Small Airway Involvement In Asthma Research Articles

Sex differences in asthma control, lung function and exacerbations: the ATLANTIS study

BackgroundAsthma is a heterogeneous disease with a prevalence and severity that differs between male and female patients.QuestionWhat are differences between male and female patients with asthma with regard to asthma...

Development of a tool to detect small airways dysfunction in asthma clinical practice.

Small airways dysfunction (SAD) in asthma is difficult to measure and a gold standard is lacking. The aim of this study was to develop a simple tool including items of the Small Airways Dysfunction Tool (SADT) questionnaire, basic patient characteristics and respiratory tests available depending on the clinical setting to predict SAD in asthma. This study was based on the data of the multinational ATLANTIS (Assessment of Small Airways Involvement in Asthma) study including the earlier developed SADT questionnaire. Key SADT items together with clinical information were now used to build logistic regression models to predict SAD group (less likely or more likely to have SAD). Diagnostic ability of the models was expressed as area under the receiver operating characteristic curve (AUC) and positive likelihood ratio (LR+). SADT item 8, "I sometimes wheeze when I am sitting or lying quietly", and the patient characteristics age, age at asthma diagnosis and body mass index could reasonably well detect SAD (AUC 0.74, LR+ 2.3). The diagnostic ability increased by adding spirometry (percentage predicted forced expiratory volume in 1 s: AUC 0.87, LR+ 5.0) and oscillometry (resistance difference between 5 and 20 Hz and reactance area: AUC 0.96, LR+ 12.8). If access to respiratory tests is limited (e.g. primary care in many countries), patients with SAD could reasonably well be identified by asking about wheezing at rest and a few patient characteristics. In (advanced) hospital settings patients with SAD could be identified with considerably higher accuracy using spirometry and oscillometry.

Small airways in asthma: from bench-to-bedside.

Historically, asthma was considered a disease predominantly of the large airways, but gradually small airways have been recognized as the major site of airflow obstruction. Small airway dysfunction (SAD) significantly contributes to the pathophysiology of asthma, and it is present across all asthma severities. Promising preclinical findings documented enhanced beneficial effects of combination therapies on small airways compared to monocomponents, thus it was questioned whether this could translate into further clinical implications from bench-to-bedside. The aim of this review was to systematically assess the state of the art of small airway involvement in asthma, especially in response to different pharmacological treatments acting on the respiratory system. A comprehensive literature search was performed in MEDLINE for randomized controlled trials (RCTs) characterizing the impact on small airways of different pharmacological treatments acting on the respiratory system. The results were extracted and reported via qualitative synthesis. Overall, 63 studies were identified from the literature search, whereas 23 RCTs met the inclusion criteria. Evidence confirms that both drug particle size and the type of inhalation devices represent two of the most important variables for an effective peripheral lung distribution. Despite the numerous methodological tools to detect SAD, there is still no gold standard diagnostic method to assess small airways, especially in severe asthma. Further research should be directed to improve primary and secondary prevention strategies by supporting the combined approach of different non-invasive techniques for an early detection of peripheral abnormalities and optimization of asthma therapy.

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.

Recent Advances in Inflammation and Treatment of Small Airways in Asthma.

Small airways were historically considered to be almost irrelevant in the development and control of pulmonary chronic diseases but, as a matter of fact, in the past few years we have learned that they are not so “silent”. Asthma is still a worldwide health issue due to the great share of patients being far from optimal management. Several studies have shown that the deeper lung inflammation plays a critical role in asthma pathogenesis, mostly in these not well-controlled subjects. Therefore, assessing the degree of small airways inflammation and impairment appears to be a pivotal step in the asthmatic patient’s management. It is now possible to evaluate them through direct and indirect measurements, even if some obstacles still affect their clinical application. The success of any treatment obviously depends on several factors but reaching the deeper lung has become a priority and, for inhaled drugs, this is strictly connected to the molecule’s size. The aim of the present review is to summarize the recent evidence concerning the small airway involvement in asthma, its physiopathological characteristics and how it can be evaluated in order to undertake a personalized pharmacological treatment and achieve a better disease control.

Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study

Small airways dysfunction (SAD) is well recognised in asthma, yet its role in the severity and control of asthma is unclear. This study aimed to assess which combination of biomarkers, physiological tests, and imaging markers best measure the presence and extent of SAD in patients with asthma. In this baseline assessment of a multinational prospective cohort study (the Assessment of Small Airways Involvement in Asthma [ATLANTIS] study), we recruited participants with and without asthma (defined as Global Initiative for Asthma severity stages 1-5) from general practices, the databases of chest physicians, and advertisements at 29 centres across nine countries (Brazil, China, Germany, Italy, Spain, the Netherlands, the UK, the USA, and Canada). All participants were aged 18-65 years, and participants with asthma had received a clinical diagnosis of asthma more than 6 months ago that had been confirmed by a chest physician. This diagnosis required support by objective evidence at baseline or during the past 5 years, which could be: positive airway hyperresponsiveness to methacholine, positive reversibility (a change in FEV1 ≥12% and ≥200 mL within 30 min) after treatment with 400 μg of salbutamol in a metered-dose inhaler with or without a spacer, variability in peak expiratory flow of more than 20% (measured over 7 days), or documented reversibility after a cycle (eg, 4 weeks) of maintenance anti-asthma treatment. The inclusion criteria also required that patients had stable asthma on any previous regular asthma treatment (including so-called rescue β2-agonists alone) at a stable dose for more than 8 weeks before baseline and had smoked for a maximum of 10 pack-years in their lifetime. Control group participants were recruited by advertisements; these participants were aged 18-65 years, had no respiratory symptoms compatible with asthma or chronic obstructive pulmonary disease, normal spirometry, and normal airways responsiveness, and had smoked for a maximum of 10 pack-years. We assessed all participants with spirometry, body plethysmography, impulse oscillometry, multiple breath nitrogen washout, CT (in selected participants), and questionnaires about asthma control, asthma-related quality of life (both in participants with asthma only), and health status. We applied structural equation modelling in participants with asthma to assess the contribution of all physiological and CT variables to SAD, from which we defined clinical SAD and CT SAD scores. We then classified patients with asthma into SAD groups with model-based clustering, and we compared asthma severity, control, and health-care use during the past year by SAD score and by SAD group. This trial is registered with ClinicalTrials.gov, number NCT02123667. Between June 30, 2014, and March 3, 2017, we recruited and evaluated 773 participants with asthma and 99 control participants. All physiological measures contributed to the clinical SAD model with the structural equation modelling analysis. The prevalence of SAD in asthma was dependent on the measure used; we found the lowest prevalence of SAD associated with acinar airway ventilation heterogeneity (Sacin), an outcome determined by multiple breath nitrogen washout that reflects ventilation heterogeneity in the most peripheral, pre-acinar or acinar airways. Impulse oscillometry and spirometry results, which were used to assess dysfunction of small-sized to mid-sized airways, contributed most to the clinical SAD score and differed between the two SAD groups. Participants in clinical SAD group 1 (n=452) had milder SAD than group 2 and comparable multiple breath nitrogen washout Sacin to control participants. Participants in clinical SAD group 2 (n=312) had abnormal physiological SAD results relative to group 1, particularly their impulse oscillometry and spirometry measurements, and group 2 participants also had more severe asthma (with regard to asthma control, treatments, exacerbations, and quality of life) than group 1. Clinical SAD scores were higher (indicating more severe SAD) in group 2 than group 1, and we found that these scores were related to asthma control, severity, and exacerbations. We found no correlation between clinical SAD and CT SAD scores. SAD is a complex and silent signature of asthma that is likely to be directly or indirectly captured by combinations of physiological tests, such as spirometry, body plethysmography, impulse oscillometry, and multiple breath nitrogen washout. SAD is present across patients with all severities of asthma, but it is particularly prevalent in severe disease. The clinical classification of SAD into two groups (a milder and a more severe group) by use of impulse oscillometry and spirometry, which are easy to use, is meaningful given its association with GINA severity stages, asthma control, quality of life, and exacerbations. Chiesi Farmaceutici SpA.

Recognition of Small Airways Obstruction in Asthma and COPD - The Road Less Travelled.

The small airways, once regarded as the silent zone in the air conducting system of the lungs are now known to be one of the initial sites of involvement in diseases like asthma and Chronic Obstructive Pulmonary Disease (COPD). Identification of the involvement of distal airways in these diseases is often difficult to assess, clinically as well as by conventional pulmonary function tests and therefore, usually remains undiscovered in early stages. Early recognition of their involvement in asthma and COPD and timely management may reduce long term morbidity in these conditions. This article aims to highlight the relatively lesser recognized facts about small airways involvement in asthma and COPD and role of imaging and newer modalities for detection.

