Sleep quality burden in chronic rhinosinusitis with nasal polyps and its modulation by dupilumab.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with a substantial burden on patients' quality of life and impaired sleep quality. The most common CRSwNP endotype is characterized by type 2 inflammation, with enhanced production of interleukin (IL)-4, IL-5, and IL-13. Dupilumab is a monoclonal antibody against IL-4 receptor-α, which inhibits both IL-4 and IL-13 signaling, and was recently approved for treatment of CRSwNP. OBJECTIVE: We investigated the effect of dupilumab on the sleep quality of patients with CRSwNP in a real-life setting. METHODS: Patients were evaluated at baseline and after 1 and 3 months of dupilumab treatment by means of the Epworth sleepiness scale (ESS), insomnia severity index (ISI), Pittsburgh sleep quality index (PSQI), and sinonasal outcome test 22 (SNOT-22) sleep domain. RESULTS: A total of 29 consecutive patients were enrolled, and their baseline sleep quality assessment were as follows: ESS of 7.9 (± 4.5); ISI of 13.1 (± 6.2); PSQI of 9.2 (± 3.7); and SNOT-22 sleep domain of 12.1 (± 4.2). Excessive daily sleepiness, insomnia, and globally impaired sleep quality were present in 24.1%, 79.3%, and 93.1% respectively. Treatment with dupilumab was associated with significant improvement in ESS, ISI, PSQI, and SNOT-22 sleep domain with concomitant reduction of the proportion of patients with insomnia and globally impaired sleep quality. CONCLUSION: CRSwNP was associated with a significant impact on global sleep quality, in particular, insomnia, and treatment with dupilumab induced a rapid improvement (after 1 single month of treatment) in all the sleep quality parameters, suggesting that sleep disturbances should be more carefully evaluated as an additional outcome in these patients.

Asthma management, focused on the use of oral corticosteroids: the opinions of Italian asthmatic patients.

OBJECTIVE: Patients' perceptions of asthma symptoms, and attitudes regarding diagnosis and management, can affect their ability to reach good asthma control. The aim of the study was to explore patients' perceptions of asthma management, with focus on treatment with oral corticosteroids (OCS). METHODS: A DOXAPHARMA survey was conducted. A questionnaire with 46 multiple choice questions was completed by 50 patients with severe uncontrolled asthma, and 258 with mild-moderate controlled or partly controlled asthma. Participants were representative of Italian asthmatic patients-with medium age, long asthma duration, delayed diagnosis, poor asthma control, and frequent exacerbations. RESULTS: Many asthmatics reported inadequate pharmacologic treatment. The majority but not all patients regularly used ICS/LABA. Oral treatment was common, mainly with OCS, particularly in severe asthmatics. One-fourth of patients did not regularly use inhaled therapy, and adherence was poor, resulting in frequent OCS use to treat exacerbations, which were common in mild-moderate cases. Patients were fairly satisfied with asthma therapies, but many had concerns about long-term corticosteroid use. Patients complained about poor management of comorbidities associated with asthma and OCS use, but were generally satisfied with their patient/doctor relationships. Many patients failed to achieve optimal health-related quality of life (HRQoL), mainly those with severe asthma who used OCS treatment and emphasized how OCS therapy impacted QoL. CONCLUSIONS: The survey results confirmed many problems related to mild-moderate and severe asthma management in Italy and highlighted the overuse of OCS rather than more effective and safe treatments, which had strong negative effects on HRQoL.

Advancing precision medicine in asthma: Evolution of treatment outcomes.

The article discusses the historical evolution of asthma treatment and highlights recent advancements in personalized medicine, specifically the use of biologics in severe asthma therapy and its potential combination with allergen immunotherapy (AIT). One of the major breakthroughs of biologics is their potential effect on airway remodeling, a crucial aspect of asthma chronicity. The article introduces the concept of disease-modifying antiasthmatic drugs, which aim to modify the course of asthma and possibly modulate or prevent airway remodeling. Furthermore, the critical importance of patient-centered outcome measures to evaluate the efficacy and effectiveness of asthma treatments is emphasized, with the innovative concept of asthma remission introduced as a potential outcome. Recent studies suggest that AIT can be used as an additional therapy to biologic agents for the treatment of allergic asthma. The combination of these treatments has been shown to induce improved clinical outcomes. However, AIT is actually not recommended for use in patients with severe asthma, but encouraging results from studies investigating the combined use of AIT and biologics indicate a novel approach to exploring these treatment modalities. In conclusion, the introduction of biologics and AIT has changed the scenario of respiratory allergy treatment, from a "one size fits all" approach to embracing "individual treatments."

