Small Airways Disease In Asthma Research Articles

Silent zone detection in asthma and its relation to T2 inflammation

Abstract Objective Study objectives are to detect small airways disease in asthma and to study T2 inflammatory markers (eosinophil count, IgE, phenotyping) in association with small airways disease. Methods and patients The retrospective study at OPC at Al Qassimi Hospital of EHS included 83 patients with confirmed asthma diagnosis. Based on their ACT scores, patients were divided into two groups. An assessment of demographic data, blood eosinophils, fractional exhaled nitric oxide, IgE, PFE25-75, FEV1%, R5-20, X5 and AX was carried out. Analyzing and collecting data. Results In this study, a significant correlation was found between the R5-20, X5, and AX values of the small airway and the asthma control test. Uncontrolled asthmatics had a higher fractional exhaled nitric oxide level and blood eosinophilic count. Conclusion In asthma management, small airways clinical impact should be investigated actively. Impulse oscillometry is an excellent marker for asthma control.

Small airways in asthma: Pathophysiology, identification and management.

The aim of this review is to summarize the current evidence regarding small airway disease in asthma, focusing on recent advances in small airway pathophysiology, assessment and therapeutic implications. A search in Medline was performed, using the keywords "small airways", "asthma", "oscillometry", "nitrogen washout" and "imaging". Our review was based on studies from adult asthmatic patients, although evidence from pediatric populations is also discussed. In asthma, inflammation in small airways, increased mucus production and airway wall remodelling are the main pathogenetic mechanisms of small airway disease. Small airway dysfunction is a key component of asthma pathophysiology, leading to increased small airway resistance and airway closure, with subsequent ventilation inhomogeneities, hyperresponsiveness and airflow limitation. Classic tests of lung function, such as spirometry and body plethysmography are insensitive to detect small airway disease, providing only indirect measurements. As discussed in our review, both functional and imaging techniques that are more specific for small airways, such as oscillometry and the multiple breath nitrogen washout have delineated the role of small airways in asthma. Small airways disease is prevalent across all asthma disease stages and especially in severe disease, correlating with important clinical outcomes, such as asthma control and exacerbation frequency. Moreover, markers of small airways dysfunction have been used to guide asthma treatment and monitor response to therapy. Assessment of small airway disease provides unique information for asthma diagnosis and monitoring, with potential therapeutic implications.

The role of small airway dysfunction in asthma control and exacerbations: a longitudinal, observational analysis using data from the ATLANTIS study

Although small airway disease is a feature of asthma, its association with relevant asthma outcomes remains unclear. The ATLANTIS study was designed to identify the combination of physiological and imaging variables that best measure the presence and extent of small airway disease in asthma, both cross-sectionally and longitudinally. In this longitudinal analysis, we evaluated which small airway parameters studied were most strongly associated with asthma control, exacerbations, and quality of life. In this observational cohort study, participants with mild, moderate, or severe stable asthma were recruited between June 30, 2014, and March 3, 2017, via medical databases and advertisements in nine countries worldwide. Eligible participants were aged 18-65 years with a clinical asthma diagnosis for at least 6 months. Participants were followed up for 1 year, with visits at baseline, 6 months, and 12 months. Physiological tests included spirometry, lung volumes, impulse oscillometry, multiple breath nitrogen washout (MBNW), and percentage decrease in forced vital capacity during methacholine challenge. CT densitometry was performed to evaluate small airway disease. We examined the associations between these measurements and asthma exacerbations, asthma control, and quality of life using univariate and multivariate analyses. A composite ordinal score comprising percent predicted R5-20 (resistance of small-to-mid-sized airways), AX (area of reactance), and X5 (reactance of more central, conducting small airways at 5 Hz) was constructed. 773 participants (median age 46 years [IQR 34-54]; 450 [58%] female) were included in this longitudinal study. Univariate analyses showed that components of impulse oscillometry, lung volumes, MBNW, and forced expiratory flow at 25-75% of FVC were significantly correlated with asthma control and exacerbations (Spearman correlations 0·20-0·25, p<0·0001 after Bonferroni correction). As a composite of impulse oscillometry, the ordinal score independently predicted asthma control and exacerbations in a multivariate analysis with known exacerbation predictors. CT parameters were not significantly correlated with asthma control, exacerbation, or quality of life. Small airway disease, as measured by physiological tests, is longitudinally associated with clinically important asthma outcomes, such as asthma control and exacerbations. Chiesi Farmaceutici.

