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Laura Tenero,1 Rachele Vaia,2 Giuliana Ferrante,1 Matteo Maule,3 Laura Venditto,1 Giorgio Piacentini,1 Gianenrico Senna,2,3 Marco Caminati3 1Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Pediatric Clinic, University of Verona, Verona, Italy; 2Allergy Unit and Asthma Center, Verona University Hospital, Verona, Italy; 3Department of Medicine, University of Verona, Verona, ItalyCorrespondence: Marco Caminati, Department of Medicine, University of Verona, Piazzala L.A. Scuro, 10, Verona, 37134, Italy, Email marco.caminati@univr.itAbstract: Allergic rhinitis (AR) is a common upper airways inflammatory condition especially in paediatric population; its burden potentially impacts on quality of life, quality of sleep and daily performance, which can be difficult to perceive but not less relevant in the middle-long term. The present review aims to provide an updated overview on AR epidemiology, diagnosis and with a special focus on its connections with bronchial asthma. In fact, when considering asthmatic pediatric population, AR is probably the most important risk factor for asthma onset and the most impactful extra-bronchial determinant of asthma control. Under this perspective, allergen immunotherapy (AIT) should always be considered in the light of a precision medicine approach. In fact, AIT does represent a unique opportunity to specifically interfere with AR immunological background, improve both AR and bronchial asthma control and prevent allergic disease evolution. Verifying the patient’s eligibility to that option should be considered as a priority for every physician managing children suffering from AR, especially when associated with bronchial asthma.Keywords: asthma, asthma control, rhinitis, immunotherapy, personalized medicine

Abstract Among the preschool children who wheeze two different groups can be identify: children who have a viral infection and those who respond to multiple triggers, such as exercise or allergens. To distinguish between these different phenotypes of wheezing, and consequently choose therapy represents a major challenge for pediatricians. Transient wheezers conditions do not improve with maintenance treatment with ICS. On the other hand they are definitely useful in children with wheeze/asthma. Increasing evidence is in favor of the potential role of leukotriene receptor antagonists in preschool children with recurrent wheezing. Oral steroid has been demonstrated not to be indicated to control acute wheezing, unless severe disease is expected in non-atopic children. The early phenotyping of preschool wheezers, upon which the appropriate treatment should be based, represents a challenging issue in the paediatric practice.

Severe asthma affects about 6.7% of adolescents worldwide, posing a substantial burden on their physical and psychosocial well-being. The impact of severe asthma on adolescents is multifaceted, with several factors that contribute to this burden, such as comorbidities including obesity, dysfunctional breathing, sleep-disordered breathing and mental health issues. Moreover, daily therapy management is often complex and may require lifestyle modification that could lead to a failure in treatment adherence and to peer-related stressors such as feelings of exclusion. Furthermore, adolescents with severe asthma are prone to risk-taking behaviours, including vaping and substance misuse. While current management strategies often fail to account for their developmental stage, digital technologies offer novel solutions to improve disease management. This narrative review aims to provide a comprehensive overview of the multifaceted impact of severe asthma on adolescents, addressing the main clinical management issues and exploring the role of innovative digital tools to enhance asthma management in this critical population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Generative AI and AI-assisted technologies were NOT used in the preparation of this work., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Introduction: Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by the production of sickle hemoglobin, leading to red blood cells sickling and hemolysis in hypoxic conditions. The resulting acute and chronic endothelial inflammation leads to chronic organ damage. Respiratory manifestations in SCD usually start from childhood and represent the leading causes of morbidity and mortality. Nevertheless, they are generally poorly addressed or recognized later in life, often contributing to a more severe course and complications., Areas Covered: This narrative review aims to outline the significant acute and chronic respiratory manifestations in children with SCD, focusing on prevention and clinical management. Compelling issues that need to be addressed in the future are also discussed. We searched the PubMed database for original papers written in English. Age restrictions were set for children (birth to 18 years). No limitations were set for the date and study country., Expert Opinion: Early detection and treatment of respiratory manifestations in SCD should be central to follow-up with patients affected by SCD. Nonetheless, studies are lacking, especially in pediatric age, and there is still no consensus on their management. Further research is strongly needed to accomplish universally accepted guidelines to guarantee patients the best care possible.

Bronchopulmonary dysplasia (BPD) is the most common respiratory disease in preterm and is still associated with increased mortality and morbidity. The great interest lies in identifying early biomarkers that can predict the development of BPD. This pilot study explores the potential of e-nose for the early identification of BPD risk in premature infants by analyzing volatile organic compounds (VOCs) in the exhaled breath condensate (EBC). Fourteen mechanically ventilated very preterm infants were included in this study. The clinical parameters and EBC were collected within the first 24 h of life. The discriminative ability of breath prints between preterms who did and did not develop BPD was investigated using pattern recognition, a machine learning algorithm, and standard statistical methods. We found that e-nose probes can significantly predict the outcome of "no-BPD" vs. "BPD". Specifically, a subset of probes (S18, S24, S14, and S6) were found to be significantly predictive, with an AUC of 0.87, 0.89, 0.82, 0.8, and p = 0.019, 0.009, 0.043, 0.047, respectively. The e-nose is an easy-to-use, handheld, non-invasive electronic device that quickly samples breath. Our preliminary study has shown that it has the potential for early prediction of BPD in preterms.

