An updated reappraisal of dupilumab in children and adolescents with moderate-severe atopic dermatitis.

Atopic dermatitis (AD) is still a demanding challenge in clinical practice. Type 2 inflammation is the most common inflammatory pathway in children and adolescents with AD. Anti-inflammatory drugs, mainly corticosteroids (CS) and immunomodulant agents are the primary therapeutic approach to dampening type 2 inflammation. However, AD patients may require long-term high CS doses or drug combinations with possibly significant adverse effects to achieve and maintain disease control. In this regard, the advent of biologics constituted a breakthrough in managing this condition. Dupilumab is a monoclonal antibody directed against the IL-4 receptor α-subunit (IL-4Rα), antagonizing both IL-4 and IL-13 and is approved for pediatric severe AD. This review presents and discusses the most recent published studies on dupilumab in children and adolescents with AD. There is convincing evidence that dupilumab is safe and effective in managing AD. It can reduce skin lesions and associated itching, reduce the need for additional medications, and improve disease control and quality of life. However, a thorough diagnostic pathway is mandatory, especially considering the different AD phenotypes. The ideal eligible candidate is a child or adolescent with AD requiring systemic treatment because of severe clinical manifestations and impaired quality of life.

Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA).

BACKGROUND: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies. METHODS: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria. RESULTS: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately). CONCLUSIONS: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.

The role of basophil activation test and component-resolved diagnostics in the workup of egg allergy in children at low risk for severe allergic reactions: A real-life study.

BACKGROUND: The gold standard for diagnosing egg allergy in children is the oral food challenge (OFC). However, OFCs are time-consuming and risky procedures. Our study aimed to evaluate the utility of the basophil activation test (BAT) and component-resolved diagnostic in the diagnostic workup of children with egg allergy. METHODS: Overall, 86 children aged 6 months to 17 years, suspected of egg allergy, underwent OFC with boiled egg according to international standardized protocols. BAT and specific immunoglobulin E (sIgE) testing to component egg proteins (Gal d 1-4) were also performed. RESULTS: Of the 22 children who reacted to boiled egg, only one experienced anaphylaxis during the challenge. BAT was performed in samples obtained by 75 of the 86 patients of our cohort. Egg white and yolk protein extracts induced CD63 upregulation in the egg-allergic (EA) children compared with sensitized children that tolerated boiled egg (we registered an overall mean of CD63 expression in the EA population of 44.4% [SD 34.1] for egg white and 34.7% [SD 31.3] for egg yolk vs. 12.5% [SD 19.1] and 10.0% [SD 16.0] in sensitized children). BAT could discriminate between true egg allergy and egg sensitization in our population. As a second-line diagnostic step, the positivity of BAT for egg white or Gal d 1-sIgE resulted in a 40.9% OFC reduction, especially for those with a positive outcome. CONCLUSION: The BAT may be implemented in the diagnostic workup of egg allergy in children and, in a stepwise approach, separately or combined with Gal d 1-sIgE, may predict the allergic status and reduce the number of positive OFCs in children with egg allergy at low risk for severe reactions.

Clinical and immunological phenotypes of selective IgM deficiency in children: Results from a multicenter study.

BACKGROUND: A few studies assessed the clinical and immunological features of selective IgM deficiency (SIgMD), especially in the pediatric age. We aimed to characterize the clinical and immunological phenotypes of a cohort of pediatric patients with SIgMD according to the different diagnostic criteria available. METHODS: In this multicenter study, we evaluated pediatric SIgMD patients diagnosed at the Pediatric Clinic in Pavia, Italy, or through the Italian Primary Immunodeficiency NETwork (IPINET) and monitored changes in their diagnosis over a time frame that ranges from several months to several years. RESULTS: Forty-eight patients with SIgMD were included (mean serum IgM: 33 mg/dL). The most common clinical manifestations were recurrent infections (67%) and allergies (48%). Subgroup analysis according to SIgMD definition criteria of the European Society for Immunodeficiencies (ESID) showed no significant difference in clinical manifestations, also considering the group with additional immunological abnormalities. Sixteen patients had long-term follow-up, during which 87% preserved their SIgMD diagnosis, while two patients showed a reduction in IgA in addition to low IgM. CONCLUSIONS: Our data suggest that the identification of a reduction in serum IgM in children should lead to a complete immunological work-up to obtain a comprehensive clinical and immunological characterization of the patient. The follow-up of these patients is fundamental to define the disease evolution and appropriate management.