Small Airway Dysfunction Predicts Asthma Control and Exacerbations : Longitudinal Data from the Assessment of Small Airways Involvement in Asthma (ATLANTIS) Study

Rationale: Although small airway disease (SAD) is a feature of asthma, the association between SAD and relevant asthma outcomes remains unclear. The Assessment of Small Airways Involvement in Asthma (ATLANTIS) study was designed to identify the combination of physiological and imaging variables that best measure the presence and extent of SAD in asthma cross-sectionally and longitudinally. In this longitudinal analysis, we determined which small airway parameters studied were most strongly associated with asthma control, exacerbations, and quality of life. Methods: Total 773 participants with mild, moderate, or severe stable asthma were followed up for one year with a six-month clinic follow-up. Physiological tests included spirometry, lung volumes, impulse oscillometry (IOS), multiple breath nitrogen washout (MBNW), and percentage fall in forced vital capacity during methacholine challenge. Computed tomography was performed to determine CT densitometry of small airways disease. We examined the associations between these measurements and asthma exacerbations, control, and quality of life using univariate and multivariate analyses. Findings: Univariate analyses revealed that components of IOS, lung volumes, MBNW, and FEF25-75 were significantly correlated with asthma control and exacerbations (Spearman correlations: 0·20–0·25, p < 0·0001 Bonferroni correction). As a composite of IOS s, the ordinal score independently predicted asthma control and exacerbation in a multivariate analysis with known exacerbation predictors. CT parameters were not significantly correlated with asthma control, exacerbation, or quality of life. Interpretation: The results confirm that SAD, as measured by physiological tests, is longitudinally associated with clinically important asthma outcomes, such as asthma control and exacerbations. Funding: Chiesi Farmaceutici Declaration of Interest: MK reports grants paid to their institution for their research from National Institutes of Health, American Lung Association, Chiesi Farmaceutici (for support of this study), AstraZeneca and Sanofi-Regeneron; reports personal fees for consultancies from Chiesi Farmaceutici, Genentech (Roche), GSK, Sanofi Regeneron, and Astra-Zeneca, Speaker fees from Chiesi Farmaceutici; personal fees from participation in a data safety and monitoring board for Astra-Zeneca and ALung and leadership in the American Thoracic Society; MR has nothing to report; BH has nothing to report; DB has nothing to report; MVB receives grants paid to their institution from Chiesi Farmaceutici (for this study), Sanofi, Genentech, GSK and Roche; LMF reported personal fees for consultancies from Chiesi Farmaceutici; Speaker fees from participation in advisory boards for Chiesi Farmaceutici, Astra-Zeneca, GSK, Alfasigma, Novartis and Verona Pharma; Travel expense reimbursement from Chiesi Farmaceutici, Novartis and Menarini; personal fees from participation in a data safety and monitoring board for Novartis; GN reports being employed by Chiesi Farmaceutici; AP reports funding by Chiesi Farmaceutici (for this and other studies), AstraZeneca, GSK, Boehringer Ingelheim, Pfizer, Teva and Sanofi paid to their institution; reports personal fees for consulting from Chiesi Farmaceutici, AstraZeneca, GSK, Novartis, Sanofi, Iqvia, Avillion, Elpen Pharmaceutic, ALS; reports personal fees for lectures and presentations from Chiesi Farmaceutici, AstraZeneca, GSK, Boehringer Ingelheim, Menarini, Novartis, Zambon, Mundipharma, Teva, Sanofi, Edmond Pharma, Iqvia, MSD, Avillion, Elpen Pharmaceutic, ALS. KFR reported support from Chiesi Farmaceutici paid to their institution for this study; reports speaker fees from Astra-Zeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Novartis, Sanofi & Regeneron, GlaxoSmithKline, Berlin Chemie and Roche Pharma; personal fees from participation in a data safety and monitoring board for Astra- Zeneca, Boehringer Ingelheim and Sanofi & Regeneron; reports leadership or fiduciary role for German Center for Lung Research, German Chest Society and American Thoracic Society; DS reports personal fees for consulting from Aerogen, Astra-Zeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Cipla, CSL Behring, Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Teva, Theravance, Verona; CB reports paid to their institution from Chiesi Farmaceutici for this study, NIHR Biomedical Research Centre, grants paid to their institution GSK, AZ, BI, Novartis, Chiesi Farmaceutici, Sanofi, Genetech, Merck, Mologic, 4DPharma, Gossamer, personal fees for consulting from GSK, AZ, BI, Novartis, Chiesi Farmaceutici, Sanofi, Genentech, Merck, Mologic, 4DPharma, Gossamer, TEVA, Regeneron, Roche, CSL Behring; SS reports funding paid to their institution from Chiesi Farmaceutici for support of this study, personal fees from GSK, Novartis, ERT Medical, Astra Zeneca, Knopp Biotech, Owlstone Medical, Mundipharma, CSL Behring, Boehringer Ingelheim; reports personal fees for lectures from Chiesi Farmaceutici. Ethical Approval: The Medical Ethics Committee of each centre approved the protocol.

