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

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

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

The prevalence of small airway dysfunction (SAD) in patients with chronic obstructive pulmonary disease (COPD) across different ethnicities is poorly understood. This study aimed to estimate the prevalence of SAD in stable COPD patients. We conducted a cross-sectional study of 196 consecutive stable COPD patients. We measured pre- and post-bronchodilator (BD) lung function and respiratory impedance. The severity of COPD and lung function abnormalities was graded in accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. SAD was defined as either difference in whole-breath resistance at 5 and 19 Hz > upper limit of normal or respiratory system reactance at 5 Hz < lower limit of normal. The cohort consisted of 95.9% men, with an average age of 66.3 years. The mean forced expiratory volume 1 second (FEV1) % predicted was 56.4%. The median COPD assessment test (CAT) scores were 14. The prevalence of post-BD SAD across the GOLD grades 1 to 4 was 14.3%, 51.1%, 91%, and 100%, respectively. The post-BD SAD and expiratory flow limitation at tidal breath (EFLT) were present in 62.8% (95% confidence interval [CI], 56.1 to 69.9) and 28.1% (95% CI, 21.9 to 34.2), respectively. COPD patients with SAD had higher CAT scores (15.5 vs. 12.8, p<0.01); poor lung function (FEV1% predicted 46.6% vs. 72.8%, p<0.01); lower diffusion capacity for CO (4.8 mmol/min/kPa vs. 5.6 mmol/min/kPa, p<0.01); hyperinflation (ratio of residual volume to total lung capacity % predicted: 159.7% vs. 129%, p<0.01), and shorter 6-minute walk distance (367.5 m vs. 390 m, p=0.02). SAD is present across all severities of COPD. The prevalence of SAD increases with disease severity. SAD is associated with poor lung function and higher symptom burden. Severe SAD is indicated by the presence of EFLT.

<b>Background:</b> ILDs are known to cause structural alterations in peripheral airways. Conventional tests like spirometry and HRCT chest are not very sensitive to diagnose small airway dysfunction(SAD) in ILD. IOS can be used as non-invasive, easy to perform method to reliably detect and measure early onset SAD in ILD patients thus offering potential pharmaceutical benefits. <b>Objective:</b> To assess the frequency of SAD in ILD patients using IOS and correlate its findings with spirometric parameters <b>Methods:</b> This prospective observational study enrolled 123 consecutive patients, aged&gt;20years, diagnosed as ILD(clinical, radiological or histopathological basis as per ATS/ERS criteria) between 2016-2017. Cardiac patients and acutely ill patients were excluded from study. All patients underwent spirometry, IOS and HRCT chest; outcome parameters were recorded in a prestructured Performa and correlated statistically. <b>Results:</b> Out of total, 26%(n=32) were found to have SAD on IOS with mean age 60.91±8.7years and female predominance(75%). Majority had symptom duration between 3-7 years(n=21) and etiology as hypersensitivity pneumonitis(n=10), sarcoidosis(n=9) and CTD-ILD(n=8). FEV₁, FVC, FEV₁/FVC ratio and FEF_25% were significantly negatively correlated with R₅, R_5-20, D_5-20%, AX and significantly positively correlated with X5. On ROC curve, X5(AUC=77.8%) and AX(AUC=77.9%) had highest diagnostic ability to detect SAD on IOS. <b>Conclusion:</b> IOS is a good modality to detect small airway dysfunction in early stages and certain occupational ILD where spirometry may remain normal and can be used as an adjunct to spirometry both for diagnosis and follow up of therapeutic outcomes in ILD.