Immunotherapy with Pru p 3 for food allergy to peach and non-specific lipid transfer protein: a systematic review.

BACKGROUND: Non-specific lipid-transfer protein (nsLTP) is a pan-allergen in the plant world, and a cause of significant concern as food allergen in the Mediterranean area, due to its general heat- and acid-resistance and hence the risk of severe allergic reactions. Pru p 3, the peach nsLTP, is considered the primary sensitizer to this allergen family and this allergy is usually persistent. Allergen-free diet and acute treatment of manifestations are the main recognized management goals in food allergy. MAIN TEXT: The role of immunotherapy for treating food allergy in adult patients is controversial, but immunotherapy for Pru p 3 could potentially represent a relevant therapeutic strategy. We systematically searched databases for studies assessing the role of immunotherapy Pru p 3 in food allergy. Overall, nine studies were included. Immunotherapy with Pru p 3 appears to be effective and with a good safety profile in both peach and LTP allergy for some foods, such as peanut, in both RCT and real-life studies. CONCLUSIONS: Immunotherapy with Pru p 3 is a possible treatment option for food allergy to the peach LTP in the Mediterranean area, although at present have not reached routinary clinical practice. Larger studies are needed to confirm these findings and identify predictive biomarkers.

Oral findings in pediatric patients with allergic rhinitis and asthma: a cohort study of an Italian setting.

Allergic rhinitis and asthma are two frequent respiratory clinical entities commonly encountered in pediatric clinical settings. Previous studies have evaluated the influence of these two conditions on oral health, but conflicting results have been obtained. The present cohort study aimed to record oral findings (i.e., caries, plaque, gingival inflammation and mouth breathing) in 50 pediatric patients diagnosed with allergic rhinitis and/or asthma in an Italian pediatric setting and to compare them to a control group of 50 healthy children. The following oral indexes were calculated: Periodontal Screening and Recording (PSR), Plaque Control Record (PCR), and Decayed Missing Filled Teeth (DMFT) Index. The absence or presence of mouth breathing was also recorded. Descriptive and inferential statistics were conducted. Statistically significant differences were found between cases and controls for PSR (p = 0.0051) and PCR scores (p < 0.0001), whereas no significant differences were detected for DMFT. Mouth breathing was found among 20 (40.00%) patients of the Case Group, while in the Control group only in 11 (22.00%) patients, and no significant differences were found between allergic rhinitis and asthma gradings for mouth breathers (p > 0.05). Finally, linear regressions showed a significant influence of PSR (p = 0.0051) and PCR (p < 0.0001) on the Case group. Mouth breathing also significantly influenced PCR scores of the Case group (p = 0.0206). Accordingly, allergic rhinitis and asthma can promote mouth breathing, plaque accumulation, and periodontal inflammation. Based on these considerations, pediatric dentists and physicians are expected to know the influence of respiratory conditions on oral health and consider this aspect when taking care of children.

The knowledge of orthodontic and craniofacial growth amongst Italian Pediatric Medical Residents for early diagnosis in growing patients: a cross-sectional study.

Paediatric residents usually visit children since the first years of life and can potentially diagnose craniofacial anomalies and malocclusions. Therefore, the aim of this study was to assess the ability of paediatric medical residents to diagnose malocclusions in growing subjects at an early stage. Eighty-three paediatric medical residents from the University of Pavia, Italy, who were enrolled in the Paediatric Residency program, participated in an online questionnaire. The questionnaire covered demographic variables, oral examination practices, dental and orthodontic knowledge, and sources of information. Following this, the residents were presented with a photographic analysis and asked to determine the treatment priority for 10 patients with malocclusions using the Index of Orthodontic Treatment Need (IOTN). On average, it was recommended that the first orthodontic visit should occur at around 4.92 years of age. The results showed that 75.9% of the residents always performed oral examinations on their patients, and 48.1% assigned a priority score of 8 or higher. The scores obtained by the paediatric residents did not significantly differ based on the year of study, frequency of oral examinations, or sources of information reported. Notably, there was a particular underestimation of treatment priority for malocclusions characterized by a significant increase in overjet. The findings suggest a potential lack of improvement in orthodontic knowledge during the medical residency program. It is recommended to increase the availability of orthodontic information sources for paediatric residents to enhance their understanding in this area.

