Biological Therapies for Pediatric Atopic Dermatitis - A Review.

Atopic dermatitis (AD) is the most frequent chronic-recurrent inflammatory skin disease in the pediatric age. It has a complex and multifactorial pathogenesis: the two key actors are impaired skin barrier function and immune system dysregulation, which represent the main targets of AD therapy. Monoclonal antibodies have revolutionized the management of moderate-to-severe AD, by selective inhibition of key cytokines in the pathogenetic process. For this reason, there is great interest in exploring AD pathogenetic mechanisms to develop new therapeutic strategies. This review aims to summarize the most recent scientific evidence on available and future biological therapies for the treatment of pediatric AD, emphasizing the molecular mechanisms underlying their action.

Safety of biological therapy in children and adolescents with severe asthma during the COVID-19 pandemic: a case series.

Background and aim  It is still unclear whether patients with severe asthma are at greater risk of developing severe COVID-19, particularly pediatric allergic patients under biologic therapy. Studies targeting pediatric patients are currently limited; thus, this study aims to assess the clinical characteristics of young patients with severe asthma under biological therapies during the COVID-19 pandemic. Methods We collected data from February 2020 to April 2021. Patients with severe asthma treated with biological therapies (omalizumab and mepolizumab) have been enrolled. We described demographic data, clinical features, therapies, comorbidities, and laboratory findings for each patient. For patients who got COVID-19, we also described the severity of the disease, the need for hospitalization, and specific therapy. Results A total of 14 patients were included in the study, 11 (78.6%) of them under treatment with omalizumab and 3 (21.6%) with mepolizumab. We identified four patients (28.6%) who tested positive for SARS-CoV-2. Two patients treated with mepolizumab had an asymptomatic disease, and two patients treated with omalizumab had mild disease. Only one patient with mild COVID-19 required hospitalization and specific therapy because of severe obesity. Conclusions No differences regarding the SARS-CoV-2 infection have been found between the two treatments groups. Furthermore, any poor outcome has been observed, confirming the safety of biological therapies. The limited number of patients enrolled and the lack of a control group did not establish a significant risk for infections for these patients.

Diagnostic therapeutic care pathway for pediatric food allergies and intolerances in Italy: a joint position paper by the Italian Society for Pediatric Gastroenterology Hepatology and Nutrition (SIGENP) and the Italian Society for Pediatric Allergy and Immunology (SIAIP).

Epidemiologic data suggest an increased prevalence of pediatric food allergies and intolerances (FAIs) during the last decades. This changing scenario has led to an increase in the overall healthcare costs, due to a growing demand for diagnostic and treatment services. There is the need to establish Evidence-based practices for diagnostic and therapeutic intervention that could  be adopted in the context of public health policies for FAIs are needed.This joint position paper has been prepared by a group of experts in pediatric gastroenterology, allergy and nutrition from the Italian Society for Pediatric Gastroenterology Hepatology and Nutrition (SIGENP) and the Italian Society for Pediatric Allergy and Immunology (SIAIP). The paper is focused on the Diagnostic Therapeutic Care Pathway (DTCP) for pediatric FAIs in Italy.

Addition of a nutraceutical to montelukast or inhaled steroid in the treatment of wheezing during COVID-19 pandemic: a multicenter, open-label, randomized controlled trial.

Background and aim Recurrent wheezing is often triggered by viral respiratory infections. The aims of our study were: i) to evaluate whether the addition of a nutraceutical (Leucodif®), could improve the efficacy of montelukast or inhaled steroids (ICS) compared to the single treatment; ii) to verify whether a treatment is more effective than another. Our study was biased by the COVID-19 pandemic, which resulted in a lockdown of almost two months in Italy. Methods The multicenter, open-label study enrolled 84 children aged 2-6 years diagnosed with recurrent wheezing and randomized them into four treatment arms for three months: ICS treatment; ii) montelukast; iii) montelukast + Leucodif; iv) ICS + Leucodif. Children were assessed at baseline and after one, two, and three months of treatment using the TRACK score for both the caregiver and the physician. Results Out of the 84 patients, 18 patients received ICS therapy, 22 patients ICS + Leucodif, 24 patients montelukast, and 20 patients montelukast + Leucodif. All four treatments resulted in a significant reduction in symptoms with no differences among the various groups. Conclusions Our study demonstrates that montelukast therapy appears to be equally effective as ICS therapy and that the addition of the nutraceutical Leucodif does not appear to improve the treatment outcome. However, in our opinion our study was strongly influenced and biased by the lockdown due to the COVID-19 pandemic, which inherently resulted in reduced exposure to the viruses that commonly cause respiratory infections in children.

