrent wheeze, defined as ≥3 episodes of physician-diagnosed wheezing. Pathway overrepresentation analysis pointed to a major involvement of the citric acid cycle (P < .001) and some amino acids (lysine, cysteine, and methionine; P ≤ .015) in differentiating between these 2 groups of children. CONCLUSION: This is the first study showing that metabolomic profiling of urine specimens from infants with bronchiolitis can be used to identify children at increased risk of developing recurrent wheezing.

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.

High-flow nasal cannula oxygen for bronchiolitis in a pediatric ward: a pilot study.

UNLABELLED: High-flow nasal cannula (HFNC) is a widely used ventilatory support in children with bronchiolitis in the intensive care setting. No data is available on HFNC use in the general pediatric ward. The aim of this study was to evaluate the feasibility of HFNC oxygen therapy in infants hospitalized in a pediatric ward for moderate-severe bronchiolitis and to assess the changes in ventilatory parameters before and after starting HFNC support. This prospective observational pilot study was carried out during the bronchiolitis season 2011-2012 in a pediatric tertiary care academic center in Italy. Interruptions of HFNC therapy and possible side effects or escalation to other forms of respiratory support were recorded. Oxygen saturation (SpO2), end-tidal carbon dioxide (ETCO2), and respiratory rate (RR), measured for a baseline period of 1 h before and at specific time intervals in 48 h after the start of HFNC were recorded. Twenty-seven infants were included (median age 1.3 months; absolute range 0.3-8.5). No adverse events, no premature HFNC therapy termination, and no escalation to other forms of respiratory support were recorded. Median SpO2 significantly increased by 1-2 points after changing from standard oxygen to HFNC (p <0.001). Median ETCO2 and RR rapidly decreased by 6-8 mmHg and 13-20 breaths per minute, respectively, in the first 3 h of HFNC therapy (p <0.001) and remained steady thereafter. CONCLUSIONS: Use of HFNC for oxygen administration is feasible for infants with moderate-severe bronchiolitis in a general pediatric ward. In these children, HFNC therapy improves oxygen saturation levels and seems to be associated with a decrease in both ETCO2 and RR.

Metabolomics Applied to Pediatric Asthma: What Have We Learnt in the Past 10 Years?

Background: Asthma is the most common chronic condition in children. It is a complex non-communicable disease resulting from the interaction of genetic and environmental factors and characterized by heterogeneous underlying molecular mechanisms. Metabolomics, as with the other omic sciences, thanks to the joint use of high-throughput technologies and sophisticated multivariate statistical methods, provides an unbiased approach to study the biochemical-metabolic processes underlying asthma. The aim of this narrative review is the analysis of the metabolomic studies in pediatric asthma published in the past 10 years, focusing on the prediction of asthma development, endotype characterization and pharmaco-metabolomics. Methods: A total of 43 relevant published studies were identified searching the MEDLINE/Pubmed database, using the following terms: "asthma" AND "metabolomics". The following filters were applied: language (English), age of study subjects (0-18 years), and publication date (last 10 years). Results and Conclusions: Several studies were identified within the three areas of interest described in the aim, and some of them likely have the potential to influence our clinical approach in the future. Nonetheless, further studies are needed to validate the findings and to assess the role of the proposed biomarkers as possible diagnostic or prognostic tools to be used in clinical practice.

Lung Function in Children with Primary Ciliary Dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is characterized by impaired mucociliary clearance that results in accumulation of mucus and bacteria in the airways. Lower respiratory tract infections lead to airway remodeling and lung function impairment. The aim of our narrative review is to discuss available data on lung function in PCD children, focusing on risk factors for lung function impairment. METHODS: Relevant published studies searching MEDLINE/Pubmed are included in this narrative review, using these terms: "primary ciliary dyskinesia" and "pulmonary function test" or "spirometry" or "lung function". Filters were language (English) and age of study subjects (0-18 years). RESULTS AND CONCLUSIONS: The majority of recent published studies showed normal spirometric values in PCD children, even if some authors described a pulmonary impairment. Together with spirometry, Lung Clearance Index has been applied for detecting peripheral airway disease, and it might have a role in early mild lung disease assessment. Studies on lung function trajectories after PCD diagnosis showed a significant heterogeneity, with some patients maintaining reasonably good lung function, whereas others showing a decline. Further studies are needed to analyze lung function prospectively from childhood into adulthood, and to evaluate whether lung function trajectories are affected by PCD clinical phenotype, ultrastructural ciliary defect or genetic background.

Impact of COVID-19 in Children with Chronic Lung Diseases.

