The Relevance of Targeting Treatment to Small Airways in Asthma and COPD.

COPD and asthma have different risk factors and pathogenesis, but they share a pathophysiologic hallmark characterized by small airways disease. Although difficult to explore and measure, modifications of distal airways' pathophysiology and biology represent an early sign of obstructive disease and should be researched and assessed in everyday clinical practice. In the last 15 years, computed microtomography scans have shed light on the anatomy and physiology of the so-called silent zone, and research devoted to investigate the effect of inhaled treatments on small airway pathophysiology has been increasing. This narrative review offers a historical summary of researchers and landmark studies that reported, defined, and advanced the research on small airways. We then discuss the latest findings on the role and characteristics of the small airways' inflammatory and cellular structure, and we describe the assessment tools available to detect small airways dysfunction in COPD and asthma and the effect of bronchodilators and inhaled steroids on functional and biological biomarkers. Finally, we analyze the newest technological therapeutic advances aimed at small airways treatment in terms of inhalation devices and small particle size molecules.

Patients beliefs on intravenous and subcutaneous routes of administration of biologics for severe asthma treatment: A cross-sectional observational survey study.

BACKGROUND: Understanding how patients generate preferences for administration route alternatives may improve health-care delivery and clinical outcomes. Recently, novel biological therapies with subcutaneous (SC) and intravenous (IV) administration routes have been approved for severe uncontrolled asthma. The aim of our study was to assess the preferred route of biologic therapy administration and related beliefs among patients with severe uncontrolled asthma. METHODS: We conducted a cross-sectional observational survey study. Patients answered an anonymous, self-administered questionnaire after an outpatient visit in pulmonary disease clinics located throughout Italy. Socio-demographic and clinical information together with the 12-Item Short Form Survey (SF-12), Work Productivity Impairment Scale and the medical resources utilization module of the Health & Work Survey were collected. Patients beliefs and preference towards SC and IV administration were investigated by means of an ad hoc 13 item questionnaire. RESULTS THE MAIN FINDINGS: 150 patients fulfilled the inclusion criteria and completed the questionnaire (47.3% males). Preference for IV and SC administration was 18.7% and 81.3%, respectively. Compared with patients preferring SC formulation, patients that favored IV were older (p â€‹= â€‹0.04), less likely to escalate corticosteroid dose (p â€‹= â€‹0.03) and had emergency room (ER) access (p â€‹= â€‹0.009) during asthma exacerbations. Patients felt that SC was more convenient than IV, but this belief was not associated with higher likelihood of preferring SC administration. IV formulations were more likely associated with quicker and more effective drug action (p â€‹= â€‹0.0001), procedural safety and medical oversight (p â€‹= â€‹0.0002) and social support (p â€‹= â€‹0.007). Predictors of IV preference were represented by the association of worse asthma control and increased use of ER services, and by beliefs toward formulation effectiveness/efficiency in reducing symptoms (p â€‹= â€‹0.04 and p â€‹< â€‹0.0001, respectively). The model achieved excellent discrimination of administration route preference (area under the curve â€‹= â€‹0.87). CONCLUSIONS: Preference is guided by partially misleading beliefs, which may generate wrong expectations that in turn can affect treatment satisfaction and adherence. Convenience and efficacy beliefs for drugs with different routes of administration always should be discussed with patients to achieve informed shared-decision making. TRIAL REGISTRATION: Not applicable.

Anti-IL-5 and IL-5Ra: Efficacy and Safety of New Therapeutic Strategies in Severe Uncontrolled Asthma.

The current developments of the new biological drugs targeting interleukin 5 (IL-5) and IL-5 receptor allowed to expand the treatment options for severe hypereosinophilic asthma. Clinicians will then be able to choose between antibodies targeting either circulating IL-5 or its receptor expressed on eosinophils and basophils. The available clinical trials consistently reported favorable results about the reduction of exacerbations rate, improvement in quality of life, and sparing of the systemic steroid use, with a favorable safety profile. Two of these new drugs are administered subcutaneously, mepolizumab every 4 weeks and benralizumab every 8 weeks, whereas reslizumab is given intravenously monthly on a weigh-based dose. In the future, the research actions will be involved in the identification of a single biomarker or multiple biomarkers for the optimal choice of biological agents to be properly prescribed.