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.

IgE-mediated fish allergy in children: is omega-3 supplementation useful?

The management of fish allergy relies on the elimination of all fish from the diet. Nevertheless, an exclusion diet can be problematic from a paediatric nutritional perspective. The issue of a substitute diet for children suffering from fish allergy seems to be not adequately addressed and the consequences of a fish exclusion diet in paediatric age are not known. Fish has an important nutritional value, it is rich in vitamins of group B, D and A, selenium, calcium and phosphorus, iron, zinc, magnesium, iodine and omega-3. While vitamins and iodine are normally present in the diet, omega-3 is present in few other foods, such as vegetable seed oils and nuts. Hence, the scientific research indicates a generic advice regarding a possible omega-3 supplementation in children with fish allergy. Given the knowledge about omega-3 supplementation having a potential good risk-benefit ratio and the absence of serious adverse events related to the omega-3 supplementation, this type of supplementation may seem advisable in children affected by fish allergy.

Prevention of recurrent respiratory infections : Inter-society Consensus.

Recurrent respiratory infections (RRIs) are a common clinical condition in children, in fact about 25% of children under 1 year and 6% of children during the first 6 years of life have RRIs. In most cases, infections occur with mild clinical manifestations and the frequency of episodes tends to decrease over time with a complete resolution by 12 years of age. However, RRIs significantly reduce child and family quality of life and lead to significant medical and social costs.Despite the importance of this condition, there is currently no agreed definition of the term RRIs in the literature, especially concerning the frequency and type of infectious episodes to be considered. The aim of this consensus document is to propose an updated definition and provide recommendations with the intent of guiding the physician in the complex process of diagnosis, management and prevention of RRIs.

Natural remedies for acute post-viral cough in children.

The post-viral acute cough is the most common symptom in childhood. Consequently, the use of cough relievers is frequent. Many products for treating cough contain natural components. An ancient tradition has always established herbal medicine and honey as effective and safe means to relieve cough. Nevertheless, very few studies adequately investigated the real effectiveness and safety of natural products in treating acute cough. There is some evidence, provided by pediatric randomized controlled trials, about honey, one multicomponent product (containing Plantagolanceolata, Grindelia robusta, Helichrysum italicum, and honey), and Pelargonium sidoides. Other group of substances, including glycerol and isolated natural compounds, can help manage cough but robust evidence still lacks in children. There is an urgent need to perform rigorous studies that confirm the natural products' efficacy and safety for relieving post-viral acute cough.Key points: Acute post-viral cough is prevalent in childhood and adolescence. There is a growing interest concerning the use of natural remedies for post-viral cough. Many herbal medicines could be used satisfactorily for this issue.

Evaluation of safety and tolerability of a rush up-dosing allergen-specific immunotherapy with grass pollen, birch, hazel, and alder allergoid in children with allergic rhinoconjunctivitis, with or without asthma.

BACKGROUND Usually, the number of injections required to achieve the maintenance dose in subcutaneous immunotherapy (SCIT) is relatively small for some of the currently used allergens, but this may still be uncomfortable for patients, thus compromising adherence and compliance. OBJECTIVE The purpose of this study was to evaluate the safety and tolerability of a dose acceleration of a conventional induction schedule using an allergoid extract of grass pollen, birch, hazel, and alder, needed to achieve the ideal maintenance dose. METHODS In this open-label study, 34 patients with allergic rhinoconjunctivitis, with or without asthma, were treated with SCIT using an allergoid for grass pollen or birch or mix trees with an increase in accelerated induction dose comprising only 3 injections, one per week, compared to a conventional induction pattern in five injections (once a week). Safety determination was assessed by evaluating local and systemic adverse events. Tolerability was evaluated by patients and physicians who performed the treatment. RESULTS No treatment-related adverse events were observed in any of the patients undergoing rush SCIT. No local reactions, no systemic reactions of any degree (WAO Grade) have been observed. Tolerability has always been rated as very good by both patients and physician. CONCLUSIONS The induction phase, needed to achieve the monthly maintenance dose for a pollen extract, can be greatly accelerated, ensuring a tolerability comparable to that of the conventional schedule.