BACKGROUND: since December 2019, the world has become victim of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The aim of our narrative review is to analyze the impact of COVID-19 in children suffering from chronic lung disease (CLD). METHODS: we searched the MEDLINE/Pubmed database using the terms "SARS-CoV-2" or "COVID-19" or "Coronavirus Diseases 2019"; AND "chronic lung diseases" or "chronic respiratory diseases" or "asthma" or "cystic fibrosis" or "primary ciliary dyskinesia" or "bronchopulmonary dysplasia"; and limiting the search to the age range 0-18 years. RESULTS AND CONCLUSIONS: although COVID-19 rarely presents with a severe course in children, CLD may represent a risk factor; especially when already severe or poorly controlled before SARS-CoV-2 infection. On the other hand, typical features of children with CLD (e.g., the accurate adoption of prevention measures, and, in asthmatic patients, the regular use of inhaled corticosteroids and T2 inflammation) might have a role in preventing SARS-CoV-2 infection. Moreover, from a psychological standpoint, the restrictions associated with the pandemic had a profound impact on children and adolescents with CLD.

Impact of air pollution exposure on lung function and exhaled breath biomarkers in children and adolescents.

A growing number of scientific papers focus on the description and quantification of the detrimental effects of pollution exposure on human health. The respiratory system is one of the main targets of these effects and children are potentially a vulnerable population. Many studies analyzed the effects of short- and long-term exposure to air pollutants on children's respiratory function. Aim of the present narrative review is to summarize the results of the available cohort studies which investigated how lung function of children and adolescents is affected by exposure to air pollution. In addition, an overview is provided on the association, in children, between pollution exposure and exhaled breath biomarkers, as possible indicators of the pathogenetic mechanisms involved in pollution-related lung damages. The identified cohort studies suggest that, beside the possible impact of recent exposure, early and lifetime exposure are the variables most consistently associated with a reduction in lung function parameters in both children and adolescents. As for the effect of air pollution exposure on exhaled breath biomarkers, the available studies show an association with increased exhaled nitric oxide, with increased concentrations of malondialdehyde and 8-isoprostane in exhaled breath condensate (EBC), and with EBC acidification. These studies, therefore, suggest lung inflammation and oxidative stress as possible pathogenetic mechanisms involved in pollution related lung damages. Taken together, the available data underscore the importance of the development and application of policies aimed at reducing air pollutant concentration, since the protection of children's lung function can have a beneficial impact on adults' respiratory health in the future.

A positive effect of a short period stay in Alpine environment on lung function in asthmatic children.

Lung function is a central issue in diagnosis and determination of asthma severity and asthma control has been previously reported to improve after a stay in mountain environment for at least 2 weeks. No data are available for shorter periods of stay, in particular for small airways during a stay at altitude. The aim of this study is to focus on changes in respiratory function, regarding both the central airways and the peripheral airways in the first 2 weeks of stay in a mountain environment in asthmatic children. In this study, 66 asthmatic children (age: 14 ± 2.8 years) were evaluated through spirometric and oscillometric tests at the time of arrival at the Istituto Pio XII, Misurina (BL), Italy, 1756 m above sea level (T0), after 24 h (T1), and 168 h (T2) of stay. FEV1%, FEF25%-75%, and FEV1/FVC increased significantly from T0 value both at T1 and T2 (respectively, p = 0.0002, p < 0.0001, p = 0.0002). Oscillometry showed a significant improvement in R5, R20, and R5-20 at both T1 and T2 as compared to T0 (respectively, p = 0.0001, p = 0.0002, and p = 0.049). Reactance at 5 Hz (X5) improved significantly at T2 versus T0, p = 0.0022. The area under reactance curve between Fres and 5 Hz (AX) was significantly reduced (p = 0.0001) both at T1 and T2 as compared to T0. This study shows an improvement in respiratory indices as soon as after 24 h of stay at altitude, persisting in the following week.

Early Oral Nutritional Supplements in the Prevention of Wheezing, Asthma, and Respiratory Infections.

Wheezing, asthma, and respiratory infections (RTI) are among the most common causes of morbidity in children and their economic and social burden could be significantly reduced by specific prevention strategies. Epidemiological studies suggest that lower levels of some nutrients are associated with higher prevalence of these conditions, but the possible protective effect of early supplementation with these nutrients has not yet been established. Aim of our review is to synthetize the available scientific evidence on the role of supplementation with pre- and probiotics, vitamin D, fish and poly-unsaturated fatty acids (PUFA), vitamin A, C, and E, given during the first year of life, in the prevention of wheezing, asthma and RTI. We searched studies published on this topic in the PubMed database between January 2000 and September 2021. As for pre- and probiotics, most of the studies showed that an early supplementation had no protective effect toward the development of asthma and wheezing, while conflicting results were reported on their role in the reduction of RTI. As for vitamin D, the available data suggest that early and regular (on a daily or weekly base) supplementation of vitamin D during infancy could have a role in the prevention of RTI, while most studies showed no effect in the prevention of wheezing or asthma. Finally, early introduction of fish in the diet in most studies has proved protective toward wheezing and asthma development.