Wheezing is a common condition in childhood, and its prevalence has increased in the last decade. Up to one-third of preschoolers develop recurrent wheezing, significantly impacting their quality of life and healthcare resources. Artificial Intelligence (AI) technologies have recently been applied in paediatric allergology and pulmonology, contributing to disease recognition, risk stratification, and decision support. Additionally, the COVID-19 pandemic has shaped healthcare systems, resulting in an increased workload and the necessity to reduce access to hospital facilities. In this view, AI and Machine Learning (ML) approaches can help address current issues in managing preschool wheezing, from its recognition with AI-augmented stethoscopes and monitoring with smartphone applications, aiming to improve parent-led/self-management and reducing economic and social costs. Moreover, in the last decade, ML algorithms have been applied in wheezing phenotyping, also contributing to identifying specific genes, and have been proven to even predict asthma in preschoolers. This minireview aims to update our knowledge on recent advancements of AI applications in childhood wheezing, summarizing and discussing the current evidence in recognition, diagnosis, phenotyping, and asthma prediction, with an overview of home monitoring and tele-management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor AL declared past co-authorships with the authors MP, GP, and GF., (Copyright © 2024 Venditto, Morano, Piazza, Zaffanello, Tenero, Piacentini and Ferrante.)

(1) Background: Sleep-disordered breathing and asthma are often interrelated. Children and adults with asthma are more susceptible to sleep apnea. Inhaled corticosteroids effectively reduce inflammation and prevent structural changes in the airways. Objective: to explore the existing literature to determine whether inhaled corticosteroids play a role in sleep-disordered breathing in patients with asthma. (2) Methods: We conducted a thorough search of the PubMed, Scopus, and Web of Science databases for English-language articles published up to 12 May 2024. We utilized the ROBINS-E tool to assess the risk of bias. (4) Conclusions: 136 articles were discerned upon conducting the literature search. A total of 13 articles underwent exhaustive full-text scrutiny, resulting in 6 being considered non-relevant. The remaining seven articles, assessed for eligibility, were incorporated into the final analysis. Five studies were identified in adults and two in children. In adult patients, inhaled corticosteroids, especially at high doses, appear to increase the risk of sleep apnea in a dose-dependent manner. Moreover, the properties of inhaled corticosteroids, such as particle size, may impact the risk of developing sleep apnea. In children, the severity of asthma is a key factor affecting the prevalence of sleep apnea, whereas inhaled corticosteroids appear to be a less significant risk factor compared to adults. All of the studies reviewed were classified as having a high risk of bias or some concerns regarding bias. Each study revealed at least one type of bias that raised notable concerns. This research highlights a complex interaction between the use of inhaled corticosteroids, the severity of asthma, and the onset of sleep apnea. Additional research is necessary to investigate these relationships further.

Hypereosinophilic syndromes (HES) represent a group of rare dis-immune conditions characterized by blood hyper-eosinophilia and eosinophilic related burden. Especially the idiopathic subtype (I-HES) is particularly difficult to diagnose because of its heterogeneous clinical presentation, the lack of specific findings on physical exam, lab tools, and imaging informative enough to unequivocally confirm the diagnosis and the overlap with other entities, including eosinophilic organ-diseases or systemic dis-immune conditions other than I-HES (from atopy to eosinophilic granulomatosis with polyangiitis [EGPA], the last often extremely difficult to distinguish from HES). Taken together, all the features mentioned above account for an extremely difficult early recognition HES and on-time referral to a specialized centre. The referral itself is challenging due to a not univocal specialist identification, because of the variability of physicians managing HES in different settings (including allergist/clinical immunologist, haematologist, internal medicine doctors, pulmonologist, rheumatologist). Furthermore, the approach in terms of personalized treatment identification and follow-up plan (timing, organ assessment), is poorly standardized. Further translational and clinical research is needed to address the mentioned unmet needs, but on practical grounds increasing the overall clinicians' awareness on HES and implementing healthcare pathways for HES patients represent a roadmap that every clinician might try to realize in his specific setting. The present review aims at providing an overview about the current challenges and unmet needs in the practical approach to HES and rare hypereosinophilic allergo-immunological diseases, including a proposal for an innovative multidisciplinary organizational model., Competing Interests: The authors declare that they have no competing interests in relation to the topic of the manuscript., (© 2024 The Author(s).)

Background: Markers of airway inflammation can be helpful in the management of childhood asthma. Residential activities, such as intensive asthma camps at alpine altitude climate (AAC), can help reduce bronchial inflammation in patients who fail to achieve optimal control of the disease. Analysis of volatile organic compounds (VOCs) can be obtained using electronic devices such as e-Noses. We aimed to identify alterations in urinary e-Nose sensors among children with asthma participating in an intensive camp at AAC and to investigate associations between urinary e-Nose analysis and airway inflammation., Methods: We analyzed data collected in children with asthma recruited between July and September 2020. All children were born and resided at altitudes below 600 m asl. Urinary VOCs (measured using the Cyranose 320® VOC analyzer), Fractional exhaled Nitric Oxide (FeNO) and spirometry were evaluated upon children's arrival at the Istituto Pio XII, Misurina (BL), Italy, at 1756 m asl (T0), and after 7 (T1) and 15 days (T2) of stay., Results: Twenty-two patients (68.2% males; median age: 14.5 years) were enrolled. From T0 to T1 and T2, the negative trend for FeNO was significant (p < .001). Significant associations were observed between e-Nose sensors S7 (p = .002), S12 (p = .013), S16 (p = .027), S17 (p = .017), S22 (p = .029), S29 (p = .021), S31 (p = .009) and ΔFeNO at T0-T1. ΔFeNO at T0-T2 was significantly associated with S17 (p = .015), S19 (p = .004), S21 (p = .020), S24 (p = .012), S25 (p = .018), S26 (p = .008), S27 (p = .002), S29 (p = .007), S30 (p = .013)., Conclusions: We showed that a decrease in FeNO levels after a short sojourn at AAC is associated with behaviors of individual urinary e-Nose sensors in children with asthma., (© 2024 Wiley Periodicals LLC.)

