Riccardo Castagnoli

Omalizumab in Children

Omalizumab is a recombinant humanized monoclonal antibody that reduces levels of circulating immunoglobulin E (IgE) and expression of IgE high-affinity receptors on mast cells and basophils, interrupting the subsequent allergic inflammatory cascade. Current indications for treatment with omalizumab in pediatric patients are clearly defined and are confined to moderate-to-severe uncontrolled allergic asthma and chronic spontaneous urticaria (CSU). Any other prescription can only be off label. Data available from clinical trials conducted in children suggest that omalizumab is clinically effective and generally well tolerated. Given its mechanism of action, recent reports have suggested its possible clinical use in other IgE-mediated disorders, such as allergic rhinitis, food allergy, and anaphylaxis. In recent years, several studies have also investigated the possible applications of omalizumab in a number of non IgE-mediated diseases. The aim of the present review is to assess all applications of omalizumab as therapy in the pediatric population. The approved indications—allergic asthma and CSU—are reviewed. Moreover, further potential applications of omalizumab are discussed in both IgE-mediated and non-IgE-mediated diseases.

The discovery and development of omalizumab for the treatment of asthma

Introduction: The evolution in immunological methods used to assess human allergic diseases has led to the identification of immunoglobulin E (IgE) as a diagnostic biomarker and a potential therapeutic target. Innovative technologies in molecular biology and immunogenetics contributed to the development of a selective blocking agent, disclosing new therapeutic perspectives in the treatment of allergic asthma. Omalizumab is the most advanced humanized anti-IgE monoclonal antibody that specifically binds serum-free IgE. Omalizumab also interrupts the allergic cascade by preventing binding of IgE with FcϵRI receptors on mast cells, basophils, antigen-presenting cells and other inflammatory cells. Areas covered: This review discusses the discovery strategy and preclinical development of omalizumab. Furthermore, it also provides a clinical overview of the key trials leading to its launch and a detailed analysis of safety and post-marketing data. Expert opinion: The clinical efficacy of omalizumab in allergic asthma has been well documented in clinical trials, involving adults, adolescents and children with moderate-to-severe and severe allergic asthma. To date, omalizumab has also been approved in chronic idiopathic urticaria for patients 12 years and older who remain symptomatic despite high dosages of H1 antihistamines. Omalizumab has also been investigated in many other different patient populations beyond allergic asthma and may yet have an application to other indications. While omalizumab is the only mAb available for treating allergic asthma, the authors anticipate that new mAbs will emerge in the future that overcome omalizumab’s current limitations.

From IgE to clinical trials of allergic rhinitis.

The current scientific research is continuously aiming at identifying new therapeutic targets with the purpose of modifying the immune response to allergens. The evolution in immunological methods has led to the identification of immunoglobulin E (IgE) as both a diagnostic biomarker and potential therapeutic target in allergic diseases, such as allergic rhinitis. Allergen immunotherapy has been used for more than 100 years to treat allergic diseases and it is today considered the only disease-modifying treatment capable of inducing a long-lasting immunological and clinical tolerance toward the causal allergen. During the past 20 years, major advances have been made in understanding the molecular and cellular mechanisms of allergen tolerance in humans. Moreover, there has been considerable progress in allergen extract modifications and additions to standard extracts. The recognition that IgE plays a pivotal role in basic regulatory mechanisms of allergic inflammation has recently stimulated research into the therapeutic potential of directly targeting this antibody. Omalizumab, the most advanced humanized anti-IgE monoclonal antibody, is currently approved for the treatment of uncontrolled allergic asthma and chronic spontaneous urticaria. Interesting results also arise from studies in which omalizumab was administered in patients with allergic rhinitis. The aim of this review is to provide an update on current findings on immunological and clinical effects of allergen immunotherapy and anti-IgE therapy, which have been shown to have synergistic modes of action for the treatment of allergic rhinitis.

Current recommendations and emerging options for the treatment of allergic rhinitis

Allergic rhinitis (AR) is one of the most common diseases and represents a global health problem, currently affecting up to 30% of the general population, with a continuously increasing prevalence and significant comorbidities and complications. The aim of this review is to provide an update on AR treatment, with a focus on current therapies defined by AR and its impact on asthma guidelines and with a particular emphasis on new and future therapeutic perspectives.

The Nose and the Lung: United Airway Disease?

Epidemiologic, pathophysiologic, and clinical evidences recently revealed the link between upper and lower airways, changing the global pathogenic view of respiratory allergy. The aim of this review is to highlight the strong interaction between the upper and lower respiratory tract diseases, in particular allergic rhinitis and asthma.

Emerging drugs for the treatment of perennial allergic rhinitis

ABSTRACT 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.

