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Abstract Short-acting bronchodilators are a class of medications commonly used to treat asthma, chronic obstructive pulmonary disease, and other respiratory conditions. The use of these medications has evolved over time as we have gained a better understanding of their effectiveness and safety in the pediatric population. This comprehensive review synthesizes the current understanding of short-acting β2-agonists and short-acting anticholinergics in children. It addresses indications, contraindications, safety considerations, and highlights areas where further research is needed to guide the most effective use of short-acting bronchodilators.

Neurotrophins (NTs) are four small proteins produced by both neuronal and non-neuronal cells; they include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). NTs can exert their action through both genomic and non-genomic mechanisms by interacting with specific receptors. Initial studies on NTs have identified them only as functional molecules of the nervous system. However, recent research have shown that some tissues and organs (such as the lungs, skin, and skeletal and smooth muscle) as well as some structural cells can secrete and respond to NTs. In addition, NTs perform several roles in normal and pathological conditions at different anatomical sites, in both fetal and postnatal life. During pregnancy, NTs are produced by the mother, placenta, and fetus. They play a pivotal role in the pre-implantation process and in placental and embryonic development; they are also involved in the development of the brain and respiratory system. In the postnatal period, it appears that NTs are associated with some diseases, such as sudden infant death syndrome (SIDS), asthma, congenital central hypoventilation syndrome (CCHS), and bronchopulmonary dysplasia (BPD).

Elevated serum IgE levels serve as a critical marker for uncovering hidden immunological disorders, particularly inborn errors of immunity (IEIs), which are often misdiagnosed as common allergic conditions. IgE, while typically associated with allergic diseases, plays a significant role in immune defense, especially against parasitic infections. However, extremely high levels of IgE can indicate more severe conditions, such as Hyper-IgE syndromes (HIES) and disorders with similar features, including Omenn syndrome, Wiskott-Aldrich syndrome, and IPEX syndrome. Novel insights into the genetic mutations responsible for these conditions highlight their impact on immune regulation and the resulting clinical features, including recurrent infections, eczema, and elevated IgE. This narrative review uniquely integrates recent advances in the genetic understanding of IEIs and discusses how these findings impact both diagnosis and treatment. Additionally, emerging therapeutic strategies, such as hematopoietic stem cell transplantation (HSCT) and gene therapies, are explored, underscoring the potential for personalized treatment approaches. Emphasizing the need for precise diagnosis and tailored interventions aims to enhance patient outcomes and improve the quality of care for those with elevated IgE levels and associated immunological disorders.

The intersociety consensus document “UPDATE - 2022 Italian guidelines on the management of bronchiolitis in infants” aimed to update the previously published clinical practice guidelines on the prevention and treatment of bronchiolitis in newborns and infants. Moreover, due to the tremendous disagreement among the clinical practice guidelines and approaches to viral bronchiolitis, the new intersociety consensus document also aimed to unify diagnostic and therapeutic criteria, reinforce the current recommendations, and integrate the most recent advances for optimal care of viral bronchiolitis. The document addresses care in both hospitals and primary care.

Brain development is a complex process that begins during pregnancy, and the events occurring during this sensitive period can affect the offspring’s neurodevelopmental outcomes. Respiratory viral infections are frequently reported in pregnant women, and, in the last few decades, they have been related to numerous neuropsychiatric sequelae. Respiratory viruses can disrupt brain development by directly invading the fetal circulation through vertical transmission or inducing neuroinflammation through the maternal immune activation and production of inflammatory cytokines. Influenza virus gestational infection has been consistently associated with psychotic disorders, such as schizophrenia and autism spectrum disorder, while the recent pandemic raised some concerns regarding the effects of severe acute respiratory syndrome coronavirus 2 on neurodevelopmental outcomes of children born to affected mothers. In addition, emerging evidence supports the possible role of respiratory syncytial virus infection as a risk factor for adverse neuropsychiatric consequences. Understanding the mechanisms underlying developmental dysfunction allows for improving preventive strategies, early diagnosis, and prompt interventions.

We report a case of a 40-day-old patient admitted to the neonatal and paediatric intensive care unit for severe cardiovascular failure with an initial sinus rhythm. The first diagnostic hypothesis was septic shock, thus antibiotics, fluid resuscitation, inotropic drugs and ventilatory supportwere immediately started. After achieving haemodynamic stability, a new cardiovascular failure occurred with supraventricular tachycardia (SVT), making diagnosis of cardiogenic shock. Cardiogenic shock should be considered, although it is a rare cause of shock in children. SVT may be a cause of cardiogenic shock, therefore it should be diagnosed whit the aid of a cardiorespiratory monitor, which represents a useful device in the differential diagnosis of the various types of shock.

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Hypovolemic shock is a circulatory failure, due to a loss in the effective circulating blood volume, that causes tissue hypoperfusion and hypoxia. This condition stimulates reactive oxygen species (ROS) and pro-inflammatory cytokine production in different organs and also in the central nervous system (CNS). Levosimendan, a cardioprotective inodilator, and dobutamine, a β1-adrenergic agonist, are commonly used for the treatment of hypovolemic shock, thanks to their anti-inflammatory and antioxidant effects. For this reason, we aimed at investigating levosimendan and dobutamine’s neuroprotective effects in an “in vitro” model of lipopolysaccharide (LPS)-induced neuroinflammation. Human microglial cells (HMC3) were challenged with LPS (0.1 µg/mL) to induce an inflammatory phenotype and then treated with levosimendan (10 µM) or dobutamine (50 µM) for 24 h. Levosimendan and dobutamine significantly reduced the ROS levels and markedly increased Nrf2 and HO-1 protein expression in LPS-challenged cells. Levosimendan and dobutamine also decreased p-NF-κB expression and turned off the NLRP3 inflammasome together with its downstream signals, caspase-1 and IL-1β. Moreover, a reduction in TNF-α and IL-6 expression and an increase in IL-10 levels in LPS-stimulated HMC3 cells was observed following treatment. In conclusion, levosimendan and dobutamine attenuated LPS-induced neuroinflammation through NF-κB pathway inhibition and NLRP3 inflammasome activation via Nrf2/HO-1 signalling, suggesting that these drugs could represent a promising therapeutic approach for the treatment of neuroinflammation consequent to hypovolemic shock.