Asthma is a disease that has been described since the times of Hammurabi. However, it is only since the 1960s that effective therapeutic strategies have been available. Pathogenic mechanisms underlying the disease have been deeply studied, contributing to creating a "patient-specific asthma" definition. Biological drugs have been approved over the last twenty years, improving disease management in patients with severe asthma via a "precision medicine-driven approach". This article aims to describe the evolution of scientific knowledge in childhood asthma, focusing on the most recent biological therapies and their indications for patients with severe asthma.

Background: Fusobacterium necrophorum is an anaerobic, gram-negative, non-motile, filamentous, non-spore forming bacillus found in the oral cavity, gastrointestinal tract, and female genital tract, responsible of a rare disease named Lemierre Syndrome, characterized by septic thrombophlebitis of the internal jugular vein, which mainly affects previously healthy adolescents and young adults; some risk factors are reported, as smoking or primary viral or bacterial infection leading to the disruption of mucosa. The syndrome originates commonly from an upper respiratory infection such as pharyngotonsillitis, acute otitis media, cervical lymphadenitis, sinusitis, or odontogenic abscess, and may result in multiorgan metastasis, more frequently leading to pulmonary complications, especially lung abscesses., Case Presentation: We describe two cases of adolescents with atypical Lemierre Syndrome evaluated in a tertiary care center, one with a confirmed infection by Fusobacterium necrophorum and one with a presumptive diagnosis based on clinical features, who developed lung abscesses needing a prolonged antibiotic course and hospitalization. Of interest, both were user of electronic cigarette, configuring a possible new risk factor. The proper diagnosis of Lemierre Syndrome is often difficult to establish, so a high degree of suspicion is needed, especially in the case of lung abscesses in otherwise healthy adolescents., Conclusion: The current study will contribute to providing insight into Lemierre Syndrome clinical presentation and management in adolescents, promoting awareness for a rare but potentially fatal disease. Moreover, it suggests a possible relationship between Lemierre syndrome and the use of electronic cigarette, that should be investigated by future studies., (© 2023. Società Italiana di Pediatria.)

Background: Obstructive sleep apnea can have a negative impact on children's and adolescents' neurocognitive abilities and hinder their academic and adaptive progress in academic, social, and/or behavioral dimensions. In this retrospective cross-sectional study, we investigated the influence of body weight conditions and allergy status on long-term mental health, cognitive development, and quality of life in children and adolescents who snored., Methods: The study sample included 47 subjects (age range 4.1 to 15.3 years) who exhibited high levels of snoring and underwent home-based polysomnography between 2015 and 2019. Follow-up assessments (3 years on average between baseline and follow-up) entailed phone interviews with the subject's parents/caregivers who completed three validated questionnaires investigating sleep, quality of life, and parental ratings., Results: We found a correlation between age at diagnosis and being retrospectively overweight and high levels of snoring. In addition to a higher risk of developing emotional symptoms (8.2% increase in retrospective overweight status for each unit increase in the emotional score at follow-up) and oppositional behavior (9% increase in retrospective overweight status for each unit of oppositional T points at follow-up), we also noted reduced long-term social symptoms (11% decrease in retrospective overweight status for each unit increase in the social score at follow-up) and cognitive symptoms (10.6% decrease in retrospective overweight status for each unit increase in the cognitive score at follow-up), as well as a 6.1% increase in retrospective allergy status for each unit increase in academic performance at follow-up., Conclusions: Snoring can have negative impacts on mental health and cognitive development in the long term. Early detection and intervention for neuropsychological disorders is important in children and adolescents who score high on snoring. In the long term, the effects of snoring on neuropsychological disorders may vary based on previous body weight and allergy status.

Pediatric obstructive sleep apnea can negatively affect children's neurocognitive function and development, hindering academic and adaptive goals. Questionnaires are suitable for assessing neuropsychological symptoms in children with sleep-disordered breathing. The study aimed to evaluate the effectiveness of using the Oxygen Desaturation Index compared to the Obstructive Apnea-Hypopnea Index in predicting long-term consequences of sleep-disordered breathing in children. We conducted a retrospective analysis of respiratory polysomnography recordings from preschool and school-age children (mean age: 5.8 ± 2.8 years) and followed them up after an average of 3.1 ± 0.8 years from the home-based polysomnography. We administered three validated questionnaires to the parents/caregivers of the children by phone. Our results showed that children with an Oxygen Desaturation Index (ODI) greater than one event per hour exhibited symptoms in four domains (physical, school-related, Quality of Life [QoL], and attention deficit hyperactivity disorder [ADHD]) at follow-up, compared to only two symptoms (physical and school-related) found in children with an Obstructive Apnea-Hypopnea Index greater than one event per hour at the time of diagnosis. Our study also found a significant correlation between the minimum SpO 2 (%) recorded at diagnosis and several outcomes, including Pediatric Sleep Questionnaire (PSQ) scores, physical, social, and school-related outcomes, and ADHD index at follow-up. These results suggest that the Oxygen Desaturation Index could serve as a valuable predictor of long-term symptoms in children with sleep-disordered breathing, which could inform treatment decisions. Additionally, measuring minimum SpO 2 levels may help assess the risk of developing long-term symptoms and monitor treatment outcomes.

