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The traditional healthcare model is focused on diseases (medicine and natural science) and does not acknowledge patients' resources and abilities to be experts in their own lives based on their lived experiences. Improving healthcare safety, quality, and coordination, as well as quality of life, is an important aim in the care of patients with chronic conditions. Person-centered care needs to ensure that people's values and preferences guide clinical decisions. This paper reviews current knowledge to develop (1) digital care pathways for rhinitis and asthma multimorbidity and (2) digitally enabled, person-centered care. 1 It combines all relevant research evidence, including the so-called real-world evidence, with the ultimate goal to develop digitally enabled, patient-centered care. The paper includes (1) Allergic Rhinitis and its Impact on Asthma (ARIA), a 2-decade journey, (2) Grading of Recommendations, Assessment, Development and Evaluation (GRADE), the evidence-based model of guidelines in airway diseases, (3) mHealth impact on airway diseases, (4) From guidelines to digital care pathways, (5) Embedding Planetary Health, (6) Novel classification of rhinitis and asthma, (7) Embedding real-life data with population-based studies, (8) The ARIA-EAACI (European Academy of Allergy and Clinical Immunology) strategy for the management of airway diseases using digital biomarkers, (9) Artificial intelligence, (10) The development of digitally enabled, ARIA person-centered care, and (11) The political agenda. The ultimate goal is to propose ARIA 2024 guidelines centered around the patient to make them more applicable and sustainable., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Severe asthma affects about 10% of the population with asthma and is characterized by low lung function and a high count of blood leukocytes, mainly eosinophils. Various definitions are used in clinical practice and in the literature to identify asthma remission: clinical remission, inflammatory remission, and complete remission. This work highlights a consensus for asthma remission using a Delphi method. In the context of the Severe Asthma Network Italy, which accounts for 57 severe asthma centers and more than 2,200 patients, a board of six experts drafted a list of candidate statements in a questionnaire, which has been revised to minimize redundancies and ensure clear and consistent wording for the first round (R1) of the analysis. Thirty-two statements were included in the R1 questionnaire and then submitted to a panel of 80 experts, which used a 5-point Likert scale to measure agreement regarding each statement. Then, an interim analysis of R1 data was performed, and items were discussed and considered to produce a consistent questionnaire for round 2 (R2) of the analysis. Then, the board set the R2 questionnaire, which included only important topics. Panelists were asked to vote on the statements in the R2 questionnaire afterward. During R2, the criteria of complete clinical remission (the absence of the need for oral corticosteroids, symptoms, exacerbations or attacks, and pulmonary function stability) and those of partial clinical remission (the absence of the need for oral corticosteroids, and two of three criteria: the absence of symptoms, exacerbations or attacks, and pulmonary stability) were confirmed. This Severe Asthma Network Italy Delphi analysis defined a valuable and independent tool that is easy to use, to test the efficacy of different treatments in patients with severe asthma enrolled into the SANI registry., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The small-airway dysfunction (SAD), detected with impulse oscillometry (IOS) methods, has been recently better characterized in patients with asthma. However, little is known about SAD in asthmatic patients with normal spirometry (NS)., Objective: In this study, we aimed to investigate, in an unselected sample of 321 patients with physician-diagnosed asthma and NS, prevalence, clinical characterization, and impact on asthma control of IOS-defined SAD. As a secondary objective of the study, we focused on comparing the difference between IOS- and spirometry-defined SAD., Methods: Consecutive patients with a previous diagnosis of asthma but normal spirometry at the moment of the enrollment were stratified by the presence of IOS-defined SAD (difference in resistance at 5 Hz and at 20 Hz [R5-R20] greater than 0.07 kPa x s x L -1 ). We have also assessed the presence of SAD defined by spirometry, according to FEF 25-75 < 65% of the predicted. Clinical and laboratory features were collected, and univariable and multivariable analyses were used to analyze cross-sectional associations between clinical variables and outcomes (SAD)., Results: IOS-defined SAD was present in 54.1% of the cohort. In contrast, spirometry-defined SAD was present in only 10% of patients. Subjects with IOS-defined SAD showed less well-controlled asthma and a higher mean inhaled corticosteroid dosage use compared with subjects without SAD (both P < .001). Overweight (odds ratio [OR], 1.14; 95% CI, 1.05-1.23), exacerbation history (OR, 3.06; 95% CI, 1.34-6.97), asthma-related night awakenings (OR, 6.88; 95% CI, 2.13-22.23), exercise-induced asthma symptoms (OR, 33.5; 95% CI, 9.51-117.8), and controlled asthma (OR, 0.22; 95% CI, 0.06-0.84) were independently associated with SAD., Conclusions: Asthmatic patients with IOS-defined SAD showed less well-controlled asthma, more severe exacerbations and higher mean inhaled corticosteroid dosage. We confirmed exercise-induced asthma, asthma-related night awakenings, exacerbation history, and overweight as independently associated with SAD, while showing well-controlled asthma as inversely associated. SAD may be overlooked by standard spirometry., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to disclose about this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Severe asthma impacts quality of life (QoL), including dyspnea, sleep, and activity limitation. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4 and -13, which are key and central drivers of type 2 inflammation. Phase 3 LIBERTY ASTHMA VENTURE (NCT02528214) and LIBERTY ASTHMA TRAVERSE open-label extension (NCT02134028) evaluated dupilumab 300 mg vs placebo every 2 weeks for 24 weeks (VENTURE) and dupilumab only for an additional 48 to 96 weeks (TRAVERSE) in patients with oral corticosteroid (OCS)-dependent severe asthma., Objective: To assess dupilumab's impact on Asthma QoL Questionnaire (AQLQ) items related to breathing symptoms, sleep, and activity limitation, and on OCS reduction., Methods: The proportion of patients with AQLQ scores of 6 or 7 for breathing symptoms-, sleeping-, and activity-related items in VENTURE and TRAVERSE, together with OCS dose reductions in VENTURE., Results: In VENTURE, significantly greater proportions of dupilumab- vs placebo-treated patients achieved scores of 6 or 7 by week 24 in breathing symptoms-related (42.7%-60.2% vs 22.4%-39.3%), sleeping-related (45.6%-65.0% vs 27.1%-47.7%), and activity-related (44.7%-51.5% vs 22.4%-34.6%) AQLQ items. Improvements were maintained through TRAVERSE in the dupilumab/dupilumab group and increased to dupilumab treatment levels in the placebo/dupilumab group. Significant OCS dose reductions were observed in VENTURE; up to 90% and 60% of dupilumab-treated vs 65% and 41% of placebo-treated patients with AQLQ scores of 6 or 7 in breathing symptoms-, sleeping-, and activity-related items achieved greater than or equal to 50% dose reduction and eliminated OCS at week 24, respectively., Conclusion: In patients with severe OCS-dependent asthma, dupilumab improved QoL related to breathing symptoms, sleep, and activity limitation, and reduced OCS use., Trial Registration: ClinicalTrials.gov Identifiers: NCT02528214 and NCT02134028., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Asthma, with several phenotypes and endotypes, is considered particularly suited for precision medicine. The identification of different non-invasive biomarkers may facilitate diagnosis and treatment. Recently, Staphylococcus aureus and its enterotoxins (SE) have been found to have a role in inducing persistent type 2 airway inflammation in severe asthma, but also in such comorbidities as chronic rhinosinusitis with nasal polyposis (CRSwNP)., Methods: The aim of this retrospective study was to evaluate the prevalence of SE-IgE sensitization in a multicentric Italian cohort of severe asthmatic patients and correlate it with demographic and clinical characteristics., Results: A total of 249 patients were included in the analysis, out of which 25.3% were staphylococcal enterotoxin B (SEB)-IgE positive. We found a meaningful association between SEB-IgE and female gender, a positive association was also measured between CRS and CRSwNP. No significant association was found between SEB-IgE sensitization and atopy, the occurrence of exacerbations and corticosteroid dosages. In the SEB-IgE-positive patient, blood eosinophil count does not appear to be correlated with the severity of the disease. Patients with SEB-IgE sensitization are, on average, younger and with an earlier disease onset, thus confirming the possibility to consider SEB-IgE sensitization as an independent risk factor for developing asthma., Conclusions: Our data confirm that the search for SE in the initial screening phase of these patients is helpful to better phenotype them, may predict the evolution of comorbidities and lead to a targeted therapeutic choice; in this point of view this represents a goal of precision medicine., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Purpose of Review: To provide a literature review of what is on the market and under study for some diseases treated with drugs targeting type 2 (T2) inflammation., Recent Findings: Literature data have shown that drugs targeting type 2 inflammation are effective in asthma and nasal polyposis, conditions for which they are on the market, and have promising expectations in the case of eosinophilic esophagitis, especially using anti-IL-5/IL-5 receptor and IL-4 receptor antibodies, while concerning eosinophilic granulomatosis with polyangitis (EGPA), mepolizumab (MEP) was approved by FDA and EMA as a drug for the treatment of this condition because of the promising results obtained in trials and in real life., Summary: The use of these drugs is certainly an important achievement in the treatment of complex diseases such as those mentioned above, which are too often orphaned from innovative treatments and limited to the use of immunosuppressants and systemic corticosteroid for their control., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although there are many asymptomatic patients, one of the problems of COVID-19 is early recognition of the disease. COVID-19 symptoms are polymorphic and may include upper respiratory symptoms. However, COVID-19 symptoms may be mistaken with the common cold or allergic rhinitis. An ARIA-EAACI study group attempted to differentiate upper respiratory symptoms between the three diseases., Methods: A modified Delphi process was used. The ARIA members who were seeing COVID-19 patients were asked to fill in a questionnaire on the upper airway symptoms of COVID-19, common cold and allergic rhinitis., Results: Among the 192 ARIA members who were invited to respond to the questionnaire, 89 responded and 87 questionnaires were analysed. The consensus was then reported. A two-way ANOVA revealed significant differences in the symptom intensity between the three diseases (p < .001)., Conclusions: This modified Delphi approach enabled the differentiation of upper respiratory symptoms between COVID-19, the common cold and allergic rhinitis. An electronic algorithm will be devised using the questionnaire., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Allergic rhinitis and asthma represent global health problems for all age groups. ARIA (Allergic Rhinitis and its Impact on Asthma) project was initiated during a WHO workshop in 1999 In its 2010 and 2017 Revisions, ARIA has developed clinical practice guidelines for the management of allergic rhinitis and asthma co-morbidities based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation). The 2019 Revision embedded real-life data into the GRADE recommendations to develop next-generation guidelines. Care pathways for allergen immunotherapy proposed a multi-sectoral approach. This paper reviews these two recent documents adding the impact of ARIA in Italy.