Impulse oscillometry usefulness in small-airway dysfunction in asthmatics and its utility in asthma control

BackgroundSmall-airway affection and its relation to clinical status in asthmatic patients became an increasing interest during the last decade. Spirometry is a basic diagnostic tool for measuring pulmonary function in asthmatics but not fully illustrative especially in assessing small airways. Impulse oscillometry (IOS) can be considered a complementary and sometimes alternative technique to spirometry because it is used during quiet breathing and so gives more data about small-airways affection in asthmatic patients.AimTo evaluate IOS usefulness in the detection of small-airways disease in asthma and its correlation to the level of disease control.Patients and methodsThe study was conducted on 44 asthmatic patients who were classified into two groups: controlled asthma and uncontrolled asthma by asthma control test questionnaire (ACT score). Spirometry and IOS were performed on all patients.ResultsSmall-airway IOS values (R5–20, X5, and AX) were found to be statistically significant between two groups. Moreover, they strongly correlated significantly with clinical symptoms, assessed by ACT. There was high sensitivity and specificity of (R5–20) 80 and 82%, (X5) 80 and 86%, and (AX) 86 and 89%, while for spirometric data only forced expiratory flow (FEF25–75%) showed a statistically significant difference between the two groups, and not FEV1% and there was poor correlation between ACT and FEF25–75%.ConclusionIOS provides an easy and rapid tool to diagnose and assess small-airways disease in adult, asthmatic patients

Modelling resistance and reactance with heterogeneous airway narrowing in mild to severe asthma.

Ventilation heterogeneity is an important marker of small airway dysfunction in asthma. The frequency dependence of respiratory system resistance (Rrs) from oscillometry is used as a measure of this heterogeneity. However, this has not been quantitatively assessed or compared with other outcomes from oscillometry, including respiratory system reactance (Xrs) and the associated elastance (Ers). Here, we used a multibranch model of the human lung, including an upper airway shunt, to match previously reported respiratory mechanics in mild to severe asthma. We imposed heterogeneity by narrowing a proportion of the peripheral airways to account for patient Ers at 5 Hz, and then narrowed central airways to account for the remaining Rrs at 18 Hz. The model required >75% of the small airways to be occluded to reproduce severe asthma. While the model produced frequency dependence in Rrs, it was upward-shifted below 5 Hz compared with in-vivo results, indicating that other factors, including more distributed airway narrowing or central airway wall compliance, are required. However, Ers quantitatively reflected the imposed heterogeneity better than the frequency dependence of Rrs, independent of the frequency range for the estimation, and thus was a more robust measure of small-airway function. Thus, Ers appears to have greater potential as a clinical measure of early small-airway disease in asthma.

Small-airway disease in asthma: pharmacological considerations.

To review the pharmacological considerations and rationale for treating small-airway disease in asthma via the inhaled and systemic route, and to also directly address the comparison between small vs. large aerosol particles in the management of asthmatic patients. Airway inflammation in patients with asthma is predominantly present within the small airways and this region is the main contributor to airflow limitation. Assessing small-airway dysfunction has advanced in the last decade, allowing us to compare this region in disease to health and also in response to treatment. Recent pharmaceutical developments have led to inhaler devices with smaller aerosols and systemic biologic treatments, enabling therapeutic drug delivery to the distal lung regions. The question therefore is does targeting the small airways directly translate into health benefits for asthmatic patients with respect to an improvement in their disease control and quality of life? Studies now show that treating the peripheral airways with smaller drug particle aerosols certainly achieve comparable efficacy (and some studies show superiority) compared with large particles, a reduction in the daily inhaled corticosteroid dose, and greater asthma control and quality of life in real-life studies. Hence, the small airways should not be neglected when choosing the optimal asthma therapy.

