Current state and advances in desensitization for peanut allergy in pediatric age.

Peanut allergy affects about 1%-3% of the pediatric population in the world, with an important increase in the last decades. Nowadays, international guidelines recommend the early introduction of peanuts in the infant diet, with poor information about the quantity and the frequency of the intake. Allergen immunotherapy may represent the only therapeutic strategy able to modify the natural history of peanut allergy. In particular, oral immunotherapy showed the most promising results in terms of efficacy, but with significant rates of adverse reactions, mostly gastrointestinal. In 2020, the Food and Drug Administration and the European Medicines Agency approved Palforzia®, an oral drug for patients aged 4-17 years. Several studies are ongoing to improve the tolerability of oral immunotherapy and standardize the desensitization protocols. Sublingual immunotherapy permits to offer much lower doses than oral immunotherapy, but fewer adverse events are shown. Subcutaneous immunotherapy is associated with the greatest systemic adverse effects. Epicutaneous immunotherapy, for which Viaskin® patch was approved, has the highest safety profile. Innovative studies are evaluating the use of biological drugs, such as omalizumab or dupilumab, and probiotics, such as Lactobacillus rhamnosus, in monotherapy or associated with oral immunotherapy. Therapy for peanut allergy is constantly evolving, and new perspectives are ongoing to develop.

Hyperthyroidism in a 15-year-old adolescent treated with Dupilumab for severe allergic asthma and atopic dermatitis.

Dupilumab is a biologic, acting on IL-4 and IL-13 pathways. Dupilumab has a pediatric indication for treating severe asthma and atopic dermatitis. We report a pediatric case concerning paucisymptomatic, transient, and self-resolving hyperthyroidism. The updated literature includes the case of an adult patient who reported with hyperthyroidism, which was transient and self-resolving. Despite that these cases were transient and self-resolving, we would suggest that thyroid function assessment could be included in the follow-up of patients treated with Dupilumab. Dupilumab discontinuation is not required pending endocrinological assessment, mainly if there is an optimal clinical response to the biologic.

Safety of allergen-specific immunotherapy in children.

Allergic respiratory diseases, such as asthma and allergic rhinitis, are global health issues and have had an increasing prevalence in the last decades. Allergen-specific immunotherapy (AIT) is the only curative treatment for allergic rhinitis and asthma, as it has a disease-modifying effect. AIT is generally administered by two routes: subcutaneous (SCIT) and sublingual immunotherapy (SLIT). Local side effects are common, but usually well-tolerated and self-limited. However, systemic side effects are rare, and associated with uncontrolled asthma and bronchial obstruction, or related to errors in administration. Physicians should constantly assess potential risk factors for not only reporting systemic reactions and fatalities but also implementing other therapies to improve AIT safety. This paper highlights recent evidence on local and systemic reactions related to SCIT and SLIT in children.

Omalizumab and allergen immunotherapy for respiratory allergies: A mini-review from the Allergen-Immunotherapy Committee of the Italian Society of Pediatric Allergy and Immunology (SIAIP).

Although currently approved to treat severe asthma and chronic spontaneous urticaria, omalizumab has also been an effective and safe add-on treatment for other allergic diseases. Namely, omalizumab has been proposed to be used as add-on therapy in patients with allergic rhinitis and asthma and undergoing specific allergen immunotherapy (AIT). AIT is the only treatment that modifies the natural history of IgE-mediated diseases. This brief review summarizes the available evidence and controversies on the efficacy and safety of omalizumab combined with specific AIT.

Eosinophilic gastrointestinal disorders and allergen immunotherapy: Lights and shadows.

Allergic diseases, such as IgE-mediated food allergy, asthma, and allergic rhinitis, are relevant health problems worldwide and show an increasing prevalence. Therapies for food allergies are food avoidance and the prompt administration of intramuscular epinephrine in anaphylaxis occurring after accidental exposure. However, allergen immunotherapy (AIT) is being investigated as a new potential tool for treating severe food allergies. Effective oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) induce desensitization and restore immune tolerance to the causal allergen. While immediate side effects are well known, the long-term effects of food AIT are still underestimated. In this regard, eosinophilic gastrointestinal disorders (EGIDs), mainly eosinophilic esophagitis, have been reported as putative complications of OIT for food allergy and sublingual immunotherapy (SLIT) for allergic asthma and rhinitis. Fortunately, these complications are usually reversible and the patient recovers after AIT discontinuation. This review summarizes current knowledge on the possible causative link between eosinophilic gastrointestinal disorders and AIT, highlighting recent evidence and controversies.

Allergen immunotherapy and asthma.

