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.

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.

Severe uncontrolled asthma in children: practical approach on diagnosis and management.

Severe uncontrolled asthma in children is a complex and heterogeneous disease and is considered a challenge for the pediatricians. Although nearly 5% of children with asthma present with a severe uncontrolled disease, these patients and their caregivers face a significant burden, including troublesome persistent symptoms, life-threatening acute attacks, medication side effects, impaired school performance, neuropsychological problems, and lower quality of life (QoL). Moreover, these patients also account for substantially higher healthcare resource use and costs than average patients with asthma. Thus, it is essential to accurately define and diagnose severe asthma in children as they potentially need close monitoring and additional treatment with advanced therapies. This review aims to update knowledge on diagnosis and management of severe uncontrolled asthma in childhood. We describe a practical approach to differentiate children with difficult-to-treat asthma from those with true severe therapy-resistant asthma. Moreover, the recent advances in the understanding of the pathogenetic mechanisms and inflammatory mediators involved in asthma have paved the way for the development of a precision medicine approach. In this context, we analyze approved personalized therapies for severe uncontrolled asthma, focusing on the pediatric indications.

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.

Food Allergies: Current and Future Treatments.

Food allergies are an increasingly public health problem, affecting up to 10% of children and causing a significant burden on affected patients, resulting in dietary restrictions, fear of accidental ingestion and related risk of severe reactions, as well as a reduced quality of life. Currently, there is no specific cure for a food allergy, so the only available management is limited to strict dietary avoidance, education on prompt recognition of symptoms, and emergency treatment of adverse reactions. Several allergen specific- and nonspecific-therapies, aiming to acquire a persistent food tolerance, are under investigation as potential treatments; however, to date, only immunotherapy has been identified as the most promising therapeutic approach for food allergy treatment. The aim of this review is to provide an updated overview on changes in the treatment landscape for food allergies.

A starch, glycyrretinic, zinc oxide and bisabolol based cream in the treatment of chronic mild-to-moderate atopic dermatitis in children: a three-center, assessor blinded trial.

BACKGROUND: Atopic dermatitis (AD) is a very common chronic inflammatory and eczematous skin condition characterized by flares and remissions. Skin barrier alteration or dysfunction is the most relevant patogenetic factor. Topical corticosteroids are the mainstay treatment of AD, especially during flare periods. The daily use of emollients and moisturizers is also considered a relevant adjunctive strategy to improve skin barrier function and skin appearance in AD patients. Long-term use of topical corticosteroids is associated with important drawbacks and side effects. A corticosteroid-free cream containing starch, glycyrretinic acid, zinc oxide and bisabolol (Dermamid™; Difa Cooper, Caronno Pertusella, Varese, Italy) has been designed for the treatment of acute eczematous conditions like diaper dermatitis. However, this formulation could be particularly suitable also for AD. We evaluated in a three-center, assessor-blinded prospective 6-week treatment trial the efficacy and tolerability of this cream in children with chronic mild-to-moderate atopic dermatitis. METHODS: A total of 30 children (mean age 5 years, 18 males and 12 females) with chronic mild to moderate AD, affecting face, lower and upper limbs or trunk, were enrolled after parents' written informed consent. Exclusion criteria were a condition of immunosuppression, acute flares or a positive history of allergy to one of the components of the cream. The primary outcome was the evolution total eczema severity score (TESS) calculated as the sum of the single eczema severity score for each body area involved. Single area Eczema Severity Score (ESS) was calculated assessing eczema, infiltration, lichenification and scraching lesions using a 4-point scale grade (with 0=no sign, and 4=severe sign). A secondary endpoint was the percentage of subjects reaching at least 50% of TESS reduction at week 6 in comparison with baseline. The TESS was evaluated at baseline and after 3 and 6 weeks of treatment (twice daily application) in an assessor-blind fashion. RESULTS: At baseline the mean (SD) TESS was 11.6 (4.7). TESS was reduced significantly (P=0.0001) to 5.7 (3) after 3 weeks (-51%), and to 3.0 (2.3) at week 6 (-74%). Similar reductions were observed for single area ESS values. The percentage of subjects with at least a >50% reduction of TESS value at the end of the study was 87%. The product was very well tolerated. Only for one patient a mild burning sensation at the application site was reported. All the subjects concluded the trial. CONCLUSIONS: This trial supports the efficacy and the tolerability of a corticosteroid-free cream containing starch, glycyrretinic acid and bisabolol in the treatment of chronic mild to moderate atopic dermatitis in children.