Treatment of small airways involvement in asthma: clinical results

Treatment of small airways involvement in asthma: clinical results

Treatment of small airways involvement in asthma

Treatment of small airways involvement in asthma

Appraising the small airways in asthma

The small airways play an important yet poorly targeted role in asthma pathophysiology, leading to increased morbidity in asthma patients. Assessing inflammation and remodeling in these airways, determining the contribution of small airways to lung dysfunction and enhancing drug delivery to the distal regions of the lung remain challenging. The purpose of this review is to highlight recent advances in our understanding of small airways involvement in asthma. Inflammation in the small airways can be evaluated through exhaled gas measurements, most often nitric oxide. However, additional exhaled biomarkers have recently been described. Considerable infiltration of mast cells in the distal lung and extensive structural changes to the small airways have also been demonstrated. Advances have been made in the functional assessment of small airways, particularly in the measurement of small airway compliance and ventilation defects and in studies investigating the impact of small particle inhaled corticosteroid treatment on lung function. Experimental assessments of small airways inflammation, remodeling and function have provided novel insights into the importance of the distal regions of the lung in asthma pathology. Further advances in drug delivery to the small airways have the potential to improve asthma control.

The role of small airways in obstructive airway diseases.

This review article is a summary of a seminar organised by the European Respiratory Society on "The role of small airways in obstructive airway diseases" which was held in October 2010 in Amsterdam, the Netherlands. The aims of the seminar were to identify important questions related to small airways involvement in asthma and chronic obstructive pulmonary disease (COPD), and to discuss future approaches based on current and evolving knowledge. Data obtained by pathological and physiological measurements in small airways and their relevance to clinical manifestations and therapeutics in asthma and COPD were reviewed. It was concluded that our knowledge on the roles of small airways in asthma and COPD is limited. Studies of large numbers of well-characterised subjects using multiple methods (genetic characterisation, cell biology and physiology, imaging) and integration of the data using mathematical models are suggested to be of interest. The availability of these techniques coupled with our ability to better target inhaled molecules to small airways provide a unique opportunity for a reappraisal of the relevance of small airways in chronic airway diseases.

Particle size matters: diagnostics and treatment of small airways involvement in asthma

Small airways are an important site of inflammation and obstruction in asthma, which contributes to the severity of airway hyperresponsiveness (AHR) that is usually measured by nebulisation of large-particle stimuli. We investigated whether small and large particle sizes of aerosolised adenosine monophospate (AMP) provoke similar severity of AHR. Additionally, effects of the small-particle inhaled corticosteroid (ICS) ciclesonide and large-particle ICS fluticasone on AHR to large- and small-particle size AMP were assessed. After a 4-week run-in period using open-label fluticasone (100 μg b.i.d.), 37 mild-to-moderate asthmatics underwent provocations with standard-size (3.7 μm), large-particle (9.9 μm) and small-particle (1.06 μm) AMP. Subjects received 4-week ciclesonide (160 μg s.i.d.) or fluticasone (100 μg b.i.d.) treatment (double-blind and double-dummy) followed by large- and small-particle AMP provocation. Small-particle AMP induced a 20% decrease in forced expiratory volume in 1 s (FEV(1)) at a significantly higher dose than large-particle AMP. Ciclesonide and fluticasone had comparable effects on AMP provocations. Not all subjects reached the provocative concentration causing a 20% fall in FEV(1) (PC(20)) at the highest AMP dose. In those who did, ciclesonide improved small-particle AMP PC(20) by 1.74 doubling doses (DD) (p = 0.03), whereas fluticasone did not. Conversely, fluticasone improved large-particle AMP PC(20) significantly (1.32 DD; p = 0.03), whereas ciclesonide did not. Small-particle AMP provocation appears to be a promising tool to assess changes in small airway inflammation. Future adjustments are necessary taking into account the very small particle size used, with large exhaled fractions. In asthmatics reaching a PC(20) with small- and large-particle AMP provocations, ciclesonide improves hyperresponsiveness to small particle size AMP, and fluticasone to large particle size. This warrants further research to target provocations and treatment to specific airway sizes.

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.

Physiology of the small airways: A gender difference?