Immunological mechanisms underlying chronic rhinosinusitis with nasal polyps.

INTRODUCTION: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common and quality-of-life impacting disorder, with an underlying immunological mechanism similar to other conditions such as eosinophilic asthma or atopic eczema. Areas covered: This review article summarizes the most recent evidence on the main immunological mechanisms involved in the pathogenesis and the perpetuation of CRSwNP, with a particular focus on the key role of epithelium-derived inflammation as a consequence of the interaction with the airborne environment. Expert commentary: The increase in knowledge of the immunology of CRSwNP leads to the development of therapeutical strategies based upon the use of biologic agents that, according to a personalized and precision medicine approach, will provide each single patient with the most suitable immunological treatment.

A critical appraisal on AIT in childhood asthma.

ABSTRACT: Allergen immunotherapy (AIT) is the only disease-modifying treatment approved for allergic rhinitis and allergic asthma and represents a suitable therapeutic option, especially in childhood, to modify the progression of respiratory allergic diseases. Starting from the previous "generic class effect" evaluation, as testified by the numerous meta analyses, AIT is now considered a product-specific pathogenic-oriented treatment. BACKGROUND: AIT was empirically proposed more than one century ago in the subcutaneous form (SCIT), but the IgE-mediated mechanism of allergy was elucidated only after 50 years of clinical use of the treatment. The sublingual administration (SLIT) was developed during the 1980 ties, to achieve an improvement in safety and convenience. While SCIT is approved in the United States for the treatment of asthmatic patients with more than 12 years, so far few trials evaluated the clinical efficacy and safety of SLIT in children with allergic asthma, although the indications and some aspects remain unclear. Certainly, due to compliance problems, the age below 3 years may be reasonably considered a practical contraindication. CONCLUSIONS: Given that some specific AIT products are effective and approved as drugs (AIFA, EMA, FDA), the use in children is still debated. Some aspects still need robust confirm: (a) the safety of AIT in asthma; (b) the optimal regimen of administration; (c) the role of AIT as preventative treatment for asthma development.

Current insights in allergen immunotherapy.

OBJECTIVE: Allergen-specific immunotherapy (AIT) in its subcutaneous and sublingual forms is currently a well-established and experimentally supported treatment for respiratory allergy and hymenoptera venom allergy. There have been advances in its use linked strictly to the advancement in the knowledge of the molecular mechanisms of allergy, the production of well-characterized extracts, and diagnostic techniques. The use of AIT in asthma and the application of new approaches are expanding. We briefly review the advances and concerns in the use of AIT. DATA SOURCES: PubMed and Scopus. STUDY SELECTIONS: The most recent and clinically relevant literature was selected and reviewed. RESULTS: The introduction of high-quality products supported by large dose-finding trials has yielded better defined indications, contraindications, and modalities of use. Some specific products in tablet form have recently been approved in the United States. Sublingual immunotherapy has been found to be effective in asthma, which until recently had been a matter of debate. Another promising therapy is oral and sublingual desensitization for food allergy, for which encouraging results have recently been reported. In the near future, other options will be available, including new routes of administration (intralymphatic and epicutaneous), allergoids, engineered allergens, and peptides. The use of component-resolved diagnosis techniques will further refine and target AIT prescriptions. CONCLUSION: This condensed and updated review shows that AIT remains a viable treatment option, especially after the introduction of standardized tablets for some allergens. Food allergy and new administration routes represent a promising expansion.

Inhaled Corticosteroids Safety and Adverse Effects in Patients with Asthma.