Introduction: Severe asthma occurs in 5-10% of asthmatic patients, with nasal polyposis as one of the most frequent comorbidity. Benralizumab was recently marketed, thus we could analyse its effects in real-life in severe asthma, and compare the effects of the drug in patients with and without polyposis., Methods: Patients with severe asthma, receiving Benralizumab were enrolled in Italian asthma centres. The efficacy criteria for asthma (exacerbation rate, oral corticosteroid intake, hospitalizations, pulmonary function, exhaled nitric oxide) were evaluated at baseline and after 24 weeks of treatment. Patients were then sub-analysed according to the presence/absence of nasal polyposis., Results: Fifty-nine patients with severe uncontrolled asthma (21 males, age range 32-78) and treated with benralizumab for at least 24 weeks has been evaluated, showing significant improvements in asthma-related outcomes, except for pulmonary function and exhaled nitric oxide. This included a reduction in the sino-nasal outcome-22 score versus baseline of 13.7 points (p = .0037) in the 34 patients with nasal polyposis. Anosmia disappeared in 31% patients (p = .0034). When comparing the groups with and without nasal polyposis, a similar reduction of exacerbations was seen, with a greater reduction of the steroid dependence in patients with polyposis (-72% vs -53%; p < .0001), whereas lung function was significantly more improved (12% vs 34%, p = .0064) without polyposis patients., Conclusions: Benralizumab, after 6 months of treatment, confirmed its efficacy in severe asthma, and also in nasal polyposis, which is the most frequent comorbidity. The efficacy of Benralizumab in reducing steroid dependence was even higher in patients with polyposis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose of Review: New biological agents, in addition to the well-established omalizumab, have been nowadays introduced into clinical practice for severe asthma. This suggested the possibility of an at-home self-administration, as currently happening for other biological agents for immune-mediated diseases., Recent Findings: In the very recent years, there were structured clinical trials investigating the self at home administrations of biologicals for severe asthma, showing with different principles, a possible advantage and convenience for the patient, and a socioeconomic saving., Summary: The literature analysis currently shows that the at-home self-administration of biologicals for severe asthma is a promising approach to improve the treatment of such disease.