Small airways are affected in asthma, but gender differences have not been investigated. This study aims to assess whether gender differences exist in the extent of small airway involvement in asthma. Sixteen patients with mild-to-moderate asthma (seven males, median (range) age 39 (19-56) years, FEV(1)%predicted 89% (62-120), PC(20) Methacholine (MCh) 0.4 mg/mL (0.1-4.2)) participated in the study. MCh-induced air trapping at end-expiratory CT scans, alveolar and bronchial exhaled Nitric Oxide (eNO), Single-Breath N(2) closing volume, FEF(25-75%), FEF(50%) and % change in FVC at PC(20) adenosine-5'-monophosphate (AMP) and at PC(20)MCh were evaluated. Multiple regression analyses evaluated whether gender, body mass index and age were explanatory variables for the severity of air trapping. Males had significantly larger MCh-induced increases in low attenuation areas on CT than females, 6% (1-9) versus 2% (-1-7), p=0.012. Males had significantly more signs of MCh-induced air trapping in the non-dependent lung lobes than females. Male gender was the sole factor explaining higher values of MCh-induced signs of air trapping. Females had higher bronchial eNO values than males, 4 nL/s (2-7) versus 2 nL/s (1-4), p=0.04. Small airway involvement in asthma as reflected by MCh-induced air trapping at CT was significantly larger in males than females even in this relatively small group. Bronchial eNO, reflecting partially small airway inflammation, was higher in females than males. These data suggest that the small airways are affected differently in males and females with asthma. Males exhibit small airway involvement by attenuated small airway patency and females by small airway inflammation.

Ciclesonide improves measures of small airway involvement in asthma

Ciclesonide is delivered as a small-particle inhaled corticosteroid and improves lung function and airway hyperresponsiveness. The objective of the present study was to assess whether ciclesonide can specifically improve small airway function in asthma. A total of 16 mild-to-moderate asthma patients (seven males; median (range) age 39 (19-56) yrs and forced expiratory volume in one second (FEV(1)) 89 (62-120)% predicted) were randomised to 5 weeks' treatment with placebo or 320 mug ciclesonide once daily. The following small airway parameters were assessed: mean forced expiratory flow between 25 and 75% of forced vital capacity (FVC), percentage fall in FVC at provocative dose of adenosine-5'-monophosphate and of methacholine (MCh) causing a 20% fall in FEV(1), expiratory lung volume on computed tomography (CT) scan after MCh challenge, single-breath nitrogen closing volume and alveolar exhaled nitric oxide (eNO). Seven subjects received placebo and nine received ciclesonide. Both alveolar eNO and CT measurements of expiratory lung volume after MCh challenge decreased significantly with ciclesonide (median (range) decrease 4.4 (54.8-1.4) ppb and 59 (1,569- -117) mL, respectively), and compared with placebo (-0.4 (7.3- -3.4) ppb and -121 (20- -236) mL respectively). Ciclesonide did not significantly improve other small airways parameters. Inflammation and patency of small airways, reflected by alveolar exhaled nitric oxide and air trapping on computed tomography scan, both improve with ciclesonide even in this small number of patients. This indicates that ciclesonide exerts anti-inflammatory effects on small airways.

Nε-(Carboxymethyl)Lysine, a Major Advanced Glycation End Product in Exhaled Breath Condensate as a Biomarker of Small Airway Involvement in Asthma

Nε -(Carboxymethyl)Lysine (CML) expression is selectively present in the lower respiratory tract. We compared CML levels in exhaled breath condensate (EBC) between 19 asthmatics and 10 normal control subjects and its levels before and after tiotropium therapy in 11 non-smoking asthmatics and 10 smoking asthmatics. CML levels were significantly lower in asthmatics than in normal control subjects. Moreover, low CML level was associated with small airway dysfunction. After tiotropium therapy, CML level in non-smoking asthmatics was unchanged, while that in smoking asthmatics was significantly increased. Therefore, CML level in EBC is a non-invasive biomarker for evaluating small airway involvements in asthma.

Montelukast improves regional air-trapping due to small airways obstruction in asthma

Quantitative image analysis of high-resolution computed tomography (HRCT) performed at residual volume, before and after methacholine, is a sensitive method of detecting small airways involvement in asthma and response to therapy targeted to the small airways. Since an oral anti-leukotriene reaches the small airways via the circulation, the present authors hypothesised that treatment with montelukast would lead to improved small airway patency. A double-blind crossover study compared the effect of montelukast versus placebo for 4 weeks in 16 mild-to-moderate steroid-naïve asthmatics. Small airways function was evaluated by HRCT at residual volume before and after methacholine to assess regional air-trapping and airways hyperresponsiveness, as well as by physiological studies of small airways. Montelukast treatment resulted in significantly less regional air-trapping on HRCT on the pre-methacholine images when compared with placebo, as well as improvement in total quality of life scores and symptom sub-scores. However, montelukast treatment had no effect on increases in regional air-trapping on HRCT in response to methacholine. No differences were noted in global measures of small airways physiology between placebo and montelukast. In conclusion, distal airways disease improves in asthmatic subjects treated with montelukast. This improvement can be detected with high-resolution computed tomography, but not with conventional physiological studies.