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.

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.

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.

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.

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.

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.

Metabolomic Profile at Birth, Bronchiolitis and Recurrent Wheezing: A 3-Year Prospective Study.

There is growing interest for studying how early-life influences the development of respiratory diseases. Our aim was to apply metabolomic analysis to urine collected at birth, to evaluate whether there is any early metabolic signatures capable to distinguish children who will develop acute bronchiolitis and/or recurrent wheezing. Urine was collected at birth in healthy term newborns. Children were followed up to the age of 3 years and evaluated for the development of acute bronchiolitis and recurrent wheezing (≥3 episodes). Urine were analyzed through a liquid-chromatography mass-spectrometry based untargeted approach. Metabolomic data were investigated applying univariate and multivariate techniques. 205 children were included: 35 had bronchiolitis, 11 of whom had recurrent wheezing. Moreover, 13 children had recurrent wheezing not preceded by bronchiolitis. Multivariate data analysis didn't lead to reliable classification models capable to distinguish children with and without bronchiolitis or with recurrent wheezing preceded by bronchiolitis neither by PLS for classification (PLS2C) nor by Random Forest (RF). However, a reliable signature was discovered to distinguish children who later develop recurrent wheezing not preceded by bronchiolitis, from those who do not (MCCoob = 0.45 for PLS2C and MCCoob = 0.48 for RF). In this unselected birth cohort, a well-established untargeted metabolomic approach found no biochemical-metabolic dysregulation at birth associated with the subsequent development of acute bronchiolitis or recurrent wheezing post-bronchiolitis, not supporting the hypothesis of an underlying predisposing background. On the other hand, a metabolic signature was discovered that characterizes children who develop wheezing not preceded by bronchiolitis.

Pediatric flexible bronchoscopy: A single-center report.

INTRODUCTION: Pediatric flexible laryngotracheal bronchoscopy (FB) is an integral part of diagnostics and treatment at tertiary pediatric respiratory centers. AIM: FBs performed between 2013 and 2018 at our Pediatric Allergy and Respiratory Medicine Unit of the Department of Women's and Children's Health at Padua University were examined in terms of the indications, findings, and adverse events. MATERIALS AND METHODS: The electronic medical records of pediatric patients who underwent FB at least once between 1 January 2013 and 31 December 2018 were considered. Patients' clinical data, indications for FB, anatomical findings, information derived from bronchoalveolar lavage (BAL) and bronchial brushing, and possible adverse events were analyzed. RESULTS: There were 447 pediatric FBs performed in 428 patients (aged from 1 month to 18 years) for diagnostic purposes (92.4%), to clear secretions (3.6%), or to monitor a known condition (4.0%). The main indications were recurrent lower respiratory tract infections (LRTI, 32.2%) and chronic wet cough (9.4%). Lower airway malacia was the most common abnormal finding in these two groups (36.1% and 28.6%, respectively). BAL bacterial culture was positive in 55 children (39.6%) with recurrent LRTI and in 25 (59.5%) with chronic wet cough, being Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis the microorganisms most commonly isolated. FB proved a safe procedure and was well tolerated. CONCLUSIONS: Pediatric FB is an essential tool at our tertiary pediatric respiratory center. It helps establish the anatomical conditions underlying several chronic respiratory conditions and any correlated microbiological findings, with a significant impact on further patient management.

Pediatric asthma control during the COVID-19 pandemic.

BACKGROUND: The lockdown imposed by the COVID-19 pandemic resulted in a completely different style of life with possible effects on the attitude toward their disease in patients with chronic lung disease, such as asthma. The aim of our study was to investigate in asthmatic children the level of asthma control and the maintenance therapy used during the lockdown. METHODS: Among asthmatic children attending our clinic, we identified those who had been prescribed the same therapy in March-April 2019 and March-April 2020. The level of asthma control (GINA-score) and the maintenance therapy used during the lockdown (March-April 2020) were compared with those of March-April 2019. We separately analyzed a small group of children with severe asthma treated with Omalizumab during the lockdown. RESULTS: We enrolled 92 asthmatic children (67 males). Compared to 2019, in 2020 a higher proportion of children modified their maintenance therapy (38% vs. 15.2%, p < .001), with a significant increase in both the proportion of children who increased (p = .033) and in that of children who decreased their therapy (p = .026). The level of control resulted as significantly higher in 2020 (March p = .023; April p = .007). Also, the 13 children treated with Omalizumab showed a good level of control in 2020. CONCLUSIONS: In asthmatic children, the COVID-19 pandemic lockdown had a significant impact on their asthma control and on their attitude toward maintenance therapy.

Children's Interstitial and Diffuse Lung Diseases (ChILD) in 2020.

The term children interstitial lung diseases (chILD) refers to a heterogeneous group of rare diseases that diffusely affect the lung. ChILD specific to children younger than 2 years of age include diffuse developmental disorders, growth abnormalities, specific conditions of undefined etiology (neuroendocrine cell hyperplasia of infancy and pulmonary interstitial glycogenosis) and surfactant protein disorders. Clinical manifestations are highly variable, ranging from the absence of relevant symptoms to a severe onset. Most commonly, chILD presents with nonspecific respiratory signs and symptoms, such as dyspnea, polypnea, dry cough, wheezing, recurrent respiratory infections and exercise intolerance. In the diagnostic approach to a child with suspected ILD, chest high resolution computed tomography and genetic tests play a central role. Then, if the diagnosis remains uncertain, laryngotracheal-bronchoscopy and lung biopsy are needed. Pharmacological treatment is mostly empiric and based on anti-inflammatory and immunomodulatory drugs including corticosteroids, hydroxychloroquine and azithromycin. Despite chILD overall rarity, pediatric pulmonologists must be familiar with these diseases in order to carry out a timely diagnosis and patient treatment.