Allergen Immunotherapy (AIT) was introduced in clinical practice on an empirical basis more than 100 years ago. Since the first attempts, AIT was administered subcutaneously. Indeed, other routes of administration were proposed and studied, in particular to improve the safety, but only the sublingual route (SLIT) achieved a credibility based on evidence and was then accepted as a viable "alternative" option to the subcutaneous route. SLIT was largely used in clinical trials and clinical practice in this last 30 years. Thus, a large amount of data is available, coming from either controlled trials and postmarketing surveillance studies. It is clear that SLIT is overall effective, but it is also clear that the efficacy is not "class-related," as derived from meta-analyses, but restricted to each specific product. The 30-year lasting use of SLIT allowed to clarify many clinical aspects, such as efficacy, safety, use in asthma, regimens of administration, and optimal doses. In parallel, the mechanisms of action of AIT were elucidated, and new indications were proposed (eg food allergy, atopic dermatitis). In addition, the introduction of molecular-based diagnosis, allowed to better refine the prescription of SLIT, based on specific sensitization profiles. The present article will describe the origin and evolution of SLIT for respiratory allergy, taking into account the clinical context that suggested this form of treatment, the recently developed aspects, the future perspectives and unmet needs, This is not, therefore, a systematic review, rather a narrative historical description of the past history, and a look forward to the future opportunities., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Purpose of Review: The introduction of high-quality and standardized extracts for immunotherapy has renewed the interest in the treatment of pediatric allergic asthma that represents a high-prevalence disease., Recent Findings: In addition to clinical trials, several systematic reviews and metaanalyses were published, confirming overall the clinical efficacy of allergen immunotherapy in pediatric asthma. In addition, new data on the preventive effect of the treatment on asthma onset were published. Despite this, many intriguing questions emerged, in parallel to the development of knowledge., Summary: Allergen immunotherapy is overall effective for the treatment of asthma in children, but a class-effect should not be claimed, rather the efficacy of each single product. According to the recent findings, the challenge for the future research will be to clarify: when to start immunotherapy in children, which are (if they exist) the predictive biomarkers for efficacy in the single individual, the magnitude of the preventive effect and the optimal duration of the treatment.