This review provides a concise overview of preventive measures against dust mite allergies in pediatric populations, emphasizing the need for a comprehensive and evolving approach. Dust mites, ubiquitous microscopic arachnids, pose a significant threat to children’s health, triggering allergies and asthma. Traditional preventive strategies such as regular cleaning, mattress covers, and humidity control are essential but warrant refinement. Empowering children through personalized hygiene education and exploring innovative bedding solutions showcase a forward-thinking paradigm. Collaboration with healthcare professionals and embracing technology-driven solutions ensures a holistic and adaptable approach to safeguarding pediatric health against dust mite-related ailments. This abstract underscores the importance of continually reassessing and innovating preventive measures to create resilient and health-conscious living environments for children.

Respiratory viruses represent the most frequent cause of mortality, morbidity and high healthcare costs for emergency visits and hospitalization in the pediatric age. Respiratory viruses can circulate simultaneously and can potentially infect the same host, determining different types of interactions, the so-called viral interference. The role of viral interference has assumed great importance since December 2019, when the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) came on the scene. The aim of this narrative review is to present our perspective regarding research in respiratory virus interference and discuss recent advances on the topic because, following SARS-CoV-2 restrictions mitigation, we are experimenting the co-circulation of respiratory viruses along with SARS-CoV-2. This scenario is raising many concerns about possible virus-virus interactions, both positive and negative, and the clinical, diagnostic and therapeutic management of these coinfections. Moreover, we cannot rule out that also climatic conditions and social behaviours are involved. Thus, this situation can lead to different population epidemic dynamics, including changes in the age of the targeted population, disease course and severity, highlighting the need for prospective epidemiologic studies and mathematical modelling able to predict the timing and magnitude of epidemics caused by SARS-CoV-2/seasonal respiratory virus interactions in order to adjust better public health interventions.

Background: Dupilumab has been shown to be a safe and effective drug for the treatment of atopic dermatitis (AD) in children from 6 months to 11 years in randomized clinical trials. Aim: The aim of this real-life study was to determine the effectiveness in disease control and safety of dupilumab at W52 in moderate-to-severe AD children aged 6-11 years. Methods: All data were collected from 36 Italian dermatological or paediatric referral centres. Dupilumab was administered at label dosage with an induction dose of 300 mg on day 1 (D1), followed by 300 mg on D15 and 300 mg every 4 weeks (Q4W). Treatment effect was determined as overall disease severity, using EASI, P-NRS, S-NRS and c-DLQI at baseline, W16, W24, and W52. Ninety-six AD children diagnosed with moderate-to-severe AD and treated with dupilumab were enrolled. Results: Ninety-one (94.8%) patients completed the 52-week treatment period and were included in the study. A significant improvement in EASI score, P-NRS, S-NRS and c-DLQI was observed from baseline to weeks 16, 24 and 52. Conclusions: Our real-life data seem to confirm dupilumab effectiveness and safety in paediatric patients. Moreover, our experience highlighted that patients achieving clinical improvement at W16 preserved this condition over time.

Abstract Bronchiolitis is an acute respiratory illness that is the leading cause of hospitalization in young children. This document aims to update the consensus document published in 2014 to provide guidance on the current best practices for managing bronchiolitis in infants. The document addresses care in both hospitals and primary care. The diagnosis of bronchiolitis is based on the clinical history and physical examination. The mainstays of management are largely supportive, consisting of fluid management and respiratory support. Evidence suggests no benefit with the use of salbutamol, glucocorticosteroids and antibiotics with potential risk of harm. Because of the lack of effective treatment, the reduction of morbidity must rely on preventive measures. De-implementation of non-evidence-based interventions is a major goal, and educational interventions for clinicians should be carried out to promote high-value care of infants with bronchiolitis. Well-prepared implementation strategies to standardize care and improve the quality of care are needed to promote adherence to guidelines and discourage non-evidence-based attitudes. In parallel, parents' education will help reduce patient pressure and contribute to inappropriate prescriptions. Infants with pre-existing risk factors (i.e., prematurity, bronchopulmonary dysplasia, congenital heart diseases, immunodeficiency, neuromuscular diseases, cystic fibrosis, Down syndrome) present a significant risk of severe bronchiolitis and should be carefully assessed. This revised document, based on international and national scientific evidence, reinforces the current recommendations and integrates the recent advances for optimal care and prevention of acute bronchiolitis.

Pleural empyema, a severe complication of bacterial pneumonia, is a rare entity in the neonatal period. Treatment with systemic antibiotics and tube drainage may fail because of the thick viscous fluid, bacterial products with fibrin deposition, and multiple involvement. Intrapleural fibrinolytic therapy with urokinase is an effective and non-invasive treatment option that avoids surgical intervention, although its use in neonates has not been studied extensively. In this report, we describe the case of a 39-day-old male newborn with pneumonia and pleural empyema, treated successfully with antibiotics, chest tube drainage and intrapleuralurokinase.