Acute cough in children and adolescents: A systematic review and a practical algorithm by the Italian Society of Pediatric Allergy and Immunology.

The current systematic review presented and discussed the most recent studies on acute cough in pediatric age. After that, the Italian Society of Pediatric Allergy and Immunology elaborated a comprehensive algorithm to guide the primary care approach to pediatric patients, such as infants, children, and adolescents, with acute cough. An acute cough is usually consequent to upper respiratory tract infections and is self-resolving within a few weeks. However, an acute cough may be bothersome, and therefore remedies are requested, mainly by the parents. An acute cough may significantly affect the quality of life of patients and their family.Several algorithms for the management of acute cough have been adopted and validated in clinical practice; however, unlike the latter, we developed an algorithm focused on pediatric age, and, also, in accordance to the Italian National Health System, which regularly follows the child from birth to all lifelong. Based on our findings, infants from 6 months, children, and adolescents with acute cough without cough pointers can be safely managed using well-known medications, preferably non-sedative agents, such as levodropropizine and/or natural compounds, including honey, glycerol, and herb-derived components.

Probiotics in the prevention and treatment of atopic dermatitis.

The use of probiotic supplements might change the composition of the intestinal flora of children, subsequently modulating the immune system's reactivity. The effects of probiotic administration for the prevention/treatment of allergic diseases and atopic dermatitis, in particular, are still so controversial that no definitive recommendation can be made at this stage. Differences in strain specificity, timing, and length of administration all contribute to diversifying the conclusions of this review.

An update on biological therapies for pediatric allergic diseases.

Allergic diseases represent a global health burden. Patients with allergic diseases may experience disability, reduced quality of life and productivity, emotional distress, and social restrictions, especially in the most severe cases. Current advances in unveiling the pathogenesis of allergic disorders have paved the way for the development of novel therapeutic strategies. Biological drugs have been widely studied in pediatric allergic asthma, with strong evidence of efficacy and safety. Moreover, promising results derive from studies on other conditions such as atopic dermatitis, chronic spontaneous urticaria, and food allergy. This review analyzes recent evidence on the role of biologic therapies for allergic diseases, focusing on the pediatric age.

Upper Respiratory Tract Infection-Associated Acute Cough and the Urge to Cough: New Insights for Clinical Practice.

Upper respiratory tract infection (URTI)-associated acute cough is the most common symptom both in children and adults worldwide and causes economic and social problems with significant implications for the patient, the patient's family, and the health care system. New pathogenic mechanisms in acute cough, including the urge to cough (UTC) mechanisms, have been recently identified. The brainstem neural network, pharyngeal sensory innervation, airway mechanical stimulation, inflammatory mediators, and postnasal drip actively participate in the onset and maintenance of acute cough and the urge to cough phenomenon. However, there is still no effective pharmacological treatment capable of interfering with the pathophysiologic mechanisms involved in URTI-associated acute cough. Moreover, severe adverse events frequently occur in administering such cough medications, mainly in children. New evidence has been provided concerning polysaccharides, resins, and honey as potential cough relievers with high antitussive efficiency, effect on the UTC, and minimal side effects.

Biologics to Treat Severe Asthma in Children and Adolescents: A Practical Update.