Airways Type-2 Related Disorders: Multiorgan, Systemic or Syndemic Disease?

Chronic rhinosinusitis (CRS) has recently undergone a significant paradigm shift, moving from a phenotypical classification towards an "endotype-based" definition that places more emphasis on clinical and therapeutic aspects. Similar to other airway diseases, like asthma, most cases of CRS in developed countries exhibit a dysregulated type-2 immune response and related cytokines. Consequently, the traditional distinction between upper and lower airways has been replaced by a "united airway" perspective. Additionally, type-2 related disorders extend beyond respiratory boundaries, encompassing conditions beyond the airways, such as atopic dermatitis. This necessitates a multidisciplinary approach. Moreover, consideration of possible systemic implications is crucial, particularly in relation to sleep-related breathing diseases like Obstructive Sleep Apnoea Syndrome (OSAS) and the alteration of systemic inflammatory mediators such as nitric oxide. The trends in epidemiological, economic, and social burden are progressively increasing worldwide, indicating syndemic characteristics. In light of these insights, this narrative review aims to present the latest evidence on respiratory type-2 related disorders, with a specific focus on CRS while promoting a comprehensive perspective on the "united airways". It also introduces a novel concept: viewing these conditions as a multiorgan, systemic, and syndemic disease.

Comparison of evidence of treatment effects in randomized and nonrandomized studies on allergen immunotherapy.

Nonrandomized studies (NRS) on allergen immunotherapy (AIT) particularly lend themselves to evaluate outcomes that are insufficiently addressed in randomized controlled studies (RCTs). However, NRS are prone to several sources of bias, which limit their validity. We aimed at comparing AIT effects between RCTs and NRS and evaluate the reasons for discrepancies in study results. In this analysis, we compared NRS on AIT (including subcutaneous and sublingual immunotherapy, SCIT and SLIT, respectively) with SLIT and SCIT RCTs from published meta-analyses, assessing the Risk of Bias (RoB) for each study and the certainty of evidence from NRS and RCTs using the GRADE approach. We found: (1) very serious RoB in the 7 NRS included in the meta-analysis showing a large difference between AIT and controls (standardized mean difference [SMD] for symptom score [SS], -1.77; 95% CI, -2.30, -1.24; p < .001; I2 = 95%) with very low certainty evidence; (2) serious RoB in the 13 SCIT-RCTs reporting a moderate-to-high difference between SCIT and controls (SMD for SS, -0.81; 95% CI, -1.12, -0.49; p < .001; I2 = 88%) with moderate certainty evidence; (3) low RoB in the 13 SLIT-RCTs reporting a small benefit (SMD for SS, -0.28; 95% CI, -0.37, -0.19; p < .001; I2 = 54.2%) with high certainty evidence. Similar results were reported for medication score. Our evidence is sufficient to conclude that the magnitude of effect estimates of NRS and RCTs directly correlate with the degree of RoB and inversely with the overall evidence certainty. NRS, which are more affected than RCTs by bias resulting in low certainty evidence, showed the largest effect size. Sound NRS are needed to complement RCTs.

Local Allergic Rhinitis: Lights and Shadows of a Mysterious Entity.

Local allergic rhinitis (LAR) is, to date, a debated and complex entity, still orphan of global consideration and a multicentric approach. LAR does not seem to find a proper positioning in the classic classifications and phenotypes of chronic rhinitis, and its pathophysiology relies specifically on the presence of local IgE. These patients in fact have a suggestive clinical history of allergic rhinitis in the presence of negative skin prick tests and serum IgE tests for the suspect allergen. Nasal allergen challenge, assessment of local IgE, basophil activation test (BAT), and nasal cytology are, at the moment, the most used tests in the diagnostic approach to the disease, despite their limitations. Considering that the correct interpretation of diagnostic tests and their clinical relevance is fundamental in the assessment of the right diagnosis and the subsequent therapy, we propose a new diagnostic approach that encompasses all of these methodologies and suggest that several pragmatic randomized control trials as well as prospective, multicentric studies directed at the long-term follow-up of LAR be carried out to further investigate this debated entity.

Asthma from immune pathogenesis to precision medicine.