A new strategy of desensitization in mucopolysaccharidosis type II disease treated with idursulfase therapy: A case report and review of the literature.

Mucopolysaccharidosis type II (MPS II) is a multisystemic lysosomal storage disorder caused by deficiency of the iduronate 2-sulfatase enzyme. Currently, enzyme replacement therapy (ERT) with recombinant idursulfase is the main treatment available to decrease morbidity and improve quality of life. However, infusion-associated reactions (IARs) are reported and may limit access to treatment. When premedication or infusion rate reductions are ineffective for preventing IARs, desensitization can be applied. To date, only two MPS II patients are reported to have undergone desensitization. We report a pediatric patient with recurrent IARs during infusion successfully managed with gradual desensitization. Our protocol started at 50% of the standard dosage infused at concentrations from 0.0006 to 0.06 mg/ml on weeks 1 and 2, followed by 75% of the standard dosage infused at concentrations from 0.0009 to 0.09 mg/ml on weeks 3 and 4, and full standard dosage thereafter, infused at progressively increasing concentrations until the standard infusion conditions were reached at 3 months. Our experience can be used in the management of MPS II patients presenting IARs to idursulfase infusion, even when general preventive measures are already administered.

Preliminary Evidence on Pulmonary Function after Asymptomatic and Mild COVID-19 in Children.

BACKGROUND: While it has been described that adults can develop long-lasting deterioration in pulmonary function (PF) after coronavirus disease 19 (COVID-19), regardless of disease severity, data on the long-term pneumological impact of SARS-CoV-2 infection in children are lacking. METHODS: Performing a single-center, prospective, observational study on children aged 6-18 years with a previous diagnosis of asymptomatic/mild COVID-19, we evaluated the long-term impact of mild severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children. RESULTS: A total of 61 subjects underwent spirometry after a mean time of 10 ± 4 months from asymptomatic or mild infection. None of the children reported any respiratory symptoms, needed any inhaled therapy, or had abnormal lung function. CONCLUSIONS: In our study, we observed that children and adolescents did not develop chronic respiratory symptoms and did not present lung function impairment after asymptomatic or mild SARS-CoV-2 infection.

Spending Time with Mothers as a Resource for Children with Chronic Diseases: A Comparison of Asthma, Type 1 Diabetes, and Cancer during COVID-19 Pandemic.

Due to the COVID-19 pandemic, many families had to manage new difficulties, especially those of chronically ill children. More and more research has focused on the negative effects of the pandemic on psychological wellbeing, while less is known about the resources. The present study aimed to explore the role of time spent with mothers in chronically ill children's populations during the COVID-19 pandemic. Moreover, it explored the differences in mothers' and children's psychosocial functioning in three clinical populations. Four groups were recruited and compared: 7-15 year old children with asthma (45), type 1 diabetes (52), and cancer (33), as well as their healthy counterparts (41), and their respective mothers. They were administered standardized questionnaires and ad hoc surveys assessing psychological wellbeing and worries. Children of the four groups scored significantly differently with respect to the concerns for contagion, internalizing symptoms, and prosocial behaviors; mothers had worries about the consequences of their children's contagion related to the chronic illness, as well as time with the child. The multiple linear regression model showed an association of being affected by cancer, suffering from type 1 diabetes, and spending less time with the child with an increase in children's internalizing problems. Time with mothers seemed to be a resource for psychological wellbeing during the pandemic. Clinical implications are discussed.

Psychosocial impact of Covid-19 outbreak on Italian asthmatic children and their mothers in a post lockdown scenario.

Italy was the first European country to fight the Covid-19 outbreak. To limit the transmission of the virus, the Italian Government imposed strict domestic quarantine policies and temporary closure of non-essential businesses and schools from March 10th,2020. Although more and more literature is exploring the impact of the pandemic on non-referred children and families, only a few studies are focused on the psychosocial impact of Covid-19 in chronically ill children and their caregivers. The present study investigates asthma control and children and mothers' psychological functioning (i.e.: psychological well-being, fear of contagion, and mothers' Covid-19 related fears) in 45 asthmatic children aged 7-to-14, compared to a control sample. The subjects were administered an online survey after the lockdown (from 28th May to 23rd August 2020). The analysis shows that asthmatic children presented higher concern in relation to contagion, however, no difference in psychological functioning was displayed between the two cohorts. Mothers reported more Covid-19 related fears, and greater worries according to the resumption of their children's activities. Moreover, they indicated a global worsening of their psychological well-being during the lockdown. Furthermore, regarding the clinical sample, the multivariate regression model showed that a worsening of mothers' psychological and children's physical well-being was associated with a worsening of children's psychological well-being during the lockdown. The results of this study indicate that mothers of asthmatic children can be more prone to experience psychological fatigue in a pandemic scenario. Special programs should be developed to support caregivers of chronically ill children.