Background: Severe asthma represents a significant challenge for children and adolescents. At the same time, it often places a burden on patients, caregivers, and society, mainly related to morbidity, mortality, and health care resources. In children and adolescents, severe asthma is mostly characterized by type 2 inflammation, which leads to bronchial eosinophilia that may be suppressed by corticosteroids. However, in this age group, a high dosage of inhaled corticosteroids combined with systemic corticosteroids sometimes results in unacceptable side effects, such as reduced growth velocity and reduced bone mineral density. Therefore, there is increasing and enthusiastic interest in today's biologics, including omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab. There is growing evidence that they may be effective and safe add-on options for children and adolescents. In 2009, omalizumab was approved by the European Medicines Agency as the first available therapeutic option for allergic asthma in patients as young as 6 years of age, followed by a similar approval by the U.S. Food and Drug Administration in 2016. Previously, omalizumab was marketed for this indication in patients ≥ age 12. Subsequent biologics, namely mepolizumab, reslizumab, and benralizumab, are IL-5 targeted agents that are presently approved in some countries for severe eosinophilic asthma starting at 6 years of age. Dupilumab is targeted against the IL-4 receptor α-chain, and it has been approved in the United States and the European Union as an add-on maintenance therapy in patients ≥12 years of age. Conclusion: This review presents the most recent evidence on approved biologics for the treatment of severe asthma and discusses the unmet needs and future perspective, focusing on the pediatric and adolescent age groups.

Biologics in Children with Allergic Diseases.

The prevalence of allergic diseases has been remarkably increased in the last decades. The global health burden of these conditions is substantial, since patients may experience disability, anxiety and emotional distress, social restrictions, and reduced quality of life and productivity, in particular, in the most severe cases. Recent advances in understanding the pathophysiology of allergic disorders have allowed identifying novel therapeutic strategies for the treatment of severe and uncontrolled allergic diseases. Although most studies have been performed in allergic asthma, biological drugs targeting other allergic diseases such as chronic spontaneous urticaria, atopic dermatitis, and food allergy are showing promising results. In this review, the most recent evidence on biologic therapies for allergic diseases, focusing on the pediatric age has been presented.

Updated Guidelines for the Management of Acute Otitis Media in Children by the Italian Society of Pediatrics: Prevention.

BACKGROUND: In recent years, new information has been acquired regarding the diagnosis, treatment and prevention of acute otitis media (AOM). The Italian Pediatric Society, therefore, decided to issue an update to the Italian Pediatric Society guidelines published in 2010. METHODS: The search was conducted on Pubmed, and only those studies regarding the pediatric age alone, in English or Italian, published between January 1, 2010 and December 31, 2018, were included. Each study included in the review was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology. The quality of the systematic reviews was evaluated using the A MeaSurement Tool to Assess systematic Reviews (AMSTAR) 2 appraisal tool. The guidelines were formulated using the GRADE methodology by a multidisciplinary panel of experts. RESULTS: The importance of eliminating risk factors (passive smoking, environmental pollution, use of pacifier, obesity, limitation of day-care center attendance) and the promotion of breastfeeding and hygiene practices (nasal lavages) was confirmed. The importance of pneumococcal vaccination in the prevention of AOM was reiterated with regard to the prevention of both the first episode of AOM and recurrences. Grommets can be inserted in selected cases of recurrent AOM that did not respond to all other prevention strategies. Antibiotic prophylaxis is not recommended for the prevention of recurrent AOM, except in certain carefully selected cases. The use of complementary therapies, probiotics, xylitol and vitamin D is not recommended. CONCLUSIONS: The prevention of episodes of AOM requires the elimination of risk factors and pneumococcal and influenza vaccination. The use of other products such as probiotics and vitamin D is not supported by adequate evidence.

Updated Guidelines for the Management of Acute Otitis Media in Children by the Italian Society of Pediatrics: prevention

In recent years, new information has been acquired regarding the diagnosis, treatment and prevention of acute otitis media (AOM). The Italian Pediatric Society, therefore, decided to issue an update to the Italian Pediatric Society guidelines published in 2010. The search was conducted on Pubmed, and only those studies regarding the pediatric age alone, in English or Italian, published between January 1, 2010 and December 31, 2018, were included. Each study included in the review was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology. The quality of the systematic reviews was evaluated using the A MeaSurement Tool to Assess systematic Reviews (AMSTAR) 2 appraisal tool. The guidelines were formulated using the GRADE methodology by a multidisciplinary panel of experts. The importance of eliminating risk factors (passive smoking, environmental pollution, use of pacifier, obesity, limitation of day-care center attendance) and the promotion of breastfeeding and hygiene practices (nasal lavages) was confirmed. The importance of pneumococcal vaccination in the prevention of AOM was reiterated with regard to the prevention of both the first episode of AOM and recurrences. Grommets can be inserted in selected cases of recurrent AOM that did not respond to all other prevention strategies. Antibiotic prophylaxis is not recommended for the prevention of recurrent AOM, except in certain carefully selected cases. The use of complementary therapies, probiotics, xylitol and vitamin D is not recommended. The prevention of episodes of AOM requires the elimination of risk factors and pneumococcal and influenza vaccination. The use of other products such as probiotics and vitamin D is not supported by adequate evidence.