Emerging drugs for the treatment of perennial allergic rhinitis.

INTRODUCTION: Allergic rhinitis is a worldwide health problem, currently affecting up to 40% of the general population, and characterized by the following symptoms in a variable degree of severity and duration: nasal congestion/obstruction, rhinorrhea, itchy nose and/or eyes, and/or sneezing. General symptoms like fatigue, reduced quality of sleep, impaired concentration and reduced productivity, if left untreated, may significantly affect quality of life. In addition, of being associated to various comorbidities, allergic rhinitis is also an independent risk factor for the development and worsening of asthma. Perennial allergic rhinitis is caused by allergens present around the year. AREAS COVERED: Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines currently recommend a stepwise therapeutic approach that combines patient education with specific allergen avoidance, symptomatic pharmacotherapy and allergen immunotherapy. The available treatment strategies provide suboptimal symptom relief in patients with moderate-to-severe disease who continue to experience symptoms while treated, even on multiple therapies. EXPERT OPINION: New insights into current therapy have been provided with the development of new symptomatic drugs with improved pharmacokinetics and safety. However, the ultimate research goal is beyond symptomatic treatment, and is mainly directed at modifying the immune response to allergens and prevent the progression of allergic rhinitis towards asthma. In this direction, promising advances are expected in the fields of allergen immunotherapy and biological drugs, such as omalizumab. Finally, significant research efforts are also focused on the growing number of new specific molecular targets involved in the Th2 pathway inflammation of allergic diseases.

Local rhamnosoft, ceramides and L-isoleucine in atopic eczema: a randomized, placebo controlled trial.

BACKGROUND: A non-steroidal, anti-inflammatory moisturizing cream containing rhamnosoft, ceramides, and L-isoleucine (ILE) (pro-AMP cream) has been recently developed for the specific treatment of atopic eczema (AE) of the face. In this trial, we evaluated the clinical efficacy and tolerability of pro-AMP cream in the treatment of facial AE in children in comparison with an emollient cream. METHODS: In a randomized, prospective, assessor-blinded, parallel groups (2:1) controlled trial, 107 children (72 allocated to pro-AMP cream and 35 allocated to control group) with mild-to-moderate chronic AE of the face were enrolled. Treatments were applied twice daily for a 6-week period. Facial Eczema Severity Score (ESS) was evaluated at baseline, week 3, and week 6, by an assessor unaware of treatment allocation. Investigator's Global Assessment (IGA) score was assessed at week 3 and at week 6. Tolerability was evaluated at week 3 and at week 6 using a4-point score (from 0: low tolerability to 3: very good tolerability). RESULTS: At baseline ESS, mean (SD) was 6.1 (2.4) in the pro-AMP cream group and 5.3 (3) in the control group. In the pro-AMP group, in comparison with baseline, ESS was significantly reduced to 2.5 (-59%) after 3 wks and to 1.0 (-84%) at week 6 (p = 0.0001). In the control group, ESS was reduced to 3 (-42%) at week 2 and to 2.6(-50%) at week 6. At week 6, ESS in pro-AMP cream was significantly lower than the control group (1.0 vs. 2.6; p = 0.001). Both products were well tolerated. CONCLUSION: Pro-AMP cream has shown to be effective in the treatment of mild-to moderate chronic lesion of AE of the face. Clinical efficacy was greater in comparison with an emollient cream. ( CLINICAL TRIAL REGISTRY: NTR4084).

Serum interleukin-9 levels are associated with clinical severity in children with atopic dermatitis.

Atopic dermatitis (AD) is an inflammatory disorder of the skin characterized by impaired immune response. Th9 cells are a sub-population of T cells that release interleukin (IL)-9. No study has investigated the role of IL-9 in AD. This study compared 64 children with AD with 45 healthy children. Serum IL-9 levels were measured and clinical symptoms were assessed. Children with AD had higher serum IL-9 levels than controls (p = 0.01). Clinical severity was significantly related to IL-9 level, indicating that IL-9 might exert a pathogenic role in symptom occurrence in individuals with AD. Children with AD may have higher serum IL-9 levels than healthy children, and IL-9 levels are significantly related to symptom severity.