Asthma is characterized by multiple immunological mechanisms (endotypes) determining variable clinical presentations (phenotypes). The identification of endotypic mechanisms is crucial to better characterize patients and to identify tailored therapeutic approaches with novel biological agents targeting specific immunological pathways. This review focused on summarizing the major immunological mechanisms involved in the pathogenesis of asthma, as well as on discussing the emergence of phenotypic features of the disease. Novel biological agents and other drugs targeting specific endotypes are discussed, as their use represent a precision medicine approach to the disease that is nowadays mandatory particularly for treating more severe patients.

Middle meatus nasal cytology compared to inferior turbinate cytology in non allergic rhinitis.

PURPOSE: Non allergic rhinitis (NAR) comprises different clinical definitions and phenotypes, including non inflammatory non allergic (NINAR) and cellular inflammatory forms. Nasal cytology, usually performed by scraping the inferior turbinate, is a non invasive, cheap and point-of-care tool to distinguish among the different NAR phenotypes, but still a relevant proportion of patients evaluated by nasal cytology receive a non precise definition of NAR phenotype. We hypothesize that collecting nasal cytology samples from middle meatus could increase the diagnostic accuracy. METHODS: Consecutive patients with chronic rhinitis without evidence of allergic sensitization were assessed for nasal cytology by means of scraping both the inferior turbinate and the middle meatus (lateral-inferior wall of the middle turbinate). RESULTS: 107 consecutive patients with NAR were enrolled in the study. According to inferior turbinate cytology, 42.1% were defined as affected by NINAR, 2.8% by bacterial rhinitis, 10.3% by non allergic rhinitis with eosinophils (NARES), 15.0% non allergic rhinitis with neutrophils (NARNE), 19.6% non allergic rhinitis with mast-cells (NARMA) and 10.3% non allergic rhinitis with eosinophils and mast-cells (NARESMA). Middle meatus cytology was in accordance with inferior turbinate cytology in only 37.6% of cases. Eosinophils and mast-cells were detectable more frequently in middle meatus samples (49.5% vs 19.6%, p < 0.01, 59.8% vs 29.9%, p < 0.01, respectively). 93.3% of NINAR patients received an inflammatory NAR phenotype at middle meatus cytology: 26.7% NARES, 24.4% NARNE, 31.1% NARMA and 11.1% NARESMA. CONCLUSION: Middle meatus cytology is more reliable than inferior turbinate cytology in phenotyping patients with NAR. Our study strengthen that nasal cytology should be implemented in clinical practice collecting samples at the middle meatus level.

Mast Cells in Upper and Lower Airway Diseases: Sentinels in the Front Line.

Mast cells (MCs) are fascinating cells of the innate immune system involved not only in allergic reaction but also in tissue homeostasis, response to infection, wound healing, protection against kidney injury, the effects of pollution and, in some circumstances, cancer. Indeed, exploring their role in respiratory allergic diseases would give us, perhaps, novel therapy targets. Based on this, there is currently a great demand for therapeutic regimens to enfeeble the damaging impact of MCs in these pathological conditions. Several strategies can accomplish this at different levels in response to MC activation, including targeting individual mediators released by MCs, blockade of receptors for MC-released compounds, inhibition of MC activation, limiting mast cell growth, or inducing mast cell apoptosis. The current work focuses on and summarizes the mast cells' role in pathogenesis and as a personalized treatment target in allergic rhinitis and asthma; even these supposed treatments are still at the preclinical stage.

Biologics and airway remodeling in severe asthma.

Asthma is a chronic inflammatory airway disease resulting in airflow obstruction, which in part can become irreversible to conventional therapies, defining the concept of airway remodeling. The introduction of biologics in severe asthma has led in some patients to the complete normalization of previously considered irreversible airflow obstruction. This highlights the need to distinguish a "fixed" airflow obstruction due to structural changes unresponsive to current therapies, from a "reversible" one as demonstrated by lung function normalization during biological therapies not previously obtained even with high-dose systemic glucocorticoids. The mechanisms by which exposure to environmental factors initiates the inflammatory responses that trigger airway remodeling are still incompletely understood. Alarmins represent epithelial-derived cytokines that initiate immunologic events leading to inflammatory airway remodeling. Biological therapies can improve airflow obstruction by addressing these airway inflammatory changes. In addition, biologics might prevent and possibly even revert "fixed" remodeling due to structural changes. Hence, it appears clinically important to separate the therapeutic effects (early and late) of biologics as a new paradigm to evaluate the effects of these drugs and future treatments on airway remodeling in severe asthma.

