Anti-IL-5 Pathway Agents in Eosinophilic-Associated Disorders Across the Lifespan.

Monoclonal antibodies targeting interleukin (IL)-5 pathways have revolutionized the treatment expectations for eosinophilic-associated conditions, particularly in patients with respiratory involvement. Mepolizumab (IL-5 antagonist monoclonal antibody), benralizumab (IL-5 receptor blocker monoclonal antibody), and reslizumab (IL-5 antagonist monoclonal antibody) have collectively contributed to the overall improvement of the disease burden in various conditions. Eosinophilic asthma currently boasts the most robust evidence across all age groups: all three biologics are approved for adults (aged ≥18 years); mepolizumab is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) also in children (aged ≥ 6 years), while bernalizumab was recently approved by the FDA for patients aged ≥6 years in the USA. In chronic rhinosinusitis with nasal polyps, subcutaneous mepolizumab is the only anti-IL-5 therapy approved so far and can be used in adult patients (aged ≥18 years). For eosinophilic esophagitis, conflicting evidence surrounds both mepolizumab, reslizumab, and benralizumab, leading to non-approval of these agents by the FDA/EMA. Recently, mepolizumab was approved for eosinophilic granulomatosis with polyangiitis patients aged ≥6 years or older and for hypereosinophilic syndrome adult patients. A phase III trial proving noninferiority of benralizumab versus mepolizumab in eosinophilic granulomatosis with polyangiitis has been recently published, while evidence on reslizumab is scant. Overall, current evidence on anti-IL-5 biologics for eosinophilic-associated disorders is mostly focused on adults, whereas data for individuals aged under 18 years and over 65 years are scarce, resulting in a lack of evidence, particularly regarding efficacy, for the use of anti-IL-5 agents in these specific patient populations. This review addresses high-quality evidence from randomized controlled trials and real-world post-marketing studies regarding the use of anti-IL-5 therapies for eosinophilic-associated disorders across all age groups, spanning childhood, adulthood, and older age.

Using the 6-min walk test to assess the clinical response to mepolizumab and conventional therapy in severe eosinophilic asthma.

Background: Severe asthma limits exercise to avoid respiratory symptoms. The objective of the present study was to investigate the role of the 6-min walk test (6MWT) in severe asthma. Methods: Consecutive patients with severe eosinophilic asthma were enrolled. A 6MWT was performed before and after 12 months. Inhaled therapy dose, oral corticosteroids dose, pulmonary function tests, eosinophil blood count, fractional exhaled nitric oxide (FeNO), Asthma Control Test (ACT) score and responses to the Asthma Quality of Life Questionnaire (AQLQ) were also recorded. Results: Of the 22 patients enrolled, 13 were treated with mepolizumab 100 mg every 4 weeks in addition to conventional therapy and nine with conventional therapy only. The majority of the patients were treated with high-dose inhaled corticosteroids/long-acting ß-agonists/long-acting muscarinic receptor antagonists, while approximately half were on continuous oral corticosteroids. After 12 months, the mepolizumab group only showed a significant improvement in pulmonary function tests (percentage forced expiratory volume in 1 s and percentage forced expiratory flow at 25-75% forced vital capacity (FEF25-75%), both p<0.001; percentage forced vital capacity, p<0.01) and clinical laboratory parameters (eosinophil count, FeNO measured at a flow rate of 50 mL·s-1, ACT and AQLQ, p<0.001). No significant changes in the proportion of patients using continuous oral corticosteroids and high-dose inhaled corticosteroids/long-acting ß-agonists/long-acting muscarinic receptor antagonists were observed in either group (p>0.05). By paired comparisons, statistically significant improvements of the mean 6-min walk distance (6MWD) were observed in the mepolizumab (p<0.001) and conventional therapy (p<0.01) groups, while no improvement was seen in dyspnoea Borg scale, heart rate, percentage oxygen saturation or systolic and diastolic blood pressure. 6MWD showed significant direct correlations with ACT (r=0.5998, p<0.001), AQLQ (r=0.3978, p=0.009) and FEF25-75% (r=0.3589, p=0.017). Conclusions: The 6MWT could complement severe asthma assessment and be relevant in evaluating the objective response to treatment, including biological therapies like mepolizumab.