Purpose of Review: Severe asthma is a serious disease affecting about 5-10% of asthmatic patients. Often patients with this kind of asthma requires periodical courses or daily intake of oral corticosteroids, to control symptoms. In the last few years several biological drugs have been developed with the aim to decrease exacerbations and reduce or suspend intake of systemic steroids in severe asthmatic patients. Clinical trials demonstrated the efficacy and the safety of biological antibodies in asthma, but it is already known that randomized controlled trials alone are not sufficient to provide complete information on a drug., Recent Findings: After marketing of monoclonal antibodies has been developed several real-life studies with the aim to observe how drugs, tested only on trial patients, are able to provide adequate effectiveness even on 'real' patients; indeed, it is well known that the latter differ in some characteristics from the patients of the trials., Summary: The results of this analysis confirm the good efficacy of the biologics similarly in real-life patients, also ensuring a promising safety even in periods of observation longer than those of the randomized controlled trials.

Introduction : The development of biologic molecules led to a drastic change in the therapeutic approach to asthma. With the prospect of acting on different pathophysiological mechanisms of the disease, the idea of precision medicine was developed, in which a single molecule is able to modify a specific triggering mechanism. Thus, it seemed limiting to stop at the distinction of patients phenotypes and the concept of endotypes became more relevant in the therapeutic approach. Areas covered : This review deepened the topic of precision medicine through the transition from phenotyping to endotyping. We performed a review of the literature, preferring articles quoted in Medline and published in journals with an impact factor. Results showed that it is fundamental to take into consideration the role of biomarkers and the related therapies currently available for precision medicine. Expert opinion : The possible overlap of patients in different phenotypes requires a more precise classification, which considers endotypization. With the development of biological drugs able to modify and modulate some pathophysiological mechanisms of the disease, the theoretical concept of endotyping becomes practical, allowing the clinician to choose the specific mechanism to 'attack' in order to control the disease.

The selection of pharmacotherapy for patients with allergic rhinitis aims to control the disease and depends on many factors. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines have considerably improved the treatment of allergic rhinitis. However, there is an increasing trend toward use of real-world evidence to inform clinical practice, especially because randomized controlled trials are often limited with regard to the applicability of results. The Contre les Maladies Chroniques pour un Vieillissement Actif (MACVIA) algorithm has proposed an allergic rhinitis treatment by a consensus group. This simple algorithm can be used to step up or step down allergic rhinitis treatment. Next-generation guidelines for the pharmacologic treatment of allergic rhinitis were developed by using existing GRADE-based guidelines for the disease, real-world evidence provided by mobile technology, and additive studies (allergen chamber studies) to refine the MACVIA algorithm., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Allergen immunotherapy (AIT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many guidelines or national practice guidelines have been produced but the evidence-based method varies, many are complex and none propose care pathways. This paper reviews care pathways for AIT using strict criteria and provides simple recommendations that can be used by all stakeholders including healthcare professionals. The decision to prescribe AIT for the patient should be individualized and based on the relevance of the allergens, the persistence of symptoms despite appropriate medications according to guidelines as well as the availability of good-quality and efficacious extracts. Allergen extracts cannot be regarded as generics. Immunotherapy is selected by specialists for stratified patients. There are no currently available validated biomarkers that can predict AIT success. In adolescents and adults, AIT should be reserved for patients with moderate/severe rhinitis or for those with moderate asthma who, despite appropriate pharmacotherapy and adherence, continue to exhibit exacerbations that appear to be related to allergen exposure, except in some specific cases. Immunotherapy may be even more advantageous in patients with multimorbidity. In children, AIT may prevent asthma onset in patients with rhinitis. mHealth tools are promising for the stratification and follow-up of patients., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Severe asthma is a disease with a heavy socio-economic burden and a relevant impact on the life of patients. Mepolizumab (MEP) was recently introduced in practice. The previous data were favourable as efficacy and safety are concerned. Nowadays, we can report the clinical data after more than one year of use of MEP in the real-life setting., Objective: To evaluate the efficacy and safety of MEP in a real life framework, mainly concerning asthma exacerbations, steroid dependence, effects on respiratory function and adverse events., Methods: This retrospective analysis was performed on 138 patients, treated with MEP for at least 12 months, and referred to eleven severe asthma clinics in Italy. All patients met the criteria for severe uncontrolled asthma according to ATS/ERS guidelines and prescribing MEP conditions according to the Italian Drug Agency (AIFA)., Results: We could observe 138 patients (78 female, age 58 ± 10 years). The average age of onset of asthma was 34 ± 16 years. The blood eosinophil count decreased from 822 ± 491/μL at baseline to 117 ± 96/μL (p < .0001) after 12 months of therapy. Exacerbations decreased from 3.8/year to 0.7/year (-81%; p < .0001). Steroid-dependent patients before MEP (80%) with a daily dose of 10.1 ± 9.4 mg prednisone decrease at 28% after 12 months with a mean of 2.0 ± 4.2 mg/day (p < .0001). The occurrence of adverse events was overall low., Conclusions & Clinical Relevance: In this real-life setting, MEP confirmed its efficacy and safety profile, already shown in clinical trials. This was apparent concerning exacerbation rate, systemic steroids intake and safety., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Mepolizumab (anti IL-5, monoclonal antibody) is commercially available in Italy since more than one year for the treatment of severe hypereosinophilic asthma. Its efficacy and safety were evaluated in several regulatory trials. The characteristics of this drug in real life began to be assessed only recently. We describe herein the drop-out rate observed with mepolizumab in real life, because this datum can indirectly reflect the safety and tolerability aspects. The demographic and clinical data of patients receiving mepolizumab for severe asthma were collected, and the number and reasons for discontinuation of the treatment were analyzed. The database involves 143 patients (67 male, age range 19-80 year) who received at least one dose of mepolizumab. The observed discontinuation rate was 6/143 (4.2%). Five out of 6 discontinuations were due to lack of response, and one was an adverse event (urticaria) probably related to the treatment. There was no clinical difference between the drop-out group and the patients still ongoing. As compared to the clinical trials published the discontinuation rate was lower in our population, especially for adverse events (7% vs 23.7%). Thus, the tolerability of mepolizumab, as derived from discontinuations, seems to be better in real-life than in clinical trials., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Asthma is a chronic inflammatory airway disease. It occurs in a 'severe' form in about 8-10% of asthmatic patients. In the last decade, the development of biological drugs (e.g. monoclonal antibodies) allowed to efficiently approach severe asthma. The current therapeutic targets available are mainly those related to TH2 inflammation. Areas covered: The main pharmacokinetic and pharmacodynamic characteristics of the monoclonal antibodies against IL-5, IL-5Ra, IL4-IL13, and IgE, that are currently marketed or understood for severe asthma are discussed in this paper. Expert opinion: The currently available biological drugs represent an excellent therapeutic add-on to traditional drugs, especially in replacing systemic corticosteroid therapies. The different pharmacokinetic and pharmacodynamic characteristics of the drugs, despite sometime sharing the same target, would allow a better personalization of the therapy, tailoring the treatment to the characteristics of the patient.