Asthma is a common inflammatory airway disease for which the most commonly used controller medications are inhaled corticosteroids (ICS). Asthma control is difficult to achieve in individuals with severe asthma, which comprise 5% to 10% of individuals with asthma, even with high doses of ICS and other anti-inflammatory drugs. In this clinical context, the adverse effects of ICS (including hypothalamic-pituitary-adrenal axis suppression, reduction in growth velocity, osteoporosis, diabetes, and respiratory infections) become more probable and impacting on the quality of life of severe asthmatics. We here summarize the evidence of ICS-related adverse effects, particularly in patients with asthma. The possibility of using biologic agents earlier for severe asthma has the potential to prevent or reduce the occurrence of corticosteroid-related adverse effects, and also reduce corticosteroid-related costs.

Non-invasive ventilation in acute respiratory failure of patients with obesity hypoventilation syndrome.

INTRODUCTION: Non-invasive ventilation (NIV) has been used successfully for the management of acute respiratory failure (ARF) more often in the last two decades compared to prior decades. There are particular groups of patients that are more likely to benefit from NIV. One of these groups is patients with obesity hypoventilation syndrome (OHS). The aim of this review is to evalue the effectiveness of NIV in acute ARF. EVIDENCE ACQUISITION: MEDLINE, EMBASE, CINHAIL, Cochrane Central Register of Controlled Trials, DARE, the Cochrane Database of Systematic Reviews, and the ACP Journal Club database were searched from January 2001 to December 2017. EVIDENCE SYNTHESIS: More than 30% of them have been diagnosed when hospitalized for ARF. NIV rarely failed in reversing ARF. OHS patients who exhibited early NIV failure had a high severity score and a low HCO3 level at admission; more than half of hypercapnic patients with decompensated OHS exhibited a delayed but successful response to NIV. CONCLUSIONS: Patients with decompensation of OHS have a better prognosis and response to NIV than other hypercapnic patients. They required more aggressive NIV settings, a longer time to reduce paCO2 levels, and showed more frequently a delayed but successful response to NIV.

Asthma: personalized and precision medicine.

PURPOSE OF REVIEW: In this review, we herein describe the progress in management of severe asthma, evolving from a 'blockbuster approach' to a more personalized approach targeted to the utilization of endotype-driven therapies. RECENT FINDINGS: Severe asthma characterization in phenotypes and endotypes, by means of specific biomarkers, have led to the dichotomization of the concepts of 'personalized medicine' and 'precision medicine', which are often used as synonyms, but actually have conceptual differences in meaning. The recent contribute of the omic sciences (i.e. proteomics, transcriptomics, metabolomics, genomics, …) has brought this initially theoretic evolution into a more concrete level. SUMMARY: This step-by-step transition would bring to a better approach to severe asthmatic patients as the personalization of their therapeutic strategy would bring to a better patient selection, a more precise endotype-driven treatment, and hopefully to better results in terms of reduction of exacerbation rates, symptoms, pulmonary function and quality of life.

Anti-Interleukin 5 (IL-5) and IL-5Ra Biological Drugs: Efficacy, Safety, and Future Perspectives in Severe Eosinophilic Asthma.

The definition of asthma has changed considerably in recent years, to the extent that asthma is no longer considered a single disease but a heterogeneous disorder that includes several phenotypes and, possibly, endotypes. A more detailed analysis of the immunological mechanisms underlying the pathogenesis of asthma shows interleukin 5 (IL-5) to be a crucial cytokine in several asthma phenotypes. In fact, IL-5 exerts selective action on eosinophils, which, in turn, sustain airway inflammation and worsen asthma symptoms and control. Clinical trials have shown drugs targeting IL-5 or its receptor alpha subunit (IL-5Ra) to be a promising therapeutic approach to severe asthma, whose characteristics render standard therapy of little use: systemic corticosteroids only partially control the disease and have well-known adverse effects, and omalizumab is used for allergic subtypes. Analysis of the design process of clinical trials reveals the importance of patient selection, taking into account both clinical data (e.g., exacerbations, lung function, and quality of life) and biomarkers (e.g., eosinophils, which are predictive of therapeutic response).