Vitamin D deficiency and insufficiency is a global health issue: an association has been demonstrated between vitamin D deficiency and a myriad of acute and chronic illnesses. Data regarding vitamin D status among children hospitalized with non-critical illnesses are scanty. We aimed to: (1) identify profiles of children hospitalized due to non-critical illnesses, using vitamin D levels as the driving outcome; (2) assess the association between patient profiles and length of stay. The study included 854 patients (1−17 years old) who underwent blood tests for detecting vitamin D levels. A regression tree was used to stratify patients. The relationship between vitamin D levels and length of stay was explored using Poisson regression. The regression tree identified three subgroups. Group A (16%): African, North African, Hispanic, and Indian patients. Group B (62%): Caucasian and Asian patients hospitalized for respiratory, metabolic, ill-defined, infective, and genitourinary diseases. Group C (22%): Caucasian and Asian patients hospitalized for digestive, nervous, and musculoskeletal diseases, blood and skin diseases, and injuries. Mean serum vitamin D level (ng/mL) was 13.7 (SD = 9.4) in Group A, 20.5 (10.0) in Group B, and 26.2 (12.6) in Group C. Group B was associated with the highest BMI z-score (p < 0.001) and the highest frequency of preterm births (p = 0.041). Mean length of stay was longer in Group A than in the other groups (p < 0.001) and decreased significantly by 9.8% (p = 0.024) in Group A and by 5% (p = 0.029) in Group B per 10 ng/mL increase in vitamin D level. We identified three subgroups of hospitalized children, defined according to ethnicity and discharge diagnosis, and characterized by increasing vitamin D levels. Vitamin D levels were associated with length of hospitalization.

Severe asthma is a rare disease affecting <5% of children with asthma. This group of patients account for about 50% of the costs of healthcare for children with asthma. Nowadays, several biological agents are available for pediatric severe asthma. One of these is dupilumab, a monoclonal antibody against the Interleukin (IL)-4 receptor α-subunit that acts as an antagonist against both IL-4 and IL-13. Dupilumab binds the subunit of the IL-4 receptor, at the level of the subunit shared by the IL-13 receptor, blocking the inflammatory cascade of these two cytokines and the progression of the Th2-inflammatory pathway. The efficacy and safety of dupilumab have been investigated in recently published randomized controlled trials including pediatric patients with asthma. Currently, its use in asthma is approved in adults, adolescents, and children with severe asthma with type 2 inflammation, that are not controlled in spite of high-dose inhaled corticosteroids plus another maintenance drug. Studies are warranted for the evaluation of long-term treatment with dupilumab, including steroid sparing effect and discontinuation of treatment. Further research should also be planned in order to investigate dupilumab potential ability to interfere with the natural history of atopy since early childhood., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Ferrante, Tenero, Piazza and Piacentini.)

In the last 20 years, the introduction of monoclonal antibodies has dramatically changed allergic diseases. At present, several monoclonal antibodies are approved for treating asthma, atopic dermatitis, chronic spontaneous urticaria, and chronic sinusitis with nasal polyps in children. Biologics have also changed the management of these diseases in the pediatric population, tending toward personalized medicine based on the type-2 inflammatory pattern., (© 2022 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background and Objectives: Exhaled breath condensate (EBC) represents a potential diagnostic tool for Primary Ciliary Diskinesia (PCD). An increased oxidative stress is present in the airways of children affected and many neutrophil chemoattractants and markers of oxidative stress can be involved. The aim of the study is to evaluate leukotriene B4 (LTB-4), interleukin 8 (IL-8), 8-isoprostane (8-IP) concentration in PCD subjects, investigating their potential role as non-invasive markers of inflammation for the diagnosis and management of PCD., Methods: Cross-sectional study. 43 patients were enrolled in the study and divided in two groups: PCD (27) and healthy subjects (16). Physical examination, lung function test, nFeNO measurement and EBC collection were performed in all subjects., Results: PCD subjects showed an EBC 8-IP concentration significantly higher than the control group (median value: 11.9 pg/ml; IQR, 5.5-24.0 vs. median, 6.7 pg/ml; IQR, 2.5-11.3, p-value of Wilcoxon rank-sum test 0.0436). LTB4 EBC concentration did not differ between the two group (median, 4.3 pg/ml; IQR, 3.0-8.8 vs. 7.5 pg/ml; IQR, 3.0-9.5; P=0.4901). No significant correlation was found between FEV1 and EBC 8-IP (r=-0.10, P=0.6314) or LTB4 concentration (r=0.03, P=0.8888) in PCD subjects. No significant correlation was found between nFeNO and EBC 8-IP (r=-0.31, P=0.1385) or LTB4 (r=0.04, P=0.8565) in PCD subjects., Conclusions: EBC 8-IP levels are significantly increased in PCD subjects, highlighting the role of oxidative stress in airway inflammation. It could have a potential role as a non-invasive marker of inflammation for the diagnosis and management of PCD, although a therapeutic application of this evidence seems far., Competing Interests: None

A 15 years-old boy came to our attention with a diagnosis of poorly controlled asthma. This case required thorough investigations: CT scan imaging revealed a flat angioma extending from the carina to the left main bronchus. Rigid bronchoscopy confirmed the presence of an angioma showing widespread mucosal diffusion involving most of the posterior tracheal wall and main bronchi, on the left side. We present this case report and these images to readers seeking for other experiences in the diagnosis of wide superficial bronchial angioma in pediatric age., Competing Interests: Authors declare that they have no conflict of interest., (© 2020 The Author(s).)