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.

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.

The recent advances in the knowledge of immunological aspects of many pulmonary diseases, allowed to identify cells, biological functions, cytokines, and receptors that are preferentially involved in each disease. This is the case of asthma, where IL-13 (together with IL-4) is recognized as a central mediator. The role of IL-13 is strictly related, via complex signaling pathways, to eosinophil recruitment and activation, to mucus secretion, periostin generation and to fibrogenic processes (which are part of the remodeling process). These peculiar roles of IL-13 have suggested the hypothesis of its role in Idiopathic Pulmonary Fibrosis, and consequently of its antagonists in the treatment of such disease. We review herein the immunological roles of IL-13 in asthma and IPF, and the currently ongoing attempts to treat IPF by IL-13 antagonism strategies., (Copyright © 2017. Published by Elsevier Ltd.)

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.

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.

Objective: Pharmacists play a relevant role in the real-life management of asthma because they are a first-line referral for patients. In fact, the role of pharmacies has been underlined and evidenced also in guidelines. Nonetheless, the true effect of pharmacy-based management of asthma has been assessed in only a few studies. We review the available literature on asthma management in a territorial pharmacy setting., Data Sources: The literature was searched for the keywords pharmacy, bronchial asthma, control, and management., Study Selections: The available studies were subdivided into observational and interventional and described., Results: Seven observational studies and 14 interventional trials were found, involving approximately 20,000 individuals. Most of those studies were performed in Europe and Australia. A high proportion of patients had poorly controlled asthma in the observational studies. The active involvement of pharmacists, in the interventional trials, consistently led to an improvement of the quality of life, a better inhalation technique, and a reduction of exacerbations., Conclusion: The literature analysis confirms the relevance of the role of pharmacists in the real-life management of bronchial asthma and underlines the need for a more specific training for those health care professionals., (Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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 β 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 βc 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.