Small airway disease in asthma: a new target for better asthma control?

Small airway disease in asthma: a new target for better asthma control?

Small airway disease in asthma: pathophysiological and diagnostic considerations.

The aim of the current review is to summarize the evidence of small airway abnormalities in asthma, the proposed diagnostic tools for small airway abnormalities and the clinical implications of small airway abnormalities in asthma. Pathological abnormalities in the peripheral membranous bronchioles less than 2 mm in diameter (i.e. small airways) can be very frequently detected in asthma patients across severity: from mild to the more severe clinical manifestations of the disease. Interestingly, not only are small airway abnormalities present in asthma, but there is evidence that the magnitude of small airway abnormalities correlates with the severity of the disease. So far no unanimously accepted method and/or algorithm is available for small airway abnormality detection; however, some functional techniques and inflammatory markers have been used as surrogates of small airway dysfunction. Clinicians, and not only researchers, must consider small airways when approaching asthma patients, particularly when dealing with patients with a 'difficult-to-treat phenotype'. The identification of subgroups of asthma patients with prominent small airway disease is not merely speculative, and carries pathophysiological and therapeutic implications.

Clinical application of inert gas Multiple Breath Washout in children and adolescents with asthma

Children with asthma often have normal spirometry despite significant disease. The pathology of the small airways in asthma may be assessed using Multiple Breath Washout (MBW) and calculating the Lung Clearance Index (LCI). There are only few studies using MBW in children with asthma and existing data regarding bronchodilator effect are contradictory. The aim of the present pilot study was to compare LCI in asthma and controls and assess the effect of salbutamol in children with asthma on the LCI. Unselected patients with a diagnosis of asthma visiting the outpatient department of our hospital between 04-2010 and 03-2011 were recruited and compared to a healthy control group. MBW was performed as inert gas MBW using sulfurhexafluorid (SF6) as the tracer gas. Clinical data were documented and spirometry and MBW (EasyOne Pro, MBW module, NDD Switzerland) were performed before and after the use of salbutamol (200-400μg). Healthy controls performed baseline MBW only. 32 children diagnosed with asthma (4.7-17.4 years) and 42 controls (5.3-20.8) were included in the analysis. LCI differed between patients and controls, with a mean LCI (SD) of 6.48 (0.48) and 6.21 (0.38) (P=0.008). Use of salbutamol had no significant effect on LCI for the group. These pilot data show that clinically stable asthma patients and controls both have a LCI in the normal range. However, in patients the LCI is significantly higher indicating that MBW may have a role in assessing small airways disease in asthma.

The role of small airway disease in asthma

This review provides an update on the importance of the peripheral 'small' airways in asthma. As the small airways account for less than 10% of total airway resistance, thus having little impact on standard lung function measures such as forced expiratory volume and peak flow, they have been referred to as the 'silent zone'. The study has revealed that small airway involvement is present in all stages of asthmatic disease, being related to important clinical phenotypes such as nocturnal asthma, exercise-induced asthma, and difficult-to-control asthma, including those with the risk of repeated asthma exacerbations. Uncontrolled small airway inflammation is related to airway remodeling and progression of the disease, with a more rapid decline in the lung function. Moreover, studies on both children and adults have shown that the involvement of the small airways represents a crucial step in asthma development. New tools have been developed and old tools have been refined, providing an opportunity to better understand small airway inflammation and dysfunction. Small airway inflammation is present in all stages of asthmatic disease and plays an important role in many key clinical conditions/phenotypes. In order to control the disease, we need to target small airway inflammation, which is not only difficult to reach by standard inhaled medications but also to some extent different. A better understanding of the important role small airways are playing in asthma will show that the 'silent zone' is by far not silent at all.

Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: A systematic review

Traditionally, asthma has been considered a disease that predominantly involves the large airways. Today, this concept is being challenged, and increasing evidence has become available showing that abnormalities in the small airways also contribute to the clinical expression of asthma. The small airways can be affected by inflammation, remodeling, and changes in the surrounding tissue, all contributing to small-airways dysfunction. In this article we have performed a systematic review of the literature on the association between small-airways dysfunction and clinical signs and symptoms of asthma. This review shows that small-airways dysfunction associates with worse control of asthma, higher numbers of exacerbations, the presence of nocturnal asthma, more severe bronchial hyperresponsiveness, exercise-induced asthma, and the late-phase allergic response. Importantly, small-airways dysfunction can already be present in patients with mild asthma. Our review provides suggestive evidence that a better response of the small airways to inhaled steroids or montelukast associates with better asthma control. For this reason, an early recognition of small-airways dysfunction is important because it enables the physician to start timely treatment to target the small airways. It is important to develop simpler and more reliable tools (eg, questionnaires or bronchial provocation tests with small-particle stimuli) to assess the presence and extent of small-airways dysfunction in daily clinical practice.

WAO-1 The assessment and importance of small airway disease in asthma

WAO-1 The assessment and importance of small airway disease in asthma

Small airways disease in asthma: a review

Small airways disease in asthma: a review

P78 Lung clearance index in children with acute exacerbation of asthma

IntroductionLung clearance index (LCI) can detect small airways disease in asthma; however there is no published LCI data collected during acute exacerbation. We aimed to investigate LCI in asthmatic children...

Assessing and treating small airways disease in asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory disorders of the respiratory tract that are characterized by airflow limitation. They are distinct conditions with different causes, structural changes, and immunopathology. The pathophysiology in asthma and COPD involves not only the proximal large airways, but also the distal small airways, and thus the small airways are an important therapeutic target in the treatment of both diseases. The assessment of diseased distal small airways is challenging. Extensive disease can be present in the small airways with little abnormality in conventional pulmonary function tests. Recent advances in imaging technologies have led to better spatial resolution to assess small airways morphology non-invasively. New physiological tests have been developed to detect disease and response to therapy in regional airways. Improving the efficiency of existing aerosolized therapy to direct drug to the appropriate lung regions may improve clinical efficacy. Approaches to target distal lung regions include developing new drug formulations with smaller aerosol particle size or using inhaler devices that emit aerosolized drug at slow inhalation flows. Large studies are needed to determine whether better distal lung deposition leads to improvements in small airways function that are translated into clinically significant patient outcomes.

Small airway disease in asthma: a need for awareness in patients and doctors

Small airway disease in asthma: a need for awareness in patients and doctors

Small Airway Disease in Asthma and COPD: Clinical Implications

Asthma and COPD have a high personal, societal, and economic impact. Both diseases are characterized by airway obstruction and an inflammatory process. The inflammatory process affects the whole respiratory tract, from central to peripheral airways that are <2 mm in internal diameter, the so-called small airways. There is an increased interest in small airway disease, and some new insights have been gained about the contribution of these small airways to the clinical expression of asthma and COPD, as reviewed in this article. Newly developed devices enable drugs to target the small airways, and this may have implications for treatment of patients with asthma, particularly those not responding to large-particle inhaled corticosteroids or those with uncontrollable asthma. The first studies in COPD are promising, and results from new studies are eagerly awaited.

P123 Impulse oscillometry (IOS) indices in severe asthma and healthy controls after deep breath manoeuvres and bronchodilator administration

IntroductionImpulse oscillometry is a non-invasive method used to measure airway impedance. There is increasing interest in utilising frequency dependence of airway resistance/reactance to study small airways disease in asthma. We...

Small airways disease in asthma

A mounting body of physiologic and pathologic evidence indicates that asthma involves the central and the more distal airways. In patients with asthma, the peripheral lung accounts for a significant portion of airway resistance and, similar to the large airways, the small airways have been shown to be hyperresponsive to nonspecific stimuli, such as methacholine. Cellular inflammation, consisting of an infiltrate rich with lymphocytes and eosinophils, is present in the small airways of patients with asthma and may be more intense than that observed in the large airways. Clinical assessment of the peripheral airways continues to be a challenge, and new techniques, such as quantitative analysis of chest CT images, have proven to be useful research tools. The recognition of small airways involvement in asthma has clinical relevance, as new formulations of inhaled corticosteroids with smaller particle aerosols may be more effective in addressing this component of asthma.