Interleukin (IL)-5 is a potent mediator of the inflammatory cascade in the allergic response. Its predominant role in atopic reactions makes this cytokine an ideal target for blocking the eosinophilic inflammatory hyper-responsiveness to allergens. The management of allergic diseases in childhood-such as severe asthma, atopic dermatitis, and eosinophilic esophagitis-is a challenge. In particular, there are concerns regarding the use of high-dose corticosteroids. Over the last few years, biologics targeting IL-5 or IL-5 receptor-that are mepolizumab, reslizumab, and benralizumab-represent a new, promising, and more personalized therapeutic option., (© 2020 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Scientific research, diagnostic tools and clinical experience have shown that children suffering from IgE-mediated fish allergy do not need to follow a strict exclusion diet. In fact, they could tolerate some species of fish, which could be reintroduced in the diet by verifying their tolerance with an oral food challenge in a clinical setting. Consequently, it is possible to look a new insight on diagnosis and management of IgE-mediated fish allergy in children, considering the use of canned tuna in clinical settings. Authors performed a literature search through the Cochrane Library and Medline/PubMed databases. All quantitative and qualitative pediatric studies involving diagnosis and management of IgE-mediated fish allergy and the use of canned tuna in clinical settings were considered. Articles related to allergological and nutritional features of fish, and especially canned tuna, were selected. This research was conducted on May 2020. Canned tuna shows peculiar allergological and nutritional characteristics. Relating to allergy, canning process, characterized by cooking the fish under pressure for a time equal to about 7 hours, can lead a conformational change in parvalbumin, making it less allergenic. In terms of nutrition, canned tuna contains B, D and A vitamins and, above all, omega-3 fatty acids and shows a favourable and significantly sustainable nutritional profile. Lower allergenicity, adequate nutritional value and its rich availability in markets at reasonable costs, could make the use of canned tuna as a solution with an excellent risk/benefit ratio in the field of IgE-mediated fish allergy.

Measuring biomarkers (e.g. volatile organic compounds [VOCs]) in exhaled breath is an attractive approach to monitor airway inflammation in asthma and other lung diseases. Olfactive technology by electronic nose (e-Nose) has been applied to identify VOCs in exhaled breath. We compared e-Nose respiratory patterns in a pediatric cohort with asthma classificate children with different asthma control. This cross-sectional study involved 38 children: 28 with asthma and 10 healthy controls . The asthmatic patients were categorized as having controlled (AC), partially controlled (APC) or uncontrolled asthma (ANC) based on level of asthma symptom control according to Global Initiative for Asthma (GINA). Clinical exams, exhaled breath collection for generating e-Nose VOC profiles, and spirometry were performed. Exhaled breath samples were obtained using a commercial electronic nose (Cyranose 320; Smith Detections, Pasadena, CA, USA). The discriminative ability of breathprints were investigated by principal component analysis and penalized logistic regression. The e-Nose was able to discriminate between the CON (controls) + AC and the ANC + APC group with an area under the curve [AUC] of 0.85 (95% confidence interval [CI] 0.72 to 0.98) and a cross-validated AUC of 0.80 (95% CI 0.70 to 0.85). Sensitivity and specificity calculated using the Youden index were 0.79 and 0.84, respectively. Exhaled biomarker patterns were easy to obtain with the device and were able to differentiate children with uncontrolled symptomatic asthma from asymptomatic controls.

A 14 year old male was diagnosed with asthma but didn't improve with appropriate inhalation therapy. Rigid bronchoscopy revealed a food fragment, almost completely occluding the lower-left bronchus lumen. Based on the reported history, it had been likely there for several years., Competing Interests: The authors declare no competing interests., (© Alessandro Bodini et al.)

Asthmatic children usually reach good control of symptoms with a low-medium dose of inhaled corticosteroids (ICS), but approximately 5% has severe asthma. In this group of patients, when the diagnosis of severe asthma is confirmed, biologic agents have to be considered when there is no control of the symptoms despite conventional treatment with controllers according to guidelines. At present, the only biologic agent available in clinical practice for severe asthma treatment in children (6-18 years) is omalizumab. Mepolizumab has been recently approved by EMA for pediatric use. Reslizumab is a monoclonal antibody anti-IL-5 that has been approved for severe eosinophilic asthma treatment only in patients >12 years. Because of their action on specific molecular targets of the asthma pathophysiology, biologic agents are very promising therapeutic options for severe asthmatic patients based on individual endotypes., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Sleep-disordered breathing (SDB) is a general term encompassing a variety of breathing problems occurring during the sleep and characterized by frequently reported signs such as sleep apneas and snoring. Published studies on this topic are increasing over time, as demonstrated by the number of papers available on on-line databases., Methods: Google Trends is a freely accessible and reliable online portal, which allows to explore internet search data. Due to the focus on of childhood SDB in published research, and because of its impact on health and wellbeing, this original study aims at investigating the worldwide popularity of most common sleep signs (apnea and snoring) from January 1st, 2004 to present time., Results: The trend of interest for 'sleep', 'sleep apneas' and 'snoring' limited to pediatric age was lower than its overall popularity in the general population, thus reflecting a lower interest of these symptoms in children than in adults. Unlike an increasing trend of ongoing research, the popularity of pediatric sleep apnea and snoring was found to be relatively low around the world, and remained fairly stable over time., Conclusions: This is a matter for concern, since the low popularity of SDB in children is counterbalanced by a need for reinforcing educational programs aimed at increasing widespread awareness, diagnosis and management of this condition., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Translational Pediatrics. All rights reserved.)