Allergen immunotherapy (AIT) has been in use since more than one century, when Leonard Noon experimentally proved its efficacy in hayfever (Noon, in Lancet 1:1572-3, 1911). Since then, AIT was administered only as subcutaneous injections (SCIT) until the sublingual route (SLIT) was proposed in 1986. The use of SLIT was proposed following several surveys from the USA and UK that repeatedly reported fatalities due to SCIT (Lockey et al. in J Allergy Clin Immunol 75(1): 166, 1985; Lockey et al. in J Allergy Clin Immunol 660-77, 1985; Committee on the safety of medicines. CSM update. Desensitizing vaccines. Br Med J, 293: 948, 1986). These reports raised serious concerns about the safety and the risk/benefit ratio of AIT. Many cases of life-threatening events with SCIT were due to avoidable human errors in administration, but a relevant fraction of them remained unexplained and unpredictable (Aaronson and Gandhi in J Allergy Clin Immunol 113: 1117-21, 2014). Subsequently, in a few years, SLIT gained credibility and was included in the official documents and guidelines (Table 1) (Bousquet et al. in J Allergy Clin Immunol 108(5 Supp):S146-S150, 2001; Canonica et al. in Allergy 64 (Supp 91):1-59, 2009) as a viable alternative to traditional SCIT. Of note, the local bronchial (aerosol) and the intranasal route of administration were attempted after the 1970s as alternatives to SCIT: the bronchial route was soon abandoned due to the poor efficacy and/or side effects, and the local nasal route, although effective and safe, was judged substantially impractical (Canonica and Passalacqua in J Allergy Clin Immunol 111: 437-48, 2003). In contrast to SCIT, SLIT was tested in very large clinical trials (need references), including hundreds of patients and with dose-ranging experimental designs, so that some products (tablets) for grass, mite, and ragweed were officially approved as commercial drugs by regulatory agencies such as the Food and Drug Administration and the European Medicines Agency and the optimal content for the maintenance dose was identified for selected allergens. In parallel, the knowledge on the mechanisms of action of AIT was rapidly refined, leading to further improvements, such as the chemically modified extracts and the use of adjuvants to enhance efficacy and safety. In addition, in the last 10 years, there has been an increasing scientific and clinical interest in AIT applied to food allergies, in particular in children, with the use of orally administered extracts (Albin and Nowak-Węgrzyn in Immunol Allergy Clin North Am 35: 77-100, 2015). The results are so far encouraging, at least for cow's milk, egg, and peanut, although the use of treatment is still restricted to clinical trials or within specialized centers. Finally, the introduction of molecular- or component-resolved diagnosis has allowed detailing the prescription of AIT, by better delineating true sensitization versus cross-reactivity (Canonica et al. in World Allergy Organ J 6(1):17, 2013). This latter point is also in strict relation to the use of recombinant, engineered or highly purified molecules, instead of raw extracts, for the desensitization process.

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.

Background: Asthma Control Test (ACT ™) validity relies on Global Initiative for Asthma (GINA) definition of control. It includes neither reversibility nor inflammation assessment despite their importance as hallmark of asthma, partially unrelated to symptoms. Furthermore though rhinitis may affect the patient's perception of asthma control, its impact on ACT accuracy has not been systematically evaluated., Objective: To explore ACT validity according to a definition of control including: forced expiratory volume in 1 s (FEV1) ≥ 80%, negative reversibility test, exhaled nitric oxide at a flow rate of 50 ml/s (FeNO) < 50 ppb., Results: 177 asthmatics referring to our Unit have been studied. ACT with cut-off score ≥20 showed a good positive predictive value (83.5%) but low sensitivity (47.8%), specificity (66.7%), and negative predictive value (26.5%). ROC curves analysis indicates that ACT in patients with mild intermittent rhinitis is more reliable (AUC: 0.714; p < 0.05) than in patients with nasal polyposis/chronic rhino-sinusitis (AUC: 0.176; p > 0.05). Considering asthma classification, the probability that ACT detects patients with uncontrolled asthma is significantly higher in moderate persistent asthma subgroup than in mild persistent asthma one (OR 5.464; IC 95%: 2.5-11,9; p < 0.05)., Conclusions: As ACT mainly relies on patient's reported outcomes, it may not completely reflect the airways inflammation and airways obstruction. The presence and severity of rhinitis may affect ACT outcome. The awareness of the variables that could influence ACT evaluation is much more important in the primary care setting where ACT may often represent the only tool for asthma assessment.

Introduction: In the last two decades the knowledge of the mechanisms of the inflammatory processes underlying asthma rapidly evolved, several key mediators (cytokines and receptors) were identified, and the laboratory techniques have allowed us to synthesize monoclonal antibodies highly specific for those target molecules. Nowadays, many biological agents are investigated in asthma (with anti IgE being the only commercially available). The clinical efficacy of some biologics was demonstrated in many cases, however, the safety issue has progressively emerged and has been recognized as a crucial aspect., Areas Covered: We summarized the currently available knowledge on the safety and side effects of biologics in asthma, as derived by reviews, meta analyses and clinical trials. PubMed was searched with the terms anti IL-x [AND] safety [OR] side effects, within the categories "clinical trial", meta-analysis" and "review". Case reports were excluded. The authors collegially selected the relevant entries to be included., Expert Opinion: Overall, the safety of most of the investigated agents seems to be satisfactory, a certain risk of side effects remains present, and is variable for the different molecules. Thus caution must be paid in evaluating the risk to benefit ratio. Specific biomarkers to predict the response to each biological are urgently needed to improve the safety profile.