Protecting youth from the vaping epidemic.

E-cigarettes (e-cigs) have been initially proposed as an aid to smoke cessation in adults, whereas they turned into a paradoxical preferential gateway to tobacco and nicotine initiation for adolescents naïve to tobacco. More than 25% of US school-age students is an e-cigs user with a steep rise over the past years. A marketing strategy on media and social network targeting youths, in the absence of rules to protect the pediatric users, resulted in an unprecedented trend up in tobacco consumption among adolescents and gave rise to a new generation of nicotine-addicted teenagers. Flavored e-cigs liquids and aerosols contain airway irritants and toxicants, that, in turn, produced an increase in asthma prevalence and its exacerbations among adolescents. In addition, since August 2019 an outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI) has been described. In view of this, e-cigs must no longer be considered harmless, especially in adolescents never used a tobacco product before. This is a call-for-action to establish effective rules and campaigns targeting youths aimed to limit their access to e-cigs, thereby preserving the potential benefit in quitting tobacco addiction described in adults. Behavioral and educational actions, out of the conventional primary care setting, have been described as a model for a youth-centered campaign. We call for stricter regulations on e-cigs products, with respect to their marketing to the youngest ones, along with public health and primary care interventions that could curb the spread of this "vaping" epidemic.

Breathomics in Asthmatic Children Treated with Inhaled Corticosteroids.

BACKGROUND: "breathomics" enables indirect analysis of metabolic patterns underlying a respiratory disease. In this study, we analyze exhaled breath condensate (EBC) in asthmatic children before (T0) and after (T1) a three-week course of inhaled beclomethasone dipropionate (BDP). METHODS: we recruited steroid-naive asthmatic children for whom inhaled steroids were indicated and healthy children, evaluating asthma control, spirometry and EBC (in asthmatics at T0 and T1). A liquid-chromatography-mass-spectrometry untargeted analysis was applied to EBC and a mass spectrometry-based target analysis to urine samples. RESULTS: metabolomic analysis discriminated asthmatic (n = 26) from healthy children (n = 16) at T0 and T1, discovering 108 and 65 features relevant for the discrimination, respectively. Searching metabolomics databases, seven putative biomarkers with a plausible role in asthma biochemical-metabolic processes were found. After BDP treatment, asthmatic children, in the face of an improved asthma control (p < 0.001) and lung function (p = 0.01), showed neither changes in EBC metabolomic profile nor in urinary endogenous steroid profile. CONCLUSIONS: "breathomics" can discriminate asthmatic from healthy children, with prostaglandin, fatty acid and glycerophospholipid as putative markers. The three-week course of BDP-in spite of a significant clinical improvement-was not associated with changes in EBC metabolic arrangement and urinary steroid profile.

Climate Change and Childhood Respiratory Health: A Call to Action for Paediatricians.

Climate change (CC) is one of the main contributors to health emergencies worldwide. CC appears to be closely interrelated with air pollution, as some pollutants like carbon dioxide (CO2), nitrogen oxides (NOx) and black carbon are naturally occurring greenhouse gases. Air pollution may enhance the allergenicity of some plants and, also, has an adverse effect on respiratory health. Children are a uniquely vulnerable group that suffers disproportionately from CC burden. The increasing global warming related to CC has a big impact on plants' lifecycles, with earlier and longer pollen seasons, as well as higher pollen production, putting children affected by asthma and allergic rhinitis at risk for exacerbations. Extreme weather events may play a role too, not only in the exacerbations of allergic respiratory diseases but, also, in favouring respiratory infections. Even though paediatricians are already seeing the impacts of CC on their patients, their knowledge about CC-related health outcomes with specific regards to children's respiratory health is incomplete. This advocates for paediatricians' increased awareness and a better understanding of the CC impact on children's respiratory health. Having a special responsibility for children, paediatricians should actively be involved in policies aimed to protect the next generation from CC-related adverse health effects. Hence, there is an urgent need for them to take action and successfully educate families about CC issues. This paper aims at reviewing the evidence of CC-related environmental factors such as temperature, humidity, rainfall and extreme events on respiratory allergic diseases and respiratory infections in children and proposing specific actionable items for paediatricians to deal with CC-related health issues in their clinical practice.

Nitric Oxide and Biological Mediators in Pediatric Chronic Rhinosinusitis and Asthma.

BACKGROUND: In the context of the so-called unified airway theory, chronic rhinosinusitis (CRS) and asthma may coexist. The inflammation underlying these conditions can be studied through the aid of biomarkers. Main body: We described the main biological mediators that have been studied in pediatric CRS and asthma, and, according to the available literature, we reported their potential role in the diagnosis and management of these conditions. As for CRS, we discussed the studies that investigated nasal nitric oxide (nNO), pendrin, and periostin. As for asthma, we discussed the role of fractional exhaled nitric oxide (feNO), the role of periostin, and that of biological mediators measured in exhaled breath condensate (EBC) and exhaled air (volatile organic compounds, VOCs). CONCLUSION: Among non-invasive biomarkers, nNO seems the most informative in CRS and feNO in asthma. Other biological mediators seem promising, but further studies are needed before they can be applied in clinical practice.