In light of the most significant burden of COVID-19 in terms of severe disease and deaths, great progress have been made on the vaccination front with a significant reduction in the severe disease course, rate of hospitalization and deaths, especially in the older population, and also suffering from chronic diseases. Looking at the paediatric population, World Health Organization (WHO) and Food Drug Administration (FDA) are currently reviewing the scientific evidence on the need and timing of vaccinating the paediatric population with the currently available COVID-19 vaccines. Herein, we briefly summarized the impact of COVID-19 on the pediatric population and reported the most recent evidence on the efficacy and safety of COVID-19 vaccination in children

Several studies have shown the effects of e-cigarettes in adults. Nowadays, few data are available in the pediatric population. This study aims to assess the relationship between asthma exacerbations and home exposure to e-cigarettes. We conducted a pilot, retrospective, monocenter, observational study. Demographic and clinical data were collected, including number of asthma exacerbations, need for rescue therapy and/or therapeutic step-up, and Asthma Control Test (ACT) and children-Asthma Control Test (c-ACT) scores. The cohort consisted of 54 patients (5–17 years old), divided into two groups: A, including patients exposed to e-cigarette aerosols; B, including unexposed patients. The statistical analysis showed no relevant variation in the number of asthma symptomatic days and need for rescue therapy in group A versus group B (p = 0.27 and 0.19, respectively). There were no statistically significant variations when also considering the number of patients who needed a therapeutic step-up (p = 0.3). The mean values of ACT and c-ACT were, respectively, 17.2 ± 7.6 and 18.3 ± 5.6 in group A and 19.6 ± 3.8 and 14.6 ± 5.8 in group B (p = 0.3 and 0.4, respectively). Although we did not find a statistically significant correlation between second-hand e-cigarette exposure and asthma exacerbations, our findings suggest that asthmatic children exposed second-hand to e-cigarettes may have increased risk of asthma symptomatic days. Future research is warranted.

Background: Despite the increasing interest in biologics for the management of allergic diseases, sparse real-world data are still available in the pediatric population. This study aimed to evaluate the early real-life efficacy and safety of omalizumab for patients with moderate-to-severe asthma and chronic spontaneous urticaria (CSU), and Dupilumab for patients with moderate-to-severe atopic dermatitis (AD). Methods: A prospective study enrolling children aged 6–18 years was designed to assess the efficacy and safety of biologic drugs at 16 weeks of treatment (T1). The effectiveness was measured using validated questionnaires (ACQ-5 for asthma, UAS7 for CSU, and EASI score for AD). Secondary outcome measures included reductions in inhaled corticosteroid (ICS) dosages, asthma-related hospitalizations/exacerbations, and quality of life (QoL) indicators (iNRS, sNRS, DLQI/cDLQI) for CSU and AD. Safety was expressed according to the descriptions of adverse events provided by EMA and FDA. Results: The study cohort consisted of eighteen children (mean age 12.9 ± 3.4 years). The omalizumab treatment significantly reduced ACQ-5 and UAS7 scores (p = 0.002 and p < 0.001, respectively). In patients with asthma, decreased ICS dosage and hospitalization/exacerbation rates were observed. QoL parameters significantly improved in CSU and AD patients. No severe adverse events were reported for either treatment. Conclusions: Our findings validate omalizumab and dupilumab as effective and safe therapeutic options for managing moderate-to-severe allergic diseases in children and adolescents.

Abstract Nutrition has a central role in child growth with long-term effects, and nutrition management in gastrointestinal disorders has great importance for child health and disease outcomes. Breast milk is the first choice for infant nutrition. When it is not available, special milk formulas are adopted in specific conditions, as a medical treatment. Moving from the strong guidelines, recommendations and the new possibilities of special diet treatment, this review will analyse the current diet treatment in different gastrointestinal disorders, including food allergy, cystic fibrosis, inflammatory bowel diseases, short-bowel syndrome, gastroesophageal reflux, and eosinophilic esophagitis. The review also aimed at understanding the role of diet and its effects on these diseases. The growth monitoring can prevent malnutrition and improve disease outcomes, particularly in children, and an appropriate dietary management targeted to specific disorders is the best therapeutic choice alone or in combination with pharmacological therapy.

Vernal keratoconjunctivitis (VKC) is a severe ocular allergic disease characterized by chronic inflammation of the cornea and conjunctiva that may lead to loss of visual acuity and blindness. The disease occurs primarily in children and is more common in geographical regions characterized by warm temperatures and high humidity. The clinical manifestations of VKC, when inadequately treated, may lead to severe complications and corneal damage. The prevalence of allergen sensitization, specific serum immunoglobulin E (IgE), and specific tear IgE was reported in approximately 55%–60% of patients with VKC, confirming the involvement of IgE-mediated and non−IgE-mediated mechanisms in the pathophysiology of the condition. This article explores current knowledge on the immunological pathways of VKC and the role of the monoclonal anti-IgE antibody, omalizumab, in its management. The review evaluated the effects of omalizumab beyond the direct IgE-mediated reactions and discusses its potential as a therapeutic target for VKC. Multiple retrospective analyses, case series, and case reports have reported the effectiveness of omalizumab in the management of VKC. A summary of the clinical data from these studies revealed that in children with VKC omalizumab treatment was well tolerated with improvement or resolution of ocular symptoms, reduction in steroid use, and enhancement of quality of life. Omalizumab may serve as a promising treatment option for VKC due to its ability to target both IgE-mediated and non−IgE-mediated pathophysiological pathways. Larger, controlled clinical trials are needed to support these findings.