Controversies in the treatment of mild asthma. What novelties and practical implications?

Mild asthma is prevalent in childhood and causes as many as 30%-40% asthma exacerbations requiring emergency visits. The management of "intermittent" and "mild persistent" asthma phenotypes is still a matter of debate, even if the role of inhaled corticosteroids, both continuous and intermittent, is a cornerstone in this field. Recent updates of the guidelines on the strategies to manage these patients are coming, since the role of inflammation in these asthma phenotypes is crucial, as well as the potential side effect and risks of short-acting beta 2 agonists overuse, prescribed as the only "as-needed" treatments. In this paper, we overview the new (r)evolution regarding intermittent and mild persistent asthma management.

Type 2 inflammation in cystic fibrosis: New insights.

Recently, type 2 inflammation has been recognized as one of the most critical factors participating in the pathogenesis of cystic fibrosis (CF). On the one hand, type 2 inflammation restores tissue homeostasis and contributes to the resolution of inflammation following an injury. On the other hand, type 2 response-activated immune cells may become dysregulated or chronically activated, causing tissue fibrosis. Among the type 2 cytokine-driven inflammatory pathways, the transforming growth factor ß (TGFß), interleukin (IL)-17, IL-33, and IL-13 have been identified as essential mediators in patients suffering from CF. Given their critical role, we firmly believe that an adequate comprehension of the type 2-mediated pathways can identify attractive targets to decrease pharmacologically the inflammation and fibrosis occurring in the pulmonary tissue of patients suffering from CF.

Rapid response to dupilumab treatment in children with moderate-to-severe atopic dermatitis: A case series.

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease characterized by itch and clinical heterogeneity regarding the age of onset, morphology, distribution, and severity of lesions. Severe AD has a significant impact on the quality of life of affected children and their caregivers. Children with moderate-severe AD inadequately controlled with topical therapy have limited treatment options, such as systemic corticosteroids or phototherapy, often prescribed as off-label treatments, often with unfavorable benefit-to-risk ratio adverse events. Dupilumab is a fully human monoclonal antibody with proven effectiveness and a relatively safe adverse effect profile in patients with type 2 inflammatory diseases, including AD. We report three pediatric cases of severe AD successfully treated with dupilumab.

Endotyping allergic rhinitis in children: A machine learning approach.

INTRODUCTION: The diversity of allergic rhinitis (AR) phenotypes is particularly evident in childhood, suggesting the need to analyze and identify new approaches to capture such clinical heterogeneity. Nasal cytology (NC) is a very useful diagnostic tool for identifying and quantifying nasal inflammation. Data-driven approaches such as latent class analysis (LCA) assign subjects to classes based on their characteristics. We hypothesized that LCA based on NC, including the assessment of neutrophils, eosinophils, and mast cells, may be helpful for identifying AR endotypes in children. METHODS: A total of 168 children were enrolled. Sociodemographic characteristics and detailed medical history were obtained from their parents. All children performed NC and skin prick tests. LCA was applied for identifying AR endotypes based on NC, using the R package poLCA. All the statistical analyses were performed using R 4.0.5 software. Statistical significance was set at p ≤ .05. RESULTS: LCA identified two classes: Class 1 (n = 126, 75%): higher frequency of children with moderate/large number of neutrophils (31.45%); almost all the children in this class had no mast cells (91.27%) and Class 2 (n = 42, 25%): higher frequency of children with moderate/large number of eosinophils (45.24%) and moderate/large number of mast cells (50%). CONCLUSIONS: The present study used a machine learning approach for endotyping childhood AR, which may contribute to improve the diagnostic accuracy and to deliver personalized health care in the context of precision medicine.

Role of air pollutants mediated oxidative stress in respiratory diseases.

Airborne particulate (PM) components from fossil fuel combustion can induce oxidative stress initiated by reactive oxygen species (ROS) that are strongly correlated with airway inflammation and asthma. A valid biomarker of airway inflammation is fractionated exhaled nitric oxide (FENO). The oxidative potential of PM2.5 can be evaluated with the dithiothreitol (DTT) dosage, which represents both ROS chemically produced and intracellular ROS of macrophages. This correlates with quality indicators of the internal environment and ventilation strategies such as dilution and removal of airborne contaminants.

Nutritional status in eosinophilic gastrointestinal disorders: A pediatric case-control study.