New Suggestions in Sublingual Immunotherapy for House Dust Mite- Related Allergic Diseases.

BACKGROUND: The indications for Allergen immunotherapy (AIT) in patients suffering from House Dust Mite (HDM)-related allergic diseases are presently based on incomplete data. This is essentially based on the fact that HDM allergy is difficult to evaluate in clinical trials, due to the largely variable allergen exposure and symptoms, and to the long periods of observation needed to assess the effects. In addition, at variance with pollen allergy, in HDM allergy asthma is more prevalent. However, several AIT products have been approved for HDM-induced allergic rhinitis, according to their ascertained clinical efficacy, tolerability and safety profile, particularly in the sublingual form (SLIT). OBJECTIVE: We reviewed herein the available data on AIT in patients with HDM-induced allergic diseases, with a particular attention to the new product MK-8237 HDM-SLIT tablets, concerning its efficacy and safety profile. METHOD: In the recent years, several randomized placebo-controlled clinical trials have been performed in Europe, North America and Japan to evaluate the efficacy of HDM-sublingual tablets in patients with HDM-induced allergic asthma and allergic rhinitis, mainly assessing the reduction of symptoms, exacerbations and corticosteroid intake. RESULTS: The results of the published clinical trials were encouraging and led to the approval and commercialization of MK-8237 HDM-SLIT tablet. CONCLUSION: The favorable efficacy and safety profile of MK-8237 HDM-SLIT tablets provided a consolidated therapeutic option for patients with HDM-induced allergic rhinitis and asthma.

Umeclidinium for the treatment of uncontrolled asthma.

INTRODUCTION: Smooth muscle cell contraction in the airways is the principal therapeutic target in asthmatic subjects and its insufficient treatment is often a cause of uncontrolled disease. For this reason, research has focused on targeting smooth muscle activity with anticholinergic agents, including umeclidinium. Areas covered: This review highlights the potential application of umeclidinium, a long acting muscarinic antagonist, as a novel therapeutic approach for patients with severe uncontrolled asthma, despite maximal therapy. Expert opinion: Umeclidinium, similarly to tiotropium, which has been recently included in guidelines, may act by contrasting cholinergic activation in airways, preventing or at least reducing smooth muscle cells contraction and the consequent bronchoconstriction. This is similar to what occurs in chronic obstructive pulmonary disease, for which umeclidinium has been regularly approved. However, available data is not sufficient and further studies are needed before regulatory approval can be sought, since only phase II clinical trials have been conducted at present. Both quality of life and objectifiable clinical data and parameters must be assessed, including lung function improvements, reduction of exacerbations and reduction of as required medications.

Targeting Interleukin-5 or Interleukin-5Rα: Safety Considerations.

Asthma is a highly prevalent chronic disease of the airways; approximately 10% of patients with asthma will experience a severe form of the disease. New understanding of the pathogenesis of asthma has enabled the development of novel drugs and provided hope for patients with asthma. Interleukin (IL)-5 and IL-5 receptor subunit α (IL-5-Rα) plays a crucial role in the development, maturation, and operation of eosinophils so were the first important therapeutic target of these new drugs. While the results of early clinical trials of these drugs were not promising, results improved once researchers discovered the drugs worked best in patients with high eosinophil levels. Patients treated with both anti-IL-5 and IL-5-Rα experienced significant decreases in exacerbations. Trials have also demonstrated promising safety profiles; adverse events have been few and frequently only observed with placebo or considered unrelated to the study drug. The positive efficacy and safety profiles of these drugs has led to trials with interesting results in other diseases that are also secondary to the action of eosinophils: Churg-Strauss syndrome, hypereosinophilic syndrome, nasal polyposis, chronic obstructive pulmonary disease, atopic dermatitis, and esophagitis. In this review, we explore the main clinical trials of anti-IL-5 and IL-5-Rα, both in asthma and in other pathologies, with particular reference to the interesting safety and efficacy results.