Abstract Background The cystic fibrosis transmembrane conductance regulator (CFTR) gene has been traditionally linked to cystic fibrosis (CF) inheritance in an autosomal recessive manner. Advances in molecular biology and genetics have expanded our understanding of the CFTR gene and its encoding products expressed in different tissues. Aim The study’s aim consists of reviewing the different pathological CF phenotypes using the existing literature. We know that alterations of the CFTR protein’s structure may result in different pathological phenotypes. Methods Open sources such as PubMed and Science Direct databases have been used for this review. We focused our selection on articles published within the last 15 years. Critical terms related to the CFTR protein have been used: “CFTR AND cancer,” “CFTR AND celiac disease,” “CFTR AND pancreatitis,” “children,” “adults,” “genotype,” “phenotype,” “correlation,” “mutation,” “CFTR,” “diseases,” “disorders,” and “no cystic fibrosis.” Results We analyzed 1,115 abstracts in total. Moreover, only 189 were suitable for the topic. We focused on the role of CFTR in cancer, gastrointestinal disorders, respiratory diseases, reproductive system, and systemic hypertension. Conclusions Mutations in CFTR gene are often associated with CF. In this review, we highlighted the broad spectrum of alterations reported for this gene, which may be involved in the pathogenesis of other diseases. The importance of these new insights in the role of CFTR relies on the possibility of considering this protein/gene as a novel therapeutic target for CF- and CFTR-related diseases.

Abstract BNT162b2 vaccine, developed by BioNTech and Pfizer ha recently approved for use in children aged 5 to 11 years. Recent data show evidence of safety on the administration and serious adverse events have been rarely reported. However, allergic systemic reactions could occur. In some cases, a correct allergic evaluation allows identifying patients at risk of developing an anaphylactic reaction. Risk assessment of allergic reactions to COVID-19 vaccines is useful to limit contraindications to vaccination and help to safely vaccinate people supposed to be at risk of allergic reactions.

Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are genetic respiratory diseases featured by chronic upper and lower airway inflammation and infection, mainly due to impaired mucociliary clearance due to genetic mutations. Sleep is crucial to healthy children’s normal physical and psychological development and has an important value in chronic respiratory diseases. Impaired sleep quality, such as sleep deprivation or insufficient sleep during the night, and sleep respiratory disorders (SRDs) are common in 5% to 30% of the general population. Sleep disruption leads to attention deficits, daytime sleepiness, fatigue and mood disorders and correlates to a worsened quality of life. Furthermore, sleep respiratory disorders (SRSs) are under-recognized comorbidities in CF and PCD patients. SRSs include a spectrum of symptoms ranging from primary snoring through upper airway resistance to obstructive sleep apnea (OSA), nocturnal hypoventilation and hypoxemia occurring in people with moderate to severe lung disease and damaging the disease-related outcomes and quality of life. Effective screening during sleep with polysomnography is very important for the timely initiation of efficacious treatments and to prevent worsened respiratory, metabolic and cardiovascular outcomes. However, the impact of SRDs on health and quality of life is still underinvestigated.

Abstract Introduction Significant variations in the management of bronchiolitis are often recorded, and, in parallel, to recommend a univocal clinical approach is challenging and still questioned. This study is aimed to evaluate the diagnostic and therapeutic management of bronchiolitis in children adopted by Italian pediatricians following the national guidelines. Material and Methods A survey study was designed and carried out by sending an email an open‐ended questionnaire developed by an expert panel of the Scientific Board of the Italian Society of Pediatric Allergology and Immunology (SIAIP). Questions were designed according to the national intersociety consensus document on treatment and prevention of bronchiolitis in newborns and infants. Results Overall, 234 pediatricians were taking part in the study. When diagnosing bronchiolitis, only 44.01% (103/234) of participants correctly followed the national guidelines. All participants (100%) would perform laboratory tests and/or radiological exams. 44.01% administered oxygen (O2) when O2 saturation was minor than 92%. About the therapeutic regimen, marked discrepancies between national guidelines and recorded answers were reported. Indications for hospital admission and discharge criteria were in line with the national guidelines. Conclusions There is a significant practice variation in the management of acute bronchiolitis among Italian physicians. Some wrong attitudes need to be further discouraged, such use of diagnostic procedures and therapeutic approaches. Further research is urgently required to define the best management of patients with bronchiolitis and implement strategies to standardize care and improve the quality of care.

The current literature shows mixed results relating to the significance of environmental exposure, such as owning a pet, and the development of atopy in children. Our review aimed to collect the most recent evidence on the association between early-life cat and dog ownership and the development of allergy and asthma. A comprehensive literature review was performed using PubMed and Scopus. The search included the main keywords of our PICO: (((early exposure) AND (children) AND (allergy)) OR (asthma)) AND (dog) OR (cat). Randomized controlled trials (RCTs), case–control studies, clinical trials, meta-analyses, and systematic reviews of children within the last five years (2018–2023) were searched and included. During the search process, 52 articles from PubMed and 43 from Scopus were found. A total of 17 articles were deemed to be suitable and included. Fairly consistent results regarding early exposure to pets, in particular dogs, and the prevention of food allergies have been described. Furthermore, there seems to be a protective effect against allergy and asthma in relation to the number of pets owned. The likelihood of a child developing allergy and asthma seems to be influenced by various factors, including the child’s genetic background and early exposure to different environmental factors, including allergens that may interact with the gut microbiota and immune system.