Pathophysiology, favoring factors, and associated disorders in otorhinosinusology.

The pathogenesis of rhinosinusitis (RS) is related to inflammation, caused by infections in the acute form of the disease but also by other agents in the chronic forms. Cytology allows to evaluate the defensive components, such as hair cells and muciparous cells, while the presence in the nasal mucosa of eosinophils, mast cells, bacteria and/or fungal hyphae, or spores indicates the nasal pathology. The anatomic and physiologic characteristics of the otorhinosinusal system account for the frequent concomitant involvement of the different components. The pivotal pathophysiologic sites are the ostiomeatal complex, the spheno-ethmoidal recess, and the Eustachian tube. The latter is the link with acute otitis media (AOM), which is the most common disease in infants and children and has major medical, social, and economic effects. Moreover, because of the strict relationship between upper and lower airways, nasal sinus disease may contribute to asthma and sinusitis may be considered as an independent factor associated with frequent severe asthma exacerbations. Concerning the role of allergy, the available data do not permit to attribute a central role to atopy in sinusitis and thus allergy testing should not be a routine procedure, while an allergologic evaluation may be indicated in children with OM, especially when they have concomitant rhinitis.

Pediatric chronic spontaneous urticaria: a brief clinician's guide.

INTRODUCTION: Chronic urticaria (CU) appears with daily or intermittent/recurrent wheals with/without angioedema for more than six weeks. When no specific eliciting factors are found, chronic urticaria is defined as spontaneous (CSU). Up to 50% of patients with CSU do not respond to therapy, leading to a prolonged disease course and the need for expensive therapies, impacting the quality of life (QoL) and healthcare resources. AREAS COVERED: Diagnosis of CSU is made when other potential causes of chronic urticaria are excluded. CSU therapy aims to achieve complete control of symptoms and normalization of QoL. Current treatment options for urticaria aim to target mast cell mediators such as histamine, or activators, such as autoantibodies. Guidelines recommend starting with second generation antihistamines (sgAHs) and adding omalizumab therapy if symptoms are not controlled. This review aims to provide a practical guide for CSU in the pediatric population. EXPERT OPINION: Treatment options for pediatric CSU are primarily based on adult data that have been extrapolated for children. Current guidelines should be reevaluated based on pediatric data, new biological treatments, and the COVID-19 pandemic. Future research is needed to investigate strategies to personalize current treatments and identify potential predictive biomarkers.

Pediatric Anaphylaxis: A 20-Year Retrospective Analysis.

BACKGROUND: Anaphylaxis is a steadily increasing global problem defined as an acute hypersensitivity multisystem reaction that is potentially fatal. In the pediatric age, the leading cause is food. In other allergic diseases, intrinsic heterogeneity has been reported in the clinical presentation, severity, and triggers of anaphylaxis. This study analyzes the features and management approach of the anaphylactic reactions in children evaluated at the pediatric clinic in Pavia. MATERIALS AND METHODS: A retrospective study was conducted on patients with anaphylaxis between 2001 and 2021. RESULTS: A total of 148 patients with a median age of 5 years were enrolled, and 80% of the patients had other atopic comorbidities that were correlated with the severity of anaphylaxis. The main trigger of anaphylaxis was food. Most reactions involved mucocutaneous, respiratory, and gastrointestinal systems, and occurred at home. Adrenaline was administered only in a minority of cases. CONCLUSIONS: Considering that anaphylaxis is a potentially life-threatening condition requiring prompt management, the use of adrenaline should be implemented. Our data also suggest the importance of educating and spreading awareness of anaphylactic management within the medical community.

Biological Therapies in Children and Adolescents with Severe Uncontrolled Asthma: A Practical Review.

Severe uncontrolled asthma is a complex and heterogeneous disease. A multidisciplinary assessment is required to correctly identify and manage children and adolescents with severe asthma because they may require strict monitoring and additional treatment with advanced targeted therapies. Recent research efforts have focused on identifying epidemiologic, clinical, and molecular mechanisms that underlie severe asthma, leading to the recognition of different phenotypes and endotypes and identifying biomarkers able to predict the response to biologic therapies. Additional progress has occurred by introducing biological therapies that have revolutionized the care of chronic allergic diseases in the adult and pediatric population. In this review, we briefly summarized the current literature on biological therapies to treat severe asthma in children and adolescents.