Reslizumab and Eosinophilic Asthma: One Step Closer to Precision Medicine?

Human eosinophils represent approximately 1% of peripheral blood leukocytes. However, these cells have the propensity to leave the blood stream and migrate into inflamed tissues. Eosinophilic inflammation is present in a significant proportion of patients with severe asthma. Asthma is a chronic inflammatory disorder that affects more than 315 million people worldwide, with 10% having severe uncontrolled disease. Although the majority of patients can be efficiently treated, severe asthmatics continue to be uncontrolled and are at risk of exacerbations and even death. Interleukin-5 (IL-5) plays a fundamental role in eosinophil differentiation, maturation, activation and inhibition of apoptosis. Therefore, targeting IL-5 is an appealing approach to the treatment of patients with severe eosinophilic asthma. Reslizumab, a humanized anti-IL-5 monoclonal antibody, binds with high affinity to amino acids 89-92 of IL-5 that are critical for binding to IL-5 receptor α. Two phase III studies have demonstrated that reslizumab administration in adult patients with severe asthma and eosinophilia (≥400 cells/µL) improved lung function, asthma control, and symptoms. Thus, the use of blood eosinophils as a baseline biomarker could help to select patients with severe uncontrolled asthma who are likely to achieve benefits in asthma control with reslizumab. In conclusion, targeted therapy with reslizumab represents one step closer to precision medicine in patients with severe eosinophilic asthma.

Mepolizumab in the management of severe eosinophilic asthma in adults: current evidence and practical experience.

Eosinophils represent approximately 1% of peripheral blood leukocytes in normal donors and their maturation and differentiation in the bone marrow are mainly regulated by interleukin (IL)-5 [Broughton et al. 2015]. IL-5, a cytokine that belongs to the ß common-chain family, together with IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), stimulates also the activation and survival of eosinophils and, to some extent, of basophils. IL-5 binds to a heterodimer receptor composed of the specific subunit IL-5Rα and a common subunit ßc shared with IL-3 and GM-CSF. Human eosinophils express approximately a three-fold higher level of IL-5Rα compared with basophils. Major sources of IL-5 are T-helper 2 (Th2) cells, mast cells, CD34+ progenitor cells, invariant natural killer (NK) T-cells, group 2 innate lymphoid cells (ILC2s), and eosinophils themselves. ILC2s control not only eosinophil number but also their circadian cycling through the production of IL-5.

Personalized Medicine in Allergy.

Allergic disease is among the most common pathologies worldwide and its prevalence has constantly increased up to the present days, even if according to the most recent data it seems to be slightly slowing down. Allergic disease has not only a high rate of misdiagnosis and therapeutic inefficacy, but represents an enormous, resource-absorbing black hole in respiratory and general medicine. The aim of this paper is to summarize principal therapeutic innovations in atopic disease management befallen in the recent years in terms of personalized/precision medicine.

MK-8237: a house dust mite vaccine for treating allergic rhinitis, asthma and atopic dermatitis.

INTRODUCTION: Since its introduction in clinical practice one century ago for the treatment of respiratory allergic diseases, allergen-specific immunotherapy (AIT) has exhibited a relevant clinical efficacy that was subsequently confirmed in controlled trials. Thus, AIT has been accepted worldwide, as testified by guidelines and international documents. AIT is considered pivotal in the management of allergic rhinitis with or without conjunctivitis and with or without asthma. These conditions, in addition to hymenoptera venom allergy, currently are the accepted indications. The use of AIT in house-dust mite allergy still remains debated, especially due to the methodological problems in assessing this form of respiratory allergy. The more recent experimental data on MK-8237 sublingual tablets provided evidence that AIT, in the sublingual form, is effective in dust mite allergy. AREAS COVERED: At present, the evidence of the efficacy of AIT in conditions other than respiratory allergy are not conclusive, but encouraging results have been obtained in food allergy and atopic dermatitis. Herein, the authors discuss the data for these indications. EXPERT OPINION: Not all patients respond to AIT in the same way. Accordingly, AIT represents a promising path to precision medicine and hopefully will be able to reduce this burden of non-responding patients.