Background: The COVID-19 pandemic has had a significant impact on the epidemiology of respiratory viruses. Non-pharmaceutical interventions (NPIs) led to a dramatic reduction in respiratory infections. However, the long-term effects on respiratory virus epidemiology remain unclear. Materials and Methods: We conducted a comparative study on hospitalized pediatric patients with respiratory illness during two seasons: 1 October 2021 to 15 March 2022 and 1 October 2022 to 15 March 2023. We compared the type of virus, mean duration of hospitalization, and disease severity. Results: In the first season, 47.1% of patients (65/138) tested positive for at least one respiratory virus, with respiratory syncytial virus (RSV) being the most frequent (23.2%). In the second season, 82.9% of patients (102/123) tested positive, with RSV and Rhinovirus being the most prevalent (28.38% and 27.03%, respectively). Other viruses, such as Influenza A/B, Metapneumovirus, and Adenovirus, also showed increased prevalence. Disease severity and mean duration of hospitalization were similar between the two seasons. Conclusions: Our study highlights increased prevalence in respiratory viruses, including RSV and Rhinovirus, following the easing of NPIs. The prevalence in respiratory viruses, including RSV and Rhinovirus, increased in the second season compared to the first one. Interestingly, RSV’s peak incidence shifted from February to November. The emergence of rhinovirus as the most prevalent respiratory virus during certain months suggests viral competition and dynamic changes in viral circulation. The overall severity of respiratory infections remained relatively stable between the seasons.

Respiratory syncytial virus (RSV) infection is recognized as an important risk factor for wheezing and asthma, since it commonly affects babies during lung development. While the role of RSV in the onset of atopic asthma is widely recognized, its impact on the onset of non-atopic asthma, mediated via other and independent causal pathways, has long been also suspected, but the association is less clear. Following RSV infection, the release of local pro-inflammatory molecules, the dysfunction of neural pathways, and the compromised epithelial integrity can become chronic and influence airway development, leading to bronchial hyperreactivity and asthma, regardless of atopic status. After a brief review of the RSV structure and its interaction with the immune system and neuronal pathways, this review summarizes the current evidence about the RSV-mediated pathogenic pathways in predisposing and inducing airway dysfunction and non-allergic asthma development.

Background Aspergillus fumigatus is a common saprophytic fungus causing allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis (CF). The recommended first-line treatment for ABPA is oral steroids, followed by antifungal therapy. However, both treatments are not free from adverse effects; thus, efforts are being made to identify new drugs showing the same effectiveness but with fewer or no side-effects. Therein, biologic drugs have been significantly implemented in clinical practice in treating ABPA in patients with CF. Objective To systematically review the available literature, providing evidence for the administration of biologic drugs as a new potential treatment of ABPA in both the paediatric and adult populations with CF. Methods A systematic review of the literature published between January 2007 and July 2021 was performed, using a protocol registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42021270932). Results A total of 21 studies focusing on the use of biologics in treating ABPA in CF patients was included. We highlighted a paucity of data providing evidence for biologic drug use in ABPA. Conclusion Scientific evidence is insufficient to support firm conclusions and randomised clinical trials are urgently required to investigate the efficacy and safety of biologics for ABPA in CF patients.

Since the beginning of 2020, a remarkably low incidence of respiratory virus hospitalizations has been reported worldwide. We prospectively evaluated 587 children, aged

High-flow nasal cannula (HFNC) oxygen therapy has rapidly become a popular modality of respiratory support in pediatric care. This is undoubtedly due to its ease of use and safety, which allows it to be used in a wide variety of settings, ranging from pediatric intensive care to patients' homes. HFNC devices make it possible to regulate gas flow and temperature, as well as allowing some nebulized drugs to be administered, features very useful in children, in which the balance between therapeutic effectiveness and adherence to treatment is pivotal. Although the physiological effects of HFNC are still under investigation, their mechanisms of action include delivery of fixed concentration of oxygen, generation of positive end-expiratory pressure, reduction of the work of breathing and clearance of the nasopharyngeal dead space, while providing optimal gas conditioning. Nevertheless, current evidence supports the use of HFNC mainly in moderate-to-severe bronchiolitis, whereas for asthma exacerbations and breath sleeping disorders there is a lack of randomized controlled trials comparing HFNC to continuous positive airway pressure (CPAP) and non-invasive ventilation (NIV), which are essentials for the identification of response and non-response predictors. In this regard, the development of clinical guidelines for HFNC, including flow settings, indications, and contraindications is urgently needed.

Abstract Background Despite to PFAPA syndrome is considered a benign and self-limited condition in childhood its impact on patients and families can be remarkable in many cases. Currently, the therapeutic options for managing are non-specific and no consensus exists about the best treatment to use. Pidotimod has been suggested as a new potential treatment in PFAPA syndrome for its immunodulatory effects. We conducted a preliminary, prospective, controlled, open, cross-over trial to assess the efficacy and the safety of Pidotimod in the treatment of children with PFAPA syndrome. Methods 22 children with PFAPA syndrome were randomly allocated to treatment with pidotimod (with 2 vials of 400 mg daily) in combination with betamethasone 0.5–1 mg on need, based on parents/caregivers’ decision (group A) or betamethasone 0.5-1 mg on need, based on parents/caregivers’ decision (group B). Each treatment period was for 3 months (Phase 1), after that patients were switched to the other arm for other 3 months (Phase 2). Efficacy was expressed in terms of number of episodes of fever, pharyngitis, or aphthous stomatitis, as well as the additional use of betamethasone on need. Safety and tolerability of the Pidotimod were evaluated on the basis of the number and type of adverse events (AEs) recorded during the treatment. Results Patients receiving Pidotimod and use betametasone showed a significant decrease in frequency of fevers (p = 0.002); number of episodes of pharyngitis (p = 0.049); aphthous stomatitis (p = 0.036) as well as the betamethasone use on need (p = 0.007). Overall, 19/22 (86.4%) showed benefits from Pidotimod administration. The safety profile of Pidotimod was excellent as no serious adverse events have been reported in the treated groups. Conclusions We firstly showed that high dosage of Pidotimod could be an effective and safe to reduce the PFAPA attacks in children.