Eosinophilic gastrointestinal disorders (EGIDs) represent an emerging group of heterogeneous diseases associated with failure to thrive, weight loss, protein-losing enteropathy, and malnutrition. To date, no studies have assessed the nutritional status, vitamin D, and other vitamin levels in patients with non-esophageal EGIDs. We aim to evaluate the nutritional profile of a cohort of children and adolescents with EGIDs. We performed a case-control study, enrolling a total of 98 patients, 38 (39%) patients with EoE, 22 (22%) patients with non-esophageal EGIDs, and 38 (39%) patients with non-allergic controls. Children with EGIDs had both mean ferritin and mean hemoglobin levels, together with other values such as folates and vitamin B12, within normal range and therefore did not have anemia. Albumin and prealbumin levels were within normal limits. Patients with EGIDs have mean vitamin D values slightly higher than non-allergic controls. Although this study is retrospective and referred to only one pediatric center, we found that Italian children and adolescents with EGIDs are neither malnourished nor deficient in vitamin D compared with controls.

Machine learning: A modern approach to pediatric asthma.

Among modern methods of statistical and computational analysis, the application of machine learning (ML) to healthcare data has been gaining recognition in helping us understand the heterogeneity of asthma and predicting its progression. In pediatric research, ML approaches may provide rapid advances in uncovering asthma phenotypes with potential translational impact in clinical practice. Also, several accurate models to predict asthma and its progression have been developed using ML. Here, we provide a brief overview of ML approaches recently proposed to characterize pediatric asthma.

Prevalence and clinical presentation of long COVID in children: a systematic review.

A systematic literature review was conducted up to 15th February 2022 to summarize long COVID evidence and to assess prevalence and clinical presentation in children and adolescents. Articles reporting long COVID prevalence and symptoms based on original data in the paediatric population were included. Case series quality was assessed through the JBI Critical Appraisal Checklist. For observational studies, adherence to STROBE checklist was evaluated. Twenty-two articles were included: 19 observational studies (12 cohort/7 cross-sectional) and 3 case series. Nine studies provided a control group. We found a high variability in terms of prevalence (1.6-70%). The most frequently reported symptoms were fatigue (2-87%), headache (3.5-80%), arthro-myalgias (5.4-66%), chest tightness or pain (1.4-51%), and dyspnoea (2-57.1%). Five studies reported limitations in daily function due to long COVID. Alterations at brain imaging were described in one study, transient electrocardiographic abnormalities were described in a minority of children, while most authors did not evidence long-term pulmonary sequelae. Older age, female sex, and previous long-term pathological conditions were more frequently associated with persistent symptoms. CONCLUSION: Long COVID evidence in children is limited, heterogeneous, and based on low-quality studies. The lockdown consequences are difficult to distinguish from long COVID symptoms. High-quality studies are required: WHO definition of long COVID should be used, controlled clinical studies should be encouraged, and the impact of new variants on long COVID prevalence should be investigated to ensure an objective analysis of long COVID characteristics in children and a proper allocation of healthcare system resources. WHAT IS KNOWN: • Children rarely develop a severe respiratory disease in the acute phase of COVID-19. • A limited number of patients develop a multisystem inflammatory condition that can lead to multiorgan failure and shock. WHAT IS NEW: • Persistent symptoms after SARS-CoV-2 infection are reported in children and limitations in daily function due to long COVID symptoms affect school attendance. • Functional complaints of post-acute COVID are difficult to be distinguished from those due to social restrictions.

Digital health interventions in children with asthma.

Although healthcare providers are actively involved in offering education, information and interventions for asthmatic patients, medication and therapeutic adherence remain low in the paediatric population, with estimates suggesting that adherence rates hover below 50%. A range of available digital health interventions has been explored in paediatric asthma with promising but variable results, limiting their widespread adoption in clinical practice. They include emerging technologies that yield the advantage of tracking asthma symptoms and medications, setting drug reminders, improving inhaler technique and delivering asthma education, such as serious games (video games designed for medical- or health-related purposes), electronic monitoring devices, speech recognition calls, text messaging, mobile apps and interactive websites. Some of the proposed digital interventions have used multiple components, including educational and behavioural strategies and interactions with medical professionals. Overall, the implementation of such interventions may offer the opportunity to improve adherence and asthma control. In a state of emergency as the COVID-19 pandemic, telemedicine can also play a central role in supporting physicians in managing children with asthma. This review evaluates the published literature examining digital health interventions for paediatric asthma and explores the most relevant issues affecting their implementation in practice and the associated evidence gaps, research limitations and future research perspectives.

