Ilaria Brambilla

Adenoids in children: Advances in immunology, diagnosis, and surgery.

Adenoids are strategically located for mediating local and regional immune functions as they are exposed to antigens from both the outside air and the alimentary tract. Recurrent or chronic respiratory infections can induce histomorphological and functional changes in the adenoidal immunological barrier, sometimes making surgical treatment necessary. Our aim in this review is to summarize the crucial points about not only the immunological histopathology of adenoidal tissue, especially in patients with adenoid hypertrophy, but also the most common and useful diagnostic techniques and surgical options. Clin. Anat. 27:346–352, 2014.

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.

Body mass index is related with bronchial function and reversibility in children with allergic rhinitis and asthma.

Several studies have outlined a possible relationship between an increased body mass index and respiratory allergic diseases, such as asthma and rhinitis. The aim of the study was to analyse the relationship between BMI and lung function, including bronchodilation test, in allergic children. The study included 153 children (103 males, mean age 12.8 years) with allergic rhinitis and mild asthma. All subjects were evaluated performing skin prick test, spirometry, and bronchodilalation test. BMI values were in the normal range as well as lung function. BMI significantly related with FEV1, FVC values and FEV1/FVC ratio both before and after bronchodilation. In conclusion, this study provides the first evidence that BMI is negatively related with bronchial reversibility in children with allergic rhinitis and asthma. As reversibility is related with bronchial inflammation, this finding might underline a link between overweight and allergic inflammation.

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.

An Update on Anti-IgE Therapy in Pediatric Respiratory Diseases

Anti-IgE treatment represents a major breakthrough in the therapeutic management of severe allergic asthma. Omalizumab is the unique biologic treatment registered for asthma therapy in children. 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. In addition, new experimental evidence suggests that omalizumab may also interfere with the cellular and molecular mechanisms underlying airway remodeling. Novel investigational anti-IgE monoclonal antibodies with improved pharmacodynamic properties are in the pipeline, potentially offering alternative mechanisms of modulating IgE pathway. The aim of this review is to update current knowledge on anti-IgE therapy in pediatric respiratory diseases.

Autosomal dominant hypocalcemia due to a truncation in the C-tail of the calcium-sensing receptor.

Autosomal Dominant Hypocalcemia (ADH) is an endocrine disorder due to activating mutations of the calcium-sensing receptor (CASR) gene. We report on a young boy who presented low serum calcium with hypercalciuria, hyperphosphatemia and low serum concentration of parathyroid hormone, not accompanied by classic clinical signs of hypocalcemia. Treatment with calcitriol and calcium did not normalize serum calcium and renal calcium excretion. The use of thiazide diuretics slightly reduced calciuria. Despite high calcium excretion, no signs of nephrocalcinosis were detected. The patient had a prolonged Q-T interval at ECG, which did not normalize during treatment. PCR amplification of CASR coding sequence and direct sequencing of PCR products. showed a novel heterozygous deletion of a cytosine (c.2682delC), responsible for a frameshift (p.S895Pfs*44) and a premature stop codon resulting in a truncation of the CaSRs C-tail. Functional studies indicated increased activity of mutant receptor compared to the wild-type.

Perception of Dyspnea in Prepubescent Children with Mild Intermittent Asthma: Is there Any Gender Difference?

Evaluating a small number of asthmatic patients, Chhabra and Chhabra (1) reported that the females were more likely to have a greater perception of dyspnea as well as a lower asthma control and a poorer quality of life than the males. In addition, they showed that female gender and poorer quality of life were independent predictors of increased perception of dyspnea in their asthmatic population (1). This study had some limitations, also recognized by authors, but the findings were interesting and may be clinically relevant as there are few reports investigating the possible gender difference about asthma symptom perception, which may vary according to a variety of factors, including disease severity and patients’ age. In this regard, we recently evaluated a cohort of 150 Italian asthmatic children (97 males, median age 9.79 years). Inclusion criteria were (a) first asthma diagnosis; (b) atopy confirmed by skin prick test positivity; (c) ability to perform spirometry, with reproducible flow/volume curves (2); and (d) mild intermittent disease, treated only with bronchodilators on demand. We selected children with mild intermittent asthma because (a) about 70–80% of new diagnosed cases belong to this severity class and (b) we wanted to avoid any interference with “controller medications.” In addition, most asthmatic patients referred to our unit are prepubescent. Therefore, children had to be prepubescent in this study as we want to evaluate whether there was a possible gender difference in asthma prior to sexual maturation. Pulmonary function tests results were compared with reference values (3) and reversibility post-bronchodilation testing was considered positive when the forced expiratory volume in 1 second (FEV1) values increased ≥12% after inhalation of 400 μg

Pediatric rhinosinusitis and asthma

Both asthma and rhinosinusitis are complex and heterogeneous diseases and, importantly, they often coexist: these diseases can be concomitant in 35-65% of affected children, according to different studies. Thus, evaluating this comorbidity in the clinical practice should be paramount. In this review, we focused our discussion on the multiple pathophysiological aspects that may link rhinosinusitis and asthma in the pediatric population. Although rhinosinusitis may exacerbate asthma through several mechanisms occurring by contiguity, actually this aspect seems to be only one component of the complex interplay between upper and lower airways. In particular, the onset of an important and persistent Th2-driven inflammatory process dominated by eosinophils presence at one site of the airways, may release into the bloodstream several cytokines; in their turn, those can lead to the stimulation of the bone marrow, which may function as a systemic amplifier of such an eosinophilic inflammation.