Abstract Background Recurrent respiratory infections (RRIs) are defined by the presence of at least one of the following criteria: (i) > 6 annual respiratory infections (RIs); (ii) > 1 monthly RIs involving the upper airways from September to April; (iii) > 3 annual RIs involving the lower airways represent a very common health problem in the first years of life. We conducted a multi-centre, prospective, single-open study to assess the efficacy and the safety of Streptococcus salivarius 24SMBc and Streptococcus oralis 89a in the prevention of upper respiratory tract infections (URTIs) in children. Methods Ninety-one children (M:F = 47:44, mean age 7.4 ± 2.3 years) with RRIs were enrolled in the study between September and November 2018. At baseline, children received Streptococcus salivarius 24SMBc and Streptococcus oralis 89a as 2 puffs for nostril twice/day for 7 days/months. The treatment lasted for 3 consecutive months. Efficacy was expressed in terms of absence or presence of fever, cough, bronchospasm, rhinorrhea and otalgia, at 1 month (T1), and 3 (T3) months. Safety and tolerability of the probiotic were evaluated on the basis of the number and type of adverse events (AEs) recorded during the treatment. Results Children treated with Streptococcus salivarius 24SMBc and Streptococcus oralis 89a showed a significant decrease of symptoms including episodes of fever, cough, bronchospasm, rhinorrhea, and otalgia (p 0.05). Conducting a subgroup analysis according to the age, it has been reported that children aged 1–3 years old showed an improvement in all symptoms, however, they become statistically significant only at the end of the 3 months of treatment (p

Overt and subclinical maternal infections in pregnancy can have multiple and significant pathological consequences for the developing fetus, leading to acute perinatal complications and/or chronic disease throughout postnatal life. In this context, the current concept of pregnancy as a state of systemic immunosuppression seems oversimplified and outdated. Undoubtedly, in pregnancy the maternal immune system undergoes complex changes to establish and maintain tolerance to the fetus while still protecting from pathogens. In addition to downregulated maternal immunity, hormonal changes, and mechanical adaptation (e.g., restricted lung expansion) make the pregnant woman more susceptible to respiratory pathogens, such as influenza virus, respiratory syncytial virus (RSV), and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Depending on the infectious agent and timing of the infection during gestation, fetal pathology can range from mild to severe, and even fatal. Influenza is associated with a higher risk of morbidity and mortality in pregnant women than in the general population, and, especially during the third trimester of pregnancy, mothers are at increased risk of hospitalization for acute cardiopulmonary illness, while their babies show higher risk of complications such as prematurity, respiratory and neurological illness, congenital anomalies, and admission to neonatal intensive care. RSV exposure in utero is associated with selective immune deficit, remodeling of cholinergic innervation in the developing respiratory tract, and abnormal airway smooth muscle contractility, which may predispose to postnatal airway inflammation and hyperreactivity, as well as development of chronic airway dysfunction in childhood. Although there is still limited evidence supporting the occurrence of vertical transmission of SARS-CoV-2, the high prevalence of prematurity among pregnant women infected by SARS-CoV-2 suggests this virus may alter immune responses at the maternal-fetal interface, affecting both the mother and her fetus. This review aims at summarizing the current evidence about the short- and long-term consequences of intrauterine exposure to influenza, RSV, and SARS-CoV-2 in terms of neonatal and pediatric outcomes.

Oxygen supplementation is widely used in neonatal care, however, it can also cause toxic effects if not used properly. Therefore, it appears crucial to find a balance in oxygen administration to avoid damage as a consequence of its insufficient or excessive use. Oxygen toxicity is mainly due to the production of oxygen radicals, molecules normally produced in humans and involved in a myriad of physiological reactions. In the neonatal period, an imbalance between oxidants and antioxidant defenses, the so-called oxidative stress, might occur, causing severe pathological consequences. In this review, we focus on the mechanisms of the production of oxygen radicals and their physiological functions in determining a set of diseases grouped together as “free radical diseases in the neonate”. In addition, we describe the evolution of the oxygenation target recommendations during neonatal resuscitation and post-stabilization phases with the aim to define the best oxygen administration according to the newest evidence.

Surgery is frequently associated with excessive oxidative stress. Melatonin acts as an antioxidant and transient melatonin deficiency has been described in neonatal surgical patients. This randomized, blinded, prospective pilot study tested the hypothesis that oral melatonin supplementation in newborn infants undergoing surgery is effective in reducing perioperative oxidative stress. A total of twenty-three newborn infants requiring surgery were enrolled: 10 received a single dose of oral melatonin 0.5 mg/kg in the morning, before surgery (MEL group), and 13 newborns served as the control group (untreated group). Plasma concentrations of melatonin, Non-Protein-Bound Iron (NPBI), Advanced Oxidation Protein Products (AOPP), and F2-Isoprostanes (F2-IsoPs) were measured. Both in the pre- and postoperative period, melatonin concentrations were significantly higher in the MEL group than in the untreated group (preoperative: 1265.50 ± 717.03 vs. 23.23 ± 17.71 pg/mL, p < 0.0001; postoperative: 1465.20 ± 538.38 vs. 56.47 ± 37.18 pg/mL, p < 0.0001). Melatonin significantly increased from the pre- to postoperative period in the untreated group (23.23 ± 17.71 vs. 56.47 ± 37.18 pg/mL; pg/mL p = 0.006). In the MEL group, the mean blood concentrations of NPBI, F2-IsoPs, and AOPP significantly decreased from the pre- to the postoperative period (4.69 ± 3.85 vs. 1.65 ± 1.18 micromol/dL, p = 0.049; 128.40 ± 92.30 vs. 50.25 ± 47.47 pg/mL, p = 0.037 and 65.18 ± 15.50 vs. 43.98 ± 17.92 micromol/dL, p = 0.022, respectively). Melatonin concentration increases physiologically from the pre- to the postoperative period, suggesting a defensive physiologic response to counteract oxidative stress. The administration of exogenous melatonin in newborn infants undergoing surgery reduces lipid and protein peroxidation in the postoperative period, showing a potential role in protecting babies from the deleterious consequences of oxidative stress.