BackgroundPersistent chronic airway inflammation and progressive airflow limitation are typical features of chronic obstructive pulmonary disease (COPD). Emerging evidence indicates that small airway dysfunction (SAD) plays a critical role in driving the sustained pathological progression of COPD. Preserved ratio impaired spirometry (PRISm) represents a spirometric pattern characterized by a reduced forced expiratory volume in 1 second (FEV₁) despite a preserved ratio. Current evidence inadequately elucidates the pathophysiological role of SAD and its intricate interplay with PRISm and COPD progression. On the other hand, impulse oscillometry (IOS) can be used as a complementary tool to spirometry to detect SAD. Detection of SAD in patients with chronic respiratory symptoms could help in the diagnosis of PRISm and COPD when spirometry is not achievable.ObjectiveTo investigate the diagnostic value of IOS for identifying SAD in patients with chronic respiratory symptoms, PRISm and COPD.MethodsBetween September 2021 and July 2023, 552 symptomatic patients without known structural lung disease who underwent both spirometry and IOS on the same day in the outpatient clinic were evaluated. The correlations between spirometry and the IOS parameters, and the ROC curves of the IOS parameters for SAD patients and COPD patients were analyzed.ResultsAmong the 552 patients included in the study, 96 patients had COPD, 39 patients had PRISm, and 417 patients had chronic cough. Among 456 chronic cough patients with preserved ratio spirometry, the incidence of PRISm was 8.55%. Based on spirometry-defined SAD, the incidence of SAD in the PRISm population was 71.8%, which was significantly higher than the 9.35% of the non-PRISm population. With increasing COPD GOLD stage, the IOS parameters R5-R20, R5, Fres, and Ax increased, whereas the traditional lung function parameters and X5 decreased. R5-R20, X5, Fres, and AX of COPD GOLD stage 1 patients were not substantially different from those of PRISm patients. In PRISm patients, R5-R20, R5 and Fres were strongly correlated with FEF25%-75%. R5-R20, R5, X5, Fres and AX were significantly associated with FEV1, FEV1/FVC, FEV1% predicted, FEF50%, FEF75% and FEF25%-75% in COPD patients. Through ROC curve analysis, the cutoffs for identifying SAD in patients with chronic respiratory symptoms and PRISm patients were obtained, with R5-R20 values of 0.075 and 0.105 kPa/L/s, respectively. The values of R5 were 0.365 and 0.375 kPa/L/s, respectively. The Fres values are 16.31 Hz and 17.11 Hz, respectively. The cutoff for detecting COPD in all patients was 0.485 kPa/L/s for R5, 0.125 kPa/L/s for R5-R20, -0.155 kPa/L/s for X5, and 17.98 Hz for Fres. Fres had the highest AUC value for both SAD and COPD detection, and it detected COPD the most in all patients, with a prevalence of 24.1%. R5 detected SAD the most in patients with chronic respiratory symptoms, with a prevalence of 47.5%. With a prevalence of 71.8%, spirometry identified SAD in patients with PRISm the most frequently.ConclusionAlmost all IOS parameters Linked to the small airways were significantly different in the PRISm population compared with patients with chronic respiratory symptoms. SAD severity in PRISm patients is similar to that in GOLD stage 2 COPD patients. The IOS can assess the disease severity of COPD.

Background: Small airway dysfunction (SAD) is a functional hallmark of chronic obstructive pulmonary disease (COPD). However, SAD prevalence and its role in COPD pathophysiology are not yet sufficiently studied.Background: Small airway dysfunction (SAD) is a functional hallmark of chronic obstructive pulmonary disease (COPD). However, SAD prevalence and its role in COPD pathophysiology are not yet sufficiently studied.Aim: To assess the prevalence of SAD in COPD patients by various functional diagnostic methods, such as spirometry, body plethysmography, and impulse oscillometry (IOS).Materials and methods: This was an cross-sectional study. Spirometry, body plethysmography and IOS were used in 132 COPD patients in remission under standard anti-COPD treatments. The presence of SAD was confirmed by at least one of the following criteria or their combination: 1) by spirometry: the difference between vital capacity (VC) and forced vital capacity (FVC) &gt; 10%; 2) the presence of air trapping by body plethysmography; 3) identification of the frequency dependence of the resistive resistance at 5 to 20 Hz (R5 - R20 &gt; 0.07 kPa x s/l), as assessed by IOS.Results: Mean forced expiratory volume in 1 s (FEV1) was 42.9% of predicted. Depending on the severity of the obstruction, the patients were divided into 4 groups: 7 patients (group 1) had the obstruction corresponding to GOLD 1 stage, 37 (group 2) to GOLD 2, 49 (group 3) to GOLD 3, and 39 (group 4) to GOLD 4. SAD was found in 96% of COPD patients, whereas in those with severe obstruction (GOLD 3-4), it was present in 100% of the cases. By spirometry, SAD was identified only in 67% of COPD patients, by body plethysmography in 75% of COPD patients (in those with severe obstruction (GOLD 3 and 4) in 88 and 97%, respectively). With IOS, it was possible to identify SAD in 94% of patients and in 100% of those with severe obstruction (GOLD 3-4).Conclusion: With deterioration of obstructive pulmonary ventilation abnormalities in COPD patients, there is a progressive increase in small airway dysfunction. Impulse oscillometry seems to be the most effective method for diagnosis of small airway dysfunction, as it helped to identify SAD in 94% of COPD patients and in 100% of those with severe and very severe obstruction.