Component resolved diagnosis and risk assessment in food allergy.

Allergy testing should only be performed in the context of the clinical history as history provides the cornerstone of diagnosis. In food allergy, some allergy tests often give rise to false positive results and thus can lead to unnecessary avoidance or delay on foods introduction. The use of Component Resolved Diagnosis in combination with conventional sensitization testing improves analytical and diagnostic performance and can lead to the reduction of diagnostic oral food challenges. Component Resolved Diagnosis can be helpful in identifying some risks for the allergic child. Molecular diagnosis can help also in predicting the development of the allergy march, in severe reactions (lipid transfer protein, seed storage proteins, etc.) in food allergy and for potential clinical cross-reactivity.

COVID vaccination and asthma exacerbation: might there be a link?

INTRODUCTION: There is ongoing debate regarding the role of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in asthma exacerbation, and its long-term impact on the lung function of individuals with asthma. In contrast, the potential impact of coronavirus disease 2019 (COVID-19) vaccination on asthma is entirely unexplored. CASE STUDY: This study examined a challenging case of severe asthma exacerbation in a 28-year-old female following two doses of the mRNA-based vaccine BNT162b2 (Pfizer-BioNTech) at IRCCS Policlinico San Matteo in Pavia, Italy. The patient, a fourth-year resident at the hospital, was vaccinated in early 2021. She was an occasional smoker with a 10-year history of asthma and seasonal allergic rhinitis. She tested negative for SARS-CoV-2 on several molecular swabs and serology tests. RESULTS: After receiving the second dose of vaccine, the patient started to experience worsening of respiratory symptoms. Following several episodes and a severe asthma attack, the patient required treatment with mepolizumab, a biologic drug (interleukin-5) antagonist monoclonal antibody. CONCLUSION: This single case study is insufficient to draw conclusions about the association between asthma exacerbation and the COVID-19 vaccine. While the cause-effect link between vaccination against SARS-CoV-2 and worsening of asthmatic disease might only be suggested at present, this case is a valuable prompt for further investigation. This is particularly true from the perspective of mass vaccination of adolescents and children currently underway across the globe.

Atopic dermatitis and atopic march: which link?

There is a long standing debate on the atopic march in childhood. The natural progression of allergic manifestations may be considered as comorbidities, which occur more frequently in a specific evolutive age. On the other hand, the natural history of allergies in children may follow trajectories that may be heterogeneous. The effects of atopic march in clinical practice have also been reported.

Food allergy in primary care.

Prevalence of food allergy has been increasing over the last decades. It may appear as an immediate or a delayed reaction. The disease has a major impact on the quality of life of patients and their families, and it is associated to elevated costs. Primary care physicians are the first healthcare providers who assist children with food allergy, especially in mild to moderate forms. Through the present review, we examine the steps that should be followed in primary care to manage food allergy, and to promptly prescribe an elimination diet and an emergency kit in case of accidental exposure to the allergen. We also focus on the special management of IgE and non-IgE mediated cow's milk allergy, and on management and prevention of egg and peanuts allergy.

Dupilumab to Treat Type 2 Inflammatory Diseases in Children and Adolescents.

During the past decade, significant therapeutic progress has been made in the field of allergic diseases, mainly concerning the pathogenic role of type 2 inflammation. Biologics targeting specific key cytokines, such as interleukin (IL)-4, IL-5, and IL-13, as well as IgE, have emerged as promising innovative therapies for allergic disorders. In this context, dupilumab has emerged as one of the most successful therapies targeting the IL-4R axis. Dupilumab is a human IgG4 antibody anti-IL-4 receptor (IL-4R) α-subunit that blocks IL-4R signaling induced by both IL-4 and IL-13, downregulating the molecular pathways that drive type 2 inflammatory diseases, including atopic dermatitis, allergic rhinitis, allergic asthma, chronic rhinosinusitis with nasal polyps, and eosinophilic esophagitis. This review presents the most recent evidence on dupilumab for the treatment of type 2 inflammatory diseases and discusses the future perspective, focusing on the pediatric age group and adolescents.

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.