Background: Children’s interstitial lung disease (chILD) is a rare group of pediatric lung diseases affecting the lung interstitium diffusely. In this work, we focused our attention on a specific infant group of chILD, also known as “specific conditions of undefined aetiology”, including pulmonary interstitial glycogenosis (PIG) and neuroendocrine cell hyperplasia of infancy (NEHI). Methods: PubMed was searched to conduct this narrative review. We searched for articles in English using the following keywords: (1) neuroendocrine cell hyperplasia of infancy; (2) NEHI; (3) pulmonary interstitial glycogenosis; (4) PIG; (5) chILD. Results: An increasing interest and insight into these two conditions have been reported. The updated literature suggests that it is possible to look at these disorders as a continuum of diseases, rather than two different entities, since they share a pulmonary dysmaturity. Conclusions: NEHI and PIG are featured by dysmaturity of airway development and consequent respiratory distress. Understanding the underlying pathogenic mechanisms would lead to identifying new targeted therapies to ameliorate the mortality and morbidity of these rare conditions.

Background: The COVID-19 pandemic has dramatically affected the global epidemiology of other infectious respiratory diseases, leading to a significant decrease in their incidence. Hence, we aimed to characterize the epidemiology of RSV-bronchiolitis in children. Methods: children aged ≤2 years diagnosed with RSV-mediated bronchiolitis admitted to our Unit from October 2018 to December 2021, were retrospectively enrolled. Results: We included 95 patients (M/F = 46/49; mean age 7.56 ± 6.6 months). Specifically, 17 infants in 2018, 34 in 2019, 0 during 2020 lockdown, 1 during 2020 post-lockdown, and 43 in 2021. Incidence was significantly lower in 2020 compared with 2018, 2019 and 2021 (p < 0.05). No differences were found concerning need for respiratory support. Discussion: Several factors related to SARS-CoV-2 pandemic, especially restrictive measures, may have contributed to a significant reduction in hospitalizations due to RSV. The new outbreak in RSV infection-related hospitalizations reported between October and December 2021 has been suggested it may be due to an increased number of susceptible individuals to RSV infection. Conclusion: The experience of the SARS-CoV-2 outbreak has led to a marked decrease in other viral respiratory infections, such as RSV. This may pave the way for new approaches in preventing respiratory infections, highlighting the role of preventive measures.

Background: Dornase alfa (DNase) is the only mucus-degrading agent that has proven efficacy in cystic fibrosis (CF). Few studies have evaluated the effects of DNase on the lung clearance index (LCI). We report the experience of two CF centers in which LCI monitoring was used to evaluate the efficacy of DNase therapy. Methods: This is a prospective and observational study, evaluating the effects of DNase therapy on LCI values in three CF children followed at CF centers in Florence and Catania, Italy. In both centers, LCI was performed routinely, every 3–6 months, based on the clinical picture and severity of the lung disease. In this study, we evaluated the LCI before and after long-term DNase therapy. Results: DNase improved LCI values in the absence of respiratory exacerbations: in case n. 1 LCI decreased by 39% in 16 months (from 11.1 to 6.8); in case n. 2 by 20% in 12 months (from 9.3 to 7.4); in case n. 3 by 24% in 16 months (from 9.3 to 7.0). Conclusions: This case series confirms the efficacy of DNase therapy in CF children, as demonstrated by the LCI reduction in treated patients. Furthermore, our results suggest that LCI is a sensitive marker of disease and can be used for the evaluation of response to treatment.

Background Asthma exacerbations in children is one of the most common medical conditions requiring urgent visits to primary healthcare providers or emergency departments, and even hospitalisations. Currently, there is significant variation in the management of asthma exacerbations expressed in guideline recommendations versus clinical practice. This disconnect affects diagnostic and treatment decisions for the clinician and patient. Objective We systematically reviewed the available guidelines providing recommendations for diagnostic and therapeutic management of asthma exacerbations in the paediatric population. Methods A systematic review of the literature for guidelines published between January 2009 and October 2019 was conducted, using a protocol registered with the international prospective register of systematic reviews (PROSPERO CRD42020221562). Results 16 asthma exacerbation clinical practice guidelines for children were included. Despite general agreement between guidelines on the definition of asthma exacerbation, there was great variability in the definition of disease severity and assessment of asthma control. This systematic review also highlighted a paucity of recommendations for criteria for hospitalisation and discharge. Many guidelines scored poorly when measured for stakeholder involvement and editorial independence. Conclusion Comprehensive and updated guidelines compliant with international standards for clinical guidelines may significantly improve clinical practice quality, promote evidence-based recommendations and provide uniformity of treatment between countries.

There is substantial evidence in the literature that patients with cystic fibrosis (CF) have higher oxidative stress than patients with other diseases or healthy subjects. This results in an increase in reactive oxygen species (ROS) and in a deficit of antioxidant molecules and plays a fundamental role in the progression of chronic lung damage. Although it is known that recurrent infection–inflammation cycles in CF patients generate a highly oxidative environment, numerous clinical and preclinical studies suggest that the airways of a patient with CF present an inherently abnormal proinflammatory milieu due to elevated oxidative stress and abnormal lipid metabolism even before they become infected. This could be directly related to cystic fibrosis transmembrane conductance regulator (CFTR) deficiency, which appears to produce a redox imbalance in epithelial cells and extracellular fluids. This review aims to summarize the main mechanism by which CFTR deficiency is intrinsically responsible for the proinflammatory environment that characterizes the lung of a patient with CF.