Childhood obstructive sleep apnea syndrome (OSAS) is characterized by anatomical and functional upper airway abnormalities as pathophysiological determinants, and clinical symptoms are frequently clear. OSAS is widely described in rare genetic disorders, such as achondroplasia, Down syndrome, Prader-Willi syndrome, Pierre Robin sequence, and mucopolysaccharidosis. Craniofacial and upper airway involvement is frequently morbid conditions. In children with genetic diseases, the clinical symptoms of OSAS are often slight or absent, and related morbidities are usually more severe and can be observed at any age. The present review is aimed to updating the discoveries regarding OSAS on Achondroplasia, Down syndrome, Prader-Willi syndrome, Pierre Robin sequence, Sickle cell disease, or encountered in our clinical practice (Ehlers-Danlos syndrome, Ellis-van Creveld syndrome, Noonan syndrome). Two additional groups of genetic disorders will be focused (mucopolysaccharidoses and osteogenesis imperfecta). The flowing items are covered for each disease: (I) what is the pathophysiology of OSAS? (II) What is the incidence/prevalence of OSAS? (III) What result from the management and prognosis? (IV) What are the recommendations? Considering the worries of OSAS, such as inattention and behavioural problems, daytime sleepiness, failure to thrive, cardiological and metabolic complications, the benefit of a widespread screening and the treatment in children with genetic diseases is undoubtful. The goals of the further efforts can be the inclusion of various genetic diseases into guidelines for the screening of OSAS, updating the shreds of evidence based on the research progression., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Asthma is the most common chronic respiratory disease in children characterized by airways inflammation, bronchial hyperresponsiveness, recurrent reversible airways obstruction, and respiratory symptoms. The diagnosis of the disease is based on clinical history, airways obstruction at spirometry, and bronchial reversibility. Asthma treatment is aimed to disease control, through the use of controller treatment and monitoring lung function. However, lung function and symptoms not always reflect the underlying airways inflammation and response to the therapy. Objective parameters of asthma inflammation could be important for the clinician in the management of patients with asthma. In the last years, some studies were focused on biomarkers to identify phenotype, inflammation, and pathobiological pathways to help the clinician in the diagnosis and in personalizing the management. Accordingly, clinically feasible tests are represented by the collection of exhaled breath condensate (EBC) and measurement of exhaled nitric oxide (FeNO). Other-methods such as the evaluation of volatile organic compound (VOCs), that reflect airways inflammation and treatment efficacy, are currently used for research purposes For some of these methods, The lack of standardization in pre-collection, collection, post-collection of samples, and interpretation of the results may a problem in clinical practice. Improved these limitations, several biomarkers will be useful to distinguish patients with a different disease condition to personalize the treatment.

Background: Structured light plethysmography (SLP) is a new noninvasive technology to capture the movement of the thoracic and abdominal wall, and to assess some parameters indicative for lung function., Objective: The purpose of the study was to evaluate the feasibility of SLP in children with asthma., Methods: A total of 52 patients were enrolled: 25 with asthma exacerbation (group 1), 13 with well-controlled asthma (group 2), and 14 healthy controls (group 3). Every patient underwent SLP evaluation and a lung function test., Results: SLP evaluations showed that the ratio of inspiratory flow at 50% of tidal volume (Vt) to expiratory flow at 50% of Vt, in which Vt is taken to be the exhaled chest wall movement, and flow is taken to be the time derivative of the chest wall movement (IE50) value increased in group 1 compared with groups 2 and 3, with statistical significance (p = 0.018); the data were consistent with the spirometry parameter. A correlation between the IE50 and forced expiratory volume in the first second of expiration was highlighted (r = -0.35, p = 0.019)., Conclusion: SLP assessed airway obstruction, and its use in clinical practice could be applied in preschool children in future studies.

The relationship between asthma and sleep-disordered breathing is bidirectional due to common risk factors that promote airway inflammation. Obstructive sleep-disordered breathing and recurrent wheeze/asthma are conditions that involve the upper and the lower respiratory system, respectively. The aim of the present study was to investigate the sleep disordered breathing in children with recurrent wheeze/asthma. This was a retrospective study concerning children older than 2 years who underwent-between January 2014 and November 2016-an in-laboratory overnight polygraphic study. We match the children between those who do or do not have recurrent wheeze/asthma disease. We examined the clinical records of 137 children. We excluded eight patients because of neurological and genetic conditions. Children with recurrent wheeze/asthma ( N = 28) were younger ( p = 0.002) and leaner ( p = 0.013) compared to non-affected children ( N = 98). Children with wheeze/asthma and unaffected ones had a similar obstructive apnea-hypopnea index ( p = 0.733) and oxygen desaturation index ( p = 0.535). The logistic regression analysis, in which the condition of wheeze/asthma (yes/no) was a dependent variable, while demographic (age, sex, body mass index (BMI) Z -score) and polygraphic results during sleep (obstructive apnea-hypopnea index, central apnea index, peripheral oxygen saturation (SpO₂), and snoring) were covariates, showed that children with wheeze/asthma had higher central apnea index (Exp(B) = 2.212; Wald 6.845; p = 0.009). In conclusion, children with recurrent wheeze/asthma showed an increased number of central sleep apneas than unaffected children. This finding may suggest a dysfunction of the breathing control in the central nervous system during sleep. Systemic or central inflammation could be the cause., Competing Interests: The authors declare no conflict of interest.