Sleep complaints and sleep breathing disorders in upper and lower obstructive lung diseases.

Upper and lower obstructive lung diseases can induce sleep complaints and can be part of the pathogenesis of sleep breathing disorders. In fact, the physiological changes of the pattern of respiration during sleep, added to the airways disease can lead to symptomatic worsening of rhinitis, asthma and chronic obstructive pulmonary diseases (COPD); moreover, their functional and anatomical features can lead to sleep breathing disorders such as obstructive sleep apnea syndrome (OSAS). This review highlights the above-mentioned relationships and the effect of disease management on its comorbidities and the patient's quality of life. Rhinitis, asthma and COPD represent causes of sleep complaints that may be reduced with optimal management of these obstructive airways diseases. Continuous positive airway pressure (CPAP) treatment of sleep apnea needs to be tailored after optimization of the therapy of concomitant diseases, but it can often ameliorate comorbid disease.

A Critical Evaluation of Anti-IL-13 and Anti-IL-4 Strategies in Severe Asthma.

Asthma is a high-prevalence disease, still accounting for mortality and high direct and indirect costs. It is now recognized that, despite the implementation of guidelines, a large proportion of cases remain not controlled. Certainly, adherence to therapy and the education of patients remain the primary objective, but the increasingly detailed knowledge about the pathogenic mechanisms and new biotechnologies offer the opportunity to better address and treat the disease. Interleukin (IL)-13 and IL-4 appear as the most suitable targets to treat the T helper 2 (TH2)-mediated forms (endotypes) of asthma. IL-13 and IL-4 partly share the same receptor and signaling pathways and both are deeply involved in immunoglobulin E (IgE) synthesis, eosinophil activation, mucus secretion and airways remodeling. Several anti-IL-13 strategies have been proposed (anrukinzumab, lebrikizunab and tralokinumab), with relevant clinical results reported with lebrikizumab. Such studies facilitate better definition of the possible predictive markers of response to a specific treatment (e.g. eosinophils, total IgE, fraction of exhaled nitric oxide and periostin). In parallel, anti-IL-4 strategies have been attempted (pascolizumab, pitakinra and dupilumab). So far, dupilumab was reported capable of reducing the severity of asthma and the rate of exacerbations. IL-13 and IL-4 are crucial in TH2-mediated inflammation in asthma, but it remains clear that only specific endotypes respond to these treatments. Although the use of anti-IL-14 and anti-IL-13 strategies is promising, the search for appropriate predictive biomarkers is urgently needed to better apply biological treatments.

The path to personalized medicine in asthma.

INTRODUCTION: Asthma is a common respiratory disorder, since about 10% of the population suffer from this disease, and up to 10% have a severe form. Recent findings have allowed a greater and deeper understanding of the pathophysiological mechanisms, distinguishing two groups of patients according to the prevalent cellular population that drives the inflammatory process, and consequentially, to intervene on different cellular targets. AREAS COVERED: Currently, several biological drugs directly interfering with these pathophysiological mechanisms (namely IgE, IL-4, IL-5, IL-13, and IL-17) are under investigation. Expert commentary: With the elucidation of mechanisms, new-targeted drugs have been developed. Asthma therapy is changing from a 'one size fits all' therapy to a 'precision medicine' model, where we may prescribe the most appropriate treatment for each patient. Moreover, in the near future, the possibility to act a 'sequential bio-combination therapy' can be envisaged, using different biological drugs in the same patient to act on different pathophysiological mechanisms.