Severe asthma in children is a highly heterogeneous disorder, encompassing different clinical characteristics (phenotypes) and immunopathological pathways (endotypes). Research is focusing on the identification of noninvasive biomarkers able to predict treatment response and assist in designing personalised therapies for severe asthma. Blood and sputum eosinophils, serum IgE and exhaled nitric oxide fraction mostly reflect type 2 airway inflammation in children. However, in the absence of available point-of-care biomarkers, the diagnosis of non-type 2 asthma is still reached by exclusion. In this review, we present the most recent evidence on biomarkers for severe asthma and discuss their implementation in clinical practice. We address the methods for guiding treatment decisions and patient identification, focusing on the paediatric age group. Key points Severe asthma in children is a highly heterogeneous disorder, encompassing different clinical characteristics (phenotypes) and immunopathological pathways (endotypes). Research is focusing on the identification of noninvasive biomarkers able to predict treatment response and assist in designing personalised therapies for severe asthma. Blood and sputum eosinophils, serum IgE and exhaled nitric oxide fraction mostly reflect type 2 airway inflammation in children. However, knowledge regarding non-type 2 inflammation and related biomarkers is still lacking. Educational aims To summarise the most recent evidence on biomarkers for severe asthma in children. To discuss their implementation in clinical practice through guiding patient identification and treatment decisions.

During the last several years, the interest in the role of microbiota in human health has grown significantly. For many years, the lung was considered a sterile environment, and only recently, with the use of more sophisticated techniques, has it been demonstrated that colonization by a complex population of microorganisms in lower airways also occurs in healthy subjects; a predominance of some species of Proteobacteria, Firmicutes, and Bacteroidetes phyla and with a peculiar composition in some disease conditions, such as asthma, have been noted. Lung microbiota derives mainly from the higher airways microbiota. Although we have some information about the role of gut microbiota in modulation of immune system, less it is known about the connection between lung microbiota and local and systemic immunity. There is a correlation between altered microbiota composition and some diseases or chronic states; however, despite this correlation, it has not been clearly demonstrated whether the lung microbiota dysbiosis could be a consequence or a cause of these diseases. We are far from a scientific approach to the therapeutic use of probiotics in airway diseases, but we are only at the starting point of a knowledge process in this fascinating field that could reveal important surprises, and randomized prospective studies in future could reveal more about the clinical possibilities for controlling lung microbiota. This review was aimed at updating the current knowledge in the field of airway microbiota.

Childhood asthma is actually defined as a heterogeneous disease, including different clinical variants and partially sharing similar immune mechanisms. Asthma management is mainly focused on maintaining the control of the disease and reducing the risk of adverse outcomes. Most children achieve good control with standard therapies, such as low doses of inhaled corticosteroids (ICS) and/or one or more controller. These medications are targeted to suppress bronchial inflammation and to restore airway responsiveness. However, they are not disease-modifying and do not specifically target inflammatory pathways of asthma; in addition, they are not significantly effective in patients with severe uncontrolled asthma. The aim of this review is to update knowledge on current and novel therapeutic options targeted to immunomodulate inflammatory pathways underlying pediatric asthma, with particular reference on biologic therapies.

ObjectivesThe nuclear protein high mobility group protein box 1 (HMGB1) is a proinflammatory mediator that belongs to the alarmin family of proinflammatory mediators, and it has recently emerged as a key player in different acute and chronic immune disorders. Several lines of evidence demonstrate that HMGB1 is actively released extracellularly from immune cells or passively released from necrotic cells. Because of the ability of HMGB1 to sustain chronic inflammation, we investigated whether the protein is present in nasal fluids of patients with different forms of rhinitis.MethodsHMGB1 levels were evaluated in nasal fluids of healthy subjects or rhinitis patients who were treated or not treated with different treatments.ResultsWe report that the level of HMGB1 was significantly increased in nasal fluids of patients with allergic rhinitis, patients with NARES (nonallergic rhinitis with eosinophiliac syndrome), as well as patients with polyps. We also found that a formulation containing the HMGB1-binding compound glycyrrhizin (GLT) reduced the HMGB1 content in nasal fluids of rhinitis patients to an extent similar to that with nasal budesonide treatment. We also found that among the cultured human leukocyte populations, eosinophils released higher amounts of HMGB1. Based on the ability of HMGB1 to sustain eosinophil survival and the ability of GLT to inactivate HMGB1, we report that GLT selectively killed cultured eosinophils and had no effect on neutrophils, macrophages, and lymphocytes.ConclusionCollectively, these data underscore the role of HMGB1 in rhinitis pathogenesis and the therapeutic potential of GLT formulations in treatment of chronic inflammatory disorders of the nasal mucosa.

Oculoauriculovertebral spectrum, or Goldenhar Syndrome, is a condition characterized by variable degrees of uni- or bilateral involvement of craniofacial structures, ocular anomalies, and vertebral defects. Its expressivity is variable; therefore, the term “expanded Goldenhar complex” has been coined. The Goldenhar Syndrome usually involves anomalies in craniofacial structures, but it is known that nervous system anomalies, including encephalocele or caudal regression, may, rarely, occur in this condition. We report two rare cases of infants affected by Goldenhar Syndrome, associated with neural tube defects, specifically caudal regression syndrome and nasal encephaloceles, to underline the extremely complex and heterogeneous clinical features of this oculoauriculovertebral spectrum. These additional particular cases could increase the number of new variable spectrums to be included in the “expanded Goldenhar complex.”