Allergen immunotherapy (AIT) represents at present the unique disease-modifying treatment strategy for IgE-mediated allergic diseases. AIT can induce clinical improvement of allergic asthma, including reduced symptoms, medication use, and improvement of quality of life, with a long-lasting effect after cessation of treatment. Notably, the current asthma guidelines are now recommending sublingual immunotherapy as an add-on therapy for asthma in adults and adolescents with house dust mite allergy. Clinical indications of AIT, with particular reference to pediatric asthma, mechanisms of clinical and immunological tolerance to allergens, and the potential biomarkers predicting clinical response are discussed.

Allergen immunotherapy in atopic dermatitis: Light and shadow in children.

Atopic dermatitis (AD) is a chronic remitting-relapsing inflammatory skin disorder. Due to the multifactorial pathogenesis, there are numerous therapeutic management approaches, mainly based on symptomatic treatments. In recent years, allergen immunotherapy (AIT) has been progressively advanced as targeted disease-modifying treatment of allergic disease. The most recent guideline from the American Academy of Dermatology concludes that data available do not support its use in AD. The Joint Task Force and The European Academy of Dermatology suggest that clinicians can consider AIT treatment in selected patients characterized by aeroallergen sensitization, prevalently HDM, severe AD, and clinical exacerbation after exposure to the causative allergen. Nevertheless, its role in AD is still under debate, especially in children.

Molecular Allergy Diagnostics in Children with Cow's Milk Allergy: Prediction of Oral Food Challenge Response in Clinical Practice.

Background: Cow's milk allergy (CMA) is the most common food allergy in early childhood. Children with CMA require a precise and punctual diagnosis. Oral food challenge (OFC) is the gold-standard procedure for diagnosing allergies, but it is laborious and requires a particular setting. The aim of the study was to identify the cutoff value of serum allergen-specific IgE values able to predict a positive response to OFC. Methods: Children with suspected CMA performed OFC with cow's milk (CM) or derivatives. Total IgE and specific IgE to raw CM, α-lactalbumin, ß-lactoglobulin, and casein were measured. Results: Seventy-two children performed OFC, and 30 (41.6%) had a positive response. The significant predictive factors were sensitization to raw CM extract (p = 0.03), α-lactalbumin (p = 0.013), ß-lactoglobulin (p = 0.09), and casein (p = 0.019). The cutoff was, respectively: 5.13 kUA/L for raw CM, 1.47 for α-lactalbumin, 1.35 for ß-lactoglobulin, and 4.87 for casein. Conclusions: This study allowed us to define a set of cutoff values for CM protein-specific IgE. However, these cutoffs should be interpreted not as a diagnostic tool for CMA but only predictive of response to OFC in a specific territory. Thus, the practical message may be that a value above the cutoff allows a good approximation to identify children to be started on OFC.

Breathlessness perception assessed by visual analogue scale and lung function in children with asthma: a real-life study.

BACKGROUND: In children with asthma, discrepancies between objective indicators of airway obstruction and symptom perception are often observed. Although visual analogue scale (VAS) has been proposed as a useful tool for assessing accurate symptom perception, previous studies conducted in children with asthma included only small cohorts. A study was therefore designed to investigate the usefulness of VAS in establishing a reliable relationship between breathlessness perception and lung function in a large cohort of children with clinical diagnosis of asthma. METHODS: A total of 703 children [470 boys and 233 girls, median age 10.29 (8.33-12.58) yr] with asthma were included in this cross-sectional, real-life study. Perception of breathlessness was assessed by using VAS, and lung volumes and expiratory flows were measured by spirometry. RESULTS: Most children had intermittent or mild persistent asthma (93.3%), and only 46 children had a significant bronchial obstruction defined by FEV(1) values <80% of predicted. Globally, VAS was significantly, even though weakly, related to lung function. Analyzing children with bronchial obstruction, a moderate relationship between both FEV(1) (r = 0.47) and FEF(25-75) (r = 0.42) and VAS was detected. A VAS value of 6 was found to be a reliable cutoff for discriminating children with bronchial obstruction (AUC 0.83 at ROC curve; OR 9.4). CONCLUSION: The present study demonstrates that VAS might be considered a useful tool to assess symptom perception, mainly in children with airflow limitation.

Oral Immunotherapy for Children with Cow's Milk Allergy: A Practical Approach.