BackgroundRecent years, idiopathic pulmonary fibrosis (IPF) is thought to be a disease of alveoli as well as small airways. This study aimed to demonstrate the clinical feature, predictor, and prognosis of small airway dysfunction (SAD) in Chinese patients with IPF.MethodsWe enrolled 416 patients with IPF who hospitalized in Beijing Chao-Yang Hospital from 2000 to 2014 in this study, and the follow-up ended at December 2016. We collected demographic information, clinical examination results, spirometry results, HRCT results, and blood gas results during the study. Logistic regression analysis was used to identify the predictor for SAD. The COX proportional hazard model was used to analysis the prognosis effect of SAD.ResultsAmong all the participants, 165 (39.66%) patients had SAD. FEV1 (% predicted) and FEV3/FVC were significantly associated with SAD in patients with IPF. IPF patients with lower FEV1 (% predicted, OR 30.04, 95% CI 9.61–93.90) and FEV3/FVC (OR 77.76, 95% CI 15.44–391.63) had increased risk for SAD. Patients with SAD were associated with significantly increased risk of mortality in patients with IPF (HR 1.73, 95% CI 1.02–2.92), as well as in IPF patients without other pulmonary comorbidities (COPD, emphysema, and asthma).ConclusionsSpirometry-defined SAD was like 40% in patients with IPF. Lower FEV1 (% predicted) and FEV3/FVC were main predictors for SAD. IPF patients with SAD showed poorer prognosis.

Should asthma evaluation include assessment of small airway function?

The small airways are an important site of inflammation in asthma. However, the relation between small airway dysfunction and clinical expression of asthma has hardly been studied. To investigate the association of small and large airway dysfunction with asthma symptoms and bronchial hyper-responsiveness (BHR). Fifty-eight patients with asthma were characterized with spirometry, body plethysmography, impulse oscillometry, alveolar and bronchial exhaled nitric oxide, and a methacholine provocation. Symptoms of nocturnal asthma, exercise-related symptoms, BHR symptoms, and respiratory symptoms were assessed with the Asthma Control Questionnaire and Bronchial Hyper-responsiveness Questionnaire. Perception of dyspnea was rated with the Borg score during the provocation test. Small and large airway dysfunction did not associate with higher scores for nocturnal, exercise-related, or BHR symptoms. Only higher scores on wheezing were significantly associated with higher values of difference between R5 and R20 (R5-R20) (r=0.367, P<0.01) and AX (r=0.354, P<0.01). Lower FEF25-75% (P=0.024) and higher R5-R20 (P=0.003) values were independently associated with more severe BHR to methacholine, but not FEV1 or R20 values. The increase in dyspnea during the methacholine provocation was strongly and independently correlated with the decrease in FEV1 and reactance of the respiratory system at 5Hertz. Small and large airway dysfunction poorly associate with asthma symptoms in our patients. However, deteriorations in small airway dysfunction are strongly related to an increase in dyspnea during bronchial provocation with methacholine. Small airway dysfunction contributes also independently to the clinical expression of asthma, as reflected by the severity of BHR.