Genistein antagonizes gliadin-induced CFTR malfunction in models of celiac disease.

In celiac disease (CD), an intolerance to dietary gluten/gliadin, antigenic gliadin peptides trigger an HLA-DQ2/DQ8-restricted adaptive Th1 immune response. Epithelial stress, induced by other non-antigenic gliadin peptides, is required for gliadin to become fully immunogenic. We found that cystic-fibrosis-transmembrane-conductance-regulator (CFTR) acts as membrane receptor for gliadin-derived peptide P31-43, as it binds to CFTR and impairs its channel function. P31-43-induced CFTR malfunction generates epithelial stress and intestinal inflammation. Maintaining CFTR in an active open conformation by the CFTR potentiators VX-770 (Ivacaftor) or Vrx-532, prevents P31-43 binding to CFTR and controls gliadin-induced manifestations. Here, we evaluated the possibility that the over-the-counter nutraceutical genistein, known to potentiate CFTR function, would allow to control gliadin-induced alterations. We demonstrated that pre-treatment with genistein prevented P31-43-induced CFTR malfunction and an epithelial stress response in Caco-2 cells. These effects were abrogated when the CFTR gene was knocked out by CRISP/Cas9 technology, indicating that genistein protects intestinal epithelial cells by potentiating CFTR function. Notably, genistein protected gliadin-sensitive mice from intestinal CFTR malfunction and gliadin-induced inflammation as it prevented gliadin-induced IFN-γ production by celiac peripheral-blood-mononuclear-cells (PBMC) cultured ex-vivo in the presence of P31-43-challenged Caco-2 cells. Our results indicate that natural compounds capable to increase CFTR channel gating might be used for the treatment of CD.

Prevention of food and airway allergy: consensus of the Italian Society of Preventive and Social Paediatrics, the Italian Society of Paediatric Allergy and Immunology, and Italian Society of Pediatrics.

BACKGROUND: Allergic sensitization in children and allergic diseases arising therefrom are increasing for decades. Several interventions, functional foods, pro- and prebiotics, vitamins are proposed for the prevention of allergies and they can't be uncritically adopted. OBJECTIVE: This Consensus document was developed by the Italian Society of Preventive and Social Paediatrics and the Italian Society of Paediatric Allergy and Immunology. The aim is to provide updated recommendations regarding allergy prevention in children. METHODS: The document has been issued by a multidisciplinary expert panel and it is intended to be mainly directed to primary care paediatricians. It includes 19 questions which have been preliminarily considered relevant by the panel. Relatively to each question, a literature search has been performed, according to the Italian National Guideline Program. Methodology, and a brief summary of the available literature data, has been provided. Many topics have been analyzed including the role of mother's diet restriction, use of breast/formula/hydrolyzed milk; timing of introduction of complementary foods, role (if any) of probiotics, prebiotics, vitamins, exposure to dust mites, animals and to tobacco smoke. RESULTS: Some preventive interventions have a strong level of recommendation. (e.g., the dehumidifier to reduce exposure to mite allergens). With regard to other types of intervention, such as the use of partially and extensively hydrolyzed formulas, the document underlines the lack of evidence of effectiveness. No preventive effect of dietary supplementation with polyunsaturated fatty acids, vitamins or minerals has been demonstrated. There is no preventive effect of probiotics on asthma, rhinitis and allergic diseases. It has demonstrated a modest effect, but steady, in the prevention of atopic dermatitis. CONCLUSIONS: The recommendations of the Consensus are based on a careful analysis of the evidence available. The lack of evidence of efficacy does not necessarily imply that some interventions may not be effective, but currently they can't be recommended.