Structured Light Plethysmography (SLP) is a non-invasive method to study chest and abdominal movement during breathing and can identify abnormal contributions of the different regions of the chest. M.D hospitalized for pneumonia, underwent SLP and spirometry at admission (T0), after 48 hours (T1), and after one month (T2). SLP parameters showed expiratory flow limitation, information consistent with the spirometric parameters collected, and reduced motion in the area effected by pneumonia, with improvement and normalization at T1 and T2. This method gave useful information about the contribution to the respiratory movement of the lung area affected by pneumonia so we can speculate a possible use in the follow-up of children affected by pneumonia or other respiratory diseases, and who are not able to perform a spirometric test.

Background: Exposure to environmental pollutants is advocated to be a major risk factor, with increased morbidity and mortality in humans due to acute and chronic airway inflammation. The aim of the present review is to show the literature research regarding the link between the sleep-disordered breathing and exposure to indoor/outdoor pollution in children. We hypothesized that environmental air pollution can play a role in childhood sleep-disordered breathing., Methods: We conducted an electronic search in Medline (with PubMed interface), Scopus and the ISI Web of Science using the keywords "sleep" or "sleep apnea" or "sleep disordered breathing" and "pollution" and "children" in "Title/Abstract/Keywords", with language restriction (non-English paper) and no date limitation to present. The tobacco smoke pollution is well established linking and is not considered for the present subject. We examined the strength of the evidence according to the Oxford Centre for Evidence-Based Medicine [2011] and the Centre for Evidence-Based Medicine [2009]., Results: A total of 105 articles were identified, but 97 of these had to be excluded after an accurate reading of the title, abstract or full text. In the end, eight studies were selected for our analysis for a total of a total of 5,826 children. The results suggest an involvement (grade C) of environmental (not from voluptuary habits) pollution in the worsening of sleep-disordered breathing in children., Conclusions: To date, some studies reported significant differences between areas with higher and lower pollutants and the interventions on indoor pollution reduced sleep-disordered breathing in children. Therefore, although the relevance of the argument is high, the number of studies and the interest in the subject seems at this time quite limited., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Study Design: This study aimed to evaluate the diagnostic accuracy of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), midregional proatrial natriuretic peptide (MR-proANP) and midregional proadrenomedullin (MR-proADM) to distinguish bacterial from viral community-acquired pneumonia (CAP) and to identify severe cases in children hospitalized for radiologically confirmed CAP. Index test results were compared with those derived from routine diagnostic tests, i.e., white blood cell (WBC) counts, neutrophil percentages, and serum C-reactive protein (CRP) and procalcitonin (PCT) levels., Methods: This prospective, multicenter study was carried out in the most important children's hospitals (n = 11) in Italy and 433 otherwise healthy children hospitalized for radiologically confirmed CAP were enrolled. Among cases for whom etiology could be determined, CAP was ascribed to bacteria in 235 (54.3%) children and to one or more viruses in 111 (25.6%) children. A total of 312 (72.2%) children had severe disease., Results: CRP and PCT had the best performances for both bacterial and viral CAP identification. The cut-off values with the highest combined sensitivity and specificity for the identification of bacterial and viral infections using CRP were ≥7.98 mg/L and ≤7.5 mg/L, respectively. When PCT was considered, the cut-off values with the highest combined sensitivity and specificity were ≥0.188 ng/mL for bacterial CAP and ≤0.07 ng/mL for viral CAP. For the identification of severe cases, the best results were obtained with evaluations of PCT and MR-proANP. However, in both cases, the biomarker cut-off with the highest combined sensitivity and specificity (≥0.093 ng/mL for PCT and ≥33.8 pmol/L for proANP) had a relatively good sensitivity (higher than 70%) but a limited specificity (of approximately 55%)., Conclusions: This study indicates that in children with CAP, sTREM-1, MR-proANP, and MR-proADM blood levels have poor abilities to differentiate bacterial from viral diseases or to identify severe cases, highlighting that PCT maintains the main role at this regard., Competing Interests: The authors have declared that no competing interests exist.

Background: Asthma is a pathology characterized by chronic inflammation and remodeling of the airways., Objectives: To evaluate the effect of montelukast treatment on markers of airway inflammation and remodeling in children with mild asthma and to evaluate if the administration of montelukast to children with mild asthma could inhibit the release of matrix metallopeptidase 9, matrix metallopeptidase 12, tissue inhibitor of metalloproteinase 1, transforming growth factor beta 1, C-peptide terminal procollagen type (PICP), and eosinophils count, which are markers of inflammation and remodeling in induced sputum., Methods: Thirty children with mild asthma were recruited. They were randomized into two groups: group A received montelukast and as needed beta-2-agonist for 8 weeks (T0-T1), whereas group B received placebo and as needed beta-2-agonist for 8 weeks. After 2 weeks of washout (T1-T2), they were reallocated for treatment according a crossover design (T2-T3). Tests for lung function, oral exhaled nitric oxide, and hypertonic saline solution-induced sputum level were performed at T0-T1-T2-T3., Results: In the placebo group, the PICP mean (standard deviation [SD]) value at baseline was 2279.42 ± 2530.77 pg/mL and 1916.00 ± 2178.75 pg/mL after treatment. Patients treated with montelukast, in contrast, showed a baseline mean (SD) value of 2439.29 ± 2834.51 pg/mL and 1406.72 ± 1508.65 pg/mL after treatment. The difference between the mean pre- and posttreatment decrease of PICP in the two groups was statistically significant (delta -690.21 pg/mL [95% confidence interval, -1220.83 to -159.5844 pg/mL]; p = 0.011). The mean (SD) percentage of the eosinophil count in the placebo group was 3.11 ± 4.03% at baseline and 4.86 ± 5.83% after treatment. Patients treated with montelukast, in contrast, showed a percentage mean (SD) value at baseline of 4.51 ± 5.48% and, after treatment, of 3.06 ± 3.29%. The difference between the mean pre- and posttreatment decrease of the percentage eosinophil count in the two groups was statistically significant (delta -2.76% [95% confidence interval, -4.65 to -0.87%]; p = 0.004)., Conclusion: This study investigated in vivo effects of montelukast on remodeling markers. The reduction of PICP levels and eosinophil count supported the hypothesis that montelukast can modulate collagen deposition in airways and reduce eosinophilic airway inflammation. Clinical Trials database clinicaltrials.gov (NCT00875082).