Impulse oscillometry defined small airway dysfunction in asthmatic patients with normal spirometry: Prevalence, clinical associations, and impact on asthma control.

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.

Oscillometry in severe asthma: the state of the art and future perspectives.

INTRODUCTION: Approximately 3-10% of people with asthma have severe asthma (SA). Patients with SA have greater impairment in daily life and much higher costs. Even if asthma affects the entire bronchial tree, small airways have been recognized as the major site of airflow limitation. There are several tools for studying small airway dysfunction (SAD), but certainly the most interesting is oscillometry. Despite several studies, the clinical usefulness of oscillometry in asthma is still in question. This paper aims to provide evidence supporting the use of oscillometry to improve the management of SA in clinical practice. AREAS COVERED: In the ATLANTIS study, SAD was strongly evident across all severity. Various tools are available for evaluation of SAD, and certainly an integrated use of these can provide complete and detailed information. However, the most suitable method is oscillometry, implemented for clinical routine by using either small pressure impulses or small pressure sinusoidal waves. EXPERT OPINION: Oscillometry, despite its different technological implementations is the best tool for determining the impact of SAD on asthma and its control. Oscillometry will also be increasingly useful for choosing the appropriate drug, and there is ample room for a more widespread diffusion in clinical practice.

Small airway dysfunction in asthmatic patients treated with as-needed SABA monotherapy: A perfect storm.

BACKGROUND: Short-acting beta agonist (SABA)-only treatment is associated with poor asthma control and adverse clinical outcomes. The importance of small airway dysfunction (SAD) is increasingly recognized in asthma, but less is known in patients using SABA-only therapy. We aimed to investigate the impact of SAD on asthma control in an unselected cohort of 60 adults with physician-diagnosed intermittent asthma treated with as-needed SABA monotherapy. METHODS: All patients underwent standard spirometry and impulse oscillometry (IOS) at the first visit and were stratified by the presence of SAD defined by IOS (fall in resistance 5-20 Hz [R5-R20]>0.07 kPa × s*L-1). Univariable and multivariable analyses were used to analyze cross-sectional relationships between clinical variables and SAD. RESULTS: SAD was present in 73% of the cohort. Compared with patients without SAD, adults with SAD had a higher number of severe exacerbations (65.9% versus 25.0%, p < 0.05), higher use of annual SABA canisters (median (IQR), 3 (1.75-3) versus 1 (1-2), p < 0.001), and significantly less well-controlled asthma (11.7% versus 75.0%, p < 0.001). Spirometry parameters were similar between patients with IOS-defined SAD and those without SAD. The multivariable logistic regression analysis showed that exercise-induced bronchoconstriction symptoms (EIB, odds ratio [OR] 31.18; 95%CI:4.85-365.00) and night awakenings due to asthma (OR 30.30; 95%CI:2.61-1141.00) were independent predictors of SAD, with a high predictive power of the model incorporating these baseline predictors (AUC 0.92). CONCLUSIONS: EIB and nocturnal symptoms are strong predictors of SAD in asthmatic patients using as-needed SABA-monotherapy, helping to distinguish subjects with SAD among patients with asthma when IOS cannot be performed.

Monoclonal antibodies targeting small airways: a new perspective for biological therapies in severe asthma.

Small airway dysfunction (SAD) in asthma is characterized by the inflammation and narrowing of airways with less of 2 mm in diameter between generations 8 and 23 of the bronchial tree. It is now widely accepted that small airways are involved in the pathogenesis of asthma and are a major determinant of airflow obstruction in this disease. In recent years, specialized tests have been developed, such as Impulse Oscillometry (IOS) and Multiple Breath Nitrogen Washout (MBNW) tests, which have been deemed more accurate in detecting SAD than conventional spirometry. Clinical studies show that SAD is associated with more severe bronchial hyperresponsiveness, worse asthma control, and a higher risk of exacerbations. Recent data from a large cohort study showed that the prevalence of SAD in asthma patients increases with asthma severity. Overall, SAD seems to represent a treatable trait, which makes it appealing for asthma control optimization and exacerbation rate reduction, especially in moderate-to-severe asthma.Biologic agents are now available for the treatment of different severe asthma phenotypes and endotypes. However, the effect of these therapies on SAD remains poorly characterized. Literature showing that biologic agents can also favorably improve small airway function is accumulating. In particular, anti-IL5 agents (mepolizumab and benralizumab) seems to have a greater impact on SAD as compared to other biological agents, but direct comparisons in prospective randomized controlled trials are lacking.In this mini-review article, we address the latest evidence on the effect of biological therapies on SAD in patients with severe asthma.