Background: Pediatric Asthma Quality of Life Questionnaire (PAQLQ) provides detailed information on QoL in asthmatic children, whereas Childhood Asthma Control Test (C-ACT) Questionnaire is the most validated instrument for asthma control. No study assessed the relationship between C-ACT and QoL in children by means of those instruments. The aim of this study was to determine whether a QoL estimation is possible using the C-ACT questionnaire in asthmatic children., Methods: Medical history, spirometry, C-ACT, and PAQLQ were assessed in 144 (60% male) outpatient asthmatic children from September 2011 to November 2014. A generalized linear model (GLM) for the prediction of PAQLQ was obtained through a stepwise procedure starting from a full model with all C-ACT items, and predictive nomograms were created., Results: Fifty-five (38%) well-controlled (WC) asthma, 37 (26%) partially controlled (PC) asthma, and 52 (36%) uncontrolled asthma (UA) patients were enrolled. Persistent asthmatics (PA) were significantly more uncontrolled (p < 0.0001). A significant reduction in FEV1 , FEV1 /FVC, and FEF25-75 (p = 0.005, p < 0.0001, and p < 0.001, respectively) was found in WC vs. UA. Through a stepwise process, a reduced model showed a positive relationship between the PAQLQ and the four items of C-ACT. The regression equations for predicted PAQLQ were ln(PAQLQ) = 1.17 + 0.05*C-ACT2 + 0.03*C-ACT3 + 0.04*C-ACT6 + 0.03*C-ACT7. Thus, a nomogram was constructed., Conclusion: The designed nomogram provides a highly predictive assessment of QoL in individual patients, facilitating a more comprehensive assessment of asthmatic children in usual clinical care., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2016 S. Karger AG, Basel.)

Although different phenotypes of severe asthma can be identified, all are characterized by common symptoms. Due to their heterogeneity, they exhibit differences in pathogenesis, etiology and clinical responses to therapeutic approaches. The identification of distinct molecular phenotypes to define severe asthmatic patients will allow us to better understand the pathophysiology of the disease and thus to more precisely target the treatment for each patient. To achieve this goal, a systematic search for new, reliable and stable biomarkers specific for each phenotype is essential. This review focuses on the current known molecular phenotypes of severe asthma and highlights the need for biomarkers that could (either alone or in combination) be predictive of the treatment outcome.

Purpose of Review: Despite that specific immunotherapy can boast being more than a century old, there is still skepticism about its real effectiveness, and therefore it is still used too little in clinical practice. The purpose of this review was to analyze the most recent articles in the literature to highlight scientific evidence for the proper use of allergen immunotherapy (AIT)., Recent Findings: In the near future, the concept of medicine for trials will have to be revised and in certain cases abandoned in favor of a personalized medicine, able to use a drug more targeted for the individual patient and not for the disease., Summary: For AIT, it will become increasingly important to use products designed properly, standardized and with a well documented effectiveness in clinical studies. We must overcome the disputes of subcutaneous immunotherapy versus sublingual immunotherapy, arrive at the concept of personalized medicine regarding AIT, framing in different phenotypes of asthma patients to use the optimal preparation for each particular patient.

Background: The prescription of allergen immunotherapy (SIT) in asthma remains a matter of debate and official guidelines often do not provide clear recommendations in this regard., Methods: An extensive review of the literature was untaken., Results: There are many robust studies with SCIT and SLIT showing positive results related to improving asthma symptoms, in particular when asthma was associated with rhinitis. In addition, there are several favourable meta-analyses, although their validity is limited by the heterogeneity of the trials included. The disease modifying effect of SIT (prevention of asthma onset and long-lasting effects) should be considered when prescribing this treatment. Regarding safety, fatalities seem to be rare: in Europe no fatality has been reported over the last two decades, and the same has been observed in USA in the last 4 years. Uncontrolled asthma is universally recognized as the most important risk factor for severe adverse events, but there is no clear demonstration that SIT can worsen or induce asthma. In contrast, of the few studies specifically designed to evaluate asthma, none had a formal sample size calculation, and pulmonary function was assessed as primary outcome only sporadically., Conclusions: According to the presently available evidence, SLIT and SCIT can be used in asthma associated with rhinitis (the most common condition), provided that asthma is adequately controlled by pharmacotherapy. In such cases, a measurable clinical benefit on asthma symptoms can be expected. SIT cannot be presently recommended as single therapy when asthma is the unique manifestation of respiratory allergy.