Recurrent wheezing have a significant morbidity and it's estimated that about one third of school-age children manifest the symptom during the first 5 years of life. Proper identification of children at risk of developing asthma at school age may predict long-term outcomes and improve treatment and preventive approach, but the possibility to identify these children at preschool age remains limited. For many years authors focused their studies to identify early children with recurrent wheezing at risk to develop asthma at school age. Different phenotypes have been proposed for a more precise characterization and a personalized plan of treatment. The main criticism concerns the inability to define stable phenotypes with the risk of overestimating or underestimating the characteristics of symptoms in these children. The aim of this review is to report the recent developments on the diagnosis and treatment of recurrent paediatric wheezing.

Background: The effect of allergen avoidance on airway inflammation is similar to that observed with treatment with inhaled steroids, whereas inhaled steroids have no effect on oxidative stress-induced inflammation., Objective: The aim of this study was to retrospectively evaluate the potential effect of an antioxidant dietary supplement on exhaled nitric oxide over a month in pediatric patients on stable antiasthma treatment., Methods: Forty-seven children with moderate-to-severe asthma were retrospectively evaluated. All the patients were sensitive to Dermatophagoides pteronyssinus and Dermatophagoides farinae, and they were receiving the minimum inhaled corticosteroid dosage required to maintain adequate control. Within a few weeks of admission at Misurina Hospital in the Alps, the regular treatment was gradually reduced, then some children who were receiving a daily dose of inhaled corticosteroids, ≤200 mcg of fluticasone propionate, were prescribed a nutraceutical dietary supplement for at least 4 weeks. Lung function and fractional exhaled nitric oxide (FeNO) measurements were recorded at the beginning and after 1 month of the dietary supplementation., Results: Baseline lung function and FeNO values did not differ between the two groups of patients. After 4 weeks of nutraceutical supplementation, FeNO values decreased, from 19.00 ppb (interquartile range, 14-31 ppb) to 11.00 ppb (interquartile range, 6-23 ppb) (p = 0.03). No significant reduction was observed in the group that did not receive the supplementation, and no significant difference between groups was observed, both at baseline and after 4 weeks of nutraceutical supplementation., Conclusion: Supplementation with a nutraceutical of antioxidants and anti-inflammatory compounds, such as curcumin, resveratrol, soy phospholipids, zinc, selenium, and vitamin D, may be associated with reduced airway inflammation, as documented by a fall in FeNO.

Wheezing is a common condition in pediatric practice, it can be defined as a musical sound, high-pitched and continuous, emitting from the chest during breath exhalation. Although almost 50% of children experiences wheeze in the first 6 years of life, only 40% of them will report continued wheezing symptoms after childhood. The classification of wheeze in preschool children is more difficult compared to school aged children. It is based on the onset and duration of symptoms and divided children in three categories: transient early wheezing, non-atopic wheezing and atopic wheezing/asthma. History and physical examination, skin prick test, exhaled nitric oxide, lung function test are the parameter to evaluate children with wheezing. The aim of management of wheezing is to finalize the control of symptoms, reduce exacerbations and improve the quality of life. All guidelines underline the complexity in making a diagnosis of asthma under five years and the need to identify phenotypes that may help paediatricians in the therapeutic choices., (© 2013.)

Colostrum contains cellular components that convey immunological protection to offspring. In the present study the main subsets of lymphocytes present in colostrum and in peripheral blood of healthy screened mothers were compared through the evaluation of >15 different flow cytometry markers. Colostrum and peripheral blood samples were collected within 3 days after full-term delivery. Flow cytometry assays and laboratory tests were performed soon after collection. Among B cells, percentages of CD19(+)CD5(+) cells, pertaining to natural immunity system, were significantly higher in colostrum than in peripheral blood (33 vs. 5%, p = 0.047). CD4(+) T cells, effector cells (CD45RA(+)/CD27(-)) and effector memory cells (CD45RA(-)/CD27(-)) were significantly higher in colostrum (p < 0.001) than in peripheral blood, as well as activated CD4(+) T cells (HLA(-)DR(+)) (36% vs. 6% p = 0.0022) and CD4(+) terminally differentiated effector T cells (CD57(+)) (p < 0.001). With regards to CD8(+) T cells, a comparable significant increase in effector (p < 0.02) and effector memory cells (p < 0.001) was also observed. Moreover, an increased surface expression of HLA-DR and CD57 (p < 0.001) on CD8(+) T cells in colostrum was detected. Colostrum contains a different distribution of lymphocyte subsets with respect to peripheral blood from mothers, confirming the observation that lymphocytes probably migrate in milk in a selective way. Colostrum T and B lymphocytes appear to be enriched with subsets possessing effector functions or belonging to the innate immune system, what could transfer a prompt line of defence to offspring.