Small Airways: The "Silent Zone" of 2021 GINA Report?

Asthma is a chronic disease, affecting approximately 350 million people worldwide. Inflammation and remodeling in asthma involve the large airways, and it is now widely accepted that the small airways (those with an internal diameter <2 mm) are involved in the pathogenesis of asthma and are the major determinant of airflow obstruction in this disease. From a clinical perspective, small airways dysfunction (SAD) is associated with more severe bronchial hyperresponsiveness, worse asthma control and more exacerbations. Unlike the GOLD guidelines which, in their definition, identify COPD as a disease of the small airways, the Global Initiative for Asthma (GINA) guidelines do not refer to the prevalence and role of SAD in asthmatic patients. This decision seems surprising, given the growing body of compelling evidence accumulating pointing out the high prevalence of SAD in asthmatic patients and the importance of SAD in poor asthma control. Furthermore, and remarkably, SAD appears to possess the characteristics of a treatable pulmonary trait, making it certainly appealing for asthma control optimization and exacerbation rate reduction. In this mini-review article, we address the most recent evidence on the role of SAD on asthma control and critically review the possible inclusion of SAD among treatable pulmonary traits in international guidelines on asthma.

The emerging roles of eosinophils: Implications for the targeted treatment of eosinophilic-associated inflammatory conditions.

Eosinophils have multiple relevant biological functions, including the maintenance of homeostasis, host defense against infectious agents, innate immunity activities, immune regulation through Th1/Th2 balance, anti-inflammatory, and anti-tumorigenic effects. Eosinophils also have a main role in tissue damage through eosinophil-derived cytotoxic mediators that are involved in eosinophilic inflammation, as documented in Th2-high asthma and other eosinophilic-associated inflammatory conditions. Recent evidence shows that these multiple and apparently conflicting functions may be attributed to the existence of different eosinophil subtypes (i.e.: tissue resident and inducible eosinophils). Therapeutic intervention with biological agents that totally deplete tissues and circulating eosinophils or, vice versa, maintain a minimal proportion of eosinophils, particularly the tissue-resident ones, could therefore have a very different impact on patients, especially when considering the administration of these therapies for prolonged time. In addition, the characterization of the predominant pathway underlying eosinophilic inflammation by surrogate biomarkers (circulating eosinophils, organ-specific eosinophils levels such as eosinophil count in sputum, bronchoalveolar lavage, tissue biopsy; total circulating IgE levels, or the use of FeNO) in the single patient with an eosinophilic-associated inflammatory condition could help in choosing the treatment. These observations are crucial in light of the increasing therapeutic armamentarium effective in modulating eosinophilic inflammation through the inhibition in different, yet complementary ways of eosinophil pathways, such as the interleukin-5 one (with mepolizumab, benralizumab, reslizumab) or the interleukin-4/13 one (with dupilumab and lebrikizumab), in severe T2-high asthma as well as in other systemic eosinophilic associated diseases, such as eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome.

Mild/Moderate Asthma Network in Italy (MANI): a long-term observational study.

OBJECTIVE: The prevalence of asthma in Italy is estimated to be around 4%; it affects approximately 2,000,000 citizens, and up to 80-90% of patients have mild-to-moderate asthma. Despite the clinical relevance of mild-to-moderate asthma, longitudinal observational data are very limited, including data on disease progression (worsening vs. improvement), the response to treatment, and prognosis. Studies are needed to develop long-term, observational, real-life research in large cohorts. The primary outcomes of this study will be based on prospective observation and the epidemiological evolution of mild and moderate asthma. Secondary outcomes will include patient-reported outcomes, treatments over time, disease-related functional and inflammatory patterns, and environmental and life-style influences. METHODS: This study, called the Mild/Moderate Asthma Network of Italy (MANI), is a research initiative launched by the Italian Respiratory Society and the Italian Society of Allergology, Asthma and Clinical Immunology. MANI is a cluster-based, real world, cross-sectional, prospective, observational cohort study that includes 20,000 patients with mild-to-moderate asthma. (ClinicalTrials.gov Identifier: NCT04796844). RESULTS AND CONCLUSION: Despite advances in asthma care, several research gaps remain to be addressed through clinical research. This study will add important new knowledge about long-term disease history, the transferability of clinical research results to daily practice, the efficacy of currently recommended strategies, and their impact on the burden and evolution of the disease. ABBREVIATIONS: MANI:Mild/Moderate Asthma Network of ItalySANI:Severe Asthma Network ItalyGINA:Global Initiative for AsthmaSABA:short acting ß2-agonistsICS:inhaled corticosteroidsCRF:Case Report Form.