Basophils activated via TLR signaling may contribute to pathophysiology of type I autoimmune pancreatitis

We read with a great interest the study published by Yaganawa et al. [1] investigating the contribution of basophils in the pathophysiology of type I autoimmune pancreatitis (AIP). Although its pathogenesis is still largely unclear, several data supported an important Th2-driven immune component in this disease where the most remarkable immune-pathological findings are represented by elevated serum levels of IgG4 and tissue infiltration with IgG4-expressing cells [2]. The innate immunity emerged as a fundamental player in several autoimmune diseases. Yamashina et al. [3] demonstrated that poly I:C (acting as TLR3 ligand) administration to MRL/Mp mice, that are prone to develop autoimmunity, was able to induce pancreatitis resembling human type I AIP. As a human counterpart, Watanabe et al. [4] showed that the activation of TLRs in basophils from patients with IgG4-related disease could induce a large production of IgG4 by B cells from healthy controls. Basophils have been demonstrated to act as innate immune cells being able to prime the adaptive immune response toward Th2 phenotype in several pathological settings [5, 6], but basophil-focused studies on type I AIP have not been provided yet. Importantly, Yanagawa et al. [1] first described the presence of basophils in the pancreatic tissue samples of most patients with type I AIP; moreover, these basophils mainly expressed TLR4 and/or TLR2, and the ratios of basophils activated by those TLRs were significantly higher than in healthy controls. Therefore, through TLRs stimulation, many infectious agents might trigger an autoimmune response in those patients, showing a kind of basophil hyper-sensitivity/hyper-expression of TLR2 and/or TLR4, which in turn would be able to promote an over-production of IgG4 and IgE, according to the cytokine profiling of activated basophils. In type I AIP, any pathogenic role of IgG4 has not been supported [7], but the occurrence of IgE autoantibodies being able to cause tissue damage has been recognized recently [8]. Accordingly, Pan et al. [9] highlighted the potential and emerging role of basophils in systemic lupus erythematosus (SLE) and, specifically, in the production of autoantibody, and we also speculated that actually these aspects might be extended to the pathogenesis of other immune-mediated diseases, such as Mycoplasma pneumoniae-related extra-pulmonary diseases (MpEPDs) [10, 11]. Gastrointestinal diseases have been reported in the setting of MpEPDs and, very recently, Valdes Lacasa et al. [12] reviewed published cases of immune-mediated pancreatitis attributed to Mycoplasma pneumoniae. In conclusion, Yanagawa et al. provided additional and interesting data to the growing burden of evidence supporting an immunological role of basophils in the pathogenesis of autoimmune diseases.

Detection of IL10-producing B cell (B10) in adenoids of atopic children with adenoidal hypertrophy

Introduction and background Regulatory cells are important for maintaining immunological homeostasis and tolerance to antigens, including self-antigens. Even though in the majority of autoimmune diseases and inflammatory processes, B cells generally play an important role due to their capacity to secrete antibodies, it has emerged that different B cell subsets may be able to down regulate immune responses, especially in experimental autoimmune disease models. Moreover, it has been demonstrated that B cells are able to drive T cell differentiation in favor of a regulatory phenotype (regulatory T cells, Treg) both in mice and humans [1]. In several studies the presence of Breg cells is often related to the development of chronic inflammation or autoimmune disease, but their pathogenic involvement is not completely understood. Researchers have described many B cell subsets with regulatory functions in mice, which are characterized by different surface markers, such as CD5B-1a cells, CD19CD1dCD5 B cells, or marginal zone (MZ) B cells [1]. Some studies have also suggested that human IL-10-producing B10 cells include CD24CD38 and CD24CD27 B cells, which have been identified by their capacity to produce IL10 after appropriate stimulation [2]. However, Breg cells represent an heterogeneous group of immunosuppressive cells subset with distinct phenotypic and functional properties, that could play a role also in the induction of immune tolerance to allergens. Breg-derived IL10 is involved not only in inhibition of Th1 polarization, but also in preventing Th2 responses and its expression in mucosal environment is important for the generation of immunological tolerance. Moreover, allergic disorders are characterized by an imbalance of immune response, typically defined by type 2 response and by a functional defect of Treg (3). In particular, allergic inflammation is mediated and regulated by allergen-specific Th2 cells that induce B cells to produce IgG1 and IgE by secreting IL-4. Moreover, Th2 cells also recruit eosinophils via IL-5 production and directly act on epithelial cells and smooth muscle cells through IL13 production. The development of the allergic environment, for example in asthma, could increase germinal center B cell numbers and MHC II and CD23 expression on follicular mature B cells in lung, bronchial lymph nodes (bLN) and spleen and affect the maturation of regulatory B cell subsets [3]. It is not clear if the alteration in Bregs differentiation in germinal centers is a consequence of the establishment of an allergic environment or vice versa contributes to allergic pathogenesis. Anyway, there is evidence that Breg cells are involved in allergic diseases [4]. A recent review by Palomares and colleagues highlights the importance of IL10and TFGβproducing Breg cells because of their immunosuppressive properties during allergic reaction. These cell subsets are increased both in mice and humans in response to highdose allergen exposure [4]. Bregs are able to promote * Correspondence: chiara.valsecchi@unipv.it Department of Clinical Surgical Diagnostic and Pediatric Sciences, University of Pavia and Fondazione IRCCS Policlinico San Matteo, P.le Golgi 19, 27100 Pavia, Italy Department of Clinical Surgical Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy Full list of author information is available at the end of the article