<b>Background:</b> Airway eosinophilic inflammation is usually linked to recurrent exacerbations in COPD. However, little is known about its role in SAD in patients with mild or at risk for COPD. We aimed to describe the association between airway eosinophilic inflammation and SAD in these patients. <b>Methods:</b> We induced sputum in 45 patients with mild stable COPD (post FEV₁/FVC&lt;70% + FEV₁≥70%pred) and in 24 smokers at risk (post FEV₁/FVC≥70%, ≥10py and CAT ≥10 or long-acting bronchodilator) from CAPTO-COPD. Lung function included spirometry, body plethysmography and SF₆ multiple breath washout (MBW). Patients were stratified based on sputum eosinophil count in eosinophil-high (≥2%) and eosinophil-low. <b>Results:</b> 19% of patients (8 COPD, 5 at risk) were eosinophil-high (mean eosinophil count: 5.6± 6.0%). Markers of SAD indicated increased acinar (S_acin 0.66±0.51 vs 0.38±0.27), global (LCI 10.6±1.2 vs 9.5±1.5) ventilation inhomogeneity and air trapping (RV/TLC 48±7 vs 41±6%) in eosinophil-high patients. Age (64±8 vs 65±8y), smoking (43±16 vs 45±25 py), airway neutrophilia (72±11 vs 70±17%) and airflow obstruction (FEV₁/FVC 58±9 vs 62±8%, FEV₁ 75±12 vs 83±13%pred) did not differ between both groups. Significant correlation between airway eosinophils and SAD (r=0.48 to 0.30, all p&lt;0.05) was found while no correlation between eosinophils and airflow obstruction was be established. <b>Conclusion:</b> In a subgroup of smokers at risk or patients with mild stable COPD, eosinophilic airway inflammation was associated with more severe SAD. Interventional trials are needed to demonstrate the benefit of early targeting airway eosinophilia on disease progression.

Background: Static lung hyperinflation (SLH) measured using body plethysmography in patients with asthma is associated with poor outcomes. The severity of SLH may be associated with small airway dysfunction (SAD), which can be measured using impulse oscillometry (IOS). Objective: This study aims to determine the correlation between SLH and SAD in patients with severe asthma and assess the improvement in SLH and SAD with treatment. We analyzed data from patients who were enrolled in the Taiwan Severe Asthma Registry, which comprises a prospective observational cohort. Plethysmography and IOS were performed regularly. The relationship between spirometry and IOS parameters was determined. Changes in the clinical outcomes in response to treatment were analyzed. Of 107 patients with severe asthma, 83 (77.6%) had SLH based on an increased residual volume to total lung capacity ratio (RV/ TLC). Most patients were older women with worse pulmonary function and SAD than those without SLH. SAD, defined as increased airway resistance/reactance, was significantly correlated with SLH. Airway reactance at 5 Hz (X5) ≤-0.21 kPa/(L/s) detected SLH with an area under the receiver operating characteristic curve of 0.84 (P<.0001; sensitivity, 85.2%; and specificity, 83.3%). After 12 months, patients who received add-on biologics (vs those who did not) had significantly reduced exacerbations, fractional exhaled nitric oxide level, and blood eosinophil counts, as well as improved forced expiratory volume in the first second, X5, and a trend toward reduced RV/TLC ratio. In severe asthma, airway reactance (X5) could be a novel parameter for assessing SLH.

Small Airway Dysfunction by Impulse Oscillometry in Symptomatic Patients with Preserved Pulmonary Function