Immune and cellular damage biomarkers to predict COVID-19 mortality in hospitalized patients.

Early prediction of COVID-19 in-hospital mortality relies usually on patients' preexisting comorbidities and is rarely reproducible in independent cohorts. We wanted to compare the role of routinely measured biomarkers of immunity, inflammation, and cellular damage with preexisting comorbidities in eight different machine-learning models to predict mortality, and evaluate their performance in an independent population. We recruited and followed-up consecutive adult patients with SARS-Cov-2 infection in two different Italian hospitals. We predicted 60-day mortality in one cohort (development dataset, n = 299 patients, of which 80% was allocated to the development dataset and 20% to the training set) and retested the models in the second cohort (external validation dataset, n = 402). Demographic, clinical, and laboratory features at admission, treatments and disease outcomes were significantly different between the two cohorts. Notably, significant differences were observed for %lymphocytes (p < 0.05), international-normalized-ratio (p < 0.01), platelets, alanine-aminotransferase, creatinine (all p < 0.001). The primary outcome (60-day mortality) was 29.10% (n = 87) in the development dataset, and 39.55% (n = 159) in the external validation dataset. The performance of the 8 tested models on the external validation dataset were similar to that of the holdout test dataset, indicating that the models capture the key predictors of mortality. The shap analysis in both datasets showed that age, immune features (%lymphocytes, platelets) and LDH substantially impacted on all models' predictions, while creatinine and CRP varied among the different models. The model with the better performance was model 8 (60-day mortality AUROC 0.83 ± 0.06 in holdout test set, 0.79 ± 0.02 in external validation dataset). The features that had the greatest impact on this model's prediction were age, LDH, platelets, and %lymphocytes, more than comorbidities or inflammation markers, and these findings were highly consistent in both datasets, likely reflecting the virus effect at the very beginning of the disease.

Asthma and COVID-19: a dangerous liaison?

The coronavirus disease 2019 (COVID-19) pandemic, caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), provoked the most striking international public health crisis of our time. COVID-19 can cause a range of breathing problems, from mild to critical, with potential evolution to respiratory failure and acute respiratory distress syndrome. Elderly adults and those affected with chronic cardiovascular, metabolic, and respiratory conditions carry a higher risk of severe COVID-19. Given the global burden of asthma, there are well-founded concerns that the relationship between COVID-19 and asthma could represent a "dangerous liaison".Here we aim to review the latest evidence on the links between asthma and COVID-19 and provide reasoned answers to current concerns, such as the risk of developing SARS-CoV-2 infection and/or severe COVID-19 stratified by asthmatic patients, the contribution of type-2 vs. non-type-2 asthma and asthma-COPD overlap to the risk of COVID-19 development. We also address the potential role of both standard anti-inflammatory asthma therapies and new biological agents for severe asthma, such as mepolizumab, reslizumab, and benralizumab, on the susceptibility to SARS-CoV-2 infection and severe COVID-19 outcomes.

Small airway dysfunction and poor asthma control: a dangerous liaison.