Impact of asthma on bronchiectasis severity and risk of exacerbations.

OBJECTIVE: Asthma is a frequent comorbidity of bronchiectasis, with possible implications for exacerbation and severity. We investigated the clinical impact of asthma on bronchiectasis in terms of disease severity and exacerbation risk. METHODS: We collected demographic, clinical, and functional characteristics of patients with a confirmed diagnosis of bronchiectasis. All patients were investigated for concomitant diagnosis of asthma. The Bhalla score was used to assess radiological severity of bronchiectasis, and the Bronchiectasis Severity Index (BSI) was used to assess the clinical severity. Blood and sputum samples were collected to assess blood cell count, erythrocyte sedimentation rate, c-reactive protein, immunological status (IgA, IgE, IgM, IgG, and IgG subclasses), and microbiological analysis. RESULTS: A total of 106 patients were enrolled in the study; 30.2% had concomitant asthma and were characterized by higher frequency of bronchiectasis exacerbation, despite higher Bhalla score and lower BSI compared to patients without asthma. Pseudomonas aeruginosa was more frequently isolated from the sputum of bronchiectasis patients without asthma. Total serum IgG, IgG1, and IgG3 were lower in patients with asthma. Blood eosinophils and exhaled nitric oxide were higher in patients with associated asthma. The presence of asthma and presence of Pseudomonas in sputum were the only significant determinants of frequent exacerbations in a binary logistic regression analysis. CONCLUSION: The coexistence of asthma and bronchiectasis is associated with an independent increase in the risk of bronchiectasis exacerbation despite lower radiological and clinical severity indexes. Asthmatic airway inflammation could promote an enhanced "Cole's Cycle" that is responsible for a higher frequency of exacerbations.

Current treatment strategies for seasonal allergic rhinitis: where are we heading?

INTRODUCTION: Allergic rhinitis (AR) is very commonly caused by pollens. The symptoms of AR consist of sneezing, nasal congestion, rhinorrhea, nasal itching and airflow obstruction. The diagnosis has long been based on clinical history, skin prick tests and in vitro measurement of specific IgE, but the innovative approach of precision medicine has made diagnostic tools of much greater accuracy available. AREAS COVERED: This review covers the advances in the treatment of seasonal AR concerning the drugs to be used according to the grade of disease and the characteristics of the patients, and the role of allergen immunotherapy (AIT), which is the only treatment capable of acting, in addition to the symptoms, on the cause of AR and therefore to modify its natural history. EXPERT OPINION: Drug treatment of AR include a large number of agents, the choice of which depends on the severity of the disease. AIT has high evidence of efficacy demonstrated by meta-analyses, and further improvement is currently apparent, as for diagnosis, applying the means of precision medicine. However, when AIT is performed in current practice, without the strict rules of controlled trials, long-term low adherence is a major problem to be solved.

Allergen immunotherapy: The growing role of observational and randomized trial "Real-World Evidence".

BACKGROUND: Although there is a considerable body of knowledge about allergen immunotherapy (AIT), there is a lack of data on the reliability of real-world evidence (RWE) in AIT, and consequently, a lack of information on how AIT effectively works in real life. METHODS: To address the current unmet need for an appraisal of the quality of RWE in AIT, the European Academy of Allergy and Clinical Immunology Methodology Committee recently initiated a systematic review of observational studies of AIT, which will use the RELEVANT tool and the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE) to rate the quality of the evidence base as a whole. The next step will be to develop a broadly applicable, pragmatic "real-world" database using systematic data collection. Based on the current RWE base, and perspectives and recommendations of authorities and scientific societies, a hierarchy of RWE in AIT is proposed, which places pragmatic trials and registry data at the positions of highest level of evidence. KEY RESULTS: There is a need to establish more AIT registries that collect data in a cohesive way, using standardized protocols. CONCLUSIONS: This will provide an essential source of real-world data that can be easily shared, promoting evidence-based research and quality improvement in study design and clinical decision-making.

One year of mepolizumab. Efficacy and safety in real-life in Italy.

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 ±â€¯10 years). The average age of onset of asthma was 34 ±â€¯16 years. The blood eosinophil count decreased from 822 ±â€¯491/µL at baseline to 117 ±â€¯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 ±â€¯9.4 mg prednisone decrease at 28% after 12 months with a mean of 2.0 ±â€¯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.