Evidence shows that sublingual immunotherapy (SLIT) is indicated in patients with allergic rhinitis (AR). In this article we discuss whether SLIT could offer benefit for children and adults with asthma.We reviewed individual trials on SLIT in asthmatic patients, but also asthma data reported in some SLIT trials conducted in AR patients. Findings were complemented with data from systematic reviews and metaanalysis on the subject since 2000 and some guidelines that mention immunotherapy for asthma treatment. In AR patients with concomitant persistent asthma, SLIT reduces medication needs while maintaining symptom control. This holds especially true for house dust mite SLIT. Data on pollen SLIT and lung symptom improvement with SLIT, however, are less convincing. Therefore, we suggest SLIT should be added as an optional add-on therapy for patients with asthma whenever a causative allergen has been demonstrated and AR is associated with asthma. For the future, SLIT should be studied in specifically designed asthma studies in allergic asthmatics without AR.

Immunotherapy can be administered either sublingually (sublingual immunotherapy [SLIT]) or subcutaneously (subcutaneous immunotherapy [SCIT]). The rate of route switching, required by patients, can provide an indirect evaluation of patients' preferences and adherence. The authors retrospectively reviewed patients' files over an 18-year period to quantify the changes in the route of administration. The clinical records of children referred for respiratory allergy between 1994 and 2011 and prescribed with SLIT or SCIT were reviewed. The specific causes of the shift from SLIT to SCIT and vice versa were always assessed, with a special attention to adverse events. The records of 4933 children (2289 male patients, aged 4-18 years) were reviewed. Six hundred forty-eight patients received SCIT and 4285 patients received SLIT. Of the 4285 SLIT patients, 340 (7.9%) shifted to SCIT, mainly with Parietaria judaica and grasses. The 85.8% of the changes were caused by a perceived low efficacy. None of the parents required the route change for side effects. Of the 648 patients initially treated with SCIT, 54 (8.3%) shifted to SLIT, 85% of them for local or systemic side effects, but none for poor efficacy. The rate of SCIT/SLIT changes is, overall, low and because of poor efficacy for SLIT and side effects for SCIT.

Allergic rhinitis and asthma represent global problems of public health affecting all age groups; asthma and allergic rhinitis frequently coexist in the same patients. In Latin American prevalence of allergic rhinitis, although variable, is very high. Allergic rhinitis and its Impact on Asthma (ARIA) started during a workshop of the World Health Organization performed in 1999 and was published in 2001. ARIA proposed a new classification of allergic rhinitis in intermittent or persistent and mild or moderate-severe. This approach of classification reflects more nearly the impact of allergic rhinitis in patients. In its review of 2010 ARIA developed guidelines for diagnosis and treatment of allergic rhinitis and of clinical practices for management of comorbidities of allergic rhinitis and asthma based on GRADE (Grading of Recommendations, Development and Evaluation). ARIA has been spread and implemented in more than 50 countries. In Latin American an intense activity has been developed to spread these recommendations in almost all the countries of the region and it is important to record the obtained goals in the diffusion and implementation of ARIA, as well as to identify the unsatisfied needs from the clinical, research and implementation points of view. Final objective is to reinforce the priority that allergy and asthma should have, especially in children, in the programs of public health, as they have been prioritized in European Union in 2011.

Purpose of Review: The aim of this review is to update readers on the growing impact of a molecular approach (CRD) to the diagnosis and treatment of children with respiratory allergies, Recent Findings: A large panel of highly purified natural or recombinant species-specific and cross-reacting allergenic molecules is now available for clinical purposes. Species-specific molecules allow identifying specific sensitization toward a given allergenic source. Cross-reacting molecules allow interpreting polysensitization patterns that cannot be detailed using routine skin prick tests or specific IgE tests based on allergenic extracts. These molecular tools are transforming and improving the interpretation of clinical and laboratory tests used to define patients' IgE-sensitization profile., Summary: The accurate dissection of the IgE repertoire offers new possibilities in the diagnosis, prophylaxis and treatment of pediatric allergic rhinoconjunctivitis and asthma.

Background: Cow's milk allergy is common in infancy, and total avoidance of this food is the only effective approach. In alternative, oral immunotherapy has been proposed to achieve tolerance. Once desensitization is achieved, daily intake of milk is recommended to maintain it, but this may be impractical for children/parents. We assessed whether a twice weekly maintenance regimen is effective., Methods: Children who were successfully desensitized with oral immunotherapy were randomized to two maintenance regimens for 1 year: group A had to eat 150-200 ml milk daily, group B had to eat 150-200 ml milk twice weekly. Both regimens were associated to a totally free diet. Maintenance of tolerance and adverse events were recorded during 1 year. Specific IgE, IgG4 and prick-by-prick test to milk were carried out before immunotherapy (T0), before maintenance (T1), and after 1 year (T2)., Results: Recorded episodes included asthma, oral itching, urticaria, rhinitis, abdominal pain variously combined, usually associated with concomitant illness or exercise. The episodes were 8 in group A and 9 in group B, with no difference. None of the children discontinued the feeding maintenance. Specific IgG4 increased at T1 and remained high at T2. Specific IgE and skin reactivity significantly decreased at T2. There was no difference in those parameters between the groups., Conclusion: After achieving desensitization to cow milk with oral immunotherapy, a maintenance regimen with milk given twice weekly is as effective as the daily maintenance., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)