Cow milk allergy (CMA) is a prevalent disease in childhood. Natural history is usually favorable as CMA can disappear by school age in many subjects. Diagnosis corresponds to treatment, as an elimination diet is a solution. However, cow's milk (CM) is real food, hardly replaceable. Thus, CM reintroduction represents a demanding challenge in clinical practice. The induction of CM tolerance could be achievable using oral immunotherapy (OIT), such as the administration of increasing milk quantities until reaching tolerance. However, the OIT schedule and procedure need to be better standardized, and performance may vary widely. Therefore, the present study reports the practical experience of a third-level pediatric allergy center in managing children with CMA and submitting them to OIT. OFC and OIT are relatively safe procedures as the reaction rate is low. Almost two-thirds of the OIT subjects tolerated CM. Reactions were associated with high IgE levels. Therefore, the present experience, developed by a qualified center, may suggest and propose a practical approach for managing children with CMA. After the initial workup, including a thorough history, physical examination, and laboratory tests, OFC and, when indicated, OIT could be performed in most children with CMA.

Role of FEF25-75 in managing children with newly-diagnosed asthma in clinical practice.

Background Reversible bronchial obstruction characterizes asthma. Spirometry is the gold standard to assess airflow, and FEV1 is the most reliable parameter in this regard. However, many children with asthma have FEV1 within the normal range despite uncontrolled asthma and worsening. Therefore, FEF25-75 has been proposed as a valuable marker of early airflow impairment. This study aimed at investigating FEF25-75 in a cohort of children with newly diagnosed asthma. Methods 381 children (122 females, mean age 11.6 years) were consecutively visited and had a new asthma diagnosis. In addition, Spirometry, type-2 phenotyping, asthma control assessment, and ACT were performed. Results 72 (18.9%) asthmatic children had impaired FEF25-75, such as <65% of predicted. Low FEF25-75 was associated with lower FVC and FEV1/FVC values (OR 1.11 and 1.32, respectively). Children with normal FEV1 but impaired FEF25-75 had more frequently uncontrolled asthma (15.8% vs. 32.4%) than children with both parameters within the normal range. Conclusions FEF25-75 deserves adequate and careful consideration in children with asthma, and the presence of impaired FEF25-75 values suggests a more compelling approach.

Small airways in children with allergic rhinoconjunctivitis: the potential role of a multicomponent nutraceutical.

Allergic rhinitis and asthma are closely linked. A progression from rhinitis to overt asthma is common. FEF25-75 is a spirometry parameter that could reflect small airways patency and could reliably predict early bronchial involvement in allergic rhinitis patients. MEF50 very strongly correlates with FEF25-75. The aim of this study was to evaluate possible spirometry change in two groups of children suffering from AR over time. The first group took a course of a nutraceutical (Lertal®) before the observation (active group, AG); a second one was considered as control (control group, CG). The children were visited at baseline, at the end of the nutraceutical course, and after 1 year. FEV1, FVC, and MEF50 were the primary outcomes. After one year, children in AG had significantly higher MEF50 than CG children (p=0.009). In conclusion, the present study showed that a course with a multicomponent nutraceutical could prevent the MEF50 decline in children with allergic rhinoconjunctivitis.

Lertal®, a multicomponent nutraceutical, could reduce the use of antihistamines in children with allergic rhinoconjunctivitis.

Antihistamines are the cornerstone treatment of allergic rhinitis (AR). To quantify the antihistaminic consume is particularly relevant in clinical practice, since a remarkable use is usually associated with severe symptoms. The aim of the study was to measure the use of antihistamines in two groups of children suffering from AR. The first group took a course of a nutraceutical (Lertal®) before the observation (active group, AG); a second one was considered as control (control group, CG). Both groups took antihistamines on demand. The children were visited at baseline and after 1 year. The number of days of antihistaminic use was the primary outcome. Children in AG had a significant reduced number of antihistamines use in comparison with CG (p=0.008). In conclusion, the current study showed that a course with a multicomponent nutraceutical could reduce the use of symptomatic antihistamines in children with allergic rhinoconjuncti- vitis.

Imatinib melylate as second-line treatment of bronchiolitis obliterans after allogenic hematopoietic stem cell transplantation in children.