Asthma is a common chronic condition, affecting approximately 339 million people worldwide. The main goal of the current asthma treatment guidelines is to achieve clinical control, encompassing both the patient symptoms and limitations and the future risk of adverse asthma outcomes. Despite randomized controlled trials showing that asthma control is an achievable target, a substantial proportion of asthmatics remain poorly controlled in real life. The involvement of peripheral small airways has recently gained greater recognition in asthma, and many studies suggest that the persistent inflammation at these sites leads to small airway dysfunction (SAD), strongly contributing to a worse asthma control. Overall, the impulse oscillometry (IOS), introduced in the recent years, seems to be able to sensitively assess small airways, while conventional spirometry does not. Therefore, IOS may be of great help in characterizing SAD and guiding therapy choice. The aim of this article is to review the literature on SAD and its influence on asthma control, emphasizing the most recent evidence.

Obesity is a Major Risk Factor for Hospitalization in Community-Managed COVID-19 Pneumonia.

OBJECTIVE: We aimed to investigate whether the stratification of outpatients with coronavirus disease 2019 (COVID-19) pneumonia by body mass index (BMI) can help predict hospitalization and other severe outcomes. PATIENTS AND METHODS: We prospectively collected consecutive cases of community-managed COVID-19 pneumonia from March 1 to April 20, 2020, in the province of Bergamo and evaluated the association of overweight (25 kg/m2 ≤ BMI <30 kg/m2) and obesity (≥30 kg/m2) with time to hospitalization (primary end point), low-flow domiciliary oxygen need, noninvasive mechanical ventilation, intubation, and death due to COVID-19 (secondary end points) in this cohort. We analyzed the primary end point using multivariable Cox models. RESULTS: Of 338 patients included, 133 (39.4%) were overweight and 77 (22.8%) were obese. Age at diagnosis was younger in obese patients compared with those overweight or with normal weight (P<.001), whereas diabetes, dyslipidemia, and heart diseases were differently distributed among BMI categories. Azithromycin, hydroxychloroquine, and prednisolone use were similar between BMI categories (P>.05). Overall, 105 (31.1%) patients were hospitalized, and time to hospitalization was significantly shorter for obese vs over- or normal-weight patients (P<.001). In the final multivariable analysis, obese patients were more likely to require hospitalization than nonobese patients (hazard ratio, 5.83; 95% CI, 3.91 to 8.71). Results were similar in multiple sensitivity analyses. Low-flow domiciliary oxygen need, hospitalization with noninvasive mechanical ventilation, intubation, and death were significantly associated with obesity (P<.001). CONCLUSION: In patients with community-managed COVID-19 pneumonia, obesity is associated with a higher hospitalization risk and overall worse outcomes than for nonobese patients.

Small-airway dysfunction in paediatric asthma.

PURPOSE OF REVIEW: Asthma is a chronic inflammatory airway disorder that can involve the entire bronchial tree. Increasing evidence shows that ventilation heterogeneity and small airway dysfunction are relevant factors in the pathogenesis of asthma and represent a hallmark in adults with persistent asthma. Little is known about the contribution of peripheral airway impairment in paediatric asthma, mainly due to the inaccessibility to evaluation by noninvasive techniques, which have only been widely available in recent years. RECENT FINDINGS: Emerging evidence suggests that small airways are affected from the early stages of the disease in childhood-onset asthma. Conventional lung function measurement, using spirometry, is unable to sensitively evaluate small airway function and may become abnormal only once there is a significant burden of disease. Recent studies suggest that chronic inflammation and dysfunction in the small airways, as detected with new advanced techniques, are risk factors for asthma persistence, asthma severity, worse asthma control and loss of pulmonary function with age, both in adults and children. Knowing the extent of central and peripheral airway involvement is clinically relevant to achieve asthma control, reduce bronchial hyper-responsiveness and monitor response to asthma treatment. SUMMARY: This review outlines the recent evidence on the role of small airway dysfunction in paediatric asthma development and control, and addresses how the use of new diagnostic techniques available in outpatient clinical settings, namely impulse oscillometry and multiple breath washout, could help in the early detection of small airway impairment in children with preschool wheezing and school-age asthma and potentially guide asthma treatment.

Prevalence and features of IOS-defined small airway disease across asthma severities.