BackgroundA number of studies report small airways involvement in patients with systemic sclerosis (SSc). Furthermore, small airways dysfunction is increasingly recognized in patients with interstitial lung disease (ILD) of idiopathic or autoimmune etiology. The objectives of this study were to evaluate small airways function in SSc patients with ILD and explore the effect of treatment on small airways function by using conventional and contemporary pulmonary function tests (PFTs).MethodsThis single-center, prospective, observational study included a total of 35 SSc patients, with and without ILD based on HRCT scan, evaluated by a special radiologist blindly. Clinical data were collected from all patients who were also assessed for HRCT findings of small airways disease. Small airways function was assessed by classic spirometry, measurement of diffusing capacity for carbon monoxide, body plethysmography, single breath nitrogen washout (N2SBW) and impulse oscillometry (IOS). The prevalence of small airways dysfunction according to R5–R20, phase III slopeN2SBW and CV/VC methodologies was calculated in the total SSc population. Pulmonary function tests were compared between: (a) SSc-ILD and non-ILD patients and (b) two time points (baseline and follow up visit) in a subset of SSc-ILD patients who received treatment for ILD and were re-evaluated at a follow up visit after 12 months.ResultsPhase III slopeN2SBW and R5–R20 showed the highest diagnostic performance for detecting small airways dysfunction among SSc patients (61 and 37.5%, respectively). Twenty three SSc patients were found with ILD and 14 of them had a 12-month follow up visit. SSc-ILD patients compared to those without ILD exhibited increased phase III slopeN2SBW ≥120% (p = 0.04), R5–R20 ≥0.07 kPa/L/s (p = 0.025), airway resistance (Raw) (p = 0.011), and special airway resistance (sRaw) (p = 0.02), and decreased specific airway conductance (sGaw) (p = 0.022), suggesting impaired small airways function in the SSc-ILD group. Radiographic features of SAD on HRCT were observed in 22% of SSc-ILD patients and in none of SSc-non-ILD patients. Comparison of PFTs between baseline and follow-up visit after 12 months in the 14 SSc-ILD treated patients, showed improvement of phase III slopeN2SBW (p = 0.034), R5–R20 (p = 0.035) and Raw (p = 0.044) but not sRaw and sGaw parameters.ConclusionPhase III slopeN2SBW and R5–R20 may reveal small airways dysfunction in SSc associated ILD before structural damage and may be partially improved in a subset of patients receiving treatment for ILD.

Small airway dysfunction (SAD) is associated with poorly controlled asthma and frequent exacerbations. Objective: To assess the prevalence of SAD in asthmatics using spirometry, body plethysmography, and impulse oscillometry (IOS). Materials and methods: The observational cross-sectional study of 61 patients with asthma was performed. Conclusion available SAD was made on the basis of identifying one of the criteria or their combination: 1) slow vital capacity (SVC) - forced vital capacity (FVC) &gt;10% according spirometry; 2) "air trapping" according body plethysmography; 3) presence of pathological frequency dependence of the resistance (R) at 5 and 20 Hz (R5-R20 &gt; 0,07 kPa•sec/l) according IOS. Results: The analysis was performed for the entire group as well as for patients with FEV1 &gt; 80 %pred. and FEV1/SVC &lt; 0,7 (group 1) and patients with FEV1 &gt; 80 %pred. and normal FEV1/SVC (group 2). SAD was most often diagnosed using IOS and the selected criterion R5-R20&gt;0,07 kPa •sec/l since 75% of patients had this deviation in the entire group, 65% of patients in group 1 and 55% of patients in group 2 whereas only in 48% and 24% of cases in the entire group according body plethysmography and spirometry, respectively. Conclusion: SAD is definitely observed in patients with asthma. IOS is a more effective method of diagnosing SAD compared to spirometry and body plethysmography and can serve as a supplement functional method, especially in cases of normal parameters of spirometry and body plethysmography in asthmatics.

The prevalence and clinical implications of small airways involvement in SSc are still to be fully elucidated. The goal of the present work is to assess the prevalence of small airways dysfunction by impulse oscillometry and to determine whether it correlates with selected disease-related features and respiratory-related quality of life. Ninety-four SSc patients and 93 healthy controls were studied by impulse oscillometry measurements. Small airways dysfunction was defined as the difference between resistance at low frequency, i.e. 5 Hz, and resistance at high frequency, i.e. 20 Hz, termed 'R5-R20', ⩾0.07 kPa/l/s. The St George's Respiratory Questionnaire was used to measure health impairment in SSc patients. Radiological features of small airways disease and parenchymal abnormalities on high resolution CT chest scans were jointly assessed by two thoracic radiologists. Small airways dysfunction was present in 21.5% of the SSc patient cohort, with a prevalence almost 5-fold higher compared with controls, and it was significantly associated with worse respiratory-related quality of life. Radiological features consistent with small airways abnormalities were detected in 25% of SSc patients, mostly in the absence of interstitial lung changes. Combining functional and radiological evaluations, one-third of the SSc cohort showed at least one feature of small airways involvement, which was associated with the lcSSc phenotype and with longer disease duration. The current study strengthens the hypothesis that small airway dysfunction might be a feature of SSc-related lung involvement, providing the first data on its significant impact on respiratory-related quality of life. A full assessment of lung function in SSc patients should include impulse oscillometry as a complementary technique, due to potential clinical and therapeutic implications.