BACKGROUND: The onset of bronchiolitis obliterans (BO) as a pulmonary manifestation of chronic graft vs host disease dramatically changes the prognosis of children undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to evaluate the overall survival (OS) of children with BO treated with imatinib mesylate (IM). METHODS: This study included children who underwent allo-HSCTs between January 2000 and December 2016. RESULTS: Among 345 patients who underwent HSCTs, 293 were evaluable for BO and 26 (8.9%) developed BO. The cumulative incidence of BO was 4.8% (95% confidence interval [CI], 2.8-7.5) at 1 year and 7.7% (95% CI, 5.1-11.1) at 3 years after transplantation. In the group of HSCTs (n = 67) complicated by chronic GvHD (c-GVHD), the incidence rate of BO was 38.8%. In total, 96.1% of patients with BO had c-GvHD worse than moderate grade, which was present in 70.7% of patients without BO (P = .011). The mortality rates were 46.1% in the BO group and 27.4% in the group without BO. Half of the patients with BO (n = 13) received IM, and the overall response rate was 76.9%. Four years after HSCT, OS was 42.6% (95% CI, 18.2-65.3) in the group without IM and 83.3% (95% CI, 27.3-97.5) in the group with IM. CONCLUSIONS: BO after HSCT in the pediatric population has a high incidence and mortality rate. In terms of overall response and tolerability, this study showed relevant improvements in the prognosis of children with BO after the introduction of IM. Further prospective studies among children are needed to confirm these results.

Allergen immunotherapy in children and adolescents with respiratory diseases.

To date, the only disease-modifying treatment strategy for allergic rhinitis and asthma is allergen immunotherapy (AIT). There is evidence that AIT improves allergic rhinitis and asthma, such as reducing symptom severity and medication use and improving of quality of life, with a long-lasting effect after the end of the course. The recent clinical trials evidenced AIT effectiveness and safety in allergic asthma. Consequently, the current version of the GINA (Global Initiative for Asthma) guidelines recommend AIT as an add-on therapy for asthma. There is also evidence that AIT may exert preventive activity on the possible progression from allergic rhinitis to asthma in children and the onset of new sensitizations.

Asthma in children and adolescents: the ControL'Asma project.

The control of asthma is the objective of asthma management. However, it is difficult to obtain in clinical practice. The Italian Society of Allergy and Clinical Immunology promoted the nationwide project "ControL'Asma" to investigate the real situation in a group of children and adolescents with asthma. The preliminary outcomes demonstrated that many asthmatic subjects do not achieve adequate asthma control. Moreover, asthma in Italian children and adolescents was usually more frequent in males, had an early onset and allergic phenotype with very frequent rhinitis comorbidity, uncontrolled and partly controlled asthma affected about the half of subjects. However, this project suggested that the assessment of asthma symptom perception by VAS could be a reliable tool in the asthma management.

Could Bet v 1 affect sensitization molecular pattern in children?

BACKGROUND: Allergy is characterized by allergen-specific IgE production. Molecular-based allergy diagnostic allows to define the precise sensitization profile. Bet v 1 is the major allergen of the PR-10 family. It has been reported that pan-allergens could affect the sensitization panel in adults. OBJECTIVE: This study aimed to evaluate the impact of Bet v 1 sensitization on clinical presentation in a sample of children with Bet v 1-sensitization; oral allergy syndrome (OAS) or anaphylaxis (ANA) were considered. METHODS: Serum IgE molecular components were assessed by ISAC method. Sera and clinical data from 132 children, 91 males (68.94%) and 41 females (31.06%), mean age 9.08 years (3.45 years), were analyzed. RESULTS: Bet v 1-sensitized children were frequently, but not exclusively, sensitized to other molecules belonging to PR-10 family. However, there was no significant difference concerning IgE levels between children with or without food allergy and between children with OAS and ANA, but hazelnut only for generic food allergy. CONCLUSIONS: The present study demonstrates that Bet v 1 sensitization may affect the sensitization pattern in children living in Genoa, a Mediterranean city located in a birch-free area, but it is unable to discriminate patients from a clinical point of view. So, ISAC test should be integrated with more precise IgE assay.

Immunotherapy and Asthma in Children.

Allergen immunotherapy (AIT) is still the only disease-modifying treatment strategy for IgE-mediated allergic diseases, with consolidated evidence both in adults and children. AIT is effective in determining clinical improvement of allergic rhinitis and asthma, such as reduced symptoms, medication use, and improvement of quality of life, with a long-lasting effect after cessation of treatment. Results from recent clinical studies have implemented the evidence of effectiveness and safety of allergen immunotherapy for the treatment of allergic asthma, so that the current asthma guidelines now recommend sublingual immunotherapy as an add-on therapy for asthma in adults and adolescents with house dust mite allergy, allergic rhinitis, and exacerbations despite low-to-moderate dose ICS, with forced expiratory volume in 1 second more than 70% predicted. AIT may also reduce the risk of progression from allergic rhinitis to asthma in children and prevent the onset of new sensitizations, thus representing a potentially preventive method of treatment. The aim of this review is to present an updated overview of the clinical indications of AIT, with particular reference to pediatric asthma, of the mechanisms of clinical and immunological tolerance to allergens, and of the potential biomarkers predicting clinical response.