BACKGROUND: Impulse oscillometry (IOS) is a noninvasive method based on the forced oscillation technique able to detect small airway dysfunction (SAD) in asthma. We aimed to analyze the prevalence and the functional features of IOS-defined SAD across the different Global Initiative for Asthma (GINA) steps. METHODS: A cross-sectional, single-center study in which 400 consecutive adult patients with physician-diagnosed, community-managed asthma underwent standard spirometry and IOS, and were stratified by stepwise GINA classification. SAD was defined by IOS as a fall in resistance from 5 to 20 Hz [R5-R20]>0.07kPa × s × L-1. RESULTS: The prevalence of IOS-defined SAD ranged between 58.3% (GINA step 2) and 78.6% (GINA step 5), without statistically significant difference within GINA steps (p > 0.05 in all comparisons). Isolated SAD (i.e. without proximal airways involvement) was similarly represented across GINA steps 2-4. Peripheral airways resistance (R5-R20) tended to a progressive increase with the worsening of GINA steps, and was significantly higher in steps 4-5 compared to the other steps (p < 0.05). The proportion of patients with FEF25-75%-defined SAD (<60%) was lower than the IOS-defined one in GINA steps 2-4 (p < 0.05). Only non-significant or weak inverse correlations between R5-R20 and FEF25-75% were observed within each GINA step, with the exception of GINA step 5, which showed a strong, inverse correlation (r = -0.80, p = 0.0005). CONCLUSIONS: This study shows that first, IOS-defined SAD is overwhelmingly present across asthma severities; second, airways resistance increases with the worsening of GINA steps; and third, SAD may be overlooked by standard spirometry, especially in milder asthma.

Clinical Characterization and Predictors of IOS-Defined Small-Airway Dysfunction in Asthma.

BACKGROUND: The involvement of small airways has recently gained greater recognition in asthma. Impulse oscillometry (IOS) is a simple and noninvasive method based on the forced oscillation technique, for the detection of small-airway dysfunction (SAD). OBJECTIVE: To identify the predictors of SAD in an unselected sample of 400 patients with physician-diagnosed asthma. METHODS: All patients underwent standard spirometry and IOS at the first visit, and were stratified by the presence of SAD defined by IOS (fall in resistance from 5 to 20 Hz [R5-R20] > 0.07 kPa × s × L-1). Univariable and multivariable analyses and classification tree method were used to analyze cross-sectional relationships between clinical variables and outcome (SAD). RESULTS: SAD was present in 62% of the cohort. Subjects with SAD showed a less well-controlled asthma, according to the Global Initiative for Asthma definition, and a higher mean inhaled corticosteroid dosage use compared with subjects without SAD (both P < .001). Increased fractional exhaled nitric oxide (odds ratio [OR], 2.05; 95% CI, 1.14-3.70), female sex (OR, 2.27; 95% CI, 1.29-4.06), smoking (OR, 3.06; 95% CI, 1.60-6.05), older age (OR, 3.08; 95% CI, 1.77-5.49), asthma-related night awakenings (OR, 3.34; 95% CI, 1.85-6.17), overweight (OR, 3.64; 95% CI, 1.99-6.85), and exercise-induced asthma symptoms (OR, 6.39; 95% CI 3.65-11.45) were independent predictors of SAD. Classification tree analysis confirmed that exercise-induced asthma, overweight, asthma-related night awakenings, smoking, and older age have potential for clinical use in distinguishing patients with SAD from those without it. CONCLUSIONS: We identified predictors of SAD and showed that especially exercise-induced asthma, overweight, asthma-related night awakenings, smoking, and older age were strongly associated with SAD.

Small airway dysfunction and bronchial asthma control : the state of the art.

According to national and international guidelines, achieving and maintaining asthma control is a major goal of disease management. In closely controlled clinical trials, good asthma control can be achieved , with the medical treatments currently available, in the majority of patients , but large population-based studies suggest that a significant proportion of patients in real-life setting experience suboptimal levels of asthma control and report lifestyle limitations with a considerable burden on quality of life. Poor treatment adherence and persistence, failure to use inhalers correctly, heterogeneity of asthma phenotypes and associated co-morbidities are the main contributing factors to poor disease control. Now, it is widely accepted that peripheral airway dysfunction , already present in patients with mild asthma, is a key contributor of worse control. The aim of this paper is to investigate the association between small-airways dysfunction and asthma symptoms/control. We therefore performed a PubMed search using keywords : small airways; asthma (limits applied: Humans, English language) and selected papers with a study population of asthmatic patients, reporting measurement of small-airways parameters and clinical symptoms/control.