The role of upper airway pathology as a co-morbidity in severe asthma

ABSTRACT Introduction: Severe asthma is a complex heterogeneous disease that is refractory to standard treatment and is complicated by multiple co-morbidities and risk factors. Several co-morbidities may contribute to worsen asthma control and complicate diagnostic and therapeutic management of severe asthmatic patients. Areas covered: A prevalent cluster of chronic upper airway co-morbid diseases is recognized in severe asthma. Evaluation for these disorders should always be considered in clinical practice. The aim of this review is to provide an updated overview of the prevalence, the pathogenetic mechanisms, the clinical impact and the therapeutic options for upper airway pathology in severe asthma, focusing on chronic rhinosinusitis and allergic rhinitis. Expert commentary: In the context of severe asthma, the clinical significance of upper airway co-morbidities is based on mutual interactions complicating diagnosis and management. A better analysis and understanding of phenotypes and endotypes of both upper and lower airway diseases are crucial to further develop targeted treatment.

New approaches for identifying and testing potential new anti-asthma agents

ABSTRACT Introduction: Asthma is a chronic disease with significant heterogeneity in clinical features, disease severity, pattern of underlying disease mechanisms, and responsiveness to specific treatments. While the majority of asthmatic patients are controlled by standard pharmacological strategies, a significant subgroup has limited therapeutic options representing a major unmet need. Ongoing asthma research aims to better characterize distinct clinical phenotypes, molecular endotypes, associated reliable biomarkers, and also to develop a series of new effective targeted treatment modalities. Areas covered: The expanding knowledge on the pathogenetic mechanisms of asthma has allowed researchers to investigate a range of new treatment options matched to patient profiles. The aim of this review is to provide a comprehensive and updated overview of the currently available, new and developing approaches for identifying and testing potential treatment options for asthma management. Expert opinion: Future therapeutic strategies for asthma require the identification of reliable biomarkers that can help with diagnosis and endotyping, in order to determine the most effective drug for the right patient phenotype. Furthermore, in addition to the identification of clinical and inflammatory phenotypes, it is expected that a better understanding of the mechanisms of airway remodeling will likely optimize asthma targeted treatment.

Impact of passive smoke and/or atopy on adenoid immunoglobulin production in children.

The adenoids are exposed to a wide number and variety of microbes, environmental pollutants, and food antigens. Atopy and passive smoke may significantly affect immune responses, mainly in children. The aim of the present study was to investigate whether passive exposure to tobacco smoke and/or atopy could affect immunoglobulin production by adenoidal lymphocytes in a cohort of children presenting with adenoid hypertrophy. A total of 277 children (151 males and 126 females; median age 5.5 years), with adenoidal hypertrophy requiring adenoidectomy and or adeno-tonsillectomy, were consecutively enrolled in the study. Adenoid mononuclear cells were in vitro stimulated with LPS or CpG. When considering both the presence of smoke exposure and atopy, we observed that the CpG-induced decrease in IgA and IgM production was significantly associated with this combination of risk factors. In the T-independent immunoglobulin production assay we found a positive association between the two risk factors and IgA and IgM production. In particular, the presence of both risk factors, showed a significant increase in IgA and IgM production after stimulation. In conclusion, this is the first study that investigated the in vitro adenoidal B cell response after different stimuli in children, also evaluating possible exposure to passive smoke and/or an atopic condition.

Omalizumab in children with severe allergic asthma: The Italian real- life experience

Background Anti-IgE treatment represents a major breakthrough in the therapeutic management of severe allergic asthma. To date, omalizumab is the only biological drug currently licensed as add-on therapy in children aged > 6 years with moderate-to-severe and severe allergic asthma uncontrolled after treatment with high dose of inhaled corticosteroids plus long-acting inhaled beta2-agonist. The clinical efficacy and safety of omalizumab treatment in the pediatric population has been extensively documented in specific trials and consistently expanded from real-life studies. Our aim is to describe the impact of omalizumab on asthma management, by reporting the results of the first Italian multicenter observational study conducted in children and adolescents with severe allergic asthma. Methods The study was a 1-year real-life multicenter survey conducted in 13 pediatric allergy and pulmonology tertiary centers in Italy. All patients with confirmed severe allergic asthma from whom Omalizumab add-on treatment was initiated between 2007 and 2015 were included in the study. Results Forty-seven patients with severe allergic asthma were included in the study. A significant reduction in the number of asthma exacerbations was observed during treatment with omalizumab, when compared with the previous year (1.03 vs 7.2 after 6 months (p<0.001) and 0.8 after 12 months (p<0.001), respectively). Hospital admissions were reduced by 96%. At 12 months, forced expiratory volume in 1 s improved and a corticosteroid sparing effect was observed.No serious adverse events were reported during the follow-up period of 12 months. Conclusion The results of the first Italian multicenter observational study confirmed that omalizumab is an effective and safe add-on therapy in uncontrolled severe allergic asthma in children.