Artificial intelligence in the diagnosis of pediatric allergic diseases.

Artificial intelligence (AI) is a field of data science pertaining to advanced computing machines capable of learning from data and interacting with the human world. Early diagnosis and diagnostics, self-care, prevention and wellness, clinical decision support, care delivery, and chronic care management have been identified within the healthcare areas that could benefit from introducing AI. In pediatric allergy research, the recent developments in AI approach provided new perspectives for characterizing the heterogeneity of allergic diseases among patients. Moreover, the increasing use of electronic health records and personal healthcare records highlighted the relevance of AI in improving data quality and processing and setting-up advanced algorithms to interpret the data. This review aimed to summarize current knowledge about AI and discuss its impact on the diagnostic framework of pediatric allergic diseases such as eczema, food allergy, and respiratory allergy, along with the future opportunities that AI research can offer in this medical area.

Social robots and therapeutic adherence: A new challenge in pediatric asthma?

Social Robots are used in different contexts and, in healthcare, they are better known as Socially Assistive Robots. In the context of asthma, the use of Socially Assistive Robots has the potential to increase motivation and engagement to treatment. Other positive roles proposed for Socially Assistive Robots are to provide education, training regarding treatments, and feedback to patients. This review evaluates emerging interventions for improving treatment adherence in pediatric asthma, focusing on the possible future role of social robots in the clinical practice.

Impact of a supervised training course on spirometry competency for primary care pediatricians.

OBJECTIVE: Spirometry is the most commonly performed lung function test, and performance, adherence to acceptability and repeatability criteria, and accurate interpretation of results help optimize the test's usefulness. This study aimed to measure the effects of spirometry training courses supported by the Italian Pediatric Respiratory Society (IPRS) on primary care pediatricians' (PCP) knowledge of spirometry test quality, ability to interpret results, and overall degree of satisfaction with the course. METHODS: Of the six face-to-face courses, four lasted two days and two lasted one day: mean duration of theoretical lessons was five and four hours respectively; and practical sessions lasted eight and six hours, respectively. At the end of each course, participants took a learning test consisting of evaluating six flow-volume curves. Degree of satisfaction was assessed by asking participants to rank the relevance, quality, and usefulness of the course. RESULTS: 261 PCPs were involved, with most (67.43%) taking two-day courses. Nearly all participants correctly identified normal and restrictive patterns. Intrathoracic large-airway obstruction was the pattern most difficult to identify correctly (70.5% overall), whereas > 80% of the participants correctly classified artifacts, obstructive-restrictive, and obstructive patterns. Participants in longer courses reported significantly higher values on the learning score. The overall degree of satisfaction average ranged between "good" and "excellent". CONCLUSIONS: This pilot study showed the greater impact of two-day courses than one-day courses for training PCPs to properly interpret spirometry, confirming that a practical module lasting at least six hours is sufficient to deliver adequate training on spirometry for healthcare professionals.

Impact that the COVID-19 pandemic on routine childhood vaccinations and challenges ahead: A narrative review.

AIM: To document the decline in vaccination coverage in the first months of 2020 as an indirect effect of the COVID-19 pandemic. METHODS: We performed a literature review in medical databases. Overall, 143 articles were initially retrieved, out of which 48 were selected and included in the review. RESULTS: Our review retrieved similar data in many countries worldwide, and, globally, preliminary data from the first 4 months of 2020 indicate a decline in diphtheria-tetanus-pertussis coverage, generally considered the marker of vaccination coverage across countries. World Health Organization recommends maintaining vaccination services, prioritising primary series vaccinations especially for measles-rubella or poliomyelitis, but it also lets each country decide whether to maintain the immunisation services evaluating the current epidemiology of vaccine-preventable diseases and the COVID-19 local transmission scenario. Successively, recovering of vaccinations should be planned. Moreover, during the pandemic, influenza vaccination should be promoted as a central public health measure. CONCLUSION: Future challenges will be to maintain the vaccination programmes, especially in children younger than 2 years old and adolescents, to plan the recovery of vaccinations for subjects who postponed them during the lockdown, and to early identify any vaccine-preventable disease outbreak.